Determination of cancer status

Abstract

The invention related to a method for determining the likely cancer status in a subject by determining the levels of LARP1 and CA125 in a biological sample and comparing them to threshold levels. Samp

Description

FIELD OF THE INVENTION The invention relates to methods for determining the cancer status of a subject, in particular ovarian cancer status. The method relies on determining the levels of LARP1 protein and CA125 protein in biological samples from the subject, optionally from samples taken longitudinally over a period of time, and determining the subject’s cancer status based on the levels detected. The methods can be used to distinguish subjects that are likely to have precancer or likely to have pre-invasive or invasive cancer, so for ovarian conditions, whether the subject has ovarian pre-cancer (such as serous tubal intraepithelial carcinomas (STIC), Secretory Cell OUT growth (SCOUT), P53-signature, FIGO stage 1A STIC lesion,or other pre-invasive cancer) or invasive ovarian cancer. The methods can then be used to inform for treatment decisions and / or select patients for particular treatment options, medications or risk reducing surgery for those likely to have pre-invasive cancer so as to remove organs (such as ovaries and / or fallopian tubes) likely to develop cancer. BACKGROUND OF THE INVENTION RNA binding proteins (RBPs) regulate the decay kinetics, translational efficiency and subcellular localisation of mRNA transcripts. In this way, the abundance and activity of mRNAs and their encoded proteins can be altered in a manner that is independent from gene transcription. As RBPs are themselves activated by growth factors and cell signals, this tightly-regulated post-transcriptional mechanism enables the cell to rapidly adjust levels of protein expression in response to intrinsic and extracellular signals. In addition, RBPs can interact with up to thousands of mRNA transcripts, allowing the coordinated synthesis of multiple proteins involved in a single physiological function (termed an RNA operon). However, when the expression of an RBP is disrupted it can potentially disrupt cellular homeostasis and autonomously drive pathological processes by uncoupling the regulation of mRNA stability from cell signalling cues. A protein identified as being an RBP is LARP1 (Castello et al Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 149: 1393-1406). LARP1 belongs to the La-related protein (LARP) family and has been implicated in cancer. LARP1 is a known oncoprotein and post-transcriptional driver of cancer metabolism (Chettle et al.,bioRxiv 2021, doi.org / 10.1101 / 2022.09.04.506559) and stress-induced cell proliferation (see e.g. Burrows etal. Nucleic Acids Res. 38(16):5542-53, 2010). LARP1 expression is elevated in almost all HGSC cases where higher staining intensity is correlated with adverse survival outcome, and in addition to its presence in tumour tissue, LARP1 protein is detectable in the circulation of OC patients (Hopkins et al. Nucleic Acids Res. 2016; 44(3):1227-46). An elevated expression of LARP1 has also been shown to correlate with clinical outcome in hepatocellular carcinoma (Xie et al., Journal of Translational Medicine 11: 272, 2013). Human LARP1 consists of 1096 amino acids with an apparent molecular weight of about 150 kDa and a monoisotopic mass of 123434.17 g / mol. WO2016 / 075455 teaches that LARP1 protein is a cancer biomarker which can be used to predict cancer progression or diagnosis and response to treatment. It discloses immunological detection such as enzyme-linked immunosorbent assay (ELISA). However, when in the circulation, LARP1 is rapidly degraded and detecting LARP1 using Sandwich ELISA can be unpredictable as, due to protein fragmentation, levels of detection can change over time. WO2021 / 064361 discloses a method for prognosing the development of cancer in a subject based on the amount of the LARP1 peptide fragment with the amino acid sequence: EGYR (glutamic acid-glycine-tyrosine-arginine; orGlu-Gly-Tyr-Arg; SEQ ID NO: 3) in a fluid sample from the subject. In particular, WO2021 / 064361 teaches that the LARP1-derived EGYR peptide (SEQ ID NO: 3) detected using using mass spectrometry in a subject plasma / serum sample correlates with the presence of STIC, and established cancers. CA125 is a mucinous glycoprotein found on the surface of ovarian cancer cells and is measurable in the circulation as a marker of ovarian cancer. Normal circulating CA125 is defined as <35 IU / ml, raised CA125 is above 35 lU / ml is an indicator of established ovarian cancer. CA125 testing is used in establishing the differential diagnosis of a pelvic mass or in the surveillance of a patient undergoing treatment for ovarian cancer. Tests for measuring CA125 levels in blood or tissues are well-established and routinely used worldwide. The CA125 blood test, while being a useful diagnostic marker of advanced OC, is rarely elevated in early-stage or precancerous disease (Rosenthal AN, Jacobs IJ. The role of CA 125 in screening for ovarian cancer. Int J Biol Markers. 1998 Oct-Dec;13(4):216-20) and screening studies using CA125 have failed to significantly improved survival (e.g., see Patsneretal. Eur J Gynaecol Oncol. 1990; 11 (5):319-21). It is now known that high grade serous carcinoma (HGSC), the commonest and most aggressive OC subtype characterised by ubiquitous mutations to the tumour suppresser gene TP53 (p53), arises from clusters of abnormal epithelial cells typically located at the fimbrial end of the fallopian tube (FT) called “p53-signatures” and serous tubal intraepithelial carcinomas (STICs) (Labidi-Galy et al. Nat Commun. 8(1):1093, 2017). During an estimated mean latency of 6-7 years, STICs are shed from the FT onto the adjacent ovary and / or into the peritoneal cavity to become invasive HGSC (see e.g. Weinberger et al. Expert Rev Anticancer Ther. 16(12):1311-1321, 2016). Although STICs are amenable to surgical resection, they are symptomless and “invisible” to conventional imaging or blood tests including CA125 test. The clinical challenge of finding STICs contributes to the uncertainty around OC pathogenesis whilst their long latency presents an unexplored window for early detection and prevention. Currently, women with a genetic predisposition (e.g. BRCA mutation carriers) to OC are advised to undergo riskreducing bilateral salpingo-oophorectomy (RRSO) from 35-40 years of age to remove their FTs and ovaries but there is no effective longitudinal surveillance / screening or non-surgical OC prevention programme (Lewis et al. Recommendations and Choices for BRCA Mutation Carriers at Risk for Ovarian Cancer: A Complicated Decision. Cancers (Basel). 10(2):57, 2018). There remains the need for more sensitive and selective methods and / or tests for predicting cancer status, such as ovarian cancer, and in particular to identify patients who are most likely to develop cancer in the short to medium term (e.g. 1-4 years), so as to allow intervention (e.g. risk reducing surgery) in order to prevent the development of the cancer, in particular invasive ovarian cancer. SUMMARY The inventors have discovered that LARP1 protein levels in the blood of a subject rise and peak between approximately 12-40 months before the onset of invasive ovarian cancer. As the affected cells move along the cancer development pathway, e.g. from pre-malignant to early stage pre-cancer and then onto more advanced / invasive cancer) the levels of LARP1 recede from the peak and the levels of CA125 start to rise. The levels of CA125 and LARP1 in a subject can therefore be used together to assess or predict a subject’s ovarian cancer status, e.g. by comparison to threshold levels or monitoring trajectory of levels overtime. Whilst LARP1 level above a threshold level has previously been reported to indicate development of STIC, by measuring LARP1 level and CA125 level, particularly longitudinally over a period of time, a more accurate assessment of ovarian cancer status can be generated. It is envisaged that LARP1 and CA125 protein levels in the blood will be included in the repertoire of screening for this disease. Identifying the subject before development of ovarian cancer may allow steps to be taken to remove the STIC or other stage of pre-invasive cancer (such as with surgery) or other, future, non-surgical approaches. The inventors have discovered that LARP1 protein levels in the blood of a subject rise and peak between approximately 25 months before the onset of STIC lesions. As the affected cells move along the cancer development pathway, e.g. from pre-malignant to early stage pre-cancer and then onto more advanced / invasive cancer) the levels of LARP1 once again rise. The levels of LARP1 in a subject can therefore be used together to assess or predict a subject’s ovarian cancer status. By measuring LARP1 level, particularly longitudinally over a period of time, a more accurate assessment of ovarian cancer status can be generated. According to a first aspect of the invention there is provided a method for determining the likely cancer status in a subject, comprising (i) determining the level of La-related protein 1 (LARP1) protein in a biological sample from a subject; (ii) determining the level of Cancer Antigen 125 (CA125) protein in a biological sample from the same subject as for (i); (iii) comparing the amounts in (i) and (ii) to threshold levels and / or to levels determined for the subject at one or more previous time points; and (iv) determining the likely cancer status in the subject based on the comparison in step (iii). In particular embodiments, steps (i) and (ii) are carried out on the same sample from the subject, or a contemporaneous sample from the subject. Determining the likely cancer status has numerous applications, including being able to diagnose whether a subject likely has pre-cancer (e.g., preinvasive cancer), or invasive cancer; determine high, medium or low risk of developing cancer; monitoring efficacy of a therapeutic treatment; determine the progression of cancer; determining the likely stage of cancer; and prognosing the development of cancer, and any others that apply knowledge of the change in levels of LARP1 and CA125 that occur at different stages of pre-cancer and cancer development. Suitably the level of biomarker protein determined (e.g. LARP1 orCA125) is the absolute level. In a particular embodiment the cancer is ovarian cancer. According to a variation of the first aspect of the invention there is provided a method for determining the likely ovarian cancer status in a subject, comprising: (i) determining the level of La-related protein 1 (LARP1) protein in a biological sample from a subject; (ii) determining the level of Cancer Antigen 125 (CA125) protein in a biological sample from the same subject as for (i); (iii) comparing the amounts in (i) and (ii) to threshold levels and / or to absolute levels determined for the subject at one or more previous time points; and (iv) determining the likely ovarian cancer status in the subject based on the comparison in step (iii). In particular embodiments, steps (i) and (ii) are carried out on the same sample form the subject, or a contemporaneous sample from the subject. Determining the likely ovarian cancer status has numerous applications, including being able to diagnose whether a subject likely has pre-cancer (e.g.preinvasive ovarian cancer), or invasive ovarian cancer; determine high, medium or low risk of developing ovarian cancer and / or whether the subject is unlikely to have pre- cancer or invasive high grade serous ovarian cancer; monitoring efficacy of a therapeutic treatment,; determine the progression of ovarian cancer; determining the likely stage of ovarian cancer; and prognosing the development of ovarian cancer, and any others that apply knowledge of the change in levels of LARP1 and CA125 that occur at different stages of ovarian pre-cancer and cancer development. According to a second aspect of the invention there is provided the use of La-related protein 1 (LARP1) and Cancer Antigen 125 (CA125) biomarker levels in a method of determining cancer status. In a particular embodiment, the LARP1 and CA125 biomarker levels are used in a method of determining ovarian cancer status. According to a third aspect of the invention there is provided a kit comprising: (a) a panel of affinity reagents that each selectively binds to CA125 or LARP1 or (b) a panel of labelled peptide standards for CA125 and LARP1 for use in mass spectrometric analysis. In a particular embodiment the kit further comprises written instructions for using the affinity reagents or labelled peptide standards to measure the levels of the CA125 and LARP1 proteins in a sample, such as one from a subject. In a particular embodiment, the kit further comprises written instructions for use of the kit for determining a subject’s cancer status, in particular the subject’s ovarian cancer status. According to a fourth aspect of the invention there is provided a method for determining whether a subject is at risk of developing ovarian cancer comprising: determining the level of LARP1 in a sample from the subject over a time period so as to provide a plurality of LARP1 values over a time-course; wherein if over the time-course the level of U\RP1 exceeds a threshold level or peaks and then drops the subject is determined to be at risk of developing ovarian cancer. Suitably the level of biomarker protein determined (e.g. I_ARP1) is the absolute level. The method for determining whether a subject is at risk of developing ovarian cancer is also a method for predicting the onset of ovarian cancer. According to a fifth aspect of the invention there is provided a method for determining ovarian cancer status of a subject comprising: determining the level of LARP1 in a sample from the subject over a time period so as to provide a plurality of LARP1 values over a time-course; and determining the ovarian cancer status based on the change in l_ARP1 detected over the time course. According to a sixth aspect of the invention there is provided a method for monitoring the progression of ovarian cancer in a subject comprising determining the level of LARP1 biomarker in the circulating blood of a subject at a first point in time and comparing the level of the l_ARP1 biomarker in the subject at one or more later points in time to determine the progression of the ovarian cancer. Suitably, the level of LARP1 in circulating blood can be determined over a timecourse and the change in LARP1 level used to determining whether a subject is at risk of developing ovarian cancer. Suitably, the level of LARP1 in circulating blood over a timecourse can be plotted and any change in level used to determine the subject’s ovarian cancer status. Because the level of I.ARP1 changes overtime as the tissues transition from pre-malignant to early stage cancer or pre-invasive cancer and through the more advanced stages of cancer a change in level can be used predict the ovarian cancer status of a subject by comparison to historical data for normal patients and / or patient at distinct stages of ovarian cancer. Suitably, LARP1 changes can be used on their own to predict ovarian cancer stage, however in particular embodiments LARP1 and CA125 levels are measured and used together to determine the subject’s ovarian cancer status. This could be from a single measurement of LARP1 and CA125 in a single sample or samples taken contemporaneously or from multiple samples over a timecourse. In a particular embodiment if a peak in level (e.g. absolute level) of LARP1 is detected for the subject they are identified as likely to have pre-cancer, particularly if their CA125 level is still in the normal range. In a particular embodiment if a peak in level of LARP1 is detected for the subject they are identified as likely to develop ovarian cancer, particularly if their CA125 level is still in the normal range. In particular embodiments, they are identified as likely to develop ovarian cancer in 12-40 months time, such as in at least 12, 18, 24, 30, 36, 40 months after a peak in level of l_ARP1 is detected for the subject. In particular embodiments, the peak in LARP1 level is detected whilst CA125 levels are within the normal range. In a particular embodiment, if the subject is identified as likely to develop ovarian cancer they are either selected for follow up diagnostic testing, watchful waiting, or are selected for risk reducing surgery. In a particular embodiment, if the subject is identified as likely to have ovarian pre-cancer they are either selected for follow up diagnostic testing, watchful waiting, or are selected for risk reducing surgery. According to a seventh aspect of the invention there is provided; a computer-implemented method to aid in determining the likely cancer status in a subject, comprising the steps of: (a) receiving a value for the absolute level of LARP1 in a biofluid sample of the subject; (b) receiving a value for the absolute level of CA125 in a biofluid sample of the subject; (c) comparing the amounts in (a) and (b) to absolute levels for LARP1 and CA125 accordingly, determined for the subject at one or more previous time points and / or to reference values; and (d) determining the likely cancer status in the subject based on the comparison in step (c). In a particular embodiment, the computer-implemented method aids in determining the likely ovarian cancer status in a subject DETAILED DESCRIPTION OF THE INVENTION As used herein, unless otherwise stated, the singular forms "a," "an," and "the" include plural reference. Thus, for example, a reference to "a protein" includes a plurality of protein molecules. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. Concentrations, amounts, and other numerical data may be expressed or presented herein in a “range” format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of "20 pg / ml / ml to 50 pg / ml" should be interpreted to include not only the explicitly recited values of 20 pg / ml / ml to 50 pg / ml, but to also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 22, 25, 28, 30, 35,40, 45 pg / ml and sub-ranges such as from 25 to 30, 27 to 32, 30 to 40, 35 to 45, 40 to 50, etc. This same principle applies to ranges reciting only one numerical value. Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described. The following definitions may be useful in the understanding of the invention. The word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. As used herein, the term "about" in reference to quantitative measurements not including the measurement of the mass of an ion, refers to the indicated value plus or minus 10%. Mass spectrometry instruments can vary slightly in determining the mass of a given analyte. The term "about" in the context of the mass of an ion or the mass / charge ratio of an ion refers to +1- 0.5 atomic mass unit (amu), such as + / - 0.3 atomic mass unit, + / - 0.2 atomic mass unit or + / - 0.1 atomic mass unit. The term “biomarker” as used herein, refers to a substance within a biological system that is used as an indicator of a biological state of said system (e.g. normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention). In the art, the term “biomarker" is sometimes also applied to means for the detection of said endogenous substances (e.g. antibodies, nucleic acid probes etc, imaging systems). In the context of present invention, the term “biomarker“shall be only applied for the substance, not for the detection means. In general a biomarker can be any kind of molecule present in a living organism, such as a nucleic acid (DNA, mRNA, miRNA, rRNA etc.), a protein (cell surface receptor, cytosolic protein etc.), a metabolite or hormone (blood sugar, insulin, estrogen, etc.), a molecule characteristic of a certain modification of another molecule (e.g. sugar moieties or phosphoryl residues on proteins, methyl-residues on genomic DNA) or a substance that has been internalized by the organism or a metabolite of such a substance; however, in the context of the present invention the biomarker is a protein (LARP1 and / or CA125). A biomarker is differentially present if the mean or median level of the biomarker in the different groups is calculated to be statistically significant. Common tests for statistical significance include, among others, t-test (e.g., student t-test), ANOVA, Kruskal-Wallis, Wilcoxon, Mann- Whitney, Receiver Operating Characteristic (ROC curve), accuracy and odds ratio. Biomarkers, alone or in combination, provide measures of relative risk that a subject belongs to one phenotypic status or another. Therefore, they are useful as markers for disease (diagnostics), therapeutic effectiveness of a drug and drug toxicity. The amount of a biomarker may also change over time as a disease state changes. This change may follow a particular pattern. As reported in Example 1 herein, the inventors have discovered that LARP1 follows a saw-tooth pattern of peaks and troughs in terms of amount of LARP1 protein released into the blood system. As cells move from normal to pre-cancerous LARP1 levels appear to rise, to a peak level approximating to the time when pre-invasive cancer arises (e.g., when STIC cells arise in ovarian setting), the level then drops down slightly before rising further as the cancer develops towards invasive or metastatic state. In the ovarian setting, in the presence of a STIC, the level of LARP1 is elevated whilst CA125 tends to be normal and the rise in CA125 level seems to occurs after a peak in level seen for LARP1. Both LARP1 and CA125 are elevated in established disease. From longitudinal studies of levels of LARP1 and CA125 it is expected to be possible to more accurately map cancer status and more reliably pick up pre-cancer or early stage cancer using an non-invasive test. This information can then be used for earlier treatment decisions / interventions. This longitudinal mapping could become part of routine vigilance testing for any subject, but particularly those with a pre-disposition to cancer (e.g. those with BRCA mutations and / or a family history of cancer). “CA125” or “CA-125”, the Carbohydrate antigen 125, sometimes named as Cancer Antigen 125 or Tumor Antigen 125, is a mucin-type glycoprotein, produced by the MUC16 gene, and associated with the cellular membrane. CA125 is a biomarker for epithelial cell ovarian cancer being derived from coelomic epithelia including the endometrium, fallopian tube, ovary, and peritoneum. CA125 levels in the body are measured by units per millimeter (U / rnL). The range of 0 to 35 U / rnL is considered within the normal guidelines. Levels over 35 U / rnL may indicate the presence of cancer or other conditions. Not all patients with a high CA125 result have cancer. For women with no ovarian cancer history, a high result usually leads to additional testing. In patients who have previously had ovarian cancer, high CA125 levels may indicate a cancer recurrence. Human mucin-16 reference protein sequences are disclosed in NP_078966 and UniProtKB / Swiss-Prot: Q8WXI7.3. As used herein, the term "LARP1" means LARP1 protein, unless the context indicates otherwise. There are at least 7 putative LARP1 mRNA transcript variants. Variant 1 (NM_015315.5) encoding the 1019 amino protein NP_056130.2, isoform 1; Variant 2 (NM_033551.5) encoding the 1096 amino acid protein NP_291029.2, isoform 2; Variants 3,4,9 (NM_1367713, NM_1367714.1 and NM_1367719.1) encoding the 891 amino acid proteins NP_1354642, NP_1354643.1 and NP_1354648.1, all known as isoform 3; Variants (NM_1367715.1) encoding the 824 amino acid protein NP_135464.1, isoform 4; Variant 6 (NM_1367716.1) encoding the 858 amino acid protein NP_1354645.1, isoform 5; Variant 7 (NM_1367717.1) encoding the 993 amino acid protein NP_ NP_1354646.1, isoform 6; and Variant 8 (NM_1367718.1) encoding the 1063 amino acid protein NP_1354647.1, isoform 7.The nucleotide sequence of a representative LARP1 mRNA (variant 1) is disclosed in SEQ ID NO: 1. The amino acid sequences of LARP1 variant 1 isoform is shown in SEQ ID NO: 2. As used herein, the term "LARP1-derived EGYR peptide" refers to the peptide or group of peptides that comprise the amino acid sequence EGYR (glutamic acid- glycine-tyrosine-arginine;SEQ ID NO: 3) which is found within the amino acid sequence of LARP1 protein. Such peptide may be 4 amino acids in length, or could be longer, possessing additional amino acids at the C- and / or N-terminus of the peptide due to trypsin mis-cleavage. Typically, such peptide will be up to 12 amino acids in length; trypsin mis-cleavage of LARP1 is predicted to produce a peptide that is either 11 or 12 amino acids long. In a particular embodiment, the LARP1-derived EGYR peptide fragment has or consists of the amino acid sequence EGYR (SEQ ID NO: 3). As used herein, the term "isolated" as applied to a polypeptide means a polypeptide that has been separated from components that naturally accompany it. Typically, the polypeptide is substantially isolated when it is at least 70%, by weight, free from other proteins and naturally occurring organic molecules with which it is naturally associated. Suitably, the polypeptide is at least 75%, such as at least 80%, at least 90% at least 95%, at least 99% or 100%, by weight, isolated. An isolated polypeptide may be obtained by standard techniques, for example, by extraction from a natural source (e.g., purification from a cell or body fluid). The percent of isolation can also be a measure of purity. Purity can be measured by any appropriate method, e.g., by column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis. As used herein, the term "purification" or "purifying" refers to a process that enriches the amount of one or more analytes of interest (e.g. peptides or polypeptides) relative to other components in the sample that may interfere with detection of the analyte of interest. As used herein, the term "sample" refers to any sample that may contain an analyte of interest. As used herein, the term "body fluid" means any fluid that can be isolated from the body of an individual. For example, "body fluid" may include blood, plasma, serum, bile, saliva, urine, tears, perspiration, and the like. In some embodiments, the sample comprises a body fluid sample from a patient. Such as a blood sample; suitably this can be plasma or serum. Serum is the liquid fraction of the blood that remains when a whole blood sample is allowed to clot. Accordingly, serum is obtained by allowing the whole blood sample to clot. This can be done, for example, by leaving the sample undisturbed at room temperature for around 15-30 minutes. The serum can be obtained by removing the clot, for example by centrifuging the sample. This can be done, for example, at 1,000-2,000 x g for 10 minutes in a refrigerated centrifuge. The resulting supernatant is serum. Plasma is produced when whole blood is treated with an anticoagulant. This can be done, for example, by collecting blood in tubes that are treated with an anticoagulant. Plasma can then be obtained by centrifugation. This can be done, for example, at 1,000-2,000 x g for 10 minutes in a refrigerated centrifuge. The resulting supernatant is plasma. As used herein, the term "solid phase extraction" or "SPE" refers to a sample preparation process in which compounds which are dissolved or suspended in a liquid mixture are separated from other compounds in the mixture according to their physical and chemical properties. SPE uses the affinity of solutes dissolved or suspended in a liquid (known as the mobile phase) for a solid through which the sample is passed (known as the stationary phase) to separate a mixture into desired and undesired components. In some instances, as the mobile phase passes through or around the solid phase, undesired components of the mobile phase may be retained by the solid phase resulting in a purification of the analyte in the mobile phase. In other instances, the analyte may be retained by the solid phase, allowing undesired components of the mobile phase to pass through or around the solid phase. In these instances, a second mobile phase is then used to elute the retained analyte off of the solid phase for further processing or analysis. As used herein, the term "chromatography" refers to a process in which a mixture of chemicals within a liquid or gas is separated into components as they pass around or over a stationary liquid or solid phase. Examples of methods of chromatographic separation include capillary-action chromatography such as paper chromatography, gel chromatography such as gel filtration chromatography, thin layer chromatography (TLC), column chromatography, fast protein liquid chromatography (FPLC), size exclusion chromatography, ion exchange chromatography, affinity chromatography, high performance liquid chromatography (HPLC), and reverse phase high performance liquid chromatography (RP-HPLC) amongst others. As used herein, the term "liquid chromatography" or "LC" refers to a process of passing a mixture of particles (ions, compounds, peptide molecules etc) to be separated through a column filled with a packing material of a finely divided substance known as the stationary phase. The separation arises from differences in adsorption, size, charge etc of the individual ions or molecules as the fluid moves relative to the stationary phase(s). Examples of "liquid chromatography" include normal phase liquid chromatography (NPLC), reverse phase liquid chromatography (RPLC), high performance liquid chromatography (HPLC) and ultra high performance liquid chromatography (UHPLC). As used herein, the term "high performance liquid chromatography" or "HPLC" (sometimes known as "high pressure liquid chromatography") refers to liquid chromatography in which the mobile phase is forced under pressure through a stationary phase, typically a densely packed column. HPLC instruments use a pump to force the mobile phase through and provide higher resolution and faster analysis time. As used herein, the term "ultra high performance liquid chromatography" or "UHPLC" (sometimes known as "ultra high pressure liquid chromatography") refers to a form of column chromatography used to separate, identify, and quantify compounds. It allows for separation and analysis of small particles both quickly and effectively. With UHPLC the mobile phase is forced under high pressure through a stationary phase, typically a densely packed column with a stationary phase comprising packing particles that have an average diameter of than 2 pM. As the mobile phase is passing through the stationary phase a detector shows the retention times of the different molecules. Retention time varies depending on the interactions between the stationary phase, the molecules being analyzed, and the solvent used. As used herein, the term "gas chromatography" or "GC" refers to a type of chromatography for analysing compounds that can be vaporized without decomposition. The sample mixture is vaporized and injected into a stream of carrier gas (such as nitrogen or helium) moving through a column containing a stationary phase composed of a liquid or, for example a particulate solid if in a packed column, and is separated into its component compounds according to the affinity of the compounds for the stationary phase. As used herein, the term "extraction column" refers to a chromatography column containing an average particle diameter greater than about 50pm. As used in this context, the term "about" means ± 10%. As used herein, the term "analytical column" refers to a chromatography column having sufficient chromatographic plates to effect a separation of materials in a sample that elute from the column sufficient to allow a determination of the presence or amount of an analyte. Such columns are often distinguished from "extraction columns", which have the general purpose of separating or extracting retained material from non-retained materials in order to obtain a purified sample for further analysis. As used in this context, the term "about" means ± 10%. In a preferred embodiment the analytical column contains particles of about 5pm in diameter. As used herein, the term "on-line" refers to a procedure performed without the need for operator intervention. In contrast, the term "off-line" as used herein refers to a procedure requiring manual intervention of an operator. Thus, if samples are subjected to precipitation, and the supernatants are then manually loaded into an autosampler, the precipitation and loading steps are off-line from the subsequent steps. In various embodiments of the methods, one or more steps may be performed in an on-line automated fashion. As used herein, the term "mass spectrometry" or "MS" refers to an analytical technique to identify compounds by their mass. Typically, a sample is analysed by generating gas phase ions from the sample, which are then separated according to their mass-to-charge ratio (m / z) and detected. MS technology generally includes (1) ionizing the compounds to form charged compounds; (2) calculating a mass-to-charge ratio (m / z). and (3) detecting the molecular weight of the charged compounds;The compounds may be ionized and detected by any suitable means. A "mass spectrometer" generally includes an ionizer and an ion detector. In general, one or more molecules of interest are ionized, and the ions are subsequently introduced into a mass spectrometric instrument where, due to a combination of magnetic and electric fields, the ions follow a path in space that is dependent upon mass ("m") and charge ("z"). Methods of generating gas phase ions from a sample include electrospray ionization (ESI), matrix-assisted laser desorption-ionization (MALDI), surface-enhanced laser desorptionionization (SELDI) and chemical ionization. Separation of ions according to their m / z ratio can be accomplished with any type of mass analyser, including quadrupole mass analysers (Q), time-of-flight (TOF) mass analysers, magnetic sector mass analysers, 3D and linear ion traps (IT), Fourier-transform ion cyclotron resonance (FT-ICR) analysers, and combinations thereof (for example, a quadrupole-time-of-flight analyser, or Q-TOF analyser). Prior to ionisation, the sample may be subjected to one or more dimensions of chromatographic separation, for example, one or more dimensions of liquid or size exclusion chromatography. As used herein, the term "operating in negative ion mode" refers to those mass spectrometry methods where negative ions are generated and detected. The term "operating in positive ion mode" as used herein, refers to those mass spectrometry methods where positive ions are generated and detected. As used herein, the term "ionization" or "ionizing" refers to the process of generating an analyte ion having a net electrical charge equal to one or more electron units. Negative ions are those having a net negative charge of one or more electron units, while positive ions are those having a net positive charge of one or more electron units. As used herein, the term "fast atom bombardment" or "FAB" refers to methods in which a beam of high energy atoms (often Xe or Ar) impacts a non-volatile sample, desorbing and ionizing molecules contained in the sample. Test samples are dissolved in a viscous liquid matrix such as glycerol, thioglycerol, m-nitrobenzyl alcohol, 18-crown-6 crown ether, 2-nitrophenyloctyl ether, sulfolane, diethanolamine, and triethanolamine. The choice of an appropriate matrix for a compound or sample is an empirical process. As used herein, the term "matrix-assisted laser desorption ionization" or "MALDI" refers to an ionization technique that uses a laser energy absorbing matrix to create ions from large molecules with minimal fragmentation. MALDI methodology is a three-step process. First, the sample is mixed with a suitable matrix material and applied to a metal plate. Second, a pulsed laser irradiates the sample and thirdly, the analyte molecules are ionized by being protonated (H+ addition) or deprotonated (H+ removal) in the hot plume of ablated gases. They can then be accelerated into whichever mass spectrometer is used to analyse them As used herein, the term "surface enhanced laser desorption ionization" or "SELDI" refers to an ionization method suitable for analysis of protein mixtures in which a non-volatile sample is exposed to laser irradiation, which desorbs and ionizes analytes in the sample by various ionization pathways, including photo- ionization, protonation, deprotonation, and cluster decay. For SELDI, the sample is typically bound to a surface before MS analysis. As used herein, the term "electrospray ionization" or "ESI," refers to methods in which a high voltage is applied to a liquid to create an aerosol of very small droplets of solution in solvent vapor. This mist of droplets flows through an evaporation chamber. As the droplets get smaller the electrical surface charge density increases until such time that the natural repulsion between like charges causes ions as well as neutral molecules to be released. ESI is different from other ionization methods in that it may produce multiple-charged ions, effectively extending the mass range of the analyser. Heated ESI is similar but includes a heat source for heating the sample while in the capillary tube. Mass spectrometry using ESI is called electrospray ionization mass spectrometry (ESI-MS). As used herein, the term "desorption" refers to the removal of an analyte from a surface and / or the entry of an analyte into a gaseous phase. Laser desorption thermal desorption is a technique wherein a sample containing the analyte is thermally desorbed into the gas phase by a laser pulse. The laser hits the back of a specially made 96-well plate with a metal base. The laser pulse heats the base and the heat causes the sample to transfer into the gas phase. The gas phase sample is then drawn into the mass spectrometer. As used herein, the term "selective ion monitoring" or “SIM” is a detection mode for a mass spectrometric instrument in which only ions within a relatively narrow mass range, typically about one mass unit, are detected. As used herein, "selected reaction monitoring" or “SRM” is a detection mode for a mass spectrometric instrument in which a precursor ion and one or more fragment ions are selectively detected. As used herein, the term “prognosis” refers to the likely outcome of a disease process or event. For example, the prognosis of a subject with cancer can indicate the likelihood that the subject will survive for a period of time (e.g. 5 years) and / or will enter remission and / or the likelihood of metastasis. The prognosis of a subject with cancer can also indicate the likelihood that the subject will remain disease-free following treatment for a period of time (e.g. 5 years). As used herein, the terms “diagnosis” or “medical diagnosis” refer to the identification of the nature and cause of a certain phenomenon, such as a disease or medical condition. Diagnosis is the process of determining which disease or condition explains an individual’s symptoms and signs. A diagnosis is the classification of an individual's condition into separate and distinct categories that allow medical decisions regarding treatment and prognosis to be made. The term "comparing" as used herein has its usual meaning, e.g. the act of examining things to see if they are similar or different. In the context of the present invention that includes comparing the level of LARP1 and / or CA125 in the sample from the subject with the reference level of the said biomarker(s) for a particular cancer status. It is to be understood that comparing as used herein usually refers to a comparison of corresponding parameters, values or scores, e.g., an absolute amount is compared to an absolute reference amount while a concentration is compared to a reference concentration or an intensity signal obtained from the biomarker in a sample is compared to the same type of intensity signal obtained from a reference sample or a collated value (e.g. score) from inputting the value of the levels of multiple biomarkers (e.g. LARP1, CA125) into an equation is compared to the reference value for the collated levels from the same biomarkers (e.g. obtained from a reference control sample or a reference cohort). As described herein the reference value can also be obtained from multiple control or reference samples, e.g. from a reference cohort with known cancer disease status (e.g. Gleason score) or from archived samples taken from subjects whose cancer status after a set period of time , e.g., 5 years from sampling is known. The comparison may be carried out manually or computer-assisted. Thus, the comparison may be carried out by a computing device. The value of the measured or detected level of the biomarker in the sample from the subject and the reference level can be, e.g., compared to each other and the said comparison can be automatically carried out by a computer program executing an algorithm for the comparison. Suitably, an algorithm (e.g. mathematical algorithm) which has been pre-determined by the analysis of, for example, historical clinical data can be applied to the measures to give a forecast or call. When multiple biomarkers are measured, the algorithm may apply a weighting to the level of each or any biomarker. The algorithm can also take into consideration longitudinal reference values. Suitably, the algorithm has been generated by machine learning trained on archived samples from patients whose cancer status is known or from clinical studies using longitudinal measurements of the biomarker(s) in conjunction with clinical outcome. For example, measuring the levels of the biomarkers in hundreds or thousands of subjects over a period of time (e.g. 3, 4, 5 or more years) and correlating the change in biomarker level with whether or not a subject developed cancer. A number of different statistical algorithms can be applied in order to generate a mathematical model combining together the protein levels of two or more proteins with a cutoff to classify the patient’s cancer. These include, but are not limited to logistic regression, multiple regression, Cox proportional hazard models, random forests, recursive partitioning, random survival forests, partial least squares, partial least squares discriminant analysis, Support Vector Machines, neural networks. For a computer-assisted comparison, the value of the measured level may be compared to values corresponding to suitable references which are stored in a database by a computer program. The computer program may further evaluate the result of the comparison, i.e. automatically provide the desired assessment in a suitable output format. For a computer- assisted comparison, the value of the measured level may be compared to values corresponding to suitable references which are stored in a database by a computer program. The computer program may further evaluate the result of the comparison, i.e. automatically provides the desired assessment in a suitable output format. The term "measurement" or "measuring" in the context of analysis preferably comprises a qualitative, a semi-quantitative or a quantitative measurement. The term “determining” or “assessing” as generally used herein in the context of assessing or working out. Accordingly, determining or assessing as used herein, includes work towards determining or identifying the cancer status of a subject, e.g. identify whether they have a particular condition or not, e.g. pre-cancer, pre-invasive cancer, invasive cancer or not. In this context the term “identifying” may be used. As will be understood by those skilled in the art, and noted elsewhere herein, the assessment made in accordance with the present invention, although preferred to be, may usually not be correct for 100% of the investigated subjects. The term, typically, requires that a statistically significant portion of subjects can be correctly assessed. Whether a portion is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools, e.g., determination of confidence intervals, p-value determination, Student's t-test, Mann-Whitney test, etc.. Details may be found in Dowdy and Wearden, Statistics for Research, John Wiley &Sons, New York 1983. Typically envisaged confidence intervals are at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%. The p-values are, typically, 0.2, 0.1, 0.05. As will be understood by those skilled in the art, the determinations made in accordance with the present invention, although preferred to be, may usually not be correct for 100% of the investigated subjects. The term, typically, requires that a statistically significant portion of subjects can be correctly assessed. Whether a portion is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools, e.g., determination of confidence intervals, p-value determination, Student's t-test, Mann-Whitney test, etc.. Details may be found in Dowdy and Wearden, Statistics for Research, John Wiley &Sons, New York 1983. Typically envisaged confidence intervals are at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%. The p-values are, typically, 0.2, 0.1, 0.05. As such, as used herein when determining whether a subject has invasive cancer, the determining / determination may be for a likelihood of someone having invasive cancer. Similarly, as used herein when determining whether a subject does not have cancer or pre-cancer (i.e. is healthy), the determining / determination may be for a likelihood of someone not having cancer. As used herein, the term “cancer” refers to a disease caused by an uncontrolled division of abnormal cells in a part of the body which has invaded nearby tissues (i.e. penetrated through the basement membrane of a tissue and has entered the deeper tissue and blood vessels) and may have spread to other parts of the body. Subjects with cancer can be referred to as having invasive cancer. “Pre-cancerous conditions” or “pre-cancer”. Cancer is frequently preceded by the development of a pre-cancerous condition, wherein a particular tissue or organ may comprise some dysplastic cells amongs normal cells but these have not invaded nearby tissues. Pre-cancer therefore refers to the state before invasive cancer. Thepre-cancer condition is associated with an increased risk of cancer. Examples of pre-cancerous conditions include, but are not limited to, those selected from the group consisting of: actinic keratosis, Barrett’s oesophagus, atrophic gastritis, dyskeratosis congenital, Sideropenic dysphagia, Lichen planus, melanoma in situ, oral submucous fibrosis, solar elastosis, cervical dysplasia, leukoplakia, erythroplakia, monoclonal gammopathy of unknown significance (MGLIS), monoclonal B-cell lymphocytosis (MBL), myelodysplastic syndromes, as well as pre-cancerous conditions of the stomach such as atrophic gastritis, gastric ulcer, pernicious anaemia, gastric stumps, gastric polyps, and Menetrier's disease. Among the listed pre-cancerous conditions of the stomach, atrophic gastritis, pernicious anaemia, gastric stumps, and certain types of gastric polyp may have particularly heightened risk of developing into cancers. Also Precancerous pancreatic, breast, cervix, lung and prostate lesions, called cancers “in situ” or Stage 0, or PDAC (pancreatic ductal carcinoma in situ), DCIS (ductal carcinoma in situ), CIN (cervical intra-epithelial neoplasia), PIN (prostatic intraepithelial neoplasia), CIS (carcinoma in situ) of lung or other organ, aberrant crypt foci (colon), dysplastic nodules (hepatocellular / liver), biliary intra-epithelial neoplasia (bile duct), VIN (vulval intraepithelial neoplasia), AIN (anal intraepithelial neoplasia), P53-signature, serous tubal intraepithelial lesions (STIL), SCOUT, and serous tubal intraepithelial carcinoma (STIC). Pre-cancerous conditions often take the form of lesions comprising dysplastic or hyperplastic cells. The severity of dysplasia can vary between different pre-cancerous conditions, or with the development of a single pre-cancerous condition over time. Generally, the more advanced dysplasia associated with a pre-cancerous condition is, the more likely it is that the pre-cancerous condition will to develop into cancer. Dysplasia is typically classified as mild, moderate or severe. Severe dysplasia usually develops into cancer if left untreated. As used herein, the term “pre-invasive cancer” means a cluster of malignant cells that has not yet invaded the deeper epithelial tissue or spread to other parts of the body. As used herein, the term “invasive cancer” means malignant cells that have invaded the deeper epithelial tissue and / or spread to other parts of the body. As used herein, the term “field precancerization” (also termed field change, field change cancerization, field carcinogenesis, cancer field effect or premalignant field defect) is a biological process in which large areas of cells at a tissue surface or within an organ are affected by carcinogenic alterations. As used herein, the term “cancer-predisposing mutations” or “driver mutations” refers to particular mutations or polymorphic forms within the nucleic acid of certain genes whose presence are associated with an increased risk of developing a cancer. Examples of genes that are recognised as being capable of possessing one or more cancer-predisposing mutations in certain patients include: BRCA1, BRCA2, RAD51C, RAD51D, PALB2, or BRIP1, KRAS, P53, ALK and HER2. As used herein “cancer staging” or “determining cancer status” means determining the location, stage, grade and / or malignant potential of a pre-cancer or cancer. Cancer status means determining the location, stage, grade and / or malignant potential of a pre-cancer or cancer. Ovarian cancer status means determining the location, stage, grade and / or malignant potential of a pre-cancer (e.g. STIC, Secretory Cell OUT growth (SCOUT), P53-signature, FIGO stage 1A STIC lesion, or other preinvasive lesion) or cancer. The term “subject” (sometimes referred to as “individual”or “patient”) as used herein refers to an animal, preferably a mammal and, more typically to a human. The subject is preferably a human female. There is a need for determining ovarian cancer status in early adulthood. Therefore, the subject is preferably a human female aged between 25 and 75 years. The inventors have found that levels of LARP1 and CA125 change over time as ovarian cancer develops. According to a first aspect of the invention there is provided a method for determining the likely cancer status in a subject, comprising (i) determining the level of La-related protein 1 (LARP1) protein in a biological sample from a subject; (ii) determining the level of Cancer Antigen 125 (CA125) protein in a biological sample from the same subject as for (i); (iii) comparing the amounts in (i) and (ii) to threshold levels and / or to levels determined for the subject at one or more previous time points; and (iv) determining the likely cancer status in the subject based on the comparison in step (iii). In particular embodiments, steps (i) and (ii) are carried out on the same sample form the subject, or a contemporaneous sample from the subject. The method can be employed for any cancer. Suitable cancers include: ovarian, breast, hepatocellular carcinoma, colorectal, cervical, lung, gastric, pancreaticendometrial or prostate cancer. In a particular embodment, the method is for determining the likely ovarian cancer status in a subject. Suitably the level of biomarker protein determined (e.g. LARP1 orCA125) is the absolute level. According to a variation of the first aspect of the invention there is provided a method for determining the likely ovarian cancer status in a subject, comprising (i) determining the level of La-related protein 1 (LARP1) protein in a biological sample from a subject; (ii) determining the level of Cancer Antigen 125 (CA125) protein in in a biological sample from the same subject as for (i); (iii) comparing the amounts in (i) and (ii) to threshold levels and / or to levels determined for the subject at one or more previous time points; and (iv) determining the likely ovarian cancer status in the subject based on the comparison in step (iii). In a particular embodiment, steps (i) and (ii) are carried out on the same sample form the subject, or a contemporaneous sample from the subject. In particular embodiments, the ovarian cancer status is selected from: no cancer, precancer, and invasive ovarian cancer. Ovarian pre-cancer has various stages including: p53 signature, SCOUT, STIL, STIC, FIGO stage 1A ovarian cancer. In particular embodiments, the ovarian cancer status is pre-cancer, optionally selected from p53 signature, SCOUT, STIL, STIC, FIGO stage 1A ovarian cancer. Suitably the level of biomarker protein determined (e.g. LARP1 orCA125) is the absolute level. Determining the cancer status, e.g. ovarian cancer status, has numerous applications that apply knowledge of the change in levels of LARP1 and CA125 that occur at different stages of pre-cancer and cancer development. Examples of applications, including: i) prognosing the development of cancer; ii) predicting the responsiveness to a therapeutic treatment; iii) identifying subjects that are in early stages of cancer development; iv) detecting the presence of pre-invasive cancer; v) detecting the presence of or development of p53 signature lesion, STIL and / or STIC (e.g. when in the context of ovarian cancer status); vi) determining the status of a cancer; vii) diagnosing cancer; and viii) monitoring the efficacy of a therapeutic treatment. In particular embodiments, the method according to the first aspect of the invention allows to determine the likely stage of ovarian cancer, including whether a subject likely has no cancer, pre- cancer including: P53 signature, SCOUT, STIL, STIC, FIGO stage 1A ovarian cancer or invasive ovarian cancer; it allows to predict high, medium or low risk of developing ovarian cancer and / or unlikely to have pre-invasive cancer or invasive high grade serous ovarian cancer; it allows to monitor efficacy of a therapeutic treatment, it allows to monitor the progression of ovarian cancer and / or prognose the development of ovarian cancer. The inventors have found that circulating levels of LARP1 and CA125 change over time and at different stages of pre-cancer and cancer development such that the level of LARP1 relative to CA125 at one or more time points can be used to gauge or predict cancer status for a subject. The inventors have found that high levels of LARP1 and CA125 over time or compared to threshold amounts; or high levels CA125 compared to a threshold amount and any levels of LARP1 over time indicates the possible / likely presence of invasive cancer, (e.g. high grade serous ovarian cancer in ovarian cancer setting). Thus, in particular embodiments, (i) high levels of LARP1 and CA125 over time or compared to threshold amounts; or (ii) high levels CA125 compared to a threshold amount and rising levels of LARP1 over time indicates the possible / likely presence of invasive cancer. Thus, in particular embodiments, (i) high levels of LARP1 and CA125 over time or compared to threshold amounts; or (ii) high levels CA125 compared to a threshold amount and rising levels of l_ARP1 overtime indicates the possible / likely presence of invasive high grade serous ovarian cancer. The inventors have found that low levels of CA125 and a rising or high level of l_ARP1 over time or compared to threshold amounts indicates the possible / likely presence of pre-cancer / pre-invasive cancer. Thus, in particular embodiments, low levels of CA125 and a rising or high level of LARP1 and over time or compared to threshold amounts indicates the possible / likely presence of pre-invasive cancer. In the context of ovarian cancer status, this could indicate a pre-cancer condition / stage selected from P53 signature, SCOUT, STIL, STIC, and FIGO stage 1A ovarian cancer. The inventors have found that low levels of LARP1 and CA125 over time or compared to threshold amounts indicates that the subject is unlikely to have pre-cancer, pre-invasive cancer or invasive cancer (e.g. high grade serous ovarian cancer when in context of ovarian cancer). Thus, in particular embodiments, low levels of LARP1 and CA125 over time or compared to threshold amounts indicates that the subject is unlikely to have pre-invasive cancer or invasive cancer. Thus, in particular embodiments, low levels of LARP1 and CA125 overtime or compared to threshold amounts indicates that the subject is unlikely to have high grade serous ovarian cancer. Typically, the actual level or amount of each biomarker measured in the sample will be calibrated or adjusted to determined the absolute level. In a particular embodiment, the absolute levels of LARP1 and CA125 in step (iii) are compared to the absolute levels determined for the subject at one or more previous time points. In a particular embodiment, the absolute levels of LARP1 and CA125 are determined from the same biological sample. In a particular embodiment, the absolute levels of LARP1 and CA125 are determined from samples taken from the subject contemporaneously. In particular embodiments, the absolute levels of LARP1 and CA125 are determined from samples taken from the subject at different time points but the change in levels can be plotted and overlaid with each other to facilitate the cancer staging. By “absolute level” we mean the concentration of a protein or peptide in a sample, e.g. original sample, e.g. blood sample. Such level can be determined by comparison to the level of a synthetic peptide with a known concentration. When comparison across samples is desired, it is important to determine the absolute value of a marker (e.g. amount of CA125 or LARP1 protein) rather than the measured value so as to compare equivalent situations (amount of sample etc), perhaps taken at different time points. This is important because the total amount of protein in a sample may change depending on the volume taken or any purification steps. An actual read (measured value) is therefore typically normalised against one or more housekeeping biomarkers (e.g. proteins) whose value should not substantially change across the outcome sub-sets (e.g. in the present case, the sub-sets could be: healthy individuals; individuals with pre-cancer; orthose with invasive cancer), so as to give an absolute value. The means for normalising and determining the absolute level of a biomarker are well known to the person of skill in the art. Absolute quantification can be also be determined by reference to a standard curve, which is prepared from samples of known template concentrations. For example, when conducting mass spectrometric quantification, absolute level of a protein or peptide in a sample can be determined by spiking unlabeled samples with known concentrations of isotopically-labeled synthetic protein or peptide and the absolute level of the biomarker protein or peptide in the sample can then be determined using this standard curve. Suitably, the measured level of each biomarker is normalised, such as by use of one or more standardised control / housekeeping protein (referred to herein as a “reference protein”). In a particular embodiment, the absolute levels of LARP1 and CA125 are determined by reference to the amount of at least one reference protein in the sample. Examples of suitable reference proteins include, CTB, HBB, HBA, A1AT, ALBU, APOA1, IGHG1, PUM1, IPO8 and IGKC. The methods provided herein may comprise providing a biological fluid sample (for example a blood sample or a urine sample) from a subject. As used herein, “provide”, "obtain" or "obtaining" in the context of a sample, can be any means whereby one comes into possession of the sample by "direct" or "indirect" means. Directly obtaining a sample means performing a process (e.g., performing a physical method such as extraction) to obtain the sample. Indirectly obtaining a sample refers to receiving the sample from another party or source (e.g., a third party laboratory that directly acquired the sample). In certain embodiments, the methods of the invention are carried out on samples that have been obtained indirectly. In certain embodiments, the methods of the invention include an additional step of directly obtaining the sample from the subject. In general, the methods described herein are ex vivo methods that are performed using a sample that has already been obtained from the subject (i.e. the sample is provided for the method, and the steps taken to obtain the sample from the subject are not included as part of the method). For the avoidance of doubt, the term "ex vivo" has its usual meaning in the art, referring to methods that are carried out in or on a sample obtained from a subject in an artificial environment outside the body of the subject from whom the sample has been obtained. In particular embodiments, the subjects biofluid sample has been previously isolated / taken from the subject and the sample isolation does not form part of the method of the invention. In another embodiment, the sample isolation can be a step of the method of the invention. In a particular embodiment, the or each sample comprises a biological sample selected from the group consisting of: a blood sample, a plasma sample, a serum sample, a urine sample, an ascites sample and a saliva sample. In a particular embodiment, the or each sample is a blood or blood-fraction sample. Whilst LARP1 and CA125 protein can be detected in serum and whole blood, the inventors have found that plasma samples yield more sensitive measurements. This may be because plasma does not contain clotting factors and other proteins that could cross-react. In particular embodiments, the blood-fraction sample is a serum or plasma sample. In a particular embodiment, the blood-fraction sample is a plasma sample. In a particular embodiment, the absolute level of LARP1 and / or CA125 is compared to a threshold value. By “threshold level or value” we mean a value which has been selected by the health authority as signifying a positive result when crossed (higher than) or a negative result if not crossed (less than). Such a threshold value may differ between patient sub-groups. For example, based on age, genetic make-up (e.g. presence of driver mutations in key genes), ethnicity etc. A threshold value is typically a value which has been determined fom clinical assessment of hundreds or thousands of subjects to be statistically significant for an outcome (e.g. pre-invasive cancer status), such that if a newly tested sample yield an absolue amount above or below the threshold (as the case might be) the subject can be categorised as likely to fall within that outcome sub-group with a certain degree of statistical significance. Over time, and particularly as more and more patients are tested and confirmed to have a particular outcome status, the threshold value indicative of an outcome sub-group can be adjusted or refined. The threshold value may also differ between different categories of patient. For example, the threshold value may differ based on age, height weight, genotype or any other factors. So, for example, the “normal” range for an individual’s blood pressure will differ for an 18-year old man compared to a 70-year old man. The threshold value signifying hypertension will therefore be different based on their age. The threshold value for any outcome sub-set of the present invention (e.g. healthy, pre-cancer, invasive cancer etc.) is preferably determined from clinical study data from matched subjects. By matched subjects we mean the same type of individual (e.g. age-matched, height or weight matched, matched by sex, matched by genoype (e.g. those with or without pre-disposing mutaions for a cancer, line BRCal or BRCa2, K-ras etc.), and the like) as the individual / subject being tested according the methods of the invention. In a particular embodiment, the threshold value has been determined based on clinical studies. The cancer status (e.g. ovarian cancer status) can be determined based on a single measurement of the absolute levels of LARP1 and CA125 at one timepoint. Suitably, the measurement of absolute level for each biomarker is determined from the same biological sample or the measurement of absolute level for each biomarker is from separate samples taken contemporaneously. Although the cancer status can be determined based on a single measurement of the absolute levels of LARP1 and CA125, e.g. in a sample or samples taken contemporaneously, more efficient status determination can be acquired if levels of LARP1 and CA125 are taken at multiple time points longitudinally. The inventors have discovered that LARP1 levels start to rise as a subject moves from normal to pre-invasive cancer (e.g., STIC in the ovarian setting). During this period CA125 levels are typically still low / normal. The level of LARP1 drops slightly before rising alongside the level of CA125 which starts to increase as the cancer status progresses to invasive ovarian cancer. Eventually, when CA125 and LARP1 levels are both high (above threshold levels) the cancer is more developed. It is at this stage that current CA125 measurement alone can be used for diagnosing / predicting ovarian cancer status. Thus LARP1 levels follows a predictive pattern with a peak at least 20-40 months prior to high grade serous ovarian cancer (HGSC) diagnosis. CA125 levels may only start to rise after the peak in LARP1 levels and shortly before HGSC diagnosis (around 12m before HGSC disgnosis). Without wishing to be bound by theory, it appears that LARP1 is a measure of high cell stress in tissue. The inventors have found that the cells in preinvasive / STICs stage have high levels of oxidative stress (these are precancerous). Hence LARP1 goes up and then transiently dips as the cells transition to cancer. The levels then continue to rise as the cancer cells overcrowd and get stressed again, i.e. before becoming metastatic. So LARP1 levels in the circulation rise and fall as the cancer condition develops. This rise and fall may follow a sawtooth pattern.In particularar embodiments, the trajectory of the sawtooth pattern is an upward incline. Ideally, one would want to catch the first upspike, which would be possible if all subjects had their LARP1 levels measured regularly from an early stage (e.g. start of adulthood), or an upspike is detected that exceeds a threshold value. On the other hand, CA125 pattern in the circulation takes on many patterns such as slow rise or a sharp rise (e.g., / - shaped) where it suddenly goes up when there is established cancer. CA125 is a poor indicator of early stage ovarian cancer and of ovarian pre-cancer. CA125 biomarker is thus unsuited to detecting pre-cancer. Thus in terms of rough staging, Low LARP1 level / low CA125 level - unlikely to have cancer or pre-invasive cancer. Rising LARP1 level / low CA125 level - likely to have pre-cancer / pre-invasive cancer. LARP1 level rising / CA125 level rising (or both above a threshold) - likely to have cancer. By combining LARP1 and CA125 protein measurements it should be possible to effect much earlier cancer status determination than currently possible. Single point measurements of LARP1 and CA125 can assist in determining the likelihood of having precancer. Longitudinal measurements will likely provide much greater granularity on the cancer status. The ability to determine the cancer status of a subject will allow more effective treatment decisions. For example, in the ovarian cancer setting, patients identified as likely to have pre-cancer, such as STIC, can be given risk-reducing surgery to remove just the fallopian tubes, or ovaries and fallopian tubes depending on the stage of disease progression, well in advance of developing invasive cancer. Patients can also be identified for much earlier therapeutic intervention. For example, as illustrated by the longitudinal levels for patient 1, from just the first few measurements of LARP1 and CA125, the methods of the present invention could have picked up that they were on the trajectory to developing ovarian cancer. The sawtoothed change in LARP1 level as a subject moves from pre-cancer through to advanced invasive ovarian cancer was previously not realised. Longitudinal measurement of LARP1 will allow more accurate determination of ovarian cancer status and so more precisely map the first upswing in U\RP1 that will correspond with ovarian precancer. In particular embodiments, the absolute level of each of LARP1 and CA125 are compared to the absolute level of the same biomarker protein (LARP1 or CA125) determined at one or more previous time points. Such analysis is referred to in the art as longitudinal studies or longitudinal measurements and it allows one to detect changes in the absolute level of a biomarker over time. Thus, in particular embodiments the level of LARP1 and CA125 are measured longitudinally. It will be appreciated that the level of LARP1 and / or CA125 need not be measured, or the sample taken, at the same time. Longitudinal measurements allow time-course plots to be prepared and so even if the LARP1 and CA125 levels, or the samples from which the measurements are determined have been taken at different times, the plots can be overlaid to allow direct comparison of values. For convenience, however, the LARP1 levels and CA125 levels are determined from the same sample, or from contemporaneously taken samples, and / or are determined / measured at the same time (or substantially the same time, e.g. one after the other, or within a few hours of each other). In a particular embodiment, the absolute level of LARP1 and / or CA125 in the sample from the subject is determined from at least three timepoints and the absolute level at each timepoint is compared to the level at one or more different timepoints. In a particular embodiment, the timepoints are at least about 3 months apart, such as approximately 3, 6, 9, 12, 18 or 24 months apart. In a particular embodiment each timepoint is at least 3 months apart from another timepoint. Suitably, the level of each measured biomarker is determined quantitatively. Suitably, the subject’s ovarian cancer status can be gauged relative to their levels of LARP1 and CA125 compared to threshold values. The inventors have found that healthy subjects (those without cancer) typically have LARP1 plasma levels of between about 5 and 24 pg / ml. Those with pre-invasive cancer (e.g. those found to have STIC by P53 measurements) typically have at least about 25 - 28 pg / ml, and those with established invasive ovarian cancer typically have absolute LARP1 levels above 35 pg / ml. Thus, in particular embodiments, a threshold level of LARP1 is selected from the group consisting of: 15, 18, 20, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 35 and 40 pg / ml. As a guide, a threshold level of LARP1 in the plasma of a subject that signifies likelihood of having pre-invasive cancer may be selected from the group consisting of: 25, 26, 27 or 28 pg / ml. It will be appreciated that the clinically accepted threshold level signifying pre-invasive cancer will be based on data from many hundreds to thousands of patients. It will also be appreciated that the threshold level will alter depending on the sample source. Thus, the threshold level for whole blood, plasma and serum may be slightly different. It will also be appreciated that an level for one subject will differ from another subject depending on a number of factors such as age, weight, sex, height, dietary habits, smoking history, family history, past cancer history, menopausal status etc. The threshold value for an outcome sub-set may therefore be adjusted based on additional factors, e.g. could be age-matched. In a particular embodiment, the threshold level for a particular stage of cancer status (including normal) has been determined using age-matched samples. In a particular embodiment, the likely cancer status determination is performed by a software classification algorithm. In particular embodiments, in the method of the invention the cancer status determination is obtained from an algorithm into which the levels of the LARP1 and CA125 have been entered. In a particular embodiment, values from individual samples taken from the subject over a time period (time-course) are used to make the status determination. In particular embodiments, the algorithm has been generated by machine learning trained on samples from subjects with pre-cancer (e.g. ovarian pre-cancer) and / or invasive cancer (e.g. ovarian invasive cancer) and / or invasive cancer and / or healthy subjects. In particular embodiments, the biomarker protein levels (i.e LARP1 and / or CA125) are transformed into a clinical outcome forecast by an algorithm. In particular embodiments, the biomarker protein levels from multiple time points are transformed into a clinical outcome forecast by an algorithm. The methods of the invention may involve analysing a sample from a subject to determine the level LARP1 protein and CA125 protein and then interpreting the data to determine whether or not the subject has cancer (e.g., ovarian cancer) and / or their cancer (e.g., ovarian) status. However, it is possible that the level(s) of the one or more biomarkers (e.g. LARP1 or CA125) has already been established but the interrogation or analysis of the data has not been undertaken so the status of the subject is not determined. It is possible that the level(s) of one of the biomarkers (LARP1 orCA125) has already been established but the level of the other has not. In that case the sample could be analysed to determine the level of the biomarker that is yet to be determined. The data of the level of the at least one of LARP1 and / or CA125 can be input into a computer, e.g. via a computer program, to conduct the analysis. Suitably, the computer comprises software with algorithms and reference values that can deliver the determination of the status of the subject. The methods of the invention provide valuable information about the status of cancer in a subject. The ability to more accurately determine whether a subject is likely to have precancer that is likely to develop into an aggressive form of cancer (invasive cancer) provides the attending physician and the subject with additional options for further diagnosis or treatment. For example, subjects which are determined to have pre-cancer / non-invasive ovarian cancer can be identified or selected for biopsy testing and or risk-reducing surgical treatment, or therapeutic treatment (such as radiotherapy, chemotherapy, hormone therapy, and the like). Thus, in particular embodiments, the determining by the methods of the invention is used to provide a treatment recommendation for the subject and / or to decide whether a tissue biopsy is needed. It will be appreciated that the methods of the invention can be carried out remotely from the subject or their attending physician, indeed, they could be carried out off-shore and the results communicated back. In particular embodiments, the results of the methods of the invention are provided to a third party, such as the subject or their attending physician, a laboratory or health centre. In a particular embodiments, if the subject is identified as having pre-cancer or pre-invasive cancer they are selected for or identified as suitable for risk reducing surgery. Suitably, in the ovarian setting, the risk reducing surgery is risk reducing salpingo-oophorectomy (RRSO) surgery or risk-reducing salpingectomy (RRS) surgery. In another embodiment, if the subject is possesses having high LARP1 levels but low CA125 levels they are selected for or identified as suitable for risk reducing surgery. Suitably, in the ovarian setting, the risk-reducing surgery is risk reducing salpingo-oophorectomy (RRSO) surgery or risk-reducing salpingectomy (RRS) surgery In a particular embodiments, the RRS surgery comprises removal of fallopian tubes only. Detection of LARP1 and / or CA125 biomarker proteins. The LARP1 and / or CA125 proteins can be detected in a biological sample from a subject using any of a number of well known techniques, including immunoassays (e.g. enzyme-linked immunosorbent assay; ELISA) capable of determine the amount of LARP1 protein, CA125 protein, or any peptide derived from either, in the sample. Suitable immunoassay methods are disclosed in WO2016 / 075455. Mass spectrometry techniques can also be used to detect and quantify the amount of a biomarker protein in a sample. WO2021 / 064361, discloses suitable mass spectrometric methods that could be employed in the present invention. In particular embodiments, the level of LARP1 and / or CA125 protein in the sample is detected using a technique selected from: bead / plate based enzyme linked immunosorbent assay (ELISA), enzyme linked oligonucleotide assay (ELONA), chromatography-tandem mass spectrometry, such as high performance liquid chromatography (HPLC) and mass spectrometry including tandem mass spectrometry. The technique for determining the LARP1 protein level can be the same or different than that used for determining the CA125 level. For example, LARP1 level could be determined using mass spectrometry whereas CA125 could be determined using ELISA. However, for convenience the level of LARP1 and CA125 is determined using the same technique. In particular embodiments, the level of LARP1 and / or CA125 level are determined using an immunoassay. In a particular embodiment the level of LARP1 and CA125 are determined using an immunoassay, such as ELISA. In particular embodiments the level of LARP1 and / or CA125 are determined using mass spectrometry. In particular embodiments, the LARP1 and / or CA125 level is determined using chromatography-tandem mass spectrometry. In a particular embodiment, the LARP1 level is determined using chromatography-tandem mass spectrometry. In a particular embodiment the level of LARP1 is measured using mass spectrometry and the level of CA125 is determined using an immunoassay, such as ELISA. In a particular embodiment, the LARP1 level is determined using chromatography-tandem mass spectrometry and the CA125 level is determined using an immunoassay, such as ELISA. In a particular embodiment the level of LARP1 is measured using an immunoassay, such as ELISA, and the level of CA125 is determined using mass spectrometry. Immunoassay LARP1 and / or CA125 protein can be detected in the test sample from a subject using any suitable assay. An immunoassay may be utilized, for example, an assay which directly detect analyte binding (e.g., by ellipsometric detection), enzyme-linked immunoassays (ELISA), radioimmunoassays (RIAs), competitive binding assays, sandwich immunoassays, and the like. Preferred assays are sandwich immunoassays, although other methods are well known to those skilled in the art (for example, the use of biosensors comprising an integrated analyte receptor and transducer, or the use of natural receptors for natriuretic peptides that are known in the art). Alternative methods of detecting LARP1 or CA125 in samples include high performance liquid chromatography (HPLC) and other high-throughput techniques. An enzyme-linked immunosorbent assay (ELISA) such as a sandwich ELISA is particularly suitable for use in the methods of the invention. In a typical sandwich ELISA, capture antibodies are attached to a surface such as a microwell plate. In the present invention, the capture antibodies are specific to LARP1 or CA125 depending on which of these two biomarkers are to be detected. Non-specific binding sites on the surface can then be blocked, for example using a blocking buffer. The serum or plasma sample is then added to the surface and any biomarker in the sample binds to the capture antibodies. Unbound antigen (i.e. contaminants) can then be removed by washing the plate. A detection antibody is then added, which binds to bound biomarker (LARP1 or CA125). A secondary antibody is then added, which is linked to an enzyme and binds to the detection antibody. The enzyme to be used can be, for example, horseradish peroxidase (HRP), which catalyses the conversion of chromogenic substrates into coloured products and produces light when acting on chemiluminescent substrates. The plate can then be washed to remove any unbound antibody-enzyme conjugates. A substance containing the substrate of the enzyme is then added. If HRP is used as the enzyme various substrates can be used, including 3,3',5,5'-tetramethylbenzidine (TMB), 3,3'- diaminobenzidine (DAB), o-phenylenediamine dihydrochloride (OPD) and 2,2'-azino-bis(3- ethylbenzothiazoline-6-sulphonic acid) (ABTS), which are all chromogenic, or an enhanced chemiluminescent substrate (ECL). The subsequent reaction produces a detectable signal in the substrate. The detectable signal can be, for example, a colour change, fluorescence or electrochemiluminescence, depending on the substrate. The strength of the signal is indicative of the amount of the antigen, in this case LARP1. When the detectable signal is a colour change, a spectrometer is often used to give quantitative values for colour strength. Anti-LARP1 antibodies and anti-CA125 are commercially available, for example from Cambridge Bioscience (UK). In one embodiment the detection is via an immunoassay that uses one or more antibodies specific for one or more epitopes of the biomarker protein in a cell sample of interest. Any biological material can be used for the detection / quantification of the biomarker protein. In particular embodiments, the immunoassay is configured such that it is suitable to detect LARP1 and / or CA125 in a sample (e.g. test sample from a human subject / patient) within 27 min or less, such as 25 min or less, in particular 20 min or less, in particular 18 min or less. The biomarker proteins can be detected in any suitable manner but are typically detected by contacting a sample from the patient with an antibody that binds the biomarker protein and then detecting the presence or absence of a reaction product. Such as, by use of labelled antibodies against cell surface markers followed by fluorescence activated cell sorting (FACS). Such antibodies are preferably labelled to permit their easy detection after binding to the gene product. Detection methodologies suitable for use in the practice of the invention include, but are not limited to, immunohistochemistry of cell containing samples or tissue, enzyme linked immunosorbent assays (ELISAs) including antibody sandwich assays of cell containing tissues or blood samples, mass spectroscopy, and immuno-PCR. Antibodies that can be used herein may be monoclonal, polyclonal, chimeric, or a fragment of the foregoing, as discussed elsewhere herein, preferably monoclonal antibodies, and the step of detecting the reaction product may be carried out with any suitable immunoassay. Antibodies can be commonly used in the art, such as fusion methods (Kohler and Milstein, European Journal of Immunology, 6: 511-519 (1976)), recombinant DNA methods (US Pat. No. 4,816,56) or phage antibody library methods (Clackson et al, Nature, 352: 624-628 (1991) and Marks et al, J. Mol. Biol., 222: 58, 1-597 (1991)). General procedures for antibody preparation are described in Harlow, E. and Lane, D., Using Antibodies: A Laboratory Manual, Cold Spring Harbor Press, New York, 1999; Zola, H., Monoclonal Antibodies: A Manual of Techniques, CRC Press, Inc., Boca Raton, Florida, 1984; And Coligan, CURRENT PROTOCOLS IN IMMUNOLOGY, Wiley / Greene, NY, 1991, which are incorporated herein by reference. An antibody is optionally conjugated with a detectable label. An intact antibody, a fragment thereof (e.g., Fab or F(ab')2), or an engineered variant thereof (e.g., sFv) can also be used. Such antibodies can be of any immunoglobulin class including IgG, IgM, IgE, IgA, IgD and any subclass thereof. Techniques for detecting antibody binding through the use of a detectable label are well known in the art. For example, antibody binding may be detected through the use of chemical reagents that generate a detectable signal that corresponds to the level of antibody binding and, accordingly, to the level of biomarker protein expression. In some embodiments, the detection antibody is coupled to an enzyme, particularly an enzyme that catalyses the deposition of a chromogen at the antigen-antibody binding site. Suitable enzymes include but are not limited to horseradish peroxidase (HRP) and alkaline phosphatase (AP). Commercial antibody detection systems may also be used to practice the invention. Although antibodies are illustrated herein for use in the invention because of their extensive characterization, any other suitable agent (e.g., a peptide, an aptamer, or a small organic molecule) that specifically binds a biomarker is optionally used in place of the antibody. For example, an aptamer that specifically binds a selected biomarker may be used. Aptamers are nucleic acid-based molecules that bind specific ligands. Methods for making aptamers with a particular binding specificity are known in the art. Immunoassays carried out in accordance with the present invention may be homogeneous assays or heterogeneous assays. In a homogeneous assay the immunological reaction usually involves the specific antibody (e.g., anti- biomarker protein antibody), a labelled analyte, and the sample of interest. The signal arising from the label is modified, directly or indirectly, upon the binding of the antibody to the labelled analyte. Both the immunological reaction and detection of the extent thereof are carried out in a homogeneous solution. Immunochemical labels that may be employed include free radicals, radioisotopes, fluorescent dyes, enzymes, bacteriophages, or coenzymes. In a heterogeneous assay approach, the reagents are usually the sample, the antibody, and means for producing a detectable signal. Samples as described above may be used. The antibody is generally immobilized on a support, such as a bead, plate or slide, and contacted with the specimen suspected of containing the antigen in a liquid phase. The support is then separated from the liquid phase and either the support phase or the liquid phase is examined for a detectable signal employing means for producing such signal. The signal is related to the presence of the analyte in the sample. Means for producing a detectable signal include the use of radioactive labels, fluorescent labels, or enzyme labels. For example, if the protein (or polypeptide) to be detected (e.g. LARP1 or CA125) contains a second binding site, an antibody which binds to that site can be conjugated to a detectable group and added to the liquid phase reaction solution before the separation step. The presence of the detectable group on the solid support indicates the presence of the antigen in the test sample. Examples of suitable immunoassays are radio-immunoassays, immunofluorescence methods, chemiluminescence methods, electrochemiluminescence or enzyme-linked immunoassays. Those skilled in the art will be familiar with numerous specific immunoassay formats and variations thereof, which may be useful for carrying out the method disclosed herein. See generally E. Maggio, Enzyme-Immunoassay, (1980) (CRC Press, Inc., Boca Raton, Fla.); see also U.S. Pat. No. 4,727,022 to Skold et al. titled "Methods for Modulating Ligand-Receptor Interactions and their Application," U.S. Pat. No. 4,659,678 to Forrest et al. titled "Immunoassay of Antigens," U.S. Pat. No. 4,376,1 10 to David et al., titled "Immunometric Assays Using Monoclonal Antibodies," U.S. Pat. No. 4,275,149 to Litman et al., titled "Macromolecular Environment Control in Specific Receptor Assays," U.S. Pat. No. 4,233,402 to Maggio et al., titled "Reagents and Method Employing Channeling," and U.S. Pat. No. 4,230,767 to Boguslaski et al., titled "Heterogenous Specific Binding Assay Employing a Coenzyme as Label." Antibodies may be conjugated to a solid support suitable for a diagnostic assay (e.g., beads, plates, slides or wells formed from materials such as latex or polystyrene) in accordance with known techniques, such as passive binding. Antibodies as described herein may likewise be conjugated to detectable groups such as radiolabels (e.g., 35S, 1251, 1311), enzyme labels (e.g., horseradish peroxidase, alkaline phosphatase), and fluorescent labels (e.g., fluorescein) in accordance with known techniques. The absolute level (amount) of a protein, like CA125, can also be determined using, e.g., a cobas e 601 analyzer and the Elecsys® Electro- Chemi Luminescence (ECL) technology. In brief, biotin-labelled and ruthenium-labelled antibodies are combined with the appropriate amount of test sample and incubated on the analyzer. Streptavidin-coated magnetic microparticles are added and incubated in order to facilitate binding of the biotin-labelled immunological complexes. After incubation the mixture is transferred into the measuring cell where the beads are magnetically captured on the surface of an electrode. ProCell M Buffer containing tri propylamine (TPA) is then introduced into the measuring cell in order to separate bound immunoassay complexes from the free particles. Induction of voltage between the working and the counter electrode then initiates the reaction causing emission of photons by the ruthenium complexes as well as TPA. The electrochemiluminescent signal produced is recorded by a photomultiplier and converted into numeric values indicating concentration level of the respective analyte. Commercial test for CA125 detection are also available and well known. Alternative methods of detecting LARP1 or CA125 protein in a sample include high performance liquid chromatography (HPLC) and other high-throughput techniques. Mass spectrometry Methods are described for detecting and / or quantifying the amount of LARP1 protein and / or CA125 protein in a sample. More specifically, mass spectrometric methods are described for detecting and quantifying one or more LARP1-derived peptides and / or one or more CA125-derived peptides in a sample. The methods may utilize solid phase extraction and / or liquid chromatography, to perform a purification of selected analytes combined with methods of mass spectrometry (MS), thereby providing a high-throughput assay system for detecting and quantifying LARP1-derived peptide and / or CA125-derived peptide in a sample. The methods are particularly well suited for application in large clinical laboratories for automated quantification. Suitably, the test sample is subjected to protein digestion followed by detecting for the presence of a biomarker-derived peptide. For U\RP1, LARP1-derived EGYR peptide (SEQ ID NO: 3) is particularly suitable. Suitably the sample is a biological sample. In one embodiment, the method includes obtaining a biological sample from a subject or individual. The subject or individual may be a mammal. The subject or individual may be a human. In another embodiment, the biological sample is from a patient with or suspected of having cancer or a pre-cancer. The methods of the invention are typically carried out on a sample that has previously been obtained from a patient / subject. Thus, the taking of the sample does not typically form part of the methods of the invention and the methods of the invention are carried out on a sample that has been obtained from a subject. In some embodiments of the invention, however, the method also comprises taking the sample from the subject, for example by taking a blood sample. Suitable test samples for use in the methods of the present invention include any sample that may contain the biomarker protein (the analyte) of interest (e.g. LARP1 or CA125). In some embodiments, a sample is a biological sample; that is, any solid or fluid sample obtained from any living organism, including without limitation, a multicellular organism such as an animal, including samples from a healthy or apparently healthy human subject or a human patient affected by a condition or disease to be diagnosed or investigated, such as cancer. The sample can be from a mammalian animal, such as a dog, cat, horse, etc. Suitably the mammalian animals are primates, and in particular, are male orfemale humans. The methods of the invention are particularly suited to testing liquid biological samples. In particular embodiments, the biological sample is selected from the group consisting of: a blood sample, a plasma sample, a serum sample, a urine sample, a cerebrospinal fluid, an ascites sample and a saliva sample. Such samples may be obtained, for example, from a patient with or suspected of having a disease or condition. The inventors have found that plasma samples yield optimal results and so in a particular embodiment, the biological sample used in the methods of the invention is a plasma sample. In particular embodiments, the methods of the invention may be used to determine the amount of LARP1 protein in a biological sample obtained from a subject / patient, or the amount of LARP1-derived EGYR peptide (SEQ ID NO: 3) in a processed sample from a subject / patient. In particular embodiments, the methods of the invention may be used to determine the amount of CA125 protein in a biological sample obtained from a subject / patient, or the amount of CA125-derived peptide in a processed sample from a subject / patient. As used herein, unless the context dictates otherwise, reference to the sample refers to the sample obtained from the patient / subject or such a sample that has been subjected to subsequent processing, such as proteolytic digestion, purification, etc. Mass spectrometry sample preparation For mass spectrometry, the sample should be treated so as to digest or cleave the proteins in the biological sample (including the biomarker protein) so as to facilitate the generation of peptides of the biomarker. The sample may thus be subjected to one or more processing steps prior to detection for one or more biomrrker-derived peptides. Examples of processing steps include: protein fragmentation (e.g. digestion, cleavage or degradation) and purification. The most appropriate means is cleavage of the protein using a proteolytic enzyme, such as one that can cleave after arginine and lysine residues. The most suitable enzyme for effecting this is trypsin, or a typsin variant / analogue. Protein cleavage In some embodiments, the sample is processed to convert the proteins into smaller peptide fragments. Internal standard may be added to the samples prior or subsequent to cleavage. This fragmentation can be effected by shearing forces, such as generated by passing the sample through a narrow bore syringe or following sonication. However, the fragmentation is preferably performed using one or more proteases capable of digesting the proteins in the sample into smaller peptides. Trypsin or its variants are particularly suitable. Optionally, prior to enzymatic cleavage, the biological sample can be subjected to physical shearing by sonication or by passing the sample through a small-bore syringe such as a G23 syringe, one or more times. In particular embodiments the protein is prepared by sonication or passing the sample through a narrow bore aperture, such as a syringe. As used herein a peptide is a short chain of 2 or more amino acids linked in a chain by peptide bonds. Peptides are distinguished from protein on the basis of size, and as an arbitrary benchmark can be understood to contain approximately 50 or fewer amino acids. LARP1 fragment peptides including the EGYR (SEQ ID NO: 3) peptide or CA125 fragment peptides can be produced by treatment with one or more endoproteases such as trypsin and its variants. In one embodiment, the sample is digested with trypsin or a trypsin variant. In particular embodiments, the proteins in the sample are reduced and alkylated by the addition of an alkylating agent such as iodoacetamide or chloroacetamide, before digestion. The purpose of alkylation is to prevent the di-sulfides from re-forming.The fragmented (e.g. sheared, digested or cleaved) sample may be subjected directly to mass spectrometric analysis or may be processed prior to MS analysis. In some embodiments, the processing steps include one or more purification steps. In some embodiments, the processing steps include solid-phase extraction, and / or applying the sample to an anion or cation exchange column under conditions suitable to retain biomarker-derived peptide (e,g, from l_ARP1 or CA125) on the column; eluting biomarker -derived peptide from the column; and collecting the eluted biomarker-derived peptide for further processing or ionization. In some embodiments, the processing steps comprises chromatography. Chromatography Prior to detection, such as via mass spectrometry, it can be advantageous to fractionate the cleaved / (e.g. digested) sample, such as by using chromatography. Methods of fractionation of a protein sample are well known in the art, and include without limitation paper chromatography, thin layer chromatography (TLC), liquid chromatography, column chromatography, fast protein liquid chromatography (FPLC), ion exchange chromatography, size exclusion chromatography, affinity chromatography, high performance liquid chromatography (HPLC), poly acrylamide gel electrophoresis (PAGE), capillary electrophoresis (CE) and reverse phase high performance liquid chromatography (RP-HPLC) amongst others. Chromatography is a well-understood field and the person skilled in the art would understand how to, and be able to, use any of these techniques to separate the proteins and peptides in a sample according to the methods of the invention, such as described in “Mass Spectrometry: A textbook by Jurgen Gross, or “Mass Spectrometry principles and applications” by Edmond de Hoffmann and Vincent Stroobant. In particular embodiments, the sample, such as the digested / cleaved sample, is subjected to chromatographic separation comprising liquid chromatography (LC). In particular embodiments, the LC is selected from: normal phase liquid chromatography (NPLC), reverse phase liquid chromatography (RPLC), high performance liquid chromatography (HPLC) and ultra high performance liquid chromatography (UHPLC). For peptide digests reverse phase liquid chromatography (RPLC), high performance liquid chromatography (HPLC) and ultra high performance liquid chromatography (UHPLC) are particularly suitable. In a particular embodiment, the liquid chromatography comprises reverse phase chromatography. In a particular embodiment, the liquid chromatography comprises high performance liquid chromatography (HPLC) or ultra-performance liquid chromatography (UPLC). Mass Spectrometry The ability to detect the presence of, and optionally the amount of a biomarker peptide in a sample can be carried out using mass spectrometry. Mass spectrometry techniques are well-understood and the person skilled in the art would understand how to, and be able to, use any of these techniques to separate the proteins and peptides in a sample according to the methods of the invention. Typically, mass spectrometry is performed using a mass spectrometer, which includes an ion source capable of generating gas phase ions from a sample (such as a sample containing biomarker fragment peptides and / or peptide standards). The gas phase ions are then separated according to their mass-to-charge ratio (m / z) and detected. Suitable techniques for producing gas phase ions for use in the disclosed methods include without limitation electrospray ionization (ESI), matrix-assisted laser desorption-ionization (MALDI), surface-enhanced laser desorption-ionization (SELDI) and chemical ionization. Separation of ions according to their m / z ratio can be accomplished with any type of mass analyser, including quadrupole mass analysers (Q), time-of-flight (TOF) mass analysers (for example linear or reflecting) analysers, magnetic sector mass analysers, 3D and linear ion traps (IT), Fourier-transform ion cyclotron resonance (FT-ICR) analysers, and combinations thereof (for example, a quadrupole-time-of-flight analyser, or Q-TOF analyser). In some embodiments, the mass spectrometric technique is tandem mass spectrometry (MS / MS) and the presence of a biomarker (e.g. LARP1 orCA125) fragment peptide is detected. Typically, in tandem mass spectrometry a fragment peptide entering the tandem mass spectrometer is selected and subjected to collision induced dissociation (CID). The spectra of the resulting fragment ion is recorded in the second stage of the mass spectrometry, as a so-called CID spectrum. Because the CID process usually causes fragmentation at peptide bonds and different amino acids for the most part yield peaks of different masses, a CID spectrum alone often provides enough information to determine the presence of a peptide such as a LARP1 or CA125 fragment peptide. Suitable mass spectrometer systems for MS / MS include an ion fragmentor and one, two, or more mass spectrometers, such as those described above. Examples of suitable ion fragmentors include, but are not limited to, collision cells (in which ions are fragmented by causing them to collide with neutral gas molecules), photo dissociation cells (in which ions are fragmented by irradiating them with a beam of photons), and surface dissociation fragmentor (in which ions are fragmented by colliding them with a solid or a liquid surface). Suitable mass spectrometer systems can also include ion reflectors. For example ionization of the sample may be performed by electrospray ionization (ESI), photon ionization, atmospheric pressure chemical ionization (APCI), photoionization, atmospheric pressure photoionization (APPI), Laser diode thermal desorption (LDTD), fast atom bombardment (FAB), liquid secondary ionization (LSI), matrix assisted laser desorption ionization (MALDI), field ionization, thermospray / plasmaspray ionization, surface enhanced laser desorption ionization (SELDI), inductively coupled plasma (ICP) and particle beam ionization. The skilled artisan will understand that the choice of ionization method may be determined based on the analyte to be measured, type of sample, the type of detector, the choice of positive versus negative mode, etc. A LARP1-derived peptide, such as EGYR (SEQ ID NO: 3), may be ionized in positive or negative mode. In some embodiments, LARP1-derived EGYR peptide (SEQ ID NO: 3) are ionized by ESI (such as by heated ESI) in positive mode. In mass spectrometry techniques generally, after the sample has been ionized, the positively or negatively charged ions thereby created may be analysed to determine a mass- to-charge ratio. Suitable analysers for determining mass-to-charge ratios include Orbitrap analysers, quadrupole analysers, ion trap analysers, and time-of-flight (TOF) analysers. Exemplary ion trap methods are described in Bartolucci, et ai, Rapid Commun. Mass Spectrom. 2000, 14:967-73. The ions may be detected using several detection modes. For example, selected ions may be detected, i.e. using a selective ion monitoring mode (SIM), or alternatively, mass transitions resulting from collision induced dissociation or neutral loss may be monitored, e.g., multiple reaction monitoring (MRM) or selected reaction monitoring (SRM). Preferably, the mass-to-charge ratio is determined using a quadrupole analyser. For example, in a "quadrupole" or "quadrupole ion trap" instrument, ions in an oscillating radio frequency field experience a force proportional to the DC potential applied between electrodes, the amplitude of the RF signal, and the mass / charge ratio. The voltage and amplitude may be selected so that only ions having a particular mass / charge ratio travel the length of the quadrupole, while all other ions are deflected. Thus, quadrupole instruments may act as both a "mass filter" and as a "mass detector" for the ions injected into the instrument. One may enhance the specificity of the MS technique by employing "tandem mass spectrometry," or "MS / MS". In this technique, a precursor ion (also called a parent ion) generated from a molecule of interest can be filtered in an MS instrument, and the precursor ion subsequently fragmented to yield one or more fragment ions (also called daughter ions or product ions) that are then analysed in a second MS procedure. By careful selection of precursor ions, only ions produced by certain analytes are passed to the fragmentation chamber, where collisions with atoms of an inert gas produce the fragment ions. Because both the precursor and fragment ions are produced in a reproducible fashion under a given set of ionization / fragmentation conditions, the MS / MS technique may provide an extremely powerful analytical tool. For example, the combination of filtration / fragmentation may be used to eliminate interfering substances, and may be particularly useful in complex samples, such as biological samples. Alternate modes of operating a tandem mass spectrometric instrument include product ion scanning and precursor ion scanning. For a description of these modes of operation, see, e.g., E. Michael Thurman, et al., Chromatographic-Mass Spectrometric Food Analysis for Trace Determination of Pesticide Residues, Chapter 8 (Amadeo R. Fernandez- Alba, ed., Elsevier 2005) (387). Various ionization sources, including for example atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), and heated ESI, may be used in embodiments of the present invention. In certain preferred embodiments, EGYR peptide (SEQ ID NO: 3) is ionized using heated ESI in positive ion mode. In some embodiments, the LARP1-derived peptide is detected by the detection of fragment ions of the EGYR fragment peptide (SEQ ID NO: 3), for example using tandem mass spectrometry. In another embodiment, the detecting comprises tandem mass spectrometry (MS:MS). Using tandem MS, the inventors have been able to fragment EGYR (SEQ ID NO: 3) peptide and detect it with a diagnostic m / z fragment peak of about 136.1. Thus, in a particular embodiment, a putative EGYR (SEQ ID NO: 3) peptide containing sample or fraction isolated by chromatography is fragmented in MS:MS mode and the presence of a moiety with an m / z of about 136.1 is searched for, and if present this is selected and quantified. In a particular embodiment, the presence of EGYR peptide (SEQ ID NO: 3) in a sample is verified if following tandem MS there is identified a molecule with an m / z of about 136.1. In any of the methods provided herein which utilize tandem mass spectrometry, tandem mass spectrometry may be conducted by any method known in the art, including for example, multiple reaction monitoring, precursor ion scanning, or product ion scanning. The methods of the invention include subjecting the sample to proteolytic fragmentation (e.g. degradation or cleavage) followed by ionization under conditions suitable to produce charged biomarker-derived peptide ions detectable by mass spectrometry; determining by mass spectrometry the amount of one or more ions from the one or more biomarker-derived peptides; and using the amount of the determined ions to determine the presence of and / or amount of the biomarker protein in the sample. One or more steps of the methods of the invention may be performed using automated machines. In certain embodiments, one or more purification steps are performed on-line, and suitably all of the purification and mass spectrometry steps may be performed in an on-line fashion. Quantitation by MS In addition to detecting for the presence of a biomarker peptide in a sample of interest it is also possible, and useful, to quantify the amount in the sample. To quantitate the amount of biomarker in the sample a standard curve of known “spiked” amounts of recombinantly produced biomarker in a control solution treated the same way as the test sample is treated and then correlating ion intensity of a isotopically labelled peptide with non-labelled peptides resulting from recombinant biomarker protein. Specific embodiments for the second and subsequent aspects of the invention are as for the first aspect mutatis mutandis. Methods of labelling peptides with heavy isotopes are well known in the art "Isotopically-labelled" refers to a molecule that includes one or more stable heavy isotopes in a greater-than-natural abundance. Examples of suitable labels include deuterium (2H), 13C, 15N 35S, 17O and 18O. One or more isotopic labels can be incorporated at one or more positions in the molecule and one or more kinds of isotopic labels can be used on the same isotopically labelled molecule. If the biomarker peptide standard is labelled it can be spiked into the test sample. By spiked we mean added to the sample in a known amount so that the amount of peptide in the test sample can be determined based on the intensity of the standard. When spiking the sample with a peptide standard it is important that the spiked peptide can be distinguished from the endogenous peptide in the sample. Suitably, the methods include comparing an amount of the biomarker fragment peptide to an peptide standard of known amount. For example, when measuring for LARP1, this is most suitably done by generating a standard curve using known amounts of recombinant LARP1, e.g. isotopically labelled. This way you will know how much of your isotopically labelled peptide corresponds to how much actual LARP1 protein in your sample. By way of example, the change in relative peak intensity before and after the addition of a peptide standard can be used to calculate the amount of biomarker peptide present in a biological sample, thus providing quantification of the biomarker in the sample. When a non-isotopically labelled peptide standard is used, a mass spectrum of the protein digest is obtained both with and without addition of the non- isotopically labelled peptide standard. The ratio of the intensity of the signals with and without the addition of the non-isotopically labelled peptide standard reflects the relative amounts (or concentrations) of the biomarker fragment peptide present in a biological sample, and thus the amount of the biomarker present in the sample. Subject The subject whose biological sample, e.g. blood or blood-derived sample, is to be assayed according to the methods of the invention can be an animal, preferably a mammal and, more typically to a human. The subject is preferably a human female. There is a need for determining ovarian cancer status in early adulthood. Therefore, the subject is preferably a human female aged between 25 and 75 years. The subject to be investigated by the method of the present invention may be a person at high-risk of developing ovarian cancer (“high-risk subject”), including those with predisposing mutations for developing ovarian cancer. There are published alogirthms to measure high risk https: / / ovarian.org.uk / risktool / questions / on the basis of personal history of breast cancer when young, family history or known genetics. Thus, in particular embodiments, the subject whose levels of LARP1 and CA125 are to be measured according to the invention is a high risk subject Suitably, the subject has been identified as “high-risk” (of developing ovarian cancer) according to the clinical guidelines (e.g. using approved algorithms as above). Individuals with cancer-predisposing mutations in their genomic DNA are at higher risk of developing ovarian cancer. Examples of these types of mutations are disclosed elsewhere herein. Thus, in particular embodiments, the subject whose levels of LARP1 and CA125 are to be measured according to the invention is one with cancer-predisposing mutations in their genomic DNA. In particular embodiments, the subject comprises germline driving mutations in a gene selected from: BRCA1, BRCA2, RAD51C, RAD51D, PALB2, or BRIP1, KRAS, P53, ALK and HER2. In particular embodiments, the subject possesses germline BRCA1 or BRCA-2 mutations. In other particular embodiments, the subject has a hereditary cancer-predisposition syndrome selected from BRCA, Lynch and Li Fraumeni identified by genetic analysis, family or personal history alone (Rahmen N. Realizing the promise of cancer predisposition genes. Nature. 2014 Jun 5;510(7503): 176. PMID: 24429628). Monitoring disease progression The disclosed methods are particularly suited for monitoring disease progression in a subject. Such methods involve detecting an amount of LARP1 and CA125 in biological sample(s) from a subject at a first time point, detecting an amount of LARP1 and CA125 in other biological sample(s) from the subject at a second time point, and comparing the amount of LARP1 and CA125 at the two time points. Monitoring therapeutic intervention The present inventors hypothesize that LARP1 and CA125 levels will also be indicative of response to therapeutic treatment,. Thus, the levels of LARP1 and CA125 can be determined before, during, and optionally after a therapeutic intervention to gauge whether the therapeutic intervention has an effect on the levels of LARP1 and CA125. A decrease in the amount of LARP1 or LARP1 and CA125 levels in the patient’s sample following a therapeutic intervention (e.g. drug treatment) indicating that the treatment is or was effective. In one embodiment, the disclosed methods can be used to monitor the efficacy of a treatment by determining the change in the amount of LARP1 protein or LARP1 and CA125 protein in the biological sample at different stages of the treatment (e.g. before, during and / or after), suitably the biological sample is a blood sample or blood-derived sample such as plasma or serum. By therapeutic treatment we mean a treatment designed to treat the cancer in the patient. By way of examples, such therapeutic treatment could be chemotherapy or radiotherapy, it could be administration of an anticancer agent / drug. In one embodiment, the biological sample is a serum or plasma sample. In one embodiment, the control sample is a pre-treatment sample from the patient. In one embodiment, the therapeutic treatment is radiotherapy or chemotherapy. In one embodiment, the therapeutic treatment is administration of an anti-cancer drug. The anti-cancer drug can be, for example, a chemotherapeutic drug such as bleomycin, carboplatin, cisplatin, cyclophosphamide, dacarbazine, docetaxel, doxorubicin, etoposide, 5-fluorouracil, folinic acid, gemcitabine, irinotecan, oxaliplatin, paclitaxel, or a combination chemotherapeutic regimen such as AC (doxorubicin and cyclophosphamide), BEP (bleomycin, etoposide and platinum agent), Carbo / taxol (carboplatin and paclitaxel), FOLFIRINOX (5-flurouraciI, folinic acid, irinotecan, oxaliplatin) or a chemotherapy agent or combination of agents given with a targeted therapy such as bevacizumab, or stem cell targeted therapy. Detecting pre-invasive cancer The levels of LARP1 and CA125 can be used to identify the likely ovarian cancer status of a subject, including whether a subject has pre-cancer / pre-invasive cancer. Suitably, the methods of the invention can predict development of ovarian cancer. The ability to pick up the development of ovarian cancer during this earlier development phase is therefore important. As part of normal cancer screening subjects could be testing for blood LARP1 levels and CA125 levels in accordance with the methods of the present invention and if the analysis indicates that the subject likely has pre-cancer and / or is at high risk of developing invasive cancer the subject could undergo further diagnostic assessments or therapeutic intervention (e.g., anti cancer treatment) or risk reducing surgery. Use of LARP1 and CA125 to determine ovarian cancer status According to a second aspect of the invention there is provided the use of La-related protein 1 (LARP1) and Cancer Antigen 125 (CA125) biomarker levels in a method of determining cancer status. Suitably, the cancer status is ovarian cancer status. Suitably, the method of determining cancer status, e.g. ovarian cancer status, is according to the first aspect of the invention as well as any embodiments of the first apect. Kit of parts The materials for use in the methods of the present invention are ideally suited for preparation of kits produced in accordance with well-known procedures. The invention thus provides kits comprising agents for the detection of the level of the disclosed biomarker in a sample. Such a kit may comprise separate containers, each with one or more of the various reagents (typically in concentrated form) utilized in the methods, e.g., the kit may contain in separate containers one or more antibodies (either already bound to a solid matrix or packaged separately with reagents for binding them to the matrix), control formulations (positive and / or negative), and / or a detectable label, packaged together in the form of a kit. Instructions (e.g., written, or on electronic medium, e.g. CD-ROM, etc.) for carrying out the assay may be included in the kit. Thus, the present invention also provides kits comprising one or more reagents suitable for determining the levels of the biomarkers measured in the methods of the invention described herein. According to a third aspect of the invention there is provided kit comprising: (a) a panel of affinity reagents wherein each reagent is capable of selectively binding to CA125 or LARP1 or (b) a panel of labelled peptide standards for CA125 and LARP1 for use in mass spectrometric analysis. According to a variation of the third aspect of the invention there is provided a kit comprising: a panel of affinity reagents capable of binding to LARP1 and CA125, wherein at least one affinity reagent can selectively bind to LARP1 and at least one affinity reagent can selectively bind to CA125; or a panel of labelled peptide standards for CA125 and LARP1 for use in mass spectrometric analysis, wherein at least one labelled peptide standard is a labelled peptide standard for LARP1 and at least one labelled peptide standard is a labelled peptide standard for CA125. In a particular embodiment the kit further comprises written instructions for using the affinity reagents or labelled peptide standards to measure the levels of the CA125 and LARP1 proteins in a sample, such as one from a subject. In a particular embodiment, the kit further comprises written instructions for use of the kit for determining a subject’s ovarian cancer status. In a particular embodiment, the affinity reagent is an antibody or a protein comprising an antigen-binding domain of an antibody. In a particular embodiment, the labelled peptide standard for LARP1 is a LARP1-derived EGYR peptide (SEQ ID NO: 3). Longitudinal measurements of LARP1 As can be seen from the data in the Examples, the level of LARP1 changes as the ovarian cancer status progresses. LARP1 levels follow a saw-toothed shape / curve over time in an upward trajectory as the ovarian tissues move from normal through pre-cancer stages to to advanced invasive cancer. Mapping whether, and if so where, a subject is on this curve can be used for ovarian cancer status determination. Such mapping is most conveniently performed from longitudinal measurements. Accordingly, longitudinal measurements of I.ARP1 alone can be used to determine ovarian cancer status. According to a fourth aspect of the invention there is provided a method for determining whether a subject is at risk of developing ovarian cancer comprising: determining the absolute level of LARP1 in a sample from the subject over a time period so as to provide a plurality of LARP1 values over a time-course; wherein if over the time-course the absolute level of LARP1 exceeds a threshold level or peaks the subject is determined to be at risk of developing ovarian cancer. In a particular embodiment if the first upswing in absolute level of LARP1 is detected for the subject they are identified as likely to have pre-cancer, e.g. a STIC lesion and being likely to develop ovarian cancer. In particular embodiments, they are identified as likely to develop ovarian cancer in 20-40 months time, such as in at least 24, 30, 36, months time after a peak in absolute level of LARP1 is detected for the subject. In particular embodiments, a peak in LARP1 level is detected whilst CA125 levels are within the normal range signifies likelihood of pre-cancer. According to a fifth aspect of the invention there is provided a method for determining ovarian cancer status of a subject comprising: determining the absolute level of LARP1 in a sample from the subject over a time period so as to provide a plurality of LARP1 values over a time-course; and determining the ovarian cancer status based on the change in LARP1 detected over the time course. According to a sixth aspect of the invention there is provided a method monitoring the progression of ovarian cancer in a subject comprising determining the level of one or LARP1 biomarker in the circulating blood of a subject at a first point in time and comparing the level of the LARP1 biomarker in the subject at one or more later points in time to determine the progression of the ovarian cancer. The embodiments of the first aspect of the invention also apply to the fourth, fifth, sixth and seventh aspects of the invention. Suitably, the level of LARP1 in circulating blood can be determined over a timecourse and the change in LARP1 level used to determining whether a subject is at risk of developing ovarian cancer. Suitably, the level of LARP1 in circulating blood over a timecourse can be plotted and any change in level used to determine the subject’s ovarian cancer status. Because the level of LARP1 changes overtime as the tissues transition from pre-malignant to pre-invasive cancer and through the more advanced stages of invasive cancer a change in level can be used predict the ovarian cancer status of a subject by comparison to historical data for normal patients and / or patient at distinct stages of ovarian cancer. The following embodiments apply to the first, fourth, fifth, sixth and seventh aspects of the invention. In a particular embodiment, the absolute level of l_ARP1 in a sample from the subject is determined from at least three timepoints and the absolute level at each timepoint is compared to the level at one or more different timepoints. In a particular embodiment, the timepoints are at least 3 months apart, such as approximately 3, 6, 9, 12, 18 or 24 months apart. In a particular embodiment each timepoint is at least 3 months apart from another timepoint. In a particular embodiments, the subject is a high risk subject and / or they have a genetic predisposition to ovarian cancer. In a particular embodiments, if the subject is determined to be at risk of developing ovarian cancer they are selected for risk-reducing surgery and / or are given risk-reducing surgery. In a particular embodiments, the risk reducing surgery is risk reducing salpingo-oophorectomy (RRSO) surgery or risk-reducing salpingectomy (RRS) surgery. In a particular embodiments, the RRS surgery comprises removal of fallopian tubes only. Detecting STIL or STIC (pre-cancer) Normal ovarian cells can develop serous tubal intraepithelial lesions (STIL) which are pre-cancerous lesions that can be recognised by p53 signature but exhibit no significant morphological change. Over time these can develop into serous tubal intraepithelial carcinoma (STIC), a pre-malignant stage where malignant cells start to replace normal tubular epithelium. Current ovarian cancer detection blood tests, that measure CA125 levels, cannot pick up STIL or STIC. There is a need in the art to pick up cancers when at the STIC stage (pre-invasive ovarian cancer stage) to allow earlier therapeutic intervention. The inventors have previously found elevated LARP1 levels in the blood of patients with STIC lesions; however, the sawtooth shaped change in LARP1 level as a subject moves from pre-cancer through to advanced invasive ovarian cancer was not realised. Longitudinal measurement of LARP1 will allow more accurate determination of ovarian cancer status. The inventors have identified that the level of LARP1 protein in circulating blood rises to a first peak once the subject has a STIC. Thus, longitudinal LARP1 level measurements can be used to predict the presence of pre-cancer, such as STIC in a subject. The summary of the invention described above is non-limiting and other features and advantages of the invention will be apparent from the following detailed description of the invention, and from the claims. Computer-implemented methods The determination of cancer status, in particular ovarian cancer status, according to the methods of the invention may be carried out manually or computer-assisted. Thus, the comparison may be carried out by a computing device. The value of the measured or detected absolute level of the biomarker in the sample (U\RP1 and / or CA125) from the subject and the reference level can be, e.g., compared to each other and the said comparison can be automatically carried out by a computer program executing an algorithm for the comparison. The computer program carrying out the said evaluation will provide the desired assessment in a suitable output format. For a computer-assisted comparison, the value of the measured level may be compared to values corresponding to suitable references which are stored in a database by a computer program. The computer program may further evaluate the result of the comparison, i.e. automatically provide the desired assessment in a suitable output format. The term "reference value" as used herein, refers to a known (e.g. predetermined) value against which a test value can be compared and so is a value to distinguish between two states (e.g. yes, no; disease / healthy; pre-invasive cancer / invasive cancer, no cancer / pre-cancer; no cancer / cancer etc). There are essentially two alternatives to determine a reference value: 1) control sample (can be an internal or external sample or a pool of samples); 2) multiple samples of a reference population with known disease status (e.g. ovarian pre-cancer and / or ovarian invasive cancer). The reference value may be one of many reference values from longitudinal measures of historical samples of known cancer status. The reference values may therefore provide a profile of LARP1 and / or CA125 levels over time indicative of levels seen in subjects with or without cancer (e.g., ovarian cancer) and / or at distinct states of cancer. Such profiles may represent a fingerprint pattern of disease progression against which test samples may be compared. Suitably a reference value can be determined from one or more control samples which is or has / have been analysed and determined in a substantially identical manner as the test sample of interest and whose information is compared to that of the test sample of interest. In one embodiment, the control sample is obtained from a control subject that does not ovarian cancer. In another embodiment, the control sample is obtained from a subject that has a particular stage of cancer, such as pre-invasive cancer or invasive cancer. Control samples can be evaluated substantially at the same time as the test sample and so be used as a direct contemporaneous comparator, or they can be from historical samples. The reference value can therefore be determined alongside that of the test sample (contemporaneously) or pre-determined. Pre-determined reference values are preferred as the actual cancer status of the subject from whom the control sample is taken may not be known. The values from the one or more control samples thereby provides a standard allowing for the evaluation of the information obtained from the sample of interest (test sample). In particular embodiments, the control sample is the same sample type as that of the sample of interest. For example, if the sample of interest is plasma, the control sample is also plasma. A control sample may be derived from a body fluid obtained from a healthy individual in particular urine, serum or plasma for a non-invasive test, thereby providing a standard of a healthy or defined disease status of a tissue, organ or individual. Alternatively, the control sample may be obtained from at least one individual that does not have aggressive cancer from the same species. In a particular embodiment, the control sample can be from an individual without cancer. The “control” individual can be the same age or in the same state or condition of health (aside from cancer status) as the subject from which the test sample is obtained. Differences between the status of the control sample and the status of the test sample of interest may be indicative of the presence of the disease or risk of disease development or the presence or further progression of such disease or disorder. A reference sample may also be derived from the same tissue, organ, body fluid or individual as the sample of interest but has been taken at an earlier time point. Differences between the status of the earlier taken reference sample and the status of the sample of interest may be indicative of the progression of the disease, i.e. a bettering or worsening of the disease over time. The control sample may be an internal or an external control sample. An internal control sample is used, i.e. the marker level(s) is(are) assessed in the test sample as well as in one or more other sample(s) taken from the same subject to determine if there are any changes in the level(s) of said marker(s). For an external control sample the level of a marker in a sample derived from the individual is compared to its level in an individual known to suffer from, or known to be at risk of, a given condition; or an individual known to be free of a given condition, i.e., "normal individual". It will be appreciated by the skilled artisan that such external control sample may be obtained from a single individual or may be obtained from a reference population that is age-matched. Typically, samples from 100 well-characterized individuals from the appropriate reference population are used to establish a "reference value". However, reference population may also be chosen to consist of, for example, 20, 30, 50, 200, 500 or 1000 individuals. Thus, alternatively, a reference value can be determined based on archived samples obtained from a reference population, e.g. archived samples of a reference population whose cancer status is later known. A skilled person can establish a reference value for the level of LARP1 and / or CA125 based on a representative reference population. Using a reference population the reference value can be determined such that the level or score value set as reference value divides the reference population into sub-classes of cancer status (e.g. pre-cancer or invasive cancer) with a certain sensitivity and specificity. The reference value may be selected differently depending on whether higher sensitivity at cost of lower specificity is desired or vice versa. The level or score separating, e.g. pre-cancer from invasive cancer can be determined using commonly known statistical methods such that a desired sensitivity and specificity is defined. The reference value that is used in the comparison with the test sample may be a value that is calculated as an average or median of more than one (e.g. two or more, five or more, ten or more, a group etc.) of control samples. Alternatively, the control sample may be a sample that originated from (i.e. is a mix of) more than one (e.g. two or more, five or more, ten or more, a group etc.) individual that is not suffering from, e.g. invasive cancer. The reference value is typically determined from statistical assessment of biomarker readouts / levels from multiple (e.g. >49, >99, >249, >499, >999) subject samples (e.g. from a reference population) with or without the particular state to be determined (e.g. invasive cancer). The reference value can be a value for the level of a single biomarker (i.e. an individual biomarker) or a score value derived from the individual levels of a combination of biomarkers (i.e. two or more biomarkers, as described herein), which levels may have been applied to an algorithm or equation to give a reference value that can be used when measuring and relying on said particular combination of biomarkers. Typically, the reference value achieves a particular statistical threshold of significance, e.g. of quantiles in the case or control distributions. For example, to determine the reference value from a certain control cohort (e.g. invasive cancer), a certain percentile may be determined (e.g. 90%, 95%, 95.7 or 97%) from the measurement values of this control cohort. E.g. when the 90th percentile is used, then 90% of the control samples have values below this cut-off, which reduces the number of false positive predictions. In a specific embodiment, the reference population for establishing a reference value (e.g. for a level of LARP1 and / or CA125) is derived from healthy individuals. In another embodiment, the reference population may contain healthy individuals and those with precancer. In another embodiment, the reference population may comprise individuals with pre-invasive cancer. In another embodiment, the reference population may comprise individuals with invasive cancer. Preferably, the reference value in each of these embodiments is a predetermined reference value established from historical control samples, e.g. derived from a reference population. Preferably, the reference population is from one or more stages of ovarian cancer. The reference value may also be a reference value for an score generated from measurements of the level of two or more biomarkers at two or more time points (longitudinally); again from a group or population of individuals whose cancer status is or was known. Such levels may be input into an equation to generate a score (e.g. a cancer status score). The equation could be a ratio or aggregate (e.g. sum) or any other equation where the level of each biomarker measured at different timepoints is used in the equation and wherein the output provides a score / value which distinguishes whether the individual falls into a particular category or not (e.g. likely has invasive cancer, likely does not have invasive cancer etc). According to a seventh aspect of the invention there is provided; a computer-implemented method to aid in determining the likely cancer status in a subject, comprising the steps of: (a) receiving a value for the level of l_ARP1 in a biofluid sample of the subject; (b) receiving a value for the level of CA125 in a biofluid sample of the subject; (c) comparing the amounts in (a) and (b) to absolute levels for LARP1 and CA125 accordingly, determined for the subject at one or more previous time points and / or to reference values; and (d) determining the likely cancer status in the subject based on the comparison in step (c). The values received in (a) and (b) can be obtained from the levels (e.g. absolute levels) of l_ARP1 and / or CA125 determined in the first aspect of the invention. As appropriate, the embodiments applicable to the first aspect of the invention can be applied to this seventh aspect of the invention. Suitably, the computer-implemented method aids in determining the likely ovarian cancer status in a subject. The term “computer-implemented” as used herein means that the method is carried out in an automated fashion on a data processing unit which is, typically, comprised in a computer or similar data processing device. The data processing unit shall receive values for the level of the biomarkers (i.e. level of l_ARP1 and / or CA125) at the or each timepoint. Such values can be the absolute amounts, relative amounts or any other calculated value reflecting the amount as described elsewhere herein in detail. Accordingly, it is to be understood that the aforementioned method does not require the determination of amounts for the biomarkers but rather uses values for already predetermined amounts. The term receiving thus contemplates the values being entered or having already been entered into the computer. The present invention also, in principle, contemplates a computer program, computer program product or computer readable storage medium having tangibly embedded said computer program, wherein the computer program comprises instructions which, when run on a data processing device or computer, the methods of the present invention as specified above or the calculations for said methods. Specifically, the present disclosure further encompasses: a computer or computer network comprising at least one processor, wherein the processor is adapted to perform the method according to one of the aspects described in this description, a computer loadable data structure that is adapted to perform the method according to one of the aspects described in this description while the data structure is being executed on a computer, a computer script, wherein the computer program is adapted to perform the method according to one of the aspects described in this description while the program is being executed on a computer, a computer program comprising program means for performing the method according to one of the aspects described in this description while the computer program is being executed on a computer or on a computer network, a computer program comprising program means according to the preceding embodiment, wherein the program means are stored on a storage medium readable to a computer, a storage medium, wherein a data structure is stored on the storage medium and wherein the data structure is adapted to perform the method according to one of the aspects described in this description after having been loaded into a main and / or working storage of a computer or of a computer network, a computer program product having program code means, wherein the program code means can be stored or are stored on a storage medium, for performing the method according to one of the aspects described in this description, if the program code means are executed on a computer or on a computer network, a data stream signal, typically encrypted, comprising a data for parameters as defined herein elsewhere, and a data stream signal, typically encrypted, comprising the assessment provided by the methods of the present invention. Other aspects / embodiments According to another aspect of the invention there is provided a method for determining the likely ovarian cancer status in a subject comprising (i) Determining the levels of La-related protein 1 (LARP1) and Cancer Antigen 125 (CA125) protein in one or more samples from the subject; (ii) Comparing the levels in (i) to threshold values or to LARP1 and CA125 levels determined in the subject at one or more earlier time points; (iii) Based on the comparison in (ii) determining the likely ovarian cancer status in the subject; wherein (a) if the subject’s sample(s) comprises (i) high LARP1 and high CA125 compared to threshold values, or (ii) high levels CA125 compared to a threshold level and rising levels of LARP1 over a measured time course, the subject is classified as possible / likely presence of invasive high grade serous ovarian cancer; (b) if the subject’s sample(s) comprises high LARP1 and low CA125 compared to threshold values, or the trend over a measured time course, the subject is classified as possible / likely presence of pre-invasive cancer but the likely absence of invasive high grade serous ovarian cancer; and (c) if the subject’s sample(s) comprises low LARP1 and low CA125 compared to threshold values, or the trend over a measured time course, the subject is classified as unlikely to have pre-invasive cancer or invasive high grade serous ovarian cancer. Suitably, the levels of the biomarkers determined are absolute levels. Suitably, the measurement of level (e.g., absolute level) for each biomarker is determined from the same biological sample from the subject, or the measurement of level for each biomarker is from separate samples taken contemporaneously or at separate time points. In particular embodimentsm the levels of LARP1 and CA125 are determined from the same or contemporaneous samples from the subject. According to another aspect of the invention there is provided a method for classifying an ovarian cancer risk status for a subject comprising: (i) Determining the levels of La-related protein 1 (LARP1) and Cancer Antigen 125 (CA125) protein in in one or more samples from the subject; (ii) Comparing the amounts in (i) to threshold values or to levels of LARP1 and CA125 determined in the subject at one or more earlier time points; (iii) Based on the comparison in (ii) assigning an ovarian cancer risk status for a subject; wherein (a) if the subject’s sample(s) comprises (i) high LARP1 and high CA125 compared to threshold values, or (ii) high absolute levels CA125 compared to a threshold level and rising absolute levels of LARP1 over a measured time course, the subject is classified as possible / likely presence of invasive high grade serous ovarian cancer; (b) if the subject’s sample(s) comprise high absolute levels of LARP1 and low absolute levels of CA125 compared to threshold values, or the trend over a measured time course, the subject is classified as possible / likely presence of pre-invasive cancer and / or the likely absence of invasive high grade serous ovarian cancer; and (c) if the subject’s sample(s) comprises low absolute levels LARP1 and low absolute levels CA125 compared to threshold values, or the trend over a measured time course, the subject is classified as unlikely to have pre-invasive cancer or invasive high grade serous ovarian cancer. Suitably, the levels of the biomarkers determined are absolute levels. Suitably, the measurement of level (e.g., absolute level) for each biomarker is determined from the same biological sample from the subject, or the measurement of level for each biomarker is from separate samples taken contemporaneously or at separate time points. According to another aspect of the invention there is provided a method of predicting the ovarian cancer status of a subject, comprising the steps of: determining the level (e.g., absolute level) of LARP1 and CA125 proteins in one or more biological samples obtained from the subject; and correlating the measurements with ovarian cancer status. In a particular embodiment, the correlation also relies on absolute levels of LARP1 and CA125 in equivalent sample(s) taken from the subject at one or more earlier timepoints. In a particular embodiment, the correlating is performed by a software classification algorithm. The embodiments of the first aspect of the invention also apply to these three other aspects. BRIEF DESCRIPTION OF THE FIGURES Figure 1.1_ARP1 plasma measurements as a diagnostic of high grade serous ovarian cancer (HGSC) in UKOPS patients (A) Levels of serum LARP1 in women with OC (n=127) were significantly higher than levels in age-matched controls (n=49), or women with benign tumours and endometriosis (n=56). (B) Graph showing Kaplan-Meier survival curves by circulating LARP1 levels. Those with high LARP1 (defined as above the mean of 23.5 pg / ml) had significantly poorer survival Hazard Ratio (HR)=2.0, compared to those with low LARP1, p 0.004. (C) Scatterplot showing correlation / complementarity between CA125 and LARP1 in samples from UKOPS study. The r=0.28 indicates a highly significant weak correlation p<0.001 between the two markers. Figure 2. Levels of plasma LARP1 measured immediately before RRSO in 38 women with cancer predisposition (e.g. BRCA1, BRCA2 as marked). Resected samples were examined using the SEE-FIM protocol and findings were later correlated with LARP1. Of 38 cases, 22 had normal FTs and ovaries, 11 had benign lesions (such as borderline tumours), 4 had clusters of p53-mutated cells without other features of STICs (termined “p53 signatures”) and 1 had a STIC. Only two patients had preoperative plasma LARP1 levels more than 2 standard deviations greater than the group mean (20.94 pg / ml), one with normal histology and the other with the pathologically confirmed STIC. In the STIC patient, LARP1 was rechecked 3 weeks after surgery by which time it had fallen from 31.8 to 24.3 pg / ml. Figure 3 (A) Longitudinal modelling of pre-diagnostic circulating UXRP1 from 36 patients diagnosed with HGSC and Fig. 3B CA125 from 28 patients who developed HGSC and Fig. 3C: 5 patients who developed STIC lesions during their participation in the UK Familial Ovarian Cancer Screening Study (UKFOCSS) cancer screening study. In this study, pre and post-menopausal women considered at high risk for OC due to BRCA mutations or a strong family history underwent blood sampling for CA125 every 4 months (Menon et al. J Clin Oncol. 33(18):2062-71, 20 June 2015). CA125 values were analysed using the ROCA algorithm which, if elevated, triggered an ultrasound scan and surgery. (A) LARP1 was measured in stored plasma samples from 36 participants who were diagnosed with HGSC during the study (and in an average of 3.4 timepoints prior to their diagnosis) and in age-and BRCA-matched controls at a single timepoint. Of the 36 HGSC patients, levels of LARP1 were shown to rise and reach a first peak at 30-40 months before ovarian cancer diagnosis. Levels of LARP1 were then shown to transiently drop before rising again within 20 months before eventual ovarian cancer diagnosis. (B) Graph showing log CA125 levels measured in 28 of the 34 patients who developed HGSC during their participation in the UKFOCSS study. This demonstrated a rise in CA125 in the 12 months prior to their ovarian cancer diagnosis. (C) Graph showing LARP1 levels measured in the 5 patients who developed STIC lesions during their participation in the UKFOCSS study. This demonstrated a peak in LARP1 approximately 25 months before their diagnosis of STIC lesions followed by a fall in LARP1 levels, indicating LARP1 is a diagnostic of early STIC lesions. Embodiments: 1. A method for determining the likely cancer status in a subject, comprising (i) determining the level of La-related protein 1 (LARP1) protein in a biological sample from a subject; (ii) determining the level of Cancer Antigen 125 (CA125) protein in a biological sample from the same subject as for (i); (iii) comparing the amounts in (i) and (ii) to threshold levels and / or to levels determined for the subject at one or more previous time points; and (iv) determining the likely cancer status in the subject based on the comparison in step (iii). 2. The method according to embodiment 1, wherein steps (i) and (ii) are carried out on the same sample from the subject, or a contemporaneous sample from the subject. 3. The method according to embodiment 1 or 2, wherein the cancer status is used for i) prognosing the development of cancer; ii) predicting the responsiveness to a therapeutic treatment; iii) identifying subjects that are in early stages of cancer development; iv) detecting the presence of pre-invasive cancer; v) detecting the presence of or development of STIL and / or STIC, when in context of ovarian disease; vi) determining the status of a cancer; vii) diagnosing cancer; and viii) monitoring the efficacy of a therapeutic treatment. 4. The method according to embodiment 1, 2 or 3, wherein the cancer status is ovarian cancer status. 5. The method according to embodiment 1, 2 or 4, wherein (i) high levels of LARP1 and CA125 over time or compared to threshold amounts; or (ii) high levels CA125 compared to a threshold amount and rising levels of LARP1 over time indicates the possible / likely presence of invasive high grade serous ovarian cancer. 6. The method according to embodiment 1, 2 or 4, wherein low levels of CA125 and a rising or high level of LARP1 and over time or compared to threshold amounts indicates the possible / likely presence of pre-invasive cancer. 7. The method according to embodiment 1, 2 or 4, wherein low levels of LARP1 and CA125 over time or compared to threshold amounts indicates that the subject is unlikely to have pre-invasive cancer or invasive high grade serous ovarian cancer. 8. The method according to any one of embodiments 1 to 7, wherein the level of LARP1 and CA125 determined are absolute levels. 9. The method according to any one of embodiments 1 to 8, wherein the levels of LARP1 and CA125 in step (iii) are compared to the levels determined for the subject at one or more previous time points. 10. The method according to any one of embodiments 1 to 9, wherein the levels of LARP1 and CA125 are determined from the same biological sample. 11. The method according to any one of embodiments 1 to 9, wherein the levels of LARP1 and CA125 are determined from samples taken from the subject contemporaneously. 12. The method according to any one of the preceding embodiments, wherein the levels of LARP1 and CA125 are determined by reference to the amount of at least one standardised control protein in the sample. 13. The method according to any one of the preceding embodiments, wherein the or each sample comprises a biological sample selected from the group consisting of: blood sample, a plasma sample, a serum sample, a urine sample, an ascites sample and a saliva sample. 14. The method according to 13, wherein the or each sample is a blood or blood-fraction sample. 15. The method according to 14, wherein the blood-fraction sample is a serum or plasma sample. 16. The method according to any one of the preceding embodiments, wherein the level of LARP1 and / or CA125 is compared to a threshold or reference value. 17. The method according to 16, wherein the threshold or reference value has been determined based on clinical studies. 18. The method according to any one of the preceding embodiments, wherein the level of LARP1 and / or CA125 is compared to the level of the same biomarker protein (LARP1 or CA125) determined at one or more previous time points. 19. The method of any one of the preceding embodiments, wherein the likely ovarian cancer status determination is performed by a software classification algorithm. 20. The method according to embodiment, wherein the threshold level of LARP1 is selected from the group consisting of: 15, 18, 20, 22, 25, 26, 27, 28, 29, 30, 31, 32 and 35 pg / ml. 21. The method according to , wherein the LARP1 threshold indicative of possible / likely presence of pre-invasive cancer is selected from the group consisting of: 25, 26, 27 or 28 pg / ml. 22. The method according to any one of the preceding embodiments, wherein the level of U\RP1 and / or CA125 protein in the sample is detected using a technique selected from: bead / plate based enzyme linked immunosorbent assay (ELISA), enzyme linked oligonucleotide assay (ELONA), chromatography-tandem mass spectrometry, such as high performance liquid chromatography (HPLC) and mass spectrometry including tandem mass spectrometry. 23. The method according to any one of the preceding, wherein the level of each measured biomarker is determined quantitatively. 24. The method according to any one of the preceding, wherein the level of each biomarker is normalised, such as by use of one or more reference proteins or genes. 25. The method according to any one of the preceding embodiments, wherein the LARP1 and / or CA125 level is determined using an immunoassay. 26. The method according to any one of the preceding embodiments, wherein the LARP1 and / or CA125 level is determined using chromatography-tandem mass spectrometry. 27. The method according to one of the preceding embodiments, wherein the LARP1 level is determined using chromatography-tandem mass spectrometry. 28. The method according to one of the preceding embodiments, wherein the LARP1 level is determined using chromatography-tandem mass spectrometry and the CA125 level is determined using an immunoassay. 29. The method according to any of the previous embodiments wherein the subject comprises cancer-predisposing mutations in its genomic DNA. 30. The method according to embodiment 29, wherein the subject possesses germline BRCA1 or BRCA-2 mutations. 31. The method according to embodiment 29 or 30, wherein the subject comprises germline driving mutations in a gene selected from: BRCA1, BRCA2, RAD51C, RAD51D, PALB2, or BRIP1, KRAS, P53, ALK and HER2. 32. The method according to embodiment any one of embodiments 1 to 298, wherein the subject has a syndrome selected from BRCA, Lynch and Li Fraumeni. 33. Use of La-related protein 1 (LARP1) and Cancer Antigen 125 (CA125) biomarker levels in a method of determining cancer status, for example wherein the cancer status is ovarian cancer status. 34. A kit comprising: (c) a panel of affinity reagents that each selectively binds to CA125 or LARP1 or (d) a panel of labelled peptide standards for CA125 and LARP1 for use in mass spectrometric analysis. 35. The kit of embodiment 34, wherein the affinity reagent is an antibody or a protein comprising an antigen-binding domain of an antibody. 36. The kit of embodiment 34 or 35, further comprising written instructions for using the affinity reagents or labelled peptide standards to measure the levels of the CA125 and LARP1 proteins in a sample, such as one from a subject. 37. The kit of any one of embodiments 34 to 36, further comprising written instructions for use of the kit for determining a subjects ovarian cancer status. 38. A method for determining whether a subject is at risk of developing ovarian cancer comprising: determining the absolute level of LARP1 in a sample from the subject over a time period so as to provide a plurality of LARP1 values over a time-course; wherein if over the timecourse the absolute level of LARP1 exceeds a threshold level or peaks and then drops the subject is determined to be at risk of developing ovarian cancer. 39. A method for determining ovarian cancer status of a subject comprising: determining the absolute level of LARP1 in a sample from the subject over a time period so as to provide a plurality of LARP1 values over a time-course; and determining the ovarian cancer status based on the change in LARP1 detected over the time course. 40. A method for monitoring the progression of ovarian cancer in a subject comprising: determining the level of one or LARP1 biomarker in the circulating blood of a subject at a first point in time and comparing the level of the LARP1 biomarker in the subject at one or more later points in time to determine the progression of the ovarian cancer. 41. The method according to any one of embodiments 38 to 40, wherein the level of LARP1 in a sample from the subject is determined from at least three timepoints and the level at each timepoint compared to the level at one or more different timepoints. 42. The method according to embodiment 41, wherein the timepoints are at least 3 months apart. 43. The method according to embodiment 42, wherein each timepoint is at least 3 months apart from another timepoint. 44. The method according to any one of embodiments 38 to 43, wherein the subject has a genetic predisposition to ovarian cancer. 45. The method according to any one of embodiments 1 to 32 and 38 to 43, wherein if the subject is determined to be at risk of developing ovarian cancer they are selected for risk-reducing surgery and / or are given risk-reducing surgery. 46. The method according to embodiment 45, wherein the risk reducing surgery is risk reducing salpingo-oophorectomy (RRSO) surgery or risk-reducing salpingectomy (RRS) surgery. 47. The method according to embodiment 46, wherein the RRS surgery comprises removal of fallopian tubes only. 48. A computer-implemented method to aid in determining the likely cancer status in a subject, comprising the steps of: a) receiving a value for the absolute level of LARP1 in a biofluid sample of the subject; b) receiving a value for the absolute level of CA125 in a biofluid sample of the subject; c) comparing the amounts in (a) and (b) to absolute levels for LARP1 and CA125 accordingly, determined for the subject at one or more previous time points and / or to reference values; and d) determining the likely cancer status in the subject based on the comparison in step (c). 49. The computer-implemented method according to claim 46, wherein the cancer status is ovarian cancer status. The following Examples serve to illustrate the invention. These Examples are in no way intended to limit the scope of the invention, but rather as examples from which equivalents will be recognized by those of ordinary skill in the art. Unless it is apparent from the context, each of the embodiments listed above can be applied for use in any of the aspects of the invention. EXAMPLES Example 1 - Longitudinal measurement of LARP1 and CA125 values from historical ovarian cancer patients. A tandem mass spectroscopy assay was performed to measure the EGYR peptide (SEQ ID NO: 3) fragment of LARP1 in serum / plasma samples as set out in WO2021064361. The method was optimised to create a bespoke, reproducible and GLP-compliant assay for all subsequent studies. Using this assay, levels of LARP1 were tested in serum from 232 participants (127 patients had established ovarian cancer and 49 were controls) in the UK Ovarian Cancer Population Study (UKOPS) (MRC Clinical Trials Unit. UK Ovarian Cancer Population Study (UKOPS). https: / / www.ctu.mrc.ac.uk / studies / all-studiesZu / ukops / . Accessed 09 / 21). Results: The mean LARP1 score (absolute level in pg / ml) was significantly higher in cancer cases (24.84 pg / ml) compared to controls (21.35 pg / ml) (Figure 1A) and there were significant correlations with survival outcome (Figure 1B) and CA125 (Figure 1C Example 2: Longitudinal measurement of LARP1 and CA125 to provide early marker of invasive ovarian cancer We assayed LARP1 in 819 plasma samples from the UK Familial Ovarian Cancer Screening Study (UKFOCSS), in which women with high risk of OC underwent four-monthly CA125 testing and blood sample were stored for future biomarker detection (Rosenthal AN. Ovarian cancer screening in the high-risk population--the UK Familial Ovarian Cancer Screening Study (UKFOCSS). Int J Gynecol Cancer. 22 Suppl 1:S27-8, 2012). Pilot longitudinal data from the cancer cases were modelled using locally weighted (LOESS) smoothing to explore the trajectory of LARP1 over time and in relation to CA125 (Austin and Steyerberg. Graphical assessment of internal and external calibration of logistic regression models by using loess smoothers. Stat Med. 33(3):517-35, 2014). Whilst CA125 was elevated during the 0-12 months before diagnosis (Figure 3B), LARP1 demonstrated a predictive pattern and having peaked around 30-40 months prior to HGSC diagnosis fell slightly before continuing to rise (Figure 3A). The latter rise in LARP1 occurs at a similar time and in the same direction as CA125 (Figures 3A &3B), indicating both its potential for significantly improving lead time, and its potential suitability for combining with CA125 to allow earlier detection of HGSC. Across these studies there were no significant correlations between LARP1 and age, or menopausal status. From longitudinal studies of LARP1 and CA125 levels the inventors have discovered that the LARP1 protein is highly expressed in STIC lesions and is detectable in plasma. Furthermore, that plasma LARP1 levels rise to peak at 30-40 months before OC diagnosis, preceding the rise in CA125 by at least 20 months. This shows that longitudinal measurement of plasma LARP1 alongside CA125 will improve the early detection of HGSC in high risk patients (e.g. those with BRCA mutations) The inventor has discovered that LARP1 levels start to rise as a subject moves from normal to pre-invasive cancer (including STIC). The levels rise to a peak and then start to decrease. During this period CA125 levels are typically still low / normal. The level of LARP1 then rises further whilst level of CA125 starts to increase as the cancer status progresses.lt is at this stage that current CA125 measurement alone can be used for diagnosing / predicting ovarian cancer status. Example 3: Longitudinal measurement of LARP1 to diagnose STIC lesion / ovarian precancer In the UK Familial Ovarian Cancer Screening Study (UKFOCSS), in which women with high risk of OC underwent four-monthly CA125 testing, 5 women were found to have STIC lesions within fallopian tubes upon prophylactic surgery. LARP1 was assayed in 33 serial samples collected from these women in the up the 6 years leading to their diagnostic surgery. The inventors discovered that LARP1 levels start to rise as a subject moves from normal to pre-invasive cancer (STIC). The levels rise to a peak and then start to decrease (Fig 3C). During this period CA125 levels are typically still low / normal Thus LARP1 shows a similar predictive pattern peaking at 25 months before STIC diagnosis indicating its expression in early STIC lesions but preceding the late rise in LARP1 that corresponds with invasive disease and CA125 rise. Without wishing to be bound by theory, it appears that LARP1 is a measure of high cell stress in gynaecological tissue. The inventors have found that the cells in preinvasive / STICs stage are highly stressed (these are precancerous). Hence LARP1 goes up and then drops as the cells transition to cancer whereupon it rises again. On the other hand, CA125 pattern in the circulation suddenly goes up (e.g., is typically / -shaped) when there is established cancer and not in the precancer stage. CA125 biomarker is thus unsuited to staging pre-cancer or pre-invasive cancer. Thus in terms of rough staging, Low LARP1 level / low CA125 level - unlikely to have cancer or pre-invasive cancer. Rising LARP1 level / low CA125 level - likely to be developing pre-cancer. LARP1 reaching a peak level / low CA125 level - likely to have established pre-invasive cancer / STIC. Any LARP1 level / CA125 level starting to rise - likely to be moving to invasive cancer Any LARP1 level / CA125 level rising (above a threshold) - likely to have (ovarian) cancer. By combining LARP1 and CA125 protein measurements it should be possible to effect much earlier cancer status determination than currently possible. Single point measurements of LARP1 and CA125 can assist in determining the likelihood of having cancer (e.g.,ovarian cancer) and its likely stage. Longitudinal measurements will likely provide much greater granularity on the cancer status. The ability to determine the ovarian cancer status of a subject will allow more effective treatment decisions, for example, patients likely to have STIC, or very early stage cancer, can undergo more minimal surgery to remove just the fallopian tubes, or ovaries and fallopian tubes depending on the stage of disease progression, well in advance of developing invasive cancer. Patients can also be identified for much earlier therapeutic intervention. For example, as illustrated by the longitudinal levels for patient 1, from just the first few measurements of LARP1 and CA125, the methods of the present invention could have picked up that they were on the trajectory to developing ovarian cancer. SEQUENCE LISTING: SEQ ID NO: 1. LARP1 mRNA (variant 1) 1 gccagagcca ggaggcagct gtgcgatctg gatgtaccta aaccctccag ggccacatag 61 tgaccccagg ccctggtcac tccatgcttt ggagggtgct tttgtcaaag aggcctcctt 121 tccctcaccc agagctggat ttccaagagg ctcccatacc tagctgccct ggcagactcc 181 cagggaggaa aaacagcgtg gccttggcag ctgccccgag gaaggagccc acaggtgaca 241 gggagaagcc attgccattc cctgtcctgg cccccttcag caaccctgaa cactctgctc 301 cagccaaggt ggtgagggca gctgttccta aacagcgcaa aggcagcaag gttggtgact 361 ttggagatgc aatcaattgg cccacacctg gagagatagc ccacaagagt gttcagccac 421 agtcccacaa gcctcagcct acccgtaaac tgccacccaa gaaggacatg aaggaacagg 481 agaaaggaga agggagtgat agtaaggaga gtccaaaaac caaatcagat gaatcagggg 541 aggaaaagaa tggagatgag gattgccagc gaggcgggca gaagaagaaa ggaaacaaac 601 acaagtgggt tccattacaa atagacatga agcctgaagt gcccagagag aaactggctt 661 cacgccccac tcgcccaccg gagcctagac acatacctgc caatcgcgga gagatcaaag 721 ggtctgagtc tgccacctac gtgcccgtgg ccccccccac cccagcctgg caaccagaga 781 tcaaaccgga gcctgcctgg cacgaccagg atgagacatc gagtgtgaag agtgatgggg 841 ctggtggggc gcgggcttcc ttccgtggcc gtggacgggg gcgtggtcgc ggccggggac 901 gcggccgggg tggcactcga acccattttg actaccagtt tggctaccga aagtttgatg 961 gtgtggaggg gcctcgtacg cccaagtaca tgaacaacat cacctactac tttgacaatg 1021 tcagcagcac cgagctttac agtgtggatc aggaactgct caaagactac atcaagcgcc 1081 agattgaata ctacttcagc gtggacaatt tagagegaga cttcttcctg egaaggaaaa 1141 tggatgctga tggtttccta cccatcaccc ttattgette cttccaccga gtgcaggccc 1201 ttaccactga catttcactc atetttgegg ccctaaagga cagcaaggtg gtggagatcg 1261 ttgatgagaa agttcgtagg agggaggaac cagaaaagtg gcctcttccc ccaatagtgg 1321 attattcaca gaetgattte tcccagcttc tcaactgccc tgaatttgtt ccccgtcagc 1381 actaccaaaa ggagacagag tcggcacctg gctctcctcg tgcagtcacc ccagtgccaa 1441 ccaaaacaga ggaggteage aacctaaaga cactacccaa gggcctgtct gccagcctgc 1501 ctgacctgga ttctgagaac tggattgaag tgaagaagag gcctcggcca tccccagcac 1561 ggcccaagaa gtcagaggag tccagatttt cccacctgac ctctctgcct cagcagctgc 1621 cttcccagca gctgatgtcc aaggatcagg atgagcaaga ggaactggat tttctgtttg 1681 aegaggagat ggagcagatg gatgggcgga agaacacctt cactgcctgg tetgatgagg 1741 aatctgacta tgagattgat gacagggatg tcaacaagat cctcattgtc acccagacac 1801 cacattacat gcgccggcac ccaggggggg accgcacagg caaccacacc tcgcgtgcca 1861 agatgagege cgaactggcc aaggteatta atgatggcct cttctactat gagcaggacc 1921 tgtgggctga aaagtttgaa cctgagtatt cccagatcaa gcaagaagtc gagaaettea 1981 aaaaggtcaa tatgatcagc cgggagcagt ttgacacact gacccctgag ccccctgtgg 2041 atcccaacca ggaagttcct cctgggccac ctcggttcca gcaagttcct acggatgccc 2101 tggccaacaa gttgtttggt gctcctgagc cctccaccat cgcccgctct ctaccaacca 2161 ctgtcccaga gtcaccaaac taccgcaaca ccaggacccc tcgcactccc cggacaccac 2221 agctcaaaga ctcaagccag acatcacggt tttacccagt ggtgaaagaa ggacggacac 2281 tggatgccaa gatgcctcga aaaagaaaga caagacacag ttcaaaccca cccttggaga 2341 gccatgtggg ctgggtgatg gattcccgtg agcacaggcc ccgtactgct tccatcagct 2401 ccagcccctc agaagggacg cctacagttg gcagctatgg ctgtacccct cagtcattgc 2461 ccaagttcca gcatccttcc catgaactgc tcaaggaaaa tggcttcaca caacacgtct 2521 accataagta tegtaggege tgccttaatg agcggaaacg cttgggcatt ggccagtctc 2581 aggagatgaa cacactcttc cgcttctggt ccttcttcct ccgagatcac ttcaacaaaa 2641 agatgtatga ggagttcaag cagctggctc tggaggaege caaagaaggc tacagatatg 2701 gtttggagtg cctttttcga tactacagtt atggcctgga aaagaagttc cggctggaca 2761 tattcaagga ttttcaggag gaaaeggtga aggactatga agctggccaa ctgtatgggc 2821 tggagaagtt ctgggccttc ttgaaatatt ccaaagccaa aaatttggac attgacccca 2881 aaetgeaaga atacctcggc aaattccgac gtettgaaga cttccgagta gatcccccca 2941 tgggtgagga gggcaaccac aagcgacact cagtggtagc aggaggtggc ggeggtgagg 3001 gcaggaagcg gtgcccctcc cagtcttcca gcaggcctgc tgccatgatc agccaacccc 3061 ctacaccacc caccggccag cctgtccggg aagatgccaa atggacaagc cagcactcga 3121 acacacagac tttgggaaag tgaaaagctc cttagccctg gggettgagg ggggaaaggg 3181 gtagggtggg taagagtcca tgggggtgcc cagtcccagg agaggggaca atgaagggac 3241 aggcctggag ttactaggac aggcctttgt gctgagtagc aatgtataca ccatttgggc 3301 tatcagaggt acccctgggc aggagcctct acatcccctt ccccctcctc tctccatgac 3361 tcttgacatc ctagcttctt ctaagggggg agggaaaggg gggagatttt tatatatata 3421 tacatatata tatatcaagt tttaaattat tgatagttca tctggattac caaaatcact 3481 ctgcagccct gcccgaggct agtaggctgc aaccctggtc cccaccccta acctcctgct 3541 ccccctcaag ccaactatgc agcccacaag aaggccctgc gggccccccc attgcccagc 3601 actgtctcat agaaggctct ggtggtacct ctgggcccca ggagcatcag ccccttgatc 3661 atctggggtt tgtcatcacc atattttctc cctgctgttc ccaccatgcc cttctgccat 3721 cttctgggag aaggaaacca aaggatctaa aactggggtt tgggggaagg tttcagcctc 3781 tccccactcc ccttgcccca caccctttac tccccagccc agagagacgc tgcttttacc 3841 aggaaagact attgaaagat gttttatttt atttttctct gacctttcca tccttgaaaa 3901 aatggggaaa aaagaagaaa aaagacaaaa tcgaccataa aagaccaaaa aaaaaaaaaa 3961 aatcagaaaa cccccaccta atccacagaa agtaatgtct ttcccctccc cttggaattt 4021 ttgttttgtt tttggaaata atattttttt aaaagttgcc ttattgtgga gcgggaatct 4081 gaaataccca aatgcctgtt ttcctcggtg gagtcaaccc gaagagctcc caccttctct 4141 ggatgtgcct gggcttggac tggctagaat ctttctctgg actgttgcat gtacagtgcc 4201 tccatcctgg aggcaagaga gttgggagtg gctcgaatca gagccgtgcc caagatatcc 4261 ctgctgttgc atcgtttgaa gctgacgtcc tgtgtctgta cactgctgcc actgttgtgt 4321 cctcgctctg cttgctgttg cctcacgcca ggccccgtcc tgccgtgaca cccttcatcc 4381 tacccttgga accccaaggc caagttggtt caaactgttg gagaacagag ttggcctgca 4441 tctggaacac acttgtcctc agcttaccat ctcctcacac cccagagtgg aaaggtgaac 4501 acctgcagct gaggcttgga aacgtttctt gtgttgccct gaaaaatctt tgagacctca 4561 gggaggctct gtctctctta aaaggtggag aaagatgcca ttctctccct aaggtctggt 4621 ggagtctccc catcttgcat acccttctgc aagccatcta tctctgctca ctctccaatt 4681 gacccgcctg ggaacaaggg atgaggagga gttgggggct ggggggaatc ctgccagttg 4741 gtgaagccct gtggcaggaa ggtatatgtg gacatagagt atacctgatt ctctttcttc 4801 agccactgac tgcttgggtt gggctgtgaa tgataatgga atggctggag tctgctgttg 4861 tcagaaggca gggagggtga tgaaggactg acccacatgg actgggatgt gtgtcggtta 4921 tgggcatgac tgcacgttca ctctcagtgg gatctgggca acatggagtt cattgtcctg 4981 ttgcttactt actgcaatgt ctttggccct ccttttcaac tggttcctct gttgggccca 5041 aaggttggga gtaggagaca gtatcccagg ctgacaaggg cttgcccttt accttgggca 5101 ccttgttaat ttttagcctg tgcccttccc cacctttgcc ctcccagtgg ttggtatgtg 5161 ggaagcccat ctcagttcct gtgacttcat gtctcaaacc aaggatgagc gtctggtctc 5221 tgctatgatg gtggtatccg aggcctttcc ctgcccagtc tggtgcctgc cccacattgt 5281 accggacact ggattcctgg acccccttct cctttccttt ctttccttca ggtcacgcag 5341 ccctgtactg tatccagcac cacagaaacc tcagtgtttt tcctctgctg gtttggggca 5401 caaggaagcc ttagggtatg gggaaaggct gttattacct agagtttact cccaggccag 5461 ggggctgcca tcttcttcac agacatccct gaaaggaagc ccctttgggg cagggaggtg 5521 aggacttcat ctcaacatcg gctggtggtt ggtaggggag ctttttcttt tctttccttt 5581 ttttttgttt ttgtttttgt ttttgttttt ggtaacatgt taggagttaa tgttgcaaag 5641 agtagtttac atcttcactt tctgaagaca cttgaattta ggaccgatgt atctgtgaca 5701 agcatgccag aagtggcagg ggccatcagg gctaaccact tcacacctac catcgtccca 5761 tggggatcca agacctgaga taaagcaaca gcctgcccag atccctctgt tcatcctatc 5821 ccttccaagg ttggtccatg ccaacataac ctctgggcat cagacatcag caggtctgtg 5881 tgcctcagcc ctgttaaggg gcaggtttct ctttagccct cttcctgcac ttgggagcaa 5941 aggcactacc agtagagaag ggccatccag ccgtgcccca gcctggaccc ctggggctca 6001 gatagaggtg ctgagcccct gtgtcaaagt tgttaaatgt ttttgttttg ttccattgta 6061 gctctttttt tttttttttc ccctttcctg gtgattgatt ttacaaaaga aagtaagctg 6121 cttagaaggc cctggaaggg aagtgaggag gagggacaag gaagatgact agttacggag 6181 ggtgagggtt gttttttgcc aaaaagcctg ggtagagtga tctgaattat ctggcaccct 6241 cctgaatgga accccagagt acctcctgtg tggaagggtc cctggatttt ccctaacacc 6301 caccctctcc cccttcagcc atgctgatgg cagagaagat aagaacttgg agcccatttc 6361 tcactggaga ggaaaacttg tcatctggct ttgcggagaa ggttccacct tacgctcgta 6421 gtacattatc tttactatgt gctaggatat catatttaaa aggacaaaaa aatgtaaaat 6481 acttgaatga gcttgtatta taacattaat attattgaga gtatctgctt tccaggctga 6541 agtgattcat tcattattct agtcctgctt tagtcctttg taatttgtgg taattatgct 6601 tttcttttta atacaaaaaa atgtataaaa ataaacactt gaaaaggcaa aa SEQ ID NO: 2 LARP1 variant 1 amino acid 1 mlwrvllskr ppfphpeldf qeapipscpg rlpgrknsva laaaprkept gdrekplpfp 61 vlapfsnpeh sapakvvraa vpkqrkgskv gdfgdainwp tpgeiahksv qpqshkpqpt 121 rklppkkdmk eqekgegsds kespktksde sgeekngded cqrggqkkkg nkhkwvplqi 181 dmkpevprek lasrptrppe prhipanrge ikgsesatyv pvapptpawq peikpepawh 241 dqdetssvks dgaggarasf rgrgrgrgrg rgrgrggtrt hfdyqfgyrk fdgvegprtp 301 kymnnityyf dnvsstelys vdqellkdyi krqieyyfsv dnlerdfflr rkmdadgflp 361 itliasfhrv qalttdisli faalkdskvv eivdekvrrr eepekwplpp ivdysqtdfs 421 qllncpefvp rqhyqketes apgspravtp vptkteevsn Iktlpkglsa slpdldsenw 481 ievkkrprps parpkksees rfshltslpq qlpsqqlmsk dqdeqeeldf Ifdeemeqmd 541 grkntftaws deesdyeidd rdvnkilivtqtphymrrhp ggdrtgnhts rakmsaelak 601 vindglfyye qdlwaekfep eysqikqeve nfkkvnmisr eqfdtltpep pvdpnqevpp 661 gpprfqqvpt dalanklfga pepstiarsl pttvpespny rntrtprtpr tpqlkdssqt 721 srfypvvkeg rtldakmprk rktrhssnpp leshvgwvmd srehrprtas issspsegtp 781 tvgsygctpq slpkfqhpsh ellkengftq hvyhkyrrrc Inerkrlgig qsqemntlfr 841 fwsfflrdhf nkkmyeefkq laledakegy rygleclfry ysyglekkfr Idifkdfqee 901 tvkdyeagql yglekfwafl kyskaknldi dpklqeylgk frrledfrvd ppmgeegnhk 961 rhsvvagggg gegrkrcpsq sssrpaamis qpptpptgqp vredakwtsq hsntqtlgk SEQ ID NO: 3 LARP1-derived EGYR peptide EGYR

Claims

1. A method for determining the likely cancer status in a subject, comprising(i) determine the level of La-related protein 1 (LARP1) protein in a biological sample from a subject;(ii) determine the level of Cancer Antigen 125 (CA125) protein in a biological sample from the same subject as for (i);(iii) comparing the amounts in (i) and (ii) to threshold levels and / or to levels determined for the subject at one or more previous time points; and(iv) determining the likely cancer status in the subject based on the comparison in step (iii), optionally wherein the level of LARP1 and CA125 determined are absolute levels.

2. The method according to claim 1, wherein the cancer status is used fori) prognosing the development of cancer;ii) predicting the responsiveness to a therapeutic treatment;iii) identifying subjects that are in early stages of cancer development;iv) detecting the presence of pre-invasive cancer;v) detecting the presence of or development of STIL and / or STIC;vi) determining the status of a cancer;vii) diagnosing cancer; andviii) monitoring the efficacy of a therapeutic treatment.

3. The method according to claim 1 or 2, for determining the likely cancer status in a subject.

4. The method according to any one of claims 1 to 3, wherein the or each sample comprises a biological sample selected from the group consisting of: blood sample, a plasma sample, a serum sample, a urine sample, an ascites sample and a saliva sample.

5. The method according to claim 4, wherein the or each sample is a blood or bloodfraction sample, such as a serum or plasma sample.

6. The method according to any one of the preceding claims, wherein the level of LARP1 and / or CA125 is compared to a threshold or reference value, optionallywherein the threshold or reference value has been determined based on clinical studies.

7. The method according to any one of the preceding claims, wherein the levels of U\RP1 and CA125 are determind from samples from the subject taken over a time course and the trajectory of LARP1 and CA125 level changes determined overtime8. The method of any one of the preceding claims, wherein the likely ovarian cancer status determination is performed by a software classification algorithm.

9. The method according to any one of the preceding claims, wherein the LARP1 threshold indicative of possible / likely presence of pre-invasive cancer is selected from the group consisting of: 25, 26, 27 or 28 pg / ml.

10. The method according to any one of the preceding claims, wherein the level of LARP1 and / or CA125 protein in the sample is detected using a technique selected from: bead / plate based enzyme linked immunosorbent assay (ELISA), enzyme linked oligonucleotide assay (ELONA), chromatography-tandem mass spectrometry, such as high performance liquid chromatography (HPLC) and mass spectrometry including tandem mass spectrometry.

11. The method according to any one of the preceding claims, wherein the level of each measured biomarker is determined quantitatively.

12. The method according to any one of the preceding claims, wherein the LARP1 and / or CA125 level is determined using an immunoassay and / or using chromatographytandem mass spectrometry13. The method according to any one of the preceding claims, wherein the LARP1 level is determined using chromatography-tandem mass spectrometry and the CA125 level is determined using an immunoassay.

14. The method according to any one of the previous claims wherein the subject comprises cancer-predisposing mutations in its genomic DNA, optionally, wherein the subject comprises germline driving mutations in a gene selected from: BRCA1, BRCA2, RAD51C, RAD51D, PALB2, or BRIP1, KRAS, P53, ALK and HER2.

15. The method according to any one of claims 1 to 14, wherein the subject has a syndrome selected from BRCA1 / 2, Lynch and Li Fraumeni or mutations to other cancer predisposition genes such as PALB2, STK11, CHK1 orCHK2.

16. Use of La-related protein 1 (LARP1) and Cancer Antigen 125 (CA125) biomarker levels in a method of determining ovarian cancer status.

17. A kit comprising:a. a panel of affinity reagents that each selectively binds to CA125 or LARP1 or b. a panel of labelled peptide standards for CA125 and LARP1 for use in mass spectrometric analysis.

18. The kit of claim 17, wherein the affinity reagent is an antibody or a protein comprising an antigen-binding domain of an antibody.

19. The kit of claim 17 or 18, further comprising written instructions for using the affinity reagents or labelled peptide standards to measure the levels of the CA125 and LARP1 proteins in a sample, such as one from a subject, and optionally further comprising written instructions for use of the kit for determining a subjects ovarian cancer status.

20. A method for determining whether a subject is at risk of developing ovarian cancer comprising:determining the absolute level of LARP1 in a sample from the subject over a time period so as to provide a plurality of LARP1 values over a time-course; wherein if over the time-course the absolute level of LARP1 exceeds a threshold level or peaks and then drops the subject is determined to be at risk of developing ovarian cancer.

21. A method for determining ovarian cancer status of a subject comprising: determining the absolute level of LARP1 in a sample from the subject over a time period so as to provide a plurality of LARP1 values over a time-course; and determining the ovarian cancer status based on the change in LARP1 detected over the time course.

22. A method for monitoring the progression of ovarian cancer in a subject comprising determining the level of one or LARP1 biomarker in the circulating blood of a subject at a first point in time and comparing the level of the LARP1 biomarker in the subjectat one or more later points in time to determine the progression of the ovarian cancer.

23. The method according to any one of claims 1 to 15 and 20 to 22, wherein the absolute level of LARP1 in a sample from the subject is determined from at least three timepoints and the level at each timepoint compared to the level at one or more different timepoints, optionally, wherein the timepoints are at least 3 months apart, optionally wherein each timepoint is at least 3 months apart from another timepoint.

24. The method according to any one of claims 1 to 15 and 20 to 23, wherein if the subject is determined to be at risk of developing ovarian cancer they are selected for risk-reducing surgery and / or are given risk-reducing surgery.

25. A computer-implemented method to aid in determining the likely ovarian cancer status in a subject, comprising the steps of:(a) receiving a value for the absolute level of LARP1 in a biofluid sample of the subject;(b) receiving a value for the absolute level of CA125 in a biofluid sample of the subject;(c) comparing the amounts in (a) and (b) to absolute levels for LARP1 and CA125 accordingly, determined for the subject at one or more previous time points and / or to reference values; and(d) determining the likely ovarian cancer status in the subject based on the comparison in step (c).Application No: GB2416075.6Examiner: Sophie MilwardClaims searched: 1-25Date of search: 20 January 2025Patents Act 1977: Search Report under Section 17Documents considered to be relevant:Category Relevant to claims Identity of document and passage or figure of particular relevance X Y X,Y X,Y X Y X,Y X Y X,Y X: 17-24; Y: 1-16, 25 X: 17-24; Y: 1-16, 25 X: 17-24; Y: 1-16, 25 X: 17-24; Y: 1-16, 25 X: 17-24; Y: 1-16, 25 X: 17-19; Y: 1-16, 25 X: 17-19; Y: 1-16, 25 US 2022 / 0326247 Al (BLADGEN) See paragraph [191] and Examples 3 and 4 Nucleic Acids Research, vol. 44, no. 3, 2016, Hopkins et al., "The RNA-binding protein LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer", pages 1227-1246. [online] Available from: https: / / academic.oup.eom / nar / article / 44 / 3 / 1227 / 2502712 (accessed 16 / 04 / 24) See "LARP1 is highly expressed in ovarian cancer and predicts prognosis", page 1241, and figure 8D. 27th World Congress on Ultrasound in Obstetrics and Gynecology, vol. 50, suppl. 1, 2017, Coosemans et al., "Pl 1.06: Could LARP1 be a driving force in ovarian cancer transformation?", pages 188-189. [online] Available from: https: / / obgyn.onlinelibrary.wiley.com / doi / full / 10.1002 / uog. 18106 (accessed 16 / 04 / 24) See whole document WO 2016 / 075455 Al (BLADGEN) See pages 11-12 and Figure 2 Taianta, vol. 206, 2020, Syzmanska et al., "A biosensor for determination of the circulating biomarker CA125 / MUC16 by Surface Plasmon Resonance Imaging", article no. 120187. See introduction and section 4.4 US 2023 / 0127069 Al (FRITSCHE &NORTHROP) See paragraphs [0353-358], Molecular Biology Reports, vol. 46, 2019, Mansha et al., "Potential risk factors of ovarian cancer and analysis of CA125, a biomarker used for its monitoring and diagnosis", pages 3325-3332. See "ROC analysis"Categories:____________________________________X Document indicating lack of novelty or inventive A stepY Document indicating lack of inventive step if P combined with one or more other documents ofDocument indicating technological background and / or state of the art.Document published on or after the declared priority date but before the filing date of this invention.same category.& Member of the same patent family E Patent document published on or after, but with priority dateearlier than, the filing date of this application.Field of Search:International Classification:Subclass Subgroup Valid From GOIN 0033 / 574 01 / 01 / 2006 GOIN 0033 / 68 01 / 01 / 2006

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