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WO2019068755A1 - Diagnostics compagnons pour cancer colorectal - Google Patents

Diagnostics compagnons pour cancer colorectal Download PDF

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Publication number
WO2019068755A1
WO2019068755A1 PCT/EP2018/076899 EP2018076899W WO2019068755A1 WO 2019068755 A1 WO2019068755 A1 WO 2019068755A1 EP 2018076899 W EP2018076899 W EP 2018076899W WO 2019068755 A1 WO2019068755 A1 WO 2019068755A1
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cancer
topoisomerase
mpp3
treatment
inhibitor
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Nils Aage BRÜNNER
Jan Stenvang
Eva BUDINSKÁ
Vlad Calin POPOVICI
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Københavns Universitet
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Københavns Universitet
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/112—Disease subtyping, staging or classification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/118—Prognosis of disease development
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the present invention relates to companion diagnostics for colorectal cancer, in particular for prediction of benefit of topoisomerase 1 inhibitor treatment, such as irinotecan treatment.
  • biomarkers will allow a personalized treatment approach with exposure only of the right patient at the right time to the cytotoxic chemicals that are the essence of chemotherapeutic treatment.
  • CRC Colorectal cancer
  • Flurouracil (5-FU)/capecitabine plus leucovorin plus oxaliplatin FOLFOX/XELOX
  • FOLFOX/XELOX leucovorin plus oxaliplatin
  • mCRC metastatic CRC today's treatment includes conventional chemotherapy based on only three cytotoxic drugs: 5-FU, oxaliplatin and irinotecan.
  • the present inventors Using extensive “omics” technologies, the present inventors have revealed molecular resistance mechanisms, and subsequent functional assays have demonstrated the importance of these in mediating drug resistance.
  • the inventors have, by analysing key resistance genes in clinical patient material, established some of these molecular resistance mechanisms as able to provide predictive information on specific types of chemotherapy, namely therapy using topoisomerase 1 inhibitors.
  • the present inventors have identified novel biomarkers suitable for prediction of clinical response to topoisomerase 1 inhibitor treatment.
  • the present disclosure relates to a method for classifying a cancer as sensitive or resistant to topoisomerase 1 inhibitors and/or metabolites thereof comprising measuring the expression level of one or more biomarkers, wherein the one or more biomarkers are selected from MPP3, TOP1 and ABCG2.
  • the expression level of MPP3 may be measured alone or in combination with one or more further biomarkers, such as one or both of TOP1 and ABCG2.
  • the present disclosure relates to a topoisomerase 1 inhibitor and/or metabolite thereof for use in the treatment of a cancer which is classified as sensitive to topoisomerase 1 inhibitor treatment based on the expression level of one or more biomarkers, wherein the one or more biomarkers are selected from the group of MPP3, TOP1 and ABCG2.
  • the expression level of MPP3 may be measured alone or in combination with one or more further biomarkers, such as one or both of TOP1 and ABCG2.
  • the present disclosure relates to a method of treating a patient suffering from cancer comprising:
  • Sensitive group is: ABCG2 (below median) AND TOP1 (above 0.75 quantile) AND MPP3 (below 0.25 quantile)
  • Resistant Group is: ABCG2 (above median) AND TOP1 (below 0.75 quantile) AND MPP3 (above 0.25 quantile).
  • Sensitive + FOLFIRI Statistical comparison of the "Sensitive + FOLFIRI" subgroup to the other curves demonstrate that the Sensitive group is statistically (P ⁇ 0.05) mores sensitive to irinotecan than all other groups:
  • MPP3-low MPP3 below 0.25 quantile estimated on stage III population.
  • MPP3-high MPP3 above 0.25 quantile estimated on stage III population.
  • Sensitive group is: (ABCG2 (above median) AND TOP1 (any)) OR (ABCG2 (any) AND TOP1 (below 0.75 quantile)) AND MPP3 (below 0.5 quantile)
  • Resistant Group is: (ABCG2 (above median) AND TOP1 (below 0.75 quantile)) OR (any other combination of ABCG2 and TOP1 AND MPP3 (above 0.5 quantile)).
  • Sensitive + FOLFIRI Statistical comparison of the "Sensitive + FOLFIRI" subgroup to the other curves demonstrate that the Sensitive group is statistically (P ⁇ 0.05) mores sensitive to irinotecan than all other groups:
  • MPP3-low MPP3 below 0.5 quantile.
  • MPP3-high MPP3 above 0.5 quantile
  • Sensitive group is: ABCG2 (below median) AND TOP1 (above 0.75 quantile) AND MPP3 (below 0.25 quantile)
  • Resistant Group is: ABCG2 (above median) AND TOP1 (below 0.75 quantile) AND MPP3 (above 0.25 quantile).
  • Sensitive + FOLFIRI Statistical comparison of the "Sensitive + FOLFIRI" subgroup to the other curves demonstrate that the Sensitive group is statistically (P ⁇ 0.05) mores sensitive to irinotecan than all other groups:
  • MPP3-low MPP3 below 0.25 quantile.
  • MPP3-high MPP3 above 0.25 quantile Furthermore the survival curves for both the MPP3-low and MPP-3 high groups are shown in response to either FOLFIRI or 5FU/LV.
  • Sensitive group is: ABCG2 (below median) AND TOP1 (above 0.75 quantile) AND MPP3 (below 0.5 quantile)
  • Resistant Group is: ABCG2 (above median) AND TOP1 (below 0.75 quantile) AND MPP3 (above 0.5 quantile).
  • Sensitive + FOLFIRI Statistical comparison of the "Sensitive + FOLFIRI" subgroup to the other curves demonstrate that the Sensitive group is statistically (P ⁇ 0.05) mores sensitive to irinotecan than all other groups:
  • MPP3-low MPP3 below 0.5 quantile.
  • MPP3-high MPP3 above 0.5 quantile Furthermore the survival curves for both the MPP3-low and MPP-3 high groups are shown in response to either FOLFIRI or 5FU/LV.
  • treatment refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological or clinical condition, or disorder, and may include even minimal changes or improvements in one or more measurable markers of the disease or condition being treated.
  • This term includes active treatment, that is, treatment directed specifically toward the
  • this term includes preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and combination treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
  • preventative treatment that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder
  • combination treatment that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
  • Treatment or “treating” does not necessarily indicate complete eradication or cure of the disease or condition, or associated symptoms thereof.
  • the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • the subject is a mammal, preferably a human.
  • administering and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration,
  • a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.
  • an “effective amount”, as used herein, refers to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition.
  • a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. Detailed description
  • the present invention relates to companion diagnostics for colorectal cancer, in particular for prediction of benefit of topoisomerase 1 inhibitor treatment.
  • Topoisomerase I inhibitors include the following without limitation: irinotecan, topotecan, camptothecin, lamellarin D and Indenoisoquinolines including active derivatives and metabolites thereof.
  • the present disclosure relates to the prediction of response to a topoisomerase 1 inhibitor, such as a topoisomerase 1 inhibitor selected from the groups consisting of irinotecan, topotecan, camptothecin, lamellarin D and
  • Indenoisoquinolines including active derivatives and metabolites thereof.
  • the present disclosure relates to classification of cancer with respect to responsiveness to irinotecan and/or its active metabolite SN-38, prediction of clinical response to irinotecan and/or its active metabolite SN-38 and treatment of a cancer predicted to be drug-sensitive with irinotecan and/or its active metabolite SN-38.
  • Irinotecan sold under the brand name Camptosar among others, is a medication used to treat colorectal cancer and small cell lung cancer.
  • colorectal cancer used interchangeably with CRC and colon cancer herein
  • fluorouracil For small cell lung cancer it is used with cisplatin. It is given by slow injection into a vein.
  • Common side effects include diarrhea, vomiting, bone marrow suppression, hair loss, shortness of breath, and fever.
  • Other severe side effects include blood clots, colon inflammation, and allergic reactions. Treating only cancers that are predicted to be sensitive to topoisomerase 1 inhibitors will overall lessen the degree of side effects experienced by the patients.
  • Irinotecan is one of several topoisomerase 1 inhibitors which are made from the natural compound camptothecin. Irinotecan is activated by hydrolysis to SN-38, an inhibitor of topoisomerase I. This is then inactivated by glucuronidation by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1 ). The inhibition of topoisomerase I by the active metabolite SN-38 eventually leads to inhibition of both DNA replication and
  • irinotecan products examples include ONIVYDE® (irinotecan as liposome injection) and ONZEALDTM (etirinotecan pegol) (a long acting TOP1 inhibitor).
  • irinotecan is not used in adjuvant treatment of CRC but only in the metastatic setting.
  • PRCT's high-powered and independent Prospective, Randomized, Controlled Trials
  • PETACC3 and CALGB 89803 including high risk stage II and stage III colon cancer and randomizing patients to 5FUL ⁇ irinotecan
  • RFS recurrence free survival
  • OS overall survival
  • Adjuvant systemic therapy FOLFOX/XELOX is mainly offered to stage III colon cancer patients due to their relatively high risk of disease recurrence.
  • stage III colon cancer patients will benefit from such treatment as evidenced by an approximately 30% 5- years recurrence rate despite adjuvant chemotherapy.
  • adjuvant treatment modalities using drugs with different mechanisms of action than FOLFOX/XELOX.
  • Irinotecan is one of the first widely used chemotherapy agents that is dosed according to the recipient's genotype.
  • an effective dose of irinotecan is usually lower for * 28 variant patients than for other patients in need of treatment with irinotecan and is fully capable of adjusting the irinotecan dose for said patients.
  • biomarkers allowing the allocation of individual patients to different treatment groups. Such biomarkers should be tailored to tumor- specific characteristics predicting increased likelihood of benefit from a particular treatment.
  • MPP3 has been selected by the inventors as a promising candidate for prediction of irinotecan response.
  • the inventors have data supporting a predictive effect of MPP3 alone and propose that the predictive value of a panel of biomarkers comprising MPP3, TOP1 and ABCG2 together will be even better than MPP3 or (TOP1 and ABCG2) alone.
  • the expression level of said biomarker can e.g. be determined in tumor tissue/cells obtained from a population of cancer patients and the expression level can then be correlated with clinical responsiveness.
  • the size of the patient population required to provide a suitable cutoff level can be determined by the skilled person. For some cancers, a suitable population size may be a population of about 200 cancer patients. The population may be a population of patients suffering from the same cancer type or subtype, e.g. CRC stage III patients. In other situations fewer or even more patients may be required to establish a suitable cutoff for distinguishing responsiveness.
  • the expression levels can be stratified according to percentiles and/or quantiles.
  • a percentile is a measure used in statistics indicating the value below which a given percentage of observations in a group of observations fall. For example, the 20 th percentile is the value (or score) below which 20% of the observations may be found. The 20 th percentile can also be denoted the 20 percentile or 0.20 quantile.
  • percentile and the related term percentile rank are often used in the reporting of scores from norm-referenced tests.
  • a score is at the 86th percentile, where 86 is the percentile rank, it is equal to the value below which 86% of the observations may be found (carefully contrast with in the 86th percentile, which means the score is at or below the value of which 86% of the observations may be found - every score is in the 100th percentile).
  • the 25th percentile is also known as the first quartile (Q1 ), the 50th percentile as the median or second quartile (Q2), and the 75th percentile as the third quartile (Q3).
  • the MPP3 gene (NCBI Gene ID: 4356) product is a member of a family of membrane-associated proteins termed MAGUKs (membrane-associated guanylate kinase homologs). MAGUKs interact with the cytoskeleton and regulate cell proliferation, signaling pathways, and intracellular junctions.
  • MPP3 Membrane Palmitoylated Protein 3
  • Membrane Protein Palmitoylated 3 Membrane Protein Palmitoylated 3
  • MAGUK P55 Subfamily Member 3 Discs Large Homolog 3 and DLG3.
  • MPP3 as a suitable biomarker for prediction of response to a topoisomerase 1 inhibitor.
  • the data herein shows that the expression level of MPP3 alone can be used to predict response to irinotecan. If combined with the expression levels of TOP1 and ABCG2, the predictive value is further improved.
  • MPP3 expression in a selected cancer patient is low as compared to the expression of MPP3 in a reference group (population) of cancer patients, this indicates that said cancer patient will benefit from treatment with a topoisomerase 1 inhibitor, i.e. the cancer may be classified as topoisomerase 1 inhibitor-sensitive.
  • MPP3 expression in a selected cancer patient is high as compared to the expression of MPP3 in a group of cancer patients, this indicates that said cancer patient will not benefit from treatment with a topoisomerase 1 inhibitor, i.e. the cancer may be classified as topoisomerase 1 inhibitor-resistant. Such patients are not likely to benefit from topoisomerase 1 inhibitor treatment.
  • an expression level below a cutoff level defined as the median expression level (i.e. the 50 percentile) of MPP3 in a group of cancer patients is indicative of a cancer being sensitive to treatment with a topoisomerase 1 inhibitor and/or metabolite thereof.
  • an expression level above a cutoff level defined as the median expression level (i.e. the 50 percentile) of MPP3 in a group of cancer patients is indicative of a cancer being resistant to treatment with a topoisomerase 1 inhibitor and/or metabolite thereof.
  • the cutoff used to classify a cancer as sensitive or resistant to a topoisomerase 1 inhibitor and/or metabolite thereof is the 25 percentile with expression below the 25 percentile (0.25 quantile) being indicative of sensitivity to treatment with a topoisomerase 1 inhibitor and expression above the 25 percentile being indicative of resistance to treatment with a topoisomerase 1 inhibitor.
  • the present disclosure relates to prediction of response to a topoisomerase 1 inhibitor based on MPP3 expression alone.
  • the expression of MPP3 is combined with the expression of one or more further biomarkers, e.g. ABCG2 and/or TOP1.
  • ABCG2 is e.g. ABCG2 and/or TOP1.
  • ABCG2 (NCBI Gene ID: 9429) is ATP-Binding Cassette Transporter G2.
  • ABCG2 mRNA expression has previously been correlated (below or above median ABCG2 mRNA expression) to patient outcome in a subset of stage III colon cancer patients enrolled in the PETACC-3 study (Jensen et al. 2015). A trend towards high
  • an ABCG2 expression level below a cutoff level defined as the median level is indicative of a cancer being sensitive to topoisomerase 1 inhibitors.
  • an ABCG2 expression level above a cutoff level defined as the median level is indicative of a cancer being resistant to topoisomerase 1 inhibitors.
  • TOP1 (NCBI Gene ID: 7150) is the Topoisomerase I enzyme.
  • TOP1 mRNA expression has been described as a predictive biomarker in the same PETACC-3 study population as ABCG2 (Nygard et al., 2016).
  • a benefit from addition of irinotecan to 5FUL was restricted to colon cancer patients with high TOP1 mRNA expression in their tumors (Nygard et al., 2016).
  • this association reached statistical significance only for OS but not for RFS.
  • a TOP1 expression level above a cutoff level defined as the 75- percentile (0.75 quantile) is indicative of a cancer being sensitive to topoisomerase 1 inhibitor treatment.
  • a TOP1 expression level below a cutoff level defined as the 75- percentile (0.75 quantile) is indicative of a cancer being resistant to topoisomerase 1 inhibitor treatment.
  • a cancer is classified as sensitive to topoisomerase 1 inhibitor treatment when:
  • MPP3 expression is low, e.g. when the MPP3 expression level is below a cutoff level defined as the median expression level (i.e. the 50 percentile/0.5 quantile) of MPP3 in a group of cancer patients; and
  • TOP1 expression is high, e.g. when the TOP1 expression level is above a cutoff level defined as the 75-percentile (0.75 quantile) of TOP1 in a group of cancer patients.
  • a cancer is classified as sensitive to topoisomerase 1 inhibitor treatment when:
  • MPP3 expression is low, e.g. when the MPP3 expression level is below a cutoff level defined as the median expression level (i.e. the 50 percentile/0.5 quantile) of MPP3 in a group of cancer patients; and
  • ABCG2 expression is low, e.g. when he ABCG2 expression level is below a cutoff level defined as the median expression level (i.e. the 50 percentile/0.5 quantile) of ABCG2 in a group of cancer patients.
  • a cutoff level defined as the median expression level (i.e. the 50 percentile/0.5 quantile) of ABCG2 in a group of cancer patients.
  • a cancer is classified as sensitive to topoisomerase 1 inhibitor treatment when: a) MPP3 expression is low, e.g. when the MPP3 expression level is below a cutoff level defined as the median expression level (i.e. the 50 percentile/0.5 quantile) of MPP3 in a group of cancer patients; and
  • TOP1 expression is high, e.g. when the TOP1 expression level is above a cutoff level defined as the 75-percentile (0.75 quantile) of TOP1 in a group of cancer patients, and
  • ABCG2 expression is low, e.g. when he ABCG2 expression level is below a cutoff level defined as the median expression level (i.e. the 50 percentile/0.5 quantile) of ABCG2 in a group of cancer patients.
  • a cutoff level defined as the median expression level (i.e. the 50 percentile/0.5 quantile) of ABCG2 in a group of cancer patients.
  • a cancer is classified as resistant to topoisomerase 1 inhibitor treatment when:
  • MPP3 expression is high, e.g. when the MPP3 expression level is above a cutoff level defined as the median expression level (i.e. the 50 percentile/0.5 quantile) of MPP3 in a group of cancer patients; and
  • TOP1 expression is low, e.g. when the TOP1 expression level is below a cutoff level defined as the 75-percentile (0.75 quantile) of TOP1 in a group of cancer patients.
  • a cancer is classified as resistant to topoisomerase 1 inhibitor treatment when:
  • MPP3 expression is high, e.g. when the MPP3 expression level is above a cutoff level defined as the median expression level (i.e. the 50 percentile/0.5 quantile) of MPP3 in a group of cancer patients; and
  • ABCG2 expression is high, e.g. when he ABCG2 expression level is above a cutoff level defined as the median expression level (i.e. the 50 percentile/0.5 quantile) of
  • a cancer is classified as resistant to topoisomerase 1 inhibitor treatment when:
  • MPP3 expression is high, e.g. when the MPP3 expression level is above a cutoff level defined as the median expression level (i.e. the 50 percentile/0.5 quantile) of MPP3 in a group of cancer patients; and
  • TOP1 expression is low, e.g. when the TOP1 expression level is below a cutoff level defined as the 75-percentile (0.5 quantile) of TOP1 in a group of cancer patients
  • ABCG2 expression is high, e.g. when he ABCG2 expression level is above a cutoff level defined as the median expression level (i.e. the 50 percentile/0.5 quantile) of ABCG2 in a group of cancer patients.
  • the present disclosure relates to the prediction of response to topoisomerase inhibitor 1 treatment based on the expression of TOP1 and ABCG2 and optionally one or more further biomarker.
  • the further biomarker is not MPP3.
  • the cancer according to the present disclosure may be any cancer which can benefit from treatment with a topoisomerase 1 inhibitor.
  • the cancer is selected from the group consisting of colorectal cancer (CRC), small cell lung cancer, pancreatic cancer, glioblastoma multiforme, upper gastrointestinal, ovarian and cervical cancer.
  • CRC colorectal cancer
  • small cell lung cancer pancreatic cancer
  • glioblastoma multiforme upper gastrointestinal, ovarian and cervical cancer.
  • the cancer may be of any stage and/or classification as determined by the skilled person.
  • the cancer is CRC, such as stage I, stage II, stage III or stage IV CRC.
  • the CRC is metastatic CRC (mCRC).
  • Stage I CRC invasion into but not through the bowel wall.
  • Stage II CRC invasion through the bowel wall but not involving lymph nodes.
  • Stage III CRC involvement of lymph nodes.
  • Stage IV CRC widespread metastases.
  • MSI microsatellite instable tumors
  • MSS microsatellite stable tumors
  • This taxonomy plays a significant role in determining pathologic, clinical and biological characteristics of colon tumors: MSS tumors are characterized by changes in chromosomal copy number and show worse prognosis.
  • MSS tumors are characterized by changes in chromosomal copy number and show worse prognosis.
  • the less common MSI tumors (about 15%) are characterized by the accumulation of a high number of mutations and show predominance in females, proximal colonic localization, poor differentiation, tumor-infiltrating lymphocytes and a better prognosis.
  • the CRC is MSS. In one embodiment the CRC is stage lll/MSS.
  • the CRC is MSI.
  • Measuring expression levels The expression level of the biomarkers discussed herein is measured in a sample obtained from a cancer, e.g. in a sample containing tumor tissue/tumor cells. Such a sample may e.g. be obtained from a biopsy. In other embodiments, the sample may be circulating tumor cells (CTCs). CTCs are cancer cells that detach from a primary tumor and travel through the bloodstream or lymphatic system to other parts of the body. This allows for a "liquid biopsy" to be obtained from a cancer patient. CTCs can thus be obtained from some cancer patients via a blood sample.
  • the expression level may be determined at the level of mRNA and/or protein. Suitable methods for determining expression of the herein disclosed biomarkers include but are not limited to measurement by PCR, in situ hybridization, sequencing, mRNA / protein array, or ELISA.
  • the present disclosure further relates to treatment of a cancer predicted to be sensitive to topoisomerase 1 inhibitor treatment according to the methods disclosed herein.
  • the present disclosure relates to a topoisomerase 1 inhibitor and/or metabolite thereof for use in the treatment of a cancer which is predicted to be sensitive to topoisomerase 1 inhibitor treatment based on the expression level of one or more biomarkers, wherein the one or more biomarkers are selected from the group consisting of MPP3, TOP1 and ABCG2.
  • the one or more biomarkers are selected from the group consisting of MPP3, TOP1 and ABCG2.
  • MPP3 expression is measured alone or in combination with one or more further biomarkers, such as one or both of TOP1 and ABCG2.
  • the present disclosure relates to use of a topoisomerase 1 inhibitor and/or metabolite thereof for the preparation of a medicament for the treatment of a cancer, wherein said cancer is predicted to be sensitive to topoisomerase 1 inhibitor treatment based on the expression level of one or more biomarkers, wherein the one or more biomarkers are selected from the group consisting of MPP3, TOP1 and ABCG2.
  • MPP3 expression is measured alone or in combination with one or more further biomarkers, such as one or both of TOP1 and ABCG2.
  • the present disclosure relates to a method of treating a subject suffering from cancer comprising:
  • the subject is preferably a human.
  • the sample obtained from said subject contains tumor tissue/tumor cells.
  • Topoisomerase 1 inhibitor treatment may be combined with administration of one or more additional anti-cancer agents, such as one or more of 5 fluorouracil (5-FU), capecitabine, leucovaorin, oxaliplatin, cisplatin and optionally targeted biological treatment, such as EGF-receptor blockade or antiangiogenic treatment.
  • additional anti-cancer agents such as one or more of 5 fluorouracil (5-FU), capecitabine, leucovaorin, oxaliplatin, cisplatin
  • optionally targeted biological treatment such as EGF-receptor blockade or antiangiogenic treatment.
  • a subject predicted to be responsive to topoisomerase 1 inhibitor treatment is treated with the FOLFIRI or CAPIRI treatment regimen.
  • FFPE formalin fixed paraffin embedded
  • the present study was prospective-retrospective in nature.
  • the statistical plan and the applied cutoff values were defined prior to the study.
  • RFS was defined as time in months from randomization until occurrence of local, regional or distant relapse, a second primary colon cancer or death.
  • OS was defined as time in months from randomization until death.
  • RFS recurrence-free survival
  • OS overall survival
  • TOP1 mRNA we used, based on our previous study, the third quantile on the whole expression data of stage II and III patients to group the patients into TOP1 high and low.
  • the Kaplan-Meier method was used to estimate RFS and OS rates, and univariate comparisons were made using the log rank test. The effect size of
  • microsatellite status results of the PETACC-3 trial. Ann Oncol. 2015 Jan;26(1 ):126-32.] and were tested alongside the clinical and pathological baseline variables: N stage, tumor localization, tumor grade, sex, and age.
  • Formal tests for statistical interaction between dichotomized ABCG2/TOP1/MPP3 status and treatment were performed in separate Cox models, including main effects and an interaction term. All results were presented by hazard ratios (HR), estimated 95% confidence intervals (CI) and P values from the Wald-test. Pearson correlation coefficients (r) were calculated to test for statistical dependence between the ABCG2/TOP1/MPP3 variables. All P values were two-sided and the significance level was set at ⁇ 0.05. All analyses were performed in R software for statistical computing version 3.4.0. (R Core Team (2017). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/). Subgroup analyses
  • MSI tumors may have different mechanisms than MSS tumors to acquire resistance
  • stage III patients we also divided the stage III patients into MSS and MSI genotypes with 470 tumors being MSS and MSI-L and 51 tumors being MSI-H (59 missing values).
  • Kaplan Meier survival statistics were used to estimate RFS and OS rates in each group according to ABCG2, TOP1 and MPP3 expression dichotomized as described above.
  • the REMARK guidelines [McShane et al. Reporting recommendations for tumor marker prognostic studies (REMARK). Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics. J Natl Cancer Inst. 2005 Aug 17;97(16):1 180- 4.] were followed wherever applicable. RESULTS
  • MPP3 is a useful biomarker for predicting response to irinotecan independent of the expression of other biomarkers
  • MPP3 is not a prognostic biomarker
  • MPP3 combined with ABCG2 and TOP1 expression improves prediction of response to irinotecan

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Abstract

La présente invention concerne des diagnostics compagnons pour le cancer colorectal, en particulier pour la prédiction du bénéfice d'un traitement à base d'un inhibiteur de la topoisomérase 1, tel que le traitement à base d'irinotécan, basé sur le niveau d'expression de biomarqueurs sélectionnés.
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