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WO2023013998A1 - Biomarqueur pour le pronostic du traitement du cancer pulmonaire et son utilisation - Google Patents

Biomarqueur pour le pronostic du traitement du cancer pulmonaire et son utilisation Download PDF

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Publication number
WO2023013998A1
WO2023013998A1 PCT/KR2022/011222 KR2022011222W WO2023013998A1 WO 2023013998 A1 WO2023013998 A1 WO 2023013998A1 KR 2022011222 W KR2022011222 W KR 2022011222W WO 2023013998 A1 WO2023013998 A1 WO 2023013998A1
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Prior art keywords
lung cancer
tet2
clonal hematopoiesis
dnmt3a
mutations
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Korean (ko)
Inventor
선충현
김수경
임호균
송한
최세훈
윤재광
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Genome Opinion Inc
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Genome Opinion Inc
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Priority claimed from KR1020220094276A external-priority patent/KR102574286B1/ko
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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

Definitions

  • the present invention relates to a biomarker and its use for predicting the prognosis of lung cancer treatment, in particular, the prognosis of non-small cell lung cancer treatment. More specifically, the present invention is intended to predict the prognosis of lung cancer patients who have received or are scheduled to receive adjuvant therapy following surgical resection.
  • Clonal hematopoiesis is a condition defined by the expansion of clonally derived hematopoietic stem cells (HSCs) harboring somatic mutations in leukemia-associated genes, which can be detected by next-generation sequencing (NGS) (Genovese G , Kahler AK, Handsaker RE, et al: Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.N Engl J Med 371:2477-87, 2014;Park SJ, Bejar R: Clonal hematopoiesis in cancer.Exp Hematol 83:105-112, 2020; and Jaiswal S, Ebert BL: Clonal hematopoiesis in human aging and disease.
  • NGS next-generation sequencing
  • CH cardiovascular diseases and hematological malignancies.
  • lung cancer is the most commonly diagnosed cancer and is a leading cause of cancer-related death worldwide.
  • surgical excision is preferentially performed when possible, but the 5-year survival rate after surgery remains at 65%. Therefore, it is important to develop predictive factors capable of predicting the prognosis after lung cancer surgery in order to increase the survival rate through additional treatment after surgery and early detection of recurrence.
  • prognostic factors such as age, gender, and cancer stage have been identified, but new factors need to be explored in the NGS era.
  • Non-Patent Document 1 Jaiswal S, Ebert BL: Clonal hematopoiesis in human aging and disease, Science 366, 2019.
  • Non-Patent Document 2 Park SJ, Bejar R: Clonal hematopoiesis in cancer, Exp Hematol 83:105-112, 2020.
  • Non-Patent Document 3 Genovese G, Kahler AK, Handsaker RE, et al: Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence, N Engl J Med 371:2477-87, 2014.
  • the object of the present invention is to solve all of the above problems.
  • An object of the present invention is to provide a method of predicting the prognosis of lung cancer treatment in a lung cancer patient or a method of providing information for predicting the prognosis of lung cancer treatment.
  • Another object of the present invention is to provide a composition for predicting the prognosis of lung cancer treatment in lung cancer patients.
  • Another object of the present invention is to provide a kit for predicting the prognosis of lung cancer treatment in lung cancer patients.
  • Another object of the present invention is to provide a panel for genetic analysis capable of detecting genetic mutations of clonal hematopoiesis in order to predict the prognosis of lung cancer treatment in lung cancer patients.
  • Another object of the present invention is to provide a method for treating lung cancer or a method for providing information for lung cancer treatment.
  • predicting the prognosis of lung cancer treatment of an individual comprising determining whether clonal hematopoiesis exists in an individual through genetic analysis of a biological sample isolated from an individual being treated for lung cancer
  • a method or method of providing information for predicting the prognosis of lung cancer treatment of an individual is provided.
  • composition for predicting the prognosis of lung cancer treatment in an individual comprising, as an active ingredient, an agent for confirming the presence of clonal hematopoiesis using a biological sample isolated from an individual being treated for lung cancer. is provided.
  • kits for predicting the prognosis of lung cancer treatment of a subject comprising the composition is provided.
  • a genetic analysis panel for detecting genetic mutations in clonal hematopoiesis comprising the composition is provided.
  • treatment of lung cancer comprising the step of determining whether clonal hematopoiesis exists in a subject through genetic analysis of a biological sample isolated from the subject prior to administration of a therapeutic agent for lung cancer treatment.
  • a method or method of providing information for treatment of lung cancer is provided.
  • the present invention when it is confirmed that there is a mutation in a gene related to clonal hematopoiesis (CH) of an individual, it is possible to predict the prognosis according to the treatment of lung cancer, particularly non-small cell lung cancer, of the individual.
  • the present invention can provide useful information for determining the application of adjuvant therapy following surgical resection in relation to lung cancer treatment, information useful for determining whether to administer a therapeutic agent for lung cancer treatment, and the like, and furthermore, lung cancer In clinical trials of drug candidates for treatment, useful information can be provided to evaluate the efficacy and safety of drug candidates for patients.
  • CONSORT Consolidated Standards of Reporting Trials
  • Figures 2a and 2b show the overall survival and recurrence-free survival of patients, respectively, according to the presence of clonal hematopoietic (CH) mutations in the entire cohort.
  • Figure 2c shows the overall survival of patients according to the presence of CH mutations after propensity score matching (PSM).
  • PSM propensity score matching
  • Figure 3 shows the cumulative mortality according to the presence of CH.
  • FIGS. 3A, 3B, and 3C show cumulative lung cancer mortality according to the presence of CH, cumulative non-lung cancer mortality according to the presence of CH, and cumulative mortality of unknown cause according to the presence of CH, respectively.
  • Figures 4a and 4b show overall survival according to the presence of CH mutations in patients receiving adjuvant therapy for stage IIB lung cancer before and after PSM, respectively.
  • 4c and 4d respectively show the overall survival rate according to the presence of CH mutation in patients without adjuvant therapy for stage IIB lung cancer before and after PSM (Tx, Treatment).
  • 5A-5C show the characteristics of CH mutations identified in the entire cohort.
  • Figure 5A shows the prevalence of CH by age of patients in the cohort.
  • 5B shows the number of mutations carried per patient.
  • Figure 5c shows the number of mutations in each CH gene.
  • Figures 6a to 6c show the overall survival of patients according to the presence of CH mutations in stages IIB, IIIA and IIIB, respectively.
  • the term "about” refers to the typical error range for each value known to one of ordinary skill in the art. Further, unless otherwise specified, all numbers, values and/or expressions expressing ingredients, conditions, compositions, amounts, etc., used herein mean that such numbers are, among other things, essentially the representations of measurements that would occur to obtain such values. Since these are approximations that reflect various uncertainties, they should be understood to be qualified by the term "about”.
  • clonal haematopoiesis refers to a condition in which, when hematopoietic stem cells undergo somatic mutations to gain an opportunity for selective proliferation, the mutated clone expands and occupies a certain portion of leukocytes.
  • subject can be used interchangeably with “patient” and includes a mammal, such as a primate (eg, a human), a companion animal (eg, a dog, cats, etc.), livestock animals (eg, cows, pigs, horses, sheep, goats, etc.) and laboratory animals (eg rats, mice, guinea pigs, etc.).
  • a primate eg, a human
  • a companion animal eg, a dog, cats, etc.
  • livestock animals eg, cows, pigs, horses, sheep, goats, etc.
  • laboratory animals eg rats, mice, guinea pigs, etc.
  • prognosis refers to the course of a disease, such as the likelihood of death or progression due to lung cancer, including onset, recurrence, metastatic spread, survival rate, disease-free survival rate, drug resistance or susceptibility of a disease such as lung cancer, and whether it is cured or not.
  • the prognosis may refer to a survival prognosis according to lung cancer treatment including surgery, chemotherapy, chemotherapy, chemoradiation, or a combination of these therapies in lung cancer patients.
  • the prognosis of lung cancer treatment may mean the patient's responsiveness to a therapeutic agent for lung cancer treatment.
  • prediction refers to preliminarily determining the possibility of a patient surviving by responding preferentially or unfavorably to a treatment such as chemotherapy or chemoradiation or a treatment for lung cancer. Predicting survival prognosis can help select the most appropriate treatment method for a patient, confirm whether the patient responds favorably to the treatment method, or predict long-term survival of the patient after performing the treatment method.
  • biological sample refers to any biological sample obtained from an individual, which is a tissue, tumor tissue, lung tumor tissue, blood, serum, plasma, lymph, saliva, sputum, Samples such as mucus or urine include, but are not limited to.
  • adjuvant therapy includes chemotherapy (CTx), chemoradiation therapy (CRTx), molecular targeted therapy, radiofrequency hyperthermia cancer therapy, immunotherapy using biological agents, etc., performed before and after tumor removal surgery to treat cancer locally.
  • CTx chemotherapy
  • CRTx chemoradiation therapy
  • molecular targeted therapy radiofrequency hyperthermia cancer therapy
  • immunotherapy using biological agents etc., performed before and after tumor removal surgery to treat cancer locally.
  • any therapy may be included as long as it can be used as an adjuvant to systemic treatment.
  • all survival rate refers to the rate at which a cancer patient survives 5 years after undergoing surgery, even if the cancer has recurred or metastasized.
  • recurrence-free survival rate refers to the rate of cancer recurrence-free survival 5 years after surgery.
  • missense mutation refers to a genetic mutation in which a single base substitution occurs at a site on a DNA chain, thereby changing the genetic code of mRNA and designating an amino acid different from the original one to affect a protein.
  • frameshift mutation refers to a genetic mutation caused by insertion or deletion of a non-divisible number of bases.
  • nonsense mutation refers to a genetic mutation in which a codon encoding an original amino acid is changed to a stop codon that does not encode an amino acid by a single base substitution, so that protein synthesis is stopped at the location of the codon.
  • splice variation refers to a variation that occurs through the use of alternative splicing sites within transcribed RNA molecules or between individually transcribed RNA molecules.
  • primer refers to a nucleic acid sequence that is capable of forming a base pair with a complementary template and serves as a starting point for copying the template strand.
  • the sequence of the primer does not necessarily have to be exactly the same as the sequence of the template, but is sufficiently complementary to allow hybridization with the template.
  • Primers can initiate DNA synthesis in the presence of reagents for polymerization and four different nucleoside triphosphates in an appropriate buffer solution and temperature. PCR conditions and lengths of sense and antisense primers can be modified based on those known in the art.
  • probe refers to a substance capable of specifically binding to a target substance to be detected in a sample, and through the binding, a substance capable of specifically confirming the presence of the target substance in the sample.
  • the probe may be prepared in the form of an oligonucleotide probe, a single-stranded DNA probe, a double-stranded DNA probe, or an RNA probe. Selection of suitable probes and hybridization conditions can be modified based on those known in the art.
  • antisense nucleic acid refers to a nucleic acid-based molecule that has a complementary sequence to a target gene variant and can form a dimer with the target gene variant, and can be used to detect the target gene variant.
  • An appropriate length of the antisense nucleic acid may be selected to increase detection specificity.
  • gene panel refers to a genetic mutation detection tool in which a panel is composed of a plurality of agents capable of detecting mutations in a plurality of target genes.
  • therapeutic agent for treating lung cancer refers to a substance exhibiting an effect of improving, alleviating or treating the symptoms of a patient with lung cancer, and noting morphological, physiological or genetic changes in lung cancer cells. As long as they are clearly indicated, their physical properties, chemical properties, biological origin, etc. are not particularly limited.
  • the therapeutic agent includes all kinds of substances that can be used in the adjuvant therapy, ie, chemotherapy (CTx), chemoradiation therapy (CRTx), molecular target therapy, immunotherapy using biological agents, and the like.
  • clinical trial refers to all processes of research on the application of pharmaceuticals to humans, as well as research procedures conducted to confirm the safety and efficacy of pharmaceuticals, as well as bioequivalence tests to prove the bioequivalence of original and generic drugs. , clinical studies or side effects studies on drugs that have already been approved and are on the market.
  • the present invention is based in part on the surprising discovery that the presence or absence of clonal haematopoiesis (CH) in individuals undergoing lung cancer treatment is significantly associated with the prognosis of lung cancer treatment.
  • CH clonal haematopoiesis
  • the present invention may include determining whether clonal hematopoiesis exists in a subject being treated for lung cancer in order to provide information necessary for prognosis of lung cancer.
  • clonal hematopoiesis exists in the subject according to the present invention, it may indicate that the prognosis of lung cancer treatment is not good compared to the case where clonal hematopoiesis does not exist.
  • individuals with clonal hematopoiesis had a poorer overall survival rate compared to individuals without clonal hematopoiesis, and even after excluding variables other than clonal hematopoiesis by applying the propensity score matching (PSM) technique, Patients who still had clonal hematopoiesis showed poorer survival compared to patients who did not (see Example 6.3 and FIGS. 2A-2C).
  • PSM propensity score matching
  • mortality due to lung cancer was similar regardless of the presence or absence of clonal hematopoiesis, but non-lung cancer mortality and mortality from unknown cause were compared with patients without clonal hematopoiesis. It was significantly higher in patients with hematopoiesis (see Example 6.3 and FIGS. 3A-3C).
  • the presence of clonal hematopoiesis was associated with poorer overall survival in patients receiving adjuvant therapy, but the presence of clonal hematopoiesis did not significantly affect overall survival in patients not receiving adjuvant therapy. It was confirmed (see Example 6.3 and FIGS. 4a to 4d).
  • confirming the presence or absence of clonal hematopoiesis can predict the prognosis of lung cancer treatment and at the same time help select an appropriate follow-up therapy following lung cancer surgery, thereby increasing the survival rate of individuals after lung cancer treatment.
  • it is possible to more efficiently and accurately evaluate the efficacy of a therapeutic agent by selecting an individual to evaluate the efficacy of a therapeutic agent used for lung cancer treatment, such as adjuvant therapy, by checking whether clonal hematopoiesis exists in the individual prior to administration of the therapeutic agent, The cost of evaluating the efficacy of such therapeutics (eg, clinical trials) can be lowered.
  • clonal hematopoiesis exists in the target patient, and patients with clonal hematopoiesis are excluded from the patient group for lung cancer.
  • Efficacy evaluation of the therapeutic agent can be performed more efficiently and accurately.
  • the efficacy of the therapeutic agent in the individual and the lung cancer treatment effect can be increased.
  • a method for predicting the prognosis of lung cancer treatment of an individual comprising the step of determining whether clonal hematopoiesis exists in an individual through genetic analysis of a biological sample isolated from the individual.
  • a method for providing information for predicting the prognosis of lung cancer treatment of an individual is provided, which includes determining whether clonal hematopoiesis exists in the individual through genetic analysis of a biological sample isolated from the individual.
  • Genes causing somatic mutations associated with clonal hematopoiesis include APC, ASXL1, ASXL2, ATM, BCL11B, BCOR, BCORL1, BIRC3, BRAF, BRCC3, CARD11, CASP8, CBL, CD58, CD79B, CNOT3, CREBBP, and CUX1 , DDX3X, DNMT3A, EP300, ETV6, EZH2, FAM46C, FBXW7, FLT3, FOXP1, GNAS, GNB1, GPS2, HIST1H1C, IDH2, IKZF1, IKZF2, JAK1, JAK2, JAK3, JARID2, KDM6A, KIT, KLHL6, KMT2D, KRAS , LUC7L2, MAP3K1, MPL, MYD88, NF1, NFE2L2, NOTCH1, NOTCH2, NRAS, PDS5B, PDSS2, PHF6, PHIP, PIK3CA, PI
  • the one or more genes are DNMT3A, ASXL1, TET2, PPM1D, ATM, BCL11B, CARD11, CBL, CD79B, CHEK2, CUX1, ETV6, FOXP1, JAK2, KMT2D, MAP3K1, MPL, NF1, NOTCH1, NOTCH2, It may include one or more selected from the group consisting of PHIP, PRPF40B, RAD21, SETD2, SF3B1, TET1, TNFAIP3, TP53, U2AF1 and ZRSR2.
  • the one or more genes are selected from the group consisting of ASXL1, CBL, CHEK2, CUX1, DNMT3A, FOXP1, JAK2, KMT2D, MPL, NOTCH1, PPM1D, PRPF40B, SF3B1, TET2, TNFAIP3, TP53, U2AF1 and ZRSR2.
  • One or more selected ones may be included.
  • the one or more genes may include one or more selected from the group consisting of DNMT3A, ASXL1, TET2, PPM1D, SF3B1, ATM, and TNFAIP3.
  • the one or more genes may include any one gene selected from the group consisting of the above-mentioned genes, and in this case, the one or more genes consist of the rest of the genes other than the selected one gene. It may further include one or more selected from the group.
  • the one or more genes may include DNMT3A.
  • the one or more genes are ASXL1, TET2, PPM1D, ATM, BCL11B, CARD11, CBL, CD79B, CHEK2, CUX1, ETV6, FOXP1, JAK2, KMT2D, MAP3K1, MPL, NF1, NOTCH1, NOTCH2, PHIP, PRPF40B, It may further include one or more selected from the group consisting of RAD21, SETD2, SF3B1, TET1, TNFAIP3, TP53, U2AF1 and ZRSR2.
  • the at least one gene is selected from the group consisting of ASXL1, CBL, CHEK2, CUX1, FOXP1, JAK2, KMT2D, MPL, NOTCH1, PPM1D, PRPF40B, SF3B1, TET2, TNFAIP3, TP53, U2AF1 and ZRSR2 Add one or more can be included with
  • the one or more genes may further include one or more selected from the group consisting of ASXL1, TET2, PPM1D, SF3B1, ATM, and TNFAIP3.
  • the presence or absence of clonal hematopoiesis may be determined based on the presence or absence of mutations in the one or more genes and the variant allele frequency (VAF). For example, through genetic analysis using a biological sample isolated from an individual, one or more mutations exist in one or more genes among the genes of the gene group, and the frequency of the variant allele is higher than a certain level, for example, about 1.8% or higher, about 1.8% or higher. If it is 1.9% or more, or about 2% or more, clonal hematopoiesis can be diagnosed as present.
  • VAF variant allele frequency
  • the "individual” may mean a patient being treated for lung cancer. Specifically, the subject may mean a patient with lung cancer. More specifically, the subject may mean a patient before or after undergoing tumor removal surgery. Additionally, the subject may be a patient prior to receiving adjuvant therapy.
  • the "lung cancer” refers to a tumor originating in the lung, and may include non-small cell cancer and small cell cancer such as squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.
  • the lung cancer may be non-small cell lung cancer.
  • the subject's non-small cell lung cancer may be stage I, stage II or a later stage.
  • the non-small cell lung cancer stage of the subject may be stage IA, stage IB, stage IIA, stage IIB, stage IIIA or stage IIIB, and more specifically stage IIB.
  • the prognosis of lung cancer treatment may refer to a survival prognosis according to lung cancer treatment including surgery, chemotherapy, anticancer immunotherapy, chemoradiation, or a combination of these therapies or the same in an individual.
  • the prognosis of lung cancer treatment may mean overall survival rate or recurrence-free survival rate according to adjuvant therapy performed before or after tumor removal surgery or lung cancer treatment including the same.
  • prognosis of lung cancer treatment may include overall survival rate or recurrence-free survival rate after tumor removal surgery or after application of adjuvant therapy following tumor removal surgery.
  • the prognosis of lung cancer treatment may include responsiveness to adjuvant therapy such as chemotherapy or radiation therapy after surgery in an individual receiving treatment for lung cancer, survival prognosis, or both thereof.
  • Anticancer chemotherapy may refer to treatment using an anticancer agent.
  • Prognosis may mean, for example, responsiveness to anticancer drugs and/or survival prognosis in lung cancer patients administered with anticancer drugs including platinum-based drugs, taxane-based drugs, vinca alkaloid-based drugs, and anti-metabolites.
  • surgery and adjuvant therapy are performed, and even among patients with similar clinical characteristics or similar stages, the response to each adjuvant therapy varies, and survival prognosis may also show significant differences.
  • a significant difference according to the presence of CH in patient mortality was not lung cancer mortality but non-lung cancer mortality. and mortality of unknown cause, and these significant differences suggest that in patients with CH, several adverse outcomes associated with CH (e.g., cardiopulmonary disease, sepsis, stroke, etc.) may be amplified by CTx or RTx, eventually affecting survival. support that there is Therefore, the presence or absence of CH in a subject undergoing lung cancer treatment enables the selection of a more appropriate adjuvant therapy.
  • adverse outcomes associated with CH e.g., cardiopulmonary disease, sepsis, stroke, etc.
  • anti-inflammatory drugs eg, cannabis
  • conventional adjuvant anticancer therapy or selected adjuvant anticancer therapy are used to improve the prognosis of lung cancer treatment.
  • Kinumab can be used.
  • the step of determining whether clonal hematopoiesis exists is before undergoing tumor removal surgery, after tumor removal surgery, before applying adjuvant therapy after tumor removal surgery, or following tumor removal surgery. This can be done after application of adjuvant therapy. For example, by confirming the presence of clonal hematopoiesis before undergoing tumor removal surgery, it is possible to determine whether chemotherapy or radiation therapy is more favorable for the patient's prognosis instead of surgical resection. As another example, after undergoing tumor removal surgery, whether or not the application of additional adjuvant therapy is favorable for the patient's prognosis can be determined according to the presence or absence of clonal hematopoiesis. As another example, after tumor removal surgery and adjuvant therapy are applied, it may be determined whether to additionally perform a complementary therapy according to the presence or absence of clonal hematopoiesis and/or the type of mutated gene.
  • Gene mutations associated with the clonal hematopoiesis include missense mutations, frameshift mutations, nonsense mutations, splice mutations, nucleotide insertions, deletions or substitutions, combinations thereof, and the like. can be in the form
  • the mutation of the DNMT3A gene may be one or more selected from the mutations listed in Table 1 below, but is not limited thereto.
  • the mutation of the TET2 gene may be one or more selected from the mutations listed in Table 2 below, but is not limited thereto.
  • Mutations of the ASXL1 gene may be one or more selected from among the mutations listed in Table 3 below, but are not limited thereto.
  • the mutation of the PPM1D gene may be one or more selected from the mutations listed in Table 4 below, but is not limited thereto.
  • the mutation at position 5073770 of the JAK2 gene may be a missense mutation in which base G at position 1849 is substituted with T.
  • the method of the present invention when it is confirmed that the mutation exists through genetic analysis of a biological sample isolated from the individual, compared to the case where the mutation does not exist, the treatment of lung cancer of the individual It may further include determining that the prognosis is indicative of poor prognosis.
  • the genetic analysis can be performed using Next Generation Sequencing (NGS) and PCR-based techniques such as real-time quantitative PCR, blocker PCR, digital droplet PCR (ddPCR), clamping PCR, ICE-COLD PCR, castPCR, ARMS PCR, BEAMing, etc., but are not limited thereto.
  • NGS Next Generation Sequencing
  • ddPCR digital droplet PCR
  • clamping PCR ICE-COLD PCR
  • castPCR ARMS PCR
  • BEAMing BEAMing, etc.
  • the practitioner can detect and identify the genetic mutation associated with clonal hematopoiesis using known genetic analysis techniques without limitation.
  • the genetic analysis may include next-generation genome sequencing analysis. For example, using next-generation genome sequencing analysis, whole genome sequencing, whole exome sequencing, RNA sequencing, etc. information can be analyzed.
  • compositions are compositions, kits and genetic panels
  • a composition for predicting the prognosis of lung cancer treatment in a subject comprising an agent for diagnosing clonal hematopoiesis as an active ingredient using a biological sample isolated from a subject being treated for lung cancer is provided. do.
  • the composition can be used in a method for diagnosing clonal hematopoiesis or predicting the prognosis of lung cancer treatment for predicting the prognosis of lung cancer treatment according to the present invention.
  • the agent is DNMT3A, ASXL1, TET2, PPM1D, ATM, BCL11B, CARD11, CBL, CD79B, CHEK2, CUX1, ETV6, FOXP1, JAK2, KMT2D, MAP3K1, MPL, NF1, NOTCH1, NOTCH2, PHIP, It may include an agent for detecting whether one or more mutations exist in one or more genes selected from the group consisting of PRPF40B, RAD21, SETD2, SF3B1, TET1, TNFAIP3, TP53, U2AF1 and ZRSR2.
  • the agent is one selected from the group consisting of ASXL1, CBL, CHEK2, CUX1, DNMT3A, FOXP1, JAK2, KMT2D, MPL, NOTCH1, PPM1D, PRPF40B, SF3B1, TET2, TNFAIP3, TP53, U2AF1 and ZRSR2 It may include an agent for detecting the presence of one or more mutations in one or more genes.
  • the agent may include an agent for detecting the presence of one or more mutations in one or more genes selected from the group consisting of DNMT3A, ASXL1, TET2, PPM1D, SF3B1, ATM, and TNFAIP3.
  • the agent may include an agent for detecting whether a mutation exists in one gene selected from the gene group, wherein the agent consists of the remaining genes except for the selected one gene. It may further include an agent for detecting whether there is a mutation in one or more genes selected from the group.
  • the agent may include an agent for detecting whether there is a mutation in DNMT3A, wherein the agent is ASXL1, TET2, PPM1D, ATM, BCL11B, CARD11, CBL, CD79B, CHEK2, CUX1, ETV6, Detecting whether there is a mutation in one or more genes selected from the group consisting of FOXP1, JAK2, KMT2D, MAP3K1, MPL, NF1, NOTCH1, NOTCH2, PHIP, PRPF40B, RAD21, SETD2, SF3B1, TET1, TNFAIP3, TP53, U2AF1 and ZRSR2 or from the group consisting of ASXL1, CBL, CHEK2, CUX1, DNMT3A, FOXP1, JAK2, KMT2D, MPL, NOTCH1, PPM1D, PRPF40B, SF3B1, TET2, TNFAIP3, TP53, U2AF1 and ZRSR2 Detecting whether there is a mutation in DN
  • the agent may include, for example, an agent capable of detecting a mutant gene, an mRNA derived therefrom, or a protein encoded by the mutant gene.
  • An agent capable of detecting the expression of the gene or mRNA may be a nucleotide sequence that complementarily binds to the mutant gene or mRNA, for example, sense and antisense primers, probes, or antisense nucleic acids, but is not limited thereto.
  • the agent may specifically be an agent for detecting a gene mutation in clonal hematopoiesis, for example, a primer, a probe, or an antisense nucleic acid.
  • probe sequence information is provided in Tables 6 to 9 below.
  • probe sequence information for chromosomal sequences in which somatic sequence mutations are detected among the entire sequences of the NGS panel for DNMT3A, TET2, ASXL1, and PPM1D genes, and the mutation detection agent is not limited thereto.
  • the composition can be used for genetic analysis of a biological sample isolated from an individual, and the genetic analysis includes Next Generation Sequencing (NGS) and PCR-based techniques such as real-time quantitative PCR, blocker PCR, digital droplet PCR (ddPCR), clamping PCR, ICE-COLD PCR, castPCR, ARMS PCR, BEAMing, and the like.
  • NGS Next Generation Sequencing
  • PCR-based techniques such as real-time quantitative PCR, blocker PCR, digital droplet PCR (ddPCR), clamping PCR, ICE-COLD PCR, castPCR, ARMS PCR, BEAMing, and the like.
  • the agent capable of detecting the protein is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, a fragment (scFv) of these antibodies, or an aptamer ( aptamer), but is not limited thereto.
  • kits for predicting the prognosis of lung cancer treatment of a subject comprising the composition is provided.
  • the kit consists of one or more other component compositions, solutions or devices suitable for the assay method.
  • the kit may be a reverse transcription polymerase chain reaction (RT-PCR) kit, a DNA chip kit, an enzyme-linked immunosorbent assay (ELISA) kit, a protein chip kit, or a rapid kit.
  • RT-PCR reverse transcription polymerase chain reaction
  • ELISA enzyme-linked immunosorbent assay
  • composition included in the kit may be in the form of a panel, but is not limited thereto.
  • a panel for genetic analysis comprising the composition.
  • the genetic analysis panel may be based on next-generation sequencing (NGS), which may be used to search for genetic mutations associated with clonal hematopoiesis or to predict prognosis in association with lung cancer treatment.
  • NGS next-generation sequencing
  • the practitioner can perform analysis on the region of the gene to be sequenced and furthermore, the region to search for mutations in the gene.
  • the operator can perform simultaneous analysis on a plurality of target genes in one analysis through the gene analysis panel.
  • the gene analysis panel may include probes having complementary nucleotide sequences for each target gene, and each probe is specific for a target gene region in a biological sample isolated from an individual by hybridization. can be antagonistically combined.
  • panels for genetic analysis for detecting genetic variants associated with clonal hematopoiesis include APC, ASXL1, ASXL2, ATM, BCL11B, BCOR, BCORL1, BIRC3, BRAF, BRCC3, CARD11, CASP8, CBL, CD58, CD79B KIT , KLHL6, KMT2D, KRAS, LUC7L2, MAP3K1, MPL, MYD88, NF1, NFE2L2, NOTCH1, NOTCH2, NRAS, PDS5B, PDSS2, PHF6, PHIP, PIK3CA, PIK3R1, PPM1D, PRDM1, PRPF40B, PTEN, PTPN11, RAD21, RIT1 , RPS15, SETD2, SETDB1, SF1, SF3A1, SF3B1, SMC1A, SMC3, SRSF2, STAG1, STAG2, STAT3, SUZ12, TBL1XR1, TET1, TET2, TNFA
  • the above probes can be used to search for nucleotide sequence mutations of the gene.
  • the gene to which the probe is attached can be amplified through PCR to prepare a library for sequencing, and the presence or absence of nucleotide sequence mutation in the gene can be finally detected through next-generation sequencing analysis.
  • treatment of lung cancer comprising the step of determining whether clonal hematopoiesis exists in a subject through genetic analysis of a biological sample isolated from the subject prior to administration of a therapeutic agent for lung cancer treatment.
  • a method or method of providing information for treatment of lung cancer is provided. As described above, the presence or absence of clonal hematopoiesis in lung cancer patients is closely related to the prognosis of lung cancer treatment. can be determined, thereby increasing the survival rate of lung cancer patients.
  • the one or more genes are selected from the group consisting of ASXL1, CBL, CHEK2, CUX1, DNMT3A, FOXP1, JAK2, KMT2D, MPL, NOTCH1, PPM1D, PRPF40B, SF3B1, TET2, TNFAIP3, TP53, U2AF1 and ZRSR2 may include one or more.
  • the one or more genes may include one or more selected from the group consisting of DNMT3A, ASXL1, TET2, PPM1D, SF3B1, ATM, and TNFAIP3.
  • the one or more genes may include any one gene selected from the group consisting of the above-mentioned genes, and in this case, the one or more genes consist of the rest of the genes other than the selected one gene. It may further include one or more selected from the group.
  • the presence or absence of clonal hematopoiesis may be determined based on the presence or absence of a mutation in the one or more genes and the variant allele frequency (VAF). For example, through genetic analysis using a biological sample isolated from an individual, one or more mutations exist in one or more genes among the genes of the gene group, and the frequency of the variant allele is higher than a certain level, for example, about 1.8% or higher, about 1.8% or higher. If it is 1.9% or more, or about 2% or more, it can be classified as an individual with clonal hematopoiesis.
  • VAF variant allele frequency
  • the step of administering a lung cancer treatment may be further included.
  • a step of determining whether to administer a lung cancer treatment may be further included. For example, when it is determined that clonal hematopoiesis exists in the subject, it may be determined not to administer the lung cancer treatment or to administer the lung cancer treatment.
  • the step of determining whether to administer the lung cancer treatment is a single CH mutation in a significant blood cell count abnormality, high VAF (> 10%), multiple CH with the presence or absence of clonal hematopoiesis (CH) Mutations, TP53 and/or PPM1D variants, DNMT3A variants, IDH1/2 hotspot mutations, and the like can be comprehensively considered.
  • the stage of lung cancer, the patient's age, medical history, and the type and number of current accompanying diseases may be additionally considered.
  • a step of administering a lung cancer treatment may be further included.
  • a lung cancer treatment that has relatively less effect on clonal hematopoiesis or has a lower probability of amplifying adverse outcomes associated with clonal hematopoiesis. administration can be selected.
  • the therapeutic agent for treating lung cancer includes a drug candidate for clinical trials.
  • the lung cancer treatment method according to the present invention can be applied to clinical trials for lung cancer therapeutics.
  • the method may further include administering a drug candidate when it is determined that the subject does not have clonal hematopoiesis.
  • the method may further include administering a drug candidate when it is determined that the subject has clonal hematopoiesis.
  • clonal hematopoiesis occurs in the individual through genetic analysis of a biological sample isolated from an individual who has participated or is scheduled to participate in a clinical trial for a lung cancer treatment. It may include a step of confirming whether or not it is present, and by selecting a population in which clonal hematopoiesis exists through this confirmation step, it is possible to increase the probability of success in a clinical trial for a lung cancer treatment.
  • the present invention can increase the probability of success of a clinical trial by selecting a clinical trial patient group according to the presence or absence of clonal hematopoiesis, which negatively affects the prognosis of lung cancer treatment.
  • the presence of clonal hematopoiesis in the subject may indicate that the safety or effectiveness of a lung cancer treatment is underestimated compared to the case where clonal hematopoiesis is not present.
  • the subject may be a subject who has or is currently conducting a clinical trial for a lung cancer treatment.
  • evaluation of safety, efficacy, etc. for a lung cancer therapeutic agent confirms the presence or absence of clonal hematopoiesis in an individual to exclude a population in which clonal hematopoiesis exists, or to exclude a population in which clonal hematopoiesis exists and clonal hematopoiesis. Hematopoiesis can be differentiated and progressed in non-existent populations.
  • the subject may be an individual scheduled to conduct a clinical trial for a lung cancer treatment or a lung cancer patient registered as a clinical trial candidate.
  • a clinical trial candidate For example, by confirming the presence or absence of clonal hematopoiesis in the process of selecting patients (individuals) for clinical trials of lung cancer therapeutics, individuals with clonal hematopoiesis are excluded from clinical trials or populations with clonal hematopoiesis are excluded.
  • a clinical trial can be conducted by separately selecting a population in which hyperclonal hematopoiesis does not exist.
  • the drug candidate has a relatively greater effect on clonal hematopoiesis.
  • Substances that are less likely to amplify adverse outcomes associated with small or clonal hematopoiesis can be chosen and administered.
  • treatment efficacy and safety for lung cancer as well as effects on clonal hematopoiesis may be evaluated.
  • the following example describes the clinical impact of preoperative clonal hematopoiesis on the survival outcome of lung cancer patients, particularly non-small cell lung cancer (NSCLC) patients who received adjuvant therapy following surgical resection in a large single-center serial surgery cohort. -scale single center consecutive surgical cohort).
  • a propensity score matching (PSM) technique was used to rule out the possibility of selection bias according to adjuvant therapy and CH status.
  • CCTx adjuvant chemotherapy
  • CRTx chemoradiation therapy
  • Targeted NGS was performed with a custom panel comprising the following 89 genes using blood-derived DNA collected from patients enrolled in this study (Table 10).
  • Sequencing libraries were prepared according to the SureSelect XT HS Target Enrichment System (Agilent, Santa Clara, CA) protocol. Libraries were sequenced on an Illumina NovaSeq6000 platform (Illumina, San Diego, CA) using 150 bp paired-ends according to the manufacturer's protocol. The average coverage depth of Analysis ready BAM was over 800 times.
  • CT computed tomography
  • PET positron emission tomography
  • EBUS bronchoscopy ultrasonography
  • EUS endoscopic ultrasonography
  • a mediastinal LN biopsy was performed using Treatment plans for biopsy-proven N2 disease were determined by a multidisciplinary team including medical oncologists, radiologists, and thoracic surgeons. Patients in the study sample were retrospectively staged according to the American Joint Committee on Cancer (AJCC) 8th edition (Detterbeck FC, Boffa DJ, Kim AW, et al: The Eighth Edition Lung Cancer Stage Classification. Chest 151 :193-203, 2017]).
  • AJCC American Joint Committee on Cancer
  • adjuvant CTx was recommended for all stage II and III patients, except when the patient was >75 years of age or in poor physical condition.
  • Systemic CTx with platinum-based therapy was recommended for a total of 4 cycles of treatment for 4 to 6 weeks postoperatively.
  • tyrosine kinase inhibitors have been primarily used when relapsed after first-line adjuvant CTx.
  • RTx adjuvant radiation therapy
  • adjuvant RTx was omitted for a significant number of patients with single N2 nodal metastases.
  • the primary endpoint was survival according to the presence of CH in patients receiving adjuvant therapy for stage IIB or stage III NSCLC, and stage IIB patients according to the presence of CH and adjuvant therapy. survival outcomes were included as secondary end points (FIG. 1).
  • 89 genes frequently detected in CH were selected and examined (see Table 10 for a list of genes), and a variant allele frequency (VAF) of 2% or more was defined as CH positive.
  • VAF variant allele frequency
  • PD potential driver
  • OS Overall survival
  • RFS Recurrence-free survival
  • Continuous variables were expressed as mean and standard deviation, and categorical variables as counts and percentages.
  • the normality of individual parameter distributions was evaluated with the Shapiro-Wilk test. Student's t- test or Wilcoxon rank-sum test was used to compare two groups in terms of continuous variables, and chi-square test or Fisher's exact test was applied for categorical variables.
  • PMM propensity score matching
  • McNemar's test and paired-sample t-test were used to analyze propensity score matching pairs.
  • OS and RFS results were defined using Kaplan-Meier curves. Differences in survival rates were analyzed using the log-rank test. Since the two causes of death were mutually exclusive, significant differences in cumulative incidence function values between subgroups were assessed using the Gray test.
  • a Cox proportional hazards model was used for univariate and multivariate analysis to determine the clinical impact of CH on survival outcomes.
  • a stepwise selection was used (refers to Table 17 in Example 6.3 below).
  • the proportional hazards assumption for the Cox regression model was tested with Schoenfeld residuals.
  • PSM was applied to adjust for possible selection bias derived from a retrospective nonrandomized cohort to generate two groups (CH-positive and CH-negative) with similar characteristics.
  • a total of 12 variables (related to Table 14 in Example 6.2 below) were used to balance the clinical characteristics of the two groups.
  • pairs of observations with equivalent propensity scores were selected with nearest-neighbor matching and a caliper width of standard deviation 0.25.
  • CH-negative patients were randomly matched with CH-positive patients in a 2:1 ratio.
  • Balance between groups was assessed using standardized mean differences (SMDs). An absolute standardized difference of 0.1 or less was considered to represent an ideal balance, and an absolute standardized difference of 0.2 or less was considered to represent an acceptable balance.
  • SMDs standardized mean differences
  • the present inventors investigated the prevalence and characteristics of clonal hematopoiesis (CH) in patients with advanced non-small cell lung cancer (NSCLC). In addition, we evaluated the clinical impact of preoperative CH on survival outcomes in all patients and in patients after PSM.
  • CH clonal hematopoiesis
  • CH is a common phenomenon associated with aging and is closely related to subsequent hematological malignancies, cardiovascular disease and poor prognosis in patients with advanced solid tumors. Cancer patients have higher CH rates than healthy individuals, and CH is associated with shorter patient survival. This is presumably due to a high genetic predisposition to malignancies, prolonged exposure to carcinogenic environments and cancer-related therapies using genotoxic therapies.
  • CH is thought to be highly relevant to CTx and RTx, meaning that local and systemic therapies can promote clonal outgrowth of hematopoietic stem cells (HSCs).
  • HSCs hematopoietic stem cells
  • cytotoxic chemotherapeutic agents including platinum-based compounds, such as cisplatin and the like, target the organ of DNA replication.
  • Conventional chemotherapy is designed to kill rapidly dividing cells, causing severe DNA damage and killing the cells.
  • mutations in cancer-related genes such as TP53, PPM1D, and CHEK2 impair the cell death process that should be normally activated by DNA damage, so that hematopoietic stem cells (HSCs) with damaged DNA continue to survive despite the action of cytotoxic drugs. make it possible Therefore, cancer-related therapies are thought to influence the evolutionary trajectory of emerging CH clones.
  • the present invention when it is confirmed that there is a mutation in a gene related to clonal hematopoiesis (CH) of an individual, it is possible to predict the prognosis according to the treatment of lung cancer, particularly non-small cell lung cancer, of the individual.
  • the present invention can provide useful information for determining the application of adjuvant therapy following surgical resection in relation to lung cancer treatment, information useful for determining whether to administer a therapeutic agent for lung cancer treatment, and the like, and furthermore, lung cancer It is expected to have great industrial value as it can provide useful information for evaluating the efficacy and safety of drug candidates for patients in clinical trials of drug candidates for treatment.

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Abstract

La présente invention concerne un biomarqueur pour le pronostic du traitement du cancer pulmonaire, en particulier du cancer pulmonaire non à petites cellules, et une utilisation de celui-ci. Selon la présente invention, lorsqu'il est confirmé qu'une mutation existe dans un gène spécifique d'un sujet, on peut établir un pronostic du traitement du cancer pulmonaire, particulièrement du cancer pulmonaire non à petites cellules, chez le sujet. En outre, la présente invention peut fournir des informations utiles pour déterminer si une thérapie adjuvante doit être appliquée après une résection chirurgicale dans le cadre du traitement du cancer pulmonaire.
PCT/KR2022/011222 2021-08-02 2022-07-29 Biomarqueur pour le pronostic du traitement du cancer pulmonaire et son utilisation Ceased WO2023013998A1 (fr)

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Citations (1)

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WO2016085876A1 (fr) * 2014-11-25 2016-06-02 The Broad Institute Inc. Hématopoïèse clonale

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016085876A1 (fr) * 2014-11-25 2016-06-02 The Broad Institute Inc. Hématopoïèse clonale

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"Ph.D. thesis, Ulsan University Graduate School", 13 June 2021, ULSAN UNIVERSITY GRADUATE SCHOOL, KOREA, Korea, article YOON JAE-GWANG: "Clinical significance of clonal hematopoiesis in patients with surgically resected non-small cell lung cancer", pages: 1 - 27, XP093033390 *
COOMBS CATHERINE C.; ZEHIR AHMET; DEVLIN SEAN M.; KISHTAGARI ASHWIN; SYED AIJAZUDDIN; JONSSON PHILIP; HYMAN DAVID M.; SOLIT DAVID : "Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes", CELL STEM CELL, ELSEVIER, CELL PRESS, AMSTERDAM, NL, vol. 21, no. 3, 10 August 2017 (2017-08-10), AMSTERDAM, NL , pages 374, XP085189927, ISSN: 1934-5909, DOI: 10.1016/j.stem.2017.07.010 *
RAVAZI PEDRAM, BOB T. LI, CHENLU HOU, RONGLAI SHEN, OLIVER VENN, RAYMOND S. LIM: "Cell-free DNA (cfDNA) mutations from clonal hematopoiesis: implications for interpretation of liquid biopsy tests.", JOURNAL OF CLINICAL ONCOLOGY, AMERICAN SOCIETY OF CLINICAL ONCOLOGY, US, vol. 1, 20 May 2017 (2017-05-20), US , pages 11526, XP093033340, ISSN: 0732-183X *
RICCIUTI BIAGIO, JOAO VICTOR MACHADO ALESSI, YVONNE Y. LI, MARISSA N. LAWRENCE, HERSH GUPTA, MIZUKI NISHINO: "DNMT3A mutation to identify a subset of non-small cell lung cancers with increased sensitivity to PD-(L) 1 blockade.", JOURNAL OF CLINICAL ONCOLOGY, AMERICAN SOCIETY OF CLINICAL ONCOLOGY, US, vol. 1, 20 May 2021 (2021-05-20), US , pages 9113, XP093033326, ISSN: 0732-183X *
YAUNG STEPHANIE, FREDERIKE FUHLBRÜCK, JOHNNY WU, FERGAL CASEY, MAUREEN PETERSON, WEI ZOU,: "Evaluation of clonal hematopoiesis in late stage NSCLC using a next-generation sequencing panel targeting cancer genes", JOURNAL OF CLINICAL ONCOLOGY, AMERICAN SOCIETY OF CLINICAL ONCOLOGY, US, vol. 37, no. 15 suppl., 20 May 2019 (2019-05-20), US , pages 9050, XP093033344, ISSN: 0732-183X *

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