WO2023178152A1 - Procédés améliorés de prédiction de réponse à des thérapies de blocage de point de contrôle immunitaire et leurs utilisations - Google Patents
Procédés améliorés de prédiction de réponse à des thérapies de blocage de point de contrôle immunitaire et leurs utilisations Download PDFInfo
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Classifications
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- G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
- G16H50/30—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for calculating health indices; for individual health risk assessment
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- 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
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- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B25/00—ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression
- G16B25/10—Gene or protein expression profiling; Expression-ratio estimation or normalisation
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- 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
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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
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- 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
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Definitions
- Program 2 is entitled “150-33-2_bipartite_helper_functions.txt” and 8,485 bytes in size.
- Program 3 is entitled “150-33- 3_bipartite_matching.txt” and 13,493 bytes in size.
- Program 4 is entitled “150-33- 4_ddr_data_object.txt” and 6,623 bytes in size.
- Program 5 is entitled “150-33-5_file_locations.txt” and 1,649 bytes in size.
- Program 6 is entitled “150-33-6_load_clinical_datasets.txt” and 39,528 bytes in size.
- Program 7 is entitled “150-33-7_load_pmec.txt” and 11,478 bytes in size.
- Program 8 is entitled “150-33-8_load_tcga_dataset.txt” and 19,905 bytes in size.
- Program 9 is entitled “150- 33-9_name_matching_scripts.txt” and 1,375 bytes in size.
- Supplemental Table 1 is entitled 150-33- PCT_SUPP_TABLE_1 and is 1,679,792 bytes in size.
- Supplemental Table 2 is entitled 150-33- PCT_SUPP_TABLE_2 and is 7,058,273 bytes in size. They are hereby incorporated by reference in their entireties. 1.
- the present disclosure provides an improved method of selecting patients for immune checkpoint blockade (ICB) treatment that complements existing methods of measuring total mutational burden (TMB) of a particular cancer in a subject.
- TMB total mutational burden
- the “background” description provided herein is for the purpose of generally presenting the context of the disclosure. Work of the presently named inventors, to the extent it is described in this background section, as well as aspects of the description which may not otherwise qualify as prior art at the time of filing, are neither expressly nor impliedly admitted as prior art against the present disclosure.
- Immune checkpoint blockade (ICB) has achieved remarkable success in many solid tumors.
- TMB tumor mutational burden
- RNA expression signatures i.e. a T cell inflamed gene expression profile
- TMB represents the balance between a tumor's exposure to a mutagenic process (i.e. UV radiation, carcinogen, etc.) and the integrity of the cellular DNA Damage Repair (DDR) pathways.
- a mutagenic process i.e. UV radiation, carcinogen, etc.
- DDR DNA Damage Repair
- Bipartite Graph-Based Expected TMB Score (BiG-BETS), that resolves the TMB Paradox, accurately defines genes associated with elevated TMB, and remarkably delineates a cohort of subjects (TMB-High, Low BiG-BETS DDR mutant) with high predictive power for ICB response and prolonged overall survival.
- the present disclosure provides a method for predicting response to immune checkpoint blockade (ICB) therapy or overall survival for a subject with cancer, comprising independently measuring or obtaining (i) a tumor mutational burden (TMB) level and (ii) defects in nucleic acids encoding DNA damage repair (DDR) genes, or their expression products, for at least ten biomarkers selected from the group consisting of APEX1, APEX2, ATM, ATR, ATRIP, BLM, BRCA1, BRCA2, BRIP1, CHEK2, ERCC1, ERCC2, EXO1, FANCB, FANCD2, FANCL, FANCM, MUS81, NHEJ1, POLB, PRKDC, RAD51, RAD52, RBBP8, TDP1, TP53BP1, TREX1, UBE2T, XPA, XRCC3, and XRCC5 in a sample from the subject, normalized against a reference set of nucleic acids encoding genes, or their expression products, in the sample, where
- a method to select a subject with cancer for immune blockade therapy comprises independently measuring or obtaining both (i) a tumor mutational burden (TMB) level and (ii) defects in DNA Damage Repair (DDR) genes or their expression products in a sample from the subject; calculating a Bipartite Graph-Based Expected TMB Score (BiG-BETS) to determine which DDR genes or expression products are associated with elevated TMB; if the subject has a high BiG-BETS determining that the defect in the DDR genes or their expression products do not add to the TMB level over measurement of TMB levels alone; and using the TMB levels alone to select a subject for ICB.
- ICB immune blockade therapy
- the DDR genes or their expression products may be at least ten biomarkers selected from the group consisting of BARD1, CHEK1, CUL5, EME1, ERCC4, ERCC5, ERCC6, FANCA, FANCC, FANCI, FEN1, GEN1, LIG4, MDC1, MLH1, MLH3, MRE11, MSH2, MSH3, MSH6, NBN, PALB2, PARP1, PMS1, PMS2, POLE, POLE3, POLL, POLM, RAD50, RNMT, SEM1, SLX1A, TDG, TOP3A, TOPBP1, UNG, XPC, XRCC2, XRCC4, and XRCC6.
- biomarkers selected from the group consisting of BARD1, CHEK1, CUL5, EME1, ERCC4, ERCC5, ERCC6, FANCA, FANCC, FANCI, FEN1, GEN1, LIG4, MDC1, MLH1, MLH3, MRE11, MSH2, MSH3, MSH6,
- a method to select a subject with cancer for immune blockade therapy comprises independently measuring or obtaining both (i) a tumor mutational burden (TMB) level and (ii) defects in DNA Damage Repair (DDR) genes or their expression products in a sample from the subject; calculating a Bipartite Graph-Based Expected TMB Score (BiG-BETS) to determine which DDR genes or expression products are associated with elevated TMB; if the subject has a low BiG-BETS determining that the defects in the DDR genes or their expression products contribute to the likelihood of benefit from ICB over measurement of TMB levels alone; and using both the TMB levels and the defects in the DDR genes or their expression products to select a subject for ICB.
- ICB immune blockade therapy
- the DDR genes or their expression products may be at least ten biomarkers selected from the group consisting of APEX1, APEX2, ATM, ATR, ATRIP, BLM, BRCA1, BRCA2, BRIP1, CHEK2, ERCC1, ERCC2, EXO1, FANCB, FANCD2, FANCL, FANCM, MUS81, NHEJ1, POLB, PRKDC, RAD51, RAD52, RBBP8, TDP1, TP53BP1, TREX1, UBE2T, XPA, XRCC3, and XRCC5.
- biomarkers selected from the group consisting of APEX1, APEX2, ATM, ATR, ATRIP, BLM, BRCA1, BRCA2, BRIP1, CHEK2, ERCC1, ERCC2, EXO1, FANCB, FANCD2, FANCL, FANCM, MUS81, NHEJ1, POLB, PRKDC, RAD51, RAD52, RBBP8, TDP1, TP53BP1, TREX1,
- the cancer may be bladder urothelial carcinoma, colon adenocarcinoma, esophageal carcinoma, invasive breast carcinoma, head and neck squamous cell carcinoma, kidney renal clear cell carcinoma, lung adenocarcinoma, melanoma, or squamous cell lung carcinoma and the defects may be mutations or copy number alterations.
- the mutations may be deletions, frameshift mutations, insertions, missense mutations, nonsense mutations, start codon loss, stop codon loss or gain, or a combination thereof.
- the detecting defects in nucleic acids encoding genes, or their expression products may comprise performing next generation sequencing (NGS), nucleic acid hybridization, quantitative RT-PCR, immunohistochemistry (IHC), immunocytochemistry (ICC), or immunofluorescence (IF).
- NGS next generation sequencing
- IHC immunohistochemistry
- ICC immunocytochemistry
- IF immunofluorescence
- the method may further comprises assessment of a medical history, a family history, a physical examination, an endoscopic examination, imaging, a biopsy result, or a combination thereof.
- the method may be used to develop a treatment strategy for the subject with cancer.
- the nucleic acids encoding genes may be isolated from a fixed, paraffin-embedded sample from the subject.
- the nucleic acids encoding genes are isolated from core biopsy tissue or fine needle aspirate cells from the subject.
- the method may further comprises treating the subject with a combination of ICB therapy and kinase inhibitor therapy.
- the disclosure provides a method for treating a subject with cancer which comprises independently measuring or obtaining a tumor mutational burden (TMB) level; and defects in nucleic acids encoding DNA damage repair (DDR) genes, or their expression products, for at least ten biomarkers selected from the group consisting of low BIG- BETS DDR genes normalized against a reference set of nucleic acids encoding genes, or their expression products, in the sample; and if the subject has a high TMB level and wild type low BIG- BETs genes, treating the subject with a combination of immune checkpoint blockcade (ICB) therapy and an inhibitor of a low BIG-BETs kinase so as to reduce the activity of the low BIG-BET kinase and thereby treat the subject
- TMB tumor mutational burden
- the low BIG-BETs kinase may be ATR, CHEK1, or WEE1.
- a kit comprising at least ten nucleic acid probes, wherein each of said probes specifically binds to one of ten distinct biomarker nucleic acids or fragments thereof selected from the group consisting of APEX1, APEX2, ATM, ATR, ATRIP, BLM, BRCA1, BRCA2, BRIP1, CHEK2, ERCC1, ERCC2, EXO1, FANCB, FANCD2, FANCL, FANCM, MUS81, NHEJ1, POLB, PRKDC, RAD51, RAD52, RBBP8, TDP1, TP53BP1, TREX1, UBE2T, XPA, XRCC3, and XRCC5.
- Fig. 1A-Fig. 1F Univariate testing inappropriately associates most genes with elevated TMB and recasting samples and mutations as a bipartite network overcomes this limitation.
- Fig.1A Distribution of Mann-Whitney U test p-values (with multiple test correction) on reversed log scale across all genes in Pan-TCGA dataset (light gray) vs DDR genes only (dark gray). For each gene, the MWU test compares distribution of TMB values for samples with a mutation in the gene vs all samples in the cohort. Right of dashed black line represents p ⁇ 0.05.
- FIG.1B Percentage of genes in which mutations are significantly associated with elevated TMB by the MWU test (with FDR correction) broken down by DDR genes (dark gray) and non-DDR genes (light gray)
- FIG.1C- Fig.1D Distribution of mean TMB values for mutated sample set for all genes (light gray) vs DDR genes (dark gray) in TCGA. Vertical dotted black line in Fig. 1D denotes the overall mean TMB for the cohort of samples.
- FIG. 1E Schematic representation of converting the mutational data in a matrix to a bipartite network.
- FIG. 1F Schematic representation of BiG-BETS network rewiring process to sample from the bipartite configuration model.
- Mann-Whitney U p-values are calculated by comparing the distribution of TMB for samples with any mutation in the genes that define a pathway (counting only once if they have multiple mutations) to the distribution of all samples, including those with mutations in the same DDR pathway.
- Fig.2B Schematic and example of the TMB paradox. Note how the addition of a single, highly mutated sample (right) only raises the average degree from 1.3 to 2 ( ⁇ 50% increase), while raising the average gene’s neighbor’s degree from 1.25 to 3 (140% increase). This effect is even larger network with a heavy tailed degree distribution.
- Fig.3A-Fig.3C Distributions of p-values for the BiG-BETS permutation test applied to all 18,000 genes in the TCGA dataset, split by non-DDR genes (light gray) vs DDR genes (dark gray).
- Fig. 3B Expected distribution of TMB values (shown in gray) for samples with mutation in ATR (top) and CHEK1 (bottom). Observed distribution of TMB for mutated tumors is shown by lighter gray curve. Distribution of means across the 400 samples from the network model shown in figure inset with dashed vertical line denoting observed mean TMB.
- Fig. 3C Comparison of z-scores derived from Samstein et al.
- Fig. 4A-Fig. 4D A networks-based model and permutation test (BiG-BETS) are superior to univariate model.
- Fig. 4A Percentage of genes that are significant (with multiple test correction) using MWU test (left two bars) and significant by the networks-based test (right two bars). Differences between DDR vs non-DDR genes computed assessed with Chi-squared test with p-value shown above the corresponding bars.
- Fig. 4B (Distribution of BiG-BETS z-scores for the DDR genes.
- Fig. 5A-Fig. 5C Fig. 5A Schematic depicting criteria for filtering variants in the TCGA cohort used to calculate the BiG-BET scores. Variants were filtered on basis of impact as defined by the sequence ontology and polphen status (see Methods for full details).
- Fig. 5B Comparison of BiG-BET scores obtained from TCGA cohort based on High Consequence mutations only (x-axis) and Moderate+High Consequences (y-axis). From left to right all genes (with hotspot genes shown in gray), DDR genes only, and the DDR pathways.
- FIG. 6B Percentage of patients that have complete or partial response in TMB-H vs TMB-L for IMvigor210. Significance assessed using Chi-square test.
- Fig. 6C Kaplan-Meier curves depicting overall survival (OS) in the IMvigor210 (left) and Samstein (right) cohorts broken down by TMB-H (light gray-lines) vs TMB-L (dark gray-lines) and into samples with a mutation in High-BiG-BETS DDR gene (bold lines) and High-BiG-BETS DDR WT tumors (dotted lines).
- FIG. 6D Percentage of patients that have complete or partial response in High BiG-BETS DDR mutant vs wild type in TMB-H and TMB-L tumors from IMvigor210. Significance assessed using Chi-square test.
- Fig. 7A-Fig. 7I TMB high tumors with mutation in a Low BiG-BETS DDR gene have improved survival and response.
- FIG.7A Kaplan-Meier curves depicting overall survival (OS) in the IMvigor210 cohort broken down by TMB-High (light gray-lines) vs TMB-Low (dark gray-lines) and into samples with a mutation in Low BiG-BETS DDR genes (bold lines) and Low BiG-BETS DDR WT tumors (dotted lines).
- Table underneath shows forest plot of coefficients for CPH model jointly testing TMB (as continuous variable), mutation in Low BiG-BETS DDR genes, as well as an interaction term between the two variables (denoted by Low BiG-BETS; TMB-H).
- TMB TMB-High vs TMB-Low
- WT Low BiG-BETS DDR gene mutation or not
- the number of patients who were responders (CR/PR) in each category from left to right is 12, 1, 28, and 10 respectively.
- CR/PR responders
- Fig. 7D KM curves depicting OS in the Weir metadataset (see Methods for full description) broken down along the same lines as (A) and (C) with corresponding coefficients in CPH model below.
- Patient counts for each category in TMB-H_MUT, TMB-H_WT, TMB-L_MUT, and TMB-L_WT were 60, 117, 33, and 201 respectively.
- FIG.7E Response rates by Low BiG-BETS DDR mutations in the Weir Metadataset.
- Fig. 7G- Fig. 7I KM curves depicting OS in a combined dataset that includes IMVigor210, Samstein et al., and Weir metadataset split out by tumor type including (Fig. 7G) bladder cancer, (Fig.7H) non-small cell lung cancer, and (Fig.7I) melanoma.
- FIG. 7A bladder cancer
- FIG.7H non-small cell lung cancer
- Fig.7I melanoma.
- KM Kaplan-Meier (KM) curves depicting overall survival (OS) in the Samstein cohort broken down by TMB-High (light gray-lines) vs TMB-Low (dark gray-lines) and into samples with a mutation in Low BiG-BETS DDR genes (bold lines) using only 17 DDR genes that overlap with IMvigor210 mutations (see Fig.5C) (bold lines) vs those that are Low BiG- BETS DDR WT (dashed line).
- Fig. 9A-Fig. 9D Mutation of Low BiG-BETS DDR genes in TMB High tumors is associated with elevated STING and IRF3 gene signatures.
- FIG. 9A- Fig. 9D Box plots of indicated gene signatures in IMVigor210 patients stratified by TMB (TMB-High vs TMB-Low) and Low BIG-BETS DDR gene mutation or not (WT). For each signature, each sample is assigned a z-score based on the average expression level of all genes in the signature compared to the average across all samples (See Methods). Significance calculated using the Mann-Whitney U test.
- Fig.10A-Fig.10D Box plots of indicated gene signatures in TCGA tumors subsetted to match Samstein (see Methods) stratified by TMB (TMB-High vs TMB-Low) and Low BIG-BETS DDR gene mutation or not (WT). For each signature, each sample is assigned a z-score based on the average expression level of all genes in the signature compared to the average across all samples (See Methods). Significance calculated using the Mann-Whitney U test. (Fig.10E) Proportion of genes in each DDR pathway that are categorized as High and Low BIG-BETS genes. [0035] Fig.11A and Fig. 11B shows a graphical abstract of the disclosure.
- Fig.11A Genes and samples are represented as a bipartite network.
- a Bipartite Graph-Based Expected TMB (Big- BET) score is determined by a random rewiring of the bipartite network.
- Fig.11B for subjects with mutations in BiG-BETs high genes, their ICB response is driven by their TMB levels. Subjects with mutations in the BiG-BETs low genes and high TMB, are more likely to respond to ICB and show increased overall survival (OS). 5.
- DETAILED DESCRIPTION OF THE DISCLOSURE [0036] Immune checkpoint blockade (ICB) has had remarkable success for treatment of solid tumors.
- TMB tumor mutational burden
- DDR DNA Damage Repair
- Examples of monoclonal antibody kinase inhibitors are trastuzumab (Herceptin®), an inhibitor of ERB-B2 and approved for breast cancer or bevacizumab (Avastin®), an inhibitor of vascular endothelial growth factor (VEGF) approved for colorectal cancer.
- Other examples of drugs approved with a companion diagnostic include drugs approved for BRCA1/2 mutations, KRAS mutations and cKIT expression. Table 1 lists a number of approved drugs including a number of kinase inhibitors. See, Janne et al., 2009 Nat. Rev. Drug Disc.8709-723; Levitzki and Klein, 2010 Mol. Aspects Med.31, 287-329; and Mellor et al.2011 Tox. Sci.120(1) 14-32; and the package inserts for the specific drugs. [0039] TABLE 1
- ALL acute lymphoblastic leukemia
- AML acute myeloid leukemia
- BrCA breast cancer
- BCC basal cell carcinoma
- CML chronic myeloid leukemia
- CMML chronic myelomonocytic leukemia
- CRC colorectal cancer
- CSCC cutaneous squamous cell carcinoma
- GIST gastrointestinal stromal tumor
- HCC hepatocellular carcinoma
- HNSCC head and neck squamous cell carcinoma
- MCC Merkle cell carcinoma
- MDS/MPD myelodysplastic syndrome/myeloproliferative disease
- NSCLC non-small cell lung cancer
- OvCA ovarian cancer
- RCC renal cell carcinoma
- STS soft tissue sarcoma
- TNBC triple negative breast cancer
- UC urothelial carcinoma.
- trastuzumab (Herceptin®) is approved for breast cancer over expressing ERB-B2 and cetuximab (Erbitux®) for patients with wild-type KRAS.
- trastuzumab (Herceptin®) is approved for breast cancer over expressing ERB-B2 and cetuximab (Erbitux®) for patients with wild-type KRAS.
- trastuzumab (Herceptin®) is approved for breast cancer over expressing ERB-B2 and cetuximab (Erbitux®) for patients with wild-type KRAS.
- kinase inhibitor approved for use with a diagnostic is crizotinib (Xalkori®) approved with a fluorescent in situ hybridization (FISH) test for ALK rearrangements (Vysis LSI ALK Dual Color, Break Apart Rearrangement Probe; Abbott Molecular, Abbott Park, IL).
- FISH fluorescent in situ hybridization
- Vemurafenib (Zelboraf®) is approved for use in patients with BRAF V600E mutation (Cobas 4800 BRAF V600 Mutation Test, Roche Molecular Diagnostics, Pleasanton, CA). Chapman et al., 2011 NEJM 3642507- 2516.
- Non-limiting examples for bladder cancer include erdafitinib (BALVERSATM) or pembrolizumab (KEYTRUDA®) in Table 1, additional therapies include avelumab (BAVENCIO®), durvalumab (IMFINZITM), or nivolumab (OPDIVO®).
- Non-limiting examples for BrCA include abemaciclib (VERZENIO®), ado- trastuzumab emtansine (KADCYLA®), alpelisib (PIQRAY®), atezolizumab (TECENTRIQ®), Everolimus (AFINITOR®), lapatinib (TYKERB®), olaparib (LYNPARZA®), palbociclib (IBRANCE®), pertuzumab (PERJETA®), ribociclib (KISQALI®) or trastuzumab (HERCEPTIN®), or trastuzumab (HERCEPTIN HYLECTA TM ) in Table 1, additional therapies include anastrozole (ARIMIDEX®), exemestane (AROMASIN®), fulvestrant (FASLODEX®), letrozole (FEMARA®), neratinib (NERLYNXTM), tamoxifen (SOLTAMOX®), or toremifene
- Non-limiting examples for CRC include bevacizumab (AVASTIN®), Cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ramucirumab (CYRAMZA®), or regorafenib (STIVARGA®) in Table 1, additional therapies include ipilimumab (YERVOY®), nivolumab (OPDIVO®), or ziv-aflibercept (ZALTRAP®).
- HCC include pembrolizumab (KEYTRUDA®), ramucirumab (CYRAMZA®), regorafenib (STIVARGA®), or sorafenib (NEXAVAR®) in Table 1, additional therapies include cabozantinib (CABOMETYXTM), lenvatinib (LENVIMA®), or nivolumab (OPDIVO®).
- kidney cancer examples include axitinib (INLYTA®), bevacizumab (AVASTIN®), cabozantinib (CABOMETYX®), Everolimus (AFINITOR®), pazopanib (VOTRIENT®), pembrolizumab (KEYTRUDA®), sorafenib (NEXAVAR®), sunitinib (SUTENT®), temsirolimus (TORISEL®) in Table 1, additional therapies include avelumab (BAVENCIO®), ipilimumab (YERVOY®), lenvatinib mesylate (LENVIMA®), or nivolumab (OPDIVO®).
- Non- limiting examples for leukemia include dasatinib (SPRYCEL®), enasidenib (IDHIFA®), gilteritinib (XOSPATA®), imatinib (GLEEVEC®), ivosidenib (TIBSOVO®), midostaurin (RYDAPT®), nilotinib (TASIGNA®), or venetoclax (VENCLEXTA®) in Table 1, additional therapies include alemtuzumab (CAMPATH®), blinatumomab (BLINCYTO®), bosutinib (BOSULIF®), duvelisib (COPIKTRATM), gemtuzumab ozogamicin (MYLOTARGTM), glasdegib (DAURISMOTM), ibrutinib (IMBRUVICA®), idelalisib (ZYDELIG®), inotuzumab ozogamicin (BESPONSA®), moxe
- Non-limiting examples for lung cancers include in Table 1 afatinib (GILORAF®), alectinib (ALECENSA®), atezolizumab (TECENTRIQ®), bevacizumab (AVASTIN®), ceritinib (LDK378/ZYKADIA®), crizotinib (XALKORI®), dabrafenib (TAFINAR®), dacomitinib (VIZIMPRO®), erlotinib (TARCEVA®), gefitinib (IRESSA®), osimertinib (TAGRISSO®), pembrolizumab (KEYTRUDA®), pemetrexed (ALIMTA®), ramucirumab (CYRAMZA®), trametinib (MEKANIST®), additional therapies include brigatinib (ALUNBRIGTM), durvalumab (IMFINZITM), lorlatinib (LORBRENA®),
- Non-limiting examples for lymphoma include acalabrutinib (CALQUENCE®), pembrolizumab (KEYTRUDA®), venetoclax (VENCLEXTA®) in Table 1, additional therapies include axicabtagene ciloleucel (YESCARTATM), belinostat (BELEODAQ®), bexarotene (TARGRETIN®), bortezomib (VELCADE®), brentuximab vedotin (ADCETRIS®), copanlisib (ALIQOPATM), denileukin diftitox (ONTAK®), duvelisib (COPIKTRATM), Ibritumomab tiuxetan (ZEVALIN®), ibrutinib (IMBRUVICA®), idelalisib (ZYDELIG®), mogamulizumab-kpkc (POTELIGEO®), nivolumab (
- Non-limiting examples for melanoma include alitretinoin (PANRETIN®), binimetinib (MEKTOVI®), cobimetinib (COTELLIC®), dabrafenib (TAFINAR®), encorafenib (BRAFTOVITM), pembrolizumab (KEYTRUDA®), trametinib (MEKANIST®), or vemurafenib (ZELBORAF®) in Table 1, additional therapies include avelumab (BAVENCIO®), cemiplimab- rwlc (LIBTAYO®), ipilimumab (YERVOY®), nivolumab (OPDIVO®), sonidegib (ODOMZO®), or vismodegib (ERIVEDGE®).
- PANRETIN® alitretinoin
- MEKTOVI® binimetinib
- COTELLIC® dabrafenib
- MM multiple myeloma
- MM multiple myeloma
- VELCADE® Bortezomib
- KYPROLIS® carfilzomib
- DARZALEXTM daratumumab
- EMPLICITITM elotuzumab
- ixazomib NINLARO®
- panobinostat FARYDAK®
- selinexor XPOVIOTM
- Non-limiting examples for prostate cancer include abiraterone acetate (ZYTIGA®) in Table 1, additional therapies include apalutamide (ERLEADATM), Cabazitaxel (JEVTANA®), darolutamide (NUBEQA®), enzalutamide (XTANDI®), radium 223 dichloride (XOFIGO®).
- ERLEADATM apalutamide
- JEVTANA® Cabazitaxel
- NUBEQA® darolutamide
- XTANDI® enzalutamide
- XOFIGO® radium 223 dichloride
- Additional drugs that may be used for cancer treatment include Denosumab (XGEVA®), Dinutuximab (UNITUXINTM), iobenguane I 131 (AZEDRA®), Lanreotide acetate (SOMATULINE® Depot), lutetium Lu 177-dotatate (LUTATHERA®), niraparib (ZEJULATM), rucaparib camsylate (RUBRACATM), ruxolitinib phosphate (JAKAFI®), Sirolimus (RAPAMUNE®), or Talazoparib (TALZENNA®).
- XGEVA® Denosumab
- Dinutuximab UNITUXINTM
- iobenguane I 131 AZEDRA®
- AZEDRA® Lanreotide acetate
- LTATHERA® Lanreotide acetate
- LUTATHERA® lutetium Lu 177-dotatate
- “about 40 [units]” may mean within ⁇ 25% of 40 (e.g., from 30 to 50), within ⁇ 20%, ⁇ 15%, ⁇ 10%, ⁇ 9%, ⁇ 8%, ⁇ 7%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, ⁇ 1%, less than ⁇ 1%, or any other value or range of values therein or there below.
- the term “about” may mean ⁇ one half a standard deviation, ⁇ one standard deviation, or ⁇ two standard deviations.
- the phrases “less than about [a value]” or “greater than about [a value]” should be understood in view of the definition of the term “about” provided herein.
- clinical signs of cancer means and includes any sign or indication of the existence of cancer in a subject, which sign or indication would be well known to the skilled artisan (e.g., oncologist, nurse practitioner).
- the clinical signs of cancer may be any symptom known to be associated with the cancer.
- Clinical signs of some cancers include, for example, chronic pain, nausea, vomiting, abnormal taste sensation, constipation, urinary symptoms (e.g., bladder spasm), respiratory symptoms, skin problems (e.g., pruritus, hair loss), or fever, among others.
- the term “reference set” may be an internal, external, or a universal reference set of nucleic acids or expression products used to calibrate a particular sample.
- an internal reference set of nucleic acids may be obtained using normal tissue or a blood sample from the subject.
- an internal reference set may based on the total RNA in the sample.
- the reference set may be a set of one or more housekeeping genes, e.g., human acidic ribosomal protein (HuPO), ⁇ -actin (BA), cyclophylin (CYC), glyceraldehyde-3- phosphate dehydrogenase (GAPDH), phosphoglycerokinase (PGK), ⁇ 2-microglobulin (B2M), ⁇ - glucuronidase (GUS), hypoxanthine phosphoribosyltransferase (HPRT), transcription factor IID TATA binding protein (TBP), transferrin receptor (TfR), human acidic ribosomal protein (HuPO), elongation factor-1- ⁇ (EF-1- ⁇ ), metastatic lymph node 51(MLN51), or ubiquitin conjugating enzyme (UbcH5B).
- HuPO human acidic ribosomal protein
- BA ⁇ -actin
- CYC cyclophylin
- GPDH glycer
- remission means and includes a period during which the symptoms of a cancer have been reduced or eliminated, as remission is ordinarily defined in the oncology art.
- “serially monitoring" levels of a biomarker in a sample refers to measuring levels of a biomarker in a sample more than once, e.g., quarterly, bimonthly, monthly, biweekly, weekly, every three days, daily, or several times per day. Serial monitoring of a level includes periodically measuring levels of biomarkers at regular intervals as deemed necessary by the skilled artisan.
- standard level refers to a baseline level of a biomarker as determined in one or more normal subjects.
- the measurement of biomarker levels may be carried out using the multiplexed copy number as described.
- "elevation" of a measured level of a biomarker relative to a standard level means that the amount or concentration of a biomarker in a sample is sufficiently greater in a subject relative to the standard to be detected by the methods described herein.
- elevation of the measured level relative to a standard level may be any statistically significant elevation which is detectable.
- Such an elevation may include, but is not limited to, about a 1%, about a 10%, about a 20%, about a 40%, about an 80%, about a 2-fold, about a 4-fold, about an 8- fold, about a 20-fold, or about a 100-fold elevation, or more, relative to the standard.
- Non-limiting examples of signaling pathway modulators or chemotherapeutic agents known in the art are 5-fluorouracil; asparaginase; bevacizumab (AVASTIN®); bleomycin; campathecins; cetuximab (ERBITUX®); crizotinib (XALKORI®); cyclophosphamide; cytarabine; dacarbazine; dactinomycin; dasatinib (SPRYCEL®); daunorubicin; DNA methyltransferase inhibitors (DNMTs) such as azacitidine (VIDAZA®) and decitabine; doxorubicin; doxorubicin; epirubicin; erbstatin; erlotinib (TARCEVA®); estramustine; etoposide; etoposide; gefitinib (IRESSA®), gemcitabine, genistein, histone acetyl transferase inhibitor
- the chemotherapeutic agent is bevacizumab (AVASTIN®), cetuximab (ERBITUX®), crizotinib (XALKORI®), dasatinib (SPRYCEL®), erlotinib (TARCEVA®), everolimus (AFINITOR®), gefitinib (IRESSA®), imatinib (GLEEVEC®), lapatinib (TYKERB®), nilotinib (TASIGNA®), panitumumab (VECTIBIX®), pazopanib (VOTRIENT®), sirolimus (RAPAMUNE®), sorafenib (NEXAVAR®), sunitinib (SUTENT®), temsirolimus (TORISEL®), trastuzumab (HERCEPTIN®), vandetanib (CAPRELSA®), or vemurafenib (ZELBORAF®).
- AVASTIN® cetuximab
- a computing device may be implemented in programmable hardware devices such as processors, digital signal processors, central processing units, field programmable gate arrays, programmable array logic, programmable logic devices, cloud processing systems, or the like.
- the computing devices may also be implemented in software for execution by various types of processors.
- An identified device may include executable code and may, for instance, comprise one or more physical or logical blocks of computer instructions, which may, for instance, be organized as an object, procedure, function, or other construct. Nevertheless, the executable of an identified device need not be physically located together but may comprise disparate instructions stored in different locations which, when joined logically together, comprise the computing device and achieve the stated purpose of the computing device.
- a computing device may be a server or other computer located within a hospital or out-patient environment and communicatively connected to other computing devices (e.g., POS equipment or computers) for managing accounting, purchase transactions, and other processes within the hospital or out-patient environment.
- a computing device may be a mobile computing device such as, for example, but not limited to, a smart phone, a cell phone, a pager, a personal digital assistant (PDA), a mobile computer with a smart phone client, or the like.
- a computing device may be any type of wearable computer, such as a computer with a head-mounted display (HMD), or a smart watch or some other wearable smart device. Some of the computer sensing may be part of the fabric of the clothes the user is wearing.
- a computing device can also include any type of conventional computer, for example, a laptop computer or a tablet computer.
- a typical mobile computing device is a wireless data access-enabled device (e.g., an iPHONE ® smart phone, a BLACKBERRY ® smart phone, a NEXUS ONETM smart phone, an iPAD ® device, smart watch, or the like) that is capable of sending and receiving data in a wireless manner using protocols like the Internet Protocol, or IP, and the wireless application protocol, or WAP.
- a wireless data access-enabled device e.g., an iPHONE ® smart phone, a BLACKBERRY ® smart phone, a NEXUS ONETM smart phone, an iPAD ® device, smart watch, or the like
- IP Internet Protocol
- WAP wireless application protocol
- Wireless data access is supported by many wireless networks, including, but not limited to, Bluetooth, Near Field Communication, CDPD, CDMA, GSM, PDC, PHS, TDMA, FLEX, ReFLEX, iDEN, TETRA, DECT, DataTAC, Mobitex, EDGE and other 2G, 3G, 4G, 5G, and LTE technologies, and it operates with many handheld device operating systems, such as PalmOS, EPOC, Windows CE, FLEXOS, OS/9, JavaOS, iOS and Android.
- these devices use graphical displays and can access the Internet (or other communications network) on so-called mini- or micro-browsers, which are web browsers with small file sizes that can accommodate the reduced memory constraints of wireless networks.
- the mobile device is a cellular telephone or smart phone or smart watch that operates over GPRS (General Packet Radio Services), which is a data technology for GSM networks or operates over Near Field Communication e.g. Bluetooth.
- GPRS General Packet Radio Services
- a given mobile device can communicate with another such device via many different types of message transfer techniques, including Bluetooth, Near Field Communication, SMS (short message service), enhanced SMS (EMS), multi-media message (MMS), email WAP, paging, or other known or later-developed wireless data formats.
- SMS short message service
- EMS enhanced SMS
- MMS multi-media message
- email WAP paging
- paging or other known or later-developed wireless data formats.
- An executable code of a computing device may be a single instruction, or many instructions, and may even be distributed over several different code segments, among different applications, and across several memory devices.
- operational data may be identified and illustrated herein within the computing device, and may be embodied in any suitable form and organized within any suitable type of data structure. The operational data may be collected as a single data set, or may be distributed over different locations including over different storage devices, and may exist, at least partially, as electronic signals on a system or network.
- the term “memory” is generally a storage device of a computing device. Examples include, but are not limited to, read-only memory (ROM) and random access memory (RAM). [0060]
- the device or system for performing one or more operations on a memory of a computing device may be a software, hardware, firmware, or combination of these.
- the device or the system is further intended to include or otherwise cover all software or computer programs capable of performing the various heretofore-disclosed determinations, calculations, or the like for the disclosed purposes.
- exemplary embodiments are intended to cover all software or computer programs capable of enabling processors to implement the disclosed processes.
- Exemplary embodiments are also intended to cover any and all currently known, related art or later developed non-transitory recording or storage mediums (such as a CD-ROM, DVD-ROM, hard drive, RAM, ROM, floppy disc, magnetic tape cassette, etc.) that record or store such software or computer programs.
- Exemplary embodiments are further intended to cover such software, computer programs, systems and/or processes provided through any other currently known, related art, or later developed medium (such as transitory mediums, carrier waves, etc.), usable for implementing the exemplary operations disclosed below.
- the disclosed computer programs can be executed in many exemplary ways, such as an application that is resident in the memory of a device or as a hosted application that is being executed on a server and communicating with the device application or browser via a number of standard protocols, such as TCP/IP, HTTP, XML, SOAP, REST, JSON and other sufficient protocols.
- the disclosed computer programs can be written in exemplary programming languages that execute from memory on the device or from a hosted server, such as BASIC, COBOL, C, C++, Java, Pascal, or scripting languages such as JavaScript, Python, Ruby, PHP, Perl, or other suitable programming languages.
- the terms “computing device” and “entities” should be broadly construed and should be understood to be interchangeable. They may include any type of computing device, for example, a server, a desktop computer, a laptop computer, a smart phone, a cell phone, a pager, a personal digital assistant (PDA, e.g., with GPRS NIC), a mobile computer with a smartphone client, or the like.
- PDA personal digital assistant
- a user interface is generally a system by which users interact with a computing device.
- a user interface can include an input for allowing users to manipulate a computing device, and can include an output for allowing the system to present information and/or data, indicate the effects of the user’s manipulation, etc.
- An example of a user interface on a computing device includes a graphical user interface (GUI) that allows users to interact with programs in more ways than typing.
- GUI graphical user interface
- a GUI typically can offer display objects, and visual indicators, as opposed to text-based interfaces, typed command labels or text navigation to represent information and actions available to a user.
- an interface can be a display window or display object, which is selectable by a user of a mobile device for interaction.
- a user interface can include an input for allowing users to manipulate a computing device, and can include an output for allowing the computing device to present information and/or data, indicate the effects of the user’s manipulation, etc.
- An example of a user interface on a computing device includes a graphical user interface (GUI) that allows users to interact with programs or applications in more ways than typing.
- GUI graphical user interface
- a GUI typically can offer display objects, and visual indicators, as opposed to text-based interfaces, typed command labels or text navigation to represent information and actions available to a user.
- a user interface can be a display window or display object, which is selectable by a user of a computing device for interaction.
- the display object can be displayed on a display screen of a computing device and can be selected by and interacted with by a user using the user interface.
- the display of the computing device can be a touch screen, which can display the display icon. The user can depress the area of the display screen where the display icon is displayed for selecting the display icon.
- the user can use any other suitable user interface of a computing device, such as a keypad, to select the display icon or display object.
- the user can use a track ball or arrow keys for moving a cursor to highlight and select the display object.
- the display object can be displayed on a display screen of a mobile device and can be selected by and interacted with by a user using the interface.
- the display of the mobile device can be a touch screen, which can display the display icon.
- the user can depress the area of the display screen at which the display icon is displayed for selecting the display icon.
- the user can use any other suitable interface of a mobile device, such as a keypad, to select the display icon or display object.
- the user can use a track ball or times program instructions thereon for causing a processor to carry out aspects of the present disclosure.
- a computer network may be any group of computing systems, devices, or equipment that are linked together. Examples include, but are not limited to, local area networks (LANs) and wide area networks (WANs).
- a network may be categorized based on its design model, topology, or architecture.
- a network may be characterized as having a hierarchical internetworking model, which divides the network into three layers: access layer, distribution layer, and core layer.
- the access layer focuses on connecting client nodes, such as workstations to the network.
- the distribution layer manages routing, filtering, and quality-of-server (QoS) policies.
- QoS quality-of-server
- the core layer can provide high-speed, highly-redundant forwarding services to move packets between distribution layer devices in different regions of the network.
- the core layer typically includes multiple routers and switches.
- the computer program product may include a computer readable storage medium (or media) having computer readable program instructions thereon for causing a processor to carry out aspects of the present subject matter.
- the computer readable storage medium can be a tangible device that can retain and store instructions for use by an instruction execution device.
- the computer readable storage medium may be, for example, but is not limited to, an electronic storage device, a magnetic storage device, an optical storage device, an electromagnetic storage device, a semiconductor storage device, or any suitable combination of the foregoing.
- a non-exhaustive list of more specific examples of the computer readable storage medium includes the following: a portable computer diskette, a hard disk, a RAM, a ROM, an erasable programmable read-only memory (EPROM or Flash memory), a static random access memory (SRAM), a portable compact disc read-only memory (CD-ROM), a digital versatile disk (DVD), a memory stick, a floppy disk, a mechanically encoded device such as punch-cards or raised structures in a groove having instructions recorded thereon, and any suitable combination of the foregoing.
- a computer readable storage medium is not to be construed as being transitory signals per se, such as radio waves or other freely propagating electromagnetic waves, electromagnetic waves propagating through a waveguide or other transmission media (e.g., light pulses passing through a fiber-optic cable), or electrical signals transmitted through a wire.
- Computer readable program instructions described herein can be downloaded to respective computing/processing devices from a computer readable storage medium or to an external computer or external storage device via a network, for example, the Internet, a local area network, a wide area network and/or a wireless network, or Near Field Communication.
- the network may comprise copper transmission cables, optical transmission fibers, wireless transmission, routers, firewalls, switches, gateway computers and/or edge servers.
- Computer readable program instructions for carrying out operations of the present subject matter may be assembler instructions, instruction-set-architecture (ISA) instructions, machine instructions, machine dependent instructions, microcode, firmware instructions, state- setting data, or either source code or object code written in any combination of one or more programming languages, including an object oriented programming language such as Java, Smalltalk, C++, Javascript or the like, and conventional procedural programming languages, such as the "C" programming language or similar programming languages.
- ISA instruction-set-architecture
- machine instructions machine dependent instructions
- microcode firmware instructions
- state- setting data or either source code or object code written in any combination of one or more programming languages, including an object oriented programming language such as Java, Smalltalk, C++, Javascript or the like, and conventional procedural programming languages, such as the "C" programming language or similar programming languages.
- the computer readable program instructions may execute entirely on the user's computer, partly on the user's computer, as a stand-alone software package, partly on the user's computer and partly on a remote computer or entirely on the remote computer or server.
- the remote computer may be connected to the user's computer through any type of network, including a local area network (LAN) or a wide area network (WAN), or the connection may be made to an external computer (for example, through the Internet using an Internet Service Provider).
- LAN local area network
- WAN wide area network
- Internet Service Provider for example, AT&T, MCI, Sprint, EarthLink, MSN, GTE, etc.
- electronic circuitry including, for example, programmable logic circuitry, field-programmable gate arrays (FPGA), or programmable logic arrays (PLA) may execute the computer readable program instructions by utilizing state information of the computer readable program instructions to personalize the electronic circuitry, in order to perform aspects of the present subject matter.
- FPGA field-programmable gate arrays
- PLA programmable logic arrays
- These computer readable program instructions may be provided to a processor of a computer, special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, create means for implementing the functions/acts specified in the flowchart and/or block diagram block or blocks.
- These computer readable program instructions may also be stored in a computer readable storage medium that can direct a computer, a programmable data processing apparatus, and/or other devices to function in a particular manner, such that the computer readable storage medium having instructions stored therein comprises an article of manufacture including instructions which implement aspects of the function/act specified in the flowchart and/or block diagram block or blocks.
- the computer readable program instructions may also be loaded onto a computer, other programmable data processing apparatus, or other device to cause a series of operational steps to be performed on the computer, other programmable apparatus or other device to produce a computer implemented process, such that the instructions which execute on the computer, other programmable apparatus, or other device implement the functions/acts specified in the flowchart and/or block diagram block or blocks.
- the description illustrates the architecture, functionality, and operation of possible implementations of systems, methods, and computer program products according to various embodiments of the present subject matter.
- each block in the flowchart or block diagrams may represent a module, segment, or portion of instructions, which comprises one or more executable instructions for implementing the specified logical function(s).
- each block of the block diagrams and/or flowchart illustration, and combinations of blocks in the block diagrams and/or flowchart illustration can be implemented by special purpose hardware-based systems that perform the specified functions or acts or carry out combinations of special purpose hardware and computer instructions.
- the sample may be from a subject suspected of having a particular cancer or from a patient diagnosed with cancer, e.g., for confirmation of diagnosis or establishing a clear margin or for the detection of cancer cells in other tissues such as lymph nodes, or circulating tumor cells.
- the biological sample may also be from a subject with an ambiguous diagnosis in order to clarify the diagnosis.
- the sample may be obtained for the purpose of differential diagnosis, e.g., a subject with a histopathologically benign lesion to confirm the diagnosis.
- the sample may also be obtained for the purpose of prognosis, i.e., determining the course of the disease and selecting primary treatment options. Tumor staging and grading are examples of prognosis.
- Samples may be obtained using any of a number of methods in the art. Examples of biological samples comprising potential cancer cells include those obtained from excised skin biopsies, such as punch biopsies, shave biopsies, core needle biopsies, fine needle aspirates (FNA), or surgical excisions; or biopsy from non- cutaneous tissues such as lymph node tissue, mucosa, other embodiments.
- excised skin biopsies such as punch biopsies, shave biopsies, core needle biopsies, fine needle aspirates (FNA), or surgical excisions
- FNA fine needle aspirates
- the sample may be from a distant metastatic site, a soft tissue, e.g., lung, liver, bone, skin, or brain.
- Representative biopsy techniques include, but are not limited to, excisional biopsy, incisional biopsy, pinch biopsy, forceps biopsy, needle biopsy, or surgical biopsy.
- An "excisional biopsy” refers to the removal of an entire tumor mass with a small margin of normal tissue surrounding it.
- An “incisional biopsy” refers to the removal of a wedge of tissue that includes a cross-sectional diameter of the tumor.
- a diagnosis or prognosis made by endoscopy or fluoroscopy may require a "core-needle biopsy" of the tumor mass, or a "fine-needle aspiration biopsy” which generally contains a suspension of cells from within the tumor mass.
- the biological sample may be a microdissected sample, such as a PALM-laser (Carl Zeiss MicroImaging GmbH, Germany) capture microdissected sample.
- a sample may also be a sample of muscosal surfaces, blood and blood fractions or products (e.g., serum, plasma, platelets, red blood cells, white blood cells, circulating tumor cells isolated from blood, free DNA isolated from blood, and the like), sputum, saliva, lymph and tongue tissue, cultured cells, e.g., primary cultures, explants, and transformed cells, stool, urine, etc.
- the sample may also be vascular tissue or cells from blood vessels such as microdissected blood vessel cells of endothelial origin.
- a sample is typically obtained from a eukaryotic organism, most preferably a mammal such as a primate e.g., chimpanzee or human, cow, dog, cat; or a rodent, e.g., guinea pig, rat, mouse, rabbit.
- a sample can be treated with a fixative such as formaldehyde and embedded in paraffin (FFPE) and sectioned for use in the methods of the invention.
- FFPE formaldehyde and embedded in paraffin
- fresh or frozen tissue may be used.
- These cells may be fixed, e.g., in alcoholic solutions such as 100% ethanol or 3:1 methanol:acetic acid.
- Nuclei can also be extracted from thick sections of paraffin-embedded specimens to reduce truncation artifacts and eliminate extraneous embedded material.
- biological samples once obtained, are harvested and processed prior to nucleic acid analysis using standard methods known in the art. Such processing typically includes protease treatment and additional fixation in an aldehyde solution such as formaldehyde. 5.3.1. Polynucleotide Sequence Amplification and Determination [0078] In many instances, it is desirable to amplify a nucleic acid sequence using any of several nucleic acid amplification procedures which are well known in the art.
- nucleic acid amplification is the chemical or enzymatic synthesis of nucleic acid copies which contain a sequence that is complementary to a nucleic acid sequence being amplified (template).
- the methods and kits of the invention may use any nucleic acid amplification or detection methods known to one skilled in the art, such as those described in U.S. Pat. Nos. 5,525,462 (Takarada et al.); 6,114,117 (Hepp et al.); 6,127,120 (Graham et al.); 6,344,317 (Urnovitz); 6,448,001 (Oku); 6,528,632 (Catanzariti et al.); and PCT Pub. No.
- the nucleic acids may be amplified by PCR amplification using methodologies known to one skilled in the art.
- amplification can be accomplished by other known methods, such as ligase chain reaction (LCR), Q ⁇ -replicase amplification, rolling circle amplification, transcription amplification, self-sustained sequence replication, nucleic acid sequence-based amplification (NASBA), each of which provides sufficient amplification.
- Branched-DNA technology may also be used to qualitatively demonstrate the presence of a sequence of the technology which may quantitatively determine the amount of this particular genomic sequence in a sample.
- Nolte reviews branched-DNA signal amplification for direct quantitation of nucleic acid sequences in clinical samples (Nolte, 1998, Adv. Clin. Chem. 33:201-235).
- the PCR process is well known in the art and is thus not described in detail herein. For a review of PCR methods and protocols, see, e.g., Innis et al., eds., PCR Protocols, A Guide to Methods and Application, Academic Press, Inc., San Diego, Calif. 1990; U.S. Pat. No.
- PCR reagents and protocols are also available from commercial vendors, such as Roche Molecular Systems. PCR may be carried out as an automated process with a thermostable enzyme. In this process, the temperature of the reaction mixture is cycled through a denaturing region, a primer annealing region, and an extension reaction region automatically. Machines specifically adapted for this purpose are commercially available. 5.3.2. High Throughput and Single Molecule Sequencing Technology [0081] Suitable next generation sequencing technologies are widely available.
- Examples include the 454 Life Sciences platform (Roche, Branford, CT) (Margulies et al.2005 Nature, 437, 376-380); lllumina’s Genome Analyzer, Illumina’s MiSeq System, Illumina’s NextSeq System, Illumina’s MiniSeq System, (Illumina, San Diego, CA; Bibkova et al., 2006, Genome Res.16, 383- 393; U.S. Pat. Nos. 6,306,597 and 7,598,035 (Macevicz); 7,232,656 (Balasubramanian et al.)); or DNA Sequencing by Ligation, SOLiD System (Applied Biosystems/Life Technologies; U.S. Pat.
- Chem.53, 1996-2001 which are incorporated herein by reference in their entirety.
- These systems allow the sequencing of many nucleic acid molecules isolated from a specimen at high orders of multiplexing in a parallel fashion (Dear, 2003, Brief Funct. Genomic Proteomic, 1(4), 397-416 and McCaughan and Dear, 2010, J. Pathol., 220, 297- 306).
- Each of these platforms allow sequencing of clonally expanded or non-amplified single molecules of nucleic acid fragments.
- Certain platforms involve, for example, (i) sequencing by ligation of dye-modified probes (including cyclic ligation and cleavage), (ii) pyrosequencing, (iii) targeted next-generation sequencing from bisulfite treated DNA and (iv) single-molecule sequencing.
- Pyrosequencing is a nucleic acid sequencing method based on sequencing by synthesis, which relies on detection of a pyrophosphate released on nucleotide incorporation.
- sequencing by synthesis involves synthesizing, one nucleotide at a time, a DNA strand complimentary to the strand whose sequence is being sought.
- Study nucleic acids may be immobilized to a solid support, hybridized with a sequencing primer, incubated with DNA polymerase, ATP sulfurylase, luciferase, apyrase, adenosine 5' phosphsulfate and luciferin. Nucleotide solutions are sequentially added and removed. Correct incorporation of a nucleotide releases a pyrophosphate, which interacts with ATP sulfurylase and produces ATP in the presence of adenosine 5' phosphosulfate, fueling the luciferin reaction, which produces a chemiluminescent signal allowing sequence determination.
- Machines for pyrosequencing are available from Qiagen, Inc. (Valencia, CA).
- An example of a system that can be used by a person of ordinary skill based on pyrosequencing generally involves the following steps: ligating an adaptor nucleic acid to a study nucleic acid and hybridizing the study nucleic acid to a bead; amplifying a nucleotide sequence in the study nucleic acid in an emulsion; sorting beads using a picoliter multiwell solid support; and sequencing amplified nucleotide sequences by pyrosequencing methodology (e.g., Nakano et al., 2003, J. Biotech.102, 117-124).
- NGS Next-generation sequencing
- dNTPs deoxyribonucleotide triphosphates
- sequencing by synthesis involves synthesizing, one nucleotide at a time, a DNA strand complimentary to the strand whose sequence is being sought.
- Study nucleic acids may be immobilized to a solid support, hybridized with a sequencing primer, and incubated with DNA polymerase in the presence of fluorescently labeled dNTPS. After each cycle, the image is scanned and the emission wavelength and intensity are recorded and used to identify the base incorporated. This process is repeated multiple times to create a specific read length of bases.
- Certain single-molecule sequencing embodiments are based on the principal of sequencing by synthesis, and utilize single-pair Fluorescence Resonance Energy Transfer (single pair FRET) as a mechanism by which photons are emitted as a result of successful nucleotide incorporation.
- the emitted photons often are detected using intensified or high sensitivity cooled charge-couple-devices in conjunction with total internal reflection microscopy (TIRM). Photons are only emitted when the introduced reaction solution contains the correct nucleotide for incorporation into the growing nucleic acid chain that is synthesized as a result of the sequencing process.
- TIRM total internal reflection microscopy
- FRET FRET based single-molecule sequencing or detection
- energy is transferred between two fluorescent dyes, sometimes polymethine cyanine dyes Cy3 and Cy5, through long-range dipole interactions.
- the donor is excited at its specific excitation wavelength and the excited state energy is transferred, non-radiatively to the acceptor dye, which in turn becomes excited.
- the acceptor dye eventually returns to the ground state by radiative emission of a photon.
- the two dyes used in the energy transfer process represent the "single pair", in single pair FRET. Cy3 often is used as the donor fluorophore and often is incorporated as the first labeled nucleotide.
- Cy5 often is used as the acceptor fluorophore and is used as the nucleotide label for successive nucleotide additions after incorporation of a first Cy3 labeled nucleotide.
- the fluorophores generally are within 10 nanometers of each other for energy transfer to occur successfully.
- An example of a system that can be used based on single-molecule sequencing generally involves hybridizing a primer to a study nucleic acid to generate a complex; associating the complex with a solid phase; iteratively extending the primer by a nucleotide tagged with a fluorescent molecule; and capturing an image of fluorescence resonance energy transfer signals after each iteration (e.g., Braslavsky et al., PNAS 100(7): 3960-3964 (2003); U.S. Pat. No.7,297,518 (Quake et al.) which are incorporated herein by reference in their entirety).
- Such a system can be used to directly sequence amplification products generated by processes described herein.
- the released linear amplification product can be hybridized to a primer that contains sequences complementary to immobilized capture sequences present on a solid support, a bead or glass slide for example. Hybridization of the primer-released linear amplification product complexes with the immobilized capture sequences, immobilizes released linear amplification products to solid supports for single pair FRET based sequencing by synthesis.
- the primer often is fluorescent, so that an initial reference image of the surface of the slide with immobilized nucleic acids can be generated. The initial reference image is useful for determining locations at which true nucleotide incorporation is occurring. Fluorescence signals detected in array locations not initially identified in the "primer only" reference image are discarded as non-specific fluorescence.
- the bound nucleic acids often are sequenced in parallel by the iterative steps of, a) polymerase extension in the presence of one fluorescently labeled nucleotide, b) detection of fluorescence using appropriate microscopy, TIRM for example, c) removal of fluorescent nucleotide, and d) return to step a with a different fluorescently labeled nucleotide.
- TIRM microscopy
- c) removal of fluorescent nucleotide and d) return to step a with a different fluorescently labeled nucleotide.
- nucleotide sequencing may be by solid phase single nucleotide sequencing methods and processes.
- Solid phase single nucleotide sequencing methods involve contacting sample nucleic acid and solid support under conditions in which a single molecule of sample nucleic acid hybridizes to a single molecule of a solid support. Such conditions can include providing the solid support molecules and a single molecule of sample nucleic acid in a "microreactor.” Such conditions also can include providing a mixture in which the sample nucleic acid molecule can hybridize to solid phase nucleic acid on the solid support.
- Single nucleotide sequencing methods useful in the embodiments described herein are described in PCT Pub. No. WO 2009/091934 (Cantor).
- nanopore sequencing detection methods include (a) contacting a nucleic acid for sequencing ("base nucleic acid,” e.g., linked probe molecule) with sequence- specific detectors, under conditions in which the detectors specifically hybridize to substantially complementary subsequences of the base nucleic acid; (b) detecting signals from the detectors and (c) determining the sequence of the base nucleic acid according to the signals detected.
- the detectors hybridized to the base nucleic acid are disassociated from the base nucleic acid (e.g., sequentially dissociated) when the detectors interfere with a nanopore structure as the base nucleic acid passes through a pore, and the detectors disassociated from the base sequence are detected.
- a detector also may include one or more regions of nucleotides that do not hybridize to the base nucleic acid.
- a detector is a molecular beacon.
- a detector often comprises one or more detectable labels independently selected from those described herein. Each detectable label can be detected by any convenient detection process capable of detecting a signal generated by each label (e.g., magnetic, electric, chemical, optical and the like). For example, a CD camera can be used to detect signals from one or more distinguishable quantum dots linked to a detector.
- the invention encompasses methods known in the art for enhancing the sensitivity of the detectable signal in such assays, including, but not limited to, the use of cyclic probe technology (Bakkaoui et al., 1996, BioTechniques 20: 240-8, which is incorporated herein by reference in its entirety); and the use of branched probes (Urdea et al., 1993, Clin. Chem. 39, 725-6; which is incorporated herein by reference in its entirety).
- the hybridization complexes are detected according to well-known techniques in the art.
- Reverse transcribed or amplified nucleic acids may be modified nucleic acids.
- Modified nucleic acids can include nucleotide analogs, and in certain embodiments include a detectable label and/or a capture agent.
- detectable labels include, without limitation, fluorophores, radioisotopes, colorimetric agents, light emitting agents, chemiluminescent agents, light scattering agents, enzymes and the like.
- capture agents include, without limitation, an agent from a binding pair selected from antibody/antigen, antibody/antibody, antibody/antibody fragment, antibody/antibody receptor, antibody/protein A or protein G, hapten/anti-hapten, biotin/avidin, biotin/streptavidin, folic acid/folate binding protein, vitamin B12/intrinsic factor, chemical reactive group/complementary chemical reactive group (e.g., sulfhydryl/maleimide, sulfhydryl/haloacetyl derivative, amine/isotriocyanate, amine/succinimidyl ester, and amine/sulfonyl halides) pairs, and the like.
- an agent from a binding pair selected from antibody/antigen, antibody/antibody, antibody/antibody fragment, antibody/antibody receptor, antibody/protein A or protein G, hapten/anti-hapten, biotin/avidin, biotin/streptavidin, folic acid/
- Modified nucleic acids having a capture agent can be immobilized to a solid support in certain embodiments.
- Next generation sequencing techniques may be applied to measure expression levels or count numbers of transcripts using RNA-seq or whole transcriptome shotgun sequencing. See, e.g., Mortazavi et al. 2008 Nat Meth 5(7) 621-627 or Wang et al. 2009 Nat Rev Genet 10(1) 57-63. Nucleic acids in the invention may be counted using methods known in the art. In one embodiment, NanoString’s nCounter® system may be used (Seattle, WA). Geiss et al. 2008 Nat Biotech 26(3) 317-325; U.S. Pat. No. 7,473,767 (Dimitrov).
- NanoString Digital Spatial Profiling (DSP) platform may be used for nucleic acid or protein detection. Blank et al., 2018 Nature Medicine 24 1655–1661; Amaria et al., 2018 Nature Medicine 24 1649–1654.
- Fluidigm Dynamic Array system may be used (South San Francisco, CA). Byrne et al. 2009 PLoS ONE 4 e7118; Helzer et al. 2009 Can Res 697860-7866.
- compositions and Kits [0093] The invention provides compositions and kits detecting the biomarkers described herein using antibodies or other reagents specific for the nucleic acids specific for the polynucleotides.
- Kits for carrying out the diagnostic assays of the invention typically include, in suitable container means, (i) a probe that comprises an antibody or nucleic acid sequence that specifically binds to the marker polynucleotides of the invention, (ii) a label for detecting the presence of the probe and (iii) instructions for how to measure the level the polynucleotide.
- kits may include several antibodies or polynucleotide sequences encoding biomarkers disclosed herein, e.g., a first antibody and/or second and/or third and/or additional antibodies that recognize the biomarkers or specific nucleic acids.
- the nucleic acids in the kit are the forward and reverse PCR primers for the biomarkers disclosed herein.
- the container means of the kits will generally include at least one vial, test tube, flask, bottle, syringe and/or other container into which a first antibody specific for one of the polypeptides or a first nucleic acid specific for one of the polynucleotides of the present invention may be placed and/or suitably aliquoted.
- kits will also generally contain a second, third and/or other additional container into which this component may be placed.
- a container may contain a mixture of more than one antibody or nucleic acid reagent, each reagent specifically binding a different marker in accordance with the present invention.
- the kits of the present invention will also typically include means for containing the antibody or nucleic acid probes in close confinement for commercial sale. Such containers may include injection and/or blow-molded plastic containers into which the desired vials are retained.
- the kits may further comprise positive and negative controls, as well as instructions for the use of kit components contained therein, in accordance with the methods of the present invention.
- the friendship paradox holds that in a social network, most people have fewer friends than their friends do (14). In other words, for most nodes in a network, their neighbors or “friends” will on average have a higher degree (number of connections) than the node itself. This arises because higher degree nodes count towards the degree in multiple neighboring nodes and thus are oversampled (see Methods: proof of friendship paradox).
- highly mutated samples contribute toward the average TMB for many of the genes in the dataset, resulting in an outsized effect (Supplemental Figure 1B). Since the univariate t-test and Mann-Whitney U tests are testing for differences in central tendencies (i.e.
- the TMB Paradox explains why the majority of genes have a highly significant association with elevated TMBs.
- the TMB paradox is therefore a manifestation of the oversampling bias introduced by highly connected nodes (i.e. High TMB tumors) and this oversampling bias is what makes univariate tests (T-test and MWU) inappropriate to identify which genes are associated with higher levels of TMB. Therefore, the majority of the 98% of genes associated with elevated TMB by the univariate approach (Figure 1A) are likely a result of the TMB paradox rather than the underlying biology.
- BiG-BETS Bipartite Graph-Based Expected TMB Score
- TCGA Pan-Cancer dataset found that BiG-BETS returned a more uniform distribution of p-values (Supplemental Figure 2A), and only a subset of DDR genes when mutated have a significant association with elevated TMB, (Figure 2A) hereafter referred to as “High BiG-BETS DDR gene” ( Figure 2B). It was reassuring to see that MMR genes such as MSH3, MLH1, MSH2 had some of the highest BiG-BET scores (Figure 2B).
- the TCGA MC3 dataset was then filtered to include only “High Consequence” non-synonymous mutations, which were defined as being categorized as a high consequence mutation by the Sequence Ontology and summarized by Ensembl here (https://m.ensembl.org/info/genome/variation/prediction/predicted_data.html) ['stop lost', 'stop gained', 'transcript ablation', 'start lost', 'frameshift variant’, ’splice_site’, ‘translation_start_site’] and were also categorized as having a Polyphen score of ‘probably damaging’, ‘possibly damaging’, or ‘unknown’.
- the bipartite network representation was used to derive a null model of TMB distribution for each gene. Specifically, random sampling (permutations) of the bipartite network was performed by stochastically rewiring the network while maintaining the degree distribution (number of edges of each node) of the original dataset (this null model is known as the configuration model, which for a bipartite network is further constrained to maintain the bipartite nature of the network) (15,16).
- This null model is known as the configuration model, which for a bipartite network is further constrained to maintain the bipartite nature of the network
- the BiG-BET score consists of comparing the observed mean TMB for each gene or pathway's mutated sample set against the expected distribution under random sampling of bipartite networks that match the degree distribution of the original dataset.
- the null model for networks in which all networks with a given degree sequence are uniformly likely is known as the configuration model (24), which has also been extended to bipartite graphs (15).
- the bipartite configuration model can be envisioned by cutting across the edges in the original network and reconnecting the “stubs" at random with each possible set of pairings respecting the bipartite structure of the original network and being equally likely under the model (visualized in Figure 1F).
- TMB is treated as a binary variable with a threshold of TMB>10 defining the high TMB group.
- TMB is treated as a continuous variable. Comparison of response across groups is conducted using a Chi-squared test. Samples were divided into groups based on the presence of a mutation within a High DDR z-score gene or Low z-score DDR gene, shown in Figure 2B.
- the High BIG-BET z-score DDR genes were: [00148] BARD1, CHEK1, CUL5, EME1, ERCC4, ERCC5, ERCC6, FANCA, FANCC, FANCI, FEN1, GEN1, LIG4, MDC1, MLH1, MLH3, MRE11, MSH2, MSH3, MSH6, NBN, PALB2, PARP1, PMS1, PMS2, POLE, POLE3, POLL, POLM, RAD50, RNMT, SEM1, SLX1A, TDG, TOP3A, TOPBP1, UNG, XPC, XRCC2, XRCC4, XRCC6.
- RNAseq expression data was obtained and filtered to the corresponding samples with mutational data. We log(1+x) transformed the data and used a robust scaling (median centered and scaled by inter-quartile range) to normalize across samples. For each signature, we calculate the average expression of all genes within the signature and then assign each sample a z-score of the basis of its expression relative to the entire cohort. Signatures used in analysis are given in below.
- GRANDVAUX_IRF3_TARGETS_UP ARG2, B4GALT5, F13B, GBP1, IFI44, IFIT1, IFIT3, ISG15, LILRB1, NR3C1, OAS2, PLCG2 PMAIP1, RSAD2 13_T_Cell_EntrezID ACTN1, ACVR2B, ADA, AKTIP, ANXA1, AOC1, APBA2, APBB1, AQP3, ARL4C, ATP13A4, ATP1A1, BCL11B, BIN2, BUB1B, C15orf62, C9orf164, CAMK4, CAPZB, CCL5, CCND2, CD2, CD247, CD28, CD3D, CD3E, CD3G, CD5, CD6, CDC14A, CEP41, CEP85L, CISH, CTSW, DISC1, DNAJB1, DNASE1L3, DOCK9, DPP4, DUSP16, DUSP2, FAM102A, FAM134B,
- Supplemental Figure 3B demonstrates excellent correlation in the BiG-BET score between the high impact and the high+moderate impact datasets, especially with regards to the DDR genes and pathways.
- TMB values for TCGA were obtained from (https://gdc.cancer.gov/about- data/publications/PanCan-CellOfOrigin) combining both Silent and Non-Silent scores for each sample.
- Clinical data used for survival analysis of the TCGA were obtained from the TCGA clinical data resource as detailed in Liu et al 2018. We looked at the effect of low and high BiG- BET DDR mutations on overall 5-year survival as detailed above.
- IMvigor210 [00158] The IMvigor210 trial is a Phase II single arm study examining the response of patients with locally advanced or metastatic urothelial bladder cancer to atezoliziumab (anti PD-L1). A full description of the characteristics of the patient cohort can be found in (7).
- the cohort consists of 260 patients with 1249 short variants across 160 different genes. Because less detailed annotations were available, we did not filter any of the mutations from this cohort.
- the class specific degree distributions as and to represent the fraction of nodes within each class with a given degree.
- the overall degree distribution, , and the class specific degree distributions are related by [00172] .
- [00173] In our gene-sample network, we are interested in the average degree across all samples with a mutation in a given gene. We show that this value, the average neighbor-of-a-gene degree, is typically greater than or equal to the average degree of the sample nodes in the network, following a proof similar to that for unipartite networks in 35 .
- class 1 is our class of interest (the sample nodes). There are m edges connected to nodes of class 1, so the probability of ending at a particular node with degree is . Since there are such nodes with degree , the probability of following an edge to a class 1 node of degree is [00175] [00176] where gives the average degree for nodes of class 1. That is, the average neighbor degree distribution is weighted by a factor of . We are more likely to choose a higher degree vertex by virtue of the simple fact that it has more edges connected to it.
- TGF ⁇ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554:544–8.
- Knijnenburg TA Wang L, Zimmermann MT, Chambwe N, Gao GF, Cherniack AD, et al. Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. Cell reports.2018;23:239-254.e6. 11. Chae YK, Anker JF, Carneiro BA, Chandra S, Kaplan J, Kalyan A, et al. Genomic landscape of DNA repair genes in cancer. Oncotarget.2016;7:23312–21. 12. Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome medicine [Internet].
- Fibroblast growth factor receptor 3 alterations and response to immune checkpoint inhibition in metastatic urothelial cancer a real world experience.
- 33. Braun DA, Hou Y, Bakouny Z, Ficial M, Angelo MS, Forman J, et al. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat Med.2020;26:909–18.
- a method for predicting response to immune checkpoint blockade (ICB) therapy for a subject with cancer comprising independently measuring or obtaining (i) a tumor mutational burden (TMB) level and (ii) defects in nucleic acids encoding DNA damage repair (DDR) genes, or their expression products, for at least ten biomarkers selected from the group consisting of APEX1, APEX2, ATM, ATR, ATRIP, BLM, BRCA1, BRCA2, BRIP1, CHEK2, ERCC1, ERCC2, EXO1, FANCB, FANCD2, FANCL, FANCM, MUS81, NHEJ1, POLB, PRKDC, RAD51, RAD52, RBBP8, TDP1, TP53BP1, TREX1, UBE2T, XPA, XRCC3, and XRCC5 in a sample from the subject, normalized against a reference set of nucleic acids encoding genes, or their expression products, in the sample, wherein subjects with both
- a method for predicting overall survival for a subject with cancer comprising independently measuring or obtaining (i) a tumor mutational burden (TMB) level and (ii) defects in nucleic acids encoding DNA damage repair (DDR) genes, or their expression products, for at least ten biomarkers selected from the group consisting of APEX1, APEX2, ATM, ATR, ATRIP, BLM, BRCA1, BRCA2, BRIP1, CHEK2, ERCC1, ERCC2, EXO1, FANCB, FANCD2, FANCL, FANCM, MUS81, NHEJ1, POLB, PRKDC, RAD51, RAD52, RBBP8, TDP1, TP53BP1, TREX1, UBE2T, XPA, XRCC3, and XRCC5 in a sample from the subject, normalized against a reference set of nucleic acids encoding genes, or their expression products, in the sample, wherein subjects with both a high TMB level and defects in at least
- Statement 3 A method to select a subject with cancer for immune blockade therapy (ICB) which comprises independently measuring or obtaining both (i) a tumor mutational burden (TMB) level and (ii) defects in DNA Damage Repair (DDR) genes or their expression products in a sample from the subject; calculating a Bipartite Graph-Based Expected TMB Score (BiG-BETS) to determine which DDR genes or expression products are associated with elevated TMB; if the subject has a high BiG-BETS determining that the defect in the DDR genes or their expression products do not add to the TMB level over measurement of TMB levels alone; and using the TMB levels alone to select a subject for ICB.
- ICB immune blockade therapy
- Statement 4 The method of Statement 3, wherein the DDR genes or their expression products are at least ten biomarkers selected from the group consisting of BARD1, CHEK1, CUL5, EME1, ERCC4, ERCC5, ERCC6, FANCA, FANCC, FANCI, FEN1, GEN1, LIG4, MDC1, MLH1, MLH3, MRE11, MSH2, MSH3, MSH6, NBN, PALB2, PARP1, PMS1, PMS2, POLE, POLE3, POLL, POLM, RAD50, RNMT, SEM1, SLX1A, TDG, TOP3A, TOPBP1, UNG, XPC, XRCC2, XRCC4, and XRCC6.
- biomarkers selected from the group consisting of BARD1, CHEK1, CUL5, EME1, ERCC4, ERCC5, ERCC6, FANCA, FANCC, FANCI, FEN1, GEN1, LIG4, MDC1, MLH1, MLH3, MRE11, M
- a method to select a subject with cancer for immune blockade therapy which comprises independently measuring or obtaining both (i) a tumor mutational burden (TMB) level and (ii) defects in DNA Damage Repair (DDR) genes or their expression products in a sample from the subject; calculating a Bipartite Graph-Based Expected TMB Score (BiG-BETS) to determine which DDR genes or expression products are associated with elevated TMB; if the subject has a low BiG-BETS determining that the defects in the DDR genes or their expression products contribute to the likelihood of benefit from ICB over measurement of TMB levels alone; and using both the TMB levels and the defects in the DDR genes or their expression products to select a subject for ICB.
- ICB immune blockade therapy
- Statement 6 The method of Statement 5, wherein the DDR genes or their expression products are at least ten biomarkers selected from the group consisting of APEX1, APEX2, ATM, ATR, ATRIP, BLM, BRCA1, BRCA2, BRIP1, CHEK2, ERCC1, ERCC2, EXO1, FANCB, FANCD2, FANCL, FANCM, MUS81, NHEJ1, POLB, PRKDC, RAD51, RAD52, RBBP8, TDP1, TP53BP1, TREX1, UBE2T, XPA, XRCC3, and XRCC5.
- biomarkers selected from the group consisting of APEX1, APEX2, ATM, ATR, ATRIP, BLM, BRCA1, BRCA2, BRIP1, CHEK2, ERCC1, ERCC2, EXO1, FANCB, FANCD2, FANCL, FANCM, MUS81, NHEJ1, POLB, PRKDC, RAD51, RAD52, RBBP8, TDP1,
- Statement 7 The method of any of Statements 1-6, wherein the cancer is bladder urothelial carcinoma, colon adenocarcinoma, esophageal carcinoma, invasive breast carcinoma, head and neck squamous cell carcinoma, kidney renal clear cell carcinoma, lung adenocarcinoma, melanoma, or squamous cell lung carcinoma.
- Statement 8 The method of any of Statements 1-6, wherein the defects are mutations or copy number alterations.
- Statement 9 The method of Statement 8, wherein the mutations are deletions, frameshift mutations, insertions, missense mutations, nonsense mutations, start codon loss, stop codon loss or gain, or a combination thereof.
- Statement 10 The method of any of Statements 1-6, wherein the detecting defects in nucleic acids encoding genes, or their expression products, for the biomarkers comprises performing next generation sequencing (NGS), nucleic acid hybridization, quantitative RT-PCR, immunohistochemistry (IHC), immunocytochemistry (ICC), or immunofluorescence (IF).
- NGS next generation sequencing
- IHC immunohistochemistry
- ICC immunocytochemistry
- IF immunofluorescence
- Statement 11 The method of any of Statements 1-6, wherein the method further comprises assessment of a medical history, a family history, a physical examination, an endoscopic examination, imaging, a biopsy result, or a combination thereof.
- Statement 12 The method of Statement 11, wherein the method is used to develop a treatment strategy for the subject with cancer.
- Statement 13 The method of any of Statements 1-6, wherein the nucleic acids encoding genes are isolated from a fixed, paraffin-embedded sample from the subject.
- Statement 14 The method of any of Statements 1-6, wherein the nucleic acids encoding genes are isolated from core biopsy tissue or fine needle aspirate cells from the subject.
- Statement 15 The method of Statements 5 or 6, which further comprises treating the subject with a combination of ICB therapy and kinase inhibitor therapy.
- a method for treating a subject with cancer which comprises independently measuring or obtaining a tumor mutational burden (TMB) level; and defects in nucleic acids encoding DNA damage repair (DDR) genes, or their expression products, for at least ten biomarkers selected from the group consisting of low BIG-BETS DDR genes normalized against a reference set of nucleic acids encoding genes, or their expression products, in the sample; and if the subject has a high TMB level and wild type low BIG-BETs genes, treating the subject with a combination of immune checkpoint blockcade (ICB) therapy and an inhibitor of a low BIG- BETs kinase so as to reduce the activity of the low BIG-BET kinase and thereby treat the subject with cancer.
- TMB tumor mutational burden
- DDR DNA damage repair
- Statement 17 The method of Statement 16, wherein the low BIG-BETs kinase is ATR, CHEK1, or WEE1.
- Statement 18 A kit comprising at least ten nucleic acid probes, wherein each of said probes specifically binds to one of ten distinct biomarker nucleic acids or fragments thereof selected from the group consisting of APEX1, APEX2, ATM, ATR, ATRIP, BLM, BRCA1, BRCA2, BRIP1, CHEK2, ERCC1, ERCC2, EXO1, FANCB, FANCD2, FANCL, FANCM, MUS81, NHEJ1, POLB, PRKDC, RAD51, RAD52, RBBP8, TDP1, TP53BP1, TREX1, UBE2T, XPA, XRCC3, and XRCC5.
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Abstract
La présente divulgation concerne un nouveau test, le score de TMB escomptée basé sur un graphe bipartite (BiG-BETS), qui résout le paradoxe de la TMB, définit avec précision des gènes associés à une TMB élevée, et délimite de manière remarquable une cohorte de sujets (mutant DDR à BiG-BETS à TMB élevée, basse) avec un pouvoir prédictif élevé pour une réponse de blocage de point de contrôle immunitaire et une survie globale prolongée pour le traitement du cancer.
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