Therapeutic Implications of Germline Testing in Patients With Advanced Cancers.

Purpose: Tumor mutational profiling is increasingly performed in patients with advanced cancer. We determined the extent to which germline mutation profiling guides therapy selection in patients with advanced cancer.
Methods: Patients with cancer undergoing tumor genomic profiling were prospectively consented for germline cancer predisposition gene analysis (2015-2019). In patients harboring germline likely pathogenic or pathogenic (LP/P) alterations, therapeutic actionability was classified using a precision oncology knowledge base. Patients with metastatic or recurrent cancer receiving germline genotype-directed therapy were determined.
Results: Among 11,947 patients across > 50 malignancies, 17% (n = 2,037) harbored a germline LP/P variant. By oncology knowledge base classification, 9% (n = 1042) had an LP/P variant in a gene with therapeutic implications (4% level 1; 4% level 3B; < 1% level 4). BRCA1/2 variants accounted for 42% of therapeutically actionable findings, followed by CHEK2 (13%), ATM (12%), mismatch repair genes (11%), and PALB2 (5%). When limited to the 9,079 patients with metastatic or recurrent cancer, 8% (n = 710) harbored level 1 or 3B genetic findings and 3.2% (n = 289) received germline genotype-directed therapy. Germline genotype-directed therapy was received by 61% and 18% of metastatic cancer patients with level 1 and level 3B findings, respectively, and by 54% of BRCA1/2 , 75% of mismatch repair, 43% of PALB2 , 35% of RAD51C/D , 24% of BRIP1 , and 19% of ATM carriers. Of BRCA1/2 patients receiving a poly(ADP-ribose) polymerase inhibitor, 45% (84 of 188) had tumors other than breast or ovarian cancer, wherein the drug, at time of delivery, was delivered in an investigational setting.
Conclusion: In a pan-cancer analysis, 8% of patients with advanced cancer harbored a germline variant with therapeutic actionability with 40% of these patients receiving germline genotype-directed treatment. Germline sequence analysis is additive to tumor sequence analysis for therapy selection and should be considered for all patients with advanced cancer.
Competing Interests: Zsofia K. StadlerConsulting or Advisory Role: Allergan (I), Genentech/Roche (I), Regeneron (I), Optos (I), Adverum (I), Novartis (I), Regenxbio (I), Gyroscope (I), Neurogene (I) Debyani ChakravartyConsulting or Advisory Role: Medendi Medical Travel Christopher J. FongStock and Other Ownership Interests: Various biotech ETFsPatents, Royalties, Other Intellectual Property: Ultra-Wideband Radar System for Animals Patent September 11, 2018, Patent issuer and number US20150181840A1, Monitoring Treatment of Peripheral Artery Disease (PAD) using Diffuse Optical Imaging, Imaging interfaces for full finger and full hand optical tomography, Systems and methods for dynamic imaging of tissue using digital optical tomography. Karen CadooHonoraria: OncLiveConsulting or Advisory Role: GlaxoSmithKline/Tesaro, AstraZeneca, MSD, GlaxoSmithKline, MJH Life SciencesResearch Funding: AstraZeneca, Syndax, MSD Ying LiuResearch Funding: AstraZeneca, Tesaro/GSK Maria I. CarloConsulting or Advisory Role: PfizerOther Relationship: Prostate Cancer Foundation, Robert Wood Johnson Foundation Alicia LathamOther Relationship: Conquer Cancer Foundation Ritika KundraStock and Other Ownership Interests: Pfizer Carol AghajanianConsulting or Advisory Role: Mersana, Eisai, Roche, AbbVie, AstraZeneca/Merck, Roche/Genentech, Repare TherapeuticsResearch Funding: Genentech/Roche, AbbVie, Clovis Oncology, AstraZeneca Nadeem Abu-RustumHonoraria: Prime OncologyResearch Funding: Stryker/Novadaq, GrailTravel, Accommodations, Expenses: Prime Oncology Anna VargheseConsulting or Advisory Role: RocheResearch Funding: Lilly, Verastem, BioMed Valley Discoveries, Bristol Myers Squibb, Silenseed, IlluminaTravel, Accommodations, Expenses: Roche Eileen M. O'ReillyConsulting or Advisory Role: Merck, Agios, AstraZeneca, Bayer, BeiGene, Berry Genomics, Celgene, CytomX Therapeutics, Debiopharm Group, Eisai, Exelixis/Ipsen, Flatiron Health, Incyte, Janssen, LAM Therapeutics, Lilly, Loxo, Genentech/Roche, Minapharma, QED Therapeutics, RedHill Biopharma, Sillajen, SOBI, Yiviva, Autem Medical, Gilead Sciences, Ipsen, Silenseed, TheraBionic, twoXAR, Vector HealthResearch Funding: AstraZeneca/MedImmune, Acta Biologica, Bristol Myers Squibb, Celgene, Genentech, Halozyme, MabVax, Roche, Silenseed Michael MorrisConsulting or Advisory Role: Bayer, Endocyte, Advanced Accelerator Applications, ORIC Pharmaceuticals, Johnson & Johnson, Curium Pharma, AthenexResearch Funding: Bayer, Sanofi, Endocyte, Progenics, Corcept Therapeutics, Roche/Genentech, JanssenTravel, Accommodations, Expenses: Endocyte, Fujifilm Wassim AbidaHonoraria: CARET, Roche, Medscape, Aptitude HealthConsulting or Advisory Role: Clovis Oncology, Janssen, MORE Health, ORIC Pharmaceuticals, Daiichi SankyoResearch Funding: AstraZeneca, Zenith Epigenetics, Clovis Oncology, GlaxoSmithKline, ORIC Pharmaceuticals, EpizymeTravel, Accommodations, Expenses: GlaxoSmithKline, Clovis Oncology, ORIC Pharmaceuticals Alexander DrilonHonoraria: Medscape, OncLive, PeerVoice, Physicans' Education Resource, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, PeerviewConsulting or Advisory Role: Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Verastem, Takeda/Millennium, BerGenBio, MORE Health, Lilly, Verastem, AbbVie, 14ner Oncology/Elevation Oncology, Remedica, Archer, Monopteros Therapeutics, Novartis, EMD Serono/Merck, Melendi, Repare TherapeuticsResearch Funding: Foundation MedicinePatents, Royalties, Other Intellectual Property: Wolters Kluwer (Royalties for Pocket Oncology)Other Relationship: Merck, GlaxoSmithKline, Teva, Taiho Pharmaceutical, Pfizer, PharmaMar, Puma Biotechnology Ahmet ZehirStock and Other Ownership Interests: Arcus Biosciences, Mirati TherapeuticsHonoraria: Illumina Marc LadanyiConsulting or Advisory Role: Bristol Myers Squibb, BayerResearch Funding: Loxo, Helsinn Therapeutics, Merus NV, Elevation Oncology David SolitStock and Other Ownership Interests: Loxo, Scorpion Therapeutics, Vividion Therapeutics, Fore TherapeuticsConsulting or Advisory Role: Pfizer, Illumina, Lilly, QED Therapeutics, BridgeBio Pharma, Scorpion Therapeutics, Vividion Therapeutics, Syros Pharmaceuticals Michael F. BergerResearch Funding: GrailPatents, Royalties, Other Intellectual Property: Provisional patent pending for “Systems and Methods for Detecting Cancer via cfDNA Screening” Luis A. DiazLeadership: Personal Genome Diagnostics, Jounce TherapeuticsStock and Other Ownership Interests: PapGene Inc, Personal Genome Diagnostics, Jounce Therapeutics, Zydecom, Thrive Earlier Detection Corp, Neophore, Amgen, Four Paws, Seer, Kinnate BiopharmaConsulting or Advisory Role: Merck, Personal Genome Diagnostics, Zydecom, Neophore, Innovatus Capital Partners, Four Paws, Seer, Kinnate BiopharmaResearch Funding: MerckPatents, Royalties, Other Intellectual Property: US-2010041048-A1—Circulating Mutant DNA to Assess Tumor Dynamics, US-2015344970-A1—Personalized Tumor Biomarkers, WO-2010118016-A2—Digital quantification of DNA methylation, US-2005202465-A1—Thymidylate synthase gene and metastasis, US-2014227271-A1—Somatic mutations in atrx in brain cancer, WO-2012094401-A2—Genes frequently altered in pancreatic neuroendocrine tumors, US-2013323167-A1—Detecting and treating solid tumors through selective disruption of tumor vasculature, EP-2912468-B1—Papanicolaou test for ovarian and endometrial cancers, US-9976184-B2—Mutations in pancreatic neoplasms, US-2017267760-A1—Checkpoint Blockade and Microsatellite Instability, US-2018171413-A1—Head and neck squamous cell carcinoma assays, US-2018086832-A1—HLA-restricted epitopes encoded by somatically mutated genes, US-2018258490-A1—Assaying ovarian cyst fluid, US-2016208340-A1—TERT Promoter Mutations in Urothelial Neoplasia, US-2015252415-A1—Arid1b and neuroblastoma, WO-2018071796-A2—Compositions and methods for identifying functional anti-tumor T cell responses, EP-3322824-A1—Detection of tumor-derived DNA in CSF, US-2016273049-A1—Systems and methods for analyzing nucleic acid, US-2018135044-A1—Non-unique barcodes in a genotyping assay, US-2017016075-A1—Neoantigen analysisTravel, Accommodations, Expenses: Merck Mark RobsonConsulting or Advisory Role: Change HealthCareResearch Funding: AstraZeneca, Pfizer, MerckOther Relationship: Research to Practice, Clinical Care Options, Physicans' Education Resource, Invitae, PfizerUncompensated Relationships: Merck, Pfizer, Daiichi Sankyo, Epic SciencesOpen Payments Link: https://openpaymentsdata.cms.gov/physician/612669/summaryNo other potential conflicts of interest were reported.