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Purpose: BRAF V600E mutations are rarely associated with objective responses to the BRAF inhibitor vemurafenib in patients with metastatic colorectal cancer (CRC). Blockade of BRAF V600E by vemurafenib causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab., Methods: One hundred six patients with BRAF V600E -mutated metastatic CRC previously treated with one or two regimens were randomly assigned to irinotecan and cetuximab with or without vemurafenib (960 mg PO twice daily)., Results: Progression-free survival, the primary end point, was improved with the addition of vemurafenib (hazard ratio, 0.50, P = .001). The response rate was 17% versus 4% ( P = .05), with a disease control rate of 65% versus 21% ( P < .001). A decline in circulating tumor DNA BRAF V600E variant allele frequency was seen in 87% versus 0% of patients ( P < .001), with a low incidence of acquired RAS alterations at the time of progression. RNA profiling suggested that treatment benefit did not depend on previously established BRAF subgroups or the consensus molecular subtype., Conclusion: Simultaneous inhibition of EGFR and BRAF combined with irinotecan is effective in BRAF V600E -mutated CRC.

Purpose: Recent advances in molecular diagnostic technologies have allowed for the evaluation of solid tumor malignancies via noninvasive blood sampling, including circulating tumor DNA (ctDNA) profiling. We sought to characterize the ctDNA genomic alteration landscape in patients with biliary tract cancers (BTCs)., Patients and Methods: From January 2015 to February 2018, 124 patients with BTC at the Mayo Clinic Comprehensive Cancer Center underwent ctDNA testing using a clinically available assay. The majority of samples (n = 122) were tested using the 73-gene panel that includes somatic genomic targets, including complete or critical exon coverage in 30 and 40 genes, respectively, and in some, amplifications, fusions, and indels., Results: A total of 138 samples were included, with approximately 70% of patients having intrahepatic BTC. All patients had locally advanced or metastatic BTC. Samples with one or more alterations, when variants of unknown significance were excluded, numbered 105 (76%). Each sample contained, on average, three alterations with a median allelic fraction of 0.52%. The overall landscape of alterations is summarized in Figures 1 and 2. After excluding variants of unknown significance, therapeutically relevant alterations were observed in 76 patients (55%), including BRAF mutations, ERBB2 amplifications, FGFR2 fusions, FGFR2 mutations, and IDH1 mutations seen in 21% of patients. A different spectrum of alterations was observed in patients with early-onset BTC (younger than age 50 years) compared with older patients (older than age 50 years)., Conclusion: Data on ctDNA in BTC is currently limited. Our study, the largest cohort reported to date to our knowledge, demonstrates the feasibility of ctDNA testing in this disease. We provide a foundation upon which the field can continue to grow.

Purpose: Gene fusions are established oncogenic drivers and emerging therapeutic targets in advanced colorectal cancer. This study aimed to detail the frequencies and clinicopathological features of gene fusions in colorectal cancer using a circulating tumor DNA assay., Methods: Circulating tumor DNA samples in patients with advanced colorectal cancer were analyzed at 4,581 unique time points using a validated plasma-based multigene assay that includes assessment of fusions in FGFR2 , FGFR3 , RET , ALK , NTRK1 , and ROS1. Associations between fusions and clinicopathological features were measured using Fisher's exact test. Relative frequencies of genomic alterations were compared between fusion-present and fusion-absent cases using an unpaired t test., Results: Forty-four unique fusions were identified in 40 (1.1%) of the 3,808 patients with circulating tumor DNA detected: RET (n = 6; 36% of all fusions detected), FGFR3 (n = 2; 27%), ALK (n = 10, 23%), NTRK1 (n = 3; 7%), ROS1 (n = 2; 5%), and FGFR2 (n = 1; 2%). Relative to nonfusion variants detected, fusions were more likely to be subclonal (odds ratio, 8.2; 95% CI, 2.94 to 23.00; P < .001). Mutations associated with a previously reported anti-epidermal growth factor receptor (anti-EGFR) therapy resistance signature (subclonal RAS and EGFR mutations) were found with fusions in FGFR3 (10 of 12 patients), RET (nine of 16 patients), and ALK (seven of 10 patients). For the 27 patients with available clinical histories, 21 (78%) had EGFR monoclonal antibody treatment before fusion detection., Conclusion: Diverse and potentially actionable fusions can be detected using a circulating tumor DNA assay in patients with advanced colorectal cancer. Distribution of coexisting subclonal mutations in EGFR , KRAS , and NRAS in a subset of the patients with fusion-present colorectal cancer suggests that these fusions may arise as a novel mechanism of resistance to anti-EGFR therapies in patients with metastatic colorectal cancer., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Katherine CliftonEmployment: WellCare (I) Stock and Other Ownership Interests: WellCare (I)Thereasa A. RichEmployment: Guardant Health Stock and Other Ownership Interests: Guardant Health, Myriad GeneticsVictoria M. RaymondEmployment: TrovaGene, Guardant Health Stock and Other Ownership Interests: TrovaGene, Guardant HealthArvind DasariConsulting or Advisory Role: Ipsen, AbbVie/Stemcentrx, Novartis, Voluntis, Lexicon Research Funding: Novartis, eFFECTOR Therapeutics, Eisai, Hutchison MediPharma, Merck, Guardant HealthJonathan M. LoreeConsulting or Advisory Role: Taiho Pharma Canada, Ipsen, Novartis, Bayer, AmgenTodd M. BauerEmployment: Tennessee Oncology Consulting or Advisory Role: Ignyta (Inst), Guardant Health, Loxo, Pfizer, Moderna Therapeutics (Inst), Pfizer (Inst), Exelixis Speakers' Bureau: Bayer Research Funding: Daiichi Sankyo (Inst), MedPacto (Inst), Incyte (Inst), Mirati Therapeutics (Inst), MedImmune (Inst), AbbVie (Inst), AstraZeneca (Inst), Leap Therapeutics (Inst), MabVax Therapeutics (Inst), Stemline Therapeutics (Inst), Merck (Inst), Eli Lilly (Inst), GlaxoSmithKline (Inst), Novartis (Inst), Pfizer (Inst), Genentech (Inst), Deciphera Pharmaceuticals (Inst), Merrimack (Inst), Immunogen (Inst), Millennium (Inst), Ignyta (Inst), Calithera Biosciences (Inst), Kolltan Pharmaceutical (Inst), Principia Biopharma (Inst), Peleton (Inst), Immunocore (Inst), Roche (Inst), Aileron Therapeutics (Inst), Bristol-Myers Squibb (Inst), Amgen (Inst), Moderna Therapeutics (Inst), Sanofi (Inst), Boehringer Ingelheim (Inst), Astellas Pharma (Inst), Five Prime Therapeutics (Inst), Jacobio Pharmaceuticals (Inst), Top Alliance BioSciences (Inst), Loxo (Inst), Janssen (Inst), Clovis Oncology (Inst), Takeda (Inst), Karyopharm Therapeutics (Inst), Onyx (Inst), Phosplatin Therapeutics (Inst), Foundation Medicine (Inst), ARMO BioSciences (Inst) Travel, Accommodations, Expenses: Astellas Pharma, AstraZeneca, Celgene, Clovis Oncology, EMD Serono, Genentech, Eli Lilly, Merck, Novartis, Pharmacyclics, SysmexYoung Kwang ChaeConsulting or Advisory Role: Foundation Medicine, Boehringer Ingelheim, Biodesix, Counsyl, AstraZeneca, Guardant Health, Takeda, Genentech, ImmuneOncia, Hanmi Speakers' Bureau: Genentech, Merck, AstraZeneca, Eli Lilly Research Funding: AbbVie, Bristol-Myers Squibb, Lexent Bio, Freenome, Biodesix Travel, Accommodations, Expenses: HanmiAxel GrotheyHonoraria: Elsevier, Aptitude Health, Imedex Consulting or Advisory Role: Genentech (Inst), Bayer (Inst), Bristol-Myers Squibb (Inst), Eli Lilly (Inst), Boston Biomedical (Inst), Amgen (Inst), Array BioPharma (Inst), Guardant Health (Inst), Daiichi Sankyo (Inst) Research Funding, Genentech (Inst), Bayer (Inst), Pfizer (Inst), Eisai (Inst), Eli Lilly (Inst), Boston Biomedical (Inst), Daiichi Sankyo (Inst), Array BioPharma (Inst) Travel, Accommodations, Expenses: Genentech, Bayer, Bristol-Myers Squibb, Boston Biomedical, Amgen, Boehringer Ingelheim, Merck Sharp & DohmeAndrew HendifarConsulting or Advisory Role: Novartis, Ipsen, Perthera, Celgene, AbbVie Research Funding: Ipsen Travel, Accommodations, Expenses: HalozymeDavid HenryHonoraria: Amgen, AMAG Pharmaceuticals Consulting or Advisory Role: AMAG Pharmaceuticals, Amgen Research Funding: Amgen Travel, Accommodations, Expenses: Amgen, AMAG PharmaceuticalsDaruka MahadevanHonoraria: Guardant Health, Caris Life Sciences Speakers' Bureau: Guardant Health, Caris Life Sciences Travel, Accommodations, Expenses: Guardant Health, Caris Life SciencesMohammad NezamiEmployment: Orange Coast Medical Center of Hope Stock and Other Ownership Interests: Sahel OncologyBenjamin TanConsulting or Advisory Role: Genentech Research Funding: Genentech, Eli Lilly, Pfizer, Bayer, Eisai, Exelixis, Merck Serono, Tyrogenex, SillaJen, Boehringer IngelheimZev A. WainbergConsulting or Advisory Role: Array BioPharma, Five Prime Therapeutics, Novartis, Eli Lilly, Merck, Merck KGaA, Bristol-Myers Squibb, Genentech, Bayer Research Funding: Novartis (Inst), Plexxikon (Inst), Pfizer (Inst), Merck (Inst), Five Prime Therapeutics (Inst) Travel, Accommodations, Expenses: GenentechRichard LanmanEmployment: Guardant Health, Veracyte Leadership: Guardant Health, Biolase Stock and Other Ownership Interests: Guardant Health, Biolase, Forward Medical Research Funding: Guardant HealthScott KopetzStock and Other Ownership Interests: MolecularMatch, Navire Consulting or Advisory Role: Roche, Genentech, EMD Serono, Merck, Karyopharm Therapeutics, Amal Therapeutics, Navire Pharma, Symphogen, Holy Stone, Biocartis, Amgen, Novartis, Eli Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca/MedImmune, Bayer Health, Pierre Fabre, EMD Serono Research Funding: Amgen (Inst), Sanofi (Inst), Biocartis (Inst), Guardant Health (Inst), Array BioPharma (Inst), Genentech (Inst), EMD Serono (Inst), MedImmune (Inst), Novartis (Inst), Eli Lilly (Inst)Van MorrisConsulting or Advisory Role: Clinical Genomics, Array Biopharma Research Funding: Bristol-Myers Squibb (Inst), Array BioPharma (Inst), EMD Serono (Inst) Travel, Accommodations, Expenses: Array BioPharma No other potential conflicts of interest were reported., (© 2019 by American Society of Clinical Oncology.)

PARP1/2 inhibitors are effective against BRCA2-deficient tumors. The PARP inhibitor (PARPi) olaparib received FDA breakthrough designation for treatment of metastatic castration-resistant prostate cancers (CRPC) carrying mutations in BRCA1/2 or ATM genes. Emergent resistance to PARPi has been associated with tumor-specific BRCA2 mutations that revert the normal open reading frame rescuing homologous recombination. We describe a case of metastatic CRPC with germline BRCA2 mutation with acquired resistance to olaparib related to biallelic BRCA2 reversion mutations of both the germline and somatic loss of function alleles detected by circulating tumor DNA testing. We also summarize a retrospective analysis of 1,534 prostate cancer cases with ctDNA analysis showing a 1.6% incidence of germline BRCA2 mutations. Within the germline BRCA2 -positive cases exposed to platinum chemotherapy or PARP inhibition, the prevalence of reversion mutations was 40%. This report documents the frequency of reversion mutations in a large cohort of prostate cancer patients carrying of BRCA mutations. It also shows the potential utility of ctDNA analyses for early detection of reversion mutation driving tumor resistance.

Competing Interests: AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or po.ascopubs.org/site/ifc.