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PURPOSE: Colorectal carcinomas (CRCs) with microsatellite-instability (MSI) are enriched for oncogenic kinase fusions (KFs), including NTRK1 , RET , and BRAF , but the mechanism underlying this finding is unclear. METHODS: The genomic profiles of 32,218 advanced CRC tumor specimens were analyzed to assess the fusion breakpoints of oncogenic alterations including KFs in microsatellite-stable and microsatellite-unstable CRC. Genomic contexts of such alterations were analyzed to obtain mechanistic insights. RESULTS: Genomic analysis demonstrated that oncogenic fusion breakpoints in MSI tumors do not preferentially involve repetitive or low-complexity sequences. Instead, their junction regions showed pronounced guanine and cytosine bias and elevated mutation frequency at G:C contexts. Elevated mutation frequency at G:C bases in relevant introns predicted prevalence of associated oncogenic fusions in MSI CRCs. CRCs harboring mismatch repair signatures had enrichment of butyrate-producing microbial species, reported to be associated with induction of 8-oxoguanine lesions in the intestine. CONCLUSION: Detailed analysis of breakpoints in MSI-associated KFs support a model in which inefficient repair and/or processing of microbiome-induced clustered 8-oxoguanine damage in MSI CRC contributes to the increased incidence of specific oncogenic fusions. Clustered 8-oxo-guanine mutations promote oncogenic fusions in MSI colorectal tumor [ABSTRACT FROM AUTHOR]

PURPOSE: Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a rare, aggressive primary liver carcinoma, with morphologic features of both hepatocellular carcinomas (HCC) and liver cholangiocarcinomas (CCA). METHODS: The genomic profiles of 4,975 CCA, 1,470 HCC, and 73 cHCC-CCA cases arising from comprehensive genomic profiling in the course of clinical care were reviewed for genomic alterations (GA), tumor mutational burden, microsatellite instability status, genomic loss of heterozygosity, chromosomal aneuploidy, genomic ancestry, and hepatitis B virus status. RESULTS: In cHCC-CCA, GA were most common in TP53 (65.8%), TERT (49.3%), and PTEN (9.6%), and 24.6% cHCC-CCA harbored potentially targetable GA. Other GA were predominantly associated with either HCC or CCA, including, but not limited to, TERT , FGFR2 , IDH1 , and presence of hepatitis B virus. On the basis of these features, a machine learning (ML) model was trained to classify a cHCC-CCA case as CCA-like or HCC-like. Of cHCC-CCA cases, 16% (12/73) were ML-classified as CCA-like and 58% (42/73) cHCC-CCA were ML-classified as HCC-like. The ML model classified more than 70% of cHCC-CCA as CCA-like or HCC-like on the basis of genomic profiles, without additional clinico-pathologic input. CONCLUSION: These findings demonstrate the use of ML for classification as based on a targeted exome panel used during routine clinical care. Classification of cHCC-CCA by genomic features alone creates insights into the biology of the disease and warrants further investigation for relevance to clinical care. [ABSTRACT FROM AUTHOR]

PURPOSE: BRCA1 or BRCA2 loss of function results in homologous recombination deficiency (HRD), which is targetable by poly (ADP-ribose) polymerase (PARP) inhibitors and other DNA-damaging agents. In cancers associated with germline BRCA1/2 alterations (BRCA1/2 -associated cancers: breast, ovarian, pancreatic, prostate), BRCA1/2 alterations result in HRD and are biomarkers for PARP inhibitor use. In other (non– BRCA1/2 -associated) cancer types, the association between BRCA1/2 alteration and HRD is less clear. METHODS: A total of 234,154 tumor samples were sequenced by hybrid capture-based comprehensive genomic profiling. Somatic, germline, and zygosity status was determined computationally. BRCA1/2 alterations were classified as predicted germline/somatic and biallelic/monoallelic. Genome-wide loss of heterozygosity (gLOH) was evaluated as a marker of HRD. RESULTS: BRCA1/2 alterations were observed at a 4.7% frequency. BRCA1/2 mutations were predicted germline in 57.4% of BRCA1/2 -associated and 37.2% of non– BRCA1/2 -associated cancers. The fraction of BRCA1/2 -altered cases that were biallelic was 68.7%, with a higher biallelic fraction in BRCA1/2 -associated (89.9%) versus non– BRCA1/2 -associated cancers (43.6%). Differences in tissue distribution of biallelic BRCA1 versus BRCA2 alterations were noted, including a higher rate of biallelic BRCA2 alteration in prostate cancer. Biallelic BRCA1/2 alteration was observed at a 3.2% frequency (BRCA1/2 -associated cancers, 8.9%; non– BRCA1/2 -associated cancers, 1.3%) and > 1% frequency in at least 13 cancer types. Across cancer types, biallelic BRCA1/2 alteration was associated with increased gLOH versus monoallelic or wild-type BRCA1/2 ; predicted germline or somatic mutations were both associated with elevated gLOH. CONCLUSION: Biallelic BRCA1/2 alterations were associated with elevated gLOH in diverse cancer types, including those not traditionally associated with BRCA1/2 cancer syndromes. Biomarker development for PARP inhibitors should integrate methods to distinguish biallelic from monoallelic BRCA1/2 status, and biallelic BRCA1/2 alteration should be broadly evaluated across cancer types as a biomarker for underlying HRD and PARP inhibitor sensitivity. [ABSTRACT FROM AUTHOR]

PURPOSE: To describe the clinical and molecular features of metastatic colorectal cancers (mCRCs) bearing uncommon atypical RAS (At- RAS) mutations at codons other than 12, 13, 59, 61, 117, and 146. MATERIALS AND METHODS: By exploiting five next-generation sequencing sources (Italian collaboration, Memorial Sloan Kettering Cancer Center, Samsung Medical Center, the Biomarker Research for Anti-EGFR Monoclonal Antibodies by Comprehensive Cancer Genomics (BREAC) study, and the Foundation Medicine database), we retrieved 175 At- RAS mutated cases. Molecular data were obtained from 163 samples from Memorial Sloan Kettering Cancer Center and the Foundation Medicine database. Clinical data were available for 27 At- RAS –positive and 467 negative cases from the Italian collaboration, Memorial Sloan Kettering Cancer Center, Samsung Medical Center, and the BREAC study. RESULTS: At- RAS mutations were identified in 163 (0.9%) of 18,270 mCRCs. Among 133 with evaluable microsatellite instability status, 11 (8%) were microsatellite instability high. POLE exonuclease domain mutations had higher frequency (7%) than expected and were found only in microsatellite-stable tumors with high tumor mutational burden (TMB). Overall, 17% (28 of 163) of At- RAS cases had TMB greater than 20 mutations/Mb. Co-occurring typical RAS /BRAF V600E mutations and NF1 mutations, presumed to cause RAS activation, were found in 30% and 12% of samples, respectively (up to 43% and 50%, respectively, in TMB-high samples). Patients with RAS/BRAF wild-type mCRC achieved a median overall survival (OS) of 42.1 months, whereas those harboring isolated At- RAS , typical RAS , or BRAF V600E mutations showed a median OS of 32.3, 30.0, and 17.9 months, respectively (P <.001). No significant OS difference (P =.240) was found between patients with At- RAS versus typical RAS -mutated mCRC. Only one of six patients evaluable for primary resistance to anti–epidermal growth factor receptors achieved tumor response. CONCLUSION: At- RAS mutations may be a marker for RAS pathway activation and can be associated with high co-occurrence of POLE exonuclease domain mutations. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 77-year-old white man with a prior history of smoking presented with shortness of breath. Chest radiograph revealed a right lower lobe (RLL) nodule. It notes Computed tomography (CT) scan of the chest confirmed a 1.5-cm irregular nodular opacity within the RLL. The article discusses activity of brigatinib in crizotinib and ceritinib-resistant ROS1- rearranged non–small-cell lung cancer.

The article presents a case study of a 68-year-old white male who was admitted with Siewert type II and adenocarcinoma which has resulted in dysphagia and weight loss. It talks about the patient being given radiotherapy along with oxaliplatin and fluorouracil in order to stable the patient. It tells about the role of immunotherapy in the treatment of adenocarcinomas.

The article presents a case study of a 48 year old woman with palpable mass in the left breast that was confirmed on mammogram and ultrasound, revealing an estrogen receptor and progesterone receptor. It talks about her being treated with left partial mastectomy and sentinel node biopsy, invasive cancer with metastatic disease was revealed in one sentinel node and she also took chemotherapy and radiation therapy for the remaining breast and nodal areas.

Purpose: Appendiceal neoplasms are heterogeneous and are often treated with chemotherapy similarly to colorectal cancer (CRC). Genomic profiling was performed on 703 appendiceal cancer specimens to compare the mutation profiles of appendiceal subtypes to CRC and other cancers, with the ultimate aim to identify potential biomarkers and novel therapeutic targets. Methods: Tumor specimens were submitted to a Clinical Laboratory Improvement Amendments–certified laboratory (Foundation Medicine, Cambridge, MA) for hybrid-capture–based sequencing of 3,769 exons from 315 cancer-related genes and 47 introns of 28 genes commonly rearranged in cancer. Interactions between genotype, histologic subtype, treatment, and overall survival (OS) were analyzed in a clinically annotated subset of 76 cases. Results: There were five major histopathologic subtypes: mucinous adenocarcinomas (46%), adenocarcinomas (30%), goblet cell carcinoids (12%), pseudomyxoma peritonei (7.7%), and signet ring cell carcinomas (5.2%). KRAS (35% to 81%) and GNAS (8% to 72%) were the most frequent alterations in epithelial cancers; APC and TP53 mutations were significantly less frequent in appendiceal cancers relative to CRC. Low-grade and high-grade tumors were enriched for GNAS and TP53 mutations, respectively (both χ2 P <.001). GNAS and TP53 were mutually exclusive (Bonferroni corrected P <.001). Tumor grade and TP53 mutation status independently predicted OS. The mutation status of GNAS and TP53 strongly predicted OS (median, 37.1 months for TP53 mutant v 75.8 GNAS - TP53 wild type v 115.5 GNAS mutant; log-rank P =.0031) and performed as well as grade in risk stratifying patients. Conclusion: Epithelial appendiceal cancers and goblet cell carcinoids show differences in KRAS and GNAS mutation frequencies and have mutation profiles distinct from CRC. This study highlights the benefit of performing molecular profiling on rare tumors to identify prognostic and predictive biomarkers and new therapeutic targets. [ABSTRACT FROM AUTHOR]

The article presents a case study of a girl in whom tumor sequencing caused identification of a new NTRK2 gene fusion in a metastatic sarcoma. Biopsy resulted in the diagnosis of Nonrhabdomyosarcoma soft tissue sarcoma which was treated by use of larotrectinib. The patient had distended abdomen with significant back pain requiring narcotics daily.

Purpose The promise of precision oncology is that identification of genomic alterations will direct the rational use of molecularly targeted therapy. This approach is particularly applicable to neoplasms that are resistant to standard cytotoxic chemotherapy, like T-cell leukemias and lymphomas. In this study, we tested the feasibility of targeted next-generation sequencing in profiles of diverse T-cell neoplasms and focused on the therapeutic utility of targeting activated JAK1 and JAK3 in an index case. Patients and Methods Using Foundation One and Foundation One Heme assays, we performed genomic profiling on 91 consecutive T-cell neoplasms for alterations in 405 genes. The samples were sequenced to high uniform coverage with an Illumina HiSeq and averaged a coverage depth of greater than 500× for DNA and more than 8M total pairs for RNA. An index case of T-cell prolymphocytic leukemia (T-PLL), which was analyzed by targeted next-generation sequencing, is presented. T-PLL cells were analyzed by RNA-seq, in vitro drug testing, mass cytometry, and phospho-flow. Results One third of the samples had genomic aberrations in the JAK-STAT pathway, most often composed of JAK1 and JAK3 gain-of-function mutations. We present an index case of a patient with T-PLL with a clonal JAK1 V658F mutation that responded to ruxolitinib therapy. After relapse developed, an expanded clone that harbored mutant JAK3 M511I and downregulation of the phosphatase, CD45, was identified. We demonstrate that the JAK missense mutations were activating, caused pathway hyperactivation, and conferred cytokine hypersensitivity. Conclusion These results underscore the utility of profiling occurrences of resistance to standard regimens and support JAK enzymes as rational therapeutic targets for T-cell leukemias and lymphomas. [ABSTRACT FROM AUTHOR]

A 74-year-old man was noted to have subcentimeter nodules on chest computerized tomography imaging performed for lung cancer screening. Formalin-fixed paraffin-embedded tumor derived from the original nephrectomy specimen was analyzed by hybridization capture of all coding exons from 315 cancer-related genes and select introns of 28 genes commonly rearranged in cancer. Serial computed tomography imaging of a patient with metastatic collecting duct carcinoma and loss of CDKN2A/B (A) before initiation of palbociclib and (B) after 3 months of therapy. For patients with CDC, additional genomic profiling studies are needed, given the response to palbociclib observed in this study, which suggests that CDK4/6 inhibitors should be further explored for patients with I CDKN2A- i altered CDC. [Extracted from the article]

The management of locally advanced esophageal and gastric cancer is an evolving field, but despite improvement in response rates and surgical techniques, recurrence rates for stage III disease remain high.[1],[2] Surgical resection is potentially curative and associated with established morbidity and mortality risk, limiting surgery to medically fit patients. Endoscopic ultrasound demonstrated uT3N1 disease, and the patient was staged as clinical stage III Siewert type 1 GEJ adenocarcinoma. The ability to identify the optimal therapy for each patient is the hallmark of the precision medicine paradigm but has largely remained elusive in esophagogastric cancers to date. [Extracted from the article]

Purpose: TMPRSS2-ERG gene fusions are frequently found in prostate cancer and are pathognomonic for prostatic origin. In a series of cancer cases assayed with comprehensive genomic profiling (CGP) in the course of clinical care, we reviewed the frequency of TMPRSS2-ERG fusions in patient tumors of various histologic subtypes. Methods: Frequency of TMPRSS2-ERG fusions was determined in CGPs from 64,263 cancer cases submitted to Foundation Medicine to assess genomic alterations suggesting benefit from targeted therapy. Genomic results are presented from an index case of prostate cancer that underwent evolution from adenocarcinoma to pure squamous cell carcinoma. Results: TMPRSS2-ERG fusions were identified for 0.86% of male patients (250 of 29,030) and not found for female patients (none of 35,233). TMPRSS2-ERG fusions were detected in six tumors classified as squamous carcinoma, five of which were of unknown primary site. The index case is a patient with a large, left retrovesical mass diagnosed as squamous carcinoma by morphologic examination and a history of Gleason score 9 prostate cancer with prior prostatectomy and salvage radiation therapy. TMPRSS2-ERG was detected by genomic profiling in the squamous cell tumor, the primary adenocarcinoma of the prostate, and in a metachronous prostatic adenocarcinoma metastasis. On the basis of these results, the patient received androgen deprivation therapy. A phylogenetic tree demonstrating clonal and histopathologic evolution of prostate cancer in the index patient was constructed. Conclusion: In this large CGP dataset, TMPRSS2-ERG fusion was seen in approximately 30% of prostate cancers regardless of histologic type; on occasion, the fusion was detected in advanced cancers not initially carrying a diagnosis of prostate carcinoma. CGP of advanced cancers in men may reveal prostatic origin by detection of the pathognomonic TMPRSS2-ERG fusion gene. [ABSTRACT FROM AUTHOR]

DNA repair pathways are disrupted in PALB2-deficient cells, thereby accounting for the tumor suppressor gene properties of I PALB2 i .[1],[2] Durable benefit from olaparib in a patient with metastatic prostate cancer and heterozygous I PALB2 i gene deletion[30] and a case of PALB2-mutant pancreatic cancer treated with mitomycin C have been reported.[31] Because it is not yet known, further study is warranted to determine how closely the PALB2 alterations described thus far share traits with cancers defined by BRCAness. Pseudopapillary neoplasm of the pancreas is a rare epithelial tumor comprising 1% to 2% of exocrine pancreatic neoplasms.[32] These tumors generally present as large encapsulated masses, although metastatic disease has been reported. Although several local therapies (eg, surgical resection, tumor embolization, and radiotherapy) have been described, no standard of care exists.[33]-[35] Our patient highlights the potential of CGP in identifying tumor-specific and actionable drug targets for uncommon neoplasms. [Extracted from the article]

We present a case of a patient with advanced estrogen receptor/progesterone receptor-positive, HER2-negative (by fluorescent in situ hybridization) breast cancer, refractory to estrogen receptor-targeted therapy. Furthermore, breast carcinomas with I ERBB2 i kinase domain (KD) mutations are marked by cosegregation with I MAP3K1 i alterations, and the majority of breast cancer cases with the G776V mutation are ER positive, which are not general features of HER2-positive or I ERBB2 i -mutant breast cancer and, thus, may denote a distinct class of breast carcinoma driven by ERBB2 KD alterations. HER2-targeted agents have shown high rates of clinical benefit in HER2-positive breast cancers and are approved for both ER-negative and ER-positive patients.[11],[12] The clinical data for HER2-negative breast carcinoma cases driven by I ERBB2 i mutations are considerably more limited. 51 Kris MG Camidge DR Giaccone Get al: Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors. [Extracted from the article]

Purpose: Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor approved in China. This double-blind phase III trial evaluated the efficacy and safety of aumolertinib compared with gefitinib as a first-line treatment for locally advanced or metastatic EGFR -mutated non-small-cell lung cancer (NSCLC; ClinicalTrials.gov identifier: NCT03849768)., Methods: Patients at 53 sites in China were randomly assigned 1:1 to receive either aumolertinib (110 mg) or gefitinib (250 mg) once daily. The primary end point was progression-free survival (PFS) per investigator assessment., Results: A total of 429 patients who were naïve to treatment for locally advanced or metastatic NSCLC were enrolled. PFS was significantly longer with aumolertinib compared with gefitinib (hazard ratio, 0.46; 95% CI, 0.36 to 0.60; P < .0001). The median PFS with aumolertinib was 19.3 months (95% CI, 17.8 to 20.8) versus 9.9 months with gefitinib (95% CI, 8.3 to 12.6). Objective response rate and disease control rate were similar in the aumolertinib and gefitinib groups (objective response rate, 73.8% and 72.1%, respectively; disease control rate, 93.0% and 96.7%, respectively). The median duration of response was 18.1 months (95% CI, 15.2 to not applicable) with aumolertinib versus 8.3 months (95% CI, 6.9 to 11.1) with gefitinib. Adverse events of grade ≥ 3 severity (any cause) were observed in 36.4% and 35.8% of patients in the aumolertinib and gefitinib groups, respectively. Rash and diarrhea (any grade) were observed in 23.4% and 16.4% of patients who received aumolertinib compared with 41.4% and 35.8% of those who received gefitinib, respectively., Conclusion: Aumolertinib is a well-tolerated third-generation epidermal growth factor receptor tyrosine kinase inhibitor that could serve as a treatment option for EGFR -mutant NSCLC in the first-line setting.

Emerging evidence suggests a correlation between the tumor mutational burden (TMB) and the response to programmed cell death-1 protein (PD-1) monotherapy across multiple cancer types. In skin cancers, as high TMB is mostly because of ultraviolet (UV) exposure, we hypothesized a correlation between the primary melanoma cutaneous location according to sun exposure and response to anti-PD-1 monotherapy., Methods: The aim of this study was to analyze, in advanced melanoma, the relationship between TMB, locations according to sun exposure, and response to PD-1 inhibitors. We conducted a prospective multicentric analysis, by sequencing the most recent metastatic sample before PD-1 inhibitors using FoundationOne assay., Results: One hundred two patients were included, with TMB available for 94 cases. In univariate and multivariate linear regression, TMB was significantly associated with sun-exposed areas of the primary melanoma location and with age (coefficients of the association with log-TMB: non-UV location, -1.05; chronic sun-exposed area, 1.12; P value for the location, < 10 -5 ; age, 0.021 per year, P value for age, .002). Molecular UV signature present on the metastatic site was associated with higher TMB ( P = .003). Melanomas bearing a high TMB had a higher probability of response to PD-1 inhibitors compared with melanomas with a low TMB, with a dose-dependent effect following an exponential curve and a negative odds ratio of 0.40 (95% CI, 0.20 to 0.72, P = .004) between log-TMB and 6-month progression., Conclusion: Cumulative sun exposure related to skin location and molecular UV signature present on the metastatic site appear to be relevant biomarkers directly linked to TMB. Because TMB is not yet available to all for routine clinical use, the location of the primary melanoma in a sun-exposed area may play an important role in clinical decisions regarding therapeutic choice., Competing Interests: Lise Boussemart Consulting or Advisory Role: BMS, Pierre Fabre, Novartis, MSD, Pfizer Patents, Royalties, Other Intellectual Property: Application PCT/EP2014/059797, published on 2014-11-20 (WO2014184211): Prognosis and predictive biomarkers and biological applications thereof No potential conflicts of interest were reported. Lise Boussemart Consulting or Advisory Role: BMS, Pierre Fabre, Novartis, MSD, Pfizer Patents, Royalties, Other Intellectual Property: Application PCT/EP2014/059797, published on 2014-11-20 (WO2014184211): Prognosis and predictive biomarkers and biological applications thereof No potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Purpose: Comprehensive genomic profiling (CGP) is increasingly used for routine clinical management of prostate cancer. To inform targeted treatment strategies, 3,476 clinically advanced prostate tumors were analyzed by CGP for genomic alterations (GAs) and signatures of genomic instability., Methods: Prostate cancer samples (1,660 primary site and 1,816 metastatic site tumors from unmatched patients) were prospectively analyzed by CGP (FoundationOne Assay; Foundation Medicine, Cambridge, MA) for GAs and genomic signatures (genome-wide loss of heterozygosity [gLOH], microsatellite instability [MSI] status, tumor mutational burden [TMB])., Results: Frequently altered genes were TP53 (44%), PTEN (32%), TMPRSS2-ERG (31%), and AR (23%). Potentially targetable GAs were frequently identified in DNA repair, phosphatidylinositol 3-kinase, and RAS/RAF/MEK pathways. DNA repair pathway GAs included homologous recombination repair (23%), Fanconi anemia (5%), CDK12 (6%), and mismatch repair (4%) GAs. BRCA1/2, ATR, and FANCA GAs were associated with high gLOH, whereas CDK12- altered tumors were infrequently gLOH high. Median TMB was low (2.6 mutations/Mb). A subset of cases (3%) had high TMB, of which 71% also had high MSI. Metastatic site tumors were enriched for the 11q13 amplicon ( CCND1/FGF19/FGF4/FGF3) and GAs in AR, LYN, MYC, NCOR1, PIK3CB, and RB1 compared with primary tumors., Conclusion: Routine clinical CGP in the real-world setting identified GAs that are investigational biomarkers for targeted therapies in 57% of cases. gLOH and MSI/TMB signatures could further inform selection of poly (ADP-ribose) polymerase inhibitors and immunotherapies, respectively. Correlation of DNA repair GAs with gLOH identified genes associated with homologous recombination repair deficiency. GAs enriched in metastatic site tumors suggest therapeutic strategies for metastatic prostate cancer. Lack of clinical outcome correlation was a limitation of this study., 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 ascopubs.org/po/authorcenter. Jon H. Chung Employment: Foundation Medicine Ninad Dewal Employment: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Ethan Sokol Employment: Foundation Medicine Paul Mathew Honoraria: Exelixis Patents, Royalties, Other Intellectual Property: Patent pending on new therapeutic invention Travel, Accommodations, Expenses: Exelixis Robert Whitehead Employment: UnitedHealthcare, Cancer Treatment Centers of America Sherri Z. Millis Employment: Foundation Medicine Garrett M. Frampton Employment: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Sumanta K. Pal Honoraria: Novartis, Medivation, Astellas Pharma Consulting or Advisory Role: Pfizer, Novartis, Aveo, Myriad Pharmaceuticals, Genentech, Exelixis, Bristol-Myers Squibb, Astellas Pharma, Ipsen, Eisai Research Funding: Medivation Richard J. Lee Consulting or Advisory Role: Janssen Pharmaceuticals, Exelixis Research Funding: Janssen Pharmaceuticals Andrea Necchi Employment: Bayer AG (I) Stock and Other Ownership Interests: Bayer AG (I) Honoraria: Roche, Merck, AstraZeneca, Janssen Pharmaceuticals, Foundation Medicine Consulting or Advisory Role: Merck Sharp & Dohme, Roche, Bayer AG, AstraZeneca, Clovis Oncology, Janssen Pharmaceuticals, Incyte, Seattle Genetics, Astellas Pharma, Bristol-Myers Squibb, Rainier Therapeutics Research Funding: Merck Sharp & Dohme (Inst), AstraZeneca (Inst) Travel, Accommodations, Expenses: Roche, Merck Sharp & Dohme, AstraZeneca, Janssen Pharmaceuticals Other Relationship: Bayer AG (I) Jeffrey P. Gregg Consulting or Advisory Role: AstraZeneca, Bristol-Myers Squibb, Roche, Foundation Medicine Speakers’ Bureau: AstraZeneca, Foundation Medicine, Bristol-Myers Squibb Primo Lara Jr Honoraria: Pfizer Consulting or Advisory Role: Exelixis, Pfizer, AstraZeneca, Bayer AG, Genentech, Roche, Janssen Pharmaceuticals, Bristol-Myers Squibb, AbbVie, Turnstone Bio, Foundation Medicine, Merck, CellMax Life, Nektar Research Funding: Millennium Pharmaceuticals (Inst), Polaris (Inst), GlaxoSmithKline (Inst), Genentech (Inst), Aragon Pharmaceuticals (Inst), Janssen Pharmaceuticals (Inst), Heat Biologics (Inst), TRACON Pharma (Inst), Merck (Inst), Pharmacyclics (Inst), Incyte (Inst) Emmanuel S. Antonarakis Honoraria: Sanofi, Dendreon, Medivation, Janssen Pharmaceuticals, ESSA, Astellas Pharma, Merck, AstraZeneca, Clovis Oncology Consulting or Advisory Role: Sanofi, Dendreon, Medivation, Janssen Pharmaceuticals, ESSA, Astellas Pharma, Merck, AstraZeneca, Clovis Oncology Research Funding: Janssen Pharmaceuticals (Inst), Johnson & Johnson (Inst), Sanofi (Inst), Dendreon (Inst), Aragon Pharmaceuticals (Inst), Exelixis (Inst), Millennium Pharmaceuticals (Inst), Genentech (Inst), Novartis (Inst), Astellas Pharma (Inst), Tokai Pharmaceuticals (Inst), Merck (Inst), AstraZeneca (Inst), Clovis Oncology (Inst), Constellation Pharmaceuticals (Inst) Patents, Royalties, Other Intellectual Property: Co-inventor of a biomarker technology that has been licensed to QIAGEN Travel, Accommodations, Expenses: Sanofi, Dendreon, Medivation Vincent A. Miller Employment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Consulting or Advisory Role: Revolution Medicines Patents, Royalties, Other Intellectual Property: Receive periodic royalties related to T790M patent awarded to Memorial Sloan Kettering Cancer Center Jeffrey S. Ross Employment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Research Funding: Foundation Medicine Siraj M. Ali Employment: Foundation Medicine Leadership: Incysus Stock and Other Ownership Interests: Exelixis, Blueprint Medicines, Agios, Genocea Biosciences Consulting or Advisory Role: Revolution Medicines, Azitra (I), Princepx Tx (I) Patents, Royalties, Other Intellectual Property: Patents through Foundation Medicine, patents through Seres Health on microbiome studies in nonneoplastic disease (I) Neeraj Agarwal Consulting or Advisory Role: Pfizer, Exelixis, Medivation, Astellas Pharma, Eisai, Merck, Novartis, EMD Serono, Clovis Oncology, Genentech, Roche, Bristol-Myers Squibb, AstraZeneca, Nektar, Eli Lilly, Bayer AG, Foundation Medicine, Argos Therapeutics

Purpose: In advanced stages, large-cell neuroendocrine carcinoma of the lung (L-LCNEC) mimics small-cell lung cancer despite its traditional classification as a non-small-cell lung cancer. Here we present a focused analysis of BRAF mutations in this population., Patients and Methods: Comprehensive genomic profiling of tumor tissues was performed from a cohort of 300 patients with biopsy-proven L-LCNEC. Specimens were either from a primary lung lesion or metastatic site., Results: In 13 patients, 14 unique BRAF alterations (amplifications, mutations) were identified. The importance of biomarker-driven therapy is subsequently highlighted with our case of a 69-year-old man diagnosed with metastatic L-LCNEC who did not respond to cisplatin plus etoposide. A significant durable response was then demonstrated with therapy targeted toward a BRAF non-V600E activating mutation (G469R) associated with biomarker response identified through circulating cell-free tumor DNA analysis. A change in clonal allele frequency from nearly 40% to nondetectable was observed., Conclusion: Although uncommon, L-LCNEC does seem to contain activating and therefore actionable alterations. We thus highlight the value of pursuing next-generation sequencing for patients with this disease.

Purpose: Dabrafenib and trametinib are approved for the management of advanced non-small-cell lung cancers (NSCLCs) that harbor BRAF V600E mutations. Small series and pan-cancer analyses have identified non-V600 alterations as therapeutic targets. We sought to examine a large genomic data set to comprehensively characterize non-V600 B RAF alterations in lung cancer., Patients and Methods: A total of 23,396 patients with lung cancer provided data to assay with comprehensive genomic profiling. Data were reviewed for predicted pathogenic BRAF base substitutions, short insertions and deletions, copy number changes, and rearrangements., Results: Adenocarcinomas represented 65% of the occurrences; NSCLC not otherwise specified (NOS), 15%; squamous cell carcinoma, 12%; and small-cell lung carcinoma, 5%. BRAF was altered in 4.5% (1,048 of 23,396) of all tumors; 37.4% (n = 397) were BRAF V600E, 38% were BRAF non-V600E activating mutations, and 18% were BRAF inactivating. Rearrangements were observed at a frequency of 4.3% and consisted of N-terminal deletions (NTDs; 0.75%), kinase domain duplications (KDDs; 0.75%), and BRAF fusions (2.8%). The fusions involved three recurrent fusion partners: ARMC10 , DOCK4, and TRIM24 . BRAF V600E was associated with co-occurrence of SETD2 alterations, but other BRAF alterations were not and were instead associated with CDKN2A , TP53 , and STK11 alterations ( P < .05). Potential mechanisms of acquired resistance to BRAF V600E inhibition are demonstrated., Conclusion: This series characterized the frequent occurrence (4.4%) of BRAF alterations in lung cancers. Recurrent BRAF alterations in NSCLC adenocarcinoma are comparable to the frequency of other NSCLC oncogenic drivers, such as ALK , and exceed that of ROS1 or RET . This work supports a broad profiling approach in lung cancers and suggests that non-V600E BR AF alterations represent a subgroup of lung cancers in which targeted therapy should be considered., Competing Interests: 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 ascopubs.org/po/author-center. Yuri SheikineConsulting or Advisory Role: Foundation MedicineDean PavlickNo relationship to discloseSamuel KlempnerConsulting or Advisory Role: Lilly, Boston Biomedical, Celgene, Astellas Pharma Speakers' Bureau: Foundation Medicine Research Funding: Leap Therapeutics (Inst)Sally E. TrabuccoEmployment: Foundation Medicine Research Funding: Foundation Medicine Travel, Accommodations, Expenses: Foundation MedicineJon ChungEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineMark RosenzweigEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineKai WangNo relationship to discloseVamsidhar VelchetiHonoraria: Novartis, Foundation Medicine, Merck, Bristol-Myers Squibb, Genentech, Roche Consulting or Advisory Role: Clovis Oncology, Genentech, Bristol-Myers Squibb, Merck, Celgene, Foundation Medicine, AstraZeneca, MedImmune, Genoptix, Amgen, Takeda Research Funding: Genentech (Inst), Trovagene (Inst), Eisai (Inst), OncoPlex Diagnostics (Inst), ALkermes (Inst), NantOmics (Inst), GEnoptix (Inst), Altor BioScience (Inst), Merck (Inst), Bristol-Myers Squibb (Inst), Atreca (Inst), Heat Biologics (Inst), Leap Therapeutics (Inst) Travel, Accommodations, Expenses: AstraZeneca/MedImmune, Eisai, Foundation Medicine, MerckGarrett M. FramptonEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineNir PeledConsulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, MSD, Novartis, Pfizer, Roche Speakers' Bureau: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, MSD, Novartis, Pfizer, RocheMolly MurrayEmployment: Foundation MedicineYoung Kwang ChaeConsulting or Advisory Role: Foundation Medicine, Boehringer Ingelheim, Biodesix, Counsyl, AstraZeneca, Guardant Health Speakers' Bureau: Merck, Genentech, Roche Travel, Accommodations, Expenses: HanmiLee A. AlbackerEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineLaurie GayEmployment: Foundation Medicine Stock and Other Ownership Interests: Gilead Sciences, Foundation MedicineHatim HusainConsulting or Advisory Role: AstraZeneca, Abbvie, Foundation Medicine Speakers' Bureau: AstraZeneca, Merck, Bristol-Myers Squibb Research Funding: Pfizer (Inst) Travel, Accommodations, Expenses: AstraZeneca, Merck, Bristol-Myers Squibb, Foundation Medicine, AbbvieJames SuhEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineSherri MillisEmployment: Foundation MedicineVenkataprasanth ReddyEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Travel, Accommodations, Expenses: Foundation MedicineJulia ElvinEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineRyan J. HartmaierEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Patents, Royalties, Other Intellectual Property: Nfe2L2 exon 2 and/or exon 3 loss from work conducted at Foundation Medicine (provisional patent filed) (Inst)Afshin DowlatiConsulting or Advisory Role: Abbvie, Stemcentrx, Ariad Research Funding: Lilly (Inst), ImClone (Inst), Amgen (Inst), Bristol-Myers Squibb (Inst), OncoMed (Inst), EMD Serono (Inst), MedImmune (Inst)Phil StephensEmployment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineJeffrey RossEmployment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Honoraria: Pfizer, EMD Merck Serono Research Funding: Foundation MedicineTrever BivonaStock and Other Ownership Interests: Driver Honoraria: Novartis, AstraZeneca, Array BioPharma, Revolution Medicine Consulting or Advisory Role: Revolution Medicine, Array BioPharma, Novartis, AstraZeneca Speakers' Bureau: Novartis Research Funding: Ignyta, Revolution MedicineVincent MillerEmployment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Patents, Royalties, Other Intellectual Property: Receive periodic royalties related to T790M patent awarded to Memorial Sloan Kettering Cancer CenterShridar GanesanEmployment: Merck (I) Stock and Other Ownership Interests: Ibris, Inspirata, Merck (I) Consulting or Advisory Role: Inspirata, Novartis Patents, Royalties, Other Intellectual Property: I hold two patents for digital imaging that may be licensed to Ibris and Inspirata Travel, Accommodations, Expenses: InspirataAlexa SchrockEmployment: Foundation Medicine Stock and Other Ownership Interests: Foundation MedicineSai-Hong OuHonoraria: Pfizer, Roche Pharma AG, Genentech, Roche, ARIAD, Takeda, Novartis, AstraZeneca, Foundation Medicine Consulting or Advisory Role: Pfizer, Roche, Genentech, Novartis, AstraZeneca, Takeda, ARIAD, Foundation Medicine Speakers' Bureau: Genentech, AstraZeneca, Takeda, ARIAD Research Funding: Pfizer (Inst), Roche Pharma AG (Inst), AstraZeneca (Inst), MedImmune (Inst), Clovis Oncology (Inst), ARIAD (Inst), Ignyta (Inst), Peregrine Pharmaceuticals (Inst), GlaxoSmithKline (Inst), Astellas Pharma (Inst), Chugai Pharma (Inst)Siraj AliEmployment: Foundation Medicine Stock and Other Ownership Interests: Exelixis, Blueprint Medicines, Agios Patents, Royalties, Other Intellectual Property: Patents via Foundation Medicine; patents via Seres Health on microbiomes in non-neoplastic disease (I), (© 2018 by American Society of Clinical Oncology.)

Purpose ROS1 rearrangement is a distinct molecular subset of non-small-cell lung cancer (NSCLC). We investigated the efficacy and safety of ceritinib in patients with ROS1-rearranged NSCLC. Patients and Methods We enrolled 32 patients with advanced NSCLC who tested positive for ROS1 rearrangement by fluorescent in situ hybridization. Ceritinib 750 mg was administered once daily. The primary end point was objective response rate. The secondary end points were disease control rate; duration of response; progression-free survival; overall survival; toxicity; and concordance among fluorescent in situ hybridization, immunohistochemistry, and next-generation sequencing. Results Between June 7, 2013, and February 1, 2016, 404 patients underwent ROS1 prescreening, and 32 patients with ROS1 rearrangement were enrolled. All patients except two were crizotinib-naïve. At the time of data cutoff, the median follow-up was 14.0 months, and 18 patients (56%) had discontinued treatment. Of the 32 patients enrolled, 28 were evaluable for response by independent radiologic review. Objective response rate was 62% (95% CI, 45% to 77%), with one complete response and 19 partial responses; duration of response was 21.0 months (95% CI, 17 to 25 months); and disease control rate was 81% (95% CI, 65% to 91%). The median progression-free survival was 9.3 months (95% CI, 0 to 22 months) for all patients and 19.3 months (95% CI, 1 to 37 months) for crizotinib-naïve patients. The median overall survival was 24 months (95% CI, 5 to 43 months). Of the eight patients with brain metastases, intracranial disease control was reported in five (63%; 95% CI, 31% to 86%). The most common adverse events (majority, grade 1 or 2) for all treated patients were diarrhea (78%), nausea (59%), and anorexia (56%). Conclusion Ceritinib demonstrated potent clinical activity in patients with ROS1-rearranged NSCLC who were heavily treated previously with multiple lines of chemotherapy.

Purpose Molecular diagnostic testing has become an integral part of the evaluation of patients with metastatic colorectal cancer (CRC). Expanded mutational testing, such as next-generation sequencing (NGS), often identifies mutations with unclear clinical or prognostic implications. One such example is BRAF mutations that occur outside of codon 600 ( non-V600 BRAF mutations). Methods We conducted this multicenter, retrospective cohort study to characterize the clinical, pathologic, and survival implications of non-V600 BRAF mutations in metastatic CRC. We pooled patients in whom non-V600 BRAF mutations were identified from NGS databases at three large molecular genetics reference laboratories. Results A total of 9,643 patients with metastatic CRC underwent NGS testing. We identified 208 patients with non-V600 BRAF mutations, which occurred in 2.2% of all patients tested and accounted for 22% of all BRAF mutations identified. Cancers with non-V600 BRAF mutations, compared with cancers with V600E BRAF ( V600E BRAF) mutations, were found in patients who were significantly younger (58 v 68 years, respectively), fewer female patients (46% v 65%, respectively), and patients who had fewer high-grade tumors (13% v 64%, respectively) or right-sided primary tumors (36% v 81%, respectively). Median overall survival was significantly longer in patients with non-V600 BRAF-mutant metastatic CRC compared with those with both V600E BRAF-mutant and wild-type BRAF metastatic CRC (60.7 v 11.4 v 43.0 months, respectively; P < .001). In multivariable analysis, non-V600 BRAF mutation was independently associated with improved overall survival (hazard ratio, 0.18; P < .001). Conclusion Non-V600 BRAF mutations occur in approximately 2.2% of patients with metastatic CRC and define a clinically distinct subtype of CRC with an excellent prognosis.