Decision-making as discovery: Vetting clinical research in a leading precision oncology service.

Based on fieldwork carried out at the Early Drug Development Service of a world-leading cancer institution, our study sheds lights on decision-making processes at the stage where decisions are made about which clinical trial to pursue and thus which experimental drugs will feed the growing pipeline of molecularly guided therapies and therapeutic strategies available to treating physicians. The paper shows how such collective decision-making practices by a translational research unit employ formal tools and ad hoc valuation strategies that interweave technical-scientific matters of concern with patient-oriented clinical ones, as part of the institutional assetization of biomedical knowledge production. In the process, decision-making practices in part define the conditions of possibility for the provision of care in what is increasingly becoming a 'clinic of variants.' They do so by reconfiguring on an evolving basis the socio-material ecosystem through which precision oncology is enacted as a rapidly evolving assemblage of patients, physicians, research and support staff, protocols, molecular markers, drugs and administrative components.

Clinical implications of drug-induced liver injury in early-phase oncology clinical trials.

BACKGROUND: Data on drug-induced liver injury (DILI) and acute liver failure (ALF) in modern phase 1 oncology trials are limited, specifically with respect to the incidence and resolution of DILI and the safety of drug rechallenge. METHODS: This study reviewed all patients who were recruited to phase 1 oncology trials between 2013 and 2017 at Memorial Sloan Kettering Cancer Center. Clinicopathologic data were extracted to characterize DILI, and attribution was assessed on the basis of data prospectively generated during the studies. Logistic regression models were used to explore factors related to DILI and DILI recurrence after drug rechallenge. RESULTS: Among 1670 cases recruited to 85 phase 1 trials, 81 (4.9%) developed DILI. The rate of DILI occurrence was similar for patients in immune-based trials and patients in targeted therapy trials (5.0% vs 4.9%), as was the median time to DILI (5.5 vs 6.5 weeks; P = .48). Two patients (0.12%) met the criteria of Hy's law, although none developed ALF. The DILI resolved in 96% of the patients. Pretreatment factors were not predictive for DILI development. Thirty-six of the 81 patients underwent a drug rechallenge, and 28% of these patients developed DILI recurrence. Peak alanine aminotransferase during the initial DILI was associated with DILI recurrence (odds ratio, 1.04; 95% confidence interval, 1.0-1.09; P = .035). CONCLUSIONS: In modern phase 1 oncology trials, DILI is uncommon, may occur at any time, and often resolves with supportive measures. Rechallenging after DILI is feasible; however, the high rate of DILI recurrence suggests that clinicians should consider the severity of the DILI episode and treatment alternatives.

Organizing precision medicine: A case study of Memorial Sloan Kettering Cancer Center's engagement in/with genomics.

Recent decades have seen a dramatic rise of in the number of initiatives designed to promote precision oncology, a domain that has played a pioneering role in the implementation of post-genomic approaches and technologies such as innovative clinical trial designs and molecular profiling. In this paper, based on fieldwork carried out at the Memorial Sloan-Kettering Cancer Center from 2019 onwards, we analyze how a world-leading cancer center has adapted, responded, and contributed to the challenge of "doing" precision oncology by developing new programs and services, and building an infrastructure that has created the conditions for genomic practices. We do so by attending to the "organizing" side of precision oncology and to the nexus between these activities and epistemic issues. We situate the work that goes into making results actionable and accessing targeted drugs within the larger process of creating a precision medicine ecosystem that includes purpose-built institutional settings, thus simultaneously experimenting with bioclinical matters and, reflexively, with organizing practices. The constitution and articulation of innovative sociotechnical arrangements at MSK provides a unique case study of the production of a large and complex clinical research ecosystem designed to implement rapidly evolving therapeutic strategies embedded in a renewed and dynamic understanding of cancer biology.

Spectrum of BRAF Mutations and Gene Rearrangements in Ovarian Serous Carcinoma.

Low-grade serous carcinoma (LGSC) is a rare type of ovarian cancer, which commonly arises from serous borderline tumor (SBT) and is characterized by frequent activating mutations in the mitogen-activated protein kinase pathway, including BRAF. The BRAF V600E mutation is associated with improved prognosis in SBT and LGSC, and responses to BRAF inhibitor therapy have been reported. We sought to characterize the clinicopathologic and molecular features of BRAF-driven tubo-ovarian and primary peritoneal serous tumors. METHODS: Retrospective analysis of our institutional cohort of SBTs (n = 22), LGSCs (n = 119) and high-grade serous carcinomas (HGSCs, n = 1,290) subjected to targeted massively parallel sequencing was performed to identify cases with BRAF genetic alterations. Putative BRAF rearrangements were confirmed using targeted RNA sequencing and/or fluorescence in situ hybridization (FISH). BRAFV600E oncoprotein expression was assessed by immunohistochemistry on selected cases. RESULTS: BRAF somatic genetic alterations were identified in 29 of 1,431 (2%) serous tumors and included mutations (n = 24), gene rearrangements (n = 3), and amplification (n = 2). BRAF mutations were more frequent in SBTs (7 of 22; 32%) compared with LGSCs (11 of 119; 9%, P = .009) and HGSCs (6 of 1,290; 0.5%; P < .0001, SBT/LGSC v HGSC). The BRAF V600E hotspot mutation was most common (n = 16); however, other BRAF driver mutations were also detected (n = 8). BRAF mutations were often clonal or truncal in SBTs and LGSCs, but subclonal in most HGSCs. Pathogenic BRAF gene fusions were identified in LGSCs (n = 2) and HGSC (n = 1) and involved distinct fusion partners (AGK, MKRN1, and AGAP3). Three patients with BRAF-mutant LGSC were treated with targeted mitogen-activated protein kinase inhibitors, one of whom was maintained on therapy for over 3 years with clinical benefit. CONCLUSION: Recognition of BRAF alterations beyond V600E mutation in LGSC may have clinical implications for appropriate targeted therapy selection.

Expanding the Molecular Characterization of Thoracic Inflammatory Myofibroblastic Tumors beyond ALK Gene Rearrangements.

INTRODUCTION: Half of inflammatory myofibroblastic tumors (IMTs) regardless of anatomic location harbor anaplastic lymphoma kinase gene (ALK) rearrangements and overexpress anaplastic lymphoma kinase protein. The wide application of next-generation sequencing and the clinical benefit to tyrosine kinase inhibitors have opened new opportunities for investigation of ALK-negative IMTs. METHODS: In this study, we have investigated a series of pediatric and adult thoracic IMTs for abnormalities in a wide spectrum of actionable kinases by applying a variety of molecular and next-generation sequencing techniques, including fluorescence in situ hybridization (FISH), targeted RNA sequencing, and NanoString assay. RESULTS: There were 33 patients with thoracic IMTs, including five children; their mean age was 37. The tumors showed a monomorphic spindle cell phenotype, except for one with an epithelioid morphologic pattern and moderate to severe atypia. By immunohistochemistry, 24 tumors were ALK positive, and 19 of the 24 showed ALK rearrangements and one ret proto-oncogene gene (RET) rearrangement by FISH. RNA sequencing was performed in the remaining four cases lacking ALK abnormalities by FISH, revealing ALK fusions involving tropomyosin 4 gene (TMP4) and echinoderm microtubule associated protein like 4 gene (EML4) as partner in three cases. NanoString assay was performed in the remaining case, revealing ALK alternative transcription initiation (ALKATI). Nine cases lacking ALK abnormalities were further tested by FISH or targeted RNA sequencing, revealing ROS1 rearrangement in six cases and ETS variant 6 gene (ETV6)-neurotrophic receptor tyrosine kinase 3 gene (NTRK3) fusion in three cases, respectively. CONCLUSIONS: By using a battery of complementary molecular techniques, we have shown that all the thoracic IMTs harbored a tyrosine kinase abnormality, with 30% involving a kinase gene other than ALK, including ROS1, NTRK3, and RET gene fusions. We have also described for the first time ALKATI-induced ALK oncogenic activation in IMTs.

Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma-like and Non-Small Cell Carcinoma-like Subsets.

PURPOSE: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm, whose biologic relationship to small cell lung carcinoma (SCLC) versus non-SCLC (NSCLC) remains unclear, contributing to uncertainty regarding optimal clinical management. To clarify these relationships, we analyzed genomic alterations in LCNEC compared with other major lung carcinoma types. EXPERIMENTAL DESIGN: LCNEC (n = 45) tumor/normal pairs underwent targeted next-generation sequencing of 241 cancer genes by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) platform and comprehensive histologic, immunohistochemical, and clinical analysis. Genomic data were compared with MSK-IMPACT analysis of other lung carcinoma histologies (n = 242). RESULTS: Commonly altered genes in LCNEC included TP53 (78%), RB1 (38%), STK11 (33%), KEAP1 (31%), and KRAS (22%). Genomic profiles segregated LCNEC into 2 major and 1 minor subsets: SCLC-like (n = 18), characterized by TP53+RB1 co-mutation/loss and other SCLC-type alterations, including MYCL amplification; NSCLC-like (n = 25), characterized by the lack of coaltered TP53+RB1 and nearly universal occurrence of NSCLC-type mutations (STK11, KRAS, and KEAP1); and carcinoid-like (n = 2), characterized by MEN1 mutations and low mutation burden. SCLC-like and NSCLC-like subsets revealed several clinicopathologic differences, including higher proliferative activity in SCLC-like tumors (P < 0.0001) and exclusive adenocarcinoma-type differentiation marker expression in NSCLC-like tumors (P = 0.005). While exhibiting predominant similarity with lung adenocarcinoma, NSCLC-like LCNEC harbored several distinctive genomic alterations, including more frequent mutations in NOTCH family genes (28%), implicated as key regulators of neuroendocrine differentiation. CONCLUSIONS: LCNEC is a biologically heterogeneous group of tumors, comprising distinct subsets with genomic signatures of SCLC, NSCLC (predominantly adenocarcinoma), and rarely, highly proliferative carcinoids. Recognition of these subsets may inform the classification and management of LCNEC patients. Clin Cancer Res; 22(14); 3618-29. ©2016 AACR.