Incorporation of Next-Generation Sequencing into Routine Clinical Care to Direct Treatment of Head and Neck Squamous Cell Carcinoma

Chau, Nicole G.; Li, Yvonne Y.; Jo, Vickie Y.; Rabinowits, Guilherme; Lorch, Jochen H.; Tishler, Roy B.; Margalit, Danielle N.; Schoenfeld, Jonathan D.; Annino, Don J.; Goguen, Laura A.; Thomas, Tom; Becker, Hailey; Haddad, Tyler; Krane, Jeffrey F.; Lindeman, Neal I.; Shapiro, Geoffrey I.; Haddad, Robert I.; Hammerman, Peter S.

doi:10.1158/1078-0432.ccr-15-2314

Cited by 54 publications

(45 citation statements)

References 32 publications

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“…We did, however, note that mutations in genes known to activate PI3K signalling were non-statistically enriched in recurrent/metastatic cases and found that there was an association between PI3K activating events and poor outcome among recurrent and metastatic NPC patients (Supplementary Fig. 14), in accordance with data presented in HNSCC24. This finding could have therapeutic implications in that targeted kinase inhibitors are often explored initially in the recurrent/metastatic setting.…”

Section: Resultssupporting

confidence: 84%

Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations

et al. 2017

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Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-kB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-kB signalling, and we observed mutual exclusivity among tumours with somatic NF-kB pathway aberrations and LMP1-overexpression, suggesting that NF-kB activation is selected for by both somatic and viral events during NPC pathogenesis.

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Section: Resultssupporting

confidence: 84%

Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations

et al. 2017

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“…In 7 patients (13%), NGS nominated targeted therapies, similar to the rate in another recent HNSCC precision oncology study (10%). 21 Four patients with alterations in PIK3CA or PTEN were treated on PI3K inhibitor trials, 1 HRAS mutation on a farnesyl transferase inhibitor trial, 1 MAPK1 mutation with an ERK inhibitor on a single-patient IND (Investigational New Drug) application, and 1 SMARCB1 deletion on an EZH2 inhibitor trial. In 6 patients (12%), the lack of actionable alterations on MSK-IMPACT prompted the decision to instead enroll on immunotherapy trials.…”

Section: Resultsmentioning

confidence: 99%

The Molecular Landscape of Recurrent and Metastatic Head and Neck Cancers

et al. 2017

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IMPORTANCE Recurrent and/or metastatic head and neck cancer is usually incurable. Implementation of precision oncology for these patients has been limited by incomplete understanding of the molecular alterations underlying advanced disease. At the same time, the molecular profiles of many rare head and neck cancer types are unknown. These significant gaps in knowledge need to be addressed to rationally devise new therapies. OBJECTIVE To illuminate the distinct biology of recurrent and metastatic head and neck cancers and review implementation of precision oncology for patients with advanced disease. DESIGN, SETTING, AND PARTICIPANTS After exclusions, 151 patients with advanced, treatment-resistant head and neck tumors, including squamous cell carcinoma (HNSCC), adenoid cystic carcinoma (ACC), and other salivary and cutaneous cancers, whose tumors were sequenced between January 2014 and July 2015 at Memorial Sloan Kettering were recruited. Next-generation sequencing of tumors as part of clinical care included high-depth (median 600×) exonic coverage of 410 cancer genes and whole-genome copy number analysis. INTERVENTIONS Next-generation sequencing of tumors and matched normal DNA. MAIN OUTCOMES AND MEASURES Feasibility, the frequency of actionable molecular alterations, the effect on decision making, and identification of alterations associated with recurrent and metastatic disease. RESULTS Overall, 151 patients (95 men and 56 women; mean [range] age, 61.8 [17-100] years) were included in the study. Next-generation sequencing ultimately guided therapy in 21 of 151 patients (14%) (13 of 53 [25%] of patients with HNSCC) by refining diagnoses and matching patients to specific therapies, in some cases with dramatic responses on basket studies. Molecular alterations were potentially actionable in 28 of 135 patients (21%). The genetic profiles of recurrent and metastatic tumors were often distinct from primary tumors. Compared to primary human papillomavirus (HPV)-positive tumors, many recurrent and metastatic HPV-positive tumors exhibited a molecular profile more similar to HPV-negative tumors, including enriched frequencies of TP53 mutation (3 of 20 tumors [15%]), whole genome duplication (5 of 20 tumors [25%]), and 3p deletion (11 of 20 tumors [55%]). There were high rates of TERT promoter mutation in recurrent and metastatic HPV-negative HNSCC (13 of 30 tumors [43%]), cutaneous SCC (11 of 21 tumors [52%]), basal cell carcinoma (3 of 4 tumors [75%]), and ACC (5 of 36 tumors [14%]). Activating NOTCH1 mutations were enriched in metastatic ACCs (8 of 36 tumors [22%]). CONCLUSIONS AND RELEVANCE These findings reveal the molecular landscape of advanced disease and rare cancer subtypes, both predominant challenges in head and neck oncology. To understand the repertoire of targetable alterations in advanced cancers, it is necessary to sequence recurrent and metastatic tumors. These data are important first steps toward implementation of precision head and neck oncology.

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“…Indeed, this initiative has enabled a large number of other more focused studies of common and uncommon tumor types and, in particular, has permitted prospective identification of relatively uncommon genomic variants to facilitate clinical trial enrollment and biomarker studies (46)(47)(48)(49)(50)(51)(52)(53)(54). Migrating to a clinical test, identifying when in the course of a patient's disease genomic profiling should be used, and triaging patients in real-time for clinical trial enrollment should contribute to determining clinical utility on a broader scale.…”

Section: Discussionmentioning

confidence: 99%

Institutional implementation of clinical tumor profiling on an unselected cancer population

Sholl¹,

Khanh²,

Shivdasani³

et al. 2016

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BACKGROUND.Comprehensive genomic profiling of a patient's cancer can be used to diagnose, monitor, and recommend treatment. Clinical implementation of tumor profiling in an enterprisewide, unselected cancer patient population has yet to be reported. METHODS.We deployed a hybrid-capture and massively parallel sequencing assay (OncoPanel) for all adult and pediatric patients at our combined cancer centers. Results were categorized by pathologists based on actionability. We report the results for the first 3,727 patients tested.RESULTS. Our cohort consists of cancer patients unrestricted by disease site or stage. Across all consented patients, half had sufficient and available (>20% tumor) material for profiling; once specimens were received in the laboratory for pathology review, 73% were scored as adequate for genomic testing. When sufficient DNA was obtained, OncoPanel yielded a result in 96% of cases. 73% of patients harbored an actionable or informative alteration; only 19% of these represented a current standard of care for therapeutic stratification. The findings recapitulate those of previous studies of common cancers but also identify alterations, including in AXL and EGFR, associated with response to targeted therapies. In rare cancers, potentially actionable alterations suggest the utility of a "cancer-agnostic" approach in genomic profiling. Retrospective analyses uncovered contextual genomic features that may inform therapeutic response and examples where diagnoses revised by genomic profiling markedly changed clinical management. CONCLUSIONS.Broad sequencing-based testing deployed across an unselected cancer cohort is feasible. Genomic results may alter management in diverse scenarios; however, additional barriers must be overcome to enable precision cancer medicine on a large scale.

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Incorporation of Next-Generation Sequencing into Routine Clinical Care to Direct Treatment of Head and Neck Squamous Cell Carcinoma

Cited by 54 publications

References 32 publications

Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations

Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations

The Molecular Landscape of Recurrent and Metastatic Head and Neck Cancers

Institutional implementation of clinical tumor profiling on an unselected cancer population

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