The Molecular Landscape of Recurrent and Metastatic Head and Neck Cancers

Abstract

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.

Molecular features of adenoid cystic carcinoma with an emphasis on microRNAexpression

“…This caveat illustrates the need for extensive sampling, which is also an important consideration in the context of genomically driven clinical trials. Collectively, we find the mutational spectrum to be diverse in ACC, which is in agreement with other studies (119,230,231). Interestingly, the NOTCH1 was found in the proline-glutamic acid-serine-threonine (PEST) domain, similar to the activating mutations in T-cell acute lymphoblastic leukemia, which has been shown to be recurrent in especially solid ACC and is a novel therapeutic target for the monoclonal antibody brontictuzumab (97,232,233).…”

Diffuse Staining for Activated NOTCH1 Correlates With NOTCH1 Mutation Status and Is Associated With Worse Outcome in Adenoid Cystic Carcinoma

“…We also noted that 3 of 4 PEST domain mutations fell in codon 2466 or 2467, a site that is mutated at low frequency in other tumors, such as T-ALL (27). Of note, of 9 NOTCH1 exon 34 mutations reported in ACC by other groups, 5 affected codon 2467 (9, 10), suggesting that this is a mutational hotspot in ACC. Enrichment for specific PEST domain mutations is not a prominent feature in T-ALL, but is characteristic of chronic lymphocytic leukemia, in which approximately 90% of mutations are a del(CT) involving codon 2514 (30, 31); the same del(CT) mutation also appears to be mutational hotspot in mantle cell lymphoma (32).…”

“…Among tumors of salivary gland and head and neck origin, activation of NOTCH1 is a common feature, but only ACCs show diffuse NICD1 positivity and NOTCH1 mutations in a subset of cases, suggesting that the selective pressure for Notch gain-of-function mutations is specific for ACC among this group of tumors. Prior NGS studies of ACC have identified NOTCH1 gain-of-function mutations in a subset of cases, varying from 0% to 19% (overall 12/172 cases, or 7%)(7–10). By contrast, we detected NOTCH1 mutations in 8 of 11 ACCs (73%) with diffuse NICD1 positivity, suggesting that NICD1 staining is effective at identifying ACCs with dysregulated NOTCH1 signaling.…”

TMEM16A/ANO1 Inhibits Apoptosis Via Downregulation of Bim Expression

“…Recent investigations into recurrent and metastatic HNSCC found a 10.4% amplification rate of chromosomal locus 11q13, which houses TMEM16A [20] - a much lower rate of amplification than the ~30% amplification rate reported by the TCGA in primary HNSCC samples [17]. Consistent with this data, analysis of the recurrent tumor tissue of 10 of the 14 cases of laryngeal cancer that recurred (data not shown), demonstrated a non-significant reduction in maximum H-score as compared to the primary tumor tissue.…”