The Molecular Landscape of Recurrent and Metastatic Head and Neck Cancers: Insights From a Precision Oncology Sequencing Platform

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.

Figure 1. Overall Survival for Patients Undergoing Clinical Tumor Sequencing

A, Overall survival from time of index treatment and time of disease recurrence and/or metastasis, for selected tumor types. Survival probabilities were calculated with the Kaplan-Meier method, and tumor types were compared using the log-rank test. B, Distribution of molecular alterations, classified by levels of evidence for actionability. HNSCC, head and neck squamous cell carcinoma. ACC, adenoid cystic carcinoma; HPV, human papillomavirus; NPC, nasopharyngeal carcinoma; Other salivary, other salivary cancer types; SCC, squamous cell carcinoma.

Figure 2. The Molecular Landscape of Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma

Genetic alterations and clinical data for 53 recurrent and/or metastatic head and neck squamous cell carcinomas. Copy number values are based on 48 cases with informative copy number data; 11q13 includes CCND1, FGF3, FGF4, and FGF19; 3q26.3 includes PIK3CA, SOX2, and DCUN1D1. Clones indicates number of subclonal populations per tumor; HPV, human papillomavirus; SCNA, somatic copy number alterations.

Figure 3. Mutation Distributions in PIK3CA, NOTCH1, TP53 and TERT in Head and Neck Squamous Cell Carcinomas

Green circles indicate missense mutations; red, truncating; black, in-frame insertions or deletions.

Figure 4. Genetic Alterations Enriched in Recurrent and/or Metastatic HPV-Positive HNSCC

A, Enrichment analysis for common alterations, comparing recurrent and/or metastatic HPV-positive tumors to primary HPV-positive tumors. Red dots indicate alterations enriched in recurrent and/or metastatic tumors, and blue dots indicate alterations enriched in primary tumors. For these comparisons, recurrent and/or metastatic tumors are MSK-IMPACT cases and primary tumors are The Cancer Genome Atlas cases. B, Differences in chromosomal instability, defined as proportion of genome copy number-altered, in TP53/RB1-mutated or wild-type HPV-positive tumors in MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets). Boxes represent interquartile ranges and whiskers represent maxima and minima. HPV indicates human papillomavirus. HNSCC, head and neck squamous cell carcinoma.

Figure 5. Mutational Landscape of Recurrent and/or Metastatic Adenoid Cystic Carcinoma

Genetic and clinical data for 36 recurrent and/or metastatic adenoid cystic carcinomas. SCNA indicates somatic copy number alterations.

Figure 6. Mutational Landscape of Recurrent and/or Metastatic Other Salivary Carcinoma Types

Genetic and clinical data for 20 recurrent and/or metastatic other salivary carcinoma types. ADC indicates adenocarcinoma; SCNA, somatic copy number alterations.

Figure 7. Mutational Landscape of Advanced Cutaneous Carcinomas of the Head and Neck

Genetic and clinical data for 27 advanced cutaneous head and neck cancers. SCNA indicates somatic copy number alterations