Frameshift events predict anti–PD-1/L1 response in head and neck cancer
Glenn J. Hanna, Patrick Lizotte, Megan Cavanaugh, Frank C. Kuo, Priyanka Shivdasani, Alexander Frieden, Nicole G. Chau, Jonathan D. Schoenfeld, Jochen H. Lorch, Ravindra Uppaluri, Laura E. MacConaill, Robert I. Haddad
Glenn J. Hanna, Patrick Lizotte, Megan Cavanaugh, Frank C. Kuo, Priyanka Shivdasani, Alexander Frieden, Nicole G. Chau, Jonathan D. Schoenfeld, Jochen H. Lorch, Ravindra Uppaluri, Laura E. MacConaill, Robert I. Haddad
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Research Article Genetics Oncology

Frameshift events predict anti–PD-1/L1 response in head and neck cancer

Abstract

Programmed cell death protein 1 (PD-1) inhibitors have efficacy in treating squamous cell carcinoma of the head and neck (SCCHN), but objective response rates are low. PD-1 ligand (PD-L1) expression alone is not considered a robust predictor of response and additional biomarkers are needed. This 3-year observational cohort followed 126 SCCHN patients treated with anti–PD-1/L1 therapy. Prior to treatment, 81 (64%) had targeted massively parallel tumor sequencing. Of these, 42 (52%) underwent fluorescence-activated cell sorting and PD-L1 immunohistochemistry for tumor immunoprofiling. Six (5%) complete responses (CRs) and 11 (9%) partial responses (PRs) were observed. Those treated with prior chemotherapy (98, 78%) versus only surgery and/or radiation had longer overall survival (OS) (10 vs. 3 months, P = 0.02). Smokers had a higher total mutational burden (TMB) (P = 0.01). Virus-positive patients had a lower TMB (P < 0.01) and improved OS (P = 0.02). Among virus-negative responders, NOTCH1 and SMARCA4 were more frequently mutated and frameshift events in tumor suppressor genes occurred more frequently (P = 0.03). Higher TMB and CD8+ T cell infiltrates predicted anti–PD-1/L1 benefit (P < 0.01, P < 0.01, respectively) among virus-negative tumors. TIM-3/LAG-3 coexpression with PD-1 was higher on T cells among nonresponders (P = 0.03 and 0.02, respectively). Somatic frameshift events in tumor suppressor genes and higher TMB among virus-negative SCCHN tumors predict anti–PD-1/L1 response.

Authors

Glenn J. Hanna, Patrick Lizotte, Megan Cavanaugh, Frank C. Kuo, Priyanka Shivdasani, Alexander Frieden, Nicole G. Chau, Jonathan D. Schoenfeld, Jochen H. Lorch, Ravindra Uppaluri, Laura E. MacConaill, Robert I. Haddad

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Figure 2

Genomic landscape among anti–PD-1/L1 responders in SCCHN.

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Genomic landscape among anti–PD-1/L1 responders in SCCHN. (A) Genomic mu...
(A) Genomic mutational landscape among anti–PD-1/L1 responders (n = 12) and those with SD (n = 20) using a targeted next-generation sequencing platform highlighting total mutational burden (TMB) grouped by high (red, > 10 mutations/Mb), medium (orange, 5–10 mutations/Mb), and low (blue, < 5 mutations/Mb). (B) Primary site of disease (key: top right), viral status (EBV+ or HPV+) and smoking status are shown. (C) The mutational plot shows somatic alterations in order of frequency (highest on top). Somatic mutation key: blue (missense), purple (nonsense), orange (in-frame or frameshift). SA, splice acceptor; SS, splice site; SR, splice region; P, promoter alteration. Only those alterations occurring in 3 or more tumor samples are included in the grid with the exception of genes involved in mismatch repair (MMR). (D) Mutational signatures are displayed (key: lower right). (E) Total indel count (TIC) per tumor sample. (F) Fraction of the genome that is copy-number altered. (G) Proportion of patients with key mutations by response. *P < 0.01 ( χ2 test, 2-sided). SCCHN, squamous cell carcinoma of the head and neck; UV, ultraviolet; CR, complete response; PR, partial response; SD, stable disease; OPC, oropharynx; OC, oral cavity; NPC, nasopharynx; LAR, larynx, hypopharynx; CUT, cutaneous; CUP, carcinoma of unknown primary; APOBEC, apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like.