Genomic and Molecular Profiling of Human Papillomavirus Associated Head and Neck Squamous Cell Carcinoma Treated with Immune Checkpoint Blockade Compared to Survival Outcomes

Abstract

Recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients overall have a poor prognosis. However, human papillomavirus (HPV)-associated R/M oropharyngeal squamous cell carcinoma (OPSCC) is associated with a better prognosis compared to HPV−negative disease. Immune checkpoint blockade (ICB) is the standard of care for R/M HNSCC. However, whether HPV and its surrogate marker, p16, portend an improved response to ICB remains controversial. We queried the Caris Life Sciences CODEai database for p16+ and p16− HNSCC patients using p16 as a surrogate for HPV. A total of 2905 HNSCC (OPSCC, n = 948) cases were identified. Of those tested for both HPV directly and p16, 32% (251/791) were p16+ and 28% (91/326) were HPV+. The most common mutation in the OPSCC cohort was TP53 (33%), followed by PIK3CA (17%) and KMT2D (10.6%). TP53 mutations were more common in p16− (49%) versus the p16+ group (10%, p < 0.0005). Real-world overall survival (rwOS) was longer in p16+ compared to p16− OPSCC patients, 33.3 vs. 19.1 months (HR = 0.597, p = 0.001), as well as non-oropharyngeal (non-OP) HNSCC patients (34 vs. 17 months, HR 0.551, p = 0.0001). There was no difference in the time on treatment (TOT) (4.2 vs. 2.8 months, HR 0.796, p = 0.221) in ICB-treated p16+ vs. p16− OPSCC groups. However, p16+ non-OP HNSCC patients treated with ICB had higher TOT compared to the p16− group (4.3 vs. 3.3 months, HR 0.632, p = 0.016), suggesting that p16 may be used as a prognostic biomarker in non-OP HNSCC, and further investigation through prospective clinical trials is warranted.

Assessment of the Mutation Profile of Tonsillar Squamous Cell Carcinomas Using Targeted Next-Generation Sequencing

“…Instead, a comprehensive NGS panel may be effective in assessing a broad spectrum of genetic alterations in TSCCs. Recent studies on oropharyngeal cancers using NGS platforms have reported high TP53 (33–55.4%) and PIK3CA (26.8%) mutation frequencies, comparable to those observed in our study [ 41 , 42 , 46 ]. Notably, 58.1% of tonsil cancers harbored candidate target mutations in 14 genes ( ALK , ATM , EGFR , ERBB2 , FGFR3 , FLT3 , IDH1 , IDH2 , KIT , KRAS , MET , PDGFRA , PIK3CA , and SMARCB1 ) with level 1 evidence in OncoKB™, which could be implicated in targeted therapies in the future.…”

“…The lack of specific clinicodemographic features concerned with PIK3CA mutation has been suggested in oropharyngeal cancers [ 27 ], although some studies have characterized rare patients with decreased exposure to tobacco or HPV-positivity by the clinicopathological features of PIK3CA mutation [ 16 , 40 ]. Previous studies have reported that TP53 mutations are common in HPV-negative tumors, while PIK3CA mutations are frequent in HPV-positive cancers [ 27 , 40 , 41 ]. Recent NGS-based studies identified TP53 (9.3–25.0% vs. 63.8–85.7%) and PIK3CA (20.1–21.4% vs. 6.4–32.1%) in HPV-positive and -negative oropharyngeal SCCs [ 42 ], respectively, indicating that although the total number of TP53 and PIK3CA mutations may differ depending on the HPV status, these may still be relatively prevalent [ 16 , 42 ].…”

“…The eighth edition of the AJCC staging system for oropharyngeal cancer has been updated with the incorporation of HPV infection and extranodal extension [ 12 ], and now offers better stratification between early or advanced stages and T or N categories for OS than the seventh edition for tonsil cancers [ 20 ]. However, the prognostic implication of the various somatic mutations in tonsil cancers has rarely been reported, with little information on staging under the eighth edition of the AJCC guidelines [ 41 , 42 ]. Under this updated staging system, we identified the AJCC stage as the best independent prognostic indicator in tonsil cancers, regardless of HPV status or adjuvant therapy.…”

An Update on the Immunotherapy for Oropharyngeal Squamous Cell Carcinoma

“…In general, HPV-positive HNSCCs exhibited a relatively low mutational burden (2.28 mutations per Mb vs. 4.83 mutations per Mb in HPV-negative cases) ( 32 ), a high proliferative index, a frequent alteration in the PIK3CA pathway, compared to HPV-negative HNSCCs ( 35 ). A current study reported that the most frequent mutation exhibited in an OPSCC cohort with 948 subjects was TP53 (33%), followed by PIK3CA (17%) and KMT2D (10.6%); and TP53 was more commonly mutated in the HPV-negative group (mutation rate: 49% vs. 10%, P < 0.0005) ( 36 ).…”

Hypermethylation of PRKCZ Regulated by E6 Inhibits Invasion and EMT via Cdc42 in HPV-Related Head and Neck Squamous Cell Carcinoma

“…Thus, a persistent HPV infection makes cancers much more likely to develop and progress [ 8 ]. Compared with HPV- HNSCC, HPV+ HNSCC has been shown to exhibit a better prognosis and sensitivity to radiotherapy and chemotherapy [ 9 ], perform a lower mutational burden, expressed a wild TP53 [ 10 , 11 ], have more tumor-infiltrating lymphocytes [ 12 ] as well as the less hypoxic [ 13 ], however, why HPV+ HNSCC performs better prognosis and the sensitivity of radiotherapy and chemotherapy still remains unclear.…”