Multi-hit <i>PIK3CA</i> mutations in clinically advanced (CA) penile squamous cell carcinoma (penSCC): A genomic landscape study.

Abstract

10 Background: Recent evidence confirms that tumors, such as advanced hormone receptor-positive breast cancer, can be highly responsive to PIK3CA inhibitors including alpelisib and inavolisib when ≥ 2 (“multi-hit”) PIK3CA mutations are identified by genomic analysis. We evaluated CA penSCC by comprehensive genomic profiling (CGP) to determine the frequency of multi-hit PIK3CA mutations in this aggressive and often chemotherapy-refractory cancer. Methods: Using the FoundationOne CDx assay, 365 CA penSCC underwent hybrid capture based CGP to identify all classes of genomic alterations (GA). Microsatellite instability status (MSI), tumor mutation burden (TMB), HRD signature, genomic ancestry, HPV status, and genomic signature were determined from the sequencing data. PD-L1 expression was determined by immunohistochemistry (IHC) using Dako TPS score (0% = negative; 1-49% = low positive; ≥50% = high positive). Results: 16 (4.4%) of CA penSCC featured ≥ 2 short variant PIK3CA mutations ( PIK3CA multi-hit+). The PIK3CA multi-hit+ group was slightly older (median age 70.5 vs 65.0; NS) and featured a slightly higher median number of GA per tumor (6.5 vs 5.0; p = .009). Genomic ancestry distribution revealed higher African ancestry in the PIK3CA multi-hit+ group and higher European ancestry in the PIK3CA multi-hit- group. Regarding putative biomarkers of anti-PD1/L1 response, median TMB was slightly higher in the PIK3CA multi-hit+ penSCC group, while PD-L1 expression ≥ 1% was relatively similar. MSI-high status was uncommon in both groups. HRD+ signature was more frequent in the PIK3CA multi-hit+ group. HPV positive status was more frequent in the PIK3CA multi-hit+ group. APOBEC genomic signature was also more frequent in the PIK3CA multi-hit+ group. Individual GA more frequent in the PIK3CA multi-hit+ penSCC (all NS) included ASXL, CCND1, ERBB2, FGFR3, KRAS , RB1. Individual GA more frequent in the PIK3CAmulti-hit- penSCC included CDKN2A, CDKN2B, EGFR, NOTCH1 which are all NS except TP53 (58.2% vs 12.5%; p = 0.012; Table). Conclusions: Multi-hit PIK3CA mutations are rare in clinically advanced penSCC but may offer opportunities for experimental therapeutic strategies, particularly in tumors with higher median TMB, HPV positivity, and co-alterations involving ERBB2 or FGFR3 . Study limitations include its retrospective design, lack of clinical / outcomes data annotation, potential selection and confounding biases. Further genomic investigation of penSCC is warranted to guide targeted drug development. PIK3CAmulti-hit+ PIK3CAmulti-hit- P-value n 16 349 MedianGA/tumor 6.5 5 0.009 Median TMB (mut/MB) 7.2 2.5 &lt;.0001 HRDsig positive (+) 6.7% 3.7% NS HPV 50.0% 28.9% NS APOBEC 31.3% 7.2% NS ERBB2 6.3% 1.1% NS FGFR3 12.5% 3.2% NS TP53 12.5% 58.2% 0.012