Pathogenic alterations in PIK3CA and KMT2C are frequent and independent prognostic factors in anal squamous cell carcinoma treated with salvage abdominoperineal resection

Abstract

The management of anal squamous cell carcinoma (ASCC) has yet to experience the transformative impact of precision medicine. Conducting genomic analyses may uncover novel prognostic biomarkers and offer potential directions for the development of targeted therapies. To that end, we assessed the prognostic and theragnostic implications of pathogenic variants identified in 571 cancer‐related genes from surgical samples collected from a homogeneous, multicentric French cohort of 158 ASCC patients who underwent abdominoperineal resection treatment. Alterations in PI3K/AKT/mTOR, chromatin remodeling, and Notch pathways were frequent in HPV‐positive tumors, while HPV‐negative tumors often harbored variants in cell cycle regulation and genome integrity maintenance genes (e.g., frequent TP53 and TERT promoter mutations). In patients with HPV‐positive tumors, KMT2C and PIK3CA exon 9/20 pathogenic variants were associated with worse overall survival in multivariate analysis (Hazard ratio (HR)KMT2C = 2.54, 95%CI = [1.25,5.17], P value = .010; HRPIK3CA = 2.43, 95%CI = [1.3,4.56], P value = .006). Alterations with theragnostic value in another cancer type was detected in 43% of patients. These results suggest that PIK3CA and KMT2C pathogenic variants are independent prognostic factors in patients with ASCC with HPV‐positive tumors treated by abdominoperineal resection. And, importantly, the high prevalence of alterations bearing potential theragnostic value strongly supports the use of genomic profiling to allow patient enrollment in precision medicine clinical trials.

HPV status and immunohistochemical analysis of p16, p53 and PD‑L1 expression as prognostic biomarkers in patients with squamous cell anal cancer receiving definitive radiotherapy/chemoradiotherapy

“…Thirdly, additional genetic alterations may influence the survival in patients with HPV-positive tumors, including somatic PIK3CA exon 9/20 and KMT2C pathogenic variants. These mutations may play a key role in tumor biology and the response to treatment, further highlighting the complexity of the molecular mechanisms involved in HPV-positive tumors ( 59 ). Finally, while efforts to further increase survival outcomes in the HPV-positive subgroup are necessary, the reduction of potential side effects is also important.…”

“…Recommendations for the HPV-negative subgroup include investigating the hypothesis that RT dose escalation based on HPV status could be successful for the HPV-negative resistant subgroup. In addition, mutational profiles that notably differ between HPV-positive and HPV-negative patients may be explored, as they could suggest multiple avenues for the investigation of targeted therapies in anal SCC ( 59 ). Also, hyperthermia could be considered as a potential means of increasing the sensitivity of cancer cells to therapeutic agents, inducing direct cytotoxicity, triggering anticancer immune responses and improving drug delivery, as supported by previous studies ( 60 , 61 ).…”