Comprehensive multiplatform biomarker analysis of 199 anal squamous cell carcinomas.

Brandon G Smaglo,Sandeep Reddy,Anteneh Tesfaye,Joshua E Meyer,David Arguello,Zoran Gatalica,Jue Wang,Thorvardur R Halfdanarson,Patrick M Boland

doi:10.18632/oncotarget.6202

Abstract

Anal squamous cell carcinoma (ASCC) is a rare, HPV-associated malignancy typically diagnosed in early stages and definitively treated with chemoradiation. In situations where patients exhibit metastatic or recurrent disease, treatment options are severely limited. In this study, molecular alterations were identified that could be used to aid in therapeutic decisions for patients with metastatic or recurrent anal squamous cell carcinoma. Specimens from patients with this cancer were tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing, protein expression by immunohistochemistry, and gene amplification with in situ hybridization. Utilizing these techniques, novel treatment strategies that could be explored were identified, including potential benefit with anti-EGFR therapies, immune checkpoint inhibitors, topoisomerase inhibitors, and taxanes. The frequency of overexpression of proteins that mark resistance to chemotherapeutic drugs, such as MRP1 (chemotherapy efflux pump), ERCC1 (resistance to platinum-based chemotherapy), and thymidylate synthase (resistance to fluoropyrimidines) were also identified, suggesting a lack of benefit. This multiplatform strategy could be explored for its potential to generate a personalized treatment selection for patients with advanced ASCC, provide a guide for future therapeutic development for this cancer, and be extended to other rare cancer types as well.

Highlights

Anal squamous cell carcinoma (ASCC) is a rare, human papilloma virus (HPV)-associated malignancy accounting for 2.5% of digestive system malignancies
199 cases of anal squamous cell carcinoma were profiled for therapeutic targets or markers of drug susceptibility
Future trials should evaluate other biomarkers and pathways besides PIK3CA/AKT/mTOR that may be worth targeting at a later date. This profile of ASCC already has revealed a number of intriguing findings that offer insights and inroads for further therapeutic investigation

Summary

Introduction

Anal squamous cell carcinoma (ASCC) is a rare, HPV-associated malignancy accounting for 2.5% of digestive system malignancies. Review of the National Cancer Database between 1985 and 2000 showed that on initial presentation, patients present with stages I, II, III and IV at rates of 25.3%, 51.8%, 17.1% and 5.7%, respectively [3]. The five-year overall survival rates for patients who had stages I, II, III and IV disease were 69.5%, 59%, 40.6%. In local and locally advanced anal squamous cell carcinoma, the standard of care for most patients is concurrent chemoradiation therapy, with a complete response rate of 80% [4]. Albeit effective, this has been the basic therapeutic paradigm for decades. Surgical resection after failure of chemoradiation comes with morbid complications, but offers some remaining opportunity for cure [6, 7]

Objectives

Methods

Results

Discussion

Conclusion