Genomic Evolution after Chemoradiotherapy in Anal Squamous Cell Carcinoma

Abstract

Purpose Squamous cell carcinoma of the anal canal (ASCC) accounts for 2-4% of gastrointestinal (GI) malignancies in the US and is increasing in incidence; however, genomic features of ASCC are incompletely characterized. Primary treatment of ASCC involves concurrent chemotherapy and radiation (CRT), but the mutational landscape of resistance to CRT is unknown. Here, we aim to compare mutational features of ASCC in the pre- and post-CRT setting. Experimental Design We perform whole exome sequencing of primary (n=31) and recurrent (n=30) ASCCs and correlate findings with clinical data. We compare genomic features of matched pre- and post-CRT tumors to identify genomic features of CRT response. Finally, we investigate the mutational underpinnings of an extraordinary ASCC response to immunotherapy. Results We find that both primary and recurrent ASCC tumors harbor mutations in genes such as PIK3CA and FBXW7 that are also mutated in other HPV-associated cancers. Overall mutational burden was not significantly different in pre- versus post-CRT tumors, and several examples of shared clonal driver mutations were identified. In two cases, clonally related pre- and post-CRT tumors harbored distinct oncogenic driver mutations in the same cancer gene (KRAS or FBXW7). A patient with recurrent disease achieved an exceptional response to anti-Programmed Death (PD-1) therapy, and genomic dissection revealed high mutational burden and predicted neoantigen load. Conclusion We perform comprehensive mutational analysis of ASCC and characterize mutational features associated with CRT. Although many primary and recurrent tumors share driver events, we identify several unique examples of clonal evolution in response to treatment.

Array comparative genomic hybridization identifies high level of PI3K/Akt/mTOR pathway alterations in anal cancer recurrences

“…In this context, we conducted a large array comparative genomic hybridization analysis in treatment-naive and recurrent ASCC. Despite previous exposure to ionizing radiation and DNA-damaging cytotoxic chemotherapy, the global load of genomic alterations was high but similar between treatmentnaive tumors and recurrences, in line with the mutational burden described in whole-exome analysis of ASCC 17 and in other types of carcinoma. 18,19 Surprisingly, several individual genomic alterations were observed more frequently in the group of treatment-naive tumors.…”

Harnessing the Immunotherapy Revolution for the Treatment of Childhood Cancers

“…Combining checkpoint inhibition with agents that can augment the frequency of NSSMs, an approach already underway with radiation in adult cancers (Haymaker et al, 2017;Herter-Spire et al, 2016;Koller et al, 2016;Liniker et al, 2016), may hold promise for children (study planned in neuroblastoma, Clinicaltrials.gov: NCT02914405). In particular, radiation has been shown to drive the clonal evolution of cancers (Findlay et al, 2016;Mouw et al, 2016), producing neoantigenic targets for antitumor T cells (Reits et al, 2006). In addition to increasing neoantigens, radiation may increase immune activation and response to checkpoint blockade through other means.…”

High IDO1 Expression Is Associated with Poor Outcome in Patients with Anal Cancer Treated with Definitive Chemoradiotherapy

“…Identifying novel biomarkers that are associated with poor prognosis will help define the cohort of patients who merit treatment escalation. Several studies have found that HPV‐negative tumors have worse outcomes, but the role of other immunohistochemical or genomic markers is less well established . Given the viral etiology of this disease, it is perhaps not surprising that prior studies have shown that the immune microenvironment in ASCC plays an important role in disease prognosis.…”