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Simple Summary: While anti-PD1 antibodies have demonstrated efficacy in some patients with metastatic anal cancer, these agents have no proven benefit for those with localized disease treated with chemoradiation. Difficulty procuring fresh tumor tissue required for RNA and protein expression analysis has limited extensive molecular profiling for this rare cancer. Our team utilized a novel digital spatial profiling technology on pretreatment anal cancer specimens to identify biomarkers associated with recurrence after chemoradiation. We observed that recurrent tumors had higher baseline expression of immune checkpoint biomarkers, higher MAPK signaling activation and higher PI3K/Akt signaling activation. These findings provide a rationale that supports future clinical trials with immunotherapy that seek to improve survival beyond chemoradiation for patients with localized squamous cell cancer of the anus. The identification of transcriptomic and protein biomarkers prognosticating recurrence risk after chemoradiation of localized squamous cell carcinoma of the anus (SCCA) has been limited by a lack of available fresh tissue at initial presentation. We analyzed archival FFPE SCCA specimens from pretreatment biopsies prior to chemoradiation for protein and RNA biomarkers from patients with localized SCCA who recurred (N = 23) and who did not recur (N = 25). Tumor cells and the tumor microenvironment (TME) were analyzed separately to identify biomarkers with significantly different expression between the recurrent and non-recurrent groups. Recurrent patients had higher mean protein expression of FoxP3, MAPK-activation markers (BRAF, p38-MAPK) and PI3K/Akt activation (phospho-Akt) within the tumor regions. The TME was characterized by the higher protein expression of immune checkpoint biomarkers such as PD-1, OX40L and LAG3. For patients with recurrent SCCA, the higher mean protein expression of fibronectin was observed in the tumor and TME compartments. No significant differences in RNA expression were observed. The higher baseline expression of immune checkpoint biomarkers, together with markers of MAPK and PI3K/Akt signaling, are associated with recurrence following chemoradiation for patients with localized SCCA. These data provide a rationale towards the application of immune-based therapeutic strategies to improve curative-intent outcomes beyond conventional therapies for patients with SCCA. [ABSTRACT FROM AUTHOR]

Background Although intensity-modulated radiation therapy (IMRT) is considered the standard of care for the treatment of squamous cell carcinoma of the anus (SCCA), few large series have reported oncologic outcomes and toxicities. In this retrospective report, we aim to describe outcomes and toxicities after IMRT-based chemoradiation (CRT) for the treatment of SCCA, evaluate the impact of dose escalation (>54 Gy), and compare concurrent fluoropyrimidine in combination with either mitomycin or with cisplatin as chemosensitizers. Methods Patients treated at The University of Texas MD Anderson Cancer Center between January 1, 2003 and December 31, 2018 with IMRT-based CRT were included. Median time to locoregional recurrence, time to colostomy, and overall survival were estimated using the Kaplan–Meier method. Results A total of 428 patients were included; median follow-up was 4.4 years. Three hundred and thirty-four patients (78.0%) were treated with concurrent cisplatin and fluoropyrimidine, and 160 (37.4%) with >54 Gy. Two- and 5-year freedom from locoregional failure, freedom from colostomy failure, and overall survival were 86.5% and 81.2%, respectively, 90.0% and 88.3%, respectively, and 93.6% and 85.8%, respectively. Neither dose escalation nor mitomycin-based concurrent chemotherapy resulted in improved outcomes. Mitomycin-based concurrent chemotherapy was associated with in approximately 2.5 times increased grade 3 or greater acute toxicity. Radiation dose >54 Gy was associated with approximately 2.6 times increased Grade 3 or greater chronic toxicity. Conclusions Our results suggest IMRT-based CRT with concurrent fluoropyrimidine and cisplatin is a safe and feasible option for patient with SCCA and may cause less acute toxicity. The role for radiation dose escalation is unclear and requires further study. [ABSTRACT FROM AUTHOR]