A Prospective Cohort Study of Biomarkers in Squamous Cell Carcinoma of the Anal Canal (SCCAC) and their Influence on Treatment Outcomes

Abstract

Background: Although Chemoradiation (CRT) is the curative treatment for SCCAC, many patients present primary resistance. Since it is a rare tumor, response predictors remain unknown. Methods: We performed a prospective cohort study to evaluate biomarkers associated with CRT response, progression-free survival (PFS), and overall survival (OS). The primary endpoint was response at 6 months (m). Tumor DNA and HPV were analyzed by next-generation sequencing, while KI-67 and PD-L1 by immunohistochemistry in tumor tissue. Results: Seventy-eight patients were recruited between October/2011 and December/2015, and 75 were response evaluable. The median age was 57 years, 65% (n=49) were stage III and 12% (n=9) were HIV positive (HIV+). At 6m, 62.7% (n=47) presented CR. On multivariate analyses, stage II patients were 4.7 more likely to achieve response than stage III (OR, 4.70; 95%CI, 1.36-16.30; p=0.015). HIV+ was associated with a worse response (OR, 5.72; 95%CI, 2.5-13.0; p<0.001). 5-year PFS and OS rates were 63.3% and 76.4%, respectively, with a median follow up of 66m. On multivariate analyses, older age (HR 1.06, p=0.022, 95%IC 1.01-1.11) and absence of CR at 6m (HR 3.36, p=0.007, 95%IC 1.39-8.09) were associated with inferior OS. The 5-year OS rate was 62.5% in HIV+ group compared to 78% among HIV- pts, although this difference was not statistically significant (p=0.4). PIK3CA, MET and TP53 mutations, HPV, Ki-67 expression, and PD-L1 expression, were not associated with PFS and OS. Conclusions: Clinical stage III and HIV+ were associated with worse response to CRT at 6m. The absence of CR was the main factor associated with poor 5-year OS.

Prognostic Factors of Long-Term Outcomes after Primary Chemo-Radiotherapy in Non-Metastatic Anal Squamous Cell Carcinoma: An International Bicentric Cohort

“…Clinical practice guidelines indicate that patients could achieve a response rate of 80%, and the remaining 15% can receive abdominal perineal resection as a salvage treatment. In terms of achieving a CR, our CR rate at 6 months was 70%, which is lower than the 90.5% rate observed in the ACT II trial at 26 weeks, but is similar to prospective trials or multicentric series with similar baseline clinical staging, where the CR rates reported were between 65% and 70% for locally advanced disease [ 37 ]. We showed in our study that CR is a good surrogate of long-term outcomes as it was associated with better PFS and OS.…”

“…This could be related to the reduced number of ASCC without HPV infection detected in our overall cohort. Moreover, efforts to stratify patients according to the HPV status were made, but its place in clinical practice remains controversial given heterogeneous results for its prognostic role [ 36 , 37 ]. One likely possibility is that retrospective cohorts evaluated in the available meta-analysis had selection biases and confounders that influenced the results [ 5 ].…”

Biomarkers in Anal Cancer: Current Status in Diagnosis, Disease Progression and Therapeutic Strategies

“…Recent systematic review and meta-analysis of 17 retrospective cohort studies demonstrated that HPV+ and p16+ tumors had improved OS compared to tumors with negative profiles [ 41 ]. On the other hand, a prospective cohort with multivariable analyses of non-metastatic patients treated with standard CRT did not show a difference in 5-year OS according to HPV status [ 42 ]. Currently, there are no recommendations for treatment modification based on HPV or p16 status ( Table 1 ).…”

“…Data regarding clinical outcomes of HIV+ SCCA patients are scarce. Studies on the prognostic and predictive impact of HIV status report conflicting results [ 42 ].…”

“…More recently, in a prospective cohort of patients treated with CRT, Ki-67 was not a useful marker to predict response, PFS or OS [ 42 ]. Therefore, it is logical to presume that a cellular proliferation marker such as Ki-67 could be a useful predictive or prognostic biomarker in anal cancer; however, studies have reported conflicting results, and the practical and clinical application remains uncertain.…”