Session Item

Purpose: Tumor hypoxia is related to reduced radiosensitivity in squamous cell carcinomas (SCC). A 15- gene hypoxia classifier has shown prognostic value in SCC of the uterine cervix and predictive value for hypoxia modifying treatment in head and neck SCC (HNSCC). The aim of this study was to investigate the prognostic value of the 15-gene hypoxia classifier on loco-regional tumor control in SCC of the anus (SCCA). 

Material: Diagnostic biopsies were collected from 2016-2019 from 79 newly diagnosed SCCA patients. All biopsies were formalin fixed and paraffin embedded with histologically verified, invasive SCC. Each tumors expression of the 15 hypoxia genes was scored using the method defined by DAHANCA (Toustrup K, Acta Oncol. 2016). A 70% cut-off was used for p16 overexpression. Patients were treated with high dose chemo-radiotherapy (CRT) with 60 – 64 Gy to tumor and pathological nodes and 49.5 – 51.2 Gy to CTV, delivered in 30-32 fractions with concomitant cisplatin-based chemotherapy, according to national Danish guidelines. Persistent disease was defined as pathological verified SCC < 6 months after CRT, and loco-regional failure was pelvic failure or inguinal node failure > 6 months after CRT. Fisher’s Exact test, Cox regression and competing risk analysis were used.  

Results: Classification of the 15 genes was conclusive in all biopsies with 53 (67%) “less” hypoxic tumors and 26 (33%) “more” hypoxic tumors. Comparison of the mean expression levels for the 15 genes showed similar expression levels for the SCCA samples as for HNSCC and SCC of the uterine cervix (figure 1) and was unrelated to p16 status. Tumor stages were 22% T1, 58% T2, 8% T3 and 10% T4, respectively. Node involvement was found in 23%, and p16 overexpression was detected in 82% of the tumors.  Patient and tumor characteristics were equally distributed between the “less” – and “more” hypoxic groups. After a median follow-up time of 42 months (range 9 – 66), eight patients (10%) had loco-regional treatment failure, including five patients with persistent disease. Four of five persistent patients had a “more” hypoxic tumor, resulting in a significantly increased risk of persistent disease for “more” hypoxic tumors compared to “less” hypoxic tumors, p = 0.04.  Loco-regional control is outlined in figure 2, showing a non-significant trend for a relation between “more“ hypoxic tumors and decreased loco-regional control compared to “less” hypoxic tumors, with a hazard ratio of 4.48 (0.82 – 24.48) and risk difference of 11.6%. 

Conclusion: Expression of the hypoxia related genes from the 15-gene hypoxia classifier is similar in SCC of the uterine cervix, HNSCC and SCCA, and independent of p16 status, indicating that the classifier is representative for hypoxia in SCC in general. This hypothesis generating study is the first to correlate hypoxia to outcome in SCCA and the results indicates that clinical studies investigating hypoxia modifying treatment for SCCA may be relevant.