PIK3CA Pathway Mutations Predictive of Poor Response Following Standard Radiochemotherapy ± Cetuximab in Cervical Cancer Patients

Abstract

Purpose: EGFR is frequently overexpressed in cervical cancer, suggesting EGFR blockade as a promising treatment approach. Cetuximab, an anti EGFR antibody, used conjointly with radiochemotherapy, was feasible in first-line treatment of cervix carcinoma limited to the pelvis.Experimental Design: This randomized phase II trial enrolled 78 FIGO stage IB2-IIIB cervical cancer patients to either cisplatinbased radiochemotherapy alone (arm B, n ¼ 38) or conjointly with a 6-week course of weekly cetuximab (arm A, n ¼ 40). Brachytherapy was given to the pelvic mass. Primary endpoint was disease-free survival (DFS) at 2 years. EGFR expression and targeted sequencing were performed in 54 of 78 patients.Results: Cetuximab over a 6-week period did not improve DFS at 24 months. At 31 months median follow-up, DFS was not significantly different (P ¼ 0.18). Complete response at 4 to 6 months was strongly predictive for excellent DFS (log-rank test; P < 0.001). PIK3CA, KRAS, and STK11 mutations were observed in 22%, 4%, and 2% of patients, respectively. No tumor with a PI3K pathway mutation showed complete response (0/8 in arm A and 0/6 in arm B), whereas 14 of 52 (27%) tumors without mutations did (P ¼ 0.021). PI3K pathway-mutated tumors showed a trend toward poorer DFS (P ¼ 0.06) following cetuximab (8/22) as compared with those following standard treatment only (6/18).Conclusions: Similar to patients with head and neck cancer, patients with cervical cancer showed no gain in DFS at 2 years following a combined treatment of cetuximab with radiochemotherapy. Although treatment tolerance and compliance were satisfactory, it remains to be demonstrated whether maintenance therapy with cetuximab could be beneficial in selected patient groups.

Biomarkers in anal cancer: from biological understanding to stratified treatment

“…In total, 30% cervical cancers harbour PIK3CA mutations associated with poor outcomes following chemoradiotherapy (McIntyre et al , 2013; de la Rochefordiere et al , 2015), but similar findings are also reported in vulval (Trietsch et al , 2014) and penile cancers (McDaniel et al , 2015). Similarly the inverse relationship between HPV involvement and TP53 mutations is documented in HNSCC (Westra et al , 2008) and vulval cancer (Trietsch et al , 2014).…”

Comparative molecular profiling of HPV‐induced squamous cell carcinomas

“…In non‐small‐cell lung cancer, EGFR expression level is predictive of cetuximab benefit; however, for head and neck SCC and colon cancer, even EGFR expression level is not informative in determining if cetuximab will improve patient outcome . Rather, evaluation of downstream signaling components (e.g., members of PI3K pathway) or other receptor tyrosine kinases (e.g., c‐MET, ROS1, ALK) seems to be more informative in predicting efficacy of anti‐EGFR therapy . More work is needed to determine what molecular signatures are indicative of a positive response to anti‐EGFR treatments.…”

Genome Analysis of Latin American Cervical Cancer: Frequent Activation of the PIK3CA Pathway

“…Interestingly, in a clinical trial of AKT inhibitors, cervical and other cancers patients with the E542K mutation had a shorter median progression-free survival than those with the H1047R mutation (14, 39); suggesting that this subtype may be more refractory to therapy. And a recent trial showed PIK3CA to be a marker of poor response (48). The data from our study and others would suggest that agents directly targeting PIK3C would have the best chance of benefit.…”