PIK3CA pathway mutations predictive of poor response following Standard radio chemotherapy +/- Cetuximab in cervical cancer patients
Mené en France sur 78 patientes atteintes d'un cancer du col de l'utérus de stade IB2-IIIB selon la classification de FIGO et traitées par chimio-radiothérapie avec ou sans cétuximab (durée médiane de suivi : 31 mois), cet essai de phase II met en évidence une mauvaise réponse au traitement chez les patientes dont la tumeur présente des mutations de la voie PIK3CA
Background : EGFR is frequently overexpressed in cervical cancer (CC), suggesting EGFR blockade as a promising treatment approach. Cetuximab, an anti EGFR antibody, used conjointly with radio-chemotherapy, was feasible in first-line treatment of cervix carcinoma limited to the pelvis. Methods : This randomized phase II trial enrolled 78 FIGO-stage IB2-IIIB CC patients to either Cisplatin based radio-chemotherapy alone (Arm B, n=38) or conjointly with a 6 week course of weekly Cetuximab (Arm A, n=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 54/78 patients. Findings : Cetuximab over a 6 week period didn't improve DFS at 24 months. At 31 months median follow-up, DFS was not significantly different (p=0•18). Complete response at 4-6 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) whilst 14/52 (27%) tumors without mutations did (p=0•021). PI3K-pathway mutated tumors showed a trend towards poorer DFS (p=0•06) following Cetuximab (8/22) as compared to those following standard treatment only (6/18). Interpretation : Similarly to Head and Neck cancer patients, CC patients showed no gain in DFS at 2 years following a combined treatment of Cetuximab with radio chemotherapy. While treatment tolerance and compliance were satisfactory, it remains to be demonstrated whether maintenance therapy with Cetuximab could be beneficial in selected patient groups.