Preoperative chemoradiation with capecitabine, irinotecan and cetuximab in rectal cancer : significance of pre-treatment and post-resection RAS mutations
Mené sur 82 patients atteints d'un adénocarcinome non métastatique du rectum traité par résection R0, cet essai multicentrique de phase II évalue, du point de vue de la qualité des marges de résection, l'intérêt d'une radiothérapie pré-opératoire en combinaison avec un traitement concomitant par capécitabine-irinotécan-cétuximab, puis analyse l'influence de la présence intratumorale de mutations de gènes impliqués dans la voie de signalisation EGFR (KRAS, NRAS, PIK3CA et BRAF) sur la réponse clinique ou pathologique et la survie globale des patients
Background : The influence of EGFR pathway mutations on cetuximab-containing rectal cancer preoperative chemoradiation (CRT) is uncertain. Methods : In a prospective phase II trial (EXCITE), patients with magnetic resonance imaging (MRI)-defined non-metastatic rectal adenocarinoma threatening/involving the surgical resection plane received pelvic radiotherapy with concurrent capecitabine, irinotecan and cetuximab. Resection was recommended 8 weeks later. The primary endpoint was histopathologically clear (R0) resection margin. Pre-planned retrospective DNA pyrosequencing (PS) and next generation sequencing (NGS) of KRAS, NRAS, PIK3CA and BRAF was performed on the pre-treatment biopsy and resected specimen. Results : Eighty-two patients were recruited and 76 underwent surgery, with R0 resection in 67 (82%, 90%CI: 73–88%) (four patients with clinical complete response declined surgery). Twenty–four patients (30%) had an excellent clinical or pathological response (ECPR). Using NGS 24 (46%) of 52 matched biopsies/resections were discrepant : ten patients (19%) gained 13 new resection mutations compared to biopsy (12 KRAS, one PIK3CA) and 18 (35%) lost 22 mutations (15 KRAS, 7 PIK3CA). Tumours only ever testing RAS wild-type had significantly greater ECPR than tumours with either biopsy or resection RAS mutations (14/29 [48%] vs 10/51 [20%], P=0.008), with a trend towards increased overall survival (HR 0.23, 95% CI 0.05–1.03, P=0.055). Conclusions : This regimen was feasible and the primary study endpoint was met. For the first time using pre-operative rectal CRT, emergence of clinically important new resection mutations is described, likely reflecting intratumoural heterogeneity manifesting either as treatment-driven selective clonal expansion or a geographical biopsy sampling miss. Keywords : locally advanced rectal cancer; cetuximab-containing chemoradiation; RAS mutations; intra-tumoural clonal heterogeneity; treatment response; next generation sequencing