Molecular Biomarker Stratification of Adjuvant Treatment for Pancreatic Adenocarcinoma
Standard adjuvant treatment for resected pancreatic adenocarcinoma is gemcitabine as shown in the CONKO-001 trial: disease-free survival with gemcitabine vs placebo was 13.4 versus 6.7 months; P <.001; and overall survival (OS) was 22.8 versus 20.2 months; P = .01.1 Adding cisplatin to gemcitabine has shown increased response rates in the advanced and metastatic settings.2 This benefit may be inhibited by high expression of excision repair cross-complementing gene-1 (ERCC1), the key enzyme in nucleotide excision repair. Postlewait and colleagues presented the results of a phase 2 prospective trial to assess outcomes of patients with resected pancreatic adenocarcinoma who were treated with adjuvant gemcitabine/cisplatin chemotherapy, stratifying results by tumor ERCC1 expression.3
Patients with resected pancreatic adenocarcinoma at a single institution received gemcitabine (1000 mg/m2)/cisplatin (50 mg/m2) on days 1, 8, and 15, every 28 days for 6 cycles. After enrolling 5 patients, this was modified to days 1 and 15 due to toxicity. Tumor ERCC1 expression was evaluated by immunohistochemistry and dichotomized into low and high expression groups. Primary outcomes were relapse-free survival (RFS) and OS stratified by ERCC1 expression, which was scored by percentage and intensity of staining.
Of 22 patients, 16 (73%) had Stage IIB disease, 5 (23%) Stage IIA, and 1 (5%) Stage IA. Thirteen (59%) patients completed all 6 cycles of therapy, 9 of whom required dose reduction. Of the remaining 9 patients, 4 completed >68% of the intended therapy.
Grade 3 and 4 toxicity occurred in 13 patients (59%), with neutropenia as the most common adverse event (n = 9; 41%). Other grade 3/4 toxicities of note included fatigue, nausea and vomiting, renal insufficiency, anemia, and thrombocytopenia; 1 patient had a pulmonary embolus. At a median follow-up for survivors of 37.5 months, median RFS was 16.7 months, and OS was 35.6 months. ERCC1 tumor expression data were available for 20 patients: 15 (75%) low and 5 (25%) high. Low compared with high ERCC1 was not associated with improved RFS (12.4 months vs 16.7 months; P = .69) or OS (median not reached vs 21.6 months; P = .22). The authors concluded that adjuvant gemcitabine/cisplatin is well-tolerated by patients with resected pancreatic adenocarcinoma, RFS and OS after adjuvant gemcitabine/cisplatin therapy appear promising compared with historic controls, but tumor ERCC1 expression is not a reliable biomarker to predict clinical response to this regimen. Further prospective trials evaluating gemcitabine/cisplatin as an adjuvant regimen and ERCC-1 as a biomarker in resected pancreatic adenocarcinoma are warranted.
- Oettle H, et al. JAMA. 2013;310:1473-1481.
- Gresham GK, et al. BMC Cancer. 2014;14:471.
- Postlewait LM, et al. ASCO 2016 Gastrointestinal Cancers Symposium. Abstract 230.