Combined HER2 analysis of biopsies and surgical specimens to optimize detection of trastuzumab-eligible patients in eso-gastric adenocarcinoma: a GERCOR study.

BACKGROUND: HER2 is overexpressed in 10 to 20% of gastro-esophageal adenocarcinoma (GE-ADK), and is a target for trastuzumab in metastatic patients. We conducted a study to compare HER2 expression between diagnostic biopsies (DBs) and surgical specimens (SSs) of GE-ADK, and to determine the influence of non-trastuzumab containing neoadjuvant chemotherapy (NAC) on this expression. PATIENTS AND METHODS: Pathological specimens from biopsies of 228 patients operated on between 2004 and 2011 were collected. Two cohorts treated (n = 141) or not (n = 87) with a NAC were constituted. Two blind independent pathological HER2 analyses on DB and on SS were carried out using immunohistochemistry (IHC) and colorimetric in situ hybridization (CISH). HER-2 overexpression (HER2+) was defined by a score 3+ in IHC, or 2+ with a positive CISH test, according to the specific HER2 scoring guidelines for GE-ADK. RESULTS: Paired HER2 status could be determined for 218 out of the 228 patients (95.6%). HER2+ rates were 13.3% on DB (29/218) and 14.7% on SS (32/218). HER2+ tumors were mainly cardial or esophageal adenocarcinomas, with a well-differentiated, intestinal histological type. HER2 status differed between DB and SS in 6% of cases. When DB analyses were added to SS analyses, the relative increase in HER2+ cases was 13.5% (17.1% for patients with NAC and 23.5% for patients with histological response to NAC, versus 7.1% for patients without NAC, P = 0.4, NS). Differences between DB and SS HER2 expression could be explained by intratumoral heterogeneity and by a HER2 expression decrease in SS after NAC in responding patients possibly due to a higher chemosensitivity of HER2-positive clones. CONCLUSION: The determination of HER2 status on DB provides results that complete those obtained with SS. Combining the analysis of DB and of SS enables to optimize the selection of trastuzumab-eligible patients in case of metastatic relapse, and particularly in previously NAC-responding patients.

Panitumumab combined with irinotecan for patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy: a GERCOR efficacy, tolerance, and translational molecular study.

BACKGROUND: The purpose of this study was to evaluate the combination of panitumumab and irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy (oxaliplatin, fluoropyrimidines-irinotecan and bevacizumab). PATIENTS AND METHODS: KRAS status was first determined locally but subsequent validation of KRAS status and additional screenings (rare KRAS, NRAS, BRAF mutations and EGFR copy number) were centrally assessed. Patients received panitumumab (6 mg/kg) and irinotecan (180 mg/m²) every 2 weeks. RESULTS: Sixty-five eligible patients were analyzed. The objective response rate (ORR) was 29.2% [95% confidence interval (95% CI) 18.2-40.3]. Median progression-free and overall survivals were 5.5 and 9.7 months, respectively. Most frequent grade 3/4 toxic effects were skin 32.3%, diarrhea 15.4% and neutropenia 12.3%. Tissue samples were available for 60 patients. For the confirmed KRAS wild-type population codon 12 or 13 mutation (n = 54), ORR was 35.2% (95% CI 22.4.1-47.9). Thirteen patients had a NRAS, a BRAF or a rare KRAS mutation, and no tumor response was observed in this subgroup when compared with 46.3% (95% CI 31.1-61.6) ORR in the subgroup of 41 patients with no identified mutation. CONCLUSION: Panitumumab and irinotecan is an active third-line regimen in a well-defined population based on biomarkers. ClinicalTrials.gov Identifier NCT00655499.

Prognostic impact of microsatellite instability in colorectal cancer patients treated with adjuvant FOLFOX.

BACKGROUND: Colorectal cancer (CRC) patients whose tumours have microsatellite instability (MSI) do not benefit from adjuvant 5-fluorouracil. However, the predictive value of MSI is not known for FOLFOX, now recommended in adjuvant setting. PATIENTS AND METHODS: MSI phenotype was assessed by the pentaplex method. Three-year relapse and disease-free survival (DFS) of patients treated for CRC with FOLFOX 4 in an adjuvant setting were compared according to MSI phenotype. RESULTS: A total of 105 patients (19 MSI, 86 microsatellite stable, MSS) were included. Stage II patients more frequently exhibited MSI (58%) than MSS (21%); (p=0.002). Patients with MSI relapsed significantly less than those with MSS (10.5% vs. 35.0%; p=0.04). DFS was similar for MSI and MSS (p=0.1). In univariate analysis, stage (p=0.0006) and MSI status (p=0.017) were significant predictors of DFS. CONCLUSION: MSI status was associated with significantly fewer relapses and a better prognosis. FOLFOX4 did not alter survival of patients with MSI and can be administered to them.

Phase II Study of Biweekly Pemetrexed Plus Irinotecan as Second-Line Therapy for Metastatic Colorectal Cancer.

Background. This open-label, single-arm, two-stage, Phase II study investigated the efficacy and safety of bi-weekly pemetrexed combined with irinotecan, in patients with metastatic colorectal cancer (mCRC), after first-line chemotherapy using FOLFOX regimen. Patients and methods. Patients received pemetrexed 400 mg/m(2) as a 10-minute intravenous infusion (with vitamin supplementation) followed by irinotecan 180 mg/m(2) as a 90-minute infusion on day 1 of a 14-day cycle, for a maximum of 12 cycles. The primary endpoint was response rate (RR; H(0) /= 20%, alpha = 0.05, power = 90%). Secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and toxicities. Results. Partial response was observed in six out of 44 patients enrolled in the study (RR = 13.6%). The median PFS and OS were 4.0 and 13.9 months, respectively. The most common grade 3-4 toxicities were fatigue: 20.5% of patients, neutropenia: 18.6%, diarrhea: 13.6%, elevated transaminases: 9.5%, anemia: 9.3%, and vomiting: 6.8%. Conclusion. Pemetrexed plus irinotecan administered every two weeks is an active and well-tolerated regimen in mCRC patients pretreated with FOLFOX regimen. However, this regimen does not seem to provide clinically relevant advantage over historical data of a classical FOLFIRI regimen.

Dual modulation of 5-fluorouracil with folinic acid and hydroxyurea in metastatic colorectal cancer.

Leucovorin and 5-fluorouracil (5-FU) can be further modulated with hydroxyurea. Sixty-eight patients with advanced colorectal cancer received every 2 weeks hydroxyurea per os 1.5 g to 2 g days -1, 1, and 2; leucovorin 200 mg/m2 iv over 2 hours started at least 1 hour after hydroxyurea and per os 100 mg/m2 12 hours later, on days 1 and 2; 5-FU, bolus 400 mg/m2 during leucovorin infusion and 24 hours continuous infusion 600 mg/m2, repeated on days 1 and 2. Two complete responses (7%), 8 partial responses (30%), 12 no change (44%), and 5 progressions (19%) were observed among 31 nonpreviously treated patients. Four partial response (11%), 15 no change (43%), and 16 progressions (46%) were observed among 37 pretreated patients. Nineteen were treated after progression on the same regimen without oral leucovorin and hydroxyurea, 1 achieved PR and 10 showed no change. Among them, 6 experienced response or stabilization of longer duration than with previous treatment. Twelve-month survival was 61% in non-pretreated and 43% in pretreated patients as of the start of chemotherapy. Toxicity was mild with nausea in 46%, diarrhea in 37%, and mucositis in 36%. The first-line response rate is in the range of leucovorin and 5-FU alone. Some pretreated patients benefited from this regimen.

Bi-weekly 2-day schedule of high-dose folinic acid, 5-fluorouracil bolus and infusion in pretreated advanced epithelial ovarian cancer: a phase II study.

Twenty patients with documented progression after two or three cisplatin-based regimens for advanced epithelial ovarian carcinoma were treated with high-dose folinic acid (200 mg/m2), 5-fluorouracil bolus (400 mg/m2) and continuous infusion (600 mg/m2) for two consecutive days every two weeks. One clinically complete and two partial responses were observed in 16 evaluable patients, with 5 remaining stable. Median survival was 9 months. Toxicity was mild. This combination achieved a 19% (95% confidence interval 4%-46%) response rate in heavily pretreated cisplatin-resistant patients.