Association of Anti-EGFR Antibody and MEK Inhibitor in Gynecological Cancer Harboring RAS Mutation: A Case Series.

Low-grade serous carcinoma represents a minority of serous carcinoma. Although they have better prognosis than high-grade serous carcinoma, they respond poorly to chemotherapy. Thus, it appears necessary to find other treatments such as targeted therapies. Since RAS or RAF mutations occur frequently in low-grade serous carcinoma and lead to constitutively activated MAPK cascade, MEK inhibition should be effective in the treatment of low-grade serous carcinoma. So, we wanted to evaluate the clinical benefit of MEK inhibitors in the management of advanced-stage low-grade serous carcinoma harboring KRAS or NRAS mutation. We report a case series of three women with advanced-stage low-grade serous carcinoma harboring RAS mutation who had stabilization of their disease during several months under targeted therapy combining anti-EGFR antibody and MEK inhibitor. We performed in vitro experiments, confirming the effectiveness of MEK inhibitor on the KRAS-mutated OVCAR-5 cell line, and the constitutively activation of MAPK cascade in RAS-mutated carcinoma. However, it seems that the anti-EGFR antibody does not provide any additional benefit. After whole exome analysis is carried out on the patient with the shortest response, we observed the appearance of RB1 loss-of-function mutation that could be a mechanism of resistance to MEK inhibitors in RAS- of RAF-mutated cancers. The MEK inhibitor is effective in the advanced stages of low-grade serous carcinoma harboring RAS mutation with acceptable tolerance. RB1 loss could be a mechanism of resistance to MEK inhibitors in RAS-mutated low-grade serous carcinoma.

Prognostic impact of positive surgical margins after resection of colorectal cancer liver metastases: reappraisal in the era of modern chemotherapy.

BACKGROUND: The purpose of the present study was to assess the prognostic impact of positive surgical margins (R1) after liver resection (LR) of colorectal liver metastases (CRLM) in the era of modern chemotherapy regimens. R1 resection is a negative prognostic factor after LR of CRLM. The significance of R1 margins in the era of effective chemotherapy is unknown. METHODS: From January 2000 to December 2009, 215 patients (177 men: 62 %; median age 60 years; range 30-84 years) underwent LR of CRLM. The LR was considered R1 (margin <1 mm) in 49 patients (23 %) and R0 in 166 patients (77 %). Overall, 108 (50 %) patients received preoperative chemotherapy and 156 (72 %) patients received postoperative chemotherapy. RESULTS: With a median follow-up of 36 months (range 1-141 months), the 5-year overall survival (OS) rate (47 vs 40 %; p = 0.05) and the disease-free survival (DFS) rate (36 vs 23 %; p = 0.006) were significantly lower in the R1 group. Recurrence developed in 152 patients (71 %) and the rate of recurrence was significantly higher (84 vs 67 %; p = 0.02) in the R1 group. On multivariate analysis, N+ status of the colorectal primary tumor (p = 0.008), presence of radiologically occult disease (p = 0.04), and R1 resection (p = 0.03) were independent adverse predictors of OS. The N+ status of the primary tumor (p = 0.003) and R1 resection (p = 0.02) were independent adverse predictors of DFS. On multivariate analysis use of postoperative chemotherapy was the only independent predictor of improved DFS (p = 0.02) in the R1 group. CONCLUSIONS: A positive resection margin remains a significant poor prognostic factor after LR of CRLM in the era of modern chemotherapy. Postoperative chemotherapy reduces recurrence rates after R1 resection of CRLM.

Real-World Data on Olaparib in Relapsed BRCA-mutated Ovarian Cancer: A Multicenter GINECO RETROLA Cohort Study.

BACKGROUND/AIM: Olaparib was approved in 2014 by the European Medicines Agency (EMA) as maintenance treatment for patients with breast cancer gene (BRCA)-mutated platinum-sensitive relapsed high-grade epithelial ovarian cancer (EOC) following the results of the Study 19. We present the results of a national real-world study on the effectiveness of olaparib in relapsed BRCA-mutated EOC patients. PATIENTS AND METHODS: Patients with EOC, peritoneal, and/or fallopian-tube cancer treated with olaparib in a French Center between May 2014 and March 2017 were included. The primary end-point of the study was progression-free survival. RESULTS: Of the 128 patients analyzed, 89 were treated according to the EMA label. The median progression-free survival was 17.0 months. The most common treatment-related toxicity was fatigue. Treatment-related myelodysplastic syndrome (n=5) and a second cancer (n=1) were diagnosed. CONCLUSION: In this real-life setting, olaparib confirmed its efficacy and safety profile, as previously shown in clinical trials.

Preliminary tolerance analysis of adjuvant chemotherapy in older patients after resection of stage III colon cancer from the PRODIGE 34-FFCD randomized trial.

BACKGROUND: Colon adenocarcinoma mainly occurs in older patients. Oxaliplatin-based adjuvant chemotherapy improved disease-free survival after stage III colon cancer resection, but this improvement was not demonstrated in older patients. METHODS: The purpose of ADAGE-PRODIGE 34, randomized open phase III trial is to compare in patients over 70 years oxaliplatin plus fluoropyrimidine with fluoropyrimidine alone in fit patients (Group 1) and fluoropyrimidine with observation in frail patients (Group 2) after resection of stage III colon adenocarcinoma. We report a preliminary tolerance analysis on 50% of the first patients enrolled. RESULTS: The analysis was conducted on 491 patients (378 in Group 1 and 113 in Group 2). Patients in Group 2 were older and showed more frailty criteria than those in Group 1. Cumulative grade 3-5 toxicities were more frequent in patients treated with oxaliplatin in Group 1 or with fluoropyrimidine in Group 2 than in patients treated with fluoropyrimidine in Group 1. At least one course was deferred in more than half of the patients in all groups. Early treatment cessation was more frequent in Group 2. CONCLUSION: No safety concerns were raised for the continuation of accrual. The frailty criteria distribution suggests that the investigator's evaluation for group allocation was accurate.