The impact of BRAF mutations in metastatic melanoma on the incidence of brain metastases and melanoma prognosis and the effect of BRAF inhibitors on the incidence of brain metastases has not been defined. Therefore, a retrospective analysis of patients with metastatic melanoma treated at three institutions was carried out to examine the impact of BRAF mutations and a BRAF inhibitor, vemurafenib, on the incidence of brain metastases. A retrospective review of 436 records revealed no difference in the incidence of brain metastases between patients with BRAF-mutated tumors versus those without (incidence rate ratio=1.11, 95% confidence interval: 0.80-1.53; P=0.53). A lower incidence of brain metastases was observed in patients with BRAF-mutated tumors who took vemurafenib before the development of brain metastases versus those who did not (incidence rate ratio=0.51, 95% confidence interval: 0.30-0.86; P=0.009). Although treatment with vemurafenib led to improvement in extracranial disease control, it did not significantly affect progression of existing intracranial disease and survival in these patients (P=0.7). Although our previous preclinical data have indicated that penetration of vemurafenib into the brain is limited, our retrospective analysis showed that there was a lower incidence of brain metastases in patients with BRAF-mutated tumors who took vemurafenib before the diagnosis of brain metastases.

BackgroundThe impact of using adjuvant chemotherapy following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with appendiceal adenocarcinoma is not known. The aim of this study was to assess the impact of adjuvant chemotherapy following complete cytoreduction in patients with appendiceal adenocarcinoma.MethodsRetrospective medical record review of all patients with appendiceal adenocarcinoma treated at our institution between 2006 and 2015. Kaplan‐Meier plots were used to summarize overall survival (OS) and relapse‐free survival over time, and log‐rank tests and Cox proportional hazards models were used to test for differences in survival between groups.ResultsA total of 103 patients with appendiceal adenocarcinoma received care at our institution during the study period. Complete cytoreduction (cytoreductive score 0‐1) was achieved in 68 patients (66%). Of these 68 patients, 26 received adjuvant chemotherapy. The most common regimens were capecitabine (n = 11), capecitabine plus oxaliplatin (n = 7), and 5‐FU plus oxaliplatin (n = 6). Tumor histopathology and grade, and the ability to achieve complete cytoreduction were significant predictors of overall survival. The median OS for non–low‐grade and well‐differentiated tumor patients who received adjuvant chemotherapy following complete cytoreduction was 9.03 years, compared to 2.88 years for patients who did not receive adjuvant chemotherapy (P = .02). Among low‐grade and well‐differentiated tumor patients who underwent complete cytoreduction, there was no statistically significant difference in OS between those who received adjuvant chemotherapy and those who did not.ConclusionAdjuvant chemotherapy seems to have benefit in appendiceal cancer patients with non–low‐grade or well‐differentiated tumor type but not in low‐grade or well‐differentiated tumors.

9048 Background: Brain metastases continue to be the major cause of morbidity and mortality in patients with metastatic melanoma. The impact of BRAF mutations and effectiveness of BRAF inhibitors on the brain metastases in these patients is lacking. Methods: Preclinical studies were conducted to assessthe steady-state brain and plasma distribution of vemurafenib, a BRAF inhibitor in FVB wild-type and Mdr1a/b-/-Bcrp1-/- mice deficient in the drug efflux transporters, p-glycoprotein (P-gp) and breast cancer resistant protein (BCRP). A retrospective analysis of patients with metastatic melanoma treated at University of Minnesota from August 2011 to December 2012 was conducted. A similar analysis of cases treated at Mayo Clinic is underway. Results: The preclinical studies in mice show that both P-gp and BCRP play a significant role in limiting the brain distribution of vemurafenib. Retrospective analysis was performed on 57 patients with Stage IIIc /IV cutaneous and mucosal melanoma. Patients with BRAF mutation had a higher incidence rate of brain metastases compared to patients without BRAF mutation, although it was not statistically significant (Incidence ratio=1.56; 95% CI=0.70-3.48; P=0.27). Vemurafenib neither reduced the incidence of brain metastases (Incidence ratio = 0.89; 95% CI: 0.30-2.60; P=0.83) nor made significant difference in overall survival. It was observed that treatment with BRAF inhibitor led to improvement in extracranial disease but did not affect progression of intracranial disease. Conclusions: In concordance with preclinical data which indicates that P-gp and BCRP play a significant role in limiting the brain distribution of vemurafenib, the retrospective analysis shows that there is improvement in extracranial disease but progression in intracranial disease with treatment with BRAF inhibitor in patients with metastatic malignant melanoma with BRAF mutation. Development of BRAF inhibitors that are not substrates for P-gp and BCRP or concomitant use of P-gp and BCRP inhibitors with vemurafenib, may be needed in order to control or prevent intracranial disease in these patients. Further analysis to improve statistical power of our observation is underway.

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