Mutations in the RAS/RAF/MEK/ERK pathway leading to constitutive activation and uncontrolled cellular growth have been identified in various human malignancies, making this pathway a target for potential therapeutics. The activating BRAFV600E mutation is one well-characterized oncogenic mutation that has been described and targeted with clinical success in various malignancies, including melanoma and hairy cell leukemia. Although BRAF-directed treatments have yielded clinical benefit in a subset of tumor types, such as melanoma, thyroid cancer, and lung cancer, BRAF inhibition fails to confer a clinical benefit in colon cancer. Identification of patients for whom BRAF inhibition may produce clinically meaningful outcomes is imperative. The incidence of BRAF mutations in neuroendocrine carcinoma (NEC) is estimated to be 5% to 10%. A recent case series demonstrated benefit in targeting the BRAFV600E mutation in metastatic high-grade rectal NECs. Combination BRAF and MEK inhibition is known to yield improved outcomes compared with BRAF inhibition alone in melanoma. This report presents 2 patients with high-grade colorectal NECs who had different responses to treatment with combined BRAF/MEK inhibition after experiencing disease progression through first-line platinum-based chemotherapy. One patient experienced an excellent initial response to therapy before ultimately experiencing progression, and in the other patient initially had stable disease before eventually experiencing progression. These cases highlight the complicated role BRAF mutations play in gastrointestinal NECs, and the need for further research to identify not only patients who may benefit from BRAF-directed therapies but also strategies to avoid development of resistance.
Jarred Burkart, Dwight Owen, Manisha H. Shah, Sherif R. Z. Abdel-Misih, Sameek Roychowdhury, Robert Wesolowski, Sigurdis Haraldsdottir, Julie W. Reeser, Eric Samorodnitsky, Amy Smith and Bhavana Konda
Hinda Boutrid, Maryam Lustberg, Jeffrey Vandeusen, Sagar Sardesai, Daniel Stover, Robert Wesolowski, Mathew Cherian, Julie Stephens, Marilly Palettas, Evan Morgan, Mohmoud Kassem, Michael Berger, Craig A. Vargo, Bhuvaneswari Ramaswamy and Nicole Williams
Background: Invasive lobular carcinoma (ILC) accounts for 5%–15% of all invasive breast cancer cases. ILC has the propensity for distant late recurrence with widespread metastatic disease. To our knowledge, there is limited data on the clinical outcomes and treatment strategies of metastatic ILC. This retrospective study evaluates the overall survival (OS) and progression-free survival (PFS) in the metastatic ILC population at a single institution, focusing on first line treatment received in the metastatic setting. Methods: A retrospective chart review was performed on patients (Pts) diagnosed with metastatic ILC diagnosed at The Ohio State University Comprehensive Cancer Center between January 1, 2004 and December 31, 2014 using an IRB approved protocol. Patient demographics, clinical characteristics, and treatment modalities were summarized with descriptive statistics. OS (time from metastasis to death or last known follow-up) and PFS (time from diagnosis of metastasis to progression) were compared between types of first-line treatment: endocrine therapy (ET), chemotherapy (chemo), chemo followed by ET, ET plus CDK 4/6 inhibitor, or other treatments. OS and PFS estimates were generated using Kaplan Meier methods and compared using Log-rank tests. Results: 60 female pts were included in this study. The median age was 59 years (24–78). 45 (75%) pts were postmenopausal, 44 (73%) ER+/PR+, 14 (23%) ER+/PR-, and 2 (3%) ER-PR-, 28 (47%) with only bone metastases, 19 (32%) with visceral and bone metastases, and 13 (22%) with liver metastases. Twenty-eight (47%) pts received first line ET therapy, 12 (20%) received ET + CDK 4/6 inhibitor, 7 (12%) received chemo alone, 4 (7%) received chemo followed by ET, and 9 (15%) received other types of first line therapy. The median OS was 3.0 years, and the median PFS was 1.4 years. No difference in the Kaplan-Meier curves was found between first-line treatment groups in OS or PFS (OS: P=.247; PFS: P=.436). Discussion: ILC is a histologically distinct disease from invasive ductal cancer. It has been previously shown that invasive lobular cancer may not be as sensitive to adjuvant chemotherapy. We showed that in the metastatic setting there was no difference in PFS and OS among first line treatment groups. ET remains preferred treatment option; however, based on our data, chemotherapy can be considered in patient with metastatic ILC in the appropriate clinical context such as visceral crisis.