Mechanisms of resistance to BRAF and MEK inhibitors and clinical update of US Food and Drug Administration-approved targeted therapy in advanced melanoma

Sunilkumar Kakadia,1 Naveen Yarlagadda,1 Ramez Awad,2 Madappa Kundranda,3 Jiaxin Niu,3 Boris Naraev,3 Lida Mina,3 Tomislav Dragovich,3 Mark Gimbel,3 Fade Mahmoud3 1Department of Internal Medicine, Division of Hematology and Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 2Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 3TW Lewis Melanoma Center of Excellence, Banner MD Anderson Cancer Center, Gilbert, AZ, USA Abstract: Approximately 50% of melanomas harbor an activating BRAF mutation. Combined BRAF and MEK inhibitors such as dabrafenib and trametinib, vemurafenib and cobimetinib, and encorafenib and binimetinib are US Food and Drug Administration (FDA)-approved to treat patients with BRAFV600-mutated advanced melanoma. Both genetic and epigenetic alterations play a major role in resistance to BRAF inhibitors by reactivation of the MAPK and/or the PI3K–Akt pathways. The role of BRAF inhibitors in modulating the immunomicroenvironment and perhaps enhancing the efficacy of checkpoint inhibitors is gaining interest. This article provides a comprehensive review of mechanisms of resistance to BRAF and MEK inhibitors in melanoma and summarizes landmark trials that led to the FDA approval of BRAF and MEK inhibitors in metastatic melanoma. Keywords: malignant melanoma, targeted therapy, BRAF inhibitor, MEK inhibitor, resistance&nbsp

Incidence and clinical significance of ESR1 mutations in heavily pretreated metastatic breast cancer patients

Jiaxin Niu,1 Grant Andres,1 Kim Kramer,2 Madappa N Kundranda,3 Ricardo H Alvarez,4 Eiko Klimant,5 Ankur R Parikh,5 Bradford Tan,6 Edgar D Staren,7 Maurie Markman8 1Department of Medical Oncology, Western Regional Medical Center at Cancer Treatment Centers of America (CTCA), Goodyear, AZ, USA; 2CTCA Medicine and Science, Zion, IL, USA; 3Department of Medical Oncology, Banner MD Anderson Cancer Center, Gilbert, AZ, USA; 4Department of Medical Oncology, Southeastern Regional Medical Center at CTCA, Newnan, GA, USA; 5Department of Medical Oncology, Eastern Regional Medical Center at CTCA, Philadelphia, PA, USA; 6Department of Pathology, Midwestern Regional Medical Center at CTCA, Zion, IL, USA; 7Advanced Individual Medicine, Phoenix, AZ, USA; 8CTCA Medicine and Science, Philadelphia, PA, USA Background: ESR1 mutation has recently emerged as one of the important mechanisms involved in endocrine resistance. The incidence and clinical implication of ESR1 mutation has not been well evaluated in heavily pretreated breast cancer patients. Methods: We conducted a retrospective review of advanced breast cancer patients with tumors who underwent next-generation sequencing genomic profiling using Foundation One test at Cancer Treatment Centers of America® regional hospitals between November 2012 and November 2014. Results: We identified a total of 341 patients including 217 (59%) estrogen receptor (ER)+, 177 (48%) progesterone receptor (PR)+, 30 (8%) hormone receptor+/HER2 positive, and 119 (32%) triple negative patients. ESR1 mutation was noted in 27/222 (12.1%) ER+ or PR+ breast cancer patients. All ER+ patients received at least one line of an aromatase inhibitor. All 28 patients were found to harbor ESR1 mutations affecting ligand-binding domain with the most common mutations affecting Y537 (17/28, 60.7%) and D538 (9/28, 32.1%). In this cohort, 19 (67.9%) patients carried three or more, seven (25%) patients had one or two additional genomic alterations and one (3.6%) patient had an ESR1 mutation only. Of 28 patients, three patients were treated with fulvestrant immediately before and two patients were treated after next-generation sequencing testing; only one patient achieved stable disease for 8 months and the other four patients had progression of disease. In all, 3/3 (100%) patients before testing and 2/4 (50%) after testing treated with exemestane and everolimus achieved stable disease for at least 6 months. Conclusion: ESR1 mutation was found in 12.1% of a large cohort of advanced breast cancer patients. Exemestane in combination with everolimus might be a reasonable option. Prospective studies are warranted to validate these findings. Keywords: ESR1 mutation, breast cancer, endocrine therapy, resistance, next-generation sequencing, genomic alteratio