38. Who's driving treatment? Two co-occurring driver mutations in Primary Lung Adenocarcinoma

Abstract

Listen

Translate article

Oncogenic driver mutations in NSCLC have been historically thought to be mutually exclusive. Tumors with co-occurring mutations are part of a rare molecular subtype with no defined targeted therapies. We report a 78-year-old Caucasian female with a history of smoking, presenting to the ER with dyspnea on exertion, intermittent cough, and chest wall discomfort. PET CT imaging revealed large bilateral hypermetabolic areas of mass-like consolidation throughout the lungs. A CT-guided left lung mass core biopsy demonstrated adenocarcinoma with acinar and micropapillary patterns. TTF-1 was positive and is consistent with a lung primary. NGS analysis detected a KRAS c.38G>A p.(G13D) mutation and a co-occurring class II BRAF c.1391G>T p.(G464V) mutation. EGFR testing, ALK and ROS1 FISH were negative and PD-L1 expression was positive. Interestingly, of the few reported co-occurring KRAS and BRAF mutation cases, all have BRAF non-V600E mutations. Class II BRAF cases have been reported to be insensitive to anti-BRAF targeted therapy and almost all KRAS mutations, except G12C, do not have a targeted therapy. However, it has been suggested that specific KRAS mutations are better candidates for immunotherapy and currently there is an mRNA vaccine being considered for KRAS mutations including G13D. Our patient has begun the first cycle of chemotherapy plus immunotherapy consisting of carboplatin + pemetrexed + pembrolizumab based on the PD-L1 expression. To the best of our knowledge, although KRAS and BRAF co-mutations have been previously described, this is the first report of these specific mutations observed together in NSCLC. Oncogenic driver mutations in NSCLC have been historically thought to be mutually exclusive. Tumors with co-occurring mutations are part of a rare molecular subtype with no defined targeted therapies. We report a 78-year-old Caucasian female with a history of smoking, presenting to the ER with dyspnea on exertion, intermittent cough, and chest wall discomfort. PET CT imaging revealed large bilateral hypermetabolic areas of mass-like consolidation throughout the lungs. A CT-guided left lung mass core biopsy demonstrated adenocarcinoma with acinar and micropapillary patterns. TTF-1 was positive and is consistent with a lung primary. NGS analysis detected a KRAS c.38G>A p.(G13D) mutation and a co-occurring class II BRAF c.1391G>T p.(G464V) mutation. EGFR testing, ALK and ROS1 FISH were negative and PD-L1 expression was positive. Interestingly, of the few reported co-occurring KRAS and BRAF mutation cases, all have BRAF non-V600E mutations. Class II BRAF cases have been reported to be insensitive to anti-BRAF targeted therapy and almost all KRAS mutations, except G12C, do not have a targeted therapy. However, it has been suggested that specific KRAS mutations are better candidates for immunotherapy and currently there is an mRNA vaccine being considered for KRAS mutations including G13D. Our patient has begun the first cycle of chemotherapy plus immunotherapy consisting of carboplatin + pemetrexed + pembrolizumab based on the PD-L1 expression. To the best of our knowledge, although KRAS and BRAF co-mutations have been previously described, this is the first report of these specific mutations observed together in NSCLC.