Purpose Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of non–small cell lung cancer (NSCLC). Recently, several case reports and small series have reported that ALK rearrangements can overlap with other oncogenic drivers in NSCLC in crizotinib-naïve and crizotinib-resistant cancers. Experimental Design We reviewed clinical genotyping data from 1,683 patients with NSCLC and investigated the prevalence of concomitant EGFR or KRAS mutations among patients with ALK-positive NSCLC. We also examined biopsy specimens from 34 patients with ALK-positive NSCLC after the development of resistance to crizotinib. Results Screening identified 301 (17.8%) EGFR mutations, 465 (27.6%) KRAS mutations, and 75 (4.4%) ALK rearrangements. EGFR mutations and ALK rearrangements were mutually exclusive. Four patients with KRAS mutations were found to have abnormal ALK FISH patterns, most commonly involving isolated 5′ green probes. Sufficient tissue was available for confirmatory ALK immunohistochemistry in 3 cases, all of which were negative for ALK expression. Among patients with ALK-positive NSCLC who acquired resistance to crizotinib, repeat biopsy specimens were ALK FISH positive in 29 of 29 (100%) cases. Secondary mutations in the ALK kinase domain and ALK gene amplification were observed in 7 of 34 (20.6%) and 3 of 29 (10.3%) cases, respectively. No EGFR or KRAS mutations were identified among any of the 25 crizotinib-resistant, ALK-positive patients with sufficient tissue for testing. Conclusions Functional ALK rearrangements were mutually exclusive with EGFR and KRAS mutations in a large Western patient population. This lack of overlap was also observed in ALK-positive cancers with acquired resistance to crizotinib.

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Statement of translational relevancePatients with active breast cancer brain metastases (BCBMs) are often excluded from clinical trials because of the concern that most drugs do not adequately penetrate the blood-tumor barrier. This impedes both discovery and validation of drug targets for treating BCBMs. We reviewed pharmacodynamic data from HER2-positive breast cancer brain metastasis mouse models and patients, which suggest that BCBMs resist HER2-targeted therapy despite adequate intracranial drug delivery and activity. In fact, evidence suggests that brain-specific molecular alterations involving the PI3K-AKT-mTOR pathway underlie BCBM resistance to HER2-targeted therapy. Thus, careful integration of data from in vivo models, non-invasive imaging and patient tissues can better determine drug activity at metastatic sites and help reveal novel resistance mechanisms. By highlighting drug resistance in brain metastases as a tractable problem, we aim to stimulate further basic and translational investigation in this underserved research field.Research. AbstractThe brain is the most common site of first metastasis for patients with HER2-positive breast cancer treated with HER2-targeting drugs. However, the development of effective therapies for breast cancer brain metastases (BCBMs) is limited by an incomplete understanding of the mechanisms governing drug sensitivity in the central nervous system. Pharmacodynamic data from patients and in vivo models suggest that inadequate drug penetration across the 'bloodtumor' barrier is not the whole story. Using HER2-positive breast cancer brain metastases as a case study, we highlight recent data from orthotopic brain metastasis models that implicates brain-specific drug resistance mechanisms in BCBMs and suggests a translational research paradigm to guide drug development for treatment of BCBMs.