PURPOSEEvidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)–positive breast cancer to the CNS are limited. We previously reported modest activity of neratinib monotherapy for HER2-positive breast cancer brain metastases. Here we report the results from additional study cohorts.PATIENTS AND METHODSPatients with measurable, progressive, HER2-positive brain metastases (92% after receiving CNS surgery and/or radiotherapy) received neratinib 240 mg orally once per day plus capecitabine 750 mg/m2 twice per day for 14 days, then 7 days off. Lapatinib-naïve (cohort 3A) and lapatinib-treated (cohort 3B) patients were enrolled. If nine or more of 35 (cohort 3A) or three or more of 25 (cohort 3B) had CNS objective response rates (ORR), the drug combination would be deemed promising. The primary end point was composite CNS ORR in each cohort separately, requiring a reduction of 50% or more in the sum of target CNS lesion volumes without progression of nontarget lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression.RESULTSForty-nine patients enrolled in cohorts 3A (n = 37) and 3B (n = 12; cohort closed for slow accrual). In cohort 3A, the composite CNS ORR = 49% (95% CI, 32% to 66%), and the CNS ORR in cohort 3B = 33% (95% CI, 10% to 65%). Median progression-free survival was 5.5 and 3.1 months in cohorts 3A and 3B, respectively; median survival was 13.3 and 15.1 months. Diarrhea was the most common grade 3 toxicity (29% in cohorts 3A and 3B).CONCLUSIONNeratinib plus capecitabine is active against refractory, HER2-positive breast cancer brain metastases, adding additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy. For optimal tolerance, efforts to minimize diarrhea are warranted.

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The AURORA US Metastasis Project was established with the goal to identify molecular features associated with metastasis. We assayed 55 females with metastatic breast cancer (51 primary cancers and 102 metastases) by RNA sequencing, tumor/germline DNA exome and low-pass whole-genome sequencing and global DNA methylation microarrays. Expression subtype changes were observed in ~30% of samples and were coincident with DNA clonality shifts, especially involving HER2. Downregulation of estrogen receptor (ER)-mediated cell–cell adhesion genes through DNA methylation mechanisms was observed in metastases. Microenvironment differences varied according to tumor subtype; the ER+/luminal subtype had lower fibroblast and endothelial content, while triple-negative breast cancer/basal metastases showed a decrease in B and T cells. In 17% of metastases, DNA hypermethylation and/or focal deletions were identified near HLA-A and were associated with reduced expression and lower immune cell infiltrates, especially in brain and liver metastases. These findings could have implications for treating individuals with metastatic breast cancer with immune- and HER2-targeting therapies.

Background: This pilot study was performed to test our ability to administer neratinib monotherapy prior to clinically-recommended craniotomy in patients with human epidermal growth factor receptor 2 (HER2)-positive, metastatic breast cancer to the central nervous system (CNS), to examine neratinib's CNS penetration at craniotomy, and to examine post-operative neratinib maintenance. Patients and Methods: Patients with HER2-positive brain metastases undergoing clinicallyindicated cranial resection of a parenchymal tumor received neratinib 240 mg orally once daily for 7-21 days pre-operatively and resumed therapy post-operatively in 28-day cycles. Exploratory evaluations of time-to-progression, survival, as well as correlative tissue, cerebrospinal fluid (CSF), and blood-based analyses examining neratinib concentrations were planned. Results: We enrolled five patients between 5/22/2013-10/18/2016. As of March 1, 2019, patients had remained on study for 1-75+ postoperative cycles. Two patients had grade 3 diarrhea. Evaluation of the CSF showed low concentrations of neratinib, nonetheless two patients remained on therapy without progression for at least 13 cycles, with one on study treatment for nearly 6 years. Neratinib distribution in surgical tissue was variable for one patient, while specimens from two others did not produce conclusive results due to limited available samples. Conclusions: Neratinib resulted in expected rates of diarrhea in this small cohort, with 2 of 5 patients on study treatment for durable periods. Although logistically challenging, we were able to test a limited number of CSF-and parenchymal-based neratinib concentrations. Our findings from resected tumor tissue in one patient revealed heterogeneity in drug distribution and tumor histopathology. ClinicalTrials.gov number: NCT01494662 MICROABSTRACT We examined neratinib administration pre-and post-operatively in 5 patients with HER2-positive brain metastases. Two patients remained on therapy for 13 cycles and nearly 6 years postoperatively. We observed low CSF drug levels and variable craniotomy specimen levels among evaluable specimens. Inclusion of novel correlative analyses will continue to be crucial in advancing our understanding of CNS drug penetration.

Ductal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We have performed the first multiscale, integrated profiling of DCIS with clinical outcomes by analyzing 677 DCIS samples from 481 patients with 7.1 years median follow-up from the Translational Breast Cancer Research Consortium (TBCRC) 038 study and the Resource of Archival Breast Tissue (RAHBT) cohorts. We made observations on DNA, RNA, and protein expression, and generated a de novo clustering scheme for DCIS that represents a fundamental transcriptomic organization at this early stage of breast neoplasia. Distinct stromal expression patterns and immune cell compositions were identified. We found RNA expression patterns that correlate with later events. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome.