Neratinib and Ado-Trastuzumab-Emtansine for Pre-treated and Untreated HER2-positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium Trial 022.

PURPOSE: Treatment options for HER2-positive breast cancer brain metastases (BCBM) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab-emtansine (T-DM1) when given in combination. In TBCRC 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. PATIENTS AND METHODS: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts (cohort 4A-previously untreated BCBM, cohorts 4B and 4C- BCBM progressing after local CNS-directed therapy without [4B] and with [4C] prior exposure to T-DM1). Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. Overall survival (OS) and toxicity were also assessed. RESULTS: Between 2018-2021, 6, 17, and 21 patients enrolled to cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% (95% confidence interval [CI]: 4.3-77.7%), 35.3% (95% CI: 14.2-61.7%), and 28.6% (95% CI: 11.3-52.2%), respectively; 38.1-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). Median OS was 30.2 months (cohort 4A; 95% CI: 21.9, not reached [NR]), 23.3 months (cohort 4B; 95% CI: 17.6, NR), and 20.9 months (cohort 4C; 95% CI: 14.9, NR). CONCLUSION: We observed Intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pre-treated.

High-dimensional immune cell profiling of cerebrospinal fluid from patients with metastatic breast cancer and leptomeningeal disease.

Leptomeningeal disease (LMD) is a devastating complication of metastatic breast cancer (MBC). In this non-therapeutic study, we enrolled 12 patients with MBC and known or suspected LMD who were undergoing a lumbar puncture as part of clinical care and collected extra cerebrospinal fluid (CSF) and a paired blood sample from each patient at a single time point. Of the 12 patients, 7 patients are confirmed to have LMD based on positive cytology and/or convincing MRI imaging (LMDpos), and 5 patients are deemed not to have LMD based on similar criteria (LMDneg). Using high-dimensional, multiplexed flow cytometry, we profile and compare the CSF and peripheral blood mononuclear cell (PBMCs) immune populations between patients with LMD and those without. Patients with LMD observe a lower overall frequency of CD45+ cells (29.51% vs. 51.12%, p < 0.05), lower frequencies of CD8+ T cells (12.03% vs. 30.40%, p < 0.01), and higher frequency of Tregs than patients without LMD. Interestingly, the frequency of partially exhausted CD8+ T cells (CD38hiTIM3lo) is ~6.5-fold higher among patients with LMD vs. those without (2.99% vs. 0.44%, p < 0.05). Taken together, these data suggest that patients with LMD may have lower overall immune infiltrates than patients without LMD, suggesting a more permissive CSF immune microenvironment but a higher frequency of partially exhausted CD8+ T cells, which may offer an important therapeutic target.

The quality of life index: a pilot study integrating treatment efficacy and quality of life in oncology.

The majority of women diagnosed with breast cancer will experience some form of drug-related toxicity and subsequent impairments in Health-related Quality of Life (HRQoL). Despite this, HRQoL is assessed inconsistently and there is no validated method to integrate HRQoL data into the assessment of therapeutic agents. This proof of concept study utilizes data from the neoadjuvant I-SPY 2 clinical trial to describe the development of the Quality of Life Index (QoLI) measure. The QoLI represents a single composite score that incorporates validated longitudinal measures of clinical efficacy and QoL and one that permits a more comprehensive, direct comparison of individual therapeutic agents. Preliminary data suggest the QoLI is able to distinguish between agents based on their efficacy and toxicity; with further validation, the QoLI has the potential to provide more patient-centered evaluations in clinical trials and help guide treatment decision making in breast cancer and other oncologic diseases.

Reactivation of hepatitis C virus after chemotherapy for colon cancer.

Hepatitis C virus (HCV) infection often goes undiagnosed in asymptomatic carriers, but may become clinically relevant during periods of immunosuppression or severe illness. We report the clinical course of HCV reactivation in a patient receiving chemotherapy for metastatic colon cancer. We also review other reports showing the significance of HCV infection in patients being treated with chemotherapy.