This is the first study to demonstrate that capecitabine and lapatinib penetrate to a significant though variable degree in human BCBM. Drug delivery to BCBM is variable and in many cases appears partially limiting. Elucidating mechanisms that limit drug concentration and innovative approaches to overcome limited drug uptake will be important to improve clinical efficacy of these agents in the central nervous system. Trial registration ID: NCT00795678.

Background Disease presentation, prognostic factors, and treatment patterns for breast cancer patients with leptomeningeal metastasis are not well-characterized. In this study, we examined patient characteristics and prognostic factors for survival after a diagnosis of leptomeningeal metastasis. Patients and Methods 318 consecutive breast cancer patients diagnosed with leptomeningeal metastasis from January 1998 to December 2013 at Memorial Sloan Kettering Cancer Center were identified. Clinico-pathologic and treatment information were obtained by retrospective review. Associations with time from leptomeningeal diagnosis to death were evaluated by Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models. Results Of the 318 patients, 44% were HR+HER2−,18% HR+HER2+, 8.5% HR−HER2+, and 25.5% triple negative; 4% had missing information. The median survival was 3.5 months (95% CI: 3.0, 4.0) with 63 patients (20%) surviving greater than 1 year. Recent diagnosis (after 2006), HER2+ subtype, higher performance status, cranial only involvement, and no evidence of non-central nervous system disease were independently associated with improved survival in multivariate analysis. Conclusions Despite the improvement noted with more recent year of diagnosis, survival following a diagnosis of leptomeningeal metastasis remains poor. Similar to patients with parenchymal brain metastasis only, the survival differs among difference receptor subtypes. A closer examination to identify factors, such as introduction of new systemic therapies that may contribute to longer-term survival may provide insight to improve management of these patients. In addition, factors we identified that are associated with survival may be considered as stratification variables in the design of future randomized clinical trials in this population.

PURPOSE To update evidence-based guideline recommendations to practicing oncologists and others on systemic therapy for patients with human epidermal growth factor receptor 2 (HER2)–positive advanced breast cancer. METHODS An Expert Panel conducted a targeted systematic literature review (for both systemic treatment and CNS metastases) and identified 545 articles. Outcomes of interest included efficacy and safety. RESULTS Of the 545 publications identified and reviewed, 14 were identified to form the evidentiary basis for the guideline recommendations. RECOMMENDATIONS HER2-targeted therapy is recommended for patients with HER2-positive advanced breast cancer, except for those with clinical congestive heart failure or significantly compromised left ventricular ejection fraction, who should be evaluated on a case-by-case basis. Trastuzumab, pertuzumab, and taxane for first-line treatment and trastuzumab deruxtecan for second-line treatment are recommended. In the third-line setting, clinicians should offer other HER2-targeted therapy combinations. There is a lack of head-to-head trials; therefore, there is insufficient evidence to recommend one regimen over another. The patient and the clinician should discuss differences in treatment schedule, route, toxicities, etc during the decision-making process. Options include regimens with tucatinib, trastuzumab emtansine, trastuzumab deruxtecan (if either not previously administered), neratinib, lapatinib, chemotherapy, margetuximab, hormonal therapy, and abemaciclib plus trastuzumab plus fulvestrant, and may offer pertuzumab if the patient has not previously received it. Optimal duration of chemotherapy is at least 4-6 months or until maximum response, depending on toxicity and in the absence of progression. HER2-targeted therapy can continue until time of progression or unacceptable toxicities. For patients with HER2-positive and estrogen receptor–positive or progesterone receptor–positive breast cancer, clinicians may recommend either standard first-line therapy or, for selected patients, endocrine therapy plus HER2-targeted therapy or endocrine therapy alone. Additional information is available at www.asco.org/breast-cancer-guidelines .

PURPOSE To provide updated evidence- and consensus-based guideline recommendations to practicing oncologists and others on the management of brain metastases for patients with human epidermal growth factor receptor 2 (HER2)–positive advanced breast cancer up to 2021. METHODS An Expert Panel conducted a targeted systematic literature review (for both systemic therapy for non-CNS metastases and for CNS metastases of HER2+ guideline updates) that identified 545 articles. Outcomes of interest included overall survival, progression-free survival, and adverse events. RESULTS Of the 545 publications identified and reviewed, six on systemic therapy were identified to form the evidentiary basis for the systemic therapy for CNS metastases guideline recommendations. RECOMMENDATIONS Patients with brain metastases should receive appropriate local therapy and systemic therapy, if indicated. Local therapies include surgery, whole-brain radiotherapy, and stereotactic radiosurgery. Memantine and hippocampal avoidance should be added to whole-brain radiotherapy when possible. Treatments depend on factors such as patient prognosis, presence of symptoms, resectability, number and size of metastases, prior therapy, and whether metastases are diffuse. Other options include systemic therapy, best supportive care, enrollment onto a clinical trial, and/or palliative care. There are insufficient data to recommend for or against performing routine magnetic resonance imaging to screen for brain metastases; clinicians should have a low threshold for magnetic resonance imaging of the brain because of the high incidence of brain metastases among patients with HER2-positive advanced breast cancer. Additional information is available at www.asco.org/breast-cancer-guidelines .

Brain metastases are the most lethal complication of advanced cancer; therefore, it is critical to identify when a tumor has the potential to metastasize to the brain.