Sarah Sammons

PURPOSE: Current systemic therapy guidelines for patients with HER2 + breast cancer brain metastases (BCBrM) diverge based on the status of extracranial disease (ECD). An in-depth understanding of the impact of ECD on outcomes in HER2 + BCBrM has never been performed. Our study explores the implications of ECD status on intracranial progression-free survival (iPFS) and overall survival (OS) after first incidence of HER2 + BCBrM and radiation. METHODS: A retrospective analysis was performed of 151 patients diagnosed with initial HER2 + BCBrM who received radiation therapy to the central nervous system (CNS) at Duke between 2008 and 2021. The primary endpoint was iPFS defined as the time from first CNS radiation treatment to intracranial progression or death. OS was defined as the time from first CNS radiation or first metastatic disease to death. Systemic staging scans within 30 days of initial BCBrM defined ECD status as progressive, stable/responding or none (isolated brain relapse). RESULTS: In this cohort, > 70% of patients had controlled ECD with either isolated brain relapse (27%) or stable/responding ECD (44%). OS from initial metastatic disease to death was markedly worse for patients with isolated intracranial relapse (median = 28.4 m) compared to those with progressive or stable/responding ECD (48.8 m and 71.5 m, respectively, p = 0.0028). OS from first CNS radiation to death was significantly worse for patients with progressive ECD (16.9 m) versus stable/responding (36.6 m) or isolated intracranial relapse (28.4 m, p = 0.007). iPFS did not differ statistically based on ECD status. Receipt of systemic therapy after first BCBrM significantly improved iPFS (HR 0.45, 95% CI: 0.25-0.81, p = 0.008) and OS (HR: 0.43 (95% CI: 0.23-0.81); p = 0.001). CONCLUSION: OS in patients with HER2 + isolated BCBrM was inferior to those with concurrent progressive or stable/responding ECD. Studies investigating initiation of brain-penetrable HER2-targeted therapies earlier in the disease course of isolated HER2 + intracranial relapse patients are warranted.

INTRODUCTION: The majority of the over 250,000 new cases of invasive breast cancer diagnosed in the United States are driven by hormone receptor signaling (HR+). Since 2015, cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have become the standard in combination with endocrine therapy (ET) for patients facing HR+ metastatic disease. AREAS COVERED: There are now three approved agents in the HR+ metastatic setting such as abemaciclib, ribociclib, and palbociclib. Due to the almost doubling of progression-free survival (PFS) and improvement in overall survival (OS) in the metastatic setting, studies were conducted to examine the benefit of adding CDK4/6i in the adjuvant setting for those patients at high risk for recurrence. Despite negative results of PALLAS (palbociclib) in this setting, monarchE (abemaciclib) showed an improvement in invasive disease-free survival (IDFS) and distant recurrence-free survival (DRFS) at the 3-year time point for patients with high-risk tumor characteristics leading to its approval. Herein, we discuss the data, the population studied and for which abemaciclib is approved as well as safety, tolerability, and dose reductions for practical management of these patients. EXPERT OPINION: Abemaciclib is appropriate and beneficial for those patients with high-risk, node-positive, hormonally driven, human epidermal growth factor receptor 2 negative (HER2-) breast cancer.

Up to half of all patients with metastatic human epidermal growth factor receptor 2-positive (HER2+) breast cancer will eventually acquire brain metastases (BrMs), which are associated with reduced overall survival and decreased quality of life. Although the median overall survival was previously less than a year, novel systemic treatments have significantly extended life expectancy in patients with HER2+ breast cancer BrMs. The current first-line standard of care for all patients with HER2+ metastatic breast cancer, regardless of BrMs status, is dual HER2 antibody therapy with pertuzumab/trastuzumab plus a taxane. Second-line systemic therapy has recently evolved, with the option of trastuzumab deruxtecan (T-DXd) or tucatinib in combination with trastuzumab and capecitabine. T-DXd has shown dramatically superior progression-free survival in comparison with trastuzumab emtansine (T-DM1) in patients with stable BrMs in the second-line setting. Patients who have untreated or locally treated/progressive BrMs may benefit from a regimen with robust intracranial response rates, such as tucatinib in combination with trastuzumab and capecitabine. Third-line therapy and beyond includes multiple options that require careful selection, with the patient's BrMs status, comorbidities, and performance status taken into account. In this review, we focus on current management and evolving strategies for the treatment of patients with HER2+ breast cancer BrMs.

BACKGROUND: Controversy exists regarding the optimal sequence of chemotherapy among women with operable node-negative breast cancers with high-risk tumor biology. We evaluated national patterns of neoadjuvant chemotherapy (NACT) use among women with early-stage HER2+, triple-negative (TNBC), and high-risk hormone receptor-positive (HR+) invasive breast cancers. METHODS: Women ≥18 years with cT1-2/cN0 HER2+, TNBC, or high recurrence risk score (≥31) HR+ invasive breast cancers who received chemotherapy were identified in the National Cancer Database (2010-2016). Cochran-Armitage and logistic regression examined temporal trends and likelihood of undergoing NACT versus adjuvant chemotherapy based on patient age and molecular subtype. RESULTS: Overall, 96,622 patients met study criteria; 25% received NACT and 75% underwent surgery first, with comparable 5-year estimates of overall survival (0.90, 95% CI 0.892-0.905 vs 0.91, 95% CI 0.907-0.913). During the study period, utilization of NACT increased from 14% to 36% and varied according to molecular subtype (year*molecular subtype p < 0.001, p-corrected < 0.001). Women with HER2+ (OR 4.17, 95% CI 3.70-4.60, p < 0.001, p-corrected < 0.001) and TNBC (OR 3.81, 95% CI 3.38-4.31, p < 0.001, p-corrected < 0.001) were more likely to receive NACT over time, without a change in use among those with HR+ disease (OR 1.58, 95% CI 0.88-2.87, p = 0.13, p-corrected = 0.17). CONCLUSION: Among women with early-stage triple-negative and HER2+ breast cancers, utilization of NACT increased over time, a trend that correlates with previously reported improved rates of pCR and options post-neoadjuvant treatment with residual disease. Future research is needed to better understand multidisciplinary decisions for NACT and implications for breast cancer patients.

BACKGROUND: We sought to identify characteristics of metastatic breast cancer (MBC) patients who may benefit most from primary tumor resection. METHODS: Recursive partitioning analysis (RPA) was used to categorize non-surgical patients with de novo MBC in the NCDB (2010-2015) into 3 groups (I/II/III) based on 3-year overall survival (OS). After bootstrapping (BS), group-level profiles were applied, and the association of surgery with OS was estimated using Cox proportional hazards models. RESULTS: All patients benefitted from surgery (median OS, surgery vs no surgery): 72.7 vs 42.9 months, 47.3 vs 30.4 months, 23.8 vs 14.4 months (all p < 0.001) in BS-groups I, II, and III, respectively. After adjustment, surgery remained associated with improved OS (HR 0.52, 95% CI 0.50-0.55). The effect of surgery on OS differed quantitatively across groups. CONCLUSION: Prognostic groups may inform the degree of benefit from surgery, with the greatest benefit seen in those with the most favorable survival.