Search

Background: Alpelisib is an oral α-specific class I PI3K inhibitor approved in combination with fulvestrant for the treatment of PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer. The tolerability of this drug with the oral chemotherapy capecitabine is unknown., Patients and Methods: This phase I trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of alpelisib (250 mg or 300 mg daily for 3-weeks) with capecitabine (1000 mg/m 2 twice daily for 2-weeks followed by a 1-week rest period) in patients with metastatic HER2-negative breast cancer, regardless of PIK3CA mutation status., Results: Eighteen patients were treated with alpelisib-capecitabine. Half of the patients had HR+ breast cancer, and 16 had prior systemic therapy for metastatic disease. The MTD of alpelisib was 250 mg daily in combination with capecitabine 1000 mg/m 2 twice daily. DLTs included hyperglycemia, QTc prolongation, fatigue, and chest pain. The most common grade 3 adverse event (AE) was hyperglycemia (28%). No grade 4 AEs were observed. Three patients discontinued therapy due to an AE. One-third of patients required dose reduction of both alpelisib and capecitabine. Four patients experienced a partial response and 8 patients experienced stable disease. The median progression-free survival was 9.7 months (95% CI 2.8-13.5 months) and median overall survival was 18.2 months (95% CI 7.2-35.2 months). Twelve patients had PIK3CA mutation testing completed, of these 2 had known or likely deleterious PIK3CA mutation., Conclusion: This study provides safety data for an oral combination therapy of alpelisib-capecitabine and defines tolerable doses for further study., Competing Interests: Disclosure YA reports consulting income from Exact Sciences, AstraZeneca and Pfizer. C.K.A. reports research funding provided by PUMA, Lilly, Merck, Seattle Genetics, Nektar, Tesaro, G1-Therapeutics, ZION, Novartis, Pfizer, Astra Zeneca, Elucida, Caris, Incyclix; consulting for Genentech, Eisai, IPSEN, Seattle Genetics, Astra Zeneca, Novartis, Immunomedics, Elucida, Athenex, Roche; royalties from UpToDate, Jones and Bartlett. L.A.C. reports research funding from Genentech/Roche, AstraZeneca, Lilly, Novartis, Veracyte, Nanostring. C.M.P. is an equity stockholder and board of director member of BioClassifer LLC and is listed as inventor on patent applications for the Breast PAM50 assay. E.C.D. reports consulting income from Sanofi, research funding from Novartis, Genentech, Bayer, Pfizer, and Merck and a family member who received past consulting income from Novartis. L.A.C reports research funding from AstraZeneca, Genentech/Roche, Lilly, Merck, Nanostring, Novartis, SeaGen, and Veracyte. P.K.M. is a full-time employee and equity stockholder with Veracyte., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The treatment of metastatic breast cancer (MBC) has improved over the past decade, however prognosis continues to be mitigated by the fact that about 1 in 5 patients with MBC will develop brain metastases (BrM) during their metastatic disease course. 1 This number is even higher for patients with triple-negative breast cancer (TNBC), with studies showing as high as 40% of patients developing BrM. 2, 3 Studies have shown that TNBC portends a worse survival after a diagnosis of BrM compared with non-TNBC subtypes. 4 Given the unique location and biologic properties of BrM, treatment options have historically been limited. Challenges to the treatment of TNBC BrM include a lack of targeted therapies and difficulties in delivery of drug to the brain past the blood-brain barrier (BBB). Herein, we will review the advances in local and systemic therapies to most effectively treat patients with TNBC BrM, including therapies on the horizon currently in clinical trials., Competing Interests: Disclosure CKA: Research funding PUMA, Lilly, Merck, Seattle Genetics, Nektar, Tesaro, G1-Therapeutics, ZION, Novartis, Pfizer, Astra Zeneca, Elucida, Caris; Consulting: Genentech, Eisai, IPSEN, Seattle Genetics, Astra Zeneca, Novartis, Immunomedics, Elucida, Athenex. Royalties: UpToDate, Jones and Bartlett., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: This pilot study was performed to test our ability to administer neratinib monotherapy before clinically recommended craniotomy in patients with HER2-positive metastatic breast cancer to the central nervous system, to examine neratinib's central nervous system penetration at craniotomy, and to examine postoperative neratinib maintenance., Patients and Methods: Patients with HER2-positive brain metastases undergoing clinically indicated cranial resection of a parenchymal tumor received neratinib 240 mg orally once a day for 7 to 21 days preoperatively, and resumed therapy postoperatively in 28-day cycles. Exploratory evaluations of time to disease progression, survival, and correlative tissue, cerebrospinal fluid (CSF), and blood-based analyses examining neratinib concentrations were planned. The study was registered at ClinicalTrials.gov under number NCT01494662., Results: We enrolled 5 patients between May 22, 2013, and October 18, 2016. As of March 1, 2019, patients had remained on the study protocol for 1 to 75+ postoperative cycles pf therapy. Two patients had grade 3 diarrhea. Evaluation of the CSF showed low concentrations of neratinib; nonetheless, 2 patients continued to receive therapy without disease progression for at least 13 cycles, with one on-study treatment lasting for nearly 6 years. Neratinib distribution in surgical tissue was variable for 1 patient, while specimens from 2 others did not produce conclusive results as a result of limited available samples., Conclusion: Neratinib resulted in expected rates of diarrhea in this small cohort, with 2 of 5 patients receiving the 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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Buparlisib is an oral pan-class I phosphotidyinositol-3-kinase (PI3K) inhibitor. The present phase I study evaluated the safety, pharmacokinetics, and efficacy of buparlisib with capecitabine in patients with metastatic breast cancer., Patients and Methods: Patients received buparlisib once daily (range, 50 to 100 mg) for 3 weeks with capecitabine twice daily (range, 1000 to 1250 mg/m 2 ) for 2 weeks with a 1-week break. Dose escalation used a traditional "3 + 3" design with standard definitions of dose-limiting toxicity (DLT) and maximum tolerated dose., Results: Of the 25 patients enrolled, 23 were evaluable for DLT and 17 were evaluable for response. The maximum tolerated dose of the combination was buparlisib 100 mg daily and capecitabine 1000 mg/m 2 twice daily. DLTs included grade 3 hyperglycemia and grade 3 confusion. The most common grade 3 toxicities were diarrhea and elevation of aspartate aminotransferase and alanine transaminase. One patient exhibited a complete response to treatment and four had a confirmed partial response. In cohorts 3 and 4, in which the buparlisib dose remained constant but the capecitabine dose was increased, significant increases in the buparlisib plasma concentration were noted., Conclusion: The combination of buparlisib with capecitabine in patients with metastatic breast cancer was generally well-tolerated, with several patients demonstrating prolonged responses. Unexpectedly low rates of PIK3CA mutations (3 of 17) were seen, and only 2 of 7 tumors with subtyping were luminal, making exploration of these putative predictive markers impossible. Further study of the combination is not unreasonable, with expanded pharmacokinetics and sequencing analysis to better elucidate potential drug-drug interactions and more accurate predictive biomarkers of response., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Given the wide adoption of human epidermal growth factor receptor 2 (HER2)-targeted therapies for advanced HER2-positive breast cancer, we studied the natural history of patients with HER2-positive breast cancer brain metastases (BCBM) over time., Patients and Methods: Patients with HER2-positive BCBM identified from a prospectively maintained database at the University of North Carolina were divided into 3 cohorts by year of BCBM diagnosis. Cohorts were selected by year of HER2-targeted therapy US Food and Drug Administration approval. Overall survival (OS), time to first metastasis, time to BCBM, and BCBM survival were estimated by the Kaplan-Meier method. Associations between OS after BCBM and clinical variables were assessed by Cox proportional hazards regression models., Results: One hundred twenty-three patients were identified. Median age was 51 years, and 58% were white and 31% African American. OS from initial breast cancer diagnosis improved over time: 3.6 years (95% confidence interval [CI], 2.8-6.1) in the 1998-2007 cohort, 6.6 years (95% CI, 4.5-8.6) in the 2008-2012 cohort, and 7.6 years (95% CI, 4.4-9.6) in the 2013-2015 cohort (P = .05). While time from initial diagnosis to first metastasis did not differ (P = .12), time to BCBM increased over time (2.6 years [95% CI, 1.3-3.5] for 1998-2007; 2.6 years [95% CI, 2.1-4.3] for 2008-2012, and 3.3 years [95% CI, 2.2-6] for 2013-2015; P = .05). Although OS from BCBM did not significantly differ by cohort, patients who received HER2-targeted therapy after BCBM had a prolonged OS (2.1 years [95% CI, 1.6-2.6] vs. 0.65 years [95% CI, 0.4-1.3]; P = .001)., Conclusion: OS from initial breast cancer diagnosis significantly improved over time for patients with HER2-positive breast cancer who develop BCBM, now exceeding 7 years; survival from BCBM diagnosis may now exceed 2 years., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Breast cancer represents a heterogeneous collection of diseases with disparate clinical behaviors, responses to treatment, and patient outcomes, despite common histopathological features at diagnosis. Examination of molecular signatures of breast cancer (based on complex gene expression patterns) enabled identification of several intrinsic molecular subtypes: luminal A, luminal B, human epidermal growth factor receptor 2 enriched, and basal like. The intrinsic subtypes are associated with measures of clinical aggressiveness, but do not perfectly predict patient outcomes. Several molecular signatures have been developed for prediction and prognostication of breast cancer outcomes. This review describes the molecular classification of breast cancer and the use of predictive/prognostic molecular signatures for guiding treatment decisions in breast cancer patients., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The incidence of breast cancer brain metastasis (BCBM) is increasing due in part to improved management of systemic disease and prolonged survival. Despite this growing population of patients, there exists little consensus for the treatment of HER2-positive BCBM. Lapatinib, the only brain permeable targeted agent for HER2-positive cancer, has demonstrated limited intracranial response rates and little improvement in progression free survival (PFS) for HER-2 positive patients. Size constraints are believed to prevent larger monoclonal antibodies, such as pertuzumab and trastuzumab, from crossing the blood brain barrier (BBB). However, emerging evidence reveals that the BBB is perturbed in the setting of metastases, allowing for improved penetrance of these larger targeted agents. The disrupted BBB may allow for passage of ado-trastuzumab emtansine (TDM1), though little clinical information about its activity in BCBM patients is currently known.

Of the estimated 1 million cases of breast cancer diagnosed annually worldwide, it is estimated that over 170,000 will harbor the triple-negative (estrogen receptor/progesterone receptor/HER2-negative) phenotype. Most, though not all, triple-negative breast cancers will be basal-like on gene expression micorarrays. The basal-like molecular subtype exhibits a unique molecular profile and set of risk factors, aggressive and early pattern of metastasis, limited treatment options, and poor prognosis. Large population-based studies have identified a higher proportion of triple-negative breast tumors among premenopausal African American women, and a suggestion that increased parity, younger age at first-term pregnancy, shorter duration of breast feeding, and elevated hip-to-waist ratio might be particular risk factors. When BRCA1 mutation carriers develop breast cancer, it is usually basal-like; given the central role of BRCA1 in DNA repair, this could have profound therapeutic implications. When diagnosed, triple-negative breast cancers illustrate preferential relapse in visceral organs, including the central nervous system. Although initial response to chemotherapy might be more profound, relapse is early and common among triple-negative breast cancers compared with luminal breast cancers. The armamentarium of "targeted therapeutics" for triple-negative breast cancer is evolving and includes strategies to inhibit angiogenesis, epidermal growth factor receptor, and other kinases. Finally, the positive association between triple-negative breast cancer and BRCA mutations makes inhibition of poly(adenosine diphosphate-ribose) polymerase-1 an attractive therapeutic strategy that is in active study.