CNS relapses in patients with HER2-positive early breast cancer who have and have not received adjuvant trastuzumab: a retrospective substudy of the HERA trial (BIG 1-01)

Paulweber, Bernhard; Holmes, Eileen; Azambuja, Evandro de; Metzger‐Filho, Otto; Hogge, Laurence; Scullion, Matt; Láng, István; Wardley, Andrew M; Lichinitser, Mikhail; Sánchez, Ramón Arias; Müller, Volkmar; Dodwell, David; Gelber, Richard D.; Piccart‐Gebhart, Martine; Cameron, David

doi:10.1016/s1470-2045(13)70017-2

Cited by 185 publications

(121 citation statements)

References 21 publications

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“…On the other side, the retrospective analysis showed no significant difference in BM development as the first site of recurrence amongst HER2-positive BC patients receiving 1-yearlong adjuvant trastuzumab against placebo (2 vs. 2%, respectively, P = 0.55) [62]. Moreover, adjuvant trastuzumab significantly reduces the non-brain recurrences (P < 0.0001).…”

Section: The Targeted Therapy For Her2-positive Breast Cancer In Viewmentioning

confidence: 93%

Mystery of the brain metastatic disease in breast cancer patients: improved patient stratification, disease prediction and targeted prevention on the horizon?

et al. 2017

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The breast cancer (BC) diagnosis currently experiences the epidemic evolution with more than half of million deaths each year. Despite screening programmes applied and treatments available, breast cancer patients frequently develop distant metastases. The brain is one of the predominant sites of the metastatic spread recorded for more than 20% of BC patients, in contrast to the general population, where brain tumours are rarely diagnosed. Although highly clinically relevant, the brain tumour mystery in the cohort of breast cancer patients has not been yet adequately explained. This review summarises currently available information on the risk factors predicting brain metastases in BC patients to motivate the relevant scientific areas to explore the data/facts available and elucidate disease-specific mechanisms that are of a great clinical utility.

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Section: The Targeted Therapy For Her2-positive Breast Cancer In Viewmentioning

confidence: 93%

Mystery of the brain metastatic disease in breast cancer patients: improved patient stratification, disease prediction and targeted prevention on the horizon?

et al. 2017

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“…Among patients with HER2-positive breast cancer, the risk of brain metastases is further elevated in the setting of hormone receptor negativity (13). Of note, CNS events in this patient population seem to be widely distributed over time (7,10). This could be the case either because of CNS seeding on a continuous basis over the course of a patient's disease, and/or awakening of dormant tumor cells in the brain, the latter of which have been demonstrated in preclinical imaging studies (14).…”

Section: Differences In Behavior By Breast Cancer Subtypementioning

confidence: 99%

“…3, 7-11). Indeed, among more than 400 patients who died during follow up on the adjuvant HERA trial, approximately half were diagnosed with CNS relapse before death (7,12). Among patients with HER2-positive breast cancer, the risk of brain metastases is further elevated in the setting of hormone receptor negativity (13).…”

Section: Differences In Behavior By Breast Cancer Subtypementioning

confidence: 99%

CNS Metastases in Breast Cancer: Old Challenge, New Frontiers

Lin

Amiri‐Kordestani

Palmieri

et al. 2013

Clinical Cancer Research

238

208

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Despite major therapeutic advances in the management of patients with breast cancer, central nervous system (CNS) metastases remain an intractable problem, particularly in patients with metastatic HER2-positive and triple-negative breast cancer. As systemic therapies to treat extracranial disease improve, some patients are surviving longer, and the frequency of CNS involvement seems to be increasing. Furthermore, in the early-stage setting, the CNS remains a potential sanctuary site for relapse. This review highlights advances in the development of biologically relevant preclinical models, including the development of brain-tropic cell lines for testing of agents to prevent and treat brain metastases, and summarizes our current understanding of the biology of CNS relapse. From a clinical perspective, a variety of therapeutic approaches are discussed, including methods to improve drug delivery, novel cytotoxic agents, and targeted therapies. Challenges in current trial design and endpoints are reviewed. Finally, we discuss promising new directions, including novel trial designs, correlative imaging techniques, and enhanced translational opportunities. Clin Cancer Res; 19(23); 6404-18. Ó2013 AACR. Disclosure of Potential Conflicts of InterestN.U. Lin has received commercial research grants from GlaxoSmithKline, Genentech, Array, and Novartis. N.U. Liu is a consultant/advisory board member for Novartis, GlaxoSmithKline, to-BBB, and Genentech. P.S. Steeg has received commercial research grants from GlaxoSmithKline and Sanofi. No potential conflicts of interest were disclosed by the other authors. CME Staff Planners' DisclosuresThe members of the planning committee have no real or apparent conflict of interest to disclose. Learning Objective(s)Upon completion of this activity, the participant should have a better understanding of brain metastases in different subtypes of breast cancer, the development of preclinical models, and the novel systemic strategies for breast cancer brain metastasis.

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“…[1][2][3][4][5][6][7] Upfront therapy for newly diagnosed brain metastases typically includes whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or both, and a small proportion of patients undergo surgical resection for limited disease. Historically, survival after diagnosis of CNS disease was poor, and many patients died of progressive disease 8 ; however, recent studies have suggested that median survival for patients with CNS disease may be improving, particularly for those with HER2-positive disease, likely as a result of advances in systemic therapy.…”

Section: Introductionmentioning

confidence: 99%

Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases

Freedman

Gelman

Wefel

et al. 2016

JCO

153

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Purpose Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)–positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial. Patients and Methods Eligible patients were those with HER2-positive brain metastases (≥ 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≥50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression—the threshold for success was five of 40 responders. Results Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≥ 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time. Conclusion Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.

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CNS relapses in patients with HER2-positive early breast cancer who have and have not received adjuvant trastuzumab: a retrospective substudy of the HERA trial (BIG 1-01)

Cited by 185 publications

References 21 publications

Mystery of the brain metastatic disease in breast cancer patients: improved patient stratification, disease prediction and targeted prevention on the horizon?

Mystery of the brain metastatic disease in breast cancer patients: improved patient stratification, disease prediction and targeted prevention on the horizon?

CNS Metastases in Breast Cancer: Old Challenge, New Frontiers

Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases

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