Temozolomide in Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases

Zimmer, Alexandra S.; Steinberg, Seth M.; Smart, Dee Dee; Gilbert, Mark R.; Armstrong, Terri S.; Burton, Eric; Houston, Nicole; Biassou, Nadia; Gril, Brunilde; Brastianos, Priscilla K.; Carter, Scott L.; Lyden, David; Lipkowitz, Stanley; Steeg, Patricia S.

doi:10.2217/fon-2020-0094

Cited by 27 publications

(15 citation statements)

References 67 publications

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“…In the future, data regarding the intracranial efficacy of systemic therapies may be improved with enrollment of more patients with breast cancer BrM in clinical trials [61–63] and evaluation of CNS‐specific outcomes within those trials [60]. Given the very high risk of BrM among patients with HER2+ MBC [51], strategies for secondary prevention of BrM (e.g., using temozolomide [64]) are also being investigated.…”

Section: Discussionmentioning

confidence: 99%

Treatment Patterns and Outcomes of Women with Symptomatic and Asymptomatic Breast Cancer Brain Metastases: A Single-Center Retrospective Study

et al. 2021

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Background. Breast cancer is the most common cancer among women worldwide, and the second leading cause of brain metastases (BrM). We assessed the treatment patterns and outcomes of women treated for breast cancer BrM at our institution in the modern era of stereotactic radiosurgery (SRS). Materials and Methods. We conducted a retrospective analysis of women (≥ 18 years old) with metastatic breast cancer who were treated with surgery, whole brain radiotherapy (WBRT) or SRS to the brain at the Sunnybrook Odette Cancer Center, Toronto, Canada between 2008 and 2018. Patients with a history of other malignancies and those with an uncertain date of diagnosis of BrM were excluded. Descriptive statistics were generated and survival analyses were performed, with subgroup analyses by breast cancer subtype.Results. Among 683 eligible patients, 153 (22.4%) had triple negative (TNBC), 188 (27.5%) had HER2+, 246 (36.0%) had hormone receptor (HR)+/HER2-, and 61 (13.3%) had breast cancer of unknown subtype. The majority of patients received fist line WBRT (n=459, 67.2%) or SRS (n=126, 18.4%). The median brain-specific progression-free survival and median overall survival (OS) were 4.1 months (IQR 1.0-9.6 months) and 5.1 months (IQR 2.0-11.7 months) in the overall patent population, respectively. Age >60 years, presence of neurological symptoms at BrM diagnosis, first line WBRT and HER2-subtype were independently prognostic for shorter OS. Conclusion. Despite the use of SRS, outcomes among patients with breast cancer BrM remain poor. Strategies for early detection of BrM and central nervous system-active systemic therapies warrant further investigation. The Oncologist 2021;9999:• • Implications for Practice: Although triple negative and HER2+ breast cancer have a predilection for metastasis to the central nervous system (CNS), patients with hormone receptor (HR)+/HER2-breast cancer represent a high proportion of patients with breast cancer brain metastases (BrM). Hence, clinical trials should include patients with BrM and evaluate CNS-specific activity of novel systemic therapies when feasible, irrespective of breast cancer subtype. In addition, given that symptomatic BrM are associated with shorter survival, we propose that screening programs for the early detection and treatment of breast cancer BrM warrant further investigation in an era of minimally toxic stereotactic radiosurgery.

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Section: Discussionmentioning

confidence: 99%

Treatment Patterns and Outcomes of Women with Symptomatic and Asymptomatic Breast Cancer Brain Metastases: A Single-Center Retrospective Study

et al. 2021

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“…In conclusion, the effectivity of a brain penetrant dual PI3K/mTOR inhibitor in low doses particularly on the prevention of brain metastases makes this approach to a plausible road for a future BM prevention trial in high-risk MM patients. Until today, only one clinical trial is active that explicitly tests prevention of BM by testing the chemotherapeutic brain-penetrant drug temozolomide in breast cancer patients (NCT03190967) 39 . Effective BM prevention by a well-tolerated drug that can be administered over prolonged periods of time could make a real difference for cancer patients in the future.…”

Section: Discussionmentioning

confidence: 99%

The PI3K/Akt/mTOR pathway as a preventive target in melanoma brain metastasis

et al. 2021

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Background Brain metastases (BM) are a frequent complication of malignant melanoma (MM), with limited treatment options and poor survival. Prevention of BM could be more effective and better tolerated than treating established BM in various conditions. Methods To investigate the temporo-spatial dynamics of PI3K/Akt/mTOR (PAM) pathway activation during BM formation and the preventive potential of its inhibition, in vivo molecular imaging with an Akt biosensor was performed, and long-term intravital multiphoton microscopy through a chronic cranial window in mice. Results In vivo molecular imaging revealed invariable PAM pathway activation during the earliest steps of brain colonization. In order to perform a long-term intravascular arrest and to extravasate, circulating MM cells needed to activate their PAM pathway during this process. However, the PAM pathway was quite heterogeneously activated in established human brain metastases, and its inhibition with the brain-penetrant PAM inhibitor GNE-317 resulted in only modest therapeutic effects in mice. In contrast, giving GNE-317 in preventive schedules that included very low doses effectively reduced growth rate and number of BM in two MM mouse models over time, and led to an overall survival benefit. Longitudinal intravital multiphoton microscopy found that the first, rate-limiting steps of BM formation - permanent intravascular arrest, extravasation, and initial perivascular growth - are most vulnerable to dual PI3K/mTOR inhibition. Conclusion These findings establish a key role of PAM pathway activation for critical steps of early metastatic brain colonization and reveal its pharmacological inhibition as a potent avenue to prevent the formation of clinically relevant BM.

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“…Moreover, the median PFS was 18.1 months among the 24 patients with asymptomatic BMs in the DESTINY-Breast01 study [21] . The efficacy of the secondary prevention effect of T-DM1 combined with temozolomide rhythm chemotherapy on locally treated HER2-positive breast cancer with BMs was evaluated in a phase I/II study [40] …”

Section: New Advances In Clinical Researchmentioning

confidence: 99%

Antibody-drug conjugates in HER2-positive breast cancer

Zhang

Liu

et al. 2021

Chinese Medical Journal

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Antibody-drug conjugates (ADCs) combine the high specificity of monoclonal antibodies with the high anti-tumor activity of small molecular cytotoxic payloads. The anti-tumor activity of ADCs is mainly achieved by the direct blocking of the receptor by monoclonal antibodies, direct action and bystander effect of cytotoxic drugs, and antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. ADCs have been used in adjuvant therapy and rescue treatment of human epidermal receptor 2 (HER2)-positive breast cancer, greatly improving the prognosis of breast cancer patients. Several ongoing clinical trials of ADC for breast cancer and other solid tumors proved the potential of ADCs will provide more promising treatment options for patients with malignant tumors. This review introduces the mechanism and latest clinical progress of ADC drugs approved for HER2-positive breast cancer to guide clinical practice and conduct research.

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Temozolomide in Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases

Cited by 27 publications

References 67 publications

Treatment Patterns and Outcomes of Women with Symptomatic and Asymptomatic Breast Cancer Brain Metastases: A Single-Center Retrospective Study

Treatment Patterns and Outcomes of Women with Symptomatic and Asymptomatic Breast Cancer Brain Metastases: A Single-Center Retrospective Study

The PI3K/Akt/mTOR pathway as a preventive target in melanoma brain metastasis

Antibody-drug conjugates in HER2-positive breast cancer

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