Systemic Treatment of Brain Metastases in HER2-Positive Breast Cancer: Current Status and Future Directions

Azim, Hamdy A.; Azim, Hatem A.

doi:10.2217/fon.11.149

Cited by 23 publications

(13 citation statements)

References 74 publications

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“…2,3 In addition, it showed interesting activity in patients with brain metastasis. [4][5][6][7] Skin rash, diarrhea, and hepatic toxicities are adverse events (AEs) that have been linked with not only lapatinib, [8][9][10][11] but also other EGFR TKIs.…”

Section: Introductionmentioning

confidence: 99%

Pattern of Rash, Diarrhea, and Hepatic Toxicities Secondary to Lapatinib and Their Association With Age and Response to Neoadjuvant Therapy: Analysis From the NeoALTTO Trial

Azim

Agbor-Tarh

Bradbury

et al. 2013

JCO

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Purpose We investigated the pattern of rash, diarrhea, and hepatic adverse events (AEs) secondary to lapatinib and their association with age and pathologic complete response (pCR) in the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (NeoALLTO) phase III trial. Patients and Methods Patients with HER2-positive early breast cancer were randomly assigned to receive lapatinib (Arm A), trastuzumab (Arm B), or their combination (Arm C) for 6 weeks followed by the addition of paclitaxel for 12 weeks before surgery. We investigated the frequency and time to developing each AE according to age (≤ 50 v > 50 years) and their association with pCR in a logistic regression model adjusted for age, hormone receptors, tumor size, nodal status, planned breast surgery, completion of lapatinib administration, and treatment arm. Results Only patients randomly assigned to arms A and C were eligible (n = 306). Younger patients (≤ 50 years) experienced significantly more rash compared with older patients (74.4% v 47.9%; P < .0001). Diarrhea and hepatic AEs were observed in 78.8% and 41.2% of patients, respectively, with no differences in rate or severity or time of onset according to age. Early rash (ie, before starting paclitaxel) was independently associated with a higher chance of pCR, mainly in patients older than 50 years (odds ratio [OR] = 3.76; 95% CI, 1.69 to 8.34) but not in those ≤ 50 years (OR = 0.92; 95% CI, 0.45 to 1.88; P for interaction = .01). No significant association was observed between pCR and diarrhea or hepatic AEs. Conclusion Our results indicate that the frequency and clinical relevance of lapatinib-related rash is largely dependent on patient age.

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Section: Introductionmentioning

confidence: 99%

Pattern of Rash, Diarrhea, and Hepatic Toxicities Secondary to Lapatinib and Their Association With Age and Response to Neoadjuvant Therapy: Analysis From the NeoALTTO Trial

Azim

Agbor-Tarh

Bradbury

et al. 2013

JCO

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“…While the higher frequency of CNS metastatic disease [19] is consistent with the inability of trastuzumab to pass the blood–brain barrier and affect brain metastases [20–22], the lower activity of trastuzumab in preventing bone relapses should be of interest for clinicians to better direct choice of therapies in these patients. Proof of the low activity of trastuzumab in countering bone metastases awaits analysis of bone relapses occurring during and after trastuzumab treatment with respect to the observational HERA patient population.…”

Section: Discussionmentioning

confidence: 99%

Effect of adjuvant trastuzumab treatment in conventional clinical setting: an observational retrospective multicenter Italian study

Campiglio

Bufalino

Sasso

et al. 2013

Breast Cancer Res Treat

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Clinical trials have shown the efficacy of trastuzumab-based adjuvant therapy in HER2-positive breast cancers, but routine clinical use awaits evaluation of compliance, safety, and effectiveness. Adjuvant trastuzumab-based therapy in routine clinical use was evaluated in the retrospective study GHEA, recording 1,002 patients treated according to the HERA protocol between March 2005 and December 2009 in 42 Italian oncology departments; 874 (87.23 %) patients completed 1-year trastuzumab treatment. In 128 patients (12.77 %), trastuzumab was withdrawn due to cardiac or non-cardiac toxicity (28 and 29 patients, respectively), disease progression (5 patients) or the clinician’s decision (66 patients). In addition, 156 patients experienced minor non-cardiac toxicities; 10 and 44 patients showed CHF and decreased LVEF, respectively, at the end of treatment. Compliance and safety of adjuvant trastuzumab-based therapy in Italian hospitals were high and close to those reported in the HERA trial. With a median follow-up of 32 months, 107 breast cancer relapses were recorded (overall frequency, 10.67 %), and lymph node involvement, estrogen receptor negativity, lymphoid infiltration, and vascular invasion were identified as independent prognostic factors for tumor recurrence, indicating that relapses were associated with advanced tumor stage. Analysis of site and frequency of distant metastases showed that bone metastases were significantly more frequent during or immediately after trastuzumab (<18 months from the start of treatment) compared to recurrences in bone after the end of treatment and wash-out of the drug (>18 months from the start of treatment) (35.89 vs. 14.28 %, p = 0.0240); no significant differences were observed in recurrences in the other recorded body sites, raising the possibility that the protection exerted by trastuzumab is lower in bone metastases.

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“…However, management of metastatic disease in the brain and/or central nervous system (CNS), observed in up to 50% of HER2 þ breast cancer patients, continues to be a clinical challenge in large part due to the inability of mAbs to sufficiently cross the blood-brain barrier. Although small-molecule inhibitors of HER2 exist and have been clinically approved, their single-agent efficacy in the context of metastatic disease to the brain has been limited (4,5). While HER2-targeted therapy in combination with conventional agents has shown some promise for the treatment of patients with metastatic breast cancer, control of brain metastases remains a significant unmet clinical need, as most patients survive less than 2 years following CNS involvement.…”

Section: Introductionmentioning

confidence: 99%

Regional Delivery of Chimeric Antigen Receptor–Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain

Priceman

Tilakawardane

Jeang

et al. 2018

Clinical Cancer Research

238

185

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Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second-generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease. Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular costimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T-cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain. Results: Here, we have shown that HER2-CARs containing the 4-1BB costimulatory domain confer improved tumor targeting with reduced T-cell exhaustion phenotype and enhanced proliferative capacity compared with HER2-CARs containing the CD28 costimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo antitumor activity in orthotopic xenograft models. Importantly, we demonstrated robust antitumor efficacy following regional intraventricular delivery of HER2-CAR T cells for the treatment of multifocal brain metastases and leptomeningeal disease. Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases. Clin Cancer Res; 24(1); 95–105. ©2017 AACR.

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Systemic Treatment of Brain Metastases in HER2-Positive Breast Cancer: Current Status and Future Directions

Cited by 23 publications

References 74 publications

Pattern of Rash, Diarrhea, and Hepatic Toxicities Secondary to Lapatinib and Their Association With Age and Response to Neoadjuvant Therapy: Analysis From the NeoALTTO Trial

Pattern of Rash, Diarrhea, and Hepatic Toxicities Secondary to Lapatinib and Their Association With Age and Response to Neoadjuvant Therapy: Analysis From the NeoALTTO Trial

Effect of adjuvant trastuzumab treatment in conventional clinical setting: an observational retrospective multicenter Italian study

Regional Delivery of Chimeric Antigen Receptor–Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain

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