Cardiac Toxicity and Efficacy of Trastuzumab Combined with Pertuzumab in Patients with Trastuzumab-Insensitive Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

Portera, Chia C.; Walshe, Janice; Rosing, Douglas R.; Denduluri, Neelima; Berman, Arlene; Vatas, Ujala; Velarde, Margarita; Chow, Catherine; Steinberg, Seth M.; Nguyen, Diana; Yang, Sherry X.; Swain, Sandra M.

doi:10.1158/1078-0432.ccr-07-4636

Cited by 152 publications

(97 citation statements)

References 43 publications

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“…However, although such a therapeutic approach is not yet available for breast cancer, our data also suggest that a ''rechallenge'' with trastuzumab alone or in combination with another HER2-specific antibody like pertuzumab could be beneficial for the treatment of tumors that have initially shown a good response to the antibody and then relapsed. In fact, this is supported by recent clinical observations (49). Moreover, the fact that MCF7 cells maintained their level of HER2 expression despite the selection pressure exerted by trastuzumab and NK cells implicates that HER2 may be much more essential for mammary than for ovarian carcinoma cells-and thus be a much better target in breast cancer (which is again in line with the clinical reality).…”

Section: Discussionsupporting

confidence: 66%

Immunoselection of Breast and Ovarian Cancer Cells with Trastuzumab and Natural Killer Cells: Selective Escape of CD44high/CD24low/HER2low Breast Cancer Stem Cells

Reim

Dombrowski²,

Ritter³

et al. 2009

Cancer Research

120

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Although trastuzumab (Herceptin) has substantially improved the overall survival of patients with mammary carcinomas, even initially well-responding tumors often become resistant. Because natural killer (NK) cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) is thought to contribute to the therapeutic effects of trastuzumab, we have established a cell culture system to select for ADCC-resistant SK-OV-3 ovarian cancer and MCF7 mammary carcinoma cells. Ovarian cancer cells down-regulated HER2 expression, resulting in a more resistant phenotype. MCF7 breast cancer cells, however, failed to develop resistance in vitro. Instead, treatment with trastuzumab and polyclonal NK cells resulted in the preferential survival of individual sphere-forming cells that displayed a CD44 high CD24 low ''cancer stem cell-like'' phenotype and expressed significantly less HER2 compared with non-stem cells. Likewise, the CD44 high CD24 low population was also found to be more immunoresistant in SK-BR3, MDA-MB231, and BT474 breast cancer cell lines. When immunoselected MCF7 cells were then re-expanded, they mostly lost the observed phenotype to regenerate a tumor cell culture that displayed the initial HER2 surface expression and ADCCsusceptibility, but was enriched in CD44 high CD24 low cancer stem cells. This translated into increased clonogenicity in vitro and tumorigenicity in vivo. Thus, we provide evidence that the induction of ADCC by trastuzumab and NK cells may spare the actual tumor-initiating cells, which could explain clinical relapse and progress. Moreover, our observation that the ''relapsed'' in vitro cultures show practically identical HER2 surface expression and susceptibility toward ADCC suggests that the administration of trastuzumab beyond relapse might be considered, especially when combined with an immunestimulatory treatment that targets the escape variants. [Cancer Res 2009;69(20):8058-66]

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Section: Discussionsupporting

confidence: 66%

Immunoselection of Breast and Ovarian Cancer Cells with Trastuzumab and Natural Killer Cells: Selective Escape of CD44high/CD24low/HER2low Breast Cancer Stem Cells

Reim

Dombrowski²,

Ritter³

et al. 2009

Cancer Research

120

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“…This was in contrast with findings from early clinical development, which suggested that pertuzumab might increase the cardiotoxicity of trastuzumab (15). Trials in neoadjuvant-and adjuvant-breast cancer will further clarify the cardiac risk in a treatment-naive, early breast cancer population.…”

Section: Discussioncontrasting

confidence: 61%

First FDA Approval of Dual Anti-HER2 Regimen: Pertuzumab in Combination with Trastuzumab and Docetaxel for HER2-Positive Metastatic Breast Cancer

Blumenthal

Scher

Cortazar

et al. 2013

Clinical Cancer Research

105

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On June 8, 2012, the U.S. Food and Drug Administration (FDA) approved pertuzumab (Perjeta, Genentech) for use in combination with trastuzumab (Herceptin, Genentech) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 808 patients with HER2-positive MBC. Patients were randomized (1:1) to receive pertuzumab (n ¼ 402) or placebo (n ¼ 406) in combination with trastuzumab and docetaxel. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). A statistically significant improvement in PFS (difference in medians of 6.1 months) was observed in patients receiving pertuzumab [HR, 0.62; 95% confidence interval (CI), 0.51-0.75; P < 0.0001]. A planned interim analysis suggested an improvement in OS (HR, 0.64; 95% CI, 0.47-0.88; P ¼ 0.0053) but the HR and P value did not cross the stopping boundary. Common adverse reactions (>30%) observed in patients on the pertuzumab arm included diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. No additive cardiac toxicity was observed. Significant manufacturing issues were identified during the review. On the basis of substantial evidence of efficacy for pertuzumab in MBC and the compelling public health need, FDA did not delay availability to patients pending final resolution of all manufacturing concerns. Therefore, FDA approved pertuzumab but limited its approval to lots not affected by manufacturing problems. The applicant agreed to multiple manufacturing and testing postmarketing commitments under third-party oversight to resolve manufacturing issues.

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“…84 In another small phase II trial that combined trastuzumab with pertuzumab, 6 of 11 patients experienced a significant reduction in left ventricular ejection fraction, of which one was severe and induced congestive heart failure symptoms. 85 In summary, given the cardioprotective effects of paracrine NRG-1/ErbB signaling in the heart, therapies that block ErbB signaling may be expected to induce ventricular dysfunction. These effects should be pronounced in conditions in which the injured or overloaded heart has progressed into a state of "ErbB signaling dependency."…”

Section: Mechanisms Of Cardiotoxicity Of Targeted Erbb Therapy: What mentioning

confidence: 99%

The Vulnerability of the Heart As a Pluricellular Paracrine Organ

Keulenaer

Doggen

Lemmens

2010

Circulation Research

178

102

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In this review, we address clinical aspects and mechanisms of ventricular dysfunction induced byanticancer drugs targeted to the ErbB2 receptor. ErbB2 antagonists prolong survival in cancer, but also interfere with homeostatic processes in the heart. ErbB2 is a coreceptor for ErbB4, which is activated by neuregulin-1. This epidermal growth factor-like growth factor is released from endothelial cells in the endocardium and in the myocardial microcirculation, hence contributing to intercellular crosstalk in the ventricle. We look at the physiological aspects of neuregulin-1/ErbB signaling in the ventricle, and review its (mal)adaptive responses in chronic heart failure. We also compare structural aspects of

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Cardiac Toxicity and Efficacy of Trastuzumab Combined with Pertuzumab in Patients with Trastuzumab-Insensitive Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

Cited by 152 publications

References 43 publications

Immunoselection of Breast and Ovarian Cancer Cells with Trastuzumab and Natural Killer Cells: Selective Escape of CD44high/CD24low/HER2low Breast Cancer Stem Cells

Immunoselection of Breast and Ovarian Cancer Cells with Trastuzumab and Natural Killer Cells: Selective Escape of CD44high/CD24low/HER2low Breast Cancer Stem Cells

First FDA Approval of Dual Anti-HER2 Regimen: Pertuzumab in Combination with Trastuzumab and Docetaxel for HER2-Positive Metastatic Breast Cancer

The Vulnerability of the Heart As a Pluricellular Paracrine Organ

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