Preoperative Chemotherapy Plus Trastuzumab, Lapatinib, or Both in Human Epidermal Growth Factor Receptor 2–Positive Operable Breast Cancer: Results of the Randomized Phase II CHER-LOB Study

Guarneri, Valentina; Frassoldati, Antonio; Bottini, Alberto; Cagossi, Katia; Bisagni, Giancarlo; Sarti, Samanta; Ravaioli, Alberto; Cavanna, Luigi; Giardina, G; Musolino, Antonino; Untch, Michael; Orlando, Laura; Artioli, Fabrizio; Boni, C.; Generali, Daniele; Serra, Patrizia; Bagnalasta, M.; Marini, Luca; Piacentini, Federico; D'Amico, Roberto; Conte, Pierfranco

doi:10.1200/jco.2011.39.0823

Cited by 331 publications

(238 citation statements)

References 28 publications

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“…S10A). Furthermore, these preclinical results are supported by clinical data in both the preoperative primary and metastatic settings (30,31). Because these findings are limited to extracranial sites (primary and metastasis), we asked if the same tumor growth delay would occur in the brain metastasis setting.…”

Section: Dual Her2 Targeting With Trastuzumab and Lapatinib Delays Brainmentioning

confidence: 49%

Combined targeting of HER2 and VEGFR2 for effective treatment ofHER2-amplified breast cancer brain metastases

Kodack¹,

Chung

Yamashita³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

132

104

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Brain metastases are a serious obstacle in the treatment of patients with human epidermal growth factor receptor-2 (HER2)-amplified breast cancer. Although extracranial disease is controlled with HER2 inhibitors in the majority of patients, brain metastases often develop. Because these brain metastases do not respond to therapy, they are frequently the reason for treatment failure. We developed a mouse model of HER2-amplified breast cancer brain metastasis using an orthotopic xenograft of BT474 cells. As seen in patients, the HER2 inhibitors trastuzumab and lapatinib controlled tumor progression in the breast but failed to contain tumor growth in the brain. We observed that the combination of a HER2 inhibitor with an anti-VEGF receptor-2 (VEGFR2) antibody significantly slows tumor growth in the brain, resulting in a striking survival benefit. This benefit appears largely due to an enhanced antiangiogenic effect: Combination therapy reduced both the total and functional microvascular density in the brain xenografts. In addition, the combination therapy led to a marked increase in necrosis of the brain lesions. Moreover, we observed even better antitumor activity after combining both trastuzumab and lapatinib with the anti-VEGFR2 antibody. This triple-drug combination prolonged the median overall survival fivefold compared with the control-treated group and twofold compared with either two-drug regimen. These findings support the clinical development of this three-drug regimen for the treatment of HER2-amplified breast cancer brain metastases.treatment resistance | tumor-stroma interaction | targeted therapy | tumor microenvironment | antiangiogenesis

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Section: Dual Her2 Targeting With Trastuzumab and Lapatinib Delays Brainmentioning

confidence: 49%

Combined targeting of HER2 and VEGFR2 for effective treatment ofHER2-amplified breast cancer brain metastases

Kodack¹,

Chung

Yamashita³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

132

104

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“…Thus, clinical data from randomized trials in neoadjuvant and metastatic setting suggest a beneficial effect of dual blockade both with the combination trastuzumablapatinib and trastuzumab-pertuzumab. [9][10][11][12][13][14] A common feature of cardiotoxicity from anti-HER2 therapies is the high rate of reversibility after discontinuation of treatment. 21 The reversibility of cardiac toxicity from these agents was observed in all the included randomized trials in our study even when a combination of anti-HER2 therapies was administered.…”

Section: Discussionmentioning

confidence: 99%

“…Among the four trials in the neoadjuvant setting, [10][11][12]14 there was also no evidence of an association between dual anti-HER2 therapy and CHF (OR: 0.74, 95% CI: 0.02- …”

Section: Subgroup Analysesmentioning

confidence: 96%

“…[9][10][11]13,14 The pooled OR of LVEF decline with dual anti-HER2 therapy versus anti-HER2 monotherapy was 0.88 (95% CI: 0.53-1.48, p-value5 0.64) (Fig. 3).…”

Section: Meta-analysis Of Lvef Declinementioning

confidence: 99%

“…12 Thus, we were not able to assess the methodological quality of this trial. Among the remaining five trials, four reported an adequate randomization mode and allocation concealment, 10,11,13,14 while two clearly reported blinding of outcome assessment. 11,13 In addition, only one trial reported that it was designed as a double-blind trial.…”

Section: Quality Of Studies-publication Bias Assessmentmentioning

confidence: 99%

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Cardiac toxicity in breast cancer patients treated with dual HER2 blockade

Valachis

Nearchou

Polyzos

et al. 2013

Intl Journal of Cancer

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Although dual HER2 blockade shows promising results in patients with HER2-positive breast cancer it is unclear whether this treatment strategy increases the risk for cardiac adverse events. We conducted a meta-analysis of randomized trials to investigate the risk of cardiac adverse events when a combination of anti-HER2 therapies compared to anti-HER2 monotherapy. We searched Medline, the Cochrane library, as well as the electronic abstract databases of the major international congresses' proceedings to identify randomized trials that evaluated the administration of anti-HER2 monotherapy (lapatinib or trastuzumab or pertuzumab) versus anti-HER2 combination (pertuzumab plus trastuzumab or trastuzumab plus lapatinib) therapy in breast cancer. The trials were considered eligible if the only systematic difference between the study arms was the type of anti-HER2 therapy used. Study outcomes were the congestive heart failure (CHF) grade 3 and left ventricular ejection fraction (LVEF) decline <50% or more than 10% from baseline. Six trials were considered eligible. Overall incidence results for CHF in the combined anti-HER2 therapy and the anti-HER2 monotherapy were 0.88% (95% CI: 0.47-1.64%) and 1.49% (95% CI: 0.98-2.23%). The incidence of LVEF decline was 3.1% (95% CI: 2.2-4.4%) and 2.9% (95% CI: 2.1-4.1%), respectively. The OR of CHF between anti-HER2 combination and monotherapy was 0.58 (95% CI: 0.26-1.27, p-value5 0.17) while the OR of LVEF decline was 0.88 (95% CI: 0.53-1.48, p-value5 0.64). This meta-analysis provides evidence supporting comparable cardiac toxicity between anti-HER2 combination therapy and anti-HER2 monotherapy.

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Association of Pathologic Complete Response to Neoadjuvant Therapy in HER2-Positive Breast Cancer With Long-Term Outcomes

et al. 2016

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Pathologic complete response in HER2-positive breast cancer is associated with substantially longer times to recurrence and death. This relationship is maintained in RCTs. For any particular new therapy the relationship between pCR and survival may differ. Quantifying the importance of pCR is necessary for designing efficient clinical trials, which should adapt to the relationship between pCR and survival for the therapy under investigation.

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Preoperative Chemotherapy Plus Trastuzumab, Lapatinib, or Both in Human Epidermal Growth Factor Receptor 2–Positive Operable Breast Cancer: Results of the Randomized Phase II CHER-LOB Study

Cited by 331 publications

References 28 publications

Combined targeting of HER2 and VEGFR2 for effective treatment ofHER2-amplified breast cancer brain metastases

Combined targeting of HER2 and VEGFR2 for effective treatment ofHER2-amplified breast cancer brain metastases

Cardiac toxicity in breast cancer patients treated with dual HER2 blockade

Association of Pathologic Complete Response to Neoadjuvant Therapy in HER2-Positive Breast Cancer With Long-Term Outcomes

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