Retreatment With Trastuzumab in Metastatic Breast Cancer
Background: Preclinical data suggest that treatment with lapatinib reinduces sensitivity to trastuzumab in human epidermal growth factor receptor 2(HER2)-positive breast cancer cells.
Patients and methods: Between January 2007 and November 2010, 179 HER2-positive metastatic breast cancer patients were treated with lapatinib and capecitabine at nine Italian institutions. We evaluated the clinical outcome of 69 patients (38.5%) retreated with trastuzumab after lapatinib progression.
Results: Visceral metastases were identified in 51 (74%) and brain metastases in 16 patients (23%). All patients were pretreated with both trastuzumab- and lapatinib-based therapy. We observed with retreatment with trastuzumab-based therapy: 1 complete remission (2%), 18 partial remission (29%) and 10 stable disease ≥6 months (14%) and 47% of clinical benefit (CB). Median duration of response was 8.1 months [95% confidence interval (CI) 5.5–10.7]. No unexpected toxic effects occurred. At a median follow-up of 13 months, median progression-free survival was 4.9 months (95% CI 4.2–5.6) and overall survival (OS) 19.4 months (95% CI 14.0–25.0). Median OS was longer for patients experiencing CB (not reached versus 13.4 months for patients without CB, P = 0.002). Brain involvement was associated with lower median OS (17.3 versus 23.3 months for patients without brain disease; P = 0.021).
Conclusion: Retreatment with trastuzumab-based therapy showed CB in 47% of patients progressing during lapatinib-based therapy, leading to a prolonged OS.
The development of trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of human epidermal growth factor receptor 2 (HER2), has represented a major breakthrough in the treatment of HER2-positive breast cancer. Randomized trials have shown that trastuzumab-based therapies prolong survival of these patients both in the metastatic and adjuvant setting.
In HER2-positive metastatic breast cancer, HER2 remains an effective therapeutic target even in the presence of disease progression due to trastuzumab treatment. Three phase III randomized trials have been conducted in HER2-positive metastatic breast cancer patients who have progressed after trastuzumab-based therapy. In two studies, trastuzumab beyond progression given in combination with capecitabine or with lapatinib (the dual HER1/HER2 tyrosine kinase) resulted more effective than capecitabine alone or single-agent lapatinib, respectively. The third study has shown that lapatinib plus capecitabine significantly improves the time to progression compared with capecitabine monotherapy, and in 2007, this combination was approved for the treatment of HER2-positive metastatic breast cancer pretreated with an anthracycline, a taxane and trastuzumab. Nonetheless, it is necessary to know how to treat patients after disease progression on lapatinib and capecitabine.
Preclinical evidence could support the reuse of trastuzumab after treatment with lapatinib. The development of acquired resistance to trastuzumab might also be due to receptor degradation and down-regulation. Lapatinib, inducing stabilization and accumulation of inactive HER2 receptor at the cytoplasmic membrane, could potentially resensitize HER2-positive tumor cells to the action of trastuzumab.
This study reports on the clinical outcome of HER2-positive metastatic breast cancer patients who were rechallenged with trastuzumab following disease progression on lapatinib.
Abstract and Introduction
Abstract
Background: Preclinical data suggest that treatment with lapatinib reinduces sensitivity to trastuzumab in human epidermal growth factor receptor 2(HER2)-positive breast cancer cells.
Patients and methods: Between January 2007 and November 2010, 179 HER2-positive metastatic breast cancer patients were treated with lapatinib and capecitabine at nine Italian institutions. We evaluated the clinical outcome of 69 patients (38.5%) retreated with trastuzumab after lapatinib progression.
Results: Visceral metastases were identified in 51 (74%) and brain metastases in 16 patients (23%). All patients were pretreated with both trastuzumab- and lapatinib-based therapy. We observed with retreatment with trastuzumab-based therapy: 1 complete remission (2%), 18 partial remission (29%) and 10 stable disease ≥6 months (14%) and 47% of clinical benefit (CB). Median duration of response was 8.1 months [95% confidence interval (CI) 5.5–10.7]. No unexpected toxic effects occurred. At a median follow-up of 13 months, median progression-free survival was 4.9 months (95% CI 4.2–5.6) and overall survival (OS) 19.4 months (95% CI 14.0–25.0). Median OS was longer for patients experiencing CB (not reached versus 13.4 months for patients without CB, P = 0.002). Brain involvement was associated with lower median OS (17.3 versus 23.3 months for patients without brain disease; P = 0.021).
Conclusion: Retreatment with trastuzumab-based therapy showed CB in 47% of patients progressing during lapatinib-based therapy, leading to a prolonged OS.
Introduction
The development of trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of human epidermal growth factor receptor 2 (HER2), has represented a major breakthrough in the treatment of HER2-positive breast cancer. Randomized trials have shown that trastuzumab-based therapies prolong survival of these patients both in the metastatic and adjuvant setting.
In HER2-positive metastatic breast cancer, HER2 remains an effective therapeutic target even in the presence of disease progression due to trastuzumab treatment. Three phase III randomized trials have been conducted in HER2-positive metastatic breast cancer patients who have progressed after trastuzumab-based therapy. In two studies, trastuzumab beyond progression given in combination with capecitabine or with lapatinib (the dual HER1/HER2 tyrosine kinase) resulted more effective than capecitabine alone or single-agent lapatinib, respectively. The third study has shown that lapatinib plus capecitabine significantly improves the time to progression compared with capecitabine monotherapy, and in 2007, this combination was approved for the treatment of HER2-positive metastatic breast cancer pretreated with an anthracycline, a taxane and trastuzumab. Nonetheless, it is necessary to know how to treat patients after disease progression on lapatinib and capecitabine.
Preclinical evidence could support the reuse of trastuzumab after treatment with lapatinib. The development of acquired resistance to trastuzumab might also be due to receptor degradation and down-regulation. Lapatinib, inducing stabilization and accumulation of inactive HER2 receptor at the cytoplasmic membrane, could potentially resensitize HER2-positive tumor cells to the action of trastuzumab.
This study reports on the clinical outcome of HER2-positive metastatic breast cancer patients who were rechallenged with trastuzumab following disease progression on lapatinib.
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