492TiP HERES trial: Trastuzumab and standard treatment with chemo- and immunotherapy as first-line treatment for HER2-positive esophageal squamous cell carcinoma patients
Kristian EgebjergLene BæksgaardR. S. GarbyalPer PfeifferTina Di CaterinoJon Kroll BjerregaardM.N. YilmazAlkwin WandersLise Bech Jellesmark ThorsenStephen Hamilton‐DutoitLise Barlebo AhlbornNiels PallisgaardMorten Mau‐Sørensen
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Purpose: Neoadjuvant chemotherapy (NAC) involving trastuzumab markedly increases pathologic complete response (pCR) rates in patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer.Despite increasing pCR rates, long-term survival gains are controversial owing to distinctive biologic behavior mediated by the presence of hormonal receptors (HRs) that may interact with HER2 receptors.We, therefore, investigated the differences in relative survival gain provided by neoadjuvant trastuzumab-based chemotherapy on HR positive (HR+) status of patients.Methods: We retrospectively ana Patient clinical characteristics were compared usin lyzed women with stage II or III HER2+ breast cancer who underwent NAC followed by a breast cancer surgery between 2008 and 2013.The survival benefits of adding trastuzumab to NAC were analyzed by classifying patients into HR+ and HR negative (HR-) groups.Results: Of 666 patients included in the study, 374 (52.1%) were HR+ and 319 (47.9%) were HR-.In the HR+ group, trastuzumab treatment led to higher pCR rates and significantly better breast cancer specific survival (BCSS) and overall survival (OS) than no trastuzumab treatment.However, among patients with HR-breast cancer, trastuzumab treatment showed no statistically significant difference between BCSS and OS following multivariate analysis. Conclusion:We found that the addition of trastuzumab to NAC improved relative survival benefit in HER2+/HR+ patients than in HER2+/HR-patients, even though the pCR rate increases were lower.Although pCR has been regarded as a surrogate marker for estimating long-term survival benefits after NAC, it alone may not translate into real long-term oncologic outcomes in particular cancer subtypes after trastuzumab-based NAC.Further longer-term evaluation of the objective survival benefit after NAC driven by a dual HER2 block according to HR status is warranted.
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The monoclonal antibody trastuzumab is at present the only modern targeted treatment which has been studied in early breast cancer. Data are available from four large and one smaller randomised trials where patients with HER2-positive operable breast cancer were randomised to trastuzumab or control in addition to standard adjuvant chemotherapy and endocrine treatment. Trastuzumab therapy resulted in relative risk reductions of 33-59% for recurrence and of 33-41% for death. Trastuzumab has become an integral part of adjuvant therapy in HER2-positive operable breast cancer.
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Lapatinib
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No single standard treatment exists for patients with small, node-negative, human epidermal growth factor receptor type 2 (HER2)-positive breast cancers, because most of these patients have been ineligible for the pivotal trials of adjuvant trastuzumab.We performed an uncontrolled, single-group, multicenter, investigator-initiated study of adjuvant paclitaxel and trastuzumab in 406 patients with tumors measuring up to 3 cm in greatest dimension. Patients received weekly treatment with paclitaxel and trastuzumab for 12 weeks, followed by 9 months of trastuzumab monotherapy. The primary end point was survival free from invasive disease.The median follow-up period was 4.0 years. The 3-year rate of survival free from invasive disease was 98.7% (95% confidence interval [CI], 97.6 to 99.8). Among the 12 relapses seen, 2 were due to distant metastatic breast cancer. Excluding contralateral HER2-negative breast cancers and nonbreast cancers, 7 disease-specific events were noted. A total of 13 patients (3.2%; 95% CI, 1.7 to 5.4) reported at least one episode of grade 3 neuropathy, and 2 had symptomatic congestive heart failure (0.5%; 95% CI, 0.1 to 1.8), both of whom had normalization of the left ventricular ejection fraction after discontinuation of trastuzumab. A total of 13 patients had significant asymptomatic declines in ejection fraction (3.2%; 95% CI, 1.7 to 5.4), as defined by the study, but 11 of these patients were able to resume trastuzumab therapy after a brief interruption.Among women with predominantly stage I HER2-positive breast cancer, treatment with adjuvant paclitaxel plus trastuzumab was associated with a risk of early recurrence of about 2%; 6% of patients withdrew from the study because of protocol-specified adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT00542451.).
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Trastuzumab is a humanized monoclonal antibody against the extracellular domain of hEGF receptor-2 (HER2). Trastuzumab in combination with chemotherapy has proven efficacy in treating both early and metastatic HER2-positive breast cancer. In the metastatic setting, the addition of trastuzumab to chemotherapy is associated with a statistically significant longer time to disease progression, higher rate of objective response and improvement in overall survival. Trastuzumab efficacy is not influenced by hormone receptor status, but differences in median overall survival exist between HER2-positive and HER2-negative states. Reassessment of the benefit of re-exposing patients with metastatic breast cancer to trastuzumab following relapse in the adjuvant setting is necessary. Ongoing research into new HER2-targeted therapies and trials involving combination anti-HER2 drug therapy without chemotherapy show promise. This review is focused on the available results obtained with the use of trastuzumab in the subset of HER2-positive breast cancer patients with metastatic disease.
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Background: This meta-analysis assessed the safety and effectiveness of retreatment with trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (HER2+MBC). Materials and methods: Randomized controlled trials (RCTs) and cohort studies that compared the clinical outcomes of continuation and termination of trastuzumab treatment in HER2+MBC after failure of trastuzumab-based regimens were analyzed. Pooled estimates of time to progression (TTP) survival, overall survival (OS), the incidence of adverse events and central nervous system (CNS) perturbations were determined. Results: Four RCTs and six cohort studies with 2,409 patients were identified. The continuation of trastuzumab presented a statistical significance in prolonging TTP (HR 0.88; 95% CI: 0.82–0.94; P <0.000) and OS (HR 0.87; 95% CI: 0.82–0.93; P <0.000). Furthermore, retreatment with trastuzumab did not add to the risk of cardiac events (relative risk, 2.48; 95% CI: 0.86–7.15) or the incidence of CNS metastasis ( P =0.83). Conclusion: Our findings confirm the clinical benefits and safety of retreatment therapy with trastuzumab for HER2-positive patients with metastatic cancer of the breast that had progressed during trastuzumab-based treatment regimens. Keywords: trastuzumab, retreatment, HER2-positive cancer, metastatic cancer of the breast, progression therapy
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