Treatment Of HER2-positive Early Breast Cancer Research Articles

Trastuzumab Emtansine: A Review of Its Adjuvant Use in Residual Invasive HER2-Positive Early Breast Cancer.

Trastuzumab emtansine (Kadcyla®), an antibody-drug conjugate of trastuzumab (Herceptin®) connected by a thioether linker to the microtubule inhibitor DM1 (a cytotoxic derivative of maytansine), provides direct intracellular delivery of the potent cytotoxin DM1 to HER2-overexpressing cells, while retaining trastuzumab activity. Its approval in metastatic/advanced breast cancer (BC) has been extended to include single-agent adjuvant treatment of HER2-positive early BC in patients with residual invasive disease in the breast and/or lymph nodes after neoadjuvant taxane-based and HER2-targeted treatment. In the pivotal KATHERINE trial in this population, significantly more trastuzumab emtansine than trastuzumab recipients were estimated to be free of invasive disease recurrence at 3years, with a 50% reduction in the risk of invasive disease recurrence or death. The tolerability of trastuzumab emtansine in early BC was consistent with its known safety profile; as expected, adverse events were more common with trastuzumab emtansine than with trastuzumab. Recently updated international and national treatment guidelines recommend trastuzumab emtansine as a preferred option in this high-risk BC population.

Clinical practice-changing trials: the HERA study paradigm

Trastuzumab, a humanized anti-HER2 monoclonal antibody targeting the extracellular domain of this oncoprotein, represents the archetype of HER2 blocking agents. Its unprecedented efficacy for HER2-positive metastatic breast cancer (BC) led to its clinical development in the adjuvant setting. The HERceptin Adjuvant (HERA) is one of the pivotal adjuvant trastuzumab trials which proved that this compound can change the natural course of early stage HER2-positive BC. The HERA study led to the registration of trastuzumab for the adjuvant treatment of early HER2-positive BC. This trial randomized more than 5000 patients between 1 and 2 years of trastuzumab and observation after the completion of locoregional therapy and (neo)-adjuvant chemotherapy. Additionally, an abundance of subsequent substudies were conducted, addressing important clinical issues for this patient population. The present review article presents a comprehensive overview of the HERA study and its major contributions to the adjuvant treatment of HER2-positive BC patients. Emphasis is given on the lessons learned from this international collaborative experience and how this can be used as a stepping stone for further improvements in the field.Trial registration: ClinicalTrial.gov identifier: NCT00593697.Trial registration: ClinicalTrial.gov identifier: NCT00712140.Trial registration: ClinicalTrial.gov identifier: NCT00629278.Trial registration: ClinicalTrial.gov identifier: NCT00615602.Trial registration: ClinicalTrial.gov identifier: NCT00615602.Trial registration: ClinicalTrial.gov identifier: NCT00490139.Trial registration: ClinicalTrial.gov identifier: NCT01358877.

Estimation of the epidemiological effect of trastuzumab over 10 years in 5 European countries

6589 Background: Trastuzumab (T) is now approved for the treatment of HER2-positive early breast cancer (EBC) in most European countries. Approval was based on the results of the HERceptin Adjuvant (HERA) trial, in which distant recurrence-free survival was reduced by half. The model assesses the long-term impact of T treatment in EBC on the annual number of patients entering the metastatic setting between 2005 and 2015 in five European countries. Methods: Annual EBC incidence for 2005–2015 was projected by applying stage-specific proportions for stages I-III, according to regional cancer registry data, to published female breast cancer incidence rates from 1990–2002. Age-specific rates for 2002 were then applied to United Nations population projections for 2003–2015. The annual number of patients with HER2-positive metastatic breast cancer (MBC) includes annual de novo MBC incidence plus patients with breast cancer recurrence. The baseline 10-year recurrence rate for standard treatment was estimated as 37%, based on 4-year follow-up in the control arm of a combined trial analysis in patients with HER2-positive breast cancer and the long-term timing of recurrence in all patients with breast cancer. To model recurrence in T-treated EBC patients, the hazard ratio (HR) from the HERA trial (0.49; 95% CI: 0.38, 0.63) was applied, resulting in an estimated 10-year recurrence rate of 18.1% (95% CI: 14.0, 23.3). Results: In 2004, prior to approval of T in EBC, the pool of de novo and relapsed MBC patients in the five countries was estimated to be 16,156. Between 2005 and 2015, the model predicts that the use of T will result in an annual decline of 2.5% (95% CI: 1.7, 3.2). The total number of patients saved from developing metastases over 10 years is projected to be 27,727 (95% CI: 20,116, 33,709). Conclusions: T treatment of HER2-positive EBC is expected to prevent nearly 28,000 women from developing metastases over a 10-year period in five countries alone, which may result in a similar number of breast cancer deaths being avoided. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration F. Hoffmann-La Roche Ltd F. Hoffmann-La Roche Ltd