What is the role of trastuzumab in the treatment of HER2-positive breast cancer?

Updated: Jul 16, 2020
  • Author: Maurie Markman, MD, MS; Chief Editor: Karl S Roth, MD  more...
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Overexpression of HER2 occurs in approximately 20% of breast cancers and was correlated with a more aggressive phenotype and worse prognosis before the development of HER2-targeted therapies. The advent of trastuzumab, a monoclonal antibody (mAb) targeting the extracellular domain of the receptor, has changed the treatment paradigm for HER2-positive breast cancer. Trastuzumab has a powerful synergism with a variety of chemotherapeutics, yet lacks the side effects (with the notable exception of cardiotoxicity, which means it generally should not be given with anthracyclines).

Results are available from studies (HERA, FinHer, NSABP B-31, BCIRG006, N9831) that have demonstrated that the inclusion of trastuzumab produces roughly a 50% improvement in disease-free survival and 33% improvement in overall survival, regardless of the chemotherapy regimen or sequence of trastuzumab delivery. These trials randomized 11,650 women with early-stage HER2-positive breast cancer to trastuzumab versus non-trastuzumab-based adjuvant chemotherapy, and based on their results, trastuzumab was approved by the US Food and Drug Administration (FDA) for the treatment of HER2-positive disease in the adjuvant setting. 

Another study from the BCIRG006 further established that adjuvant trastuzumab for 1 year improved disease-free and overall survival among women with early-stage HER2-positive breast cancer at 5 years, and found that a nonanthracycline regimen plus trastuzumab had a more favorable risk-benefit ratio than anthracycline-based regimens due to similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. [8]

Whether the combination of 2 anti-HER2-targeted therapies with chemotherapy will prove beneficial in early-stage disease is currently being tested in the ongoing phase III ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Options) trial, as well as the similar Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial.

In February 2019, the FDA approved trastuzumab/hyaluronidase (Herceptin Hylecta) in combination with chemotherapy for the treatment of select patients with HER2-positive early breast cancer, in combination with paclitaxel in patients with metastatic HER2-positive breast cancer as a frontline treatment, and alone for patients with metastatic disease who had received at least 1 prior chemotherapy regimen. This new subcutaneous (SC) formulation includes trastuzumab in combination with recombinant human hyaluronidase PH20, an enzyme that allows a ready-to-use formulation for slow SC administration (ie, given over 2-5 minutes) instead of a 30-90 minute IV infusion. [9]

Approval of trastuzumab/hyaluronidase was based on 2 randomized trials, HannaH (NCT00950300) and SafeHER (NCT01566721). In HannaH, patients with HER2-positive operable or locally advanced breast cancer were randomized to receive 8 cycles of either SC trastuzumab or IV trastuzumab concurrently with chemotherapy, followed by surgery and continued therapy with either formulation of trastuzumab, for an additional 10 cycles. The endpoints for HannaH were pathologic complete response (pCR) and pharmacokinetics of both SC and IV trastuzumab. Pathologic complete response was observed in 45.4% of patients receiving Herceptin Hylecta and in 40.7% of patients receiving IV trastuzumab. [10]

SafeHER was a prospective, two-cohort, nonrandomized, multinational, open-label trial assessing the overall safety and tolerability of SC trastuzumab with chemotherapy in patients with HER2-positive breast cancer. SafeHER confirmed safety and tolerability of adjuvant SC trastuzumab for HER2-positive early breast cancer. [11]

In May 2019, the FDA approved ado-trastuzumab emtansine for the adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane- and trastuzumab-based treatment. Approval was based on KATHERINE, a randomized, multicenter, open-label clinical trial that compared the use of ado-trastuzumab emtansine versus trastuzumab as adjuvant therapy in patients with HER2-positive early-stage breast cancer who had residual invasive disease after receiving neoadjuvant chemotherapy and trastuzumab. The study showed ado-trastuzumab emtansine reduced the risk of an invasive recurrence or death by 50%. The invasive disease–free survival events occurred in 12.2% of patients in the ado-trastuzumab emtansine arm, compared with 22% in the trastuzumab arm. Secondary efficacy endpoints of disease-free survival and distant recurrence–free survival interval also showed clinically meaningful improvements with ado-trastuzumab emtansine relative to trastuzumab. [12]

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