What is the role of tamoxifen and trastuzumab emtansine (T-DM1) in the adjuvant treatment of estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2 (HER2)-positive breast cancer?

Adjuvant Therapy for ER+/HER2+ Breast Cancer

For patients with ER-positive/HER2-positive early breast cancer who have residual invasive disease after neoadjuvant therapy, switch from trastuzumab to trastuzumab emtansine (T-DM1) for 14 cycles and continue tamoxifen (or other appropriate endocrine therapy) concurrently and beyond completion of T-DM1. 1

T-DM1: The Standard for Residual Disease After Neoadjuvant Therapy

T-DM1 reduces the risk of recurrence or death by 50% compared to continuing trastuzumab in patients with any residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy. 1, 2 The KATHERINE trial demonstrated that among 1,486 patients with HER2-positive early breast cancer and residual invasive disease, invasive disease-free survival at 3 years was 88.3% with T-DM1 versus 77.0% with trastuzumab (HR 0.50; 95% CI 0.39-0.64; P<0.001). 2

• T-DM1 should be administered for exactly 14 cycles in the adjuvant setting after surgery. 3, 1
• This represents the established standard of care for patients with residual disease—continuing trastuzumab in this scenario is a missed opportunity for substantial benefit. 1
• T-DM1 is only indicated for the adjuvant setting in patients with residual disease, never as neoadjuvant therapy. 1

Concurrent Endocrine Therapy: Tamoxifen or Aromatase Inhibitors

Tamoxifen should be administered concurrently with T-DM1 and continued for a total duration of 5-10 years appropriate to the adjuvant endocrine therapy indication. 1 For premenopausal women, tamoxifen remains the primary endocrine therapy option. 3 For postmenopausal women, both tamoxifen and aromatase inhibitors are appropriate options. 3

• Adjuvant endocrine therapy is recommended for all patients with ER-positive breast cancer regardless of HER2 status, patient age, lymph node status, or whether adjuvant chemotherapy is administered. 3
• Meta-analysis data demonstrate similar disease-free survival with tamoxifen versus aromatase inhibitors specifically in HER2-positive, HR-positive early-stage breast cancer (HR 1.06,95% CI 0.65-1.73, P=0.81). 4
• While some retrospective analyses suggest HER2-positive tumors may be relatively less sensitive to endocrine therapy, the favorable toxicity profile supports endocrine therapy use in most women with hormone receptor-positive disease regardless of HER2 status. 3

Critical Safety Monitoring

Regular cardiac monitoring with left ventricular ejection fraction (LVEF) assessment is mandatory before starting, during treatment, and following HER2-targeted therapy. 1

• T-DM1 should never be given concomitantly with anthracyclines due to cardiotoxicity risk. 1
• Grade 3 or higher adverse events occurred in 26.1% of patients receiving T-DM1, with the most common being thrombocytopenia (28.5%), hepatotoxicity (37.3%), peripheral neuropathy (32.3%), hemorrhage (29.2%), and pulmonary toxicity (2.8%). 5
• Patients with clinical congestive heart failure or significantly compromised LVEF should be evaluated on a case-by-case basis before initiating HER2-targeted therapy. 3

Common Pitfalls to Avoid

• Do not re-examine hormone receptor or HER2 status in residual disease—systemic therapy choice should be based on initial diagnostic biopsy results. 1
• Do not continue standard trastuzumab in patients with residual disease—this represents suboptimal care given the 50% reduction in recurrence risk with T-DM1. 1, 2
• Do not withhold endocrine therapy based on HER2-positive status—the presence of hormone receptors mandates endocrine therapy regardless of HER2 status. 3
• For premenopausal women with higher-risk disease, consider ovarian function suppression with an aromatase inhibitor or tamoxifen, as this reduces recurrence and improves overall survival versus tamoxifen alone. 3