Patients with residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy for HER2-positive breast early stage breast cancer have a higher risk of disease recurrence or death compared with patients with no residual cancer. In the KATHERINE study, a phase 3, open-label trial, 1,486 patients with metastatic breast cancer previously treated with chemotherapy plus HER2-targeted therapy were randomly assigned to receive either adjuvant trastuzumab emtansine (T-DM1) or standard trastuzumab for 14 cycles. Results revealed that patients treated with adjuvant T-DM1 were 50% less likely to experience recurrence of invasive breast cancer or death compared with patients treated with trastuzumab. In an interview with i3 Health, study author Charles Geyer, MD, FACP, spoke about the significance of these findings and their implications for community oncologists.
What is the most challenging aspect of treating patients with residual invasive breast cancer after they received neoadjuvant chemotherapy plus HER2-targeted therapy?
Charles Geyer, MD, FACP: Prior to the outcome of the KATHERINE trial, the most challenging aspect was the disappointment and heightened fear of recurrence experienced by patients with residual invasive breast cancer after they had received one of the standard neoadjuvant regimens, which eliminate invasive cancer in more than half of patients with HER2-positive early breast cancer. Patients with residual disease that is also estrogen receptor (ER)-positive begin adjuvant endocrine therapy, which offers some reassurance, but we have not had an effective additional therapy to offer those with ER-negative disease beyond completing the year of planned therapy with trastuzumab with or without pertuzumab.
Why is trastuzumab emtansine more effective than trastuzumab for patients with HER2-positive disease?
Dr. Geyer: T-DM1 is an immunoconjugate that links the chemotherapy drug emtansine to trastuzumab. The trastuzumab portion binds to the HER2 receptors on residual HER2-positive cells and is internalized with the emtansine chemotherapy. The lysozymes within the cancer cells degrade the immunoconjugate, and the emtansine is released at a high level, killing the cancer cell by interfering with microtubule polymerization.
When a HER2-positive cancer cell is killed by emtansine, the intact drug is released in the local environment at high levels and may kill adjacent cancer cells which may not express as much HER2 on their surface. If cancer cells have survived the initial exposure to neoadjuvant trastuzumab in combination with chemotherapy, it was reasonable to hypothesize that T-DM1 would be more effective than continuing trastuzumab.
Are there serious safety considerations that oncologists should know about?
Dr. Geyer: The magnitude of the reduction in risk for recurrence demonstrated in KATHERINE among patients with HER2-positive breast cancer and residual invasive cancer following neoadjuvant therapy was substantial and clinically meaningful. These patients had already received neoadjuvant regimens with a more substantial toxicity profile than T-DM1, and the large majority of the toxicities seen on KATHERINE with T-DM1 were grade 1/2. Grade 3 toxicities were infrequent and were generally laboratory abnormalities that are transient and not associated with symptoms and can be effectively managed with standard dose reductions. Patients meeting the eligibility criteria for KATHERINE should be considered for an initial trial of T-DM1 to assess their tolerance to the therapy, which is favorable for the large majority of patients.
What advice would you give to oncologists who administer trastuzumab emtansine to their patients?
Dr. Geyer: Oncologists are already familiar with administering T-DM1 to their patients with metastatic HER2-positive breast cancer, so they have the knowledge and experience to administer the therapy safely in this setting. The critical new advice is that both medical oncologists and breast surgeons need to recognize that the only way to identify the patients who may benefit from adjuvant T-DM1 is to routinely employ neoadjuvant therapy in patients with HER2-positive breast cancer.
About Dr. Geyer
Charles Geyer, MD, FACP, is a Professor in the Department of Internal Medicine in the Division of Hematology, Oncology & Palliative Care at Virginia Commonwealth University School of Medicine. Dr. Geyer's research interests include developing treatments for HER2-positive breast cancer.
For More Information
Von Minckwitz G, Huang CS, Mano MS, et al (2019). Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med, 380(7):617-628. DOI:10.1056/NEJMoal1814017
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily represent the views of i3 Health.
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