Adjuvant T-DM1 Plus Concurrent Radiation Not Associated With Increased Cardiotoxicity in HER2+ Breast Cancer

Mridula George, MD

Adjuvant ado-trastuzumab emtansine (T-DM1; Kadcyla) plus concurrent radiation therapy did not result in cardiotoxicities in patients with early-stage HER2-positive breast cancer, according to data from an retrospective institutional study presented in a poster at the 2022 San Antonio Breast Cancer Symposium.

The institutional review from the Rutgers Cancer Institute of New Jersey identified 31 patients with early-stage HER2-positive breast cancer who received adjuvant T-DM1 with concurrent radiation for stage I to III breast cancer from January 2020 to January 2022. Findings showed that the mean pre-radiation left ventricle injection fraction (LVEF) was 60% compared with the post-radiation LVEF was 61%. Investigators noted that there was no statically significant difference in LVEF after radiation (P = .343).

“Based on this small study, we have sufficient data to say that [adjuvant trastuzumab emtansine plus breast radiation] is safe. However, the sample size is a limitation of the study. A larger study looking at this question, specifically using more sensitive cardiac biomarkers, would give us more information,” lead study author Mridula George, MD, explained in an interview with OncLive^®.

George discussed the methods used to evaluate cardiotoxicity associated with this regimen, elaborated on findings from the retrospective study, and explained what implications these data may have on the use of trastuzumab emtansine plus radiation in patients with early-stage HER2-positive breast cancer. George is a medical oncologist at the Stacy Goldstein Breast Cancer Center, Rutgers Cancer Institute of New Jersey, and an assistant professor of medicine at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey.

OncLive^®: What was the rationale of investigating cardiotoxicity associated with adjuvant trastuzumab emtansine and concurrent radiation therapy?

George: Trastuzumab emtansine has been approved for the treatment of metastatic HER2-positive breast cancer, and [since] 2019­—based on the data from the [phase 3] KATHERINE study [NCT01772472], which showed a benefit in invasive disease-free survival [vs trastuzumab (Herceptin)] in patients who had residual disease after neoadjuvant systemic therapy—adjuvant trastuzumab emtansine has been used.

However, in the adjuvant setting after patients are done with surgery, they also need adjuvant breast radiation. There is a concern whether the concurrent use of trastuzumab emtansine with breast radiation would increase the risk of cardiotoxicity.

Trastuzumab emtansine, along with [other] HER2-targeted therapies, such as trastuzumab, increase the risk of cardiotoxicity that ranges from 2% to 4%. Radiation also increases the risk of ischemic heart disease, especially in women receiving left-sided breast radiation, given the proximity of the left breast to the heart.

Radiation oncologists, as well as medical oncologists, have a concern about cardiotoxicity. I've talked to providers who don't use trastuzumab concurrently with trastuzumab emtansine, given this concern of cardiotoxicity with concurrent use.

Based on this need, we did a retrospective study within [Rutgers Cancer Institute of New Jersey], looking at patients who were receiving trastuzumab emtansine and concurrent breast radiation to determine if there was a decline of cardiac function, specifically [in] left ventricular ejection fraction [LVEF].

What findings from this institutional review were shared at the 2022 San Antonio Breast Cancer Symposium?

We identified [32] patients who had concurrent trastuzumab emtansine with adjuvant breast radiation. These patients also were monitored by echocardiograms on at least a 3-month interval. That gave us the opportunity to look at the changes in cardiac function while they were getting the drug [concurrently with] adjuvant radiation.

All [patients] were women. Thirteen out of the 31 patients had left-sided breast cancer, so they received left-sided breast radiation. Nineteen had right-sided breast cancer.

Fifteen patients had a history of hypertension, which increases the risk for cardiac dysfunction. We looked at the LVEF before patients started treatment, as well as post-treatment, and there wasn’t a significant difference of LVEF in patients who received concurrent trastuzumab emtansine and radiation.

However, during the course of the study, there were 2 patients who had a greater than 10% decline in their LVEF. Both patients were older, in their late 60s. They had a history of hypertension, but with the discontinuation of the drug, both of them had a restoration of their LVEF. They did not have any symptoms of heart failure, and they were both followed by cardiologists.

What does this research indicate about the future use of adjuvant trastuzumab emtansine and radiation therapy in patients with early-stage HER2-positive breast cancer?

Our study is a small institutional study. We could do a larger study looking at this question [of cardiotoxicity associated with concurrent trastuzumab emtansine and breast radiation], especially looking at cardiac biomarkers to see if there is a change in cardiac biomarkers while patients are receiving radiation.

With the use of radiation, there is an increased risk of ischemic heart disease, especially in women receiving left-sided breast radiation. A longer follow-up of these patients is needed to determine if the concurrent use of trastuzumab emtansine and radiation does increase the risk of ischemic heart disease, especially in women receiving left-side of breast radiation.

What steps should physicians take when treating patients who are at a higher risk of cardiotoxicity with this regimen?

There are some concerns, especially among radiation oncologists, about giving radiation to patients receiving trastuzumab emtansine. Based on these data and other studies that have looked at this information, I believe it is safe at this time to use adjuvant radiation with trastuzumab emtansine.

However, a patient’s cardiac function should be closely monitored with echocardiograms. If patients have underlying risk factors, such as poorly controlled hypertension, hyperlipidemia, obesity, or a history of smoking, those patients should be more closely monitored, and if needed, they should be referred to a cardiologist if they have early signs of cardiac dysfunction.

Reference

George MA, Farooq F, Cason D, et al. Evaluating the risk of cardiotoxicity associated with concurrent trastuzumab emtansine (TDM1) and radiation therapy in patients with early-stage HER2 positive breast cancer. Presented at: San Antonio Breast Cancer Symposium 2022; December 6-10, 2022. San Antonio, TX. Abstract P5-07-08.