Adjuvant T-DM1 With Concurrent Radiotherapy Is Not Associated with Cardiotoxic Concerns in Early-Stage HER2+ Breast Cancer

Adjuvantado-trastuzumab emtansine (T-DM1; Kadcyla) with concurrent radiotherapy did not lead to a significant drop in ejection fraction or global longitudinal strain(GLS) in patients with early-stage, HER2-positive breast cancer, according to a poster that was presented at the 2022 San Antonio Breast Cancer Symposium.

In an analysis of 32 patients, 2 (6%) experienced a drop in ejection fraction following radiation. The median preradiation ejection fraction was 60% and the median ejection fraction radiation was 61%. In addition, paired t-testing revealed that there was no statistically significant difference in ejection fraction after radiation (P = .343).

Among 16 patients who were evaluable for GLS measurements, there were no statistical differences with concurrent radiation (P = .18). According to the study authors, most patients tolerated radiation. Most experienced grade 2 skin dermatitis, although 1 patient developed grade 3 skin dermatitis. Unfortunately, 1 patient had to discontinue radiation early because of grade 3 skin dermatitis.

HER2-positive breast cancers represent 20% of breast cancer and are linked to aggressive clinical behavior and poor prognoses, according to the study authors. Although HER2 targeted therapies have dramatically shifted the treatment landscape—reducing the risk of recurrence by 50% and improving survival by 33%—these therapies are often associated with cardiotoxicity.

Following neoadjuvant HER2-targeted therapy, adjuvant T-DM1 is the current standard of care in this setting. However, this targeted treatment is linked to an increased risk of cardiotoxicity, specifically a decline in left ventricular ejection fraction (LVEF). According to a pooled analysis from 7 metastatic breast cancer trials assessing T-DM1, there was a 3.37% incidence of congestive heart failure (CHF), cardiac ischemia, cardiac arrhythmia, or grade 1/2 LVEF drop with this treatment.

Moreover, patients who are at a high risk of recurrence often receive adjuvant breast radiation. Breast radiotherapy is also associated with a long-term risk elevation for cardiac disease, for even 10 years post therapy. The HERA trial (NCT00045032), which assessed adjuvant trastuzumab (Herceptin), revealed that patients who received trastuzumab in conjunction with concurrent radiation therapy had higher rates of cardiotoxicity than those receiving trastuzumab alone (left sides > right sides), thought the rates were not found to be statistically significant. A multivariate analysis of the study did not highlight baseline cardiovascular risk factors as significant risk factors for this toxicity, but radiation therapy did demonstrate a borderline correlation (HR, 1.258; 95% CI, 1.00-1.58; P = .049).

As T-DM1 is increasingly being used in the adjuvant setting, and with a lack of sufficient evidence surrounding the cardiotoxicity of the agent in combined use with radiotherapy, investigators sought to understand the combination’s cardio-toxic effects in patients with early-stage breast cancer.

In this study, investigators conducted a review of clinical database to identify patients who had received adjuvant T-DM1 with recurrent radiotherapy for patients with stage I-III breast cancer between January 2020 and January 2022. Age, date of diagnosis, history of cardiac disorders, echocardiogram findings, radiation dose, final pathologic stage, and molecular subtypes of cancer, were all clinical parameters. All evaluated patients had ejection fraction. Moreover, GLS, which the authors described to be a more sensitive and reproducible indicator of cardiac dysfunction than LVEF, was also collected.

Ultimately, 38% (n = 12), 50% (n = 16), and 12% (n = 4) of patients developed grade 1, 2 or 2, radiation dermatitis, respectively.

Study authors acknowledged that the sample size was small for this study; however, they asserted that the data still strong clinical implications and should be assessed on a broader scale.

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.