TRAIN-2 Trial Changes Breast Cancer Treatment for HER2+ Patients

The effects of the TRAIN-2 trial's findings on patients with HER2-positive breast cancer are discussed by Neil Vasan, MD, Ph.D., assistant professor of medicine at Columbia University's Herbert Irving Comprehensive Cancer Center.

438 patients with stage II or stage III HER2-positive breast cancer were randomly assigned to phase 3 TRAIN-2 trial to receive 3 cycles of fluorouracil, epirubicin, and cyclophosphamide, followed by 6 cycles of paclitaxel and carboplatin, or 9 cycles of paclitaxel and carboplatin, after neoadjuvant therapy. Every three weeks, both groups got trastuzumab (Herceptin) and pertuzumab (Perjeta). The aim was to compare an anthracycline regimen, such as epirubicin, to one without one in terms of event-free survival (EFS), overall survival (OS), and safety.

After three years of follow-up, it was reported in 2021 that 10.5% of the anthracycline group and 9.6% of the non-anthracycline group had experienced EFS episodes, with a hazard ratio of 0.90 in favor of the non-anthracycline group (95 percent CI, 0.50-1.63). The three-year EFS and OS rates were comparable between the groups, at 92.7 and 97.7 percent in the anthracycline group and 93.6 and 98.2 per cent, respectively, in the non-anthracycline group.

Routines comprising anthracyclines, like doxorubicin, are no longer chosen in this situation due to their lack of benefits and dangers of cardiotoxicity and other adverse events. Docetaxel, carboplatin, trastuzumab, and pertuzumab are now in popularity.

The phase 3 TRAIN-2 trial is another study that has proven to be crucial in terms of treatment. In this experiment, patients were randomly assigned to receive chemotherapy with anti-HER2 therapy in either an anthracycline-containing regimen or an anthracycline-free regimen in order to determine if anthracyclines are required in the treatment of [patients with] HER2-positive breast cancer.

There were a few restrictions and the [EFS] rates were comparable. For instance, if we were to provide anthracyclines as they were, we would typically do so every two weeks rather than every three. However, because there was no evidence of a benefit from adding an anthracycline, oncologists are now treating HER2-positive breast tumors that may be slightly more advanced, have a larger tumor, or involve lymph nodes differently.

Docetaxel and carboplatin, together with trastuzumab and pertuzumab, are two chemotherapy medicines that make up the TCHP regimen, which is currently the gold standard of care. Notably, it is devoid of the anthracycline medication doxorubicin. Because of how drastically the trial altered clinical practice, ACTHP [doxorubicin and cyclophosphamide followed by paclitaxel, trastuzumab, and pertuzumab] is no longer recommended in the most recent NCCN [National Comprehensive Cancer Network] guidelines.

I believe it demonstrates how this has altered the therapeutic landscape for patients where we must provide a more active, conventional therapy—but not too aggressive so that we may spare them from the adverse effects (AEs) of anthracyclines, which include cardiotoxicity.