TRAIN-2 Trial Leads to Changes in Treatment of HER2+ Breast Cancer


Neil Vasan, MD, PhD, discusses how the results of the TRAIN-2 trial impacted the treatment of patients with HER2-positive breast cancer.

Neil Vasan, MD, PhD, assistant professor of medicine at Herbert Irving Comprehensive Cancer Center, Columbia University, discusses how the results of the TRAIN-2 trial (NCT01996267) impacted the treatment of patients with HER2-positive breast cancer.

The phase 3 TRAIN-2 trial randomized 438 patients with stage II or III HER2-positive breast cancer 1:1 following neoadjuvant therapy to receive 3 cycles of fluorouracil, epirubicin, and cyclophosphamide followed by 6 cycles of paclitaxel and carboplatin, or 9 cycles of paclitaxel and carboplatin. Both groups received trastuzumab (Herceptin) and pertuzumab (Perjeta) every 3 weeks. The goal was to compare event-free survival (EFS), overall survival (OS), and safety for a regimen containing an anthracycline like epirubicin versus one that did not.

At 3 years of follow-up reported in 2021, 10.5% of the anthracycline group had EFS events versus 9.6% in the non-anthracycline group, with a hazard ratio of 0.90 favoring the non-anthracycline group (95% CI, 0.50-1.63). Three-year EFS and OS were similar between the groups: 92.7% and 97.7% in the anthracycline group versus 93.6% and 98.2% in the non-anthracycline group, respectively.

Based on the lack of benefit from anthracyclines and the risks of cardiotoxicity and other adverse events, regimens containing anthracyclines such as doxorubicin are no longer preferred in this setting. Now in favor are docetaxel, carboplatin, trastuzumab, and pertuzumab.


0:08 | Another trial that has been very important from a treatment point of view is the phase 3 TRAIN-2 trial. This trial looked at the question: Are anthracyclines necessary in the treatment of [patients with] HER2-positive breast cancer, and patients received either chemotherapy with anti-HER2 therapy with an anthracycline-containing regimen versus an anthracycline-free containing regimen.

The [EFS] rates were similar, and there were a couple caveats. For instance, the way the anthracyclines were given every 3 weeks—commonly, if it were given, we would give it every 2 weeks. But because no demonstrated benefit with the addition of an anthracycline, this has changed the way that oncologists treat HER2-positive breast cancers that might be a little bit larger, a tumor that’s larger or patients with lymph node involvement.

The predominant standard of care is a regimen called TCHP, which is 2 chemotherapy drugs, docetaxel and carboplatin, with trastuzumab and pertuzumab. Notably, it does not contain an anthracycline drug, doxorubicin. That trial has been so practice changing that even [in] the NCCN [National Comprehensive Cancer Network] guidelines recently, ACTHP [doxorubicin and cyclophosphamide followed by paclitaxel, trastuzumab, and pertuzumab] is not a preferred regimen.

So I think that goes to show how this has changed the therapeutic landscape for patients where we need to give a more standard, aggressive therapy—but not too aggressive so that we can spare them from the AEs from anthracyclines, which include cardiotoxicity.

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