Neil Vasan, MD, PhD

Neil Vasan, MD, PhD, assistant professor of medicine at Herbert Irving Comprehensive Cancer Center, Columbia University, discusses how past studies have supported de-escalated approaches and other improvements to treatment for patients with HER2-positive breast cancer.

Vasan says that previous approaches included multiple chemotherapies given along with HER2-targeted agents such as pertuzumab (Perjeta) as well as dual HER2 therapies.

Trials were then initiated to investigate a de-escalated approach focusing on patients with T1 tumors of 2 cm or less. The phase 2 APT trial (NCT00542451) enrolled patients with node-negative HER2-positive breast cancer who had tumors of 3 cm or less, the vast majority of whom had T1 tumors. Patients received adjuvant paclitaxel and trastuzumab (Herceptin). The trial resulted in 93% rate of 7-year disease-free survival (DFS) while offering less toxicity than more aggressive treatment.

Vasan adds that further improvements are being made to improve outcomes of early treatment, including the antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1; Kadcyla) being used to reduce the risk of recurrence when offered in the adjuvant setting in the KATHERINE trial (NCT01772472), and the use of therapies that can reduce residual disease for patients who previously received neoadjuvant chemotherapy before resection.

There used to be a one-size-fits-all type of treatment approach for these tumors, which used to be polychemotherapy—multiple chemotherapy agents—with anti-HER2 therapies. And certainly, with the development of pertuzumab in the metastatic setting, that made its way into the curable setting, as well. So anti-HER2 therapy was often what we call dual anti-HER2 therapy, 2 agents.

But de-escalation trials were run several years ago, especially looking at these patients with smaller tumors, T1 tumors, tumors that are 2 cm or less. This trial did include a couple, about 10% of patients with tumors larger than 2 cm, but most of the patients [had tumors] less than 2 cm and [were] lymph-node negative.

They found—this was a single-arm study; this is what is called the APT trial, which was published in [the 

], and this trial was a single-arm phase 2 trial—that patients who received just 1 chemotherapy agent, paclitaxel, and 1 anti-HER2 therapy, trastuzumab, had excellent DFS rates that persisted even at the 7-year follow-up. This is fantastic news for our patients because this means that we can give less therapy, less chemotherapy, less anti-HER2 therapy, and not surprisingly there are fewer [adverse events], and patients can still have excellent outcomes and excellent chances of cure.

Certainly in this HER2 space, we are now starting to see other drugs like T-DM1….This is an ADC that is approved in the metastatic setting that has [also] been tested in clinical trials in the adjuvant setting. We also have drugs that we can offer to patients who have residual disease after having received neoadjuvant therapy; [these patients received] chemotherapy initially to downstage the tumor and then [underwent] surgery.

Making sense of all these therapeutic options is something that oncologists have to do every day for our patients. But it’s very motivating because we are trying to tailor treatment as best as possible.

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Neil Vasan, MD, PhD, discusses how past studies have supported de-escalated approaches and other improvements to treatment for patients with HER2-positive breast cancer.

Background of De-Escalation Approach to HER2+ Breast Cancer Treatment

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 

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.

 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.

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 | Authors

Articles

Background of De-Escalation Approach to HER2+ Breast Cancer Treatment

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