Neoadjuvant Therapy Selection: Are Abbreviated Regimens an Option in HER2+ Breast Cancer?

Adrienne G. Waks, MD

Staying within the standard of care (SOC), abbreviated neoadjuvant regimens are not yet ready for primetime in HER2-positive breast cancer, according to Adrienne G. Waks, MD, who added that data from the ongoing phase 2 CompassHER2-pCR trial (NCT04266249) will help to elucidate the future role of abbreviated regimens in this patient population.

Waks noted that future data from CompassHER2-pCR will answer the questions of whether de-escalation following pathologic complete response (pCR) to docetaxel, trastuzumab (Herceptin), and pertuzumab (Perjeta) is appropriate, but results are not yet published.¹

“For patients who are very chemotherapy averse, have many comorbidities, or are older, and [for whom] you are particularly worried about chemotherapy toxicities, it’s reasonable to abbreviate the neoadjuvant chemotherapy backbone outside of a clinical trial,” Waks said in an interview with OncLive^®. “But aside from those patient population [caveats], I don’t believe it’s something to do outside of a clinical trial yet.”

In the interview, Waks, also detailed how anthracycline- and taxane-based regimens factor into neoadjuvant regimen selection in HER2-positive breast cancer. Waks is associate director of Breast Oncology Clinical Research and a senior physician at Dana-Farber Cancer Institute, and an assistant professor of medicine at Harvard Medical School, in Boston, Massachusetts.

OncLive: Can abbreviated neoadjuvant regimens currently be used for the treatment of patients with HER2-positive breast cancer?

Waks: Right now, within the true SOC the answer is no—we can’t yet use an abbreviated neoadjuvant regimen with complete confidence that it’s equivalent to a full neoadjuvant regimen in terms of long-term outcomes. [This is] assuming that after the neoadjuvant regimen if a patient has a pCR to an abbreviated neoadjuvant regimen, you would [therefore] not [administer] additional therapy in the adjuvant setting. We’re not there yet in terms of widespread uptake by the entire early-stage HER2-positive breast cancer population.

The data we have from many smaller trials that have looked at how patients do long term when they get an abbreviated neoadjuvant regimen and then don’t get additional therapy in the adjuvant setting post-pCR all look good. [It appears that] those patients all do well in the long-term [follow-up], even with the abbreviation of the neoadjuvant therapy. But those cohorts are small and they’re not enough to implement a widespread practice change yet.

What key findings from the CompassHER2-pCR and PHERGain trials could help determine the utility of an abbreviated neoadjuvant regimen?

CompassHER2-pCR is the main trial that will answer this question, and it has completed accrual, which is wonderful news. Hopefully, in the coming few years we will have those data and they will provide an answer to the question, but there are no current findings from that trial so it can’t guide our practice at this point.

[Findings from] the phase 2 PHERGain trial [NCT03161353], which examined neoadjuvant trastuzumab and pertuzumab and then adjuvant trastuzumab and pertuzumab only if patients had a pCR, tell us that we should move forward with designs of larger trials that incorporate [markers] like PET scans to select patients who are going to have a good response to neoadjuvant therapy. Other markers to incorporate [include] ctDNA or breast MRI imaging. PHERGain shows us that if we design larger trials where we incorporate early markers of favorable or unfavorable responses in the neoadjuvant setting, and then patients have a pCR, we [may] find that it’s perfectly safe and that there are very low recurrence rates long-term with the omission of chemotherapy.

But [there were] 86 patients in PHERGain [for whom] that was done. We should be looking at that in larger trials going forward, but I don’t believe it’s a current standard outside of a unique situation of a patient who couldn’t tolerate chemotherapy.

How do anthracycline- and taxane-based regimens compare with one another as neoadjuvant options?

Cardiotoxicity can be greater when a regimen contains both an anthracycline and [one of] the HER2-targeted agents that all patients are receiving. There’s an important toxicity difference there and a very slight difference [with] the rates of secondary leukemias, which are slightly more common with the anthracycline-based regimens. Many data sets show that those toxicity differences are important.

In terms of efficacy—long-term and how much the different types of regimens protect against recurrence in HER2-positive breast cancer—the data that we have are reassuring that they are equivalent. But we completely lack data that were powered to look at long-term outcomes between an anthracycline and non-anthracycline chemotherapy backbone. The data that we have are reassuring but weren’t primarily designed to compare long-term outcomes [with] the 2 regimens. Given the toxicity differences, which are well established, and the reassuring but not definitive data that we have about long-term outcomes, omitting the anthracycline in the neoadjuvant and adjuvant setting is the standard and the right thing to do for most patients at this point.

Is there any ongoing research that you’re participating in that you’d like to highlight?

There’s a lot of exciting research in both early-stage and metastatic HER2-positive breast cancer. One trial to highlight that’s still in development is going to be opening [soon] through the Alliance [for Clinical Trials in Oncology] in collaboration with SWOG. We’re [examining that question] of if a patient has early-stage breast cancer and a pCR, can we do less than our current SOC in terms of toxic therapy and maintain long-term outcomes?

This phase 2 trial, STOP-HER2 [NCT05721248], is [for] patients who had modest- to moderate-risk clinical stage HER2-positive early-stage disease at baseline, stage 1 or 2, received a neoadjuvant regimen, and then had a pCR. Patients will be randomly assigned to either finish a full 1 year of HER2-directed therapy—which is the current standard as we give a full 1 year of HER2-directed therapy to everybody regardless of pCR, tumor characteristics, etc— or complete 6 months of anti-HER2 therapy in the adjuvant setting post-pCR. [This is the experimental arm] because we know very well from previous meta-analyses [and] the phase 3 SHORT-HER [trial (NCT00629278)] data, that the difference in disease-free survival for 12 vs 6 months [of anti-HER2 therapy] is incredibly minor and negligible, especially if you select a favorable risk population, which is what pCR selection would do.

I’m excited about that trial coming through the cooperative groups that will help us understand if we can get away from our current across-the-board standard of 12 months of anti-HER2 therapy [if] the patient experienced a pCR to neoadjuvant HER2-directed therapy.

Reference

1. CompassHER2-pCR: decreasing chemotherapy for breast cancer patients after pre-surgery chemo and targeted therapy. ClinicalTrials.gov. Updated April 18, 2024. Accessed July 22, 2024. https://clinicaltrials.gov/study/NCT04266249