pCR in HER2+ Breast Cancer Predicts Long-Term Survival

Susan London

October 21, 2020

A pathologic complete response (pCR) to targeted therapy in HER2-positive breast cancer portends good long-term outcomes, according to final results of the phase 3 NeoALTTO/BIG 1-06 trial. In fact, for the majority of women, pCR appears to be a marker of cure.

The trial was conducted among 455 women with HER2-positive breast cancer tumors measuring at least 2 cm who were randomized to neoadjuvant trastuzumab, lapatinib, or both drugs in combination, each together with paclitaxel, followed by more chemotherapy and more of the same targeted therapy after surgery.

Relative to trastuzumab alone, trastuzumab plus lapatinib improved rates of pCR, as shown by data published in The Lancet in 2012. However, the dual therapy did not significantly prolong event-free or overall survival, according to data published in The Lancet Oncology in 2014. Findings were similar in an update at a median follow-up of 6.7 years, published in the European Journal of Cancer in 2019.

Study investigator Paolo Nuciforo, MD, PhD, of the Vall d'Hebron Institute of Oncology in Barcelona, reported the trial's final results, now at a median follow-up of 9.7 years, at the 12th European Breast Cancer Conference.

There were no significant differences in 9-year outcomes by specific HER2-targeted therapy. However, in a landmark analysis among women who were event free and still on follow-up 30 weeks after randomization, those achieving pCR with any of the therapies were 52% less likely to experience events and 63% less likely to die. Benefit was greatest in the subset of patients with hormone receptor–negative disease.

"The long-term follow-up confirms that, independent of the treatment regimen that we use – in this case, the dual blockade was with lapatinib, but similar results can be expected with other dual blockade – the pCR is a very robust surrogate biomarker of long-term survival," Nuciforo commented in a press conference, noting that dual trastuzumab and pertuzumab has emerged as the standard of care.

"If we really pay attention to the curve, it's maybe interesting to see that, after year 6, we actually don't see any events in the pCR population. So this means that these patients are almost cured. We cannot say the word 'cure' in cancer, but it's very reassuring to see the long-term survival analysis support the use of pCR as an endpoint," he elaborated.

"Our results support the design of future trial concepts in HER2-positive early breast cancer which use pCR as an early efficacy readout of long-term benefit to escalate or deescalate therapy, particularly for hormone receptor–negative tumors," Nuciforo concluded.

Support for Current Practice

"The study lends support for the current practice of risk-stratifying by pCR as well as making treatment decisions regarding T-DM1 [trastuzumab emtansine], and there hasn't been a big change between 5-year and 9-year outcomes," Lisa A. Carey, MD, of the University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center, commented in an interview.

The lack of late events in the group with pCR technically meets the definition of cure, Carey said. "I think it speaks to the relatively early relapse risk in HER2-positive breast cancer and the impact of anti-HER2 therapy that carries forward. In general, these are findings similar to long-term findings of other trials and I suspect will be the same for any regimen."

Although the analysis of dual lapatinib-trastuzumab therapy was underpowered, the trends seen align with favorable results in the adjuvant APHINITY trial (which combined trastuzumab with pertuzumab) and the neoadjuvant CALGB 40601 trial (which combined trastuzumab with lapatinib), according to Carey. "There has been a trend in every other study [of dual therapy] performed, so this is consistent."

Study Details

NeoALTTO is noteworthy for having the longest follow-up among all neoadjuvant studies of dual HER2 blockade in early breast cancer, Nuciforo said.

He reported no significant difference in survival between the treatment arms at 9 years.

The 9-year rate of event-free survival was 69% with lapatinib-trastuzumab, 63% with lapatinib alone, and 65% with trastuzumab alone. The corresponding 9-year rates of overall survival were 80%, 77%, and 76%, respectively.

However, there were significant differences in event-free and overall survival among women who achieved pCR and those who did not.

"pCR was achieved for almost twice as many patients treated with dual HER2 blockade, compared with patients in the single-agent arms," Nuciforo pointed out. The pCR rate was 51.3% with lapatinib-trastuzumab, 24.7% with lapatinib alone, and 29.5% with trastuzumab alone.

Relative to peers who did not achieve pCR, women who did had better 9-year event-free survival (77% vs. 61%; adjusted hazard ratio, 0.48; P = .0008). The benefit was stronger in hormone receptor–negative disease (HR, 0.43; P = .002) than in hormone receptor–positive disease (HR, 0.60; P = .15).

The pattern was similar for overall survival at 9 years – 88% in those who achieved a pCR and 72% in those who did not (adjusted HR, 0.37; P = .0004). Again, greater benefit was seen in hormone receptor–negative disease (HR, 0.33; P = .002) than in hormone receptor–positive disease (HR, 0.44; P = .09).

"Biomarker-driven approaches may improve selection of those patients who are more likely to respond to anti-HER2 therapies," Nuciforo proposed.

From 6 years onward, there were no additional fatal adverse events or nonfatal serious adverse events recorded, and no additional primary cardiac endpoints were recorded.

The study was funded by Novartis. Nuciforo and Carey disclosed no conflicts of interest.

SOURCE: Nuciforo P et al. EBCC-12 Virtual Conference, Abstract 23.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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