In the treatment of HER2-positive early breast cancer, patients who receive dual HER2-targeted therapy in both the neoadjuvant and adjuvant settings are less likely to experience recurrence than those who received dual therapy only as neoadjuvant treatment, according to a pooled analysis of neoadjuvant trials led by Sandra M. Swain, MD, FASCO, Associate Dean for Research Development and Professor of Medicine at Georgetown University Medical Center, Washington, DC. These findings were presented at the 2019 San Antonio Breast Cancer Symposium.¹

Sandra M. Swain, MD, FASCO

Furthermore, achievement of pathologic complete response after HER2-directed neoadjuvant therapy reduced the risk of recurrence; however, under some circumstances, up to 18% of such patients still experienced recurrence. This finding supports the notion that many women still need anti-HER2 therapy in the adjuvant setting. In fact, the question is more about who does not need it, said Dr. Swain. Although this pooled analysis is not a comparative study, the findings do suggest, she said, “that giving pertuzumab is a good thing.”

Continued HER2-targeted therapy is the standard of care for patients who achieve a pathologic complete response, but there is no consensus as to the optimal approach. The question of whether patients achieving a pathologic complete response still require dual HER-2 targeted adjuvant therapy has not been addressed in a randomized trial. The current study is a large pooled analysis of five trials that examined the risk of recurrence among pathologic complete responders under a variety of treatment scenarios.

Study Details

The analysis included data on 1,764 patients from the following five trials on neoadjuvant therapy: HannaH, NeoSphere, TRYPHAENA, BERENCE, and KRISTINE. One trial treated patients with single-agent trastuzumab as both neoadjuvant and adjuvant therapies; two trials used pertuzumab plus trastuzumab as neoadjuvant therapy, followed by trastuzumab; and two trials combined the anti-HER2 agents in both neoadjuvant and adjuvant settings. One of the studies had randomized arms of combination neoadjuvant therapy and trastuzumab monotherapy. Follow-up ranged from 22 months (for dual therapy followed by dual therapy) to 72 months for trastuzumab followed by trastuzumab.

"Although this pooled analysis is not a comparative study, the findings do suggest that giving pertuzumab is a good thing.”

— Sandra M. Swain, MD, FASCO

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The primary objective of the analysis was event-free survival (the time from randomization to disease recurrence or progression or death from any cause). Investigators defined pathologic complete response as the absence of residual invasive cancer in the resected breast specimen and in the axillary lymph nodes after neoadjuvant therapy (ypT0/Tis ypN0).

Key Findings

The pooled analysis showed that event-free survival was highest in patients who received trastuzumab plus pertuzumab as neoadjuvant therapy, followed by both drugs in the adjuvant setting. This approach reduced the risk of recurrence by 61%, compared with trastuzumab followed by trastuzumab.

This effect remained after adjustments for imbalances in baseline risk factors; however, “the caveat is that, in this group, there were more patients with lower-stage (stage II) disease who therefore had a better prognosis, and the group also had shorter follow-up,” Dr. Swain cautioned. The analysis did, however, use a weighted Cox model to make the comparisons “fairer and more equal,” she added.

Effect of Pathologic Complete Response

Not surprisingly, achievement of a pathologic complete response was associated with improved outcomes, but there were still recurrences despite pathologic complete response. Overall, patients who achieved a pathologic complete response had a 67% lower risk of recurrence as compared with patients who did not—a benefit that held up irrespective of hormone receptor status, disease stage, or treatment modality.

Nevertheless, recurrence risk was not insignificant, reaching 18.2% among patients treated with trastuzumab followed by trastuzumab but dropping to 9.2% after trastuzumab/pertuzumab followed by trastuzumab and to 1.7% when patients received both drugs in both the neoadjuvant and adjuvant settings. In other words, the magnitude of risk reduction varied among the different anti-HER2 therapeutic strategies and was strongest when the treatment included two targeted therapies before and after surgery, Dr. Swain said.

Distant recurrence was the most common event-free survival event, irrespective of response status. Single-agent trastuzumab before and after surgery was associated with the highest recurrence rate for each type of event-free survival event.

Remaining Questions

“If you compare trastuzumab monotherapy followed after surgery to trastuzumab monotherapy vs dual anti-HER2 targeted therapy, those patients who received the dual therapy had better outcomes,” Dr. Swain noted. In fact, in the recent report of the end-of-study analysis of the CLEOPATRA trial,² dual blockade of pertuzumab and trastuzumab, plus docetaxel, yielded an “8-year landmark overall survival rate of 37%.” However, Dr. Swain added, “if you compare outcomes in patients who received dual anti-HER2 targeted therapy in the neoadjuvant setting then in the adjuvant setting with those who had trastuzumab monotherapy in the adjuvant setting, the benefit was less and not statistically significant. So, we still have the question of whether you need to give pertuzumab with trastuzumab after neoadjuvant therapy with trastuzumab and pertuzumab.”

Based on results also presented in San Antonio for the APHINITY trial,³ in some situations, dual HER2-targeted therapy is needed in both settings, according to Dr. Swain. The second analysis of overall survival showed fewer deaths in the pertuzumab-containing arm, although the 0.9% difference was not statistically significant, and the clinical benefit of pertuzumab was mainly seen in patients with node-positive disease. This subgroup derived almost a 5% benefit from pertuzumab treatment.

“Based on APHINITY, if the patient definitely has node-positive disease, I would give pertuzumab after neoadjuvant therapy, even if she had a pathologic complete response,” Dr. Swain said, adding that even some patients with clinically node-negative disease may warrant it. “Studies have shown that about one-third of patients with clinically node-negative disease actually had positive nodes,” she pointed out. “Personally, I would give pertuzumab because that one-third of patients are at higher risk and you don’t know for sure who those patients are. The big conundrum is what to do with these patients.”

Additional Commentary

John T. Cole, MD

Breast cancer specialist John T. Cole, MD, Director of Clinical Cancer Research at Ochsner Health System, New Orleans, commented on the pooled analysis presented by Dr. Swain. “I would say that since ado-trastuzumab emtansine (TDM-1) is now standard in patients not achieving a pathologic complete response, that likely makes dual therapy irrelevant after neoadjuvant dual anti-HER2 therapy in that setting. Also, if the patient achieves a pathologic complete response with neoadjuvant dual anti-HER2 therapy, then the value of dual therapy is likely to be small,” Dr. Cole said. “Perhaps different HER2 subgroups need different approaches, but we don’t have that information at this time.”

DISCLOSURE: Dr. Swain has served as a consultant for Cardinal Health, Daiichi Sankyo, Lilly, Roche, Genomic Health, Inivata, and Pieris Pharmaceuticals; has contracted research from Roche; has a professional services agreement from BIG/AstraZeneca for data and safety monitoring committee; has received travel expenses from Bristol-Myers Squibb, Caris Life Sciences, Daiichi Sankyo, Lilly, and Roche; and has received third-party writing assistance from Roche. Dr. Cole reported no conflicts of interest.

REFERENCES

1. Swain SM, Macharia H, Cortes J, et al: Risk of recurrence and death in patients with early HER2-positive breast cancer who achieve a pathological complete response after different types of HER2-targeted therapy: A retrospective exploratory analysis. 2019 San Antonio Breast Cancer Symposium. Abstract P1-18-01. Presented December 11, 2019.

2. Swain SM, Miles D, Kim SB, et al: Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): End-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol 21:519-530, 2020.

3. Piccart M, Procter M, Fumagalli D, et al: Interim overall survival analysis of APHINITY (BIG 4-11): A randomized multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab vs chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer. 2019 San Antonio Breast Cancer Symposium. Abstract GS1-04. Presented December 11, 2019.