Risk of Recurrence Reduced With Dual Anti-HER2 Therapy in Breast Cancer

Sandra M. Swain, MD

According to a pooled analysis of neoadjuvant trials presented at the San Antonio Breast Cancer Symposium, a pathologic complete response (pCR) to HER2-directed neoadjuvant therapy reduced the risk of recurrence in patients with early HER2-positive breast cancer but did not eliminate it, supporting the common practice of continued anti-HER2 therapy.¹

Overall, patients who achieved a pCR had a 67% lower risk of recurrence as compared with patients who did not have a pCR. The benefit held up irrespective of hormone receptor status, disease stage, or treatment modality. Still, recurrence rates after pCR ranged as high as 18.2% across the studies included in the analysis.

The analysis also showed that the benefits appeared greatest when the treatment included pertuzumab (Perjeta) and trastuzumab (Herceptin) in both the neoadjuvant and adjuvant settings, said Sandra M. Swain, MD, associate dean for Research Development and a professor of medicine at Georgetown University Medical Center in Washington.

Overall recurrence with combined anti-HER2 therapy in the neoadjuvant and adjuvant settings was 1.7% versus 18.2% for trastuzumab in the neoadjuvant and adjuvant settings and 9.2% for pertuzumab and trastuzumab in the neoadjuvant and trastuzumab in the adjuvant settings, respectively.

“This is a pooled analysis, so it can’t really compare anything, but it suggests that giving pertuzumab is a good thing,” Swain toldOncLive^®. “If a patient were node positive at the beginning, I would definitely continue pertuzumab. The conundrum involves patients who are clinically node negative and have a pCR, and we don’t have the right answer. What I would do right now is to continue the pertuzumab.”

The current standard of care for patients who achieve pCR after neoadjuvant HER2-targeted therapy and chemotherapy is to continue HER2-targeted therapy in the adjuvant setting.^2,3,4However, no consensus exists about the optimal approach.

“What do you do after a patient has a pCR?” Swain asked. “Do you continue with pertuzumab and trastuzumab, do you just use trastuzumab, or do you give nothing? There’s really no answer, because the question hasn’t been addressed in a randomized trial.”

She and her colleagues set out to determine the risk of recurrence and death in patients with HER2-positive early breast cancer who achieved a pCR with neoadjuvant therapy. They also evaluated the impact on outcomes in the neoadjuvant and adjuvant settings based on the type of therapy used.

The analysis included data from 5 trials of neoadjuvant therapy and a combined total of 1764 patients. In one of the trials, patients received single-agent trastuzumab as both neoadjuvant and adjuvant therapy; 2 trials used pertuzumab-trastuzumab neoadjuvant therapy followed by trastuzumab; and 2 combined the anti-HER2 agents in neoadjuvant and adjuvant settings. One of the studies had randomized arms of combination neoadjuvant therapy and trastuzumab monotherapy.

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

Overall, pCR was associated with an EFS hazard ratio of 0.33 versus no pCR (95% CI 0.25-0.43). The magnitude of risk reduction varied among the different anti-HER2 therapeutic strategies.

Patients who received combined anti-HER2 neoadjuvant therapy followed by adjuvant trastuzumab had a 43% reduction in the EFS hazard. Combined anti-HER2 therapy in both the neoadjuvant and adjuvant settings reduced the hazard by 75%. Combined anti-HER2 therapy in both settings reduced the hazard for an EFS event by 19% as compared with combined neoadjuvant therapy followed by single-agent trastuzumab as adjuvant therapy.

In absolute terms, patients who received single-agent trastuzumab as neoadjuvant and adjuvant therapy (irrespective of pCR status) had a recurrence rate of 30.9%, decreasing to 18.0% for patients who received combination neoadjuvant therapy followed by single-agent trastuzumab. Patients who received the combination in both the neoadjuvant and adjuvant settings had a recurrence rate of 5.6%.

An analysis with inverse probability of treatment weighting produced similar results. Regardless of pCR status, combined anti-HER2 therapy in the neoadjuvant and adjuvant settings was associated with lower rates of recurrence than either of the other 2 strategies. Combination therapy followed by trastuzumab monotherapy was associated with lower recurrence rates than single-agent trastuzumab as both neoadjuvant and adjuvant therapy.

Distant recurrence was the most common type of EFS event, irrespective of pCR status. All categories of EFS events were reduced the most by combined anti-HER2 therapy in the neoadjuvant and neoadjuvant settings, followed by combined neoadjuvant therapy with trastuzumab alone in the adjuvant setting. Single-agent trastuzumab before and after surgery was associated with the highest recurrence rate for each type of EFS event.

References:

1. Swain SM, Macharrla 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 pooled analysis. Presented at: San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Poster 1151.
2. Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2019;30(8):1194-1220. doi: 10.1093/annonc/mdz173.
3. Ditsch N, Untch M, Thill M, et al. AGO recommendations for the diagnosis and treatment of patients with early breast cancer: update 2019. Breast Care. 2019;14:224-245. doi: 10.1159/000501000.
4. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer, Version 3.2019. nccn.org/professionals/physician_gls/pdf/breast.pdf. Updated September 6, 2019. Accessed December 12, 2019.