Addressing De-Escalation of Treatment in HER2+ Breast Cancer

Priya Rastogi, MD

Data from the NSABP B-52, PERSEPHONE, and APT trials have called into question the optimal duration of treatment for patients with HER2-positive breast cancer.

In a presentation during the 2018 OncLive^® State of the Science Summit™ on Breast Cancer, Priya Rastogi, MD, senior associate medical director, NSABP Medical Affairs, associate professor of Medicine, University of Pittsburgh, addressed this question by discussing the data surrounding de-escalation of treatment for patients with HER2-positive breast cancer.

The NSABP B-52 trial investigated the regimen of docetaxel, trastuzumab (Herceptin), and pertuzumab (Perjeta) alone or in combination with endocrine therapy in patients with hormone receptor—positive, HER2-positive breast cancer. These patients then went on to have surgery, with a primary endpoint of pathologic complete response (pCR).

"With the blocked therapy with HER2-targeted therapy, you may see an escape mechanism through HER1 or EGFR. One of the rationales, when we were designing NSABP B-52, was that if you add estrogen deprivation, you may be able to completely block HER and the ER," explained Rastogi.

Findings presented at the 2016 San Antonio Breast Cancer Symposium showed a numeric improvement in pCR for breast and nodes, increasing from 40.9% to 46.1% with the addition of estrogen deprivation.¹ There was also an increase in pCR of the breast, with an increase from 44.2% to 47.4% with the addition of estrogen deprivation. These findings were numerically significant but not statistically, Rastogi said.

The conclusion from this study was that the addition of estrogen deprivation to neoadjuvant chemotherapy was not antagonistic and did not increase toxicity.

"Given the toxicity of standard chemotherapy observed on this trial, findings from NSABP B-52 argued for a tailored de-escalation approach, where toxic treatments are replaced with less toxic treatments without compromising outcomes," explained Rastogi.

At the 2018 ASCO Annual Meeting, findings from the PERSEPHONE trial were presented. In this study, investigators assessed the duration of trastuzumab in the treatment of patients with HER2-positive early breast cancer. Patients on this study were randomized to either 6 months of adjuvant trastuzumab or the standard 12-month course.

At a 5-year follow-up, the 4-year disease-free survival (DFS) rate was 89.4% with the 6-month course compared with 89.8% with the 12-month course, meeting the criteria for noninferiority (HR, 1.07; 90% CI, 0.93-1.24; P = .01).² The sample size was 4088 patients, and the investigators had estimated a DFS of about 80%, Rastogi said.

Data with quality of life, patient-reported outcomes, and health economic endpoints are still awaited, but a reduction in cardiac and other toxicities were observed with the 6-month course compared with the 12-month course, as well lower costs to both patients and healthcare systems.

Additionally, a predefined subgroup analysis showed that patients who were estrogen receptor—negative, had taxane-based chemotherapy, or had concurrent chemotherapy with trastuzumab derived more benefit with the 12-month course. Rastogi added that there was also only a small difference in overall survival (OS).

Another practice-changing study trial the APT study, Rastogi said. Retrospective data suggested that patients with small HER2-positive breast cancer have more than a minimal risk of disease recurrence. Rastogi added that the majority of the pivotal adjuvant trials, including NSABP B-52, excluded these patients. Therefore, APT was designed to address the treatment for this population.

Findings presented at the 2017 ASCO Annual Meeting showed that at a follow-up of 7 years, adjuvant trastuzumab/paclitaxel is associated with few recurrences and 4 distant recurrences in patients with node-negative, HER2-positive breast cancer.³ The 7-year DFS rate was 93.3%, and the 7-year relapse-free interval—including invasive locoregional disease, distant recurrences, and deaths due to breast cancer—was 97.5%.

Investigators concluded that adjuvant trastuzumab/paclitaxel should be the standard regimen for patients with stage I HER2-positive breast cancer who have received chemotherapy and trastuzumab.

"With longer-term follow-up, adjuvant paclitaxel and trastuzumab is associated with excellent outcomes, suggesting that it remains a standard regimen for the majority of patients with stage I HER2-positive breast cancer," said Rastogi. "Work is ongoing to further characterize intrinsic subtypes, and formal analyses will be conducted to see how the distribution compares with larger HER2-positive tumors from other data sets."

The ongoing ATEMPT trial (NCT01853748) is building on what was demonstrated in the APT trial, Rastogi added. This trial is comparing ado-trastuzumab emtansine (T-DM1; Kadcyla) with paclitaxel plus trastuzumab. This phase II trial is active, but recruitment has closed.

References

1. Rimawi MF, Cecchini RS, Rastogi P, et al. A phase III trial evaluating pCR in patients with HR+, HER2-positive breast cancer treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) +/- estrogen deprivation: NRG Oncology/NSABP B-52. In: Proceedings from the 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, Texas. Abstract S3-06. doi: 10.1158/1538-7445.SABCS16-S3-06.
2. Earl HM, Hiller L, Vallier A-L, et al. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. J Clin Oncol. 2017;36(suppl; abstr 506).
3. Tolaney SM, Barry WT, Guo H, et al. Seven-year (yr) followup of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC). J Clin Oncol. 2017;35(suppl 15):511. doi: 10.1200/JCO.2017.35.15_suppl.511.