Progress and Considerations in De-Escalating Therapy for HER2-Positive Breast Cancer

Progress and Considerations in De-Escalating Therapy for HER2-Positive Breast Cancer

As mortality rates for breast cancer have improved in high-income countries over the last several decades, there is increasing focus on patient quality of life and avoiding long-term morbidities.1,2 Several abstracts presented during the 2018 ASCO Annual Meeting discussed de-escalating breast cancer therapy, primarily for patients with early-stage, HER2-positive breast cancer in either the adjuvant or neoadjuvant setting.

“HER2-positive breast cancer used to be the subtype with the worst prognosis,3,4 and at least 50% of patients used to relapse before 2000.5 With the approval of anti-HER therapy such as trastuzumab, that number is now closer to 5%,”6 Jose I. Mayordomo, MD, PhD, of the University of Colorado School of Medicine, said. “Now that we are doing so much better at keeping patients from relapsing, we want to make treatment shorter and better tolerated.”

Commenting on Abstracts 506, 509, 510, and 511, which were about de-escalating therapy for HER2-positive breast cancer,7-10 Dr. Mayordomo (who was not involved in these studies) said, “all four are very important.” The findings suggest that patients may receive similar benefit from shorter trastuzumab treatment in the adjuvant setting, and that a chemotherapy-free regimen in the adjuvant and even neoadjuvant settings may be feasible for certain groups of patients.

Two additional abstracts suggested that a chemotherapy-free, targeted therapy regimen in the neoadjuvant setting may be efficacious for patients with triple-positive (HER2-positive, estrogen receptor–positive, progesterone receptor–positive) breast cancer and metastatic breast cancer with a BRCA mutation.11,12

Shortening Duration of Adjuvant Trastuzumab

The results of PERSEPHONE, a phase III randomized clinical trial, suggest that 6 months of trastuzumab combined with chemotherapy may be noninferior to a 12-month trastuzumab course with chemotherapy, which is the standard of care for early-stage, HER2-positive breast cancer in the adjuvant setting.7 Four-year disease-free survival (DFS) was 89.4% and 89.8% in the 6-month and 12-month treatment arms, respectively, meeting the noninferiority threshold.

Shorter trastuzumab duration would be desirable to reduce treatment cost and risk of cardiotoxicity, Dr. Mayordomo said. In PERSEPHONE, 8% of patients in the 12-month treatment arm and 4% in the 6-month treatment arm had to discontinue therapy because of cardiotoxicity. Although cardiotoxicity typically only occurs in 5% to 10% of patients, and it is typically low-grade and reversible, there is hope that shorter treatments could lower the cardiotoxicity risk further, Dr. Mayordomo said.

PERSEPHONE “has raised a lot of interest because this is the fourth trial exploring shorter duration trastuzumab,” Dr. Mayordomo said. The two previous trials that compared 6-month and 12-month treatment durations, PHARE and HORG, likely failed to demonstrate noninferiority because they had smaller patient populations and shorter follow-up than PERSEPHONE, which enrolled 4,089 patients and had a 4-year median follow-up, he added.

“The PERSEPHONE trial results should broaden the use of trastuzumab around the globe. Women who have to stop trastuzumab early should no longer be very anxious,” said Martine J. Piccart-Gebhart, MD, PhD, FASCO, of the Institut Jules Bordet in Belgium, who was the discussant for the abstract.7 Nevertheless, she cautioned that the 12-month duration appeared to be superior for subgroups of patients with estrogen receptor–negative disease and those who receive concurrent trastuzumab and chemotherapy, a nonanthracycline regimen, or neoadjuvant chemotherapy.

Dr. Piccart-Gebhart also said that “we are more interested today in de-escalating chemotherapy rather than anti-HER2 therapy.”

De-Escalating Adjuvant Chemotherapy in HER2-Positive Disease

In women age 70 to 80 with invasive HER2-positive breast cancer, adjuvant trastuzumab monotherapy may be noninferior to trastuzumab combined with a prespecified chemotherapy regimen (including paclitaxel, docetaxel, and docetaxel plus cyclophosphamide), according to the results of the phase III RESPECT trial.9 The restricted mean survival time (RMST) at 3 years differed by only 0.45 months between the two groups.

“Prior to this trial, we had zero data worldwide about adjuvant therapy with trastuzumab alone,” Dr. Mayordomo said. There were not enough events to evaluate the DFS difference between the two arms, a common problem with noninferiority trials because the standard of care treatment is so effective, he explained.

“The beauty of this trial is that it shows that trastuzumab alone is an option for patients who cannot tolerate chemotherapy,” Dr. Mayordomo said, adding that older patients generally do not tolerate chemotherapy well. In the RESPECT trial, there was a statistically significant decrease in common adverse events (anorexia, alopecia, and nonhematologic events) and increase in FACT-G score, a quality-of-life measure, in the trastuzumab monotherapy arm.

“An obvious consideration for a patient is, ‘Would you go through a minimum of 12 weeks of chemotherapy in order to gain 2 weeks of overall survival?’ This is a question for doctors and patients to discuss,” Dr. Mayordomo said.

Extending De-Escalation to the Neoadjuvant Setting

De-escalating therapy for HER2-positive, early-stage breast cancer in the neoadjuvant setting may be difficult because the standard-of-care therapy of docetaxel, carboplatin, and trastuzumab plus pertuzumab achieves pathologic complete response (pCR) in about 50% of patients,13 Dr. Mayordomo said. “Treatment is very successful, but it is also very toxic” because of docetaxel and carboplatin, he added.

A pair of abstracts addressed approaches to predict which patients would achieve pCR with anti-HER2 therapy alone. A retrospective analysis of PAMELA and TBCRC006 phase II trials found that the HER2-enriched subtype and high ERBB2 expression, determined at baseline, were both associated with higher likelihood of pCR with trastuzumab and lapatinib (and letrozole or tamoxifen) among patients with hormone receptor–positive disease.8

TBCRC026 was a phase II trial of 88 women with stage II/III HER2-positive, estrogen receptor–negative breast cancer receiving neoadjuvant trastuzumab and pertuzumab. Patients who had changes in standardized uptake values on PET imaging between baseline and 15 days into treatment were more likely to achieve pCR.10

The approaches in these two abstracts are complementary, Dr. Mayordomo said. Ideally, clinicians would predict the effectiveness of a chemotherapy-free regimen pretreatment, but evaluating metabolic response by PET scan early into treatment would also be reasonable, he explained.

“We used to treat all-comers with HER2 overexpression breast cancer equally, but the dogma is being challenged,” Dr. Mayordomo said. The next steps will be to compare anti-HER2 monotherapy with anti-HER2 therapy plus chemotherapy in the neoadjuvant setting in randomized trials, he said.

–Carina Storrs, PhD