Regimen Could Reduce Cardiotoxicity in HER2+ Breast Cancer

Kelly K. Hunt, MD

Women with operable HER2-positive breast cancer had similar long-term survival outcomes with either concurrent or sequential chemotherapy in the neoadjuvant setting, according to newly published results from the phase III ACOSOG Z1041 trial. Combined with previous findings linking the sequential regimen to lower cardiotoxicity, these results suggest this strategy could improve patients’ quality of life.

At a median of 5.1 years of follow-up (range, 26 days to 6.2 years), investigators observed no differences between treatment groups in rates of disease-free survival (DFS; stratified HR, 1.02; 95% CI, 0.56-1.83; stratified log-rank P = .96) or overall survival (OS; stratified HR, 1.17; 95% CI, 0.48-2.88; stratified log-rank P = .73).¹

In the sequential arm, the pathologic complete response (pCR) rate in the breast and nodes was 52.9% (95% CI, 44.2-61.5) compared with 50% (95% CI, 41.5%-58.5%) in the concurrent arm. Patients in the sequential arm experienced 2 second primary cancers and 18 recurrences compared with 3 and 22, respectively, in the concurrent arm.

Results from ACOSOG Z1041 published in 2013 showed that ventricular ejection fraction (EF) fell below the institutional lower limit of normal in 1 (0.8%) patient in the sequential arm by week 12 compared with 4 (2.9%) in the concurrent arm. Nine (7.1%) patients in the sequential arm and 6 (4.6%) in the concurrent arm had abnormally low EF at week 24. As assessed by the cardiac review panel, 11 patients in the sequential arm had asymptomatic decreases of left ventricular EF compared with 15 in the concurrent arm.²

Furthermore, the earlier findings showed that administering fluorouracil, epirubicin, cyclophosphamide (FEC) followed by the combination of paclitaxel plus trastuzumab (Herceptin) sequentially produced a similar rate of pCR in the breast compared with concurrent treatment (56.5% vs 54.2%).

“Our findings from both studies allow for all women with this class of breast cancer to be spared of cardiotoxicities associated with anthracycline and trastuzumab given at the same time,” corresponding author Kelly Hunt, MD, professor and chair of Breast Surgical Oncology at The University of Texas MD Anderson Cancer Center, said in a statement.

“The research also offers physicians definitive clinical guidance. Many have opted to treat with a more aggressive approach because the patient’s disease was a higher stage, or because of the woman’s young age,” Hunt added. “Our study confirms that for HER2-positive breast cancer patients, less is more.”

A total of 282 women with invasive HER2-positive breast cancer enrolled in ACOSOG Z1041 (NCT00513292) from September 2007 to December 2011. The median age was 50 years (range, 28-76) and most patients (82.9%) were white.

Seventy-six (27.1%) patients had clinical T stage 1 to stage 2, N stage 0 disease, and 112 (40.0%) had ER-negative/PR-negative disease.

Patients in the sequential arm (n = 138) received FEC on day 1 of a 21-day cycle for 4 cycles, followed by 80 mg/m2 of paclitaxel plus trastuzumab weekly for 12 weeks. Trastuzumab was administered at a 4 mg/kg initial dose followed by subsequent doses of 2 mg/kg.

Patients in the concurrent arm (n = 142) received the same regimen of paclitaxel/trastuzumab followed by FEC every 3 weeks administered along with weekly trastuzumab for 12 weeks.

All patients received 1 year of trastuzumab therapy, and women with hormone receptor—positive disease also received endocrine therapy. Physicians had the discretion to administer radiotherapy.

Rate of pCR in the breast was the primary endpoint. Secondary endpoints included DFS, OS, and pCR rate in the breast and lymph nodes.

“Nationally, the trend is to give patients more than one type of anti-HER2 treatment upfront before their surgery. There are now multiple options approved to treat women with HER2+ disease, but with significant toxicity and financial costs,” lead author Aman Buzdar, MD, vice president, Division of Clinical Research at MD Anderson, said in a statement.

“Our findings reinforce that approach is unnecessary. Rather, we should save those therapies for patients that don’t achieve complete pathologic remission at surgery and are at high risk of recurrence. Our research needs to focus on a better understanding of the biology of the disease for these patients,” added Buzdar.

References

1. Buzdar AU, Suman VJ, Meric-Bernstam F, et al. Disease-free and overall survival among patients with operable HER2-positive breast cancer treated with sequential vs concurrent chemotherapy: the ACOSOG Z1041 (Alliance) randomized clinical trial [published online September 6, 2018]. JAMA Oncol. doi:10.1001/jamaoncol.2018.3691.
2. Buzdar AU, Suman VJ, Meric-Bernstam F, et al. Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol. 2013; 14(13): 1317—1325. doi: 10.1016/S1470-2045(13)70502-3.