Study finds no difference in disease-free, overall survival for HER2+ breast cancer patients receiving treatment concurrently or sequentially

Clinical trial findings important as treatment options, disease management evolves

New research in women with HER2+ breast cancer found no difference in disease-free survival (DFS) and overall survival (OS) when receiving anthracycline-based chemotherapy and trastuzumab concurrently or sequentially in the neoadjuvant setting. Findings from The University of Texas MD Anderson Cancer Center-led study published today in JAMA Oncology.

The Phase III study was conducted through the American College of Surgeons Oncology Group (ACOSOG), now the Alliance for Clinical Trials in Oncology.

The new research is follow-up to a Phase III MD Anderson-led study that found these patients also can achieve a high pathological complete response (pCR), or no evidence of disease at the time of surgery, when the same therapy regimen is given sequentially. Receiving the combination sequentially rather than concurrently eliminates the known cardiac toxicities associated when chemotherapy and HER2 therapy are given at the same time.

According to the American Cancer Society, more than 252,000 women are expected to be diagnosed with breast cancer in 2018; approximately 20 percent of those will have HER2+ disease. Once a breast cancer subtype with a dismal prognosis, MD Anderson has been at the forefront of practice-changing clinical research and survival outcomes for these women. In 1999, the institution conducted the first neoadjuvant clinical trial that demonstrated the disease could be eradicated in almost 60 percent of patients when combination chemotherapy and trastuzumab was given concurrently.

 “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,” says Kelly Hunt, M.D., professor and chair, Breast Surgical Oncology, and the study’s corresponding author. “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. Our study confirms that for HER2+ breast cancer patients, less is more.”

The randomized Phase III trial enrolled 280 women with operable HER2+ invasive breast cancer at 36 centers across the country from September 2007 through December 2011. Patients were assigned to neoadjuvant anthracycline-based chemotherapy and trastuzumab (commercially known as Herceptin) regimens, either given sequentially or concurrently. Therapy was followed by surgery.

The sequential arm (Arm 1) enrolled 138 patients who received: three-drug chemotherapy combination regimen known as FEC on day one of a 21-day cycle for four cycles, followed by paclitaxel plus trastuzumab weekly for 12 weeks.

The concurrent arm (Arm 2) enrolled 142 patients who received: paclitaxel plus trastuzumab weekly for 12 weeks, followed by FEC on day one of a 21-day cycle trastuzumab on days one, eight and 15 of the 21-day cycle for four cycles.

All patients enrolled received a total of one year trastuzumab therapy. Women with hormone-receptor positive tumors received endocrine therapy; patients underwent radiation at their physician’s discretion.  

The trial’s primary endpoint was the pCR rate in the breast. Secondary endpoints were the pCR rate in the lymph nodes, DFS and OS. The researchers previously reported no difference in pCR rates between the two arms. Similarly in this study, with the median follow-up time of five years, they found no difference in either DFS or OS rates with concurrent or sequential delivery. In Arm 1, 18 women recurred and two were diagnosed with secondary cancers; 22 recurrences and three secondary cancers were diagnosed in Arm 2. 

Given the myriad anti-HER2 treatment options now on the market, the impressive extended OS on trastuzumab – the original anti-HER2 therapy – should have important clinical and financial implications.

“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,” says Aman Buzdar, M.D., vice president, Clinical Research, and the lead author on the pCR study findings.

“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.”

Buzdar and Hunt also note that the majority of HER2+ breast cancer patients are still undergoing surgery first, despite more than half of patients achieving a pCR with neoadjuvant therapy.

“The best way to determine whose cancer is sensitive to therapy is to give it when the cancer is intact. We need to focus on offering additional treatments to patients who still have persistent disease at surgery, thereby avoiding unnecessary costs and toxicities,” says Hunt.

Based on responses to systemic therapies, the next research frontier is the de-escalation of loco-regional therapies, including extent of radiation, and determining those patients for whom surgery may not be necessary. Relevant studies are ongoing at MD Anderson. 

In addition to Hunt and Buzdar, Funda Meric Bernstam, M.D., professor and chair, Investigational Cancer Therapeutics, MD Anderson, also is an author on the study. Other authors include: Vera J. Suman, Ph.D., and Judy C. Boughey, M.D., both of Mayo Clinic; Ann Marilyn Leitch, M.D., University of Texas Southwestern Medical Center; Matthew J. Ellis, M.D., Ph.D., Baylor College of Medicine; Gary W. Unzeitig, M.D., Doctor’s Hospital of Laredo; and Melanie E. Royce, M.D., University of New Mexico.