MAC15 RxPONDER trial presented at the San Antonio Breast Cancer Symposium

Not all women with ER positive and HER 2 negative, node positive breast cancer require chemotherapy

Postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer that has spread to a limited number of lymph nodes, and whose recurrence risk is relatively low, do not benefit from chemotherapy when it is added to hormone therapy, according to initial results from the MAC15 RxPONDER trial presented at the 2020 San Antonio Breast Cancer Symposium. These findings may save tens of thousands of postmenopausal women each year the time, money, and harmful side effects that come with chemotherapy infusions.

This is the first evidence in a randomized phase III trial that postmenopausal women with HR-positive, HER2-negative breast cancer that has spread to one to three lymph nodes can safely forgo chemotherapy if their recurrence score on a genomic tumor tissue test is 25 or less. The trial also demonstrated, after a median of five years of follow-up, that premenopausal women with the same disease characteristics benefited from chemotherapy. 

“The five-year data from the MAC15 RxPONDER study indicate that post-menopausal women with one to three node-positive estrogen receptor positive, HER2 negative disease and a Recurrence Score result of 25 or less can be spared chemotherapy,” said Dr. Stephen Chia, the CCTG Co-Chair of the Breast Disease Site, Head of the University of British Columbia Division of Medical Oncology and Oncologist, UBC Cancer. “For the 25% of Canadian women with hormone receptor positive, HER2 negative breast cancer who have one to three lymph nodes involved and a Recurrence Score result, these practice-changing data provide a new level of confidence to physicians and their patients as they make these critical treatment decisions.”

RxPONDER follows the ground-breaking TAILORx study, which showed that postmenopausal women with lymph node-negative, HR-positive, HER2-negative breast cancer and recurrence scores of 25 or less on a genomic tumor tissue test saw no benefit from the addition of chemotherapy to hormone therapy compared with hormone therapy alone. These results, however, left open the question of the most effective way to treat women diagnosed with more advanced breast cancer that has spread to the lymph nodes.

“The decision to recommend adjuvant chemotherapy to women with breast cancer is a balance between the survival benefits and potential life altering side effects of treatment. The MAC15 RxPONDER trial is an important step forward, demonstrating that not all women with ER positive and HER 2 negative, node positive breast cancer require chemotherapy,” says Dr. Bindi Dhesy-Thind, the other CCTG study lead and Oncologist at Hamilton Health Sciences. “The practice changing results of this landmark trial will pave the way for further de-escalation of treatment in this favourable prognosis group.”

The RxPONDER team screened 9,383 women with HR-positive, HER2-negative breast cancer and one to three positive lymph nodes to identify those with recurrence scores of 25 or less. A total of 5,083 such patients were randomly assigned to receive hormone therapy alone or hormone therapy plus several months of intravenous chemotherapy with taxane and/or anthracyclines, chemotherapy drugs that are considered standard treatment for this type of cancer.

RxPONDER was an international effort, conducted at 632 sites in nine countries — the United States, Canada, Mexico, Colombia, Ireland, France, Spain, Korea, and Saudi Arabia. 

“The Canadian Cancer Trials Group under the leadership of Dr. Chia and Dr. Dhesy-Thind, participated in the RxPONDER trial and randomized 328 women to the study or 6.5% of the overall accrual. Women were recruited from across Canada and their generosity of participation has contributed to this exciting study results,” says CCTG Senior Investigator Dr. Lois Shepherd. “In Canada we had 24 sites participate testing 734 women - 328 of those were randomized.”

All women were monitored for a median of five years to assess the trial’s primary endpoint, invasive disease-free survival, or IDFS, a measure that counts which patients develop cancer that spreads outside of the breast, develop a new tumor inside a breast, or die from any cause. Overall survival was a secondary endpoint. As an independent data and safety monitoring committee began reviewing the trial results, they noticed a surprising pattern — one that was clear enough for the committee to recommend that findings be reported publicly before the final results were complete. When NCI received the committee’s recommendation, they agreed.

The researchers were surprised to find that in the study population overall, there was no association between recurrence score and chemotherapy benefit. In other words, patients with a higher recurrence score did not have a greater benefit from chemotherapy than those with a lower score. However, there was an association with menopausal status. Postmenopausal women saw no benefit from chemotherapy, regardless of recurrence score. Among postmenopausal women, the five-year IDFS rate was 91.6% for the chemotherapy plus hormone therapy group and 91.9% for the hormone therapy-only group.
                                 
By contrast, among premenopausal women, the study found a statistically significant benefit from chemotherapy in IDFS: The five-year IDFS rate in premenopausal women was 94.2% for the chemotherapy and hormone therapy group, compared with 89.0% for the hormone therapy-only group. This benefit was seen regardless of recurrence score. Premenopausal women also appeared to experience an overall survival benefit in these early results. At five years, the overall survival rate was 98.6% for those receiving chemotherapy plus hormone therapy and 97.3% for women in the hormone therapy-only group. 

“This study represents an important step toward the goal of matching patients with the most appropriate therapies and ensuring that patients do not receive treatments that are unlikely to benefit them,” said Larissa Korde, M.D., M.P.H., head of Breast Cancer and Melanoma Therapeutics in NCI’s Cancer Therapy Evaluation Program. “These findings and additional results from this clinical trial can be expected to help improve the care of many women with a common form of breast cancer.” 

RxPONDER will follow patients for 15 years, so additional data and insights are to come. One unknown is why premenopausal women in the study benefited from chemotherapy while postmenopausal women did not. One possible explanation is that chemotherapy can induce menopause, starving the cancer of the hormones it needs to grow. Additional research is needed to explore whether treatment with medications that induce menopause given in combination with standard hormone therapy would have the same effect on risk of recurrence as that seen with chemotherapy in this study.