Women with estrogen-sensitive breast cancer now receive anti-hormonal therapy. Researchers have discovered that postmenopausal women with low-risk tumors experience long-term benefits for at least 20 years, whereas younger women with similar tumor characteristics who have not yet gone through menopause benefit for a shorter period.
“Younger women generally have a higher risk of recurrence than older postmenopausal women, but most studies on anti-hormonal therapy have primarily included postmenopausal women. We therefore wanted to compare the long-term benefit of the treatment in both groups,” says Linda Lindstrom, associate professor and research group leader at the Department of Oncology-Pathology, Karolinska Institutet, who led the study.
In Sweden, 9,000 women are diagnosed with breast cancer each year, with hormone-sensitive breast cancer accounting for about 75 percent of these cases. In patients with hormone-sensitive breast cancer, tumor growth is mainly driven by estrogen, so they are treated with estrogen-suppressing drugs, often tamoxifen.
However, anti-hormonal treatment can reduce quality of life, and the question has been how long the benefits against recurrence last. About a third of women diagnosed with breast cancer are younger and premenopausal, and they are known to have an increased risk of recurrence.
The study includes more than 1,200 women diagnosed with hormone-dependent breast cancer between 1976 and 1997, of which nearly 400 were premenopausal. At the start of the study, it was unclear whether anti-hormonal treatment was beneficial, so women were randomized to either treatment with tamoxifen for at least two years or no anti-hormonal treatment (the control group). The outcome of interest was breast cancer metastasis or distant recurrence, and follow-up data is available for more than 20 years after the initial diagnosis.
“From the regional breast cancer registry, we have almost complete follow-up data on all patients, and this, along with a control group that did not receive anti-hormonal treatment, makes the study unique. There is also complete data on whether the women were pre- or postmenopausal at diagnosis, which is otherwise often estimated based on age,” says Annelie Johansson, researcher at the same department and the study’s first author.
The women’s tumors were classified as low or high risk based on clinically used markers. Low-risk tumor characteristics were defined as a tumor size of two centimeters or less, no lymph node spread, low tumor grade, progesterone receptor positivity, and a low genomic risk, which was determined by a molecular signature measuring the expression of 70 different genes.
Women with high-risk tumors showed less benefit against distant recurrence, regardless of whether they were pre- or postmenopausal. Women with low-risk tumors after menopause experienced a long-term benefit of 20 years or more. However, for younger women who had not gone through menopause at diagnosis, a long-term benefit could not be predicted using clinically used markers. Therefore, new markers are needed, the researchers say.
“We need to work further to understand which tumor characteristics influence the long-term risk of recurrence and benefit in younger patients. We want patients to benefit from their treatment for as long as their risk of recurrence remains elevated,” says Linda Lindstrom.
In the next step, the researchers aim to link more complex tumor characteristics to the long-term risk and benefit of anti-hormonal therapy, in order to individualize treatment for those who will benefit the most.
“For example, we plan to perform multi-protein analyses and use machine learning for image analysis of breast cancer tumors to understand more about tumor heterogeneity—that is, differences between and within tumors—and how it affects risk and treatment benefit,” says Linda Lindstrom.