This article was updated on July 17, 2023.

Even 20 years after a diagnosis, women with a type of breast cancer fueled by estrogen still face a substantial risk of cancer returning or spreading, according to an analysis from an international team of investigators published in the New England Journal of Medicine in 2017.

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Standard treatment for estrogen receptor-positive, or ER-positive, breast cancer includes five years of the endocrine-based treatments tamoxifen or aromatase inhibitors, both of which are taken daily as a pill.

Researchers from the Early Breast Cancer Trialists' Collaborative Group analyzed data from 88 clinical trials involving 62,923 women with ER-positive breast cancer. The patients all received endocrine therapy for five years and were free of cancer when they stopped therapy.

Over the next 15 years, however, a steady number of these women saw their cancer spread throughout the body, as late as 20 years after the initial diagnosis.

"Even though these women remained free of recurrence in the first five years, the risk of having their cancer recur elsewhere (for example in the bone, liver or lung) from years five to 20 remained constant," said senior study author Daniel F. Hayes, M.D., Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Rogel Cancer Center.

The risk of recurrence was directly tied to the original cancer's size and characteristics, and to the number of lymph nodes that were cancerous.

Among patients who were recurrence-free when they stopped endocrine therapy after five years, the highest risk of recurrence was for those with originally large tumors and cancer that had spread to four or more lymph nodes. These women had a 40% risk of a distant cancer recurrence over the next 15 years. Women with small, low-grade cancers and no spread to the lymph nodes had a much lower 10% risk of cancer spreading distantly during the next 15 years.

"It is remarkable that breast cancer can remain dormant for so long and then spread many years later with this risk remaining the same year after year and still strongly related to the size of the original cancer and whether it had spread to the nodes," said Hongchao Pan, Ph.D., M.Sc., lead author from the University of Oxford.

Doctors have long known that five years of tamoxifen reduces recurrence by about half during treatment and by nearly a third over the next five years. Aromatase inhibitors, which work only in postmenopausal women, are even more effective than tamoxifen at reducing recurrence and death from breast cancer.

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Newer studies have suggested an additional five years of endocrine therapy is even more effective, sparking the question of whether every woman should continue on this therapy for 10 years.

Life-threatening side effects are rare with these therapies, but they can affect patients' quality of life. Side effects mimic menopausal symptoms, such as hot flashes or vaginal dryness. Aromatase inhibitors can cause osteoporosis, joint pain and carpal tunnel syndrome. Studies suggest that some patients choose to stop endocrine therapy because of these side effects.

"As we look at extending endocrine therapy for 10 years, we wanted to determine whether there were certain subgroups of women whose risk of recurrence was so low they might not need to continue endocrine therapy after five years," Hayes said.

The researchers subdivided patients to analyze those with the best prognosis — small tumors with less-aggressive properties and no positive lymph nodes. Even these women had appreciable recurrence rates between years five and 20, at about 1% per year, or 10% over 15 years.

But co-lead author Richard Gray, Ph.D., M.Phil., from the University of Oxford, offers a caveat.

"To assess 20-year risks, we had to study women who received their breast cancer diagnosis many years ago. We know that treatments have improved since then, so recurrence rates will be somewhat lower for women who were diagnosed more recently," he said.

The data suggest that women with ER-positive breast cancer should at least consider taking anti-estrogen therapy beyond five years, the authors say.

"These data can be used by patients and their health care providers as they consider whether to continue taking anti-estrogen therapy beyond five years, weighed against side effects and toxicity of the therapies," Hayes said.

Learn more about breast cancer and breast cancer treatment at the U-M Rogel Cancer Center

Since 2017, researchers have built upon these results to determine if one of the now many different available genomic-based assays (tests that analyze a tumor sample to determine how active certain cancer-related genes are) can tell clinicians and patients whether a patient should undergo chemotherapy or not. They can also assist in determining whether a patient who has reached five years without developing metastases might benefit from further therapy or could safely discontinue it, avoiding the side effects and toxicities of the anti-estrogen therapy.

Several large prospective clinical trials using genomic-based assays have demonstrated the ability to detect when chemotherapy can be safely withheld at the time of initial diagnosis for patients with ER-negative and ER-positive disease.

Although genomic-based assay tests for cancer recurrence have provided some promising results, they have limited use thus far.

Another approach to identifying patients who might safely stop extended endocrine therapy involves the use of “liquid biopsies.” A liquid biopsy is a blood test that provides information regarding the patient’s internal tumor status by measuring tumor-associated proteins, or cell free DNA, or even tumor cells themselves the blood. Researchers have reported that patients who have a positive liquid biopsy, even after five years of anti-estrogen therapy have a higher risk of subsequent detectable metastases. However, these data are not confirmed and furthermore the precise clinical strategy to follow in such a patient is unknown.

Therefore, the decision to continue endocrine therapy continues to rest mainly on the patient’s original tumor size, characteristics and lymph node status, as well as her tolerance and input into the decision.