Alex E. Denes, MD
In 1995, the National Institutes of Health released a clinical alert encouraging oncologists to discontinue therapy with tamoxifen after 5 years in patients with estrogen receptor (ER)-positive early breast cancer, a decision that is still not understood to this day, explained Alex E. Denes, MD.
Since then, clinical trials have examined the optimal duration of extended adjuvant endocrine therapy. Another approach involves replacing tamoxifen with an aromatase inhibitor, although Denes added that there could be associated long-term toxicities.
Today, the decision to extend adjuvant endocrine therapy with tamoxifen or an aromatase inhibitor is an individualized one, according to Denes. That decision is made harder, with mixed findings of clinical trials across breast cancer populations.
“You’re treating 20 to 30 patients with a drug for 10 years to help one patient,” said Denes. “We have to figure out how to better identify that one patient and let the other patients live happy lives.”
In an interview at the 2018 OncLive®
State of the Science Summit™ on Breast Cancer, Denes, associate professor of medicine, School of Medicine, Oregon Health and Science University, discussed the mixed results looking at the optimal duration of adjuvant endocrine therapy in postmenopausal women with breast cancer.
OncLive: What does the adjuvant landscape of ER-positive breast cancer for postmenopausal women look like?
: The concept of adjuvant therapy is not a very new concept. Dr Bernard Fisher at the University of Pittsburgh hypothesized that breast cancer is a systemic disease, as opposed to a localized cancer, in a majority of women. He proposed that if we could eliminate the micrometastases these patients harbored, we could improve the cure rate.
Around the same time, Dr Anna M. Bonadonna at the National Cancer Institute (NCI) of Italy had the same thought. Around that time, they started their first adjuvant chemotherapy trials. These trials were positive and have stood the test of time with 20-year and 30-year follow-up. Patients who received a course of adjuvant chemotherapy following mastectomy had a better survival, even 20 to 25 years after their diagnosis. Of course, we came to the understanding that most women with breast cancer are ER positive. This came after the identification of the ER. The majority of patients with breast cancer are postmenopausal. In the United States, the median age for breast cancer is 62, and 80% of these women are ER positive.
The development of drugs, such as tamoxifen, led to the availability of effective hormone therapy for patients with advanced breast cancer and also early breast cancer. We have to credit Dr Bernard Fisher and the National Surgical Adjuvant Breast and Bowel Project (NSABP) for the initial study of 5 years of tamoxifen compared with placebo, known as the NSABP-B14 trial. That study clearly showed a benefit of 5 years of tamoxifen.
At that time, we didn’t really know the ER status of many women, although most of them were postmenopausal. There were also premenopausal women as well, as well as women with negative and positive nodes. Tamoxifen improved survival in those women. Tamoxifen was initially tried for 1, 2, and 5 years. Five years of tamoxifen was shown to be more effective than 1 or 2 years of tamoxifen and therefore became the standard.
Then the new class of drugs, the aromatase inhibitors, were approved for the treatment of advanced breast cancer in the 1990s. Subsequently, there were large randomized trials that looked at each of the 3 aromatase inhibitors versus tamoxifen. All of these trials showed that there was a small but definite increase in disease-free survival (DFS) and a decrease in the recurrence rate with aromatase inhibitors.
About that same time, the observation was made that about half of recurrences occur after completing 5 years of therapy in women with ER-positive breast cancer. Really, about two-thirds to three-fourths of deaths from breast cancer in ER-positive women occur after 5 years.
Several hypotheses were generated, but it was felt that one possible way to reduce the death rate from breast cancer was by extending adjuvant therapy beyond 5 years. It was thought that women who had done well on tamoxifen for 5 years without signs of cancer should continue the therapy for another 5 years.
There were several approaches to this. The 2 most discussed trials are the aTTom and ATLAS trials. The aTTom trial was out of the United Kingdom, and the ATLAS trial was an international study. Women had to have been 5 years out from diagnosis and completed 5 years of tamoxifen.
These women were randomized to continue tamoxifen for 5 years or stop therapy at that point. Both of the trials were hailed as positive because they improved DFS. In the high-risk patients in the ATLAS trial, there was also an improvement in survival.