How does endocrine therapy (aromatase inhibitor) effect women with endocrine responsIVE breast cancer? The POSITIVE study which was presented at this year's San Antonio Breast Cancer Symposium (SABCS) was a prospective clinical trial designed to evaluate the safety of and pregnancy outcomes with interrupting endocrine therapy for early stage hormone receptor positive breast cancer in order to attempt pregnancy.
Young women with early stage hormone receptor positive breast cancer were eligible for the trial if they desired pregnancy and had completed 18 to 36 months of adjuvant endocrine therapy. Following enrollment participants stopped their endocrine treatments for at least 3 months prior to attempting pregnancy to allow for a washout period of the medications, and the intent was that participants would be off of their endocrine treatment for no more than about 2 years to allow that washout period.
Attempting pregnancy, completing pregnancy if able as well as any nursing if desired or possible, and breast cancer patients were then encouraged to resume the endocrine therapy to complete their planned treatment course. The primary endpoint of the clinical trial was breast cancer free interval, and based on prior studies, it was felt that the annual risk of recurrence should not exceed about 4% in this population.
And if it did exceed that number, that would indicate a safety concern for interrupting pregnancy, interrupting endocrine therapy (aromatase inhibitor) during pregnancy. In addition to providing a comparison in the analysis, the participants in the POSITIVE study were matched with similar participants in the SOFT and TEXT trials. And those were studies looking at different endocrine treatments for premenopausal early stage breast cancer.
And the trial also looked at pregnancy related outcomes. So the results from the primary study endpoint showed that the rate of breast cancer free interval events at 3 years was 8.9%. That was actually very similar to the breast cancer free interval event rate that had been observed in the matched breast cancer patients in the SOFT and TEXT clinical trials, where the event rate was 9.2%.
So, at least in the short term, it appears that interrupting endocrine therapy to attempt pregnancy is indeed safe. The study also looked at pregnancy outcomes, about 74% of the participants had become pregnant at the time of the data analysis, and about 64% of trial participants had at least one live birth at the time of the analysis.
So far, there have been a total of 365 babies born to participants on this study and that those came from 317 individual women. And most of these participants did end up resuming their endocrine treatment after completing the planned pregnancies. So these findings really provide reassurance for young women with hormone receptor positive breast cancer who wish to become pregnant.
There's no suggestion of an increased (high) risk of recurrence at 3 years in spite of temporary interruption of their treatment. So hopefully these findings can help guide breast cancer patients and their providers to make the best decisions for themselves regarding interrupting treatment to attempt pregnancy. Of course, long-term follow up will be very important and there is a plan to continue to observe this population for 10 years.
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Frequently, premenopausal women with breast malignancies that express the estrogen and/or progesterone receptor (ER and/or PR-positive) are advised to take tamoxifen for five years. This medication inhibits the actions of estrogen on cancer cells and reduces the chance of breast cancer recurrence in women of any age by about 50 percent.
Tamoxifen can also lessen the risk of developing a new breast cancer in the breast that is not currently affected. In some instances, women younger than 35 to 40 years of age may also be considered for combination endocrine therapy with drugs that temporarily inhibit ovarian function.
Despite the absence of menstruation, it is likely that these women still have functioning ovaries and premenopausal hormone levels. Additionally, ovarian function may return unexpectedly. Thus, aromatase inhibitors should not be recommended to premenopausal women, regardless of whether they experience temporary menopause due to medication (unless they are participating in specific clinical research studies). Aromatase inhibitors are typically reserved for women with breast cancer who are postmenopausal.
Tamoxifen side effects are often modest and diminish over time. They consist of:
Reduced desire for sexual activities
insomnia or sleep disturbances
Some negative effects can be mitigated with symptom management and other lifestyle modifications.
Blood clots (deep venous thrombosis or pulmonary embolism) or uterine (endometrial) cancer are among the rare but severe side effects of tamoxifen, especially in women less than 50 years old.
So one of the questions that people have asked is whether there was a difference in outcomes among breast cancer patients who actually became pregnant versus those who did not become pregnant while on the study, and that was analyzed. For breast cancer patients who became pregnant within the first 18 months of follow up, there was no increase in the risk of recurrence, you know, related to pregnancy, hormones, et cetera.
And if anything those breast cancer patients who became pregnant actually appeared to do a little better than those who did not become pregnant. In terms of how these data will affect our practice today, I think it really informs our discussions with our breast cancer patients. A decision to attempt pregnancy following a cancer diagnosis can be very complex, particularly in the setting of hormone sensitive cancer and when long-term treatment is not compatible with pregnancy. So some breast cancer patients may wait until completing 5 to 10 years of hormonal treatment before attempting pregnancy, and they might experience more fertility concerns because they will be older at that time.
Other breast cancer patients might choose not to take hormonal treatment for their cancer at all because pregnancy might be so important to them. So I think this study really provides an approach that seems to provide a safe balance between appropriately treating the cancer and improving the prospects for pregnancy.
And again, I think in terms of next step for this research, it's really going to be important to have that long-term follow up. There are also a number of translational research projects that will look at ovarian reserve, ovarian function, as well as, circulating tumor DNA, which might help to inform future pregnancies.
I think oncologists should take away from this that, in the short term, a temporary interruption of endocrine (adjuvant therapy) treatment for pregnancy does not appear to increase the risk of breast cancer recurrence. However, recurrences do happen, so it is important to discuss with breast cancer patients their individual breast cancer risk factors of distant recurrence as they contemplate this very complex decision about pregnancy following a breast cancer diagnosis.
So I think the fact that this trial enrolled so well, underscores the importance for many young women of having children even after a breast cancer diagnosis. And I would remind clinicians not to wait until treatment completion to discuss these issues. Rather, concerns related to future fertility should really be discussed as early as possible following a breast cancer diagnosis in order to expand the options available to these patient.
Halle Moore, MD, is the Director of Breast Medical Oncology in the Cleveland Clinic Taussig Cancer Institute's Department of Hematology and Oncology. She is Co-Director of the Comprehensive Breast Cancer Program at the Cleveland Clinic. She is also board-certified in medical oncology and an associate professor of medicine at the Cleveland Clinic Lerner College of Medicine. She completed a residency in internal medicine at the University Hospitals of Cleveland and a fellowship in hematology and medical oncology at the Hospital of the University of Pennsylvania.
Dr. Moore is an expert in the medical therapy of breast cancer from a clinical standpoint. Her research focuses on breast cancer treatment and cancer survivorship issues. She was the principal investigator and author of the practice-altering New England Journal of Medicine article describing the POEMS research establishing a way for protecting ovarian function during breast cancer adjuvant chemotherapy treatment in young women. Dr. Moore is co-chair of the national Survivorship Committee for the SWOG Cancer Research Network and a member of the Survivorship Panel for the National Comprehensive Cancer Network Clinical Practice Guidelines.