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SABCS 2016: Phase III Trial Shows Limited Benefit From Extended Letrozole Therapy

Postmenopausal women with hormone receptor-positive breast cancer may need to weigh risks and benefits before extending letrozole therapy beyond five years. By Srivani Ravoori, PhD

Data from the NSABP B-42 (NRG Oncology) trial presented Dec. 7 at the San Antonio Breast Cancer Symposium showed that five additional years of the aromatase inhibitor (AI) therapy letrozole (Femara) following an initial five years of AI-based adjuvant hormone therapy did not significantly improve survival outcomes in postmenopausal women with early-stage HR-positive breast cancer. The additional five years did improve some outcomes related to recurrence.


​Terry Mamounas | © MedMeetingImages/Todd Buchanan 2016
Data from this trial and from another small study presented Dec. 9 also indicate increased cardiovascular side effects of AI therapy. These results indicate that postmenopausal women with HR-positive breast cancer and their clinicians should use caution in making treatment decisions.

How Long for Hormone Therapy
An important topic of discussion in HR-positive breast cancer treatment is the length of hormonal therapy that will yield maximum survival benefit to the patients.

Prior studies have shown that about half of the recurrences and about two-thirds of the deaths among patients with HR-positive early-stage breast cancer occur after the first five years from diagnosis, explains study lead author and medical oncologist Terry Mamounas of UF Health Cancer Center at Orlando Health. Mamounas is also on the NRG Oncology Breast Cancer Committee.

Postmenopausal women with HR-positive breast cancer are currently treated with five years of hormone therapy. Many large clinical trials have studied whether extending adjuvant hormonal therapy for longer than five years can lower the rates of breast cancer recurrence and death. Data from these studies have shown that:
 
• taking adjuvant tamoxifen for 10 years results in fewer recurrences than taking it for five years, and
• adjuvant AI for five years after five years of adjuvant tamoxifen results in fewer recurrences than just five years of adjuvant tamoxifen.

The NSABP B-42 trial was designed to address whether giving five years of the AI letrozole, compared with placebo, to patients who have completed five years of endocrine therapy that included an AI would improve disease-free survival (DFS), which is the time after treatment during which the patient has no signs of cancer.

The investigators randomly assigned 3,966 patients to 2.5 mg letrozole or placebo daily for five years. After a median follow-up of 6.9 years, extended letrozole therapy resulted in a 15 percent reduction in the risk of a DFS event. However, the risk reduction was not statistically significant—which means the findings could be attributed to chance. A DFS event included a recurrence of the original breast cancer, cancer in the opposite breast, a non-breast malignancy, or death from any cause prior to the occurrence of one of the other DFS events.

Extended letrozole therapy did not improve overall survival. However, patients on extended letrozole were less likely to have a recurrence in their breasts, with a 29 percent reduction in the risk of breast cancer recurrence or cancer in the opposite breast as a first event. Additionally, researchers observed a 28 percent statistically significant reduction in the cumulative risk of recurrence at a distant site in the body.

Cardiovascular Side Effects Are a Concern
While there was no significant increase in the overall risk of developing blood clots in the arteries in this trial, Mamounas notes that the risk became elevated for letrozole-treated patients after 2.5 years.

“Postmenopausal patients with early-stage breast cancer who approach completion of five years of therapy with an aromatase inhibitor should carefully weigh and discuss with their physician some of the above-mentioned factors before making a decision to continue or to stop therapy,” he says.

“Such an assessment needs to include patient and tumor characteristics [e.g., age and nodal status at diagnosis], existing co-morbidities, information on bone mineral density, as well as how well the patient tolerated the first five years of endocrine therapy,” Mamounas adds.

This seems to be the conclusion drawn by the investigators of another study presented Dec. 9, in which postmenopausal women with breast cancer who took aromatase inhibitors were found to have endothelial dysfunction, which impairs the ability of blood vessels to relax and contract. It is an early predictor of cardiovascular disease.

The study examined several components of endothelial function in 25 healthy postmenopausal women and 36 postmenopausal women taking AI therapy to treat breast cancer.

Researchers found that women taking an AI had significantly higher mean systolic blood pressure and lowered elasticity of the large and small arteries.
 
Lead author of the study and oncologist Anne H. Blaes of the University of Minnesota in Minneapolis says, “It is important for women with breast cancer to look at the pros and cons of each medication being prescribed, as well as their risk of breast cancer recurrence.

“For example, a woman whose cancer type or stage predicts a high rate of recurrence may opt to stay on the AI for 10 years, but a woman with early-stage cancer who has other risk factors for cardiovascular disease may want to limit her time on the AI,” she notes.

Patient Advocate: Some Positive Results Offer Hope
Tracy Leduc, a breast cancer survivor who advocates for “better breast cancer research and for better treatment for patients,” says that from a patient’s perspective, the findings that extended letrozole improved breast cancer-free interval and lowered the risk for distant recurrence are positive and significant.

“As a patient, I didn’t find this study as having totally negative results,” she says.

Given that the side effects from endocrine therapies are fairly well known, she, like the researchers who presented their data, also feels that patients and their clinicians need to consider the benefits and comorbidities and decide on the amount of time the patient needs to be on AI.

Leduc, who is attending SABCS for the sixth time, says, “The first time I attended … I had no idea what to expect, but I learned so much and I realized that by attending I was learning things that my oncologist didn’t yet know about.”
 

Srivani Ravoori, PhD, is associate director of science communications at the American Association for Cancer Research in Philadelphia.

12/09/2016
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