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Extended Adjuvant Therapy Beneficial for Some Women with Breast Cancer

June 22, 2016, by NCI Staff

Credit: National Cancer Institute

Results from a recent clinical trial showed that extending adjuvant therapy with an aromatase inhibitor to 10 years after initial treatment can have important benefits for postmenopausal women with early-stage hormone receptor (HR)–positive breast cancer. The longer treatment improved 5-year disease-free survival and decreased the women’s risk of developing cancer in the opposite breast, called contralateral breast cancer.

The findings were published in the New England Journal of Medicine on June 5 and presented at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

The trial is the first to show that extending adjuvant therapy with an aromatase inhibitor beyond 5 years in this patient group can improve outcomes, explained the trial’s lead investigator, Paul Goss, M.D., Ph.D., of Massachusetts General Hospital in Boston. There is no evidence yet that the longer duration of therapy improves overall survival, but in a press briefing at the ASCO meeting Dr. Goss called the reduced risk of contralateral breast cancer a “major benefit.”

Tailoring treatment to individual patients will be important, stressed Jo Anne Zujewski, M.D., of NCI’s Division of Cancer Treatment and Diagnosis. In particular, Dr. Zujewski said, clinicians need to talk with their patients about the risks of side effects with aromatase inhibitors, namely bone-related effects such as fractures, and appropriately manage them in women taking these drugs.

Building on Earlier Trial Findings

Tamoxifen (Nolvadex®), which blocks the activity of the hormone estrogen, has been the drug of choice for preventing breast cancer recurrence since the 1980s and is still used by many clinicians, often in combination, or sequentially, with aromatase inhibitors. 

Aromatase inhibitors block aromatase, an enzyme that the body uses to make estrogen. These drugs are used primarily in postmenopausal women, whose ovaries have stopped making estrogen. Postmenopausal women whose breast tumors rely on hormones to fuel their growth have been found to benefit the most from aromatase inhibitor therapy.

In a previous clinical trial, Dr. Goss and his colleagues showed that in women with HR-positive  breast cancer who had already undergone 5 years of tamoxifen treatment, an additional 5 years of treatment with the aromatase inhibitor letrozole (Femara®) improved survival outcomes. The trial, called MA.17, also showed that extended letrozole therapy reduced the risk of developing contralateral breast cancer.

However, even with successful initial treatment, women with HR-positive early-stage breast cancer continue to have a risk of their disease returning. Some women can have recurrences even two decades after their initial treatment, Dr. Goss said.

10 Years versus 5 Years of Adjuvant Therapy

So in this new trial, named MA.17R, the researchers wanted to see whether extending letrozole therapy for an additional 5 years—for a total of 10 years of adjuvant treatment—could further reduce recurrence risk. The trial enrolled nearly 2,000 women who had already received 4.5 to 6 years of adjuvant aromatase inhibitor therapy, many of whom were in the MA.17 trial. Within 2 years after completing treatment with an aromatase inhibitor, the women were randomly assigned to receive letrozole or a placebo daily for another 5 years.

After a median follow up of 6.3 years, the women who received letrozole had higher rates of 5-year disease-free survival (95% versus 91%) and lower annual incidence rates of contralateral breast cancer (0.21% versus 0.49%) than the women who received placebo. The 5-year overall survival rate was essentially the same in the two groups: 93% for those who took letrozole, and 94% for those who took placebo.

Quality-of-life measures were also similar for both groups of women. However, women who took letrozole had more bone pain, bone fractures, and newly diagnosed osteoporosis than women who took placebo. Although women in the trial generally fared well in terms of side effects, Dr. Goss stressed that the women in the trial were a highly selected group—those who had already been able to take aromatase inhibitors for 5 years without any major problems.

This is a group of women “who can tolerate the drug, whose quality of life is unchanged and … who [have] no particular toxicities” to aromatase inhibitor therapy, noted Dr. Goss.

For women who are at high risk of recurrence, said Dr. Zujewski, these findings indicate a greater chance that extended aromatase inhibitor therapy may reduce chances of a recurrence. Conversely, if a patient is at low risk of recurrence, lengthening treatment will likely be of little benefit. “You cannot cure a patient twice,” she said.

Dr. Zujewski said that she considers bone density measures when trying to decide whether to recommend tamoxifen, which protects women’s bones after menopause, or an aromatase inhibitor, which can harm bone.

“For patients who use aromatase inhibitors for an extended period of time, I recommend a bisphosphonate for bone protection—and studies of bisphosphonates suggest that this may help decrease the risk of metastatic disease as well.

“Monitoring bone health and using bone protecting agents when appropriate in these patients is really important,” said Dr. Zujewski. “In this trial, only about half of the women who had fractures used bisphosphonates. As clinicians, we need to do a better job of protecting the bones of women we consider for extended adjuvant therapy.”

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