AIs and Bisphosphonates Save Lives in Postmenopausal Breast Cancer

Liam Davenport

July 24, 2015

Two types of drugs that are now available as inexpensive generic products — aromatase inhibitors (AIs) and bisphosphonates — can reduce breast cancer mortality in postmenopausal women and could be used together to further improve outcomes, according to an international group of oncologists.

The Early Breast Cancer Trialists' Collaborative Group conducted a meta-analysis of clinical trial data for each class of drug.

The group concludes that for postmenopausal women in the decade after beginning treatment, 5 years of AI therapy reduces the risk of dying from breast cancer by around 40%, compared with no endocrine therapy (and reduces the risk for breast cancer mortality by about 15% compared with tamoxifen). In addition, 2 to 5 years of bisphosphonates, which are typically used to treat osteoporosis, reduces the risk of dying from breast cancer by 18%.

The two meta-analyses — one looking at AI therapy and the other looking at bisphosphonate therapy — were published online July 24 in the Lancet.

"These studies provide really good evidence that both of these inexpensive generic drugs can help reduce breast cancer mortality in postmenopausal women," said Richard Gray, MA, MSc, from the Clinical Trial Service Unit at the University of Oxford in the United Kingdom, who was lead statistician for both studies.

"About two-thirds of all women with breast cancer are postmenopausal with hormone-sensitive tumors, so could potentially benefit from both drugs," he said in a statement.

"The drugs are complementary," he added. "The main side effect of aromatase inhibitors is an increase in bone loss and fractures, while bisphosphonates reduce bone loss and fractures, as well as improve survival."

Meta-analysis of AI Clinical Data

The data on AIs come from a meta-analysis conducted by Mitch Dowsett, FMedSci, PhD, from the Institute of Cancer Research in Sutton, United Kingdom, and colleagues. They found nine randomized trials involving 31,920 postmenopausal women with estrogen-receptor-positive early breast cancer who had been treated with an AI or with tamoxifen.

Ten-year breast cancer mortality was lower with AIs than with tamoxifen (12.0% vs 14.2%; rate ratio [RR], 0.85; = .009).

The significant difference in breast cancer mortality held even if tamoxifen patients were later switched to AIs. The RR was 0.79 when the treatments differed and RR was 0.89 subsequently. Overall RR was 0.86 (P = .0005).

"Treatment with tamoxifen for 5 years reduces recurrence by about half during years 0 to 4 and one-third during years 5 to 9, and reduces the breast cancer mortality rate by about 30% throughout the first decade and beyond," the researchers write.

"Therefore, 5 years of an aromatase inhibitor compared with no endocrine therapy would reduce breast cancer recurrence by about two-thirds during treatment and by about one-third during years 5 to 9, and would reduce the breast cancer mortality rate by around 40% throughout the first decade, and perhaps beyond," they add.

The researchers also looked at early breast cancer recurrence.

The first-event RR for breast cancer recurrence after 5 years of AI therapy, compared with 5 years of tamoxifen therapy, was 0.64 during years 0 and 1 and 0.80 during years 2 to 4. There was no significant difference between the therapies after year 4.

Further analysis indicated that switching patients from tamoxifen to AIs eliminated the significant difference in the RR of recurrence between patients who originally started on AIs and those who started on tamoxifen; RR was 0.70 when the treatments differed and 0.93 subsequently (P = .08).

The recurrence RRs were largely unaffected when age, body mass index, tumor stage or grade, progesterone-receptor status, and HER2 status were taken into account.

Although the 10-year incidence of endometrial cancer was lower in the AI group than in the tamoxifen group (0.4% vs 2.1%; RR, 0.33), the 5-year risk for bone fracture was higher in the AI group (8.2% vs 5.5%; RR, 1.42). Non-breast cancer mortality was similar in the two groups.

Adverse-effect profiles and patient preferences are critical when choosing the initial therapy, write Harold J. Burstein, MD, PhD, and Erica L. Mayer, MD, MPH, from the Dana-Farber Cancer Institute in Boston, in an accompanying comment.

"Women on antiestrogen treatments endure substantial side effects, including menopausal symptoms such as hot flashes and night sweats," they point out.

Ultimately, the best choice for adjuvant endocrine therapy is a treatment the patient is willing to take.

"Aromatase inhibitors, in particular, are also associated with bone pain and arthralgias, vaginal dryness, sexual dysfunction, osteoporosis, bone fracture, and hair thinning," they add. "Ultimately, the best choice for adjuvant endocrine therapy is a treatment the patient is willing to take,"

For most patients, especially as we envision an era of longer durations of endocrine therapy, it will be more important to ensure that they are on a tolerable medication than to be unyielding over prescribing a specific bottle that sits untouched in the medicine cabinet," Drs Burstein and Mayer explain.

"These data are nice because they support an overall survival benefit [for AIs], and that has been a debate for about 15 years," said Rowan T. Chlebowski, MD, PhD, a medical oncologist at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, California, who is a member of the Early Breast Cancer Trialists' Collaborative Group.

"I enjoyed Burstein and Mayer's comment, but that's probably a little bit more cautious...than many other US physicians would be," he told Medscape Medical News.

"I think the big thing there is that, in all the studies, you got more early recurrences on tamoxifen in the first 2 years if you give them for 2 years or 5 years, and you're getting a recurrence that is an otherwise avoidable cause of premature death," Dr Chlebowski said. "I think most US oncologists would try to give the aromatase inhibitors first."

Meta-analysis of Bisphosphonate Data

The bisphosphonate meta-analysis was conducted by Robert Coleman, MBBS, MD, FRCP, from the Department of Oncology at the Cancer Clinical Trials Centre, University of Sheffield, United Kingdom, and colleagues. It involved 26 randomized trials of 18,766 women with early breast cancer comparing 2 to 5 years of bisphosphonate therapy with no bisphosphonate therapy

During a median follow-up of 5.6 woman-years, there were 3453 first breast cancer recurrences and 2106 subsequent deaths. Overall, the reductions in recurrence, distant recurrence, and breast cancer mortality with bisphosphonate therapy were of borderline significance, although the reduction in bone recurrence was significant (RR, 0.83; P = .004).

However, subsequent analysis revealed that although bisphosphonates had no benefit in premenopausal women, they had significant effects in the 11,767 postmenopausal women.

In the subgroup of postmenopausal women, bisphosphonates produced significant reductions in breast cancer recurrence (RR, 0.86; P = .002), distant recurrence (RR, 0.82; P = .0003), bone recurrence (RR, 0.72; P = .0002), and breast cancer mortality (RR, 0.82; P = .002).

The findings were unaffected by bisphosphonate class, treatment schedule, estrogen-receptor status, nodes, tumor grade, or concomitant chemotherapy.

Bisphosphonate therapy was also associated with a significant reduction in bone fractures (RR, 0.85; P = .02). However, the treatment was not associated with any differences in non-breast cancer mortality.

"The use of bisphosphonates in breast cancer is mainly to reduce bone loss and risk of fracture in postmenopausal women with estrogen-receptor-positive disease treated with aromatase inhibitors," the researchers note.

"Our results show that such bisphosphonate treatment can, in addition, provide oncological benefit, and suggest that adjuvant bisphosphonates should be considered in a broader range of postmenopausal women," they add.

The mode of action of the oncologic benefits seen with bisphosphonates is addressed in an accompanying comment by Adam Brufsky, MD, PhD, and Aju Mathew, MD, from the University of Pittsburgh Cancer Institute.

"Bisphosphonate action seems to be bone centric, in that bisphosphonates do not appear to prevent contralateral breast cancer, locoregional disease, or metastases to nonosseous sites," they write.

Because the benefits were seen only in postmenopausal women, they suggest that the increased bone turnover after menopause might explain the preferential benefit of bisphosphonates in reducing bone recurrence in postmenopausal women."

Bisphosphonates are given either as pills or as an injection. However, multiple pills need to be taken, "which people don't usually do well with," Dr. Chlebowski told Medscape Medical News.

In contrast, "the injection is once every 6 months. It's a short injection and you do it for 3 years, so you get 6 injections, and maybe a 30% reduction in risk for recurrence, which is a terminal disease. So it's really very attractive in that regard," he added. "I think this [study] will get more people who are sitting on the fence and waiting for something, to say, 'Well, why not adopt it?'"

"Of course, when the controversy was going, the drugs were expensive, so there was a lot of interest maybe 8 or 10 years ago. When the drugs go generic, a lot of academic interest falls off because there's no money," Dr Chlebowski explained. "The questions are just as important, but they're not money-supported questions."

Where do the current findings leave the future of drug research for early breast cancer?

"Even with these two drugs, there'll be enough breast cancer recurrences in postmenopausal women to still have a [drug therapy] target," he said.

"Compared with nothing, they should reduce the risk of recurrence by around 75% to 80% — that's a lot," Dr. Chlebowski explained. There may not be that much left in advanced disease to target with newer drugs.

Both studies were funded by Cancer Research UK and the UK Medical Research Council. Many of the researchers have financial relationships, as indicated in the publications.

Lancet. Published online July 24, 2015. AI abstract, AI comment, Bisphosphonate abstract, Bisphosphonate abstract


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