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Exemestane superior to tamoxifen for early-stage breast cancer
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CHICAGO — Premenopausal women with hormone-sensitive, early-stage breast cancer demonstrated a significantly reduced risk for recurrence when they received adjuvant exemestane compared with tamoxifen after ovarian function suppression, according to results of a joint analysis of two phase 3 studies presented at the ASCO Annual Meeting.
“When treating premenopausal women with HR–positive breast cancer, the optimal adjuvant endocrine therapy is still uncertain,” researcher Olivia Pagani, MD, clinical director of the Breast Unit at the Oncology Institute of Southern Switzerland in Bellinzona, said during a press conference. “For postmenopausal women, over the past 15 years clinical trials have shown adjuvant aromatase inhibitors for 5 years are more effective than 5 years of tamoxifen. This treatment was not available for premenopausal women, because aromatase inhibitors require low estrogen levels that occur after menopause. This can be achieved in young women with ovarian suppression.”
Pagani and colleagues evaluated data from 4,690 women enrolled on the TEXT and SOFT trials who had a median age of 43 years. Forty-two percent of women had tumors in their axillary lymph nodes, and 36% of women had tumors larger than 2 cm.
Women enrolled on the TEXT trial received 5 years of exemestane with ovarian function suppression (Aromasin, Pfizer) or tamoxifen with ovarian function suppression and optional chemotherapy within 12 weeks of surgery. Women on the SOFT trial received one of the same combinations or tamoxifen alone, within 12 weeks of surgery if they did not receive chemotherapy, or within 8 months of completing neoadjuvant chemotherapy.
Ovarian function suppression included 5 years of triptorelin (Trelstar, Watson Labs), oophorectomy or ovarian irradiation.
After a median of 5.7 years of follow-up, 514 DFS events occurred in the intent-to-treat population of both trials. The tamoxifen-only arm was excluded from this analysis.
Overall, 5-year DFS was significantly improved among patients who received ovarian suppression with exemestane compared with those who received tamoxifen (91.1% vs. 87.3%; HR=0.72; 95% CI, 0.60-0.86).
Exemestane was also associated with superior 5-year breast cancer-free interval (92.8% vs. 88.8%; HR=0.66; 95 CI, 0.55-0.80) and distant recurrence-free interval (HR=0.78; 95% CI, 0.62-0.97).
However, patients who received exemestane did not demonstrate superior 5-year OS (95.9% vs. 96.9%; HR=1.14; 95% CI, 0.86-1.51).
“Overall, more than 96% of women are alive at 5 years,” Pagani said. “There were currently no significant differences in survival between the two groups, but conclusions about survival are premature at this early point of follow-up.”
Grade 3 to grade 4 adverse events occurred in 31% of patients who received exemestane, compared with 29% who received tamoxifen. Only 14% of patients total discontinued treatment prematurely.
Almost 43% of women did not receive chemotherapy, including patients with high-risk features, Pagani said. More than 97% of these women who received exemestane were free of disease at 5 years.
“In our opinion, these results clearly indicate that some premenopausal women with HR–positive breast cancer may have excellent prognosis when treated with 5 years of highly effective adjuvant endocrine therapy without chemotherapy,” Pagani said.
For more information:
Pagani O. Abstract #LBA1. Presented at: ASCO Annual Meeting; May 30-June 3, 2014; Chicago.
Disclosure: The study was funded by Ipsen, Pfizer and the NCI. One researcher reports funding from Novartis and Pfizer.
Perspective
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Nancy E. Davidson, MD
I agree that exemestane and ovarian function suppression is a treatment option for premenopausal women with hormone-responsive early breast cancer. I think it is indeed premature to evaluate the impact, if any, on survival. It is true that the side-effect profile is similar to aromatase inhibitors in postmenopausal women, but we need to remember that these premenopausal women do suffer the inconvenience of monthly injection of LHRH agonists. Finally, I agree that some of these women do well with hormone therapy alone, and that long-term follow-up is needed.
These results show that ovarian function suppression plus aromatase inhibitors is an evidenced-based approach, and they provide support to use the combination in women who cannot take tamoxifen, or perhaps in those with very high risk, especially if they don’t take chemotherapy. But for now, I’m waiting for the results of the SOFT trial to finalize my approach.
In the meantime, I’m pondering how we’re going to integrate results that support 10 years of tamoxifen from the ATLAS and aTTom trials, vs. an extended adjuvant approach of 5 years of tamoxifen with a switch to 5 years of aromatase inhibitor for those who become postmenopausal during their tamoxifen from the MA.17 trial, vs. 5 years of aromatase inhibitor plus ovarian function suppression like we see in SOFT and TEXT. Now, if these benefits of ovarian function suppression with aromatase inhibitors hold up, then we may well want to revisit the role of oophorectomy in selected patients who want to avoid injections and have a permanent menopause.
We want to make sure we maximize bone health, although I’m not prepared to use bisphosphonates as a routine form of adjuvant therapy in these young women just yet. It is clear that long-term follow-up of TEXT and SOFT for benefit and toxicity will be vital, and I hope the investigators will be able to use these trials to evaluate the role of obesity and newer predictive markers to allow us to better tailor these therapies.
We should remember the power of endocrine therapy in properly selected patients of all ages. Not every premenopausal patient needs chemotherapy. This is another important piece of the puzzle for treatment options for premenopausal hormone responsive breast cancer, and I look forward to December when we can hope to see the last piece with the rest of the SOFT analysis.
Perspective
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Clifford A. Hudis, MD, FACP
We have known since 1896, when Dr. George Beatson reported the impact of surgical removal of the ovaries, that some breast cancers respond when they’re deprived of estrogen. That was the beginning of modern oncology, and in the way that was the beginning of targeted therapy, although they couldn’t measure the target of the estrogen receptor.
This is a long-awaited study that addresses the question that has its seeds a century ago, simply stated, do young women need to be made menopausal to get the best possible outcome for breast cancer? While this result will definitely support the use of ovarian suppression and aromatase inhibitors in those people who already believe that ovarian suppression is valuable, there will be discussion on the fact that the tamoxifen-alone control arm, the typical North American standard, is not yet reported. In that discussion, people who argue that we can’t get a changed standard are essentially saying that tamoxifen alone might be better than tamoxifen and ovarian suppression, and I will say that seems highly unlikely. If tamoxifen is not better than tamoxifen and ovarian suppression, then the marginal bump in DFS in this study could be convincing evidence for people focused on that endpoint.
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