CHICAGO—A combined analysis of two studies with a total of 4,620 premenopausal women with hormone-receptor positive early-stage breast cancer showed that adjuvant treatment with exemestane plus suppression of ovarian function significantly reduced the risk of disease recurrence compared with use of tamoxifen plus suppression. Unfortunately, though, the analysis did not answer a more basic question of whether ovarian function suppression adds any benefit to use of tamoxifen alone.
This is a critical question because the most common treatment for this patient population is tamoxifen alone.
The report, presented here at the American Society of Clinical Oncology Annual Meeting (Abstract LBA1), was a joint analysis of the Phase III TEXT and SOFT trials, led by the International Breast Cancer Study Group in collaboration with the Breast International Group and the North American Breast Cancer Group, a worldwide collaboration in 27 countries and six continents. The research was supported in part by Pfizer, Ipsen, the International Breast Cancer Study Group, and the U.S. National Cancer Institute.
Exemestane plus ovarian function suppression was found to reduce the relative risk of women developing a subsequent invasive cancer by 28 percent, and specifically reduced the relative risk of breast cancer recurrence by 34 percent, compared with tamoxifen plus ovarian function suppression.
“For years, tamoxifen has been the standard hormone therapy for preventing breast cancer recurrences in young women with hormone-sensitive disease,” said lead study author Olivia Pagani, MD, Clinical Director of the Breast Unit in the Oncology Institute of Southern Switzerland. “These results confirm that exemestane with ovarian function suppression constitutes a valid alternative.”
Study Will Nevertheless Have an Impact
ASCO 2013–2014 President Clifford A. Hudis, MD, commented that whether the ovaries should be removed or shut down after surgery in the adjuvant setting remains one of the unresolved questions in breast cancer. “And that question is still not answered because these researchers are not reporting on the tamoxifen-alone arm,” he said. “All this study says is that aromatase inhibition works in young women because it shows a progression-free survival advantage for the aromatase-inhibitor arm, which mirrors what is seen in postmenopausal women.”
Hudis said that while the report does not directly say that women should undergo ovarian ablation, many doctors will still argue that the exemestane aromatase-inhibition arm is better than tamoxifen because they do not believe that tamoxifen and ovarian ablation is worse than tamoxifen alone. He predicted that the report will push some doctors to think about taking that aggressive step that so many have been biased toward for years, that young women at high risk should have ovarian ablation and aromatase inhibition.
“Many docs have thought they knew the answer for years, but the data has been mixed,” he said. “And this will be controversial because it does not show an overall survival difference at all.”
And of course there is also the toxicity of menopause and aromatase inhibition in young women to consider, he added. “But I think that come Monday, more patients with high-risk disease will be getting ovarian ablation and aromatase inhibition.”
The SOFT trial did compare tamoxifen alone with tamoxifen plus ovarian-function suppression, but Pagani said the results will not be available until late this year.
The joint analysis of the TEXT and SOFT trials studied the outcomes of 4,690 women, whose average age was 43, who were randomized to receive exemestane plus ovarian-function suppression or tamoxifen plus ovarian-function suppression for five years. Ovarian-function suppression was achieved through treatment with triptorelin, surgical oophorectomy, or ovarian irradiation. Some women also received adjuvant chemotherapy, as decided with their physician.
The TEXT trial randomly assigned women within 12 weeks of surgery to five years of exemestane plus ovarian-function suppression or five years of tamoxifen plus ovarian-function suppression. Chemotherapy was optional and concurrent with ovarian-function suppression.
SOFT randomly assigned women to five years of exemestane plus ovarian function suppression, or to five years of tamoxifen plus ovarian-function suppression, or to five years of tamoxifen alone within 12 weeks of surgery if no chemotherapy was planned, or within eight months of completing neoadjuvant chemotherapy. The primary endpoint was disease-free survival from randomization until invasive local, regional, distant recurrence, or contralateral breast involvement, second malignancy, or death.
Pagani explained that due to the low rate of events, protocol amendments in 2011 changed the analysis plans to answer the aromatase inhibitor question—i.e., exemestane plus ovarian-function suppression versus tamoxifen plus ovarian-function suppression—by joint analysis of TEXT and SOFT.
Progression-free survival at five years was 91 percent in the exemestane plus ovarian-function suppression group versus 87 percent in the tamoxifen plus ovarian-function suppression group, a 28 percent relative reduction in risk. There was a 34 percent relative reduction in breast cancer recurrence risk in the exemestane plus ovarian-function suppression group compared with the tamoxifen plus ovarian-function suppression group and a 22 percent relative reduction in distant recurrence risk.
Five-year overall survival rates were high in both groups—95.9 percent in the exemestane plus ovarian-function suppression group and 96.9 percent in the tamoxifen plus ovarian-function suppression group.
But there was no significant difference in overall survival (hazard ratio 1.14) at this early follow-up with 194 deaths (4%).
‘Side Effects Cannot Be Ignored’
The side effects were similar to those reported in previous studies comparing adjuvant aromatase inhibitors and tamoxifen in postmenopausal women, and differed depending on the agent, Pagani reported.
Grade 3/4 targeted adverse events occurred in 31 percent of exemestane plus ovarian-function suppression patients versus 29 percent in tamoxifen plus ovarian-function suppression patients.
She noted that only 14 percent of TEXT and SOFT participants discontinued treatment—an adherence rate higher than that seen in everyday practice, an important point for clinicians who recommend this treatment to patients, she said.
But the ASCO-designated expert for the study, Don S. Dizon, MD (@drdonsdizon), founder and Director of the Oncology Sexual Health Clinic at Massachusetts General Hospital, noted in a tweet after the news conference that “sexual health suffers on exemestane: 52% [of patients experience] vaginal dryness, 45% libido decrease, and 31% dyspareunia. These effects can't be ignored.”
‘Did Not Include Control Arm’
Asked for her opinion for this article, Angela DeMichele, MD, Co-Leader of the Breast Cancer Program and Director of Clinical Trials at the University of Pennsylvania, said the study is very important because there have been so many questions: “We have had questions about whether we should be suppressing the ovaries even when we use an oral agent, we have had questions about the safety of aromatase inhibitors in premenopausal women, about whether we can truly suppress their ovaries, and questions about optimal management of these patients.
“The problem with the [reported] data was that it did not include a control arm.”
The tamoxifen-alone arm is critical to the puzzle, she said, because without knowing how the two ovarian-suppression arms compare with tamoxifen it is difficult to know what to do with patients who are on tamoxifen alone, which is the standard of care.
“For my own patients who continue to menstruate on tamoxifen, I offer them the option of ovarian suppression,” DeMichele said. “Many take me up on it, but some do not, and we have been at equipoise over whether or not this is beneficial.”
She said the question really needs to be answered, because once it is know whether ovarian suppression adds to tamoxifen, then the data from this report become much more relevant: “If we can say that tamoxifen plus ovarian suppression is better than tamoxifen alone, now we have a comparison with the exemestane, and that would make me more likely to move toward the exemestane.
“If, on the other hand, the tamoxifen results come back that it is equivalent to tamoxifen plus suppression, then we may not need to go to the extra expense and hassle of suppression, and we may not have to think about going to an aromatase inhibitor.
“Because there is a price to pay—for the slight increase in the percentage of patients who will benefit, there are the side effects of aromatase inhibitors, some so bad that patients discontinue the treatment—we see that not uncommonly.”
Moreover there is the cost and inconvenience of ovarian suppression.
Waiting for San Antonio
The Discussant for the report, Nancy E. Davidson, MD, Director of the University of Pittsburgh Cancer Institute and Associate Vice Chancellor for Cancer Research, said the study used a very stringent definition of hormone responsive, and the study arms were well balanced.
Potential limitations included a revised joint analysis plan put into place well after the trials were into accrual, to compensate for a lower than expected event rate and better outcomes than anticipated. Davidson, a former ASCO President, said this is an increasingly common feature in adjuvant breast cancer trials.
She said she thought the follow-up of 5.7 years was relatively short in the adjuvant endocrine therapy world, where follow-up would be better in decades. Another limitation was that the chemotherapy regimens used were heterogeneous.
And the trials accrued patients over an eight-year period, which was longer than she would have liked, she said. During that time there have been major changes including improvements in local therapy of breast cancer, increased understanding of breast cancer biology factors such as luminal A and B, and increased use of bisphosphonates.
Davidson said she agreed with the study's conclusion that exemestane plus ovarian suppression is a treatment option for premenopausal women with hormone-responsive early breast cancer. But she said it is premature to evaluate the impact, if any, on survival.
She said she is waiting for the final results of SOFT comparing tamoxifen alone with tamoxifen plus ovarian suppression, expected to be reported at the San Antonio Breast Cancer Symposium in December. If the combination is shown to be superior, she said, “we may want to revisit the role of oophorectomy in selected patients who want to avoid injections and have a permanent menopause.”