SOFT update
Initial results of the SOFT trial, reported after a median follow-up of 5.6 years, showed that adding OFS to tamoxifen did not significantly improve disease-free survival over tamoxifen alone in the entire trial population (N Engl J Med. 2015;372:436-46). However, there was benefit for women who received chemotherapy and remained premenopausal.
The updated SOFT analysis, now with a median follow-up of 8 years, focused mainly on the 1,018 women given tamoxifen alone and the 1,015 women given tamoxifen plus OFS. (Another 1,014 women were given exemestane plus OFS.)
“SOFT is now positive for its primary endpoint,” reported first author Gini Fleming, MD, director of the Medical Oncology Breast Program and medical oncology director of Gynecologic Oncology at University of Chicago Medicine. The 8-year disease-free survival rate was 83.2% with tamoxifen plus OFS, compared with 78.9% with tamoxifen alone (HR, 0.76; P = .009), corresponding to a 4.2% gain in this outcome. The relative benefit was identical whether patients had received chemotherapy or not, but absolute benefit was greater for those who had (5.3%), as well as for patients younger than 35 years (8.7%).
In addition, exemestane plus OFS was superior to tamoxifen alone (85.9% vs. 78.9%; HR, 0.65), with an absolute benefit of 7.0%. Again, absolute benefit was more pronounced among women who had received prior chemotherapy (9.0%) or were younger than 35 years (13.1%).
The relative disease-free survival benefit of tamoxifen plus OFS over tamoxifen alone was similar across most subgroups stratified by disease characteristics, but patients with HER2-positive disease derived greater relative benefit from the combination as compared with their HER2-negative counterparts (P = .04 for interaction). “When we look at the combination of exemestane plus OFS versus tamoxifen, this heterogeneity is no longer seen,” Dr. Fleming noted.
In the entire trial population, there was no significant benefit of tamoxifen plus OFS over tamoxifen alone for distant recurrence-free interval and a small, significant absolute 1.9% gain in overall survival.
“The cohort who had elected to receive no prior chemotherapy did exceedingly well regardless of therapy,” she said, with little difference in overall survival across the three arms. “There were only 24 deaths total in this cohort, and 12 of those deaths were in the setting of no distant recurrence.”
On the other hand, among the women who received chemotherapy, there were significant absolute overall survival benefits of 4.3% with tamoxifen plus OFS and 2.1% with exemestane plus OFS, over tamoxifen alone. “This late emergence of an overall survival benefit is consistent with the time course of events in estrogen receptor–positive breast cancer,” Dr. Fleming commented.
The proportion of patients who stopped their oral endocrine therapy early was 22.5% with tamoxifen alone and 18.5% with tamoxifen plus OFS. (It was 27.8% with exemestane plus OFS.) “Almost a quarter of the patients on either tamoxifen arm were using extended oral endocrine therapy at 6 years or later prior to any disease progression. Only about 12% of patients in the exemestane group were doing so,” she noted.
There were more cases of endometrial cancer with tamoxifen alone than with tamoxifen plus OFS (7 vs. 4 cases). Thrombosis/embolism of grade 2-4 occurred in 2.2% of each group (and 0.9% of the exemestane plus OFS group). Musculoskeletal symptoms of grade 3 or 4 occurred in 6.7% of patients with tamoxifen alone and 5.9% with tamoxifen plus OFS, but 12.0% with exemestane plus OFS. Respective rates of osteoporosis grade 2-4 were 3.9%, 6.1%, and 11.9%.
“The addition of OFS to tamoxifen significantly improves disease-free survival at 8 years’ median follow-up, and disease-free survival benefits are further improved by the use of exemestane plus OFS,” Dr. Fleming summarized. “Follow-up, which is critically important given the long natural history of ER-positive disease, continues.”
Session attendee Matthew P. Goetz, MD, of the Mayo Clinic, Rochester, Minn., commented, “For the primary endpoint, I was looking at the tail for tamoxifen. It seemed that there was a relatively rapid drop-off between year 5 and this 8-year follow-up. Have you looked carefully to see whether there is a difference between those who stayed on their therapy versus those who went off it per protocol? That is, extended versus not extended? The question is whether there is a carry-over effect, if you will, that is different in those with OFS versus those not.”
“The percent who went on to extended therapy between the tamoxifen and the tamoxifen plus OFS was fairly similar,” Dr. Fleming replied. “But the answer is no, we have not yet done any sort of per protocol analysis.”
Session attendee Steven Vogl, MD, of Montefiore Medical Center, New York, commented, “I worry about your control group. I’m worried, first, how many of your tamoxifen patients lost their menses and became postmenopausal in those 5 years? And of those, why didn’t they switch to an aromatase inhibitor? Only 25% of the patients continued after the 5 years according to your slide, and all of those patients should either have stayed on tamoxifen or switched to an aromatase inhibitor, now probably for 2 years at least.”
“We have not yet looked at data for who became amenorrheic during treatment, although we have it. However, it’s certainly possible to become amenorrheic on tamoxifen and not be postmenopausal, and we didn’t regularly collect estradiol levels on any but the very small subset of women in the SOFT-S trial. So I don’t know that we have exactly the data that you’re looking for,” Dr. Fleming said. “Many of these women are obviously at very, very low risk and have done well with 5 years of tamoxifen alone, and I don’t know, even given current guidelines, that extended tamoxifen would add a lot to that.”
Finally, session attendee Richard Gray, professor of medical statistics at the University of Oxford (England), wondered, “What is the certainty that follow-up will happen? Because obviously, prolonged follow-up is expensive and there are controversies about that. But this would be the one study you would really want to have 15- and 20-year data on.”
“We are working very, very hard on that,” Dr. Fleming replied. “NCI granted additional funds to institutions for prolonging follow-up, and IBCSG has been ceaselessly working to look for funding to continue it. So I think it’s relatively certain that it will happen.”
Dr. Francis disclosed that she has received fees for non-CME services from AstraZeneca and has given an overseas lecture for Pfizer. Dr. Fleming disclosed that she had no relevant financial relationships with commercial interests. The trials received financial support from Pfizer and Ipsen.
SOURCES: Francis et al. SABCS Abstract GS4-02; Fleming et al. SABCS Abstract GS4-03