UPDATED December 16, 2014 — Results from the huge international Suppression of Ovarian Function Trial (SOFT) are practice changing for the adjuvant treatment of premenopausal women with early-stage hormone receptor (HR)-positive breast cancer, say both the investigators and several experts discussing the results here at the San Antonio Breast Cancer Symposium (SABCS) 2014.
While tamoxifen has long been the standard of care for this patient population, the new data show that ovarian suppression with endocrine therapy has striking benefits for some of these patients.
The results have led to a new algorithm for the adjuvant treatment of premenopausal women with HR-positive breast cancer, said Hope Rugo, MD, from the University of California, San Francisco, who acted at a discussant at the SABCS meeting. She outlined two distinct treatment approaches.
Women who have not received chemotherapy, are at low risk, have smaller tumors, negative nodes, grade 1, and are older but still premenopausal can be reasonably and well treated with tamoxifen alone, she said.
For women who are clearly at high risk, particularly those who are under 35 years of age, ovarian suppression appears to provide a marked and clinically meaningful reduction in breast cancer recurrence. The reduction is significantly greater when the ovarian suppression is added onto exemestane, compared with tamoxifen, but Dr. Rugo noted that the two drugs have different toxicity profiles, and this should also be taken into account in the decision-making process.
For the remaining women who are at intermediate risk, maybe with small tumors but positive nodes or larger tumors but low grade, Dr. Rugo said that it would be reasonable to use ovarian suppression with endocrine therapy in some of these patients, and use tamoxifen alone in others.
SOFT Results Change Practice
The latest results from SOFT were presented here at the meeting by Prudence Francis, MD, from the Peter MacCallum Cancer Center in Melbourne, Australia, and published simultaneously in the New England Journal of Medicine. They add to previously released data, from a joint analysis of SOFT and the Tamoxifen and Exemestane Trial (TEXT), presented earlier this year at the annual meeting of the American Society of Clinical Oncology, and also published at that time (N Engl J Med. 2014;371:107-118).
SOFT enrolled 3066 premenopausal women with breast cancer, and randomized them to receive treatment with tamoxifen alone for 5 years, or ovarian suppression with tamoxifen, or ovarian suppression with exemestane (Aromasin, Pfizer). About half of the patients had received chemotherapy after surgery. The median follow-up was 5.6 years, and the primary end point was disease-free survival.
In most women, ovarian suppression was achieved by monthly injection of triptorelin, but some opted for permanent options of surgery (bilateral oophorectomy) or irradiation to both ovaries.
In the overall population, there was no significant difference in breast cancer recurrence between the three treatment groups.
However, a big difference was seen in some patient subgroups.
The most striking effect was seen in younger women (≤35 years), noted Dr. Francis. In this subgroup of 350 patients (11.5% of the total), nearly all of these women (94%) had received chemotherapy, she noted.
In this subgroup of all women 35 years and younger, the 5-year breast-cancer-free rate was 67.7% in those on tamoxifen alone, 78.9% in those on tamoxifen plus ovarian suppression, and 83.4% in those on exemestane plus ovarian suppression. Dr. Francis also presented the results in another way: one in three women on tamoxifen alone had a breast cancer recurrence within 5 years, compared with one in six on exemestane plus ovarian suppression.
There was also a striking effect seen in the subgroup of 1084 women who had received chemotherapy and then remained premenopausal (i.e., the chemotherapy had not stopped the ovaries from functioning, as determined by estradiol blood levels). These women had a median age of 40 years, Dr. Francis noted.
In this subgroup of women who were premenopausal after chemotherapy, the 5-year breast-cancer-free rate was 78.0% with tamoxifen alone, 82.5% with tamoxifen plus ovarian suppression, and 85.7% with exemestane plus ovarian suppression. Again, Dr. Francis expressed the results in another way: tamoxifen plus ovarian suppression resulted in a 22% reduction in relative risk of recurrence versus tamoxifen alone, and exemestane plus ovarian function resulted in a 35% relative risk reduction versus tamoxifen alone.
The absolute improvement was 4.5% and 7.7%, respectively. This translates into seven or eight fewer women out of 100 having a breast cancer recurrence within 5 years on exemestane plus ovarian suppression, compared with tamoxifen alone, Dr. Francis said.
In contrast, there was no benefit from adding ovarian suppression to endocrine therapy in the subgroup of 949 women who did not receive chemotherapy. These women had a median age of 46 years, and were closer to their natural menopause, she commented. These women did well on tamoxifen alone, Dr. Francis noted.
"These results will change practice," Dr. Francis said in a statement.
"For the youngest women with hormone-sensitive breast cancer, ovarian suppression will increasingly be recommended," she said. At the press briefing, she emphasized that she would recommend, rather than discuss, this option for such patients.
"For women who have not reached menopause and have a hormone-sensitive breast cancer that carries sufficient risk of recurrence to warrant chemotherapy, doctors are likely to discuss the option of ovarian suppression plus an aromatase inhibitor as an alternative to tamoxifen," she added.
However, the additional therapy carries with it a burden of additional toxicity.
Adding ovarian suppression to endocrine therapy increased adverse effects, most notably menopausal symptoms (hot flushes and sweats), problems with sexual functioning (loss of libido, vaginal dryness), and depression (reported in 50%). The researchers also note that exemestane combined with ovarian suppression was associated with more adverse events than tamoxifen plus ovarian suppression, including musculoskeletal and bone density effects.
In a review of adjuvant therapy at the meeting, Nancy Davidson, MD, from the University of Pittsburgh, highlighted these new data in premenopausal women, and suggested that they were practice changing for some women. She agreed with the new treatment algorithm proposed by Dr. Rugo, but added that when it came to using ovarian suppression with endocrine therapy, she would lean toward using an aromatase inhibitor instead of tamoxifen, unless there was a reason not to.
Both Dr. Davidson and Dr. Rugo emphasized that the data are immature, and that it is too early yet to look at survival end points. The median follow-up is just over 5 years, and at this point 95% of these women are still alive, so they are doing "extraordinarily well," Dr. Davidson commented.
Experts Agree Data Are Practice-Changing
Several breast cancer clinicians approached by Medscape Medical News at the meeting agreed that the data were practice-changing for the treatment of some premenopausal women with breast cancer.
Beverley Moy, MD, clinical director at the Massachusetts General Hospital Cancer Center in Boston, commented that the breast cancer community had been waiting for years to hear these data on whether there was an extra benefit from ovarian suppression. In the overall population, there was no significant benefit, but Dr Moy highlighted the significant difference seen in the population of women who were premenopausal after chemotherapy; these women tended to be younger and have more aggressive disease, she said. In absolute terms, these women, after 5 years, had 7.7% fewer breast cancer events with exemestane and ovarian suppression compared with tamoxifen alone. "I do think the data are practice-changing in this subset of patients," Dr Moy told Medscape Medical News. "However, you have to temper that benefit with the fact that the combination had significantly more side effects. Making premenopausal women abruptly menopausal can lead to many side effects — hot flashes, sexual dysfunction, depression...and also joint pain and potentially osteoporosis with the aromatase inhibitor."
"You have to weigh the risks against the benefits," she said. "It's a difficult clinical situation that we face. These are young women with aggressive disease, and I'm delighted that we have found a treatment option that provides benefit, but it comes at a cost. "
Claudine Isaacs, MD, from the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, said that the results are practice-changing, and that clinicians will now be grappling with these new data and how to integrate ovarian suppression, with all its attendant adverse effects, into the treatment of premenopausal women with breast cancer. She told Medscape Medical News that she felt the data were convincing for two subsets — women aged less than 35 years and those who remain premenopausal after chemotherapy. There is a pretty significant benefit for those subsets of patients when compared with tamoxifen alone, which is currently the standard of care, she said. These women are at high risk for recurrence, and the addition of ovarian suppression made a big difference, she said. Dr Isaacs said that she felt that the effect on recurrence was sufficient for practice changes to be made now, without waiting for the data to mature to show an effect on survival. "It may not be suitable for every woman in these subsets, but this new option should now be discussed with these patients," she said.
Clifford Hudis, MD, chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center in New York City, said, "I think these data contribute to an evolving change in the standard of care," adding that "this is the end of a very long story."
The idea that ovarian suppression would be of benefit was first reported in 1896, when a Scottish surgeon showed that removing ovaries led to breast cancer becoming smaller, he said. "We know now that this was a result of reducing estrogen in the circulation." Decades later, this effect was later achieved by a drug, tamoxifen, but it was only in 1995 that the world reached a consensus that tamoxifen was useful in premenopausal women with breast cancer, he noted. This was the beginning of standardization of adjuvant therapy globally, he said, and tamoxifen alone has been the standard of care for premenopausal women with breast cancer.
"But there has always been this assumption that the low estrogen environment resulting from removal or blockade of the ovaries would allow conventional endocrine therapy with tamoxifen or others to work better," Dr Hudis explained. "But historically, clinical trials in this area have not been very positive...and the side effects of ovarian suppression in young women are real and long-lasting, and so there has been this tension in our field where there is a bias that this is the right thing to do, but mixed evidence of benefit, and clear evidence of toxicity."
Now we have two trials: TEXT, which assumed that ovarian suppression was necessary and showed that adding exemestane was superior to adding tamoxifen, and SOFT, which essentially duplicated this trial but added a third group of tamoxifen alone. Earlier this year, when the combined analysis of TEXT and SOFT was reported, several experts said that they wanted to wait and see the results of the tamoxifen-alone group, the remaining analysis from SOFT, which was now presented at this meeting.
Now we can see that indeed tamoxifen plus ovarian suppression is nominally better than tamoxifen alone; there was a trend, but the difference was not significant, Dr Hudis said. "But the big step up was adding exemestane to ovarian suppression, and this now substantiates what we saw last summer."
So exemestane plus ovarian suppression will now become a standard of care for high-risk women with premenopausal women with breast cancer, Dr Hudis agreed. But he emphasized that there is a trade-off in terms of adverse effects, and so the benefit has to be weighed up against the risk, he added.
SOFT had financial support from Pfizer, the IBCSG, and the National Cancer Institute. Pfizer and Ipsen provided drug supply. The pharmaceutical companies had no role in the reporting or interpretation of the trials, other than a minority representation on the Steering Committee. Dr. Francis has disclosed no relevant financial relationships.
San Antonio Breast Cancer Symposium (SABCS) 2014: Abstract S3-08. Presented December 11, 2014.
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Cite this: New Algorithm for Treatment of Premenopausal Breast Cancer - Medscape - Dec 12, 2014.