Two Major Trials: AIs Work in Premenopausal Breast Cancer Too

New Option for Treatment of Hormone-Sensitive Disease

Nick Mulcahy

June 01, 2014

CHICAGO — Are clinicians in the United States ready to change their approach to adjuvant endocrine therapy in young women with hormone-receptor-positive breast cancer, or at least to consider a new option?

That question surrounds results from a joint analysis of 2 large clinical trials, which were presented here at the 2014 Annual Meeting of the American Society of Clinical Oncology® (ASCO).

The results, simultaneously published online in the New England Journal of Medicine, come from the phase 3 Tamoxifen and Exemestane Trial (TEXT) and the Suppression of Ovarian Function Trial (SOFT).

Both trials were designed to compare the aromatase inhibitor (AI) exemestane with tamoxifen in premenopausal women with early breast cancer who also received ovarian suppression. The joint analysis involved 4690 patients.

Dr. Olivia Pagani

The findings indicate that exemestane plus ovarian suppression significantly reduced recurrence, compared with tamoxifen plus ovarian suppression, said lead author Olivia Pagani, MD, from the Institute of Oncology of Southern Switzerland in Bellinzona.

At 5 years, disease-free survival was better with exemestane than with tamoxifen (91.1% vs 87.3%; P < .001). Thus, the absolute difference in progression-free survival was 3.8% between the 2 groups. Overall survival was not significantly different. Median follow-up was 68 months. The average patient age was 43 years.

Exemestane plus ovarian suppression provides a new adjuvant treatment option [for premenopausal women]," she reported during a meeting press conference.

However, there has been a lot of discussion about these results at the meeting, and a key question is how this approach compares with tamoxifen used alone, which is the current standard in premenopausal women. This will be answered by the full results of SOFT, which included a group treated with tamoxifen alone. They will be presented in December at the San Antonio Breast Cancer Symposium.

Aromatase inhibitors work in premenopausal women as well.

"Aromatase inhibitors work in premenopausal women as well," Dr. Pagani told Medscape Medical News. She explained that because AIs require "low estrogen levels" to be effective, they have been used mostly in postmenopausal women.

But when combined with ovarian suppression to achieve such low estrogen, exemestane can also be used in premenopausal women.

In TEXT and SOFT, ovarian suppression was achieved with triptorelin, a gonadotropin-releasing-hormone (GnRH) agonist, oophorectomy, or ovarian radiation.

"We need to figure out who really needs this because an AI plus ovarian suppression is going to have more toxicity than just tamoxifen," said Claudine Isaacs, MD, from the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.

We need to figure out who really needs this.

Dr. Isaacs, who was not involved in the final analysis of the studies, explained that, in the United States, tamoxifen alone is the adjuvant endocrine standard of care for premenopausal women.

She explained that, on the basis of these results, medical oncologists in the United States must ask themselves: "Should I change my standard of care?"

European clinicians tend to favor an AI and ovarian suppression in young women with hormone-receptor-positive breast cancer, said Dr. Pagani. But she suggested that the results are powerful enough to change clinical practice everywhere.

The absolute difference in progression-free survival in the joint analysis (3.8%) is in the "same neighborhood" as what was seen with AIs in the BIG 1-98 and Arimidex, Tamoxifen, Alone or in Combination (ATAC) trials, which changed clinical practice in postmenopausal women, she explained.

But Dr. Pagani emphasized that choice of treatment should be individualized on the basis of risk, age, use of chemotherapy, and other factors.

Dr. Isaacs agreed. "The adjuvant therapy discussions are typically a dialogue between a patient and her healthcare team, because we are not able to individualize benefits," she said, adding that preferences are very important.

For example, a young woman might prefer to undergo chemotherapy for a relatively short period of time and skip 5 years of endocrine therapy, she said. Some women will want to avoid a prolonged menopause-like existence.

Another clinician suggested that the results might be more likely to reinforce — rather than change — pre-existing treatment preferences in this setting.

"This result will definitely support the use of ovarian suppression and aromatase inhibitors among clinicians who already believe that ovarian suppression is valuable," said ASCO president Clifford Hudis, MD, who moderated the press conference. He is from the Memorial Sloan-Kettering Cancer Center in New York City.

I am awaiting the results of SOFT to finalize my approach.

Acting as discussant for the joint analysis, Nancy Davidson, MD, from the University of Pittsburgh Cancer Institute, said that she is undecided about how to proceed with patients. "For now, I am awaiting the results of SOFT to finalize my approach," she said.

The SOFT results are important because they will include data on the use of tamoxifen alone, which is the standard of care in this setting, said Dr. Davidson

Unlike TEXT, which had 2 groups, SOFT is a 3-group trial that includes tamoxifen only. However, suitably mature data from the tamoxifen-only group are not expected until the end of 2014.

TEXT and SOFT were led by the International Breast Cancer Study Group (IBCSG), in collaboration with the Breast International Group (BIG) and the North American Breast Cancer Group (NABCG).

Originally, each trial was slated to be analyzed separately first and then later jointly. However, a shortfall of events led the investigators to issue this joint study, which is the first analysis.

Chemotherapy Findings Are Important

Dr. Pagani reported that the rate of freedom from breast cancer at 5 years was better with exemestane than with tamoxifen (92.8% vs 88.8%; P < .001).

The rates of grade 3/4 adverse events — most frequently hot flushes, musculoskeletal symptoms, and hypertension — were similar in the exemestane and tamoxifen groups (30.6% vs 29.4%).

The adverse events were typical of a low-estrogen environment, and the rates were "similar" to events in postmenopausal women in other trials, Dr. Pagani and colleagues report.

Osteoporosis (T-score < –2.5) was reported in 13.2% of patients in the exemestane group and 6.4% in the tamoxifen group. Self-reported quality of life did not differ between the 2 groups.

Complete cessation of protocol treatments before the end of the 5-year treatment period was low. "Compliance was very good," said Dr. Pagani.

Another result of paramount importance, she added, were the findings on chemotherapy.

A large swath of the joint-analysis population (43%; 1996 patients) did not receive chemotherapy, which was a decision reached by individuals and their clinicians. For patients who did not receive chemotherapy, the rate of freedom from breast cancer at 5 years was 97%. And 98% were alive at 5 years, Dr. Pagani added.

Notably, in many of the women, the early breast cancer was considered high risk because of positive nodes (42%) and/or tumors larger than 2 cm (36%).

"In our opinion, these results clearly indicate that some premenopausal women with hormone-receptor-positive breast cancer may have an excellent prognosis when treated with 5 years of highly effective adjuvant endocrine therapy without chemotherapy," Dr. Pagani concluded.

The improvement in disease-free survival with exemestane plus ovarian suppression in TEXT and SOFT "surprised a number of us," said Eric Winer, MD, from the Dana-Farber Cancer Institute in Boston, during a Highlights of the Day session.

The ABCSG12 trial compared, in combination ovarian suppression, the AI anastrozole with tamoxifen, and found no difference in outcomes. "This makes me cautious," Dr. Winer said.

He questioned whether an AI plus ovarian suppression is a new standard of care. There was improvement in disease-free survival and a small reduction in the risk for distant metastases, but so far there has been no difference in overall survival, he noted.

Plus, adding ovarian suppression really adds to the adverse events. The combination is "pretty tough to take," especially for young women, he said. In the analysis of TEXT and SOFT, discontinuation rates were higher in the exemestane group than in the tamoxifen group (16.1% vs 11.2%).

But the biggest question is whether ovarian suppression adds much to tamoxifen. "Its not clear that the ovarian suppression is adding anything, and it may be that tamoxifen alone is enough," Dr. Winer said. That data will be available soon.

For now, he said, "hold off routine use of an AI plus ovarian suppression."

2014 Annual Meeting of the American Society of Clinical Oncology (ASCO): Abstract LBA1. Presented June 1, 2014.


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