Joint Analysis of Phase III Trials Will Change Practice in Premenopausal HR+ Breast Cancer

Olivia Pagani, MD

A joint analysis of two phase III trials involving a total of 4690 premenopausal women with hormone-receptor—positive (HR+) breast cancer demonstrated that adjuvant use of the aromatase inhibitor (AI), exemestane, reduced relative risk of developing subsequent invasive cancer by 28% compared with tamoxifen when both agents were combined with ovarian function suppression (OFS). The exemestane + OFS treatment arm also showed a relative reduction in risk of breast cancer recurrence of 34%.

“The trials demonstrate that an aromatase inhibitor, previously recommended only for postmenopausal women is also effective for premenopausal women when combined with ovarian function suppression,” said Olivia Pagani, MD, of the Institute of Oncology of Southern Switzerland, who presented the combined results on behalf of the International Breast Cancer Study Group (IBCSG), June 1, 2014 at the 50^thAnnual Meeting of ASCO.

“As a physician who routinely recommends ovarian function suppression as adjuvant therapy for some young patients, these results will change my practice. I will combine ovarian function suppression with an aromatase inhibitor rather than with tamoxifen.”

“Tamoxifen, for at least 5 years, with the option of adding OFS has been the standard treatment,” Pagani said regarding premenopausal woman with HR+ breast cancer. Using adjuvant AIs for 5 years is a more effective treatment strategy than 5 years of tamoxifen in many postmenopausal women, according to Pagani; however, this AI treatment was not available to premenopausal women, because AIs require the low estrogen levels that occur after menopause, and these levels can only be achieved in young women with OFS.

TEXT (Tamoxifen and EXemstane Trial) and SOFT (Suppression of Ovarian Function Trial) were designed to determine whether or not adjuvant therapy with exemestane + OFS improved outcomes in premenopausal women compared with tamoxifen + OFS.

The TEXT trial randomized 2672 premenopausal women with HR+ breast cancer who were ≤12 weeks from surgery (with or without planned chemotherapy or OFS) to tamoxifen + OFS for 5 years or exemestane + OFS for 5 years. The SOFT trial randomized 3066 premenopausal women with HR+ breast cancer who were ≤12 weeks from surgery (with no chemotherapy or ≤8 months from chemotherapy) to 5 years of tamoxifen, tamoxifen plus OFS, or exemestane plus OFS.

According to study data, enrolled patients were an average age of 43 years, and 42% of patients were node positive. Thirty-six percent had tumors that were larger than 2 cm, and 57% of patients also received chemotherapy. Triptorelin, surgical oophorectomy, or ovarian irradiation were methods used for OFS. The primary endpoint was disease-free survival. Due to low event rates, protocol amendments in 2011 changed the analysis plans to answer the AI question by joint analysis of TEXT and SOFT, according to the study authors. The median follow-up for the joint analysis was 5.7 years.

Cancer-free survival at 5 years was 91.1% in the exemestane + OFS arm compared with 87.3% in the tamoxifen + OFS arm. Similar 5-year overall survival rates occurred in both arms, with a 95.9% survival in the exemestane + OFS arm compared with a 96.9% survival in the tamoxifen + OFS arm.

The exemestane + OFS combination was well tolerated. “As clinicians we should be reassured that, in the two treatments studied, the patient-reported quality of life results were similar overall, as was the frequency of severe side effects,” said study cochair Barbara Walley, MD, medical oncologist at the Tom Baker Cancer Center in Calgary, Canada in an IBCSG press release. “The side effects reported in this premenopausal population are similar to those in the postmenopausal women in which tamoxifen and aromatase inhibitors are widely prescribed.”

Grade 3 to 4 targeted AEs were reported in 31% of patients in the exemestane + OFS arm compared with 29% in the tamoxifen + OFS arm. Completed cessation of protocol treatments prior to 5 years was 14%. Follow-up will continue to assess long-term prognosis, tolerability, and side effects.

“Young women with breast cancer have long needed additional treatment options after surgery, and now they may have one,” stated ASCO president Clifford A. Hudis, MD, FACP. “Tamoxifen has been a gold standard for decades and has significant benefits. Now with ovarian suppression, aromatase inhibitors are an option offering a further reduction in the risk of recurrence.”

Pagani stresses that although the data for exemestane + OFS is positive, administration of this treatment is an individual decision.

“This does not mean that you need to giveallpremenopausal women with hormone-receptor positive the combination. There are some women for whom tamoxifen alone is fine, as there are some women in the postmenopausal age for whom tamoxifen alone is fine. This is another opportunity and then it is up to the doctor to balance the risk of the patients, the age, the severity of the disease, and whether they [the patients] need chemotherapy or not. And then you have a decision that is personal.” Pagani also mentioned that the Group plans to release data for the tamoxifen-only data (SOFT) by the end of 2014.

Pagani O, Regan MM, Walley B, et al; SOFT and TEXT Investigators and International Breast Cancer Study Group. Randomized comparison of adjuvant aromatase inhibitor (AI) exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Joint analysis of IBCSG TEXT and SOFT. Presented at the Annual Meeting of ASCO, June 1, 2014. Abstract LBA1.

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