These outcomes suggest that fulvestrant is as viable and perhaps even preferred first-line therapy for postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer. The impressive results from this trial are likely, because the study used the 500-mg dose of fulvestrant, which is twice the dose used in the original trials. However, the 500-mg dose has previously been studied, and long-term outcome data suggest both safety and efficiency. The large randomized, double-blinded phase 3 CONFIRM trial, published in 2013, compared the 250-mg dose with the 500-mg dose and found that the higher dose was associated with a 19% reduction in the risk of death and a 4.1 month increase in median overall survival (OS) without any new safety concerns. 5
Palbociclib
The FDA recently granted accelerated approval to palbociclib in combination with letrozole for the first-line therapy of advanced hormone receptor-positive, HER2-negative breast cancer in postmenopausal women. Palbociclib is an oral small-molecular inhibitor of cyclindependent kinases 4 and 6. Preclinical data suggested synergy with anti-estrogen therapies and inhibition of breast cancer cell growth.7
A phase 2, open-label randomized trial (PALOMA-1/TRIO-18) enrolled 165 patients. Progression-free survival (PFS) was 20.2 months for the palbociclib plus letrozole arm and 10.2 months for the letrozole alone arm. Significant toxicities were noted in the palbociclib arm, including 54% of people experiencing grade 3 to 4 neutropenia (vs 1% in the letrozole arm), leukopenia in 19% (vs 0%) and fatigue in 4% (vs 1%). A phase 3 trial is currently enrolling patients. 7 While we await the results of the phase 3 trial and long-term follow-up data, palbociclib plus letrozole is a new, viable option for metastatic hormone receptor-positive advanced breast cancer.
Although many practitioners will continue to reasonably use any AI or selective ER modulator when treating metastatic breast cancer, both fulvestrant and palbociclib in combination with letrozole are new evidence-based, first-line options worth considering.
Early-Stage Treatment Options
There are many acceptable therapeutic options for treating early stage breast cancer. Tamoxifen has traditionally been used in the adjuvant setting for premenopausal women, whereas AIs are often used in postmenopausal women. There has also been a long-standing debate about the role of ovarian suppression in premenopausal women.
The recently published phase 3 TEXT and SOFT trials attempted to provide answers to these long-standing therapeutic dilemmas. The SOFT trial randomly assigned 3,066 premenopausal women to 5 years of tamoxifen, 5 years of tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The TEXT trial randomly assigned 2,672 women to receive either exemestane plus ovarian suppression or tamoxifen plus ovarian suppression. The studies showed that subjecting all women receiving tamoxifen to ovarian suppression did not provide any significant benefit. 8,9
However, the subgroup of women with high-risk disease who required adjuvant chemotherapy and remained premenopausal experienced improved outcomes from ovarian suppression. This high-risk subgroup when given tamoxifen plus ovarian suppression had a 4.5% absolute reduction in breast cancer recurrence at 5 years compared with the group that received tamoxifen alone. When this high-risk subgroup was given exemestane plus ovarian suppression, the women had a 7.7% absolute reduction in breast cancer recurrence at 5 years compared with the group that received tamoxifen alone. 8