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FACT: An Open-Label Randomized Phase III Study of Fulvestrant and Anastrozole in Combination Compared With Anastrozole Alone as First-Line Therapy for Patients With Receptor-Positive Postmenopausal Breast Cancer

07 Mar 2012
Breast cancer
Tamer Refaat

For decades, Tamoxifen has been the gold standard breast cancer hormonal therapy. In addition, various aromatase inhibitors (AIs) have been investigated in both the adjuvant and metastatic settings.  Several randomized clinical trials have attempted to achieve higher oestrogen depletion among post-menopausal patients and subsequently better disease control. In the hormone receptor positive metastatic breast cancer setting, the use of AIs has demonstrated an improvement in progression free survival.  An overall survival advantage, however, has almost never been exhibited when comparing each subtype of AI with each other or  tamoxifen.  In comparison to the partial oestrogen receptor (ER) α antagonist properties of Tamoxifen, Fulvestrant is an ER α specific antagonist and thus falls into a different class of antioestrogen therapy.  Preclinical studies utilizing transplanted human ER α positive breast cancer cell lines into MCF-7 xenografts have demonstrated a greater efficacy for fulvestrant when compared to tamoxifen. In addition, clinical studies have demonstrated a dose-response effect for intramuscularly administered fulvestrant in the dose range of 50 to 250 mg.

Fulvestrant and Anastrozole Combination Therapy (FACT) study is an open-label, prospective, and randomized phase III multi-centre international clinical trial comparing a loading-dose (LD) schedule of fulvestrant (250 mg) together with anastrozole versus anastrozole alone in postmenopausal women with hormone receptor positive breast cancer treated at first relapse and considered to be candidates for primary endocrine therapy. 514 patients from 11 countries and 77 centres were randomly assigned to fulvestrant plus anastrozole (experimental arm; n = 258) or anastrozole alone (standard arm; n = 256).

With a median follow-up time of 8.9 months, no statistically significant difference was found in the median Time To Progression of 10.8 and 10.2 months in the experimental versus standard arm, respectively (HR = 0.99; 95% CI, 0.81 to 1.20; P = .91) as well as the median overall survival of 37.8 months versus 38.2 months, respectively (HR = 1.0; 95% CI, 0.76 to 1.32; P = 1.00). Treatment induced adverse events were similar in both groups and included mostly mild to moderate gastrointestinal disorders, joint disorders, urinary tract infections, and thromboembolic manifestations.  Hot flashes, however, were greater in the combination arm (P = 0.023). The incidence of adverse events leading to treatment discontinuation was doubled in the combination arm (6.3% vs 3.1%).  Death from adverse events was reported in 11 (4.3%) and five (2.0%) patients in the experimental versus standard arm, respectively. The FACT study failed to show any advantage for the combination arm in comparison to the control arm.

The FACT study directly follows the National Cancer Institute funded SWOG S0226 trial presented at the San Antonio Breast Cancer symposium in December of 2011.  The SWOG study included 707 patients from 72 institutions with similar inclusion criteria.  The combination of anastrozole and fulvestrant extended the median survival time by more than six months when compared to anastrozole alone (47.7 months vs 41.3 months). The combination therapy also lengthened the median time to disease progression (15 months vs 13.5 months). In a subset analysis, the overall survival benefit was further improved for women who were not previously exposed to tamoxifen therapy. Among this tamoxifen-naive group (approximately 60 percent of patients in each arm), the median overall survival time for the combination therapy arm was 47.7 months as compared to 39.7 months for those taking only anastrozole.  This may explain the inferior results revealed in the FACT study where one third of the patients were hormonal therapy naive and all the remaining patients (except eight) received antioestrogen therapy in the adjuvant setting. However, according to a SWOG press release, this «prior tamoxifen treatment factor» is suspect at best as it is derived from an unplanned secondary analysis.

Over the past decade, hormone receptor positive breast cancer therapies have had no new treatment advances that have contributed to a further improvement in overall survival.  As mentioned by Mehta RS, the concept of combination therapy utilizing oestrogen withdrawal and oestrogen receptor antagonism appears promising and potentially more efficacious than a sequential approach.  Investigations, however, fail to reveal consistent results as evidenced by the FACT and SWOG S0226 studies. Therefore, a better understanding of these findings and a further evaluation of these studies are necessary before proceeding with final conclusions and recommendations.  Potential future areas of evaluation include increasing the dose of Fulvestrant from 250mg to 500mg, using alternative AIs in the combination setting, analysing the intensity of hormone receptor positivity, and assessing other tumour characteristics including molecular factors.  This would allow for a refinement of the patient selection process and potentially improve the outcome of hormonal therapy in metastatic breast cancer patients, which many agree is still below a satisfactory level. 

Last update: 07 Mar 2012

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