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Combination of Anastrozole and Fulvestrant in Metastatic Breast Cancer

12 Dec 2012
Breast cancer
Dimitrios Zardavas, Evandro de Azambuja

Hormone receptor positive breast cancer represents the most common type of breast cancer, with endocrine therapy remaining a cornerstone of the treatment for patients with metastatic disease. Selective aromatase inhibitors, i.e. anastrozole, letrozole and exemestane, are significant members of our current therapeutic armamentarium in postmenopausal women, mediating their therapeutic effect by inactivating aromatase, which is the responsible enzyme for the conversion of androgenic substrates into oestrogens. Fulvestrant represents another potent endocrine treatment in the setting of metastatic breast cancer, mediating the degradation of oestrogen receptor and thus serving as a selective oestrogen receptor downregulator. Preclinical evidence indicates a high efficacy of fulvestrant in a low-estrogen environment, which can be achieved through aromatase inhibition, so that a combination of these two classes of agents could be clinically preferable. Moreover, the fulvestrant-anastrozole combination has been shown to be superior to any either alone in a xenograft breast cancer model.

In August 2012, the results of a randomised phase III study investigating the combination of anastrozole and fulvestrant in metastatic breast cancer patients were published in The New England Journal of Medicine.  In the SWOG S0226 study, postmenopausal women with hormone receptor positive metastatic breast cancer and no previous exposure to systemic treatment for metastatic disease were randomly assigned to receive anastrozole alone (1 mg orally every day; 345 patients) or combination therapy with anastrozole and fulvestrant (intramuscular administration at a dose of 500 mg on day 1 and 250 mg on days 14 and 28 and monthly thereafter; 349 patients). In February 2011, the protocol was amended to increase fulvestrant dose to 500 mg monthly. This increase was due to the results of trials showing the superiority of higher doses of fulvestrant compared to lower doses (Di Leo, A. et al. J. Clin. Oncol. 2010;28:4594-4600) The primary endpoint was progression free survival (PFS), with overall survival (OS), clinical benefit rate (CBR) and rate of response (RR) being secondary endpoints. Patients were stratified according to status of prior receipt of tamoxifen in the adjuvant setting (yes versus no). Prior exposure to aromatase inhibitor in the adjuvant setting was allowed if therapy was completed more than 12 months prior to enrolment. For patients experiencing progression after anastrozole monotherapy, crossover to low-dose fulvestrant was strongly recommended.

The study met its primary endpoint, since patients treated in the combination arm had a significant improvement in PFS compared to patients treated with anastrozole monotherapy (HR 0.80; 95% CI 0.68-0.94, P=0.007; 15.0 months versus 13.5 months, respectively. In an exploratory unplanned analysis, patients having received tamoxifen in the adjuvant setting had no substantial benefit of the combination, whereas patients not having received adjuvant tamoxifen had a 4.4 months improvement in PFS (HR 0.74; 95% CI 0.59-0.92). Importantly, the interaction between treatment and use of prior adjuvant tamoxifen was not significant (P=0.22). In terms of OS outcomes, results favoured the combination treatment, since patients treated with anastrozole monotherapy achieved an OS of 41.3 months as compared to  47.7 months for patients receiving the combination (two-sided P=0.049). The estimated HR for death with combination therapy was 0.81 (95% CI, 0.65 to 1.00). Both CBR (70% versus 73%, P=0.39)) and RR (22% versus 27%, P=0.26) were comparable in the two arms. Importantly, 41% of patients experiencing progression during anastrozole monotherapy continued to receive fulvestrant (albeit low-dose and not the current standard of care). In terms of toxicity the two arms showed comparable profiles, with toxic effects of grade 3 or higher occurring in 12.7% of patients in the anastrozole monotherapy arm and in 14.7% of patients in the combination treatment arm (P=0.44).

The aforementioned results showed that the combination anastrozole-fulvestrant improved PFS and OS in women with hormone receptor positive metastatic breast cancer. The toxicity profile was acceptable. Nevertheless, the authors did not report on the number of patients receiving low versus high dose fulvestrant. Also, no information on patients previously treated with AI was provided. Notably, this is the first randomised clinical trial to prove a superiority of combination endocrine treatment, as compared to monotherapies, since similar trials in the past were negative (e.g. the Anastrozole Monotherapy Versus Maximal Oestrogen Blockade with Anastrozole and Fulvestrant Combination Therapy [FACT] Trial). Potential reasons for this inconsistency might be the smaller sample size of the past trial, along with a fewer reported number of efficacy events. An important question raises with the SWOG S0026 trial results: Is the combination of fulvestrant plus anastrozole a promising adjuvant regimen for women with hormone receptor positive early stage breast cancer? To address such question only large randomised clinical trials will be able to do so. In the meantime, the combination of fulvestrant plus anastrozole is a therapeutic option for patients with hormone receptor positive metastatic breast cancer who do not require treatment with chemotherapy. Also on the same line, the combination of exemestane with everolimus has been proven to be efficacious in this same setting (Baselga, J. et al. N. Engl. J. Med. 2012;366(6):520-529). While all these options create a dilemma for oncologists, they represent a big hope for patients.

Last update: 12 Dec 2012

Conflict of interests: None.

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