Journal Article
. 2019 Mar;380(13).
doi: 10.1056/NEJMoa1811714.

Overall Survival with Fulvestrant plus Anastrozole in Metastatic Breast Cancer

Rita S Mehta 1 William E Barlow 1 Kathy S Albain 1 Ted A Vandenberg 1 Shaker R Dakhil 1 Nagendra R Tirumali 1 Danika L Lew 1 Daniel F Hayes 1 Julie R Gralow 1 Hannah H Linden 1 Robert B Livingston 1 Gabriel N Hortobagyi 1 
Affiliations
  • PMID: 30917258
  •     16 References
  •     19 citations

Abstract

Background: We previously reported prolonged progression-free survival and marginally prolonged overall survival among postmenopausal patients with hormone receptor-positive metastatic breast cancer who had been randomly assigned to receive the aromatase inhibitor anastrozole plus the selective estrogen-receptor down-regulator fulvestrant, as compared with anastrozole alone, as first-line therapy. We now report final survival outcomes.

Methods: We randomly assigned patients to receive either anastrozole or fulvestrant plus anastrozole. Randomization was stratified according to adjuvant tamoxifen use. Analysis of survival was performed by means of two-sided stratified log-rank tests and Cox regression. Efficacy and safety were compared between the two groups, both overall and in subgroups.

Results: Of 707 patients who had undergone randomization, 694 had data available for analysis. The combination-therapy group had 247 deaths among 349 women (71%) and a median overall survival of 49.8 months, as compared with 261 deaths among 345 women (76%) and a median overall survival of 42.0 months in the anastrozole-alone group, a significant difference (hazard ratio for death, 0.82; 95% confidence interval [CI], 0.69 to 0.98; P = 0.03 by the log-rank test). In a subgroup analysis of the two strata, overall survival among women who had not received tamoxifen previously was longer with the combination therapy than with anastrozole alone (median, 52.2 months and 40.3 months, respectively; hazard ratio, 0.73; 95% CI, 0.58 to 0.92); among women who had received tamoxifen previously, overall survival was similar in the two groups (median, 48.2 months and 43.5 months, respectively; hazard ratio, 0.97; 95% CI, 0.74 to 1.27) (P = 0.09 for interaction). The incidence of long-term toxic effects of grade 3 to 5 was similar in the two groups. Approximately 45% of the patients in the anastrozole-alone group crossed over to receive fulvestrant.

Conclusions: The addition of fulvestrant to anastrozole was associated with increased long-term survival as compared with anastrozole alone, despite substantial crossover to fulvestrant after progression during therapy with anastrozole alone. The results suggest that the benefit was particularly notable in patients without previous exposure to adjuvant endocrine therapy. (Funded by the National Cancer Institute and AstraZeneca; ClinicalTrials.gov number, NCT00075764.).

Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial.
John F R Robertson, Igor M Bondarenko, +15 authors, Matthew J Ellis.
Lancet, 2016 Dec 03; 388(10063). PMID: 27908454
Highly Cited.
Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer.
Gabriel N Hortobagyi, Salomon M Stemmer, +34 authors, Joyce O'Shaughnessy.
N Engl J Med, 2016 Nov 03; 375(18). PMID: 27717303
Highly Cited.
MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer.
Matthew P Goetz, Masakazu Toi, +15 authors, Angelo Di Leo.
J Clin Oncol, 2017 Oct 03; 35(32). PMID: 28968163
Highly Cited.
Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer.
Nicholas C Turner, Dennis J Slamon, +16 authors, Massimo Cristofanilli.
N Engl J Med, 2018 Oct 23; 379(20). PMID: 30345905
Highly Cited.
Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial.
Debu Tripathy, Seock-Ah Im, +23 authors, Yen-Shen Lu.
Lancet Oncol, 2018 May 29; 19(7). PMID: 29804902
Highly Cited.
The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study.
Richard S Finn, John P Crown, +15 authors, Dennis J Slamon.
Lancet Oncol, 2014 Dec 20; 16(1). PMID: 25524798
Highly Cited.
Phase III Trial Evaluating Letrozole As First-Line Endocrine Therapy With or Without Bevacizumab for the Treatment of Postmenopausal Women With Hormone Receptor-Positive Advanced-Stage Breast Cancer: CALGB 40503 (Alliance).
Maura N Dickler, William T Barry, +12 authors, Clifford A Hudis.
J Clin Oncol, 2016 May 04; 34(22). PMID: 27138575    Free PMC article.
Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer: the letrozole/fulvestrant and avastin (LEA) study.
Miguel Martín, Sibylle Loibl, +16 authors, Juan R De la Haba-Rodriguez.
J Clin Oncol, 2015 Feb 19; 33(9). PMID: 25691671
Combination anastrozole and fulvestrant in metastatic breast cancer.
Rita S Mehta, William E Barlow, +8 authors, Gabriel N Hortobagyi.
N Engl J Med, 2012 Aug 03; 367(5). PMID: 22853014    Free PMC article.
Highly Cited.
Palbociclib and Letrozole in Advanced Breast Cancer.
Richard S Finn, Miguel Martin, +12 authors, Dennis J Slamon.
N Engl J Med, 2016 Dec 14; 375(20). PMID: 27959613
Highly Cited.
Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial.
Stephen Rd Johnston, Lucy S Kilburn, +19 authors, SoFEA investigators.
Lancet Oncol, 2013 Aug 02; 14(10). PMID: 23902874
Highly Cited.
Fulvestrant 500 mg Versus Anastrozole 1 mg for the First-Line Treatment of Advanced Breast Cancer: Overall Survival Analysis From the Phase II FIRST Study.
Matthew J Ellis, Antonio Llombart-Cussac, +5 authors, John F R Robertson.
J Clin Oncol, 2015 Sep 16; 33(32). PMID: 26371134    Free PMC article.
Highly Cited.
Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer.
Angelo Di Leo, Guy Jerusalem, +12 authors, Miguel Martin.
J Clin Oncol, 2010 Sep 22; 28(30). PMID: 20855825
Highly Cited.
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.
Jonas Bergh, Per-Ebbe Jönsson, +6 authors, Roger Henriksson.
J Clin Oncol, 2012 Mar 01; 30(16). PMID: 22370325
Highly Cited.
First-line vs second-line fulvestrant for hormone receptor-positive advanced breast cancer: A post-hoc analysis of the CONFIRM study.
Angelo Di Leo, Guy Jerusalem, +5 authors, Miguel Martin.
Breast, 2018 Jan 13; 38. PMID: 29324303
Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3.
Dennis J Slamon, Patrick Neven, +18 authors, Guy Jerusalem.
J Clin Oncol, 2018 Jun 05; 36(24). PMID: 29860922
Highly Cited.
Using frailty and quality of life measures in clinical care of the elderly in Canada to predict death, nursing home transfer and hospitalisation - the frailty and ageing cohort study.
Ted Rosenberg, Patrick Montgomery, Vikki Hay, Rory Lattimer.
BMJ Open, 2019 Nov 15; 9(11). PMID: 31722953    Free PMC article.
Rethinking the combination treatment of fulvestrant and anastrozole for metastatic breast cancer: an integrated reanalysis of aromatase-estrogen receptor axis.
Xing Huang.
Clin Transl Med, 2019 Nov 20; 8(1). PMID: 31741086    Free PMC article.
CDK4/6 inhibition in low burden and extensive metastatic breast cancer: summary of an ESMO Open-Cancer Horizons pro and con discussion.
Ahmad Awada, Joseph Gligorov, +3 authors, Christoph Zielinski.
ESMO Open, 2019 Dec 05; 4(6). PMID: 31798979    Free PMC article.
Review.
Should All Patients With HR-Positive HER2-Negative Metastatic Breast Cancer Receive CDK 4/6 Inhibitor As First-Line Based Therapy? A Network Meta-Analysis of Data from the PALOMA 2, MONALEESA 2, MONALEESA 7, MONARCH 3, FALCON, SWOG and FACT Trials.
Valentina Rossi, Paola Berchialla, +11 authors, Alessandra Fabi.
Cancers (Basel), 2019 Nov 14; 11(11). PMID: 31717791    Free PMC article.
[Ribociclib in combination with endocrine therapy improves overall survival of pre-/perimenopausal breast cancer patients].
David Krug, Alexander Fabian, Jürgen Dunst.
Strahlenther Onkol, 2020 Jan 18; 196(3). PMID: 31950201
Does adjuvant therapy reduce postmetastatic survival?
M K Fink.
Ann Oncol, 2019 May 17; 30(8). PMID: 31095301    Free PMC article.
International Consensus Conference for Advanced Breast Cancer, Lisbon 2019: ABC5 Consensus - Assessment by a German Group of Experts.
Christoph Thomssen, Diana Lüftner, +21 authors, Katja Ziegler-Löhr.
Breast Care (Basel), 2020 Apr 02; 15(1). PMID: 32231503    Free PMC article.
Drug repurposing for breast cancer therapy: Old weapon for new battle.
Sadhna Aggarwal, Sumit Singh Verma, Sumit Aggarwal, Subash Chandra Gupta.
Semin Cancer Biol, 2019 Sep 25;. PMID: 31550502    Free PMC article.
Review.
Breast Cancer: A Molecularly Heterogenous Disease Needing Subtype-Specific Treatments.
Ugo Testa, Germana Castelli, Elvira Pelosi.
Med Sci (Basel), 2020 Mar 27; 8(1). PMID: 32210163    Free PMC article.
Review.
Novel prognostic nomograms for female patients with breast cancer and bone metastasis at presentation.
Zhan Wang, Yonggang Cheng, +8 authors, Zhaoming Ye.
Ann Transl Med, 2020 Apr 21; 8(5). PMID: 32309344    Free PMC article.
First-line endocrine therapy for postmenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer: a systematic review and meta-analysis.
Tatsunori Shimoi, Yasuaki Sagara, +2 authors, Hiroji Iwata.
Breast Cancer, 2020 Feb 12; 27(3). PMID: 32043218    Free PMC article.
Major clinical research advances in gynecologic cancer in 2019.
Miseon Kim, Dong Hoon Suh, +6 authors, Jae Weon Kim.
J Gynecol Oncol, 2020 Apr 23; 31(3). PMID: 32319232    Free PMC article.
Review.
Advances in endocrine and targeted therapy for hormone-receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer.
Le-Sang Shen, Xiao-Yan Jin, +2 authors, Jian Huang.
Chin Med J (Engl), 2020 Apr 09; 133(9). PMID: 32265426    Free PMC article.
ABC5 International Consensus Conference on Advanced Breast Cancer, Lisbon, 16 November 2019: Commentary by the German panel of experts on the ABC5 voting results.
Michael Untch, Rachel Würstlein, +20 authors, Nadia Harbeck.
Geburtshilfe Frauenheilkd, 2020 Jun 23; 80(6). PMID: 32565549    Free PMC article.
Case report: 5-year progression free survival and complete liver response in a patient with metastatic breast cancer treated with everolimus plus exemestane.
Eriseld Krasniqi, Giacomo Barchiesi, +4 authors, Patrizia Vici.
Medicine (Baltimore), 2020 Aug 07; 99(31). PMID: 32756099    Free PMC article.
Half-dose fulvestrant plus anastrozole as a first-line treatment for hormone receptor-positive metastatic breast cancer: a cost-effectiveness analysis.
Xiaoting Huang, Xiuhua Weng, +5 authors, Pinfang Huang.
BMJ Open, 2020 Sep 02; 10(8). PMID: 32868353    Free PMC article.
Endocrine-Resistant Breast Cancer: Mechanisms and Treatment.
Andreas D Hartkopf, Eva-Maria Grischke, Sara Y Brucker.
Breast Care (Basel), 2020 Sep 29; 15(4). PMID: 32982644    Free PMC article.
Review.
Metastatic status of sentinel lymph nodes in breast cancer determined with photoacoustic microscopy via dual-targeting nanoparticles.
Yanfeng Dai, Xiang Yu, +5 authors, Zhihong Zhang.
Light Sci Appl, 2020 Oct 06; 9. PMID: 33014359    Free PMC article.
The efficacy of gefitinib supplementation for breast cancer: A meta-analysis of randomized controlled studies.
Jing Ye, Tian Tian, Xiaopin Chen.
Medicine (Baltimore), 2020 Oct 31; 99(43). PMID: 33120749    Free PMC article.
Systematic Review.