Combination endocrine treatments unproven in breast cancer
Authors: Aman U Buzdar
Journal: The Lancet Oncology (2013)

Ovarian ablation, which was introduced more than 100 years ago, was the first endocrine treatment for advanced breast cancer, followed by adrenalectomy and hypophysectomy. These ablative therapies have since been replaced by antioestrogen treatments, luteinising-hormone-releasing hormone agonists, and aromatase inhibitors.1Barrios C Forbes JF Jonat W et al.The sequential use of endocrine treatment for advanced breast cancer: where are we?.Ann Oncol. 2012; 23: 1378-1386Crossref PubMed Scopus (49) Google Scholar Other endocrine treatments with different mechanisms of action have also become available for breast cancer: oestrogens, progestins, androgens, antiandrogens, and selective oestrogen-receptor downregulators.Although the superiority of combinations of chemotherapeutic agents with different mechanisms of action to single agents has been established in the treatment of early and advanced breast cancer,2Early Breast Cancer Trialists' Collaborative GroupEffects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer: an overview of 61 randomized trials among 28 896 women.N Engl J Med. 1988; 319: 1681-1692Crossref PubMed Scopus (869) Google Scholar that of combinations of endocrine treatments has not been shown.1Barrios C Forbes JF Jonat W et al.The sequential use of endocrine treatment for advanced breast cancer: where are we?.Ann Oncol. 2012; 23: 1378-1386Crossref PubMed Scopus (49) Google Scholar Several combinations of hormonal agents have been assessed in patients with advanced breast cancer, with no consistent improvement in either time to progression of disease or survival.3Michaud LB Jones KL Buzdar AU Combination endocrine therapy in the management of breast cancer.Oncologist. 2001; 6: 538-546Crossref PubMed Scopus (18) Google Scholar Additionally, the combination of an antioestrogen treatment (tamoxifen) and ovarian suppression with a luteinising-hormone-releasing hormone agonist does not lead to improvements in disease-free or overall survival when compared with antioestrogen treatment alone in premenopausal women with early breast cancer.4LHRH-agonists in Early Breast Cancer Overview groupUse of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials.Lancet. 2007; 369: 1711-1723Summary Full Text Full Text PDF PubMed Scopus (331) Google Scholar A large, prospective, double-blind trial5The ATAC (ArimidexTamoxifen Alone or in Combination) Trialists' GroupAnastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial.Lancet. 2002; 359: 2131-2139Summary Full Text Full Text PDF PubMed Scopus (1849) Google Scholar comparing tamoxifen with an aromatase inhibitor (anastrozole) and tamoxifen or anastrozole alone as adjuvant treatment for breast cancer showed that the combination did not improve either disease-free or overall survival. Indeed, the group who received the combination was discontinued after initial analysis of the data.5The ATAC (ArimidexTamoxifen Alone or in Combination) Trialists' GroupAnastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial.Lancet. 2002; 359: 2131-2139Summary Full Text Full Text PDF PubMed Scopus (1849) Google ScholarBecause preclinical data6Jelovac D Macedo L Goloubeva OG Handratta V Brodie AM Additive antitumor effect of aromatase inhibitor letrozole and antiestrogen fulvestrant in a postmenopausal breast cancer model.Cancer Res. 2005; 65: 5439-5444Crossref PubMed Scopus (96) Google Scholar suggested that the combination of an aromatase inhibitor and fulvestrant—a member of the newest class of hormonal agents, selective oestrogen receptor downregulators—was superior to either agent alone against breast tumours in mice, three prospective studies7Johnston SRD Kilburn LS Ellis P et al.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.Lancet Oncol. 2013; (published online July 29.)http://dx.doi.org/10.1016/S1470-2045(13)70322-XPubMed Google Scholar, 8Bergh J Jönsson PE Lidbrink EK et al.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.J Clin Oncol. 2012; 30: 1919-1925Crossref PubMed Scopus (229) Google Scholar, 9Mehta RS Barlow WE Albain KS et al.Combination anastrozole and fulvestrant in metastatic breast cancer.N Engl J Med. 2012; 367: 435-444Crossref PubMed Scopus (323) Google Scholar have assessed this approach in postmenopausal women with advanced breast cancer. In The Lancet Oncology, Stephen Johnston and colleagues report results of a phase 3, European, multicentre trial.7Johnston SRD Kilburn LS Ellis P et al.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.Lancet Oncol. 2013; (published online July 29.)http://dx.doi.org/10.1016/S1470-2045(13)70322-XPubMed Google Scholar Postmenopausal women with hormone-receptor-positive breast cancer who had relapsed or progressed while receiving a non-steroidal aromatase inhibitor were randomly assigned to receive fulvestrant plus anastrozole, fulvestrant plus anastrozole-matched placebo, or the steroidal aromatase inhibitor exemestane. No improvement in progression-free survival was recorded in the group who received fulvestrant plus anastrozole (median 4·4 months, 95% CI 3·4–5·4) compared with fulvestrant plus placebo (4·8 months, 3·6–5·5; hazard ratio [HR] 1·00, 95% CI 0·83–1·21; log-rank p=0·98), or in the group given fulvestrant plus placebo compared with exemestane (3·4 months, 3·0–4·6; HR 0·95, 0·79–1·14; log-rank p=0·56).Another phase 3 study8Bergh J Jönsson PE Lidbrink EK et al.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.J Clin Oncol. 2012; 30: 1919-1925Crossref PubMed Scopus (229) Google Scholar comparing the combination of anastrozole and fulvestrant as first-line treatment in postmenopausal patients with hormone-receptor-positive advanced breast cancer also showed no advantages in terms of clinical efficacy for the combination compared with anastrozole alone. By contrast, a phase 3 trial from North America9Mehta RS Barlow WE Albain KS et al.Combination anastrozole and fulvestrant in metastatic breast cancer.N Engl J Med. 2012; 367: 435-444Crossref PubMed Scopus (323) Google Scholar compared the combination of anastrozole and fulvestrant with anastrozole alone as first-line treatment in postmenopausal women with hormone-receptor-positive advanced breast cancer, and showed increased control of disease and survival with the combination of fulvestrant and anastrozole. However, the apparent improvements could have been due to imbalances in prognostic characteristics between the two study groups.Therefore, there are still no consistent data to support the notion that combination endocrine therapy is superior to treatment with one agent in early or advanced breast cancer. However, as understanding of the mechanisms of resistance to endocrine treatment has improved, targeting of some pathways has resulted in new approaches that offer hope for disease control. For example, postmenopausal patients with hormone-receptor-positive, HER2-positive advanced breast cancer given endocrine and anti-HER2 treatments have had longer control of disease than have those given endocrine treatment alone.1Barrios C Forbes JF Jonat W et al.The sequential use of endocrine treatment for advanced breast cancer: where are we?.Ann Oncol. 2012; 23: 1378-1386Crossref PubMed Scopus (49) Google Scholar Indeed, a combination of an aromatase inhibitor with an anti-HER2 treatment has been approved by the US Food and Drug Administration for the management of postmenopausal patients with hormone-receptor-positive, HER2-positive advanced breast cancer.1Barrios C Forbes JF Jonat W et al.The sequential use of endocrine treatment for advanced breast cancer: where are we?.Ann Oncol. 2012; 23: 1378-1386Crossref PubMed Scopus (49) Google Scholar Another effective approach has been the combination of an mTOR inhibitor (everolimus) with exemestane.10Baselga J Campone M Piccart M et al.Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.N Engl J Med. 2012; 366: 520-529Crossref PubMed Scopus (2168) Google Scholar The combination of exemestane with a histone deacetylase inhibitor (entinostat) has also had encouraging results.11Yardley DA Ismail-Khan RR Melichar B et al.Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor.J Clin Oncol. 2013; 31: 2128-2135Crossref PubMed Scopus (309) Google ScholarIn conclusion, a combination of endocrine agents with different mechanisms of action will probably not result in a meaningful improvement in outcomes for patients with breast cancer. Sequential use of endocrine agents remains the standard of care in patients with advanced breast cancer. However, understanding of the mechanisms of resistance to hormonal agents continues to advance, and combinations of endocrine treatment with targeted agents that block resistance pathways should improve the outlook for patients with breast cancer that is resistant to endocrine treatment.I declare that I have no conflicts of interest. Ovarian ablation, which was introduced more than 100 years ago, was the first endocrine treatment for advanced breast cancer, followed by adrenalectomy and hypophysectomy. These ablative therapies have since been replaced by antioestrogen treatments, luteinising-hormone-releasing hormone agonists, and aromatase inhibitors.1Barrios C Forbes JF Jonat W et al.The sequential use of endocrine treatment for advanced breast cancer: where are we?.Ann Oncol. 2012; 23: 1378-1386Crossref PubMed Scopus (49) Google Scholar Other endocrine treatments with different mechanisms of action have also become available for breast cancer: oestrogens, progestins, androgens, antiandrogens, and selective oestrogen-receptor downregulators. Although the superiority of combinations of chemotherapeutic agents with different mechanisms of action to single agents has been established in the treatment of early and advanced breast cancer,2Early Breast Cancer Trialists' Collaborative GroupEffects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer: an overview of 61 randomized trials among 28 896 women.N Engl J Med. 1988; 319: 1681-1692Crossref PubMed Scopus (869) Google Scholar that of combinations of endocrine treatments has not been shown.1Barrios C Forbes JF Jonat W et al.The sequential use of endocrine treatment for advanced breast cancer: where are we?.Ann Oncol. 2012; 23: 1378-1386Crossref PubMed Scopus (49) Google Scholar Several combinations of hormonal agents have been assessed in patients with advanced breast cancer, with no consistent improvement in either time to progression of disease or survival.3Michaud LB Jones KL Buzdar AU Combination endocrine therapy in the management of breast cancer.Oncologist. 2001; 6: 538-546Crossref PubMed Scopus (18) Google Scholar Additionally, the combination of an antioestrogen treatment (tamoxifen) and ovarian suppression with a luteinising-hormone-releasing hormone agonist does not lead to improvements in disease-free or overall survival when compared with antioestrogen treatment alone in premenopausal women with early breast cancer.4LHRH-agonists in Early Breast Cancer Overview groupUse of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials.Lancet. 2007; 369: 1711-1723Summary Full Text Full Text PDF PubMed Scopus (331) Google Scholar A large, prospective, double-blind trial5The ATAC (ArimidexTamoxifen Alone or in Combination) Trialists' GroupAnastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial.Lancet. 2002; 359: 2131-2139Summary Full Text Full Text PDF PubMed Scopus (1849) Google Scholar comparing tamoxifen with an aromatase inhibitor (anastrozole) and tamoxifen or anastrozole alone as adjuvant treatment for breast cancer showed that the combination did not improve either disease-free or overall survival. Indeed, the group who received the combination was discontinued after initial analysis of the data.5The ATAC (ArimidexTamoxifen Alone or in Combination) Trialists' GroupAnastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial.Lancet. 2002; 359: 2131-2139Summary Full Text Full Text PDF PubMed Scopus (1849) Google Scholar Because preclinical data6Jelovac D Macedo L Goloubeva OG Handratta V Brodie AM Additive antitumor effect of aromatase inhibitor letrozole and antiestrogen fulvestrant in a postmenopausal breast cancer model.Cancer Res. 2005; 65: 5439-5444Crossref PubMed Scopus (96) Google Scholar suggested that the combination of an aromatase inhibitor and fulvestrant—a member of the newest class of hormonal agents, selective oestrogen receptor downregulators—was superior to either agent alone against breast tumours in mice, three prospective studies7Johnston SRD Kilburn LS Ellis P et al.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.Lancet Oncol. 2013; (published online July 29.)http://dx.doi.org/10.1016/S1470-2045(13)70322-XPubMed Google Scholar, 8Bergh J Jönsson PE Lidbrink EK et al.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.J Clin Oncol. 2012; 30: 1919-1925Crossref PubMed Scopus (229) Google Scholar, 9Mehta RS Barlow WE Albain KS et al.Combination anastrozole and fulvestrant in metastatic breast cancer.N Engl J Med. 2012; 367: 435-444Crossref PubMed Scopus (323) Google Scholar have assessed this approach in postmenopausal women with advanced breast cancer. In The Lancet Oncology, Stephen Johnston and colleagues report results of a phase 3, European, multicentre trial.7Johnston SRD Kilburn LS Ellis P et al.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.Lancet Oncol. 2013; (published online July 29.)http://dx.doi.org/10.1016/S1470-2045(13)70322-XPubMed Google Scholar Postmenopausal women with hormone-receptor-positive breast cancer who had relapsed or progressed while receiving a non-steroidal aromatase inhibitor were randomly assigned to receive fulvestrant plus anastrozole, fulvestrant plus anastrozole-matched placebo, or the steroidal aromatase inhibitor exemestane. No improvement in progression-free survival was recorded in the group who received fulvestrant plus anastrozole (median 4·4 months, 95% CI 3·4–5·4) compared with fulvestrant plus placebo (4·8 months, 3·6–5·5; hazard ratio [HR] 1·00, 95% CI 0·83–1·21; log-rank p=0·98), or in the group given fulvestrant plus placebo compared with exemestane (3·4 months, 3·0–4·6; HR 0·95, 0·79–1·14; log-rank p=0·56). Another phase 3 study8Bergh J Jönsson PE Lidbrink EK et al.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.J Clin Oncol. 2012; 30: 1919-1925Crossref PubMed Scopus (229) Google Scholar comparing the combination of anastrozole and fulvestrant as first-line treatment in postmenopausal patients with hormone-receptor-positive advanced breast cancer also showed no advantages in terms of clinical efficacy for the combination compared with anastrozole alone. By contrast, a phase 3 trial from North America9Mehta RS Barlow WE Albain KS et al.Combination anastrozole and fulvestrant in metastatic breast cancer.N Engl J Med. 2012; 367: 435-444Crossref PubMed Scopus (323) Google Scholar compared the combination of anastrozole and fulvestrant with anastrozole alone as first-line treatment in postmenopausal women with hormone-receptor-positive advanced breast cancer, and showed increased control of disease and survival with the combination of fulvestrant and anastrozole. However, the apparent improvements could have been due to imbalances in prognostic characteristics between the two study groups. Therefore, there are still no consistent data to support the notion that combination endocrine therapy is superior to treatment with one agent in early or advanced breast cancer. However, as understanding of the mechanisms of resistance to endocrine treatment has improved, targeting of some pathways has resulted in new approaches that offer hope for disease control. For example, postmenopausal patients with hormone-receptor-positive, HER2-positive advanced breast cancer given endocrine and anti-HER2 treatments have had longer control of disease than have those given endocrine treatment alone.1Barrios C Forbes JF Jonat W et al.The sequential use of endocrine treatment for advanced breast cancer: where are we?.Ann Oncol. 2012; 23: 1378-1386Crossref PubMed Scopus (49) Google Scholar Indeed, a combination of an aromatase inhibitor with an anti-HER2 treatment has been approved by the US Food and Drug Administration for the management of postmenopausal patients with hormone-receptor-positive, HER2-positive advanced breast cancer.1Barrios C Forbes JF Jonat W et al.The sequential use of endocrine treatment for advanced breast cancer: where are we?.Ann Oncol. 2012; 23: 1378-1386Crossref PubMed Scopus (49) Google Scholar Another effective approach has been the combination of an mTOR inhibitor (everolimus) with exemestane.10Baselga J Campone M Piccart M et al.Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.N Engl J Med. 2012; 366: 520-529Crossref PubMed Scopus (2168) Google Scholar The combination of exemestane with a histone deacetylase inhibitor (entinostat) has also had encouraging results.11Yardley DA Ismail-Khan RR Melichar B et al.Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor.J Clin Oncol. 2013; 31: 2128-2135Crossref PubMed Scopus (309) Google Scholar In conclusion, a combination of endocrine agents with different mechanisms of action will probably not result in a meaningful improvement in outcomes for patients with breast cancer. Sequential use of endocrine agents remains the standard of care in patients with advanced breast cancer. However, understanding of the mechanisms of resistance to hormonal agents continues to advance, and combinations of endocrine treatment with targeted agents that block resistance pathways should improve the outlook for patients with breast cancer that is resistant to endocrine treatment. I declare that I have no conflicts of interest. 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 trialAfter loss of response to NSAIs in postmenopausal women with hormone-receptor-positive advanced breast cancer, maximum double endocrine treatment with 250 mg fulvestrant combined with oestrogen deprivation is no better than either fulvestrant alone or exemestane. 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