Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Feb 12;7(1):11.
doi: 10.1038/s41523-021-00222-y.

Meta-analyses of visceral versus non-visceral metastatic hormone receptor-positive breast cancer treated by endocrine monotherapies

John F R Robertson  1 , Angelo Di Leo  2 , Stephen Johnston  3 , Stephen Chia  4 , Judith M Bliss  5 , Robert J Paridaens  6 , Jasmine Lichfield  7   8 , Ian Bradbury  9 , Christine Campbell  9
Affiliations

Meta-analyses of visceral versus non-visceral metastatic hormone receptor-positive breast cancer treated by endocrine monotherapies

John F R Robertson et al. NPJ Breast Cancer. .

Abstract

Endocrine therapy (ET) is recommended as first-line therapy for the majority of patients with hormone receptor-positive (HR+), human epidermal growth factor 2-negative advanced breast cancer (ABC); however, the efficacy of ET in patients with visceral metastases (VM) versus patients whose disease is limited to non-visceral metastases (non-VM) is debated. Meta-analyses including available data from randomised controlled trials of first- and second-line endocrine monotherapies for patients with HR+ ABC were performed to address this question. In one and two-stage meta-analyses, progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and duration of clinical benefit (DoCB) outcomes were analysed. In the first-line meta-analysis (seven trials; n = 1988) tamoxifen and fulvestrant significantly improved PFS, OS and CBR for patients with non-VM versus those whose disease included VM. The most substantial hazard ratios were observed for fulvestrant 500 mg; 0.56 (95% confidence interval [CI] 0.45-0.70) and 0.55 (95% CI 0.42-0.72) for PFS and OS, respectively. In the second-line meta-analysis (seven trials; n = 2324), all ET combined was more effective (in terms of PFS, OS and DoCB) for non-VM versus VM. In both meta-analyses, patients with non-liver VM had better clinical outcomes than patients with liver VM for all types of ET. Patients whose disease included non-VM sites had better clinical outcomes with endocrine monotherapy compared with patients whose disease included VM. These findings may facilitate better informed treatment decision-making.

PubMed Disclaimer

Conflict of interest statement

J.F.R.R. has received consulting fees from, and has performed contracted research on behalf of, AstraZeneca, Bayer, Novartis and Oncimmune; has given expert testimony for AstraZeneca; and holds stock with Oncimmune. A.D.L. reports personal fees from AstraZeneca, Bayer, Celgene, Daichii-Sankyo, Eisai, Eli Lilly, Genentech, Genomic Health, Ipsen, Pierre Fabre, Roche and Seattle Genetics; and grants and personal fees from Novartis and Pfizer Inc. S.J. has received consultancy fees from, and has performed contacted research on behalf of, AstraZeneca, Eli Lilly, Novartis, Pfizer Inc and Puma Biotechnology; and has been a member of the speakers’ bureaus for AstraZeneca, Eisai, Novartis and Pfizer Inc. S.C. received consulting fees from AstraZeneca, Novartis, Pfizer Inc and Roche; and has performed contracted research on behalf of AstraZeneca, Bristol-Myers Squibb, Genetech, Hoffmann-La Roche, Novartis and Pfizer Inc. J.M.B. has received grant funding and non-financial support from AstraZeneca, Clovis Oncology, Janssen-Cilag, Merck, Pfizer Inc, Puma Biotechnology, and Merck Sharp and Dohme; and grant funding from Medivation. J.L. is an employee of Eisai; and a stockholder and a former employee of AstraZeneca. R.J.P., I.B. and C.C. have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1. Study-selection flow chart.
1 L first line, 2 L second line, AI aromatase inhibitor, BC breast cancer, HR+ hormone receptor-positive, IPD individual patient data, n number of patients, SERD selective estrogen receptor degrader, SERM selective estrogen receptor modulator, VM visceral metastases.
Fig. 2
Fig. 2. Clinical outcome measures for VM versus non-VM in the first-line setting.
a Forest plots of PFS, OS, DoCB and CBR. *Random effect for trial were fitted to AI and all data. †Fixed effects for trial were fitted in all models. ‡OS data for Study 0027 are based on aggregated mature survival data. §Fixed effect for trial was fitted in all models. Fixed-effect model was fitted to the SERD, SERM and all data; random effects for trial were included in the models for AI. b Projected probability of PFS, OS and DoCB. Kaplan–Meier curves are for ET combined and do not include FALCON data. Median (95% CI) PFS/OS/DoCB in months. AI aromatase inhibitor, CBR clinical benefit rate, DoCB duration of clinical benefit, HR hazard ratio, non-VM non-visceral metastases, n number of patients, OS overall survival, PFS progression-free survival, SERD selective estrogen receptor degrader, SERM selective estrogen receptor modulator, VM visceral metastases. Statistics for full models: PFS: SERM: p = 0·008, heterogeneity test p = 0·26; AI: p = 0·122, heterogeneity test p < 0·05; SERD: p < 0·001, heterogeneity test p = 0·40; All: p < 0·001, heterogeneity test p < 0·05. OS: SERM: p = 0·031, heterogeneity test p = 0·21; AI: p = 0·002, heterogeneity test p = 0·24; SERD: p < 0·001, heterogeneity test p = 0·68; All: p < 0·001, heterogeneity test p = 0·24. DoCB: SERM: p = 0·527, heterogeneity test p = 0·57; AI: p = 0·446, heterogeneity test p = 0·33; SERD: p = 0·018, heterogeneity test p = 0·13; All: p = 0·04, heterogeneity test p = 0·28.CBR: SERM: p = 0·009, heterogeneity test p = 0·19, AI: p = 0·388, heterogeneity test p = 0·02; SERD: p < 0·001, heterogeneity test p = 0·78; All: p < 0·001, heterogeneity test p = 0·18.
Fig. 3
Fig. 3. Clinical outcome measures for VLM versus VnLM in the first-line setting.
a Forest plots of PFS, OS, DoCB and CBR. Data for VLM are not available for the EORTC trial. *Fixed effect for trial was fitted in all models. †Random effect for trial were fitted in model for AI. ‡OS data for Study 0027 are based on aggregated mature survival data. b Projected probability of PFS, OS and DoCB. Median (95% CI) PFS/OS/DoCB in months. AI aromatase inhibitor, CBR clinical benefit rate, DoCB duration of clinical benefit, HR hazard ratio, n number of patients, non-VM non-visceral metastases, PFS progression-free survival, OR odds ratio, OS overall survival, SERD selective estrogen receptor degrader, SERM selective estrogen receptor modulator, VLM visceral liver metastases, VM visceral metastases, VnLM visceral non-liver metastases. Statistics for full models: VLM vs VnLM PFS: SERM: p = 0·005, heterogeneity test p = 0·91; AI: p = 0·008, heterogeneity test p = 0·81; SERD: p < 0.001, heterogeneity test p = 0·95; All: p < 0·001, heterogeneity test p = 0·99. OS: SERM: p = 0·020, heterogeneity test p = 0·89; AI: p = 0·106, heterogeneity test p < 0·05; SERD: p < 0.001, heterogeneity test p = 0·34; All: p < 0·001, heterogeneity test p = 0·24. DoCB: SERM: p = 0·255, heterogeneity test p = 0·93; AI: p = 0·229, heterogeneity test p = 1·00; SERD: p < 0·001, heterogeneity test p = 0·08; All: p = 0·001, heterogeneity test p = 0·58. CBR: SERM: p = 0·077, heterogeneity test p = 0·72; AI: p = 0·008, heterogeneity test p = 0·43; SERD: p = 0·012, heterogeneity test p = 0·43; All: p < 0·001, heterogeneity test p = 0·80.
Fig. 4
Fig. 4. Clinical outcome measures for non-VM and VnLM versus VLM in the first-line setting.
a Forest plots of PFS, OS, DoCB and CBR. Data for VLM are not available for the EORTC trial. *Fixed effect for trial was fitted in all models. ‡OS data for Study 0027 are based on aggregated mature survival data. §“one−stage” fixed−effects logistic regression models. b Projected probability of PFS, OS and DoCB. Median (95% CI) PFS/OS/DoCB in months. AI aromatase inhibitor, CBR clinical benefit rate, DoCB duration of clinical benefit, HR hazard ratio, n number of patients, non-VM non-visceral metastases, PFS progression-free survival, OR odds ratio, OS overall survival, SERD selective estrogen receptor degrader, SERM selective estrogen receptor modulato, VLM visceral liver metastases, Non-VM non-visceral metastases, VnLM visceral non-liver metastases. Statistics for full models: VLM vs VnLM vs non-VM. PFS: SERM: Interaction test p = 0.55; AI: Interaction test p = 0.25; SERD: Interaction test p = 0.22; All: Interaction test p = 0.29. OS: SERM: Interaction test p = 0.42; AI: Interaction test p = 0.06; SERD: Interaction test p = 0.54; All: Interaction test p = 0.25. DoCB: SERM: Interaction test p = 0.81; AI: Interaction test p = 0.54: SERD: Interaction test p = 0.07; All: Interaction test p = 0.07. CBR: SERM: Interaction test p = 0.26; AI: Interaction test p = 0.05; SERD: Interaction test p = 0.85; All: Interaction test p = 0.46.
Fig. 5
Fig. 5. Clinical outcomes for VM versus non-VM in the second-line setting.
a Forest plots of PFS, OS, DoCB and CBR. *Fixed effect for trial was fitted in all models. †Fixed-effect model was fitted to the SERD 250 mg, SERD 500 mg and all data; random effects for trial were included in the models for AI. b Projected probability of PFS, OS and DoCB. Median (95% CI) PFS/OS/DoCB in months. AI aromatase inhibitor, CBR clinical benefit rate, DoCB duration of clinical benefit, HR hazard ratio, n number of patients, non-VM non-visceral metastases, PFS progression-free survival, OR odds ratio, OS overall survival, SERD selective estrogen receptor degrader, SERM selective estrogen receptor modulator, VLM visceral liver metastases, VM visceral metastases, VnLM visceral non-liver metastases. Statistics for full models:PFS: AI: p < 0·001, heterogeneity test p = 0·13; SERD (250 mg): p < 0·001, heterogeneity test p = 0·08; SERD (500 mg): p = 0·048, heterogeneity test p = 0·83; All: p < 0·001, heterogeneity test p = 0·17. OS: AI: p = 0·036, heterogeneity test p = 0·35; SERD (250 mg): p < 0·001, heterogeneity test p = 0·95; SERD (500 mg): p = 0·161, heterogeneity test p = 1·00; All: p < 0·001, heterogeneity test p = 0·86. DoCB: AI: p = 0·007, heterogeneity test p = 0·40; SERD (250 mg): p = 0·023, heterogeneity test p = 0·08; SERD (500 mg): p = 0·720, heterogeneity test p = 0·31; All: p < 0·001, heterogeneity test p = 0·19. CBR: AI: p = 0·454, heterogeneity test p = 0·87; SERD (250 mg): p = 0·503, heterogeneity test p = 0·03; SERD (500 mg): p = 0·021, heterogeneity test p = 0·52; All: p = 0·109, heterogeneity test p = 0·10.
Fig. 6
Fig. 6. Clinical outcomes for VLM versus VnLM in the second-line setting.
a Forest plots of PFS, OS, DoCB and CBR. *Random effects for trial were fitted in SERD (500) model. †Fixed effect for trial was fitted in all models. b Projected probability of PFS, OS and DoCB. Median (95% CI) PFS/OS/DoCB in months. AI aromatase inhibitor, CBR clinical benefit rate, DoCB duration of clinical benefit, HR hazard ratio, n number of patients, non-VM non-visceral metastases, PFS progression-free survival, OR odds ratio, OS overall survival, SERD selective estrogen receptor degrader, SERM selective estrogen receptor modulator, VLM visceral liver metastases, VM visceral metastases, VnLM visceral non-liver metastases. Statistics for full models: PFS: AI: p < 0·001, heterogeneity test p = 0·12; SERD (250 mg): p < 0·001, heterogeneity test p = 0·93; SERD (500 mg): p = 0·286, heterogeneity test p < 0·05; All: p < 0·001, heterogeneity test p = 0·20. OS: AI: p < 0·001, heterogeneity test p = 0·78; SERD (250 mg): p < 0·001, heterogeneity test p = 0·95; SERD (500 mg): p = 0·212, heterogeneity test p = 1·00; All: p < 0·001, heterogeneity test p = 0·66. DoCB: AI: p = 0·283, heterogeneity test p = 0·66; SERD (250 mg): p < 0·001, heterogeneity test p = 0·90; SERD (500 mg): p = 0·247, heterogeneity test p < 0·05; All: p < 0·001, heterogeneity test p = 0·35. CBR: AI: p < 0·001, heterogeneity test p = 0·72; SERD (250 mg): p < 0·001, heterogeneity test p = 0·98; SERD (500 mg): p = 0·003, heterogeneity test p = 0·17; All: p < 0·001, heterogeneity test p = 0·93.
Fig. 7
Fig. 7. Clinical outcomes for non-VM and VnLM versus VLM in the second-line setting.
a Forest plots of PFS, OS, DoCB and CBR. *Fixed effect for trial was fitted in all models. †Fixed-effect model was fitted to the AI SERD 250 mg and SERD 500 mg data; random effects for trial were included in the models for all data. §“one−stage” fixed−effects logistic regression models. b Projected probability of PFS, OS and DoCB. Median (95% CI) PFS/OS/DoCB in months. AI aromatase inhibitor, CBR clinical benefit rate, DoCB duration of clinical benefit, HR hazard ratio, n number of patients, non-VM non-visceral metastases, PFS progression-free survival, OR odds ratio, OS overall survival, SERD selective estrogen receptor degrader, SERM selective estrogen receptor modulator, VLM visceral liver metastases, Non-VM non-visceral metastases, VnLM visceral non-liver metastases. VLM vs VnLM vs non-VM. PFS: AI: Interaction test p = 0.15; SERD (250): Interaction test p = 0.18; SERD (500): Interaction test p = 0.05; All: Interaction test p = 0.06. OS: AI: Interaction test p = 0.66; SERD (250): Interaction test p = 0.98; SERD (500): Interaction test p = 0.98; All: Interaction test p = 0.78. DoCB: AI: Interaction test p = 0.59; SERD (250): Interaction test p = 0.10; SERD (500): Interaction test p = 0.11; All: Interaction test p = 0.03.CBR: AI: Interaction test p = 0.90; SERD (250): Interaction test p = 0.20; SERD (500): Interaction test p = 0.33; All: Interaction test p = 0.47.
See this image and copyright information in PMC

References

    1. Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018). - PubMed
    1. Anderson WF, Chatterjee N, Ershler WB, Brawley OW. Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database. Breast Cancer Res. Treat. 2002;76:27–36. doi: 10.1023/A:1020299707510. - DOI - PubMed
    1. Rosa Mendoza ES, Moreno E, Caguioa PB. Predictors of early distant metastasis in women with breast cancer. J. Cancer Res. Clin. Oncol. 2013;139:645–652. doi: 10.1007/s00432-012-1367-z. - DOI - PMC - PubMed
    1. Harb WA. Management of patients with hormone receptor-positive breast cancer with visceral disease: challenges and treatment options. Cancer Manag. Res. 2015;7:37–46. doi: 10.2147/CMAR.S72592. - DOI - PMC - PubMed
    1. Cardoso F, et al. 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4) dagger. Ann. Oncol. 2018;29:1634–1657. doi: 10.1093/annonc/mdy192. - DOI - PMC - PubMed

LinkOut - more resources