Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 3/2019

Open Access 01-08-2019 | Breast Cancer | Review

Surrogate threshold effect based on a meta-analysis for the predictive value of progression-free survival for overall survival in hormone receptor-positive, HER2-negative metastatic breast cancer

Authors: Michael Patrick Lux, Sarah Böhme, Stephanie Hücherig, Ulli Jeratsch, Niclas Kürschner, Diana Lüftner

Published in: Breast Cancer Research and Treatment | Issue 3/2019

Login to get access

Abstract

Purpose

Clinical trials investigating therapies for metastatic breast cancer (mBC) generally use progression-free survival (PFS) as primary endpoint, which is not accepted as patient-relevant outcome within the German benefit assessment. Hence a validation of PFS as surrogate endpoint for overall survival (OS) is needed, e.g., in the indication of HR+, HER2-negative mBC.

Methods

A systematic search was conducted. RCT were included if at least one study arm investigated fulvestrant, letrozole, tamoxifen, exemestane, or anastrozole. Additionally, hazard ratios reported for OS/PFS including confidence interval or standard error were mandatory. Pearson correlation coefficient was calculated to estimate the relation of surrogate endpoint PFS and patient-relevant outcome OS as well as the surrogate threshold effect (STE) which is used to determine thresholds for the estimate of the surrogate endpoint.

Results

16 studies with 5324 patients in total were included in the analyses. The correlation between hazard ratios of PFS and OS was statistically significant (r = 0.72, 95% CI 0.35–0.90) representing a positive linear relationship. STE analysis was applied. The meta-regression model revealed a STE for HRPFS of 0.60 and sensitivity analyses underlined robustness of the results.

Conclusions

Based on the derived STE, it is possible to draw conclusions on a significant effect in OS for a hypothetical trial demonstrating an upper confidence limit of HRPFS < 0.60 in PFS. However, only final OS results are able to confirm if a clinical relevant difference in survival time can be achieved.
Appendix
Available only for authorised users
Literature
1.
2.
Saad ED, Katz A (2009) Progression-free survival and time to progression as primary end points in advanced breast cancer: often used, sometimes loosely defined. Ann Oncol 20(3):460–464CrossRef
3.
Burzykowski T, Buyse M, Piccart-Gebhart MJ, Sledge G, Carmichael J, Luck HJ et al (2008) Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer. J Clin Oncol 26(12):1987–1992CrossRef
4.
5.
6.
Seidman AD, Bordeleau L, Fehrenbacher L, Barlow WE, Perlmutter J, Rubinstein L et al (2018) National Cancer Institute Breast Cancer Steering Committee Working Group Report on meaningful and appropriate end points for clinical trials in metastatic breast cancer. J Clin Oncol. 36(32):3259–3268
7.
8.
Di Leo A, Bleiberg H, Buyse M (2003) Overall survival is not a realistic end point for clinical trials of new drugs in advanced solid tumors: a critical assessment based on recently reported phase III trials in colorectal and breast cancer. J Clin Oncol 21(10):2045–2047CrossRef
9.
Sargent DJ, Hayes DF (2008) Assessing the measure of a new drug: is survival the only thing that matters? J Clin Oncol 26(12):1922–1923CrossRef
10.
Chabot I, Rocchi A (2014) Oncology drug health technology assessment recommendations: Canadian versus UK experiences. Clinicoecon Outcomes Res 6:357–367CrossRef
11.
Thill M, Liedtke C, Solomayer EF, Muller V, Janni W, Schmidt M et al (2017) AGO recommendations for the diagnosis and treatment of patients with advanced and metastatic breast cancer: update 2017. Breast Care (Basel) 12(3):184–191CrossRef
12.
Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) (2011) IQWiG-Berichte Nr. 80—Aussagekraft von Surrogatendpunkten in der Onkologie. Rapid Report
13.
Tumorregister München (2015) Spezielle Auswertungen Mammkarzinom (C50): Metastasierte Patientinnen—Diagnosejahr 2002–2013
14.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247CrossRef
15.
Burzykowski T, Molenberghs G, Buyse M (2005) The evaluation of surrogate endpoints. Springer, New YorkCrossRef
16.
17.
Viechtbauer W (2010) Conducting meta-analyses in R with the metafor Package. J Stat Softw 36(3):1–48CrossRef
18.
Bergh J, Jonsson PE, Lidbrink EK, Trudeau M, Eiermann W, Brattstrom D et al (2012) 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 30(16):1919–1925CrossRef
19.
Dickler MN, Barry WT, Cirrincione CT, Ellis MJ, Moynahan ME, Innocenti F et al (2016) 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). J Clin Oncol 34(22):2602–2609CrossRef
20.
Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G et al (2012) Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 30(22):2718–2724CrossRef
21.
Burstein HJ, Cirrincione CT, Barry WT, Chew HK, Tolaney SM, Lake DE et al (2014) Endocrine therapy with or without inhibition of epidermal growth factor receptor and human epidermal growth factor receptor 2: a randomized, double-blind, placebo-controlled phase III trial of fulvestrant with or without lapatinib for postmenopausal women with hormone receptor-positive advanced breast cancer-CALGB 40302 (alliance). J Clin Oncol 32(35):3959–3966CrossRef
22.
Clemons MJ, Cochrane B, Pond GR, Califaretti N, Chia SK, Dent RA et al (2014) Randomised, phase II, placebo-controlled, trial of fulvestrant plus vandetanib in postmenopausal women with bone only or bone predominant, hormone-receptor-positive metastatic breast cancer (MBC): the OCOG ZAMBONEY study. Breast Cancer Res Treat 146(1):153–162CrossRef
23.
Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R et al (2010) 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. J Clin Oncol 28(30):4594–4600CrossRef
24.
Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R et al (2014) Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial. J Natl Cancer Inst 106(1):djt337CrossRef
25.
Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO et al (2015) 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. Lancet Oncol 16(1):25–35CrossRef
26.
Iwata H, Masuda N, Ohno S, Rai Y, Sato Y, Ohsumi S et al (2013) A randomized, double-blind, controlled study of exemestane versus anastrozole for the first-line treatment of postmenopausal Japanese women with hormone-receptor-positive advanced breast cancer. Breast Cancer Res Treat 139(2):441–451CrossRef
27.
Johnston SR, Kilburn LS, Ellis P, Dodwell D, Cameron D, Hayward L et al (2013) 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 14(10):989–998CrossRef
28.
Llombart-Cussac A, Ruiz A, Anton A, Barnadas A, Antolin S, Ales-Martinez JE et al (2012) Exemestane versus anastrozole as front-line endocrine therapy in postmenopausal patients with hormone receptor-positive, advanced breast cancer: final results from the Spanish Breast Cancer Group 2001-03 phase 2 randomized trial. Cancer 118(1):241–247CrossRef
29.
Martin M, Loibl S, von Minckwitz G, Morales S, Martinez N, Guerrero A et al (2015) 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. J Clin Oncol 33(9):1045–1052CrossRef
30.
Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR et al (2012) Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med 367(5):435–444CrossRef
31.
Piccart M, Hortobagyi GN, Campone M, Pritchard KI, Lebrun F, Ito Y et al (2014) Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2dagger. Ann Oncol 25(12):2357–2362CrossRef
32.
Robertson JF, Ferrero JM, Bourgeois H, Kennecke H, de Boer RH, Jacot W et al (2013) Ganitumab with either exemestane or fulvestrant for postmenopausal women with advanced, hormone-receptor-positive breast cancer: a randomised, controlled, double-blind, phase 2 trial. Lancet Oncol 14(3):228–235CrossRef
33.
Yamamoto Y, Ishikawa T, Hozumi Y, Ikeda M, Iwata H, Yamashita H et al (2013) Randomized controlled trial of toremifene 120 mg compared with exemestane 25 mg after prior treatment with a non-steroidal aromatase inhibitor in postmenopausal women with hormone receptor-positive metastatic breast cancer. BMC Cancer 13:239CrossRef
34.
Yardley DA, Ismail-Khan RR, Melichar B, Lichinitser M, Munster PN, Klein PM et al (2013) 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 31(17):2128–2135CrossRef
35.
Muller V, Nabieva N, Haberle L, Taran FA, Hartkopf AD, Volz B et al (2018) Impact of disease progression on health-related quality of life in patients with metastatic breast cancer in the PRAEGNANT breast cancer registry. Breast 37:154–160CrossRef
36.
37.
Broglio KR, Berry DA (2009) Detecting an overall survival benefit that is derived from progression-free survival. J Natl Cancer Inst 101(23):1642–1649CrossRef
38.
Golan T, Sela T, Margalit O, Amit U, Halpern N, Aderka D et al (2017) Short and long-term survival in metastatic pancreatic adenocarcinoma, 1993–2013. J Natl Compr Canc Netw. 15(8):1022–1027CrossRef
39.
Lobbezoo DJ, van Kampen RJ, Voogd AC, Dercksen MW, van den Berkmortel F, Smilde TJ et al (2013) Prognosis of metastatic breast cancer subtypes: the hormone receptor/HER2-positive subtype is associated with the most favorable outcome. Breast Cancer Res Treat 141(3):507–514CrossRef
40.
Smith I (2006) Goals of treatment for patients with metastatic breast cancer. Semin Oncol 33(Suppl 2):2–5CrossRef
Metadata
Title
Surrogate threshold effect based on a meta-analysis for the predictive value of progression-free survival for overall survival in hormone receptor-positive, HER2-negative metastatic breast cancer
Authors
Michael Patrick Lux
Sarah Böhme
Stephanie Hücherig
Ulli Jeratsch
Niclas Kürschner
Diana Lüftner
Publication date
01-08-2019
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 3/2019
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-019-05262-4

Other articles of this Issue 3/2019

Breast Cancer Research and Treatment 3/2019 Go to the issue

Preclinical study

Elevated serum levels of sialyl Lewis X (sLeX) and inflammatory mediators in patients with breast cancer

Epidemiology

Impact of long-term lipid-lowering therapy on clinical outcomes in breast cancer

Clinical trial

Weekly carboplatin plus neoadjuvant anthracycline-taxane-based regimen in early triple-negative breast cancer: a prospective phase II trial by the Breast Cancer Task Force of the Belgian Society of Medical Oncology (BSMO)

Preclinical study

Clinical and analytical validation of Ki-67 in 9069 patients from IBCSG VIII + IX, BIG1-98 and GeparTrio trial: systematic modulation of interobserver variance in a comprehensive in silico ring trial

Clinical trial

Prospective evaluation of finger two-point discrimination and carpal tunnel syndrome among women with breast cancer receiving adjuvant aromatase inhibitor therapy

Epidemiology

Breast cancer risk in relation to plasma metabolites among Hispanic and African American women
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits