Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer.
OBJECTIVE
Overall survival (OS) can be observed only after prolonged follow-up, and any potential effect of first-line therapies on OS may be confounded by the effects of subsequent therapy. We investigated whether tumor response, disease control, progression-free survival (PFS), or time to progression (TTP) could be considered a valid surrogate for OS to assess the benefits of first-line therapies for patients with metastatic breast cancer.


METHODS
Individual patient data were collected on 3,953 patients in 11 randomized trials that compared an anthracycline (alone or in combination) with a taxane (alone or in combination with an anthracycline). Surrogacy was assessed through the correlation between the end points as well as through the correlation between the treatment effects on the end points.


RESULTS
Tumor response (survival odds ratio [OR], 6.2; 95% CI, 5.3 to 7.0) and disease control (survival OR, 5.5; 95% CI, 4.8 to 6.3) were strongly associated with OS. PFS (rank correlation coefficient, 0.688; 95% CI, 0.686 to 0.690) and TTP (rank correlation coefficient, 0.682; 95% CI, 0.680 to 0.684) were moderately associated with OS. Response log ORs were strongly correlated with PFS log hazard ratios (linear coefficient [rho], 0.96; 95% CI, 0.73 to 1.19). Response and disease control log ORs and PFS and TTP log hazard ratios were poorly correlated with log hazard ratios for OS, but the confidence limits of rho were too wide to be informative.


CONCLUSIONS
No end point could be demonstrated as a good surrogate for OS in these trials. Tumor response may be an acceptable surrogate for PFS.
Burzykowski
Tomasz
T
Hasselt University, Center for Statistics, Agoralaan, Bldg D, 3590 Diepenbeek, Belgium. tomasz.burzykowski@uhasselt.be
Buyse
Marc
M
Piccart-Gebhart
Martine J
MJ
Sledge
George
G
Carmichael
James
J
Lück
Hans-Joachim
HJ
Mackey
John R
JR
Nabholtz
Jean-Marc
JM
Paridaens
Robert
R
Biganzoli
Laura
L
Jassem
Jacek
J
Bontenbal
Marijke
M
Bonneterre
Jacques
J
Chan
Stephen
S
Basaran
Gul Atalay
GA
Therasse
Patrick
P
D018943:Anthracyclines / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015415:Biomarkers; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D015203:Reproducibility of Results; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
D018943:Anthracyclines; D015415:Biomarkers; D043823:Taxoids