Prognostic factors versus predictive factors: Examples from a clinical trial of erlotinib

Abstract

It would be helpful to have factors that could identify patients who will, or will not, benefit from treatment with specific therapies. Ideally, these should be molecular-based factors. When results with molecular-based factors are disappointing, physicians often use clinical characteristics to make treatment decisions. Several characteristics have been suggested to predict sensitivity to epidermal growth factor receptor inhibitors in patients with non-small lung cancer, including gender, histology, smoking history. This report demonstrates that gender and histology are actually prognostic, rather than predictive factors. Before biomarkers or clinical characteristics are included in guidelines for selecting patients for specific treatments, it is imperative that the prognostic effects of these factors are distinguished from their ability to predict a differential clinical benefit from the specific treatment.

Figure 1

Survival of patients in NCIC CTG Study BR.21 by gender. (A) Survival of patients on the erlotinib arm by gender. Median survival for females was 8.4months (n=173); median survival for males was 5.7months (n=315); Hazard ratio (HR) for death (females:males)=0.85 (95% confidence interval 0.69–1.05). (B) Survival of patients on the placebo arm by gender. Median survival for females was 6.2months (n=83); median survival for males was 4.5months (n=160); HR for death (females:males)=0.80 (95% confidence interval 0.60–1.07). These results indicate that gender is a prognostic factor for survival in this study. (C) Survival of female patients by treatment arm. Median survival in the erlotinib arm was 8.4months (n=173); median survival in the placebo arm was 6.2months (n=83); HR for death (erlotinib:placebo)=0.80 (95% confidence interval 0.59–1.07). (D) Survival of male patients by treatment arm. Median survival in the erlotinib arm was 5.7months (n=315); median survival in the placebo arm was 4.5months (n=160); HR for death (erlotinib:placebo)=0.76 (95% confidence interval 0.62–0.84). (E) Survival of patients by gender and treatment arm. Test for interaction between gender and treatment benefit was not statistically significant (P=0.76) indicating that gender was not a predictive factor for differential survival benefit from erlotinib relative to placebo in this study.

Figure 2

Survival of patients in NCIC CTG Study BR.21 by histology. (A) Survival of patients on the erlotinib arm by histology. Median survival for patients with adenocarcinoma was 7.8months (n=246); median survival for patients with squamous cell carcinoma was 5.6months (n=144); HR for death (adenocarcinoma:squamous cell)=0.66 (95% confidence interval 0.52–0.83). (B) Survival of patients on the placebo arm by histology. Median survival for patients with adenocarcinoma was 5.4months (n=119); median survival for squamous cell carcinoma was 3.6months (n=78); HR for death (adenocarcinoma:squamous cell)=0.65 (95% confidence interval 0.48–0.88). These results indicate that histology is a prognostic factor for survival in this study. (C) Survival of patients with adenocarcinoma by treatment arm. Median survival in the erlotinib arm was 7.8months (n=246); median survival in the placebo arm was 5.4months (n=119); HR for death (erlotinib:placebo)=0.71 (95% confidence interval 0.56–0.92). (D) Survival of patients with squamous cell carcinoma by treatment arm. Median survival in the erlotinib arm was 5.6months (n=144); median survival in the placebo arm was 3.6months (n=78); HR for death (erlotinib:placebo)=0.67 (95% confidence interval 0.50–0.90). (E) Survival of patients by histology and treatment arm. Test for interaction between histology and treatment benefit was not statistically significant (P=0.97) indicating that histology was not a predictive factor for differential survival benefit from erlotinib relative to placebo in this study.

Figure 3

Survival of patients in NCIC CTG Study BR.21 by smoking history. (A) Survival of patients on the erlotinib arm by smoking history. Median survival for never smokers was 12.3months (n=104); median survival for current or former smokers was 5.5months (n=358); HR for death (never:current or former smoker)=0.54 (95% confidence interval 0.41–0.71). (B) Survival of patients on the placebo arm by smoking history. Median survival for never smokers was 5.6months (n=42); median survival for current or former smokers was 4.6months (n=187); HR for death (never:current or former smoker)=1.01 (95% confidence interval 0.71–1.45). These results indicate that smoking history is not a prognostic factor for survival in this study. (C) Survival of never smokers by treatment arm. Median survival in the erlotinib arm was 12.3months (n=104); median survival in the placebo arm was 5.6months (n=42); HR for death (erlotinib:placebo)=0.42 (95% confidence interval 0.28–0.64). (D) Survival of current or former smokers by treatment arm. Median survival in the erlotinib arm was 5.5months (n=358); median survival in the placebo arm was 4.6months (n=187); HR for death (erlotinib:placebo)=0.87 (95% confidence interval 0.71–1.05). (E) Survival of patients by smoking history and treatment arm. Test for interaction between smoking history and treatment benefit was statistically significant (P=0.006) indicating that smoking history was a strong predictive factor for differential survival benefit from erlotinib relative to placebo in this study.