PCR After Neoadjuvant Chemo and Breast Cancer Subtypes
Of the 1856 patients originally randomized, only 1289 were assessable for the relationship between subtype and outcome, and 1212 for the landmark analysis of pCR, subtype and outcome. The reasons for ineligibility are shown in the Consort diagram (Supplementary Figure S2, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/suppl/2014/03/11/mdu118.DC1). The characteristics of patients included in this sub-study and those who were excluded were similar (Supplementary Table S1, available at Annals of Oncology online).
The median follow-up was 56 months from randomization and 51 months from date of surgery. The subtypes repartition is given on supplementary Table S2, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/suppl/2014/03/11/mdu118.DC1. Among patients with HER-positive tumours, 120 of 365 (33%) received adjuvant trastuzumab and none received neoadjuvant trastuzumab.
A pCR was observed in 222 of 1212 (18%) assessable patients ( Table 1 ). pCR rates differed significantly (P < 0.001) across intrinsic subtypes, with the lowest rate for luminal A-like (7.5%) and the highest rate for HER2+/non-luminal (36%). A multivariate logistic regression analysis was carried out to assess whether these differences persist when adjusting for other known predictive factors for pCR. First, the effect of two interactions (TP53 and intrinsic subtypes; treatment assigned and intrinsic subtypes) on pCR rate was examined, but neither were significant. Next, the effect of TP53 and treatment assigned were tested, and both were non-significant. Only intrinsic subtype (P < 0.001) and cT stage (P < 0.001) were found to be independent predictors for pCR (Supplementary Table S3, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/suppl/2014/03/11/mdu118.DC1).
Supplementary Figure S3, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/suppl/2014/03/11/mdu118.DC1 shows a significant difference in the survival end points according to subtype [P < 0.001 for EFS, distant metastasis-free survival (DMFS) and overall survival (OS)]. Patients in the luminal A-like group had the best outcome across all three survival measures despite experiencing the lowest pCR rates ( Table 1 ). Events contributing to EFS are detailed in Supplementary Table S5, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/suppl/2014/03/11/mdu118.DC1.
EFS Curves (Figure 1) and Univariate Analysis (Figures 2 and 3). There was no evidence of an interaction between subtype and the prognostic influence of pCR (P = 0.95) (Figure 2). Overall, regardless of subtype, pCR was prognostic for EFS (Figure 2). Furthermore, in the univariate Cox regression models, pCR predicts for a better EFS in the luminal B/HER2-positive, HER2-positive/non-luminal and TN breast cancer patients. Although a similar trend is seen for the other two subtypes, the effect is neither statistically significant on its own nor significantly different from the other subtypes (Figure 2).
(Enlarge Image)
Figure 1.
Effect of pCR on EFS by intrinsic subtype (N = 1212 eligible and assessable patients). pCR, pathological complete response; EFS, event-free survival.
(Enlarge Image)
Figure 2.
Effect of pCR on EFS by intrinsic subtype: univariate Cox regression models (N = 1212 eligible and assessable patients). pCR, pathological complete response; EFS, event-free survival; HR, hazard ratio; CI, confidence interval; HER2, human epidermal growth factor 2; df, degrees of freedom.
(Enlarge Image)
Figure 3.
Effect of pCR on event-free survival by intrinsic subtype and TP53 status: univariate Cox regression models (N = 1212 eligible and assessable patients). pCR, pathological complete response; HR, hazard ratio; CI, confidence interval; HER2, human epidermal growth factor 2; df, degrees of freedom. Two hundred and thirty-seven patients with p53 status missing were not considered in this graph.
Figure 3, limited to those patients with assessable TP53 status, shows that, within the subtypes, there is no evidence of an interaction between TP53 status and pCR (P ranging between 0.51 for HER2 positive/non-luminal and 0.95 for Luminal B/HER2 positive and TN). Although in all subgroups, pCR seems to be associated with better EFS, this association is significant only in HER2 positive/non-luminal with TP53 wild type and TN with p53 mutated.
Two-step Multivariate Analysis. First, we tested the effect of the three interactions (pCR and intrinsic subtypes, TP53 and intrinsic subtypes and treatment assigned and intrinsic subtypes) on EFS. Only the interaction between TP53 and intrinsic subtypes was of borderline statistical significance (P = 0.1), with the two other P values being 0.835 and 0.926, respectively, indicating that pCR and treatment do not interact differently with EFS according to subtype. The multivariate model was thus refitted without the non-significant interactions. Table 2 shows the results of this model, with subtype-specific HRs for TP53 and overall HRs for pCR and treatment on EFS. Both pCR and treatment contribute significantly to the overall prediction of EFS [HR = 0.40, P < 0.001 in favour of pCR, and HR = 0.73, P = 0.004 in favour of three cycles of docetaxel then three cycles of eprirubicin/docetaxel (T-ET)].
Results
Baseline Characteristics by Intrinsic Subtype
Of the 1856 patients originally randomized, only 1289 were assessable for the relationship between subtype and outcome, and 1212 for the landmark analysis of pCR, subtype and outcome. The reasons for ineligibility are shown in the Consort diagram (Supplementary Figure S2, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/suppl/2014/03/11/mdu118.DC1). The characteristics of patients included in this sub-study and those who were excluded were similar (Supplementary Table S1, available at Annals of Oncology online).
The median follow-up was 56 months from randomization and 51 months from date of surgery. The subtypes repartition is given on supplementary Table S2, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/suppl/2014/03/11/mdu118.DC1. Among patients with HER-positive tumours, 120 of 365 (33%) received adjuvant trastuzumab and none received neoadjuvant trastuzumab.
Pathological Responses by Intrinsic Subtypes and TP53 Status
A pCR was observed in 222 of 1212 (18%) assessable patients ( Table 1 ). pCR rates differed significantly (P < 0.001) across intrinsic subtypes, with the lowest rate for luminal A-like (7.5%) and the highest rate for HER2+/non-luminal (36%). A multivariate logistic regression analysis was carried out to assess whether these differences persist when adjusting for other known predictive factors for pCR. First, the effect of two interactions (TP53 and intrinsic subtypes; treatment assigned and intrinsic subtypes) on pCR rate was examined, but neither were significant. Next, the effect of TP53 and treatment assigned were tested, and both were non-significant. Only intrinsic subtype (P < 0.001) and cT stage (P < 0.001) were found to be independent predictors for pCR (Supplementary Table S3, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/suppl/2014/03/11/mdu118.DC1).
Survival Outcome Measures (EFS, DMFS and OS) by Intrinsic Subtype
Supplementary Figure S3, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/suppl/2014/03/11/mdu118.DC1 shows a significant difference in the survival end points according to subtype [P < 0.001 for EFS, distant metastasis-free survival (DMFS) and overall survival (OS)]. Patients in the luminal A-like group had the best outcome across all three survival measures despite experiencing the lowest pCR rates ( Table 1 ). Events contributing to EFS are detailed in Supplementary Table S5, available at Annals of Oncology online http://annonc.oxfordjournals.org/content/suppl/2014/03/11/mdu118.DC1.
Effect of pCR, TP53 and Treatment on EFS Across Intrinsic Subtypes (Landmark Analysis)
EFS Curves (Figure 1) and Univariate Analysis (Figures 2 and 3). There was no evidence of an interaction between subtype and the prognostic influence of pCR (P = 0.95) (Figure 2). Overall, regardless of subtype, pCR was prognostic for EFS (Figure 2). Furthermore, in the univariate Cox regression models, pCR predicts for a better EFS in the luminal B/HER2-positive, HER2-positive/non-luminal and TN breast cancer patients. Although a similar trend is seen for the other two subtypes, the effect is neither statistically significant on its own nor significantly different from the other subtypes (Figure 2).
(Enlarge Image)
Figure 1.
Effect of pCR on EFS by intrinsic subtype (N = 1212 eligible and assessable patients). pCR, pathological complete response; EFS, event-free survival.
(Enlarge Image)
Figure 2.
Effect of pCR on EFS by intrinsic subtype: univariate Cox regression models (N = 1212 eligible and assessable patients). pCR, pathological complete response; EFS, event-free survival; HR, hazard ratio; CI, confidence interval; HER2, human epidermal growth factor 2; df, degrees of freedom.
(Enlarge Image)
Figure 3.
Effect of pCR on event-free survival by intrinsic subtype and TP53 status: univariate Cox regression models (N = 1212 eligible and assessable patients). pCR, pathological complete response; HR, hazard ratio; CI, confidence interval; HER2, human epidermal growth factor 2; df, degrees of freedom. Two hundred and thirty-seven patients with p53 status missing were not considered in this graph.
Figure 3, limited to those patients with assessable TP53 status, shows that, within the subtypes, there is no evidence of an interaction between TP53 status and pCR (P ranging between 0.51 for HER2 positive/non-luminal and 0.95 for Luminal B/HER2 positive and TN). Although in all subgroups, pCR seems to be associated with better EFS, this association is significant only in HER2 positive/non-luminal with TP53 wild type and TN with p53 mutated.
Two-step Multivariate Analysis. First, we tested the effect of the three interactions (pCR and intrinsic subtypes, TP53 and intrinsic subtypes and treatment assigned and intrinsic subtypes) on EFS. Only the interaction between TP53 and intrinsic subtypes was of borderline statistical significance (P = 0.1), with the two other P values being 0.835 and 0.926, respectively, indicating that pCR and treatment do not interact differently with EFS according to subtype. The multivariate model was thus refitted without the non-significant interactions. Table 2 shows the results of this model, with subtype-specific HRs for TP53 and overall HRs for pCR and treatment on EFS. Both pCR and treatment contribute significantly to the overall prediction of EFS [HR = 0.40, P < 0.001 in favour of pCR, and HR = 0.73, P = 0.004 in favour of three cycles of docetaxel then three cycles of eprirubicin/docetaxel (T-ET)].