At 10 years time, there was no overall difference in survival for all breast cancer types between the JGH and VGH centers (p = .17) and TNP tumors made up 14% of cases in both series (JGH, 27 tumors, VGH, 36 tumors). In the combined series, the median age at diagnosis was 9.4 years younger in the TNP group (p = .0006) and the median length of follow up in survivors was 6.75 years in the TNP groups versus 9.09 years in the non-TNP group, p = .02. Exclusion of subjects who did not die of breast cancer and were lost to follow up before 10 years did not alter the statistical significance of the study results. There was a significant overlap between the TNP and CBP groups with 49/58 (84%) of TNP cases also falling in the CBP group. Comparison of clinical features in TNP and non-TNP cases in the combined series (Table ) showed that TNP cases had an increased likelihood of a higher histological grade (odds ratio (OR), for grade 3: 17.7 [95% confidence interval, C.I., 6.05–51.5], p < .0001), a larger tumor (OR for tumor >2 cm: 1.85 [95% C.I. 1.04–3.32], p = .04) but had a decreased likelihood of positive lymph nodes (OR = 0.44 [95% C.I. 0.23–0.84], p = .01). While there was a clear correlation between tumor size and the mean number of positive lymph nodes in both the non-TNP and the TNP group, this correlation was less strong with the TNP group (P = 0.01) and the interaction between tumor size and TNP status on lymph node status was of borderline significance (p = 0.10, Figure ). Breast cancer survival at 3 and 10 years correlated closely with histological grade, size and lymph node involvement (Table ). The effect of TNP on prognosis was stronger at 3 years than at 10 years, with TNP conferring a univariate RR of 4.06 [95% C.I. 2.11–7.82], p = .0001 at 3 years (Table ) compared to 1.71 [95% C.I. 1.05–2.78], p = .03 at 10 years (Table ). Although there is a degree of overlap between the confidence intervals at 3 years and at 10 years, this is small and the fact that the TNP parameter is not present in parsimonious model 1 at 10 years (Table ) but is present in the same model at 3 years provides further evidence indicating that the differences are real. A similar pattern was seen with the CBP variable. Predictably, TNP cases were less likely to receive hormone therapy and more likely to receive chemotherapy (Table ). At 10 years, survival was 63% in TNP cases treated with chemotherapy versus 66% in the no treatment group; the corresponding figures for CBP were 68% and 62%. These differences were not significant and there was also no difference in survival with adjuvant hormone therapy.
Age at diagnosis, tumor characteristics and treatment given in the TNP and non-TNP groups.
Poisson regression curve examining the relationship between tumor size, lymph node status and TNP group. The number of positive lymph nodes showed a closer correlation with tumor size in the non-TNP group compared to the TNP group.
Univariate Cox proportional hazards model for survival until death from breast cancer at 3 years and 10 years.
Cox proportional model for survival until death from breast cancer at 3 years.
Cox proportional model for survival until death from breast cancer at 10 years time.
In the combined JGH/VGH series, the difference in survival between the TNP and non-TNP groups (Figure ) was most marked at 3 years with an absolute reduction of 16.7% in the TNP group (76.8% versus 93.5%, p < .0001). Although the absolute reduction in survival of 9.2% at 10 years in the TNP group was still significant (p = .03), the difference appeared to be reducing with time, suggesting that long term survivors in the TNP group may have a comparable survival to non-TNP cases. When using CBP instead of TNP a similar overall survival pattern emerged with a significant difference at 3 years (77.4% versus 93.4%, p =< .0001) that also became less marked at 10 years.
Survival until breast cancer death by TNP status. Survival at 3 years time was 76.8% in the TNP cases versus 93.5% among non-TNP cases (p < .0001); Survival at 10 years time were, respectively 65.0% and 74.2% (p = .03).
However, when tumors negative for CK5/6 and EGFR expression were compared to tumors that expressed either CK5/6 or EGFR (Figure ) the absolute survival difference was notably greater at 10 years (17.1%, p = .0007), than that at 3 years (7.8%, p = .02). This was reflected in the multivariate parsimonious models (Table and ) which showed that at 3 years time, both TNP and CBP parameters not only remained in their respective parsimonious models but both also worked well in predicting outcome (models 1 and 2). As both models share ER negative and HER2 negative status, these appear to be the main driving factors predicting early outcome. Indeed, when all components of TNP and CBP are analyzed separately (model 3), only ER negative and HER2 negative status remained in the parsimonious model while positive PR status and [CK5/6+ and/or EGFR+] status fell out of the model.
Figure 3 Survival until breast cancer death by Ck5/6 and EGFR status. Survival at 3 years time was 85.6% among CK5/6 and/or EGFR positive cases versus 93.4% among cases that were negative for both CK5/6 and EGFR (p = .02); Survival at 10 years time was 61.4% and (more ...)
In contrast, the data at 10 years indicates that ER negative and HER negative status diminishes in influence with increasing time, with [CK5/6+ and/or EGFR+] status becoming the main driving factor. Therefore CBP (which incorporates CK5/6 and/or EGFR+) may be a better model at 10 years.