Time dependence of biomarkers: non-proportional effects of immunohistochemical panels predicting relapse risk in early breast cancer

Abstract

Background:We investigated the impact of follow-up duration to determine whether two immunohistochemical prognostic panels, IHC4 and Mammostrat, provide information on the risk of early or late distant recurrence using the Edinburgh Breast Conservation Series and the Tamoxifen vs Exemestane Adjuvant Multinational (TEAM) trial.Methods:The multivariable fractional polynomial time (MFPT) algorithm was used to determine which variables had possible non-proportional effects. The performance of the scores was assessed at various lengths of follow-up and Cox regression modelling was performed over the intervals of 0–5 years and >5 years.Results:We observed a strong time dependence of both the IHC4 and Mammostrat scores, with their effects decreasing over time. In the first 5 years of follow-up only, the addition of both scores to clinical factors provided statistically significant information (P<0.05), with increases in R2 between 5 and 6% and increases in D-statistic between 0.16 and 0.21.Conclusions:Our analyses confirm that the IHC4 and Mammostrat scores are strong prognostic factors for time to distant recurrence but this is restricted to the first 5 years after diagnosis. This provides evidence for their combined use to predict early recurrence events in order to select those patients who may/will benefit from adjuvant chemotherapy.

Tumour profiling tests to guide adjuvant chemotherapy decisions in early breast cancer: a systematic review and economic analysis

“…Eleven separate validation cohorts 24,25,58,73,74,77,[122][123][124][125][126][127][128][129] have reported prognostic performance data for IHC4, with a total of 13,434 patients. 127 and the study from Taiwan.…”

“…124 TransATAC, 46 WSG PlanB, 73,74,77 GEICAM 9906, 129 WSG-AGO-Doc, 123 the Kaiser Permanente cohort, 125 the Institut Curie 128 cohort and the Chinese 58 cohort all recruited or reported a subgroup of HER2-patients. Only one validation cohort (Stephen et al 126 ) treated 100% of patients with endocrine monotherapy, and the remainder treated varying proportions of patients with endocrine therapy and chemotherapy. Two observational studies were from East Asia; 58,124 clinical advice received by the EAG suggests that these two East Asian studies may be less generalisable to the English context because (1) patients were treated in accordance with usual clinical practice and this may differ between these countries and England enough to affect prognostic outcomes and (2) it is possible that people of different ethnicities have different underlying risk profiles and disease natural histories.…”

Clinical utility of the IHC4+C score in oestrogen receptor-positive early breast cancer: a prospective decision impact study

“…It was developed from a retrospective analysis of 1125 patients with ER-positive disease from the TransATAC cohort who did not received chemotherapy, validated in an independent cohort of 786 patients and has been shown to perform similarly to the Genomic Health recurrence score (RS) in predicting distant recurrence ( Cuzick et al , 2011 ). In this journal, Stephen et al , 2014 showed that in an endocrine treated population from the TEAM trial, the IHC4 provided stronger prognostic information when compared with the Mammostrat score.…”

Selecting postoperative adjuvant systemic therapy for early stage breast cancer: A critical assessment of commercially available gene expression assays

“…In the 915 patients, the authors examined the likelihood ratio for both IHC4 and BCI; IHC4 appeared prognostic for recurrence to 5 years in multivariable analysis. Stephen and colleagues also showed that IHC4 was prognostic to 5 years using independent Cox analysis in samples from the Edinburgh BCI series and TEAM trial . However, others have shown that a nomogram constructed from St. Gallen guidelines and Adjuvant Online (AOL), combined with IHC4 + CTS, provides prognostic information beyond that from IHC4 + CTS alone …”