The Influence of HER2 Status on the Recurrence Pattern in Oestrogen Receptor Positive (ER+) Early Breast Cancer (EBC).
Authors: Mansell J. , Sian T. , Angerson W. , Doughty J. 
Published: December 2010

Abstract
IntroductionAromatase inhibtors (AI) are recommended in the adjuvant management of oestrogen receptor positive (ER+) early breast cancer (EBC). With no consensus regarding the decision between starting AIs upfront or after an initial period of tamoxifen identifying factors that predict early recurrence on tamoxifen would help guide clinicians to choose the appropriate treatment strategy. HER2 overexpression and progesterone receptor (PR) negativity are poor prognostic factors in ER+ EBC. We aim to investigate whether these factors are particularly strong predictors of early recurrence.MethodsER, PR and HER2 receptor analysis was performed on a retrospective cohort of women with symptomatic early breast cancer diagnosed between 1980 – 2002 who received adjuvant tamoxifen. The primary endpoint was disease free survival (DFS) and recurrence was defined as invasive disease at any site as determined by histopathology or a high index of suspicion upon radiological investigation. Univariate and multivariate time dependent Cox regression analysis, using ≤2.5yrs as the time dependent term, were performed. The pattern of recurrence over the first five years was charted using an Epanechnikov smoothing function.ResultsA total of 402 tumours were confirmed as ER+ and therefore included in the analysis. The median age of the cohort was 63yrs with a median follow up of 6.1yrs. 241 (60.0%) of the tumours were PR+ and 51 (12.7%) were HER2 positive. On univariate analysis tumour size, grade, nodal status and PR status were significantly associated with DFS (p &lt;0.001; except PR status, p = 0.002). In univariate time dependent analysis only HER2 status had a significant interaction with the time dependent term (p = 0.004) with a hazard ratio (HR) of 2.78 (95% CI 1.47-5.26) for DFS within the first 2.5yrs following diagnosis and a HR of 0.48 (0.18-1.34) beyond 2.5yrs. Following adjustment for pathology and PR status this interaction remained significant (p = 0.004; &lt;2.5yrs HR 2.54 (1.21-5.32); &gt;2.5yrs HR 0.33 (0.10-1.11)). Fig 1. clearly demonstrates a peak in the annual recurrence rate at 2yrs in the HER2 positive group.ConclusionsThis data shows that HER2 positive patients are at a significantly higher risk of recurrence within the first 2.5yrs following diagnosis of ER+ EBC. Whilst TransATAC and BIG 1-98 subgroup analysis demonstrate that HER2 is not predictive for response to AIs over tamoxifen, HER2 positive patients did show a significant reduction in recurrence on an AI in line with the remainder of the cohorts. We would therefore suggest that delaying initiation of AI therapy potentially leaves women at greater risk of early recurrence. Perhaps more importantly we should ensure that all ER positive HER2 positive patients receive trastuzumab along with their endocrine therapy as there is now significant in vitro and clinical evidence that inhibition of growth factor pathways is essential for endocrine sensitivity.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4045.