Unfortunately, many individuals with HER2 positive breast cancer are likely to experience disease recurrence. Trastuzumab is an effective agent in this setting; however, many patients have tumours that show resistance to trastuzumab, according to Amir Sonnenblick, Breast Cancer Translational Research Laboratory, Institute Jules Bordet, Brussels, Belgium. Professor Sonnenblick presented findings from a study of specific molecules expressed on some tumours that may confer resistance to trastuzumab at the IMPAKT Breast Cancer Conference held 7-9 May 2015 in Brussels, Belgium.
Signal Transducer and Activator of Transcription 3 protein (STAT3) is a transcription factor that is persistently tyrosine phosphorylated (pSTAT3) in response to numerous oncogenic signalling pathways. pSTAT3 is constitutively activated in 30-40% of breast cancers. It inhibits native anti-tumour immunity and activates pathways that result in cell proliferation and anti-apoptotic mechanisms.
Expression of a pSTAT3 associated gene signature associates with trastuzumab resistance in patients with HER2 positive tumours
Prof. Sonnenblick and colleagues hypothesised that expression of pSTAT3 may associate with trastuzumab resistance and, therefore, may be predictive of poorer response to trastuzumab breast cancer therapy. The investigators identified a pSTAT3-associated gene signature (pSTAT3-GS) in an independent dataset (TCGA) that predicts pSTAT3 status; this characteristic set of STAT3 dependent-induced changes may play a role in HER2-positive cancers, area under the curve (AUC) = 0.78 (p = 0.01).
Tumours with high levels of pSTAT3-GS were found to associate with trastuzumab resistance (log rank p = 0.49), which was confirmed in the fin-HER prospective randomised controlled study. In this study, data from protein evaluated by reverse phase protein array were integrated with gene expression data from 95 HER2-positive breast cancer samples from patients treated with trastuzumab in the adjuvant setting.
Upon statistical analysis, samples of oestrogen receptor negative tumours showed a strong relationship between pSTAT3-GS and trastusumab resistance (interaction test p = 0.02).
Interestingly, when subjected to false discovery rate (fdr) analysis, which allows for multiple comparisons, constitutively activated pSTAT3 in tumours associated with loss of PTEN (r =- 0.4, fdr = 0.025), elevated interleukin 6 (IL6) (r=0.4, p = 4.72e−05) and stromal reactivation.
Prof. Sonnenblick discussed further how this study provides compelling evidence of a link between pSTAT3 and trastuzumab resistance in HER2 positive primary breast cancers. These findings suggest that adding agents that target the STAT3 pathway to trastuzumab treatment may increase the activity of trastuzumab or restore efficacy in patients with HER2-positive breast cancer demonstrating trastuzumab resistance.
Dr Lisa Carey of the University of North Carolina, USA, who discussed the study results, said that pSTAT3 expression segregates HER2-positive breast cancers into two molecularly distinct groups, luminal and HER2-enriched, with HER2-enriched having relatively low STAT3 expression. Low pSTAT3 status is relevant for HER2-targeting only in ER-negative disease, and ER-negative tumours are more than 50% of HER2-enriched tumours. pSTAT3 association with stromal reactivation is an intriguing finding given that stromal reactivation and EMT are both associated with drug resistance. Due to the explosion of good (but expensive) options for HER2-targeting, we must find out who needs more from the treatment and who needs less.
The authors concluded that pSTAT3 activation is associated with distinct gene expression profiles in HER2-positive breast cancer and its activation mediates primary trastuzumab resistance. Furthermore, there is a link between IL6-pSTAT3-PTEN loss and stroma reactivation in HER2 tumours.