Translational results from randomised phase III TEX trial show that breast cancer relapse characteristics display aggressive features with an over-representation of ER-negative, HER2-positive and highly proliferative tumours. The molecular subtype of breast cancer metastases significantly influences post-relapse survival, according to the presentation of Dr Nicholas Tobin of the Oncology-Pathology Department, Karolinska Institute, Stockholm, Sweden. The study was presented at Best abstracts session of the IMPAKT 2014 Breast Cancer Conference (8-10 May 2014, Brussels, Belgium).
Breast cancer researchers have previously demonstrated the propensity of standard breast cancer markers to alter their expression throughout tumour progression with subsequent impact on patient survival. Investigation of tumour characteristics at relapse has potential to improve patient management and survival.
The aim of translational part of the TEX study was to better understand the biology of breast cancer metastases and how it can influence patient post-relapse survival. The researchers applied molecular markers with previously demonstrated biological relevance and prognostic significance in the primary tumour setting to the metastatic samples from the TEX trial.
Molecular investigations at relapse may provide prognostically relevant information
The Swedish multicenter, randomised TEX trial enrolled 287 patients with a morphologically confirmed loco-regional or distant breast cancer relapse from December 2002 until June 2007. The patients were treated with epirubicin/paclitaxel vs. epirubicin/paclitaxel/capecitabin chemotherapy.
The translational part of the trial included 120 relapse biopsies from 111 patients, yielding sufficient tumour RNA for gene expression profiling. Each gene expression array was individually background corrected and normalised using robust multichip averaging. The gene expression modules and the PAM50 intrinsic subtypes were assessed.
Metastatic sites included breast in 14% of cases, liver in 23%, lung/pleura in 2%, lymph node in 36%, skeleton in 5%, skin in 19% and other sites in 1%.
Gene modules showed an over-representation of aggressive relapse tumour characteristics including low ER signalling, as well as high proliferation, HER2 and angiogenic signalling. In particular, alow ESR1 module score was associated with poor post-relapse survival. A low CASP3 module score was associated with poor post-relapse survival.
The PAM50 intrinsic breast cancer subtypes revealed that 25% of relapses were basal, 32% HER2, 10% luminal A, 28% luminal B, and 5% lormal-like. Importantly, intrinsic subtype at relapse was significantly associated with post-relapse survival (p = 0.012).
Contrasting two consecutive relapse biopsies from the same patient, using hierarchical clustering of gene module genes, the researchers noted that 2 out of 7 patients exhibited different gene expression patterns, suggesting intratumour heterogeneity in these relapses.
The Swedish investigators concluded that their findings indicate that the molecular subtype of a breast cancer relapse significantly influences post-relapse survival. Metastases tend to be more aggressive, with an over-representation of ER-negative, HER2-positive and highly proliferative tumours comparing to the primary tumour setting. Molecular investigations at breast cancer relapse may provide prognostically relevant information with the potential to improve patient management and post-relapse survival.
Prof. Peter Dubsky, who discussed the results, said that the study findings suggest over-representation of low ER signalling, high proliferation, HER2 and angiogenic signalling, and association with post-relapse overall survival. The findings represent an elegant proof of principle that individual types of breast cancer change during disease progression. The data clearly adds detailed biology to what we know from immunohistochemistry. However, the technique used is currently of uncertain clinical validity. It is unlikely that it could detect more “actionable changes” than immunohistochemistry and it is with a little potential to find new actionable targets.
Abstract 12O: N.P. Tobin, J.C. Harrell, S. Egyhazi Brage, et al. Molecular subtype of breast cancer metastases significantly influences patient post-relapse survival. Annals of Oncology (2014) 25 (suppl_1): i5-i7. 10.1093/annonc/mdu065. View the abstract
From the list of authors, Dr Thomas Hatschek declared that receives unrestricted grants from BMS, Pfizer and Roche for the TEX clinical trial, paid to Karolinska University Hospital; Jonas Bergh receives research funding from Merck, paid to Karolinska Institute and from Amgen, Roche, Sanofi-Aventis and Bayer, paid to Karolinska University Hospital; Charles Perou is an equity stock holder, and Board of Director Member, of BioClassifier LLC and University Genomics. He is also listed as an inventor on a patent application on the PAM50 molecular assay. All other authors have declared no conflicts of interest.
IMPAKT is an annual conference that was launched in 2009 by the Breast International Group (BIG) and the European Society for Medical Oncology (ESMO), in collaboration with a multidisciplinary alliance of European breast cancer organisations and patient groups - referred to as partners. Partners include the Foundation St. Gallen Oncology Conferences and the EBC Council. It is designed for breast cancer researchers and clinicians who have a specific interest in translational research, new agents, molecular and functional diagnostics, biomarkers and cutting-edge research applications in the clinical setting.The theme of IMPAKT 2014 was 'Anticipating the future of personalised medicine in breast cancer'.