Abstract 4247
Background
Despite ER positive IHC staining, some patients do not respond to neoadjuvant endocrine therapy, suggesting that ER staining lacks specificity to predict response. We developed a method to infer a quantitative signal transduction pathway activity score (PAS) from mRNA levels (microarray, qPCR) of pathway-associated transcription factor target genes. Initial studies suggest that ER PAS may have higher specificity than ER IHC in predicting endocrine therapy response. In this study, we correlated pre-treatment ER PAS and changes in ER PAS during neoadjuvant letrozole treatment to therapy response and DFS.
Methods
We collected fresh frozen RNA from tumor samples of 30 ER IHC positive post-menopausal patients with primary localized breast cancer, treated with neoadjuvant letrozole at Edinburgh Western General. In total, 30 pre, 25 mid (median 27 days), and 29 post-treatment (median 136 days) samples were analysed. Clinical outcome was assessed (RECIST, n = 29) at circa 3 months treatment by 3D ultrasound, with 1 complete (CR), 21 partial responses (PR), 2 stable (SD), and 5 progressive diseases (PD). Using RT-qPCR, target gene expression was measured for ER, androgen receptor, PI3K, Hedgehog, TGFβ and Wnt pathways. PAS were expressed on a normalized scale (0 to 100).
Results
Pre-treatment ER PAS was significantly higher in responders (CR/PR) than non-responders (SD/PD), PAS=45 vs 24, respectively, T-test p = 0.01. Pre-treatment ER PAS correlated with decrease in ER PAS during treatment (cor=0.87 and 0.7, mid and-post treatment, respectively). At mid-treatment, ER PAS of responders had decreased to PAS of non-responders (20 vs 19, respectively), remaining low during further treatment. Decrease in ER PAS was significantly higher in responders (-30) than non-responders (-6), p = 0.01. Higher ER PAS after treatment correlated to shorter DFS (COX proportional hazards p = 0.02). Baseline PAS of other pathways did not correlate with response, but changed significantly during treatment.
Conclusions
This study confirms that ER PAS in ER-positive patients, measured before and after neoadjuvant endocrine therapy, has potential to predict and assess therapy response, and predict DFS.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Philips Electronics Nederland B.V., acting through its HealthWorks Molecular Pathway Dx.
Funding
Has not received any funding.
Disclosure
M. A. Inda: Full / Part-time employment: Philips Reseach. A. van de Stolpe: Full / Part-time employment, has Philips stocks: Philips Research. D. Keizer: Full / Part-time employment: Philips. D. Clout: Full / Part-time employment: Philips Reasearch. H. van Zon: Full / Part-time employment: Philips Reasearch. M. Akse: Full / Part-time employment: Philips. All other authors have declared no conflicts of interest.
Resources from the same session
3180 - Genomic analysis of hepatobiliary lithiasis associated cholangiocarcinoma revealed a distinct subtype feature.
Presenter: Lunda Gu
Session: Poster Display session 2
Resources:
Abstract
4891 - Comparison of the impact of stereotactic body radiation therapy vs. radiofrequency ablation on liver function in patients with single hepatocellular carcinoma: A propensity score matching analysis
Presenter: Masayuki Ueno
Session: Poster Display session 2
Resources:
Abstract
3203 - Exploratory analysis based on tumor location and early metabolic tumor response of REACHIN, a randomized double-blinded placebo-controlled phase II trial of regorafenib after failure of gemcitabine/platinum-based chemotherapy for advanced and metastatic biliary tract tumors.
Presenter: Anne Demols
Session: Poster Display session 2
Resources:
Abstract
1602 - Predictive Value of Neutrophil-Lymphocyte Ratio (NLR) And Platelet-Lymphocyte Ratio (PLR) In Hepatocellular Carcinoma (HCC) Patients Treated with Nivolumab (N)
Presenter: Sirish Dharmapuri
Session: Poster Display session 2
Resources:
Abstract
2848 - Preliminary Safety and Pharmacokinetics of a New Lysosomotropic Oral Agent, GNS561, in a First-in-Human Study in Advanced Primary Liver Cancer Patients
Presenter: Ahmad Awada
Session: Poster Display session 2
Resources:
Abstract
1396 - A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): updated results
Presenter: Josep Llovet
Session: Poster Display session 2
Resources:
Abstract
1139 - Multicentric prospective study of validation of angiogenesis-related gene polymorphisms in HCC patients treated with sorafenib: Final results of INNOVATE study
Presenter: Andrea Casadei-gardini
Session: Poster Display session 2
Resources:
Abstract
4688 - Prognostic and predictive factors from the phase 3 CELESTIAL trial of cabozantinib (C) versus placebo (P) in previously treated advanced hepatocellular carcinoma (aHCC)
Presenter: Tim Meyer
Session: Poster Display session 2
Resources:
Abstract
1492 - A phase Ib study of pembrolizumab following trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): PETAL.
Presenter: David Pinato
Session: Poster Display session 2
Resources:
Abstract
3159 - Anlotinib for advanced hepatocellular carcinoma: interim results from the phase II ALTER0802 study
Presenter: AiPing Zhou
Session: Poster Display session 2
Resources:
Abstract