3797 - Exploring candidate signal transduction pathways for targeted therapy in esophageal cancer

Background

To reveal candidate signaling pathways for targeted therapy in esophageal cancer (EC), and esophageal adenocarcinoma (EAC) in particular, we investigated key signal transduction pathways in material available in clinical routine, before and after neoadjuvant chemoradiation (nCRT), and for primary tumor and recurrent disease.

Methods

Paraffin-embedded material from three cohorts was used; (i) resectable EC; patients treated with an esophagectomy or receiving nCRT prior to resection, including cases with an available pre-nCRT biopsy of the primary tumor and corresponding resection; (ii) recurrent EC; patients of whom a resection and metachronous recurrence could be obtained. In addition, to explore the possibility to use patient-derived-xenografts (PDX) as a model to identify novel therapies, (iii) PDX of matched patient material was analyzed. Digitally annotated tumor areas ≥2 mm² were transferred to a consecutive hematoxylin-stained slide and scraped for RNA extraction. Subsequently, a panel of qPCRs was performed, to infer signal transduction activity of the AR-, ER-, PI3K- (inverse of FOXO), HH-,TGF-β- and Wnt pathway.

Results

In pre-treatment EAC biopsies (i), high PI3K- and low TGF-β-pathway activity were correlated with poor pathological response. During treatment, a significant increase in PI3K- and decrease in TGF-β activity was observed in EAC poor nCRT responders compared to good responders (p = 0.003 and p = 0.042, respectively). Patients with a post-nCRT poor responder profile (high PI3K/ low TGF-β pathway activity) showed inferior disease free survival (median 17 vs. 97 months p = 0.055). Moreover, in nCRT treated patients, higher PI3K and lower TGF-β activities were seen in metachronous recurrences compared to resected tumors (ii) (p = 0.001 and p = 0.007, respectively). Pathway activity profiles were conserved between PDX and primary patient material (iii).

Conclusions

Loss of tumor-suppressive TGF-β and concurrent high PI3K pathway activity are associated with poor response to nCRT in EAC. This poor-responder profile is preserved in recurrences of nCRT pre-treated patients and PDX models, providing a valuable tool to experimentally test targeting candidate signal pathways such as PI3K.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Philips Research.

Funding

Philips Research.

Disclosure

L. Holtzer: Full / Part-time employment: Philips. M. Stoffels: Research grant / Funding (self), Full / Part-time employment: Philips. H. van Ooijen: Licensing / Royalties, Full / Part-time employment: Philips. A.G.C. van Brussel: Research grant / Funding (self), Licensing / Royalties, Full / Part-time employment: Philips. E.M.G. Aussems-Custers: Research grant / Funding (self), Licensing / Royalties, Full / Part-time employment: Philips. A. van de Stolpe: Licensing / Royalties, Full / Part-time employment: Philips. M.F. Bijlsma: Research grant / Funding (self): Celgene; Advisory / Consultancy: Servier. H.W.M. van Laarhoven: Advisory / Consultancy, Research grant / Funding (self): Celgene; Advisory / Consultancy, Research grant / Funding (self): BMS; Advisory / Consultancy, Research grant / Funding (self): Nordic; Advisory / Consultancy, Research grant / Funding (self): Lilly; Research grant / Funding (self): Merck Serono; Research grant / Funding (self): Bayer; Research grant / Funding (self): MSD; Research grant / Funding (self): Philips; Research grant / Funding (self): Roche. All other authors have declared no conflicts of interest.