485P - Link between PODXL and the EGFR axis in metastatic colorectal cancer and in vitro: Implications for improved treatment stratification

Background

The introduction of targeted therapies has resulted in significant improvements in the survival of patients with metastatic colorectal cancer (mCRC). However, apart from RAS and BRAF mutation status, reliable predictive markers for anti-EGFR treatment are still missing. Podocalyxin-like protein 1 (PODXL) has in several studies been validated as an independent biomarker of poor prognosis in CRC and is frequently co-expressed with EGFR. This study investigated the prognostic role of PODXL in mCRC, also in relation to anti-EGFR treatment, and further interrogated the functional link between PODXL and the EGFR axis in vitro.

Methods

Immunohistochemical expression of EGFR and PODXL was determined in tissue microarrays with tumours from 452 mCRC cases in a prospective, population-based Scandinavian cohort. Kaplan-Meier and Cox regression analyses were applied to determine the impact of PODXL and EGFR expression on overall survival (OS). Several human CRC cell lines were transfected with siRNA suppressing PODXL or EGFR and incubated with cetuximab to investigate treatment response.

Results

High PODXL expression was an independent factor of shorter OS (HR=3.14; 95% CI 1.75-5.64), and EGFR expression added to the prognostic information (median OS for patients with PODXL_high/EGFR_high, PODXL_high/EGFR_low, PODXL_low/EGFR_high, and PODXL_low/EGFR_low tumours was 3, 10, 9, and 12 months, respectively). Median OS was 33 vs 13 months for cetuximab-treated vs untreated patients with PODXL_high tumours receiving first line combination chemotherapy and second line. Silencing of PODXL in vitro led to a reduction of EGFR expression, whereas silencing of EGFR did not affect PODXL levels. Moreover, silencing of PODXL but not EGFR rendered CRC cells more resistant to cetuximab compared to control cells.

Conclusions

PODXL is an independent biomarker of poor prognosis also in mCRC, and its link with the EGFR axis is further confirmed. These findings bear potential clinical significance for further improved treatment stratification of patients with mCRC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Berta Kamprad Foundation, Swedish Research Counsil.

Disclosure

All authors have declared no conflicts of interest.