Lack of ERCC1 and Olfactomedin 4 (Olfm4) Protein Expression Predicts Neoadjuvant Therapy Sensitivity in GE Junction Adenocarcinoma (GEJAd)
EL Courville, A Srivastava, TS Hong, OH Yilmaz, LN Calvo, BI Zaki, M Mino-Kenudson. Massachusetts General Hospital, Boston; Dartmouth-Hitchcock Medical Center, Lebanon
Background: GEJAds are often treated with platinum-based neoadjuvant regimens but the overall survival remains poor. Biomarkers that predict response to neoadjuvant therapy can be of clinical importance by guiding appropriate chemoradiation therapy protocols with increased efficacy. ERCC1 is an enzyme involved in DNA repair mechanisms and may be a predictor of resistance to platinum-based chemotherapy. Olfm4 is a marker of intestinal stem cells that has been linked to therapeutic resistance in colorectal cancers. In this study, we retrospectively examined the role of ERCC1 and Olfm4 protein expression in predicting response to neoadjuvant therapy in GEJAds.
Design: 51 patients with GEJAd (average age 62 yrs, M:F = 44:7), treated with a platinum-based agent with (n=48) or without (n=3) radiation, and followed by resection were analyzed. The tumors were graded as well, moderate, or poorly differentiated in the pre-treatment biopsy. The biopsies were stained with ERCC1 and Olfm4 by immunohistochemistry. ERCC1 and Olfm4 expressions were scored as positive or negative based on previously published methods. The response to neoadjuvant therapy was evaluated by AJCC TNM staging in the resection specimen.
Results: ERCC1 and Olfm4 immunoreactivity did not correlate with post-treatment T and N stages, completeness of eradication (Table 1) or with tumor grade. However, tumors negative for both ERCC1 and Olfm4 were more sensitive to the neoadjuvant therapy than tumors positive for one or both markers. Sensitivity, Specificity, PPV, and NPV of ERCC1 and Olfm4 double negative lesions for the neoadjuvant therapy response were 80%, 58%, 17% and 96%, respectively.
Conclusions: The results of our study indicate that lack of expression of both ERCC1 and Olfm4 proteins may predict sensitivity to platinum-based neoadjuvant regimens in GEJAds and this finding warrants further investigation in future prospective studies.
|ypT||ERCC1+ (%)||Olfm4+ (%)||ERCC1- and Olfm4- (%)|
|T0 (n=7)||1 (14)||1 (14)||5 (71)|
|T1(n=11)||5 (46)||2 (18)||5 (46)|
|T2 (n=13)||3 (23)||5 (39)||5 (38)|
|T3 (n=20)||10 (50)||2 (10)||8 (40)|
|N0 (n=30)||9 (30)||8 (27)||14 (47)|
|N1 (n=20)||10 (50)||2 (10)||8 (40)|
|Yes (n=5)||1 (20)||0 (0)||4 (80)|
|No (n=45)||18 (40)||10 (22)||18 (40)|