ERCC1 immunohistochemical expression and cancer-specific survival in patients with locally advanced squamous-cell carcinoma of the head and neck treated by cisplatin-based induction chemotherapy

Abstract

6011 Background: The excision repair cross-complementation group 1 (ERCC1) enzyme is a key element of the nucleotide excision repair (NER) pathway which removes cisplatin-induced DNA adducts and has been associated with resistance to platinum-based chemotherapy. We assessed the correlation of ERCC1 immunohistochemical expression with objective tumor response and cancer-specific survival in patients with locally advanced head and neck squamous-cell carcinoma (HNSCC) treated with cisplatin-based induction chemotherapy (CBIC). Methods: The initial cohort comprised 107 patients who had received CBIC (modified Al Saraf protocol) from 1992 to 1996 for locally advanced HNSCC. P53 mutations had been previously studied. Pre-therapeutic biopsy samples from 96 patients with a known tumor response were available. Two independent observers blinded to clinical annotations evaluated ERCC1 expression using the H-score protocol. The median H-score value was a priori selected as the cutpoint in order to dichotomize ERCC1 expression for statistical analysis. Results: In 68 cases [71%, 95% CI: 61% - 79%] tumors expressed ERCC1 intensively and diffusely. Using the logistic regression method, the 28 patients [29 %, 95% CI:21%-39%] with tumors expressing ERCC1 at lower levels had a four time greater odds of benefiting from an objective response to chemotherapy [OR 4.3, 95% CI: 1.4 - 13.4; p = 0.01]. ERCC1 and p53 status, but not their association, were independent predictors of tumor response. In a Cox proportional hazard model adjusted on well-established prognosticators including age, T, N, M, tumor differentiation and localization, ERCC1 low expression was associated with a lower risk of cancer death [RR 2.13, 95% CI: 1.03 - 4.43; p=0.04], while p53 status had no prognostic value. Conclusions: Patients with ERCC1 negative tumors are more likely to derive a substantial benefit from CBIC, translated to a lower risk for cancer-related death compared to patients with ERCC1 positive tumors. Large prospective trials should evaluate ERCC1 and other critical biomarkers involved in DNA damage repair process as molecular predictors of responsiveness to chemotherapy in patients with HNSCC. No significant financial relationships to disclose.