Analysis of ERCC1, BRCA1, RRM1 and TUBB3 as predictors of prognosis in patients with non-small cell lung cancer who received cisplatin-based adjuvant chemotherapy: A prospective study

Abstract

Although adjuvant platinum-based chemotherapy has been demonstrated to improve survival in patients with completely resected non-small cell lung cancer (NSCLC), individualized approaches to therapy are urgently required to improve the treatment efficacy and reduce unnecessary toxicity. It was hypothesized in the present study that the protein levels of excision repair cross-complementation group 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase M1 (RRM1) and class III β-tubulin (TUBB3) may influence the therapeutic effect of adjuvant cisplatin-based chemotherapy. The expression of ERCC1, BRCA1, RRM1 and TUBB3 in tissues obtained from 84 patients with NSCLC was analyzed in the present non-interventional study by immunohistochemistry prior to adjuvant chemotherapy. All patients received adjuvant cisplatin-based chemotherapy. The primary endpoint in the present study was disease free survival (DFS). Out of the 84 tumors, the expression of ERCC1, BRCA1, RRM1 and TUBB3 was identified in 46 (55%), 11 (13%), 73 (87%) and 76 (90%) tissues, respectively. A beneficial response to adjuvant cisplatin-based chemotherapy in DFS was associated with the absence of the expression of ERCC1 [hazard ratio (HR), 2.166; 95% confidence interval (CI), 1.049-4.474; P=0.037] and BRCA1 (HR, 2.419; 95% CI, 1.127-5.193; P=0.023), but not with the expression status of RRM1 (HR, 0.568; 95% CI, 0.234-1.379; P=0.212) or TUBB3 (HR, 1.874; 95% CI, 0.448-7.842; P=0.39). In addition, patients lacking the expression of ERCC1 and BRCA1 benefited more from adjuvant cisplatin-based chemotherapy compared with patients that expressed either ERCC1 or BRCA1 (HR, 3.102; 95% CI, 1.343-7.163; P=0.008). The expression of ERCC1 and BRCA1 was significantly associated with the DFS time in patients with NSCLC treated with adjuvant cisplatin-based chemotherapy, respectively. The combination of the ERCC1 and BRCA1 expression levels may be a promising prognostic prediction for adjuvant cisplatin-based chemotherapy.

Keywords: breast cancer 1; class III β-tubulin; excision repair cross-complementation group 1; non-small cell lung cancer; ribonucleotide reductase M1.

Figure 1.

Procedure of patient selection. Reasons for withdrawal consisted of patient decision (n=5), Eastern Cooperative Oncology Group performance status ≥2 (n=5), mortality (n=1) and did not complete four cycles of chemotherapy (n=8).

Figure 2.

Immunohistochemical staining of squamous cell carcinoma. The tumor specimens (original magnification, ×400) reveal strong expression (staining score 3)of (A) excision repair cross-complementation group 1, (B) breast cancer 1, (C) ribonucleotide reductase M1 and (D) class III β-tubulin.

Figure 3.

Kaplan-Meier estimates of the probability of survival with adjuvant cisplatin-based chemotherapy. (A) Disease-free survival according to ERCC1 expression (median, 33.6 vs. 19.0 months; P=0.032). (B) Disease-free survival according to BRCA1 expression (median, 24.4 vs. 23.9 months; P=0.019). (C) Disease-free survival according to RRM1 expression (median, 23.0 vs. 24.0 months; P=0.205). (D) Disease-free survival according to TUBB3 expression (median, 33.4 vs. 23.3 months; P=0.382). (E) Disease-free survival according to ERCC1 and BRCA1 expression (median, 32.2 vs. 14.8 months; P=0.005). (F) Overall survival according to ERCC1 and BRCA1 expression (median, 32.2 vs. 23.4 months; P=0.117). ERCC1, excision repair cross-complementation group 1; BRCA1, breast cancer 1; RRM1, ribonucleotide reductase M1; TUBB3, class III β-tubulin.