Prognostic and Predictive Biomarkers in Early Stage NSCLC
The protein encoded by breast cancer susceptibility gene 1 (BRCA1) has a crucial role in DNA repair as well as in cell-cycle checkpoints and mitotic spindle assembly. BRCA1 sensitizes cancer cells to apoptosis induced by antimicrotubule drugs, such as taxanes and vinca alkaloids, while conferring resistance to DNA-damaging agents, including platinum agents. The potential prognostic role of a panel of nine candidate biomarkers including BRCA1 was investigated in two independent cohorts of chemotherapy naive patients with early-stage NSCLC. BRCA1 was the only independent factor affecting OS. In a group of patients with locally advanced NSCLC, treated with neo-adjuvant cisplatin and gemcitabine followed by surgery, those with the lowest levels of BRCA1 mRNA expression had significantly greater benefit from chemotherapy in terms of clinical and pathological downsizing and OS.
For its localization to sites of DNA double strand breaks, the upstream activity of the receptor-associated protein 80 (RAP-80) is required for BRCA1. In a first line study in advanced NSCLC patients with the lowest expression of both BRCA1 and RAP-80 receiving cisplatin plus gemcitabine it was shown that RAP-80 can modulate the effect of BRCA1. In addition to a close correlation with BRCA1, RAP-80 expression was identified as an independent predictor for OS. In a phase II feasibility study of adjuvant chemotherapy in patients with stage II-IIIA NSCLC, those with high BRCA1 transcriptional levels received single agent docetaxel, whereas those with intermediate and low BRCA1 expression were treated with cisplatin-doublets and OS did not differ between the treatment arms.
A recent meta-analysis of 23 studies assessed the role of BRCA1 as a predictor of clinical outcome in platinum- and paclitaxel-based chemotherapy in NSCLC patients. In 17 platinum-based studies, low/negative BRCA1 was associated with better objective response rate [ORR] (OR =1.70, 95% CI, 1.32–2.18), longer OS and event-free survival [EFS] (HR =1.58, 95% CI, 1.27–1.97, and HR =1.60, 95% CI, 1.07–2.39 for OS and EFS, respectively). In 4 paclitaxel-based chemotherapy studies, patients with high/positive BRCA1 had better ORR (OR =0.41, 95% CI, 0.26–0.64) while OS and EFS were not evaluated because of the insufficient data available. Some studies reported that ERCC1 expression is closely linked to RRM1 and BRCA1 levels, with concordant levels in 70–80% of cases.
Breast Cancer Susceptibility Gene 1
The protein encoded by breast cancer susceptibility gene 1 (BRCA1) has a crucial role in DNA repair as well as in cell-cycle checkpoints and mitotic spindle assembly. BRCA1 sensitizes cancer cells to apoptosis induced by antimicrotubule drugs, such as taxanes and vinca alkaloids, while conferring resistance to DNA-damaging agents, including platinum agents. The potential prognostic role of a panel of nine candidate biomarkers including BRCA1 was investigated in two independent cohorts of chemotherapy naive patients with early-stage NSCLC. BRCA1 was the only independent factor affecting OS. In a group of patients with locally advanced NSCLC, treated with neo-adjuvant cisplatin and gemcitabine followed by surgery, those with the lowest levels of BRCA1 mRNA expression had significantly greater benefit from chemotherapy in terms of clinical and pathological downsizing and OS.
For its localization to sites of DNA double strand breaks, the upstream activity of the receptor-associated protein 80 (RAP-80) is required for BRCA1. In a first line study in advanced NSCLC patients with the lowest expression of both BRCA1 and RAP-80 receiving cisplatin plus gemcitabine it was shown that RAP-80 can modulate the effect of BRCA1. In addition to a close correlation with BRCA1, RAP-80 expression was identified as an independent predictor for OS. In a phase II feasibility study of adjuvant chemotherapy in patients with stage II-IIIA NSCLC, those with high BRCA1 transcriptional levels received single agent docetaxel, whereas those with intermediate and low BRCA1 expression were treated with cisplatin-doublets and OS did not differ between the treatment arms.
A recent meta-analysis of 23 studies assessed the role of BRCA1 as a predictor of clinical outcome in platinum- and paclitaxel-based chemotherapy in NSCLC patients. In 17 platinum-based studies, low/negative BRCA1 was associated with better objective response rate [ORR] (OR =1.70, 95% CI, 1.32–2.18), longer OS and event-free survival [EFS] (HR =1.58, 95% CI, 1.27–1.97, and HR =1.60, 95% CI, 1.07–2.39 for OS and EFS, respectively). In 4 paclitaxel-based chemotherapy studies, patients with high/positive BRCA1 had better ORR (OR =0.41, 95% CI, 0.26–0.64) while OS and EFS were not evaluated because of the insufficient data available. Some studies reported that ERCC1 expression is closely linked to RRM1 and BRCA1 levels, with concordant levels in 70–80% of cases.