RRM1 and ERCC1 are determinants of survival after surgical treatment of early-stage, non-small-cell lung cancer.

OverviewLung cancer is the leading cause of cancer-related death in the United States. An estimated 219,440 new cases (116,090 men; 103,350 women) of lung and bronchus cancer were diagnosed in 2009, and 159,390 deaths (88,900 men; 70,490 women) occurred from the disease.1 Only 15% of all lung cancer patients are alive 5 years or more after diagnosis

Less than half of US physicians are following the guidelines from the American Society of Clinical Oncology, which suggest that all patients of childbearing age should be informed about FP.

Purpose: The initial goal of this study was to test the immunologic and clinical effects of a new cancer vaccine consisting of dendritic cells (DC) transduced with the full-length wild-type p53 gene delivered via an adenoviral vector in patients with extensive stage small cell lung cancer. Experimental Design: Twenty-nine patients with extensive stage small cell lung cancer were vaccinated repeatedly at 2-week intervals. Most of the patients received three immunizations. p53-specific responses were evaluated, and phenotype and function of Tcells, DCs, and immature myeloid cells were analyzed and correlated with antigen-specific immune responses. Objective clinical response to vaccination as well as subsequent chemotherapy was evaluated.Results: p53-specificTcell responses to vaccination were observed in 57.1% of patients. Immunologic responses to vaccination were positively associated with a moderate increase in the titer of antiadenovirus antibodies, and negatively with an accumulation of immature myeloid cells. One patient showed a clinical response to vaccination whereas most of the patients had disease progression. However, we observed a high rate of objective clinical responses to chemotherapy (61.9%) that immediately followed vaccination. Clinical response to subsequent chemotherapy was closely associated with induction of immunologic response to vaccination. Conclusions: This study provides clinical support for an emerging paradigm in cancer immunotherapy, wherein optimal use of vaccination might be more effective, not as a separate modality, but in direct combination with chemotherapy.

The results strongly suggest that tumoral RRM1 expression is a major predictor of disease response to gemcitabine/platinum chemotherapy. ERCC1 expression is predictive of response albeit to a lesser degree.

Purpose: No chemotherapy regimen, including the widely used combination of gemcitabine/cisplatin, confers significantly improved survival over any other in metastatic non-small cell lung cancer (NSCLC); however, the selection of patients according to key genetic characteristics can help to tailor chemotherapy. Ribonucleotide reductase subunit M1 (RRM1) is involved in DNA synthesis and repair and in gemcitabine metabolism, and the excision repair crosscomplementing group 1 (ERCC1) gene has been related to cisplatin activity.Experimental Design: Patients were part of a large randomized trial carried out from September 1998 to July 2000, comparing gemcitabine/cisplatin versus gemcitabine/cisplatin/vinorelbine versus gemcitabine/vinorelbine followed by vinorelbine/ifosfamide. We analyzed RRM1 and ERCC1 mRNA expression in paraffin-embedded samples obtained from bronchoscopy by real-time quantitative reverse transcription-PCR. Results were correlated with survival using the Kaplan-Meier method.Results: A total of 100 patients were assessed. There was a strong correlation between RRM1 and ERCC1 mRNA expression levels (Spearman r ‫؍‬ 0.410; P < 0.001). In the gemcitabine/cisplatin arm, patients with low RRM1 mRNA expression levels had significantly longer median survival than those with high levels [13.7 versus 3.6 months; 95% confidence interval (CI), 9.6 -17.8 months; P ‫؍‬ 0.009]. Median survival was also significantly longer among patients with low mRNA expression levels of both RRM1 and ERCC1 (not reached), than among those with high levels of both genes (6.8 months; 95% CI, 2.6 -11.1 months; P ‫؍‬ 0.016).Conclusions: RRM1 mRNA expression is a crucial predictive marker of survival in gemcitabine/cisplatin-treated patients. Genetic testing of RRM1 mRNA expression levels can and should be used to personalize chemotherapy.

For an isolated adrenal metastasis from NSCLC, patients with a synchronous metastasis who underwent adrenalectomy had a shorter median overall survival than those with a metachronous metastasis. However, a durable long-term survival is achieved in approximately 25% in both groups.

Purpose: Signal transducers and activators of transcription 3 (Stat3), a member of the STAT family of transcription factors, regulates multiple oncogenic pathways, including pathways regulating tumor cell survival.We evaluated Stat3 activation in early stage non^small cell lung cancers (NSCLC) and how this relates to upstream epidermal growth factor receptor (EGFR) activation, tumor apoptosis, and prognosis. Experimental Design: High-density tissue microarrays using tissues from 176 surgically resected NSCLC were evaluated for expression of phosphorylated Stat3 (pStat3) and epidermal growth factor receptor (pEGFR) along with tumor apoptosis. Using NSCLC cell lines, we evaluated how pStat3 expression relates to EGFR mutations and sensitivity of cells to gefitinib. Results: We identified nuclear pStat3 expression in 54% of tumors. pStat3 expression was correlated with smaller tumors (P < 0.0001) and with limited smoking history (P = 0.02).We identified a trend toward higher pStat3 expression in adenocarcinomas compared with other tumor histology (P = 0.09). No relationship was found between pStat3 and prognosis following surgical resection. Importantly, we found a strong positive correlation between pEGFR expression and pStat3 expression (P <0.0001) and an inverse correlation between pStat3 and apoptosis (P = 0.01) consistent with less apoptosis in tumors expressing high amounts of pStat3. Cell lines with mutant EGFR have increased levels of pStat3 compared with cell lines without mutant EGFR and this correlates with their sensitivity to gefitinib. Finally, antisense-mediated knockdown of Stat3 induces apoptosis in EGFR mutant lung cancer cells. Conclusions: Early-stage NSCLC tumors have activated EGFR-Stat3 signaling with low apoptosis. Our findings suggest that pStat3 expression may be helpful in identifying patients appropriate for treatment with EGFR tyrosine kinase inhibitors.