Since cisplatin and carboplatin are the most commonly used base agents for combination chemotherapy for the treatment of advanced NSCLC, many studies have focused on the benefit of platinum doublets.
Older randomized trials repeatedly failed to identify differences in survival between any of these doublets, which gave way to the new era of personalized chemotherapy and the selection of patients with ERCC1 negative expression for receiving platinum-based chemotherapy.
Adjuvant therapy with platinum doublet showed benefit in the ERCC1-negative and the ERCC1-positive population of patients.10 In 1995, the Non-Small-Cell Lung Cancer Collaborative Group (NSCLCCG) published a meta-analysis showing a strong trend in favor of adjuvant cisplatin-based chemotherapy (hazard ratio[HR], 0.87; 95% confidence interval [CI], 0.74–1.02; P = 0.08), with an absolute improvement in the 5-year survival rate of 5%.
Although the benefit was not statistically significant, this observation prompted additional clinical trials to address the appropriate role of adjuvant chemotherapy in patients with resected NSCLC (Table 2).11
The standard of care for stage II–IIIA NSCLC patients is adjuvant cisplatin-based doublet chemotherapy after appropriate surgical resection to improve OS. The benefit for patients with stage IB NSCLC is less apparent, likely because of the heterogeneity of this population. The latest revisions to the TNM staging criteria should assist in risk stratification.11
Our data confirm the benefits of ERCC1 selectivity in improving the outcome of patients with NSCLC. Among the patients who received platinum-based therapy, those who were negative for ERCC1 had significantly longer overall survival than those who were positive as shown in Table 1.
The degree of ERCC1-positive expression also correlated well with the overall survival, but this could also be attributed to the fact that most of our patient population (80%) received platinum-based therapy as per the standard guidelines.
(To view a larger version of Table 2, click here.)
We were unable to test for ribonucleotide reductase messenger RNA (RRM1) expression, the marker of resistance to gemcitabine therapy.12,13 In spite of that, our patient population with advanced NSCLC showed better survival when treated with gemcitabine, whether first or second line, compared to other regimens (19 versus 13 months; P = 0.003).
This contrasts with the group of patients receiving platinum therapy, in whom platinum therapy was only significantly associated with improved overall survival in ERCC1-negative patients. This is the first study, however, that shows that gemcitabine therapy would influence the overall survival of patients with advanced NSCLC if we do not have the tools to test for the specific RRM1 unlike ERCC1 and platinum therapy.
The VEGF (VEGF-A, -C, -D) and the VEGF receptors (VEGFR-1, -2, and -3) are important molecular markers in angiogenesis and lymphangiogenesis. A study by Donnem et al.14 elucidated the prognostic significance of these molecular markers in tumor cells, as well as in the tumor stroma of resected NSCLC tumors. In that study, high tumor cell expression of VEGF-A, VEGFR-1, VEGFR-2, and VEGFR-3 was a significant negative prognostic indicator of disease-specific survival (DSS).14
In tumor stroma, however, high expression of VEGF-A, VEGF-C, VEGF-D, VEGFR-1, and VEGFR-2 correlated with good prognosis. In multivariate analyses, high expression of VEGFR-3 in tumor cells was an independent negative prognostic factor for DSS, whereas in stromal cells, high VEGF-C had an independent positive association with survival.14
In our study, however, the tumor tissue was obtained at biopsy for advanced stage disease. The abundance of tumor tissue made the discrimination between the tumor stromal tissue and the tumor cells very challenging. Our data regarding VEGF and VEGF-R tumor expression were not statistically significant in relation to overall survival; this could be attributed not only to the limited patient population, but also to the limited volume of tumor tissue obtained during biopsy rather than surgical resection.
This might lead to the conclusion that VEGF and VEGF-R expression data should be reviewed with caution especially given data on stromal or tumor tissue expression as well as available information on the amount of available tumor tissue examined prior to any conclusions for prognosis or selection of therapy.
In another study on 115 patients, serum levels of 14-3-3σ were associated with a significantly longer survival in the methylation-positive group (15.1 versus 9.8 months; P = 0.004).15
In our study, however, we tested 14-3-3σ in paraffin-embedded tumor tissue, and both the positive and negative groups had similar survival. This suggests that the expression of 14-3-3σ may be of more value for prognostic stratification of patients with NSCLC if measured in the serum rather than by IHC analysis of paraffin-embedded tissues.
Over-expression of pAKT and loss of PTEN expression in NSCLC have been previously correlated with poor differentiation, lymph node involvement, distant metastasis, late stages as well as worse overall survival.16 Unfortunately, our study did not confirm these findings. In fact, both negative and positive expressions of both receptors had almost equal survival.
NF-kB, also known as p65, is a key transcription factor thought to play a major role in carcinogenesis, and its expression was shown to be significantly higher in advanced TNM stages (III–IV) than in earlier stages (I–II).16 In that study, 394 formalin-fixed and paraffin-embedded specimens from surgically resected lung tumors were examined.
The overall survival analysis in patients with NSCLC (n = 298) showed that NF-kB did not significantly influence the overall survival or disease-free survival.16 Our results, however, are only relevant to the advanced stages of NSCLC (stage III, IV). In our study, patients with positive expression of NF-kB had a median survival of 9.9 months compared to 13 months in those with negative expression.
However, only 4 of 46 patients had positive expression, making this a limited sample to draw broader conclusions. A larger scale study of NF-kB expression is warranted, especially with the ongoing research in targeted therapy utilizing NF-kB inhibitors in patients with lung cancer.17
For the future implications of our study, we are currently investigating the role of pharmacogenomics in relation to the k-ras mutation and have presented an abstract at IASLC/AACR (Abstract) and the potential use of these markers if used in combination with molecular profiling.