Background ERCC1 and RRM1 are molecular determinants that predict sensitivity or resistance to platinum agents and gemcitabine, respectively. Tailored therapy using these molecular determinants suggests patient benefit in a previously reported phase II trial. Here we report an individual patient analysis of prospectively accrued patients treated with the ‘personalized therapy’ approach versus other ‘standard’ non-customized approaches. Patients and Methods NSCLC patients with extranodal metastatic disease and an ECOG PS of 0/1 were accrued to four phase II clinical trials conducted at the H Lee Moffitt Cancer Center (HLMCC): Trial A) carboplatin/gemcitabine first-line followed by docetaxel; Trial B) docetaxel and gefitinib therapy in patients aged 70 years or older; Trial C) combination therapy with carboplatin/paclitaxel/atrasentan; Trial D) personalized therapy (PT) based on ERCC1 and RRM1. Patients with low RRM1/low ERCC1 received gemcitabine/carboplatin; low RRM1/high ERCC1, gemcitabine/docetaxel; high RRM1/low ERCC1, docetaxel/carboplatin; high RRM1/high ERCC1, vinorelbine/docetaxel. Patients treated on trials A, B and C were pooled together and analyzed as the ‘standard therapy’ group. Patients accrued to trial D were called the ‘personalized therapy’ group. Individual patient data were updated as of 02/08/11. Overall Survival (OS) and progression free Survival (PFS) were estimated using the Kaplan-Meier method. Results There was a statistically significant improvement in responses (44% versus 22%; p=0.002), OS (median OS; 13.3 months vs. 8.9; p= 0.016) and PFS (median PFS 7.0 vs. 4.3; p= 0.03). Conclusions This individual patient analyses suggests that ERCC1 and RRM1 tailored selection of first-line therapy improves survival over standard treatment selection approaches.

BACKGROUND This is a phase 2 study of chemotherapy‐naive patients, 70 years of age or older, with nonsmall‐cell lung cancer (NSCLC) who were treated with docetaxel and gefitinib. The primary endpoint was response rate (RR). Secondary endpoints were overall survival (OS) and progression‐free survival (PFS). METHODS Eligible patients were treated with docetaxel 75 mg/m2 every 3 weeks and gefitinib 250 mg orally, daily. Docetaxel and gefitinib were given for 2 cycles beyond maximal response. Gefitinib was continued until disease progression. Comorbidities and activities of daily living were assessed (IADL). RESULTS Forty‐four patients initiated therapy between March 2003 and May 2005. Seventeen patients (40%; 95% confidence interval [CI], 26%–57%) had a partial response and 48% had stable disease. The median PFS was 6.9 months (95% CI, 3.95–7.8 months). Median survival time was 9.6 months (95% CI, 4.6–16.3 months). On univariate analyses, sex, Eastern Cooperative Oncology Group Performance Status (ECOG PS), and Charlson comorbidities index (CCI) score were predictors of improved survival. On multivariate analyses female sex was a statistically significant predictor of survival. The median survivals were 22.8 months in women and 4.8 months in men. This regimen was well tolerated, with the most common adverse events being hyperglycemia, fatigue, and lymphopenia. CONCLUSIONS Docetaxel combined with gefitinib is active and well tolerated in patients with advanced NSCLC who are 70 years of age and older. This paradigm of treatment merits further investigation as a first‐line treatment strategy. Female sex‐specific confirmatory clinical trials with this regimen may be warranted. Cancer 2008. © 2008 American Cancer Society.

Several molecules and profiles are emerging with promising utility as predictive and prognostic parameters in non-small cell lung cancer independent of the standard clinical parameters, such as stage, performance status, and gender. These include the genes ERCC1, RRM1, and BRCA1, which are involved in nucleotide metabolism and DNA damage repair, epidermal growth factor receptor, which is involved in cell proliferation and survival, and oligonucleotide expression array profiles, which are signatures of global gene expression associated with specific tumor phenotypes.

We estimated the total inorganic fluxes of nitrogen (N), sulfur (S), chloride (Cl − ), sodium (Na + ), calcium (Ca 2+ ), magnesium (Mg 2+ ), potassium (K + ) and hydronium (H + ). The resistance deposition algorithm that is programmed as part of the CALMET/CALPUFF modeling system was used to generate spatially-distributed deposition velocities, which were then combined with measurements of urban and rural concentrations of gas and particle species to obtain dry deposition rates. Wet deposition rates for each species were determined from rainfall concentrations and amounts available from the National Acid Deposition Program (NADP) monitoring network databases. The estimated total inorganic nitrogen deposition to the Tampa Bay watershed (excluding Tampa Bay) was 17 kg-N ha −1 yr −1 or 9,700 metric tons yr −1 , and the ratio of dry to wet deposition rates was ∼2.3 for inorganic nitrogen. The largest contributors to the total N flux were ammonia (NH 3 ) and nitrogen oxides (NO x ) at 4.6 kg-N ha −1 yr −1 and 5.1 kg-N ha −1 yr −1 , respectively. Averaged wet deposition rates were 2.3 and 2.7 kg-N ha −1 yr −1 for NH + 4 and NO − 3 , respectively.

Random selection of a chemotherapy regimen improves responses and survival only modestly in patients with advanced non-small cell lung cancer. Chemotherapy that is selected based on the molecular determinants of the tumor may further augment response rates and survival. This requires an in-depth understanding of the prognostic and predictive significance of the molecular determinants. The ultimate clinical utility of these molecular determinants will depend on the feasibility and ease of estimating these parameters using, in primary tumors, techniques that are widely applicable and relatively inexpensive. Using our work with excision repair cross-complementation group 1 (EERC1) and ribonucleotide reductase M1 (RRM1) as a paradigm, we demonstrate the step-wise development of molecular determinants as tools to aid in the selection of chemotherapy. We show that molecular determinant-based selection of chemotherapy is both feasible in the clinical setting and suggests clinical benefit. These findings are currently being confirmed in a Phase III trial. This paradigm could be used for developing customized treatment strategies for other cancers with other chemotherapeutic and targeted agents. In the future, identifying a molecular determinant could be an integral part of drug development. Developing functional imaging techniques for widely used molecular determinants would also mitigate the need for repeated invasive biopsies, allowing us to evaluate the change in the status of molecular determinants in response to treatment.