Jett, James R.

Abstract Purpose: Many studies have highlighted the aberrant expression and prognostic significance of individual proteins in either the Rb (particularly cyclin D1, p16INK4A, and pRb) or the p53 (p53 and p21Waf1) pathways in non–small cell lung cancer. We hypothesize that cumulative abnormalities within each and between these pathways would have significant prognostic potential regarding survival. Experimental Design: Our study population consisted of 106 consecutive surgically resected cases of predominantly early-stage non–small cell lung cancer from the National Cancer Institute-Mayo Clinic series, and assessment of proteins involved both immunohistochemical (cyclin D1, p21Waf1, pRb, p16INK4A, and p53) and mutational analysis (p53) in relationship to staging and survival. Results: Cyclin D1 overexpression was noted in 48% of the tumors, p16INK4A negative in 53%, pRb negative in 17%, p53 immunopositive in 50%, p53 mutation frequency in 48%, and p21Waf1 overexpression in 47%, none with prognostic significance. Cyclin D1 overexpression in pRb-negative tumors revealed a significantly worse prognosis with a mean survival of 2.3 years (P = 0.004). A simultaneous p53 mutation dramatically reduced the mean survival time to 0.9 years (P = 0.007). Cyclin D1 overexpression with either a p53 mutation or a p53 overexpression was also associated with a significantly poorer prognosis (P = 0.0033 and 0.0063, respectively). Conclusions: Some cumulative abnormalities in the Rb and p53 pathways (e.g., cyclin D1 overexpression and p53 mutations) significantly cooperate to predict a poor prognosis; however, the complexity of the cell cycle protein interaction in any given tumor warrants caution in interpreting survival results when specific protein abnormalities are taken in isolation.

8580 Background: This pooled analysis examined the relationship between single-item and multiple-item quality of life (QOL) measures and assessed the agreement between changes in QOL and patient-reported adverse events (AE). Methods: Data from six lung cancer clinical trials involving 358 patients were pooled. All trials incorporated the UNISCALE and one of three multiple-item assessments: the Functional Assessment for Cancer Therapy-Lung, the Lung Cancer Symptom Scale, or the Symptom Distress Scale. A clinically significant decline (CSD) in QOL was defined as a 10-point drop from baseline. A CSD in AE was defined as a change from ≤ grade 2 at baseline to ≥ grade 3 post-baseline. Spearman rank correlations and Bland-Altman approach were used to assess agreement. The Kaplan-Meier method was used to evaluate the time to the first occurrence of a severe (grade 3+) AE and first CSD in QOL. Results: Correlations between the UNISCALE and multi-item assessments were modest (rho=0.49–0.66). At least one 10-point decline in the UNISCALE and multi-item assessments were reported by 58% and 40% respectively. At least one severe AE was reported in 44% of patients post-baseline. The percent agreement between experiencing a severe AE and a CSD in QOL was 49% and 59% for UNISCALE and the multi-item tools. For individual AE, the percent agreement between a CSD in AE and a CSD in QOL ranged from 37% to 50% for UNISCALE and 44% to 69% for the multi-item tools. The median time to the first CSD in QOL for UNISCALE and multi-item tools was 67 and 142 days respectively. The median time to the first occurrence of a severe AE was 304 days. Conclusions: QOL and AE provide quantifiably different information. A 10-point decline in QOL occurs earlier than CTC AE reporting. Patient reported outcomes may be more sensitive in identifying clinically relevant problems than physician rated symptom assessments. No significant financial relationships to disclose.

7605 Background: Overall survival (OS) can be partitioned into progression-free survival (PFS) and PPS. PPS helps to understand trial results, especially when PFS and OS data on trial treatment effects are discordant. At ASCO 2011, we reported that the magnitude of difference in the PFS estimates using different DP date methods was large enough to alter trial conclusions. Here, we investigate the impact of the DP date method on 1) PPS estimates, and 2) predictive utility of DP metrics on subsequent OS (SOS). Methods: Individual patient (pt) data from 14 trials were pooled. DP date was determined using: reported progression date (RPD) (method 1, M1), one day after last progression-free (PF) scan (M2), and midpoint between last PF scan and RPD (M3). PPS was estimated using the method of Kaplan-Meier for the 3 DP date methods. A flexible landmark analysis at 2, 4, and 6 months (mos) using Cox proportional hazards model was used to assess the impact of DP status (progression versus no-progression) on SOS (using M1, M2, or M3). Results: Among NSCLC (SCLC), 87% (91%) of pts reported DP. As expected, the PPS estimates were the lowest for RPD, highest for M2, and in-between for M3 (a direct consequence of the DP date method); with no difference by arm for the randomized trials. Regardless of the DP date method, patients who were progression-free had improved SOS (NSCLC: Hazard ratio, HR<=0.33; p < 0.0001; SCLC: HR<=0.48; p < 0.002) at each landmark time point, with comparable concordance index (SCLC: 0.57-0.65; NSCLC: 0.63-0.67), i.e., ability to discriminate patients with different SOS outcomes. Conclusions: While the DP date methods do not impact the predictive utility of the DP metrics, they significantly impact PPS estimates. The translation of a significant treatment effect on PFS to an effect on OS is influenced by PPS (longer PPS dilutes effect on OS). Standards for declaring DP date are thus critical to trial design and for trial go/no-go decisions. [Table: see text]

13013 Background: The glutathione metabolic pathway is directly involved in the inactivation of platinum compounds. Our earlier work indicated that genotypes corresponding to varied glutathione-related enzyme activities may predict survival in patients with advanced lung cancer. Herein, we evaluated the role of glutathione-related genotypes on clinical outcomes in stage IIIB/IV non-small cell lung cancer patients who were stable or responding from one prior platinum-based chemotherapy. Methods: DNA samples from patients who had tumor regression or stable disease after treatment with one platinum based chemotherapy regimen were analyzed using 6 polymorphic DNA markers that encode 5 important enzymes in the glutathione metabolic pathway. The contrasting genotypes used in the analysis were GCLC (homozygous repeat 77 vs. heterozygous 7*), GPX1 (CC vs. other), GSTP1-I105V (AA vs. other), GSTP1-A114V (CC vs. other), GSTM1 (null vs. present), and GSTT1 (null vs. present). Multivariable Cox proportional hazards models adjusted for age, gender, treatment arm, ECOG performance status, stage, and prior tumor response, were used to evaluate the prognostic significance of the genotypes at each locus. Results: Data from 112 patients with a median follow-up of 10.6 (range: 0.4–56.3) months was used. No significant difference in time to disease progression was observed for any of the genotypes. Among the 6 genomic DNA markers, the GCLC genotype was an important prognostic factor for overall survival after adjusting for other factors. In particular, patients carrying a 77 repeat genotype (homozygous) had a significantly worse survival (Hazard ratio = 1.67, 95% CI: 1.05–2.63). Conclusions: Genotypes of glutathione-related enzymes, especially GCLC, may be used as host factors in predicting patients’ prognosis after platinum-based chemotherapy. Further investigation to define and measure the effects of these genes in chemotherapeutic regimens is needed. (This work was partly supported by NIH research grants CA77118, CA80127, and CA84354.) No significant financial relationships to disclose.

18037 Background: Platinum compounds are major chemotherapeutic agents in lung cancer and are metabolized by the glutathione pathway enzymes. We reported that genotypes of glutathione-related enzymes, especially GCLC, may be host factors in predicting survival of patients with stage IIIB/IV non-small cell lung cancer who were stable or responding from prior platinum-based chemotherapy (Yang et al., ASCO 2006). NCCTG investigators previously correlated allelic variants in 5-FU metabolizing genes with QOL in colorectal cancer patients (Sloan et al., ASCO 2004). We sought to evaluate the role of glutathione pathway genotypes on QOL. Methods: DNA samples were analyzed using 6 polymorphic DNA markers in the glutathione metabolic pathway. The contrasting genotypes in the analysis were GSTM1 and GSTT1 (null vs. present), GSTP1-I105V (AA vs. GA/GG), GSTP1-A114V (CC vs. CT/TT), GPX1 (CC vs. TT/TC), and GCLC (homozygous repeat 77 vs. heterozygous 7*). Forty-six patients completed the FACT-L and the UNISCALE QOL questionnaires at baseline and week-8, and we have results for all 6 genotypes. A clinically significant decline (CSD) in QOL was defined as a 10% decrease from baseline to week-8. A multivariate logistic regression model was used to evaluate the association of all 6 genotypes with a CSD in QOL. Results: Patients carrying the GPX1-CC genotype had a CSD in the UNISCALE (Odds Ratio (OR): 10.0; p=0.02), total FACT-L score (OR: 7.9; p=0.03), the FACT-L physical well being construct (OR: 13.7; p=0.02), and the FACT-L functional well being construct (OR: 5.3; p=0.05). Other constructs, i.e., emotional, social and family, and additional concerns were not significantly associated with the genotypes. Conclusions: Genotypes of glutathione-related enzymes, especially GPX1 may be inherited factors in predicting patients’ QOL after platinum-based chemotherapy. Further investigation to define and measure the direct or indirect effects of these genes on QOL is critical, particularly, via drug responses, toxicities, and disease recurrence. (This work was partly supported by NIH grants CA77118, CA80127, and CA84354.) No significant financial relationships to disclose.

7723 Background: It is critical that we understand the impact of patient, tumor, and treatment-related factors on patient prognosis for the proper design and analysis of Small Cell Lung Cancer (SCLC) trials. An analysis of 15 SCLC trials was performed to investigate and improve our understanding of several factors on OS. Methods: Data from 1623 patients (pts) were used. Age, gender, performance status (PS), tumor stage, body mass index (BMI), creatinine levels, hemoglobin levels, white blood cell counts (WBC), platelet counts, and bilirubin levels were tested for prognostic significance for OS both univariately and multivariately using a Cox Proportional Hazards Model. Models were stratified by protocol, and analyses carried out on the complete data available based on the selected covariates. Model discrimination (i.e., ability to discriminate patients with different survival times) was evaluated using the concordance index (COI). Results: Median follow-up was 63.1 months (range: 1.9 to 155.7). 58% and 42% of pts had extensive-stage or limited-stage SCLC, respectively. Patients with extensive-stage disease, PS>0, increased age, and male gender had significantly worse OS both univariately and multivariately. Patients with increased WBC had significantly worse OS univariately, however, WBC was not a significant predictor when adjusted for other factors. None of the other factors were prognostic for OS. Model discrimination improved by 6.3% when age, gender, PS, and stage were included in a model compared to a model with stage alone (COI improved from 0.63 to 0.67). Conclusions: Age, gender, PS and stage did better at predicting OS than stage alone. Further refinement of this model, including the addition of number of metastatic sites at baseline and treatment related factors, is currently underway. No significant financial relationships to disclose. [Table: see text]

7613 Background: Factors influencing the pattern of disease relapse after curative surgical resection in early stage NSCLC is unknown. We sought to evaluate the effect of tumor- and patient-related characteristics on the pattern of disease recurrence (local relapse and/or metastatic disease) and survival in relation to surgical resection for NSCLC. Methods: A consecutive retrospective series of 488 patients seen at Mayo Clinic Rochester who had complete resection of NSCLC between 1997 and 1998 was utilized. Cox proportional hazards model was used to evaluate the effect of age, gender, smoking status, TNM stage, number of lymph node (LN) involved, number of LN resected, and histopathologic diagnosis on RFS. Logistic regression was used to evaluate the effect on recurrence or death within the first 2 years after surgical resection. Results: Data on 342 patients with a median follow-up of 85 months (range: 0.1 to 162) are reported. 60% were male, and 81% had N0 stage at diagnosis. There were 26 (7.6%) never smokers. Median number of LN resected was 20 (interquartile range [IQR]: 14–29). Median age at surgery was 71 years (IQR: 64 to 76). A bi-modal pattern of local recurrence (N=62) after surgery for early stage NSCLC was observed, with 57% of patients having a local recurrence within 2 years and 21% of patients having a local recurrence from 5–7 years post-surgery. The median duration from surgery to first documented recurrence was 16 months (IQR: 8 to 39). While age, N stage, number of LN involved, and T stage were significant predictors of RFS univariately, only lesser LN resected (p=0.008), older age (p<0.0001) and higher T-stage (p=0.003) were significant adverse predictors of RFS in the multivariate analysis when adjusted for all factors. Higher T-Stage was associated with a significantly increased risk of recurrence or death within the first 2 years after surgical resection (p =0.004). Updated results using data from all 488 patients will be presented in the meeting. Conclusions: A trend towards a bimodal distribution of local recurrences after surgical resection of early stage NSCLC was observed. Increased number of LN resected, younger age and lower T stage were associated with better RFS. No significant financial relationships to disclose.

7547 Background: Sorafenib is a multikinase inhibitor with single-agent activity in previously treated NSCLC. In an effort to evaluate its single agent activity in previously untreated NSCLC, the NCCTG undertook a front-line “window of opportunity” study. Materials and Methods: Patients with stage IIIB (pleural effusion) or stage IV NSCLC received sorafenib dosed at 400 mg BID continuously, with a cycle defined as 4 weeks. Patients were evaluated weekly during the first 2 cycles with those who progressed rapidly going on to receive standard chemotherapy. Based on a two-stage Fleming design, if only at most 1 confirmed response was observed in the first 20 patients enrolled to stage I, the regimen would be considered ineffective. If 2 or more responses were observed, the study would proceed to stage 2 and accrue an additional 22 patients. If 5 or more confirmed responses were observed, the regimen would be recommended for further testing. Results: The study did not meet the stage I efficacy criteria (only 1 confirmed partial response in the first 20 patients) and was permanently closed after enrolling 25 evaluable patients [15 females, 10 males; 4 stage IIIB, 21 stage IV; median age 67 (45–85)]. 2 patients are still receiving treatment (14 and 15 months). No grade 3 or higher hematologic adverse events were observed. Thirteen (52%) patients had a grade 3 non-hematologic adverse event with fatigue (20%), diarrhea (8%), and dyspnea (8%) being the most common. There was one grade 4 pulmonary hemorrhage. A total of 3 (12%) PRs; and 7 (28%) SD were observed in the 25 patients 7 (28%) patients were progression- free at 24 weeks. Median survival and median time to progression were 8.8 and 2.9 months respectively. Conclusion: While the pre- specified efficacy endpoints were not met, the objective response rate of 12% and median survival of 8.8 months suggest that single agent sorafenib has activity similar to two-drug combinations. The feasibility and utility of the “window of opportunity” design in estimating the activity of novel compounds was demonstrated. Finally, the single-agent activity of sorafenib argues for combination studies with standard chemotherapy agents. No significant financial relationships to disclose.