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8040 Background: Advanced NSCLC pts with Zubrod PS2 are often excluded from clinical trials and platinum-based therapy. In SWOG 0341, ERL in PS 2 pts yielded progression-free (PFS) and overall surv...

High grade prostatic intraepithelial neoplasia is likely a premalignant lesion of the prostate. Decreasing the frequency of high grade PIN may decrease the risk of prostate cancer. In the Prostate Cancer Prevention Trial we evaluated the impact of finasteride on the risk of a needle biopsy diagnosis of high grade prostatic intraepithelial neoplasia.The Prostate Cancer Prevention Trial was a randomized, placebo controlled clinical trial that enrolled 18,882 men without evidence of prostate cancer, prostate specific antigen less than 3.0 ng/ml and normal digital rectal examination, and randomized them to 5 mg finasteride daily or placebo. Subjects were followed for 7 years with biopsy recommended for prostate specific antigen greater than 4.0 ng/ml, adjusted in the finasteride group to achieve an equal number of biopsy recommendations or for abnormal digital rectal examination. All cancer-free subjects were recommended to undergo biopsy after 7 years on study. We evaluated the diagnosis of high grade prostatic intraepithelial neoplasia with or without concomitant prostate cancer in these 2 study groups.The number of men evaluable for high grade prostatic intraepithelial neoplasia was 4,568 in the finasteride group and 4,886 in the placebo group. High grade prostatic intraepithelial neoplasia alone was diagnosed in 276 men (6.0%) in the finasteride group vs 347 (7.1%) in the placebo group (RR 0.85, 95% CI 0.73-0.99, p=0.04). High grade prostatic intraepithelial neoplasia accompanied by prostate cancer was diagnosed in 144 men (3.2%) in the finasteride group vs 223 (4.6%) in the placebo group (RR 0.69, 95% CI 0.56-0.85, p=0.0004). Finasteride significantly decreased the overall risk of high grade prostatic intraepithelial neoplasia (alone and with cancer) from 570 cases (11.7%) in the placebo group to 420 (9.2%) in the finasteride group (HR 0.79, 95% CI 0.70-0.89, p0.001).Finasteride significantly decreased the risk of high grade PIN. This observation may explain how finasteride decreased prostate cancer in the Prostate Cancer Prevention Trial, supporting the notion that high grade prostatic intraepithelial neoplasia is a premalignant lesion of the prostate, and it provides new information relevant to the consideration of finasteride for prostate cancer prevention.

CC and CXC chemokines may play a role in mother-to-child HIV-1 transmission by blocking HIV-1 binding to chemokine receptors and impeding viral entry into cells.To define correlates of breastmilk chemokines and associations with infant HIV-1 acquisition, chemokines in breastmilk and infant HIV-1 infection risk were assessed in an observational, longitudinal cohort study. We measured MIP-1alpha, MIP-1beta, RANTES, and SDF-1 in month 1 breastmilk specimens from HIV-1-infected women in Nairobi and HIV-1 viral load was calculated in maternal plasma and breastmilk at delivery and 1 month postpartum. Infant infection status was determined at birth and months 1, 3, 6, 9, and 12.Among 281 breastfeeding women, 60 (21%) of their infants acquired HIV-1 during follow-up, 39 (65%) of whom became infected intrapartum or after birth. MIP-1alpha, MIP-1beta, RANTES, and SDF-1 were all positively correlated with breastmilk HIV-1 RNA (P0.0005). Women with clinical mastitis had 50% higher MIP-1alpha and MIP-1beta levels (P0.001 and P=0.006, respectively) and women with subclinical mastitis (breastmilk Na(+)/K(+)1) had approximately 70% higher MIP-1alpha, MIP-1beta and RANTES (P0.002 for all) compared to women without mastitis. Independent of breastmilk HIV-1, increased MIP-1beta and SDF-1 were associated with reduced risk of infant HIV-1 (RR=0.4; 95% CI 0.2-0.9; P=0.03 and RR=0.5; 95% CI=0.3-0.9; P=0.02, respectively) and increased RANTES was associated with higher transmission risk (RR=2.3; 95% CI 1.1- 5.3; P=0.04).These observations suggest a complex interplay between virus levels, breastmilk chemokines, and mother-to-child HIV-1 transmission and may provide insight into developing novel strategies to reduce infection across mucosal surfaces.

Human leukocyte antigen (HLA) molecules regulate the cellular immune system and may be determinants of infant susceptibility to human immunodeficiency virus type 1 (HIV-1) infection. Molecular HLA typing for class I alleles was performed on infants followed in a Kenyan perinatal cohort. Early HIV-1 infection status was defined as infection occurring at birth or month 1, while late infection via breast milk was defined as first detection of HIV-1 after 1 month of age. Likelihood ratio tests based on a proportional hazards model adjusting for maternal CD4 T cell count and HIV-1 viral load at 32 weeks of gestation were used to test associations between infant allelic variation and incident HIV-1 infection. Among 433 infants, 76 (18%) were HIV-1 infected during 12 months of follow-up. HLA B*18 was associated with a significantly lower risk of early HIV-1 transmission [relative risk (RR) = 0.26; 95% confidence interval (CI) 0.04-0.82], and none of the 24 breastfeeding infants expressing HLA B*18 who were uninfected at month 1 acquired HIV-1 late via breast milk. We observed a trend toward increased early HIV-1 acquisition for infants presenting HLA A*29 (RR = 2.0; 95% CI 1.0-3.8) and increased late HIV-1 acquisition via breast milk for both Cw*07 and Cw*08 (RR = 4.0; 95% CI 1.0-17.8 and RR = 7.2; 95% CI 1.2-37.3, respectively). HLA B*18 may protect breast-feeding infants against both early and late HIV-1 acquisition, a finding that could have implications for the design and monitoring of HIV-1 vaccines targeting cellular immune responses against HIV-1.

Human herpesvirus-8 (HHV-8) is frequently detected in oropharyngeal secretions from HIV-infected men who have sex with men (MSM), and contact with saliva may be an important mode of HHV-8 transmission. A total of 196 MSM were followed over 2 years to determine the correlates of HHV-8 oropharyngeal shedding. A total of 134 (68%) of 196 participants were HHV-8 seropositive upon enrollment, and 9 (15%) of 62 participants seroconverted to HHV-8 during follow-up. HHV-8 DNA was detected in 43 (22%) of 196 participants: 39 (27%) of 134 HHV-8 seropositive, 4 (8%) of 53 HHV-8 seronegative, and 5 (56%) of 9 seroconverters to HHV-8. HHV-8 was detected in 101 (15%) of 696 total oral specimens: 84 (17%) of 481 samples from HHV-8-seropositive men, 6 (3%) of 180 samples from HHV-8-seronegative men, and 11 (31%) of 35 samples from seroconverters. Using adjusted marginal structural models, HHV-8 shedding was higher in men not receiving highly active antiretroviral therapy (odds ratio 2.4, 95% CI 1.0-6.0, P = 0.06), with CD4 counts > 200 cells/mm (odds ratio 4.8, 95% CI 1.0-22.8, P = 0.05), or with detectable oral leukocyte esterase (odds ratio 5.0, 95% CI 2.0-12.5, P < 0.01). CD4 count, antiretroviral therapy, and oral inflammation may influence HHV-8 oropharyngeal shedding.

e11584 Background: Brain metastases occur late in the course of metastatic breast cancer and the median survival from time of brain metastases has historically been ~4 months. Stereotactic radiosur...

Human immunodeficiency virus (HIV) type 2 infection is characterized by slower disease progression to acquired immunodeficiency syndrome than results from HIV-1 infection. To better understand the biological factors underlying the different natural histories of infection with these 2 retroviruses, we examined the relationship between HIV RNA and DNA levels and the rate of CD4(+) T cell decline among 472 HIV-1- and 114 HIV-2-infected individuals from Senegal. The annual rate of CD4(+) T cell decline in the HIV-2 cohort was approximately one-fourth that seen in the HIV-1 cohort. However, when the analysis was adjusted for baseline plasma HIV RNA level, the rates of CD4(+) T cell decline per year for the HIV-1 and HIV-2 cohorts were similar (a rate increase of approximately 4% per year for each increase in viral load of 1 log(10) copies/mL). Therefore, plasma HIV load is predictive of the rate of CD4(+) T cell decline over time, and the correlation between viral load and the rate of decline appears to be similar among all HIV-infected individuals, regardless of whether they harbor HIV-1 or HIV-2.

7511 Background: ES-SCLC patients (pts) with progressive disease (PD) following plat-based chemo are traditionally categorized as plat-sensitive (PD >/= 90 days from last plat dose) or refractory (PD < 90 days). This practice arose from seminal observations in the early 1980s of worse survival in refractory pts. Subsequent trial designs accounted for plat-sensitivity status, resulting in higher sample sizes and increased resource use. Whether this relationship holds in the modern era is less clear. Methods: Updated data from recent SWOG trials in 2nd and/or 3rd line ES-SCLC (S0802: topotecan + aflibercept: S0435: sorafenib; and S0327: PS-341) were pooled. Accrual goals were specified for sensitive and refractory in each trial. Hazard ratios (HRs) for overall (OS) and progression-free survival (PFS) were calculated using Cox Proportional Hazard (PH) models [unadjusted and adjusted]. Results: Of 329 pts, 151 were classified as sensitive, 178 refractory; median age = 63 years; males = 52%; PS 1 = 67%; weight loss >5% = 28%; > 2 prior chemo = 16%; and elevated LDH = 43%. HRs from unadjusted Cox models for OS for refractory vs. sensitive were 1.0 (95% CI 0.81-1.25, p=0.98) and 1.24 (95% CI 0.99, 1.57; p=0.06). Cox PH models adjusted for baseline prognostic factors for PFS and OS are shown. Conclusions: In this large database analysis, plat-sensitivity status is no longer a significant independent variable for OS or PFS. Baseline PS, sex, LDH, and weight loss remain independent OS variables. These data have critical implications in the design of future trials in ES-SCLC. [Table: see text]

7510 Background: We previously demonstrated that PFS may be a candidate surrogate endpoint for OS in ES-SCLC using data from 3 randomized trials (Foster, Cancer 2011). Here, we sought to formally assess the patient- and trial-level surrogacy of PFS using data from 9 additional randomized phase II and III trials conducted by the NCI-funded cancer cooperative groups since 1986. Methods: Individual patient data from all 12 trials (3178 patients: 9 phase III and 3 phase II) were pooled. OS was the primary endpoint in all phase III trials; 3 phase III and 1 phase II trial were positive per protocol. Patient-level surrogacy (Kendall’s tau) was assessed using the Clayton copula bivariate survival model. Trial-level surrogacy was assessed via association of the log hazard ratios on OS and PFS across trials, including: weighted (by trial size) least squares regression of Cox model effects (R² WLS) and weighted (by trial size) correlation of the copula effects (R² Copula). One trial had 4 treatment arms thus 14 total two-arm comparisons were made. Results: With a median follow-up of 41.8 months in the 106 patients still alive, the median OS and PFS across trials were 9.7 months (95% CI: 9.5, 9.9) and 5.7 months (95% CI: 5.5, 5.8), respectively. There were 3120 PFS events in total (2564 disease progressions and 556 deaths without progression). The median time from progression to death was 4.1 months (95% CI: 3.9, 4.3). PFS showed modest association with OS at the patient-level (tau= 0.56) and at the trial-level (R² WLS = 0.58; R² Copula (standard error) = 0.55 (0.29)). The 95% CIs for the predicted HR for OS given observed HR on PFS under a weighted leave-one-out prediction always included the observed HR for OS; however such intervals were wide, suggesting uncertainty on the practical use of PFS as a surrogate for OS in this setting. Conclusions: PFS failed to demonstrate surrogacy for OS in ES-SCLC based on this large pooled analysis. Given that the difference in the median PFS and OS is less than 6 months, we recommend using OS as the primary endpoint in phase III trials of previously untreated ES-SCLC.

7527 Background: The VEGF/VEGFR and PDGF/PDGFR pathways are potential therapeutic targets in mesothelioma. Cediranib, a VEGFR/PDGFR inhibitor, showed anti-tumor activity in a salvage monotherapy study S0509. Methods: S0905 combined cediranib (2 dose cohorts 30 mg and 20 mg daily) with cisplatin and pemetrexed for 6 cycles followed by maintenance cediranib in unresectable chemo-naïve MPM patients. Results: A total of 20 patients (7 to cohort 1 - 30 mg, 13 to cohort 2 - 20 mg) were enrolled. In first cohort, 2 patients reported grade 3 DLTs of diarrhea and fatigue. Cohort 2 DLTs included 2 patients with grade 3 hyponatremia/dehydration and mucositis. For all cycles, 12 patients reported Grade 3 AEs, the most common being diarrhea (4), dehydration (3), fatigue (3) and neutropenia (3). Two grade 4 thrombocytopenia were reported with 1 treatment-related death (cohort 2) due to pneumonia/sepsis. Based on the toxicity profile, a decision was made to proceed with cediranib 20 mg daily for the remaining phase I/II trial. Two radiographic response measurements were utilized (RECIST 1.1, modified RECIST). 18/20 patients were evaluable for response by RECIST 1.1 (7 - 30 mg cohort, 11 - 20 mg cohort). The RECIST 1.1 RR was 22% (95% CI: 6% - 48%) and median PFS was 14 months (95% CI: 8 – 17). Two patients had inadequate assessments and are classified as non-responders. There were 19 patients measurable by modified RECIST with RR 53% (95% CI: 29%-76%) and median PFS 10 months (7-13). For all patients, the median OS was 16 months (95% CI: 11-19). One patient in the 30 mg cohort remains on trial after 25 cycles of therapy; 2 patients at the 20 mg cohort remain on trial on cycles 19 and 15 of therapy. Conclusions: Cisplatin-pemetrexed-cediranib shows significant clinical activity and acceptable toxicity with cediranib 20 mg/day. The randomized phase II portion of the trial is ongoing. Clinical trial information: NCT01064648. [Table: see text]

7517 Background: Despite recent changes to lung adenoCa pathologic classification, adv stage BAC remains a definable and clinically applicable entity. Patients (pts) with BAC, as well as never-smoking (NS) pts with adv lung adenoCa, have emerged as relevant clinical subpopulations with a high probability of clinical benefit from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), likely related to the high proportion of activating mutations in the EGFR gene in such pts. Based on these results and the potential for increased clinical activity conferred by addition of B to E, SWOG initiated a pair of phase II trials of this combination in pts with adv BAC (S0635) or NS pts with adv lung adenoCa (S0636). Methods: NS pts with BAC or adenoBAC were preferentially enrolled on S0636. A total of 78 and 85 eligible pts were enrolled and treated on the S0635 and S0636 trials, respectively. Patients received E 150 mg PO daily and B 15 mg/kg IV q21 days until progression or prohibitive toxicity. Tumor tissue submission for pathologic review and assessment of molecular markers was mandated. Results: Pt demographics of the two trials are as shown in the table below. RECIST response rate among 61 BAC pts on S0635 with measurable disease was 18%, and among 53 NS pts on S0636, it was 47%. Median progression-free survival is 5 and 8 months (mo) on S0635 and S0636, respectively; median overall survival (OS) is 17 and 26 mo on S0635 and S0636, respectively. Toxicity consisted primarily of rash, diarrhea, and hypertension; no treatment-related deaths were reported. Molecular marker studies will be presented separately. Conclusions: In populations selected by clinical parameters, E withB is associated with modest toxicity and encouraging clinical efficacy that exceeded the prespecified OS threshold of 16 mo in studies of both adv BAC and NS pts, exceeding two years in NS pts. [Table: see text]

7552 Background: S0636 investigated the combination of erlotinib and bevacizumab in never-smoking NSCLC patients with confirmed adenocarcinoma histology (H. West ASCO 2011). Patient eligibility was not restricted by molecular selection. Median PFS and OS were encouraging at 8 and 26 months. An analysis of molecular markers was undertaken, focusing initially on the EGFR pathway. Methods: EGFR analysis included gene copy number, mutation and protein expression. Copy number was conducted by FISH using the Colorado scoring system. An immunohistochemistry H score was developed for EGFR protein expression analysis, ranging from 0 to 400. Specimens were evaluable from 42 of the 85 eligible patients. Results: FISH positivity was identified in 17/35 pts (49%), 11 with high polysomy and 6 with true gene amplification. EGFR activating mutations were seen in 10/33 pts (30%). IHC H-score >200 was observed in 17/40 pts (43%). All EGFR markers were significantly correlated with one another. In the EGFR WT subgroup, FISH-positive patients outperformed FISH-negative pts (mPFS 20 vs, 6 months, p=0.06). Conclusions: Careful analysis of EGFR markers (mutation, FISH and IHC) identified S0636 patients with favorable PFS and encouraging trends for OS. EGFR FISH and IHC provided additional predictive information beyond that of EGFR mutation status. Supported in part by DHHS: CA32102 and CA38926, and in part by Genentech. [Table: see text]

7570 Background: In 1999, SWOG published a study demonstrating the underrepresentation of patients 65 years and older on clinical trials (Hutchins NEJM). A second report published in 2006 demonstrated increasing proportions of patients > 65 years (31% 1997-2000; 38% 2001-2003) being enrolled into SWOG trials (Unger JCO). Older patient enrollment was still disproportionately low compared to the US cancer population. The current analysis focuses on patients with lung cancer from 1993-2008. Methods: The proportions of enrollment onto SWOG lung cancer treatment trials by age (65-69, 70-79, ≥80 years) and gender were computed for 4-year time intervals between 1993 and 2008; corresponding rates in the US were derived from US Census and National Cancer Institute SEER data. Proportions in the SWOG trials were compared to the SEER proportions using a 1-sample binomial test of proportions. Time trends within SWOG were evaluated using linear regression. Results: The proportion of patients 65-69 was significantly higher than the US population between 1993 and 2004, but was not significantly different after 2004. Proportions of patients on SWOG trials 70-79 years old and ≥ 80 were significantly smaller than the US population. Females were underrepresented from 1993-2004. Between 2005 and 2008 female enrollment was not significantly different from the US population. Conclusions: Currently, the proportion of patients 65-69 years of age and of female gender enrolled in SWOG trials is representative of the general lung cancer population. Although some progress has been made in increasing trial participation of patients > 70, enrollment remains disproportionately low. The disparity is most evident in patients > 80. Continued efforts are needed to increase older patient participation in lung cancer trials. Supported in part by PHS Cooperative Agreement grants awarded by the National Cancer Institute: DHHS, CA32102 and CA38926. [Table: see text]

7005 Background: In advanced lung cancer, overall survival is largely influenced by the DP status. At ASCO 2010, we reported that the PFS estimates are significantly impacted by the approach used f...

7013 Background: The Intergroup molecular epidemiology study S0424 was designed to investigate relationships between tumor biology with tobacco carcinogen exposure and gender in a cohort of early s...

8015 Background: Cetuximab (CX) plus platinum-based chemotherapy improves overall survival (OS) in advanced NSCLC (FLEX). SWOG previously showed that EGFR FISH is associated with efficacy outcomes in patients (pts) receiving CB/P/CX (S0342). Bevacizumab (B) plus chemotherapy also increases survival (E4599) in eligible pts. Given the biologic rationale for combining EGFR and VEGFR targeted agents, S0536 investigated the safety and efficacy of carboplatin (CB), paclitaxel (P) and CX plus B. Methods: Eligibility: treatment-naïve advanced stage non-squamous cell NSCLC, no requirement for EGFR positivity, PS 0–1, no brain metastases or hemoptysis. Treatment: CB AUC 6, P 200 mg/m2, B 15 mg/kg IV day 1 every 3 weeks, CX 400 mg/m2 day 1 then 250 mg/m2 weekly for up to 6 cycles; then B 15 mg/kg every 3 weeks and CX 250 mg/m2 weekly until progression. Primary endpoint: feasibility defined by the frequency and severity of ≥grade 4 hemorrhagic toxicities. Secondary endpoints: response rate, progression-free survival (PFS), OS and toxicity. Results: 110 pts enrolled from August 2006 to September 2007; 104 assessable. Pt characteristics: median age 64 years (42–78), Male/Female 52/52, PS 0/1 43/61, stage IIIB/IV 9/95, adenocarcinoma: 81, current/former smoker: 82. Overall toxicities were acceptable and comparable to S0342 and E4599. Primary endpoint was met: grade ≥4 hemorrhage: 2% (95% CI: 0–7%). There were 4 treatment-related deaths: lung hemorrhage (2), infection (1), unknown (1). Partial response (PR): 51/95 assessable (54%; 43%-64%); Stable disease (SD): 22/95 (23%). Disease control rate (PR+SD): 77%. With median follow up of 15 months (mos), PFS is 7 mos (18 pts remain progression-free) and OS is 14 mos. 1 year survival is 57% (47–67%). EGFR IHC by H score (>0 vs 0) showed a nonsignificant trend toward improved survival: 15 vs 11 mos (p=0.14). Conclusions: CB/P, CX plus B demonstrates safety, tolerability and efficacy in advanced NSCLC and is the most active regimen studied to date in SWOG. Additional S0536 biomarker studies including EGFR FISH will be presented. S0819, a Phase III trial of CB/P ± CX (plus B in eligible pts) is under development and is designed to validate EGFR FISH as a predictive biomarker. [Table: see text]

11076 Background: High EGFR gene copy number is associated with efficacy in NSCLC patients (pts) receiving combined chemotherapy and cetuximab (S0342). EGFR protein is typically overexpressed in tumors with high copy number but no consistent association has yet been demonstrated between EGFR protein expression and outcome in pts treated with chemotherapy plus cetuximab. EMT is associated with aggressive biological behavior and resistance to anti-EGFR TKI therapy in NSCLC. Our objective was to identify any association between EGFR protein and EMT and to correlate findings with pt outcomes from cetuximab/chemotherapy in SWOG trials S0342 (paclitaxel [P]-carboplatin [CB] plus sequential or concurrent cetuximab [CX]) and S0536 (P-CB-CX + bevacizumab). Methods: Paraffin sections were stained by immunoperoxidase methods using monoclonal antibodies against EGFR and the EMT markers vimentin, E-cadherin and Zeb1. Sections were scored on continuous scale ranging from 0–300 based on the H score (sum of % positive at each intensity from 0–3). Results were compared to outcome by Kaplan-Meier plot. Results: 79 samples from S0342 were evaluated for EGFR and EMT markers. 67 samples from S0536 were assessed for EGFR only. Mean EGFR H score was 153 and 137 for S0342 and S0536 respectively. At all cut points tested (scores 0, [Table: see text]

8027 Background: S0124 was a large North American phase III trial (n=651) that failed to confirm a survival benefit for cisplatin/irinotecan over cisplatin/etoposide in patients with E-SCLC, contrary to the results of J9511, a phase III trial exclusively in Japanese patients (n=154). As S0124 and J9511 protocols used identical treatment regimens and similar eligibility criteria, we compared demographics, toxicity, and outcomes using patient-level data and a “common arm” analysis to explore potential reasons for the divergent results. Methods: In both trials, patients with documented E-SCLC and adequate end-organ function were randomized to receive either cisplatin 60 mg/m2 day 1 + irinotecan 60 mg/m2 days 1, 8, & 15 Q 4 weeks or cisplatin 80 mg/m2 day 1 + etoposide 100 mg/m2 days 1–3 Q 3 weeks. Demographics and outcomes data were compared among 805 patients enrolled in J9511 and S0124 receiving identical treatment using a logistic model adjusted for age, sex, and performance status. Results: Of 671 patients in S0124, 651 were eligible. Patient characteristics (J9511 & S0124, respectively): Mean age - 61 & 62 years; Male sex - 132 (86%) & 370 (57%), p [Table: see text] [Table: see text]

8022 Background: KRAS mutations occur in NSCLC with a frequency of 15–25% and have been associated with a poor response to EGFR tyrosine kinase inhibitors. In colorectal cancer, benefit from the EGFR-targeted monoclonal antibody cetuximab is largely limited to patients (pts) whose tumors are KRAS wild-type (WT). However, in cetuximab-treated NSCLC, a predictive role for KRAS mutations has not been established. We evaluated KRAS status in specimens from two cetuximab-based front-line multicenter SWOG phase II trials in advanced NSCLC. Methods: DNA extracted from archival tumor and plasma specimens from S0342 (carboplatin-paclitaxel plus sequential vs. concurrent cetuximab) and S0536 (carboplatin-paclitaxel-cetuximab-bevacizumab) was analyzed for KRAS mutations by micro-dissection/sequencing and/or Scorpion-ARMS (DxS LTD). Results: For S0342, 45 archival tissues and 90 plasma specimens were analyzed. Combined, KRAS mutations were detected in 24% of pts. No differences between mutant and WT tumors were observed for response rate (p=0.62) or progression-free survival (PFS; p=0.65). Overall survival (OS) was non-significantly higher for pts with WT vs. mutant KRAS [median OS: 11 vs. 8 mo.; p=0.39]. When evaluated with EGFR copy number analysis conducted previously (JCO 10:3351, 2008), pts with both low EGFR copy number and mutant KRAS trended towards a worse OS [7 mo. vs. 17 mo. for all others, p=0.08, n=31]. For S0536, 6/26 pt specimens (23%) harbored KRAS mutations. In the limited sample set available from S0536, no associations were observed between KRAS status and clinical outcome [response rate: p=0.83; PFS: p=0.93; OS p=0.89]. Conclusions: These data suggest that KRAS mutations may not play a significant predictive role for cetuximab-based therapy in NSCLC, contrary to colorectal cancer. KRAS analysis in recently completed phase III trials of chemotherapy ± cetuximab will be of interest to confirm these observations. Trends in favorable OS in pts with WT KRAS may reflect prognostic effects of KRAS mutations. [Table: see text]

7511 Background: Preclinical studies suggest the autocrine growth loop involving VEGF and its receptors is a relevant therapeutic target for malignant pleural mesothelioma (MPM). We evaluated AZD2171, a potent tyrosine kinase inhibitor (TKI) of VEGFR1/2 in MPM. Methods: MPM patients (pts) after platinum-based chemotherapy, with PS 0–2, measurable disease and adequate organ function were treated with oral daily dosing of AZD2171 45 mg. Study endpoints were response rate, progression free survival (PFS), overall survival (OS), frequency/severity of toxicities, and correlation of clinical outcomes with tumor and serum biomarkers. Results: 54 pts were registered between November 2005 and April 2008; 45 pts are eligible for response and 46 for toxicity analysis. Median age was 66.8 yrs; M/F: 37/9. Tumor response by RECIST was seen in 4/45 (9%) of pts; of these responders, 2 pts with bulky disease had 56% and 91% tumor shrinkage, respectively. 15/45 (33%) had SD; 21/45 (47%) had PD; 1/45 (2%) had early death. Thirty-five pts have died. For 46 pts, median PFS is estimated at 3 months; median OS is estimated at 10 months. For 46 pts, frequent grade 1–3 toxicities included anorexia (30%), diarrhea (63%), fatigue (60%), hypertension (67%), and proteinuria (28%). There were 8 grade 4 events: Cognitive disturbance, colitis, confusion, ileal perforation, hypertension, hyponatremia, hypotension, and renal failure. Conclusions: AZD2171 has antitumor activity in MPM, with a DCR (CR/PR/SD) of 42% by RECIST, which has limitations in measuring response in pleural tumors. Notably, 2 pt tumors were exquisitely sensitive to this drug. Toxicities were consistent with those of the anti-angiogenic TKI class of drugs. Studies correlating outcome measures with tumor hypoxia- and angiogenesis-related gene expression and circulating endothelial cells are underway. Based on these data, we are proceeding in SWOG with a study of pemetrexed/cisplatin ± AZD2171 (S0905). This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102, CA38926, CA14028, CA46441, CA105409, CA13612, CA45808, CA20319, CA86780, CA35090, CA67663, CA46282, CA42777, CA76448, CA04919, CA35176, CA63848, CA27057, CA16385. [Table: see text]

7523 Background: Tumor hypoxia reduces the efficacy of chemo-radiation. TPZ, a hypoxic cell cytotoxin, potentiates the effectiveness of RT and chemotherapy in preclinical models. A SWOG pilot study...

7524 Introduction: J9511 demonstrated a significant survival benefit for Cis/CPT11 over Cis/VP16 in Japanese patients (pts) with E-SCLC (Noda, et al. NEJM 2002). S0124 is the confirmatory North American phase III trial (accrual completed) using the identical J9511 protocol. We hypothesized that toxicities would differ between North American & Japanese pts due in part to differences in the distribution of genetic polymorphisms involved in chemotherapy metabolism. Methods: Toxicity data were compared among 706 pts enrolled in J9511 & S0124 receiving common treatment using a logistic model adjusted for age, sex, and performance status (PS). Select polymorphisms of the UGT1A1, ABCB1, & OATP genes in genomic DNA were evaluated in 142 pts in S0124 only (67 Cis/CPT11; 75 Cis/VP16). Associations between toxicity & genotype within each arm were assessed using logistic regression. Results: Pt demographics for J9511 & S0124 respectively: Mean age − 61 & 62 years; Male sex − 131 (86%) & 315 (57%); PS 0 − 19 (13%) & 173 (31%); PS>0 − 133 (87%) & 372 (68%). Comparative toxicities (≥ grade 3) are summarized ( table ). PG analysis in S0124 pts: ABCB1 (C3435T) T/T was associated with an increased risk of CPT11 grade 3+ diarrhea (p=0.04) versus C/C and C/T. UGT1A1 (G3156A) A/A was associated with increased risk of CPT11 neutropenia (p=0.009) & leukopenia (p=0.05). UGT1A1*28 TA7, typically associated with increased CPT11 toxicity, was seen in only 4 pts (2 Cis/CPT11; 2 Cis/VP16); thus no correlation was done. No gene tested was associated with VP16 toxicity. Conclusions: Significant differences in treatment-related myelosuppression exist between J9511 and S0124 pt populations. Certain polymorphisms in genes involved in CPT11 metabolism are significantly associated with CPT11 toxicities in S0124. Additional analyses are ongoing. These results support the hypothesis that toxicities may be associated with distribution of genetic polymorphisms. No significant financial relationships to disclose. [Table: see text]

7198 Background: OPN is a secreted glycoprotein with a diverse array of functions, including induction of uPA & increased cell migration. OPN has been shown to be elevated in a number of tumor types, & its downregulation reduces tumorigenicity & metastasis in tumor models. High levels have also been associated with tumor hypoxia/angiogenesis, as are vascular endothelial growth factor (VEGF) & plasminogen activator inhibitor (PAI-1). We hypothesized that secreted levels of these biomarkers would correlate with clinical outcome after treatment. Methods: Plasma concentrations of OPN, VEGF & PAI-1 were measured by ELISA in 160 NSCLC patients enrolled on the Southwest Oncology Group (SWOG) trial S0003 (paclitaxel/carboplatin ± the hypoxic cytotoxin tirapazamine). Post-treatment plasma samples were available in 56 patients. Results: Baseline OPN plasma levels correlated significantly with patient overall survival (OS). High interpatient variability was observed, with levels ranging from undetectable to 2560 ng/ml, (median: 606.5 ng/ml). When dichotomized, median OS was 11 months for patients below median OPN levels & 7 months for those above (p = 0.004). Survival decreases with increasing OPN concentration. Furthermore, OPN levels correlated with response rate (RR) (median responders: 497; median non-responders: 698 ng/ml. Wilcoxon rank-sum p = 0.03). No association between baseline levels of either VEGF or PAI-1 with RR or OS was observed. However, plasma levels of both PAI-1 & VEGF were significantly inter-related & trended together (p < 0.0001), & both decreased significantly after treatment (p = 0.0004 & 0.04, respectively). Median decrease: OPN: 17%, PAI: 44%, VEGF: 42%. No significant differences were observed between study arms, suggesting that OPN is prognostic in NSCLC, but not predictive for response to tirapazamine. Conclusions: 1) There is a great need for development of tumor biomarkers which can be serially assessed pre- & post-therapy. 2) High OPN plasma levels were significantly associated with reduced RR & OS for patients on this trial. OPN is a strong candidate for inclusion in a panel of prognostic (& perhaps predictive) markers for NSCLC. Supported by the Hope Foundation & R01-CA107228. No significant financial relationships to disclose.

7006 Background: Although objective response (CR/PR) & overall survival (OS) are typical efficacy measures for new treatments in advanced stage NSCLC, each has its limitations; e.g., some patients (pts) have no measurable disease or achieve only disease stabilization (SD) while OS is influenced by effective salvage therapies. Alternative methods of determining “clinical benefit” are needed. Methods: Pooled data from 984 pts entered onto 3 randomized SWOG trials of platinum-based chemotherapy (S9509: carbo/paclitaxel (CP) vs. cisplatin/vinorelbine; S9806: carbo/gemcitabine ->P or cisplatin/vinorelbine -> docetaxel; & S0003: CP ± tirapazamine) were analyzed for survival using the Landmark method. Results: Pt characteristics: median age = 62 years; male sex = 647 pts (66%); stage IV = 826 pts (84%); weight loss ≥ 5% = 404 pts (42%); performance status (PS) 0/≥1 = 340 (36%)/606 (64%). Tumor response was seen in 260 pts (26%). Median time to response (TTR), time to progression (TTP) & OS were 1.9, 4.3 and 8.9 months. PS > 0 & weight loss were associated with worse survival (hazard ratio [HR] 1.38 and 1.28; p 0 (HR 0.75, p=0.03) and weight loss (HR 0.74, p = 0.03). Shorter TTP was associated with PS>0, stage IV, & weight loss (HR 1.34, 1.08, 1.34 and p = 0.0001, 0.01, < 0.00001). Of 886 pts alive at month 2 (time of initial response assessment following 2 treatment cycles), 62% had SD while19% had CR/PR for a disease control rate (CR+PR+SD, aka DCR) of 81%; 18% had progressive disease (PD). Although CR/PR at month 2 was associated with longer survival (HR 0.62, p No significant financial relationships to disclose.

Background Transmission of human immunodeficiency virus (HIV) from mother to child occurs in utero, during delivery or during breastfeeding. Less than one-third of infants born to HIV-positive mothers become infected, however, and there is evidence that innate, humoral and cellular immune responses all contribute to protection in these infants. Several investigators have detected HIV-specific cytotoxic T-lymphocyte (CTL) induction in some HIV-negative infants exposed to HIV. Identifying correlates of this induction would both allow for better predictions of which mothers are most at risk for transmitting HIV to their offspring, and further our understanding of the transmission and pathogenesis of HIV. Methods Pregnant, HIV-positive women were recruited through the “CTLs and Prevention of Breastmilk HIV Transmission” study. Their infants were serially assessed for HIV-1 DNA, HIV-1 RNA, and HIV-1-specific gamma-interferon-producing CD8+ cells. Infants that remained HIV-negative throughout the study period, and had Enzyme-Linked Immunosorbent Spot (ELISPOT) assays performed at month one, month three or both, were considered for the analysis (N=269). Our two end-points were positive ELISPOT assay at one and three months of age. Univariate analysis was performed using logistic regression, and for all tests, p ≤0.05 was used to determine a statistically significant association. Odds ratios and 95% confidence intervals were calculated for both continuous and categorical potential correlates. Results Potential correlates relating to maternal health, deliveries, feeding practices, and infant health were considered. Mother9s blood plasma log viral load at the time of delivery was associated with a lower odds of a positive infant CTL response at one month (OR=0.61 95% CI = 0.38-0.98 p = 0.041) and month three (OR = 0.56 95% CI = 0.34-0.94 p = 0.028). Conversely, breastmilk log viral load at one month post-partum was significantly associated with an increased odds of a positive infant CTL response at month three (OR = 2.0 95% CI = 1.2-3.3 p = 0.009). No significant relationships were found for the other potential correlates considered. Discussion Our study suggests that the nature of the exposure to HIV, whether in blood plasma or breastmilk, may be an important determinant of whether an exposed, uninfected infant develops an HIV-specific CTL response. This may have relevance for development of vaccines that target cellular immunity against HIV.

This article provides a summary of discussions from the American Statistical Association (ASA) Biopharmaceutical (BIOP) Section Open Forum organized by the ASA BIOP Statistical Methods in Oncology ...