Citations

1565 Background: Understanding the prevalence of cancer screening in the US and the factors associated with its accessibility is important for public health promotion. Methods: The 2004 and 2010 Behavioral Risk Factor Surveillance Systems were used to ascertain cancer screening rates among populations indicated for each test by age, gender, and the American Cancer Society recommendation for cancer screenings [fecal occult blood test (FOBT) or endoscopy for colorectal cancer (CRC) screening, digital rectal examination (DRE) or prostate specific antigen (PSA) for prostate cancer screening, clinical breast examination (CBE) or mammogram for breast cancer screening, and Papanicolaou (Pap) test for cervical cancer screening]. Results: Over this period, CRC and breast cancer screening rates significantly increased (15.9%, 13.9%) while prostate and cervical cancer screening rates significantly decreased (1.2%, 5.2%). Race/ethnicity might be an influence in CRC and cervical cancer screening accessibility. Prostate cancer screening accessibility might be influenced by education and income. The older-aged populations (70-79, >79) had high prevalence of CRC, prostate and breast cancer screenings even though there is insufficient evidence for the benefits and harms of screenings in the older-aged group. Conclusions: The disparities in age, race/ethnicity, health insurance, education, employment, and income for the accession to cancer screening of the US population have decreased since 2004. The trajectory of increasing rates of CRC and breast cancer screenings should be maintained. To reverse the trend, the causes of the decreased rate of cervical cancer screening and the high rates of screenings in older-aged populations should, however, be further explored. [Table: see text]

e22093 Background: Biomarkers are an integral part of cancer care. A variety of testing methods exist, allowing institutional selection of which technologies to use and in what order to run them. This descriptive study provides a benchmark on methods used in practice for biomarker testing in breast (BC), gastric/esophageal (GC), and non-small cell lung cancers (NSCLC). Methods: We conducted an IRB-approved web survey of the 58 NCI designated cancer centers (pathologists and oncologists) providing adult care in BC, GC, and NSCLC. We developed a survey instrument with 14 BC, 5 GC, and 10 NSCLC items asking about methods used, order of testing, turn around time (TAT) and if tests are internally developed (ID). Results: For BC, 32% (18/57) of sites run concurrent rather than reflex HER2 FISH and IHC testing, citing quality assurance reasons. Average TAT for concurrent vs reflex testing is 6.5 and 9.5 days. Rates of ID tests are 14% (8/57) for PgR, 12% (7/57) for ER and 7% (4/57) for HER2. For GC, 39% (21/54) of sites run concurrent HER2 FISH and IHC tests, citing reasons of quality assurance and evolving guidelines. TAT for concurrent vs reflex testing is 6.3 and 9.5 days. 19% (10/54) of sites use ID HER2 tests. All reporting sites use EGFR and ALK testing in NSCLC and 96% use KRAS. 24% (13/55) of sites run them concurrently with an average TAT of 7.6 days, while the average TAT for sites with sequential testing is 22.8 days. CAP recommends a 10 day TAT for NSCLC tests, and 92% (12/13) of sites with concurrent testing meet this guideline vs only 11% (4/38) of sites with sequential testing (p<.0001). Rates of ID tests are 57% (30/53) for KRAS, 47% (26/55) for EGFR and 35% (19/55) for ALK, for which a kit is listed on the FDA drug label. There is a difference in the use of ID tests between BC and NSCLC, p<.0148. Conclusions: Concurrent testing for BC and GC HER2, and for NSCLC markers is a common practice at NCI cancer centers; and it improves TAT. Concurrent NSCLC testing allows meeting CAP TAT guideline, but sequential testing does not. New markers (GC HER2, EGFR, KRAS and ALK) are commonly adopted, with a higher rate of internally developed tests than for BC HER2. [Table: see text]

7555 Background: In a retrospective exploratory analysis of E4599, patients (pts) > 70 yo had a higher frequency of and more severe toxicities without apparent survival benefit from the addition of B to C+paclitaxel. We hypothesized that in this pt population, B will have better safety and efficacy profile when used in combination with C+P. Methods: Pts >/= 70 yo with previously untreated stage IIIB/IV (TNM 6th ed) nonsquamous NSCLC, ECOG PS 0-1, measurable disease and adequate organ function were eligible. C at AUC 6, P at 500 mg/m2 and B at 15 mg/kg were administered on day 1 of each 21-day cycle for up to 6 cycles followed by maintenance P+B in patients with CR, PR or SD. The primary endpoint was 6-month progression-free survival (PFS) rate. The treatment would be considered promising based on a single arm one-stage binomial design if 34 or more successes out of 55 patients were observed. This design had an exact significance level of 0.05 at 93% power to detect a true success rate of at least 70%. Polymorphisms in VEGFA, FPGS, GGH, SLC19A1 and TYMS in germline DNA were correlated with treatment outcome. Results: 58 eligible pts were enrolled; 29 males/29 females. Median age was 75. Median treatment cycles received was 6. Grade 3 or higher adverse events (AE) were reported in 49 (85%) pts. There were no treatment-related deaths. The most common grade 3/4 AEs(regardless of attribution) were hypertension (10%), fatigue (28%), dehydration (9%), neutropenia (43%) and thrombocytopenia (21%). There were 3 (5%) grade 3/4 hemorrhagic events. 8 (14%) had grade 4 neutropenia and 3 (5%) had grade 4 thrombocytopenia. Grade 3/4 ischemic/thromboembolic events occurred in 6 pts (10%). Thirty-four out of the first 54 (63%, 95% CI: 48.7-75.7%) evaluable pts met the primary endpoint (4 pts were lost to follow-up prior to 6 months). The confirmed ORR was 37.9% (95% CI: 25.5-51.6%). Median time to treatment failure was 4.8 months (95% CI: 3.9-6.4). Median PFS was 7.1 months (95% CI: 5.9-11.7), median OS was 13.7 months (95% CI: 9.4-15.7). Results of SNP analysis will be presented. Conclusions: C+P+B followed by maintenance P+B is an active and tolerable first-line regimen for elderly patients with good PS.

7073 Background: In preclinical studies, combinations of bortezomib and RT result in synergistic tumor killing (Cancer Chemother Pharmacol. 2007;59:207-15). Our group reported the results from the phase I portion of this study previously (J Clin Oncol. 200;28 (suppl; abstr 7085)). Based on these data, we undertook a phase II study of bortezomib in combination with paclitaxel/CBCDA and RT. Methods: Based on results from our previously reported phase I trial, systemic therapy included bortezomib (1.2 mg/m² IV days 1,4,8,11), paclitaxel (175 mg/m² IV day 2), and carboplatin (CBCDA; AUC=6 day 2) given every 3 weeks for 2 cycles. Thoracic radiotherapy (RT) included 60Gy/30 daily fractions starting day 1. The primary endpoint was the 12-month survival rate. If 41 or more of these 60 patients (68%) were alive at least 12 months after study entry, the trial would be deemed as positive and further study would be warranted. Results: 27 pts were enrolled to the phase II portion: M/F=17/10; stage IIIA/IIIB=13/14; ECOG PS 0/1=9/18; and median age: 58 (range 43-79). 18 pts (67%) completed therapy per protocol. At a planned interim analysis, 23 of 26 evaluable patients (88.5%, 95% CI: 70-98%) survived for at least 6 months, which exceeded the boundary of 21 or more needed to continue to full accrual. This trial could have continued per protocol, but was closed early due to slow accrual. With a median follow-up of 15.0 months in the 17 patients still alive, the 12-month survival rate was 71% (95% CI: 49 – 85). The median OS was 19 months (95% CI: 11 – no upper). Grade 3 or higher adverse events (regardless of attribution) were reported in 22 (82%) patients. Grade 4/5 adverse events were reported in 15 (56%) patients. There was one grade 5 event (pneumonitis). The most common (5 or more patients) grade 3/4 adverse events were fatigue (22%), leukopenia (63%), neutropenia (67%), and thrombocytopenia (44%). Conclusions: The addition of bortezomib resulted in high levels of severe hematologic toxicity, but also demonstrated evidence of activity with a 12-month survival rate of 71% and a median OS of 19 months. Further testing of this regimen in a larger study appears warranted.

14044 Background: XL647 is an orally bioavailable small molecule inhibitor of multiple receptor tyrosine kinases involved in tumorigenesis, angiogenesis, and metastasis, including EGFR/ErbB1, ErbB2/HER2, VEGFR2/KDR, and EphB4. In a previous Phase I study, the MTD was 350 mg when XL647 was dosed orally for 5 consecutive days every 14 days. Of 41 pts treated, one pt with NSCLC achieved a PR and 14 pts had prolonged stable disease (3.5–14+ months). The purpose of the present study is to determine the MTD of XL647 administered orally on a continuous daily schedule. Methods: Pts are enrolled in successive cohorts to receive XL647 daily for repeated 28 day cycles. PK sampling is performed to determine Cmax, and AUC at each dose level. Plasma samples are analyzed by ELISA for mechanism-of-action related molecules. Eyebrow hair bulbs are being evaluated by IHC to monitor effects of XL647 on signal transduction pathways downstream of EGFR. Tumor response is assessed every 8 weeks by RECIST. Pts remain on study until PD or unacceptable AEs. Results: Twelve pts have been enrolled. The starting dose was 75 mg (n=3) and has been escalated to150 mg (n=3), 200 mg (n=3) and 300 mg (n=3). To date, dose escalation continues as no DLTs have occurred and the MTD has not been determined. Ten pts remain on study, including 4 with stable disease for at least 3 months. In cohort 2, eyebrow samples from 3 pts were analyzed. XL647 caused a significant reduction in the phosphorylation of the EGFR downstream signaling kinases AKT (up to 73%) and ERK (up to 78%) in 2/3 and 3/3 pts, respectively. Preliminary analysis of potential plasma protein biomarkers from pts in cohorts 1 and 2 showed a trend towards upregulation of PlGF plasma levels in 4/6 pts during XL647 treatment. Conclusions: XL647 is well-tolerated when administered daily at doses tested to date. Dose escalation will continue until the MTD is defined. Analysis of eyebrow samples demonstrated its feasibility as a potential surrogate epidermal tissue for assessing inhibition of EGFR downstream targets by XL647. Updated safety, PK and pharmacodynamic results will be presented. [Table: see text]

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.

3598 Background: Drug resistance to topotecan can be the result of BCRP/ABCG2 expression. BCRP is a member of the ABC transporter family that pumps anticancer drugs out of the cell. Lapatinib is a potent and selective dual inhibitor of epidermal growth factor receptor (EGFR or ErbB1) and ErbB2 (Her2/Neu). 4-aminoquinazoline tyrosine kinase inhibitors have been shown to enhance the cytotoxicity of topotecan through inhibition of BCRP-mediated drug efflux in cancer cells. Methods: Thirty-seven patients with advanced stage cancers were enrolled at escalating dose levels of lapatinib and topotecan in cohorts IA, IB and IIB (MTD). Treatment schedule included lapatinib (750 - 1500 mg/d) daily for 21 (cohort IA) or 28 days (cohort IB) and topotecan (2.4 - 4.0 mg/ m2), days 1, 8 and 15; cycles were repeated every 28 days. Three patients were treated at each dose level, 18 on cohort IA, 9 on cohort IB and 10 at MTD (cohort IIB). Assessments of toxicity were performed with each cycle and clinical response was determined per RECIST criteria every other cycle. Results: The MTD for cohorts IA and IB was reached at a dose of 1250 mg of lapatinib and 3.2 mg/m2 of IV topotecan on days 1, 8 and 15. No DLT were seen during the dose escalation stage of cohorts IA and IB. Ten patients were enrolled at the MTD. There were no grade 4+ events. Thirteen grade 3+ events, considered to be related to treatment, were seen in 6 patients. The most common grade 3+ toxicities included dehydration (2) diarrhea (2), nausea (3), vomiting (2), neutropenia (1), thrombocytopenia (1), and fatigue (1). No abnormalities in left ventricular ejection fraction were noted. Stable disease was seen in 46% of the 37 patients. Conclusions: The combination of lapatinib and topotecan is a well-tolerated regimen. The MTD for the combination is lapatinib 1,250 mg orally once daily for 21 or 28 days and topotecan 3.2 mg/m2 on days 1, 8 and 15. Pharmacokinetic analysis for drug interaction will be available for presentation at the meeting. Supported in part by GSK and Mayo Clinic No significant financial relationships to disclose.

Abstract Background and Aims Oral systemic pan-Janus kinase [JAK] inhibition is effective for ulcerative colitis [UC] but is limited by toxicities. We describe preclinical to clinical translation of TD-1473—an oral gut-selective pan-JAK inhibitor—from in vitro characterization through a Phase 1b study in patients with UC. Methods TD-1473 JAK inhibition potency was evaluated in vitro; plasma pharmacokinetics, safety and efficacy were assessed in mice. In a first-time-in-human study, plasma pharmacokinetics and safety were assessed after single and multiple [14 days] ascending doses administered orally to healthy subjects. The Phase 1b study randomized patients with moderately to severely active UC to receive once-daily oral TD-1473 20, 80 or 270 mg, or placebo for 28 days. Plasma and colonic tissue concentrations were measured; safety was assessed; and efficacy was evaluated by UC clinical parameters, disease-surrogate biomarkers, endoscopy, histology and colonic tissue JAK signalling. Results TD-1473 exhibited potent pan-JAK inhibitory activity in vitro. Oral TD-1473 administration to mice achieved high, biologically active colonic tissue concentrations with low plasma exposure and decreased oxazolone-induced colitis activity without reducing blood cell counts vs placebo. TD-1473 administration in healthy human subjects and patients with UC yielded low plasma exposure and was generally well tolerated; treatment in patients with UC resulted in biologically active colonic tissue concentrations and descriptive trends toward reduced clinical, endoscopic and histological disease activity vs placebo. Conclusion Gut-selective pan-JAK inhibition with TD-1473 administration resulted in high intestinal vs plasma drug exposure, local target engagement, and trends toward reduced UC disease activity. [Clinicaltrials.gov NCT02657122, NCT02818686]

Introduction: Alcohol use is common in the United States. Most studies describe a J-shaped relationship between alcohol consumption and cognitive function: frequent heavy consumption alters brain functions and decreases cognitive performance; regular light and moderate consumption may have protective impact. We are unaware of any reports utilizing longitudinally collected data to derive a cumulative exposure of alcohol use and assess its association with cognitive function. Hypothesis: Cumulative 30-year exposure to alcohol has a J-shaped association with mid-life cognitive function. Methods: We included 3,068 participants aged 18-30 years at the baseline examination (1985-86) and having up to 8 follow-up exams at 2- to 5-year intervals including at 30 years (2015-16). Cumulative “drink-years” exposure to alcohol was estimated at each exam by multiplying the usual number of drinks/day reported by the number of years since last exam, and then summing across exams. We used multivariable adjusted linear regression models to assess the independent associations of number of drink-years with 6 measures of cognitive function studied at Year 30: Rey Auditory Verbal Learning Test (RAVLT), Digit Symbol Substitution Test (DSST), Stroop Test, Montreal Cognitive Assessment (MoCA), Category Fluency Test, and Letter Fluency Test. We used inverse probability of censoring weighting to account for potential informative censoring. Linear regression models estimated standardized mean test scores for the cumulative alcohol use categories (drink-years: >0 and <15, 15-29.9, 30+). Too few participants were available for assessment of higher categories of use. Results: Compared with never drinking, the 3 categories of cumulative exposure were unassociated with any of the cognitive function measures. Conclusions: Cumulative 30-year alcohol use is not associated with cognitive function in middle-aged adults in the CARDIA study.

AbstractPrevious transcriptome‐wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome‐wide association studies (GWAS), but analyses of breast cancer subtype‐specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta‐analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case‐only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS‐significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast‐cancer gene in three of six regions harboring multiple TWAS‐significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.