Citations

520 Background: Targeted therapy using trastuzumab (an anti-HER-2 receptor monoclonal antibody) has significantly improved survival in breast carcinoma patients (pts), but determining which pts will respond to this therapy remains a challenge. We previously reported (Miller DV, ASCO 2004 abstract #568) a subset of pts with breast cancers demonstrating focal HER-2 amplified clones (FHAC) amidst otherwise nonamplified tumor cells by fluorescence in-situ hybridization. These accounted for 21% of the HER-2 amplified but immunohistochemistry (IHC) negative cases and 30% of the HER-2 amplified but IHC equivocal cases. The clinical significance of this phenomenon was unclear at that time. We now report the disease-free survival (DFS) data on 91 FHAC pts with a comparison to the diffusely amplified (DA) cases in this trial group. Methods: Breast tumors were evaluated for HER-2 gene amplification using PathVysion™. FHAC cases demonstrated 2–40% of cells with >10 HER-2 signals and HER-2:CEP17 ratio >5.0, regardless of the overall HER-2:CEP17 ratio. Patient and disease characteristics were compared using chi-square tests. Cox regression models compared DFS between pts randomized to arms A (standard chemotherapy) and C (standard chemotherapy with concurrent trastuzumab) within 91 FHAC and 1571 DA cases. Median follow up was 4.0 years. Results: Age, race, menopausal status, surgical procedure, nodal status, histologic type and grade, and tumor size, were not significantly different between pateints with FHAC and DA. Pateints with FHAC had more frequent hormone receptor positivity compared to DA cases (66% vs 50%; p = 0.004). Hazard ratios between pts with FHAC and DA showed that both groups of pts had similar DFS (A: HR = 0.86, p = 0.65; C: HR = 0.72, p = 0.57). Hazard ratios between arms within FHAC and DA groups demonstrated similar benefit from trastuzumab in each group (FHAC: HR = 0.50, p = 0.30; DA: HR = 0.59, p < 0.0001). Results remained consistent when including hormone receptor status in the model. Conclusions: Based on a small number (n = 91) of pts with FHAC, benefit from trastuzumab appears to be similar whether the population of HER-2 amplified cells with breast carcinomas is focal or diffuse. [Table: see text]

e11527 Background: 118 Her2 positive invasive carcinomas were retested centrally at the Mayo Clinic for Her2 status confirmation prior to inclusion in Mayo Clinic Cancer Research Consortium study RC0639 phase II study of cardiac safety and tolerability of adjuvant chemotherapy plus trastuzumab with lapatinib for resected Her2+ breast cancer (MCCRC RC0639). Methods: Central confirmatory methods were immunohistochemical (IHC) Dako HercepTest on a Dako Autostainer using the manufacturer's recommendations and HercepTest kit epitrope retrieval kit and fluorescent in situ hybridization (FISH) using Vysis PathVysion probe kit. Test results are interpreted using ASCO/CAP guidelines (IHC >30%, Her2:CEP 17 ratio >2.2). Results: There is local and central test 3+ IHC concordance in 48 of 53 tumors (agreement 90.6%) and FISH amplification in 29 of 33 tumors (agreement 87.9%), improved or similar results using identical methods to results in NCCTG N9831 adjuvant trial (n=1063, 81.6% IHC; n=813, 88.1% FISH). Of 92 centrally tested 3+ IHC positive tumors, 88 (95.7%) were FISH amplified. 5 centrally tested patients interpreted as Her2 positive by pre-ASCO/CAP guidelines (IHC >10%; HER2:CEP17 ratio >2) are Her2 ineligible using ASCO/CAP guidelines. IHC not confirmed centrally was reviewed by a second pathologist in 16 of 118 specimens. IHC concordance between two central pathologists was 10/16 (62.5%) in negative or equivocal (≤30% IHC staining) specimens; 7/10 (70%) with two reader agreement were FISH amplified and 4/6 (66%) with disagreement were FISH amplified. Conclusions: Concordance in IHC and FISH results between local and central labs is similar or improved since N9831. New ASCO/CAP Her2 testing guidelines change eligibility based on Her2 status in 4.2 % of patients. Equivocal IHC results falling between pre- and post- ASCO/CAP IHC positive thresholds (>10% and <30% IHC strong staining) are only partially resolved by repeat IHC review and/or FISH testing. No significant financial relationships to disclose.

ABSTRACT Introduction: We hypothesize that a patient (pt) with accelerated thrombin generation, time to peak height (ttPeak), will have a greater odds of meeting critical administration threshold (CAT) criteria (> 3 packed red blood cell [pRBC] transfusions [Tx] per 60 min interval), within the first 24 h after injury, independent of international normalized ratio (INR). Methods: In a prospective cohort study, trauma patients were enrolled over a 4.5-year period and serial blood samples collected at various time points. We retrospectively stratified pts into three categories: CAT+, CAT− but receiving some pRBC Tx, receiving no Tx within the first 24 h. Blood collected prior to Tx was analyzed for thrombin generation parameters and prothrombin time (PT)/INR. Results: A total of 484 trauma pts were analyzed: injury severity score = 13 [7,22], age = 48 [28, 64] years, and 73% male. Fifty pts met criteria for CAT+, 64 pts CAT−, and 370 received no Tx. Risk factors for meeting CAT+: decreased arrival systolic blood pressure (OR 2.82 [2.17, 3.67]), increased INR (OR 2.09, [1.66, 2.62]) and decreased time to peak OR 2.27 [1.74, 2.95]). These variables remained independently associated with increased risk of requiring Tx in a multivariable logistic model, after adjusting for sex and trauma type. Conclusions: Pts in hemorrhagic shock, who meet CAT+ criteria, are characterized by accelerated thrombin generation. In our multivariable analysis, both ttPeak and PT/INR have a complementary role in predicting those injured patients who will require a high rate of Tx.

Abstract Background Modern-day penile prostheses use infection retardant coating to decrease rates of postoperative infection, subsequently reducing explantation and revision rates as well. The Coloplast Titan models are dipped into antimicrobial solutions right before implantation, and the components used for dipping can be tailored toward the patient. Aim To compare infection, explantation, and revision rates among different dipping solutions used before implantation for patients with diabetes receiving a Coloplast Titan implant. Methods We systematically reviewed 932 patients with diabetes receiving a primary penile implant across 18 different centers from the period April 2003 to August 2018. Of those patients, 473 received a Coloplast device, whereas 459 received an AMS device. Data regarding the type of antimicrobial solution used before implantation were recorded for 468 patients receiving a Coloplast Titan, including whether or not they suffered a postoperative infection and if they underwent explantation and/or revision. Outcome rates were compared using Fisher’s exact and Pearson’s chi-square tests, and logistic regression modeling was performed to account for covariates. Outcomes The main outcome measures of this study were postoperative infection, explantation, and revision rates. Results Of the total 932 patients reviewed, 33 suffered a postoperative infection. Of 468 patients receiving Coloplast implants, there was a 3.4% infection rate. The most commonly used antibiotic combination before dipping was vancomycin + gentamicin (59.0%). There was a significantly lower rate of postoperative infection, explantation, and revision when vancomycin + gentamicin was used than those associated with the use of all other dipping solutions ([1.4% vs 6.4%; P = .004], [1.1% vs 8.3%; P &lt; .001], and [2.5% vs 12.5; P &lt; .001], respectively). After adjusting for age, body mass index, preoperative blood glucose level, and hemoglobin A1c, the use of other dips was an independent predictor of postoperative infection (odds ratio: 0.191; P = .049). The inclusion of rifampin in the dipping solution trended toward being a significant risk factor for infection (P = .057). Including antifungals in the dipping solution did not affect infection (P = .414), explantation (P = .421), or revision (P = .328) rates. Clinical Implications Vancomycin + gentamicin was the most efficacious combination of antibiotics used for dipping in terms of preventing postoperative infection and subsequent explantation and revision. Strengths and Limitations Data were sampled across multiple institutions providing a large sample that may be more representative of the population of interest. A key limitation of the study was its retrospective nature, which prevented us from controlling certain variables. Conclusion The use of rifampin did not provide the same type of protection, possibly representing a shift in resistance patterns of common bacteria responsible for device infection.

Abstract Protective associations of fruits, vegetables, and fiber intake with colorectal cancer risk have been shown in many, but not all epidemiologic studies. One possible reason for study heterogeneity is that dietary factors may have distinct effects by colorectal cancer molecular subtypes. Here, we investigate the association of fruit, vegetables, and fiber intake with four well-established colorectal cancer molecular subtypes separately and in combination. Nine observational studies including 9,592 cases with molecular subtypes for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS genes, and 7,869 controls were analyzed. Both case-only logistic regression analyses and polytomous logistic regression analyses (with one control set and multiple case groups) were used. Higher fruit intake was associated with a trend toward decreased risk of BRAF-mutated tumors [OR 4th vs. 1st quartile = 0.82 (95% confidence interval, 0.65–1.04)] but not BRAF-wildtype tumors [1.09 (0.97–1.22); P difference as shown in case-only analysis = 0.02]. This difference was observed in case–control studies and not in cohort studies. Compared with controls, higher fiber intake showed negative association with colorectal cancer risk for cases with microsatellite stable/MSI-low, CIMP-negative, BRAF-wildtype, and KRAS-wildtype tumors (Ptrend range from 0.03 to 3.4e-03), which is consistent with the traditional adenoma-colorectal cancer pathway. These negative associations were stronger compared with MSI-high, CIMP-positive, BRAF-mutated, or KRAS-mutated tumors, but the differences were not statistically significant. These inverse associations for fruit and fiber intake may explain, in part, inconsistent findings between fruit or fiber intake and colorectal cancer risk that have previously been reported. Significance: These analyses by colorectal cancer molecular subtypes potentially explain the inconsistent findings between dietary fruit or fiber intake and overall colorectal cancer risk that have previously been reported.

Abstract Background: Several studies have suggested that vitamin D may have antiproliferative and anticarcinogenic properties and a protective effect against breast cancer. Alaskan Natives have demonstrated high rates of vitamin D deficiency, particularly in young individuals. Hence, high breast density has been associated with increased breast cancer risk. Therefore, we examined the association between serum vitamin D levels and mammographic breast density in a population of Alaskan Native women. Methods: Patients seen in the Mayo Clinic-Alaska Native Medical Center telemedicine program from December 2014 to December 2017 were offered to enroll in the study. Consent was obtained by a study coordinator in Minnesota using a telemedicine platform. Participants were asked to complete the Breast Cancer Risk Questionnaire, which includes questions on hormonal, lifestyle factors and family history. Serum vitamin D levels (25-hydroxyvitamin D2 and D3) were obtained and later correlated with mammographic breast density (percent density). Data were summarized with frequencies and percentages or medians and interquartile ranges (IQR), as appropriate. Pearson correlation was used to estimate the association between breast density and vitamin D levels. Results: 33 women were included; median age was 53 years (IQR 45-58), 70% self-identified as American Indian/Alaskan Native, 12% as White, 6% as Native Hawaiian/Pacific islander and 12% as other. Median BMI was 31 kg/m² (IQR 26.4-34.3), menarche was at age 12 or older for 23 (70%) of the participants and 20 women were postmenopausal at the time enrollment. 10 participants had a hysterectomy, of whom 60% also had oophorectomy. 76% reported history of hormonal birth control use and 23% postmenopausal hormonal supplementation. Median number of pregnancies was 3 (IQR 2-5), and 20 women reported breastfeeding. Fifteen women were current or former smokers (&gt;100 cigarettes) and 19 reported none or low alcohol consumption. Median serum vitamin D level was 39 ng/mL (IQR 30-52) and 9 (27%) women had low vitamin D levels. In regard to breast density, median percentage (average of images) was 15% (IQR 7.5-24.9) with a median dense area of 21.8 cm² (IQR 16.4-34.2). Median time from blood draw to mammogram was 110 days (IQR 41-172) and 19 (58%) participants were taking vitamin D supplementation at the time of study enrollment; doses ranged from 400 to 50,000 units. No correlation was identified between breast density and serum vitamin D levels (correlation=0.02). Conclusion: In this cohort, no association between serum vitamin D levels and breast density was observed. More than half of the participants were on vitamin D supplementation and this could have obscured our observations. Larger studies controlling for vitamin supplementation are needed, as this association could potentially impact breast cancer rates in populations at risk for vitamin D deficiency. Citation Format: Narjust Duma, Ivana Croghan, Sarah Jenkins, Loni Neal, Karthik Ghosh, Sandhya Pruthi. Assessing vitamin D and mammographic breast density in a population of Alaskan Native women [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C088.

Abstract Background: The four most commonly-mutated genes in clear cell renal cell carcinoma (ccRCC) tumors are BAP1, PBRM1, SETD2 and VHL. And, there are currently 14 known RCC germline variants that have been reproducibly shown to be associated with RCC risk. However, the association of germline genetics with tumor genetics and clinical aggressiveness are unknown.Methods: We analyzed 420 ccRCC patients from The Cancer Genome Atlas (TCGA). Molecular subtype was determined based on acquired mutations in BAP1, PBRM1, SETD2 and VHL. Aggressive subtype was defined clinically using Mayo SSIGN score and molecularly using the ccA/ccB gene expression subtype. Publically-available Hi-C data were used to link germline risk variants with candidate target genes. Results: The 8q24 variant rs35252396 was significantly associated with VHL mutation status (OR=1.6, p=0.0037) and SSIGN score (OR=1.9, p=0.00094), after adjusting for multiple comparisons. We observed that, while some germline variants have interactions with nearby genes, some variants demonstrate long-range interactions with target genes.Conclusions: These data further demonstrate the link between rs35252396, HIF pathway and ccRCC clinical aggressiveness, providing a more comprehensive picture of how germline genetics and tumor genetics interact with respect to tumor development and progression.

Abstract Background We report the analysis involving patients treated on the initial CODEL design. Methods Adults (&gt;18) with newly diagnosed 1p/19q World Health Organization (WHO) grade III oligodendroglioma were randomized to radiotherapy (RT; 5940 centigray ) alone (arm A); RT with concomitant and adjuvant temozolomide (TMZ) (arm B); or TMZ alone (arm C). Primary endpoint was overall survival (OS), arm A versus B. Secondary comparisons were performed for OS and progression-free survival (PFS), comparing pooled RT arms versus TMZ-alone arm. Results Thirty-six patients were randomized equally. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients progressed, versus 37.5% (9/24) on the RT arms. PFS was significantly shorter in TMZ-alone patients compared with RT patients (hazard ratio [HR] = 3.12; 95% CI: 1.26, 7.69; P = 0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) on the RT arms. OS did not statistically differ between arms (comparison underpowered). After adjustment for isocitrate dehydrogenase (IDH) status (mutated/wildtype) in a Cox regression model utilizing IDH and RT treatment status as covariables (arm C vs pooled arms A + B), PFS remained shorter for patients not receiving RT (HR = 3.33; 95% CI: 1.31, 8.45; P = 0.011), but not OS ((HR = 2.78; 95% CI: 0.58, 13.22, P = 0.20). Grade 3+ adverse events occurred in 25%, 42%, and 33% of patients (arms A, B, and C). There were no differences between arms in neurocognitive decline comparing baseline to 3 months. Conclusions TMZ-alone patients experienced significantly shorter PFS than patients treated on the RT arms. The ongoing CODEL trial has been redesigned to compare RT + PCV versus RT + TMZ.

Abstract Background: Regular use of nonsteroidal anti-inflammatory drugs (NSAID) is associated with lower risk of colorectal cancer. Genome-wide interaction analysis on single variants (G × E) has identified several SNPs that may interact with NSAIDs to confer colorectal cancer risk, but variations in gene expression levels may also modify the effect of NSAID use. Therefore, we tested interactions between NSAID use and predicted gene expression levels in relation to colorectal cancer risk. Methods: Genetically predicted gene expressions were tested for interaction with NSAID use on colorectal cancer risk among 19,258 colorectal cancer cases and 18,597 controls from 21 observational studies. A Mixed Score Test for Interactions (MiSTi) approach was used to jointly assess G × E effects which are modeled via fixed interaction effects of the weighted burden within each gene set (burden) and residual G × E effects (variance). A false discovery rate (FDR) at 0.2 was applied to correct for multiple testing. Results: Among the 4,840 genes tested, genetically predicted expression levels of four genes modified the effect of any NSAID use on colorectal cancer risk, including DPP10 (PG×E = 1.96 × 10−4), KRT16 (PG×E = 2.3 × 10−4), CD14 (PG×E = 9.38 × 10−4), and CYP27A1 (PG×E = 1.44 × 10−3). There was a significant interaction between expression level of RP11-89N17 and regular use of aspirin only on colorectal cancer risk (PG×E = 3.23 × 10−5). No interactions were observed between predicted gene expression and nonaspirin NSAID use at FDR &lt; 0.2. Conclusions: By incorporating functional information, we discovered several novel genes that interacted with NSAID use. Impact: These findings provide preliminary support that could help understand the chemopreventive mechanisms of NSAIDs on colorectal cancer.