Dueck, A. C.

Abstract Background: Adding adjuvant trastuzumab to chemotherapy for patients (pts) with resected HER2+ breast cancer (BC) improves disease free and overall survival (Perez EA, et al. J Clin Oncol 2011). Understanding which pts are most likely to benefit from these therapies is a goal of our team. Methods: Baseline 1639 annotated tumor specimens from pts enrolled in the phase III N9831 adjuvant trastuzumab trial (NCT00005970) were processed via the >29,000 gene probe DASL technology (Illumina) to identify genomic predictors of pt outcome to Arm A chemotherapy or Arm C chemotherapy plus concurrent trastuzumab. Samples were spotted in 96 well plates, with appropriate replicates. Extensive quality control and internal validation were performed. The association of each gene with recurrence-free survival (RFS) was determined for each treatment arm separately using CoxPH models adjusted for clinical and tumor risk factors. A p < 0.0001 was used to define significance. A geneset analysis (using 408 Kegg/BioCarta genesets) was performed to determine pathways associated with RFS. Results: PRPF4B, EWSR1, BMI1, CNNM1, FOXO4, CLIP2, MCCC1, CHRM2 were found to be significantly associated with RFS for Arm A and AAK1, DAZAP2, TP53INP1, MACF1 and ADHFE1 were associated with RFS for Arm C. The most significant pathway associated with RFS in Arm A was the KEGG hypertrophic cardiomyopathy pathway and for Arm C, the BioCarta pertussis toxin-insensitive CCR5 signaling in macrophage pathway. Conclusions: We have identified 8 genes associated with RFS for pts treated with adjuvant chemotherapy, and 5 genes associated with RFS for pts treated with concurrent trastuzumab and chemotherapy in pts with HER2 early stage BC. In addition, geneset analysis identified BioCarta and Kegg pathways associated with RFS for each arm. Validation in an independent cohort is expected to be completed by the end of 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD10-04.

Key Points Distinct clusters exist within polycythemia vera, essential thrombocythemia, and myelofibrosis. Clusters are not direct surrogates for current prognostic scores.

Abstract Purpose: This study investigated the association between tumor MYC protein expression and disease-free survival (DFS) of patients randomized to receive chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) in the N9831 (Alliance) adjuvant HER2+ trastuzumab breast cancer trial. Experimental Design: This analysis included 1,736 patients randomized to Arms A, B, and C on N9831. Nuclear MYC protein expression was determined in tissue microarray sections containing three biopsies per patient or whole tissue sections using standard immunohistochemistry (clone 9E10). A tumor was considered positive for MYC protein overexpression (MYC+) if the nuclear 3+ staining percentage was more than 30%. Results: Five hundred and seventy-four (33%) tumors were MYC+. MYC+ was associated with hormone receptor positivity (χ2, P = 0.006), tumors 2 cm or more (χ2, P = 0.02), and a higher rate of nodal positivity (χ2, P < 0.001). HRs for DFS (median follow-up: 6.1 years) for Arm C versus A were 0.52 (P = 0.006) and 0.65 (P = 0.006) for patients with MYC+ and MYC− tumors, respectively (Pinteraction = 0.40). For Arm B versus A, HRs for patients with MYC+ and MYC− tumors were 0.79 (P = 0.21) and 0.74 (P = 0.04), respectively (Pinteraction = 0.71). For Arm C versus B, HRs for patients with MYC+ and MYC− tumors were 0.56 (P = 0.02) and 0.89 (P = 0.49), respectively (Pinteraction = 0.17). Conclusions: Our data do not support an impact of tumor MYC protein expression on differential benefit from adjuvant trastuzumab. Clin Cancer Res; 19(20); 5798–807. ©2013 AACR.

BACKGROUNDIncreased soluble human epidermal growth factor receptor 2 (sHER2) is an indicator of a poor prognosis in HER2‐positive metastatic breast cancer. In this study, the authors evaluated levels of sHER2 during treatment and at the time of disease recurrence in the adjuvant North Central Cancer Treatment Group N9831 clinical trial.METHODSThe objectives were to describe sHER2 levels during treatment and at the time of recurrence in patients who were randomized to treatment arms A (standard chemotherapy), B (standard chemotherapy with sequential trastuzumab), and C (standard chemotherapy with concurrent trastuzumab). Baseline samples were available from 2318 patients, serial samples were available from 105 patients, and recurrence samples were available from 124 patients. The cutoff sHER2 value for the assay was 15 ng/mL. Statistical methods included repeated measures linear models, Wilcoxon rank‐sum tests, and Cox regression models.RESULTSThere were differences between groups in terms of age, menopausal status, and hormone receptor status. Within treatment arms A, B, and C, patients who had baseline sHER2 levels ≥15 ng/mL had worse disease‐free survival than patients who had baseline sHER2 levels <15 ng/mL (arm A: hazard ratio, 1.81; P = .0014; arm B: hazard ratio, 2.08; P = .0015; arm C: hazard ratio, 1.96; P = .01). Among the 124 patients who experienced disease recurrence, sHER2 levels increased from baseline to the time of recurrence in arms A and B but remained unchanged in arm C. Patients who had recurrence sHER2 levels ≥15 ng/mL had a shorter survival after recurrence with a 3‐year overall survival rate of 51% compared with 77% for those who had recurrence sHER2 levels <15 ng/mL (hazard ratio, 2.36; 95% confidence interval, 1.19‐4.70; P = .01).CONCLUSIONSIn patients with early stage, HER2‐positive breast cancer, a high baseline sHER2 level was identified as a prognostic marker associated with shorter disease‐free survival, and a high sHER2 level at recurrence was predictive of shorter survival. Cancer 2013;119:2675–2682. © 2013 American Cancer Society.

Purpose It has been suggested that PTEN, a negative regulator of PI3K/AKT signaling, is involved in tumor sensitivity to trastuzumab. We investigated the association between tumor PTEN protein expression and disease-free survival (DFS) of patients randomly assigned to receive chemotherapy alone (arm A) or chemotherapy with sequential (arm B) or concurrent trastuzumab (arm C) in the phase III early-stage human epidermal growth factor receptor 2 (HER2) –positive trial—North Central Cancer Treatment Group (NCCTG) N9831. Patients and Methods The intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections containing three cores per block (n = 1,286) or in whole tissue sections (WS; n = 516) by using standard immunohistochemistry (138G6 monoclonal antibody). Tumors were considered positive for PTEN (PTEN-positive) if any core or WS had any invasive cells with ≥ 1+ staining. Median follow-up was 6.0 years. Results Of 1,802 patients included in this analysis (of 3,505 patients registered to N9831), 1,342 (74%) had PTEN-positive tumors. PTEN positivity was associated with hormone receptor negativity (χ2 P < .001) and nodal positivity (χ2 P = .04). PTEN did not have an impact on DFS within the various arms. Comparing DFS of arm C to arm A, patients with PTEN-positive and PTEN-negative tumors had hazard ratios (HRs) of 0.65 (P = .003) and 0.47 (P = .005), respectively (interaction P = .16). For arm B versus arm A, patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 (P = .009) and 0.85 (P = .44), respectively (interaction P = .47). Conclusion In contrast to selected preclinical and limited clinical studies suggesting a decrease in trastuzumab sensitivity in patients with PTEN-negative tumors, our data show benefit of adjuvant trastuzumab for patients with HER2-positive breast cancer, independent of tumor PTEN status.

AbstractBackgroundIt is not known whether preclinical cognitive decline is associated with fibrillar β‐amyloid (Aβ) deposition irrespective of apolipoprotein E (APOE) ε4 status.MethodsFrom a prospective observational study of 623 cognitively normal individuals, we identified all subjects who showed preclinical decline of at least 2 standard deviations beyond the decline of the entire group in memory or executive function. Fourteen decliners were matched by APOE ε4 gene dose, age, sex, and education with 14 nondecliners. Dynamic Pittsburgh compound B (PiB) positron emission tomography (PET) scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest were used to characterize and compare cerebral‐to‐cerebellar PiB distribution volume ratios (DVRs), reflecting fibrillar Aβ burden.ResultsAt P < .005 (uncorrected), decliners had significantly greater DVRs in comparison to nondecliners.ConclusionsAsymptomatic longitudinal neuropsychological decline is associated with subsequent increased fibrillar amyloid deposition, even when controlling for APOE ε4 genotype.

BACKGROUNDData suggest that weight, and specifically body mass index (BMI), plays a role in breast cancer development and outcome. The authors hypothesized that there would be a correlation between BMI and clinical outcome in patients with early stage, human epidermal receptor 2 (HER2)‐positive breast cancer enrolled in the N9831 adjuvant trial.METHODSPatients were grouped according to baseline BMI as follows: normal (BMI <25 kg/m2), overweight (BMI ≥25 kg/m2 and <30 kg/m2), and obese (BMI ≥30 kg/m2). Disease‐free survival (DFS) was estimated using the Kaplan‐Meier method. Comparisons between treatment arms A, B, and C (chemotherapy with or without trastuzumab) were performed using a stratified Cox proportional hazards model.RESULTSAnalysis was completed on 3017 eligible patients. Obese patients were more likely to be older and postmenopausal (P < .0001 for both), to have larger tumors (P = .002), and to have positive lymph nodes (P = .004). In the pooled analysis cohort, differences in DFS among the BMI groups were statistically significant (5‐year DFS rate: 82.5%, 78.6%, and 78.5% for normal weight, overweight, and obese women, respectively; log‐rank P = .02). The adjusted hazard ratio comparing the DFS of overweight women with the DFS of normal women was 1.30 (95% confidence interval, 1.06‐1.61); and, comparing the DFS of obese women with the DFS normal women, the adjusted hazard ratio was 1.31 (95% confidence interval, 1.07‐1.59). There were no statistically significant differences in DFS by weight group for women within any trial arm.CONCLUSIONSPatients with early stage, HER2‐positive breast cancer and normal BMI had a better 5‐year DFS compared with overweight and obese women. The current results indicated that adjuvant trastuzumab improves clinical outcome regardless of BMI. Cancer 2013;119:2447‐2454. © 2013 American Cancer Society.

AbstractObjectiveA National Institute on Aging–sponsored work group on preclinical Alzheimer's disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD.MethodsSeventy‐one apolipoprotein E (APOE) ε4 homozygotes, 194 ε3/ε4 heterozygotes, and 356 ε4 noncarriers age 21 to 87 years who were cognitively healthy underwent neuropsychological testing every 2 years. Longitudinal trajectories of test scores were compared between APOE subgroups.ResultsThere was a significant effect of age on all cognitive domains in both APOE ε4 carriers and noncarriers. A significant effect of APOE ε4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross‐sectional comparisons did not discriminate the groups.ConclusionsAlthough cognitive aging patterns are similar in APOE ε4 carriers and noncarriers, preclinical AD is characterized by a significant ε4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory‐sensitive measures and longitudinal design.

BackgroundThe purpose of this study was to report the treatment outcomes of patients with advanced oropharyngeal cancer treated with transoral laser microsurgery (TLM) followed by radiation therapy (RT) at Mayo Clinic in Arizona.MethodsA retrospective study of 80 patients treated from January 1, 2000 to November 7, 2011 was performed. All patients had stage III/IV oropharyngeal tumors and underwent TLM with neck dissection. Adjuvant RT was then given. Thirty‐seven patients received concurrent adjuvant chemotherapy. The primary outcome was locoregional control.ResultsMedian follow‐up was 47.3 months (range, 9.7–139.2 months). The 3‐year locoregional control, recurrence‐free survival, and overall survival rates were 98.6% (95% confidence interval [CI], 91% to 100%), 91.1% (95% CI, 81% to 96%), and 93.7% (95% CI, 84% to 98%), respectively. There were a total of 5 treatment failures, 1 regional and 4 distant. Twenty‐six patients underwent neck only RT with exclusion of the primary site.ConclusionTLM followed by RT for advanced oropharyngeal cancer results in excellent locoregional control rates. © 2013 Wiley Periodicals, Inc. Head Neck 36: 220–225, 2014

AbstractBackgroundTOMM40 (translocase of the outer mitochondrial membrane pore subunit) is in linkage disequilibrium with apolipoprotein E (APOE). APOE e4 is linked to long (L; 21–29 T residues) poly‐T variants within intron 6 of TOMM40, whereas APOE e3 can be associated with either a short (S; <21 T residues) or very long (VL; >29 T residues) variant. To assess the possible contribution of TOMM40 to Alzheimer's disease onset, we compared the effects of TOMM40 and APOE genotype on preclinical longitudinal memory decline.MethodsAn APOE e4–enriched cohort of 639 cognitively normal individuals aged 21 to 97 years with known TOMM40 genotype underwent longitudinal neuropsychological testing every 2 years. We estimated the longitudinal effect of age on memory using statistical models that simultaneously modeled cross‐sectional and longitudinal effects of age on the Auditory Verbal Learning Test Long‐Term Memory score by APOE, TOMM40, and the interaction between the two.ResultsThere were significant effects overall for both TOMM40 (linear effect, P = .04; quadratic effect, P = .03) and APOE (linear effect, P = .06; quadratic effect, P = .008), with no significant interaction (P = .63). In a piecewise model, there was a significant TOMM40 effect before age 60 years (P = .009), characterized by flattened test–retest improvement (VL/VL subgroup only) but no significant APOE effect, and a significant APOE effect after age 60 years (P = .006), characterized by accelerated memory decline (e4 carriers) but no significant TOMM40 effect.ConclusionBoth TOMM40 and APOE significantly influence age‐related memory performance, but they appear to do so independently of each other.