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520 Background: There is considerable interest in developing HER2 testing criteria for adjuvant H. We used the 21-gene assay to examine the relationship of HER2 mRNA to benefit from H. Methods: N9831 compared adjuvant chemotherapy AC-T to concurrent chemotherapy-trastuzumab AC-TH in stage I-III HER2+ breast cancer. Recurrence Score (RS) and HER2 mRNA expression were determined by Oncotype DX (neg2 expression units). Cox regression was used to assess the association of HER2 expression with H benefit for distant recurrence. Results: Median follow-up: 7.4 yrs. Of 1,940 total pts, 901 had consent and sufficient tissue. HER2 by RT-PCR was neg in 130 (14%), equiv in 85 (9%), and pos in 686 (76%) pts. Concordance between HER2 assessments was 95% for RT-PCR vs central IHC (>10% + cells = +), 91% for RT-PCR vs central FISH (≥2.0 = pos) and 94% for central IHC vs central FISH. In the primary analysis, the association of HER2 expression with H benefit was marginally non-significant (P=0.057). In hormone receptor pos pts (local IHC) the association was significant (P=0.002). The association was nonlinear with the greatest estimated benefit at lower and higher HER2 mRNA expression levels. The observed treatment benefit in low HER2 pts was not due to imbalance between arms in RS and individual gene expression values. Conclusions: Concordance among HER2 assessments by central IHC, FISH, and RT-PCR was high. Association of HER2 mRNA expression with H benefit was marginally non-significant. A consistent benefit of trastuzumab irrespective of mHER2 levels was observed in the pts with either IHC+ or FISH+ tumors. Benefit was observed in pts with high HER2 by RT-PCR but also observed for the small groups of pts with negative results by quantitative RT-PCR or FISH (Table). Plausible mechanisms for this observation will be discussed. [Table: see text]

55 Background: The aim of this retrospective study was to examine the overall survival (OS) of metastatic breast cancer patients over a decade and assess for any differences with respect to age, tumor characteristics, and ECOG status. Methods: Data on metastatic breast cancer cases from 1999-2010 were retrieved from the institutional cancer registry and linked to electronic medical records. Through chart review of 240 metastatic breast cancer cases, we determined hormone receptor (HR), HER2/neu (HER2), ECOG, age at diagnosis of metastatic cancer and mortality data. Kaplan-Meier survival curves for OS were used and compared between HR status, HER2 status, ECOG, and age at diagnosis using log-rank regression and Cox Regression analysis was performed to control for these variables. A 95% confidence interval (CI) was used. Results: The median OS of the sampled cases was 2.2 years (CI: 1.8-2.5 years). Analysis for overall survival by pre-determined age groups demonstrated no significant difference between the age groups (p value 0.46), but did yield a statistical difference based on ECOG status (p value 0.0001). Cox regression analysis showed consistent findings where survival was significantly affected by HR, HER2 status and ECOG but not age (HR: p value

8053 Background: Lenalidomide (LEN) is an immunomodulatory agent that has shown significant single-agent anti-lymphoma activity in patients with relapsed disease and in combination may enhance the efficacy of rituximab by various mechanisms. There is limited data on the role of LEN in combination regimens for treatment-naïve patients. This phase II single arm trial was designed to evaluate tumor response, toxicity (AE) and survival with a combination of LEN, rituximab, cyclophosphamide (CTX) and dexamethasone (DEX) (LR-CD) in symptomatic untreated patients with low grade B-cell non-Hodgkin lymphoma. Methods: Eligibility required age ≥18, ECOG PS ≤2, confirmed diagnosis of low-grade B-cell lymphoma (FL1-2, SLL, MZL or LPL/WM), measurable nodes ≥2cm or IgM ≥400mg/dL(LPL/WM), ANC ≥1400/mm3, platelets ≥100,000/mm3, creatinine ≤2mg/dL, signed informed consent and in need of therapy. Treatment consisted of IV rituximab 375mg/m2 D1, oral LEN 20mg D1-21, CTX 250mg/m2 D1, 8, 15, DEX 40mg D1, 8, 15, 22 and ASA 325 mg daily in a 28 day cycle. Treatment continued 2 cycles beyond best response (max 12). Toxicity was assessed by NCI CTCAE v3.0. Results: 28 patients have enrolled at Mayo Clinic with 25 evaluable for toxicity and 21 for response: Median age 65(43-83), 72% male, FL 24%, MZL 28%, LPL/WM 38%, and SLL 4%. Median number of cycles given was 5. Overall response in 21 patients with response data is 95% (95% CI 76-100%) with 19% CR (95% CI 5-42%), and 76% PR (confirmed and unconfirmed, 95% CI 53-92%). The ORR in 8 patients with LPL/WM with response data was 88%, all PR (95% CI 47-100%). At a median f/u of 14.7 months 96% are alive without progression. 1 death (unrelated) occurred 7.7 months after completing 12 cycles of treatment. The most common grade ≥3 AEs were neutropenia (37.5%), leukopenia (16.7%), anemia (12.5%) and fatigue (12.5%). Conclusions: The combination LR-CD with the novel agent LEN is feasible, well tolerated and produces high response rates in symptomatic patients with low grade B-cell NHL. Toxicities are manageable and similar to reported data of single agent LEN.

6108 Background: This pilot study evaluated whether providing clinicians with patient(pt) QOL results and symptom management pathways linked to QOL domains at the time of clinical appointment would result in improvement in QOL and treatment (tx) satisfaction. The objective was to obtain preliminary effect size estimates and logistical evidence for design of a larger, definitive trial. Methods: Oncology pts receiving 5-7 weeks of radiotherapy (RT) electronically completed QOL assessments (LASA) at baseline and biweekly prior to seeing clinicians. Was It Worth It (WIWI) and Interpersonal Patient-Provider Relationship (IPPRS) were measured at tx end. Pt endpoints (pro-rated primary endpoint LASA area under the curve (AUC), LASA changes from baseline, and WIWI responses) and clinician endpoints (IPPRS) were compared between the control group (Phase 1: no QOL feedback) and the intervention group (Phase 2: QOL feedback) via Wilcoxon, Chi-square and Fisher Exact tests. There was 80% power to detect a 10 point difference in average AUC. Results: 148 pts enrolled (79 Phase 1, 69 Phase 2) from 11/28/2008 to 09/20/2011 (sites GI (27%), Lung (22%) and Head and Neck (52%)). 68% received RT and chemo. There were consistently moderate effect sizes observed but no statistically significant differences in any AUC nor end of tx change from baseline scores. 20% fewer pts in phase 2 reported clinical deficits in overall QOL (pain). In pts receiving 7 weeks of RT, end of tx average overall QOL, mental well-being (WB), physical WB and pain severity were significantly better in Phase 2 pts. WIWI results showed 76% found participation worthwhile, 95% would participate again, and 92% would recommend the study to others. No differences between groups were found in communication between clinicians and pts (IPPRS). Conclusions: Preliminary estimates indicate potentially clinically significant improvements of moderate effect size in mental and physical WB and pain severity when clinicians received QOL real time with symptom management pathways. Further study is warranted in larger trial setting.

6133 Background: Patient (pt) trial experience may give insight to quality of life (QOL) factors affecting accrual, retention and outcome. While pts are vital to clinical trial success, we know little about their post-trial opinions. This trial examined pt opinion of their trial and treatment decision making (TDM). Methods: Pts enrolled on designated North Central Cancer Treatment Group (NCCTG) phase II or III treatment trials completed the TDM Control Preferences Scale at baseline and the Was It Worth It (WIWI) satisfaction assessment at the ends of cycle 1 and active protocol treatment. The primary endpoint was the proportion of pts reporting worthwhile participation. Fisher Exact tests compared pt opinion across subgroups. Results: As of 01/15/2012, 264 pts were enrolled on 25 protocols and treated at 79 sites. 86% of pts were in phase II studies and 89% had stage IV disease. At the end of cycle 1, pts felt the trial was worthwhile (74%), would do it again (85%), and would recommend it to others (82%). 85% of pts reported undiminished QOL and only 7% rated the trial worse than expected. End of treatment responses were similar. Satisfaction rates varied by tumor site (p=0.04). 11% of pts having tumor response rated the trial as not worthwhile, and 66% of pts with progressive disease rated it worthwhile (see table). Pts with concordant preferred and actual TDM roles rated participation higher than pts with discordant TDM roles (see table). Conclusions: Most pts endorsed their clinical trial experience. Contrary to popular beliefs, treatment outcome did not have an overwhelming impact on pt satisfaction, and was just one of many factors such as TDM role discordance. Assessing pt satisfaction will inform future study design that can potentially improve pt accrual and retention. [Table: see text]

8010 Background: Carfilzomib is a proteasome inhibitor that irreversibly binds its target with favorable toxicity profile that has shown significant activity in relapsed multiple myeloma (MM). Here we used carfilzomib as the center of a 4 drug induction regimen designed for MM patients pre stem cell transplant (SCT). Methods: We conducted a phase I safety run in 6 patients with no DLT observed before expanding to phase II. The phase II regimen is shown below. Treatment was for 4 cycles with expected SCT post induction. For the phase II portion of this trial, the primary endpoint is the proportion of patients who have ≥ very good partial response to treatment. All patients received herpes zoster prophylaxis and ASA daily. Results: Twenty seven patients were enrolled. Median age was 65 (range 27-74). ORR for evaluable patients (n=17) at phase II dosing is 100%: CR 35%, VGPR 48%, PR 18% after 4 cycles of CYCLONE. Grade 3 toxicity was reported in 52% of patients and 14% experienced a grade 4 toxicity. Grade 3/4 toxicities occurring in >5% of patients included fatigue, neutropenia, lymphopenia, thromboembolism, myopathy. Toxicities of any grade seen in >20% of patients included fatigue, constipation, lethargy, thrombocytopenia, somnolence, creatinine increased, malaise. Four patients (20%) developed grade 1 sensory neuropathy; no higher grade or painful neuropathy was evident. All patients are alive. All patients advancing to SCT successfully collected stem cells. One patient with t(4;14) disease who was not transplanted has progressed. 94% remain progression free. Conclusions: The 4 drug CYCLONE regimen has remarkable efficacy (83% ≥VGPR) and manageable toxicity in newly diagnosed patients with multiple myeloma. Especially notable was the low incidence of neuropathy and depth of response (CR 35%) after only 4 cycles. Given the relative lack of toxicity an extension of this regimen at higher doses of carfilzomib (20/45mg/m2) has been initiated. [Table: see text]

9047 Background: Symptomatic adverse events (AE) in cancer trials are reported by clinicians using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE). To integrate the patient perspective into AE reporting, NCI contracted (HHSN261201000043C) to create a patient-reported outcomes companion tool (PRO-CTCAE). We report the validity and reliability of PRO-CTCAE’s 124 items reflecting 78 symptomatic AEs. Methods: English-speaking subjects (n=869; 44% male; median [mdn] age 59; 32% racial/ethnic minority; 34% high school or less; 17% ECOG Performance Status [PS] 2-4) receiving treatment for a range of cancers at 4 NCI-designated cancer centers and 5 sites in NCI's Community Cancer Centers Program completed a web-based survey in clinic including PRO-CTCAE and EORTC QLQ-C30. Pearson correlations were computed between PRO-CTCAE items and QLQ-C30 scales. Differences in PRO-CTCAE item scores between clinician-reported ECOG PS (0-1 vs 2-4) groups were computed. Test-retest reliability of 48 prespecified items was evaluated in a subset (n=79). Results: Correlations in the expected direction were observed for 116/124 PRO-CTCAE items with the QLQ-C30 global health scale (mdn r=-.21; range .08 to -.57). Stronger correlations were seen for PRO-CTCAE items with conceptually related QLQ-C30 domains: fatigue with physical, role and social functioning (-.54 to -.66); anxiety and depression with emotional functioning (-.54 to -.70); and concentration and memory problems with cognitive functioning (-.62 to -.72) [all p

13 Background: A Memorial Sloan Kettering Cancer Center (MSKCC) nomogram predicts disease−specific survival (DSS) following R0 resection for gastric adenocarcinoma using patient and tumor factors, with predictive ability superior to that of the current AJCC staging system. However, validation has only been performed in high−volume, specialized institutions. The goal of this study is to compare nomogram-predicted survival with actual survival by using a population database with the largest sample size reported to date. Methods: A retrospective review of all gastric cancer patients from Surveillance, Epidemiology and End Results (SEER) registry data from 1988 to 2000 was conducted. Data for patient age, tumor size, gender, primary location of tumor, Lauren histology, depth of tumor invasion, and % (+) and (-) lymph nodes was entered into the nomogram calculator for each patient. Nomogram-derived 5−year DSS was compared with actual DSS survival using Cox proportional hazards regression and Kaplan-Meier estimates. Results: 4,700 patients were identified. Mean patient age was 68.7 years (SD 12.3), and mean tumor size was 4.8 cm (SD 2.7). The commonest tumor location was the body/middle third of stomach (1519, 32%), followed by the gastro−esophageal junction (1381, 29%) and the antrum (1376, 29%). The majority of patients (76%) had intestinal histology. The estimated proportion of patients surviving 5 years was 23%, 48%, 58%, and 82% for survival groups defined by nomogram likelihoods of 5−year DSS of 0−25%, 26−50%, 51−75%, and 76−100%, respectively. Relative to patients in the 76−100% 5−year nomogram group, patients in the 0−25%, 26−50%, and 51−75% group had significantly higher likelihood of death with hazard ratios of 7.0 (95% CI 6.1−8.0), 3.3 (95% CI 2.8−4.0), and 2.6 (95% CI 2.2−3.0), respectively (all p Conclusions: There is good discrimination of survival between nomogram-predicted survival groups. Our results validate the use of the MSKCC nomogram in the setting of the general population, outside of specialized institutions, for predicting DSS following resection of gastric adenocarcinoma.

1126 Background: In N0531 (Roy et al, Ann Oncol 2009) NP+G was effective and tolerable in MBC, with complete + partial response rate (CR+PR) 50%, proportion with 6-month progression free survival (...

10504 Background: Preclinical data suggest that PTEN, a regulator of PI3K/AKT signaling, tumor growth and invasion, is involved in tumor sensitivity to trastuzumab. Thus, we sought to investigate the impact of PTEN expression on the benefit of trastuzumab in the prospective phase III HER2+ adjuvant N9831 study (Perez EA, et al. JCO 2010) We evaluated PTEN prevalence, relationship with demographic data, and association with disease-free survival (DFS) of patients (pts) randomized to chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C). Methods: The % of cells with PTEN staining at 0 (none), 1+ (weak), 2+ (moderate), and 3+ (strong) intensity was determined in TMA sections containing 3 cores per block (N=1286) or in whole tissue sections (WS) (N=515) using immunohistochemistry (rabbit polyclonal PTEN Ab, Cell Signaling; dilution 1:200, overnight incubation). A tumor was considered positive (PTEN+) if any TMA or WS had ≥1+ cytoplasmic staining in >0% invasive c...

10503 Background: Preclinical evidence suggests that increased IGF1R (insulin-like growth factor receptor) signaling interferes with trastuzumab action, suggesting a possible mechanism of resistanc...

1542 Background: Diabetes and cancer are both common diseases, but more data is needed about the population in order to develop clinical programs to treat the patients (pts) with these two complex ...

6130 Background: Clinically significant effect sizes have been the focus of much research for assessing patient-reported outcomes (PROs). Methods such as the empirical rule effect size or ½ standar...

TPS274 Background: Adverse symptoms in cancer clinical trials are reported by clinicians using the NCI's standard lexicon for adverse event reporting, the Common Terminology Criteria for Adverse Events (CTCAE). To directly include the patient perspective into this process, the NCI contracted to create patient-reported outcomes measures of CTCAE symptoms (N02-PC-85002-29; PI: Basch). Items representing 77 CTCAE symptoms were developed and refined via cognitive interviewing. In the current study, we will assess the validity, reliability, and sensitivity to change of these items; compare 1-, 2-, 3-, and 4-week recall periods versus daily reports; and compare patient- and clinician-reported symptom ratings. Methods: This NCI-sponsored multi-site validation study will accrue 700 patients receiving chemotherapy or radiotherapy representing the diversity of disease burden and symptoms at five cancer centers (Memorial Sloan-Kettering; Mayo; Duke; M.D. Anderson; Dana-Farber) and selected community sites in NCI's C...

1157 Background: In the absence of curative treatment for the majority of patients with metastatic breast cancer (MBC), the goal of therapy is focused on symptom control, improved quality of life, and prolongation of survival. Past studies have demonstrated a subset of patients that can achieve long-term survival who in general tended to be young patients with good performance status, fewer sites of metastases and smaller disease burden. An update of characteristics of long-term survivors is necessary as the MBC patient population and treatment options have changed over the last decade. Methods: We reviewed phase II and III trial data for 1,747 patients from 23 NCCTG MBC trials that enrolled patients from 1996 to 2008. We defined patients with survival beyond 3 years from the initiation of systemic treatment of breast cancer as long-term survivors (3YLTS). Univariate association between 3YLTS status and baseline demographics were performed using a t test for age and tumor size and Chi- square test for cat...

2081 Background: This study establishes Perfusion MRI (pMRI) correlation with tissue microvasculature and accuracy to predict histopathologic diagnosis of tumor recurrence or post-treatment radiati...

TPS129 Background: Insulin-like growth factor (IGF) signaling has been implicated as a mechanism of resistance to therapies targeting the HER2 pathway in breast cancer, such as trastuzumab and lapatinib. Cixutumumab (IMC-A12) is an IgG1 monoclonal antibody that binds IGF-1 receptor (IGF-1R), blocking ligand activation of the IGF system and stimulating receptor down-regulation. The addition of cixutumumab to capecitabine and lapatinib in HER2+ breast cancer may improve the clinical benefit of this regimen. Methods: N0733 is CTEP-sponsored, NCCTG-led, multicooperative group supported randomized phase II trial investigating the clinical activity of capecitabine plus lapatinib ± cixutumumab. Patients with advanced or metastatic HER2+ breast cancer treated previously with trastuzumab and an antracycline and/or a taxane with measureable disease and adequate organ function are eligible for participation. Following an initial safety cohort testing the safety and tolerability of cixutumumab in combination with cap...

e21075 Background: BRCA mutations increase the risk for breast cancer. Breast cancers with HER2-overexpression/amplification (HER2+) have a more aggressive natural history and are responsive to HER...

565 Background: The nonanthracycline regimen of docetaxel (T), carboplatin (C), and trastuzumab (H) is available for patients with early HER2+ breast cancer. We sought to evaluate the tolerability ...

10075 Background: NCR prior to resection of STS is used routinely at our institution. Outcomes with NCR are compared to neoadjuvant radiation (NR) or surgery alone (SA). In addition, the initial ex...

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 No significant financial relationships to disclose.

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]

539 Background: An increased baseline sHER-2 concentration is an indicator of poor prognosis in the metastatic and adjuvant settings of HER-2+BC. This study evaluated the levels of sHER-2 during treatment and at time of recurrence in N9831. Methods: Aims were to describe sHER-2 levels during treatment and at time of recurrence in patients (pts) randomized to Arms A (standard chemotherapy) and C (standard chemotherapy with concurrent trastuzumab). Baseline serum samples of 1506 pts from both arms along with 86 recurrence serum samples were analyzed for sHER-2 (ng/mL). In addition, 556 serial samples were obtained in 148 patients over the treatment period. Median follow up was 4.5 years. Statistical methods included repeated measures linear models, Wilcoxon rank sum tests, and Cox regression models. Results: Analyzing serial sHER-2 levels during treatment, mean log sHER-2 remained constant in Arm C (estimated slope = 0.004, p = 0.44) while the estimated increase per month was 0.026 (on log e scale) for Arm A (p = 0.0003). Based on the linear model at 18 months, the mean log sHER-2 was 2.98 (95% CI: 2.87–3.09) and 2.55 (95% CI: 2.40–2.70) for Arms A and C, respectively. Among pts with disease recurrence, sHER-2 levels increased in Arm A from baseline to time of recurrence (mean = 72.9, median = 1.7, p =0.005) while sHER-2 levels remained unchanged in Arm C (mean = 9.2, median = -0.9, p = 0.65). While all 86 recurrence patients had baseline sHER2 levels [Table: see text]

11095 Background: Biologic characterization of CTCs is increasingly important in determining metastatic breast cancer (MBC) patient (pt) prognosis and treatment prediction. Combined preliminary results from two earlier metastatic BC NCCTG trials, N0234 & N0336, suggested that the change in CTC mammaglobin (MGB1) gene expression between baseline and two cycles of chemotherapy predicted tumor response (p=0.04). The objectives of this study were to 1) determine CTC gene expression of CK19 and MGB1 before, during, and after treatment in N0436 & N0437 and 2) determine associations between baseline and post-treatment gene expression and treatment response. Methods: CTCs were enriched using CD45-depletion from ∼10ml EDTA blood obtained from metastatic BC pts before, after two cycles, and at end of treatment with either first/second-line irinotecan plus cetuximab (N0436) or first-line paclitaxel poliglumex and capecitabine (N0437). CK19 and MGB1 mRNA levels were determined using quantitative RT-PCR in baseline and serial CTC samples of up to 19 pts from N0436 and 40 pts from N0437. The relative gene expressions were normalized to β2-microglobulin and calibrated to healthy blood using the 2-ΔΔCt algorithm; a value of 2 was defined as positive for the respective marker. Results: CK19+ mRNA was detected in 58% of baseline samples from N0436 (11/19) and N0437 (23/40). MGB1+ mRNA was detected in 32% (6/19) and 38% (15/40) of N0436 and N0437 baseline samples, respectively. CK19+ mRNA was detected in 50% (7/14) and 56% (29/52) of N0436 and N0437 serial CTC samples, respectively. MGB1+ mRNA was detected in 29% (4/14) and 27% (14/52) of N0436 and N0437 serial CTC samples, respectively. Of the 66 serial samples, 27% of samples (18/66) had turned positive from baseline for CK19 or MGB1. CK19 mRNA was detected in 85% (33/39) of MGB1+ mRNA samples but their baseline mRNA levels were not correlated. Conclusions: CK19 mRNA was detected in MBC pts with similar frequencies to the CellSearch imaging system. CK19 was detected at a higher frequency than MGB1. In the majority of cases, MGB1 was co-expressed with CK19. Associations between gene expression and treatment response using Chi-Squared analyses and Cox regression models will be presented. No significant financial relationships to disclose.

22110 Background: Preliminary results from the National Surgical Adjuvant Breast and Bowel (NSABP) adjuvant trastuzumab breast cancer (BC) trial, B-31, suggested that HER2-positive BC patients with...

8543 Background: Lenalidomide (len) with dexamethasone (dex) is increasingly used as induction therapy in newly diagnosed myeloma patients prior to transplant. We performed a retrospective chart re...

529 Background: sHER2 is a circulating oncoprotein cleaved from full-length, membrane-bound HER2. Previous data support that increased sHER concentration is an indicator of poor prognosis and predictor of poor response to chemotherapeutic and hormone treatment in metastatic breast cancer. The role of sHER2 level on the outcome of patients in the adjuvant setting has not been defined, which we evaluated in the context of N9831. Methods: The objectives were to analyze the association between baseline sHER2 and disease-free survival (DFS) in patients (pts) randomized to Arms A (standard chemotherapy) and C (standard chemotherapy with concurrent trastuzumab) of N9831. Baseline serum samples of 1,423 pts from both arms were analyzed for sHER2 using the ADVIA Centaur HER2 assay (Siemens Diagnostics; Tarrytown, NY). Cut off value of 15 ng/mL was used as recommended by the manufacturer/FDA. Patients who cancelled prior to receiving therapy, ineligible pts, and pts whose HER2 status was not corroborated by central...

6627 Background: Methodological issues hamper efficacy assessment of agents to prevent osteoporosis in cancer survivors. The diagnosis of osteoporosis can vary depending upon which bone mineral den...

576 Background: In node-negative, ER + breast cancer, gene expression profiling can identify level of risk and, in the case of ODX, may also identify pts with a higher chance of benefiting from adjuvant chemotherapy. Because the gene profile in ODX includes an assessment of ER, HER2, and proliferation, we hypothesized that clinicians using standardized criteria could discriminate risk (high versus low/intermediate) as specified by ODX. Methods: We identified Mayo Clinic patients with node-negative, ER + breast cancer, for whom ODX scores were available. Tumor slides were reviewed by an expert breast pathologist to confirm tumor size, histology, and tumor grade. Both ER and PR were quantitated; HER-2 was determined by IHC (FISH, if 2+). These clinical cases were presented to six academic oncologists, blinded to the ODX score, to predict ODX risk (low, intermediate, or high) and give their recommendation for chemotherapy (CTX) (yes/no). Afterwards, they were presented with the same cases with the actual ODX score, to give recommendations regarding CTX. Results: ODX scores in tumors from 31 patients were low in 18 pts, intermediate in 10 pts, and high in 3 pts. Concordance between predicted and actual ODX scores being low/intermediate vs high exceeded 87% for each oncologist. The most frequent discrepancies were actual low scores predicted as intermediate (31/80 discordant) and actual intermediate scores predicted as low (29/80 discordant). Overall agreement of predicted scores (high vs low/intermediate) among the oncologists was substantial (kappa=0.75, p No significant financial relationships to disclose.

612 Background: The adoption of new breast surgical techniques has been rapid for early stage breast cancer. The utilization of these techniques in patients with high risk operable breast cancer has not been thoroughly investigated. Methods: Retrospective surgical data was summarized for patients entered into N9831 “Phase III Trial of Doxorubicin and Cyclophosphamide Followed by Weekly Paclitaxel With or Without Trastuzumab as Adjuvant Treatment for Women With HER-2 Over-expressing or Amplified Node Positive or High-Risk Node Negative Breast Cancer.” Results: 3,505 patients were entered into N9831 from 2000–2005 following primary surgery for breast cancer. The median age was 50 and 43% were premenopausal. 93% of patients underwent a diagnostic biopsy prior to their definitive surgical procedure. Whether HER2-neu status was available at time of definitive surgery is unknown. 61% underwent a mastectomy whereas 39% underwent breast conserving surgery (BCS). The rate of BCS was relative stable over the course of the trial. Patients with T1 tumors had a higher rate of BCS (49%) compared to T2 tumors (37%) and T3 tumors (6%). Sentinel lymph node (SLN) biopsy was performed in 54% of the cases. The rate of SLN biopsy increased from 40% in 2000 to 66% in 2005. Patients who underwent mastectomy had a lower rate of SLN biopsy than patients who underwent BCS (44% versus 71%, respectively). Tumor size was also associated with the rate of SLN biopsy: T1 (60%), T2 (53%), and T3 (36%). Data on local and regional recurrences are still maturing. Conclusions: Surprisingly, low numbers of patients on this trial underwent BCS whereas the adoption of the SLN biopsy procedure among the same group of surgeons was relatively high. The relatively low rate of BCS in this study population needs further investigation to determine what surgeon and patient factors impacted the surgical decision. No significant financial relationships to disclose.

9005 Background: Hot flashes can be a major problem in men with prostate cancer; effective non-hormonal options are needed. Methods: A four-arm, double-blinded, placebo-controlled randomized trial was developed to evaluate gabapentin for hot flashes. Men with bothersome hot flashes (at least 14/week) related to androgen deprivation therapy were randomized to receive either a placebo or gabapentin doses of 300 mg qd, 300 mg bid or 300 mg tid; men were treated for 4 weeks. Hot flashes numbers and scores (hot flash number times mean severity) were measured using a validated daily hot flashes diary. A one-week baseline period preceded initiation of study tablets. The primary endpoint was the average intrapatient difference in hot flash score between baseline and treatment termination. With the planned sample size of 50 evaluable patients per arm, the study provided 80% power to detect a difference in change from baseline at 4 weeks between each gabapentin arm and the placebo arm of 1.3 hot flashes per day or 3.3 points in hot flash score. Results: 223 patients were randomized between 12/21/2001 and 11/10/2006. The study arms were well balanced. The following table illustrates the percentage of baseline hot flash scores and frequencies during the fourth treatment week, compared to the baseline week for 179 eligible patients, utilizing the data available at time of this abstract preparation. Patients receiving 900 mg/d dose of gabapentin also reported significantly less hot flash distress and more hot flash control satisfaction than did the placebo group. The gabapentin was remarkably well tolerated, without any statistically significantly worse patient-reported side effects on the gabapentin arms. Conclusion: Gabapentin at the 900 mg/d dose can reduce hot flashes, in men receiving androgen deprivation therapy for prostate cancer. No significant financial relationships to disclose. [Table: see text]

6116 Background: Analyses of patient-reported outcomes rely on the dependability of patients to complete and submit assessments in a timely manner – not all data is obtained. In recent work focusing on quality of life (QOL) data and imputation, it has been found that most methods do not alter study results. But how much data can be missing before study results are affected? Methods: Missing data was investigated using a 2-arm study (109 patients) who completed Linear Analogue Self Assessments at 4 intervals. Patients (11%) had missing data at the second interval. Existing data was analysed for differences in scores between arms, then cases were randomly deleted to create increasing percentages (12%-20%) of missing data. Ten simulations were conducted per percent. Imputation methods applied were carrying forward the last value (LVCF), average value (AVCF), and maximum value (MVCF). Student’s t-tests were performed between arms for each simulation. Results: Imputation did not alter results of our study data which was statistically significant (SS) between arms for overall QOL (p=0.036) and spiritual well-being (SWB) (p=0.006), and not statistically significant (NS) for mental well-being (MWB) (p=0.174). After data deletion and t-test calculations, AVCF did not impact results. For overall QOL, data deletion changed the p-value to NS in 1 of 10 simulations starting at 12% missing data and 5 of 10 simulations starting at 16% missing data. No matter what percentage of missing data, imputation produced a SS p-value over 80% of the time. Data deletion and subsequent imputation did not affect the study decision for SWB. For MWB, all differences between arms were NS prior to imputation. After imputation, there was at most a 7% disagreement in conclusions. LVCF and MVCF performed equally in all simulations. Conclusions: For this particular study, when p-values are close to the study-defined alpha, the increase in missing data can change the study results and imputation methods are more likely to determine SS differences. The further the p-values are from the study alpha, there is little effect from increasing missing data or applying imputation. These results are for one particular study and further research is needed. No significant financial relationships to disclose.

6023 Background: The addition of trastuzumab (H) to a standard adjuvant therapy regimen (doxorubicin, cyclophosphamide, and paclitaxel; AC→T) is associated with a 52% reduction in risk (p < 0.0001) of disease recurrence in patients with HER2 positive operable breast cancer (Romond et al, NEJM 2005). A cost-effectiveness analysis was performed to assess the lifetime clinical and economic implications of this important clinical finding. Methods: A Markov model with three health states (disease-free survival [DFS], recurrence, and death) was used to estimate the likely cost-effectiveness (CE) for a 50 yr old woman. Efficacy results from both trials (NCCTG N9831/NSABP B-31) were used through 4 years, and projections of time to recurrence and death were based on the literature (EBCTCG, Lancet 2005). After 4 years, annual transition probabilities to recurrence and death are assumed to be the same in both arms. Cardiotoxicity was higher with H (Perez EA, ASCO 2005). Actual total dose of H was used which was lower than scheduled dose. Incremental costs associated with addition of H to adjuvant therapy were estimated using average wholesale prices, Medicare reimbursement rates and other published data. These costs included testing for HER2 status, drug and administration costs for H, cardiac monitoring, treatment of cardiotoxicity, treatment following recurrence, and end-of-life costs for dying patients. Utility estimates were derived from the literature. Results: Over a lifetime, the cost per quality-adjusted life year gained (QALY; discount rate 3%) is $27,800, with a range of $17,900 to $39,100 under multi-way sensitivity analysis. Projected life expectancy from the Markov model is 3 years longer for H patients (19.4 v 16.4 yrs). Over a 20-year horizon, addition of H to AC→T is estimated to cost an additional $46,300 on average, with an expected gain of 1.28 QALYs-a cost/QALY of $36,100. The key drivers of CE are the cost of treatment and the improvement in DFS. Conclusion: The model projects a cost-utility ratio that is below that of many treatments used for oncology patients. The use of trastuzumab in the adjuvant setting for HER2+ breast cancer is projected to be cost-effective. [Table: see text]

523 Background: Adjuvant trastuzumab (Herceptin [H]) with chemotherapy improves outcome in HER2+ breast cancer (BC). Preclinical studies suggest H may enhance RT. We herein assess if H given with adjuvant RT increases adverse events (AE) after breast conserving surgery or mastectomy. Methods: N9831 randomized 3505 women with pT1–3N1–2M0, pT2–3N0M0, or pT1cN0M0 (ER/PR negative) HER2+ BC to doxorubicin (A) and cyclophosphamide (C) followed by weekly paclitaxel (T), AC→T→H, or AC→TH→H. Post-lumpectomy breast ± nodal RT was recommended, as was post-mastectomy chest wall + nodal RT (>3 nodes +); internal mammary RT was prohibited. RT started within 5 weeks of completion of T and allowed concurrently with H. 2324 eligible patients were enrolled on study prior to April 25, 2004: 1460 patients receiving RT are available for analysis of RT-associated AEs. Also, 1286 patients on +H arms who completed T (908 +RT and 378 -RT) are available for analysis of clinical cardiac events (CE). Rates of RT-associated AEs were compared across treatment arms, and rates of CE were compared for +RT vs -RT patients within +H arms. All reported p-values are for chi-squared statistics. Results: With a median follow-up of 1.5 years, significant differences among arms in RT-associated AEs were not identified. No significant differences across arms in +RT patients existed in the incidence of skin reaction (p=0.78), pneumonitis (p=0.78), dyspnea (p=0.87), cough (p=0.54), esophageal dysphagia (p=0.26), or neutropenia (p=0.16). There was a significant difference in +RT patients in the incidence of leukopenia (p=0.02) with higher incidence rates in the arms receiving H. RT did not increase the frequency of CE. In the AC→T→H arm, the incidence of CE was 2.2% in +RT patients versus 2.9% in -RT patients. In the AC→TH→H arm, the incidence of CE was 1.5% in +RT patients versus 6.3% in -RT patients. No difference in CE was seen between left- and right-sided RT fields in +RT patients in either +H arm. Conclusion: Concurrent administration of adjuvant RT with H in early stage breast cancer patients is not associated with an increased incidence of acute RT AEs. Further follow-up is required to assess late AEs. No significant financial relationships to disclose.