Background BRAF genomic alterations (GA) occur in multiple tumor types and BRAF/MEK targeted therapies are approved in melanoma and NSCLC. Diverse mechanisms of AR to these therapies have been proposed but have not been comprehensively assessed. Methods Hybrid-capture based comprehensive genomic profiling (CGP) was performed on FFPE (n = 228,629) or blood-based cell free DNA (cfDNA, n = 15,069) samples for 222,952 patients (pts). Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA. Samples without evidence of tumor DNA or known to have not received RAF/MEK inhibitors were excluded. Paired samples were collected >60 days apart (median 523, range 71-5571). Results Paired samples with BRAF V600E (64%) or other activating BRAF GA (36%) were available for 154 pts with NSCLC (20%), melanoma (19%), CRC (15%) myeloma (8.4%) glioma (7.1%) or other (30%) cancers. Acquired GA previously described preclinically or clinically including in BRAF, KRAS, NRAS, MEK1, PIK3CA, PTEN, MET, and CCND1 occurred in 34 cases (Table). 56 additional cases had reportable acquired GA in other genes (eg. STK11, NF1). Median TMB was 4.0 vs 5.2 mut/Mb in the first vs second sample (p = 0.23). In 12% of cases (9 tissue, 9 cfDNA) a BRAF GA was not detected in the second sample. Most AR mechanisms (MET amp, KRAS mut, secondary BRAF GA) were tumor agnostic, but PIK3CA and PTEN GA were enriched in brain samples and absent in CRC, and NRAS mut were exclusive to melanoma (Table). Treatment status was available for a subset of cases. Notably V600E CRC, NSCLC and melanoma each had acquired MET amp post-dabrafenib + trametinib, and a V600E myeloma had acquired MEK C121S post-trametinib + vemurafenib. Additional clinical data will be presented. Table: 1878PD . Potential AR mechanism No. cases# AR subtypes Disease Histologies Associated Primary BRAF GA Biopsy location * KRAS mut 7 G12D (2), G12R, G12V, G13D, Q61H, K117N CRC (2), NSCLC (2), cholangiocarcinoma, multiple myeloma, CLL V600E (6), G466A omentum (2), liver NRAS mut 4 G12C, G13R, G13R/Q61H, Q61H/K melanoma (4) V600E (2), V600R, G469A brain (1), lymph node (1), soft tissue (1) NRAS amp 1 amp estimated copies: 41 NSCLC V600E pericardial fluid Secondary BRAF GA 10 N-terminal deletion exons 2-8 (6), duplications exons 10-18, L505H, N581I/D594G, amp estimated copies: 6 NSCLC (4), CRC (2), melanoma (2), multiple myeloma, pancreatic V600E (9), G466A liver (3), lymph node (2), lung, abdominal wall, brain MEK1 mut 1 C121S multiple myeloma V600E NA PIK3CA mut 5 H1047R (2), G1049R, R88Q, S405F glioma (3), NSCLC, thyroid V600E (3), N486_T491>K, R506_K507insVLR brain (4), lung PTEN GA 5 E7fs * , R130 * , G129R, splice site 165-1G>A, loss melanoma (2), glioma, NSCLC, UP neuroendocrine V600E, V600K, R506_K507insVLR, KHDRBS2-BRAF fusion brain (2), abdomen, soft tissue CCND1 amp 2 amp estimated copies: 9, 10 NSCLC, thyroid V600E, G464V brain, pleural fluid MET amp 4 amp estimated copies: 12, 14, 15, 56 NSCLC, CRC, melanoma, UP adenocarcinoma V600E (4) lymph node, colon, brain, liver * Indicated for tissue samples only (NA= not applicable); #5 cases had AR alterations in multiple genes included here; NSCLC: non-small cell lung cancer, CRC: colorectal carcinoma; CLL: chronic lymphocytic leukemia; UP: unknown primary; AR: acquired resistance; mut: mutation; amp: amplification. Conclusions Novel and previously observed potential AR alterations in paired BRAF altered clinical samples were detected using CGP. Most AR mechanisms appeared independent of tumor type and biopsy site. Additional clinical studies to explore effective treatments for these AR subsets are needed. Legal entity responsible for the study The authors. Funding Foundation Medicine. Disclosure F. Pietrantonio: Advisory / Consultancy: Roche; Advisory / Consultancy: Amgen; Advisory / Consultancy: Eli-Lily; Advisory / Consultancy: Bayer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Servier; Advisory / Consultancy: Merck Serono. J. Lee: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. L. Boussemart: Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre. G. Srkalovic: Speaker Bureau / Expert testimony: Foundation Medicine. R. Madison: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. J.S. Ross: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. V.A. Miller: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche; Advisory / Consultancy: Revolution Medicines. B.M. Alexander: Leadership role, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. S.M. Ali: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. A.B. Schrock: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. All other authors have declared no conflicts of interest.

Abstract BACKGROUND: Genomic signatures are revolutionizing the definition, identification, and treatment of breast cancer subtypes. The ability of genomic signatures to enable fine grained stratification of breast cancers to the granular disease level is still generally untested because of the difficulties in aggregating large clinical data sets. In order to stratify breast cancers into actionable subtypes both the full genome data and clinical data must be collected for patients at scale. DESIGN & METHODS: FLEX is designed as a novel, large-scale, population based, prospective registry. All patients with stage I-III breast cancer who receive MammaPrint (MP) or BluePrint (BP) testing on a primary breast tumor are eligible. FLEX utilizes an adaptive design which enables additional study arms at low incremental effort and cost by allowing targeted substudies to be added. Patients who are enrolled in the initial study will also be eligible for inclusion in any additional study arm where they meet all criteria. Additional study arms and substudies may be investigator-initiated. SPECIFIC AIMS: Primary: Create a big-data registry of full genome expression data and clinical data to investigate new gene associations with prognostic and/or predictive value. Secondary: Generate hypotheses for targeted subset analyses and trials based on full genome data. To date the following substudies have been proposed: DR. JENNIFER A. CROZIER, BAPTIST MD ANDERSON CANCER CENTER (1) MP and BP in male breast cancer TYPE: SUBSTUDY; NO ADDITIONAL CONSENT (ICF) REQUIRED. ARMS: ALL (2) MP BP evaluation in breast cancer patients ≥70. TYPE: SUBSTUDY; NO ADDITIONAL ICF REQUIRED. ARMS: ALL (3) FG evaluation in ILC. TYPE: SUBSTUDY; NO ADDITIONAL ICF REQUIRED. ARMS: ALL (4,5) MP BP relation to PR positivity, Ki67. TYPE: SUBSTUDY; NO ADDITIONAL ICF REQUIRED. ARMS: ALL (6) MP BP in metaplastic breast cancer. TYPE: SUBSTUDY; NO ADDITIONAL ICF REQUIRED. ARMS: ALL DR. ADAM M. BRUFSKY, UNIVERSITY OF PITTSBURGH MEDICAL CENTER MAGEE WOMENS HOSPITAL (1) Response to standard chemotherapy regimens in clinically ER+/PR+/HER2+ (triple positive) patients according to BP molecular subtypes. (2) Expression signatures by response to bisphosphonates in ER+ patients receiving adjuvant therapy, or for osteoporosis after primary treatment. (3) Gene expression in breast cancer patients with obesity. TYPE: SUBSTUDY; DUAL ICF UTILIZED. ARMS: NEOADJUVANT AND ADJUVANT DR. IAN GRADY, NORTH VALLEY BREAST CLINIC Impact of genomic risk classification on travel time to receive breast cancer care. TYPE: SUBSTUDY; NO ADDITIONAL ICF REQUIRED. ARMS: ALL DR. THOMAS LOMIS, VALLEY BREAST CARE Complementary data collection for patients participating in the ODM-201 trial. FLEX provides gene expression for exploratory and signature discovery. TYPE: COMPLEMENTARY; DUAL ICF UTILIZED. ARM: NEOADJUVANT DR. PAT WHITWORTH, NASHVILLE BREAST CENTER Genomic reclassification of large tumors eligible to receive NCT therapy. TYPE: SUBSTUDY; NO ADDITIONAL ICF REQUIRED. ARM: NEOADJUVANT ELIGIBILITY, ACCRUAL FLEX will enroll a minimum of 10000 patients aged ≥18 with stage I-III breast cancer who sign ICF. Enrollment began April 2017 and 623 patients have been enrolled as of June 2018. Citation Format: Brufsky AM, Crozier JA, Grady I, Lomis T, Whitworth P, Rehmus E, Srkalovic G, Lee L, Blumencranz P, Baron P, Mavromatis B, Untch S, Blumencranz L, Yoder EB, Audeh W, FLEX Investigators Group. MammaPrint, BluePrint, and full-genome data linked with clinical data to evaluate new gene expression profiles (FLEX) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-13-01.

Abstract Background: IMPACt is a prospective, case-only study to measure the effect of MammaPrint (MP) and BluePrint (BP) on treatment decisions in breast cancer patients. Here, we report the results of the primary objective in women aged ≥18 years with histologically proven invasive stage I-II, hormone receptor (HR) positive, and HER2-negative breast cancer. Methods: The study included 369 women from 18 US institutions. The recommended treatment plan was captured before and after receiving results for MP and BP. Treatment was started after obtaining results. In addition to the effect of results on physician treatment decisions involving chemotherapy (CT) and physician confidence, the distribution of MP High Risk (HR) and Low Risk (LR) patients was also evaluated. Results: MP classified patients to 62% (n=228) LR and 38% (n=141) HR. Treatment decisions were changed for 25% (n=92) of women after receiving MP and BP results. Of the LR patients initially prescribed CT, 68% (45/66) had CT removed from their treatment recommendation. Of the HR patients who initially were not prescribed CT, 66% (42/64) had CT added. Overall, 89% (202/228) of LR patients did not receive CT, and likewise 84% (119/141) of HR patients did receive CT after receiving MP. Among those who did not change treatment (n=277), 68% of physicians reported having greater confidence in their prescribed therapy. Conclusions: The IMPACt trial shows MP generates a 25% overall treatment change in clinical practice. The highest impact is for women with LR results, where 68% are spared chemotherapy in favor of endocrine therapy alone. Additionally, 73% of physicians report having higher confidence in treatment decisions for their patient after MP. Table 1: Treatment changesTreatment Decision Pre- to Post-MPMP HRMP LRTotalCT to CT772198no CT tp CT42547CT to no CT04545no CT to no CT22157179Total141228369 Citation Format: Soliman H, Rehmus E, Shah V, Srkalovic G, Mahtani R, Levine E, Mavromatis B, Srinivasiah J, Kassar M, Gabordi R, Yoder E, Qamar R, Audeh W, IMPACt Investigators Group I. IMPACt trial: MammaPrint and BluePrint molecular subtyping guide treatment decisions in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-13-04.

Purpose/Objective(s)The addition of Bevacizumab (Bev) to conventional treatment of newly diagnosed Glioblastoma (GBM) in RTOG 0825 was not associated with improved clinical benefit or survival (OS or PFS). Given that a proposed mechanism of action of Bev centers on normalization of tumor vasculature it remains unknown if Bev preferentially benefits GBM patients with subtotal resection (STR) who are more likely to have intact tumor vasculature. We conducted a secondary analysis exploring the impact of Bev on Neurocognitive Function (NCF), Quality of life (QOL), and symptom burden in newly diagnosed GBM patients with a STR.Materials/MethodsPatients enrolled in RTOG 0825 who participated in the net clinical benefits (NCB) component were included in the analysis. Objective NCF [Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test (TMT), and Controlled Oral Word Association (COWA)] and select components of patient reported outcomes (symptom burden-MDASI-BT and HRQOL-EORTC QLQ30-BN20) data from RTOG 0825 were analyzed. Patients with surgeon defined STR were examined for response to treatment with Bev in an unplanned secondary analysis. Changes from baseline to week 22 were examined by Wilcoxon test to assess differences between STR patients receiving placebo and STR patients receiving Bev.ResultsFive hundred eight patients who participated in the NCB were analyzed with STR identified in 183 patients (36%). A total of 94 patients with STR were treated with placebo on the control arm as compared with 89 patients treated with Bev. Clinical and demographic characteristics were well balanced with regard to age, gender, KPS, neurologic function, MGMT methylation status, RPA class, tumor location, and steroid use. When the median change score was analyzed from baseline to 22 weeks, there was no difference in changes in NCF or HRQOL for those patients with STR who received Bev as compared with STR who received placebo. STR patients receiving Bev relative to patients receiving placebo demonstrated a smaller degree of improvement from baseline to 22 weeks in symptom severity as measured by the MDASI-BT (median reduction in symptom burden of -0.3 vs -0.7, P = .032) and symptom interference scores (median reduction in symptom interference of -0.3 vs -0.7, P = .047).ConclusionNewly diagnosed patients with STR of GBM receiving Bev on RTOG 0825 did not demonstrate greater improvement in objective testing, symptom burden or HRQOL. In contrast to hypotheses, the addition of Bev resulted in significantly less improvement in self-reported symptom burden and interference in daily life. This data demonstrates an absence of significant benefit to Bev use as compared with placebo, despite including only those patients with STR.Acknowledgment(s)This project was supported by grants U10CA21661, U10CA37422, U10CA180868, U10CA21661, UG1CA189867 from the National Cancer Institute (NCI) and Genentech. Purpose/Objective(s)The addition of Bevacizumab (Bev) to conventional treatment of newly diagnosed Glioblastoma (GBM) in RTOG 0825 was not associated with improved clinical benefit or survival (OS or PFS). Given that a proposed mechanism of action of Bev centers on normalization of tumor vasculature it remains unknown if Bev preferentially benefits GBM patients with subtotal resection (STR) who are more likely to have intact tumor vasculature. We conducted a secondary analysis exploring the impact of Bev on Neurocognitive Function (NCF), Quality of life (QOL), and symptom burden in newly diagnosed GBM patients with a STR. The addition of Bevacizumab (Bev) to conventional treatment of newly diagnosed Glioblastoma (GBM) in RTOG 0825 was not associated with improved clinical benefit or survival (OS or PFS). Given that a proposed mechanism of action of Bev centers on normalization of tumor vasculature it remains unknown if Bev preferentially benefits GBM patients with subtotal resection (STR) who are more likely to have intact tumor vasculature. We conducted a secondary analysis exploring the impact of Bev on Neurocognitive Function (NCF), Quality of life (QOL), and symptom burden in newly diagnosed GBM patients with a STR. Materials/MethodsPatients enrolled in RTOG 0825 who participated in the net clinical benefits (NCB) component were included in the analysis. Objective NCF [Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test (TMT), and Controlled Oral Word Association (COWA)] and select components of patient reported outcomes (symptom burden-MDASI-BT and HRQOL-EORTC QLQ30-BN20) data from RTOG 0825 were analyzed. Patients with surgeon defined STR were examined for response to treatment with Bev in an unplanned secondary analysis. Changes from baseline to week 22 were examined by Wilcoxon test to assess differences between STR patients receiving placebo and STR patients receiving Bev. Patients enrolled in RTOG 0825 who participated in the net clinical benefits (NCB) component were included in the analysis. Objective NCF [Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test (TMT), and Controlled Oral Word Association (COWA)] and select components of patient reported outcomes (symptom burden-MDASI-BT and HRQOL-EORTC QLQ30-BN20) data from RTOG 0825 were analyzed. Patients with surgeon defined STR were examined for response to treatment with Bev in an unplanned secondary analysis. Changes from baseline to week 22 were examined by Wilcoxon test to assess differences between STR patients receiving placebo and STR patients receiving Bev. ResultsFive hundred eight patients who participated in the NCB were analyzed with STR identified in 183 patients (36%). A total of 94 patients with STR were treated with placebo on the control arm as compared with 89 patients treated with Bev. Clinical and demographic characteristics were well balanced with regard to age, gender, KPS, neurologic function, MGMT methylation status, RPA class, tumor location, and steroid use. When the median change score was analyzed from baseline to 22 weeks, there was no difference in changes in NCF or HRQOL for those patients with STR who received Bev as compared with STR who received placebo. STR patients receiving Bev relative to patients receiving placebo demonstrated a smaller degree of improvement from baseline to 22 weeks in symptom severity as measured by the MDASI-BT (median reduction in symptom burden of -0.3 vs -0.7, P = .032) and symptom interference scores (median reduction in symptom interference of -0.3 vs -0.7, P = .047). Five hundred eight patients who participated in the NCB were analyzed with STR identified in 183 patients (36%). A total of 94 patients with STR were treated with placebo on the control arm as compared with 89 patients treated with Bev. Clinical and demographic characteristics were well balanced with regard to age, gender, KPS, neurologic function, MGMT methylation status, RPA class, tumor location, and steroid use. When the median change score was analyzed from baseline to 22 weeks, there was no difference in changes in NCF or HRQOL for those patients with STR who received Bev as compared with STR who received placebo. STR patients receiving Bev relative to patients receiving placebo demonstrated a smaller degree of improvement from baseline to 22 weeks in symptom severity as measured by the MDASI-BT (median reduction in symptom burden of -0.3 vs -0.7, P = .032) and symptom interference scores (median reduction in symptom interference of -0.3 vs -0.7, P = .047). ConclusionNewly diagnosed patients with STR of GBM receiving Bev on RTOG 0825 did not demonstrate greater improvement in objective testing, symptom burden or HRQOL. In contrast to hypotheses, the addition of Bev resulted in significantly less improvement in self-reported symptom burden and interference in daily life. This data demonstrates an absence of significant benefit to Bev use as compared with placebo, despite including only those patients with STR. Newly diagnosed patients with STR of GBM receiving Bev on RTOG 0825 did not demonstrate greater improvement in objective testing, symptom burden or HRQOL. In contrast to hypotheses, the addition of Bev resulted in significantly less improvement in self-reported symptom burden and interference in daily life. This data demonstrates an absence of significant benefit to Bev use as compared with placebo, despite including only those patients with STR.

Abstract Introduction: CTC are detectable in approximately 75% of patients with metastatic breast cancer (MBC), and are elevated (≥5CTC/7.5 ml whole blood (WB)) in about half. Elevated CTC at baseline are associated with a worse prognosis, and a decline in CTC levels suggests response to therapy. We initiated a prospective randomized clinical trial (SWOG S0500) to test whether a change in chemotherapy after failure to clear CTC after one cycle of first line chemotherapy would improve outcomes of patients starting first line cytotoxic chemotherapy for MBC. Methods: Patients initiating first-line chemotherapy for MBC were enrolled. All patients had measurable or evaluable disease that included bone metastases. Patients with elevated CTC at baseline and who continued to have elevated CTC after 21 days of therapy were randomly assigned to either continue initial therapy until progression or to change to a second line chemotherapy (physician choice) immediately at cycle 2. Patients with elevated CTC at baseline, which were not elevated at the 21-day follow-up were maintained on their initial therapy. Patients without elevated CTC at baseline were followed in an observation arm. The primary endpoint was overall survival, and progression-free survival was a secondary endpoint. It was expected that approximately 500-650 patients would have to be screened to enroll 120 patients in the randomized trial. Power was 81% with 2-sided α = 0.05 to detect a 70% increase in median overall survival for patients randomized to change therapy. Three interim analyses were planned during the course of the trial. Results: From 10/1/2006 until 3/15/2012, 624 patients were registered of whom 612 were eligible. A baseline CTC was obtained in 593 (97%) eligible patients of whom 317 (53%) had elevated CTC at baseline. Thirty-one patients (10%) with elevated baseline CTC did not complete the follow-up CTC due to death, progression, withdrawal, or assay failure. Of the 286 remaining patients, 123 patients (43%) continued to have elevated CTCs after the first cycle of chemotherapy and were randomly assigned to either maintain original chemotherapy (n = 64) or switched to new chemotherapy (n = 59). Final outcome results will be analyzed in October 2013 and will be reported if released by the SWOG Data Safety Monitoring Board. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-07.

This report describes an unusual case of cyclin D1 expression by an otherwise typical follicular lymphoma, of low histological grade. BCL2-IGH and CCND1-IGH fusions were identified by interphase fluorescence in situ hybridisation.

e19517 Background: The multikinase inhibitor sorafenib targets several serine/threonine and receptor tyrosine kinases by blocking RAF kinase, a critical component of the RAF/MEK/ERK signaling pathway regulated by the Ras oncogene, which is mutated both in primary patient samples and in human MM lines (35–50%). As the frequency of these mutations increases with advancing disease and increasing drug resistance, inhibition of the RAF/MEK/ERK signaling pathway, as well the angiogenic VEGFR-2/PDGFR beta cascade by sorafenib may be a useful new approach for the treatment of MM. Methods: SWOG evaluated the effect of sorafenib as a single agent in relapsed/refractory MM patients. In this phase II study we assessed response rate, overall (OS) and progression-free survival (PFS) as well as toxicities associated with this treatment. Twenty-three heavily pretreated MM patients were enrolled in the study. Sorafenib was started at oral dose of 400 mg daily until progression or toxicity. This dose was based on the label for metastatic renal cell carcinoma. Results: The study was closed as planned due to lack of efficacy in first 18 patients who were assessable for toxicity and response. Three patients experienced Grade 4 toxicity consisting of thrombocytopenia, anemia and renal failure. 8 cases suffered Grade 3 toxicities including thrombocytopenia, neutropenia, anemia, hand-foot syndrome, diarrhea and dyspnea. No responses were observed. 3 patients had stable disease (2.4–15.9 months) and the remainder progressed. Median PFS is one month, and OS at 12 months is 50%. Conclusions: Thus, single agent sorafenib did not show activity in this group of heavily pretreated MM patients previously exposed to bortezomib. As the frequency of RAS oncogene mutations increases resulting in resistance to traditional chemotherapeutic agents as well as possibly supporting cytokine resistance to immune modulators, sorafenib might have a supportive role in combination therapy with bortezomib, lenalidomide or everolimus in relapsed/refractory MM which is currently being evaluated in ongoing studies. No significant financial relationships to disclose.

15089 Background: Although it is agreed that patients with stage III disease benefit from adjuvant treatment, whether all patients with stage II disease should receive such treatment remains debatable. In this study we analyzed factors influencing survival of patients with Stage II colon cancer seen and treated at Sparrow Hospital from February 1996 till January 2006. Methods: Included in the analysis were: age, gender, stage (IIA vs. IIB), surgery type, number of examined lymph nodes, pathological grade, tumor size and the use of chemotherapy. All survival analyses were performed using SAS system (V9.3, Cary NC). Results: Analysis was done on 187 patients with Stage II colon cancer age 71± 13 years (29 to 97). 108 patients were female (58 %) and 79 (42 %) males. Subtotal collectomy was performed on 134 (71 %), partial and total collectomy and partial resection on 37 (20%), 13 (7%) and 3 (2%) patients, respectively. Average number of removed lymph nodes was 18 ± 13 (1–103). Chemotherapy treatment ( 5-FU ± leucovorin) was given to 45 (24 %) patients, while the rest (142, 76 %) were followed expectantly. The mean length of follow up for all patients was 48 ± 33 months (0.1 - 133) and 56 ± 33 (0.2 - 133) for survivors. There were 85 deaths (45 %) recorded during the follow up. Overall survival for all patients was 90% at 12, 82% at 24 and 56% at 60 months mark. Of all analyzed risk factors only age exhibits a statistically significant relationship to survival (HR = 1.05, 95% CI = 10.3 - 1.07, p < 0.001). Treatment with chemotherapy showed definite trend toward superior survival with risk of dying from colon cancer been reduced by 42% (HR = 0.58, CI = 0.33–1.03). However, it was not statistically significant ( p=0.06). Number of removed lymph nodes was also showing possible relationship to the survival, although again not statistically significant (HR = 0.98, CI = 0.33–1.03, p=0.07). Other investigated factors were not significant correlates. Conclusions: In conclusion, our analysis showed that chemotherapy could potentially be beneficial for the survival of patients with Stage II colon cancer. In addition it seems that number of resected lymph nodes could be survival factor not only in Stage III, but also in Stage II disease. However, the most important factor for survival is still age of the patients No significant financial relationships to disclose.

14601 Continued efforts to improve local control and to maximize sphincter preservation in patients with rectal carcinoma led to consideration of preoperative chemoradiation. The purpose of this retrospective study is to examine clinical outcomes and find out which prognostic factors are related to survival in patients treated with neoadjuvant chemoradiation in Sparrow Hospital from 1998–2003. Forty two patients with biopsy proven rectal carcinoma without evidence of extra pelvic spread were treated in this fashion. Radiation therapy was administered for a total dose of 5.00 cGy. Chemotherapy used was 5-FU in 37 patients, and in combination with leucovorin in additional 5 patients. Surgical treatments performed were abdominoperineal resection (23 pts), low anterior resection in 13 pts., transanal excisions (2 pts), 2 patients had only exploratory laparotomy and for 2 patients records were not available. Cox proportional hazards regression techniques were used to estimate survival rates. Univariate and multivariate Cox proportional hazards analyses were used to evaluate relationship between risk factors and the survival. The SAS system (V9.1.3, Cary NC) was used for all analyses. Out of 42 patients analyzed 25 were males and 17 females. Mean age was 65 years (range 31 - 85). Median follow-up time was 57 months with a range from 7 to 98 months. After the surgery 4 patients had complete response, 12 were stage I, 10 stage II, 12 patients stage III, one patient had metastatic disease and for 2 patients records were inadequate. Analysis of disease free survival showed actuarial 5-year disease free survival to be 59%. Actuarial 5-year overall survival was 67%. Median overall survival was still not reached, while median disease-free survival is 78 months . Univariate and multivariate analyses showed that only postoperative stage was associated significantly with overall survival. Specifically, there was an increase in the risk of mortality of just over 3-fold for each increment in post-operative stage. In conclusion, in the community settings preoperative chemoradiation seem to provide good overall and disease free survival for patients with rectal cancer. Postoperative stage appears to be the most important prognostic factor for the survival. No significant financial relationships to disclose.

BACKGROUND. Bortezomib, a first-in-class proteasome inhibitor, has shown clinical activity in relapsed, refractory multiple myeloma in a pivotal Phase 11 trial, SUMMIT.METHODS. Patients received bortezomib 1.3 mg/m(2) on Days 1, 4, 8, and 11 followed by a 10-day rest period for up to 8 cycles. Dexamethasone 20 mg on the day of and the day after bortezomib was permitted for suboptimal response. Extended treatment beyond 8 cycles was offered to patients whose physicians felt they would benefit from additional therapy. Follow-up was conducted in all patients for a median of 23 months, an additional 13 months from the original report.RESULTS. Of 202 patients enrolled in SUMMIT, 193 were evaluable for response. Seven (4%) patients achieved a complete response, 12 (6%) achieved a nearly complete response, 34 (18%) achieved a partial response, and 14 (7%) had a minimal response while on bortezomib. The updated median duration of response to bortezomib alone was 12.7 months. The median overall time to progression for all SUMMIT patients was 7 months. For responding patients, the median time to progression was 13.9 months, whereas for those with progressive disease (PD) or who were not evaluable, the median time to progression was 1.3 months. The median overall survival (OS) for all SUMMIT patients was 17.0 months. Whereas the median OS for patients with PD or who were not evaluable was 8 months, the median OS for responding patients was not reached at 23 months of follow-up.CONCLUSIONS. These data demonstrate that treatment with bortezomib results in meaningful long-term benefit for patients with relapsed and refractory myeloma.

BACKGROUND:Lenalidomide is active and well tolerated in relapsed and refractory multiple myeloma. We conducted a phase I/II trial of the combination of lenalidomide and chemotherapy to evaluate the safety and efficacy of the combination.METHODS:The 62 patients enrolled received liposomal doxorubicin 40 mg/m(2) i.v. and vincristine 2 mg i.v. on day 1, dexamethasone 40 mg p.o. on days 1-4 (DVd), and lenalidomide on days 1-21 in 28-day cycles. Primary end points were maximum tolerated dose (MTD) of lenalidomide with DVd chemotherapy and overall response rate (ORR) by Southwest Oncology Group criteria of the combination.FINDINGS:The median age was 62 years, 70% of patients were males and 65% had refractory multiple myeloma. The MTD of lenalidomide with DVd chemotherapy was 10 mg and the dose-limiting toxicity was non-neutropenic sepsis. After 7.5 months of median follow-up, the ORR of the combination was 75%, with 29% of patients achieving a complete or near complete remission. The median progression-free survival was 12 months, while the median overall survival has not yet been reached.INTERPRETATION:The combination of lenalidomide and DVd chemotherapy was well tolerated and resulted in high response rates in this mostly refractory patient population. Evaluation of this combination in newly diagnosed patients is warranted.

Bortezomib, a first‐in‐class proteasome inhibitor, has shown clinical activity in relapsed, refractory multiple myeloma in a pivotal Phase II trial, SUMMIT.

Bortezomib, a first‐in‐class proteasome inhibitor, has shown clinical activity in relapsed, refractory multiple myeloma in a pivotal Phase II trial, SUMMIT.

OBJECTIVE:To study the efficacy of daily low-dose aspirin (81 mg orally) in decreasing the incidence of venous thromboembolic events (VTEs) in patients with multiple myeloma receiving pegylated doxorubicin, vincristine, and decreased-frequency dexamethasone, plus thalidomide (DVd-T).PATIENTS AND METHODS:In this phase 2 clinical trial of DVd-T, conducted by the Cleveland Clinic Foundation from August 2001 to October 2003, 105 patients were enrolled. The first 35 patients experienced increased numbers of VTEs. von Willebrand levels and platelet aggregation to ristocetin before and after treatment with DVd-T increased significantly, suggesting a pathophysiology involving platelet-endothelial interaction. Aspirin was added to the regimen, thus generating 3 patient groups: group 1 received aspirin from the start of DVd-T treatment before the study began (58 patients), group 2 received aspirin after the start of DVd-T treatment and after the study began (26 patients), and group 3 did not receive daily low-dose aspirin during the study (19 patients). Two patients being treated with warfarin for other indications were excluded from the study. The primary end point for this study was the incidence of VTE in the form of either deep venous thrombosis or pulmonary embolism. Secondary end points were the time to the first VTE, time to the composite end point of death or first VTE, and incidence of bleeding complications.RESULTS:After a median follow-up of 24 months, on an intent-to-treat basis, 26 posttreatment VTEs occurred after a median of 90 days, with 19% occurring in group 1, 15% in group 2, and 58% in group 3. Following multivariate time-to-event analysis, aspirin use continued to be associated with lower relative risk of VTE (hazard ratio, 0.22; confidence interval, 0.10-0.47; P<.001) and of the composite end point (hazard ratio, 0.28; confidence interval, 0.15-0.51; P<.001).CONCLUSION:Daily low-dose aspirin (81 mg orally) given to patients with newly diagnosed and relapsed/refractory multiple myeloma who were receiving DVd-T reduced the incidence of VTEs without an increase in bleeding complications.

BACKGROUND. Bortezomib, a first-in-class proteasome inhibitor, is active with manageable toxicities in relapsed and/or refractory myeloma,METHODS. Bortezomib 1.0 or 1.3 mg/m(2) was administered Days 1, 4, 8, and 11 every 21 days for tip to 8 cycles to patients with relapsed and/or refractory myeloma participating in two Phase II trials. Dexamethasone IIcould be added because of progressive disease after 2 cycles or stable disease after 4 cycles. Continuation of or retreatment with bortezomib was offered to patients who, in the investigator's opinion, would benefit from extended treatment.RESULTS. Sixty-three patients with relapsed/refractory myeloma treated in this extension trial received a median of 7 additional cycles of therapy, for a total of 14 cycles (range, 7-32) over a median duration of therapy of 45.1 weeks in the parent and extension studies. Seventy-eight percent of patients completed this study at the same or higher bortezomib dose than they started on during this study, and the treatment schedule of twice-weekly administration remained unchanged in 89%. Overall, 75% of patients received dexamethasone in combination with bortezomib for a median of 5 cycles starting either in the parent or extension study. The safety profile was similar between the extension mid parent trials, with no evidence of new cumulative toxicity. The most commonly reported Grade 3/4 toxicities were thrombocytopenia (29%), with a consistent pattern of recovery during the rest period of each cycle, diarrhea (11%), anemia (11%), and neutropenia (10%). Neuropathy was reported less frequently.CONCLUSIONS. Retreatment with or continuation of bortezomib +/- dexamethasone beyond 6 months was safe, and toxicities were manageable, in patients with relapsed and/or refractory myeloma. (c) 2005 American Cancer Society.

BACKGROUND:Bortezomib is a potent, reversible proteasome inhibitor that has been approved for the treatment of recurrent and/or refractory multiple myeloma, but its activity in patients with renal impairment has not been studied to date. METHODS:Response rates, safety, and 20S proteasome activity were assessed in relation to baseline creatinine clearance (CrCl) among patients with recurrent and/or refractory myeloma (n = 256 patients) who were treated with bortezomib in 2 Phase II trials. Bortezomib was administered by intravenous bolus on Days 1, 4, 8, and 11 of a 21-day cycle at 2 doses, 1.0 mg/m2 (n = 28 patients) and 1.3 mg/m2 (n = 228 patients). RESULTS:Of 10 patients with CrCl < or = 30 mL/minute, 7 patients completed the protocol-specified 8 cycles of treatment; 4 patients received the 1.3 mg/m2 bortezomib dose, and 3 patients received the 1.0 mg/m2 bortezomib dose. Using the European Group for Blood and Marrow Transplantation criteria, responses were assigned by an independent committee to 3 of the 10 patients (2 partial responses and 1 minimal response), a response rate similar to that of the overall treated population. Patients with CrCl > 80 mL/minute (n = 105 patients), 51-80 mL/minute (n = 99 patients), and < or = 50 mL/minute (n = 52 patients) had similar rates of discontinuation and similar adverse event profiles. Renal function did not appear to affect the 1-hour postdose proteasome inhibition or its recovery. CONCLUSIONS:Clinical experience in a limited number of patients with impaired renal function suggests that bortezomib provides clinical benefit with manageable toxicities in this high-risk population.

New options are needed for the treatment of B-cell chronic lymphocytic leukemia (CLL). Proteasome inhibitors represent a potential therapeutic strategy. One such agent, bortezomib, was recently approved for the treatment of refractory multiple myeloma. In this study, lymphocytes were isolated from the blood of CLL patients, treated in vitro with bortezomib, and evaluated for apoptosis by flow cytometry. Bortezomib promoted apoptosis in CLL cells in a dose- and time-dependent manner. At 18h incubation time, 10nM bortezomib induced an average 4.27 fold (+/−2.57) increase in the percentage of apoptotic cells versus untreated controls. These data indicate that bortezomib has in vitro activity in CLL and support further investigations of this promising new drug.

ATO is a novel anticancer agent whose unique multifaceted mechanisms of action offer a scientific rationale for investigation in different hematologic malignancies. 2 phase II studies of ATO in advanced, heavily treated MM reported ≥25% decrease(40–50% of treated pts) in serum M-protein concentrations. Data from both studies suggest that long term therapy might result in enhanced quality of responses. It has been shown that ATO sensitizes myeloma cells to Dex in-vitro and AA potentiates the effect of ATO on different myeloma and human cell lines. We therefore initiated a phase II trial combining ATO with Dex & AA. MM pts with active, progressive disease who failed < 2 different regimens were eligible for enrollment. SWOG response criteria was used to assess efficacy to therapy. Treatment regimen consisted of 12 weeks (wks) treatment blocks with the 1st block considered induction, containing intense steroid schedule, and 1–2 more 12 wks blocks for consolidation with reduced steroid schedule. Regimen details;Cycle 1:Wk 1, loading with ATO at 0.25mg/kg IV d1-5,AA 1000mg IV within 30 minutes after each ATO infusion & Dex 40 mg orally d1-4. Wks 2 through 12; ATO at 0.25mg/kg IV twice weekly,AA 1000mg IV within 30 minutes after each ATO infusion & Dex 40 mg orally d11–14,29–32,39–42,57–60,& 67–70. Wks 13 through 15, is a rest period. Cycles 2 & 3 are the same as cycle 1 except Dex frequency is reduced to once a month (m) as follows;Dex 40 mg orally d1–4,29–32,57–60,& 67–70. Pts achieving SD or better were initiated on maintenance with the regimen administered for 5 wks with a 2m break and steroids given once a month. 20 pts were enrolled & evaluable for response and toxicity. Median age is 64,β2 microglobulin 3.2mg/dl & median serum albumin is 3.85. Six,7,2 & 5 patients were on study for a median duration of 58, 151, 351 and 511 days respectively.17 pts were taken off study;14 for disease progression,1 for grade 4 painful neuropathy,1 for refusal of therapy &1 developed colon cancer. Median survival for the 14 pts alive is 18.3 m (2.5–24.2). The regimen was well tolerated with 6 pts experiencing either grade 3 hyperglycemia, headaches, burning at IV site, neutropenia, dehydration, syncope, or fatigue. 1 patient experienced grade 4 painful neuropathy and was taken off study with the event resolving in 4 wks without any therapy. 3/5 pts who proceeded to maintenance decided against the 3rd consolidation cycle because of travel logistics, absence of further reduction of protein, or normalization of performance status. The most common cause to reduce the number of loading dose days and the biweekly treatment during maintenance is grade 2 paraesthesia that resolved with dose reduction. 8 pts achieved >50% reduction of the m-protein following cycle 1 of therapy;2CR,1NCR,5PR,10SD & 3PD. None of the pts but 1 showed further improvement in the m-protein after the1st cycle of therapy. Mean duration of therapy was 1.9 years. TAD results in an over all response rate of 45% & 85% SD or better with a mean survival of 18.3 months. Further expansion of the study to confirm this data is warranted, and utilizing the complementary mechanism of action of other immunomodulatory agents such as thalidomide with this regimen is ongoing.