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PURPOSE: To evaluate the outcome of patients with rhabdomyosarcoma (RMS) treated with complete surgical resection and multiagent chemotherapy, with or without local radiotherapy (RT). PATIENTS AND METHODS: Four hundred thirty-nine patients with completely resected (ie, group I) RMS were further treated with chemotherapy (vincristine and actinomycin D ± cyclophosphamide, doxorubicin, and cisplatin) on Intergroup Rhabdomyosarcoma Studies (IRS) I to III between 1972 and 1991. Eighty-three patients (19%) also received local RT as a component of initial treatment. RESULTS: Eighty-six patients relapsed (10-year failure-free survival [FFS] 79%, overall survival 89%). Six percent of failure sites were local, 6% were regional, and 7% were distant. Poor prognostic factors were tumor size greater than 5 cm, alveolar or undifferentiated histology, primary tumor sites other than genitourinary, and treatment on IRS-I or II. For patients with embryonal RMS who were treated with RT, there was a trend for improved FFS but no difference in overall survival. On IRS-I and II, patients with alveolar or undifferentiated sarcoma who received RT compared with those who did not receive RT had greater 10-year FFS rates (73% v 44%, respectively; P = .03) and overall survival rates (82% v 52%, respectively; (P = .02). Such patients who received RT on IRS III also benefited more than those who did not receive RT (10-year FFS, 95% v 69%; P = .01; overall survival, 95% v 86%; P = .23). CONCLUSION: Patients with group I embryonal RMS have an excellent prognosis when treated with adjuvant multiagent chemotherapy without RT. Patients with alveolar RMS or undifferentiated sarcoma fare worse; however, FFS and overall survival are substantially improved when RT is added to multiagent chemotherapy (IRS-I and II). The best outcome occurred in IRS-III, when RT was used in conjunction with intensified chemotherapy.

535 Background: Prior ARIES analyses showed that BV-treated mCRC patients (pts) receiving chemotherapy (CT)/biologics + BV within 2 months (mo) after 1st progressive disease (PD) had longer post-progression survival (PPS) than pts receiving only CT/biologics. The present analysis evaluated whether this effect of BV was consistent when used with common 2L CT regimens— irinotecan- (iri-) and oxaliplatin- (ox-) based—in mCRC pts exposed to 1L BV in ARIES. Methods: ARIES enrolled mCRC pts receiving 1L CT + BV. No tx regimens or assessments were protocol specified. This analysis evaluated 1L BV-treated mCRC pts who had PD, survived ≥2 mo after PD, and received 2L iri- or ox-based tx. PPS was estimated by Kaplan-Meier methods. Cox regression was used to estimate hazard ratios (HRs), while adjusting for covariates (eg, 1L time to progression). Results: Of 1550 1L pts in ARIES, 1074 had 1st PD and survived ≥2 mo after PD. Of these 1074, 390 and 114 received 2L iri- and ox-based tx, respectively, ± BV ( table ). Baseline characteristics were generally similar between groups. The incidence of targeted adverse events (TAEs) was as expected and similar between the BV and No BV groups over time. In pts receiving 2L iri- or ox-based CT tx, PPS in BV-treated pts was longer compared to those not on BV. Analyses may be limited by small pt numbers in some groups. Conclusions: Consistent with prior ARIES analyses, the continued use of BV after 1st PD was associated with prolonged PPS regardless of the 2L CT backbone used. [Table: see text]

249 Background: HA, a glycosaminoglycan in the tumor matrix, accumulates in 20-30% of solid tumors and ≥28%, ≥42% and ≥87% of colon, gastric and pancreatic ductal adenocarcinoma (PDA) tumors, respectively. Tumors that accumulate HA can develop high interstitial fluid pressure (IFP) and are resistant to chemotherapy. HA in human PDA is associated with disease progression and poor prognosis. In animal models, PEGPH20 reduced tumor-associated HA, tumor IFP and tumor growth, and increased efficacy of chemotherapy. Pharmacodynamic (PD) activity of PEGPH20 is being evaluated in Phase 1 (Ph1) trials. Methods: Two Ph1 studies in pts with advanced solid tumors refractory to prior therapy examined the safety, tolerability, PK, PD and MTD of single-agent IV PEGPH20. Dosing in Study 1 was 2x/wk and then reduced to q21d and in Study 2 is 1-2x/wk x 4wks and 1x/wk thereafter with dexamethasone pre-medication regimen. Biomarkers evaluated: Histochemistry to detect depletion of tumor HA, serum HA catabolites, Dynamic Contrast Enhanced (DCE)-MRI and FDG-PET. Results: In Study 1, the first 3 pts demonstrated musculoskeletal events (MSE; 2 pts dosed with 50 µg/kg 2x/wk, severe; 1 pt dosed with 0.5µg/kg 2x/wk, moderate) not predicted from GLP safety studies. The frequency of drug administration was reduced to q21d and the next 10 pts tolerated ≤1.5 µg/kg. In Study 2, dexamethasone pre-medication regimen was evaluated while dosing at 1-2x/wk. Nine pts were dosed ≤5.0 µg/kg. Doses ≤3.0 µg/kg administered 2x/wk were tolerated with intermittent Grade 1-2 MSE. Activity of PEGPH20 was reflected by increased HA serum catabolites. Pre- and post-dose biopsies from 2 colon pts demonstrated a 23-60% reduction in tumor HA after 4 wks of PEGPH20 dosing. DCE-MRI of PDA and FDG-PET of lung metastases increased tumor perfusion (Ktrans) and decreased metabolic activity 8 and 24hrs post-PEGPH20 dose and was still apparent after 4 wks of treatment with PEGPH20. Conclusions: Ongoing Ph1 studies have shown in vivo activity of PEGPH20 through HA plasma catabolites, tumor HA depletion, DCE-MRI and FDG-PET.

96 Background: In the last decade there has been an increase in the incidence of contralateral prophylactic mastectomy (CPM) for unilateral breast cancer. Although many factors have been proposed to explain this trend, the impact of breast reconstruction on the decision to undergo CPM has not been extensively studied. Methods: A retrospective review of breast cancer patients from Surveillance, Epidemiology and End Results (SEER) registry data (2004-2008) was conducted. Characteristics of patients undergoing CPM were evaluated. Results: 71,176 patients with a diagnosis of stage I-III infiltrating ductal or lobular breast cancer underwent mastectomy for their primary lesion. Among these, 10,558 patients (15%) underwent a CPM. A significantly higher proportion of women undergoing CPM had reconstruction performed (44%) than those patients not undergoing CPM (13%), p<0.001. On multivariate analysis (Table), significant variables predicting CPM included age <50 years (OR 10.12), breast reconstruction (OR 3.58), and lobular histology (OR 1.41), all p<0.001. Of the 12,466 patients (18%) who underwent reconstruction, 4,636 (37%) had implant reconstruction, 4,498 (36%) had tissue reconstruction, and 1,122 (9%) had combined tissue/implant reconstruction (no data for 18%). On multivariate analysis, predictors of reconstruction included age <50 years (OR 20.5; CI 18.5-22.7), year of surgery (2008 vs. 2004; OR 1.60; CI 1.49-1.71), low tumor grade (OR 1.19; CI 1.13-1.25) and ER+ status (OR 1.16; 95% CI 1.10-1.23). The use of radiation therapy was associated with a lower likelihood of pursuing reconstruction (OR 0.61; CI 0.58-0.65). Conclusions: Apart from age, the factor most strongly associated with CPM is the decision to have reconstructive surgery performed. This suggests that CPM may not be purely associated with risk-reduction but also with treatment factors such as cosmesis. [Table: see text]

147 Background: The Institute of Medicine recommends development of cancer survivorship care models that are patient centered. We designed a cross-sectional survey to determine the medical and psychosocial needs and preferences of breast cancer survivors. Methods: We identified a random sample, stratified by age and chemotherapy usage, of 600 women from MN, WI, and IA, ages 18-99, within 1-5 years of diagnosis of stage 0-3 breast cancer and seen at our institution. Results: We received 329 surveys (response rate 55%). Respondents were a mean age of 58 years (range 26-89) and a mean of 3.3 years from cancer diagnosis (range 1.2-5.4). 96% were white and stage distribution was: 15% stage 0, 35% stage 1, 32% stage 2, 15% stage 3, and 3% missing. Treatment included mastectomy (60%), lumpectomy (40%), radiation (61%), chemotherapy (55%) and hormonal therapy (50%). Most common treatment-related sequelae were neuropathy (38%), chest wall or arm pain (27%), and lymphedema (26%). Over half (52%) report worry and 45% report fatigue as a problem in the past week. 74% stated that their medical needs were met, whereas 49% said their psychological and spiritual needs were met (p<0.01). 68% understood the follow-up plan after treatment was complete. Perceived barriers to follow up care were anxiety (30%) and lack of coordination (10%). When queried about post-treatment care, the following aspects were considered important (% of patients ranking ≥7 on scale 0-10: 0=not important, 10=very important): breast/chest wall exam (88%); screening for osteoporosis (71%), colorectal cancer (69%), and heart disease (65%); educational materials (64%); mammography (63%); physical therapy (61%); diet and exercise counseling (60%); and complementary/alternative medicine information (53%). Less important were psychology (44%), gynecology (43%), chaplain services (35%), support groups (32%), social work (20%), and infertility experts (4%). 60% expressed interest in attending a survivorship clinic. Conclusions: This survey provides unique data on breast cancer survivors, and efforts should be made to optimize medical and psychosocial care in line with their needs and preferences. These results will be imperative in designing a wellness and survivorship clinic.

480 Background: COs associated with varying Tx patterns in mCRC pts are poorly understood because patterns diverge from the randomized trials (RCT). The RCTs of BV (Avastin) plus chemotherapy (CT) in mCRC pts continued BV until progressive disease (PD), even if CT was stopped/changed. Some RCTs of BV+CT in mCRC show ∼50% of pts stopping Tx early for reasons other than PD with possible lessening of benefit. It is unclear if this is due to use of a particular CT regimen or other practice pattern. While the beneficial effect of post-PD BV Tx has been shown in ARIES (HR 0.52 BBP vs No BBP) [A Cohn, ASCO 2010], the effect of stopping BV or CT before PD is unclear. ARIES, a community based observational study with a large cohort of 1st line BV-treated mCRC pts, will assess the COs associated with different 1st line Tx patterns (BV and CT) based on real world practice. Methods: ARIES enrolled mCRC pts receiving first- or second-line CT+BV. No Tx regimens or assessments are protocol specified. Data are collected prospectively at baseline (BL) and quarterly. Analyses included first-line pts with PD. Tx patterns of pts initially treated with FOLFOX/BV or FOLFIRI/BV are described and preliminary COs (PFS and OS) are estimated from K-M curves. Tx duration is calculated from enrollment date. Results: As of 2/5/10, 1,548 first-line mCRC pts enrolled (median follow up = 21 m); 1,133 pts had PD. Of 1,133 pts with PD, most had FOLFOX/BV (63%) or FOLFIRI/BV (16%) as first CT. BL characteristics were similar, but the FOLFOX/BV group had more stage 4 pts (74%). Main reasons for stopping BV include AE, max benefit achieved and CT holiday. Tx patterns and COs are in the table. Conclusions: ARIES first-line mCRC pts treated with FOLFOX/BV or FOLFIRI/BV had similar Tx patterns and COs despite the common opinion that they may differ in tolerability and possibly effectiveness. Additional analyses will assess the impact of stopping BV and/or CT before PD. [Table: see text] [Table: see text]

CRA3507 Background: FOLFOX is standard adjuvant therapy for stage III CC. Adding Cmab to FOLFOX benefits pts with metastatic CC WT KRAS tumors. N0147 assessed the potential benefit of Cmab added to FOLFOX. Methods: 21-56 days following resection and informed consent, KRAS status was centrally determined. Pts with wtKRAS CC were randomized to 12 biweekly cycles of oxaliplatin 85 mg/m2 d1, with leucovorin 400 mg/m2, 5FU 400 mg/m2 bolus IV, then 46-hr IV 5FU 2,400 mg/m2 on d1-2 (mFOLFOX6), without (arm A) or with Cmab (arm D) 250 mg/m2 d1&8, with Cmab at 400 mg/m2, cycle 1, d1. Primary endpoint was 3-yr disease free survival (DFS). Secondary endpoints included overall survival (OS) and toxicity. Planned accrual of 2,070 wtKRAS pts provided 90% power to detect hazard ratio (HR) of 1.33 with 2-sided α=0.05; with interim analyses after 25%, 50%, and 75% of planned events. Results: 1,760 wtKRAS pts (Arm A-858, Arm D-902) were enrolled at the time of closure; median follow-up on 1,624 pts is 15.9 months. Trial closed to accrual when preplanned interim analysis after 50% of planned events demonstrated no benefit to addition of Cmab. 3-yr DFS favored FOLFOX alone (HR 1.18, 95% CI 0.92-1.52; p=0.33). No benefit of Cmab was observed in any subgroups assessed. Any grade ≥ 3 AE, diarrhea, and failure to complete 12 cycles was significantly increased in arm D. Increased toxicity and greater differences in all outcomes were observed in pts aged ≥ 70 ( Table ). Conclusions: In this randomized phase III trial the addition of Cmab to mFOLFOX6 was of no benefit for pts with resected stage III wtKRAS CC. Supported by NIH Grant CA25224, Bristol-Myers Squibb, ImClone, Sanofi-Aventis, and Pfizer. [Table: see text] [Table: see text]

Purpose Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 (HER2) –targeted monoclonal antibodies, and trastuzumab emtansine (T-DM1) is an antibody–drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1. T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study. Methods In the MARIANNE study, 1,095 patients with centrally assessed, HER2-positive, advanced breast cancer and no prior therapy for advanced disease were randomly assigned 1:1:1 to control (trastuzumab plus taxane), T-DM1 plus placebo, hereafter T-DM1, or T-DM1 plus pertuzumab at standard doses. Primary end point was progression-free survival (PFS), as assessed by independent review. Results T-DM1 and T-DM1 plus pertuzumab showed noninferior PFS compared with trastuzumab plus taxane (median PFS: 13.7 months with trastuzumab plus taxane, 14.1 months with T-DM1, and 15.2 months with T-DM1 plus pertuzumab). Neither experimental arm showed PFS superiority to trastuzumab plus taxane. Response rate was 67.9% in patients who were treated with trastuzumab plus taxane, 59.7% with T-DM1, and 64.2% with T-DM1 plus pertuzumab; median response duration was 12.5 months, 20.7 months, and 21.2 months, respectively. The incidence of grade ≥ 3 adverse events was numerically higher in the control arm (54.1%) versus the T-DM1 arm (45.4%) and T-DM1 plus pertuzumab arm (46.2%). Numerically fewer patients discontinued treatment because of adverse events in the T-DM1 arms, and health-related quality of life was maintained for longer in the T-DM1 arms. Conclusion T-DM1 showed noninferior, but not superior, efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive, advanced breast cancer.