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Under current AJCC staging criteria, stage IIC patients paradoxically have worse outcomes than IIIA patients despite the lack of nodal metastatic disease. This study sought to identify additional clinicopathologic characteristics correlated with worse patient outcomes. Retrospective chart review of stage IIC and IIIA melanoma patients were evaluated between 1995 and 2011 with clinical follow-up through 2015. Records were reviewed for demographics, clinical characteristics, and tumor pathology. Fisher's exact test and Wilcoxon's rank-sum test were used to assess group differences. Clinicopathologic features were evaluated relative to overall survival (OS), time to distant metastases, and local/regional recurrence. Overall, 128 patients were included (45 stage IIC and 83 stage IIIA) with a median follow-up time of 5.7 years. Compared with stage IIIA patients, stage IIC patients were older, and their melanomas were more likely to be nodular, amelanotic, thicker, have higher mitotic rate, tumor lymphocytic infiltrate, no radial growth phase, and less likely to have associated precursor lesions. Stage IIC patients had shorter OS and time to distant metastases; multivariate regression revealed that older age (>55 years) and mitotic rate (>5 mitoses/mm) were independent predictors of OS. Melanomas in stage IIC disease may be biologically distinct from those that are seen in stage IIIA. While sentinel node biopsies remain the standard-of-care, these results suggest that clinicians may want to assess the clinicopathologic characteristics described above to aggressively counsel, screen for distant disease, and consider adjuvant therapy, in particular for older patients and higher mitotic rates in thicker primary tumors, regardless of nodal status.

Although targeted sequencing improves outcomes for many cancer patients, it remains uncertain how somatic and germ-line whole-exome sequencing (WES) will integrate into care. We conducted surveys and interviews within a study of WES integration at an academic center to determine oncologists’ attitudes about WES and to identify lung and colorectal cancer patients’ preferences for learning WES findings. One-hundred sixty-seven patients (85% white, 58% female, mean age 60) and 27 oncologists (22% female) participated. Although oncologists had extensive experience ordering somatic tests (median 100/year), they had little experience ordering germ-line tests. Oncologists intended to disclose most WES results to patients but anticipated numerous challenges in using WES. Patients had moderately low levels of genetic knowledge (mean 4 correct out of 7). Most patients chose to learn results that could help select a clinical trial, pharmacogenetic and positive prognostic results, and results suggesting inherited predisposition to cancer and treatable noncancer conditions (all ≥95%). Fewer chose to receive negative prognostic results (84%) and results suggesting predisposition to untreatable noncancer conditions (85%). The majority of patients want most cancer-related and incidental WES results. Patients’ low levels of genetic knowledge and oncologists’ inexperience with large-scale sequencing present challenges to implementing paired WES in practice. Genet Med 18 10, 1011–1019.

Background. Tissue from research biopsies provides access to insights into tumor biology. We aimed to determine medical oncologists’ (MOs’) attitudes toward research biopsies in patients with metastatic breast cancer (MBC). Materials and Methods. A total of 309 breast MOs from National Cancer Institute (NCI)-designated cancer centers were invited to complete a self-administered survey about their attitudes toward approaching patients for research purpose-only biopsies (RPOBs), performed as a standalone procedure, or additional biopsies, performed with a clinically indicated biopsy. The MOs were asked to predict what proportion of their MBC patients would consider undergoing research biopsies. Results. Of the 309 MOs, 221 (72%) responded. Of these 221 MOs, 30 were ineligible, leaving 191 eligible responders. Nearly all the MOs reported they were comfortable approaching patients regarding research biopsies of blood or skin. One fifth of MOs were uncomfortable approaching patients for RPOBs of the breast. One half of MOs were uncomfortable approaching patients for RPOBs of the liver. A significant variation was found in the perceptions by MOs of their patients’ willingness to undergo research biopsies. The factors associated with increased comfort in approaching patients for research biopsies included fewer years in practice, caring for patients who had undergone recent research biopsies, and the predicted willingness of patients to consent to biopsies. The risk of a biopsy and biopsy-related pain were the most common reasons for reluctance to refer patients for research biopsies. Conclusion. Significant variation exists, even at NCI centers, in the comfort level of MOs in approaching MBC patients for research biopsies. MOs’ attitudes toward research biopsies might be a modifiable factor in increasing tissue collection for research. Implications for Practice: Tissue-based research is critical in advancing our understanding of cancer biology, and obtaining tissue from a research biopsy provides an essential resource. This study demonstrates the variability of oncologists’ attitudes toward research biopsies and elicits factors associated with increased comfort levels with approaching patients for research biopsies. Biopsy risk and biopsy-related pain were commonly cited reasons not to refer patients for research biopsies. If the risk of a research biopsy is deemed sufficiently low enough to be acceptable, oncologists’ attitudes might be a potential target for education and change, which may assist in increasing the availability of tissue for cancer research.

Background: Patients (pts) with breast cancer treated with neo-adjuvant therapy on clinical trials are often asked to consent to pre-treatment and on-treatment research biopsies. There is increasing interest in obtaining tissue samples at similar time points in pts treated with neo-adjuvant therapy outside of clinical trials. However, medical oncologists’ (MOs) attitudes towards approaching pts about research biopsies in this setting are unknown. Methods: Three hundred and nine academic breast MOs identified from websites of the National Cancer Institute (NCI) – designated cancer centers were asked to complete a survey either by paper or online. Eligible MOs (MOs who saw breast cancer pts and who saw pts >4 hours/week.) were asked to predict what proportion of their pts with newly diagnosed, non-metastatic breast cancer would consent to research purposes only biopsies (RPOBs) i.e., biopsies with no clinical benefit to pt. Median values are reported. Two-sided Fisher’s exact test was used to compare categorical variables using a α level of .05. Results: Of 221 (101F,85M, 5 unknown) MOs who completed the survey, 30 MOs were ineligible (response rate=221/309,72%). Median age was 50 (Range 33-80). Median years of oncology experience was 15 (Range 1-45). MOs predicted that 14%, 63% and 21% of their pts would definitely/probably, maybe, probably not/definitely not consent to a RPOB of the breast. Forty-one percent, 34%, 19%, 3% of MOs were very comfortable, somewhat comfortable, somewhat uncomfortable, and very uncomfortable asking pts to consent to RPOBs respectively. The only factor associated with increased comfort discussing an RPOB was MOs’ years in practice. MOs with fewer years (15 years) (Adjusted RR=1.2, p =0.02). Gender, number of pts enrolled onto clinical trials, and MOs with pts who had research biopsies in the last 3 months was not associated with increased comfort. MOs who were more comfortable in approaching pts for RPOBs were associated with estimating a larger proportion of their pts as willing to undergo RPOB. For example, nearly one third of MOs who were very comfortable with approaching pts for RPOBs estimated that greater than 50% of their pts would consent to research biopsies. In contrast, nearly all the MOs who were very uncomfortable with approaching pts for RPOBs estimated that less than 25% of their pts would consent to research biopsies. The 3 most common reasons why MOs were reluctant to consent pts for a RPOB include pain/discomfort of a biopsy (59%), risk of a biopsy procedure complication, (44%), and inconvenience to the pt (33%). Conclusions: Academic breast MO’s predicted that fewer than 1 in 5 women with newly diagnosed, non-metastatic breast cancer would definitely or probably agree to a request for an RPOB outside of the context of a therapeutic trial, and approximately one-quarter of MOs expressed discomfort in approaching pts for such procedures. Our results have important implications regarding the feasibility of such research efforts, and identify potential barriers to target for intervention. Citation Format: Davinia SE Seah, Sarah Scott, Hao Guo, Julie Najita, Ruth Lederman, Elizabeth Frank, Jessica Sohl, Zsofia Stadler, Stuart G Silverman, Jeffrey Peppercorn, Eric P Winer, Steve E Come, Nancy U Lin. Attitudes of medical oncologists towards research breast biopsies in patients with newly diagnosed stage I-III breast cancer not enrolled in a clinical trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-17-01.

Background: Understanding is an important goal of the informed consent process in research. We sought to assess the interrater reliability (IRR) and concurrent validity of two measures of understanding in child and young adult subjects and their parents. Methods: We conducted a cross-sectional survey and interview-based study of children and young adults participating in a clinical trial for cancer, along with one parent per child or young adult subject. We estimated the IRR of the Semi-Structured Comprehension Interview (SSCI) and the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR). We also estimated concordance between the SSCI, the MacCAT-CR, and the Quality of Informed Consent (QuIC). Results: For our sample of 32 subjects (16 parent–child pairs), IRR estimates were high for total score on the SSCI (intraclass correlation coefficient [ICC] = 0.88, 95% confidence interval [CI] = 0.76–0.94), as well as on the understanding (ICC = 0.93, 95% CI = 0.86–0.97) and reasoning (ICC = 0.97...

Background: There is increasing interest in studying tissue from patients (pts) with metastatic breast cancer (MBC). Historically, limited tissue has been available. Possible barriers to research biopsies (bx) include pt and provider opinions; the contribution of each factor is unknown. Methods: 309 academic breast medical oncologists (MOs) identified from the websites of each of the National Cancer Institute - designated cancer centers were invited to complete either a self-administered paper or online survey. Eligible MOs (MOs who saw breast cancer pts and who saw pts 4 hours/week.) were asked to predict what proportion of their pts with MBC would consent to additional bx (ABs, additional bx performed with a clinically indicated bx) or research purposes only bx(RPOBs, research bx performed as a standalone procedure). They were also asked about their comfort levels in asking pts with MBC to consider participating in ABs or RPOBs for various organs. Median values are reported. Two-sided Fisher's exact test was used to compare categorical variables using a a level of .05. Results: 191 (101F,85M, 5 unknown) eligible MOs completed the survey. 29 MOs were ineligible (response rate = 191/280,68%). Median age was 50 (Range 33-80). Median years of oncology experience was 15 (Range 1-45). MOs predicted that 90%, 75%, 70% and 50%, of their pts would definitely/probably consider ABs of blood, skin, breast, or liver respectively. MOs predicted that 90%, 60%, 33%, and 20% of their pts would definitely/probably consider RPOBs of blood, skin, breast, or liver. 98% (95% CI 96%-100%), 96% (95% CI 92%-98%), 93% (95% CI 88%-96%) and 70% (95% CI 63%-77%) of MOs were very/somewhat comfortable asking pts for an AB of blood, skin, breast and liver respectively. 98% (95% CI 95%-99%), 93% (95% CI 89%-96%), 78% (95% CI 72%-84%) and 50% (95% CI 43%-58%) of MOs were very/somewhat comfortable asking pts to participate in a RPOB of blood, skin, breast and liver respectively. No demographic characteristics (eg. sex, age) were associated with MOs’ comfort levels of asking pts to have an AB of blood, skin and breast. Factors associated with increased comfort discussing an AB of the liver were: age < 50 years (p = 0.01), in practice for < 15 years (p = 0.01), ≥ 1 pt enrolled on clinical trials per month (p = 0.02), or having pts who had undergone bx for research in prior 3 months (p MOs with ≥ 4 patients enrolled on clinical trials/month or whose pts had undergone research bx in the past 3 months were more likely to feel comfortable asking pts to have a RPOB of the breast (p The 3 most common reasons why MOs were reluctant to refer pts for participation in an AB include risk of a bx procedure (n = 128, 67%), pain/discomfort of a bx (n = 125, 65%), and logistical barriers (n = 42, 22%). These reasons are similar for RPOB; risk of a bx procedure, (n = 137, 72%), pain/discomfort of a bx (n = 134, 70%), and inconvenience to pt (time involved, travel, etc) (n = 58, 30%). Conclusions: Many MOs predict that the majority of their MBC pts will consider ABs of various organs. However, this decreases with RPOBs, particularly as the procedure becomes more invasive. More research is needed to understand factors that may influence MOs’ comfort levels asking pts to participate in such studies. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-19-01.

Background Trastuzumab is associated with improvements in overall survival (OS) among patients with HER2-positive metastatic breast cancer (MBC); however disease course and patterns of care in individual patients are highly variable. Methods 113 HER2-positive patients diagnosed with MBC from 1999 to 2005 who received trastuzumab-based therapy were retrospectively identified to allow for a minimum of 5 years of follow-up time. Median OS and median duration of therapy were determined using Kaplan–Meier methodology and group comparisons were based on the log-rank test. Hazard ratios (HR) were obtained using a Cox proportional hazards model. Results Median OS was 3.5 years (95% CI 3.0–4.4) from time of initiation of first therapy in the metastatic setting. On univariate analysis, central nervous system (CNS) disease at first recurrence was associated with a shorter OS compared with liver and/or lung metastases or other sites (CNS: 1.9 years CI 0.1–5.9, liver/lung: 3.2 years CI 2.5–4.2, other: 4.6 years CI 2.7–8.0; p = 0.05), however, this was not predictive of survival outcome in multivariate analysis. CNS metastases developed in 62 (55%) patients by the time of death or last follow-up. Median duration of therapy was similar up to 6 lines of treatment, and ranged from 5.2 months to 7.2 months. Conclusions The natural history of HER2-positive MBC has evolved with trastuzumab-based therapy with median OS now exceeding 3 years. CNS disease is a major problem with continued risk of CNS progression over time. Patients demonstrate clinical benefit to multiple lines of HER2-directed therapy.

Previous studies have shown decreased pregnancy rates and early menopause in female cancer survivors; however, infertility rates and reproductive interventions have not been studied. We investigated infertility and time to pregnancy in female childhood cancer survivors, and analysed treatment characteristics associated with infertility and subsequent pregnancy.The Childhood Cancer Survivor Study (CCSS) is a cohort study including 5 year cancer survivors from 26 Canadian and US institutions who were younger than 21 years at the time of diagnosis between Jan 1, 1970, and Dec 31, 1986, and a sibling control group. We included women aged 18-39 years who had ever been sexually active. We gathered demographic, medical, and reproductive data via a baseline questionnaire, and quantified exposure to alkylating agents and radiation therapy. Self-reported infertility, medical treatment for infertility, time to first pregnancy in survivors and siblings, and the risk of infertility in survivors by demographic, disease, and treatment variables were analysed.3531 survivors and 1366 female sibling controls who enrolled between Nov 3, 1992, and April 4, 2004, were included. Compared with their siblings, survivors had an increased risk (relative risk [RR] 1·48 [95% CI 1·23-1·78]; p0·0001) of clinical infertility (ie,1 year of attempts at conception without success), which was most pronounced at early reproductive ages (RR 2·92 [95% CI 1·18-7·20], p=0·020, in participants ≤24 years; 1·61 [1·05-2·48], p=0·029, in those aged 25-29 years; and 1·37 [1·11-1·69], p=0·0035, in those aged 30-40 years). Despite being equally likely to seek treatment for infertility, survivors were less likely than were their siblings to be prescribed drugs for treatment of infertility (0·57 [95% CI 0·46-0·70], p0·0001). Increasing doses of uterine radiation and alkylating agent chemotherapy were strongly associated with infertility. Although survivors had an increased time to pregnancy compared with their siblings (p=0·032), 292 (64%) of 455 participants with self-reported clinical infertility achieved a pregnancy.A more comprehensive understanding of infertility after cancer is crucial for counselling and decision making about future conception attempts and fertility preservation.National Cancer Institute, American Lebanese Syrian Associated Charities, Swim Across America.

ObjectiveTo evaluate the relationship between recently trained paediatricians' ethics knowledge and exposure to a formal ethics or professionalism curriculum during residency.MethodsWe conducted a cross-sectional survey of recently trained paediatricians which included a validated 23-item instrument called the Test of Residents' Ethics Knowledge for Pediatrics. The sample included paediatricians who completed medical school in 2006–2008, whose primary specialty was paediatrics or a paediatric subspecialty, and who completed paediatric residency training in 2010–2011. This sample was stratified based on residency programme variables: presence of a formal curriculum in ethics or professionalism, programme size and American Board of Pediatrics certifying exam passage rate. Paediatricians were randomly selected from each stratum for survey participation.ResultsAmong the 370 responding paediatricians (55%), the mean knowledge score was 17.3 (SD 2.2) out of a possible 23. Presence of a formal curriculum in ethics and/or professionalism was not significantly associated with knowledge. Knowledge was lowest on items about parental requests for a child to undergo genetic testing (2 items, 44% and 85% incorrect), preserving patient confidentiality over email (55% incorrect), decision-making regarding life-sustaining technologies (61% incorrect), and decision-making principles such as assent and parental permission (2 items, 47% and 49% incorrect).ConclusionsThis study highlights several areas in which paediatricians' knowledge may be low and that are amenable to targeted educational interventions. These findings should prompt discussion and research among ethicists and educators about how ethics and professionalism curricula can more consistently influence paediatricians' knowledge.

Public health concerns over the occurrence of developmental abnormalities that can occur as a result of prenatal exposure to drugs, chemicals, and other environmental factors has led to a number of developmental toxicity studies and the use of the benchmark dose (BMD) for risk assessment. To characterize risk from multiple sources, more recent analytic methods involve a joint modeling approach, accounting for multiple dichotomous and continuous outcomes. For some continuous outcomes, evaluating all subjects may not be feasible, and only a subset may be evaluated due to limited resources. The subset can be selected according to a prespecified probability model and the unobserved data can be viewed as intentionally missing in the sense that subset selection results in missingness that is experimentally planned. We describe a subset selection model that allows for sampling pups with malformations and healthy pups at different rates, and includes the well-known simple random sample (SRS) as a special case. We were interested in understanding how sampling rates that are selected beforehand influence the precision of the BMD. Using simulations we show how improvements over the SRS can be obtained by oversampling malformations, and how some sampling rates can yield precision that is substantially worse than the SRS. We also illustrate the potential for cost saving with oversampling. Simulations are based on a joint mixed effects model, and to account for subset selection, use of case weights to obtain valid dose-response estimates.

Background: In the era of molecularly targeted therapy, developing an understanding of the molecular basis of cancer is a principal or secondary goal of many research studies. For this reason, studies collecting tissue for research purposes are increasingly common. Understanding patients' attitudes towards research biopsies may lead to improvement in accrual to research biopsy studies. Methods: Patients with metastatic breast cancer from two academic and two community hospitals completed a self-administered paper survey consisting of 29 questions in clinic to evaluate their willingness to consider providing additional biopsies (additional biopsy performed with a clinically indicated biopsy) and research purposes only biopsies (RPOB) (research biopsy performed as a stand alone procedure). Results: 160 patients (n = 80 academic, n=80 community) completed the survey, with a response rate of 98%. As expected, demographic variables differed between sites, with patients from academic sites likely to be younger (p = 0.01), more educated (p = 0.002), employed (p = 0.01), have prior trial participation (P In univariate analyses of patients' willingness to have additional biopsies, patients in academic sites were more likely to agree to additional biopsies than those at community sites (RR = 1.2, 95% CI 1.0–1.5, p = 0.03). Statistically significant differences based on demographic characteristics such as age, education, marital status, prior trial participation, number of prior biopsies, and travel time were not observed. For RPOB, patients having had more prior biopsies were less likely to consider research biopsies (RR = 0.6, 95% CI 0.4–1.0, p = 0.03). The following variables did not reach statistical significance: type of practice, age, education, marital status, prior trial participation, and travel time. Patients' willingness in both academic and community sites to consider RPOB declined with more invasive biopsies. Although differences were observed, none were statistically significant between academic and community; skin (56%, 65%), bone marrow (30%, 27%), breast (43%, 49%) or liver (24%, 19%). Of the 13/160 (8%) patients who would not consider additional biopsies, the most common reasons cited included pain or discomfort (n = 8/13, 62%), risk of biopsy (n = 8/13, 62%) and anxiety related to the biopsy (n = 6/13, 46%). Of the 37/160 (23%) patients who would not consider RPOB, the most common reasons cited included pain or discomfort (n = 23/37, 62%), risk of biopsy (n = 15/37, 41%) and inconvenience of the procedure to the patient (n = 13/37, 35%). Conclusions: The majority of patients in this study indicated they would consider research biopsies, with a larger proportion willing to consider additional biopsies; patients seen at academic hospitals were more likely to consider additional biopsies compared to those seen at community hospitals. Breast cancer patients' willingness to undergo research biopsies may be higher than generally expected by clinicians and may not be the primary barrier to obtaining research biopsies. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-16-04.

Background Women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) can respond to multiple lines of anti-HER2 therapy. It is unknown whether these patients will derive further clinical benefit following treatment with trastuzumab-MCC-DM1 (T-DM1). Patients and methods: We retrospectively identified HER2-positive MBC patients treated with T-DM1 and characterized outcomes during subsequent lines of anti-HER2 therapy. Response was determined by a blinded radiology review. Time-dependent analyses were carried out using Kaplan–Meier estimates. Results We identified 23 patients treated with single-agent T-DM1 and report on the 20 patients who discontinued protocol therapy. All patients received trastuzumab-based metastatic therapy before initiation of T-DM1 [median 7 regimens (range 3–14)]. Of these 20 patients, 75% (15 of 20) received further therapy with or without anti-HER2 agents after discontinuing T-DM1. Partial response to either first- or second-subsequent line(s) of therapy was seen in 5 of 15 (33%) treated patients, including 33% (4 of 12) who received a regimen containing trastuzumab and/or lapatinib. Median durations of therapy to first- and second-subsequent regimens after T-DM1 were 5.5 and 6.4 months, respectively. Conclusions In heavily pretreated HER2-positive MBC patients, prior exposure to T-DM1 does not exhaust the potential benefit of ongoing anti-HER2 therapy with trastuzumab- and/or lapatinib-based regimens.

Background Patients (pts) with (w/) node-negative HER2−positive BCA have a higher risk of recurrence than those with node-negative HER2−negative disease. Several randomized trials have shown the benefit of chemotherapy (most with an anthracycline) and trastuzumab (H) for pts with node-positive and high-risk node-negative BCA. However, the benefit of chemotherapy and H needs to be further explored in the node-negative group. Due to the 2–4% risk of symptomatic congestive heart failure (CHF) with an anthracycline-based treatment (Rx) followed by H, we set out to conduct a study of a taxane-based Rx with H in a node-negative population. Design: This is a single arm, multicenter, phase II study of paclitaxel (T) (80 mg/m2) and trastuzumab (H) x 12 weekly (w) (4 mg/kg load →2 mg/kg) → H x 52 w (2 mg/kg weekly or 6 mg/kg q 3 w). Pts with HER2−positive BCA (IHC 3 + or FISH amplified at ≥ 2.0) with negative nodes (micrometastasis later allowed) and with a tumor size ≤ 3 cm were enrolled. The primary endpoint is disease-free survival. Secondary endpoints include the incidence of G 3/4 left ventricular systolic dysfunction or congestive heart failure (CHF). Pts had serial left ventricular ejection fraction (LVEF) monitored at baseline (BSLN), and at month (mo) 3, mo 6, and mo 12 w/a multigated acquisition scan or echocardiogram. H was held for significant asymptomatic (Asx) LVEF ↓ (10-15% ↓ from BSLN and < lower limit of normal or ≥ 16% ↓ from BSLN), and H was stopped for CHF. Results: From 10-9-2007 to 9-3-2010, 406 pts were enrolled. The median (med) age was 55 years (range 23–84 years); 118/406 (29%) had hypertension and 30/406 (7%) had diabetes. As of 6-1-2011, 307 are reported as off Rx of which 261 have completed protocol therapy; 99 remain on therapy. To date, 100%, 94%, 84%, and 83% of pts had LVEF monitoring at BSLN, mo 3, mo 6, and mo 12. The med LVEF at BSLN was 65% (range 50%-81%), at mo 3 was 64% (range 45%-81%), at mo 6 was 64% (range 45%-81%), and at mo 12 was 65% (range 37%-90%). Two pts had CHF; 1 pt had CHF at mo 11 (LVEF was 55% at BSLN and 37% w/CHF event) and 1 pt had CHF at mo 6 (LVEF was 66% at BSLN and 49% w/CHF event). To date, 13 pts had H held for significant Asx LVEF ↓; details on those who had appropriate LVEF recovery and had H restarted will be provided. All patients will have completed 12 mo of Rx by October 2011, and an accurate report of the incidence of CHF will be available. Conclusion: This represents the cardiac report of pts receiving TH as adjuvant Rx for node-negative (micrometastasis allowed) HER2 positive BCA. Both the CHF events and number of pts w/H hold due to significant Asx ↓ LVEF appear low. Overall, the serial med LVEFs remain stable throughout the 12 mo of Rx. Final data on all 406 pts will be available in December 2011. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-18-02.

Background We evaluated the safety and efficacy of L+T in pts with 0–2 prior lines of chemotherapy (CT) for HER2+ MBC. In the context of this phase II trial, we evaluated metabolic response by FDG-PET and explored the relationship between metabolic response and clinical outcomes. Methods: Pts with measurable, HER2+ MBC were eligible. Cohort 1: No prior T, L, or CT +T for MBC, and >1 yr from adjuvant T, if received. Cohort 2: 1–2 prior lines of CT for MBC, including T, or relapse within 1 yr of adjuvant T. Pts received L 1,000 mg QD + T (2 mg/kg weekly or 6 mg/kg Q3W). Staging studies were done with CT or MRI at baseline (BL) and every 2 cycles (1 cycle=4 weeks [wks]). Objective response was assessed by local investigator according to RECIST 1.0. FDG-PET/CT was performed at BL, Wk 1, and Wk 8 per NCI guidelines. Central quality assurance, review, and analysis were performed on FDG-PET studies. Up to 5 target lesions were identified on BL FDG-PET images based on hypermetabolic uptake. Percent change in the summed maximum standardized uptake value (SUVmax) of target lesions was calculated at Wk 1 or Wk 8, compared to BL. Metabolic response was assessed according to EORTC criteria for % change in SUVmax (progressive disease [PD]: ≥25% increase; partial response [PR]: ≥25% decrease; stable disease [SD]: Results: 87 pts were registered to the study. Of these, one pt did not begin protocol therapy and one pt did not have MBC on further testing, and are not included. 81/85 pts had FDG-PET data at Wk 1; 75/85 had data at Wk 8. Metabolic PR at Wk 1 was observed in 28/39 (72%) pts in Cohort 1 and 20/42 (48%) pts in Cohort 2. Metabolic PR at Wk 8 was observed in 27/34 (79%) pts in Cohort 1 and 18/41 (44%) pts in Cohort 2. Wk 1 and Wk 8 metabolic responses were similar. In cohort 1, 18/28 (64%) pts who achieved Wk 1 metabolic PR had clinical benefit by RECIST. Of pts with Wk 1 metabolic SD, 2/9 (22%) had clinical benefit. In cohort 2, 9/20 (45%) pts who achieved Wk 1 metabolic PR had clinical benefit; 5/22 (23%) who achieved Week 1 metabolic SD had clinical benefit. Exploratory analysis of progression-free survival (PFS) showed that pts in Cohort 1 who achieved Wk 1 metabolic PR experienced a median PFS of 9.3 months ([mos]; 95% CI 5.6−22.3); for pts with metabolic SD, median PFS was 1.9 mos (95% CI 0.8−5.5). For pts in Cohort 2, Wk 1 metabolic PR was associated with median PFS of 5.6 mos (95% CI 3.7−7.8), whereas for pts with metabolic SD, median PFS was 3.7 mos (95% CI 1.8−5.5). Conclusions: L+T is associated with a high rate of early and sustained metabolic response by FDG-PET. Exploratory analyses suggest that metabolic PR may be associated with clinical benefit and longer PFS. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-07.

Observational studies demonstrate an association between physical activity and improved outcomes in breast and colon cancer survivors. To test these observations with a large, randomized clinical trial, an intervention that significantly impacts physical activity in these patients is needed. The Active After Cancer Trial (AACT) was a multicenter pilot study evaluating the feasibility of a telephone-based exercise intervention in a cooperative group setting. Sedentary (engaging in

We sought to evaluate the survival of patients who received breast surgery prior to any other breast cancer therapy following a metastatic diagnosis. Standard treatment for stage IV breast cancer is systemic therapy without resection of the primary tumor. Registry-based studies suggest that resection of the primary tumor may improve survival in stage IV cancer. We performed a retrospective analysis using data from the National Comprehensive Cancer Network (NCCN) Breast Cancer Outcomes Database. Patients were eligible if they had a metastatic breast cancer diagnosis at presentation with disease at a distant site and either received surgery prior to any systemic therapy or received systemic therapy only. Eligible patients who did not receive surgery were matched to those who received surgery based on age at diagnosis, ER, HER2, and number of meta-static sites. To determine whether estimates from the matched analysis were consistent with estimates that could be obtained without matching univariate and multivariable analyses of the unmatched sample were also conducted. There were 1,048 patients in the NCCN database diagnosed with stage IV breast cancer from 1997 to 2007. 609 meta-static breast cancer patients were identified as eligible for the study. Among the 551 patients who had data available for matching, 236 patients who did not receive surgery were matched to 54 patients who received surgery. Survival was similar between the groups with a median of 3.4 years in the nonsurgery group and 3.5 years in the surgery group. The groups were similar after adjusting for the presence of lung metastases and use of trastuzumab therapy (HR = 0.94, CI 0.83–1.08, P = 0.38). When matching for the variables associated with a survival benefit in previous studies, surgery was not shown to improve survival in the stage IV setting for this subset

Background: Women with HER2-positive metastatic breast cancer (MBC) can have clinical responses to multiple lines of anti-HER2 therapy. However, it is unknown whether these patients will derive further clinical benefit following treatment with the novel antibody-drug conjugate trastuzumab-MCC-DM1 (T-DM1), which has significant activity in trastuzumab-refractory breast cancer. Methods: We retrospectively identified patients treated with T-DM1 monotherapy on clinical trials for HER2-positive MBC at Dana-Farber Cancer Institute and characterized clinical outcomes during subsequent lines of anti-HER2 therapy. Response was determined by an independent and blinded radiology review using modified RECIST 1.1 criteria without confirmatory scans; patients without radiologic assessment were considered non-responders. Duration of therapy was defined from initiation of therapy until treatment discontinuation, and for patients continuing on therapy, times were censored at date of last visit; analysis was performed using Kaplan-Meier estimates. Results: We identified 23 patients treated on protocol-based therapy with single-agent TDM-1 and report on the 20 patients who had discontinued protocol, and hence, T-DM1 therapy. All patients received trastuzumab in the metastatic setting prior to initiation of T-DM1, with a median number of 6 (range 1-14) prior regimens. Most (75%) were taken off study secondary to progressive disease and the remainder discontinued therapy for toxicity. Of these 20 patients, 75% (15 of 20) received further therapy with or without anti-HER2 agents after concluding T-DM1; reasons for not receiving additional treatment after T-DM1 include death (3) and interruption of therapy due to physician or patient request (2). The majority (12 of 15; 80%) of patients treated beyond T-DM1 received a regimen containing either trastuzumab and/or lapatinib at some point during their course. Partial response to either first-or second-subsequent line(s) of therapy was seen in 5 of 15 (33%) treated patients, including 33% (4 of 12) who received a regimen containing trastuzumab and/or lapatinib (Figure 1). Three patients did not have radiographic assessments; however, all 3 demonstrated clinically stable disease (as determined by review of clinical data) to first treatment after T-DM1. Median duration of therapy to first-subsequent regimen after T-DM1 was 5.5 months. Of the 9 patients that received a second-subsequent regimen, the median duration of therapy to the second-subsequent treatment was 6.4 months. Conclusions: In heavily pretreated HER2-positive MBC patients, prior exposure to T-DM1 does not exhaust the potential benefit of ongoing anti-HER2 therapy with trastuzumab and/or lapatinib-based regimens. Maximum Decrease in Target Lesion Diameter Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-08.

BACKGROUND: Female survivors of therapeutic chest radiation often question whether they will have difficulty with breast feeding, given their prior exposure to breast radiation. In the current study, the rates of successful breastfeeding in long-term survivors who received chest radiotherapy (CXRT) as a treatment for Hodgkin lymphoma (HL) were examined. METHODS: A survey study of survivors of HL who were treated at the Joint Center for Radiation Therapy in Boston from 1969 through 1996 was performed. Patients were queried about childbearing and breastfeeding. The authors analyzed self-reported breastfeeding success in women who reported live births after CXRT and compared them with a sibling control group. RESULTS: Overall, 83 female survivors of HL who were treated with CXRT reported at least 1 birth after treatment. There were a total of 141 post-HL pregnancies resulting in births. In these women, the median age at the time of the HL diagnosis was 23 years (range, 14-40 years) and the median radiation dose was 41 grays (Gy) (range, 27-46 Gy). For survivors, 57 of the 94 (61%) breastfeeding attempts were successful, whereas within the control group, 74 of the 94 (79%) attempts were successful (P = .044). Accounting for maternal age at first birth and birth era, multivariable analysis suggested that HL survivors treated with CXRT may be less likely to breastfeed successfully than their siblings (odds ratio, 0.42; 95% confidence interval, 0.2-1.0 [P = .06]). CONCLUSIONS: The majority of female HL survivors who were treated with CXRT report being able to breastfeed successfully. However, the results of the current study indicate a trend toward less successful breastfeeding in survivors as a previously unreported late effect of radiation. Cancer 2010. © 2010 American Cancer Society.

Purpose To evaluate risk of suicide ideation (SI) after childhood cancer, prevalence of SI in a cohort of adult survivors of pediatric cancers was compared with prevalence in a sibling comparison group. The relationship of SI to cancer treatment and current health was examined, and the hypothesis that poor physical health is significantly associated with suicidality, after adjusting for depression, was specifically tested. Methods Nine thousand one hundred twenty-six adult survivors of childhood cancer and 2,968 siblings enrolled onto the Childhood Cancer Survivor Study completed a survey describing their demographics and medical and psychological functioning, including SI in the prior week. Results Of survivors, 7.8% reported SI compared with 4.6% of controls (odds ratio = 1.79; 95% CI, 1.4 to 2.4). Suicidality was unrelated to age, age at diagnosis, sex, cancer therapy, recurrence, time since diagnosis, or second malignancy. SI was associated with primary CNS cancer diagnosis, depression, and poor health outcomes including chronic conditions, pain, and poor global health rating. A logistic regression analysis showed that poor current physical health was significantly associated with SI even after adjusting for cancer diagnosis and depression. Conclusion Adult survivors of childhood cancers are at increased risk for SI. Risk of SI is related to cancer diagnosis and post-treatment mental and physical health, even many years after completion of therapy. The association of suicidal symptoms with physical health problems is important because these may be treatable conditions for which survivors seek follow-up care and underscores the need for a multidisciplinary approach to survivor care.

Summary Public health concerns over the occurrence of birth defects and developmental abnormalities that may occur as a result of prenatal exposure to drugs, chemicals and other environmental factors has led to an increasing number of developmental toxicity studies. Because fetal pups are commonly evaluated for multiple outcomes, data analysis frequently involves a joint modelling approach. We focus on modelling clustered binary and continuous outcomes in the setting where both outcomes are potentially observable in all offspring but, owing to practical limitations, the continuous outcome is only observed in a subset of offspring. The subset is not a simple random sample but is selected by the experimenter under a prespecified probability model. Although joint models for binary and continuous outcomes have been developed when both outcomes are available for every fetus, many existing approaches are not directly applicable when the continuous outcome is not observed in a simple random sample. We adapt a likelihood-based approach for jointly modelling clustered binary and continuous outcomes when the continuous response is missing by design and missingness depends on the binary trait. The approach takes into account the probability that a fetus is selected in the subset. Through the use of a partial likelihood, valid estimates can be obtained by a simple modification to the partial likelihood score. Data involving the herbicide 2,4,5-trichlorophenoxyacetic-acid are analysed. Simulation results confirm the approach.

Purpose Lapatinib plus trastuzumab improves outcomes relative to lapatinib alone in heavily pretreated, human epidermal growth factor receptor 2–positive metastatic breast cancer (MBC). We tested the combination in the earlier-line setting and explored the predictive value of [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) for clinical outcomes. Patients and Methods Two cohorts were enrolled (cohort 1: no prior trastuzumab for MBC and ≥ 1 year from adjuvant trastuzumab, if given; cohort 2: one to two lines of chemotherapy including trastuzumab for MBC and/or recurrence < 1 year from adjuvant trastuzumab). The primary end point was objective response rate by RECIST v1.0; secondary end points included clinical benefit rate (complete response plus partial response plus stable disease ≥ 24 weeks) and progression-free survival. [18F]FDG-PET scans were acquired at baseline, week 1, and week 8. Associations between metabolic response and clinical outcomes were explored. Results Eighty-seven patients were registered (85 were evaluable for efficacy). The confirmed objective response rate was 50.0% (95% CI, 33.8% to 66.2%) in cohort 1 and 22.2% (95% CI, 11.3% to 37.3%) in cohort 2. Clinical benefit rate was 57.5% (95% CI, 40.9% to 73.0%) in cohort 1 and 40.0% (95% CI, 25.7% to 55.7%) in cohort 2. Median progression-free survival was 7.4 and 5.3 months, respectively. Lack of week-1 [18F]FDG-PET/computed tomography ([18F]FDG-PET/CT) response was associated with failure to achieve an objective response by RECIST (negative predictive value, 91% [95% CI, 74% to 100%] for cohort 1 and 91% [95% CI, 79% to 100%] for cohort 2). Conclusion Early use of lapatinib and trastuzumab is active in human epidermal growth factor receptor 2–positive MBC. Week-1 [18F]FDG-PET/CT may allow selection of patients who can be treated with targeted regimens and spared the toxicity of chemotherapy.

Background: Circulating tumor cells (CTCs) with evidence of HER2 amplification can occur in patients (pts) with clinically HER2 negative metastatic breast cancer. While these findings potentially have profound implications for CTCs as a biomarker for treatment, prospective validation and characterization of this subgroup is necessary. Methods: We created a prospective cohort of pts with metastatic breast cancer that were HER2 negative by IHC and/or FISH on all available primary and metastatic biopsies. Blood samples were collected at study entry and then again at ≥ 3 weeks if available. CTCs were enumerated by a modification of the Veridex CellSearch Profile kit. FISH was performed on each CTC sample and reported as positive if the HER2/CEP17 ratio was ≥ 2.0. Analyses are descriptive. Results: 66 pts were consented for study and this report includes the 65 pts with detectable CTCs. Median number of CTCs was 226 (range 112 to > 3000). At initial testing, 23 pts (35%) had HER2 positive CTCs, median HER2:CEP17 ratio of 3.4. 50% (11 of 22) of the pts with lobular or ductal/lobular histology had HER2 amplified CTCs, compared to only 27% (10 of 36) of patients with ductal histology. Women with ER positive disease had HER2 positive CTCs in 40% of cases (20 of 49) compared to 19% of ER negative pts (3 of 16). To assess concordance of HER2 amplification of CTCs over time, 34 pts consented to be retested at a median 5.9 weeks after initial screening (range 3.3 - 17 weeks) and all but 1 had detectable CTCs. Baseline characteristics of these 34 pts were similar to the original population, with HER2 amplified CTCs detected in 35% (12 of 34) pts at initial screening. HER2 positive CTCs were concordant at time of retesting in 83% (10 of 12) pts; the 2 women with discordant CTCs were receiving HER2 directed therapy. Of the pts with HER2 negative CTCs at initial screening, 81% (17 of 21) continued to have HER2 negative CTCs at time of retesting. Conclusion: We observed a higher prevalence of HER2 positive CTCs among pts with ER positive disease and evidence of lobular histology. The presence of HER2 positive CTCs is concordant over time in the majority of pts. The functional significance of HER2 positive CTCs in patients with clinically HER2 negative breast cancer will be tested in a prospective study with HER2−directed therapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD05-07.

Background Neoadjuvant chemotherapy and trastuzumab is an established treatment for locally advanced HER2-positive breast cancer, providing favorable rates of clinical response and pCR. Minimal data describe long-term outcomes after neoadjuvant HER2-directed therapy. This study aimed to explore long-term efficacy and toxicity after neoadjuvant trastuzumab and chemotherapy for HER2-positive breast cancer. Patients and Methods Eligible patients participated in 1 of 2 single-arm phase II neoadjuvant trials, receiving either paclitaxel/trastuzumab (TH) or vinorelbine/trastuzumab (NH) for stage II-III HER2-positive disease. Postoperative chemotherapy, with or without trastuzumab, was offered. Charts were reviewed to identify recurrence, death, and treatment-related toxicities. Association of long-term outcomes with baseline characteristics and pathological response to primary therapy was explored. Results Eighty patients were identified; 33 (41.3%) received TH and 47 (58.8%) received NH. Fourteen (17.5%) had pCR at surgery. Most (96.3%) received anthracycline-based adjuvant chemotherapy; 78.7% of NH patients also received adjuvant trastuzumab. At a median follow-up of 8.8 years, 23 (28.8%) patients have experienced recurrence, with 16 breast cancer-related deaths. Four-year RFS in patients with pCR was 92.9% (95% confidence interval [CI], 79.4%-100%) versus 72.4% without pCR (95% CI, 63.9%-82.1%). All initial symptomatic cardiotoxicity resolved during extended follow-up. New symptomatic cardiotoxicity in long-term follow-up was rare, primarily occurring in patients requiring retreatment with a cardiotoxic agent. Conclusion Neoadjuvant chemotherapy and trastuzumab for HER2-positive breast cancer resulted in favorable long-term survival with minimal late toxicity. Trends in this data set suggest an association between pCR and improved long-term RFS. Retreatment with cardiotoxic agents might increase risk of late cardiotoxicity.

Cluster variable aperture (CVA) simulated annealing (SA) is an inversion technique to construct fluid flow models in fractured rocks based on the transient pressure data from hydraulic tests. A two-dimensional fracture network system is represented as a filled regular lattice of fracture elements. The algorithm iteratively changes element apertures for a cluster of fracture elements in order to improve the match to observed pressure transients. This inversion technique has been applied to hydraulic data collected at the Raymond field site, CA to examine the spatial characteristics of the flow properties in a fractured rock mass. Two major conductive zones have been detected by various geophysical logs, geophysical imaging techniques and hydraulic tests; one occurring near a depth of 30 m and the other near a depth of 60 m. Our inversion results show that the practical range of spatial correlation for transmissivity distribution is estimated to be approximately 5 m in the upper zone and less than 2.5 m in the lower zones. From the televiewer and other fracture imaging logs it was surmised that the lower conductive zone is associated with an anomalous single open fracture as compared to the upper zone, which is an extensive fracture zone. This would explain the difference in the estimated practical range of the spatial correlation for transmissivity.

Inverse modeling has become a standard technique for estimating hydrogeologic parameters. These parameters are usually inferred by minimizing the sum of the squared differences between the observed system state and the one calculated by a mathematical model. The robustness of the least squares criterion, however, has to be questioned because of the tendency of outliers in the measurements to strongly influence the outcome of the inversion. We have examined alternative approaches to the standard least squares formulation. The robustness of these estimators has been tested by means of Monte Carlo simulations of a synthetic experiment, in which both non-Gaussian random errors and systematic modeling errors have been introduced. The approach was then applied to data from an actual gas-pressure-pulse-decay experiment. The study demonstrates that robust estimators have the potential to reduce estimation bias in the presence of noisy data and minor systematic errors, which may be a significant advantage over the standard least squares method.

A multicenter NCI-sponsored phase II study was conducted to analyze the safety and efficacy of the combination of ixabepilone with trastuzumab in patients with metastatic HER2-positive breast cancer.Two cohorts were enrolled: cohort 1 had received no prior chemotherapy or trastuzumab for metastatic disease and cohort 2 had received 1-2 prior trastuzumab-containing regimens for metastatic disease. Patients in both cohorts received ixabepilone 40 mg/m(2) as a 3-h infusion and trastuzumab on day 1 of a 21-day cycle. Tumor biomarkers that may predict response to trastuzumab were explored.Thirty-nine women entered the study with 15 patients in cohort 1 and 24 patients in cohort 2. Across both cohorts, the overall RR was 44%, with a clinical benefit rate (CR + PR + SD for at least 24 weeks) of 56%. Treatment-related toxic effects included neuropathy (grade ≥2, 56%), leukopenia (grade ≥2, 26%), myalgias (grade ≥2, 21%), neutropenia (grade ≥2, 23%), and anemia (grade ≥2, 18%).This represents the first study of the combination of ixabepilone with trastuzumab for the treatment of metastatic HER2-positive breast cancer. These results suggest that the combination has encouraging activity as first and subsequent line therapy for metastatic breast cancer.

Background Research studies involving human tissue are increasingly common. However, patients' attitudes toward research biopsies are not well characterized, particularly when the biopsies are carried out outside the context of therapeutic trials. Patients and methods One hundred sixty patients with metastatic breast cancer (MBC) from two academic (n = 80) and two community (n = 80) hospitals completed a 29-item self-administered survey to evaluate their willingness to consider providing research purposes only biopsies (RPOBs) (as a stand-alone procedure) and additional biopsies (ABs) (additional needle passes at the time of a clinically indicated biopsy). Results Eighty-two (51%) of 160 patients would consider having RPOBs, of which 42 (53%) and 40 (50%) patients were from academic and community hospitals, respectively. Patients who had more prior biopsies were less likely to consider RPOBs (RR = 0.6, 95% CI: 0.4–1.0, P = 0.03). Of 160 patients, 115 (72%) patients would consider having ABs. Of these, 64 (80%) and 51 (64%) patients from academic and community hospitals, respectively, would consider ABs (RR = 1.2, 95% CI: 1.0–1.5, P = 0.03). Conclusions Many patients with MBC in both academic and community settings report willingness to consider undergoing biopsies for research. Further research is needed to understand ethical, logistical and provider-based barriers to broader participation in such studies.

Background: Administration of recombinant human thrombopoietin (rhTPO) with G-CSF for stem cell mobilization is associated with high CD34+ stem cell yield, rapid neutrophil recovery following autologus transplantation (ASCT), and decreased red blood cell (rbc) and platelet (plt) transfusions (Solomo, G. et al. Blood 1999). However, clinical development of rhTPO was complicated by the formation of neutralizing anti-TPO antibodies (Li, J. et al. Blood 2001), prompting discontinuation of further clinical development of recombinant TPO. Eltrombopag (Elt) is an orally bioavailable small molecule thrombopoietin receptor (TPO-R) agonist approved by the FDA for treatment of chronic immune thrombocytopenic purpura (ITP). In vitro studies have demonstrated that Elt promotes megakaryocyte proliferation and differentiation of CD34+ bone marrow progenitor cells (Erickson-Miller CL Stem Cells 2009), suggesting that Elt might be a surrogate for rhTPO for stem cell mobilization. In this pilot trial, we evaluated the combination of Elt plus standard G-CSF and cyclophosphamide (C) for stem cell mobilization in patients (pts) with multiple myeloma (MM), a disease for which ASCT remains a standard of care (Blade et al. Blood 2010). Methods: Primary objectives included determination of the median number of CD34+ cells/kg mobilized and the maximum tolerated dose (MTD) of Elt. Pts had MM that was stable or responsive to at least two cycles of chemotherapy with plans for stem cell mobilization and ASCT. Four pts were to be enrolled in each of four dose escalation arms in which they received 0 (Arm D), 50 (Arm A), 100 (Arm B), or 150 mg (Arm C) of eltrombopag in combination with standard C + G-CSF. Adverse events (AEs) were graded by NCI-CTCAE v4. Results: 17 pts have been screened and enrolled to date. Two patients withdrew consent prior to receiving Elt and were excluded from statistical analysis. 15 patients have completed participation in the study to date and two patients remain to be enrolled in Arm C. The first subject in Arm A experienced delayed engraftment that was determined to be unrelated to ELT; rather, the event was attributed to administration of a one-time high dose of corticosteroid for management of a severe hypersensitivity reaction to DMSO that occurred during stem cell infusion. A second subject in Arm A had undergone mobilization with Elt prior to the previously described delayed engraftment event, and to ensure safety underwent a second mobilization with G-CSF and plerixafor. During ASCT, this patient received cells from the second mobilization procedure. While neither event met criteria for a dose-limiting toxicity, the protocol was amended such that three additional patients enrolled in Arm A underwent two rounds of mobilization - the first with Elt plus C and G-CSF and a second with G-CSF plus plerixafor - and received as part of ASCT cells mobilized with Elt. Each of these patients engrafted successfully. The median number of CD34+ cells/kg collected during the first collection day of apheresis in Arms D, A, B, and C was 8.0, 11.0, 15.3, and 26.4. The median total number of CD34+ stem cells collected following mobilization with Elt plus C and G-CSF in Arms D, A, B, and C was 13.2, 12.7, 15.4, and 26.4. The percentage of patients in Arms D, A, B, and C who achieved a target collection of 8 x 10^6 CD34+ stem cells in one collection day was 50, 60, 75, and 100%. There have been no severe adverse events related to Elt . Conclusions: Administration of Elt in combination with C plus G-CSF for stem cell mobilization in pts with MM undergoing ASCT was safe and well tolerated, with no DLTs or severe AEs attributable to Elt. The small size of this pilot study precludes formal statistical comparison of outcomes across treatment Arms, but there appears to be a trend toward increase in yield of CD34+ cells and decrease in apheresis procedures required with increasing doses of Elt. Disclosures Richardson: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

BACKGROUND: Young adult survivors of childhood cancer have an increased risk for treatment-related morbidity and mortality. In this study, the authors assessed how treatment for childhood cancer affects older-adult health and health practices. METHODS: One hundred seven adults treated for childhood cancer between 1947 and 1968, known to have survived past age 50 years, were identified from a single-institution cohort established in 1975. Updated vital status on eligible cases was obtained from public records. Survivors and a control group of their age-matched siblings and cousins completed a mailed survey to assess physical and social function, healthcare practices, and the prevalence of common adult illnesses. RESULTS: Of the 107 survivors known to be alive at age 50 years, 16 were deceased at follow-up; 7 deaths could be associated with prior treatment (second malignancy in radiation field [3], small bowel obstruction after abdominal radiation [2], and cardiac disease after chest irradiation [2]). The 55 survivors (median age, 56 years; range, 51-71 years), and 32 family controls (median age, 58 years; range, 48-70 years), reported similar health practices, health-related quality of life, and social function. However, survivors reported more frequent visits to healthcare providers (P < .05), more physical impairments (P < .05), fatigue (P = .02), hypertension (P = .001), and coronary artery disease (P = .01). An increased risk of hypertension was associated with nephrectomy during childhood (odds ratio, 18.9; 95% confidence interval, 3.0-118.8). CONCLUSIONS: The oldest adult survivors of childhood cancer continue to be at risk for treatment-related complications that potentially decrease their life expectancy and compromise their quality of life. Cancer 2010. © 2010 American Cancer Society.

BACKGROUND: The number of long-term US cancer survivors is expected to double by the year 2050. Although primary care physicians (PCPs) provide the majority of care for long-term cancer survivors, to the authors' knowledge, few data to date have detailed PCP practice patterns, attitudes, and challenges in caring for long-term cancer survivors. METHODS: Self-administered surveys were mailed to 406 community- and academic-based general internal medicine physicians in Denver, Colorado. Survey development included in-depth physician interviews and pretesting. Of the 299 responses, 72 were ineligible; an analysis of the data from 227 surveys is presented. RESULTS: The response rate was 76%. Community-based PCPs comprised 70% of completed surveys. Reported care patterns were assessed to create a multidimensional care score reflecting levels of attention to 4 areas of survivorship care: monitoring for cancer recurrence, management of late effects, sexual functioning, and mental health. Only 24% of PCPs met criteria for routinely providing more multidimensional survivorship care. More recent medical school graduates reported providing less multidimensional survivorship care when compared with their more experienced colleagues. Approximately 82% of PCPs believed that primary care guidelines for adult cancer survivors are not well defined, and 47% of PCPs cited inadequate preparation and lack of formal training in cancer survivorship as a problem when delivering care to long-term survivors. CONCLUSIONS: Although PCPs provide the bulk of care for long-term survivors within the survivorship phase of the cancer trajectory, only a small subset have reported providing multidimensional survivorship care. Results underscore a need for substantially increased training in survivorship care to support the delivery of multidimensional primary care for long-term survivors. Cancer 2009;115(18 suppl):4409–18. © 2009 American Cancer Society.

As part of its Resource Conservation and Recovery Act (RCRA) Corrective Action Program (CAP), the Lawrence Berkeley National Laboratory (LBNL) Environmental Restoration Program conducted an evaluation of naturally occurring metals in soils at the facility. The purpose of the evaluation was to provide a basis for determining if soils at specific locations contained elevated concentrations of metals relative to ambient conditions. Ambient conditions (sometimes referred to as 'local background') are defined as concentrations of metals in the vicinity of a site, but which are unaffected by site-related activities (Cal-EPA 1997). Local background concentrations of 17 metals were initially estimated by LBNL using data from 498 soil samples collected from borings made during the construction of 71 groundwater monitoring wells (LBNL 1995). These concentration values were estimated using the United States Environmental Protection Agency's (USEPA's) guidance that was available at that time (USEPA 1989). Since that time, many more soil samples were collected and analyzed for metals by the Environmental Restoration Program. In addition, the California Environmental Protection Agency (Cal-EPA) subsequently published a recommended approach for calculating background concentrations of metals at hazardous waste sites and permitted facilities (Cal-EPA 1997). This more recent approach differs from that recommended by the USEPA and used initially by LBNL (LBNL 2002). The purpose of the 2002 report was to apply the recommended Cal-EPA procedure to the expanded data set for metals that was available at LBNL. This revision to the 2002 report has been updated to include more rigorous tests of normality, revisions to the statistical methods used for some metals based on the results of the normality tests, and consideration of the depth-dependence of some sample results. As a result of these modifications, estimated background concentrations for some metals have been slightly revised from those presented in the original 2002 report. In cases where estimated background concentrations were reduced, site data were reviewed to assess whether significant changes to results of the RCRA CAP findings would result. This assessment indicated that no significant changes in RCRA CAP findings would result from the revisions.

Cluster variable aperture (CVA) simulated annealing has been used as an inversion technique to construct fluid flow models of fractured formations based on transient pressure data from hydraulic tests. A two-dimensional fracture network system is represented as a filled regular lattice of fracture elements. The algorithm iteratively changes element apertures for a cluster of fracture elements in order to improve the match to observed pressure transients. Aperture size is chosen randomly from a list of discrete apertures. The cluster size is held constant throughout the iterations. Since hydraulic inversion is inherently nonunique, it is important to use additional information. We investigated the relationship between the scale of heterogeneity and the optimal cluster size and shape to enhance convergence of the inversion and improve the results. In a spatially correlated transmissivity field, a cluster size corresponding to about 20 % to 40 % of the practical range of the spatial correlation is optimal. Inversion results of the Raymond test site data are also presented and based on an optimal cluster size; the practical range of the spatial correlation is estimated to be 5 to 10 m.

Background We observed 2 cases of Pneumocystis carinii pneumonia (PCP) occurring in HIV-negative patients during treatment with dose-dense chemotherapy with doxorubicin/cyclophosphamide (AC) followed by paclitaxel (T). These represent the first case reports of PCP occurring during dose-dense chemotherapy for breast cancer. Because lymphocyte depletion is thought to predispose patients to PCP, we explored whether the shortened intervals between cycles during dose-dense chemotherapy might place patients at risk for lymphocyte depletion and thereby a potentially increased risk of opportunistic infection. Patients and Methods Three cohorts of patients were analyzed. Cohort 1 involved 135 patients receiving dose-dense AC → T on a phase II study. Cohort 2 included 64 patients who received treatment with dose-dense AC → albumin-bound paclitaxel on a phase II clinical trial. Cohort 3 consisted of 59 patients who received AC → T given every 3 weeks who were identified from the Clinical Research Information System database at Dana-Farber Cancer Institute. For cohorts 1 and 3, the electronic medical record was reviewed to determine absolute lymphocyte counts (ALCs) and absolute neutrophil counts (ANCs) for day 1 of each of the 8 cycles of treatment. For cohort 2, data was prospectively collected and entered into an electronic database. The lowest ALC obtained by each patient on day 1 of any cycle was termed the nadir. Results Patients experienced grade 3 (ALC 3 ) or grade 4 (ALC 3 ) lymphopenia in all 3 cohorts: 63% with dose-dense AC →T, 23.4% in dosedense AC → albumin-bound paclitaxel, and 69% with dose-dense AC → T every 3 weeks. Patients experienced their lowest median ALC count at cycle 5 of treatment in all 3 cohorts, with a median nadir of 400 cells/mm 3 in cohort 1, 690 cells/mm 3 in cohort 2, and 400 cells/mm 3 in cohort 3. Conclusion The majority of patients receiving AC → T every 2 or 3 weeks experience grade 3/4 lymphopenia. Median lymphocyte counts appear to be lowest around cycle 5, the point at which we observed 2 cases of PCP. Lymphocyte counts appear to be reaching a low enough level to place patients at risk for opportunistic infection during treatment with dosedense AC → T and with AC → T given every 3 weeks.

Importance Trastuzumab is a life-saving therapy but is associated with symptomatic and asymptomatic left ventricular ejection fraction (LVEF) decline. We report the cardiac toxic effects of a nonanthracycline and trastuzumab-based treatment for patients with early-stage human epidermal growth factor receptor 2 (ERBB2, formerly HER2 or HER2/neu)-positive breast cancer. Objective To determine the cardiac safety of paclitaxel with trastuzumab and the utility of LVEF monitoring in patients with node-negative, ERBB2-positive breast cancer. Design, Setting, and Participants In this secondary analysis of an uncontrolled, single group study across 14 medical centers, enrollment of 406 patients with node-negative, ERBB2-positive breast cancer 3 cm, or smaller, and baseline LVEF of greater than or equal to 50% occurred from October 9, 2007, to September 3, 2010. Patients with a micrometastasis in a lymph node were later allowed with a study amendment. Median patient age was 55 years, 118 (29%) had hypertension, and 30 (7%) had diabetes. Patients received adjuvant paclitaxel for 12 weeks with trastuzumab, and trastuzumab was continued for 1 year. Median follow-up was 4 years. Interventions Treatment consisted of weekly 80-mg/m 2 doses of paclitaxel administered concurrently with trastuzumab intravenously for 12 weeks, followed by trastuzumab monotherapy for 39 weeks. During the monotherapy phase, trastuzumab could be administered weekly 2-mg/kg or every 3 weeks as 6-mg/kg. Radiation and hormone therapy were administered per standard guidelines after completion of the 12 weeks of chemotherapy. Patient LVEF was assessed at baseline, 12 weeks, 6 months, and 1 year. Main Outcomes and Measures Cardiac safety data, including grade 3 to 4 left ventricular systolic dysfunction (LVSD) and significant asymptomatic LVEF decline, as defined by our study, were reported. Results Overall, 2 patients (0.5%) (95% CI, 0.1%-1.8%) developed grade 3 LVSD and came off study, and 13 (3.2%) (95% CI, 1.9%-5.4%) had significant asymptomatic LVEF decline, 11 of whom completed study treatment. Median LVEF at baseline was 65%; 12 weeks, 64%; 6 months, 64%; and 1 year, 64%. Conclusions and Relevance Cardiac toxic effects from paclitaxel with trastuzumab, manifesting as grade 3 or 4 LVSD or asymptomatic LVEF decline, were low. Patient LVEF was assessed at baseline, 12 weeks, 6 months, and 1 year, and our findings suggest that LVEF monitoring during trastuzumab therapy without anthracyclines could be simplified for many individuals.

9078 Background: Sentinel lymph node (SLN) status is used in melanoma AJCC staging to distinguish between stage I or II and stage III disease. However patients (pts) with stage IIC (Breslow > 4 mm,...

To analyze the differences of occurrence of pediatric rheumatic disease among various ethnic groups in a culturally diverse isolated geographic area.A retrospective study of pediatric rheumatic diseases in a multiethnic area during a 6 year period.A group of 922 patients was categorized based on predominant ethnicity, and their risk of having acute rheumatic fever (ARF), juvenile rheumatoid arthritis (JRA), and systemic lupus erythematosus (SLE) was studied. Odds ratios (OR) were computed for each illness with Caucasians as the reference group. Results indicated that Polynesians were overrepresented among patients with ARF, having elevated OR that were significantly different from Caucasians (22.5-120.7, p0.0001). For SLE, the highest OR were obtained for Samoans, Filipinos, and Japanese. In contrast, for JRA, Filipinos and Japanese had OR less than one, and no Samoans were diagnosed with JRA, possibly indicating a protective effect against developing JRA.This unique retrospective study examined the ethnic variations of expression of certain rheumatic diseases in an isolated region. Results reveal that certain ethnic groups are at risk for ARF and SLE, but are protected against JRA. These findings suggest investigating possible immunogenetic similarities and differences in these illnesses.

1535 Background: The introduction of whole-exome sequencing (WES) into routine cancer care presents novel challenges for patient education and informed consent. In light of the recent American Coll...

Observational studies have demonstrated a 30-50% lower risk of disease-specific and overall mortality in physically active breast and colorectal cancer patients as compared to sedentary individuals. However, there have been no randomized trials looking at the impact of physical activity on cancer outcomes, and the optimal design of such a trial is not yet well-defined. The Active After Cancer Trial (AACT) is a multicenter feasibility study designed to evaluate the ability of a telephone-based intervention to increase physical activity in patients with breast and colorectal cancer. Methods: Sedentary (reporting less than 60 minutes/week of recreational activity) individuals with stage I-III breast or colorectal cancer were eligible for enrollment after completion of all adjuvant chemotherapy and radiation. Participants were randomized 1:1 to a centralized telephone coaching intervention, with a target goal of 180 minutes/week of physical activity, or to a usual care control group. Intervention participants received an average of 10 telephone contacts over 16-weeks. Initial calls focused upon building self-efficacy and later calls concentrated upon relapse prevention and maintenance of exercise behaviors. Participants underwent assessment of physical activity behaviors (7-Day Physical Activity Recall), fitness (6-Minute Walk Test), physical functioning (EORTC QLQ C-30), fatigue (FACIT) and exercise self-efficacy at baseline and 16 weeks after enrollment. Results: One hundred and twenty-one patients were enrolled through 10 Cancer and Leukemia Group B (CALGB) institutions; 100 patients had breast cancer and 21 had colorectal cancer. Average age was 54.3, 74% of patients had received chemotherapy and mean time since completion of adjuvant treatment was 24 months. Participants randomized to the exercise group experienced significant improvements in fitness and physical functioning as compared to controls. Table. Baseline measures and change (post-minus pre) scores in intervention and control patients (±SD) Intervention participants also reported a doubling in minutes of weekly physical activity, but this was not a significant increase compared to controls. Conclusions: Sedentary breast and colorectal cancer survivors can be enrolled in a physical activity intervention. A centralized telephone coaching intervention successfully increased fitness and physical functioning, although self-reported exercise time was not significantly changed. A large-scale clinical trial within the co-operative groups is feasible. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD08-09.

For environmental remediation, management of nuclear waste disposal, or geothermal reservoir engineering, it is very important to evaluate the permeabilities, spacing, and sizes of the subsurface fractures which control ground water flow. Cluster variable aperture (CVA) simulated annealing has been used as an inversion technique to construct fluid flow models of fractured formations based on transient pressure data from hydraulic tests. A two-dimensional fracture network system is represented as a filled regular lattice of fracture elements. The algorithm iteratively changes an aperture of cluster of fracture elements, which are chosen randomly from a list of discrete apertures, to improve the match to observed pressure transients. The size of the clusters is held constant throughout the iterations. Sensitivity studies using simple fracture models with eight wells show that, in general, it is necessary to conduct interference tests using at least three different wells as pumping well in order to reconstruct the fracture network with a transmissivity contrast of one order of magnitude, particularly when the cluster size is not known a priori. Because hydraulic inversion is inherently non-unique, it is important to utilize additional information. The authors investigated the relationship between the scale of heterogeneity and the optimum cluster size (and its shape) to enhance the reliability and convergence of the inversion. It appears that the cluster size corresponding to about 20--40 % of the practical range of the spatial correlation is optimal. Inversion results of the Raymond test site data are also presented and the practical range of spatial correlation is evaluated to be about 5--10 m from the optimal cluster size in the inversion.

e11100 Background: Trastuzumab (T) is associated with improvements in overall survival (OS) among patients (pts) with HER2+ MBC; however disease course in individual pts is highly variable. We aime...

528 Background: To identify mechanisms of resistance to trastuzumab (T), we developed and characterized T-resistant HER2+ breast cancer (BC) cell lines; these lines acquired EGFR amplification and were sensitive to both lapatinib (L) and gefitinib. To validate this finding, we prospectively assessed EGFR copy number in circulating tumor cells (CTC) from patients (pts) on TBCRC003, a multicenter clinical trial of L and T. Methods: Pts with measurable, HER2+ metastatic BC (MBC) were eligible. Cohort 1: No prior T, L, or chemotherapy (CT) for MBC, and > 1 yr from adjuvant T, if received. Cohort 2: 1-2 prior lines of CT for MBC, including T, or relapse within 1 yr of adjuvant T. Pts received L 1,000 mg QD + T (2 mg/kg weekly or 6 mg/kg Q3W). CTC were collected using a modification of the CellSearch Profile Kit (Veridex) at baseline, 4wk, and progression. CTC were analyzed by FISH for EGFR and CEP7 and amplification was defined as EGFR/CEP7≥2. Results: EGFR amplification was present in CTC at baseline in 11/39...

e11074 Background: Neoadjuvant chemotherapy (C) plus trastuzumab (H) improves pathologic complete response (pCR) rate over C alone. Whether pCR after CH is predictive of survival is not known. We e...

549 Background: Alterations in the PI3-Kinase (PI3K) pathway, loss of HER2 amplification, and activation of growth factor receptors have all been implicated in resistance to H. This preoperative study evaluated two H-based regimens and explored resistance mechanisms. Methods: 80 planned patients (pts) with stage II/III HER2+ disease underwent biopsies at baseline and 7-14d after a single dose of H (8 mg/kg) before starting chemotherapy. 67 pts were randomized to 12 weeks of VH (V 25 mg/m2 qwk + H 2mg/kg qwk) or 12 weeks of TCH (docetaxel 75 mg/m2 q3wk + C AUC 6 q3wk + H 2 mg/kg qwk) and 13 were treated (8 VH, 5 TCH) based on physician choice prior to definitive surgery. Pathologic complete response in breast/nodes (pCR) was assessed. Correlative studies included expression profiling at baseline and post-H monotherapy, PIK3CA mutation screen, baseline and posttreatment HER2 and EGFR FISH. Amplification was defined as HER2/CEP17 or EGFR/CEP7 ≥ 2.0. Results: 7/41 pts treated with VH (17%, CI = 10%-41%) and 1...

572 Background: The Oncotype DX recurrence score (RS) independently predicts the likelihood of benefit from adjuvant chemotherapy. However, the clinical factors that influence chemotherapy recommendations in addition to RS are not well characterized. We sought to determine how clinicians integrate the RS and standard clinicopathologic data when choosing adjuvant chemotherapy. Methods: We identified women with ER+, HER2-, LN- breast cancer seen at DFCI in whom RS testing was performed between November 2004 and October 2008. Clinical and pathological characteristics, RS and chemotherapy treatment were identified from electronic medical records. A multivariable model was used to examine which factors drove the decision to administer chemotherapy. Results: RS was performed on 269 women with the following case distribution: RS low (30) 9%. Chemotherapy was given to 7% of women with low RS, compared to 42% and 86% of women with intermediate and high RS, respectively. Tumor grade, T stage, progesterone receptor expression and RS were associated with receipt of chemotherapy in univariate analyses but age, LVI and menopausal status were not. In a multivariable logistic regression model, tumor grade, size, and RS were independent predictors of chemotherapy administration. Conclusions: Oncotype DX RS plays a critical role in medical decision making for women with early stage breast cancer at this single academic institution. However, other tumor and clinical features independently contribute to chemotherapy decisions, suggesting that tailored treatment does, and should, integrate both traditional and molecular pathological factors. [Table: see text] No significant financial relationships to disclose.

Abstract #3137 Background: The epitholones are a new class of antineoplastic agents which are microtubule inhibitors with low susceptibility to several mechanisms of drug resistance. Ixabepilone (BMS-247550, aza-epothilone B) has demonstrated efficacy as monotherapy or in combination with capecitabine (in anthracycline- and taxane-pretreated metastatic breast cancer) and has recently been approved for use in refractory breast cancer. A multicenter NCI-sponsored study was conducted to analyze the safety and efficacy of the combination of ixabepilone with trastuzumab in patients with metastatic HER2-positive breast cancer. Methods: This phase II nonrandomized study enrolled two cohorts of patients. Cohort 1 received no prior chemotherapy or trastuzumab for metastatic disease and cohort two received one or two prior trastuzumab-containing regimens for metastatic disease. Patients in each cohort received the same treatment regimen of ixabepilone and trastuzumab. Patients received ixabepilone 40 mg/m2 as a 3-hour continuous infusion on day 1 of a 21-day cycle plus trastuzumab once every 21 days. For the initial treatment of trastuzumab, patients received 8 mg/kg IV, and for all subsequent trastuzumab treatments 6 mg/kg. Treatment was continued until disease progression or unacceptable toxicity. Endpoints included response rate (RR), time to progression (TTP), toxicity, and predictive biomarkers. Results: 39 women entered the study (median age 51, range 29-74) with 15 patients in cohort 1 and 24 patients in cohort 2. A median of 7 cycles of therapy were administered in each cohort. In cohort 1, there were 12 partial responses (PR), and 1 patient with stable disease for 5 months (SD). In cohort 2, there were 8 PRs and 9 patients with SD. Across both cohorts, the overall RR was 51%, with a clinical benefit rate (CR + PR + SD for at least 6 months) of 56%. Treatment-related toxicities included neuropathy (grade ≥2, 55%), myalgias (grade ≥2, 20%), anemia (grade ≥2, 18%), neutropenia (grade ≥2, 23%), and elevated transaminases (grade ≥2, 10%). There were no episodes of grade 2 or higher cardiac toxicity. Biomarker data will be presented. Conclusion: This represents the first study of the combination of ixabepilone with trastuzumab for the treatment of metastatic HER2-positive breast cancer. These results suggest that the combination has an encouraging response rate as first- and subsequent- line therapy for metastatic breast cancer. Clinically significant neuropathy was the major toxicity, and appeared to be cumulative. Based on these results, further evaluation of ixabepilone plus trastuzumab is warranted. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3137.

Abstract #4124 Background: Vaccination with tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF) generates potent, specific, and long-lasting anti-tumor immunity in multiple tumor models. At DF/HCC, over 100 patients with melanoma, ovarian cancer, and lung cancer have been vaccinated. These studies have led to the identification of targets of immune-mediated tumor destruction. Here, we present analysis on the safety, feasibility, and biologic activity of an autologous GM-CSF-secreting breast cancer vaccine. Methods:27 patients with metastatic breast cancer have undergone tumor procurement for vaccine from malignant pleural effusions (23), ascites (1), tumor nodules (2), lymph node (1), and 12 patients have received vaccine. Cells were transduced with a replication defective adenoviral vector encoding GM-CSF, irradiated, and GM-CSF secretion was measured by ELISA. Patients were required to have received at least one prior chemotherapy for metastatic disease and have an ECOG performance status 0-1. Vaccine was delivered s.c. and i.d. weekly for three weeks, then every other week. Immune monitoring included skin biopsies of vaccine sites, measurement of leukocyte populations, and proteomic-based assessment of antibody responses. Results: Sufficient viable tumor cell yields for vaccination were obtained from all patients, with cellular yields ranging from 1.1-679 x 106 cells and viabilities ranging from 71-100%. Dose levels were based on cellular yield, ranging from 105 -107 cells/dose. The average yield of GM-CSF was 838 ng/106 cells/24 hrs (range: 24.4-5696), higher than the average yields for lung cancer and melanoma. Vaccinated patients were 34-69 years, and received 3-23 vaccines. 9 patients had progressive disease after 3-10 vaccines (1-4 months). One patient had stable disease after 23 vaccines (11 months), resumed vaccination at 16 months for progression and remains on study. One other patient remains on study, and one patient did not have measurable disease. Toxicities related to treatment include grade I/II local injection-site reactions, grade I/II inflammation at tumor sites as well as grade I/II fatigue, fever, nausea, and edema. Skin biopsies of vaccination sites revealed mild-moderate infiltration of lymphocytes, granulocytes, and macrophages. Conclusion: Breast cancer cells can be harvested in sufficient number for autologous vaccine production from solid tumor as well as from malignant effusions. Autologous vaccination can induce coordinated immune responses with limited toxicity. The proteomic-based identification of antigen-specific immune responses following vaccination will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4124.