Gradishar, William J.

Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.

1032 Background: Obesity is a predictor of poor outcomes in women with early-stage breast cancer (BC). Some reports suggest that obesity is associated with aggressive tumor histology. We examined the relationship between BMI at diagnosis and PAM50 subtype, and explored the interaction between BMI and subtype on prognosis in early BC. Methods: CALGB 9741 evaluated dose-density and sequence in node-positive BC. All patients received doxorubicin, cyclophosphamide and paclitaxel dosed by actual body weight without cap or dose adjustment. The primary endpoint was RFS. Height and weight at diagnosis were abstracted from patient records; the PAM50 assay was performed using the Nanostring platform. Association between PAM50 and BMI was assessed by a chi-squared test. The prognostic value of BMI conditional on PAM50 was tested as a continuous variable using Cox models for RFS adjusted for number of involved nodes, tumor size, menopausal status, drug sequence, and dose density. Results: Baseline height and weight were available for 1909 of 2005 enrolled patients; 1272 also had subtype determination by PAM50. Distribution of subtypes differed significantly by BMI (p=0.03), with all weight groups having similar proportions of Basal and HER-2 Enriched subtypes and with obese patients having lower rates of Luminal A (30 vs 35%) and higher rates of Luminal B (39 vs 26%) tumors as compared to normal-weight individuals. In multivariate analyses, BMI and subtype were independent predictors of RFS (p=0.011 and p<0.001, respectively). Exploratory analyses did not show a significant interaction between subtype and the relationship between increased BMI and RFS (p=0.15), although largest differences were seen among Luminal cancers (Table). Conclusions: Biologic subtypes were distributed differently in obese and non-obese individuals. The association between BMI and RFS did not differ significantly by subtype in this study. More work is needed to further explore the interaction of BMI and subtype, especially in a larger cohort of Luminal tumors. [Table: see text]

e22093 Background: Biomarkers are an integral part of cancer care. A variety of testing methods exist, allowing institutional selection of which technologies to use and in what order to run them. This descriptive study provides a benchmark on methods used in practice for biomarker testing in breast (BC), gastric/esophageal (GC), and non-small cell lung cancers (NSCLC). Methods: We conducted an IRB-approved web survey of the 58 NCI designated cancer centers (pathologists and oncologists) providing adult care in BC, GC, and NSCLC. We developed a survey instrument with 14 BC, 5 GC, and 10 NSCLC items asking about methods used, order of testing, turn around time (TAT) and if tests are internally developed (ID). Results: For BC, 32% (18/57) of sites run concurrent rather than reflex HER2 FISH and IHC testing, citing quality assurance reasons. Average TAT for concurrent vs reflex testing is 6.5 and 9.5 days. Rates of ID tests are 14% (8/57) for PgR, 12% (7/57) for ER and 7% (4/57) for HER2. For GC, 39% (21/54) of sites run concurrent HER2 FISH and IHC tests, citing reasons of quality assurance and evolving guidelines. TAT for concurrent vs reflex testing is 6.3 and 9.5 days. 19% (10/54) of sites use ID HER2 tests. All reporting sites use EGFR and ALK testing in NSCLC and 96% use KRAS. 24% (13/55) of sites run them concurrently with an average TAT of 7.6 days, while the average TAT for sites with sequential testing is 22.8 days. CAP recommends a 10 day TAT for NSCLC tests, and 92% (12/13) of sites with concurrent testing meet this guideline vs only 11% (4/38) of sites with sequential testing (p<.0001). Rates of ID tests are 57% (30/53) for KRAS, 47% (26/55) for EGFR and 35% (19/55) for ALK, for which a kit is listed on the FDA drug label. There is a difference in the use of ID tests between BC and NSCLC, p<.0148. Conclusions: Concurrent testing for BC and GC HER2, and for NSCLC markers is a common practice at NCI cancer centers; and it improves TAT. Concurrent NSCLC testing allows meeting CAP TAT guideline, but sequential testing does not. New markers (GC HER2, EGFR, KRAS and ALK) are commonly adopted, with a higher rate of internally developed tests than for BC HER2. [Table: see text]

6533 Background: Although it can be rewarding, caring for patients with cancer is also demanding and stressful. Oncologists work long hours, supervise administration of highly toxic therapy, and continually observe death and suffering. While isolated studies have explored burnout in national samples of U.S. oncologists (last in 2003), little is known about the personal and professional characteristics related to burnout and career satisfaction. Methods: Between October 2012 - January 2013, ASCO conducted a national surveyof ~3000 U.S. oncologists evaluating burnout and career satisfaction. The survey sample was constructed from the member registry to include an equal number of men/women and an equal proportion of individuals from all career stages (<10 yrs, 10-19 yrs, >20 yrs). Validated tools were used to assess burnout and well-being. Results: As of January 2012, 1041 (35%) oncologists had returned surveys (median age 52 years; 50% women). Among responders, 355 (34%) were in academic practice (AP) and 447 (43%) in private practice (PP) with the remainder in other settings (e.g. military, veterans, industry). Oncologists worked an average of 51 hours/week and saw a mean of 51 outpatients/week. Although average hours worked for oncologists in PP and academic practice were similar (AP=54.6/wk; PP=54.2/wk), profound differences in other practice characteristics were observed with respect to sub-specialization (AP=81%; PP=17%), time devoted to clinical care, patients seen per week (AP=37; PP=74), time devoted to education, and method of compensation. Relative to 2011, 23% of oncologists reported a >10% decline in take home pay in 2012 (>10% decline AP=8%; PP=34%). Overall, 454 (45%) of oncologists had at least one symptom of burnout (e.g. emotional exhaustion, depersonalization) on the Maslach Burnout Inventory (AP=47%; PP=51%; p=0.19). While a majority were satisfied with their career (83%) and specialty (80%) choice, both measures of career satisfaction were lower for PP relative to AP (all p<0.005). Conclusions: Burnout is common among oncologists. Detailed multivariate analyses to identify personal and professional characteristics associated with burnout and career satisfaction are underway and will be presented.

These NCCN Guidelines Insights highlight the updated recommendations for use of multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for women with hormone receptor–positive, HER2-negative early-stage invasive breast cancer. This report summarizes these updates and discusses the rationale behind them.

PurposeBevacizumab improves progression-free survival but not overall survival in patients with metastatic breast cancer. E5103 tested the effect of bevacizumab in the adjuvant setting in patients with human epidermal growth factor receptor 2–negative disease.Patients and MethodsPatients were assigned 1:2:2 to receive placebo with doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (arm A), bevacizumab only during AC and paclitaxel (arm B), or bevacizumab during AC and paclitaxel followed by bevacizumab monotherapy for 10 cycles (arm C). Random assignment was stratified and bevacizumab dose adjusted for choice of AC schedule. Radiation and hormonal therapy were administered concurrently with bevacizumab in arm C. The primary end point was invasive disease–free survival (IDFS).ResultsFour thousand nine hundred ninety-four patients were enrolled. Median age was 52 years; 64% of patients were estrogen receptor positive, 27% were lymph node negative, and 78% received dose-dense AC. Chemotherapy-associated adverse events including myelosuppression and neuropathy were similar across all arms. Grade ≥ 3 hypertension was more common in bevacizumab-treated patients, but thrombosis, proteinuria, and hemorrhage were not. The cumulative incidence of clinical congestive heart failure at 15 months was 1.0%, 1.9%, and 3.0% in arms A, B, and C, respectively. Bevacizumab exposure was less than anticipated, with approximately 24% of patients in arm B and approximately 55% of patients in arm C discontinuing bevacizumab before completing planned therapy. Five-year IDFS was 77% (95% CI, 71% to 81%) in arm A, 76% (95% CI, 72% to 80%) in arm B, and 80% (95% CI, 77% to 83%) in arm C.ConclusionIncorporation of bevacizumab into sequential anthracycline- and taxane-containing adjuvant therapy does not improve IDFS or overall survival in patients with high-risk human epidermal growth factor receptor 2–negative breast cancer. Longer duration bevacizumab therapy is unlikely to be feasible given the high rate of early discontinuation.

Abstract Purpose: This phase II trial evaluated the efficacy and safety of cixutumumab, a human anti–insulin-like growth factor receptor 1 (IGF-1R) monoclonal IgG1 antibody, and explored potential biomarkers in postmenopausal women with hormone receptor–positive breast cancer. Experimental Design: Patients with hormone receptor–positive breast cancer that progressed on antiestrogen therapy received (2:1 randomization) cixutumumab 10 mg/kg and the same antiestrogen (arm A) or cixutumumab alone (arm B) every 2 weeks (q2w). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety. Correlative analyses of IGF-1R, total insulin receptor (IR), and IR isoforms A (IR-A) and B (IR-B) expression in tumor tissue were explored. Results: Ninety-three patients were randomized (arm A, n = 62; arm B, n = 31). Median PFS was 2.0 and 3.1 months for arm A and arm B, respectively. Secondary efficacy measures were similar between the arms. Overall, cixutumumab was well tolerated. IGF-1R expression was not associated with clinical outcomes. Regardless of the treatment, lower IR-A, IR-B, and total IR mRNA expression in tumor tissue was significantly associated with longer PFS [IR-A: HR, 2.62 (P = 0.0062); IR-B: HR, 2.21 (P = 0.0202); and total IR: HR, 2.18 (P = 0.0230)] and OS [IR-A: HR, 2.94 (P = 0.0156); IR-B: HR, 2.69 (P = 0.0245); and total IR: HR, 2.72 (P = 0.0231)]. Conclusions: Cixutumumab (10 mg/kg) with or without antiestrogen q2w had an acceptable safety profile, but no significant clinical efficacy. Patients with low total IR, IR-A, and IR-B mRNA expression levels had significantly longer PFS and OS, independent of the treatment. The prognostic or predictive value of IR as a biomarker for IGF-1R–targeted therapies requires further validation. Clin Cancer Res; 22(2); 301–9. ©2015 AACR.

Purpose To evaluate the career plans, professional expectations, and well-being of oncology fellows compared with actual experiences of practicing oncologists. Methods US oncology fellows taking the 2013 Medical Oncology In-Training Examination (MedOnc ITE) were invited to participate in an optional postexamination survey. The survey evaluated fellows' career plans and professional expectations and measured burnout, quality of life (QOL), fatigue, and satisfaction with work-life balance (WLB) using standardized instruments. Fellows' professional expectations and well-being were compared with actual experiences of US oncologists assessed simultaneously. Results Of the 1,637 oncology fellows in the United States, 1,373 (83.9%) took the 2013 MedOnc ITE. Among these, 1,345 (97.9%) completed the postexamination survey. The frequency of burnout among fellows decreased from 43.3% in year 1 to 31.7% in year 2 and 28.1% in year 3 (P < .001). Overall, the rate of burnout among fellows and practicing oncologists was similar (34.1% v 33.7%; P = .86). With respect to other dimensions of well-being, practicing oncologists had lower fatigue (P < .001) and better overall QOL scores (P < .001) than fellows but were less satisfied with WLB (P = .0031) and specialty choice (P < .001). Fellows' expectations regarding future work hours were 5 to 6 hours per week fewer than oncologists' actual reported work hours. Levels of burnout (P = .02) and educational debt (P ≤ .004) were inversely associated with ITE scores. Fellows with greater educational debt were more likely to pursue private practice and less likely to plan an academic career. Conclusion Oncology fellows entering practice trade one set of challenges for another. Unrealized expectations regarding work hours may contribute to future professional dissatisfaction, burnout, and challenges with WLB.