Citations

Purpose To determine the optimal dose and schedule of anthracycline and taxane administration as adjuvant therapy for early-stage breast cancer. Patients and Methods A 2 × 2 factorial design was used to test two hypotheses: (1) that a novel continuous schedule of doxorubicin-cyclophosphamide was superior to six cycles of doxorubicin-cyclophosphamide once every 2 weeks and (2) that paclitaxel once per week was superior to six cycles of paclitaxel once every 2 weeks in patients with node-positive or high-risk node-negative early-stage breast cancer. With 3,250 patients, a disease-free survival (DFS) hazard ratio of 0.82 for each randomization could be detected with 90% power with two-sided α = .05. Overall survival (OS) was a secondary outcome. Results Interim analyses crossed the futility boundaries for demonstrating superiority of both once-per-week regimens and once-every-2-weeks regimens. After a median follow-up of 6 years, a significant interaction developed between the two randomization factors (DFS P = .024; OS P = .010) in the 2,716 patients randomly assigned in the original design, which precluded interpretation of the two factors separately. Comparing all four arms showed a significant difference in OS (P = .040) but not in DFS (P = .11), with all treatments given once every 2 weeks associated with the highest OS. This difference in OS seemed confined to patients with hormone receptor–negative/human epidermal growth factor receptor 2 (HER2) –negative tumors (P = .067), with no differences seen with hormone receptor–positive/HER2-negative (P = .90) or HER2-positive tumors (P = .40). Conclusion Patients achieved a similar DFS with any of these regimens. Subset analysis suggests the hypothesis that once-every-2-weeks dosing may be best for patients with hormone receptor–negative/HER2-negative tumors.

AimsBile salt export pump (BSEP) is a transporter expressed exclusively at hepatic canaliculi and drives bile‐salt efflux. Minimal data exist about BSEP expression in tumours. We hypothesized that BSEP immunohistochemistry would be specific for hepatocellular carcinoma (HCC).Methods and resultsTissue microarrays, including 48 HCC, 41 cholangiocarcinomas and 24 metastatic tumours in liver, were immunostained for BSEP. Expression was compared with common markers of hepatocytic differentiation including CD10, hepatocyte paraffin‐1 antigen (HepPar‐1), carcinoembryonic antigen, arginase‐1 (ARG) and glypican‐3 (GPC‐3). BSEP expression was assessed in normal tissues. Special attention was given to adrenal gland (normal and neoplasia). BSEP was easy to interpret and showed no background staining. Canalicular expression was seen in all normal livers, but not in other normal tissue. BSEP was 90% sensitive and 100% specific for HCC (canalicular in 33 of 43 positive cases). The sensitivity of ARG was slightly higher, but specificity was slightly lower (94% for both). HepPar‐1 was 90% sensitive and 97% specific. CD10, polyclonal carcinoembryonic antigen (pCEA) and GPC‐3 all had lower sensitivity (74, 81 and 54%, respectively).ConclusionsIn malignant tumours in the liver, BSEP marking was 100% specific and 90% sensitive for HCC. The specificity of BSEP for HCC obviates the need to identify a ‘canalicular’ pattern, which can limit the utility of other canalicular markers.

Abstract Background: Retrospective studies suggest that primary breast surgery is associated with improved overall survival (OS) in Stage IV breast cancer. TBCRC 013 is a multi-center prospective registry study evaluating the role of surgery for the primary tumor in Stage IV disease. Methods: From 7/09 - 4/12, 128 eligible pts from 14 sites were enrolled in two cohorts (A: Stage IV with intact primary tumor (n = 112); B: metastases (mets) within 3 months of primary surgery (n = 16)). Baseline patient and tumor characteristics, and surgery of the primary were correlated with 2yr overall survival (OS) using log rank, Kaplan Meier and Cox regression for all patients. Comparisons were also made between cohorts A and B and within cohort A stratified by response to systemic therapy. Responders included those with any response (partial,complete) or stable disease at distant sites. Results: Median pt age was 52yrs(21-79) and median primary tumor size 3.2cm(0.7-15). Phenotypes were ER+ 106 (83%), HER2neg 91(71%), and triple neg 10(8%). 60(47%) had bone-only mets. The only significant baseline difference between cohorts A and B was the presence of palpable nodes (A:62% vs B:0%, p<0.001). There were no differences in age, tumor size, ECOG scores, ER or HER2 status, number or sites of mets between cohorts A and B. At a median follow-up of 25 mo (95%CI, 23-31), 2yr OS for all pts is 86% (80-92) and is superior in cohort B as compared to A, (100% vs 84%, p = 0.03). On multivariate analysis (MVA) including all pts, only surgery, ER and HER2 positivity were associated with improved OS (table). Among 112 pts with an intact primary (Arm A), 17(15%) were non-responsive (NR) to systemic therapy, 3(18%) of whom required palliative surgery at a median time of 10.4mos. 2yr OS among NR was 33% (15-69) as compared to 94% (88-99) in Arm A responders (R) (p<0.001). ER positivity was the only baseline difference between NR (65%) and R (88%) within Arm A (p = 0.02). Among 94(85%) Arm A responders, 39(41%) had elective surgery (median 8.4 mos, 95%CI:6.9-10.3) and only 1 of the remaining 47(2%) required palliation. When limited to Arm A responders, elective surgery was not associated with improved 2yr OS (surgery vs not: 94% vs 92%, p = 0.5). Median time to progression following elective surgery was 12 mos (95%CI,8-19mos). When cohort B (n = 16) and cohort A surgery groups (n = 39) are combined, surgery of the primary tumor is associated with improved 2yr OS (96% vs 74%, p = 0.002). Conclusions: In this prospective registry study, patients diagnosed with mets within 3 months of primary breast surgery have an improved 2yr OS. When all pts having surgery (A + B) are examined, surgery is associated with improved OS on MVA, but when limited to Arm A responders, elective surgery does not improve OS. Given that the number of Arm A responders is small, results from the prospective randomized trial will be needed to address this question. These data also demonstrate that the need for surgical palliation of the primary tumor is uncommon in the modern era. Multivariate Analysis for OSN = 128HR Death (95%CI)pvalueSurgery0.28 (0.10-0.74)0.01ER positivity0.28 (0.10-0.72)0.01HER2 positivity0.21 (0.06-0.74)0.01MVA included: age, tumor size, ECOG, ER, PR, HER2, met sites, and surgery Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-18-09.

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.

In the era of targeted therapies, patients with gynecologic malignancies have not yet been major beneficiaries of this new class of agents. This may reflect the fact that the main tumor types—ovarian, uterine, and cervical—are a highly heterogeneous group of cancers with variable response to standard chemotherapies and the lack of models in which to study the diversity of these cancers. Cancer-derived cell lines fail to adequately recapitulate molecular hallmarks of specific cancer subsets and complex microenvironments, which may be critical for sensitivity to targeted therapies. Patient-derived xenografts (PDX) generated from fresh human tumor without prior in vitro culture, combined with whole genome expression, gene copy number, and sequencing analyses, could dramatically aid the development of novel therapies for gynecologic malignancies. Gynecologic tumors can be engrafted in immunodeficient mice with a high rate of success and within a reasonable time frame. The resulting PDX accurately recapitulates the patient's tumor with respect to histologic, molecular, and in vivo treatment response characteristics. Orthotopic PDX develop complications relevant to the clinic, such as ascites and bowel obstruction, providing opportunities to understand the biology of these clinical problems. Thus, PDX have great promise for improved understanding of gynecologic malignancies, serve as better models for designing novel therapies and clinical trials, and could underpin individualized, directed therapy for patients from whom such models have been established.

Abstract 4-1BB, a member of the TNFR superfamily, is a costimulatory receptor primarily expressed on activated T cells. It has been shown that the administration of agonistic anti-4-1BB Abs enhances tumor immunity and allogenic immune responses. Paradoxically, we found that the administration of an agonistic anti-4-1BB mAb (2A) dramatically reduced the incidence and severity of experimental autoimmune encephalomyelitis (EAE). Adoptive transfer of T cells from such treated mice failed to induce EAE, whereas anti-4-1BB treatment following adoptive transfer of encephalitogenic T cells did not prevent EAE pathogenesis. These results suggest that anti-4-1BB treatment during the induction phase inhibits autoreactive T cell immune responses rather than preventing T cell trafficking into the CNS. This was substantiated by the observations that draining lymph node cells from anti-4-1BB-treated mice failed to respond to Ag stimulation in vitro. In addition, we found that such treatment initially promotes the activation and proliferation of Ag-specific CD4+ T cells but subsequently increases their probability of undergoing activation-induced cell death, thereby inhibiting effector T cell responses. More importantly, 2A treatment also inhibits the relapse of EAE in a clinically relevant murine model of multiple sclerosis. This study indicates that the agonistic Ab against 4-1BB can potentially be used as a novel immunotherapeutic agent for treating autoimmune diseases.