Citations

BACKGROUNDPublished studies have suggested that most patients with early stage breast cancer are willing, for modest survival benefits, to receive 6 months of adjuvant cyclophosphamide, methotrexate, and 5‐fluorouracil, an older regimen that is used infrequently today. We examined preferences regarding the survival benefit needed to justify 6 months of a contemporary chemotherapy regimen.METHODSThe Eastern Cooperative Oncology Group Protocol 5103 was a phase 3 trial that randomized breast cancer patients to receive standard adjuvant doxorubicin, cyclophosphamide, and paclitaxel with either bevacizumab or placebo. Serial surveys to assess quality of life were administered to patients enrolled between January 1, 2010, and June 8, 2010. Survival benefit needed to justify 6 months of chemotherapy by patients was collected at the 18‐month assessment. A parallel survey was sent to physicians who had enrolled patients in the study.RESULTSOf 519 patients who had not withdrawn at a time point earlier than 18 months, 87.8% responded to this survey. A total of 175 physicians participated. We found considerable variation in patient preferences, particularly for modest survival benefits: for 2 months of benefit, 57% would consider 6 months of chemotherapy, whereas 96% of patients would consider 6 months of chemotherapy for 24 months. Race and education were associated with the choices. Physicians who responded were less likely to accept chemotherapy for modest benefit.CONCLUSIONSAmong patients who received contemporary adjuvant chemotherapy in a randomized controlled trial, we found substantial variation in preferences regarding benefits that justified undergoing chemotherapy. Differences between patients' and physicians' choices were also apparent. Eliciting preferences regarding risks and benefits of adjuvant chemotherapy is critical. Cancer 2017;123:2821–28. © 2017 American Cancer Society.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies lacking effective therapeutic strategies. Here, we show that the noncanonical IκB-related kinase, IKBKE, is a critical oncogenic effector during KRAS-induced pancreatic transformation. Loss of IKBKE inhibits the initiation and progression of pancreatic tumors in mice carrying pancreatic-specific KRAS activation. Mechanistically, we demonstrate that this protumoral effect of IKBKE involves the activation of GLI1 and AKT signaling and is independent of the levels of activity of the NF-κB pathway. Further analysis reveals that IKBKE regulates GLI1 nuclear translocation and promotes the reactivation of AKT post-inhibition of mTOR in PDAC cells. Interestingly, combined inhibition of IKBKE and mTOR synergistically blocks pancreatic tumor growth. Together, our findings highlight the functional importance of IKBKE in pancreatic cancer, support the evaluation of IKBKE as a therapeutic target in PDAC, and suggest IKBKE inhibition as a strategy to improve efficacy of mTOR inhibitors in the clinic. Cancer Res; 77(2); 320–9. ©2017 AACR.

Abstract Background: Data regarding patients (pts) and physicians' preferences for modern adjuvant chemotherapy (CT) are limited. Prior studies suggested that most pts with early stage breast cancer were willing to receive 6 months of adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) for modest survival benefits (e.g. most women would have accepted 3-6 months extension of life). Methods: E5103 was a phase III trial which randomized node positive or high risk node negative breast cancer pts to receive adjuvant CT (doxorubicin, cyclophosphamide and paclitaxel) with either placebo or bevacizumab. Telephone based surveys were administered to all pts enrolled on E5103 between 01/Jan/10 and 08/Jun/10, as part of a Decision-Making/Quality of Life component. Results presented here are part of the 18 months post-enrollment follow-up. Pts were asked to rate the survival benefit needed to justify 6 months of CT. A complementary survey was sent to all physicians who registered at least one pt on E5103. Results: 465 out of 519 eligible pts (90%) responded to this survey at 18 months. Main reasons for non response were: inability to reach the patient (6%) or patient refusal (2%). Median pts age was 51 (25-76); 42% of pts had at least a college degree. The majority had at least Stage II cancer. 179 (16%) physicians participated, among whom median age was 50 (35-70). The median years in practice was 17 (3-38); 78% of physicians worked on large size practices, 72% saw at least 5 new breast cancer pts/month, and 77% enroll between 1-4 pts on trials/month. We found considerable variation in pts preferences particularly for modest survival benefits: a substantial minority of pts (24%) would consider 6 months of CT definitely worthwhile for 1 month survival benefit, 18% would possibly consider it and 56% would not. The percentage considering CT definitely worthwhile increased with greater benefit, but did not reach 100%, even with 24 months survival benefit. About half of pts considered 6 months of CT definitely worthwhile for 9 months benefit, 70% for 12 months and 84% for 24 months. Physicians were less likely to accept CT for a small chance of benefit (34% of pts vs. 5% of physicians would definitely consider CT worthwhile for 2 months of benefit). For longer benefit, pts and physicians choices were similar (84% of pts vs. 92% of physicians would definitely consider CT worthwhile for 24 months benefit). Table Yes, definitely worthwhileYes, maybeNo, not worthwhileNo answerConsider 6 months of CT to live:PtsPhysiciansPtsPhysiciansPtsPhysiciansPts/Physicians*1 month longer24%3%18%15%56%80%2%2 months longer34%5%23%32%41%60%2%6 months longer44%32%35%54%19%12%2%9 months longer53%51%34%42%11%5%2%12 months longer70%75%23%22%5%1%2%24 months longer84%92%12%5%2%1%2%n Pts= 465; n Physicians= 179; * equal results in both groups Conclusions: This subgroup of pts who had undergone modern adjuvant CT in a large multicenter randomized controlled trial and these physicians who registered pts on the same trial had different cutoffs for acceptable levels of benefits and risks when considering adjuvant chemotherapy. It is important to engage pts in determining whether CT is or is not a "reasonable" option for treatment. Citation Format: Vaz Luis I, O'Neill A, Sepucha K, Miller KD, Baker E, Dang CT, Northfelt DW, Winer EP, Sledge GW, Schneider BP, Partridge A. Survival benefit needed to undergo chemotherapy: Patients and physicians preferences. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-11-02.

Despite years of preclinical development, biological interventions designed to treat complex diseases such as asthma often fail in phase III clinical trials. These failures suggest that current methods to analyze biomedical data might be missing critical aspects of biological complexity such as the assumption that cases and controls come from homogeneous distributions. Here we discuss why and how methods from the rapidly evolving field of visual analytics can help translational teams (consisting of biologists, clinicians, and bioinformaticians) to address the challenge of modeling and inferring heterogeneity in the proteomic and phenotypic profiles of patients with complex diseases. Because a primary goal of visual analytics is to amplify the cognitive capacities of humans for detecting patterns in complex data, we begin with an overview of the cognitive foundations for the field of visual analytics. Next, we organize the primary ways in which a specific form of visual analytics called networks has been used to model and infer biological mechanisms, which help to identify the properties of networks that are particularly useful for the discovery and analysis of proteomic heterogeneity in complex diseases. We describe one such approach called subject‐protein networks, and demonstrate its application on two proteomic datasets. This demonstration provides insights to help translational teams overcome theoretical, practical, and pedagogical hurdles for the widespread use of subject‐protein networks for analyzing molecular heterogeneities, with the translational goal of designing biomarker‐based clinical trials, and accelerating the development of personalized approaches to medicine.

Abstract Background: A previous feasibility trial (E2104 – Ann Oncol 23(2):331–7,2012) suggested incorporation of B into anthracycline-containing adjuvant therapy was feasible but ongoing cardiac monitoring was required to define the true impact of B on cardiac function. Methods: Patients (pts) were assigned 1:2:2 to one of three treatment arms. In addition to doxorubicin and cyclophosphamide followed by weekly paclitaxel, patients received either placebo (Arm A – AC>T) or B during chemotherapy (Arm B - BAC>BT), or B during chemotherapy followed by B monotherapy (15 mg/kg q3wk) for an additional 10 cycles (Arm C – BAC>BT>B). Randomization was stratified and B dose adjusted for choice of AC schedule (classical q3wk − 15 mg/kg; dose dense(dd) q2 wk − 10 mg/kg). When indicated, radiation and hormonal therapy were administered concurrently with B (for Arm C pts). The primary cardiac endpoint was the incidence of clinically apparent cardiac dysfunction (CHF)defined as symptomatic decline in left ventricular ejection fraction (LVEF) to below the lower limit of normal (LLN) or symptomatic diastolic dysfunction as assessed by independent review. Cumulative toxicity data as of Jan 23, 2012 are presented. Results: From 11.07 to 2.11, 4994 pts were enrolled. Median age was 52; 80% received ddAC. Chemotherapy associated toxicities including myelosuppression (Grade 4 neutropenia 16/20/19%) and neuropathy (Grade ≥ 3 8/8/8%) were similar across all arms. Grade ≥ 3 hypertension/thrombosis/proteinuria/hemorrhage was reported by 7/3/<1/<1% of B-treated pts. 99 pts developed CHF, most commonly reported at the post-AC or post-T evaluation. After a median follow-up of 26 months, the cumulative incidence of clinical CHF at 15 months from randomization in Arm A/B/C was 1.0/1.7/2.9% respectively. Median age of CHF pts was 57; median baseline LVEF of CHF pts was 60. Conclusion: Incorporation of B into anthracycline and taxane containing adjuvant therapy results in a significant but small increase in clinical CHF. The rate of clinical CHF is similar to that predicted by E2104 (2.5–2.9%) and reported In the FDA label for anthracycline pre-treated pts(3.8%). No unexpected toxicities were encountered. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-17-01.