Kerin B. Adelson

The Theoretical Basis of Transcriptional Therapy of Cancer: Can It Be Put Into Practice?

Aberrant gene silencing is a frequent event in cancer and plays a critical role in the molecular pathogenesis of malignant transformation. The two major mechanisms of silencing in cancer include transcriptional repression by mutated or aberrantly expressed transcription factors, and aberrant epigenetic silencing by hypermethylation of tumor suppressor or DNA repair-related genes. Both of these mechanisms require the activities of multiprotein chromatin remodeling and modifying machines, several of which may be mutated in cancer. The end result is genetic reprogramming of cells to express combinations of genes that confer the neoplastic phenotype. Recent discoveries in transcriptional biochemistry and gene regulation indicate that therapeutic agents can be engineered to specifically target these mechanisms. We provide a framework for the clinical or translational scientist to consider how such drugs might be developed and what their impact might be on restoring cells to normal genetic programming.

Standardized Criteria for Palliative Care Consultation on a Solid Tumor Oncology Service Reduces Downstream Health Care Use

PURPOSE Hospitalized patients with advanced cancer have a high symptom burden and need for support. Integration of palliative care (PC) improves symptom control and decreases unwanted health care use, yet many patients are never offered these services. In 2016, ASCO called for incorporation of PC into oncologic care for all patients with metastatic cancer. To improve the quality of cancer care, we developed standardized criteria, or triggers, for PC consultation on the inpatient solid tumor service. METHODS Patients were eligible for this prospective cohort study if they met at least one of the following eligibility criteria: had an advanced solid tumor; prior hospitalization within 30 days; hospitalization > 7 days; and active symptoms. During the intervention, patients who met the criteria received automatic PC consultation. RESULTS When we compared patients in the intervention group with control subjects, there were increases in PC consultations (19 of 48 [39%] to 52 of 65 [80%]; P ≤ .001) and hospice referrals (seven of 48 [14%] to 17 of 65 [26%]; P = .03), and there were declines in 30-day readmission rates (17 of 48 [35%] to 13 of 65 [18%]; P = .04) and receipt of chemotherapy after discharge (21 of 48 [44%] to 12 of 65 [18%]; P = .03). There was an overall increase in support measures following discharge ( P = .004). Length of stay was unaffected. CONCLUSION To our knowledge, this is the first study to demonstrate that among patients with advanced cancer admitted to an inpatient oncology service, the standardized use of triggers for PC consultation is associated with substantial impact on 30-day readmission rates, chemotherapy following discharge, hospice referrals, and use of support services following discharge. Expansion of this model to other hospitals and health systems should improve the value of cancer care.

Trends in end-of-life cancer care in the Medicare program

OBJECTIVES To examine contemporary trends in end-of-life cancer care and geographic variation of end-of-life care aggressiveness among Medicare beneficiaries. MATERIALS AND METHODS Using the Surveillance, Epidemiology, and End Results-Medicare data, we identified 132,051 beneficiaries who died as a result of cancer in 2006-2011. Aggressiveness of end-of-life care was measured by chemotherapy received within 14 days of death, >1 emergency department (ED) visit within 30 days of death, >1 hospitalization within 30 days of death, ≥1 intensive care unit (ICU) admission within 30 days of death, in-hospital death, or hospice enrollment ≤3 days before death. Using hierarchical generalized linear models, we assessed potentially aggressive end-of-life care adjusting for patient demographics, tumor characteristics, and hospital referral region (HRR)-level market factors. RESULTS The proportion of beneficiaries receiving at least one potentially aggressive end-of-life intervention increased from 48.6% in 2006 to 50.5% in 2011 (P<.001). From 2006 to 2011, increases were apparent in repeated hospitalization (14.1% vs. 14.8%; P=.01), repeated ED visits (34.3% vs. 36.6%; P<.001), ICU admissions (16.2% vs. 21.3%; P<.001), and late hospice enrollment (11.2% vs. 12.9%; P<.001), whereas in-hospital death declined (23.5% vs. 20.9%; P<.001). End-of-life chemotherapy use (4.4% vs. 4.5%) did not change significantly over time (P=.12). The use of potentially aggressive end-of-life care varied substantially across HRRs, ranging from 40.3% to 58.3%. Few HRRs had a decrease in aggressive end-of-life care during the study period. CONCLUSIONS Despite growing focus on providing appropriate end-of-life care, there has not been an improvement in aggressive end-of-life cancer care in the Medicare program.

Standardized criteria for required palliative care consultation on the solid tumor oncology service.

37 Background: Studies have shown that routine integration of Palliative Care (PC) for patients with advanced cancer is associated with improved symptom control, clearer understanding of prognosis, lower utilization of health care resources, and increased hospice use. The 2012 ASCO guidelines call for incorporation of PC for any patient with metastatic cancer and/or high symptom burden. Despite a top-rated PC division at Mount Sinai, our Solid Tumor (ST) Division utilized PC and hospice less than other medical centers. Our inpatient ST service consistently demonstrated poor quality metrics. Our 2011-2012 UHC statistics were: mortality index, 1.35 (target <1), 30-day readmission rate, 21.7%, (target < 10.3%) and length of stay (LOS) index, 1.23 (target <1). We hypothesized that implementing standardized criteria for PC consultation would improve these metrics. METHODS During this 3-month pilot, criteria for PC consultation included patients with one or more of the following: stage IV disease, Stage III lung or pancreatic cancer, hospitalization within prior 30 days, >7 day hospitalization, uncontrolled symptoms (pain, nausea, dyspnea, delirium, distress). We looked at two baseline groups for comparison: 1) patients who met eligibility in a six week period prior to the intervention 2) For UHC index data, we used the hospital dashboard average over a 1-year period prior to the intervention. This included all ST patients who were eligible for the intervention (60%) and those who were not (40%). Primary outcomes were: hospice utilization, ST mortality index, 30-day readmission rate and LOS. RESULTS Comparing Group 1 to the Pilot Group, palliative care consultation doubled from 41% to 82%, 30-day readmission decreased from 36% to 17% (p= .022), and hospice utilization increased from 14% to 25% (p=.146). UHC data (Group 2 vs. Pilot) showed: mortality index improved (1.35 to .59) and 30-day readmission rates decreased (21.7% to 13.5%, p=.026). LOS was unchanged (1.23 to 1.25). CONCLUSIONS Mandating palliative care consults for patients at the highest risk for in hospital death and readmission improved hospice utilization, 30-day readmission, oncology service mortality and adherence with ASCO guidelines.

Implementation of Electronic Chemotherapy Ordering: An Opportunity to Improve Evidence-Based Oncology Care

PURPOSE The degree to which electronic health records (EHRs) enhance the quality of patient care depends on use of the system to monitor and improve practice. In planning the transition to Epics Beacon electronic chemotherapy ordering platform, we saw an opportunity to measure our performance and increase evidence-based practice. METHODS Advanced planning began 2 years before implementation and included formation of a chemotherapy council charged with reviewing references and approving each chemotherapy protocol; a readiness assessment; design of electronic flow-sheet adherent with Oncology Nursing Society guidelines. To monitor use of evidence-based treatments, we created a novel quality metric: the rate of evidence-based adherence (REBA). RESULTS A full infusion schedule was maintained through implementation, with a transient 1-month increase in wait time. Our overall REBA of 0.86 significantly exceeded our prespecified goal of 0.80 (P = .001). REBA varied from 0.50 to 0.95 between disease groups. Antiemetic use increased by 20% after Beacon implementation. Provider satisfaction at 8 months ranged from 76% to 80%. CONCLUSION The transition to electronic chemotherapy ordering offers an institution the chance to develop evidence-based oncology practice, standardize supportive care, and enhance patient safety. The key elements that made our transition so successful were (1) extensive involvement of oncology leadership, (2) use of a chemotherapy council to enforce evidence-based practice, (3) ongoing collaboration between clinical operations and information technology. Finally, the REBA is a powerful tool to monitor adherence to evidence-based chemotherapy prescribing.

Lactation opposes pappalysin‐1‐driven pregnancy‐associated breast cancer

Pregnancy is associated with a transient increase in risk for breast cancer. However, the mechanism underlying pregnancy‐associated breast cancer (PABC) is poorly understood. Here, we identify the protease pappalysin‐1 (PAPP‐A) as a pregnancy‐dependent oncogene. Transgenic expression of PAPP‐A in the mouse mammary gland during pregnancy and involution promotes the deposition of collagen. We demonstrate that collagen facilitates the proteolysis of IGFBP‐4 and IGFBP‐5 by PAPP‐A, resulting in increased proliferative signaling during gestation and a delayed involution. However, while studying the effect of lactation, we found that although PAPP‐A transgenic mice lactating for an extended period of time do not develop mammary tumors, those that lactate for a short period develop mammary tumors characterized by a tumor‐associated collagen signature (TACS‐3). Mechanistically, we found that the protective effect of lactation is associated with the expression of inhibitors of PAPP‐A, STC1, and STC2. Collectively, these results identify PAPP‐A as a pregnancy‐dependent oncogene while also showing that extended lactation is protective against PAPP‐A‐mediated carcinogenesis. Our results offer the first mechanism that explains the link between breast cancer, pregnancy, and breastfeeding.

Association of Broad-Based Genomic Sequencing With Survival Among Patients With Advanced Non–Small Cell Lung Cancer in the Community Oncology Setting

Importance Broad-based genomic sequencing is being used more frequently for patients with advanced non–small cell lung cancer (NSCLC). However, little is known about the association between broad-based genomic sequencing and treatment selection or survival among patients with advanced NSCLC in a community oncology setting. Objective To compare clinical outcomes between patients with advanced NSCLC who received broad-based genomic sequencing vs a control group of patients who received routine testing for EGFR mutations and/or ALK rearrangements alone. Design, Setting, and Participants Retrospective cohort study of patients with chart-confirmed advanced NSCLC between January 1, 2011, and July 31, 2016, and who received care at 1 of 191 oncology practices across the United States using the Flatiron Health Database. Patients were diagnosed with stage IIIB/IV or unresectable nonsquamous NSCLC who received at least 1 line of antineoplastic treatment. Exposures Receipt of either broad-based genomic sequencing or routine testing (EGFR and/or ALK only). Broad-based genomic sequencing included any multigene panel sequencing assay examining more than 30 genes prior to third-line treatment. Main Outcomes and Measures Primary outcomes were 12-month mortality and overall survival from the start of first-line treatment. Secondary outcomes included frequency of genetic alterations and treatments received. Results Among 5688 individuals with advanced NSCLC (median age, 67 years [interquartile range, 41-85], 63.6% white, 80% with a history of smoking); 875 (15.4%) received broad-based genomic sequencing and 4813 (84.6%) received routine testing. Among patients who received broad-based genomic sequencing, 4.5% received targeted treatment based on testing results, 9.8% received routine EGFR/ALK targeted treatment, and 85.1% received no targeted treatment. Unadjusted mortality rates at 12 months were 49.2% for patients undergoing broad-based genomic sequencing and 35.9% for patients undergoing routine testing. Using an instrumental variable analysis, there was no significant association between broad-based genomic sequencing and 12-month mortality (predicted probability of death at 12 months, 41.1% for broad-based genomic sequencing vs 44.4% for routine testing; difference −3.6% [95% CI, −18.4% to 11.1%]; P = .63). The results were consistent in the propensity score–matched survival analysis (42.0% vs 45.1%; hazard ratio, 0.92 [95% CI, 0.73 to 1.11]; P = .40) vs unmatched cohort (hazard ratio, 0.69 [95% CI, 0.62 to 0.77]; log-rank P < .001). Conclusions and Relevance Among patients with advanced non–small cell lung cancer receiving care in the community oncology setting, broad-based genomic sequencing directly informed treatment in a minority of patients and was not independently associated with better survival.

Randomized phase II trial of fulvestrant alone or in combination with bortezomib in hormone receptor-positive metastatic breast cancer resistant to aromatase inhibitors: a New York Cancer Consortium trial

The proteasome inhibitor bortezomib enhances the effect of the selective estrogen receptor (ER) downregulator (SERD) fulvestrant by causing accumulation of cytoplasmic ER aggregates in preclinical models. The purpose of this trial was to determine whether bortezomib enhanced the effectiveness of fulvestrant. One hundred eighteen postmenopausal women with ER-positive metastatic breast cancer resistant to aromatase inhibitors (AIs) were randomized to fulvestrant alone (Arm A—500 mg intramuscular (i.m.) day −14, 1, 15 in cycle 1, and day 1 of additional cycles) or in combination with bortezomib (Arm B—1.6 mg/m2 intravenous (i.v.) on days 1, 8, 15 of each cycle). The study was powered to show an improvement in median progression-free survival (PFS) from 5.4 to 9.0 months and compare PFS rates at 6 and 12 months (α=0.10, β=0.10). Patients with progression on fulvestrant could cross over to the combination (arm C). Although there was no difference in median PFS (2.7 months in both arms), the hazard ratio for PFS in Arm B versus Arm A (referent) was 0.73 (95% confidence interval (CI)=0.49, 1.09, P=0.06, 1-sided log-rank test, significant at the prespecified 1-sided 0.10 α level). At 12 months, the PFS proportion in Arm A and Arm B was 13.6% and 28.1% (P=0.03, 1-sided χ2-test; 95% CI for difference (14.5%)=−0.06, 29.1%). Of 27 patients on arm A who crossed over to the combination (arm C), 5 (18%) were progression-free for at least 24 weeks. Bortezomib likely enhances the effectiveness of fulvestrant in AI-resistant, ER-positive metastatic breast cancer by reducing acquired resistance, supporting additional evaluation of proteasome inhibitors in combination with SERDs.

Impacts of Early Guideline-Directed 21-Gene Recurrence Score Testing on Adjuvant Therapy Decision Making

PURPOSE The 21-gene recurrence score (RS) assay is used to help formulate adjuvant chemotherapy recommendations for patients with estrogen receptor-positive, early-stage breast cancer. Most frequently, medical oncologists order RS after surgery. Results take an additional 2 weeks to return, which can delay decision making. We conducted a prospective quality-improvement project to assess the impact of early guideline-directed RS ordering by surgeons before the first visit with a medical oncologist on adjuvant therapy decision making. MATERIALS AND METHODS Surgical oncologists ordered RS testing following National Comprehensive Cancer Network guidelines at time of diagnosis or at time of surgery between July 1, 2015 and December 31, 2015. We measured the testing rate of patients eligible for RS, time to chemotherapy decisions, rates of chemotherapy use, accrual to RS-based clinical trials, cost, and physician acceptance of the policy and compared the results to patients who met eligibility criteria for early guideline-directed testing during the 6 months before the project. RESULTS Ninety patients met eligibility criteria during the testing period. RS was ordered for 91% of patients in the early testing group compared with 76% of historical controls ( P < .001). Median time to chemotherapy decision was significantly shorter in the early testing group (20 days; 95% CI, 17 to 23 days) compared with historical controls (32 days; 95% CI, 29 to 35 days; P < .001). There were no significant differences in time to chemotherapy initiation, chemotherapy use, RS-based trial enrollment, or calculated costs between the groups. CONCLUSION Early guideline-directed RS testing in selected patients is an effective way to shorten time to treatment decisions.

Speed of Adoption of Immune Checkpoint Inhibitors of Programmed Cell Death 1 Protein and Comparison of Patient Ages in Clinical Practice vs Pivotal Clinical Trials

Importance The US Food and Drug Administration (FDA) is increasing its pace of approvals for novel cancer therapeutics, including for immune checkpoint inhibitors of programmed cell death 1 protein (anti–PD-1 agents). However, little is known about how quickly anti–PD-1 agents agents reach eligible patients in practice or whether such patients differ from those studied in clinical trials that lead to FDA approval (pivotal clinical trials). Objectives To assess the speed with which anti–PD-1 agents agents reached eligible patients in practice and to compare the ages of patients treated in clinical practice with the ages of those treated in pivotal clinical trials. Design, Setting, and Participants This retrospective cohort study, performed from January 1, 2011, through August 31, 2016, included patients from the Flatiron Health Network who were eligible for anti–PD-1 agents treatment of selected cancer types, which included melanoma, non–small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Main Outcomes and Measures Cumulative proportions of eligible patients receiving anti–PD-1 agents treatment and their age distributions. Results The study identified 3089 patients who were eligible for anti–PD-1 agents treatment (median age, 66 [interquartile range, 56-75] years for patients with melanoma, 66 [interquartile range, 58-72] years for patients with RCC, and 67 [interquartile range, 59-74] years for patients with NSCLC; 1742 male [56.4%] and 1347 [43.6%] female; 2066 [66.9%] white). Of these patients, 2123 (68.7%) received anti–PD-1 agents treatment, including 439 eligible patients with melanoma (79.1%), 1417 eligible patients with NSCLC (65.6%), and 267 eligible patients with RCC (71.2%). Within 4 months after FDA approval, greater than 60% of eligible patients in each cohort had received anti–PD-1 agents treatment. Overall, similar proportions of older and younger patients received anti–PD-1 agents treatment during the first 9 months after FDA approval. However, there were significant differences in age between clinical trial participants and patients receiving anti–PD-1 agents treatment in clinical practice, with more patients being older than 65 years in clinical practice (range, 327 of 1365 [60.6%] to 46 of 72 [63.9%]) than in pivotal clinical trials (range, 38 of 120 [31.7%] to 223 of 544 [41.0%]; all P < .001). Conclusions and Relevance Anti-PD-1 agents rapidly reached patients in clinical practice, and patients treated in clinical practice differed significantly from patients treated in pivotal clinical trials. Future actions are needed to ensure that rapid adoption occurs on the basis of representative trial evidence.