Citations

PURPOSE: Routine use of extended-fraction (> 10 fractions) radiation therapy (RT) for palliation of bone metastases is recognized as a low-value intervention by the American Society for Radiation Oncology. We examined contemporary practice patterns of, and physician characteristics associated with extended-fraction RT use. MATERIALS AND METHODS: We conducted a retrospective cohort study using Medicare fee-for-service data. We included patients who underwent 2- or 3-dimensional external-beam RT for bone metastases between January 1, 2016, and December 31, 2018. Physicians treating > 10 patients over the study period were analyzed for their individual practice. Hierarchic logistic regression modeling was used to identify patient- and physician-level factors associated with extended-fraction RT use. RESULTS: A total of 12,221 patients (median age, 75.6 years; 40.9% women, 87.6% white) were included. The rate of extended-fraction RT was 23.4%. A total of 1,432 physicians treated any patient. Among the 382 physicians treating > 10 patients, 127 (33.2%) used extended-fraction RT > 30% (consensus threshold). Physician factors associated with decreased odds of extended-fraction RT were years since medical school graduation (≤ 10 years and 11-20 years v ≥ 31 years: adjusted odds ratio [aOR], 0.32 [95% CI, 0.20 to 0.51] and 0.64 [95% CI, 0.44 to 0.93]) and practicing in the Northeast or Midwest versus the South (aOR, 0.36 [95% CI, 0.22 to 0.58] and 0.48 [95% CI, 0.31 to 0.74]). Physicians treating > 20 patients ( v 11-14 patients) over the study period had increased odds of delivering extended-fraction RT (aOR, 1.53 [95% CI, 1.10 to 2.12]). CONCLUSION: In this study, almost one fourth of patients received extended-fraction RT, and one third of physicians had an extended-fraction RT use rate of > 30%. Personalized feedback of performance data, clinical pathways and peer review, and updated reimbursement models are potential mechanisms to address this low-value care.

PURPOSE To develop recommendations for management of patients with breast cancer (BC) with germline mutations in BC susceptibility genes. METHODS The American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology convened an Expert Panel to develop recommendations based on a systematic review of the literature and a formal consensus process. RESULTS Fifty-eight articles met eligibility criteria and formed the evidentiary basis for the local therapy recommendations; six randomized controlled trials of systemic therapy met eligibility criteria. RECOMMENDATIONS Patients with newly diagnosed BC and BRCA1/ 2 mutations may be considered for breast-conserving therapy (BCT), with local control of the index cancer similar to that of noncarriers. The significant risk of a contralateral BC (CBC), especially in young women, and the higher risk of new cancers in the ipsilateral breast warrant discussion of bilateral mastectomy. Patients with mutations in moderate-risk genes should be offered BCT. For women with mutations in BRCA1/ 2 or moderate-penetrance genes who are eligible for mastectomy, nipple-sparing mastectomy is a reasonable approach. There is no evidence of increased toxicity or CBC events from radiation exposure in BRCA1/ 2 carriers. Radiation therapy should not be withheld in ATM carriers. For patients with germline TP53 mutations, mastectomy is advised; radiation therapy is contraindicated except in those with significant risk of locoregional recurrence. Platinum agents are recommended versus taxanes to treat advanced BC in BRCA carriers. In the adjuvant/neoadjuvant setting, data do not support the routine addition of platinum to anthracycline- and taxane-based chemotherapy. Poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and talazoparib) are preferable to nonplatinum single-agent chemotherapy for treatment of advanced BC in BRCA1/ 2 carriers. Data are insufficient to recommend PARP inhibitor use in the early setting or in moderate-penetrance carriers. Additional information available at www.asco.org/breast-cancer-guidelines .

The World Health Organization (WHO) has declared coronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a pandemic. Global health care now faces unprecedented challenges with widespread and rapid human-to-human transmission of SARS-CoV-2 and high morbidity and mortality with COVID-19 worldwide. Across the world, medical care is hampered by a critical shortage of not only hand sanitizers, personal protective equipment, ventilators, and hospital beds, but also impediments to the blood supply. Blood donation centers in many areas around the globe have mostly closed. Donors, practicing social distancing, some either with illness or undergoing self-quarantine, are quickly diminishing. Drastic public health initiatives have focused on containment and “flattening the curve” while invaluable resources are being depleted. In some countries, the point has been reached at which the demand for such resources, including donor blood, outstrips the supply. Questions as to the safety of blood persist. Although it does not appear very likely that the virus can be transmitted through allogeneic blood transfusion, this still remains to be fully determined. As options dwindle, we must enact regional and national shortage plans worldwide and more vitally disseminate the knowledge of and immediately implement patient blood management (PBM). PBM is an evidence-based bundle of care to optimize medical and surgical patient outcomes by clinically managing and preserving a patient’s own blood. This multinational and diverse group of authors issue this “Call to Action” underscoring “The Essential Role of Patient Blood Management in the Management of Pandemics” and urging all stakeholders and providers to implement the practical and commonsense principles of PBM and its multiprofessional and multimodality approaches.

Abstract As part of a randomized, prospective clinical trial in large cell lymphoma, we conducted serial fluorodeoxyglucose positron emission tomography (FDG-PET) at baseline, after 2 cycles of chemotherapy (interim PET [i-PET]), and at end of treatment (EoT) to identify biomarkers of response that are predictive of remission and survival. Scans were interpreted in a core laboratory by 2 imaging experts, using the visual Deauville 5-point scale (5-PS), and by calculating percent change in FDG uptake (change in standardized uptake value [ΔSUV]). Visual scores of 1 through 3 and ΔSUV ≥66% were prospectively defined as negative. Of 524 patients enrolled in the parent trial, 169 agreed to enroll in the PET substudy and 158 were eligible for final analysis. In this selected population, all had FDG-avid disease at baseline; by 5-PS, 55 (35%) remained positive on i-PET and 28 (18%) on EoT PET. Median ΔSUV on i-PET was 86.2%. With a median follow-up of 5 years, ΔSUV, as continuous variable, was associated with progression-free survival (PFS) (hazard ratio [HR] = 0.99; 95% confidence interval [CI], 0.97-1.00; P = .02) and overall survival (OS) (HR, 0.98; 95% CI, 0.97-0.99; P = .03). ΔSUV ≥66% was predictive of OS (HR, 0.31; 95% CI, 0.11-0.85; P = .02) but not PFS (HR, 0.47; 95% CI, 0.19-1.13; P = .09). Visual 5-PS on i-PET did not predict outcome. ΔSUV, but not visual analysis, on i-PET predicted OS in DLBCL, although the low number of events limited the statistical analysis. These data may help guide future clinical trials using PET response-adapted therapy. This trial was registered at www.clinicaltrials.gov as #NCT00118209.

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 369 nominally genome-wide significant loci ( P < 5 × 10 −8 ) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 360 loci for which replication data were available, 241 loci influencing surface area and 66 influencing thickness remained significant after replication, with 237 loci passing multiple testing correction ( P < 8.3 × 10 −10 ; 187 influencing surface area and 50 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation ( r G = −0.32, SE = 0.05, P = 6.5 × 10 −12 ), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 46 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function. Identifying genetic influences on human cortical structure. ( A ) Measurement of cortical surface area and thickness from MRI. ( B ) Genomic locations of common genetic variants that influence global and regional cortical structure. ( C ) Our results support the radial unit hypothesis that the expansion of cortical surface area is driven by proliferating neural progenitor cells. ( D ) Cortical surface area shows genetic correlation with psychiatric and cognitive traits. Error bars indicate SE. IMAGE CREDITS: (A) K. COURTNEY; (C) M. R. GLASS

5544 Background: Pazopanib, an orally bioavailable multitargeted inhibitor of kinases including VEGF-R, demonstrated impressive activity in metastatic differentiated thyroid cancer (49% durable RECIST PRs) and promising preclinical activity in anaplastic thyroid cancer (ATC) models, prompting its evaluation also as a candidate therapeutic in advanced ATC. Methods: A multicenter single arm phase II trial of 800 mg pazopanib daily was undertaken with the primary endpoint of RECIST response rate. The trial was designed such that there would be a 90% chance of detecting a response rate of >20% at the 0.10 significance level when the true tumor response rate is >5%. A pre-specified stopping rule designated that enrollment would cease unless 1 or more RECIST PRs+CRs were observed in the first 14 of 33 potential patients. Eligibility required informed consent, >18 years of age, performance status ECOG 0-2, systolic blood pressure (BP) <140 mm Hg and diastolic BP <90 mm Hg at entry, QTc interval <480 msecs, and measurable disease by RECIST criteria. Anatomical imaging and toxicity evaluations were required every 4 weeks. Results: Sixteen patients were enrolled. One patient withdrew prior to therapy, leaving 15 evaluable patients – 33.3% were male, with a median age of 66 years (range 45-77); 11 of 15 patients had progressed through prior systemic therapy. Four patients required 1-2 dose reductions, with the most common severe toxicities (CTC-AE version 3.0 grades 3-5) hypertension (13%) and pharyngolaryngeal pain (13%). Reasons for treatment discontinuation included: disease progression (12 pts), death on study due to a vascular event possibly related to treatment (1 pt.), and intolerability (radiation recall tracheitis – 1 pt, and uncontrolled hypertension – 1 pt). Although transient disease regression was observed in several patients, there were no confirmed RECIST tumor responses, triggering study closure at time of interim analysis. Two patients are alive with disease 9.9 months and 2.9 years post-registration; the remaining 13 died of disease. The median time to progression was 62 days and the median survival time was 111 days. Conclusions: Pazopanib has poor single agent activity in advanced anaplastic thyroid cancer.

1059 Background: Relapsed TNBC is characterized by its poor prognosis. B is a synthetic DNA minor groove binding non-cross resistant agent that is fully active against DNA-mismatch repair deficient tumor cells. C increases GSH/GST in which enhances the efficacy of B. Methods: Phase II study in pts with mTNBC. C Day 1 followed by B Day 2, repeated every 21 days. Aim: Efficacy of C + B in mTNBC. Primary endpoint: PFS at 3 mo. Secondary endpoints include ORR, duration of response (DOR), 6-mo PFS, OS and AE profile. Tertiary endpoints include assessment of baseline GSH levels, prevalence of BCRA1 mutation and pERK, and correlations with outcome. Results: Closed 3/2012. 48 pts accrued (1 ineligible pt). Median f/u 11.4 mo (6.6-14.8); 2 pts still on treatment. 47 pts evaluable for the PFS endpoint and AEs. 49% received therapy as 3rd-5th line. Median number of cycles = 4 (range 1-15). There are currently 9 confirmed responses (8 PR and 1 CR); DOR = 2.6-14.5 mo. The 3-mo PFS = 51%; 6-mo PFS = 28%; the median TTP is 3.2 mo. AE data: 75% G3/4 hematologic AE: febrile neutropenia 19%. Non-hematologic AEs included G3 (47%) and G4 (15%): G3 fatigue 17%; and no G5 non-heme AE. No correlation of GSH/GST levels with outcome was found. Among 35 pts with evaluable data, no association between BRCA1 expression and outcomes was found. pERK expression was negatively associated with 3-mo PFS, but not 6-mo PFS. Cytoplasmic pERK expression was negatively associated with tumor response (p=0.03). No significant effect of BRCA-1 or pERK expression was found on OS. Conclusions: This trial showed B + C is an active regimen, especially in heavily pretreated mTNBC pts. Correlative data demonstrated a negative association between pERK expression and outcomes. A randomized phase II trial is in development. Clinical trial information: NCT01091454.

Abstract Aims Left ventricular (LV) remodelling after ST-segment elevation myocardial infarction (STEMI) worsens outcome. The effect of sex on LV post-infarct remodelling is unknown. We therefore investigated the sex distribution and long-term prognosis of LV post-infarct remodelling after STEMI in the contemporary era of primary percutaneous coronary intervention (PCI) and optimal pharmacotherapy. Methods and results Data were obtained from an ongoing primary PCI STEMI registry. LV remodelling was defined as ≥20% increase in LV end-diastolic volume at either 3, 6, or 12 months post-infarct, and LV remodelling impact on outcome was evaluated with a log-rank test. A total population of 1995 STEMI patients were analysed (mean age 60 ± 12 years): 1527 (77%) men and 468 (23%) women. The mean age of male patients was 60±11 versus 63±13 years for women (P &lt; 0.001). A total of 953 (48%) patients experienced LV remodelling in the first 12 months of follow-up, and it was equally frequent amongst men (n = 729, 48%) and women (n = 224, 48%). After a median follow-up of 94 (interquartile range 69–119) months, 225 patients died: 171 (11%) men and 54 (12%) women. No survival difference was seen between remodellers and non-remodellers in the male (P = 0.113) and female (P = 0.920) groups. Conclusion LV post-infarct remodelling incidence, as well as long-term survival of LV remodellers and non-remodellers, was similar in men and women who were treated with primary PCI and optimal pharmacotherapy post-STEMI.

Background: Novel agent induction and AHCT remains the preferred initial therapeutic strategy for transplant-eligible MM patients. Current prognostic tools in MM focus solely on disease-specific factors at diagnosis to determine patient prognosis-International Staging System (ISS) and revised-ISS (R-ISS). A major limitation to both, the ISS and R-ISS, is that they are not specific for HCT-eligible patients and do not take into account other patient factors that may enter into a decision to pursue AHCT. The data used to generate these staging systems were from broad populations with varying upfront treatment strategies and included patients who were ineligible for intensive therapy. Additionally, there is considerable interest in identifying the population that relapses early despite modern induction/AHCT approaches who are candidates for novel approaches for maintenance/consolidation. To address these problems, we used data from the Center for Blood and Marrow Transplant Research (CIBMTR) registry to identify disease-, patient-, and transplantation-specific variables that are associated with progression-free survival (PFS) in patients undergoing upfront AHCT (within 12 months of diagnosis). Methods: We used the outcomes of 2528 MM patients undergoing upfront AHCT from 2008-2017 reported to the CIBMTR. Patients were divided into training and validation sets with a 50% random split. High risk cytogenetics was defined as the presence of one or more of the following: t(4;14), t (14;16), t (14;20), del 13q, del 17p, 1q gain, or 1p deletion. We used a Cox multivariable model to identify factors prognostic of progression free survival (PFS) in a training subset. The regression coefficients of the final model was transformed into a risk score with an appropriate transformation. A weighted score using these factors was assigned to the training cohort (n = 917) and validation cohort (n=897) using subset that had all values that entered the final model. Kaplan-Meier estimates of the individual scores were used to classify patients into risk groups for both cohorts. Results: Baseline characteristics of these patients are shown in Table 1. No cytogenetic abnormality, VRD induction, pre-AHCT bone marrow plasma cells (BMPCs) &lt;10% and 1 line of induction chemotherapy were assigned 0 points. Pre-AHCT BMPCs ≥10% (hazard ratio HR, 1.47; 95% CI, 1.19-1.83), use of ≥2 lines of induction chemotherapy prior to AHCT (HR 1.32; 95% CI 1.06-1.64), standard cytogenetic risk vs. no abnormality (HR 1.41; 95% CI 1.13-1.77) and induction regimens (non-VRD regimens vs. VRD) (HR 1.4, 95% CI 1.17-1.74) were associated with increased hazard of progression and assigned 1 point in the scoring system. Presence of high-risk cytogenetics vs. no abnormality (HR 1.87; 95% CI 1.45-2.42) was assigned 2 points, and the use of thalidomide and dexamethasone (TD) as an induction regimen (HR 2.19; 95% CI 1.48-3.2) was assigned 3 points. A two-category system was created based on the scoring: low risk (0-3) and high risk (4-6). The scoring system was prognostic for PFS when applied to both cohorts. High-risk group was found to have significantly higher risk of progression and/or death compared to low risk in training (HR 2.2; 95% CI 1.74-2.86; p&lt;0.0001) and validation cohort (HR 1.7, 95% CI 1.30-2.22; p=0.0001) respectively (Table 2). The 3-year PFS in the training cohort was 60% (95% CI 56%-64%) in low risk and 27% (95% CI 17%- 36%) in high risk while in the validation cohort was 51% (95% CI 47%-55%) in low risk and 28% (95% CI 16%- 39%) in high risk (Figure 1A and 1B). Conclusions: We describe a prognostic model specifically for patients undergoing upfront AHCT in MM which can identify patients at very high risk for early relapse/progression. These patients should be ideal candidates for studies of immunotherapy or other interventions after AHCT aimed at reducing relapse. Disclosures Dhakal: Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Shah:Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees; University of California, San Francisco: Employment; Poseida: Research Funding; Indapta Therapeutics: Equity Ownership; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding. Qazilbash:Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy; Bioclinical: Consultancy; Genzyme: Other: Speaker. D'Souza:EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees. Hari:AbbVie: Consultancy, Honoraria; Cell Vault: Equity Ownership; Sanofi: Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Amgen: Research Funding; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.