Citations

PURPOSE To improve the outcomes of patients with T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL), the proteasome inhibitor bortezomib was examined in the Children's Oncology Group phase III clinical trial AALL1231, which also attempted to reduce the use of prophylactic cranial radiation (CRT) in newly diagnosed T-ALL. PATIENTS AND METHODS Children and young adults with T-ALL/T-LL were randomly assigned to a modified augmented Berlin-Frankfurt-Münster chemotherapy regimen with/without bortezomib during induction and delayed intensification. Multiple modifications were made to the augmented Berlin-Frankfurt-Münster backbone used in the predecessor trial, AALL0434, including using dexamethasone instead of prednisone and adding two extra doses of pegaspargase in an attempt to eliminate CRT in most patients. RESULTS AALL1231 accrued 824 eligible and evaluable patients from 2014 to 2017. The 4-year event-free survival (EFS) and overall survival (OS) for arm A (no bortezomib) versus arm B (bortezomib) were 80.1% ± 2.3% versus 83.8% ± 2.1% (EFS, P = .131) and 85.7% ± 2.0% versus 88.3% ± 1.8% (OS, P = .085). Patients with T-LL had improved EFS and OS with bortezomib: 4-year EFS (76.5% ± 5.1% v 86.4% ± 4.0%; P = .041); and 4-year OS (78.3% ± 4.9% v 89.5% ± 3.6%; P = .009). No excess toxicity was seen with bortezomib. In AALL0434, 90.8% of patients with T-ALL received CRT. In AALL1231, 9.5% of patients were scheduled to receive CRT. Evaluation of comparable AALL0434 patients who received CRT and AALL1231 patients who did not receive CRT demonstrated no statistical differences in EFS ( P = .412) and OS ( P = .600). CONCLUSION Patients with T-LL had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. Systemic therapy intensification allowed elimination of CRT in more than 90% of patients with T-ALL without excess relapse.

Abstract Background: Cyclin dependent kinase (CDK) 4/6 inhibitors (CDK 4/6i) can improve outcomes in ER-positive/HER2-negative (ER+/HER2-) breast cancer. The choice of CDK 4/6i selection and dose depends on clinical context and/or potential side effect of profile of each unique CDK 4/6i. The objective of this study was to evaluate practice patterns in patients initiated on CDK 4/6i and assess adherence to recommended laboratory monitoring in breast cancer patients in both an institutional and national dataset. Methods: The institutional cohort (IC) involved a retrospective chart review of patients newly initiated on palbociclib between May 8, 2018 - June 4, 2019 at Mayo Clinic, Rochester. The national cohort (NC) reviewed medical and pharmacy claims data from the OptumLabs Data Warehouse (OLDW) and included patients who were initiated on palbociclib (P), ribociclib (R) or abemaciclib (A) between February 6, 2015 - September 30, 2019. NC patients were required to have a minimum of 6 months baseline coverage, 6 months coverage after first prescription and Day 1 labs drawn. For both cohorts, patients were ≥18 years old with metastatic ER+/HER2- breast cancer. Data was collected for up to 6 cycles of treatment and included cycle start dates, doses, dates of lab draws and dose changes. Laboratory adherence was defined as a complete blood count being drawn +/- 3 days of the defined timepoint for the IC and +/- 5 days for the NC with a l4-day window for Cycle 1, Day 1 labs. Results: The IC included 81 patients and the NC 2600. In the NC, the most prescribed CDK 4/6i was P (90%), followed by A (6%) and R (4%). Prescription breakdown by geographic region was Midwest (26%), Northeast (14%), South (47%), West (13%). Ethnic breakdown of the group was White (68%), Black (15%), Hispanic (8%), Asian (3%) and unknown (6%). P practice pattern data were available for both the IC and NC, but R and A data in the NC only. In the IC, the initial P dose was 125 mg (95%), 100 mg (1%) and 75 mg (4%). In the NC, P (n=2329) dose was 125 mg (81%), 100 mg (15%) and 75 mg (4%). Dose reductions were common with 25% and 28% of patients requiring one dose reduction and 16% and 9% of patients requiring two dose reductions in the IC and NC, respectively. In NC patients initially treated with P, 5% were subsequently treated with A and 2% with R. In the NC, A (n=163) was initiated at 200 mg (7%), 150 mg (79%), 100 mg (10%) and 50 mg (4%). One dose reduction was required in 25% of patients and 6% required two dose reductions. Of those initially treated with A, 16% were subsequently treated with P and 1% with R. In the NC, R (n=108) was initiated at 600 mg (81%), 400 mg (8%) and 200 mg (11%). One dose reduction was required in 17% of patients and 2% required two dose reductions. Of those initially treated with R, 7% each were subsequently treated with P and 10% with A. Laboratory adherence was assessed for P only. For the IC, a total of 81 patients were included (mean age 61±13 years, 98% female and 95% White). The NC included 2329 patients (mean age 66±12 years, 99% female and 69% White). Laboratory adherence is listed in the table below: Conclusions: P was the most commonly prescribed CDK 4/6i. Dose reductions were less common with R. Adherence to laboratory monitoring was higher in our institutional cohort than in a national administrative claims database. Initiatives to ensure that labs are drawn at recommended timepoints during P therapy will be important for safety. ICNCC1D193%100%C1D1589%61%C2D191%71%C2D1558%55%C3D199%62%C4D190%55%C5D184%53%C6D178%50%C = cycle, D = day. Citation Format: Jodi Taraba, Kavya Swarna, Allison Golbach, Lindsey Sangaralingham, Kathryn Ruddy, Kristin Mara, Matthew Smith, Tufia Haddad, Karthik Giridhar. Evaluation of CDK 4/6 inhibitor practice patterns and institutional versus national adherence to palbociclib laboratory monitoring in breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-23-05.

Abstract Background. DCIS consists of a molecularly heterogeneous group of premalignant lesions, with variable risk of invasive progression. Understanding biomarkers for invasive progression could help individualize treatment recommendations based upon tumor biology. As part of the NCI Human Tumor Atlas Network (HTAN), we conducted comprehensive genomic analyses on two large DCIS case-control cohorts. Methods. We performed smart3-seq and low-pass whole genome sequencing on two independent, retrospective, longitudinally sampled DCIS case-control cohorts. TBCRC 038 was a multicenter cohort diagnosed with DCIS between 1998 and 2016 at one of the Translational Breast Cancer Research sites; the RAHBT (Resource of Archival Human Breast Tissue) cohort included women identified through the St. Louis Breast Tissue Repository, and the Women’s Health Repository diagnosed between 1997 and 2001. We studied the spectrum of molecular changes present and sought genomic predictors of subsequent ipsilateral breast events (iBEs: DCIS recurrence or invasive progression) in both DCIS epithelium and stroma in formalin fixed paraffin embedded tissue. We generated de novo tumor and stroma-centric subtypes for DCIS that represents fundamental transcriptomic organization. Copy number analysis was performed using low-pass DNA sequencing. Non-negative matrix factorization (NMF) was applied to the RNA expression of all coding genes to identify clusters. A negative-binomial regression model was used to identify differentially expressed genes. Results. We analyzed 677 DCIS samples from 481 patients with 7.1 years median follow-up. In TBCRC samples, we identified three clusters via NMF in TBCRC referred to as ER low, quiescent, and ER high. The ER-low cluster had significantly higher levels of ERBB2 and lower levels of ESR1 compared to quiescent and ER-high clusters. Quiescent cluster lesions were less proliferative and less metabolically active than ER high and ER low subtypes. These findings were replicated in the RAHBT cohort. Focusing on the stromal component of DCIS from laser capture microdissection in RAHBT samples, we identified four distinct DCIS-associated stromal clusters. A “normal-like” stromal cluster with ECM organization and PI3K-AKT signaling; a “collagen-rich” stromal cluster; a “desmoplastic” stromal cluster with high fibroblast and total myeloid abundance, mostly associated with macrophages and myeloid dendritic cells (mDC); and an “immune-dense” stromal cluster. Further, we compared differentially expressed genes in patients with or without subsequent iBEs within 5 years of diagnosis. Hypothesizing that the resulting 812 DE genes (DESeq2) represent multiple routes to subsequent iBEs, we leveraged NMF to identify paths to progression. In both TBCRC and RAHBT cohorts, poor outcome groups exhibited increased ER, MYC signaling, and oxidative phosphorylation, supporting that these pathways are important for DCIS recurrence and progression. Conclusion. Comprehensive genomic profiling in two independent DCIS cohorts with longitudinal outcomes shows distinct DCIS stromal expression patterns and immune cell composition. RNA expression profiles reveal underlying tumor biology that is associated with later iBEs in both cohorts. These studies provide new insight into DCIS biology and will guide the design of diagnostic strategies to prevent invasive progression. Citation Format: Siri H Strand, Belén Rivero-Gutiérrez, Kathleen E Houlahan, Jose A Seoane, Lorraine M King, Tyler Risom, Lunden Simpson, Sujay Vennam, Aziz Khan, Timothy Hardman, Bryan E Harmon, Fergus J Couch, Kristalyn Gallagher, Mark Kilgore, Shi Wei, Angela DeMichele, Tari King, Priscilla F McAuliffe, Julie Nangia, Joanna Lee, Jennifer Tseng, Anna Maria Storniolo, Alastair Thompson, Gaorav Gupta, Robyn Burns, Deborah J Veis, Katherine DeSchryver, Chunfang Zhu, Magdalena Matusiak, Jason Wang, Shirley X Zhu, Jen Tappenden, Daisy Yi Ding, Dadong Zhang, Jingqin Luo, Shu Jiang, Sushama Varma, Cody Straub, Sucheta Srivastava, Christina Curtis, Rob Tibshirani, Robert Michael Angelo, Allison Hall, Kouros Owzar, Kornelia Polyak, Carlo Maley, Jeffrey R Marks, Graham A Colditz, E Shelley Hwang, Robert B West. The Breast PreCancer Atlas DCIS genomic signatures define biology and correlate with clinical outcomes: An analysis of TBCRC 038 and RAHBT cohorts [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS4-07.

Abstract Polatuzumab vedotin (PV) is an antibody–drug conjugate targeting CD79b that is approved for patients with relapsed/refractory large B-cell lymphoma (LBCL). Patients who relapse after chimeric antigen receptor (CAR) T-cell therapy were not included in the registration study, and reports of PV use after CAR T cells are limited. This multicenter retrospective analysis included patients with LBCL who relapsed or progressed after CAR T-cell therapy and subsequently received PV with or without rituximab and bendamustine between July 2019 and May 2021. Response to treatment and progression were assessed based on the 2014 Lugano criteria. Fifty-seven patients were included in the study: 18 (32%) patients were primary refractory to CAR T-cell therapy, and 34 (60%) patients received PV-based therapy immediately after CAR T-cell therapy. PV was combined with rituximab in 54 (95%) patients and administered with bendamustine in 35 (61%) patients. A response was achieved in 25 (44%) patients, including complete remission in 8 (14%). No significant association between baseline characteristics and response was observed. After a median follow-up of 47 weeks (95% confidence interval [CI], 40-54), 46 (81%) patients had disease progression or died, and the median progression-free survival was 10 weeks (95% CI, 5-15). On a multivariate analysis, bone marrow involvement (hazard ratio, 5.2; 95% CI, 1.8-15; P = .003) and elevated lactate dehydrogenase levels (hazard ratio, 5.0; 95% CI, 1.4-16; P = .01) were associated with shorter progression-free survival. Studies aimed at better characterizing the intrinsic mechanism of resistance and identifying optimal consolidation strategies for these patients are warranted.

Abstract Background Anorectal manometry (ARM) comprehensively assesses anorectal sensorimotor functions. Purpose This review examines the indications, techniques, interpretation, strengths, and weaknesses of high‐resolution ARM (HR‐ARM), 3‐dimensional high‐resolution anorectal manometry (3D‐HR‐ARM), and portable ARM, and other assessments (i.e., rectal sensation and rectal balloon expulsion test) that are performed alongside manometry. It is based on a literature search of articles related to ARM in adults. HR‐ARM and 3D‐HR‐ARM are useful for diagnosing defecatory disorders (DD), to identify anorectal sensorimotor dysfunction and guide management in patients with fecal incontinence (FI), constipation, megacolon, and megarectum; and to screen for anorectal structural (e.g., rectal intussusception) abnormalities. The rectal balloon expulsion test is a useful, low‐cost, radiation‐free, outpatient assessment tool for impaired evacuation that is performed and interpreted in conjunction with ARM. The anorectal function tests should be interpreted with reference to age‐ and sex‐matched normal values, clinical features, and results of other tests. A larger database of technique‐specific normal values and newer paradigms of analyzing anorectal pressure profiles will increase the precision and diagnostic utility of HR‐ARM for identifying abnormal mechanisms of defecation and continence.

Background The association of social isolation or lack of social network ties in older adults is unknown. This knowledge gap is important since the risk of heart failure (HF) and social isolation increase with age. The study examines whether social isolation is associated with incident HF in older women, and examines depressive symptoms as a potential mediator and age and race and ethnicity as effect modifiers. Methods and Results This study included 44 174 postmenopausal women of diverse race and ethnicity from the WHI (Women's Health Initiative) study who underwent annual assessment for HF adjudication from baseline enrollment (1993–1998) through 2018. We conducted a mediation analysis to examine depressive symptoms as a potential mediator and further examined effect modification by age and race and ethnicity. Incident HF requiring hospitalization was the main outcome. Social isolation was a composite variable based on marital/partner status, religious ties, and community ties. Depressive symptoms were assessed using CES‐D (Center for Epidemiology Studies‐Depression). Over a median follow‐up of 15.0 years, we analyzed data from 36 457 women, and 2364 (6.5%) incident HF cases occurred; 2510 (6.9%) participants were socially isolated. In multivariable analyses adjusted for sociodemographic, behavioral, clinical, and general health/functioning; socially isolated women had a higher risk of incident HF than nonisolated women (HR, 1.23; 95% CI, 1.08–1.41). Adding depressive symptoms in the model did not change this association (HR, 1.22; 95% CI, 1.07–1.40). Neither race and ethnicity nor age moderated the association between social isolation and incident HF. Conclusions Socially isolated older women are at increased risk for developing HF, independent of traditional HF risk factors. Registration URL: http://www.clinicaltrials.gov ; Unique identifier: NCT00000611.

Background Associations between depression, incident heart failure (HF), and mortality are well documented in predominately White samples. Yet, there are sparse data from racial minorities, including those who are women, and depression is underrecognized and undertreated in the Black population. Thus, we examined associations between baseline depressive symptoms, incident HF, and all‐cause mortality across 10 years. Methods and Results We included Jackson Heart Study (JHS) participants with no history of HF at baseline (n=2651; 63.9% women; median age, 53 years). Cox proportional hazards models tested if the risk of incident HF or mortality differed by clinically significant depressive symptoms at baseline (Center for Epidemiological Studies–Depression scores ≥16 versus <16). Models were conducted in the full sample and by sex, with hierarchical adjustment for demographics, HF risk factors, and lifestyle factors. Overall, 538 adults (20.3%) reported high depressive symptoms (71.0% were women), and there were 181 cases of HF (cumulative incidence, 0.06%). In the unadjusted model, individuals with high depressive symptoms had a 43% greater risk of HF ( P =0.035). The association remained with demographic and HF risk factors but was attenuated by lifestyle factors. All‐cause mortality was similar regardless of depressive symptoms. By sex, the unadjusted association between depressive symptoms and HF remained for women only ( P =0.039). The fully adjusted model showed a 53% greater risk of HF for women with high depressive symptoms ( P =0.043). Conclusions Among Black adults, there were sex‐specific associations between depressive symptoms and incident HF, with greater risk among women. Sex‐specific management of depression may be needed to improve cardiovascular outcomes.