Citations

Neoadjuvant chemotherapy (NAC) remains the cornerstone of the treatment for triple negative breast cancer (TNBC), with the goal of complete eradication of disease. However, for patients with residual disease after NAC, recurrence and mortality rates are high and the identification of novel therapeutic targets is urgently needed. We quantified tyrosine phosphorylation (pTyr)-mediated signaling networks in chemotherapy sensitive (CS) and resistant (CR) TNBC patient-derived xenografts (PDX), to gain novel therapeutic insights. The antitumor activity of SFK inhibition was examined in vivo. Treated tumors were further subjected to phosphoproteomic and RNAseq analysis, to identify the mechanism of actions of the drug. We identified Src Family Kinases (SFKs) as potential therapeutic targets in CR TNBC PDXs. Treatment with dasatinib, an FDA approved SFK inhibitor, led to inhibition of tumor growth in vivo. Further analysis of post-treatment PDXs revealed multiple mechanisms of actions of the drug, confirming the multi-target inhibition of dasatinib. Analysis of pTyr in tumor specimens suggested a low prevalence of SFK-driven tumors, which may provide insight into prior clinical trial results demonstrating a lack of dasatinib antitumor activity in unselected breast cancer patients. Taken together, these results underscore the importance of pTyr characterization of tumors, in identifying new targets, as well as stratifying patients based on their activated signaling networks for therapeutic options. Our data provide a strong rationale for studying SFK inhibitors in biomarker-selected SFK-driven TNBC.

Context.— Neoadjuvant systemic therapy refers to the use of systemic agent(s) for malignancy prior to surgical treatment and has recently emerged as an option for most breast cancer patients eligible for adjuvant systemic therapy. Consequently, treated breast carcinomas have become routine specimens in pathology practices. A standard protocol has not yet been universally adopted for the evaluation and reporting of these specimens. The American Joint Committee on Cancer staging system recognizes the challenges in staging breast carcinomas after neoadjuvant treatment and provides important data points but does not currently provide detailed guidance in estimating the residual tumor burden in the breast and lymph nodes. The Residual Cancer Burden system is the only Web-based system that quantifies treatment response as a continuous variable using residual tumor burden in the breast and the lymph nodes. Objective.— To provide clarifications and guidance for evaluation and reporting of postneoadjuvant breast specimens, discuss issues with the current staging and reporting systems, and provide specific suggestions for future modifications to the American Joint Committee on Cancer system and the Residual Cancer Burden calculator. Data Sources.— English-language literature on the subject and the data from the I-SPY 2, a multicenter, adaptive randomization phase 2 neoadjuvant platform trial for early-stage, high-risk breast cancer patients. Conclusions.— This article highlights challenges in the pathologic evaluation and reporting of treated breast carcinomas and provides recommendations and clarifications for pathologists and clinicians. It also provides specific recommendations for staging and discusses future directions.

Abstract Introduction: The ALTERNATE trial randomized postmenopausal women with ER Allred 6-8 HER2- breast cancer to 6 months of NET with anastrozole (A), fulvestrant (F) or the combination (A+F). Biopsies were taken preNET and after 4-weeks(wks). Patients with Ki67 values >10% at 4-wks were offered triage to neoadjuvant chemotherapy. Patients with on-treatment Ki67 ≤ 10% who completed NET underwent surgery and Ki67 was reassessed. The primary endpoint was endocrine-sensitive disease rate (ESDR). ESD is defined as pCR or PEPI-0 residual disease (pT1-2, pN0, Ki67 ≤ 2.7%). We previously reported that the ESDR difference between the F-containing arms and the A arm was not >10% (ASCO 2020) and that baseline RNA-seq-based intrinsic subtypes predicted outcomes overall (SABCS 2021). Herein we describe relationships between PAM50 intrinsic subtype and Ki67 values by treatment arm because comparative drug effectiveness in adjuvant endocrine therapy studies in ER+ HER2- breast cancer can be predicted by the degree of Ki67 suppression (PMC3518447). Methods: 743 of the 1297 eligible patients (A: 264; F: 231; A+F: 248) had RNA extracted from preNET frozen tumor biopsies with >50% tumor content and subjected to RNA seq. Intrinsic subtypes were then assigned as LumA, LumB, and NonLum (Basal or HER2-E) using open-source PAM50-based informatics. Differences in the proportion with wk4 Ki67 > 10%, % change in wk4 ki67, and surgical CCCA (Ki67 ≤ 2.7%) rate (sxCCCA) between treatments and by intrinsic subtype was assessed using stratified logistic regression, Wilcoxon rank sum test, and Fisher’s exact test, respectively. Analysis of sxCCCA excluded those who failed to complete NET for reasons other than disease progression or early Ki67 >10%. Results: Amongst the 358 LumA cases there were no significant differences in Ki67-based endpoints between treatments. Among the 292 LumB cases, the wk4 ki67 > 10% rate was lower with A+F (19.4%) than A (43%) (P=0.0002) and was somewhat lower in F (31%) versus A (P=0.076). The % change in wk4 Ki67 in LumB cases, adjusted for baseline Ki67, showed markedly superior suppression for A+F versus A (-90% vs. -77%; P=<0.0001) and versus F (-90% vs. -80%; P=0.0026). Furthermore sxCCCA rates were significantly higher with A+F than A (53% vs. 25% P = <0.0001) and somewhat higher for F (37%) than A (p=0.068), indicating that superior antiproliferative effects for A+F persist after 6 months on therapy. Lack of Ki67 suppression in response to treatment was observed in the majority of 43 NonLum samples regardless of treatment. Conclusion: The combination of A+F was significantly more effective than either drug alone for the control of LumB breast cancer cell proliferation. This suggests that A+F may be a more effective adjuvant endocrine therapy than A alone in LumB disease. The lower Ki67 suppression with A alone also suggests that poorer outcome in some LumB tumors may be due to insufficient ER targeting rather than ER-independent tumor growth Support: U10CA180821, U10CA180882, U24CA196171, UG1CA189856, U10CA180868 (NRG), NCI BIQSFP, BCRF, Genentech, AstraZeneca. https://acknowledgments.alliancefound.org. (MJE) CPRIT RR140033, P50-CA186784, P50-CA58223, U01-CA214125, U24-CA210954, Gift from Ralph and Lisa Eads, McNair Scholarship. ClinicalTrials.gov Identifier: NCT01953588 Citation Format: Matthew J. Ellis, Meenakshi Anurag, Jeremy Hoog, Aranzazu Fernandez-Martinez, Cheng Fan, Richard Gibbs, Souzan Sanati, Kiran Vij, Mark Watson, Travis Dockter, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erica Crouch, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J. Hieken, Yang Wang, A. Marilyn Leitch, Gary W. Unzeitig, Eric Winer, Anna Weiss, Kelly Hunt, Ann H. Partridge, Charles M. Perou, Vera Suman, Cynthia X. Ma, Lisa A. Carey. The effect of intrinsic subtype on inhibition of tumor growth by anastrozole vs. fulvestrant vs. the combination: Results from the Alliance neoadjuvant endocrine therapy (NET) ALTERNATE trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT026.

Reproducibility is an important quality criterion for the secondary use of electronic health records (EHRs). However, multiple barriers to reproducibility are embedded in the heterogeneous EHR environment. These barriers include complex processes for collecting and organizing EHR data and dynamic multi-level interactions occurring during information use (e.g., inter-personal, inter-system, and cross-institutional). To ensure reproducible use of EHRs, we investigated four information quality dimensions and examine the implications for reproducibility based on a real-world EHR study. Four types of IQ measurements suggested that barriers to reproducibility occurred for all stages of secondary use of EHR data. We discussed our recommendations and emphasized the importance of promoting transparent, high-throughput, and accessible data infrastructures and implementation best practices (e.g., data quality assessment, reporting standard).

Patient portals have been widely used by patients to enable timely communications with their providers via secure messaging for various issues including transportation barriers. The large volume of portal messages offers an invaluable opportunity for studying transportation barriers reported by patients. In this work, we explored the feasibility of cutting-edge deep learning techniques for identifying transportation issues mentioned in patient portal messages with deep semantic embeddings. The successful creation of annotated corpus and identification of 7 transportation issues showed the feasibility of this strategy. The developed annotated corpus could aid in developing an artificial intelligence tool to automatically identify transportation issues from millions of patient portal messages. The identified specific transportation issues and the analysis of patient demographics could shed light on how to reduce transportation gaps for patients.

Background Persons who accumulate chronic conditions at a rate faster than their peers may experience accelerated aging and poor health outcomes, including functional limitations. Methods Adults aged ≥40 years who resided in Olmsted County, Minnesota on 1 January 2006 were identified. The prevalence of 21 chronic conditions was ascertained, and age-specific quartiles of the number of chronic conditions was estimated within 4 age groups: 40–54, 55–64, 65–74, and ≥75 years. Difficulty with nine patient-reported functional limitations (including basic and instrumental activities of daily living and mobility activities) were ascertained through 31 October 2018. Cox regression was used to model associations of chronic condition quartiles with new-onset functional limitations considered separately. We estimated absolute risk differences and hazard ratios stratified by age group, and adjusted for sex, race, ethnicity, marital status, education, and the residual effect of age. Results Among 39,624 persons (44.5% men, 93.2% white), the most common reported new functional limitations were difficulty with climbing stairs, walking, and housekeeping. For all functional limitations, the absolute risk differences were largest among the oldest age group (≥75 years). Approximately twofold increased hazard ratios were observed among those in the highest vs. lowest quartile for the three oldest age groups, and approximately threefold or higher hazard ratios were observed for persons aged 40-54 years. Conclusion Persons with increased accumulation of chronic conditions experience increased risks of developing functional limitations compared to their peers. These findings underscore the importance of assessing health status and of employing interventions to prevent and effectively manage multi-morbidity at all ages.

Abstract Introduction End‐of‐life care differs by serious illness diagnosis. Cancer and dementia are serious illnesses that have been associated with less intensive end‐of‐life health care use. It is not known how health care utilization varies in the presence of >1 serious illness. Methods We used the Rochester Epidemiology Project to identify persons living in a midwestern area who died on July 1, 2017–June 30, 2018 at age ≥65 years, and were seriously ill. We examined the number of emergency department (ED), hospital, and intensive care unit (ICU) stays in the last 6 months and the last 30 days of life. We used Poisson regression to determine the incidence rate ratio for ED, hospital, and ICU stay in the last 6 months and 30 days of life by number of serious illness diagnoses. For cancer and dementia, we examined the effect of an additional serious illness. Results We included a population of 1372 adults who were, on average, 84 years, 52% female, and 96% white. Approximately 41% had multiple serious illnesses. Compared to older adults with 1 serious illness diagnosis, rates of hospitalization, and ICU stay for adults with 2 or ≥3 serious illness diagnoses were at least 1.5 times higher in the last 6 months and the last 30 days of life. Rates of ED visits were significantly higher for older adults with 2 or ≥3 serious illness diagnoses in the last 6 months of life, but only higher for those with ≥3 versus 1 serious illness diagnosis in the last 30 days of life. For both cancer and dementia, rates of ED visits, hospitalization and ICU stay were lower for the condition alone than when an additional serious illness diagnosis was present. Conclusion Having multiple serious illnesses increases the risk of health care utilization at the end of life.

Abstract Background: Chronic non-specific low back pain (CNLBP) is a common complaint about medical care and carries a heavy social burden. The efficacy of Tuina (TN) or physiotherapy (PT) for CNLBP has been evaluated in previous systematic reviews. However, there is no high-quality evidence to support the efficacy of Tuina. Therefore, this study aims to conduct a large-scale, multicenter, high-quality clinical trial to provide evidence for Tuina to treat CNLBP. Methods: This is a multicenter, assessor-, and analyst-blinded, randomized controlled trial with 3 parallel arms: TN, PT, and TN combined with PT (Tuina combined with physiotherapy) group. Six hundred twelve eligible CNLBP patients will be randomly assigned to the groups in a 1:1:1 ratio in 3 centers. The TN intervention includes 9-step routine techniques, while the PT intervention includes a physiotherapy treatment plan based on a patient's symptoms. The interventions for both groups will last for 30 minutes and will be carried out for 6 sessions in 8 weeks. The primary outcome will be the visual analog scale pain score. And the secondary outcomes will include the Oswestry Disability Index, spinal range of motion, 36-item short-form health survey. Safety evaluation will be recorded during the whole study. All data in this randomized controlled trial will be analyzed by SAS 9.4. Discussion: The results of this trial will provide evidence to evaluate the efficacy of Tuina's value as a treatment for CNLBP. Trial registration: Chinese Clinical Trial Registry (ChiCTR2000040288, November 27, 2020).