tbuckley/cabot-search huggingface dataset:
Outcome and immune landscape of HER2-positive invasive lobular carcinoma in the North Central Cancer Treatment Group (NCCTG) N9831 (Alliance) trial.
Authors: Saranya Chumsri, Zhuo Li, Tracy Shachner, Pooja Advani, Kostandinos Sideras, Alvaro Moreno-Aspitia, Gerardo Colon-Otero, Keith L. Knutson, Aziza Nassar, Edith A. Perez, E Aubrey Thompson
Journal: Journal of Clinical Oncology (2021)

535 Background: Invasive lobular carcinoma (ILC) is a rarer form of breast cancer, accounting for 10% of the disease cases. HER2 overexpression in ILC is infrequent and limited data exist regarding clinical characteristics and outcome of HER2-positive (HER2+) ILC patients (pts) treated with adjuvant trastuzumab. Methods: Patient characteristics were compared between ILC and invasive ductal carcinoma (IDC) using Wilcoxon rank sum test for continuous variables and Chi-square test for categorical variables. Kaplan-Meier (KM) method was used to estimate the freedom from mortality and recurrence. Cox regression model was used to evaluate the association between ILC and outcomes adjusted for other characteristics. NanoString technology was used to quantify mRNA to develop immune-related gene signatures. Results: From a total of 3,304 pts, 122 (3.7%) pts had ILC. Pts with ILC were significantly older (median age 54 vs. 49 years), had larger tumors, lower grade, more ER and PR positive tumors, and more lymph node involvement (25.4% had N3 disease compared to 12.7% in IDC). Overall, with KM analysis, pts with ILC had significantly worse overall survival (OS, p = 0.005) and recurrence-free survival (RFS, p = 0.046) compared to IDC. The 15-year freedom from recurrence was merely 57.67% in ILC compared to 72.68% in IDC. A significant number of hormone receptor-positive (HR+) ILC pts developed late recurrence with cumulative event rates increasing from 23% at 5 years to 42% at 15 years. Nevertheless, in multivariate Cox regression analysis adjusting for other clinical characteristics, including age, tumor size, grade, ER/PR, and lymph node status, lobular histology was not significantly associated with worse outcome for OS (HR = 1.19, 95%CI 0.67-2.1, p = 0.55) and RFS (HR = 1.5, 95%CI 0.9-2.5, p = 0.12), as compared with IDC. However, ILC pts appeared to have similar degree of benefit from trastuzumab, with RFS HR = 0.58 compared to HR = 0.67 in the entire population. For immune landscape, there was no significant difference in gene signatures related to CD45, CD8, B cells, or cytotoxic cells. However, ILC had more enrichment in mast cell gene signature and fewer macrophage, NK CD56dim, and regulatory T cell signatures compared to IDC (p &lt; 0.05). Conclusions: HER2+ ILC has distinct clinical characteristics and immune landscape compared to IDC. ILC pts appeared to have worse outcome compared to IDC likely because ILC pts often presented with more locally advanced disease. However, similar benefit of trastuzumab was observed in ILC pts. Due to high risk of late relapse in HR+ HER2+ ILC, extended adjuvant endocrine therapy should be considered in this group of high-risk pts. Clinical trial information: NCT00005970.
Safety profile and disease stabilization in late stage, heavily pretreated, solid tumor patients in a first-in-human (FIH) study of ATX-101, a drug targeting proliferating cell nuclear antigen (PCNA).
Authors: Charlotte Rose Lemech, Ganessan Kichenadasse, Jens-Peter Marschner, Kostas Alevizopoulos, Marit Otterlei, Michael Millward
Journal: Journal of Clinical Oncology (2021)

3067 Background: PCNA is a conserved scaffold protein orchestrating DNA replication, repair or bypass pathways as well as cellular signaling and apoptosis. More than 500 protein-PCNA interactions have been identified which are mediated via two binding motifs, the PIP-box and APIM. Cellular stress, to which cancer cells and cells of tumor microenvironment are exposed, increases the affinity of the APIM motif. APIM-containing proteins bind to PCNA and mediate processes of escape mechanisms and survival of cancer cells. ATX-101 is a cell penetrating peptide containing APIM. It inhibits protein binding via APIM, resulting in cancer cell death and altered cellular signaling. Anticancer effects of ATX-101 have been demonstrated in vitro and in vivo. Methods: A FIH study using a 3+3 dose escalation design was conducted. Patients with late-stage solid tumors received weekly infusions of 20, 30, 45 and 60 mg/m² over 6 weeks. Primary objective was safety, secondary objectives were PK and efficacy. Patients with stable disease (SD) after 6 weeks could continue treatment in a long-term follow-up (LTFU) study. Results: As of January 2021, 22 patients have been treated. All patients received in average 3.8 [1-9] prior treatment lines, all but one had progressive disease at study entry and 80% were refractory to the last therapy. No dose limiting toxicity or death and no treatment related Grade 3/4 or serious adverse events were reported. The maximum tolerated dose was not reached. Mild to moderate infusion related reactions (IRR) were observed in 73% of patients. They were not dose dependent and resolved completely after treatment interruption and/or symptomatic treatment. IRRs occurred despite premedication and could cause infusion interruptions with extended infusion duration. Experiments in dogs indicate that transiently increased histamine levels may cause IRRs. However, elevated histamine and tryptase levels could not be measured in patients so far. ATX-101 exposure was dose-dependent. Cmax was reached either at the middle or at the end of infusion. ATX-101 disappeared quickly from plasma and was not detectable 5 - 60 minutes post infusion. 13 patients finished the FIH study, 10 had SD after 6 weeks. 9 of 10 patients moved into the LTFU study. The treatment duration in the LTFU study varied from 2.1 to 15.6 months (median 4.2 months). Conclusions: ATX-101 is well tolerated at all dose levels with IRRs being the most frequent AEs. Drug exposure is dose dependent with rapid plasma clearance, which confirms in vivo data demonstrating the quick uptake by cells of all organs. The observed duration of SD may be attributed to ATX-101 activity. Proof of concept combination studies are being initiated. Clinical trial information: 375262.
CMV exposure drives long-term CD57+ CD4 memory T-cell inflation following allogeneic stem cell transplant
Authors: Albert C. Yeh, Antiopi Varelias, Anupama Reddy, Sierra M. Barone, Stuart D. Olver, Kate Chilson, Lynn E. Onstad, Kathleen S. Ensbey, Andrea S Henden, Luke Samson, Carla A Jaeger, Timothy Bi, Kimberly B. Dahlman, Tae Kon Kim, Ping Zhang, Mariapia A. Degli-Esposti, Evan W. Newell, Madan H. Jagasia, Jonathan M. Irish, Stephanie J. Lee, Geoffrey R. Hill
Journal: Blood (2021)
Conditional Long-Term Survival Among Diffuse Large B-Cell Lymphoma (DLBCL) Patients Treated with Autologous Hematopoietic Cell Transplantation (AHCT)
Authors: Jessica ElAsmar, Lisa Rybicki, Brian J. Bolwell, Mohamed A Kharfan-Dabaja, Robert M. Dean, Betty K. Hamilton, Rabi Hanna, Deepa Jagadeesh, Matt Kalaycio, Hien D. Liu, Brad Pohlman, Ronald Sobecks, Brian T. Hill, Navneet S. Majhail
Journal: Blood (2017)
Clinical and demographical factors associated with fertility counseling in colorectal cancer.
Authors: Chengwei Peng, Lena Masri, Stefanie Roman, Scott Sherman, Daniel Jacob Becker
Journal: Journal of Clinical Oncology (2021)

e24047 Background: The incidence of colorectal cancer in patients younger than 50 has been increasing over the past 2 decades. This demographic shift has important implications for survivorship care, in particular regarding issues of future fertility especially in light of USPSTF’s recommendation for colorectal cancer screening to begin at 45. Although ASCO has longstanding recommendations for fertility counseling in patients with cancer, the rates of fertility counseling in younger patients with colorectal cancer are unknown. Methods: Records for new patient visits for colorectal cancer in patients younger than age 55 in a large academic cancer center between 2012 and 2019 were queried for patient demographics, disease characteristics, and documentation of fertility counseling. Associations between demographic/clinical characteristics and fertility counseling were explored. Univariate and multivariable logistical regression analyses were performed using SAS v9.4. Results: Among 194 patients who met inclusion criteria, 39.2% of patients were female, 10.4% were African American, 31.4% had rectal cancer, and 69.6% were treated with curative intent. Approximately 14.5% of patients had Medicaid insurance. Age ranged from 22-55. The overall rate of fertility counseling among all patients was 15.5%. Of these patients, 43.3% were male. In univariate analysis, age less than or equal to 40 (p &lt; 0.01), female gender (p = 0.03) and curative intent therapy (p = 0.03) were associated with fertility counseling. These factors were again statistically significant in multivariate analysis: age &lt; 40, female, and curative intent therapy (Table). Race, stage of cancer, insurance status, prior exposure to chemotherapy, year of diagnosis and colon vs rectal cancer were not associated with counseling. Conclusions: The rate of fertility counseling was very low among patients with colorectal cancer, and exceptionally low among men. Despite changes in the demographics of colorectal cancer, it does not appear that appropriate changes have been made in fertility counseling. Increases in fertility counseling were not seen in more recent years despite recognition of increasing incidence in younger patients. Additional studies to identify barriers to counseling and strategies to improve survivorship care are urgently needed.[Table: see text]
Cutaneous adverse events associated with immune checkpoint blockade: A meta-analysis.
Authors: Yiqun Han, Jiayu Wang, Binghe Xu
Journal: Journal of Clinical Oncology (2021)

e14500 Background: Dermatological toxicity is the most common immune-related adverse events (irAEs) following immune checkpoint inhibitors (ICIs). A better understanding of this side effect enables early recognition, diagnosis, and management in clinical practice. Methods: We did a meta-analysis of literature published on ClinialTrials.gov, Pubmed, Embase, and Cochrane Library up to April 30, 2020. Randomized controlled trials (RCTs) which reported the cases of cutaneous irAEs following ICIs (anti-PD-1, anti-PD-L1, anti-CTLA-4) were included. We comprehensively assessed the differences in cutaneous irAEs among ICIs, the effect from dosage and combined treatment on the incidence, the correlations of cutaneous irAE with other organ-specific irAEs, and the predictive values for prognosis. This study was prospectively registered in the PROSPERO platform (ID: CRD42020182247). Results: A total of 687 publications were initially identified and 46 eligible RCTs involving 28569 patients were included. Compared with that in patients receiving anti-CLTA-4 antibody, the overall risk of dermatological irAEs tended to be lower in patients receiving anti-PD-1 antibody (RRrash, 0.60; 95%CrI, 0.36-0.99; RRpruritus, 0.51; 95%CrI, 0.22-1.10) and was lower in those receiving anti-PD-L1 antibody (RRrash, 0.63; 95%CrI, 0.43-0.90; RRpruritus, 0.37; 95%CrI, 0.20-0.67). In general, neither treatment in combination nor dosage were estimated to add additional risk to the incidence of cutaneous irAEs. Dermatological toxicity was positively associated with immune-related hepatitis (P = 0.006), neuropathy (P = 0.040) and gastrointestinal dysfunctions (P = 0.038). The cutaneous irAEs was not confirmed as a surrogate predictor for survival with ICIs monotherapy. Conclusions: This study indicates that cutaneous irAEs are dose-independent and agent-specific immune reactions with the highest risk observed in CTLA-4 blockade, and the occurrence is associated with hepatic, neurological, and gastrointestinal disorders. The exploration in the predictive value of cutaneous irAEs for response and survival outcomes will be warranted in the future.
Women and the American Diabetes Association
Authors: Cynthia E. Munoz, Ruth S. Weinstock, Tracey D. Brown, Robert A. Gabbay
Journal: Diabetes Care (2021)

The data presented by Dunne et al. (1,2) are clear and add to the growing literature describing hurdles faced by women in health care and academia. Gender disparities are evident in diabetes-related professions, and in the structure of diabetes associations and governmental research funding sources, these disparities are unfortunately no surprise. As pointed out by the authors, as well as by Sandoval et al. (3,4), the reasons for this gender gap are multiple, spanning social, institutional, cultural, governmental, and organizational domains. These complex issues demand deliberate attention and actions at all organizational and governmental levels. We recognize our collective history and have been striving toward rectifying these disparities.

The American Diabetes Association (ADA) stands for equal treatment of all people, irrespective of gender, race, and ethnicity. One of our strategic priorities is helping people thrive, which can only be fully realized when we embrace diversity, equity, and inclusion (DEI). This needs to be firmly rooted in our organizational structure, volunteer composition, and community conversations. In recent years, the ADA has taken steps to improve processes, policies, practice, and culture to reduce inequalities. This evolution starts within. Here we describe the steps ADA has taken …
Efficacy of everolimus-containing chemotherapy in HER2 negative metastatic breast cancer patients with PI3K/AKT/mTOR mutations: A retrospective study.
Authors: Rong Wang, Xiaojia Wang, Zhan-hong Chen, Jin Niu, Yuan Huang, Jiani Pan, Weiwu Ye, Wenming Cao
Journal: Journal of Clinical Oncology (2021)

e13069 Background: The PI3K/AKT/mTOR pathway is frequently altered in breast cancer. Everolimus is a selective inhibitor of mammalian target of Rapamycin (mTOR).The benefit of everolimus in metastatic breast cancer patients with PI3K/AKT/mTOR mutations remains unclear, especially in TNBC patients. Our study aimed to investigate the efficacy of the everolimus-containing chemotherapy in metastatic breast cancer patients with PI3K/AKT/mTOR mutations. Methods: 13 cases of HER2- metastatic breast cancer with PI3K/AKT/mTOR mutations treated with everolimus-containing chemotherapy were analyzed. The genetic profile in PI3K/AKT/mTOR pathway was studied. Results: Overall, 4 cases were hormone receptor (HR) positive and 9 were TNBC. 7 patients only had PIK3CA mutations, 1 patient had only PIK3R1 mutations, and 5 patients had other mutations in the pathway in addition to PIK3CA, including PTEN, PIK3CB, CTNNB1, FGFR1 and TSC2. 5 cases were treated as first or second line chemotherapy, and 8 were as third line or above. The ORR (CR+PR) was 38.5% (5/13), and DCR (CR+PR+SD) was 84.6% (11/13), including 5 cases of PR, 6 cases of SD, and 2 cases of PD. The median PFS was 5.8 months (95% CI 3.7-9.7), and the median OS was 14.3 months (95% CI 6.47-null). However, the ORR of TNBC patients was higher than that of HR-positive, which were 44.4% (4/9) and 25% (1/4), respectively ( p = 0.070). The mPFS was also longer than that of HR-positive with 5.8 months versus 1.7 months, as well as the mOS with 14.3 versus 3.8 months. We also found that the patients carrying other mutations besides PIK3CA in the PI3K/AKT/mTOR pathway had a longer PFS compared to the patients without other mutations, which was 9.7 months and 4.3 months respectively ( p = 0.272). And the DCR of the two groups were 100% and 75% respectively ( p = 0.451). Conclusions: We found that everolimus-containing chemotherapy was effective in the treatment of HER2- metastatic breast cancer with PI3K/AKT/mTOR pathway activation. TNBC patients had a trend of longer mPFS than HR+ patients. And the patients carrying other mutations besides PIK3CA in the PI3K/AKT/mTOR pathway have a trend of longer PFS and higher DCR compared to the patients without other mutations. However, trails with larger samples are needed for further verification.
Racial disparities and medical care accessibility in cancer statistics.
Authors: Noha Soror, Amany Keruakous
Journal: Journal of Clinical Oncology (2021)

e18510 Background: Cancer is one of the leading causes of death worldwide. It continues to be the second leading cause of death in the United States despite all national efforts aiming to reduce cancer burden and mortality. Delays in medical care and subsequently age-appropriate screening leads to increased cancer burden which reflect on the overall prognosis. Medical care accessibility has been a challenge that is reported by approximately one third of the USA adult population. We aimed to identify health care disparities and its correlation with prevalence of cancer as well as delays in medical care due to financial challenges among Texas residents. Methods: We analyzed data from the Behavioral Risk Factor Surveillance System (BRFSS) 2017. We measured specific health care disparities including patient’s gender, age, race/ethnicity, body mass index (BMI), annual income, alcohol consumption, history of cancer, and delays in medical care due to financial burden, among respondents to the 2017 BRFSS survey from Texas. We computed the difference between our comparison groups using chi-square test for categorical variables and t-test for continuous variables. Results: We analyzed the differences in health care disparities among respondents with and without history of cancer. We report results from 11,165 adult respondents who reside in Texas, among which nine percent were diagnosed with cancer. We noticed a higher proportion of females than males among participants with a history of cancer (64% females p &lt; 0.0001). Age did differ between both groups, with the majority of participants with cancer are aged 50 years and older. Interestingly, BMI did not differ between both groups (p-value = 0.6930). Although annual income did not differ between both groups, twelve percent of participants with cancer diagnosis suffered from delays in medical care due to financial burden. Racial disparities were statistically different between participants with or without cancer (p &lt; .0001). Seventy seven percent of patients with cancer diagnosis were White and non-Hispanic with a cancer prevalence rate of 12% in that racial group. On a stratified analysis to compute the relationship between delayed medical care due to financial burden and cancer diagnosis among all ethnic groups, it was not statistically different (p-value = 0.1063). We showed that prevalence of cancer among multiracial participants and other racial minorities was higher in the group of participants who reported delays in medical care due to financial burden (11% versus 7%). Conclusions: Racial and ethnic disparities could affect accessibility to medical services. Race is a significant variable that is associated with cancer, with higher prevalence of cancer in White and non-Hispanic. Delayed medical care due to financial burden is more pronounced in multiracial population and racial minorities and should be targeted in future quality improvement projects.
LGG-11. BH3-MIMETICS TARGETING BCL-XL SELECTIVELY IMPACT THE SENESCENT COMPARTMENT OF PILOCYTIC ASTROCYTOMA
Authors: Florian Selt, Romain Sigaud, Philipp Sievers, Julia Zaman, Heike Peterziel, Jessica W Tsai, Romain Guiho, Juan Pedro Martínez-Barbera, Stefan Pusch, Martin U Schuhmann, Ahmed El Damaty, Pratiti Bandopadhayay, Stefan M Pfister, Ina Oehme, Felix Sahm, David T W Jones, Olaf Witt, Till Milde
Journal: Neuro-Oncology (2021)

Abstract Introduction Pilocytic astrocytoma (PA) is the most common brain tumor in children. Activation of the mitogen-activated protein kinase (MAPK) pathway is a hallmark of PA. Complete remission in non-resectable tumors is infrequently observed with current therapeutic approaches. Most PA tumors cells are in oncogene-induced senescence (OIS), which may explain the benign growth behavior of PAs but also account for resistance to therapy. Therefore, treatment of PA with senolytic agents such as BH3-mimetics is a promising new approach. Methods Three patient-derived PA cell lines, DKFZ-BT66, DKFZ-BT308 (both KIAA1549:BRAF-fusion positive) and DKFZ-BT314 (BRAF V600E-mutation positive) were used. Depending on inducible expression or repression of SV40 large T antigen all models can reflect both states of PA, proliferation and OIS. Cells in both states were treated with different BH3-mimetics. Inhibition of metabolic activity was measured after 72 hours. Target expression was assessed by RT-qPCR and Western blot. On-target activity of BH3-mimetics was determined by immunoprecipitation (IP) of Bcl-xL/BAK. Results BH3-mimetics with strong binding affinity for Bcl-xL (Navitoclax, A-1131852, A-1155463) showed selectivity for senescent cells in 2/3 models (DKFZ-BT66 and DKFZ-BT314) and acted in nanomolar ranges. IC50s for Navitoclax (Cmax 6600nM in patients) were 40nM (OIS) vs. 200nM (proliferation) and 170nM (OIS) vs. 3700nM (proliferation) in DKFZ-BT66 and DKFZ-BT314, respectively. Target engagement was evident in the Bcl-xL/BAK-IP, and target expression of Bcl-xL was similar in all models studied. The relative resistance of senescent DKFZ-BT308 despite on-target activity is currently being investigated. Conclusion Senolytic treatment of PA with BH3-mimetics targeting Bcl-xL is a promising new strategy directly targeting the major senescent part of the tumor in clinically archivable concentrations. However, our data suggests that not all PAs may respond to treatment. The analysis of comparative gene expression analysis and BH3-profiling is ongoing to define predictive biomarkers.