tbuckley/cabot-search huggingface dataset:
Effect of AURKA targeting on nuclear PD-L1 and the efficacy of immune checkpoint inhibitors in triple-negative breast cancer.
Authors: Andrew Takchi, Antonino Bonaventura D'assoro
Journal: Journal of Clinical Oncology (2024)

e13153 Background: Aurora-A mitotic kinase (AURKA) plays a role in Triple Negative Breast Cancer (TNBC) progression through activation of epithelial to mesenchymal transition (EMT)-mediated cancer cell plasticity. Cancer cells that undergo EMT acquire a CD44 high /CD24 low and/or ALDH high cancer stem-like phenotype (Cancer Stem Cells) characterized by intrinsic drug resistance. Cancer Stem Cells (CSCs) shows high PD-L1 expression that induces tumor immune escape through CD8+ T-cells exhaustion. Significantly, “undraggable” nuclear PD-L1 may play a key role in induction of immune therapy resistance and cancer cell plasticity. Methods: (1) TNBC Models: MDA-MB 231, unique MDA-MB 231/LM Durvalumab resistant (DUV-R) and TNBC-M40 cells established from metastatic PDXs; (2) In Vitro Studies: TNBC cells were treated with the AURKA inhibitor alisertib (50nM). PD-L1 expression was evaluated by immunoblotting. Apoptosis was measured by immunofluorescence using Cleaved-PARP antibodies. To assess stemness capacity, TNBC cells were cultured under non-adherent conditions to form mammospheres. ALDH activity (functional stemness marker) was measured using the Aldefluor Kit. (3) In Vivo Studies: 1x10 6 MDA-MB 231/LM cells were injected into the mammary fat pad of humanized NSG-CD34+ female mice. Animals were treated with anti-PD-L1 ICI atezolizumab (20 mg/Kg) and alisertib (25 mg/Kg) as monotherapy or in combination. 1x10 6 MDA-MB 231/LM cells were also injected into the mammary fat pad of humanized NSG-CD34+ female mice and treated with durvalumab (20 mg/Kg) to develop durvalumab-resistant models. PD-L1, CD44, Vimentin expression and tumor infiltration of CD8+ T-cells were assessed by immunofluorescence. Results: Treatment of MDA-MB 231/LM xenografts with alisertib decreased the levels of CD44 and PD-L1 expression and increased CD8+ T-cells tumor infiltration. Because PD-L1 genetic targeting enhanced in vitro alisertib-induced apoptosis, MDA-MB 231/LM xenografts were treated with alisertib and the anti-PD-L1 ICI atezolizumab. Com- bination of atezolizumab and alisertib resulted in the reduced expression of the EMT marker vimentin that was linked to lack of organ metastasis. Combination of atezolizumab and alisertib also induced a significant reduction of ALDH High CSC in ex-vivo 3D-Organoids established from TNBC-M40 cells. MDA-MB 231/LM DUV-R cells showed increased nuclear PD-L1 compared to parental cells. The combination of alisertib with Immune Checkpoint Inhibitors (ICIs) induced apoptosis of MDA-MB 231/LM DUV-R cells through down-regulation of intra-tumoral nuclear PD-L1 expression. Conclusions: This study provides innovative pre-clinical rationale for combining AURKA inhibitors with ICIs to reduce “ undruggable” nuclear PD-L1 expression and impair cancer cell plasticity of metastatic TNBCs that currently have limited effective therapeutic options.
Using machine learning for targeted advance care planning (ACP) conversations in patients with cancer: A quality improvement initiative.
Authors: Mihir Patel, Alexandria Mara, Yvonne Acker, Jamie Gollon, Steven Wolf, Yousuf Zafar, Thomas William LeBlanc, Jessica Ma
Journal: Journal of Clinical Oncology (2024)

1552 Background: Despite improvements, patients with advanced cancer often do not receive goal-concordant care at the end of life (EOL). Challenges with prognostication contribute to delays ACP conversations and result in more aggressive care, gaps in symptom management, and hospice underuse. Early identification of patients at high risk for mortality provides an avenue to implement targeted ACP conversations. Methods: We used a validated machine learning model that integrates demographics, lab values, vital signs, and medications to predict in-hospital, 30-day, and 6-month mortality risk for patients with a solid malignancy admitted from the emergency department (ED) to a dedicated solid malignancy oncology unit at Duke University Hospital. This unit includes one oncology and one palliative care attending physician, advance practice providers, and nurse coordinators. Providers received an email when a patient was identified as high risk for mortality. A pre-post study design compared ACP documentation and other EOL healthcare utilization before and after the notification intervention. The pre-intervention cohort included patients hospitalized from 1/7/2019 to 10/25/2019 and the post-intervention cohort from 9/19/2020 to 8/31/2021. We excluded patients admitted to the intensive care unit in the first 24 hours. We used chi-square or Fisher’s exact tests for categorical variables and Kruskal-Wallis tests for continuous variables; we stratified comparisons of categorical variables by physician division using Cochran-Mantel-Haenszel tests. Results: The pre-intervention cohort comprised 105 hospitalizations and 88 unique patients. Mean (SD) age was 64.9 (11.4); 60.0% (n=63) were White, 3.8% (4) Hispanic/Latino, and 65.7% (69) married. The post-intervention cohort comprised 84 hospitalizations and 77 patients. Mean (SD) age was 66.0 (12.2); 52.4% (44) were White, 2.4% (2) Hispanic/Latino, and 60.7% (51) married. Considering index hospitalizations, an ACP note was written for 2.3% (2) of hospitalizations pre-intervention vs. 80.5% (62) post-intervention (p &lt;0.0001). This relationship held even if the physician was in palliative care (4.1% [2] vs. 84.6% [33]) or oncology (0% [0] vs. 76.3% [29]) (p &lt;0.0001). Inpatient length of stay (LOS), hospice referral, code status change, ICU admission rate or LOS, 30-day readmissions, 30-day ED visits, and inpatient and 30-day deaths did not differ significantly between groups. Conclusions: Identification of hospitalized cancer patients with high mortality risk via machine learning led to a substantial increase in documented ACP conversations but did not impact EOL healthcare utilization. Further integration of the model in clinical practice is ongoing. Our intervention showed promise in changing clinician behavior, and additional work is needed to evaluate downstream impacts.
The DNA methyltransferase inhibitor 5-aza-4’-thio-2’-deoxycytidine induces C&amp;gt;G transversions and acute lymphoid leukemia development
Authors: Ryan M. Bertoli, Yang Jo Chung, Michael J. Difilippantonio, Anthony Wokasch, Madison R.B. Marasco, Haley Klimaszewski, Susannah Gammell, Yuelin J. Zhu, Robert L. Walker, Dengchao Cao, Ajay Khanna, Matthew J. Walter, James H. Doroshow, Paul S. Meltzer, Peter D. Aplan
Journal: Cancer Research (2024)

Abstract DNA methyltransferase inhibitors (DNMTi), most commonly cytidine analogs, are compounds that decrease 5′-cytosine methylation. DNMTi are used clinically based on the hypothesis that cytosine demethylation will lead to re-expression of tumor suppressor genes. 5-Aza-4′-thio-2′-deoxycytidine (Aza-TdCyd or ATC) is a recently described thiol-substituted DNMTi that has been shown to have anti-tumor activity in solid tumor models. In this study, we investigated the therapeutic potential of ATC in a murine transplantation model of myelodysplastic syndrome. ATC treatment led to the transformation of transplanted wild-type bone marrow nucleated cells into lymphoid leukemia, and healthy mice treated with ATC also developed lymphoid leukemia. Whole-exome sequencing revealed 1,000 acquired mutations, almost all of which were C&amp;gt;G transversions in a specific 5′-NCG-3′ context. These mutations involved dozens of genes involved in human lymphoid leukemia, such as Notch1, Pten, Pax5, Trp53, and Nf1. Human cells treated in vitro with ATC showed 1,000 acquired C&amp;gt;G transversions in a similar context. Deletion of Dck, the rate-limiting enzyme for the cytidine salvage pathway, eliminated C&amp;gt;G transversions. Taken together, these findings demonstrate a highly penetrant mutagenic and leukemogenic phenotype associated with ATC. Significance: Treatment with a DNA methyltransferase inhibitor generates a distinct mutation signature and triggers leukemic transformation, which has important implications for the research and clinical applications of these inhibitors.
Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC): Updated data and subgroup analyses by age, sites of disease, and use of intervening therapies.
Authors: Laura Ann Huppert, Reshma L. Mahtani, Samantha Catherine Fisch, Naomi Dempsey, Sarah Premji, Angelina Taylor, Saya Jacob, Laura Quintal, Michelle E. Melisko, Amy Jo Chien, Ana Cristina Sandoval-Leon, Lauren Carcas, Manmeet Singh Ahluwalia, Natasha Harpalani, Jenna Hoppenworth, Dame Idossa, Ruta D. Rao, Karthik Giridhar, Hope S. Rugo
Journal: Journal of Clinical Oncology (2024)

1083 Background: T-DXd and SG are both FDA-approved treatments for patients (pts) with HER2-low MBC, but little data exists on the sequential use of these ADCs. Methods: In this multicenter retrospective cohort study, we identified pts with HER2-low MBC treated sequentially with both T-DXd and SG in either order, with or without intervening therapies (IntTx), at 5 academic centers between 2020-2023. We previously reported real-world progression free survival (rwPFS) and real-world overall survival (rwOS) by HR-status and ADC sequence order. Here we provide updated rwPFS and rwOS data, as well as new subgroup analyses by age, sites of disease, and use of IntTx between ADCs for HR- and HR+ disease. Results: 84 pts with HER2-low MBC treated with both T-DXd and SG were included, including 56 pts with HR+/HER2-low MBC (66.7%) and 28 pts with HR-/HER2-low MBC (33.3%). Prior to the start of ADC1, median age was 58 yrs and 22 pts were &gt;65 yrs (26.2%), 65 pts (77.4%) had visceral disease, and 14 pts (16.7%) had central nervous system (CNS) disease. 36 pts (42.9%) had an IntTx between ADCs. Table 1 shows updated rwPFS and rwOS data by HR-status and ADC sequence order. For pts with HR+ and HR- MBC, there was no difference in ADC1 rwPFS or ADC2 rwPFS by age ≤65 vs. &gt;65 yr or by presence vs. absence of visceral disease. For pts with HR- MBC, ADC1 rwPFS and rwOS was shorter for pts with CNS disease vs. pts without CNS disease (rwPFS 5.4 mo (n=6) vs. 8.5 mo (n=22), p=0.03; rwOS 11.6 mo vs. 21.1 mo, p&lt;0.01 respectively). For pts with HR+ and HR- MBC, there was no difference in ADC2 rwPFS with or without receipt of IntTx. There was no difference in time to treatment failure for first IntTx vs. ADC2 if no InTx was given. Conclusions: This is one of the largest multicenter cohorts of pts treated with sequential ADCs for HER2-low MBC. Median rwPFS was longer for ADC1 than ADC2 in all subgroups, regardless of HR-status, ADC sequence order, age ≤65 or &gt;65 yr, presence of visceral disease, or use of IntTx. Among pts with HR-/HER2-low MBC, pts with CNS disease had shorter ADC1 rwPFS and rwOS than pts without CNS disease. [Table: see text]
Results of a retrospective study on the efficacy and safety of alpelisib in patients with HR+/HER2- metastatic breast cancer in real-world clinical practice.
Authors: Alexander Valerievich Sultanbaev, Irina Vladimirovna Kolyadina, Konstantin Menshikov, Shamil Musin, Nadezda Sultanbaeva, Danila Lipatov
Journal: Journal of Clinical Oncology (2024)

e13058 Background: The combination of alpelisib and fulvestrant is an optimal therapy option for patients with hormone receptor-positive (HR+), HER2-negative (HER2–) metastatic breast cancer with PIK3CA gene mutations. The aim of this work to retrospectively analyze the efficacy and safety of alpelisib in real-world clinical practice in patients with pre-treated luminal HER2– negative metastatic breast cancer. Methods: The study included an analysis of 33 patients with widespread luminal HER2- negative breast cancer with detected PIK3CA gene mutation. The median age was 57 ± 13 months (95% CI 52-62). In 12 (36.4%) patients, the PIK3CA gene mutation was detected in exon 9, and in 21 (63.6%) – in exon 20. Alpelisib was prescribed to pre-treated patients in different lines. Most women (32/33; 97%) had received ET combined regimens with CDK4/6 inhibitors before starting alpelisib therapy: 14 (42.4%) patients underwent palbociclib therapy in combination with fulvestrant; 4 (12.1%) – palbociclib with aromatase inhibitors; 13 (39.5%) – ribociclib in combination with fulvestrant; 1 (3.0%) – ribociclib with aromatase inhibitors. It is important to note that 63.6% of patients had previous progression on fulvestrant monotherapy and 72.7% on aromatase inhibitor therapy. Patients with luminal B-subtype of breast cancer dominated - 72.7% (24/33). Results: The median overall survival (OS) in this study was 14 ± 2.5 months (95% CI: 9-18.9), and the median progression-free survival (PFS) was 6 ± 2.7 months (95% CI: 0.7-11.3). The rate of objective response was 30.3%, and prolonged disease stabilization was observed in 24.2% of cases. Prognostic factors were brain metastases (increasing the risk of death by 18 times) and discontinuation of the drug for any reason (increasing the risk of death by 8 times). It should be noted that the main reason for discontinuation or disruption of the drug's timing was unmanageable toxicity. All patients registered adverse events of varying degrees, with 21 (63.6%) patients experiencing hyperglycemia (grade 3-4 – 30.3%) and 14 (42.4%) patients experiencing skin toxicity (grade 3-4 – 15.2%). In the SOLAR-1 study, the frequency of hyperglycemia was comparable (64.8%), and rash was noted in a third of all patients, which is comparable to our data. Conclusions: The results of using alpelisib with fulvestrant confirm its effectiveness in real-world clinical practice in patients with pre-treated HR+HER2- negative widespread breast cancer with the presence of somatic PIK3CA gene mutation. Brain involvement is an unfavorable prognostic factor in patients with PIK3CA mutation and increases the risk of death by 18 times, requiring the need to optimize the therapeutic algorithm, including through radiation methods. Discontinuation of the drug, which increases the risk of death by 8 times.
Comprehensive analysis of TROP2, PD-L1, stromal (s)TILs, and HER2 expression patterns in patients (pts) with metastatic HR+HER2- breast cancer.
Authors: Chiara Corti, Hillary Heiling, Melissa E. Hughes, Busem Binboğa Kurt, Molly DiLullo, Tianyu Li, Nabihah Tayob, Giuseppe Curigliano, Elizabeth A. Mittendorf, Nancy U. Lin, Sara M. Tolaney, Ana Christina Garrido-Castro
Journal: Journal of Clinical Oncology (2024)

1062 Background: Immune checkpoint inhibitors (ICI) have shown limited efficacy in hormone receptor positive (HR+) metastatic breast cancer (mBC) and the optimal ICI-based combination is unknown. The TROP2 antibody-drug conjugate sacituzumab govitecan (SG) demonstrated antitumor activity with a 5.5-month median PFS in endocrine refractory HR+ mBC. Given SG's potential for anticancer immunity, we sought to evaluate expression patterns of biomarkers of interest in HR+ mBC. Methods: This retrospective study included pts with HR+HER2- mBC identified at DFCI between 10/2020 and 12/2021 who received 0-1 prior lines of chemotherapy in the metastatic setting and consented to analysis of archival FFPE tissue samples. We aimed to 1) characterize expression patterns of TROP2 (SP295 H-score), PD-L1 (22C3 CPS), sTILs and HER2 (per central pathology review) in the most recent available sample; 2) assess the prognostic value of selected biomarker combinations for overall survival (OS) defined as the time from consent to either death due to any cause or last follow-up (Cox proportional hazard models; p-value &lt;0.05 considered significant). Results: Among 142 pts included, median age at diagnosis was 46 yrs (IQR: 40–56). Baseline characteristics are shown (Table). At least one biomarker was available for 123 subjects (86.6%). TROP2 expression (n=61) was Medium/High (M-H: 101-300) in 43 pts (70.5%) and Low (L: 0-100) in 18 (29.5%). PD-L1 central assessment (n=120) revealed CPS ≥1 (PD-L1+) in 32 pts (26.7%) and &lt;1 (PD-L1-) in 88 (73.3%); only 7 (5.8%) pts had CPS ≥10. sTILs (n=87) were ≥10% in 14 pts (16.1%) and &lt;10% in 73 (83.9%). When analyzing TROP2 and PD-L1 (n=61), 15 pts (24.6%) were TROP2-M-H/PD-L1+, 28 (45.9%) were TROP2-M-H/PD-L1-, 5 (8.2%) were TROP2-L/PD-L1+, and 13 (21.3%) were TROP2-L/PD-L1-. When analyzing TROP2 and sTILs (n=54), 6 pts (11.1%) were TROP2-M-H/sTILs ≥10%, 32 (59.3%) were TROP2-M-H/sTILs &lt;10%, 2 (3.7%) were TROP2-L/sTILs ≥10% and 14 (25.9%) were TROP2-L/sTILs &lt;10%. For TROP2 and HER2 (n=46), 26 pts (56.5%) had TROP2-M-H/HER2-low tumors, 7 (15.2%) TROP2-M-H/HER2-0, 3 (6.5%) TROP2-L/HER2-low, and 10 (21.7%) TROP2-Low/HER2-0. Median OS (n=138) was 43.8 months; stratification for selected biomarker combinations will be presented although no statistical significance was found. Correlations with NGS data and HER2DX are ongoing and will be presented. Conclusions: Analyzing biomarkers of interest in pts with HR+ mBC unveiled diverse patterns, without associations with OS. Patient characteristics. [Table: see text]
Antigen specificities and proviral integration sites differ in HIV-infected cells by timing of antiretroviral treatment initiation
Authors: Jaimy Joy, Ana Gervassi, Lennie Chen, Brent Kirshenbaum, Sheila Styrchak, Daisy Ko, Sherry McLaughlin, Danica Shao, Ewelina Kosmider, Paul T. Edlefsen, Janine Maenza, Ann C. Collier, James I. Mullins, Helen Horton, Lisa M. Frenkel
Journal: Journal of Clinical Investigation (2024)

Despite effective antiretroviral therapy (ART), persons living with HIV (PWH) harbor reservoirs of persistently infected CD4+ cells, which constitute a barrier to cure. Initiation of ART during acute infection reduces the size of the HIV reservoir, and we hypothesized that in addition, it would favor integration of proviruses in HIV-specific CD4+ T cells, while initiation of ART during chronic HIV infection would favor relatively more proviruses in herpesvirus-specific cells. We further hypothesized that proviruses in acute-ART-initiators would be integrated into antiviral genes, whereas integration sites in chronic-ART-initiators would favor genes associated with cell proliferation and exhaustion. We found the HIV DNA distribution across HIV-specific vs. herpesvirus-specific CD4+ T cells was as hypothesized. HIV integration sites (IS) in acute-ART-initiators were significantly enriched in gene sets controlling lipid metabolism and HIF-1α-mediated hypoxia, both metabolic pathways active in early HIV infection. Persistence of these infected cells during prolonged ART suggests a survival advantage. IS in chronic-ART-initiators were enriched in a gene set controlling EZH2 histone methylation; and methylation has been associated with diminished LTR transcription. These differences we found in antigen specificities and IS distributions within HIV-infected cells might be leveraged in designing cure strategies tailored to the timing of ART initiation.
Comparison of concurrent care and traditional hospice at a regional VA.
Authors: Jeremy Shi Zhang, Rachel A. Hadler, Ann Broderick, William Andrew Zeitler
Journal: Journal of Clinical Oncology (2024)

e24065 Background: While hospice care offers many patients services promoting comfort and quality of life, the traditional hospice model described in Medicare policy presents numerous barriers to utilization. Notably, since hospice pays for all therapies related to a terminal illness, patients are often forced to make a difficult choice to stop disease-directed therapies in order to enroll in hospice. Poor provider understanding of hospice also contributes to the common scenario in which hospice is offered too late to make a meaningful impact for patients and their families. These issues were prominent in the VA population in 2006, when only 5% of eligible Veterans received hospice services. Consequently, the VA Comprehensive End-of-Life Care Initiative in 2009 created the concurrent care hospice model in where Veterans no longer had to stop all disease-directed therapies to enroll. Initial national VA data in lung cancer suggested that concurrent care may be better than traditional hospice by decreasing aggressive treatments, ICU hospitalizations, and medical costs. Our regional VA developed a Hospice Flag system that tagged patients in the electronic medical record who had either a concurrent or traditional hospice enrollment to better inform health care providers. This project investigates how the concurrent care hospice model may help achieve an important Veteran-centered outcome, which is to die in the home setting and improve access to hospice care. Methods: We retrospectively reviewed all Veterans with a hospice flag from October 2017 to July 2021 and cancer as the primary hospice diagnosis. Our primary aim was to establish correlation between hospice type and Veterans’ ultimate location of death with the percentage at home versus institution (e.g. care center, hospital, or hospice house). A secondary measure was median length-of-stay (LOS) in hospice. Results: 317 total Veterans were enrolled in concurrent care hospice (96) and traditional hospice (221) from Oct 2017 to July 2021. 72% of Veterans in concurrent care (69/96) died at home compared to only 57% in traditional hospice (125/221) with the remainder dying in an institution; this result was statistically significant by Chi-square analysis (p = 0.01). Median LOS in hospice was 62 days for concurrent care and 26 days for traditional hospice. Conclusions: This project demonstrates that concurrent care hospice is significantly associated with Veterans being able to die in their own home. Concurrent care was also correlated with longer median LOS in hospice, suggesting greater duration of support services provided to patients and families.