tbuckley/cabot-search huggingface dataset:
Unveiling the complexity: Liquid biopsy-based proteomic exploration of triple-negative breast cancer in women.
Authors: Debora Aparecida Pires de Campos Zuccari, Guilherme Tamarindo, Adriana Alonso Novais, Barbara Maria Frigieri, Juliano Coelho da Silveira, Fabiana Ferreira de Souza, Carlos Alberto Labate, Luis Gustavo de Almeida Chuffa
Journal: Journal of Clinical Oncology (2024)

e13138 Background: This groundbreaking study places a spotlight on breast cancer in women, with a specific emphasis on the challenging triple-negative breast cancer (TNBC) subtype. Delving into the intricate world of extracellular vesicles (EVs) from TNBC-diagnosed individuals, the research meticulously compares various conditions, including healthy controls, benign tumors, recurrent tumors, and those in remission. Employing cutting-edge techniques like liquid biopsy and LC-MS/MS, the study meticulously explores the proteomic profile of serum exosomes, aiming to pinpoint diagnostic and prognostic markers in breast cancer. Methods: In the initial phase, EVs were expertly isolated and characterized from blood plasma samples exclusively from women, utilizing state-of-the-art methods such as ultracentrifugation and nanoparticle tracking analysis (NTA). Despite applying rigorous statistical criteria, the study found no significant differences in EV concentrations and sizes among the diverse groups. However, the ensuing proteomic analysis uncovered 130 proteins, with Cystatin A and Histone H2A emerging as promising biomarkers for TNBC. To validate them, the study intricately tested tumor cell lines from distinct subtypes, representing luminal, triple-negative, and HER2 overexpressed. The examination of gene and protein expression through RT-qPCR and western blotting added a layer of depth to the research, unraveling the complexity of regulatory processes within cells and demonstrating a remarkable congruence between protein levels found in the proteomics from patients’ serum and in immortalized cell lines. Results: The proteomic analysis brought to light the absence of CSTA and HIST1H2A expression in benign tumor patients, varied levels in malignant tumor patients, and a substantial increase in TNBC patients pre-mastectomy. Validating these findings through western blotting further accentuated the potential of these proteins as distinguishing factors. Conclusions: In conclusion, this pioneering study not only underscores the immense potential of liquid biopsy-based proteomic analysis in identifying crucial diagnostic and prognostic markers in breast cancer but also sheds light on the intricate nuances of the challenging TNBC subtype. Our findings unveil valuable insights that pave the way for future personalized treatment strategies, marking a significant stride forward in breast cancer research.
Racial disparities among triple negative breast cancer clinical trial enrollees between 2010-2023.
Authors: Divya Rao, Paige Brabant, Isabelle Chau, Megan Darrell, Chi-Yen Yao, Melanie Roth, Maya Pandit, Monique Gary, Mill Etienne
Journal: Journal of Clinical Oncology (2024)

1093 Background: Despite the social construct of race lacking biological significance, it plays a significant role in health disparities and necessitates examination to address social stratification and health inequities. Not reporting race in medical research neglects the reality of social stratification, injustices, and implications for population health. Additionally, excluding racial demographic data from research publications may conceal health disparities. This study focuses on Triple Negative Breast Cancer (TNBC) clinical trials, aiming to meta-analyze the inclusion of racial data and assess racial representation. Methods: A meta-analysis of 81 completed TNBC trials (2011-2023) from ClinicalTrials.gov was conducted. Demographic data on race and sex were extracted and analyzed using Microsoft Excel. Two independent reviewers extracted study-level data for a random-effects analysis. The primary outcome was identifying the prevalence of studies lacking racial data. The secondary outcomes are the prevalence of each racial category (White, Black, Asian, Hispanic/Latino, and Combined Other) among all TNBC clinical trials that reported demographic information. The Combined Other category includes American Indian, Native Hawaiian, more than one race, and unknown/unreported. Results: Of 81 trials, 29.63% did not report racial data. The remaining 57 trials (8,196 participants) revealed 73.98% White, 10.29% Asian, 7.85% Black, 8.02% Hispanic/Latino, and 4.12% "combined other" participants. U.S.-based trials (36 studies, 3,348 participants) showed 77.96% White, 12.03% Black, 4.51% Asian, and 4.96% Hispanic/Latino participants. Moreover, we conducted a comparative analysis between the racial distribution in U.S. clinical trials and the prevalence of TNBC in the U.S. population, utilizing the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Public Use Datasets (2010-2019). The analysis revealed a significant discrepancy with White (p&lt;.001) participants being overrepresented, and Black (p&lt;.001), Asian (p&lt;.001), Hispanic/Latino (p&lt;.001), American Indian (p&lt;.001), more than one race (p&lt;.02), and Other/Unknown (p&lt;.001) populations being underrepresented. Conclusions: Globally, 29.63% of TNBC trials did not report racial data, raising concerns about generalizability. U.S.-based studies exhibited overrepresentation of White participants and underrepresentation of Black, Asian, Hispanic/Latino, American Indian, Native Hawaiian, and other categories. Notably, Black and Hispanic/Latino individuals, comprising a substantial portion of TNBC patients, were underrepresented. These findings underscore racial/ethnic disparities in breast cancer trial participation, warranting further investigation into recruitment barriers for equitable participation.
The efficacy of PARP inhibitors in the treatment of patients with synchronous breast cancer.
Authors: Kamila Izrailbekova, Sergey Kamishov, Sunnatilla Saydullaev, Shakhnoza Khamoydinovna Niyozova, Mirzagaleb Tillyashaykhov, Gulnoza Olimjonova, Abdurakhmon Sobitov
Journal: Journal of Clinical Oncology (2024)

e13041 Background: Currently, the role of BRCA1/2 in the development of primary and multiple malignant breast tumors is under discussion, along with the effectiveness of targeted therapy for this oncopathology. At the same time, there is a lack of sufficient research dedicated to the treatment of patients with synchronous breast cancer (BC) concurrent with ovarian cancer (OC) and the outcomes of using PARP inhibitors in this patient population. Methods: A retrospective analysis of treatment outcomes based on long-term survival indicators was conducted for 23 patients with synchronous BC, where the second tumor was OC. These patients underwent evaluation and treatment between 2017 and 2022. The average age of the patients was 45.3±5.6 years, with a prevalence of patients in stages IIb-IIIa of BC and IIb-IIIc of OC. Germline mutations in the BRCA1/2 genes were detected in 8 patients, among whom 5 exhibited the triple-negative phenotype of BC. The 1 st group included 11 (47.8%) patients without BRCA1/2 mutations, who received neoadjuvant chemotherapy with paclitaxel 175 mg/m 2 + carboplatin AUC 6 once every 3 weeks. In the 2 nd group, consisting of 12 (52.2%) patients, olaparib 800 mg was added to this chemotherapy regimen. This group also included 8 patients with BRCA1/2 mutations. Results: In the majority of patients in both groups, a significant elevation in CA125 levels in serum was observed, averaging 563 U/mL, with practically normal CA153 levels at 32 U/mL. Identified mutations included 5382insC and 4154delA mutations in the BRCA1 gene, as well as the 6174delT mutation in the BRCA2 gene. Patients underwent three courses of treatment, and four weeks after completing the last course, surgical intervention was performed in the form of radical mastectomy, hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Following surgical treatment, patients received adjuvant chemotherapy following the same regimens. In the 2 nd group, patients continued to receive olaparib for one year, and no signs of unacceptable toxicity were reported. The median overall survival in the first group of patients was 34.2 months (95% CI: 28.6-37.5), while in the second group, it was 36.8 months (95% CI: 31.4-41.1). The addition of bevacizumab significantly increased the median time to progression from 13.8 months (95% CI: 11.8-14.5) to 15.2 months (95% CI: 12.4-15.8), p=0.042. Lethal outcomes primarily occurred due to the progression of ovarian cancer. Conclusions: Thus, the addition of the PARP inhibitor olaparib to a platinum-based chemotherapy regimen in patients with synchronous breast cancer, associated with germline mutations in BRCA1/2 genes and the presence of ovarian cancer as a second tumor, has a positive impact on treatment outcomes. This contributes to the resectability of patients and significantly increases the median time to progression.
Dietary commensal wrestles iron from tumor microenvironment to activate antitumoral macrophages
Authors: Amanda H. Lee, Simran K. Randhawa, Marlies Meisel
Journal: Cancer Research (2024)

The microbiome dictates the response to cancer immunotherapy efficacy. However, the mechanisms of how the microbiota impacts therapy efficacy remain poorly understood. In a recent issue of Nature Immunology, Sharma and colleagues elucidate a multifaceted, macrophage-driven mechanism exerted by a specific strain of fermented food commensal plantarum strain IMB19, LpIMB19. LpIMB19 activates tumor macrophages, resulting in the enhancement of cytotoxic cluster differentiation 8 (CD8) T cells. LpIMB19 administration led to an expansion of tumor-infiltrating CD8 T cells and improved the efficacy of anti-PD-L1 therapy. Rhamnose-rich heteropolysaccharide, a strain-specific cell wall component, was identified as the primary effector molecule of LplMB19. Toll-like receptor 2 signaling and the ability of macrophages to sequester iron were both critical for rhamnose-rich heteropolysaccharide-mediated macrophage activation upstream of the CD8 T-cell effector response and contributed to tumor cell apoptosis through iron deprivation. These findings reveal a well-defined mechanism connecting diet and health outcomes, suggesting that diet-derived commensals may warrant further investigation. Additionally, this work emphasizes the importance of strain-specific differences in studying microbiome-cancer interactions and the concept of "nutritional immunity" to enhance microbe-triggered antitumor immunity.
Real-world (RW) elacestrant use patterns and therapeutic outcomes in patients (pts) with hormone receptor-positive (HR+)/HER2-negative advanced breast cancer (aBC).
Authors: Maxwell Roger Lloyd, Azka Ali, Caroline M. Weipert, Sheila R Solomon, Jayati Saha, Marla Lipsyc-Sharf, Erika P. Hamilton, Kevin Kalinsky, Aditya Bardia, Nicole Zhang, Seth Andrew Wander
Journal: Journal of Clinical Oncology (2024)

1071 Background: Elacestrant was the first novel endocrine therapy (ET) to receive FDA approval in over two decades. In the EMERALD study, pts with ESR1-mutant ( ESR1m) HR+/HER2-negative aBC had a median progression free survival (PFS) of 3.8 months (mos). Here, we use a large clinical-genomic database to assess the RW use of elacestrant and examine the impact of line of therapy (LOT) and number of ERS1m on pt outcomes. Methods: Pts with HR+/HER2- aBC were identified via the GuardantINFORM database; all pts with ESR1m detected on circulating tumor DNA (ctDNA) testing done in routine clinical care and treated with elacestrant after the FDA approval date were included. Real-world time to treatment discontinuation (TTD) and time to next treatment (TTNT) were used as proxies for PFS (measured in mos). For TTD/TTNT, Kaplan-Meier curves and median time-to-event with 95% confidence intervals (CI) were used. For outcomes specific to single versus &gt;1 ESR1m, only pts with an ESR1m detected within the 6 months prior to elacestrant start were included. Results: 418 aBC pts were treated with elacestrant, with a median age of 62 years. Elacestrant was used across metastatic LOT (2 nd : 12%, 3 rd : 18%, 4 tH : 17%, 5 th +: 53%). Considering all prior therapies, pts commonly received prior aromatase inhibitors (AI) (89%), CDK4/6i (73%), fulvestrant (63%), and chemotherapy (49%). Of 312 pts with testing within 6 months of elacestrant start, 56% harbored a single ESR1m, with a maximum of 11 ESR1m detected in a single patient. TTD was 5.4 mos (95% CI: 4.2 - not reached [NR]) and TTNT was 6.2 mos (95% CI: 5.7 - NR); most pts were censored at the time of analysis (65% for TTD, 71% for TTNT). There were no significant differences in TTD or TTNT based on number of prior LOT or number of ESR1m mutations (Table 1). Data was not yet mature to assess differences in outcomes based on prior ET use, duration of prior CDK4/6i exposure, specific ESR1m, or co-occurring alterations. Conclusions: Using a clinical-genomic database, we present early RW insights of aBC pts treated with elacestrant. Initial outcomes, as assessed via TTD and TTNT, exceed the PFS reported in the EMERALD trial, perhaps due to multiple factors impacting patient selection and restaging protocols, which can differ in prospective trials versus routine clinical care. Factors such as prior LOT and number of ESR1m did not impact patient outcomes; additional factors such as prior ET use, duration of CDK4/6i treatment, specific ESR1m, and co-occurring mutations will be assessed as data matures. [Table: see text]
PRE-ISPY phase I/Ib oncology platform program (PRE-I-SPY-P1).
Authors: Paula R Pohlmann, David Alexander Potter, Nan Chen, Jason A Mouabbi, Murtuza Rampurwala, Shayan Rayani, Antoinette R. Tan, Roberto Antonio Leon-Ferre, Karthik Giridhar, Judy Caroline Boughey, Hyo S. Han, Laura Carpin Kennedy, Elaine M. Walsh, Debashish Tripathy, Shabnam Jafari, Martin Eklund, Rita Nanda, Funda Meric-Bernstam, Douglas Yee, Laura Esserman
Journal: Journal of Clinical Oncology (2024)

e12641 Background: Many promising agents or combinations regimens relevant to breast cancer lack sufficient clinical information for use in the neoadjuvant setting. To enable acceleration of drug development by reducing time and cost of clinical trial planning and conduct, the Phase I initiative PRE-ISPY Program was created. Methods: The PRE-ISPY Program is built within the I-SPY network, with the overall aim to streamline the regulatory pathway and the processes of trial design, contracting, activation, enrollment, execution, data gathering and analysis, as well as reporting of new therapeutic agents or combinations of relevance to breast cancer. Results: The PRE-ISPY trial is an open-label platform phase IB study designed to evaluate compelling single agent or combination regimens with the overall goal of moving promising drug regimens into I-SPY2 Trial and/or into other oncology-based trials in a timely manner. Graduation of a PRE-ISPY regimen to I-SPY2 is not mandatory. The primary objectives in each study Arm are to determine safety and to obtain preliminary efficacy data of the new regimen in patients with metastatic cancer, including a cohort of breast cancer patients. Each Arm may contain a Part 1 (dose finding) and a Part 2 (dose expansion). The new treatment can be tested also in patients with other solid malignancies than breast cancer, in which the treatment may be applicable, as specified in the design of the Arm. A breast cancer specific cohort is required in Part 2. Candidate treatment regimens are selected with advice from the I-SPY2 Agent Selection Working Group. The PRE-ISPY/Phase IB trial has multiple ongoing drug regimen Arms subsequently added as new protocol appendices through amendments to a Master protocol. There is no randomization; participants are enrolled, and treatment selected according to the relevance of therapy to their disease. Prospective companion biomarkers are evaluated. The current arms under study are PRE1: ALX-148 combined with trastuzumab deruxtecan; PRE2: tucatinib combined with zanidatamab; and PRE3: vidutolimod combined with cemiplimab. Selected agents or therapeutic combinations are tested through this protocol in the I-SPY Network Centers that participate in the PRE-ISPY Program. Toxicities are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). Clinical responses are evaluated based on RECIST v1.1 criteria. Conclusions: Once safety is established, promising regimens can be rapidly transitioned to I-SPY 2.2 or other phase 2/3 trials. The first patient was enrolled on 2/1/2023. Clinical trial information: NCT05868226 .
Identifying and addressing real-world challenges to triple-negative breast cancer (TNBC) care: A quality improvement initiative.
Authors: Kelly E. McKinnon, Aditya Bardia, Jose Alemar, Ilona Dewald, Janet Storey, Samuel Dooyema, Jeffrey D. Carter, Cherilyn Heggen
Journal: Journal of Clinical Oncology (2024)

e13143 Background: Recent introduction of novel therapies into advanced TNBC management has greatly increased complexity of care. This study aimed to identify real-world challenges and practice gaps in evidence-based treatment for TNBC in the community oncology setting. Methods: In March-August 2023, 48 health care providers (HCPs) at 4 US community oncology clinics completed surveys on practice gaps and challenges related to care delivery, treatment selection, adverse event management, and shared decision making (SDM) in TNBC. HCPs (n=47) then participated in audit/feedback (AF) sessions to review clinical evidence and develop clinic-specific action plans to address identified gaps. Follow-up surveys evaluated the impact of real-world clinical practice changes stemming from the initiative. Results: HCPs reported sequencing of therapies across multiple lines of treatment, coordinating care and care transitions, and providing patient-centered supportive care as their top 3 challenges. They also reported challenges with managing adverse events, particularly neutropenia (46%) and cardiotoxicity (25%). Most HCPs (~70%) reported providing nutritional support services, healthy lifestyle counseling, and financial counseling, while distress screening, quality of life assessment, and end-of-life counseling were less frequently used (~40%). Two-thirds of HCPs said that they often or always engaged in SDM with their patients, with top barriers identified as lack of time, patients’ low health literacy, and lack of support staff. Changes that were considered most likely to improve care were improved collaboration across interprofessional teams (31%) and improved follow-up and monitoring for early signs of recurrence/progression (21%). When asked about support necessary to for changes across their healthcare system, HCPs selected improved workflows/protocols to support collaboration across disciplines (tumor boards, specialty care teams, etc) as their top resource need. After the AF sessions, action plans included use of new communication channels to discuss patient side effects or confirm plans for biomarker testing, improved treatment sequencing protocols, workflow standardization for patients transitioning to specialty care teams, and implementation of checkpoints to ensure continued patient engagement and timely identification of adverse events. On a follow-up survey, clinics reported they had improved follow-up and monitoring for adverse events (83%) and were engaging patients more frequently in SDM (67%). Conclusions: Community oncology clinics face multiple ongoing challenges that may be impeding the ability to integrate newer therapies into TNBC management. Further research on multidisciplinary communication, collaboration, and needed workflow changes has the potential to improve care for patients with TNBC.
Targeted genotyping for recurring variants in cancer susceptibility genes in non-Ashkenazi Jewish patients with breast cancer diagnosed ≥ 50 years.
Authors: Rinat Bernstein-Molho, Narmeen Abu Shhada, Yael Laitman, Iris Netzer, Shelly Shoval, Eitan Friedman
Journal: Journal of Clinical Oncology (2024)

e12547 Background: Several recurring pathogenic variants (PVs) in BRCA1/BRCA2 and additional cancer susceptibility genes are described in ethnically diverse Israeli population. Since 2019 testing for these recurring PVs is reimbursed unselectively for all breast cancer (BC) patients in Israel, while extended multi-gene panel testing is reimbursed based on specific clinical criteria. We aimed to evaluate the yield of genotyping for these recurring PVs in non-Ashkenazi Jewish BC patients diagnosed ≥ 50 years. Methods: Clinical and genotyping data of all BC patients undergoing oncogenetic counseling at the Oncology institute at Sheba medical center from June 2017 to December 2023 were reviewed. Results: Of 2706 BC patients (mean age at diagnosis 54 years; range, 20-92 years) counseled, 515 patients of non-Ashkenazi Jewish (all 4 grandparents) descent, diagnosed ≥ 50 years of age were genotyped, 55 with triple-negative BC (TNBC) and 460 with non-TNBC. One of the recurring PVs in BRCA1/BRCA2 were detected in 12.7% (7/55) of TNBC patients and 0.65% (3/460) in non-TNBC. One patient with non-TNBC had PMS2 PV. Low-penetrance variants (not all in BC related genes) were found in 2.5% of genotyped TNBC and in 3.7% of non-TNBC patients, including CHEK2 c.499G&gt;A (n=3), APC c.3920T&gt;A (n=4), and heterozygous MUTYH c.1187G&gt;A (n=5). Following first-pass genotyping, 146 patients performed multigene panel testing, none carried a BRCA1/BRCA2 PV, and only 5/127 non-TNBC (3.9%) harbored PVs in CHEK2 (n=2), ATM c.103C&gt;T (n=2) and NBN (n=1). Conclusions: The observed low rates of PV detection in non-Ashkenazi Jewish non-TNBC cases older than 50 years at diagnosis, mostly for clinically insignificant variants, questions the justification of unselected genotyping in this subset of patients.