tbuckley/cabot-search huggingface dataset:
Efficacy and genomic analysis of <i>HER2</i>-mutant, metastatic triple-negative breast cancer treated with neratinib alone or in combination with trastuzumab in the phase 2 SUMMIT basket trial.
Authors: Komal L. Jhaveri, Sara A. Hurvitz, Adam Brufsky, Ron Bose, Maria J. de Miguel, Ella Evron, Nisha Unni, Sonya A. Reid, David I. Quinn, Devalingam Mahalingam, Cristina Saura, Jose A. García-Sáenz, Alejandro Martinez-Bueno, Angel Guerrero, Christelle De La Fouchardiere, Hans Wildiers, Georg Friedrich Bischof, Judith D. Bebchuk, Lisa DeFazio Eli, David B. Solit
Journal: Journal of Clinical Oncology (2024)

1094 Background: Genomic analyses of the SUMMIT metastatic breast cancer (mBC) cohorts suggested that resistance to neratinib (N) occurred primarily via acquisition of additional HER2alterations [Smyth et al. Cancer Discovery 2020]; this finding was independently confirmed in the MutHER clinical trial [Ma et al. Clin Cancer Res 2022]. Addition of trastuzumab (T) to N + fulvestrant (F) in HR+, HER2-negative, HER2-mutant mBC revealed increased efficacy compared to N+F [Jhaveri et al. Ann Oncol 2023]. Here, we report final data from SUMMIT evaluating whether the addition of T to N could improve outcomes in patients (pts) with HER2-mutant, triple-negative mBC (representing up to 3% of triple-negative mBCs) and performed next-generation sequencing (NGS) of serial biopsies to evaluate mechanisms of sensitivity and resistance. Methods: Pts with HER2-mutant triple-negative mBC received N (original SUMMIT cohort) or N+T (in the subsequent cohort): oral N 240 mg/d, i.v. T 8 mg/kg initially followed by 6 mg/kg q3w. Loperamide prophylaxis was mandatory during the first two cycles. Efficacy endpoints: confirmed objective response rate and clinical benefit rate (RECIST v1.1 or modified PERCIST); duration of response; progression-free survival. Retrospective central NGS was performed by MSK-IMPACT (tissue) or MSK-ACCESS (plasma). Results: 10 and 17 pts with triple-negative mBC were enrolled in the N and the N+T cohorts, respectively. Median no. of prior systemic regimens for metastatic disease was 2.5 (range 0–6) for the N and 2 (range 0–7) for the N+T cohort. Efficacy findings are summarized (Table). Diarrhea was the most commonly reported adverse event (N 80% any grade; 20% grade 3; N+T 100% any grade; 18% grade 3; no grade 4/5 or permanent discontinuations in either cohort). Correlation of efficacy to central NGS analysis is ongoing and will be reported. Conclusions: Treatment with either N and/or N+T yielded promising clinical efficacy and has been included in recent NCCN guidelines for HER2-mutant, triple-negative mBC. Molecular mechanisms of intrinsic or acquired sensitivity/resistance per genomic analysis will be reported. Clinical trial information: NCT01953926 . [Table: see text]
Immune checkpoint inhibition for the treatment of metastatic breast cancer with high tumor mutational burden: Real world clinical and genomic correlates of response.
Authors: Nicholas Mai, Anton Safonov, Antonio Marra, Yuan Chen, Sarat Chandarlapaty, Pedram Razavi, George Plitas
Journal: Journal of Clinical Oncology (2024)

1078 Background: Pembrolizumab has received tumor-agnostic approval for the treatment of unresectable/metastatic solid tumors carrying a tumor mutational burden (TMB) &gt;10 mut/Mb. The registrational KEYNOTE-158 study, however, did not include any patients with metastatic breast cancer (MBC). Here we present a retrospective study of patients with TMB-high MBC treated with immune checkpoint inhibition (ICI) and report real-world efficacy endpoints, including progression free survival as well as clinical and genomic characteristics that may be associated with duration of response. Methods: All patients with MBC treated with an ICI at MSK and with TMB-high tumors (&gt;10 mut/Mb) assessed by tumor-normal targeted sequencing (MSK-IMPACT) were included. Clinicopathological and demographic data were obtained via the MSK Breast Cancer Translational Program. Mutational signatures were determined using the Signature Multivariate Analysis (SigMA) algorithm. Real world progression free survival (PFS) was determined clinically and analyzed using Kaplan-Meier estimates. Univariate and multivariate analyses were performed using Cox-proportional hazards models. Results: Of 688 patients with TMB-high breast cancer at MSKCC, 87 had received ICI-based therapy for estrogen receptor positive (ER+), triple negative breast cancer (TNBC), and HER2+ MBC. Of those, 45 patients were treated with ICI monotherapy (29 ER+, 11 TNBC, 5 HER2), 31 were treated with ICI + chemotherapy (12 ER+, 19 TNBC), and 11 were treated with combinations of ICI and targeted therapy (8 ER+, 1 TNBC, 2 HER2). Median age at time of ICI treatment across all patients was 60. ICI was the median 5 th line therapy for all patients (range 1-16). Median PFS of ICI for all patients was 3.17 months (95%CI 2.27-5.5). Multivariable analysis did not show statistically significant differences in PFS based upon treatment regimen (monotherapy vs. chemoIO HR 1.03, 95%CI 0.54-1.96, p= 0.92, monotherapy vs combination IO HR 1.66, 95%CI 0.69-4.02, p=0.26), ER status (ER- vs ER+, HR 1.20, 95%CI 0.63-2.28, p=0.57), or HER2 status (HER2- vs HER2+, HR 1.63, 95%CI 0.51-5.20, p=0.41. However, longer PFS was significantly associated with TMB&gt;30 (HR 0.35, 95%CI 0.13-0.92, p=0.03) and dominant APOBEC signature score (APOBEC- vs APOBEC+, HR 0.49, 95%CI 0.25-0.98, p=0.04). Shorter PFS was significantly associated with later treatment line at the time of ICI exposure (continuous, HR 1.22, 95%CI 1.11-1.36, p=0.0001). Conclusions: In this heavily pretreated real-world cohort, ICI in TMB high MBC shows modest clinical activity. Our analysis suggests that ICI may be more effective in MBC patients that are less heavily pre-treated, have TMB&gt;30, and have a predominantly APOBEC mutational signature. Further translational work is necessary to explore the mechanisms of these findings.
Real world experience of trastuzumab deruxtecan for the treatment of metastatic breast cancer in the UK.
Authors: Andy Cheng, Suzanne Frank, Katherine Baines, Mark Nathan, Rosalie V. Douglas, Rushan Sylva, Jessica Ball, Constantinos Savva, Thomas Talbot, Olga Oikonomidou, Jenny Smith, Alastair Thomson, Felicity Ross, Apostolos Konstantis, Nicola Ainsworth, Pietro Luciano, Pooja Iyer, Shyamika Acharige, Shaikh Rana, Judy King
Journal: Journal of Clinical Oncology (2024)

1024 Background: Trastuzumab deruxtecan (TDXd), an antibody drug conjugate, was first approved in the UK for the treatment of human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer (mBC) in 2021. We aimed to review the efficacy and tolerability of TDXd in a real-world UK setting. Methods: We collected clinical and demographic data from medical records on HER2+ mBC patients treated with TDXd in the UK from Jan 2021 to Dec 2023 inclusive. This included: radiological response, the frequency of dose reductions and treatment delays, and reasons for discontinuation. Clinical trial patients were excluded. Descriptive statistical techniques were applied. Results: Data was collected from 26 UK cancer centres on 280 patients. The median age at TDXd initiation was 56 years (range 29-85). Median treatment duration was 9 cycles (range 1-40). 239 patients (85%) had visceral disease. 257 and 196 patients (92% and 70%, respectively) had received prior Trastuzumab and Pertuzumab, respectively. 233 patients (83%) had received prior TDM1. The median number of lines of treatment prior to TDXd was 3 (range 1 to 9). 20 patients (7%) were initiated on a reduced dose and 115 further patients (41%) required at least one dose reduction. 151 patients (54%) had at least one dose interruption due to: infection or neutropenia (n=61), other toxicity (n=85), interstitial lung disease (ILD) investigation (n=39), patient request (n=81), other concurrent illness (n=10), and cardiac investigation (n=6). Of these, 55 patients had more than one treatment break. 157 patients (56%) had discontinued TDXd treatment due to: disease progression or death (n=100), drug toxicity (n=39) of which 22 were due to ILD, and patient choice (n=8). 123 patients remained treatment at the time of analysis. The overall response rate of TDXd was 63% overall: stable disease 23%, partial response 56%, complete response 7%. Conclusions: The real-world data set is not directly comparable to either the DB02 or DB03 trials, as it included patients who had received TDXd in both the second line and later line settings. However, the majority (80%) of these patients were treated in the third line and beyond. The rates of drug interruption and reduction were higher in the real-world data set than in DB02, which may impact on efficacy in the real-world setting. Overall response rate is similar between trial data and our real-world data, although the latter was not measured by RECIST. Data collection is ongoing, including an analysis of real-world progression free survival. [Table: see text]
Impact of use of antibody drug conjugates on the prognostic outcome of patients with HR+ve/HER2-ve MBC: Results from a real world dataset.
Authors: Shaheenah S. Dawood, Gema Hernández, Alba Segovia
Journal: Journal of Clinical Oncology (2024)

1076 Background: Two antibody drug conjugates trastuzumab deruxtecan (T-DXd - in the HER2 low cohort) and sacituzumab govitecan (SG) have been shown to improve both PFS and OS among pts with HER-ve MBC. The objective of this retrospective analysis was to look at trends in the use of and associated prognostic outcome associated with T-DXd and SG among pts with HR+ve/HER2-ve MBC in the real-world setting. Methods: We utilized a federated network of de-identified health data representing approximately 107 million pt lives available through the TriNetX Research Network. We identified pts with HR+ve/HER2-ve MBC diagnosed between Jan 2004 and Jan 2024. Propensity score matching analysis by age, site of metastases and chemotherapy was carried. OS was computed using the Kaplan Meier product limit method. Results: 17,133 pts with HR+ve/HER2-ve MBC treated with endocrine therapy and CDK4/6i were identified of whom 249 pts (1.45%) and 162 pts (0.94%) received SG and T-DXd respectively. 32 pts (0.19%) received T-DXd + SG. Median time from diagnosis of MBC to start of SG and T-DXd was 625 days and 233 days respectively. 5-yr OS for the whole cohort was 58.1%. 5-yr OS among pts who did and did not receive T-DXd was 74.8% and 52.2% respectively (HR 0.44, 95% CI 0.28 - 0.69; p = 0.0002). 5-yr OS among pts who did and did not receive SG was 73.4% and 64.7% respectively (HR 0.62 95% CI 0.42 - 0.90, p=0.012). 5-yr OS among pts who did and did not receive T-DXd + SG was 77.4% and 62.4% respectively (HR 0.55, 95% CI 0.19 - 1.59, p=0.26). 5-yr OS was 68.1% and 74.5% among pts who had received SG alone or T-DXd alone respectively (HR 1.31, 95% CI 0.84 - 2.03, p =0.22). Conclusions: In a real-world data set we report on the OS benefit associated with the use of SG and/or T-DXd at some time point in the therapy of pts with HR+ve/HER2-ve breast cancer who have progressed on endocrine therapy and CDK4/6i.
Trilaciclib combined with sacituzumab govitecan (SG) in metastatic triple-negative breast cancer (mTNBC): Updated phase 2 safety and efficacy results.
Authors: Lasika C. Seneviratne, Kathleen Kiernan Harnden, Sibel Blau, Michael A. Danso, David Berz, Delia Constanza Guaqueta, John F. Schwerkoske, Joyce O'Shaughnessy, Debra A. Patt, Aditya Bardia, Kelly Elizabeth McCann, Andrew Paul Beelen, Jingshan Zhang, John S. Yi, Sara A. Hurvitz, Mabel Alejandra Mardones
Journal: Journal of Clinical Oncology (2024)

1091 Background: Trilaciclib, a reversible cyclin-dependent kinase 4/6 inhibitor, protects hematopoietic stem and progenitor cells during chemotherapy (myeloprotection). In a phase 2 trial in mTNBC (NCT02978716), administering trilaciclib prior to chemotherapy enhanced T-cell activity and modulated antitumor immunity. In a phase 3 trial (ASCENT; NCT02574455), the antibody–drug conjugate SG significantly extended overall survival (OS) versus single-agent chemotherapy (12.1 vs 6.7 months) but was associated with increased neutropenia (any grade, 63% vs 43%; grade 3/4, 51% vs 33%) and diarrhea (any grade, 59% vs 12%; grade 3/4, 10% vs &lt; 1%). This phase 2 single-arm trial was designed to assess safety and efficacy of trilaciclib prior to SG in mTNBC (NCT05113966). Methods: Eligible patients (≥ 2 prior systemic therapies [≥ 1 in the metastatic setting]; measurable disease; confirmed hormone receptor- and human epidermal growth factor receptor 2-negative status; Eastern Cooperative Oncology Group performance status 0 or 1) received intravenous trilaciclib 240 mg/m 2 prior to SG 10 mg/kg on days 1 and 8 of each 21-day cycle until disease progression or toxicity. Tumor assessments occurred at screening, every 6 weeks through week 26, then every 9 weeks until disease progression or subsequent anticancer therapy. Endpoints included antitumor efficacy, myeloprotection, and safety and tolerability. Results: As of January 2, 2024, 30 female patients had been enrolled (median age, 56 years) and completed a median 6 (range, 2–29) cycles. Median follow-up was 11.2 months. Safety is summarized in the Table. The confirmed overall response rate (95% CI) was 23.3% (9.9–42.3), the clinical benefit rate was 46.7% (28.3–65.7), and the median duration of response was 9.1 (4.0–not estimable) months. Median progression-free survival was 4.1 (2.2–7.3) months. OS data are not yet mature; currently, median OS among patients receiving trilaciclib prior to SG is 17.9 (9.9–not estimable) months. Conclusions: Adding trilaciclib prior to SG reduces the rate and severity of multiple adverse events, notably neutropenia and diarrhea, compared with results from trials of SG alone. Preliminary data suggest clinically meaningful OS outcomes among patients receiving trilaciclib prior to SG compared with historical data for SG alone; however, caution should be exercised when interpreting results from cross-trial comparisons. Mature OS data will be presented. Clinical trial information: NCT05113966 . [Table: see text]
Identifying mutations in ctDNA to predict antibody-drug conjugate response in breast cancer.
Authors: Luis Chinea, Isaac Chan, Hannah Chang
Journal: Journal of Clinical Oncology (2024)

e13074 Background: Metastatic breast cancer (mBC) is a complex disease, and outcomes remain poor because new therapies are needed. A new class of drugs, antibody-drug conjugate (ADC), has shown effectiveness across all breast cancer subtypes. Yet FDA- approval for these therapies is restricted only to HER2 and triple-negative subtypes. Therefore, we urgently need to identify which patients, regardless of subtype, will respond to ADCs. The advent of circulating tumor DNA (ctDNA) offers a unique noninvasive method to capture breast cancer (BC) heterogeneity. Recently, ctDNA testing has been employed in clinical practice to guide targeted therapies for mBC, particularly in cases of hormone receptor positive (HR+) disease with mutations in PIK3CA and ESR1. The clinical implications to predict response to ADC therapy in BC remains unclear. Here we test the hypothesis that ctDNA can detect mutations that predict response to novel ADCs. Methods: We analyzed a subset of patients from the Dallas Metastatic Breast Cancer Study comprised of patients with mBC who underwent ctDNA testing using the Tempus xF liquid biopsy ctDNA sequencing panel. The data was analyzed from a single academic medical center between the initial year of ctDNA collection in 2019 to 2023. We identified detectable mutations from patients and addressed a relationship by using Metascape. Relevant signaling pathways were identified: APOBEC, ErbB signaling, p53 and Ras-MAPK pathway. Patients with triple negative, HER2, and HR BC were examined for ADC response and associated mutations. Survival analyses were estimated using Kaplan-Meier and Gehan Breslow Wilcoxon test for statistical analysis. Results: We identified 43 patients with HR+ mBC who had at least one mutation within the Ras-MAPK pathway and 10 of 43 received ADC therapy. Median survival of patients who received ADC therapy 58 months (n=10) vs not receiving ADC therapy 33 months (n=33) (p &lt; 0.05). Of the ten patients who received ADC treatment, 60% had 1+ HER2 staining on tissue biopsy. 70% of patients received Trastuzumab deruxtecan (T-DXd) and 30% received Sacituzumab govitecan (SG). SG was given to patients with negative HER2 staining on biopsy. Patients with at least one mutation within ABOBEC, ErbB signaling, and p53 pathways did not have statistically significant differences in mOS. Conclusions: In HR+ mBC, detection of mutated genes associated with the Ras-MAPK pathway by ctDNA was associated with a more favorable response when treated with ADCs. These findings are exciting because HR+ BCs are being targeted with ADCs regardless of HER2 or TROP2 expression, highlighting the need for new biomarkers to distinguish which HR+ patients to treat. Our retrospective analysis findings are limited by the number of patients with ctDNA testing and also timing of testing. Further studies are needed to solidify the observed correlation between Ras-MAPK pathway mutations and favorable response to ADC treatment.
Developing an Ethics and Policy Framework for Psychedelic Clinical Care: A Consensus Statement
Authors: Amy L. McGuire, I. Glenn Cohen, Dominic Sisti, Matthew Baggott, Yuria Celidwen, Neşe Devenot, Sabrina Gracias, Charles Grob, Ifetayo Harvey, Brent Kious, Mason Marks, Michael Mithoefer, Elizabeth Nielson, Dost Öngür, Alexandra Pallas, Andrew Peterson, Eduardo E. Schenberg, Paul Summergrad, Brett Waters, Monnica T. Williams, David B. Yaden
Journal: JAMA Network Open (2024)

Importance As government agencies around the globe contemplate approval of the first psychedelic medicines, many questions remain about their ethical integration into mainstream medical practice. Objective To identify key ethics and policy issues related to the eventual integration of psychedelic therapies into clinical practice. Evidence Review From June 9 to 12, 2023, 27 individuals representing the perspectives of clinicians, researchers, Indigenous groups, industry, philanthropy, veterans, retreat facilitators, training programs, and bioethicists convened at the Banbury Center at Cold Spring Harbor Laboratory. Prior to the meeting, attendees submitted key ethics and policy issues for psychedelic medicine. Responses were categorized into 6 broad topics: research ethics issues; managing expectations and informed consent; therapeutic ethics; training, education, and licensure of practitioners; equity and access; and appropriate role of gatekeeping. Attendees with relevant expertise presented on each topic, followed by group discussion. Meeting organizers (A.L.M., I.G.C., D.S.) drafted a summary of the discussion and recommendations, noting points of consensus and disagreement, which were discussed and revised as a group. Findings This consensus statement reports 20 points of consensus across 5 ethical issues (reparations and reciprocity, equity, and respect; informed consent; professional boundaries and physical touch; personal experience; and gatekeeping), with corresponding relevant actors who will be responsible for implementation. Areas for further research and deliberation are also identified. Conclusions and Relevance This consensus statement focuses on the future of government-approved medical use of psychedelic medicines in the US and abroad. This is an incredibly exciting and hopeful moment, but it is critical that policymakers take seriously the challenges ahead.
Effects of Developmental Lead and Phthalate Exposures on DNA Methylation in Adult Mouse Blood, Brain, and Liver: A Focus on Genomic Imprinting by Tissue and Sex
Authors: Rachel K. Morgan, Kai Wang, Laurie K. Svoboda, Christine A. Rygiel, Claudia Lalancette, Raymond Cavalcante, Marisa S. Bartolomei, Rexxi Prasasya, Kari Neier, Bambarendage P.U. Perera, Tamara R. Jones, Justin A. Colacino, Maureen A. Sartor, Dana C. Dolinoy
Journal: Environmental Health Perspectives (2024)

Maternal exposure to environmental chemicals can cause adverse health effects in offspring. Mounting evidence supports that these effects are influenced, at least in part, by epigenetic modifications. It is unknown whether epigenetic changes in surrogate tissues such as the blood are reflective of similar changes in target tissues such as cortex or liver.
Frequency of dose reductions of abemaciclib in metastatic and early-stage hormone positive, HER2 negative breast cancer.
Authors: Anna Ter-Zakarian, Lauren N. Donovan, Farah Nasraty
Journal: Journal of Clinical Oncology (2024)

e13099 Background: Abemaciclib is a CDK4/6 inhibitor which in combination with endocrine therapy (ET) improves progression-free survival in hormone receptor (HR)-positive, HER2 negative advanced breast cancer, as well as invasive disease free-survival in high-risk early-stage breast cancer. However, abemaciclib is associated with adverse events which may limit treatment adherence. In this single-center study, we describe real-world safety outcomes of early-stage and advanced HR-positive, HER2 negative breast cancer patients prescribed abemaciclib in conjunction with ET. Specifically, we analyze the frequency of adverse events and dose reductions (DR). Methods: We conducted a retrospective study of patients treated at Scripps Clinic between 1/1/2019-1/1/2023 with HR-positive, HER2 negative breast cancer prescribed abemaciclib with ET. Primary analyses were performed to discern clinical characteristic differences between groups. Categorical variables were summarized as frequencies and compared between arms by Chi-Square tests or Fisher’s Exact Tests. All continuous variables were summarized as means and standard deviations and compared between arms by T-Tests if normally distributed or summarized as medians and compared between arms by Mann-Whitney Tests otherwise. Statistical significance was set to 0.05 and all analyses were conducted in R. Results: A total of 77 patients were analyzed including 62% in the adjuvant setting and 38% in the metastatic setting. 51% of patients required DR. Patients requiring DR were older relative to those not requiring DR (59 vs 52 years of age, p=0.019). Those requiring DR remained on abemaciclib longer relative to those without DR (509 vs 350 days, p=0.057). Among those requiring DR, there were higher rates of grades II-IV diarrhea (p&lt;0.001) and Loperamide use (p=0.083). Those requiring DR also had higher rates of neutropenia (54% vs 29%, p=0.027), abdominal cramping (39% vs 8%, p=0.002), nausea (39% vs 13%, p=0.011), and fatigue (51% vs 32%, p=0.079). Among 9 patients who expired on abemaciclib, 7 were in the metastatic setting and 1 was linked to an adverse effect from abemaciclib; none required DR (24% vs 0%, p&lt;0.001). Finally, patients in the adjuvant setting remained on abemaciclib longer relative to those in the metastatic setting (526 vs 281 days, p=0.01). 95% of patients experienced symptom improvement with DR (p&lt;0.001). Conclusions: Our study describes real-world safety outcomes of patients with HR-positive, HER2 negative breast cancer treated with abemaciclib and ET. More than half of patients required DR. Those who reduced their abemaciclib dose had improvement of clinical symptoms and remained on therapy longer. Based on our findings and given the importance of adherence in treatment efficacy, a lower starting dose of abemaciclib may be a more tolerable strategy, especially among older patients who required more DR in our study.