tbuckley/cabot-search huggingface dataset:
Metastatic breast cancer in elderly women: A retrospective cohort study in Morocco.
Authors: Kaoutar Maadin, Nawfel Mellas, Zineb Benbrahim, Karima Oualla, Lamiae Amaadour, Samia Arifi
Journal: Journal of Clinical Oncology (2024)

e13073 Background: Breast cancer (BC) stands as the predominant malignancy among women worldwide, presenting a significant global public health problem. In Morocco, it is the leading cause of cancer-related mortality in females. However, there exists a limited understanding of outcomes and treatment patterns for elderly patients with metastatic breast cancer (MBC) in our context. Methods: We conducted a retrospective cohort study at the Department of Medical Oncology, Hassan II University Hospital of Fez, focusing on 92 female patients aged 65 years or older diagnosed with MBC, between January 2012 and December 2016. The primary objectives were to estimate overall survival (OS) and progression-free survival (PFS), describe treatment patterns, and characterize the clinicopathological, and prognostic aspects of MBC in elderly women in Morocco. Results: The cohort’s median age was 70.88 (range, 65-88years) with 45.6% of patients aged of 65 to 69 years, 34.8% between 70 to 74 years old, and 19.6% over 75. Most patients (77.2%) had an Eastern Cooperative Oncology Group (ECOG) score of 0 to 1, and only 33.7% had comorbidities. De novo stage IV constituted 59.8% of all cases. Metastatic recurrences represent 40.2% with 16.2% having recurrence within 12 months, and 83.8% having a recurrence interval exceeding 12 months. The median time to recurrence was 45.5 months. Invasive ductal carcinoma (IDC) was the predominant histological type (81.1%), with SBR grade II (51%) and grade III (21.7%). Metastases were observed in pleuropulmonary (78.3%), bone (56.5%), lymph nodes (33.7%) and liver (30.4%). With 71.7% having metastases in fewer than three sites, while 28.3% had metastases in three or more sites. Molecular profiling showed Luminal A (38%) and Luminal B (26.1%) subtypes as the most prevalent, followed by triple-negative (17.4%) and HER2+ (15.2%). Treatment modalities included chemotherapy (50%), hormone therapy (15.2%) or a combination of the two (17.4%), and anti-HER2 targeted (14.1%). Median OS was 37 months (95% CI: 16.86 - 57.13 months), and median PFS was 33.16 ± 4.1 months. Anti-HER2 therapy showed a significant association with survival (p = 0,05). Conclusions: This study highlights the characteristics, survival, and treatment modalities of elderly patients with MBC in Morocco. Despite the predominance of luminal BC an intriguing observation was the frequent use of chemotherapy as first line modality.
A machine learning algorithm based on multi-omics biomarkers for the detection of tumor microsatellite instability.
Authors: Kyle C Strickland, Sarabjot Pabla, Zachary D Wallen, Mary K Nesline, Heidi Chwan Ko, Rebecca A. Previs, Jeffrey M Conroy, Pratheesh Sathyan, Kamal S. Saini, Taylor J. Jensen, Brian Caveney, Marcia Eisenberg, Shakti H Ramkissoon, Eric A Severson
Journal: Journal of Clinical Oncology (2024)

1554 Background: Microsatellite instability (MSI) occurs via defects in mismatch repair (MMR) and is characterized by high tumor mutational burden (TMB) and a robust inflammatory response. Accurate MSI-high classification of immune-evasive tumors is vital due to the effectiveness of immune checkpoint inhibitor (ICI) therapy, such as pembrolizumab, which is FDA approved for all MSI-high tumors irrespective of anatomic origin. Detection methods of MSI-status vary widely, including immunohistochemistry (IHC), polymerase chain reaction (PCR), and next-generation sequencing (NGS). We developed a machine learning (ML) model to predict MSI status in patients with solid tumors using comprehensive genomic and immune profiling (CGIP), independent of direct sequencing data from microsatellite sites. Methods: We analyzed samples from 1,838 patients with colorectal cancer (CRC) by CGIP, which included DNA panel testing (523 genes) for pathogenic single nucleotide variants (pSNV) and determination of TMB (mut/Mb), and RNA sequencing (397 genes) for gene expression (GEX). The Boruta algorithm was used to select key genomic and GEX changes associated with MSI status. A distributed gradient boosting algorithm created a predictive model that was trained on 70% of the cohort. The model was tested on the remaining CRC cohort (Test), and in the PanCancer Atlas CRCs (TCGA), endometrial adenocarcinomas (EMCA), and CRC with indeterminate MSI testing by CGIP. Performance of the trained model was assessed using sensitivity, specificity, and positive (PPV) and negative (NPV) predictive value. Results: Feature selection identified 79 genes with pSNVs, 63 GEX changes, and TMB as informative for MSI prediction. The model showed high predictive accuracy in differentiating MSI-H tumors. Of the 39 cases that failed MSI component of CGIP (Indeterminate), 17 had MMR IHC results available, of which 1 demonstrated loss of MLH1/PMS2 and the other 16 showed intact (normal) expression. Testing of this cohort identified 3 cases as MSI-high, at least one of which was confirmed by IHC. No cases with intact MMR protein IHC were identified as MSI-high by the algorithm. Conclusions: Our ML-driven approach accurately assessed MSI status of CRC and EMCA using CGIP data. This approach also identified potential cases with MSI-high status where direct sequencing of microsatellites failed. This study highlights a method to identify patients with potential MSI-high status for orthogonal screening with the MSI component of a test fails. [Table: see text]
Fulvestrant with or without the cyclin-dependent kinase 7 (CDK7) inhibitor samuraciclib in advanced hormone receptor positive (HR+) breast cancer after CDK4/6 inhibition: Phase II SUMIT-BC study.
Authors: Sonia Pernas, Carmen Hinojo, Javier Pascual, Sercan Aksoy, Glen Clack, Stuart McIntosh
Journal: Journal of Clinical Oncology (2024)

TPS1126 Background: CDK7 enhances oncogene transcription and upregulates anti-apoptotic genes, accelerates the cell cycle via CDK phosphorylation, and activates estrogen receptors (ERs) that can drive resistance to hormonal therapy in cancer. CDK7 inhibition therefore represents a potential anticancer strategy in cancer. Samuraciclib (CT7001) is a small molecule, ATP competitive, selective oral inhibitor of CDK7 that inhibits these key effects of CDK7. Samuraciclib had a favorable safety profile and showed clinical activity when combined with fulvestrant in a phase I study in patients with HR+/HER2− advanced breast cancer (BC) who had previously been treated with a CDK4/6 inhibitor. Patients with no detectable TP53 mutation in ctDNA at baseline and those without baseline liver metastases appeared to have better outcomes. The instant release capsule formulation of samuraciclib used in this study released large amounts of samuraciclib high in the gastrointestinal (GI) tract, which may have contributed to the observed low grade GI adverse events, which were managed with prophylaxis and counselling (1). Methods: A phase 2 open-label randomized study has been designed to evaluate the efficacy, safety, pharmacokinetics (PK), and quality of Life (QoL) of samuraciclib combined with fulvestrant compared to fulvestrant monotherapy (SUMIT-BC; NCT05963984). Eligible patients (n=60) are ≥18 years, have histologically or cytologically confirmed ER+/HER2− advanced or metastatic BC not amenable to resection or radiotherapy of curative intent, have received an aromatase inhibitor combined with a CDK4/6 inhibitor in the adjuvant or advanced setting, are receiving a luteinizing hormone-releasing hormone agonist if pre/perimenopausal, and have RECIST v1.1 evaluable disease. Prior SERD, mTOR inhibition, or chemotherapy for advanced BC are not permitted. All patients undergo baseline Guardant360 ctDNA analysis to establish TP53 and other mutation status. Patients are randomized 1:1:1 to fulvestrant alone (500 mg IM administered on days 1, 15 and 29 and then monthly), fulvestrant and samuraciclib 240 mg QD, or fulvestrant and samuraciclib 360 mg QD. In preparation for phase 3 development, a novel single tablet formulation of samuraciclib is used, which may enhance GI tolerability. Patients undergo RECIST v1.1 evaluation at baseline, every 8 weeks until week 48, and every 12 weeks thereafter. The primary endpoint is clinical benefit response at 24 weeks. Secondary endpoints are tolerability, progression free survival, overall response rate, duration of response, and PK of fulvestrant and samuraciclib. QoL (Functional Assessment of Cancer Therapy - Breast questionnaire [FACT-B]) and correlations between TP53 mutation and efficacy/safety will be assessed. 1. Coombes et al. Nature Comms 2023. Clinical trial information: NCT05963984 .
Cryptolepine: A naturally derived alkaloid inhibits breast cancer progression by blocking cell cycle progression and inducing apoptosis.
Authors: Manzoor Ahmad Mir, Hina Qayoom
Journal: Journal of Clinical Oncology (2024)

e13151 Background: Triple Negative Breast cancer is an aggressive breast cancer subtype. TNBC has a more aggressive clinical course, an earlier age of beginning, a larger propensity for metastasis, and worse clinical outcomes as evidenced by a higher risk of recurrence and a shorter survival rate when compared to hormone receptor-positive or HER2-positive illness. Currently, the primary options for TNBC treatment are surgery, radiation, and chemotherapy. These treatments, however, remain ineffective due to recurrence. However, given that p53 mutations have been identified in more than 60–88% of TNBC, translating p53 into the clinical situation is particularly important in TNBC. Given the scope that some natural drugs can be used as specifically targeting prospective therapeutic in TNBC and to sensitize this aggressive malignancy while reducing side effects. In this study, we screened and evaluated the therapeutic potential of CRP in TNBC in-vitro models being an anti-malarial drug it could be repurposed as an anti-cancer therapeutic in TNBC. Moreover, the cytotoxicity activity of cryptolepine to TNBC cells and a detailed anti-tumor mechanism in mutant P53 has not been reported. Methods: MTT assays were used to examine the cytotoxicity and cell viability activity of Cryptolepine in TNBC, non-TNBC T47D and MCF-7 and non-malignant MCF10A cells. Scratch wound and clonogenic assay was used to evaluate cryptolepine’s effect on migration and colony forming ability of TNBC cells. Flow cytometry, MMP and DAPI was used to assess cell cycle arrest and cell apoptosis. The expression of proteins was detected by western blots. The differential expression of RNAs was evaluated by RT-PCR and the interaction between P53 and drug was evaluated computationally using in-silico approach and in-vitro using ChIP assay. Results: In this study, we found that cryptolepine has more preferential cytotoxicity in TNBC than non-TNBC cells. Notably, our studies revealed the mechanism that cryptolepine can induce intrinsic apoptosis and inhibit migration, colony formation ability, induce cell cycle arrest by inducing conformational change in the mutant P53 thereby increasing its DNA binding ability and also inducing its own transcriptional activation to synthesize new P53 protein and hence activating its tumor suppressing potential significantly. Conclusions: Our study revealed that CRP significantly reduced the proliferation, migration and colony forming ability of TNBC cells lines. Moreover, it was revealed that CRP induces cell cycle arrest and apoptosis by activating mutant P53 and enhancing its DNA binding ability to induce its tumor suppressing ability.
International phase 3 clinical trial evaluating PF-07220060 plus fulvestrant in patients with HR+/HER2− advanced/metastatic breast cancer with progression after a prior CDK4/6 inhibitor.
Authors: Antonio Giordano, Michail Ignatiadis, Carlos H. Barrios, Francois Clement Bidard, Binghe Xu, Alicia M Vana, Jason Gong, Ariadna Holynskyj, Prashanth Gopalakrishna, Hope S. Rugo
Journal: Journal of Clinical Oncology (2024)

TPS1129 Background: Substantial improvement in survival outcomes has been achieved with cyclin-dependent kinase (CDK) 4/6 inhibitors plus endocrine therapy (ET) in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced/metastatic breast cancer (BC); however, resistance to this therapy ultimately occurs. PF-07220060 is an oral, highly potent, selective, next generation inhibitor of CDK4 with sparing of CDK6. A first-in-human phase 1/2a study evaluated PF-07220060 (300/400 mg BID) plus ET in patients with HR+/HER2− advanced/metastatic BC who progressed on a prior CDK4/6 inhibitor plus ET (n = 26). At the data cutoff date of November 1, 2022, in patients with measurable disease (n = 21), 6 (29%) had confirmed objective response (OR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and 11 (52%) had a clinical benefit response (CBR). Of all patients (n = 26), median progression-free survival (PFS) was 24.7 weeks, and 8 (31%) patients continued treatment without progression for 60 or more weeks (1). Methods: This international (29 countries; 356 proposed sites), phase 3, open-label, randomized, parallel-group clinical trial will evaluate whether PF-07220060 plus fulvestrant improves clinical outcomes compared with the investigator-chosen therapies in adult female and male patients with HR+/HER2− advanced/metastatic BC with progression after prior therapy of CDK4/6 inhibitor plus a nonsteroidal aromatase inhibitor.Key eligibility criteria include advanced/metastatic BC with measurable disease or non-measurable bone-only disease, documented HR+/HER2− status, and progressive disease/recurrence during or within 12 months after the last dose of prior CDK4/6 inhibitor given in the advanced or adjuvant setting, respectively. One additional prior line of approved treatment in the advanced setting targeting ESR1, PIK3CA, AKT1, PTEN, or BRCA is allowed. Approximately 500 patients will be randomly assigned (1:1) to receive PF-07220060 (orally and continuously in a 28-day cycle) plus fulvestrant (intramuscular injection on days 1 and 15 of cycle 1 and then on day 1 of each cycle thereafter) or investigator’s choice of fulvestrant alone or everolimus plus exemestane, which must be declared before randomization. The primary endpoint is PFS by blinded independent central review, which is defined as the time from the date of randomization to the date of first documented disease progression, as determined per RECIST v1.1, or death due to any cause, whichever occurs first. Secondary objectives include overall survival, OR, duration of response, CBR, safety, patient-reported outcomes, and pharmacokinetics. 1. Yap. JCO. 2023;41:3009. Clinical trial information: NCT06105632 .
A phase Ia/b trial of ARX788 combined with toripalimab for HER2-low advanced breast cancer (ABC) and other HER2-expressing solid tumors.
Authors: Xiying Shao, Ming Kuang, Zhanhong Chen, Yabing Zheng, Guangliang Li, Xia-Bo Shen, Ping Huang, Wenming Cao, Lixia Xu, Xiaojia Wang
Journal: Journal of Clinical Oncology (2024)

e13159 Background: ARX788 has been proved with superior PFS compared with a combination of capecitabine and lapatinib in the randomized phase Ⅱ/Ⅲ study for HER2-positive ABC (Ambrx, 2023). Here we report the preliminary safety and efficacy of ARX788 plus toripalimab in HER2-low ABC and other HER2-expressing solid tumors. Methods: This was a phase Ⅰ study conducted in China. Eligible patients were HER2-low (IHC2+ and FISH- or IHC1+) ABC or HER2-expressing (IHC 2+ or 3+) solid tumors. Dose exploration with ARX788 is 1.3, 1.5mg/kg, IV, Q3W plus toripalimab 240mg, IV, Q3W. Primary endpoint was safety and RP2D of Ⅰa and efficacy of Ⅰb. Results: Totally, 12 patients were enrolled in phase Ⅰa, 10 patients were diagnosed with ABC, 1 was diagnosed with BTC and 1 was CRC. 6 patients each were treated with 1.3 and 1.5mg/kg. No DLTs were observed. 12 patients (100%) experienced ≥1 ADRs. The most common (≥20%) ADRs were AST increased (75%), platelet count decreased (75%), alopecia (41.67%), white blood cell count decreased (25%), ALT increased (25%), dry eye (25%), interstitial lung disease (25%) and neutrophil count decreased (25%). 1.5mg/kg dose level showed a slightly higher incidence in hematologic toxicities, interstitial lung disease and alopecia. Grade 3 ADRs occurred in 8 patients (66.67%) with equal incidence of the 2 dose levels, those were ocular events (41.7%, 2 of each level), interstitial lung disease (8.3%, 1 of 1.5mg/kg), platelet count decreased (8.3%, 1 of 1.5mg/kg), jaundice (8.3%, 1 of 1.3mg/kg) and immune-mediated myocarditis (8.3%, 1 of 1.3mg/kg). No grade 4 or 5 ADRs occurred. All ADRs were manageable and have recovered. ORR was 41.7% in 12 patients, with 33.3% and 50% in 1.3 and 1.5mg/kg dose level. In 10 patients with ABC, ORR was 50%, with 40% and 60% in each level. DCR was 83.33% and 100%, respectively. Thus, 1.5mg/kg was determined as RP2D and phase Ⅰb is ongoing with HER2-low ABC patients. Conclusions: ARX788 with 1.5mg/kg combined with toripalimab was shown acceptable safety profile with promising efficacy, no significant increase in adverse reactions or serious unexpected immune-related adverse reactions compared with ARX788 monotherapy, which supports further evaluation for HER2-low ABC in a larger sample in Ⅰb trial. Clinical trial information: CTR20222247.
TACTIVE-K: Phase 1b/2 study of vepdegestrant, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, in combination with PF-07220060, a cyclin-dependent kinase (CDK)4 inhibitor, in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer.
Authors: Melinda L. Telli, Chelsea D. Gawryletz, Mei Wei, Amita Patnaik, Dongrui R. Lu, Marco Mazzoletti, Olga Valota, Swapnil S Parmar, Weiwei Tan, Toru Mukohara
Journal: Journal of Clinical Oncology (2024)

TPS1131 Background: Vepdegestrant (ARV-471) is an investigational, orally administered PROTAC ER degrader. Initial results from a phase 1b cohort of a first-in-human phase 1/2 study (NCT04072952) showed that vepdegestrant, in combination with the CDK4/6 inhibitor palbociclib, had robust clinical activity (clinical benefit rate [CBR]: 63.0%) in heavily pretreated patients (pts) with ER+/HER2- advanced breast cancer. PF-07220060 is an investigational CDK4-selective inhibitor, which in contrast to CDK4/6 inhibitors, spares CDK6 blockade and demonstrates less neutropenia in in vivo models. A first-in-human phase 1/2a study (NCT04557449) demonstrated promising antitumor activity with PF-07220060 in pts with advanced solid tumors with a CBR of 52.4%. Preclinical tumor models have shown that vepdegestrant + PF-07220060 effectively suppresses tumor growth to a greater extent than either agent alone. This open-label, multicenter phase 1b/2 study (NCT06206837) will evaluate the combination of vepdegestrant + PF-07220060 in pts ≥18 y with confirmed ER+/HER2- advanced breast cancer. Methods: The phase 1b portion will use an escalation/de-escalation approach to determine the recommended phase 2 dose (RP2D) of the combination of vepdegestrant and PF-07220060. The phase 2 portion will further evaluate the preliminary antitumor activity, safety, and pharmacokinetics (PK) of the combination at the RP2D. Pts (N≈65) will receive vepdegestrant orally once daily continuously and PF-07220060 orally twice daily continuously. The primary endpoint of the phase 1b portion is the number of pts with dose-limiting toxicities; secondary endpoints are antitumor activity (objective response rate [ORR], duration of response [DOR], CBR), progression-free survival (PFS), safety, and PK. The primary endpoint of the phase 2 portion is ORR; secondary endpoints are antitumor activity (DOR, CBR), PFS, safety, plasma concentrations of study drugs, and changes in circulating tumor DNA. Previously presented at ESMO Breast Cancer 2024, FPN: 264TiP, M Telli, et al. Reused with permission. Clinical trial information: NCT06206837 .
Activating HR+/HER2- and triple-negative breast cancer care teams and their patients in shared decision-making.
Authors: Kelly E. McKinnon, Ilona Dewald, Janet Storey, Samuel Dooyema, Jeffrey D. Carter, Cherilyn Heggen, Reshma L. Mahtani
Journal: Journal of Clinical Oncology (2024)

1547 Background: In the rapidly evolving treatment landscape of metastatic breast cancer (MBC), shared decision-making (SDM) is critical to individualize care and improve patient outcomes. To help facilitate improved SDM, we developed an educational toolkit for health care providers (HCPs) to use with HR+/HER2- and triple negative breast cancer (TNBC) patients (pts) and evaluated the implementation of this toolkit at 5 community oncology clinics. Methods: In May-June 2022, pts (N=94) and HCPs (N=18) completed surveys assessing attitudes, confidence, goals, and barriers to SDM in MBC care. HCPs then led collaborative learning sessions with their pts using the SDM toolkit to provide education regarding treatment options and side effects, and to better align on shared goals and treatment plans. Results: In surveys, only 50% of pts reported that they decide on a treatment plan together with their HCPs , 38% reported being asked about treatment preferences, and 34% reported discussing supportive care, such as mental health care or pain relief. Additionally, very few pts reported high knowledge of BC treatments and side effects. HCPs and pts were misaligned on patient goals and barriers to SDM. For example, 56% of HCPs thought pts were too overwhelmed/anxious/fatigued to make treatment decisions, but only 21% of pts agreed that was a top challenge. While pts and HCPs were aligned on top treatment decision factors of effectiveness and quality-of-life, HCPs underestimated the importance of concerns about side effects (HCPs 11% vs pts 32%), and the cost and duration of treatment (17% vs 30%, and 22% vs 30%, respectively). HCPs correctly identified survival (56%) as a top goal for pts but were less likely to identify progression/recurrence as important to pts (39%). Additionally, 28% of pts reported their top challenge was worrying about being unable to work or meet responsibilities at home; however, only 19% of HCPs recognized this as a top challenge. Following pt-HCPs collaborative education sessions, in which HCPs used the SDM toolkit to facilitate pt education and SDM, HCPs and pts reported improved confidence in pt-HCP communication. Additionally, 46% of pts reported discussing treatment goals with their HCPs and 46% reported taking a more active role in their care following the learning session. Conclusions: These findings reveal misalignments between HCPs and patients with BC regarding treatment decision-making. The gaps identified are critical to address as they are pre-requisites for SDM. The downloadable shared decision-making toolkit developed as part of this implementation science initiative can be adopted by breast cancer clinical teams to help facilitate patient education and SDM, empowering patients to be active participants in their care.