tbuckley/cabot-search huggingface dataset:
Transcriptomic analysis of cAMP/PKA/CREB signaling in invasive lobular breast cancer.
Authors: Susrutha Puthanmadhom Narayanan, Abdalla Wedn, Osama Shah Shiraz, Jian Chen, Daniel B Brown, Priscilla F. McAuliffe, Adrian V. Lee, Steffi Oesterreich
Journal: Journal of Clinical Oncology (2024)

1109 Background: Invasive lobular breast cancer (ILC) is the most common special type of breast cancer and has unique clinicopathological and molecular hallmarks that differentiate it from the more common invasive carcinoma – no special type (NST). Despite these differences, ILC and NST are treated as a single entity and there is a lack of ILC-targeted therapies. To fill this gap, we sought to identify novel molecular alterations in ILC that could be exploited for targeted therapies. Methods: Differential gene expression and Geneset Enrichment and Variation analyses were performed on RNA-seq data from three large public breast cancer databases – the Sweden Cancerome Analysis Network-Breast (SCAN-B; luminal A ILC N=263, luminal A NST N=1162), The Cancer Genome Atlas (TCGA; luminal A ILC N=157, luminal A NST N=307) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; luminal A ILC N=65, luminal A NST N=533). Pathways enriched in overlapping differentially expressed genes from these datasets were clustered using Jaccard similarity to identify pathways enriched in ILC. The cAMP/PKA/CREB signaling was studied in ILC, ILC-like and NST cell lines and patient-derived organoids (PDOs) using forskolin, an activator of the pathway. Results: Clinicopathological features of patients with ILC and NST in SCAN-B were similar to prior population-based studies. There was a consistent pattern of up-regulation of cAMP/PKA/CREB related signaling in ILC compared to NST in SCAN-B, TCGA and METABRIC. Treatment with forskolin resulted in a greater increase in phospho-CREB in ILC cell lines and organoids than NST. CRISPR deletion of CDH1 in NST cell lines did not alter response of cells to forskolin as measured by phospho-CREB. Forskolin treatment caused growth inhibition in ILC and NST, with ILC cell lines being more sensitive to forskolin-mediated growth inhibition. Conclusions: In three separate datasets, cAMP/PKA/CREB signaling was identified to be higher in ILC than NST. This in silico finding was validated in cell line and organoid models. Loss of CDH1 was not sufficient to mediate this phenotype. Future studies should investigate the mechanisms for differential cAMP/PKA/CREB signaling and the potential for therapeutic targeting in patients with ILC.
Trastuzumab, pertuzumab and nab-paclitaxel plus pyrotinib or not in neoadjuvant treatment of HER2-positive breast cancer: A multi-center, randomized, open-label, phase II study.
Authors: Xiaosong Chen, Jiahui Huang, Yiwei Tong, Weili Ren, Jing Yu, Weiqi Gao, Siji Zhu, Jin Hong, Jiayi Wu, Ou Huang, Jianrong He, Weiguo Chen, Yafen Li, Kunwei Shen
Journal: Journal of Clinical Oncology (2024)

e12634 Background: Trastuzumab plus pertuzumab (TP) combined with chemotherapy is the standard neoadjuvant treatment regimen for HER2+ breast cancer. Anti-HER2 tyrosine kinase inhibitor, pyrotinib, shows great efficacy in HER2+ metastatic breast cancer, but lacking efficacy data on the basis of TP and chemotherapy in the neoadjuvant setting. This study aims to evaluate the efficacy and safety of TP plus nab-paclitaxel with or without pyrotinib as neoadjuvant treatment in HER2+ breast cancer. Methods: Stage II-III HER2+ breast cancer patients, stratified by disease stage (II vs. III) and hormone receptor (HR) status (positive vs. negative), were randomized 1:1 into the pyrotinib group or the control group. Both groups received a combination of 3-weekly TP and weekly nab-paclitaxel for 12 weeks. The pyrotinib group was concurrent given 320mg pyrotinib once daily. Primary endpoint was the total pathological complete remission (tpCR), defined as no invasive cancer in the breast and axillary lymph node. Results: From Nov 2020 to Apr 2023, a total of 109 patients were enrolled, with 108 receiving treatment: 55 in the pyrotinib group and 53 in the control group.The tpCR rate was 65.5% (95% CI: 51.4%, 77.8%) in the pyrotinib group, which shows no significant difference with the control group [60.4% (95% CI: 46.0%,73.5), P = 0.585). The breast pathological complete response (bpCR) rates were 70.9% (95% CI: 57.1%,82.4%) and 64.2%(95% CI: 49.8%,76.9%) in the pyrotinib and control group, respectively (P = 0.453). In the pyrotinib group, 52 (94.5%), 31 (56.4%), and 23 (41.8%) patients experienced dose-interruption, dose-reduction, and discontinuation of pyrotinib, respectively. The most common grade ≥3 adverse events in the pyrotinib and control groups were diarrhea (58.1% vs. 0%), decreased neutrophil count (23.6% vs. 15.1%), and decreased white blood cell count (16.4% vs. 7.5%). Conclusions: Our study showed pyrotinib didn’t significantly improve tpCR rate with pyrotinib on the basis of TP and nab-paclitaxel neoadjuvant therapy of HER2+ breast cancer. Concurrent pyrotinib treatment with TP was associated with a high rate of severe diarrhea. Further biomarker analyses are needed to identify which population would receive great benefit with neoadjuvant pyrotinib therapy in HER2+ breast cancer. Clinical trial information: NCT04398914 .
Real-world comparison of the efficacy of three CDK4/6 inhibitors (CDK4/6i) in the first-line treatment of endocrine-sensitive advanced breast cancer (aBC): Single institution experience.
Authors: Natalija Dedic Plavetic, Katarina Čular, Dora Gudelj, Kristina Kaceljak, Marija Križić, Marina Popovic, Stela Bulimbašić, Maja Sirotković-Skerlev, Sanda Bubanović, Tajana Silovski
Journal: Journal of Clinical Oncology (2024)

e13080 Background: The combination of CDK4/6i and endocrine therapy (ET) is the standard of care in the first-line treatment of hormone receptor positive (HR+), HER2- aBC. In registrational studies, the progression-free survival (PFS) of all three CDK4/6i ranged from 23.8 to 28.12 months and overall survival (OS) from 53.9 to 66.8. In Croatia, both ribociclib and palbociclib were approved for clinical use in August 2018 and abemaciclib in November 2019. Methods: This retrospective study included patients with endocrine-sensitive HR+, HER2- aBC treated with aromatase inhibitor (AI) and CDK4/6i in the first-line setting between August 2018 and October 2023 at University Hospital Centre Zagreb. Ethics committee approval was obtained before the study was commenced. Patient demographics, clinical presentation, tumor characteristics and treatment data were collected. Real-world PFS (rwPFS) and OS analyses were done with the final data cut-off date of December 31, 2023, using type 1 right censoring. Data were analyzed using the Kaplan-Meier method. Results: Of the 274 patients treated with a combination of CDK4/6i and ET in the first-line setting, 172 with endocrine-sensitive tumors (98 de novo metastatic and 74 with treatment-free interval longer than 12 months) were eligible for the study, of which 41.86% (72/172) received ribociclib, 44.19% (76/172) palbociclib, and 13.95% (24/172) abemaciclib. Overall rwPFS was 48 months (95% CI:35-53). In the abemaciclib group, median rwPFS and OS were not reached in the follow-up period. The rwPFS was 48 (95% CI:27-53) for ribociclib and 47 (95% CI:30-49) for palbociclib. The overall OS was 62 months (95% CI:47-62). Median OS in the ribociclib group was 62 months (95% CI:40-62) and in the palbociclib group 52 (95% CI:42-54) months. Conclusions: The PFS and OS results for palbociclib and ribociclib in this retrospective real-world study correlate with results from randomized clinical trials, confirming some inferiority of palbociclib compared to ribociclib in the context of OS. Due to the later availability of the drug, larger sample size and longer follow-up will be needed to make definitive conclusions on the efficacy of abemaciclib.
Effect of HER2-low expression on the efficacy of CDK4/6 inhibitors in breast cancer: A meta-analysis.
Authors: Lingling Ye, Yan Dai, Liushan Chen, Yuqi Liang, Jiafa He, Shenying Chen, Xue Song, Wei Luo, Rui Xu, Qianjun Chen
Journal: Journal of Clinical Oncology (2024)

e13034 Background: The effect of human epidermal growth factor receptor 2 (HER2)-low expression on the efficacy of CDK4/6 inhibitors in breast cancer is unclear. Therefore, the aim of this meta-analysis was to determine the effect of HER2-low on the efficacy of CDK4/6 inhibitors in advanced breast cancer. Methods: We searched 10 databases and meeting minutes up to July 15, 2023, to identify studies that reported median progression-free survival (mPFS) and overall survival (OS) among HR+/HER2-low breast cancer patients and HER2-zero breast cancer patients receiving treatment with CDK4/6 inhibitors. We calculated pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Results: A total of 9 retrospective studies involving 1494 patients were included. HER2-low breast cancer patients accounted for 52.48% of the sample, and HER2-zero breast cancer patients accounted for 47.52% of the sample. The mPFS was significantly worse for HR+/HER2-low breast cancer patients treated with CDK4/6 inhibitors combined with endocrine therapy than for HER2-zero breast cancer patients (risk ratio = 1.29, 95% CI: 1.15-1.44, p &lt; 0.00001). There was no significant difference in the median overall survival (mOS) between patients with HER2-low breast cancer and patients with HER2-zero breast cancer (risk ratio = 1.07, 95% CI: 0.69-1.66%, p = 0.78). The mPFS was significantly worse for HR+/HER2-low breast cancer patients receiving first-line treatment with CDK4/6 inhibitors combined with endocrine therapy (risk ratio = 1.25, 95% CI: 1.07-1.47, p = 0.0002). Conclusions: The mPFS of patients with advanced HER2-low breast cancer and first-line salvage patients receiving CDK4/6 inhibitors combined with endocrine therapy was significantly inferior to that observed in HER2-zero breast cancer patients. However, there were no discernible differences in the mOS between the two patient groups.
The association of hormone receptor expression level and clinical efficacy of CDK4/6 inhibitor in hormone receptor-positive, HER2-negative metastatic breast cancer.
Authors: Kelvin K. H. Bao, Carol HY Wong, Jackie Yung, Venus Tam, Ka Man Cheung, Jeffrey CH Chan, Harry HY Yiu
Journal: Journal of Clinical Oncology (2024)

e13069 Background: In patients with hormone receptor-positive, HER2-negative metastatic breast cancer (HR+ HER2- MBC), the correlation between the level of expression of HR and the clinical efficacy of CDK4/6 inhibitors remains undefined. Methods: We identified consecutive patients with HR+ HER2- MBC starting a CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib) plus either an aromatase inhibitor or fulvestrant between Jan 2018 - Oct 2023 from an institutional cancer registry. Expression level of HR was stratified as high (H) (Allred score 7-8), moderate (M) (Allred score 5-6) or low (L) (Allred score 3-4) for both estrogen (ER) and progesterone receptors (PR). Patients were evaluated from start of treatment to December 2023, last visit or death, whichever came earlier. Median progression-free survival (mPFS) and overall survival (mOS) were endpoints. We evaluated the association of HR expression levels with mPFS and mOS using log-rank test and multivariate Cox regression modelling. Results: We examined data from 436 women with HR+ HER2- MBC. Median age at treatment was 60.5 yr. Majority of patients received the treatment in the first-line setting (72.5%), with palbociclib (54.1%), ribociclib (31.9%) and abemaciclib (14.0%) as the CDK4/6 inhibitor. In the population that received first-line treatment, ER expression levels were H (83.5%), M (11.4%) and L (5.1%) respectively. ER expression levels were strongly associated with mPFS and mOS. For ER H, M and L expressions, mPFS were 29.4m, 9.2m and 2.9m ( p&lt;0.001); mOS were 52.1m, 40.6m and 11.6m ( p&lt;0.001), respectively. In multivariate analysis, ER expression levels remain strongly predictive for both mPFS and mOS after adjustment for clinicopathological risk factors (ER L vs H, mPFS HR 10.6, p&lt;0.001; mOS HR 4.66, p&lt;0.001; ER M vs H, mPFS HR 4.90, p&lt;0.001; mOS HR 2.06, p=0.05). Findings were similar for the second line and beyond population. In the ER-high expression cohort, the PR expression levels also correlate strongly with treatment efficacy and survival, with mPFS of 40.8m, 24.5m, 24.0m, 14.1m ( p&lt;0.001) and mOS of NR, 53.3m, 48.1m, 26.9m ( p&lt;0.001) respectively for PR H, M, L and zero expressions. Conclusions: In this real-world cohort of patients with HR+ HER2- MBC, we observed that the semi-quantitative HR expression level subgrouping is a strong predictor for the efficacy of treatment with CDK4/6 inhibitors. In contrast to patients with high HR expression levels, the small population with ER-low expression derived very limited benefits from the standard endocrine therapy with CDK4/6 inhibitors. Our findings provided a practical tool to guide the selection of the appropriate systemic therapy for individual patients.
Effect of timing of recurrence on outcomes in patients with metastatic breast cancer treated with CDK4/6 inhibitors.
Authors: Sujan Niraula, Diego Villamarin, Tae Smith, Ramandeep Babbra, Akhil Mahant, Myla S. Strawderman, Zeni Kharel, Christie Tinkham, Michael Tiongson, Nikhil Bamarajpet, Samin Houshyar, Erica Kim, Anna Weiss, Carla Isadora Falkson, Ruth O'Regan, Huina Zhang, Ajay Dhakal
Journal: Journal of Clinical Oncology (2024)

e13067 Background: CDK4/6 inhibitors (CDKi) + endocrine therapy (ET) comprise the standard 1st line treatment for ER+ HER2- metastatic breast cancer (MBC). However, there is a gap in understanding how timing of MBC recurrence affects clinical outcomes on CDKi. We conducted a study to compare clinical outcomes of MBC patients on CDKi based on timing of MBC recurrence. Methods: This retrospective study enrolled ER+ HER2- MBC patients diagnosed from Jan 2015 to Jan 2023, who received CDKi + ET as 1st line treatment for MBC. Patients were categorized as de novo MBC (dMBC), if they had 1. Stage 4 disease at initial diagnosis or 2. MBC diagnosed &lt; 6 months of the primary breast cancer (PBC) diagnosis and before starting any systemic treatment for PBC. Patients with distant recurrence occurring &lt; 5 years, 5-10 years, and &gt;10 years from PBC were categorized as early, intermediate, and late MBCs (eMBC, iMBC, laMBC). Endpoints were Progression-Free Survival (PFS) and Overall Survival (OS) from MBC diagnosis. Baseline variables were compared using t-tests (continuous) and Chi-square tests (categorical). Endpoint analyses were conducted using Kaplan-Meier method and compared using Log rank test. Multivariate analyses were performed using Cox models. Results: Out of 280 patients enrolled, 67 were dMBC, 75 eMBC, 56 iMBC, and 82 laMBC. The laMBC group had a higher mean age (years) compared to other groups (71 vs. 62 in dMBC+ eMBC + iMBC, p&lt;0.001). 64.5% of laMBC had visceral disease compared to 50.5% of dMBC + eMBC + iMBC (p=0.031). 65.7% of dMBC patients were treated with palbociclib compared to 80.8% of eMBC + iMBC + laMBC (p=0.010). Higher % of eMBC were PR- vs other cohorts (41.3 vs 23.9 dMBC + iMBC + laMBC, p&lt;0.001). Among the 3 non dMBC groups, prior ET sensitivity (no recurrence for 2 years on adjuvant ET) was lower in eMBC (45.3%) compared to iMBC + laMBC (81.9%, p&lt;0.001). 61.3% of eMBC patients were on adjuvant ET at recurrence compared to 17.4% of iMBC + laMBC (p&lt;0.001). Other variables were similar. Table shows unadjusted endpoint analyses. In multivariate analyses, the risk of PFS events were not significantly different among cohorts (age&lt;=65, ECOG performance status (PS) &gt;=2 and PR- were independently associated with shorter PFS); risk of death was higher in eMBC vs laMBC (HR 1.73, p=0.047). Conclusions: In this retrospective study of ER+ HER2- MBC patients treated with 1st line CDKi + ET, timing of MBC recurrence was not associated with PFS differences after adjusting for other variables. However, patients with MBC recurring &lt; 5 years of PBC had the higher likelihood of death compared to those recurring &gt;10 years of PBC. [Table: see text]
Economic impact of longer treatment duration in first-line for HR+/HER2- metastatic breast cancer: A retrospective analysis.
Authors: Ibrahim M. Abbass, Carmen Ng, Allison Dillon, Anna Cheng, Yolande Du Toit, Reva K Basho
Journal: Journal of Clinical Oncology (2024)

1072 Background: Real-world treatment duration (TD) in the first line of therapy (1LOT) has demonstrated a strong correlation with progression-free survival (PFS). Increased TD for cancer patients (pts) in earlier lines has been linked to reduced healthcare costs by mitigating the need for costly therapies in subsequent lines, but the extent to which 1LOT costs vary based on the duration pts stay on treatment in 1LOT remains largely unknown. This study investigates the relationship between the TD of endocrine therapy (ET) plus CDK4/6 inhibition (CDKi) in 1LOT (serving as a proxy for PFS) and various healthcare cost measures incurred in 1LOT among newly diagnosed pts with HR+/HER2- metastatic breast cancer (mBC). Methods: Using the IQVIA PharMetrics Plus database, we identified adult women with newly diagnosed HR+/HER2- mBC whose 1LOT within 90 days of metastatic diagnosis (met dx) was ET + CDKi between 10/01/2016 - 06/30/2022. Pts with at least 6 months of follow-up post-met dx were included. The study followed pts from ET+ CDKi initiation until a switch, discontinuation, or a gap exceeding 90 days. Baseline characteristics were assessed 12 months before met dx. Healthcare costs (adjusted to 2022 USD) during the follow-up period were measured per patient per month (PPPM). TD was categorized based on percentile (p) distribution into six groups (&lt;10p; ≥10p to &lt;25p; ≥25p to &lt;50p; ≥50p to &lt;75p; ≥75p to &lt;90p; and ≥90p). Cost measures included total, inpatient (inp), outpatient (outp), ER, and pharmacy (rx) costs. Generalized linear and two-part models examined the relationship between various cost measures and TD, adjusting for age, region, payer type, and Elixhauser comorbidity index (ECI). Results: The study included 1,536 pts receiving ET+ CDKi in 1LOT, with a median age of 59. The median ET + CDKi TD in 1LOT was 23.7 months. PPPM costs were $18,716; $1,044; $2,899; $63; and $14,711 for total, inp, outp, ER, and rx services, respectively. Models results indicate lower PPPM total, inp, outp and ER costs as TD increases (Table). PPPM costs were higher for the bottom 10th p (shortest TD group) compared to the top 10th p (longest TD group)(difference $6,411; $2,735; $3,297; and $205 higher for total, inp, outp, and ER visits respectively). PPPM rx costs did not vary with TD. Conclusions: Real-world TD of ET+ CDKi closely aligns with PFS reported in ET + CDKi trials, further demonstrating a strong correlation with PFS. Prolonging TD in 1LOT yields significant cost savings, primarily driven by reductions in inp, outp, and ER costs. The results underscore the need for ongoing optimization of pts selection for 1LOT for HR+ mBC. The study findings also suggest that the economic evaluation of investigated treatments should take into account treatment duration. [Table: see text]
A meta-analysis of the difference in response to trastuzumab-deruxtecan (T-DXd) based on HER2 immunohistochemistry (IHC) in HER2 low metastatic breast cancer (mBC).
Authors: Prashanth Ashok Kumar, Michael Sandhu, Metlapalli Venkata Sravanthi, Vishnu Charan Suresh Kumar, Sam Benjamin
Journal: Journal of Clinical Oncology (2024)

e13164 Background: HER2 low BC have an IHC staining of 1+ or 2+ with negative fluorescence in situ hybridization (ISH). Although T-DXd is approved for this, difference in activity between 1+ and 2+ is uncertain. Methods: A systematic search with controlled vocabulary encompassing BC and T-DXd was conducted in PubMed, Embase, Scopus, and Cochrane on November 11 2023 with no search restrictions. 2318 records were identified and duplicates were removed using Mendeley. The remaining 1189 records were imported into Rayyan, and the titles were screened independently by 2 reviewers. 47/75 full texts were relevant, of which 4 [3 clinical trials, 1 retrospective study] were included for analysis. Only studies that provided outcome data for HER2 1+ and 2+ ISH- were included. RevMan was used to analyze the Risk Ratio (RR) and Odds Ratio (OR) with 95% Confidence Interval (CI), derived from Random Effects (RE) model with Mantel-Haenszel (MH) method. Pooled proportions (PP) were determined using OpenMeta. Results: There were a total of 264 patients in 1+ and 204 in 2+ISH-. Median age was 57 years. All studies had pre-treated mBC. T-DXd dose was at least 5.4 mg/kg every 3 weeks. Visual inspection of our funnel plots revealed no bias. PP (3/4 studies) for patients achieving an Objective Response Rate (ORR) [Complete Response (CR)+Partial Response (PR)] was 42.9% (31.6-54.2%) in 1+ and 38% (26.3-49.7%) in 2+. The median Progression free survival (2/4 studies) was 8.6 (1+) and 7.95 (2+) months respectively. RE RR (3/4 studies) for Progressive Disease (PD) showed no difference between 1+ and 2+ [0.93 (0.80, 1.10), p=0.4, I²=0%]. Similarly, RE OR (3/4 studies) for Disease Control Rate (DCR) [CR+PR+Stable disease (SD)] [1.20 (0.78, 1.85), p=0.41, I²=0%], ORR [1.17 (0.58, 2.34), p=0.66, I²=0%], and PR [1.05 (0.52, 2.11), p=0.89, I²=0%] showed no significant difference between 1+ and 2+ (Table). Conclusions: Our results indicate no difference in response to T-DXd between 1+ and 2+, solidifying its role as a treatment option in HER2 low mBC. Limited number and heterogeneity between studies are limitations of our study, which ought to be addressed in future trials through clear subgroup stratification between 1+ and 2+. [Table: see text]