bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of unobserved incidence of cancer in earlier stages with the observed incidence.
Authors: Chhatwal Jagpreet , ElHabr Andrew , Tyson Christopher , Merdan Selin , Cao Xiting , Raoof Sana , Ozbay A. Burak , Fendrick A. Mark , Limburg Paul J. , Beer Tomasz M. , Deshmukh Ashish 
Published: June 2023

10634 Background: Population-level cancer registries report observed (screening or clinically detected) incident cancer cases. However, the underlying true cancer incidence may be higher than observed. We estimate the unobserved cancer incidence by stage for eight different cancers. Methods: Using the CDC’s National Program of Cancer Registries (NPCR) and the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) combined incidence databases, we first estimated observed incidence rates by cancer type and stage. Newly observed cancers in later stages must have existed at a previous point in time at an earlier stage (and age). Considering that, we used backward induction approach to estimate the unobserved incidence rate of cancer. We also accounted for mortality from competing factors before cancer was detected. Cancer progression between stages was defined by dwell times, which were synthesized in an ensemble approach from published literature and empirical estimates. We estimated unobserved annual incidence cases in early-stage (stages I and II) for the age 50+ population and compared them with observed incidence cases for each cancer type between 2015-2019. Results: The below table shows the annual unobserved and total (unobserved plus observed) cancer incidence by stage for the eight most prevalent cancers. We estimated that the top three cancers with the highest proportion of unobserved early-stage annual incident cases were lung (157,400 cancers unobserved out of 226,400 total), with 70% unobserved; pancreatic (34,700 annual unobserved out of 52,500 total), with 66% unobserved, and non-Hodgkin’s lymphoma (46,400 unobserved out of 73,600 total), with 78% unobserved. In contrast, the cancers with the lowest proportion of unobserved early-stage incident cases were breast (29,100/203,400 [14%]), urinary bladder (27,000/81,800 [33%]), and prostate (110,600/258,900 [43%]). Cancers with a high screening rate have lower unobserved early stage incidence than cancers with a low screening rate or without a screening test. Conclusions: We estimated a large undiagnosed incidence of cancer in early stages. This represents an opportunity for novel early detection technologies to detect cancer in earlier stages. [Table: see text]
Efficacy analysis of CDK4/6 inhibitors (CDKi) + endocrine therapy (ET) treatment in hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer (aBC): Biomarker analysis including chemoendocrine score (CES) by CDKi type in SOLTI-1801_CDK-PREDICT study.
Authors: Tolosa Ortega Pablo , Pascual Tomás , Hernando Cristina , Servitja Sonia , Fernández-Abad María , Brasó-Maristany Fara , Benitez Fuentes Javier David , Lema Laura , Parrilla Rubio Lucia , Ruano Yolanda , Roncero Ana María , Sanchez-Bayona Rodrigo , Alva Bianchi Manuel , Villacampa Guillermo , Cobos-Fernández María Ángeles , Moreno María del Rocío , Canes Jordi , Salvador Fernando , Prat Aleix , Ciruelos Eva M 
Published: June 2023

1065 Background: CDKi + ET improved progression-free survival (PFS) and ribociclib also overall survival (OS) in HR+/HER2- aBC first-line setting. Intrinsic subtypes (IS) are prognostic and predict benefit from CDKi + ET (Finn. SABCS 2017, Prat. JCO 2021, Tolosa. SABCS 2022). We previously reported a PAM50-based CES in HR+/HER2-negative early BC (Prat et al. CCR 2016). Here, we evaluated the association of CES with PFS following CDKi therapy in aBC. Methods: CDK-PREDICT prospectively evaluated 113 HR+/HER2- aBC patients (pts) treated in the first-line setting with CDKi + ET. RNA from FFPE metastatic tumors was analyzed at the nCounter (Nanostring Technologies) using a 72 custom gene panel including the PAM50 genes. CES was evaluated as a continuous variable, and categorically (CES-E[endocrine-sensitive], CES-I[intermediate] and CES-C[chemo-sensitive]) using the previously reported cut-offs. Multivariable analyses were used to test CES association with PFS. Results: The median follow-up for PFS was 18.5 m. PAM50 IS and CES distribution are shown. No statistically significant difference in mPFS by CDKi. CES (as a continuous variable or as group categories) was found significantly associated with mPFS. mPFS for CES-E pts was NR (95% CI: 26.0 - NR), 20.7m for CES-I (95% CI: 14.2 – 31.7m; HR= 1.98, p<0.05) and 11.7m for CES-C (CI 95%: 7.0 - 18.8; HR= 3.72, p<0.05). CES-C was associated with lower PFS compared to CES-I (aHR= 0.55, p=0.10) and CES-E (aHR= 0.29, p<0.05) independent of CDKi, ET, intrinsic subtype (Luminal versus not), endocrine sensitivity, onset metastatic and visceral disease. CES-C was significantly associated with higher expression of, MIA and lower expression of CCND1, CCNE1, FOXA1, MLPH and UBE2T compared with CES-E (p< 0.05). In CES-E pts mPFS for palbociclib was NR (IC95:22.9-NR) compare with 43.8 m for ribociclib (IC95: 12.0-NR); aHR=1.17 p=0.546), in CES-I pts mPFS for palbociclib was 18.9 m (IC95: 5.8-27.3) compare with 31.7 m for ribociclib (IC95: 12.2-NR); aHR=0.50 p=0.294), and in CES-C pts mPFS for palbociclib was 11.6 m (CI95: 2.7-15-7) compare with 10.0 m for ribociclib (CI95: 2.1-NR; aHR=0.48 p=0.102). Abemaciclib not reported due to low numbers (n=16). Conclusions: We confirmed independent prognostic value of CES in first-line setting, suggesting a not statistically significant benefit with ribociclib vs palbociclib in CES-I. [Table: see text]
Capivasertib (C) and fulvestrant (F) for patients (pts) with aromatase inhibitor (AI)-resistant HR+/HER2– advanced breast cancer (ABC): Characterization and management of common adverse events (AEs) from the phase 3 CAPItello-291 trial.
Authors: Rugo Hope S. , Oliveira Mafalda , Howell Sacha Jon , Dalenc Florence , Cortes Javier , Gomez Henry Leonidas , Hu Xichun , Iwata Hiroji , Jhaveri Komal L. , Loibl Sibylle , Morales Murillo Serafin , Okera Meena , Park Yeon Hee , Sohn Joohyuk , Zhukova Lyudmila , Logan Jill , Twomey Ken , Khatun Mahmuda , D'Cruz Celina M. , Turner Nicholas C. 
Published: June 2023

1067 Background: In the CAPItello-291 trial in eligible pts with AI-resistant HR+/HER2– ABC, the addition of C (a potent, selective pan-AKT inhibitor) to F significantly improved PFS (primary endpoint) compared with placebo (P) in the overall (HR 0.60; 95% CI 0.51–0.71; p<0.001) and AKT pathway-altered population (HR 0.50; 95% CI 0.38–0.65; p<0.001). We report a detailed analysis of AEs. Methods: Pts were randomized 1:1 to receive F (500 mg IM on days 1 and 15 of cycle 1, and day 1 of each subsequent 28-day cycle) with either P or C (400 mg BID; 4 days on, 3 days off). Pts with HbA1c <8.0% and diabetes not requiring insulin were eligible. Incidence, management, and time to onset were summarized for common AEs (>10% any grade and >2.0% grade ≥3; CTCAE v5.0). Results: Overall, 708 pts were randomized to C+F (n=355) vs P+F (n=353); safety population C+F (n=355) vs P+F (n=350). Baseline risk factors potentially associated with hyperglycemia were a history of diabetes in 34 pts (10%) in the C+F arm vs 20 pts (6%) in the P+F arm (baseline median [range] HbA1c 5.4% [4.0–8.3] vs 5.4% [3.9–7.7]), median weight 65.0 kg (34–150) vs 66.5 kg (37–147) and 54% vs 53% of pts overweight/obese in the C+F vs P+F arms, respectively. Common AEs were diarrhea, rash, and hyperglycemia; maximum AE grade was mostly 1/2 and led to low rates of discontinuation. In the C+F arm, medications for the management of AEs were used in 151/257 pts (59%) with diarrhea (mostly loperamide; n=135), 109/135 pts (81%) with rash (mostly antihistamines; n=75/topical corticosteroids; n=64), and 28/60 pts (47%) with hyperglycemia (mostly metformin; n=18). Conclusions: Diarrhea, rash, and hyperglycemia, the most commonly reported AEs associated with AKT pathway inhibition, occur early in treatment with C+F, are generally low grade and manageable, and are associated with low rates of dose modifications/discontinuations. Clinical trial information: NCT04305496 . [Table: see text]
Relation between circulating biomarkers at diagnosis of early luminal-like breast cancer and subsequent risk of distant metastases.
Authors: Lambrechts Yentl , Garg Abhishek , Floris Giuseppe , Punie Kevin , Neven Patrick , Nevelsteen Ines , Govaerts Jannes , Richard François , Laenen Annouschka , Desmedt Christine , Wildiers Hans , Hatse Sigrid 
Published: June 2023

1077 Background: Predicting development of distant metastases after treatment of early luminal breast cancer (BC) remains a major challenge. Besides clinical-pathological features of the primary tumor, baseline circulating factors could also play a role as prognostic biomarkers. Methods: Patients with newly diagnosed early BC (grade 2/3, ER+, HER2-non- amplified) were selected from our institutional BC registry, with associated blood biobank collecting baseline plasma/serum samples at diagnosis. Circulating biomarkers potentially modulating the metastatic process (chemokines, micro-RNAs (miRNAs), Leukemia Inhibitory Factor (LIF), and osteopontin), and serum-induced functional myeloid interferon (IFN)) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling-responses, were measured at early BC diagnosis (before any treatment) in patients who subsequently developed distant metastasis within five years after diagnosis and therapy (META group) and in a 1:1 control group of patients, pairwise matched for age, tumor grade, stage, and histological subtype, who remained disease-free for at least seven years (NON-META group). All blood biomarkers were analyzed pair-wisely using the univariable Wilcoxon signed rank test (two-tailed). Multiple testing correction was done by applying a false discovery rate (FDR) of 0.05. In addition, a multivariable logistic regression analysis (MVA) was performed to find blood biomarkers signatures that can predict the development of metastases at first diagnosis of early BC. Results: 102 matched patient pairs were included. Univariable paired analysis showed significantly increased baseline expression of LIF (p=0.012) and six miRNAs (miR-143-3p: p=0.015; miR-197-3: p:<0.001; miR-223-3p: p=0.006; miR-223-5p: p=0.045; miR-338-3p: p=0.045; miR-365a-3p: p=0.025), and decreased serum-induced myeloid -IFN-responses (p=0.023) and ten miRNAs (let-7b-5p: p=0.006; miR-106a-5p: p=0.045; miR-106b-5p: p=0.015; miR-107: p=0.014; miR-144-3p: p=0.015; miR-15a-5p: p=0.045; miR-15b-3p: p=0.032; miR-185-5p: p=0.045; miR-18a-5p: p=0.015; miR-30b-5p: p=0.045) in the META group compared to the NON-META group. MVA yielded a seven-biomarker signature, which includes miR-197-3p (p=0.008), miR-139-5p (p<0.001), LIF (p=0.007), miR-106b-5p (p=0.003), serum-induced IFN/ISG response (p=0.006), miR-652-3p (p=0.015), and miR-133b (p=0.025) with a C-index of 0.79 (0.70-0.88) to predict distant metastases. After 5-fold internal cross-validation, C-index was 0.63 (0.52-0.74). Conclusions: Baseline circulating miRNAs, LIF, and serum-induced IFN-response levels at early luminal BC diagnosis are associated with subsequent distant metastases. Further external validation is required to confirm the prognostic value of these biomarkers.
Real-world (RW) outcomes of patients (pts) with advanced breast cancer (aBC) with and without resistance alterations (alts) detected in cell-free circulating tumor DNA (ctDNA) prior to CDK4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) treatment.
Authors: Wander Seth Andrew , Weipert Caroline M. , Liao Jiemin , Safonov Anton , Zhang Nicole , Bardia Aditya , Razavi Pedram 
Published: June 2023

1081 Background: CDK4/6i plus ET is standard of care first-line (1L) therapy for hormone receptor positive (HR+), HER2- aBC. While molecular analyses from trials and pts have identified several mechanisms of resistance to CDK4/6i plus ET, currently, no biomarkers (outside of hormone status) are used for therapy selection. We utilized RW data to assess impact of putative baseline CDK4/6i+ET resistance alts (CDK4/6i+ET-R) on clinical outcomes among pts with aBC treated with CDK4/6i. Methods: Pts with aBC were identified via the Guardant INFORM database; those with a ctDNA test within 90 days prior to CDK4/6i start were included in this analysis. Based on previous studies, oncogenic or likely oncogenic alterations (as characterized by OncoKB) in the following genes were considered CDK4/6i+ET-R alts: RB1, PTEN, AKT1, CCNE1, ERBB2, FGFR1, FGFR2, and KRAS. Pts with >1 CDK4/6i+ET-R alt were compared to pts without any CDK4/6i-R alts. Kaplan-Meier plots, log-rank tests (LR) and multivariate Cox proportional hazards models (HR) adjusted (adj) for age, sex, year of ctDNA test and line of therapy were used to assess differences in time to next treatment (TTNT) and overall survival (OS). Results: 1075 pts with aBC treated with CDK4/6i (27% receiving 1L treatment) met inclusion criteria, 293 of whom (27%) had >1 alt in a CDK4/6i+ET-R gene. Pts with CDK4/6+ETi-R alts had significantly shorter TTNT (8.7 mos vs 14.2 mos, LR p=0.001; adj HR 1.36, 95%CI 1.11-1.66, adj p=0.003) and OS (28.3 mos vs 60.9 mos, LR p=<0.0001; adj HR 2.19, 95%CI 1.69-2.82, adj p=<0.0001) compared to those without. This divergence was more pronounced for patients receiving 1L CDK4/6i (TTNT: 10.7 mos vs 24.6 mos, LR p=0.006, adj HR 1.84, 95%CI 1.18-2.87, adj p=0.007; OS: 23.8 mos vs 67.3 mos, LR p<0.0001, adj HR 3.27, 95%CI 1.89-5.62, adj p<0.0001). Individual gene contributions towards less favorable TTNT are shown. Conclusions: We demonstrate via RW data that patients with >1 pre-treatment ctDNA alt in a curated list of CDK4/6i+ET-R genes have significantly worse outcomes on CDK4/6i plus ET treatment, a difference more pronounced among patients receiving 1L therapy. This data is among the first successful efforts to validate a clinically useful multi-gene clinical biomarker that has the potential to predict CDK4/6i plus ET resistance. Further exploration of this signature’s prognostic and predictive utility for CDK4/6i plus ET use is ongoing to better refine personalized treatment selection in HR+/HER2- aBC. [Table: see text]
Influence of chromatin remodeling molecule ARID1A on metastatic heterogeneity in triple negative breast cancer: Binding of YAP.
Authors: Wang Ye , Guo Duancheng , Tao Zhonghua , Hu Xichun 
Published: June 2023

1085 Background: Heterogeneity is the prominent character of TNBC and one predominant cause of treatment failure. As a key nuclear SWI/SNF protein complex subunit, ARID1A plays a critical role in tumor identity determining by manipulating gene expression. The present study aimed to investigate whether and how ARID1A determined the metastatic heterogeneity of triple-negative breast cancer. Methods: This study retrospectively collected and analysed clinical and pathological data from 258 patients diagnosed with triple-negative breast cancer at Fudan University Cancer Hospital from August 2015 to June 2016 to define the prognostic ability of ARID1A.CRISPR/Cas9 or plasmids-mediated ARID1A were used to determine the ARID1A function in regulating the metastatic character in TNBC. Cell morphology, tumor invasion, and metastasis were analyzed in terms of ARID1A status both in vitro and in vivo experiments. The molecular mechanism of ARID1A determining metastasis potential of TNBC was explored by RNA-Seq and nuclear positioning. Results: ARID1A low expression was found to have independent prognostic value for poor OS (43.9 vs 53.6 months, P=0.0001) and RFS (31.0 vs 45.5 months, P=0.0029) in TNBC patients. Both nuclear and cytoplasmic protein analysis and Immunofluorescent localization assay confirm that ARID1A recruits the Hippo pathway effector YAP into nucleus in human triple negative breast cancer cells. Next we designed the YAP truncator plasmid and confirmed by Co-Immunoprecipitation that ARID1A could competitively bind to the WW domain of YAP to form the ARID1A/YAP complex. Furthermore, down-regulation of ARID1A promoted migration and invasion both in human triple negative breast cancer cells and xenograft model through Hippo/YAP signaling axis. Conclusions: Our study provides new insights into the previously unrecognized role of ARID1A in TNBC metastasis, which might provide new therapeutic options for patients with TNBC.
The overall survival analysis of FUTURE-C-PLUS: Combination of famitinib with camrelizumab plus nab-paclitaxel as first-line treatment for advanced, immunomodulatory triple-negative breast cancer—An open-label, single-arm, phase 2 trial.
Authors: Chen Li , Zhimin Shao , Wang Zhonghua , Yang Wentao , Jiang Yizhou , Wu Songyang , Wu Jiong , Di Genhong , Liu Guangyu , Yu Keda , Fan Lei , Li Junjie , Hou Yifeng , Hu Zhen , Chen Canming , Huang Xiaoyan , Cao Ayong , Hu Xin , Zhu Xiaoyu 
Published: June 2023

1086 Background: Camrelizumab and nab-paclitaxel demonstrated promising anti-tumour activity in refractory metastatic immunomodulatory triple-negative breast cancer (TNBC) in FUTURE trial. Anti-angiogenic agents have been reported to facilitate immune infiltration. Famitinib is a tyrosine kinase inhibitor targeting VEGFR-2, PDGFR and c-kit. The FUTURE-C-PLUS trial (NCT04129996) which added famitinib to camrelizumab and nab-paclitaxel is a single-arm, phase 2 trial evaluating this novel triplet combinatorial strategy in patients with advanced immunomodulatory TNBC. Study design and the primary endpoint ORR has been reported previously (Zhi-ming Shao, et al. ASCO 2021, Abstract 1007). The final PFS data had been published in Clinical Cancer Research (Clin Cancer Res 2022;28:2807–17). Here, we reported the final overall survival of this trial. Methods: Briefly, this study enrolled women aged 18-70 years, with previously untreated, histologically confirmed, unresectable, locally advanced, recurrent or metastatic immunomodulatory TNBC. Immunomodulatory TNBC was defined as CD8 expression on at least 10% of cells using immunohistochemistry analysis. Eligible patients received the triple therapy. Results: Forty-eight patients were enrolled and treated between Oct 2019 and Oct 2020. The median follow-up was 33.1 months (range, 31.8–34.4). 39 (81.3%, 95% CI 70.2-92.3) patients had a confirmed objective response which has been reported in ASCO 2021. At this updating data cutoff (Feb 1, 2023), the median progression-free survival was 13.6 months (95% CI, 8.4-18.8). While overall survival was 29.4 months (95% CI, 23.3-35.5). The disease control rate was 95.8% (46/48). The most common treatment-related grade 3 or 4 adverse events were neutropenia (16 [33.3%]), anemia (5 [10.4%]), febrile neutropenia (5 [10.4%]), and thrombocytopenia (4 [8.3%]). No new safety concerns were detected. No treatment-related deaths were reported. Conclusions: These data, combined with those from our previous reports, provide further evidence for the triplet combination of famitinib, camrelizumab and nab-paclitaxel as an active therapy in advanced Immunomodulatory TNBC. To our knowledge, this is the best overall survival reached in first-line treatment of advanced TNBC. A randomized controlled FUTURE-Super trial is ongoing to further validate these findings. Clinical trial information: NCT04129996 .
ARID1A deficiency in triple-negative breast cancer induces adaptive immune resistance and sensitivity to immune checkpoint inhibitors.
Authors: Chen Margaret , Li Bin , Wang Ye , Hu Xichun , Tao Zhonghua 
Published: June 2023

1088 Background: Adaptive immune resistance (AIR) is pivotal to triple-negative breast cancer (TNBC) progression. Although immune checkpoint inhibitors (ICIs) shed new light on reversing AIR, the treatment effect and predictive markers of immunotherapy remain controversial. The present study focused on epigenetic regulation for TNBC AIR and explored whether this could be clinically targeted. Methods: Through screening an epigenetic gene set in TNBC patients from The Cancer Genome Atlas (TCGA), ARID1A was pinpointed as most significantly correlated with AIR. Humanized immune system (HIS) mice were adopted for TNBC transplantation, identifying CD8+ T cells as most significantly correlated with TNBC ARID1A. To probe the mechanism underlying TNBC ARID1A deficiency-induced CD8+ T cell malfunction and AIR, RNA-seq of both TNBC patients and TNBC cell lines were analyzed and the candidate mediator gene, PD-L1, was identified and verified through western blot, qPCR, IHC, dual luciferase reporter assay and cell co-culture. Chromatin immunoprecipitation and ATAC-seq further demonstrated direct binding of ARID1A to NPM1 promoter to regulate PD-L1 expression. Finally, HIS mice were treated with ICI and the clinical trial CTR20191353 was retrospectively analyzed. Results: Among a series of epigenetic modulators, we first observed that ARID1A, a core subunit of the chromatin remodeling complex SWI/SNF, demonstrated highest correlation with AIR in TNBC patients. This was verified in HIS TNBC mice and a patient cohort from Fudan University Shanghai Cancer Center by higher malignancy observed in ARID1A-deficient TNBC. Both bulk and single-cell RNA-seq in TNBC patients uncovered an immunosuppressive microenvironment induced by TNBC ARID1A deficiency, and CD8+ T cells was identified as the immune cell type most significantly correlated with TNBC ARID1A. CD8+ T cell malfunction and AIR in ARID1A-deficient TNBC was induced by upregulated PD-L1, but ARID1A did not directly regulate PD-L1 expression. We found that ARID1A bound to the NPM1 promoter and that ARID1A deficiency increased NPM1 chromatin accessibility as well as gene expression, further activating PD-L1 transcription. In HIS mice, ICI demonstrated the potential to reverse TNBC ARID1A deficiency-induced AIR manifested by reducing tumor malignancy and activating antitumor immunity. In CTR20191353, a phase 1b clinical trial of pucotenlimab combined with chemotherapy for TNBC, patients with ARID1A deficiency demonstrated significantly better prognosis and the longest progression-free survival was found in ARID1A-low/PD-L1-high group. Conclusions: In AIR epigenetics, TNBC ARID1A deficiency induced AIR via the ARID1A/NPM1/PD-L1 axis, leading to poor outcome. While ARID1A deficiency provided survival advantage for TNBC cells, it simultaneously left the Achilles' heel which could be targeted with ICI.