bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinico-molecular characteristics associated with outcomes in breast cancer patients treated with CDK4/6 inhibitors: Results from the AURORA Molecular Screening Initiative.
Authors: Agostinetto Elisa , Sotiriou Christos , Ignatiadis Michail , Antoniolli Crestani Thayane , Venet David , Tyekucheva Svitlana , Irrthum Alexandre , Seoane Jose A. , Piccart-Gebhart Martine J. , Cameron David A. , Knox Susan , ROTARU CRISTINA EMILIA , Romagnoli Dario , Zoppoli Gabriele , Aftimos Philippe Georges , Oliveira Mafalda , Regan Meredith M. , Malorni Luca , Benelli Matteo , Hilbers Florentine 
Published: June 2023

1019 Background: CDK4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) is the recommended first line standard of care for patients with estrogen receptor positive (ER+), HER2-negative (HER2-) advanced breast cancer (ABC). However, not all patients derive the same benefit from this treatment. We aimed to identify factors associated with outcome in patients treated with CDK4/6i in a real-world setting. Methods: AURORA (NCT02102165) is an international program aimed at studying ABC by performing multi-omics profiling on paired primary tumors and metastases. Here we present exploratory results from AURORA patients treated with first line CDK4/6i + ET. DNA from primary and/or metastatic lesions and germline DNA was sequenced for 411 cancer-related genes. Endocrine resistance was defined according to the 5th ABC international consensus guidelines at the start of the first line. Local histology assessment of the primary tumor was used. Progression-free survival (PFS) was calculated from the start of CDK4/6i treatment until disease progression or death (whichever occurred first). Results: We analyzed 339 patients treated with CDK4/6i + ET in the first line. PFS differed significantly among the endocrine resistance subgroups (p<0.001). Both TP53 and acquired ESR1 mutations were associated with shorter PFS (hazard ratio [HR] 1.59 [95% CI 1.43-6.73], p=0.004 and 3.10 [95% CI 1.16-2.18], p=0.004 respectively). In a multivariable analysis, acquired ESR1 mutations were significantly associated with worse PFS independently of endocrine resistance status (HR 2.42 [95% CI 1.01-5.79], p=0.048). Mutations in PIK3CA were not associated with outcome (HR 0.84 [95% CI 0.63-1.13], p=0.25). No PFS difference was observed between lobular and ductal tumors (HR 1.07 [95% CI 0.66-1.75], p=0.61). Conclusions: Endocrine resistance status and TP53 and acquired ESR1 mutations were associated with shorter PFS. Factors associated with poor outcome may be used to select patients to test alternative treatment strategies in clinical trials. Clinical trial information: NCT02102165 . [Table: see text]
Prostate-specific membrane antigen (PSMA) expression in patients with metastatic triple negative breast cancer: Initial results of the PRISMA study.
Authors: Nader Marta Guilherme , Wimana Zena , Taraji Loubna , Critchi Gabriela , Aftimos Philippe Georges , Piccart-Gebhart Martine J. , Flamen Patrick , Gebhart Geraldine 
Published: June 2023

1025 Background: Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) prolongs survival of patients (pts) with prostate cancer. Preliminary immunohistochemistry (IHC)-based studies suggest that PSMA is highly expressed in triple negative breast cancer (TNBC). The PRISMA study aims to assess PSMA expression in pts with metastatic TNBC (mTNBC) via positron-emission tomography/computed tomography (PET/CT) to evaluate the feasibility of PSMA-targeted RLT for TNBC. Methods: PRISMA is a prospective, single-center study that enrolled pts with progressive mTNBC and measurable disease on 18F-FDG PET/CT to undergo 68Ga-PSMA-11 PET/CT. TNBC definition (ASCO/CAP) was based on the IHC of the primary breast cancer (BC) or metastasis. Target lesions (TL) were defined as metastatic lesions ≥1.5 cm with significant uptake in 18FDG-PET/CT. The same TL regions were propagated to the 68Ga-PSMA-PET/CT. 68Ga-PSMA-11 maximum standard uptake value (SUVmax) was measured for each TL. PSMA patterns A and B were defined according to presence of a majority (pattern A) or a minority (pattern B) of positive TL on 68Ga-PSMA (ie. uptake greater than that of normal liver parenchyma). Mann-Whitney U test was used to assess differences in median SUVmax (mSUVmax) between subgroups. Results: Ten pts with progressive mTNBC were enrolled. One pt was excluded due to lack of TL on 18FDG-PET/CT. Median age was 48 years (range 36-68), median number of TL per patient was 8 (5-18). Five pts had a TNBC IHC since the initial BC diagnosis, while 4 had a switch to TNBC (4 with initial estrogen receptor [ER]-positive and 1 with HER2-positive BC). All evaluable pts had inter- and intra-organ heterogeneity in PSMA uptake in TL and 2 pts had some mismatch with FDG-positive and PSMA-negative TL. mSUVmax was 2.99 (range 1.7-6.3) in the overall population and was higher in pts with pattern A (5.1 vs 2.6 in patterns A and B, respectively, p = 0.03). mSUVmax was numerically higher in younger pts (5.0 vs 2.6 in pts <50y and ≥50y, p = 0.28), PD-L1-positive (5.0 vs 2.7 in PD-L1-positive and -negative, p = 0.14), de novo metastatic disease (5.0 vs 2.9 in de novo and recurrent BC, p = 0.38) and those with ER-negative primary breast tumor (3.4 vs 3.0 in ER-negative and ER-positive primary BC, p = 0.9). Conclusions: A significant PSMA uptake was observed in a proportion of pts with mTNBC. Inclusion of additional pts and translational analyses will allow the identification of PSMA expression determinants. PSMA-targeted RLT may be considered as an innovative therapeutic strategy to be explored in selected pts with mTNBC. [Table: see text]
Gene expression profiling of paired primary breast cancers and brain metastases to identify brain metastases-specific biological changes.
Authors: Griguolo Gaia , Dieci Maria Vittoria , Fineberg Susan , Pinato Claudia , Bottosso Michele , Bauchet Luc , Miglietta Federica , Jacob Jack , Zarrilli Giovanni , Rigau Valerie , Guarascio Maria Cristina , Zanconato Francesca , Schiavi Francesca , Fassan Matteo , Jacot William , Piccolo Stefano , Darlix Amelie , Guarneri Valentina 
Published: June 2023

1032 Background: Despite the clinical impact of breast cancer (BC) brain metastases (BM), their biological complexity still remains poorly understood. We here evaluate the genomic profile of paired primary and metastatic samples to characterize biological changes acquired by BC during metastatization to the brain. Methods: The expression of 758 BC–related genes was evaluated using the BC360 Panel (nCounter platform) in matched primary BC and their associated BM. Intrinsic molecular subtyping was determined using the PAM50 subtype predictor (Parker et al. JCO 2009). Hormone receptor (HR) and HER2 status were evaluated on the BCBM. A False Discovery Rate (FDR) corrected paired two-class SAM was used to identify changes in single genes expression between paired BC and BMs samples. Results: Twenty-one matched primary BC and BMs samples were analyzed. BC subtype evaluated on the BMs was distributed as follows: 24% (N=5) HR-/HER2-, 24% (N=5) HR+/HER2- and 52% (N=11) HER2+. A considerable shift in PAM50 subtype was observed between primary BC and paired BM. While subtype concordance was high for HER2-enriched (HER2-E) tumors (100%), all Luminal A (LumA) primary BCs switched to either HER2-E (75%) or Luminal B (LumB, 25%) on the BM sample, as did 45% of Basal-like BCs (Basal to HER2-E). A clinical switch from HER2- primary BC to HER2+ BM (defined by IHC and ISH) was observed in only one pair (5%). Consistently, HER2-E (p<0.001) and LumB (p=0.001) PAM50 signatures were significantly more expressed, while the LumA (p<0.001) and Normal-like (p=0.001) signatures were significantly less expressed in BMs as compared to paired primary BCs (FDR-corrected Wilcoxon paired signed rank test). No significant change was observed in the expression of the Basal-like signature (p=0.562). Among the 758 evaluated genes, 60 and 318 genes, respectively, were significantly up- and downregulated in BMs as compared to primary BC (FDR<5%). Upregulated genes were enriched, among others, in genes involved in survival and migration (e.g. FGFR4), cell proliferation (e.g. CCNB1, CDK1) and HER2-amplicon (e.g. ERBB2, GRB7). Downregulated genes were enriched in genes involved in immune response (e.g. CD8A, CCL5, PDCD1LG2, TNF), angiogenesis (e.g. PDGFRB) and response to hormonal stimuli (e.g. ESR1, BCL2). Conclusions: Gene-expression profiling of matched primary BCs and BMs shows recurrent gene expression modifications in metastatic samples which might have potential therapeutic implications (e.g. acquisition of HER2-E subtyping and increase in ERBB2 mRNA levels). [Table: see text]
Metastatic breast cancer (MBC) with ultra-high tumor mutational burden (UHTMB): A comprehensive genomic profiling (CGP) study.
Authors: Fanucci Kristina , Lustberg Maryam B. , Fischbach Neal A. , Pelletier Maureen , Sivapiragasam Abirami , Ashok Kumar Prashanth , Kallem Mansi , Danziger Natalie , Sokol Ethan , Sivakumar Smruthy , Pavlick Dean C. , Ross Jeffrey S. , Pusztai Lajos 
Published: June 2023

1036 Background: Pts with MBC whose tumors feature high TMB (≥ 10 mutations/Mb) are eligible for on label immune checkpoint inhibitor (ICI) treatment. This study evaluated the genomic landscape of MBC with “Ultra high” TMB, defined at > 20 mutations/Mb. Methods: 2049 MBC underwent hybrid capture-based CGP to evaluate all classes of genomic alterations (GA), TMB, microsatellite instability (MSI) and trinucleotide mutational signatures. HER2 IHC results were available in a subset of pts. PD-L1 expression on immunocytes was determined by IHC (Ventana SP142). Results: 45/2049 (2.2%) of MBC were UHTMB. 45 (100%) pts had metastatic disease. 38 (84%) had documented Stage IV disease and 7 documented axillary LN metastases at the time of sequencing. Local breast tumor was used for CGP in 19 (42.2%) MBC and metastatic site biopsy was used in 26 (57.8%). When compared with 2004 non-UHTMB pts with UHTMB were older (mean 64.6 yrs vs 58.2 yrs p < .0001), more often had lobular histology (40.0% vs 14.5% p < .0001) and ER+ disease (86.6% vs 70.0%). Of the 35 UHTMB cases with HER2 IHC data available, 11 (31.4%%) were HER2 IHC negative (0+), 21 (60.0%) were HER2-low status (9 1+ and 12 2+/ISH negative) and 3 (8.6%) were HER2 IHC positive (3+). 1/3 HER2 IHC2+ cases and 2/45 (4.4%) of all UHTMB cases were positive for HER2 copy number gain on CGP. UHTMB cases had more driver GA/tumor (mean 9.8 vs 5.7 p < .0001) and were less often TNBC (13.3% vs 27.0% p = .041) compared to non-UHTMB high cancers. Mutation signature analysis revealed APOBEC was predominant in UHTMB samples (82.5%); MMR signature was also observed in 10% of cases. MSI high status was significantly more frequent in UHTMB high cases (11.6% vs 0.4% p < .0001). GA more frequently identified in UHTMB cases included CDH1 (45.5% vs 14.3% p < .0001), PIK3CA (81.8% vs 37.9% p < .0001), CDKN2A (11.4% vs 3.2% p = .017), ARID1A (25.0% vs 5.0% p < .0001) and NF1 (20.5% vs 5.9% p = .0014). PD-L1 ( CD274) gene amplification (2.3% vs 1.3%) or protein expression by the Ventana SP142 assay (57.14% vs 51.10%) were not significantly different among groups. Conclusions: UHTMB MBC is a rare, yet clinically important subset of clinically advanced breast cancer driven by APOBEC mutagenesis, with high incidence of ER+ lobular histology and frequent alterations in CDH1 and PIK3CA. In addition to potential benefit from ICI based treatment, UHTMB MBC present with a high frequency of HER2-low status which may impact therapy decisions for this rare disease. [Table: see text]
Artificial intelligence–powered tumor-infiltrating lymphocytes analyzer to reveal distinct immune landscapes in breast cancer by molecular subtype and HER2 score.
Authors: Shin Seunghwan , Cho Soo Youn , Cho Eun Yoon , Kim So-Woon , Jung Minsun , Song Seung-Geun , Lim Yoojoo , Cho Soo Ick , Kim Sukjun , Park Gahee , Song Heon , Ma Minuk , Yoo Donggeun , Ock Chan-Young 
Published: June 2023

1049 Background: Tumor-infiltrating lymphocytes (TIL) reflect an ongoing anti-tumor immune response in the tumor microenvironment (TME) and have been studied as a predictive as well as prognostic biomarker in breast cancer (BC). The immune profile differs depending on BC molecular subtypes, with triple-negative BC (TNBC) and HER2-positive BC more frequently infiltrated by higher numbers of TIL than hormone receptor (HR)-positive tumors. In this study, we analyze TIL and immune phenotype by molecular subtype in BC and explore differences based on HER2 scores using an AI-powered TIL analyzer. Methods: A total of 1,973 cases of BC with molecular subtype, HER2 immunohistochemistry (IHC) or in situ hybridization (ISH) results, and TIL analysis from H&E slides from TCGA (n=1021), Samsung Medical Center (SMC, n=663), and KyungHee Medical Center (KHMC, n=289) were included in the analysis. The density of TIL were spatially analyzed from H&E WSI, and the immune phenotype (IP) was analyzed for each 1 mm2-sized patch. Tumor microenvironment (TME) was categorized into three types: inflamed (TIL distributed intratumorally), Immune-excluded (TIL excluded, out of cancer stroma), immune-desert (scant TIL in TME), and the score for each IP was calculated as the percentage of the total patches in WSI. Results: TNBC showed the highest TIL density in both cancer epithelium (214.5 ± 299.7/mm2) and stroma (1133.3 ± 1245.9/mm2), and a high percentage of inflamed IP (35.7%), IS (28.4 ± 28.1) than other subtypes (inflamed IP: 17.5%, IS 16.2±20.2, both p<0.001). HER2-positive BCs showed higher sTIL density (904.0 ± 901.7/mm2) compared to HR- positive BC (616.7 ± 794.1/mm2) but were associated with a higher percentage of immune-excluded IP (71.2%) and IES (57.6 ± 24.6). HR-positive BC had a high percentage of immune-desert IP (30.4%). In both HR-positive and negative BCs, higher IES was observed as the HER2 score increased. HER2-positive BC significantly showed a higher proportion of cancer stroma in the cancer region from WSI (Stromal ratio, 0.682 ± 0.149 vs. 0.578 ± 0.176, p<0.001). Conclusions: Different TIL densities and IP were seen in BC for each molecular subtype, pointing to a distinct immune landscape. HER2 score was associated with immune-excluded IP despite having higher TIL density, which should be considered for immunotherapy in BC.
Ancestry-adjusted genomic analysis to identify known and novel associations with single and multiple cancer phenotypes.
Authors: Joseph Vijai , Ravichandran Vignesh , Ostrovnaya Irina , Liu Ying L , Tkachuk Kaitlyn , Khurram Aliya , Kemel Yelena , Mandelker Diana , Bandlamudi Chaitanya , Walsh Michael Francis , Conry Michael T , Syed Aijazuddin , Schultz Nikolaus , Solit David B. , Berger Michael F. , Robson Mark E. , Stadler Zsofia Kinga , Offit Kenneth 
Published: June 2023

10504 Background: Germline cancer risks are impacted by cancer type, stage, specific mutation, and ancestry. This study aims to determine the magnitude of genetic risks for commonly tested genes across patients with single and multiple primary cancers (MPC). Methods: We conducted a partially de-identified, retrospective cohort study of all patients consented to using the MSK-IMPACT, a matched tumor-normal sequencing assay, over a five-year period. Approximately 83% of IMPACT testing is derived from patients with metastatic disease. We collected data on demographics and clinical cancer features through cBioPortal and institutional databases. MPC were classified based on the IARC guidelines. Clinically actionable, pathogenic variants in cases and gnomAD non-cancer controls were identified using PathoMAN. Statistical methods incorporated ancestry adjusted, weighted generalized linear model, and ancestry specific methods to estimate risk. Biallelic losses were analyzed from paired tumors. Results: We analyzed 28,000 individuals across 35 cancer types, where germline variants were discovered within 100 cancer predisposition genes. 16% carried pathogenic, clinically actionable variants in known and novel cancer predisposition genes (15% in those with single primary and 21% in MPC). We discovered statistically significant novel associations of germline variants with several cancer phenotypes, including BRCA2 and biliary cancer (OR = 4.5, CI = 2.2-8); ATM and BRCA2 with mesothelioma (OR = 4.8, CI = 2.1-9.2; OR = 8, CI = 3.1-16.6, respectively); NF1 and breast cancer (OR = 5.8, CI = 2.4-12.1); NBN and lung cancer (OR = 4.2, CI = 2.3-6.9), bladder with ATR and others. We replicated known associations and discovered pleiotropy of BRCA1/2, NF1, ATM, TP53 with several cancer types. We failed to replicate reported associations such as PALB2 and ovarian cancer and CHEK2 and colon cancer. Amongst cancer pairs of multiple primaries, we observed mismatch repair genes MSH2, MSH6 and MLH1 to be associated with increased risks for stomach, bowel, and uterine cancer pairs, and TP53 in breast MPC compared to breast single primaries. Conclusions: An ancestry adjusted, weighted analysis of a large real-world case-cohort enriched with metastatic disease did not confirm some prior genotype-phenotype correlations, while suggesting novel associations with hereditary cancer types.
Integrating polygenic risk scores into clinical breast cancer models: Influence on prediction in diverse cohorts.
Authors: Busby George B.J. , Bolli Alessandro , Kintzle Jen , Kulm Scott , Neary John , Di Domenico Paolo , Morganstern Daniel , Botta Giordano 
Published: June 2023

10506 Background: Breast cancer (BC) is the second leading cause of cancer death in women worldwide. Periodic mammography screening has been shown to reduce breast cancer mortality by around 20% in average-risk women and several BC risk models are currently used to identify women at higher risk who can be targeted with increased or earlier screening. However, despite their broad use, these models display only moderate discrimination performance (AUC ranging between 0.51 to 0.68). Here we explore the potential of integrating PRS into a BC risk model using a testing dataset comprising over 175,000 women of diverse ancestry in the UK Biobank and Women Health’s Initiative Cohorts. Methods: We built and validated novel ancestry-specific BC PRSs utilizing novel methodology that leverage multiple Genome Wide Association Studies (GWASs) and linkage disequilibrium maps. We assessed genetic ancestry from 5 continental level ancestry groups across all individuals and applied the PRSs to our testing dataset to assess the clinical implications of integrating genetic information to the Tyrer-Cuzick (TC) breast cancer clinical risk model. Results: The PRSs were well calibrated and displayed high risk stratification (Odds Ratios per Standard Deviation: 1.41 (1.28-1.62) to 1.76 (1.40-2.20; Table) which were comparable or better than benchmarking comparisons with previously published PRS panels. Across genetic ancestries, integrating PRS led to a relative increase of women identified at high lifetime BC risk (20% or higher) from between 1.7 fold (East-Asian ancestry) to around 3 fold (European ancestry). The Net Reclassification Improvement compared to the TC-only model was around 12% for East-Asian (0.001-0.254), European (0.111-0.133), and Admixed American ancestries (0.002-0.228), 17% (0.079-0.266) for South-Asians, and 5% (0.008-0.094) for African ancestry individuals (Table). Conclusions: Our results demonstrate that optimizing PRSs for genetic ancestries and integrating them into BC risk models can lead to a significant improvement in risk stratification. This can enable more targeted use of enhanced screening and prevention strategies improving their cost/benefit ratio.[Table: see text]
Lung cancer metabolomics: A pooled analysis in the cancer prevention studies.
Authors: Tang Ziyin , Liang Donghai , Deubler Emily L , Sarnat Jeremy A , Chow Sabrina S. , Diver Ryan , Wang Ying 
Published: June 2023

10508 Background: Lung cancer is a heterogeneous disease, often diagnosed at advanced stages, with low overall survival rate. To better understand the lung cancer etiology and discover screening and early detection biomarkers, we performed a nested case-control study to examine the metabolic perturbation related to lung cancer. Methods: This study included 741 case-control pairs (mean age = 67 years) from the ongoing Cancer Prevention Study (CPS) cohorts. Participants completed a comprehensive exposure and health questionnaire at enrollment. Pre-diagnosis blood samples were collected between 1998-2001 in CPS-II and 2006-2013 in CPS-3. Cases and controls were 1:1 matched on date of birth, blood draw date, gender, and race/ethnicity. All eligible controls were cancer-free at the time of case diagnosis. Odds ratios (ORs) per standard deviation and 95% confidence intervals (CIs) were estimated using conditional logistic regression, controlling for potential confounders including body mass index, fruit and vegetable consumption, smoking status, and hormone use. We further performed stratified analyses by smoking status (never/former/current) and follow-up time (i.e., within 3 years/ beyond 3 years between blood draw and diagnosis). Statistical significance was determined as false discovery rate (FDR) < 0.2. Results: Sphingomyelin (d18:0/22:0), a bioactive sphingolipid of cell membranes, was associated with lung cancer risk (OR:1.32, 95% CI: [1.15, 1.53], FDR = 0.12). When stratified by follow-up time, participants diagnosed within 3 years of blood draw had a 59% higher risk of lung cancer per standard deviation increase in sphingomyelin (d18:0/22:0) (OR:1.58, 95% CI: 1.16, 2.15, p = 0.004) and 25% higher risk for those diagnosed beyond 3 years (OR:1.27, 95% CI: 1.08, 1.50, p = 0.005). Metabolites associated with lung cancer at raw p-value < 0.05 indicated the perturbation mostly in lipid, amino acid, and xenobiotics metabolism. We observed variants in perturbed metabolic pathways between never-smoker lung cancer cases and current-smoker lung cancer cases. Conclusions: This is the largest prospective study examining lung cancer risk and metabolic response using an untargeted metabolomics platform. These findings provide preliminary support for sphingomyelin (d18:0/22:0) as a potential screening and early detection biomarker for lung cancer. Results also highlight that lipid metabolism including sphingolipid and bile acid metabolism may play an important role in lung cancer etiology.