bluuebunny/crossref_metadata_2025_split huggingface dataset:
The real-world modeling of benefits demonstrated in major clinical trials on 2 HR+/HER2− metastatic breast cancer treatment with CDK4/6 inhibitor in the US: PALOMA-2 and MONALEESA-3.
Authors: Pilehvari Asal , Kimmick Gretchen Genevieve , You Wen , Bonilla Gloribel , Anderson Roger T 
Published: June 2023

e13070 Background: This retrospective study addresses the question of whether real-world treatment with CDK4/6 inhibitors in combination with Endocrine Therapy (ET) for advanced hormone receptor positive (ER+) HER2 negative breast cancer yields similar benefits as reported by the major clinical trials: PALOMA-2 and MONALEESA-3. Methods: This study used the nationwide electronic health record-derived-Flatiron Health de-identified database to test the benefits demonstrated in major clinical trials on MBC patients under treatment with CDK4/6 + Letrozole (PALOMA-2) or CDK4/6 + Fulvestrant (MONALEESA-3). Regarding PALMOMA-2, a total of 1,774 patients with ≥ 3 months of follow-up received either CDK4/6 + Letrozole (n=1,277) or Letrozole alone (n=497) as the first line of treatment between February 3, 2015, and November 02, 2021. To test the benefits reported in MONALEESA-3, 1,187 patients are selected who were treated with either CDK4/6 + Fulvestrant (n=786) who received no or up to 1 line of prior ET or Fulvestrant alone (n=401). We conducted inverse probability weighting to balance the baseline demographic and clinical characteristics between patients in all subgroups. Kaplan-Meier method and Cox proportional hazards were used to test for the association of CDK4/6 treatment on rwPFS as the primary outcome and rwOS as the secondary outcome while adjusting for patient characteristics (e.g., age, race, ECOG PS value, health insurance, etc). Results: The real-world analysis of PALOMA-2 showed similar results as demonstrated in the clinical trials. The findings showed receiving CDK4/6 + Letrozole as the first-line treatment was associated with significantly longer median PFS compared to receiving Letrozole alone (28.3 vs 18 months; hazard ratio [HR], 0.57; 95% CI, 0.46–0.69; P < 0.0001). Median OS was 56.5 months for the group with first line CDK4/6 + Letrozole and 50.4 months for the group with Letrozole alone (HR=0.76, 95% CI, 0.61–0.93, P-value = 0.01). Analysis of real-world practices of MONALEESA-3 also endorsed the results reported from the trial. Median PFS was 17.5 months for the group treated with CDK4/6 + Fulvestrant who received no or up to 1 line of prior ET, while it was about 14.3 months for patients treated with only Fulvestrant (HR=0.64, 95% CI, 0.52–0.80, P-value < 0.0001). Consistent OS benefit was observed in patients treated with CDK4/6 + Fulvestrant compared to those treated with only Fulvestrant (44.72 vs 35.83 months; hazard ratio [HR], 0.70; 95% CI, 0.52–0.94; P < 0.0001). Conclusions: Consistent with what was reported in major clinical trials: PALOMA-2 and MONALEESA-3, receiving CDK4/6 inhibitor plus endocrine therapy (Letrozole or Fulvestrant) was associated with improved progression free survival compared with patients treated with ET alone in this “real-world” population of patients with HR+/HER2− MBC.
Sustained prognostic impact of primary tumor characteristics on long-term (overall) survival after distant metastasis in young ER+ HER2- breast cancer.
Authors: Lee Janghee , Kang Eunhye , Shin Dong Seung , Bae Soong June , Lee Jun-Hee , Cheun Jong-Ho , Lee Han-Byoel , Ryu Jai Min , Ahn Sung Gwe 
Published: June 2023

e13074 Background: Estrogen receptor (ER)+HER2- breast cancer has a good prognosis and is known to have more prolonged survival than other subtypes even after developing distant metastasis (DM). Predicting and improving long-term survival after DM is important, especially for young breast cancer patients with a long-life expectancy. This study aimed to analyze factors associated with long-term survival after DM in young ER+HER2- breast cancer (age ≤ 45). Methods: We retrospectively collected 2,951 young ER+HER2- breast cancer patients (age ≤ 45) who received primary surgery at three academic institutes between January 2000 and December 2011. Patients with survival data for at least 60 months after developing DM were analyzed. The patients must have received endocrine therapy for more than 24 months or until DM. Patients who had received neoadjuvant chemotherapy were excluded. Cox proportional hazard and binary logistic models were used to identify the factors related to post-metastatic overall survival (PMOS) and those associated with short- ( < 60 months) versus long- (≥ 60 months) term survival after DM. Results: Of the 245 patients with DM, 188 had expired. The median follow-up was 117 (12–271) months from primary surgery and 38 (0–196) months from DM. In multivariate Cox analysis, lymph node (LN) metastasis of the primary tumor was identified as a risk factor of PMOS (hazard ratio [HR], 1.84; 95% confidence intervals [CI], 1.28–2.64; P = 0.001). LN metastasis of the primary tumor was a risk factor for short-term ( < 60 months) survival (odds ratio [OR], 3.36; 95% CI, 1.66–6.79; P < 0.001), and histologic grade (HG) I of the primary tumor was a favorable factor for long-term (≥ 60 months) survival (OR, 0.15; 95% CI, 0.03–0.76; P = 0.026) on multivariate analysis. In addition, early recurrence ( < 60 months) (OR, 1.90; 95% CI, 1.04–3.47; P = 0.037), accompanying locoregional recurrence (LRR) (OR, 4.56; 95% CI, 1.96–10.59; P < 0.001), and metastasis at multiple sites (OR, 2.90; 95% CI, 1.56–5.42); P < 0.001) were negative indicators for long-term survival after DM. Conclusions: This study revealed that primary tumor characteristics such as LN metastasis and HG are sustained as prognostic factors for long-term survival after developing DM in young ER+HER2- breast cancer. Early recurrence ( < 60 months), accompanying LRR, and metastasis at multiple sites were also poor prognostic factors.
Integrating radiation therapy with CDK4/6 inhibitors for breast cancer: A systematic review and meta-analysis of toxicity.
Authors: Becherini Carlotta , Visani Luca , Kirby Anna , Bhattacharya Indrani S. , Morgan Gilberto , Salvestrini Viola , Coles Charlotte E , Cortés Javier , de Azambuja Evandro , Harbeck Nadia , Isacke Clare , Kaidar-Person Orit , Marangoni Elisabetta , Offersen Birgitte Vrou , Rugo Hope S. , Morandi Andrea , Lambertini Matteo , Poortmans Philip , Livi Lorenzo , Meattini Icro 
Published: June 2023

e13075 Background: Over the past years, the treatment landscape of breast cancer (BC) has significantly evolved. Several new anticancer agents entered clinical use. Among them CDK4/6i have revolutionised both curative and advanced BC scenarios. The availability of new drugs raises the crucial question on how to integrate them with local and regional treatments. Strong levels of evidence on the safety profile of CDK4/6i in combination with different RT techniques or schedules are currently missing. We aim to systematically review and summarise the published data on the safety profile of palliative and ablative RT combined with CDK4/6i in early and metastatic BC settings. Methods: A literature search (PUBMED/MedLine, Embase, and Cochrane databases) was conducted to identify original studies on the safety profile of the combination of CDK4/6i with RT. This systematic review and meta-analysis project is part of the ESTRO Guidelines Committee consensus recommendations on integration of RT with targeted treatments for breast cancer, an initiative developed by a multidisciplinary Core Group and Expert Panel of medical, clinical, radiation oncologists, preclinical specialists, and patient advocates. Results: Eleven articles finally met all eligible criteria and were included in the meta-analysis. Data could not be collected in the adjuvant setting due to lack of data in the current literature. Pooling data of the included studies show a moderate incidence of hematological toxicities grade 3+ (21.0 %) and a very low-grade 3+ non-hematological toxicity were observed. Conclusions: The safety profile of CK4/6i and RT combination is acceptable. However, international consensus guidelines regarding the safety issue of CDK4/6i and RT combination for breast cancer are warranted.
Potential therapeutic implications of next generation sequencing (NGS)-based molecular profiling in HR+/HER2- metastatic breast cancer (mBC).
Authors: Avesani Barbara , Giontella Elena , Caldart Alberto , De Noni Alessandro , Muzzarelli Alice , Borghesani Giulia , Insolda Jessica , Biondani Pamela , Parolin Veronica , Pellini Francesca , Scarpa Aldo , Nottegar Alessia , Lawlor Rita T , Mafficini Andrea , Paris Ida , Minucci Angelo , Pasciuto Tina , Fabi Alessandra , Fiorio Elena , Milella Michele 
Published: June 2023

e13079 Background: BC is the most frequent malignancy in women and is potentially sensitive to hormonal treatment (HR+, HER2+ or -) in approximately 70% of cases. PIK3CA is among the most frequently mutated genes in BC (approximately 40% of cases) and its mutations portend sensitivity to PI3K inhibitors, such as alpelisib, in combination with hormonal treatment in HR+/HER2- cases. However, extended NGS-based testing is not currently recommended by national and international guidelines. Methods: Women aged 18 years or older, with cytological or histological diagnosis of HR+/HER2- mBC, for whom suitable tissue samples were available, were subjected to extended NGS profiling using the FoundationOne, analyzing 324 genes and gene signatures, such as tumor mutational burden (TMB) and microsatellite instability (MSI); and Illumina TruSight Oncology 500, analyzing 500 genes. DNA was isolated from formalin-fixed, paraffin-embedded (FFPE) samples, from either the primary or metastatic site. Results: Patients (pts) were analyzed (ductal histology: 52%; lobular: 15%; mixed ductal-lobular: 12%; NOS: 21%), among which 7 (12%) had inadequate pathological material and were considered screening failures. A full molecular report was obtained in 53 patients. The most frequent pathogenic and likely pathogenic alterations (class 5 and 4), listed in descending order of prevalence, are: PIK3CA in 51% of pts (E545K>H1047R>N345K>E542K); CDH1 in 21% (prevalence in lobular carcinoma: 75%; in ductal carcinoma: 3,5%). CCND1 in 28% (all amplifications). FGFR1-2 in 21%, TP53 in 15%, WHSC1L1 and ZNF703 in 13%, RAD21 and TBX3 in 9%. Homologous recombination-related genes, such as BRCA1/2 and PALB2 were altered in <5% while ATM altered in 9% of cases. Many other pathogenic mutations (affecting 69 individual genes) were identified, all with a prevalence <10%. TMB was high (>17 mutations/Mb) in 13% of cases, in one of which MSI was also detected. Conclusions: In our analysis PIK3CA was confirmed to be the most frequently mutated gene (51% of cases); however, due to the specific European regulatory constraints, it was deemed to be actionable in a minority of cases, suggesting that NGS profiling should be performed early on after the diagnosis of metastatic disease, in order to inform the overall therapeutic strategy. Other potentially actionable alterations (FGFR1/2, AKT, HER2 ex 20 mutations) emerged from extended NGS profiling, suggesting its potential utility in selected HR+/HER2- mBC pts.
Differences in treatment outcomes in relation to level of human epidermal growth factor receptor-2 (HER2) expression, HER2-low vs HER2-zero, in patients with hormone receptor-positive metastatic breast cancer treated with cyclin dependent kinase CDK4/6 inhibitors: A systematic review and meta-analysis.
Authors: Sharaf Baha' , Alhajahjeh Abdulrahman Ahmad , Batarseh Lana I , Abu-Fares Hala , Abdel-Razeq Hikmat 
Published: June 2023

e13081 Background: Patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancers (MBC) are usually treated with endocrine therapy (ET) in combination with cyclin dependent kinase (CDK4/6) inhibitors. Such combinations have significantly improved treatment outcomes. HER2-negative MBC have recently been divided into two subgroups: HER2-zero, with an immunohistochemistry (IHC) score of 0, and HER2-low, with an IHC score of 1+ or 2+ and a negative in situ hybridization (ISH) assay. The aim of this meta-analysis is to compare treatment outcomes of these two groups of MBC patients when treated with a combination of ET and CDK4/6 inhibitors. Methods: A systematic literature review was conducted to identify relevant studies on the level of HER2 expression in breast cancer patients treated with CDK4/6 inhibitors. The review included articles in databases such as Medline via PubMed, Embase, and Cochran Library, as well as abstracts from the ASCO meeting and SABCS conference updated tell January 2023. Eligible studies included randomized controlled trials, prospective or retrospective studies, and case-control studies that compared the difference in PFS between HER2-low and HER2-zero among breast cancer patients treated with CDK4/6 inhibitors in first-line or beyond setting. A meta-analysis was performed to determine the pooled hazard ratio for progression-free survival (PFS). In addition, a pooled survival curve was created by digitizing the Kaplan-Meier curves to create pseudo-individual patients’ data following the methodology outlined by Combescure et. al (2014). Results: In total, 7 different studies were identified that included a total of 1,341 patients. The random effect model shows a statically significant shorter PFS in the HER2-low group; 17.2 months compared to 24.0 months in HER2-zero group (HR=1.55; 95% CI [1.27-1.84]; p <0.001). There was no statically significant heterogeneity between the studies (I2=51% p-value=0.07). The PFS rates at 12, 24, 36, and 48 months for HER2-low were as follow: (66.2%; 95% CI [50.0%-87.5%]), (33.2 %; 95% CI= 17.4%-63.4%), (26.2%; 95% CI= 12.8%-53.38%), and (22.05%; CI95%= 10.32%-47.12%), respectively compared to: (77.73%; 95% CI= 64.45%-93.75%), (50.00%; 95% CI= 34.66%-72.13%),(43.58%; 95% CI= 22.91%-82.89%), and (36.85%; 95% CI= 17.60%-77.15%) among patients with HER2-zero. Conclusions: In patients with MBC treated with CDK4/6 inhibitors, level of HER2 negativity may affect treatment outcomes; patients with HER2-zero had better PFS compared to those with HER2-low disease. Such findings, if confirmed in larger studies, may change the landscape of treatment of this group of patients.
Retrospective cohort study of CDK4/6-inhibitor-induced alopecia in patients with breast cancer.
Authors: Minta Abena , Rose Lucy , Park Candice , Trovato Stephanie , Lustberg Maryam B. , Sudheendra Preeti Khetarpal , Cherian Mathew Amprayil , Gatti-Mays Margaret Elena , Stover Daniel G. , Wesolowski Robert , Sardesai Sagar D. , Ramaswamy Bhuvaneswari , Williams Nicole Olivia , Dulmage Brittany 
Published: June 2023

e13083 Background: The synergistic effects of novel combined cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) and endocrine therapy has increased their utilization for treatment of metastatic breast cancer. When compared to endocrine monotherapy, CDK4/6i may increase the risk of alopecia by nearly two-fold (Eiger D, et al. PMID: 32167397; Chan D, et al. J Clin Oncol.). The prevalence of this adverse effect underscores the importance of characterizing CDK4/6i-induced alopecia (CDKIA) and investigating therapeutic options. Methods: A retrospective cohort of 28 female patients with breast cancer and endocrine-induced alopecia (EIA) or CDKIA. Onset of alopecia was measured by time (months) between initiation of anticancer therapy and dermatology referral. Therapeutic response to minoxidil (LDOM or topical [5%] solution or foam) was assessed by both Dean Scale and qualitative clinical improvement by comparison of pre-treatment and post-treatment clinical images by 2 board certified academic dermatologists (ST and BD). Results: Androgenetic alopecia was the most common hair loss distribution (n=27, 96.4%), with CDKIA patients having preferential vertex involvement (n=7 [70.0%] CDKIA vs. n=4 [36.4%] EIA; p=0.04). Patients on CDK4/6i had shorter times to dermatology referral (mean time [months]: 44.6±37.1 for EIA vs. 9.4±13.7 CDKIA; p=0.003). After 16-24 weeks of minoxidil, moderate to significant improvement of alopecia occurred in 80% of CDKIA patients versus 94.4% of EIA patients. Despite similar baseline alopecia grade severity, significant improvement was only observed in EIA patients (mean pretreatment Dean Score – post-treatment Dean Score: -0.44; p=0.0002). Conclusions: Compared to EIA, the onset of CDKIA happened more rapidly and was more resistant to minoxidil. The preferential vertex involvement observed among patients with CDKIA may suggest combination therapy with topical or oral minoxidil and topical anti-androgens may lead to more favorable outcomes. Prompt dermatology referral should be considered for patients treated with CDK4/6i + ET. [Table: see text]
Reliance of agency-approved and guideline-recommended therapies on surrogate endpoints in triple-negative breast cancer (TNBC).
Authors: Gala Kinisha , Kalucha Ankit , Pérez-Granado Judith , Requesens Maria Garcia , Vidal Laura , Larvol Bruno , Gramling Mark , Saini Kamal S. 
Published: June 2023

e13085 Background: Surrogate endpoints, such as progression-free survival (PFS) and event-free survival (EFS), are used for accelerated approval in various cancers, including TNBC. Here we review the use of surrogates and clinical outcomes in determining agency approval and guideline recommendation. Methods: Phase 2/3 TNBC trials and trials including TNBC subgroups reporting hazard ratios (HR) for clinical and surrogate endpoints were identified through a systematic search of LARVOL CLIN, PubMed, and conference proceedings. Trials that only evaluated cytotoxic agents and did not report EFS, PFS and/ or overall survival (OS) HR values were excluded. We performed a descriptive analysis of agency and guideline approvals in relation to therapeutic benefit as measured by surrogate outcomes and OS. Results: 21 TNBC cohorts and 1 pooled analysis studying 17 different targeted therapies for TNBC were included. There are 3 targeted therapies that have agency approval and 7 targeted therapies that are recommended by either the NCCN, EMA and ASCO guidelines. Of the two FDA and EMA-approved therapies, pembrolizumab + chemotherapy (PBL + CHT) showed PFS/EFS benefit for early TNBC and PDL1+ metastatic (m) TNBC but only OS benefit for PDL1+ mTNBC, whereas sacituzumab showed significant benefit for both PFS and OS for mTNBC. Four therapies (olaparib for BRCA+ mTNBC, bevacizumab for early TNBC, talazoparib for BRCA+ mTNBC and PBL + CHT for PD-L1+ mTNBC) are recommended by guidelines without having a significant OS benefit. Conclusions: Surrogate outcomes are heavily relied upon for TNBC guideline recommendation. Despite the need for timely access to novel TNBC therapeutics, clinical outcomes should be followed to ensure benefit once they have been reached. An up-to-date digitized trial results repository would ensure expedient review of clinical endpoints. [Table: see text]
Extracellular mechanical forces and ferroptosis in triple negative breast cancer (TNBC): Targeting of aurora kinase A (AURKA).
Authors: Wang Jinyan , Tao Zhonghua , Xie Yizhao , Wang Ye , Guo Duancheng , Li Bin , Cao Jianing , Qiao Xiaosu , Hu Xichun 
Published: June 2023

e13086 Background: The mechanics of tumor microenvironment, primarily induced by extracellular matrix (ECM), function to regulate cell biological behaviors. However, it is unclear if and how triple negative breast cancer (TNBC) cells adapt their biological characteristics to variable extracellular mechanical forces. Methods: TNBC tissues of different stiffness from patients were harvested for untargeted metabolomics to investigate the potential effects of mechanical forces on metabolism. TNBC cells were cultured within gels of different type I collagen (Col-I) densities, which were the major component of ECM, to simulate the effects of extracellular mechanical forces on cells. The metabolic changes of TNBC cells were also examined by using untargeted metabolomics. TNBC cells bathed in different Col-I densities were injected subcutaneously into the breast pad of nude mice. Ferroptosis indicators were evaluated between different groups of mechanical force both in vitro and in vivo. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot were carried out to examine the expression of ferroptosis-related genes and proteins between different groups of mechanical force. Results: Untargeted metabolomics studies showed significant differences in ferroptosis-related metabolites between TNBC tissues with different stiffness, which were also verified in TNBC cells subjected to different extracellular mechanical forces. In vitro experiment suggested that TNBC cells cultured within high Col-I density (strong extracellular forces) exhibited higher levels of lipid peroxidation, reactive oxygen accumulation, mitochondria membrane potential and iron concentration, and lower levels of total glutathione and reduced glutathione concentration, compared with low Col-I density (weak extracellular forces). In addition, mitochondria in high Col-I density group appeared to have volume decrease, fracture and fuzzy cristae. The above results indicated that extracellular mechanical force significantly induced ferroptosis in TNBC. RT-qPCR and western blot of ferroptosis-related genes and protein showed that both mRNA and protein levels of aurora kinase A (AURKA) were significantly decreased in TNBC cells with strong extracellular mechanical force. In addition, overexpression of AURKA inhibited ferroptosis caused by mechanical forces. Furthermore, this cause and effect among mechanical force, AURKA and ferroptosis was also evident in vivo experiments. Conclusions: Our data clarified the role of extracellular mechanical forces in TNBC and showed that the extracellular mechanical forces induced ferroptosis through decreasing the expression of AURKA.