bluuebunny/crossref_metadata_2025 huggingface dataset:
First line combination of ribociclib and letrozole in patients (pts) with metastatic breast cancer (MBC): Focus on hepatic toxicity in the context of a real–world setting the Italian, multicenter Hermione–8 study.
Authors: Piazza Francesca , Bonelli Candida , Lui Stefania , di Nunzio Camilla , Collova Elena , Bozzoli Elisabetta , Vici Patrizia , Gebbia Vittorio , Valerio Maria Rosaria , Zustovich Fable , Vanella Paola , Coltelli Luigi , Pistelli Mirco , Giotta Francesco , Torri Valter , Cazzaniga Marina Elena
Published: June 2023

e13064

Background: The introduction in the clinical practice of CDK4 / 6 inhibitors, in combination with endocrine therapy, has been a breakthrough in the therapeutic scenario of hormone receptor+ve/Human Epidermal growth Factor 2–ve (HR+/HER2–) MBC pts. However, despite the outstanding results in terms of OS and quality of life achieved up to now, it is important to consider that the highly selected population of clinical trials doesn’t always accurately predict the clinical impact of therapies in the general population, hence having real world data is an essential tool to guide physicians in daily clinical practice. Methods: In this observational, multicentre, prospective study, we evaluated the safety profile and the incidence of dose reductions, temporary interruptions and treatment discontinuation due to adverse events, in a real–world cohort of Italian pre or postmenopausal HR+/HER2– MBC pts who received a first line combination of ribociclib and letrozole. Results: A total of 78 MBC patients were included in the analysis. The median duration of treatment was 17 (1–61) months. At the time of ribociclib initiation, 13 (16.7%) pts already presented an altered transaminase value whereas liver metastases were present in 17 pts (21.8%). Ten (12.8%) pts experienced hepatic toxicity while on treatment. The median number of cycles for liver toxicity was 3 (1–18). The most common hepatic event was transaminase level increase in 7 (8.8%) pts. Such event occurred more frequently in the group of pts with normal baseline liver function. Hepatic toxicity was grade 1 in 3 (3.8%) pts, grade 2 in 3 (3.8%) pts, grade 3 in 3 (3.8%) pts and grade 4 in 1 (1.3%) pt. Dose reduction due to hepatic toxicity occurred in 3 (3.8%) pts, in particular one of them needed dose reduction from 600 mg to 400 mg, one from 600 mg to 200 mg whereas treatment discontinuation was applied in the last patient. Median time of treatment interruption due to hepatotoxicity was 29 (14–45) days and 3 (3.8 %) pts discontinued ribociclib due to adverse events. No deaths due to liver failure have been reported. Conclusions: Hermione–8 trial support a manageable safety profile of the combination ribociclib and letrozole in MBC patients treated in a real–world clinical setting, confirming toxicity profile in line with the results presented in the MONALEESA clinical trials. Dose reductions, temporary interruptions and discontinuation of treatment due to adverse events have been limited and seems comparable to the results from MONALEESA trials. [Table: see text]
Feasibility of treatment with another CDK4/6 inhibitor after severe ribociclib liver toxicity.
Authors: Zurcher Jean-Philippe , Goujon Morgan , Cottu Paul H. , Desmoulins Isabelle , Teixeira Luis , Mansi Laura , Meynard Guillaume , Dobi Erion , Rowinski Elise , Stacoffe Marion , Augereau Paule , Robert Marie , Mottaz Yann , Gaiffe Anaïs , Grandvuillemin Aurélie , Fleury Mapi , Dolcan Ana , Stravodimou Athina , Zaman Khalil , Curtit Elsa
Published: June 2023

e13067

Background: Ribociclib is, for now, the only CDK4/6 inhibitor having demonstrated a statistically significant increase of overall survival in first-line in hormone receptor-positive, HER2-negative advanced breast cancer. One of the limiting toxicities of ribociclib is the occurrence of grade III/IV hepatobiliary toxicity in approximately 5% of patients. It contraindicates the reintroduction of the drug. Therapeutic options after this type of adverse event are challenging because there are very limited data regarding cross reactivity in risk for hepatic injury between ribociclib, palbociclib or abemaciclib. Methods: We describe a cohort of 28 patients who presented with grade III and/or IV ribociclib-induced hepatitis and who subsequently received another CDK4/6 inhibitor. Cases were collected from the French pharmacovigilance database and additional cases were obtained through institutional databases. Data were retrospectively obtained from patients’ reports. Results: Twenty-eight patients, from 11 centers, presented a grade III (71%, 20 patients) or a grade IV (29%, 8 patients) transaminase elevation with ribociclib. Median transaminase elevation was 12.3 x ULN (upper limit normal) for AST and 15.2 x ULN for ALT. This toxicity occurred within the first 6 months of treatment for all patients except one. Ribociclib was associated with letrozole in 21 patients, fulvestrant in 5 patients and anastrozole or exemestane in 2 patients. No acute liver failure occurred. All patients switched to another CDK4/6 inhibitor (23 patients - 82% - palbociclib and 5 - 18% - abemaciclib) without significant reoccurrence of liver toxicities. Four patients (14%) presented a transient grade 1 or 2 hepatic toxicity (all of them with palbociclib), 20 patients (71%) received the second CDK4/6 inhibitor at full dose. The median follow-up was 16 months. Conclusions: Treatment with palbociclib or abemaciclib after grade III or IV transaminase elevation due to ribociclib is feasible and none of the patients in this cohort exhibited reoccurrence of significant liver toxicity afterwards. Ribociclib liver toxicity occurs mainly during the first 6 months of treatment and takes several months to recover. [Table: see text]
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.
Shugoshin as a key mediator in the metastasis of triple negative breast cancer.
Authors: Hernandez Valeria Julia , Jusino Shirley , Rivera Rivera Yainyrette , Chardon Colon Camille , Rodriguez Rodriguez Patrcia C. , Roman Gonzalez Janeishly , Isidro Angel , Saavedra Harold I.
Published: June 2023

e13098

Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the lack of estrogen, progesterone, or human epidermal growth factor 2 (HER2) receptor expression. TNBC has poor prognosis due to its high metastatic potential and limited treatment options. Shugoshin-1 (Sgo1), a centromeric protein that maintains stability in chromatids during mitosis, has been thought to play an important role in the progression of TNBC. Previous publications from our group have shown that the transient downregulation of Sgo1 in TNBC cells decrease the epithelial-to-mesenchymal transition (EMT), which is a precursor of metastasis. Our purpose with this study is to evaluate the role of long-term effects of Sgo1 downregulation in cell invasion, cell migration, tumor growth, and metastasis. Methods: To achieve our goal, MDA-MB-231 cells were stably transfected with a lentivirus containing a shRNA Sgo1 sequence or a scramble shRNA control. Cell invasion and migration were evaluated by Boyden chamber assays. Meanwhile, tumor growth and metastasis were evaluated using an immunocompromised orthotopic mice model. Female NOD-SCID Gamma (NSG) mice were injected either with 2.5 X 106 shRNA Control (n= 10) or shRNA Sgo1 (n= 10) MDA-MB-231 cells. Tumor growth was measured for eight weeks using a vernier caliper. Afterwards, primary, and metastatic tumors as well as primary organs were harvested. Lung and liver samples were embedded in paraffin and stained with hematoxylin and eosin. A Student t test was used to evaluate the differences between groups. A p-value < 0.05 was considered significant. Results: Our results show a significant reduction in cell invasion and migration in MDA-MB-231 cells treated with shRNA Sgo1. Moreover, we observed a significant reduction in tumor growth and metastasis to lymph nodes, liver, and lungs in the mice treated with shRNA Sgo1 when compared to shRNA Control group. Conclusions: These results suggest that Sgo1 is an important regulator in TNBC tumor growth and metastasis through the modulation of EMT genes. Thus, targeting Sgo1 early in the course of TNBC can be a potential therapeutic treatment of TNBC.
Identification of a novel squalene epoxidase function in breast cancer brain metastasis.
Authors: Wang Shu-Ping , Yeh Jia-Yun , Lee Pony Yu-Ling , Lin Kun-Yuan , Chang Chao Di , Yang Chih-Chieh , Cheng Shan-Yun , Hung Ya Wen , Yu Yung-Lung
Published: June 2023

e13101

Background: Brain metastases are serious complications of breast cancer and there is no effective treatment. The major therapeutic issues can be attributed to the unique brain microenvironment as well as the difficulty of drug delivery to the brain due to the blood-brain barrier (BBB). BBB limits access of nutrients from the circulation and thereby makes the brain in a special condition that is hypoxic and composed of depleted metabolites, growth factors, and proteins. Nevertheless, tumor cells that are able to metastasize to the brain can necessitate metabolic adaptations for their nutrient availability and thereby succeed to colonize in the brain. However, it is still poorly understood how breast cancer cells alter their metabolic systems to manipulate brain metastasis by overcoming nutritional limitations. Methods: To probe the molecular mechanism of breast cancer to brain metastasis, we compared gene signatures in primary breast tumors and breast-to-brain metastatic tumors, and identified that SQLE (encodes squalene epoxidase, the second rate-limiting enzyme in the cholesterol biosynthesis) could be a leading-edge gene in breast-to-brain metastasis. Using the brain metastatic MDA-MB-231-BR (231-BR) and its parental MDA-MB-231 (231) cell line expressing SQLE shRNAs, we evaluated the effects of SQLE loss on cancer cell migration, invasion, and stemness by wound-healing, transwell invasion/migration, and tumorsphere formation assays. The in vitro cell-based BBB model and in vivo mouse models that develop 231-BR brain metastases were established to verify our hypothesis. Results: While loss of SQLE greatly attenuated cell invasiveness and stemness in both 231 and 231-BR cells, loss of SQLE could only affect the cell migration activity on 231 cells but not 231-BR cells. Since the ability to invade, migrate, and penetrate is critical for invasion of cancer cells, our results strongly imply the novel function of SQLE in breast cancer cell invasion, penetration, and colonization in the brain. Our RNA-seq data further identified a subset of SQLE-affected genes that is uniquely enriched in 231-BR cells and favors brain extravasation and colonization. The in vitro cell-based BBB model and in vivo mouse models that develop 231-BR brain extravasation and colonization finally verified our hypothesis that SQLE may play a unique function to promote breast cancer metastasis into the brain. Conclusions: Our findings provide new insights into contributions by SQLE in breast-to-brain extravasation and colonization and indicate that targeting SQLE may represent a therapeutic opportunity for breast cancer brain metastases.
Survival outcomes and clinicopathological factors analysis of breast cancer patients. A single-institution cohort from 2012 to 2020 in a Mexican population.
Authors: Grajales Rocio , Gutierrez Alicia , Pichardo Christian , Gutierrez Marcos , Dip Borunda Abdel Karim
Published: June 2023

e13104

Background: In Mexico, The Instituto Mexicano del Seguro Social (IMSS) is a tripartite contribution which provides care to more than 74 million beneficiaries, which represents more than 50% of the general population of the country. Although Mexican breast cancer statistics have been reported, it is imperative to know the updated statistics on the epidemiology in our Institution. The aim of this study is to describe the survival outcomes and the clinical-pathological characteristics of patients with breast cancer. Methods: Records of breast cancer patients treated at the Oncology Hospital from Centro Medico Nacional Siglo XXI of IMSS, from January 2012 to December 2020 were included. We analyzed clinical and demographic characteristics of the population, as well as survival outcomes at 5-years. Results: A cohort of 5,264 patients was included. Median follow up was 54.9 months. Forty-three percent (n = 2,274) were diagnosed in early-stage breast cancer (I–IIA), 43.1% (n = 2,269) in stages IIB-III, and 7% (n = 383) in stage IV. The most common immunophenotype was hormone receptor (HR) positive, HER2-negative (70.8%, n = 3,726). HER2-positive represents 19.3% (n = 1011), among HR-positive were 12.4% (n = 650) and HR-negative, 6.9% (n = 361). 527 patients (10.1%) were triple negative. At 5-years, disease-free survival was 74.9% (95% CI, 73.5 to 76.3) and overall survival was 90.4% (95% CI, 89.4 to 91.3). High histologic grade (HR 1.51; 95% CI, 1.33 to 1.7; p < 0.001) and lymphovascular invasion (HR 1.84; 95% CI, 1.62 to 2.1; p < 0.001) were associated with higher risk of recurrence. Adjuvant chemotherapy was significantly associated to a 42% reduction in the risk of recurrence, HR 0.58 (95% CI, 0.49 to 0.69; p < 0.0001), and 54% in the risk of death, HR 0.46 (95% CI, 0.33 to 0.63; p < 0.0001) in stage III. Lobular histology was also associated with worse survival, HR 1.41 (95% CI, 1.069 to 1.859; p = 0.015). Conclusions: An update of breast cancer Mexican patients treated at IMSS is presented. We highlight the impact of adjuvant treatment and pathological risk factors for recurrence and death. This work can contribute to evaluate areas for improvement in management and outcomes in our population.
A pilot study of the combination of entinostat with capecitabine in high-risk breast cancer after neoadjuvant therapy.
Authors: Humphrey Clare , Millard Trish Ann , Brenin Christiana , Dhakal Ajay , Falkson Carla Isadora , Petroni Gina R. , Wages Nolan , Dillon Patrick Michael
Published: June 2023

e13107

Background: Breast cancer has an unacceptably high recurrence rate when residual disease is found following neo-adjuvant treatment of high-risk disease. Based on clinical data suggesting an adjuvant role for epigenetic modifying agents in breast cancer and preclinical data suggesting synergistic activity of entinostat combined with capecitabine, we conducted a phase I, open label study of these agents in metastatic breast cancer (MBC). Both agents have published doses for use in combination therapy, but the agents had not previously been combined with each other in a human trial. Methods: A multisite phase I dose escalation study was performed at two academic centers. Patients with pretreated, HER2 negative MBC, and measurable disease were enrolled. Dual dose escalation was performed via a Bayesian partial order continual assessment method. Dose levels ranged from entinostat 3mg to 5mg and capecitabine 800mg/m2 to 1000mg/m2. Results: Thirteen patients with MBC and a median of 4 lines of prior therapy were enrolled across four dose level combinations. The most common toxicities were neutropenia, thrombocytopenia, and palmar- plantar erythrodysesthesia, which were expected toxicities. No new safety signals were observed. One dose-limiting toxicity was observed, which did not exceed a pre-specified toxicity rate of 25%. The median treatment duration was 2.37 months. No partial nor complete responses were observed. The study was halted early prior to entering an expansion phase. Conclusions: The tested dosing combinations of entinostat and capecitabine are likely safe in heavily pretreated metastatic breast cancer patients. Entinostat clinical investigation in breast cancer was halted while this study was ongoing. Clinical trial information: NCT03473639 .
Prognosis of patients with HER2-low breast cancer brain metastasis: A single-institution experience.
Authors: Xu Hangcheng , Wang Yan , Han Yiqun , Wu Yun , Sa Qiang , Wang Jiayu
Published: June 2023

e13109

Background: Many patients with breast cancer were reported to suffer from brain metastasis in the advanced setting. Traditionally, the HER2-low entity was classified as HER2-negative when evaluating prognosis and administrating treatment in patients with breast cancer brain metastasis (BCBM). Trastuzumab deruxtecan (T-DXd) was proved to have potent efficacy in HER2-low breast cancer, even with brain metastasis, which made this subtype a distinct entity. However, the evidence regarding HER2-low BCBM is scarce. Methods: Based on the clinical database of our institution, the BCBM patients with available HER2 status between January 2010 and July 2021 were selected. The enrolled patients with HER2 1/2+ in immunohistochemistry and negative for fluorescence in situ hybridization (FISH) were classified as HER2-low. The comparisons were conducted between HER2-low and HER2-zero category. We predefined the primary endpoint as the overall survival (OS) after the diagnosis of BCBM, which were further analyzed basing the status of hormone receptor (HR). The Kaplan–Meier curves with log-rank test and Cox proportional hazards model were utilized to analyze the survival outcomes. Results: A total of 272 cases were included in the database, among which the patients with HER2-zero (n=64) and HER2-low (n=71) subtypes were analyzed eventually. The OS of patients with HER2-low BCBM was better than the HER2-zero counterparts in the overall population (p=0.002) and the HR-negative group (p=0.008), while the similar tendency was not observed in the HR-positive patients. Moreover, the Cox regression analysis demonstrated that the HER2-low status was a significant prognostic factor for the better clinical outcome in the HR-negative patients (p=0.046 for multivariate analysis). Conclusions: The patients with HER2-low BCBM had better prognosis than the HER2-zero counterparts, especially in the HR-positive subgroup. The low expression of HER2 is supposed to be related to the long-term survival of BCBM patients.
Cancer recurrence: Detection and diagnostic intervals in Danish primary care.
Authors: Grooss Kasper , Rasmussen Linda Aagaard , Christensen Kaj Sparle , Pedersen Anette Fischer , Vedsted Peter
Published: June 2023

e13110

Background: Danish cancer survivors receive hospital-based, specialized follow-up care with one central aim to detect cancer recurrence (CR) at an early stage. Nevertheless, CR is frequently detected outside of scheduled follow-up visits as 40-60% of CR patients encounter and present symptoms. The family physician (FP) is presumed to facilitate most of these diagnostic pathways. However, little is known about CR detection in primary care. We aim to examine diagnostic intervals, actions taken by the FP and sub-optimal events for patients presenting symptoms of CR in primary care. Methods: We are conducting a retrospective, national cohort study based on questionnaire data linked to register data at the individual level. Patients diagnosed with CR of melanoma, lung, breast, colorectal, bladder, ovarian and endometrial cancer between Jan 2022 and May 2024 are included. Patients are identified consecutively using validated, register-based algorithms. All Danish citizens have access to free healthcare and 99% are listed with a specific FP. The affiliated FP is invited to complete a questionnaire on the diagnostic pathway utilizing the patient medical record. Danish health registers provide information on the primary cancer, CR diagnosis date, comorbidity, education, sex, and age. Results: We aim to include 3,000 CR patients and expect to receive information on 1,000 CR diagnostic pathways initiated in primary care. We will present preliminary results from the first 500 responders. The proportion of diagnostic pathways initiated in primary care was 33%, hospital-based follow-up was 44%, and another route was 23%. The FPs initiated the diagnostic pathway by referral to cancer specific urgent pathway for 31% of patients, by referral to specialized private or hospital-based physician including diagnostic imaging for 30% of patients. For 31% of diagnostic pathways, the FPs reported sub-optimal or delaying events. The most frequently reported sub-optimal event was regarding clinical decisions by the FP (12%). For patients with CR of breast cancer (n=53), the mean diagnostic interval (time from first contact to CR diagnosis) was 86 days [95% CI = 61 to 112days]. Conclusions: One third of diagnostic pathways for CR was initiated in primary care. This project will provide novel, comprehensive evidence on these diagnostic pathways to inform the efforts for early detection of CR and survivorship in primary care.
B-TREUH results: A single-arm phase II pilot study of euthyroid hypothyroxinemia in metastatic breast carcinoma.
Authors: Trehan Shruti , Cheng Suzan S. , Rawal Anisha , Amos Mary , Collins Kathleen , Hercbergs Aleck
Published: June 2023

e13111

Background: Thyroid abnormalities are prevalent in up to 1/3 breast cancer patients. T4/L-thyroxine is the most commonly prescribed treatment for hypothyroidism. However, T4 has been shown to be a potent pro-oncogenic agent by stimulating mitogenesis and angiogenesis, and inhibiting apoptosis, anti-PDL-1 and radiation effects. T3/triiodothyronine is significantly less oncogenic and mitogenic. Hence, using T3 rather than T4 might have anti-oncogenic effects, resulting in slower disease progression and improved outcomes. Methods: Adults with metastatic breast carcinoma on active treatment with estimated life expectancy of > 3months and hypothyroidism on T4 and normal TSH were eligible. Following informed consent, participants discontinued T4 and initiated T3 after a washout period. T3 dosing and titration was based on their previous dose of T4 and thyroid function testing to maintain levels of free T4 at < 50% normal range. The treatment period was 9 months and follow up for 12 months. The primary endpoint was progression free survival. Secondary endpoints were prevalence of hypothyroidism in the cohort, overall survival, quality of life, and time to achieve euthyroid hypothyroxinemia. Results: The trial was terminated early due to the pandemic and relocation of the PI and Sub-I. 7 female patients from a community medical oncology practice were enrolled between March 2019 and March 2022, Duration of metastatic breast cancer 7-223 months (average 62 months). Progression-free survival at 9 months was 5/7 (71%). Progression free survival (PFS) at 12 months, calculated in 6 patients due to data cut-off deadline and premature study closure, was 4/6 (67%). Overall survival at 9 months was 6/7 (85%). 1 patient died due to disease progression. The prevalence of hypothyroidism was 26/126 (21%). Euthyroid hypothyroxinemia was achieved in 100%, in average time of 59.6 days. 0% of the 14 serious adverse events were attributed to T3. Quality of life FACT-B scores on T4 vs T3 were not statistically significant. Conclusions: B-TREUH is the first prospective trial of euthyroid hypothyroxinemia in hypothyroid metastatic breast cancer. The transition from T4 to T3 was well tolerated with no serious adverse side effects or on quality of life. In this heavily pretreated population, PFS was 71% at 9 months and 67% at 12 months. The small number and heterogeneity of this cohort make interpretation of the PFS challenging. This unique study is simple yet provocative. Larger, broader studies are needed to explore this concept further. The low cost and easy availability of T3 and high prevalence of hypothyroidism make it an exceptionally attractive agent for future oncology research. Clinical trial information: NCT03787303 .
The mutational landscape of Chinese breast cancer by liquid biopsy.
Authors: Fan Jing , Yin Yan , Hu Bo , Peng Bo
Published: June 2023

e13117

Background: Breast cancer is the most common malignancy worldwide. The novel technique of liquid biopsy provides further prospect of breast cancer management. However, the clinical application of liquid biopsy for breast cancer remains clearly defined. Methods: Blood samples of 145 Chinese patients diagnosed as breast cancer were collected. cfDNA were analyzed by next-generation sequencing technique using Haplox HapOnco panel. The mutations of cfDNA were analyzed and compared with genomic mutations detected within tumor tissues of breast cancer patients. Results: In total, 327 genetic mutations were detected in 145 patients using cfDNA. The top 5 high frequent alterations were TP53(50.3%), PIK3CA (42.8%), SYNE1 (16.6%), ESR1 (10.3%), CSMD3 (9.0%). Within TP53 mutations, 13.7% were frame shift insertions or deletions, 5.5% were in-frame insertions or deletions, 9.6% were splice site mutations. Within PIK3CA mutations, 1.6% were in-frame insertions or deletions, 1.6% were copy number variations. The average number of mutations for each patient was 7.2 (5.5 to 9.0, 95% CI). The mutated genes in cfDNA were compared with those in tumor tissues in publications. 208 mutated genes in tumor tissues were also detected in cfDNA. There was no significant difference in mutation rate for 83.6% genes in blood and tumor tissues. Conclusions: Most mutated genes in tumor tissues of breast cancer patients could be detected in cfDNA. The mutation rate for most genes had no significant difference in blood and tumor tissues, which indicated that liquid biopsy using cfDNA is a promising technique to improve breast cancer management.