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By the end of 2020, there were more than 8 million women alive who had received a breast cancer diagnosis in the previous 5 years, making it the most prevalent neoplasia in the world. About 70% of breast-cancer cases present positivity for estrogen and/or progesterone receptors and a lack of HER-2 overexpression. Endocrine therapy has traditionally been the standard of care for ER-positive and HER-2-negative metastatic breast cancer. In the last 8 years, the advent of CDK4/6 inhibitors has shown that adding them to endocrine therapy doubles PFS. As a result, this combination has become the gold standard in this setting. Three CDK4/6 inhibitors have been approved by the EMA and the FDA: abemaciclib, palbociclib, and ribociclib. They all have the same indications, and it is at each physician’s discretion to choose one or the other. The aim of our study was to perform a comparative efficacy analysis of the three CDK4/6i using real-world data. We selected patients diagnosed with endocrine-receptor-positive and HER2-negative breast cancer who were treated with all three CDK4/6i as first-line therapy at a reference center. After 42 months of retrospective follow up, abemaciclib was associated with a significant benefit in terms of progression-free survival in endocrine-resistant patients and in the population without visceral involvement. In our real-world cohort, we found no other statistically significant differences among the three CDK4/6 inhibitors.

Introduction and objectives: Cyclin dependent kinase (CDK) 4/6 inhibitors along with endocrine therapy (ET) is the standard first-line for endocrine receptor (ER)-positive HER2-negative metastatic breast cancer. Three CDK 4/6 inhibitors have the FDA and EMA approval: abemaciclib, palbociclib and ribociclib. They appear to have notable differences in their pharmacokinetic characteristics and ability to inhibit every cyclin. Nevertheless, the natural history of disease associated with each CDK 4/6 inhibitor remains unclear. The aim of this study is to establish a risk prediction model for disease progression under the different therapeutic regimes and assess whether there are differences in terms of efficacy between them. Methods: This is a retrospective observational study in which patients treated with ET plus abemaciclib, palbociclib or ribociclib as front line for metastatic breast cancer in Virgen del Rocio Hospital between April 2014 and April 2021 were selected. Patients in this population were followed for a period of 36 months. They were studied according to their clinical characteristics and disease outcome using descriptive analysis. The risk of progression was studied by a transversal method using a univariate logistic regression model. Moreover, Kaplan Meier curves were used to estimate progression-free survival (PFS) and the Breslow test to estimate the p value. All statistical analyses were performed with SPSS 28.0 (Statistical Package for the Social Sciences). Results: A total of 189 patients were selected. 55(29.1%) of them received abemaciclib, 83(44%) palbociclib and 51(27%) ribociclib. 50(27%) patients had de novo metastatic disease, while 139(73%) were recurrences of previous disease. Almost half of the patients (45%) received fulvestrant and 104 (55%) patients received aromatase inhibitors. Table 1 represents the proportion of patients with visceral involvement and endocrine resistance in each arm. The univariate logistic regression model showed that patients treated with palbociclib had 2.36(CI95% 1.165-4.765) times the risk of progression compared to abemaciclib, while patients treated with ribociclib had 2.50(CI95% 1.139-5. 475) times the risk of progression compared to abemaciclib. Overall PFS was 30.03 months. A tendency towards best PFS with abemaciclib in comparison with the other CDK 4/6 inhibitors was appreciated, but it did not reach statistical significance (abemaciclib-palbociclib p=0.289; abemaciclib-ribociclib; p= 0.293; palbociclib-ribociclib p=0.979). Conclusions: In our sample of patients with ER-positive HER2-negative metastatic breast cancer treated with the different CDK 4/6 inhibitors as front line therapy, patients with abemaciclib achieved a lower risk of progression and a trend toward longer PFS. Further follow-up will be necessary to determine whether abemaciclib provides greater benefit in PFS. Table 1. Proportion of patients with visceral involvement and endocrine resistance in each arm. Visceral metastases: Liver, Lung, central nervous System; Non-Visceral: Bone, skin, Lymph node. Citation Format: Mónica Cejuela, M. ángeles Castilla, Marta Benavent, Sonia Molina-Pinelo, Maria A Dominguez-Cejudo, Ana Gil, Alejandro Falcon, Francisco Javier Salvador Bofill. Palbociclib, ribociclib and abemaciclib in real-world data: risk of disease progression on first-line treatment of metastatic breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-01-13.

This work was supported by the Instituto de Salud Carlos III (ISCIII; Grant No. PI080971 to JP) and the Ministerio de Ciencia e Innovacion (MICINN), co-financed by the European Development Regional Fund (Grant No. RD06/0020/0013 to JP), the Junta de Andalucia (Consejeria de Salud; Grant Nos PI-0384/2007 and PI0581/2009, to JP), MICINN (Grant No. SAF-2010-21143; Consolider-Ingenio Grant No. CSD2007-00017 to AC; Grant No. SAF2010-20175 to GMB), Comunidad de Madrid (Grant No.S2010/BMD-2303, to AC and GMB), Asociacion Espanola Contra el Cancer (Grant No. AECC 2011, to GMB) and ISCIII-Ministerio de Economia y Competitividad (MINECO; Grant No. RD12/0036/0064 to JP; Grant No. RD12/0036/0007 to AC). JDM is a PhD researcher funded by the Consejeria de Salud, Junta de Andalucia (Grant No. PI0581/2009). MAC and ADL are PhD researchers funded by the ISCIII (Grant No. RD06/0020/0013 and Sara Borrell contracts, respectively).

Although TAZ, the final effector of the Hippo pathway that modulates epithelial to mesenchymal transition and stemness, has been implicated in the development of different types of cancer, its role in endometrial cancer has not yet been studied. Thus, we evaluated the expression of TAZ in different types of endometrial cancer by immunohistochemistry. TAZ expression was detected in 76% of undifferentiated endometrial carcinomas, 54% of endometrial carcinosarcomas, 46% of endometrial serous carcinomas, 36% of grade 3 endometrioid carcinomas, and 18% of grade 1-2 endometrioid carcinomas, with statistically significant differences. We analyzed the WWTR1 gene that encodes TAZ by FISH and MassARRAY spectrometry, ruling out gene amplification and differential promoter methylation as the main mechanisms that modulate TAZ expression in endometrial tumors. However, we did detect a significant association between Scribble hypoexpression and delocalization with TAZ expression. Moreover, we demonstrated that TAZ promoted invasiveness, and it favored cell motility and tumor growth, in endometrial cancer cell lines. In addition, TAZ expression was associated with the transition from an epithelial to mesenchymal phenotype, both in vitro and in human tumors. Together, these data reveal a previously unknown role for TAZ and the Hippo pathway in the progression of aggressive subtypes of endometrial cancer., This work was supported by grants from Spanish Ministry of Health, Instituto de Salud Carlos III (RD12/0036/0064 and PI13/02477 to JP and RETICC RD12/0036/0007 and PI13/00132 to GM-B); the European Development Regional Fund, ‘A way to achieve Europe’ EDRF to JP; the Community of Madrid (S2010/BMD-2303) and AECC Foundation to GMB; and by TV3 La Marató-2013 to GM-B and JP. LR-P is a recipient of a PFIS fellowship (Grant No. F109/00193). PG-S is funded by the AECC-2011. AM is a predoctoral student supported by a FPU fellowship (Spanish Ministry of Education, Culture and Sport). JD-M is a PhD researcher funded by the Consejería de Salud, Junta de Andalucía (PI0581/2009). MH-R is a PhD researcher funded by Community of Madrid. MAC is a PhD researcher funded by the ISCIII (RD06/0020/0013).

Although it is becoming clear that certain miRNAs fulfil a fundamental role in the regulation of the epithelial-to-mesenchymal transition (EMT), a comprehensive study of the miRNAs associated with this process has yet to be performed. Here, we profiled the signature of miRNA expression in an in vitro model of EMT, ectopically expressing in MDCK cells one of seven EMT transcription factors (SNAI1, SNAI2, ZEB1, ZEB2, TWIST1, TWIST2 or E47) or the EMT inducer LOXL2. In this way, we identified a core subset of deregulated miRNAs that were further validated in vivo, studying endometrial carcinosarcoma (ECS), a tumour entity that represents an extreme example of phenotypic plasticity. Moreover, epigenetic silencing through DNA methylation of miRNA genes of the miR-200 family and miR-205 that are down-regulated during EMT was evident in both the in vitro (MDCK transfectants) and in vivo (ECS) models of EMT. The strong correlation between expression and DNA methylation suggests a major role for this epigenetic mark in the regulation of the miR-141-200c locus.

Undifferentiated endometrial carcinomas are very aggressive high-grade endometrial carcinomas that are frequently under-recognized. This study aimed to analyze the molecular alterations underlying the development of these endometrial carcinomas, focusing on those related to dedifferentiation. We assessed a series of 120 tumors: 57 grade 1 and 2 endometrioid endometrial carcinomas, 15 grade 3 endometrioid endometrial carcinomas, 27 endometrial serous carcinomas, and 21 undifferentiated endometrial carcinomas. We found a high frequency of DNA mismatch repair deficiency (38%) and moderate rate of p53 overexpression (∼33%) in undifferentiated carcinomas. In contrast to the characteristic endometrioid phenotype, there was a dramatic downregulation of E-cadherin expression in the undifferentiated subtype. Quantitative methylation studies dismissed CDH1 promoter hypermethylation as the mechanism responsible for this change in gene expression, while immunohistochemistry revealed that the E-cadherin repressor ZEB1 was frequently overexpressed (62%) in undifferentiated endometrial carcinomas. This finding was accompanied by a sharp downregulation in the expression of the miR-200 family of microRNAs, well-known targets of ZEB1. Furthermore, there was enhanced expression of epithelial-to-mesenchymal transition markers in undifferentiated endometrial carcinomas, such as N-cadherin, cytoplasmic p120, and osteonectin. In addition, HMGA2, a regulator of epithelial-to-mesenchymal transition that is expressed in aggressive endometrial tumors, such as endometrial serous carcinomas and carcinosarcomas, was expressed in >20% of undifferentiated carcinomas. These results suggest that ZEB1 overexpression, associated with E-cadherin and miR-200s downregulation, and the expression of mesenchymal markers might enhance the metastatic potential of undifferentiated endometrial carcinomas, leading to a poor prognosis. In addition, our observations suggest that the immnohistochemical analysis of E-cadherin and ZEB1 can aid in the differential diagnosis of the more agressive undifferentiated endometrial carcinomas from grade 3 endometrioid carcinomas.

Endometrial cancer (EC) is the most common gynaecological malignancy in the western world and it comprises a heterogeneous group of tumours with distinct risk factors, clinical presentation, and histopathological features. Two main groups of EC exist, endometrioid endometrial carcinomas (EECs or type I) and non endometrioid endometrial carcinoma (NEECs or type II), which evolve via distinct molecular pathways. The most common molecular alterations associated with EECs affect the phosphoinositide 3-kinase (PI3K)/Akt pathway due to mutations in PTEN or PI3KCA. Other pathways, such as the RAS-RAF-MEK-ERK, FGF and WNT signalling pathways are also frequently affected by gene mutations or epigenetic changes. In addition, a group of sporadic EECs are characterized by microsatellite instability due to DNA mismatch repair (MMR) deficiency secondary to promoter hypermethylation of MLH1. In addition, EC is the second most frequent malignancy in hereditary Lynch syndrome. MMR deficiency in these patients is secondary to germline mutations in MLH1, MSH2 or MSH6. Finally, ARID1A mutations have been recently described in a subset of EECs. Endometrial serous carcinoma is the most frequent histological type of NEEC and is characterized by alterations in TP53 with secondary chromosomal instability, which leads to multiple chromosomal gains and losses, including amplification of oncogenes and loss of important tumour suppressor genes. By contrast, the molecular alterations in clear cell carcinomas, another histological type of NEEC, are poorly defined. Differences in genetic and epigenetic alterations between EEC and NEEC tumours are reflected in distinct gene expression profiles observed amongst different EC types. In the near future, careful molecular characterization of ECs must be necessary in order to implement new directed targeted therapies. Endometrial carcinoma (EC) is a primary malignant epithelial tumour that arises in the endometrium and that can invade the myometrium in order to spread to distant sites [1]. In developed countries, EC is the most common malignant primary tumour of the female genital tract, and it represents the fourth and fifth most-frequently diagnosed cancer in women in Europe and the USA respectively, although this incidence is lower in Japan and developing countries. Moreover, while the incidence of EC among black women is approximately half that in white women, the proportion of EC-related deaths is greater in black than in white women for reasons that remain poorly understood [2]. The median age at which these tumours are diagnosed is 61 years, although some specific subtypes are diagnosed later, such as serous or clear cell carcinoma.