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© 2022 The Authors; Published by the American Association for Cancer Research. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 International (CC BY-NC-ND), Purpose: Cetuximab is an EGFR-targeted therapy approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, about 60% of these patients show innate resistance to cetuximab. To increase cetuximab efficacy, it is crucial to successfully identify responder patients, as well as to develop new therapeutic approaches to overcome cetuximab resistance. Experimental design: We evaluated the value of EGFR effector phospholipase C gamma 1 (PLCγ1) in predicting cetuximab responses, by analyzing progression-free survival (PFS) of a multicentric retrospective cohort of 94 treated patients with mCRC (log-rank test and Cox regression model). Furthermore, we used in vitro and zebrafish xenotransplant models to identify and target the mechanism behind PLCγ1-mediated resistance to cetuximab. Results: In this study, levels of PLCγ1 were found increased in RAS WT tumors and were able to predict cetuximab responses in clinical samples and in vitro and in vivo models. Mechanistically, PLCγ1 expression was found to bypass cetuximab-dependent EGFR inhibition by activating ERK and AKT pathways. This novel resistance mechanism involves a noncatalytic role of PLCγ1 SH2 tandem domains in the propagation of downstream signaling via SH2-containing protein tyrosine phosphatase 2 (SHP2). Accordingly, SHP2 inhibition sensitizes PLCγ1-resistant cells to cetuximab. Conclusions: Our discoveries reveal the potential of PLCγ1 as a predictive biomarker for cetuximab responses and suggest an alternative therapeutic approach to circumvent PLCγ1-mediated resistance to cetuximab in patients with RAS WT mCRC. In this way, this work contributes to the development of novel strategies in the medical management and treatment of patients with mCRC., M. Martins' research was supported by Liga Portuguesa Contra o Cancro (LPCC): Terry Fox Fundation; Investigador FCT- Fundação para a Ciência e Technologia (IF/00409/2014) and IMM Bridge grant; RC-D research was supported by Fundação para a Ciência e Technologia (SFRH/BD/139138/2018). A. Fernandes was supported by LPCC-IMM BIOBANK; R. Fior was supported by Champalimaud Foundation and L. Costa was supported by Merck Serono.

BackgroundCyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have changed the paradigm of Estrogen-receptor positive (ER+) / human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC) treatment and represent a new standard of care in metastatic setting. Neutropenia is a well-established adverse event associated with CDK4/6i treatment, but the impact of these agents in BC patients’ immune profile is unknown. This study aimed to characterize changes in host circulating immune cell subsets in BC patients undergoing CDK4/6i therapy and investigate how these changes associate with clinical benefit, by assessing progression-free survival (PFS). MethodsA prospective cohort of metastatic ER+/HER2- BC patients treated with CDK4/6i (palbociclib or ribociclib) was included. Baseline and every 12−14-week peripheral blood samples were collected and objective tumor status evaluated by RECIST criteria at the same time points. Cohort was categorized in CDK4/6i therapy non-responders (CDK4/6i NResp, progression < 6.0 months) and responders (CDK4/6i Resp, PFS ≥6.0 months) using primary resistance to endocrine therapy definition of metastatic BC. A total of 66 different immune populations were assessed by flow cytometry, mainly: B cells, natural killer T (NKT), natural killer (NK), effector (Eff; CD4+, CD8+ and γδ T), effector memory (EM; CD4+, CD8+ and γδ T), central memory (CM; CD4+, CD8+ and γδ T) and naive (CD4+, CD8+ and γδ T), and regulatory T (Treg subtypes I, II and III) cells. Statistical analysis of longitudinal data was performed using Linear Mixed Effects models (LME) and Generalized estimation equations models (GEE) in R (version 3.6.1) and RStudio (version 1.2.5019). Models allowed to estimate and compare variation rates of each cell population in time. ResultsA total of 26 patients were included, with a median age of 58 years (min-max, 27−79). All patients received letrozole or fulvestrant, together with LHRH agonist if premenopausal. Fifteen patients received palbociclib and 11 ribociclib, with 17 (65.4%) and 9 (34.6%) patients treated in 1st and 2nd line, respectively.With a median follow-up of 17.18 months (CI 95% 12.84 - 21.52), 6 (23.1%) patients were CDK4/6i NResp, with a median PFS (mPFS) of 3.61 months (IQR 2.28 - 4.42); only two patients in 1st line setting had PFS Citation Format: Soraia Lobo-Martins, Patrícia Corredeira, Patrícia Borges Alves, Marília Antunes, Ângela Rodrigues, António Quintela, André Mansinho, Pedro Filipe, Leonor Ribeiro, Rita Teixeira de Sousa, Conceição Pinto, Catarina Abreu, Gisela Gordino, Julie Ribot, Karine Serre, Marta Martins, Ana Cavaco, Sandra Casimiro, Bruno Silva-Santos, Luís Costa. Immune cell populations in peripheral blood of metastatic breast cancer patients under CDK4/6 inhibitors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-37.

© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/., Colorectal cancer (CRC) is one of the most lethal malignancies. The extreme heterogeneity in survival rate is driving the need for new prognostic biomarkers. Human endogenous retroviruses (hERVs) have been suggested to influence tumor progression, oncogenesis and elicit an immune response. We examined multiple next-generation sequencing (NGS)-derived biomarkers in 114 CRC patients with paired whole-exome and whole-transcriptome sequencing (WES and WTS, respectively). First, we demonstrate that the median expression of hERVs can serve as a potential biomarker for prognosis, relapse, and resistance to chemotherapy in stage II and III CRC. We show that hERV expression and CD8+ tumor-infiltrating T-lymphocytes (TILs) synergistically stratify overall and relapse-free survival (OS and RFS): the median OS of the CD8-/hERV+ subgroup was 29.8 months compared with 37.5 months for other subgroups (HR = 4.4, log-rank P < 0.001). Combing NGS-based biomarkers (hERV/CD8 status) with clinicopathological factors provided a better prediction of patient survival compared to clinicopathological factors alone. Moreover, we explored the association between genomic and transcriptomic features of tumors with high hERV expression and establish this subtype as distinct from previously described consensus molecular subtypes of CRC. Overall, our results underscore a previously unknown role for hERVs in leading to a more aggressive subtype of CRC., The biobanking of CRC from Hospital Santa Maria, Lisbon, Portugal, was supported by a grant from the Official Portuguese Funding Agency for Science and Technology (FCT: PIC/IC/82821/2007).

Colorectal cancer (CRC) is one of the most frequent and lethal cancer types worldwide. While surgery with chemotherapy and radiotherapy remains the only curative approach for localized CRC, for metastatic disease the therapeutic landscape has significantly evolved over the last years. Development and approval of novel targeted therapies, such as monoclonal antibodies against EGFR and VEGF, have significantly increased the median survival of patients with metastatic disease, with some trials reporting a benefit over 40 months. Increasing accessibility of high throughput sequencing has unraveled several new therapeutic targets. Actionable alterations, such as HER2 overexpression, BRAF mutations, and NTRK fusions, are currently available in metastatic disease, providing significant therapeutic opportunities for these patients, while new emerging agents, as immune checkpoint inhibitors, promise better treatment options in the near future. In this chapter, an overview of established and future CRC targeted therapies in the clinical setting is provided, as well as their mechanism of action, limitations, and future applicability.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)., The fibroblast growth factor (FGF) signaling pathway plays a key role in tumorigenesis and is recognized as a potential therapeutic target. In this study, the authors aimed to assess the impact of serum FGF23 levels in the prognosis of patients with cancer and bone metastases from solid tumors. A cohort of 112 patients with cancer and metastatic bone disease were treated with bone-targeted agents (BTA). Serum baseline FGF23 was quantified by ELISA and dichotomized in FGF23high and FGF23low groups. Additionally, the association between FGF23 and overall survival (OS) and time to skeletal-related events (TTSRE) was investigated. Baseline characteristics were balanced between groups, except for the median urinary N-terminal telopeptide (uNTX) level. After a median follow-up of 26.0 months, a median OS of 34.4 and 12.2 months was found in the FGF23low and FGF23high groups, respectively (multivariate HR 0.18, 95% CI 0.07⁻0.44, p = 0.001; univariate HR 0.27, p = 0.001). Additionally, TTSRE was significantly longer for patients with FGF23low (13.0 vs 2.0 months, p = 0.04). Overall, this study found that patients with FGF23low at baseline had longer OS and TTSRE. Further studies are warranted to define its role as a prognostic biomarker and in the use of drugs targeting the FGF axis., This research received funding from an anonymous non-pharma related individual in the form of donation. This study was supported by project UID/BIM/50005/2019 of Fundação para a Ciência e a Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through State Budget funding.

Background: Receptor activator of NF-kB (RANK) pathway regulates bone remodeling and is involved in breast cancer (BC) progression. RANK over-expression in primary BC associates with poor prognosis and metastasis development. In patients with BC, RANK and RANK-ligand (RANKL) single nucleotide polymorphisms (SNPs) have also been associated with BC risk and bone metastasis (BM)-free survival , respectively. Here we analyze the association of five RANK missense SNPs with prognosis of patients with BM from BC. Methods: Missense RANK SNPs (rs34945627, rs12721431, rs35184120, rs35993683, rs61751992) were genotyped in germline DNA from a retrospective cohort of 76 patients with BM from BC, under bisphosphonates; and a cohort of 80 healthy volunteers (samples from Biobanco-IMM, Lisbon, Portugal). Genotypic allelic frequencies were assessed using TaqMan assays (Applied Biosystems). SNP rs34945627 was analyzed with regard to clinicopathological characteristics, skeletal-related events (SRE), bone progression-free interval (BPFi), and overall survival (OS). Univariate association with clinicopathological characteristics was performed using Fisher's exact test and Wilcoxon rank-sum test; univariate differences between survival rates were tested for significance using the log-rank test, while multivariate analysis for survival was tested using Cox proportional hazards models. Results: SNP rs34945627 had a minor allele frequency of 11.84% (n=9) in BC patients versus 1.25% (n=1) in healthy individuals, whereas the remaining SNPs had a minor allele frequency of 2.60% (n=2) in BC patients. Therefore, for inferential analysis only SNP rs34945627 was considered. No differences between alleles were observed regarding clinicopathological characteristics, including treatment. Homozygous patients (CC) had increased OS when compared to heterozygous patients (CT) controlling for age at diagnosis, visceral involvement, radiographic pattern of BM and baseline urine NTX (adjusted HR 5.76, 95% CI 2.10-15.81; p Conclusions: RANK SNP rs34945627 seems to be a marker of poor prognosis in patients with BC and BM. Further studies are required to characterize the biological and clinical significance of this finding. Citation Format: Casimiro S, Ferreira A, Alho I, Melo M, Brás R, Costa AL, Sousa AR, Mansinho A, Abreu C, Pulido C, Macedo D, Pacheco TR, Costa L. The prognostic role of RANK single nucleotide polymorphisms in breast cancer patients with bone metastases. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-09-06.

YB-1 (Y-box binding protein 1) is a multifunctional cold-shock protein that has been implicated in all hallmarks of cancer. Elevated YB-1 protein level was associated with poor prognosis in several types of cancers, including breast cancer (BC), where it is a marker of decreased overall survival (OS) and distant metastasis-free survival across all subtypes. YB-1 is also secreted by different cell types and may act as an extracellular mitogen; however the pathological implications of the secreted form of YB-1 (sYB-1) are unknown. Our purpose was to retrospectively evaluate the association between YB-1 measured by ELISA in serum and disease characteristics and outcomes in patients with BC and bone metastases (BM). In our cohort, sYB-1 was detected in the serum of 22 (50%) patients, and was associated with the presence of extra-bone metastases (p=0.044). Positive sYB-1 was also associated with faster bone disease progression (HR 3.1, 95% CI 1.09-8.95, P=0.033), but no significant differences were observed concerning OS, and time to development of skeletal-related events. Moreover, patients with positive sYB-1 also had higher levels of IL-6, a known osteoclastogenic inducer. Therefore, detection of sYB-1 in patients with BC and BM may indicate a higher tumor burden, in bone and extra-bone locations, and is a biomarker of faster bone disease progression.

577 Background: The activation of the mammalian target of rapamycin (mTOR) pathway is associated with resistance to endocrine therapy in breast cancer. Our aim was to evaluate changes in activation...

// Arlindo Ferreira 1, 2, * , Irina Alho 1, * , Ines Vendrell 2 , Marta Melo 1 , Raquel Bras 1 , Ana Lucia Costa 2 , Ana Rita Sousa 2 , Andre Mansinho 2 , Catarina Abreu 2 , Catarina Pulido 2 , Daniela Macedo 2 , Teresa Pacheco 1, 2 , Lurdes Correia 3 , Luis Costa 1, 2 , Sandra Casimiro 1 1 Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal 2 Oncology Division, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal 3 Pathology Division, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal * These authors contributed equally to this work Correspondence to: Sandra Casimiro, email: scasimiro@medicina.ulisboa.pt Luis Costa, email: luiscosta.oncology@gmail.com Keywords: breast cancer, bone metastases, RANK/RANKL pathway, single nucleotide polymorphism, prognostic factor Received: March 02, 2016 Accepted: March 31, 2016 Published: May 13, 2016 ABSTRACT Receptor activator of NF-kB (RANK) pathway regulates bone remodeling and is involved in breast cancer (BC) progression. Genetic polymorphisms affecting RANK-ligand (RANKL) and osteoprotegerin (OPG) have been previously associated with BC risk and bone metastasis (BM)-free survival, respectively. In this study we conducted a retrospective analysis of the association of five missense RANK SNPs with clinical characteristics and outcomes in BC patients with BM. SNP rs34945627 had an allelic frequency of 12.5% in BC patients, compared to 1.2% in the control group ( P = 0.005). SNP rs34945627 was not associated with any clinicopathological characteristics, but patients presenting SNP rs34945627 had decreased disease-free survival (DFS) (log-rank P = 0.039, adjusted HR 2.29, 95% CI 1.04–5.08, P = 0.041), and overall survival (OS) (log-rank P = 0.019, adjusted HR 4.32, 95% CI 1.55–12.04, P = 0.005). No differences were observed regarding bone disease-free survival (log-rank P = 0.190, adjusted HR 1.68, 95% CI 0.78–3.66, P = 0.187), time to first skeletal-related event (log-rank P = 0.753, adjusted HR 1.28, 95% CI 1.42–3.84; P = 0.665), or time to bone progression (log-rank P = 0.618, adjusted HR 0.511, 95% CI 0.17–1.51; P = 0.233). Our analysis shows that RANK SNP rs34945627 has a high allelic frequency in patients with BC and BM, and is associated with decreased DFS and OS.