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- Oncobiology and treatment of breast cancer in young womenPublication . Kumar, Rakesh; Marques, Catarina; Toi, Masakazu; Saini, Sunil; Casimiro, Sandra; Arora, Anshika; Paul, Aswathy Mary; Velaga, Ravi; Rameshwar, Pranela; Lipton, Allan; Gupta, Sudeep; Costa, LuisFemale breast cancer emerged as the leading cancer type in terms of incidence globally in 2020. Although mortality due to breast cancer has improved during the past three decades in many countries, this trend has reversed in women less than 40 years since the past decade. From the biological standpoint, there is consensus among experts regarding the clinically relevant definition of breast cancer in young women (BCYW), with an age cut-off of 40 years. The idea that breast cancer is an aging disease has apparently broken in the case of BCYW due to the young onset and an overall poor outcome of BCYW patients. In general, younger patients exhibit a worse prognosis than older pre- and postmenopausal patients due to the aggressive nature of cancer subtypes, a high percentage of cases with advanced stages at diagnosis, and a high risk of relapse and death in younger patients. Because of clinically and biologically unique features of BCYW, it is suspected to represent a distinct biologic entity. It is unclear why BCYW is more aggressive and has an inferior prognosis with factors that contribute to increased incidence. However, unique developmental features, adiposity and immune components of the mammary gland, hormonal interplay and crosstalk with growth factors, and a host of intrinsic and extrinsic risk factors and cellular regulatory interactions are considered to be the major contributing factors. In the present article, we discuss the status of BCYW oncobiology, therapeutic interventions and considerations, current limitations in fully understanding the basis and underlying cause(s) of BCYW, understudied areas of BCYW research, and postulated advances in the coming years for the field.
- Predictive and therapeutic implications of a novel PLCγ1/SHP2-driven mechanism of cetuximab resistance in metastatic colorectal cancerPublication . Duarte, Raquel; Rebelo de Almeida, Cátia; Negrão, Magda; Fernandes, Afonso; Borralho, Paula; Sobral, Daniel; Gallego-Paez, Lina M.; Machado, Daniel; Gramaça, João; Vílchez, José; Xavier, Ana T.; Ferreira, Miguel Godinho; Miranda, Ana R.; Mansinho, Helder; Brito, Maria J.; Pacheco, Teresa; Marques, Catarina; Lucia Costa, Ana; Mansinho, André; Fior, Rita; Costa, Luis; Martins, MartaPurpose: 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.
- Levels of circulating Fibroblast Growth Factor 23 (FGF23) and prognosis in cancer patients with bone metastasesPublication . Mansinho, André; Ferreira, Arlindo; Casimiro, Sandra; Alho, Irina; Vendrell, Ines; Costa, Ana Lúcia; Sousa, Rita; Marques, Catarina; Pulido, Catarina; Macedo, Daniela; Pacheco, Teresa; Correia, Lurdes; Costa, LuisThe 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.
- Clinical experience of a cardio-oncology consultation at a tertiary university hospital in Portugal: an observational studyPublication . Fiuza, Manuela; Magalhaes, Andreia; Menezes, Miguel Nobre; Costa, Paula; Ribeiro, Maria Leonor; Marques, Catarina; Brás, Raquel; Vieira, Joana; Afonso, Ana I.; Morais, Pedro; Valente Silva, Beatriz; Costa, Luis; Pinto, Fausto J.Introduction: Heart disease and cancer are the two leading causes of morbidity and mortality worldwide. Advances in cancer screening and management have led to longer survival and better quality of life. Despite this progress, many cancer patients experience cardiovascular complications during and after cancer treatment. This study describes the experience of a cardio-oncology program at tertiary academic hospital. Methods: In this retrospective observational study, cancer patients referred to the CHULN cardio-oncology consultation (COC) between January 2016 and December of 2019 were included. Data collected included: patient demographics, cancer type, reason for referral, cardiovascular risk factors, cardiac and oncologic treatments and clinical outcomes. Results: A total of 520 patients (mean age: 65 ± 14 years; 65% women) were referred to the COC. The main reasons for referral were suspected heart failure (26%), pre-high risk chemotherapy assessment (20%) and decreased LVEF (15%). Pre-existing cardiovascular risk factors were common (79%) and 309 (59%) were taking cardiac medications. The most common type of malignancy was breast cancer (216, 41%) followed by gastrointestinal (139, 27%). More than half received anthracycline-based regimens (303, 58%). Most patients (401; 77%) successfully completed cancer therapy. At the time of last data collection, the majority of patients were alive (430, 83%). Cardiac-related mortality was observed in 16%. Conclusions: The close collaboration between cardiology and oncology teams and timely cardiac monitoring was the key to the majority of patients to completing their prescribed cancer therapy.
- HERVs establish a distinct molecular subtype in stage II/III colorectal cancer with poor outcomePublication . Golkaram, Mahdi; Salmans, Michael L.; Kaplan, Shannon; Vijayaraghavan, Raakhee; Martins, Marta; Khan, Nafeesa; Garbutt, Cassandra; Wise, Aaron; Yao, Joyee; Casimiro, Sandra; Marques, Catarina; Macedo, Daniela; Costa, Ana Lúcia; Alvim, Cecilia; Mansinho, André; Filipe, Pedro; Marques da Costa, Pedro; Fernandes, Afonso; Borralho, Paula; Ferreira, Cristina; Aldeia, Fernando; Malaquias, João; Godsey, Jim; So, Alex; Pawlowski, Traci; Costa, Luis; Zhang, Shile; Liu, LiColorectal 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.
- Exploring new pathways in endocrine-resistant breast cancerPublication . Soares De Pinho, Inês; Marques, Catarina; Fernandes Gomes, Inês; Casimiro, Sandra; Pacheco, Teresa; Sousa, Rita Teixeira de; Costa, LuisThe most common breast cancer (BC) subtypes are hormone-dependent, being either estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), or both, and altogether comprise the luminal subtype. The mainstay of treatment for luminal BC is endocrine therapy (ET), which includes several agents that act either directly targeting ER action or suppressing estrogen production. Over the years, ET has proven efficacy in reducing mortality and improving clinical outcomes in metastatic and nonmetastatic BC. However, the development of ET resistance promotes cancer survival and progression and hinders the use of endocrine agents. Several mechanisms implicated in endocrine resistance have now been extensively studied. Based on the current clinical and pre-clinical data, the present article briefly reviews the well-established pathways of ET resistance and continues by focusing on the three most recently uncovered pathways, which may mediate resistance to ET, namely receptor activator of nuclear factor kappa B ligand (RANKL)/receptor activator of nuclear factor kappa B (RANK), nuclear factor kappa B (NFκB), and Notch. It additionally overviews the evidence underlying the approval of combined therapies to overcome ET resistance in BC, while highlighting the relevance of future studies focusing on putative mediators of ET resistance to uncover new therapeutic options for the disease.
- Genetic and microenvironmental intra-tumor heterogeneity impacts colorectal cancer evolution and metastatic developmentPublication . Sobral, Daniel; Martins, Marta; Kaplan, Shannon; Golkaram, Mahdi; Salmans, Michael; Khan, Nafeesa; Vijayaraghavan, Raakhee; Casimiro, Sandra; Fernandes, Afonso; Borralho, Paula; Ferreira, Cristina; Pinto, Rui; Marques, Catarina; Costa, Ana Lúcia; Zhang, Shile; Pawlowski, Traci; Godsey, Jim; Mansinho, André; Macedo, Daniela; Lobo-Martins, Soraia; Filipe, Pedro; Esteves, Rui; Coutinho, Joao; Costa, Paulo M.; Ramires, Afonso; Aldeia, Fernando; Quintela, António; So, Alex; Liu, Li; Grosso, Ana Rita; Costa, LuisColorectal cancer (CRC) is a highly diverse disease, where different genomic instability pathways shape genetic clonal diversity and tumor microenvironment. Although intra-tumor heterogeneity has been characterized in primary tumors, its origin and consequences in CRC outcome is not fully understood. Therefore, we assessed intra- and inter-tumor heterogeneity of a prospective cohort of 136 CRC samples. We demonstrate that CRC diversity is forged by asynchronous forms of molecular alterations, where mutational and chromosomal instability collectively boost CRC genetic and microenvironment intra-tumor heterogeneity. We were able to depict predictor signatures of cancer-related genes that can foresee heterogeneity levels across the different tumor consensus molecular subtypes (CMS) and primary tumor location. Finally, we show that high genetic and microenvironment heterogeneity are associated with lower metastatic potential, whereas late-emerging copy number variations favor metastasis development and polyclonal seeding. This study provides an exhaustive portrait of the interplay between genetic and microenvironment intra-tumor heterogeneity across CMS subtypes, depicting molecular events with predictive value of CRC progression and metastasis development.
- Prevention of nausea and vomiting in patients undergoing oral anticancer therapies for solid tumorsPublication . Costa, Ana Lúcia; Marques, Catarina; Pacheco, Teresa; Macedo, Daniela; Sousa, Ana Rita; Pulido, Catarina; Quintela, António; Costa, LuisChemotherapy-induced nausea and vomiting (CINV) is still a common and debilitating side effect despite recent advances in its prevention and treatment. The intrinsic emetogenicity of chemotherapy agents allowed grouping into four risk groups (high, moderate, low, and minimal risk of emetogenicity). The prevention of acute and delayed CINV for intravenous agents and one day regimens is well studied, although, there are few data about management of CINV induced by oral cytotoxic agents and targeted therapies, usually administered in extended regimens of daily oral use. Until now treatment of nausea and vomiting caused by oral antineoplastic agents remains largely empirical. The level of evidence of prophylactic antiemetics recommended for these agents is low. There are differences in the classification of emetogenic potential of oral antineoplastic agents between the international guidelines and different recommendations for prophylactic antiemetic regimens. Herein we review the evidence for antiemetic regimens for the most used oral antineoplastic agents for solid tumors and propose antiemetic regimens for high to moderate risk and low to minimal risk of emetogenicity.
- Clinical and translational pharmacology of drugs for the prevention and treatment of bone metastases and cancer‐induced bone lossPublication . Dionísio, Maria Rita; Mansinho, André; Marques, Catarina; Cavaco-Silva, Joana; Casimiro, Sandra; Costa, LuisBone disease is a frequent event in cancer patients, both due to cancer spread to bone and to cancer therapies. Bone is the organ most frequently affected by metastatic disease when considering the two most frequent cancers in the Western world (breast and prostate cancers). Bone metastases can have a substantial detrimental effect on patients' quality of life, as well as significant morbidity due to complications collectively known as skeletal-related events (SREs), which include hypercalcaemia, pathological fractures, spinal cord compression, and need of radiotherapy or surgery to the bone. These have been successfully mitigated with the development of bone-targeted agents (BTAs; bisphosphonates and denosumab), focused on inhibiting osteoclast activity. The potential direct antitumour effect of bisphosphonates, as well as the impact of osteoclast inhibition with subsequent decrease in bone metabolism, have also propelled investigation on the role of BTAs in preventing cancer relapse in bone. In this review, the authors aimed to discuss the role of BTAs in the treatment and prevention of bone metastases, as well as their potential value in preventing cancer treatment-induced bone loss (CTIBL). The review will focus on breast and prostate cancers, with the aim of providing the most relevant clinical data emerging from bench to bedside translational research in the field of cancer-induced bone disease.