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- Using Portuguese BRCA pathogenic variation as a model to study the impact of human admixture on human healthPublication . Andaluz, S; Zhao, B; Sinha, S; Lagniton, PN; Alpium Costa, D; Ding, X; Brito, M; Wang, SMBackground: Admixture occurs between different ethnic human populations. The global colonization in recent centuries by Europeans led to the most significant admixture in human history. While admixture may enhance genetic diversity for better fitness, it may also impact on human health by transmitting genetic variants for disease susceptibility in the admixture population. The admixture by Portuguese global exploration initiated in the 15th century has reached over 20 million of Portuguese-heritage population worldwide. It provides a valuable model to study the impact of admixture on human health. BRCA1 and BRCA2 (BRCA) are two of the important tumor suppressor genes. The pathogenic variation (PV) in BRCA is well determined to cause high risk of hereditary breast and ovarian cancer. Tracing the distribution of Portuguese BRCA PV in Portuguese-heritage population will help to understand the impact of admixture on cancer susceptibility in modern humans. In this study, we analyzed the distribution of the Portuguese-originated BRCA variation in Brazilian population, which has high degree Portuguese-heritage. Methods: By comprehensive data mining, standardization and annotation, we generated a Portuguese-derived BRCA variation dataset and a Brazilian-derived BRCA variation dataset. We compared the two BRCA variation datasets to identify the BRCA variants shared between the two populations. Results: The Portuguese-derived BRCA variation dataset consists of 220 BRCA variants including 78 PVs from 11,482 Portuguese cancer patients, 93 (42.2%) in BRCA1 and 127 (57.7%) in BRCA2. Of the 556 Portuguese BRCA PV carriers carrying the 78 PVs, 331 (59.5%) carried the three Portuguese-BRCA founder PVs of BRCA1 c.2037delinsCC, BRCA1 c.3331_3334del and BRCA2 c.156_157insAlu. The Brazilian-derived BRCA variation dataset consists of 255 BRCA PVs from 7,711 cancer patients, 136 (53.3%) in BRCA1 and 119 (46.6%) in BRCA2. We developed an open database named dbBRCA-Portuguese ( https://genemutation.fhs.um.edu.mo/dbbrca-portuguese/ ) and an open database named dbBRCA-Brazilian ( https://genemutation.fhs.um.edu.mo/dbbrca-brazilian ) to host the BRCA variation data from Portuguese and Brazilian populations. We compared the BRCA PV datasets between Portuguese and Brazilian populations, and identified 29 Portuguese-specific BRCA PVs shared between Portuguese and Brazilian populations, 14 in BRCA1 including the Portuguese founder BRCA1 c.3331_3334del and BRCA1 c.2037delinsCC, and 15 in BRCA2 including the Portuguese founder BRCA2 c.156_157insAlu. Searching the 78 Portuguese BRCA PVs in over 5,000 ancient human genomes identified evolution origin for only 8 PVs in Europeans dated between 37,470 and 3,818 years before present, confirming the Portuguese-specificity of Portuguese BRCA PVs; comparing the 78 Portuguese BRCA PVs Portuguese, 255 Brazilian BRCA PVs, and 134 African BRCA PVs showed little overlapping, ruling out the possibility that the BRCA PVs shared between Portuguese and Brazilian may also be contributed by African. Conclusion: Our study provides evidence that the admixture in recent human history contributed to cancer susceptibility in modern humans.
- Trastuzumab deruxtecan in human epidermal growth factor receptor 2-positive breast cancer brain metastases: a systematic review and meta-analysisPublication . Michelon, I; Vilbert, M; Marinho, AD; Castro, CER; Dacoregio, MI; Stecca, C; Soares, LR; Batista, MV; Braga, S; Saeed, A; Cavalcante, LBackground: Trastuzumab deruxtecan (T-DXd) has shown promising results in patients with breast cancer brain metastases (BCBMs). We conducted a systematic review and meta-analysis to evaluate the effectiveness and safety of T-DXd in the human epidermal growth factor receptor 2 (HER2)-positive BCBM population. Patients and methods: We searched PubMed, Embase, and Cochrane Library databases as well as American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and San Antonio Breast Cancer Symposium (SABCS) websites for clinical trials (CTs) and observational studies evaluating T-DXd in patients with HER2-positive BCBM. Heterogeneity was assessed with I2 statistics. Random effects models were used for all statistical analyses, which were carried out using R software (version 4.2.2). Results: Ten studies were included, six CTs (n = 189) and four observational studies (n = 130), with a total of 319 patients. The median progression-free survival was 15 months [95% confidence interval (CI) 13.9-16.1 months]. The objective response rate (ORR) was 61% (95% CI 52% to 70%), and the intracranial (IC)-ORR was 61% (95% CI 54% to 69%). No significant differences in ORR and IC-ORR were observed between CTs and observational studies (P = 0.31 and 0.58, respectively). The clinical benefit rate (CBR) was 80% (95% CI 52% to 94%), and the IC-CBR was 70% (95% CI 54% to 82%). The ORR was 68% (95% CI 57% to 77%) in the subgroup of patients with stable BMs and 60% (95% CI 48%-72%) in patients with active BM, with no significant difference between groups (P = 0.35). Conclusions: Our systematic review and meta-analysis supports the IC activity of T-DXd in patients with stable BM and active BM. Trial registration: International Prospective Register of Systematic Reviews (PROSPERO) under the protocol number CRD42023422589.
- Improving the identification of high-risk non-metastatic castration-resistant prostate cancer patients in clinical practicePublication . Rosinha, A; Rabaça, C; Calais, F; Pinto, JM; Barreira, JV; Fernandes, R; Ramos, R; Fialho, AC; Palma dos Reis, JNon-metastatic castration-resistant prostate cancer (nmCRPC) represents a challenging disease state in prostate cancer care. nmCRPC patients with a high risk of progression to metastatic disease who are identified by a prostate-specific antigen doubling time (PSADT) ≤10 months are eligible for treatment with the novel androgen receptor inhibitors (ARIs), shown to delay disease progression and extend survival. However, nmCRPC is often unexploited in clinical practice due to a lack of standardization in the methodology and in the tools used for its identification. In this article, a group of Urology and Oncology specialists with acknowledged expertise in prostate cancer reviews the state of the art in the management of high-risk nmCRPC patients, identifies gaps and unmet needs, and proposes strategies to optimize the identification of this patient subgroup in the clinical practice and improve their health outcomes.
- Personalized medicine: paradigm shift in ALK positive non-small cell lung cancer: a case reportPublication . Barreira, JV; Mendes, JL; Parmanande, ABackground: Since the identification of multiple therapeutic targets, as is the case of anaplastic lymphoma kinase (ALK) translocation, the paradigm of treating patients with non-small cell lung cancer (NSCLC) has improved. In order to guarantee the possibility of longer survival outcomes with a better quality of life we must invest in the determination, in suitable time, of the consensual biomarkers and in the availability of the best treatments to our patients. Case presentation: We present a case of a caucasian male in his fifth decade of life, non-smoker, who highlights the complex journey of ALK-positive patients. This particular case, demonstrates the efficacy and tolerability of the new ALK target therapies, allowing our patients to maintain their routines without compromising the effectiveness of the therapy. Conclusion: Focusing on the reality of ALK positive patients and the impact that this therapy has on the daily lives of our patients, we can contribute to the awareness of this specific pathology.
- Influence of HER2 expression on prognosis in metastatic triple-negative breast cancer—results from an international, multicenter analysis coordinated by the AGMT Study GroupPublication . Gampenrieder, SP; Dezentjé, V; Lambertini, M; de Nonneville, A; Marhold, M; Le Du, F; Cortés Salgado, A; Alpuim Costa, D; Vaz Batista, M; Chic Ruché, N; Tinchon, C; Petzer, A; Blondeaux, E; Del Mastro, L; Targato, G; Bertucci, F; Gonçalves, A; Viret, F; Bartsch, R; Mannsbart, C; Deleuze, A; Robert, L; Saavedra Serrano, C; Gion Cortés, M; Sampaio-Alves, M; Vitorino, M; Pecen, L; Singer, C; Harbeck, N; Rinnerthaler, G; Greil, RBackground: Triple-negative breast cancer (TNBC) is associated with poor prognosis, and new treatment options are urgently needed. About 34%-39% of primary TNBCs show a low expression of human epidermal growth factor receptor 2 (HER2-low), which is a target for new anti-HER2 drugs. However, little is known about the frequency and the prognostic value of HER2-low in metastatic TNBC. Patients and methods: We retrospectively included patients with TNBC from five European countries for this international, multicenter analysis. Triple-negativity had to be shown in a metastatic site or in the primary breast tumor diagnosed simultaneously or within 3 years before metastatic disease. HER2-low was defined as immunohistochemically (IHC) 1+ or 2+ without ERBB2 gene amplification. Survival probabilities were calculated by the Kaplan-Meier method, and multivariable hazard ratios (HRs) were estimated by Cox regression models. Results: In total, 691 patients, diagnosed between January 2006 and February 2021, were assessable. The incidence of HER2-low was 32.0% [95% confidence interval (CI) 28.5% to 35.5%], with similar proportions in metastases (n = 265; 29.8%) and primary tumors (n = 425; 33.4%; P = 0.324). The median overall survival (OS) in HER2-low and HER2-0 TNBC was 18.6 and 16.1 months, respectively (HR 1.00; 95% CI 0.83-1.19; P = 0.969). Similarly, in multivariable analysis, HER2-low had no significant impact on OS (HR 0.95; 95% CI 0.79-1.13; P = 0.545). No difference in prognosis was observed between HER2 IHC 0/1+ and IHC 2+ tumors (HR 0.89; 95% CI 0.69-1.17; P = 0.414). Conclusions: In this large international dataset of metastatic TNBC, the frequency of HER2-low was 32.0%. Neither in univariable nor in multivariable analysis HER2-low showed any influence on OS.
- Mutation Patterns in Portuguese Families with Hereditary Breast and Ovarian Cancer SyndromePublication . Vicente, R; Alpuim Costa, D; Vitorino, M; Mendes, AD; Santos, C; Fontes-Sousa, MGermline pathogenic variants in the Breast Cancer Genes 1 (BRCA1) and 2 (BRCA2) are responsible for Hereditary Breast and Ovarian Cancer (HBOC) syndrome. Genetic susceptibility to breast cancer accounts for 5-10% of all cases, phenotypically presenting with characteristics such as an autosomal dominant inheritance pattern, earlier age of onset, bilateral tumours, male breast cancer, and ovarian tumours, among others. BRCA2 pathogenic variant is usually associated with other cancers such as melanoma, prostate, and pancreatic cancers. Many rearrangements of different mutations were found in both genes, with some ethnic groups having higher frequencies of specific mutations due to founder effects. Despite the heterogeneity of germline BRCA1/BRCA2 mutations in Portuguese breast or/and ovarian cancer families, the first described founder mutation in the BRCA2 gene (c.156_157insAlu) and two other variants in the BRCA1 gene (c.3331_3334del and c.2037delinsCC) contribute to about 50% of all pathogenic mutations. Furthermore, the families with the BRCA1 c.3331_3334del or the c.2037delinsCC mutations share a common haplotype, suggesting that these may also be founder mutations in the Portuguese population. Identifying specific and recurrent/founder mutations plays an important role in increasing the efficiency of genetic testing since it allows the use of more specific, cheaper and faster strategies to screen HBOC families. Therefore, this review aims to describe the mutational rearrangements of founder mutations and evaluate their impact on the genetic testing criteria for HBOC families of Portuguese ancestry.
- Impact of brain biopsy on management of nonneoplastic brain diseasePublication . Santos, M; Roque, R; Rainha Campos, A; Albuquerque, L; Pimentel, JIntroduction: Diagnostic yield of brain biopsy in neoplastic brain disease is high and its clinical impact is well established. In nonneoplastic brain disease with negative conventional investigation, decision to undergo invasive procedures is difficult due to its inherent risk and known lower diagnostic yield. Research question: What is the clinical impact of brain biopsy results on management of nonneoplastic brain disease ? Material and methods: A multidisciplinary team retrospectively reviewed and included all nonneoplastic brain disease cases submitted to biopsy between 2009 and 2019, in a tertiary hospital in Lisbon. Baseline characteristics were registered, including immunosuppression status, diagnostic workup, and treatment prior to biopsy. Diagnostic yield, clinical impact and in-hospital complication rates were assessed. Results: Sixty-four patients were included, 20 (31.3%) of them immunosuppressed (15 HIV + patients). Thirty-five (67.7%) were previously treated with steroids or antiinfectious agents, with higher percentage (93.3%) in the immunosuppressed group. Biopsy results were diagnostic in 46 (71.9%) cases. More frequent diagnosis was infectious in 20 (31.2%), neoplastic in 12 (18.8%) and inflammatory diseases in 8 (12.5%). Brain biopsy resulted on impact on patient's clinical management in 56 (87.5%), of which 37(57.8%) were submitted to treatment change. In-hospital complications were registered in 4 (6.6%) patients. Discussion and conclusion: Brain biopsy had clinical impact, including a change in treatment, in most patients studied, and may be considered a useful diagnostic option in nonneoplastic brain disease. However, associated complication rate is not negligible, and previous thorough workup, patient selection and risk-benefit assessment are important.
- Local Breast Microbiota: A “New” Player on the BlockPublication . Vitorino, M; Alpuim Costa, D; Vicente, R; Caleça, T; Santos, CThe tumour microenvironment (TME) comprises a complex ecosystem of different cell types, including immune cells, cells of the vasculature and lymphatic system, cancer-associated fibroblasts, pericytes, and adipocytes. Cancer proliferation, invasion, metastasis, drug resistance and immune escape are all influenced by the dynamic interaction between cancer cells and TME. Microbes, such as bacteria, fungi, viruses, archaea and protists, found within tumour tissues, constitute the intratumour microbiota, which is tumour type-specific and distinct among patients with different clinical outcomes. Growing evidence reveals a significant relevance of local microbiota in the colon, liver, breast, lung, oral cavity and pancreas carcinogenesis. Moreover, there is a growing interest in the tumour immune microenvironment (TIME) pointed out in several cross-sectional studies on the correlation between microbiota and TME. It is now known that microorganisms have the capacity to change the density and function of anticancer and suppressive immune cells, enabling the promotion of an inflammatory environment. As immunotherapy (such as immune checkpoint inhibitors) is becoming a promising therapy using TIME as a therapeutic target, the analysis and comprehension of local microbiota and its modulating strategies can help improve cancer treatments.
- Hyperbaric oxygen therapy as a complementary treatment for radiation proctitis: Useless or useful? – A literature reviewPublication . Alpuim Costa, D; Amaro, CE; Nunes, A; Cardoso, JS; Daniel, PM; Rosa, I; Branco, JVRadiotherapy (RT) is the backbone of multimodality treatment of more than half of cancer cases. Despite new modern RT techniques, late complications may occur such as radiation proctitis (RP). The natural history of RP is unpredictable. Minor symptoms may resolve spontaneously or require conservative treatment. On the other hand, for similar and uncomplicated clinical contexts, symptoms may persist and can even be refractory to the progressive increase in treatment measures. Over the last decades, an enormous therapeutic armamentarium has been considered in RP, including hyperbaric oxygen therapy (HBOT). Currently, the evidence regarding the impact of HBOT on RP and its benefits is conflicting. Additional prospective and randomised studies are necessary to validate HBOT's effectiveness in the 'real world' clinical practice. This article reviewed the relevant literature on pathophysiology, clinical presentation, different classifications and discuss RP management including a proposal for a therapeutic algorithm with a focus on HBOT.
- Next-Generation Sequencing in Breast Cancer Management: A Case Report of Genomic Tumour Evolution over TimePublication . Batista, MV; Alpuim Costa, D; Borralho, P; Braga, SThe clinicopathological breast cancer subtypes are used in clinical practice to better anticipate biological behaviour and guide systemic treatment strategy. In the adjuvant setting, genomic assay recurrence scores became widely available for luminal-like disease. Recently, next-generation sequencing (NGS) platforms have been used, essentially, in more advanced disease setting, in situations refractory to conventional treatment, or even in rare cancers for which there are no established treatment guidelines. Moreover, subpopulations of cancer cells with unique genomes within the same patient may exist across different regions of a tumour or evolve over time, which is called intratumoural heterogeneity. We herein report a case of a 38-year-old woman with breast cancer whose primary and metastatic disease exhibited discordant expression of hormone receptors, with the former being positive and the latter negative. Furthermore, the NGS analysis revealed slight and dynamic changes of mutational profiles between different metastatic lesions, potentially impacting breast cancer management and prognosis. These alterations may reflect tissular and temporal changes in tumour subclones and may also be due to the selective pressure caused by antineoplastic treatment. The use of genomic analyses in order to improve cancer treatment has been studied prospectively with encouraging results. The widespread use of NGS tests in clinical practice also creates new challenges. The most relevant may be to know which genomic alterations detected should be valued and how they should be targeted.