A comprehensive study on surveillance outcomes of a male population followed at a hereditary breast cancer high-risk consultation at a Portuguese tertiary hospital.

INTRODUCTION: Men born with pathogenic/likely pathogenic variants in genes associated with the Hereditary Breast and Ovarian Cancer Syndrome have a higher risk to develop breast cancer and other cancers (such as prostate cancer) and should undergo adequate surveillance protocols in highly specialized Centers. METHODS: A retrospective study was conducted to assess these genetic variants' epidemiological and phenotypical manifestations in male carriers, as well as the efficacy of the surveillance protocol and compliance toward it through a survey. During follow-up, a genetic panel for testing was implemented, the starting age for surveillance was delayed, and the six-month screening interval was extended to annual. RESULTS: A total of 104 men from a tertiary hospital's High-Risk Consultation were included, 102 with positive genetic testing for BRCA1 (n = 31), BRCA2 (n = 55), both BRCA2 and another gene (n = 5), CDH1 (n = 2), CHEK2 (n = 4), NF1 (n = 1), RAD51C (n = 4), and an additional two men with no actionable genetic variant identified. The follow-up period ranged from 1 to 13 years, and only one man developed cancer. Survey responses from 48 men in active surveillance showed that more than half recognizes their carrier status and consequent surveillance impact on their life, including the risk of transmission to offspring, fear of future cancer, meaningful distress, and feeling of injustice. Biannual surveillance was not actively detecting more cancer disease cases, confirming the adequacy of the currently implemented protocol CONCLUSION: With support of Genetics to fulfill the current gaps in high-risk management, the proposed redefinition of surveillance protocol would adapt it to the population needs and concerns.

Differences among a Portuguese cohort of BRCA pathogenic/likely pathogenic variants carriers choosing risk-reducing mastectomy or intensive breast surveillance.

PURPOSE: Women with BRCA1 and BRCA2 (BRCA1/2) pathogenic/likely pathogenic (P/LP) variants have a higher risk to develop breast and ovarian cancer. In structured high-risk clinics, risk-reducing measures are adopted. This study aimed at characterizing these women and identify factors that may have influenced their choice between risk reduction mastectomy (RRM) and intensive breast surveillance (IBS). METHODS: This study reviewed retrospectively 187 clinical records of affected and unaffected women with P/LP variants of the BRCA1/2 genes, from 2007 to 2022, of which 50 chose RRM, while 137 chose IBS. The research focused on personal and family history and tumor characteristics and their relation with the preventive option chosen. RESULTS: Among women with personal history of breast cancer, a higher proportion opted for RRM compared to those asymptomatic (34.2% vs 21.3%, p = 0.049), with younger age determining the option for RRM (38.5 years vs 44.0 years, p < 0.001). Among women with personal history of ovarian cancer, a higher proportion opted for RRM compared to those without that history (62.5% vs 25.1%, p = 0.033), with younger age determining the option for RRM (42.6 years vs 62.7 years, p = 0.009). Women who had bilateral salpingo-oophorectomy were more likely to choose RRM than those who did not (37.3% vs 18.3%, p = 0.003). Family history was not associated with preventive option (33.3% vs 25.3, p = 0.346). CONCLUSIONS: The decision for the preventive option is multifactorial. In our study, personal history of breast or ovarian cancer, younger age at diagnosis, and previous bilateral salpingo-oophorectomy were associated with the choice of RRM. Family history was not associated with the preventive option.

Clinical Outcome of Patients Submitted to Liver Resection in the Context of Metastatic Breast Cancer: A Study of a Tertiary Hospital Center.

INTRODUCTION: Breast cancer is the most incident cancer in the world, accounting for 25% of new cancers per year in females. It is the most frequent malignancy in women, being the fifth cause of death from cancer worldwide. Approximately 5 to 10% of patients already present with metastases at diagnosis, and the liver is the site of metastases in half of these cases. Liver metastasis (LM) resection, performed after neoadjuvant systemic treatment, has been reported to increase median overall survival in this population. AIM: The aim of this analysis is to assess the outcomes of patients undergoing breast cancer liver metastasis surgical resection, including impact on survival, compared to patients where metastasectomy was not performed. METHODS: retrospective review of 55 female patients with breast cancer liver metastases, diagnosed and treated in a single tertiary university hospital from January 2011 to December 2016 was performed. RESULTS: In 32/55 patients (58.2%), multi-organ metastases were identified (the most common sites being bone, lungs, and lymph nodes). Of the remaining 23 patients, the liver was the unique metastatic site; thirteen patients had diffuse bilobar hepatic metastases. The remaining ten patients were proposed for surgical treatment; three of them had peritoneal carcinomatosis identified during surgery, and no hepatic metastasectomy was performed. As a result, only seven (12.7%) patients underwent liver metastasectomy. Overall survival was higher in patients who had LM surgery (65 months [Interquartile Range (IQR) 54-120]), in comparison to those diagnosed with diffuse bilobar hepatic metastases (17.5 months [IQR 11-41]), and with those showing concurrent liver and bone metastases (16.5 months [IQR 6-36]) (p = 0.012). In univariable analysis, the latter two groups showed worse overall survival outcomes (Hazard Ratio (HR) = 3.447, 95%CI: 1.218-9.756, p = 0.02 and HR = 3.855, 95% Confidence Interval (CI): 1.475-10.077, p = 0.006, respectively) when compared to patients with LM. CONCLUSION: In our series, patients submitted to metastasectomy had a median overall survival after diagnosis of LM three times greater than the non-operated patients with isolated LM, or concurrent LM and bone metastases (65 vs. 17.5 and 16.5 months, respectively). As is vastly known for colorectal cancer liver metastasis, resection of breast cancer liver metastasis may reduce tumor burden, and therefore may improve patient outcome.

The CDH1 c.1901C>T Variant: A Founder Variant in the Portuguese Population with Severe Impact in mRNA Splicing.

Hereditary diffuse gastric cancer (HDGC) caused by CDH1 variants predisposes to early-onset diffuse gastric (DGC) and lobular breast cancer (LBC). In Northern Portugal, the unusually high number of HDGC cases in unrelated families carrying the c.1901C>T variant (formerly known as p.A634V) suggested this as a CDH1-founder variant. We aimed to demonstrate that c.1901C>T is a bona fide truncating variant inducing cryptic splicing, to calculate the timing of a potential founder effect, and to characterize tumour spectrum and age of onset in carrying families. The impact in splicing was proven by using carriers' RNA for PCR-cloning sequencing and allelic expression imbalance analysis with SNaPshot. Carriers and noncarriers were haplotyped for 12 polymorphic markers, and the decay of haplotype sharing (DHS) method was used to estimate the time to the most common ancestor of c.1901C>T. Clinical information from 58 carriers was collected and analysed. We validated the cryptic splice site within CDH1-exon 12, which was preferred over the canonical one in 100% of sequenced clones. Cryptic splicing induced an out-of-frame 37bp deletion in exon 12, premature truncation (p.Ala634ProfsTer7), and consequently RNA mediated decay. The haplotypes carrying the c.1901C>T variant were found to share a common ancestral estimated at 490 years (95% Confidence Interval 445-10,900). Among 58 carriers (27 males (M)-31 females (F); 13-83 years), DGC occurred in 11 (18.9%; 4M-7F; average age 33 ± 12) and LBC in 6 females (19.4%; average age 50 ± 8). Herein, we demonstrated that the c.1901C>T variant is a loss-of-function splice-site variant that underlies the first CDH1-founder effect in Portugal. Knowledge on this founder effect will drive genetic testing of this specific variant in HDGC families in this geographical region and allow intrafamilial penetrance analysis and better estimation of variant-associated tumour risks, disease age of onset, and spectrum.

[Fluorescence-Guided Sentinel Lymph Node Biopsy in Breast Cancer: Detection Rate and Diagnostic Accuracy]. / Biópsia do Gânglio Sentinela Guiada por Fluorescência no Cancro da Mama: Taxa de Deteção e Performance Diagnóstica.

INTRODUCTION: Sentinel lymph node biopsy is currently the standard surgical procedure for lymph node staging in patients with early stage breast cancer. It is performed using different techniques, such as the injection of vital dyes and / or radioisotopes and, more recently, guided by fluorescence using Indocyanine green. The aim of this study is to assess the detection rate of sentinel lymph node using Indocyanine green in breast cancer patients according to factors related to the patient and the tumor. MATERIAL AND METHODS: Retrospective study of a random sample of patients with breast cancer, treated and followed at Centro Hospitalar São João, in Porto, between 2012 and 2016. RESULTS: Indocyanine green detection rate was over 90% and its diagnostic accuracy was similar to other methods described in the presence of metastatic involvement of lymph nodes. DISCUSSION: There was no statistically significant difference between the three methods in the detection rates in subgroups of older women, with normal weight and in those who underwent previous surgery in breast or axilla or neo-adjuvant chemotherapy. CONCLUSION: Indocyanine green is a potential alternative method to other sentinel lymph node screening techniques, appearing as a future option for breast cancer centers with no nuclear medicine department. However, it is essential to carry out further research in order to define the ideal patients' profile that maximizes the method's effectiveness.

Introdução: A biópsia do gânglio sentinela é atualmente o procedimento cirúrgico standard para o estadiamento ganglionar em doentes com cancro da mama em estádio precoce, sendo realizado com recurso a diferentes técnicas, como a injeção de corantes vitais e/ou de radioisótopos e, mais recentemente, guiada por fluorescência utilizando o verde de indocianina. O objetivo deste estudo é avaliar a acuidade global do verde de indocianina na identificação do gânglio sentinela em doentes com cancro da mama e de acordo com fatores relacionados com a doente e com o tumor. Material e Métodos: Estudo retrospetivo numa amostra aleatória de doentes com cancro da mama seguidas e tratadas no Centro Hospitalar São João no período entre 2012 e 2016. Resultados: Obtivemos uma taxa de deteção do gânglio sentinela no cancro da mama pelo verde de indocianina superior a 90% e uma performance diagnóstica deste método similar às outras técnicas descritas na presença de metástases ganglionares. Discussão: Não se verificaram diferenças estatisticamente significativas entre os três métodos relativamente às taxas de deteção no subgrupo de mulheres mais velhas, normoponderais, nas que tinham realizado tratamento prévio à mama ou à axila e nas que foram submetidas a quimioterapia neo-adjuvante. Conclusão: O verde de indocianina é um potencial método alternativo a outras técnicas de pesquisa do gânglio sentinela, afigurando-se como opção futura para os hospitais que não possuem serviço de Medicina Nuclear. Contudo, é essencial a realização de novos estudos no sentido de definir o perfil das doentes que maximiza a sua eficácia.

Improved malignancy prediction by B3 breast lesions subclassification.

Core-needle biopsy (CNB) of breast lesions can be classified into 5 categories according to lesion type and associated risk of malignancy. B3 category (lesion of uncertain malignant potential) constitutes a challenging problem in clinical decision, with most ending in excisional biopsy. Therefore, the aim of this study was to establish the incidence of malignancy on excision biopsy of B3 lesions and assess if subclassification (in B3a and B3b categories) according to the presence of atypia in otherwise B3 lesions better predicts malignancy on excision. Forty-eight cases with diagnosis of B3 lesion on CNB and matched surgical excision specimen were included to evaluate the positive predictive value (PPV) and odds for malignancy in CNB. All cases were further subclassified into B3a and B3b categories. B3 category lesions had an overall PPV for malignancy of 12.5% and significant low odds of malignancy of 0.14. When subclassified, B3b (lesions with atypia) demonstrated a higher PPV for malignancy (36.36%) with a nonsignificant odds. Inversely, B3a (lesions without atypia) demonstrated a PPV for malignancy of only 5.41% and a significant low odds of malignancy of only 0.06. The described low rate of malignancy in some of B3 lesions additionally reinforces the practice of avoiding surgical excision in selected patients and provides data that additionally support B3 lesion subclassification according to the presence of atypia. Subclassification of B3 category can further refine the current classification of associated risk of malignancy with possible implications in clinical management.

Is face-only photographic view enough for the aesthetic evaluation of breast cancer conservative treatment?

The breast cancer conservative treatment. cosmetic results (BCCT.core) is a new software tool created for the automatic and objective evaluation of the aesthetic result of BCCT. It makes use of a face-only photographic view of each patient and might thus have been considered insufficient for an accurate evaluation, as others have used multiple views of each patient. The purpose of this work is to compare the performance of the BCCT.core (using face-only views) with a subjective expert analysis using both the face-only and four-view assessment. Photographs in four-views of 150 patients, were evaluated by a panel of experts and a consensus classification was obtained. The agreement between the consensus and the BCCT.core (face-only view) was calculated using the kappa (k) and weighted kappa (wk) statistics. Face-only views, of the same 150 patients, were subsequently sorted out in a different order and sent for individual evaluation by three specialists from the previous panel of experts. The individual agreement between the face-only view and the four-view evaluation by each of the three experts and the consensus was calculated using the same methods. Obtained results were compared to the BCCT.core performance. The software obtained a moderate agreement with the consensus (k = 0.57; wk = 0.68). The highest value of agreement, from the three experts, between the four-view evaluation and the consensus was identical to the software agreement (k = 0.55; wk = 0.67). In the face-only view experiment, the highest value of agreement between the experts and the consensus was only fair (k = 0.37; wk = 0.54). Performance of the software was thus considered equal to that obtained by experts using a four-view evaluation.

Turning subjective into objective: the BCCT.core software for evaluation of cosmetic results in breast cancer conservative treatment.

Twelve expert observers from nine different countries convened in a workshop to evaluate the validity of the Breast Cancer Conservative Treatment. Cosmetic results (BCCT.core) software, an objective method for the aesthetic evaluation of breast cancer conservative treatment. Experts were initially asked to subjectively classify the aesthetic results of 30 photographed cases submitted to breast cancer conservative treatment according to the four-point Harris scale. It was pre-established that if at least two-thirds [Cardoso MJ, Cardoso J, Santos AC, Barros H, Oliveira MC. Interobserver agreement and consensus over the esthetic evaluation of conservative treatment for breast cancer. Breast 2005] of participants provided the same classification this would be considered a consensual evaluation for that case. For cases where such agreement was not reached, consensus was obtained using a nominal group technique. Experts then individually performed objective evaluation of the same set of photographs using the BCCT.core software. This provides an automatic rating of aesthetic results, once scale and reference points in the photograph have been chosen. Agreement between observers, between each observer and the consensus, for computer evaluation obtained by the different participants and between software and consensus was calculated using multiple kappa (k) and weighted kappa (wk) statistics. In the subjective assessment, first-round consensus was achieved in 17 (57%) cases. Overall interobserver agreement was fair to moderate (k=0.40, wk=0.57). In the objective assessment there was a higher level of concordance between participants (k=0.86, wk=0.90). Agreement between software and consensus classification was fair (k=0.34, wk=0.53), but was higher in the 17 cases that reached first-round consensus (k=0.60, wk=0.73). Merging the two middle classes of the Harris scale, to form a three-point scale, led to an improvement of all non-weighted measures of agreement. These results show that the BCCT.core software provides consistent evaluation of cosmesis. It has the potential to become a gold standard method for assessment of breast cosmesis in clinical trials, as it can be used simultaneously by a panel of observers from different parts of the world to provide more reliable assessments than has been possible previously.