Marina De Brot

The germline landscape of hereditary breast cancer has been characterized predominantly in populations of European ancestry, with limited evidence from populations with different demographic histories. We investigated germline diversity and genotype–phenotype associations in a single-center ambispective cohort at a tertiary referral cancer center in Brazil. Among 10,098 individuals who underwent germline genetic testing, 503 adults with invasive or microinvasive breast cancer met the predefined eligibility criteria and carried 514 pathogenic or likely pathogenic germline variants. Analyses assessed gene distribution, recurrent and founder variants, ecological diversity metrics, and associations with clinicopathological characteristics and survival outcomes. BRCA1 (31.6%) and BRCA2 (21.7%) were the most frequently altered susceptibility genes, followed by TP53 (13.1%), including the Brazilian founder variant TP53 p.R337H (10.7%). Diversity analyses indicated substantial heterogeneity beyond BRCA1/2. In exploratory unadjusted analyses, BRCA1-associated tumors more frequently exhibited triple-negative phenotype, high histological and nuclear grade, elevated Ki-67, and increased tumor-infiltrating lymphocytes, whereas tumors associated with BRCA2, ATM, CHEK2, and mismatch repair genes more frequently exhibited luminal phenotypes. Recurrent variants included alleles previously reported in different geographic and population contexts. Exploratory survival analyses detected no statistically significant differences among genetic groups within a five-year analytical horizon. These findings describe a heterogeneous germline spectrum and exploratory genotype–phenotype associations in a Brazilian cohort. Heterogeneous genetic testing coverage and the absence of individual genomic ancestry assessment limit interpretation; the findings should not be considered ancestry-specific or nationally representative. Further studies with uniform genetic testing and genomic ancestry assessment are warranted in broader Brazilian and Latin American cohorts.

Aims: Phyllodes tumours of the breast (PTs) present complex histological features that challenge classification. The WHO 5th Edition (2019) defines malignancy based on five simultaneous criteria, which may under‐recognize tumours with metastatic potential. Alternative diagnostic systems have been proposed, but comparative data are limited. Methods and results: We reviewed 62 PTs diagnosed as borderline or malignant between 2015 and 2025. Histological features were re‐evaluated, and tumours were classified according to WHO (2019), Tan et al. (2025), and the Refined Criteria (2023). After exclusion of 4 reclassified benign cases, 58 tumours (42 borderline, 16 malignant) were analysed. The mean patient age was 45 years, and the mean tumour size was 6.7 cm. After a median follow‐up of 31.7 months, 6 borderline PTs recurred locally without metastasis. Among malignant PTs, seven developed distant metastases, with two disease‐related deaths. High stromal mitotic activity (≥30/10 HPF, P = 0.005) and malignant heterologous elements ( P < 0.001) were independently associated with metastasis. Tan et al. 's classification showed 97% concordance with WHO 2019, whereas the Refined Criteria reclassified 52% of borderline tumours as malignant; none of the reclassified tumours developed distant metastases during the available follow‐up. Conclusions: In this cohort, high stromal mitotic activity and malignant heterologous elements were the strongest predictors of recurrence in PTs. Tan et al. 's classification system demonstrated close concordance with the WHO (2019) criteria, whereas the Refined Criteria classified a substantially greater proportion of tumours as malignant without improving prognostic discrimination during the available follow‐up period. Comprehensive tumour sampling remains essential for accurate classification and reliable prognostic assessment of PTs of the breast.

Currently, breast cancer (BC) is the most common cancer among women worldwide, accounting for more than 2.3 million cases annually¹ 1. World Health Organization. WHO launches new roadmap on breast cancer [Internet]. 2024. [cited on 2023 Jul 17]. Available from: https://www.who.int/news/item/03-02-2023-who-launches-new-roadmap-on-breast-cancer https://www.who.int/news/item/03-02-2023... , and the leading cause of cancer death in women² 2. Anderson BO, Ilbawi AM, Fidarova E, Weiderpass E, Stevens L, Abdel-Wahab M, et al. The global breast cancer initiative: a strategic collaboration to strengthen health care for non-communicable diseases. Lancet Oncol. 2021;22(5):578-81. https://doi.org/10.1016/S1470-2045(21)00071-1 https://doi.org/10.1016/S1470-2045(21)00... .

Background: Triple‐negative breast cancer (TNBC) is the neoplasia most associated with BRCA1 germline pathogenic variants (PV) and is more likely to develop metastases than the other breast cancer (BC) subtypes, mainly in the lungs and the central nervous system (CNS). Recently, BRCA2 carriers were shown to have a higher risk for developing CNS metastases. However, the patterns of recurrence and metastases of BRCA2 carriers with TNBC are unknown.Methods: TNBC patient data attending the A.C. Camargo Cancer Center, from 1998 through 2020, were verified either by medical records or by BRCA1/2 genetic testing carried out. Multivariable logistic regression models were fit to the data to assess the independent factors for bone and CNS metastases. Adjustment was done using all independent variables with p < 0.2 in the univariable Cox model to describe the relationship between the independent variables until time of death.Results: A total of 388 TNBC patients were evaluated. We identified PV in BRCA1/2 genes in 21% (82/388), being 17.7% (69/388) in BRCA1 and only 3.3% (13/388) in BRCA2. A total of 120 patients (31%) developed distant metastases. Bone or CNS metastases were observed in 40% and 60% of BRCA2 PV carriers (p = 0.155), respectively. The BRCA2 carriers tended to have a higher likelihood of developing bone metastases (OR, 4.06; 95% CI, 0.82–20.01; p = 0.085), when compared to BRCA1 carriers (OR, 0.6; 95% CI, 0.12–2.87; p = 0.528). BRCA2 carriers had an OR of 1.75 (95% CI, 0.33–9.14; p = 0.503) for CNS metastasis development, while BRCA1 carriers had an OR of 0.72 (95% CI, 0.23–2.23; p = 0.574).Conclusions: Patients with TNBC and PV in the BRCA2 gene had higher frequencies of secondary bone involvement and CNS in the course of the disease. However, the BRCA2 PV did not represent an independent outcome predictor of metastases and overall survival. Efforts to increase the number of BRCA2 carriers among TNBC patients are crucial for determining their risk of developing bone and CNS metastases compared to BRCA2 noncarriers.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer (BC). Neoadjuvant chemotherapy has proven efficacy in its treatment, and a pathological complete response (pCR) to therapy is predictive of improved long-term survival. The immune response is key to successful neoadjuvant chemotherapy, as indicated by the relation between the percentage of stromal tumour-infiltrating lymphocytes (TILs) in pre-treated tumour tissue samples and the likelihood of achieving pCR. Here we studied systemic immune mediators from volunteer TNBC patients before undergoing neoadjuvant chemotherapy to determine the systemic response association with TIL intensity, treatment response and survival. Patients were classified into pCR responder or non-responder at time of surgery. We found higher levels of immune mediators before treatment began in patients that went on to be pCR responders versus non-pCR, with area under the curve (AUC) values of 0.64-0.80. We also observed a positive correlation between inflammatory systemic immune mediators and the percentage of TILs in pCR responder patients. Combining TILs and systemic immune mediator levels provided stronger AUC values (range of 0.72-0.82). Last, performing a progression-free survival analysis with several of the systemic cytokines that predict pCR, segregated the patients into long- and short-survival groups based on high and low production of the cytokines, respectively. Our study demonstrates that circulating cytokines, before treatment begins, predict pCR in TNBC patients treated with neoadjuvant chemotherapy. Moreover, they may act as a surrogate marker of high TILs or together with TILs to better predict pCR and survival.

Intraductal and intralobular proliferative lesions or epithelial hyperplasias of the breast comprise a heterogeneous spectrum of proliferations that generally originate in the terminal duct-lobular units (TDLUs) of the breast and are confined to the ductal-lobular system¹ 1 International Agency for Research on Cancer. WHO classification of tumours editorial board. Breast tumours. WHO classification of tumour series. 5th ed. Lyon: International Agency for Research on Cancer; 2019. . Such lesions are subdivided into two major categories based on cytological and architectural criteria: ductal and lobular. The magnitude of the risk of subsequent breast cancer varies widely, and part of these proliferations represent risk indicators, whereas others act as true precursors of invasive breast carcinomas (IBCs)¹ 1 International Agency for Research on Cancer. WHO classification of tumours editorial board. Breast tumours. WHO classification of tumour series. 5th ed. Lyon: International Agency for Research on Cancer; 2019. –⁵ 5 Collins LC, Baer HJ, Tamimi RM, Connolly JL, Colditz GA, Schnitt SJ. The influence of family history on breast cancer risk in women with biopsy-confirmed benign breast disease: results from the nurses’ health study. Cancer. 2006;107(6):1240-7. https://doi.org/10.1002/cncr.22136 https://doi.org/10.1002/cncr.22136... .

Aims: Paget’s disease of the nipple (PDN) is a rare type of cancer of the nipple-areola complex. We examined GATA3 protein expression in PDN to determine its potential value as an adjunct marker in the differential diagnosis with other nipple lesions.Methods and results: Chart review documented clinicopathological data. H&E slides were re-evaluated and immunohistochemistry (IHC) for GATA3 was performed. Amongst 3614 breast cancer patients, 74 had PDN and 41 cases were selected for our study (mean age, 55 years). Amid PDN cases, 4 (10%) patients showed PDN alone, 22 (65%) had an underlying ductal carcinoma in situ and 15 (37%) had invasive breast carcinomas (IBC), including 11 invasive carcinoma of no special type, 2 lobular, 1 mucinous and 1 micropapillary carcinoma. Additionally, 9 cancers were classified as luminal B, 4 as HER2 overexpression and 2 as luminal A. GATA3 expression was detected in all 41 PDN cases and in all underlying cancers. Furthermore, IHC for S-100, HMB45 and Melan-A was performed in PDN-only, ensuing negative results. Positivity for cytokeratin 7 or AE1/AE3 was demonstrated in all cases and HER2 overexpression was seen in 2/4 lesions. GATA3 expression was noted in all lesions, including one CK7-negative case.Conclusion: Our findings indicate that GATA3 is consistently expressed in PDN. Although not entirely specific, positivity for GATA3 reinforces the non-melanocytic nature of PDN and its mammary origin, thus representing a potential adjunct tool for the diagnosis of PDN in tricky situations, particularly PDN variants or unusual lesions.

Introduction: Phyllodes tumor (PT) of the breast, particularly malignant phyllodes tumor (mPT), is a rare fibroepithelial neoplasm. A complex diagnosis is based on pathologic, radiologic, and clinical findings, with controversies about what is the best therapeutic strategy. Objective: Our objective was to provide an overview of the clinical, pathologic, and therapeutic aspects of this rare tumor. Conclusions: mPT is a rare presentation of breast cancer and a challenge in clinical practice. A multidisciplinary approach should take into account some aspects like pathogenic mutations and hereditary syndromes. Oncologic surgery is the fundamental approach, and the use of adjuvant therapies is still controversial due to the lack of clinical trials. Treatment recommendations should be individualized according to patient risk and preferences. Prospective studies are fundamental to clarifying the best treatment for these tumors.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer defined by the lack of expression of estrogen receptor, progesterone receptors, and of the human epithelial growth factor receptor 2. Neoadjuvant chemotherapy has proven efficacy in the treatment of TNBC, and a pathological complete response (pCR) is predictive of improved long-term survival. The immune response exerts a vital role in response to neoadjuvant chemotherapy, as indicated by the relation between the percentage of stromal tumor-infiltrating lymphocytes (TILs) in pre-treated tumor tissue samples and the likelihood of achieving pCR. Despite this, the relationship between the systemic immune response and the tumor microenvironment is unclear. In this prospective study, we determined the systemic plasma immune profile of TNBC patients before treatment using a panel of 27 immune mediators and measured the percentage of TILs from the same patients. Patients who demonstrated pCR had significantly higher systemic immune mediators; GM-CSF, FGF-basic, VEGF, IL-2, and IL-5, than the non-responders. Moreover, responders displayed a strong positive correlation between the cytokines IFN-γ and IL-7 with the percentage of TILs, while non-responders had a negative or no correlation. Finally, systemic immune mediator levels before treatment predict pCR (AUC range 0.64 - 0.71), and the combination of immune mediators and TILs improved pCR prediction (AUC 0.71 - 0.82). In conclusion, increased systemic immune mediators reflect increased TILs percentage and act as potential predictive biomarkers of pCR for TNBC patients submitted to neoadjuvant chemotherapy.