Pregnancy after breast cancer in BRCA1/2 mutation carriers

Funding Information: This research is supported (not financially) by the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS)?Project ID No 739547. ERN GENTURIS is partly co-funded by the European Union within the framework of the Third Health Programme ?ERN-2016?Framework Partnership Agreement 2017?2021. Funding Information: This research is supported (not financially) by the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS)—Project ID No 739547. ERN GENTURIS is partly co-funded by the European Union within the framework of the Third Health Programme “ERN-2016—Framework Partnership Agreement 2017–2021. Publisher Copyright: © 2022, The Author(s).Background: Often young women affected with BRCA1/2 positive breast cancer have not finished or even not started their childbearing before the onset of the disease. The aim of our mini-review is to summarize state of art knowledge on pregnancy after breast cancer in BRCA1/2 carriers. Methods: A broad review of the literature was conducted using MEDLINE (via PubMed) for relevant articles published. Main body of the abstract: This review summarizes the impact of different cytotoxic agents on a fertility, fertility preservation, maternal and fetal prognosis after pregnancy in breast cancer survivors with BRCA1/2. Conclusion: According to the existing literature evidence pregnancy after therapy for breast cancer in BRCA carriers is safe for the mother and offspring, but patients’ needs, oncofertility counseling and fertility-sparing strategy should be carefully planned before starting the cytotoxic treatment.publishersversionPeer reviewe

Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort

Funding Information: This work (L.A.J.H. and J.R.V.) was financially supported by the PTEN Research Foundation . E.R.W. and D.G.E. are supported by the NIHR Manchester Biomedical Research Centre (Grant Reference Number 1215–200074 ). E.T. is supported by Region Stockholm (Grant ID, 2020-500306 DS ). L.R. is supported by the Estonian Research Council (Grant ID PRG471 ). Funding Information: This research is supported (not financially) by the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS)—Project ID No 739547. ERN GENTURIS is partly co-funded by the European Union within the framework of the Third Health Programme “ERN-2016—Framework Partnership Agreement 2017–2021”. Publisher Copyright: © 2022 The AuthorsBackground: Pathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study. Methods: Information was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age. Results: At time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5–3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1–2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1–3.5), with trends up to 2–4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3–0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4–0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2. Conclusion: The PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants.publishersversionPeer reviewe

Allelic variants of breast cancer susceptibility genes PALB2 and RECQL in the Latvian population

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Role of percutaneous needle biopsy of axillary lymph nodes to evaluate node positive breast cancer after neoadjuvant chemotherapy

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Ultrasound guided needle biopsy of axilla to evaluate nodal metastasis after preoperative systemic therapy in cohort of 106 breast cancers enriched with BRCA1/2 pathogenic variant carriers.

BACKGROUND: Aim of the study is to evaluate the role of ultrasound guided fine needle aspiration cytology (FNAC) in the restaging of node positive breast cancer after preoperative systemic therapy (PST). METHODS: From January 2016 - October 2020 106 node positive stage IIA-IIIC breast cancer cases undergoing PST were included in the study. 18 (17 %) were carriers of pathogenic variant in BRCA1/2. After PST restaging of axilla was performed with ultrasound and FNAC of the marked and/or the most suspicious axillary node. In 72/106 cases axilla conserving surgery and in 34/106 cases axillary lymph node dissection (ALND) was performed. RESULTS: False Positive Rate (FPR) of FNAC after PST in whole cohort and BRCA1/2 positive subgroup is 8 and 0 % and False Negative Rate (FNR) - 43 and 18 % respectively. Overall Sensitivity - 55 %, specificity- 93 %, accuracy 70 %. CONCLUSION: FNAC after PST has low FPR and is useful to predict residual axillary disease and to streamline surgical decision making regarding ALND both in BRCA1/2 positive and negative subgroups. FNR is high in overall cohort and FNAC alone are not able to predict ypCR and omission of further axillary surgery. However, FNAC performance in BRCA1/2 positive subgroup is more promising and further research with larger number of cases is necessary to confirm the results

Blood Arsenic Levels as a Marker of Breast Cancer Risk among BRCA1 Carriers

Funding Information: Funding: The study was funded by the National Centre for Research and Development Projects. INNOMED/1/16/NCBR/2014 and PBS3/B7/26/2015. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.An important group of breast cancers is those associated with inherited susceptibility. In women, several predisposing mutations in genes involved in DNA repair have been discovered. Women with a germline pathogenic variant in BRCA1 have a lifetime cancer risk of 70%. As part of a larger prospective study on heavy metals, our aim was to investigate if blood arsenic levels are associated with breast cancer risk among women with inherited BRCA1 mutations. A total of 1084 participants with pathogenic variants in BRCA1 were enrolled in this study. Subjects were followed from 2011 to 2020 (mean follow-up time: 3.75 years). During that time, 90 cancers were diagnosed, including 67 breast and 10 ovarian cancers. The group was stratified into two categories (lower and higher blood As levels), divided at the median (<0.85 µg/L and ≥0.85 µg/L) As level among all unaffected participants. Cox proportional hazards models were used to model the association between As levels and cancer incidence. A high blood As level (≥0.85 µg/L) was associated with a significantly increased risk of developing breast cancer (HR = 2.05; 95%CI: 1.18–3.56; p = 0.01) and of any cancer (HR = 1.73; 95%CI: 1.09–2.74; p = 0.02). These findings suggest a possible role of environmental arsenic in the development of cancers among women with germline pathogenic variants in BRCA1.Peer reviewe

Challenges in the management of a patient with Cowden syndrome: case report and literature review

We would like to present a patient with a classical phenotype of a rare disorder - Cowden syndrome, its diagnostics and management challenges. A breast surgeon has to be aware of this rare condition when treating a patient with breast manifestations of Cowden syndrome and has to refer the patient to a clinical geneticist for further evaluation. Sequencing of the PTEN gene showed the Asp24Gly mutation. According to the latest literature data, the lifetime risk of breast cancer for Cowden syndrome patients is 81% and surgery is a justified option to reduce the risk of breast cancer. Bilateral risk-reducing mastectomy with immediate reconstruction was performed to eliminate further risk of breast cancer. 3 years after the risk-reducing breast surgery the patient is satisfied with the outcome. This is to our best knowledge the first reported Cowden syndrome case with follow-up data after risk-reducing measures have been taken

Recapitulation of Transcriptomic Characteristics of Primary Breast Tumours in Patient-Derived 3D Cultures in Vitro

Breast cancer (BC) is the most common cause of cancer-related deaths among women in Europe and worldwide. Adherent (2D) cell cultures have been the routine in vitro model system employed in preclinical BC research for the last half-century. Over the past decade, new protocols have been developed allowing patient-derived three-dimensional organoid (3D) cell culture development from a range of solid tumours, including BC. These 3D models offer a promise of closer resemblance to the native tumour than the 2D cultures. To test the assumption that an in vitro 3D BC model system provides increased faithfulness to the molecular processes happening in vivo, as compared to 2D BC cultures, post-operational material from three BC patients was used to simultaneously develop 2D and 3D cultures in vitro. When analysed by quantitative polymerase chain reaction (PCR), the gene expression patterns of the cells from 3D cultures resembled the original tissues, while the gene expression patterns of the conventional 2D cultures were more distant

Role of Percutaneous Needle Biopsy of Axillary Lymph Nodes to Evaluate Node Positive Breast Cancer after Neoadjuvant Chemotherapy

The aim of the study was to evaluate the role of ultrasound guided fine needle aspiration cytology (FNAC) in the restaging of node positive breast cancer after neoadjuvant chemotherapy (NAC). From January 2016 – October 2018, 90 node positive stage IIA-IIIC breast cancer cases undergoing NAC were included in the study. The largest, most superficial and the most caudal axillary node metastasis confirmed by fine needle aspiration cytology (FNAC) was marked with clip. After NAC, restaging of axilla was performed with ultrasound and FNAC of the marked and/or the most suspicious axillary node. Of the 90 cases, 58 with available ultrasound guided percutaneous needle biopsy data were further evaluated. Axilla conserving surgery was performed in 37 of 58 cases and axillary lymph node dissection (ALND) in 21 of 58 cases. False Positive Rate (FPR) of FNAC after NAC was 12%, False Negative Rate (FNR) — 58%, sensitivity — 54%, specificity — 82%, accuracy 62%. FNAC after NAC had low FPR and was found to be useful in predicting residual axillary disease and to streamline surgical decision making regarding ALND. However, FNR was unacceptably high and FNAC alone was not able to predict ypCR and omission of further axillary surgery