Breast cancer (BC) is the most prevalent malignancy in women with Li-Fraumeni syndrome (LFS). The literature on BC in LFS is limited due to its rarity worldwide. A TP53 founder pathogenic variant (c.1010G>A; p.R337H) is responsible for the higher prevalence of this syndrome among women of Brazilian ancestry.PurposeThe aim of the study was to describe the BC phenotype expressed by Brazilian female LFS carriers and compare the data between p.R337H and other TP53 germline pathogenic/likely pathogenic variants (non-p.R337H carriers).MethodsWe searched for cases of TP53 germline pathogenic/likely pathogenic variant carriers affected by BC included between 2015 and 2020 in the BLiSS (Brazilian Li-Fraumeni Study) registry at the Sírio-Libanês Hospital.ResultsAmong 163 adult female carriers from the registry, 91 (56%) had received a BC diagnosis, including 72 p.R337H carriers. BC was the first cancer diagnosed in 90% of cases. Early onset BC (age ≤45 years) was diagnosed in 78.2% of cases (11.5% <31 years; 66.7% 31–45 years; 21.8% >45 years). The median age of BC diagnosis for p.R337H carriers was 39.5 years (range 20–69 years) compared to 34 years (range 21–63 years) for non-p.R337H carriers (p = 0.009). In total, 104 breast tumors were observed in 87 women. Bilateral BC was observed in 29.3% of cases. Histology was available for 96 tumors, comprising 69 invasive breast carcinomas, which were mostly invasive ductal carcinomas (95.6%), 25 ductal in situ carcinomas and 2 soft-tissue sarcomas. Overall, 90.5% of invasive breast carcinomas were hormone receptor (HR)-positive, 39.5% were human epidermal growth factor receptor 2 (HER2)-positive, and 32.8% showed HR and HER2 co-expression. In addition, 55.4% of patients opted for contralateral prophylactic mastectomy after a first BC diagnosis. There were no significant differences in the risk of developing contralateral BC or in the immunohistochemical profile between p.R337H and non-p.R337H groups.ConclusionsThe expressed phenotype of p.R337H is similar to that of other TP53 pathogenic/likely pathogenic variants, except for an average older age at the onset of disease; however, this is still younger than the general population.

RESUMO:Manter a privacidade e confidencialidade dos pacientes é crítico na ética. Realizamos estudo exploratório, quanti-qualitativo, com 'potenciais usuários do Sistema Único de Saúde' para identificar como esperam que os profissionais de saúde se comportem quando um dos parceiros de casal heterossexual tem sífilis. Os sujeitos foram funcionários de uma universidade pública. A coleta de dados usou questionário anônimo, auto aplicado, com alternativas de como o profissional deveria agir quando marido com sífilis não quer que sua esposa saiba da doença e pede à equipe que solicitem o exame dela, sem dizer-lhe nada. Como resultado os respondentes esperam a manutenção da confidencialidade, deixando a cargo do marido a revelação da verdade à esposa. O profissional é visto como um mediador da situação, de quem esperam orientação e apoio na revelação. Saber o que esperam os pacientes pode ajudar os enfermeiros a lidar com situações eticamente problemáticas em saúde sexual. PALAVRAS-CHAVE: Bioética; Privacidade; Comunicação sigilosa; Ética profissional; Doenças sexualmente transmissíveis. SEXUALLY TRANSMITED DISEASES: TO PRESERVE THE HUSBAND'S CONFIDENTIALITY OR TO PROTECT WOMAN'S HEALTH?ABSTRACT: To maintain the privacy and confidentiality of patients is a critical issue for ethics. We developed an exploratory, quantitative and qualitative study with potential users of the Unique Health System to identify how they expect that health personnel would behave when one of the heterosexual partner has syphilis. Subjects were employees of a public University. Data collection was developed through an anonymous and self reported questionnaire, with questions about how the health professional should behave when a husband with syphilis doesn't want his wife to know about the disease and ask the health team to get her examined without knowing about his problem. As results, interviewees expect the maintenance of confidentiality, leaving the husband in charge of telling his wife the truth. Health professionals are seen as a mediator of the situation, of whom they expect orientation and support in the revelation of health problems. To know what the patients expect from health professionals could help nurses to deal with ethical situations that might be a problem among the issues of sexual health. KEYWORDS: Bioethics; Privacy; Confidentiality; Ethics, professional; Sexually transmitted diseases. ENFERMEDADES DE TRASMISIÓN SEXUAL: ¿PRESERVAR LA CONFIDENCIALIDAD DEL MARIDO O PROTEGER LA SALUD DE LA MUJER?RESUMEN: Mantener la privacidad y confidencialidad de los pacientes es crítico en la ética. Realizamos estudio exploratorio, cuanti-cualitativo con "potenciales usuarios del Sistema Único de Salud" para identificar como esperan que los profesionales de salud se comporten cuando uno de los compañeros de la pareja heterosexual tiene sífilis. Los sujetos fueron funcionarios de una universidad pública. La colecta de datos usó cuestionario anónimo, autoaplicado, con alternativas de cómo el profesional debería actuar cuando el marido con síf...

Estudo exploratório que buscou, junto a usuários da Liga de Combate à Sífilis e outras Doenças Sexualmente Transmissíveis do Hospital das Clínicas da Universidade de São Paulo suas percepções acerca da privacidade e confidencialidade em situação hipotética com casal heterossexual, quando um dos parceiros tem sífilis, e compará-las às percepções encontradas em estudos realizados com profissionais da Estratégia Saúde da Família e "Potenciais usuários do Sistema Único de Saúde". A coleta de dados, realizada através de entrevista semiestruturada, perguntava como o profissional deveria agir numa situação em que um dos parceiros com sífilis não quer revelar o fato à esposa, porém pede que se realize o exame diagnóstico e o tratamento, sem o conhecimento de sua mulher. Foram entrevistados 32 usuários, e a análise dos dados mostrou que existe aceitação da participação do profissional no processo de revelação da verdade, e aproximações entre as percepções dos diversos grupos estudados.

Hereditary breast cancer (BC) corresponds to 5% of all BC and a larger parcel of early-onset disease. The incorporation of next-generation sequencing (NGS) techniques reduced the cost of molecular testing and allowed the inclusion of additional cancer predisposition genes in panels that are more comprehensive. This enabled the identification of germline pathogenic variants in carriers and the introduction of risk-reducing strategies. It also resulted in the identification of the co-occurrence of more than one germline pathogenic variant in BC genes in some families. This is a rare event, and there are few reports on its impact on cancer risk. We conducted a single-institution retrospective study in which 1,156 women with early onset BC and/or a family history of cancer were tested by a germline multi-gene hereditary cancer panel. Germline pathogenic variants in high- and/or moderate-penetrance BC genes were identified in 19.5% of the individuals (n = 226). The most frequent variants were found in TP53 (69 of 226; 55 of them represented by p.R337H), BRCA1 (47 of 226), and BRCA2 (41 of 226). Double heterozygous (DH) variants were detected in 14 cases, representing 1.2% of all individuals assessed. There were no significant differences in age of BC onset and risk for bilateral BC in DH carriers when compared with those with one germline variant.

Background The microphthalmia-associated transcription factor gene (MITF) belongs to the MYC supergene family and plays an important role in melanocytes’ homeostasis. Individuals harboring MITF germline pathogenic variants are at increased risk of developing cancer, most notably melanoma and renal cell carcinoma. Case presentation We describe a cohort of ten individuals who harbor the same MITF c.952G > A (p.Glu 318Lys), or p.E318K, germline pathogenic variant. Six carriers developed at least one malignancy (4 cases of breast cancer; 1 cervical cancer; 1 colon cancer; 1 melanoma; 1 ovarian/fallopian tube cancer). A significant phenotypic heterogeneity was found among these individuals and their relatives. Breast cancer was, overall, the most frequent malignancy observed in this case series, with 13 occurrences of 60 (21.67 %) total cancer cases described among the probands and their relatives. Conclusions Our retrospective analysis data raise the hypothesis of a possible association of the MITF p.E318K pathogenic variant with an increased risk of breast cancer.

IntroductionBreast cancer patients with germline pathogenic variants may benefit from risk-reducing surgeries, intensive screening, and targeted cancer therapies. There is a paucity of data regarding prevalence and distribution of germline pathogenic variants in the Brazilian population. Our primary endpoint was the description of prevalence and distribution of germline pathogenic variants among breast cancer patients who underwent next-generation sequencing (NGS) panel testing. Secondary endpoint was the assessment of predictive factors of a positive test.MethodsWe analyzed NGS results, personal, and family history data from a prospectively collected cohort of breast cancer patients from August 2013 to May 2019. Exact logistic regression was used to perform multivariable analysis.ResultsOf 370 breast cancer patients, we found 59 pathogenic variants in 57 (15%) patients. Pathogenic variants were identified in BRCA1 (24%), ATM (14%), BRCA2 (10%), TP53 (8%), PALB2 (8%), CHEK2 (7%), CDH1 (3%), RAD51C (3%), MITF (2%), PMS2 (2%), RAD51D (2%), and TERT (2%). Monoallelic MUTYH pathogenic variants were found in 15%. After multivariable analysis, age of diagnosis (OR 0.89, 95% CI: 0.81–0.95, for each year increase), triple-negative subtype (OR 17.2, 95% CI: 3.74–114.72), and number of breast cancers in the family (OR 2.46, 95% CI 1.57–4.03, for each additional case) were associated with BRCA1 pathogenic variants. In the present study, a quarter of triple-negative breast cancer patients harbored a germline pathogenic variant and two-thirds of those were BRCA1 carriers.ConclusionsPrevalence and distribution of germline pathogenic variants in this Brazilian sample of breast cancer patients are mostly similar to other populations. However, there is a trend to an overrepresentation of TP53 pathogenic variants that merits confirmation in further studies. Early-onset breast cancer patients should be offered genetic counseling, particularly those with triple-negative subtype.

Li-Fraumeni syndrome (LFS) is a hereditary genetic condition that predisposes to a wide variety of tumors. Early-onset breast cancer is the most prevalent tumor in female carriers, with a 49% risk by age 60. The risk of developing a second primary breast cancer in LFS remains unknown but it is estimated to be 33%. The Toronto protocol was proposed by Villani et al. (2011) and defined effective strategies for cancer screening in carriers. Risk-reduction mastectomy (RRM) may reduce over 90% breast cancer risk. Due to a founder mutation, TP53 p.R337H, LFS has been observed in a higher-than-expected prevalence in Brazil. This mutation occurs in the oligomerization domain and seems to have a milder lifetime penetrance than regular DNA binding domain mutations. Due to its estimated high frequency in the Brazillian population, this is a public health problem and implementation of effective strategies in breast cancer risk-reduction are needed. In this study, we have evaluated risk-reduction mastectomy in women who carried the founder TP53 p.R337H mutation. A total of 106 women from the Brazilian LFS TP53 p.R337H cohort were included in this study. Imaging surveillance was offered and RRM was discussed. All participants received genetic counseling and signed informed consent. The study was approved by the local ethics committee (HSL-02433418.5.0000.5461). A total of 65.1% (69/106) did not develop breast cancer at the time of this study. Among those, four women opted to perform bilateral prophylactic mastectomy (5.8% - 4/69). Overall, 34.9% (37/106) developed breast cancer prior to enrollment and 12 women were lost to follow-up. A total of 25 women opted to continue surveillance. Eleven (44%) opted to undergo RRM and 14 (66%) chose to continue annual breast magnetic resonance imaging (MRI), according to the Toronto protocol. A total of 32% (8/25) had been diagnosed with a second primary breast cancer prior to the study enrollment. The most common breast cancer histopathological subtype was invasive ductal carcinoma, present in 64% (16/25) in our study population. Only one woman was diagnosed with invasive lobular carcinoma (4%). Twelve percent (3/25) were in situ carcinomas. Estrogen and progesterone receptors stained positive in 76% (19/25). HER-2 was negative in 52% (13/25) of all cases. Our findings show that BPM was not a common procedure in carriers (5.8%). Nevertheless, RRM was performed in 44% of all women who have been previously diagnosed with breast cancer. Ductal invasive carcinoma is the most common cancer in TP53 p.R337H women and most of them have hormone receptor status positive. Unlike other previously published studies on LFS breast can cancer, HER-2 gene was non-amplified in most cases (52%). This is the first study to evaluate the frequency of RRM in a cohort of women with breast cancer carrying the same germline pathogenic variant, TP53 p.R337H. Citation Format: Mariana Cartaxo Alves, Renata Lazari Sandoval, Janina Pontes Pisani, Carla Vanessa Quirino, Elizabeth Santana Santos, Maria Isabel Achatz. Breast cancer in Li-Fraumeni syndrome and risk-reduction mastectomy in TP53 p.R337H carriers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-18.

Significant progress has been made in the identification of inherited genetic factors underlying hereditary cancers. Inherited pathogenic variants in cancer predisposition genes that confer moderate to high risk of breast cancer (BC) are found in 10% of BC cases. Pathogenic variants in BRCA1 and BRCA2 genes are the underlying alterations in hereditary BC. Women with a pathogenic variant in BRCA1 or BRCA2 are at substantially higher risk of developing breast, ovarian and pancreatic cancers and represent 25-28% of hereditary BC cases. The gold standard for molecular diagnosis of a hereditary cancer syndrome is aNext Generation Sequencing (NGS) panel that includes all genes known to confer moderate to high-risk for BC (TP53, PTEN, CHEK2, ATM, PALB2 STK11, RAD51C and BRIP1). Identifying who is eligible to perform genetic testing remains a challenge but presently age at the time of tumor diagnosis, family history and disease stage are still the best predictors. The identification of a germline pathogenic variant enables appropriate genetic counseling, risk-reducing interventions. The detection of variants in BRCA1, BRCA2 and PALB2 may also determine treatment options in patients with advanced or metastatic disease. The known non-BRCA1/2-associated hereditary BC comprise a heterogeneous group of tumors, for most of which the prevalence of histologic and immunohistochemical (IHQ) phenotypes are yet to be identified while triple-negative BC is the most prevalent in BRCA1 carriers. The co-occurence of more than one germline pathogenic variant in BC genes is a rare event and it may affect cancer risk and penetrance is still unknown. Only a few reports on cases and series of double mutation carriers have been described in BRCA1, BRCA2, PALB2, CHEK2, BLM or NBN. In this series case we report patients with double heterozygous (DH) mutation in BC, their age at diagnosis, presence of second neoplasia and cancer phenotype in moderate and high penetrance genes on germline panels. Considering this scenario, we performed an active search among the 2651 women from the Hereditary Cancer Registry at Hospital Sirio-Libanes, São Paulo, Brazil, between January 2013 and June 2020. We have included 229 patients with a histopathological confirmation of a BC who have tested positive for pathogenic/likely pathogenic variant. Of these, 4,3% (10/229) women were identified with DH mutation in high and moderate penetrance genes in BC (table 1). All patients carried a germline pathogenic variant in at least one high-penetrance gene. A total of 7 cases (7/10) carried at least one BRCA1/2 pathogenic variant. Two women (2/10) included had developed bilateral BC. The occurrence of a second primary cancer was described in three patients (3/10). The median age at first BC diagnosis was 36,7 years old. Two BC were found to be triple negative, five cases were of Luminal subtype and one was HER2+. The age at diagnosis is similar to most hereditary BC related to those developed by BRCA1 and TP53 germline variant carriers. In this case series there is no evidence of additive effect on the risk of tumor development. Larger series of DH mutation carriers are needed to estimate the risk in double heterozygous populations and to determine whether the presence of DH have a synergistic interaction or additive effect on cancer risk. Table1 - Breast Cancer double variantsBreast Cancer double VariantsGeneVariantAge of Breast Cancer onset IHQ statusBilateral BCOther prymary neoplasia (age)BRCA1c.5266dupC36 yoER- PR- HER2 +YesPancreas (40), Lung (53)TP53c.1010G>ABRCA1c.4165.4166delAG32yoN/ANoBreast (37), Skin (50)PALB2c.1240C>TBRCA1c.5266dupC33yoER - RP- HER2 -NoNoATMc.6729_6730delAABRCA1c.3748G>T33yoER- PR -HER2-NoNoRECQL4c.1568_1573delinsCCCCCBRCA2c.2516dupA49yoER+ PR+ HER2 -NoNoPMS2c.2182_2184delinsGBRCA2c.8960del32yoER+ PR+ HER2-NoNoATMc.901+1G>ABRCA1c.1687C>T38yoER+NoBreast Cancer (58)NBNc.1142delC PR +MUTYHc.536A>G Her2-TP53c.1010G>A35yoN/ANoNoMUTYHc.1187G>AATMc.4906C>T42yoER+NoNoTP53c.1010G>APR+HER2-PALB2c.2711G>A37yoER+yesNoCHEK2c.319+2T>APR+HER2-BRCA2c.8960del32yoER+ PR+ HER2-NoNo Citation Format: Thais Megid, Maria Isabel Achatz, Janina Pontes Pisani, Mariana Cartaxo. Double heterozygous pathogenic variants prevalence in a cohort of hereditary breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-12.