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OBJECTIVE: To investigate alterations of homologous recombination repair (HRR) and especially BReast CAncer 1/2 (BRCA1/2) gene on overall survival (OS). Moreover, to explore the effect of inhibition of poly(ADP-ribose)-polymerase (PARPi) as systemic therapy for metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Of all HRR-screened patients with metastatic prostate cancer, baseline characteristics were sampled. Kaplan-Meier estimates and multivariable Cox regression models predicted the effect of HRR/BRCA1/2 alterations on OS. RESULTS: Of 196 eligible patients, 61 (31%) harboured any HRR and 40 (20%) BRCA1/2 alterations. Of HRR alterations, 40 (66%) vs six (10%) vs five (8.2%) vs four (6.6%) vs two (3.3%) vs four (6.6%) were BRCA1/2 vs Ataxia-telangiectasia mutated kinase (ATM) vs checkpoint kinase 2 (CHEK2) vs cyclin-dependent kinase 12 (CDK12) vs Fanconi anaemia complementation Group A (FANCA) vs positive for other mutations. Of these, 30% received a PARPi. OS differed significantly between HRR-positive vs -negative patients. Specifically in hormone-sensitive prostate cancer, the median OS was 63 (HRR positive) vs 57 (BRCA1/2 positive) vs 113 months (HRR negative) (P ≤ 0.01). In mCRPC, OS was 42 (HRR positive) vs 41 (BRCA1/2 positive) vs 70 months (HRR negative) (P ≤ 0.01). HRR and BRCA1/2 alterations were associated with worse OS after multivariable adjustment. Finally, patients with mCRPC with BRCA1/2 mutation treated without PARPi harboured worse OS than patients with BRCA1/2 mutation and PARPi therapy (median OS: 33 vs 48 months, P < 0.03). CONCLUSION: Incidence of HRR alteration in a clinical real-world setting is high when using blood- and tissue-based tests. Patients with HRR/BRCA alterations have worse outcomes resulting in significant OS differences between HRR/BRCA-positive patients with mCRPC with and without PARPi usage vs HRR/BRCA-negative patients.
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Olaparib was the first poly ADP-ribose polymerase inhibitor approved for patients with cancer with mutations in either BRCA1 or BRCA2 in China. To the best of our knowledge, however, no study has described the efficacy of olaparib for patients with breast cancer with double mutations in BRCA1 and BRCA2. The present case report describes a patient with breast cancer with deleterious germline mutations in both BRCA1 and BRCA2. The 56-year-old patient with multiple metastatic breast cancer underwent breast cancer resection with 12 years interval between removal of the left and right breast. Germline mutations in both BRCA1 (S405X) and BRCA2 (W2990X) were identified by NGS. She received two cycles of chemotherapy with a combination of albumin-bound paclitaxel and capecitabine; the response was progressive disease. Subsequently, the patient was treated with a gradual dosage of decreasing olaparib (600 to 300 mg BID) for 6 months until grade 3 anemia could not be alleviated by giving erythropoietin and iron, and CT imaging showed a partial response (35% reduction). The patient then switched to exemestane therapy due to the continuous grade 3 anemia. In conclusion, the present study reported a female patient with double heterozygosity of BRCA1 and BRCA2 who benefited from olaparib monotherapy. Thus, olaparib may be a suitable treatment for such patients.
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OBJECTIVE: Previvor is a term applied to a person with an identified, elevated lifetime cancer risk but without an actual cancer diagnosis. Previvorship entails the selection of risk management strategies. For women with a genetic mutation that increases their predisposition for a breast cancer diagnosis, bilateral risk-reducing mastectomy (BRRM) is the most effective prevention strategy. However, BRRM can change a woman's breast appearance and function. The purpose of this qualitative metasynthesis (QMS) was to better understand the decision-making process for BRRM among previvors. METHODS: A theory-generating QMS approach was used to analyze and synthesize qualitative findings. Research reports were considered for inclusion if: (1) women over 18 years of age possessed a genetic mutation increasing lifetime breast cancer risk or a strong family history of breast cancer; (2) the sample was considering, or had completed, BRRM; (3) the results reported qualitative findings. Exclusion criteria were male gender, personal history of breast cancer, and research reports which did not separate findings based on cancer diagnosis and/or risk-reduction surgery. RESULTS: A theory and corresponding model emerged, comprised of seven themes addressing the decision-making process for or against BRRM. While some factors to decision-making were decisive for surgery, others were more indefinite and contributed to women changing, processing, or suspending their decision-making for a period of time. CONCLUSIONS: Regardless of the decision previvors make about BRRM, physical and psychosocial well-being should be considered and promoted through shared decision-making in the clinical setting.
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Neoplasias da Mama , Mastectomia , Feminino , Masculino , Humanos , Adolescente , Adulto , Mastectomia/psicologia , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Neoplasias da Mama/prevenção & controle , Risco , Mutação , Comportamento de Redução do RiscoRESUMO
This is a case of a previously healthy 29-year-old female with erythema and skin excoriations of the left breast nipple-areolar complex (NAC). After a repeat trial and failure of topical hydrocortisone, a diagnostic mammogram and nipple biopsy revealed Paget's disease (PD) of the nipple with ductal carcinoma in situ (DCIS). A subsequent genetic analysis found a breast cancer 2 (BRCA2) gene mutation. Treatment consisted of a left breast skin-sparing simple mastectomy with sentinel lymph node (SLN) biopsy and immediate tissue expander placement for implant reconstruction. Further management involved right breast short-interval surveillance with annual mammography and magnetic resonance imaging (MRI) with the possibility of prophylactic surgery along with oophorectomy after childbearing.
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BACKGROUND: The process of gamete formation and early embryonic development involves rapid DNA replication, chromosome segregation and cell division. These processes may be affected by mutations in the BRCA1/2 genes. The aim of this study was to evaluate BRCA mutation inheritance and its effect on early embryonic development according to the parental origin of the mutation. The study question was approached by analyzing in vitro fertilization cycles (IVF) that included pre-implantation testing (PGT-M) for a BRCA gene mutation. METHODS: This retrospective cohort study compared cycles of pre-implantation genetic testing for mutations (PGT-M) between male and female patients diagnosed with BRCA 1/2 mutations (cases), to a control group of two other mutations with dominant inheritance (myotonic dystrophy (MD) and polycystic kidney disease (PKD)). Results were compared according to mutation type and through a generalized linear model analysis. RESULTS: The cohort included 88 PGT-M cycles (47 BRCA and 41 non-BRCA) among 50 patients. Maternal and paternal ages at oocyte retrieval were comparable between groups. When tested per cycle, FSH dose, maximum estradiol level, oocytes retrieved, number of zygotes, and number of embryos available for biopsy and affected embryos, were not significantly different among mutation types. All together 444 embryos were biopsied: the rate of affected embryos was comparable between groups. Among BRCA patients, the proportion of affected embryos was similar between maternal and paternal mutation origin (p = 0.24). In a generalized linear model analysis, the relative oocyte yield in maternal BRCA patients was significantly lower (0.7, as related to the non BRCA group)(p < 0.001). Zygote formation and blastulation were not affected by the BRCA gene among paternal cases (P = 0.176 and P = 0.293 respectively), nor by paternal versus maternal BRCA carriage (P = 0.904 and P = 0.149, respectively). CONCLUSIONS: BRCA PGT-M cycles performed similarly compared to non-BRCA cycles. Inheritance rate and cycle parameters were not affected by the parental origin of the mutation.
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Proteína BRCA1 , Diagnóstico Pré-Implantação , Gravidez , Humanos , Masculino , Feminino , Estudos de Coortes , Proteína BRCA1/genética , Estudos Retrospectivos , Diagnóstico Pré-Implantação/métodos , Proteína BRCA2/genética , Testes Genéticos/métodos , Fertilização in vitro/métodos , Mutação , Aneuploidia , PaisRESUMO
INTRODUCTION: Female carriers of BRCA1/2 genes have an increased lifetime risk of breast cancer. Options for managing risk include imaging surveillance or risk-reducing surgery (RRS). This mixed methods study aimed to identify factors affecting risk-management decisions and the psychosocial outcomes of these decisions for high-risk women and their partners. METHODS: Semi-structured qualitative interviews were performed with women at high breast cancer risk who had faced these choices. Partners were also interviewed. Analysis used a framework approach. A bespoke questionnaire was developed to quantify and explore associations. RESULTS: A total of 32 women were interviewed. Of these, 27 had partners of whom 7 (26%) agreed to be interviewed. Four main themes arose: perception of risk and impact of increased risk; risk-management strategy decision-making; impact of risk-management strategy; support needs and partner relationship issues. The questionnaire response rate was 36/157 (23%). Decision satisfaction was high in both surveillance and RRS groups. Relationship changes were common but not universal. Common causes of distress following RRS included adverse body image changes. Both groups experienced generalised and cancer-specific anxiety. Drivers for surgery included having children, deaths of close family from breast cancer and higher levels of cancer anxiety. CONCLUSIONS: Levels of psychosocial and decision satisfaction were high for women choosing both RRS and surveillance but, for a minority, risk-reducing measures result in long-term psychosocial morbidity. Efforts to recognise women at increased risk of psychological morbidity may allow targeted support.
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Neoplasias da Mama , Criança , Feminino , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Proteína BRCA1 , Proteína BRCA2 , Gestão de RiscosRESUMO
OBJECTIVE: The companion diagnosis for olaparib, a poly (ADP-ribose) polymerase inhibitor for prostate cancer, aims to detect BRCA1/2 gene variants. In clinical practice, the frequency of germline BRCA1/2 variants in patients receiving castration-resistant prostate cancer treatment is unknown. We aimed to evaluate the prevalence of germline BRCA1/2 variants and their relationship to prognosis and treatment efficacy in castration-resistant prostate cancer. METHODS: Between June 2021 and 2023, 92 patients receiving castration-resistant prostate cancer treatment were examined for germline BRCA1/2 variants using BRACAnalysis CDx®. Furthermore, the associations between BRCA1/2 pathogenic variants and clinical outcomes were assessed. RESULTS: Of the 92 patients referred for genetic testing, 6 (6.5%) carried germline pathogenic variants in BRCA1/2. The BRCA2 variant was the most frequent (n = 5), followed by BRCA1 variant (n = 1). Among the five variants in BRCA2, the p.Asp427Thrfs*3 variant was identified for the first time in prostate cancer. Overall survival from castration-resistant prostate cancer for patients with BRCA1/2 variants was significantly shorter than for patients without BRCA1/2 variants (P = 0.043). Progression-free survival of androgen receptor signaling inhibitors for patients with BRCA1/2 variants was significantly shorter than for those without (P = 0.003). Progression-free survival of taxane chemotherapy was significantly shorter in patients with BRCA1/2 variants than in those without (P = 0.0149). CONCLUSIONS: In clinical practice, 6.5% of patients treated with castration-resistant prostate cancer carried germline BRCA1/2 pathogenic variants. Japanese castration-resistant prostate cancer patients with germline BRCA1/2 mutants have a poor prognosis and may be less responsive to treatment with androgen receptor signaling inhibitors and taxane-based chemotherapy for castration-resistant prostate cancer.
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Antineoplásicos , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Proteína BRCA1/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Proteína BRCA2/genética , Receptores Androgênicos/uso terapêutico , Prevalência , Japão/epidemiologia , Antineoplásicos/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Taxoides/uso terapêutico , Células GerminativasRESUMO
Breast cancer (BC), a significant global health concern, impacts millions of women worldwide. A key genetic factor in this disease is the presence of BReast CAncer gene (BRCA) mutations, which increase susceptibility to BC. This narrative review explores the crucial role of poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors in treating metastatic BC in individuals with BRCA gene mutations. In BRCA mutation carriers, these inhibitors induce synthetic lethality, leading to cell death due to the accumulation of lethal DNA breaks. Clinical trials have demonstrated the effectiveness of PARP inhibitors, such as olaparib and talazoparib, in extending progression-free survival and response rates, especially in patients without prior chemotherapy. Moreover, this review discusses combination therapies, where PARP inhibitors are combined with cytostatic drugs like platinum-based chemotherapy. Some studies show the synergy of these approaches, even in patients without homologous recombination deficiency. In summary, PARP inhibitors offer hope for improving outcomes in metastatic BC patients with BRCA gene mutations. As research advances, PARP inhibitors continue to hold promise in the fight against BC.
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Breast cancer is the most prevalent form of cancer worldwide. Every year, it affects a significant number of women in the UK and is considered one of the leading causes of cancer-related deaths globally. While breast cancer is primarily linked to adult women, its occurrence in children and adolescents is exceedingly rare. This study conducted a narrative review spanning from 1999 to 2023, examining 32 case reports to investigate the characteristics of breast cancer in the paediatric age group. These reports focused on patients under 18 years old who were diagnosed with primary glandular breast cancer, excluding cases originating from other tissues like angiosarcoma, leukaemia, and metastatic cancer. The data analysis encompassed various parameters, including gender, age, histology, receptor status, lymph node involvement, treatment methods, and genetic characteristics. From the published case reports, it was concluded that the most common type of breast cancer affecting children and adolescents is secretory breast carcinoma and predominantly occurs in females. It is typically hormone receptors negative, and the preferred treatment approach involves mastectomy as breast conservation surgery to preserve the developing breast tissue is a real challenge due to limited breast tissue volume in this age group.
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BACKGROUND: Radiomics nomogram analysis is widely preoperatively used to assess gene mutations in various tumors. PURPOSE: To explore the value of computed tomography (CT)-based radiomics nomogram analysis for assessing BRCA gene mutation status of patients with high-grade serous ovarian cancer (HGSOC). MATERIAL AND METHODS: In total, 96 patients with HGSOC were retrospectively screened and randomly divided into primary (n = 68) and validation cohorts (n = 28). The clinical model was constructed based on clinical features and CT morphological features using univariate and multivariate logistic analyses. Maximum-relevance and minimum-redundancy (mRMR) and least absolute shrinkage and selection operator (LASSO) were performed for feature dimensionality reduction and radiomics score was calculated. The nomogram model combining the clinical model and the radiomics score was constructed using multivariate logistic regression. Receiver operating characteristic (ROC) curves were generated to assess models' performance. The calibration analysis and decision curve analysis (DCA) were also performed. RESULTS: The clinical model consisted of CA125 level and supradiaphragmatic lymphadenopathy and yielded an area under the curve (AUC) of 0.69 (primary cohort) and 0.81 (validation cohort). The radiomics model was built with seven selected features and showed an AUC of 0.87 (primary cohort) and 0.81 (validation cohort). The nomogram finally showed the highest AUC of 0.89 (primary cohort) and 0.87 (validation cohort). The nomogram presented favorable calibrations in both the primary and validation cohorts. DCA further confirmed the clinical benefits of the constructed nomogram. CONCLUSION: CT-based radiomics nomogram provides a non-invasive method to discriminate BRCA gene mutation status of HGSOC and potentially helps develop precise medical strategies.
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The use of multigene panel testing for patients with a predisposition to Hereditary Breast and Ovarian Cancer syndrome (HBOC) is increasing as the identification of mutations is useful for diagnosis and disease management. Here, we conducted a retrospective analysis of BRCA1/2 and non-BRCA gene sequencing in 4630 French HBOC suspected patients. Patients were investigated using a germline cancer panel including the 13 genes defined by The French Genetic and Cancer Group (GGC)-Unicancer. In the patients analyzed, 528 pathogenic and likely pathogenic variants (P/LP) were identified, including BRCA1 (n = 203, 38%), BRCA2 (n = 198, 37%), PALB2 (n = 46, 9%), RAD51C (n = 36, 7%), TP53 (n = 16, 3%), and RAD51D (n = 13, 2%). In addition, 35 novel (P/LP) variants, according to our knowledge, were identified, and double mutations in two distinct genes were found in five patients. Interestingly, retesting a subset of BRCA1/2-negative individuals with an expanded panel produced clinically relevant results in 5% of cases. Additionally, combining in silico (splicing impact prediction tools) and in vitro analyses (RT-PCR and Sanger sequencing) highlighted the deleterious impact of four candidate variants on splicing and translation. Our results present an overview of pathogenic variations of HBOC genes in the southeast of France, emphasizing the clinical relevance of cDNA analysis and the importance of retesting BRCA-negative individuals with an expanded panel.
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The breast cancer susceptibility gene (BRCA) is an important tumor suppressor gene, including BRCA1 and BRCA2, a biomarker that assesses the risk of breast cancer and influences a patient's individualized treatment options. BRCA1/2 mutation (BRCAm) increases the risk of breast cancer. However, breast-conserving surgery is still an option for BRCAm, and prophylactic mastectomy and nipple-sparing mastectomy may also reduce the risk of breast cancer. BRCAm is sensitive to Poly (ADP-ribose) polymerase inhibitor (PARPi) therapy due to specific types of DNA repair defects, and its combination with other DNA damage pathway inhibitors and endocrine therapy and immunotherapy are also used for the treatment of BRCAm breast cancer. The current treatment and research progress of BRCA1/2 mutant breast cancer in this review provides a basis for the individualized treatment of patients with this type of breast cancer.
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Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteína BRCA1/genética , Proteína BRCA2/genética , Mastectomia , Antineoplásicos/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , MutaçãoRESUMO
The BRCA1 and BRCA2 are genes that encode a protein that ensures the integrity of DNA and prevents the unregulated cells from proliferating. Mutations in the sequence of these genes are associated with the birth of inherited breast cancers. The research for possible human breast cancer treatment remains a vital step in the drug development process. In this study, in silico investigations involving a computational method for the discovery of active phytochemicals from Carica papaya against the BRCA-1 gene were carried out. The in silico studies for these phytochemicals datasets as BRCA-1 breast cancer therapeutic agents showed promising results through pharmacokinetics and pharmacodynamics studies. The Carica papaya compounds were found to follow the rule of five and have good bioavailability. The ADMET and drug-likeness screening score of the identified ligands also recognized their potential as a promising drug candidate against BRCA-1 while the DFT also confirm better biological and chemical reactivity of Carica papaya compounds with excellent intra-molecular charge transfer between electron donor and electron acceptor site. The results of the molecular docking provided useful information on possible target-lead interactions, demonstrating that the newly developed leads showed a high affinity for BRCA-1 targets and might be investigated for further research.
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Neoplasias da Mama , Carica , Humanos , Feminino , Extratos Vegetais/química , Neoplasias da Mama/tratamento farmacológico , Carica/química , Simulação de Acoplamento Molecular , Compostos Fitoquímicos/farmacologiaRESUMO
The identification of PARP1 as a therapeutic target for BRCA1/2-deficient cells has led to a paradigm shift for the treatment of human malignancies with BRCA1/2 mutations. However, our understanding of the mechanism of action of PARP1 inhibitors (PARPi) is still evolving. It is being increasingly appreciated that the immunomodulatory function of PARPi is a critical contributor of the anti-tumor effects of these compounds. Here, we identify a novel cell death effector pathway for PARPi where PARPi induces inflammatory pyroptosis that is mediated by caspase 3-dependent cleavage of GSDME. Caspase 3 is activated upon PARPi treatment which directly cleaves GSDME and, subsequently induces pyroptosis. Genetic and pharmacological experiments show that the presence of the PARP1 protein with uncompromised DNA binding capability is required for PARPi-induced pyroptosis, suggesting that PARP1 trapping is a key driver of this phenomenon. Importantly, we show that PARPi-induced GSDME cleavage and pyroptosis occurred only in the BRCA1-deficient cells, but not in those reconstituted with BRCA1 wild-type (WT). These findings suggest that pyroptosis could be a novel aspect of the immunomodulatory function of PARPi. Our studies could also offer new insights to the potential biomarkers and therapeutic strategies to achieve better anti-tumor effects of PARPi for BRCA-deficient tumors with low GSDME expression.
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Neoplasias , Piroptose , Humanos , Gasderminas , Caspase 3/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Morte Celular , Neoplasias/patologiaRESUMO
BACKGROUND: Germline pathogenic variants mutations) in the BRCA1 and BRCA2 genes cause an increased risk of breast cancer and ovarian cancer. Mainstream cancer genetic testing (MCG) was introduced for breast cancer patients in our unit in 2013. Non-geneticist clinicians have been trained to offer genetic testing during initial treatment planning. We assessed the impact of timely test results on surgical decision-making. METHODS: Women who had undergone mainstream genetic testing for breast cancer between September 2013 and September 2018 were identified from a prospective database. Surgical data were collected retrospectively. RESULTS: 580 eligible women had mainstream genetic testing. For 474 this was their first breast cancer diagnosis. The median age was 46 years (interquartile range (IQR) 38-57). The indications were: age ≤45 years for 233 (49%); triple negative disease for 192 women (40.5%); bilateral breast cancer age <60 for 39 (8%) and other for 72 (14%) women. The median time for test initiation to result was 18 days (IQR 15-21). 302 (64% received results before surgery. 88% of those found to have a BRCA mutation before surgery opted for bilateral mastectomy (compared to 5% with BRCA wild type). An additional 106 patients had a new diagnosis on a background of previous treatment. Of these all with a pathogenic variant chose bilateral mastectomy. CONCLUSION: Timely BRCA gene testing influences surgeons' and patients' choice of surgery. It reassures women with a negative result and allows those with a positive result to take an active decision about the management of their future risk.
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Neoplasias da Mama , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Neoplasias da Mama/patologia , Mastectomia/métodos , Estudos Retrospectivos , Genes BRCA1 , Testes Genéticos , MutaçãoRESUMO
This study aimed to investigate whether female BRCA1- and BRCA2 mutation carriers have a reduced ovarian reserve status, based on serum anti-Mullerian hormone (AMH) levels, antral follicle count (AFC) and ovarian response to ovarian hyperstimulation. A prospective, multinational cohort study was performed between October 2014 and December 2019. Normo-ovulatory women, aged 18-41 years old, applying for their first PGT-cycle for reason of a BRCA mutation (cases) or other genetic diseases unrelated to ovarian reserve (controls), were asked to participate. All participants underwent a ICSI-PGT cycle with a long-agonist protocol for controlled ovarian hyperstimulation. Linear and logistic regression models were used to compare AMH, AFC and ovarian response in cases and controls. Sensitivity analyses were conducted on BRCA1- and BRCA2 mutation carrier subgroups. Thirty-six BRCA mutation carriers (18 BRCA1- and 18 BRCA2 mutation carriers) and 126 controls, with mean female age 30.4 years, were included in the primary analysis. Unadjusted median AMH serum levels (IQR) were 2.40 (1.80-3.00) ng/ml in BRCA mutation carriers and 2.15 (1.30-3.40) ng/ml in controls (p = 0.45), median AFC (IQR) was 15.0 (10.8-20.3) and 14.5 (9.0-20.0), p = 0.54, respectively. Low response rate was 22.6% among BRCA mutation carriers and 9.3% among controls, p = 0.06. Median number of retrieved oocytes was 9 (6-14) in carriers and 10 (7-13) in controls, p = 0.36. No substantial differences were observed between BRCA1- and BRCA2 mutation carriers. Based on several biomarkers, no meaningful differences in ovarian reserve status were observed in female BRCA mutation carriers compared to controls in the context of ICSI-PGT treatment.
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Reserva Ovariana , Feminino , Animais , Reserva Ovariana/genética , Estudos de Coortes , Estudos Prospectivos , Proteína BRCA2/genética , Mutação , Hormônio AntimüllerianoRESUMO
A 65-year-old female with a history of multicentric invasive ductal breast carcinoma with lobular features and prior mastectomy presented with a chief complaint of two new raised mildly erythematous lesions on the right upper arm. The lesions were visualized during examination, and the patient noted no symptoms associated with them. Tangential shave biopsies were obtained for each lesion and were sent to the lab for testing. Both lesions were found to be metastatic breast carcinoma. Wide local excisions were performed on each site. The patient followed up with radiation therapy and was prescribed Faslodex and Ibrance. FoundationOne testing on the lesions revealed BRCA2 loss in the tumor, and germline DNA testing was performed in light of this. The test yielded negative results for harmful BRCA1 and 2 mutations. The patient was treated with Lynparza (olaparib), and two years following the start of this medication has had no additional recurrences.
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Background: Olaparib-induced anemia is a frequently occurring complication in patients with advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer and is associated with a marked deterioration in patients' health-related quality of life. This study aimed to clarify patient-specific risk factors for severe anemia in patients with advanced ovarian or breast cancer receiving olaparib monotherapy in a real-world setting. Methods: This multicenter, retrospective, observational study enrolled consecutively presenting patients with advanced ovarian or breast cancer who received olaparib monotherapy as maintenance or palliative treatment between April 2018 and December 2020 at three participating medical institutions in Japan. The primary endpoint was patient-associated risk factors underlying the onset of grade ≥3 anemia from olaparib treatment initiation to 90 days after treatment. Receiver operating characteristic curves were constructed and univariable and multivariable logistic regression analyses were performed to evaluate the association between patient-associated risk factors and grade ≥3 anemia. Results: Of 113 patients evaluated in this study, 32.7% (n = 37) had grade ≥3 anemia. Multivariable logistic regression analysis revealed that low baseline red blood cell (RBC) count (<3.3 × 106 cells/µL), low baseline hematocrit level (<35%), low baseline hemoglobin level (<11.6 g/dL), and breast cancer susceptibility (BRCA1/2) mutation were significantly associated with the onset of grade ≥3 anemia (adjusted odds ratio [OR], 3.39; 95% confidence interval [CI], 1.28-9.62; P = 0.017, adjusted OR, 3.63; 95% CI, 1.28-11.64; P = 0.021, adjusted OR, 3.89; 95% CI, 1.39-12.21; P = 0.014, and adjusted OR, 4.09; 95% CI, 1.55-11.67; P = 0.006, respectively). Conclusions: Our findings suggest that low baseline RBC count, low baseline hematocrit level, and low baseline hemoglobin level might be the patient-associated risk factors for severe anemia induced by olaparib monotherapy. Additionally, BRCA1/2 mutation was suggested to be a patient-related risk factor for anemia regardless of severity. Therefore, applying these patient-associated risk factors would help classify and screen patients at risk of severe anemia.
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OBJECTIVE: To investigate the prevalence and spectrum of BRCA1 and BRCA2 mutations in Chinese Hakka patients with breast and ovarian cancer. METHODS: A total of 1,664 breast or ovarian cancer patients were enrolled for genetic testing at our hospital. Germline mutations of the BRCA gene were analysed by next-generation sequencing, including the coding regions and exon intron boundary regions. RESULTS: The 1,664 patients included 1,415 (85.04%) breast cancer patients and 245 (14.72%) ovarian cancer patients, while four (0.24%) patients had both the breast and ovarian cancers. A total of 151 variants, including 71 BRCA1 variants and 80 BRCA2 variants, were detected in the 234 (14.06%) patients. The 151 variants included 58 pathogenic variants, 8 likely pathogenic variants, and 85 variants of unknown significance (VUS). A total of 56.25% (18/32) and 65.38% (17/26) of pathogenic variants (likely pathogenic variants are not included) were distributed in exon 14 of BRCA1 and exon 11 of BRCA2, respectively. The most common pathogenic variants among this Hakka population are c.2635G > T (p.Glu879*) (n = 7) in the BRCA1 gene and c.5164_5165del (p.Ser1722Tyrfs*4) (n = 7) in the BRCA2 gene among the Hakka population. A hotspot mutation in the Chinese population, the BRCA1 c.5470_5477del variant was not found in this Hakka population. The prevalence and spectrum of variants in the BRCA genes in the Hakka patients are different from that in other ethnic groups. CONCLUSIONS: The most common pathogenic variant in this population is c.2635G > T in the BRCA1 gene, and c.5164_5165delAG in the BRCA2 gene in this population. The prevalence and spectrum of variants in the BRCA1 and BRCA2 genes in the Hakka patients from southern China are different from those in other ethnic groups.
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Neoplasias da Mama , Neoplasias Ovarianas , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Epitelial do Ovário/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Células Germinativas/patologia , Mutação em Linhagem Germinativa , Humanos , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genéticaRESUMO
Recent studies have demonstrated that hereditary breast cancer (BC) has a prevalence of 5-10% among all BC diagnoses. Nowadays, significant technological advances in the identification of an increasingly broad spectrum of genetic mutations allow for the discovery of an ever-growing number of inherited pathogenic (P) or likely pathogenic (LP) variants of breast cancer susceptibility genes. As the management of BC patients carrying mutations in the BRCA1/2 genes or other high-penetrance genes is currently a challenge, extensive research is being carried out and a lively scientific debate has been taking place on what the most appropriate local therapy, especially surgical treatment, of patients with inherited BC should be. In many studies, BC outcomes in BRCA carriers and non-carriers have been compared. A number of them showed that, when compared with mastectomy, breast-conserving surgery in BRCA patients is oncologically safe in terms of overall survival, although an increased risk of ipsilateral recurrence was reported. In these patients, devising a specific therapeutic strategy is an inevitably complex process, as it must take into consideration a series of factors, require a multimodal approach, guarantee personalization, strictly adhere to scientific international guidelines, and consider all available evidence. The present narrative review purposes to identify and illustrate evidence from significant selected studies that discussed those issues, as well as to suggest useful tools to clinicians managing this specific clinical condition in daily clinical practice.