RESUMO
BACKGROUND: The GENEVIEVE study, comparing neoadjuvant cabazitaxel versus paclitaxel in triple-negative breast cancer (TNBC) and luminal B/human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC), previously reported significant differences in pathological complete response (pCR) rates. Effects on long-term outcome are unknown. PATIENTS AND METHODS: GENEVIEVE randomized patients with cT2-3, any cN or cT1, cN+/pNSLN+, centrally confirmed TNBC or luminal B/HER2-negative BC (latter defined as estrogen/progesterone receptor-positive and >14% Ki-67-stained cells) to receive either cabazitaxel 25 mg/m2 q3w for four cycles or paclitaxel 80 mg/m2 weekly for 12 weeks. Anthracycline-containing chemotherapy was allowed in case of histologically proven invasive residuals as neoadjuvant treatment or after surgery as adjuvant treatment. Here we report the secondary endpoints invasive disease-free survival (iDFS), distant disease-free survival (DDFS), and overall survival (OS). RESULTS: Of the 333 patients randomized, 74.7% and 83.2% completed treatment in the cabazitaxel and paclitaxel arms, respectively. After a median follow-up of 89.3 months (interquartile range 68.8-97.3 months), 80 iDFS events (43 after cabazitaxel and 37 after paclitaxel) and 47 deaths (23 after cabazitaxel and 24 after paclitaxel) were reported. IDFS rates were not significantly different between the cabazitaxel and paclitaxel arms after a 3-year (83.6% versus 85.0%) and 5-year follow-up (76.2% versus 78.3%) [hazard ratio (HR) = 1.27, 95% confidence interval 0.82-1.96, P = 0.294], respectively. DDFS rates at 3 years (88.6% versus 87.8%) and 5 years (82.1% versus 82.8%) for cabazitaxel and paclitaxel were comparable (HR = 1.15, P = 0.573). Similarly, OS rates at 3 years (91.6% versus 91.8%) and 5 years (89.2% versus 86.8%) showed no significant differences (HR = 1.05, P = 0.872). Subgroup analysis for TNBC and luminal B/HER2-negative BCs indicated no significant variations in 3- or 5-year iDFS, DDFS, or OS. CONCLUSIONS: The significant differences in pCR rates observed in both treatment arms did not significantly impact long-term outcomes for patients treated with cabazitaxel versus paclitaxel in the GENEVIEVE trial.
Assuntos
Terapia Neoadjuvante , Paclitaxel , Taxoides , Neoplasias de Mama Triplo Negativas , Humanos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Feminino , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Terapia Neoadjuvante/métodos , Pessoa de Meia-Idade , Adulto , Taxoides/uso terapêutico , Taxoides/farmacologia , Idoso , Resultado do Tratamento , Receptor ErbB-2/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Intervalo Livre de DoençaRESUMO
PURPOSE: Tumor protein p53 (TP53) pathogenic variant (PV) carriers are identified during genetic testing for hereditary causes of cancer. PVs in TP53 are associated with the Li-Fraumeni syndrome (LFS), and thus, surveillance and preventive measures are important for TP53 PV carriers. However, the penetrance of TP53 PVs can be low if the Chompret criteria are not fulfilled. In this study, we compared the phenotypic characteristics of families that did and did not fulfill the LFS criteria according to Chompret. METHODS: The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) database was used to identify index patients with a likely pathogenic/pathogenic TP53 variant and their family members. The study investigated the type of variant, pedigree, age of onset, number of primary tumors, and histological type of BC. RESULTS: TP53 PV were present in the index cases of 35 families, 57% (20/35) of which fulfilled the Chompret criteria. The median age of onset at first BC diagnosis was lower in families that fulfilled the Chompret criteria compared to those who did not. Four of all diseased individuals were minors (4%; 4/105) when malignancy was first diagnosed. Sarcomas and brain tumors occurred in 10% (10/105) and in 7% (7/105) of all diseased persons, respectively. BC was the most frequently occurring first tumor (60%; 62/105) and additional malignancy (45%; 20/44) in this cohort. Subsequent malignancies developed in 31% (20/65) of the individuals who fulfilled the Chompret criteria compared with 15% (6/40) of those who did not. CONCLUSION: The tumor spectrum and age of onset found in this study showed that tumors other than BC had low disease penetrance in TP53 PV carriers identified using the GC-HBOC criteria for genetic testing.
Assuntos
Neoplasias da Mama , Síndrome de Li-Fraumeni , Neoplasias Ovarianas , Humanos , Feminino , Proteína Supressora de Tumor p53/genética , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Fenótipo , Mama , Síndrome de Li-Fraumeni/epidemiologia , Síndrome de Li-Fraumeni/genética , Células GerminativasRESUMO
BACKGROUND: Addition of immune checkpoint inhibitors to neoadjuvant chemotherapy (NACT) is a promising strategy in early breast cancer, but the optimal duration of therapy is currently unknown. In the GeparNuevo (NCT02685059) trial, addition of durvalumab to NACT as previously reported led to a moderate increase in pathological complete response (pCR) rate by an absolute 9% (P = 0.287). PATIENTS AND METHODS: Patients with cT1b-cT4a-d triple-negative breast cancer (TNBC) received durvalumab 1.5 g or placebo every 4 weeks added to nab-paclitaxel 125 mg/m2 weekly for 12 weeks, followed by durvalumab/placebo every 4 weeks plus epirubicin/cyclophosphamide every 2 weeks followed by surgery. Durvalumab was not continued after surgery. The primary objective was pCR. Secondary endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS). RESULTS: A total of 174 patients were randomised between June 2016 and October 2017. After a median follow-up of 43.7 months, 34 events had occurred. Despite a non-significant increase in the pCR rate, significant differences were observed for 3-year iDFS, DDFS and OS: iDFS was 85.6% with durvalumab versus 77.2% with placebo [hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.24-0.97, stratified log-rank P = 0.036]; DDFS 91.7% versus 78.4% (HR 0.31, 95% CI 0.13-0.74, P = 0.005); OS 95.2% versus 83.5% (HR 0.24, 95% CI 0.08-0.72, P = 0.006). pCR patients had 3-year iDFS of 95.5% with durvalumab and 86.1% without (HR 0.22, 95% CI 0.05-1.06). In the non-pCR cohort 3-year iDFS was 76.3% versus 69.7% (HR 0.67, 95% CI 0.29-1.54). Multivariable analysis confirmed a durvalumab effect independent of the pCR effect. No new safety signals occurred. CONCLUSIONS: Durvalumab added to NACT in TNBC significantly improved survival despite a modest pCR increase and no adjuvant component of durvalumab. Additional studies are needed to clarify the optimal duration and sequence of checkpoint inhibitors in the treatment of early TNBC.
Assuntos
Terapia Neoadjuvante , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida , Intervalo Livre de DoençaRESUMO
Physical activity (PA) helps prevention and aftercare of sporadic breast cancer (BC), cardiopulmonary fitness (CPF) being an age-independent predictor of tumor-specific mortality. Therefore, we wanted to identify predictors of CPF (represented by peak oxygen uptake: VO2peak) in BRCA1/2 mutation carriers whose risk of developing BC is high. We used cross-sectional data from 68 BRCA1/2 germline mutation carrying women participating in the randomized, prospective, controlled clinical study LIBRE-1. Assessments included cardiopulmonary exercise testing, medical and lifestyle history plus socioeconomic status. Additionally, the participants completed a psychological questionnaire regarding their attitude, subjective norms, perceived behavior control and intention towards PA. A multivariate logistic regression model was used to identify predictors for participants reaching their age- and sex-adjusted VO2peak reference values. 22 participants (median age: 40 years, interquartile range (IQR) 33-46) were cancer-unaffected and 46 cancer-affected (median age: 44 years, IQR 35-50). The strongest predictor for reaching the reference VO2peak value was attitude towards PA (Odds Ratio 3.0; 95% Confidence Interval 1.3-8.4; p = 0.021). None of the other predictors showed a significant association. A positive attitude towards PA seems to be associated with VO2peak, which should be considered in developing therapeutic and preventive strategies.Trial registrations: NCT02087592; DRKS00005736.
Assuntos
Atitude Frente a Saúde , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Teste de Esforço , Exercício Físico/psicologia , Mutação em Linhagem Germinativa , Consumo de Oxigênio , Adulto , Neoplasias da Mama/etiologia , Neoplasias da Mama/psicologia , Estudos Transversais , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e QuestionáriosRESUMO
BACKGROUND: The efficacy and toxicity of olaparib as combination therapy in early breast cancer (BC) patients with homologous recombinant deficiency (HRD) [score high and/or germline (g) or tumour (t) BRCA1/2 mutation] is not well described. GeparOLA (ClinicalTrials.gov, NCT02789332) investigated olaparib in combination with paclitaxel in HER2-negative early BC with HRD. PATIENTS AND METHODS: Patients with untreated primary HER2-negative cT2-cT4a-d or cT1c with either cN+ or pNSLN+ or cT1c and triple-negative breast cancer (TNBC) or cT1c and Ki-67>20% BC with HRD were randomised either to paclitaxel (P) 80 mg/m2 weekly plus olaparib (O) 100 mg twice daily for 12 weeks or P plus carboplatinum (Cb) area under the curve 2 weekly for 12 weeks, both followed by epirubicin/cyclophosphamide (EC). Stratification factors were hormone receptor (HR) status (HR+ versus HR-) and age (<40 versus ≥40 years). The primary endpoint was pathological complete response (pCR; ypT0/is ypN0). A two-sided one-group χ2-test was planned to exclude a pCR rate of ≤55% in the PO-EC arm. Secondary end points were other pCR definitions, breast conservation rate, clinical/imaging response, tolerability and safety. RESULTS: A total of 107 patients were randomised between September 2016 and July 2018; 106 (PO N = 69; PCb N = 37) started treatment. Median age was 47.0 years (range 25.0-71.0); 36.2% had cT1, 61.0% cT2, 2.9% cT3, and 31.8% cN-positive tumours; grade 3 tumours: 86.8%; Ki-67>20%: 89.6%; TNBC: 72.6%; confirmed gBRCA1/2 mutation: 56.2%. The pCR rate with PO was 55.1% [90% confidence interval (CI) 44.5% to 65.3%] versus PCb 48.6% (90% CI 34.3% to 63.2%). Analysis for the stratified subgroups showed higher pCR rates with PO in the cohorts of patients <40 years and HR+ patients. CONCLUSION: GeparOLA could not exclude a pCR rate of ≤55% in the PO arm. PO was significantly better tolerated and the combination merits further evaluation.
Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Ciclofosfamida/efeitos adversos , Recombinação Homóloga , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/efeitos adversos , Ftalazinas , Piperazinas , Receptor ErbB-2/genética , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genéticaRESUMO
BACKGROUND: Female BRCA mutation carriers have an increased lifetime risk for breast and ovarian cancer compared to the general population. Women who carry this mutation have several options to deal with their cancer risk, such as risk-reducing surgeries or intensified breast cancer screening. Previous research has shown that preferences in this scenario are highly dependent on affected women's personalities and value systems. To support these women in the decision-making process, a structured decision support consisting of decision coaching combined with a decision aid might be helpful. METHODS/DESIGN: A randomized controlled trial will be conducted in order to compare usual care with structured decision support alongside usual care. The decision support program entails nurse-led decision coaching as well as an evidence-based patient decision aid. Nurses are qualified by a 4-day training program in informed decision-making and decision coaching. Six centers for Familial Breast and Ovarian Cancer in Germany will be included in the study, with a planned sample size of 398 women. The primary outcome is the congruence between the preferred and the actual played role in the decision-making process as measured by the Control Preferences Scale. It is hypothesized that the structured decision support will enable women to play the preferred role in the decision-making process. Secondary outcomes include the knowledge and attitudes about preventive options, decisional conflict, depression and anxiety, coping self-efficacy, impact of event, and self-concept. A process evaluation will accompany the study. DISCUSSION: The EDCP-BRCA study is the first study to implement and evaluate decision coaching combined with a decision aid for healthy BRCA mutation carriers worldwide. TRIAL REGISTRATION {2A}: DRKS-ID: DRKS00015527. Registered 30 October 2019.
Assuntos
Neoplasias da Mama/enfermagem , Genes BRCA1 , Genes BRCA2 , Aconselhamento Genético/métodos , Relações Enfermeiro-Paciente , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Técnicas de Apoio para a Decisão , Feminino , Predisposição Genética para Doença , Alemanha , Heterozigoto , Humanos , Estudos Multicêntricos como Assunto , Mutação , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Combining immune-checkpoint inhibitors with chemotherapy yielded an increased response rates in patients with metastatic triple-negative breast cancer (TNBC). Therefore, we evaluated the addition of durvalumab to standard neoadjuvant chemotherapy (NACT) in primary TNBC. PATIENTS AND METHODS: GeparNuevo is a randomised phase II double-blind placebo-controlled study randomising patients with TNBC to durvalumab or placebo given every 4 weeks in addition to nab-paclitaxel followed by standard EC. In the window-phase durvalumab/placebo alone was given 2 weeks before start of nab-paclitaxel. Randomisation was stratified by stromal tumour-infiltrating lymphocyte (sTILs). Patients with primary cT1b-cT4a-d disease, centrally confirmed TNBC and sTILs were included. Primary objective was pathological complete response (pCR) (ypT0 ypN0). RESULTS: A total of 174 patients were randomised, 117 participated in the window-phase. Median age was 49.5 years (range 23-76); 47 patients (27%) were younger than 40 years; 113 (65%) had stage ≥IIA disease, 25 (14%) high sTILs, 138 of 158 (87%) were PD-L1-positive. pCR rate with durvalumab was 53.4% (95% CI 42.5% to 61.4%) versus placebo 44.2% (95% CI 33.5% to 55.3%; unadjusted continuity corrected χ2P = 0.287), corresponding to OR = 1.45 (95% CI 0.80-2.63, unadjusted Wald P = 0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR = 2.22, 95% CI 1.06-4.64, P = 0.035; interaction P = 0.048). In both arms, significantly increased pCR (P < 0.01) were observed with higher sTILs. There was a trend for increased pCR rates in PD-L1-positive tumours, which was significant for PD-L1-tumour cell in durvalumab (P = 0.045) and for PD-L1-immune cell in placebo arm (P = 0.040). The most common immune-related adverse events were thyroid dysfunction any grade in 47%. CONCLUSIONS: Our results suggest that the addition of durvalumab to anthracycline-/taxane-based NACT increases pCR rate particularly in patients treated with durvalumab alone before start of chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT02685059.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/análise , Terapia Neoadjuvante/métodos , Neoplasias de Mama Triplo Negativas/terapia , Adulto , Idoso , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/análise , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Mama/patologia , Mama/cirurgia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Método Duplo-Cego , Epirubicina/administração & dosagem , Epirubicina/efeitos adversos , Feminino , Humanos , Hipertireoidismo/induzido quimicamente , Hipertireoidismo/epidemiologia , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/epidemiologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Mastectomia , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Placebos/administração & dosagem , Placebos/efeitos adversos , Estudos Prospectivos , Receptor ErbB-2/análise , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Glândula Tireoide/efeitos dos fármacos , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Adulto JovemRESUMO
Background: In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD). Patients and methods: Patients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study end points disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in formalin-fixed, paraffin-embedded tumor samples of 193/315 (61.3%) participants with TNBC. Homologous recombination (HR) deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA). Results: A significantly better DFS (hazard ratio 0.56, 95% CI 0.34-0.93; P = 0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) [odds ratio (OR) 2.60, 95% CI 1.26-5.37, P = 0.008]. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540; test for interaction P = 0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46-9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17-1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23-1.04, P = 0.059). Conclusions: The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Reparo de DNA por Recombinação/genética , Neoplasias de Mama Triplo Negativas/terapia , Antraciclinas/farmacologia , Antraciclinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteína BRCA1/genética , Proteína BRCA2/genética , Mama/patologia , Mama/cirurgia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Carboplatina/farmacologia , Intervalo Livre de Doença , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Seguimentos , Humanos , Mastectomia , Pessoa de Meia-Idade , Mutação , Terapia Neoadjuvante/métodos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Polietilenoglicóis/farmacologia , Polietilenoglicóis/uso terapêutico , Prognóstico , Análise de Sobrevida , Taxoides/farmacologia , Taxoides/uso terapêutico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Breast cancer surveillance programs for the general population are not adequate for the small number of women with hereditary breast and ovarian cancer syndrome. Breast cancer screening for women in Germany starts at the age of 50 years, but nearly half of all women with familial risk are already diagnosed with breast cancer at that time. Moreover, mammography alone is not suitable for an early diagnosis of breast cancer in young women from high-risk families. Their typical dense breast tissue causes a high rate of false-negative cases. Therefore, national and international prospective clinical trials were initiated to offer a multimodal breast cancer surveillance program including magnetic resonance tomography for the breast and semi-annual screening intervals to women with BRCA1/2 mutations and those from high-risk families who tested negative for BRCA1/2 mutations. This program will currently be evaluated by the 15 centers of the German Consortium for Hereditary Breast and Ovarian Cancer.
Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Detecção Precoce de Câncer/estatística & dados numéricos , Predisposição Genética para Doença/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Vigilância da População/métodos , Comorbidade , Detecção Precoce de Câncer/métodos , Feminino , Predisposição Genética para Doença/epidemiologia , Testes Genéticos/métodos , Testes Genéticos/estatística & dados numéricos , Alemanha , Humanos , Neoplasias Ovarianas/epidemiologia , Prevalência , Prognóstico , Medição de RiscoRESUMO
Purpose: Nowadays, most gynaecologists are female and the compatibility of job-related career and family life is an upcoming issue. The working group "Gender and Career" of the German Society for Gynaecology and Obstetrics (DGGG) designed a survey to reflect the present situation with a focus on the compatibility of career and family. Material and Methods: A web-based 74-item survey was filled out by members of the DGGG. In total, there were 1037 replies, 75â% female (n = 775) and 25â% male (n = 261) gynaecologists. Results: 62â% of the female and 80â% of the male respondents had already finished their doctoral theses and 2â% female and 13â% male had finished their PhD. Mean number of children was 1.06 (SD 1.08) in female and 1.68 (SD 1.34) in male gynaecologists. The majority of females desired day care for their children, but only 5 to 13â% of employers offer any day care. 88â% of the female and 72â% of the male physicians think that job-related career and family are not compatible. Conclusion: The majority of female gynaecologists wished to have professional child care, but most employers or other institutions do not offer this. This might be one of the reasons why career and family appear incompatible.
RESUMO
An estimated 5â% of breast cancers and 10â% of ovarian cancers may be due to inherited autosomal dominant breast and ovarian cancer alleles BRCA1 und BRCA2. According to population-based studies 1 or 2 women per 1000 carry such a risk allele. The cumulative cancer risk for healthy women with a BRCA-mutation is between 60 and 85â% for breast cancer and between 20 and 60â% for ovarian cancer. Recent studies have reported an increased risk for contralateral breast cancer in women after unilateral breast cancer. Since 1997 the German Cancer Aid has supported an interdisciplinary approach for high-risk women consisting of genetic testing, counselling and prevention in 12 specialised centres. Since 2005 this concept has received additional support from health insurance companies, and results have been assessed with regard to outcomes (e.g. reduced mortality due to more intensive early diagnosis). The number of centres has increased to 15 at various university hospitals. These interdisciplinary centres offer women the opportunity to participate in a structured screening programme for the early diagnosis of breast cancer and provide non-directive counselling on the options for risk-reducing surgery, e.g., prophylactic bilateral salpingo-oophorectomy, prophylactic bilateral mastectomy or contralateral prophylactic mastectomy after unilateral breast cancer. Such surgical interventions can significantly reduce the risk of disease, the respective disease-specific mortality and - particularly prophylactic bilateral salpingo-oophorectomy - total mortality in BRCA-mutation carriers.
RESUMO
Although BRCA1-associated breast carcinomas are frequently detected in nodal-negative stage, they typically present with an aggressive histopathological phenotype that is reflected by a poor prognosis and an increased risk for distant metastatic spread. Recent in vitro data suggest a high sensitivity of BRCA1-associated carcinomas to platinum-based chemotherapy and a lower sensitivity to anthracyclines and taxanes. This is explained by the key role of BRCA1 in DNA double-strand repair via homologous recombination, thereby leading to a higher sensitivity to DNA intercalating agents, such as platinum. Here we present the case of a woman suffering from BRCA1-associated metastatic breast carcinoma that was resistant to docetaxel, but responded strongly to cisplatin-containing chemotherapy. This supports the rationale of ongoing clinical studies.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Genes BRCA1 , Mutação em Linhagem Germinativa , Compostos Organoplatínicos/uso terapêutico , Adulto , Feminino , HumanosRESUMO
Distant metastases in small cell carcinomas of the uterine cervix are rare, and a disseminated manifestation of the disease is uncommon. This is a case report of a 40-year-old woman treated with platin-based radio-chemotherapy for a moderately differentiated squamous cell cervical cancer FIGO Stage IB 1 (with positive paraaortic lymph nodes). One year later she presented with remarkably unusual cutaneous metastases of the left thumb and scalp as the first signs of spread of disease, including kidney, lung and brain metastases. An advanced retrospective immunohistochemical staining of the cervical biopsy discovered a small neuroendocrine component of the carcinoma as the presumably causative factor for the rare metastastic pattern and poor prognosis.
Assuntos
Carcinoma de Células Pequenas/diagnóstico , Carcinoma de Células Pequenas/secundário , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapia , Adulto , Carcinoma de Células Pequenas/tratamento farmacológico , Evolução Fatal , Feminino , Humanos , Doenças Raras , Neoplasias Cutâneas/secundário , Crânio/patologia , Polegar/patologia , Neoplasias do Colo do Útero/tratamento farmacológicoRESUMO
Malignant extragonadal tumors arising from endometriosis are rare. We report on two cases. A 41-year-old gravida 1, para 1 (G1P1), with adenocarcinoma of the right parametrium arising from endometriosis and a 51-year-old G1P1 with endometriosis-associated rectovaginal adenocarcinoma were treated. Treatment included radical surgery plus radiation therapy. While the former patient was doing well 2 years after the primary diagnosis, the latter suffered a local pelvic recurrence 2 years later. Although there are no randomized controlled studies, radical surgery followed by radiation therapy seems generally to be the treatment of choice. The analysis of PTEN in various forms of endometriosis and its malignant transformation may help in understanding the early steps of tumorigenesis.
Assuntos
Adenocarcinoma/etiologia , Endometriose/complicações , Neoplasias Pélvicas/etiologia , Neoplasias Retais/etiologia , Neoplasias Vaginais/etiologia , Adenocarcinoma/genética , Adenocarcinoma/terapia , Adulto , Antineoplásicos/uso terapêutico , Carboplatina/uso terapêutico , Transformação Celular Neoplásica , Colectomia , Endometriose/genética , Feminino , Procedimentos Cirúrgicos em Ginecologia , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , PTEN Fosfo-Hidrolase/genética , Neoplasias Pélvicas/genética , Neoplasias Pélvicas/terapia , Radioterapia Adjuvante , Neoplasias Retais/genética , Neoplasias Retais/terapia , Resultado do Tratamento , Neoplasias Vaginais/genética , Neoplasias Vaginais/terapiaRESUMO
INTRODUCTION: Unclassified variants (UVs) of unknown clinical significance are frequently detected in the BRCA2 gene. In this study, we have investigated the potential pathogenic relevance of the recurrent UV S384F (BRCA2, exon 10). METHODS: For co-segregation, four women from a large kindred (BN326) suffering from breast cancer were analysed. Moreover, paraffin-embedded tumours from two patients were analysed for loss of heterozygosity. Co-occurrence of the variant with a deleterious mutation was further determined in a large data set of 43,029 index cases. Nature and position of the UV and conservation among species were evaluated. RESULTS: We identified the unclassified variant S384F in three of the four breast cancer patients (the three were diagnosed at 41, 43 and 57 years of age). One woman with bilateral breast cancer (diagnosed at ages 32 and 50) did not carry the variant. Both tumours were heterozygous for the S384F variant, so loss of the wild-type allele could be excluded. Ser384 is not located in a region of functional importance and cross-species sequence comparison revealed incomplete conservation in the human, dog, rodent and chicken BRCA2 homologues. Overall, the variant was detected in 116 patients, five of which co-occurred with different deleterious mutations. The combined likelihood ratio of co-occurrence, co-segregation and loss of heterozygosity revealed a value of 1.4 x 10-8 in favour of neutrality of the variant. CONCLUSION: Our data provide conclusive evidence that the S384F variant is not a disease causing mutation.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Variação Genética , Mutação em Linhagem Germinativa , Perda de Heterozigosidade , Polimorfismo de Nucleotídeo Único , Adulto , Substituição de Aminoácidos , Segregação de Cromossomos , DNA de Neoplasias/genética , Feminino , Lateralidade Funcional , Humanos , Pessoa de Meia-IdadeRESUMO
Chronic inversion of the uterus is a serious obstetric complication often requiring laparotomy as manual replacement alone usually fails. We report on the successful laparoscopic-assisted replacement of a chronically inverted puerperal uterus on the 11th day post partum. The scientific literature back to the 19th century is briefly discussed.
Assuntos
Laparoscopia/métodos , Inversão Uterina/cirurgia , Adulto , Feminino , Humanos , Período Pós-Parto , GravidezRESUMO
We report on the association of Mayer-von Rokitansky-Küster-Hauser syndrome (MRKHS) with a unique form of Holt-Oram syndrome (HOS) with an aorto-pulmonary window. A 24-year-old Turkish woman was referred to our hospital because of primary amenorrhoea. Both her vagina and uterus were absent, and the diagnosis of MRKHS was established. Laparoscopic creation of a neovagina by the modified Vecchietti technique was performed. A rare congenital malformation of the heart, namely an aorto-pulmonary window, had required cardiac surgery when the patient was a 6-month-old infant. This cardiac malformation plus associated upper limb anomalies led to the clinical diagnosis of HOS. To the best of our knowledge, this is only the second report in the scientific literature on the concurrence of MRKHS and HOS, and the first published case of HOS with an aorto-pulmonary window as the cardiac malformation.
Assuntos
Anormalidades Múltiplas/patologia , Defeito do Septo Aortopulmonar/patologia , Útero/anormalidades , Vagina/anormalidades , Adulto , Braço/anormalidades , Feminino , HumanosRESUMO
An asymptomatic woman (age 38 years) with a family history of ovarian malignancies was referred for presymptomatic genetic testing of mutations in the BRCA genes. A familial Swyer syndrome with the occurrence of dysgerminomas is the most likely diagnosis. However, in our case, all known causes of this heterogeneous disorder have been excluded pointing to the existence of another yet unknown genetic locus. The family history revealed three affected paternal aunts. Two of them developed ovarian malignancies at 13 and 15 years of age, and died at ages 19 and 20. The third aunt, 82 years old, was affected by this disease at the age of 35. She underwent hormonal treatment for 3 years starting at the age of 15 because of primary amenorrhea. Under this treatment she developed nearly complete secondary sexual characteristics. Karyotype analysis revealed a normal male karyotype (46 XY, QFQ). Pelvic ultrasound showed an uterus of normal size, incompatible with an androgen resistance syndrome or a defect in testosterone biosynthesis. We excluded a mutation in the sex-determining region on chromosome Y (SRY) by direct sequencing of the SRY gene. An involvement of the subtelomeric region of chromosome 9p (9p 24.3) recently reported to be involved in XY-sex reversal phenotypes was excluded by molecular testing for loss of heterozygosity as well as fluorescence in situ hybridization studies. Analyses of the DAX1 gene in the dosage sensitive sex reversal locus on chromosome Xp21 by Southern blot analysis showed no duplications.
Assuntos
Disgenesia Gonadal 46 XY/genética , Cariotipagem , Fenótipo , Cromossomos Sexuais , 17-alfa-Hidroxiprogesterona/sangue , Adulto , Androstenodiona/sangue , Cromossomos Humanos Par 9/genética , Cromossomos Humanos X/genética , Análise Mutacional de DNA , Di-Hidrotestosterona/sangue , Transtornos do Desenvolvimento Sexual , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Genitália/patologia , Disgenesia Gonadal 46 XY/sangue , Disgenesia Gonadal 46 XY/patologia , Humanos , Hibridização in Situ Fluorescente , Hormônio Luteinizante/sangue , Masculino , Neoplasias Ovarianas/genética , Linhagem , Progesterona/sangue , Prolactina/sangue , Valores de Referência , Análise de Sequência de DNA , Testosterona/sangue , Ultrassonografia , Útero/diagnóstico por imagemRESUMO
The case of a 36-year-old pregnant patient is reported. On account of the limited radiological possibilities, establishing the diagnosis was complicated. When symptoms are persisting, the diagnosis should always be reconsidered.