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INTRODUCTION: The role of cytoreductive surgery in the poly-ADP ribose polymerase inhibitors era is not fully investigated. We evaluated the impact of surgery performed prior to platinum-based chemotherapy followed by olaparib maintenance in platinum-sensitive BRCA-mutated recurrent ovarian cancer. METHODS: This retrospective study included platinum-sensitive recurrent ovarian cancer BRCA-mutated patients from 13 Multicenter Italian Trials in Ovarian cancer and gynecological malignancies centers treated between September 2015 and May 2019. The primary outcomes were progression-free survival and overall survival. Data on post-progression treatment was also assessed. RESULTS: Among 209 patients, 72 patients (34.5%) underwent cytoreductive surgery followed by platinum-based chemotherapy and olaparib maintenance, while 137 patients (65.5%) underwent chemotherapy treatment alone. After a median follow-up of 37.3 months (95% CI: 33.4 to 40.8), median progression-free survival in the surgery group was not reached, compared with 11 months in patients receiving chemotherapy alone (P<0.001). Median overall survival was nearly double in patients undergoing surgery before chemotherapy (55 vs 28 months, P<0.001). Post-progression therapy was assessed in 127 patients: response rate to chemotherapy was 29.2%, 8.8%, and 9.0% in patients with platinum-free interval >12 months, between 6 and 12 months, and <6 months, respectively. CONCLUSION: Cytoreductive surgery performed before platinum therapy and olaparib maintenance was associated with longer progression-free survival and overall survival in BRCA-mutated platinum-sensitive relapsed ovarian cancer patients. In accordance with our preliminary results, the response rate to chemotherapy given after progression during olaparib was associated with platinum-free interval.
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Proteína BRCA1/efectos de los fármacos , Proteína BRCA2/efectos de los fármacos , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Procedimientos Quirúrgicos de Citorreducción/métodos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Ftalazinas/uso terapéutico , Piperazinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Carcinoma Epitelial de Ovario/mortalidad , Femenino , Humanos , Persona de Mediana Edad , Mutación , Ftalazinas/farmacología , Piperazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Supervivencia sin Progresión , Estudios RetrospectivosRESUMEN
OBJECTIVES: Olaparib is approved as maintenance therapy in patients with BRCA mutated platinum sensitive (PS) recurrent ovarian cancer (OC) after response to last platinum based therapy. Few data are available regarding the use out of the registration trials and on response to further treatments after progression. MATERIALS AD METHODS: In this non interventional, retrospective study, patients treated with olaparib in 13 centers, according to the label, have been collected and analyzed. Primary objectives of the study are to describe effectiveness and safety of olaparib in a real world setting with a focus on post progression treatments and response. RESULTS: 234 patients were analyzed. All patients were BRCA mutated and most of them had germline mutations. Around 50% of the patients received olaparib after 3 or more lines of platinum based chemotherapy achieving a radiologic complete (CR) or partial response. 12.4% patients with stable disease were also included. Median PFS was 14.7 months (95% CI:12.6-18), with statistically longer PFS in patients with normal serum Ca125 at baseline, a CR after last platinum based therapy and that received olaparib after second platinum based therapy. Median OS was not reached. Most frequent G3-G4 toxicity was anaemia (6%) with dose discontinuation and dose reduction in 11 (4.7%) and 49 (20.9%) of cases, respectively. Among 66 patients receiving further treatment after olaparib progression and evaluable for response, ORR was 22.2, 11.1% and 9.5% in patients with Platinum Free interval (PFI) of more than 12 months, between 6 and 12 months and less than 6 months, respectively. CONCLUSIONS: Olaparib is effective and safe in real world setting. Data on post-progression treatments seem to suggest cross resistance with chemotherapy and need to be confirmed in larger studies because of the potential importance in clinical practice decisions.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Antineoplásicos/administración & dosificación , Femenino , Genes BRCA1 , Genes BRCA2 , Mutación de Línea Germinal , Humanos , Quimioterapia de Mantención , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Supervivencia sin Progresión , Estudios RetrospectivosRESUMEN
Olaparib is the first poly(ADP-ribose) polymerase inhibitor approved as maintenance therapy of recurrent ovarian cancer (OC) patients with a BRCA mutation. To achieve the maximum clinical benefit, adherence to olaparib must be persistent. However, in clinical practice, this is challenged by the frequent suboptimal management of toxicities. In view of the expanding use of olaparib also in Italy, physicians must learn how to adequately and promptly manage drug toxicities not to unnecessarily interrupt or reduce the dose. The experts agreed that nausea,vomiting, anemia, and fatigue are the most frequent events experienced by OC patients on olaparib, and that these toxicities usually develop early during treatment, are mainly of grade 1-2 and transient and can be managed with simple non-pharmacological interventions. By sharing their real-world experiences, the panel prepared, for each toxicity, an algorithm organized by grade and besides the procedures indicated in the local label, included supportive care interventions based also on nutritional and lifestyle modifications and psycho-oncology consultation. Moreover, in view of the tablet entry into the Italian market, the full and reduced dosages of capsules and tablets were compared. This practical guidance is intended to be a tool to support especially less-experienced physicians in the management of these complex patients, with the aim to help preventing the worsening of patients' conditions and the unnecessary interruption/reduction of olaparib dosage, which may jeopardize treatment efficacy.
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Antineoplásicos/efectos adversos , Neoplasias Ováricas/tratamiento farmacológico , Ftalazinas/efectos adversos , Piperazinas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Anemia/inducido químicamente , Antineoplásicos/uso terapéutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Fatiga/inducido químicamente , Femenino , Humanos , Italia , Mutación , Náusea/inducido químicamente , Náusea/terapia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/genética , Ftalazinas/uso terapéutico , Piperazinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Vómitos/inducido químicamenteRESUMEN
This article evaluates the breast cancer (BC) screening efficacy of biannual ultrasound (US) in three different risk categories. In a single-center, prospective, nonrandomized comparison study, BRCA mutation carriers and women with high risk (HR) or intermediate risk (IR) received mammography (MMG), ultrasound, (US) and Magnetic Resonance Imaging (MRI), scheduled according to the risk categories. Single and combined sensitivity were evaluated in specific groups of risk and the US performance at six-monthly interval was notably considered. Among 2,313 asymptomatic women at different risk (136 mutation carriers, 1,749 at HR and 428 at IR) 211 developed a BC, of which 193 (91.5%) were screen detected BC (SDBC) and 18 (8.5%) were interval BC (IBC). The SDBC detection rate (DR) was 11.2 per 1.000 person-years (37.9, 8.5 and 16.1 for BRCA, HR and IR, respectively); 116 BC were detected by MMG (DR = 6.6 × 1,000 persons-years), 62 by US (DR = 3.6 × 1,000 persons-years) and 15 by MRI, that was applied only in 60 BRCA women (DR = 37 × 1,000 persons-years). At the six-monthly US, 52 BC were detected (DR = 3.0 × 1,000 persons/years), of which 8 were BRCA-related. The most sensitive technique was MRI (93.7%) followed by MMG (55%) and US (29.4%). Combined sensitivity for MMG plus US was 100% in HR and 80.4% for IR women (p < 0.01). In BRCA mutated patients, MRI alone with annual US performed after six months, could be offered. In HR patients, MMG plus biannual US provide the most sensitive diagnosis and for IR group an annual MMG could be sufficient.
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Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Neoplasias de la Mama/genética , Detección Precoz del Cáncer/métodos , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Mamografía , Persona de Mediana Edad , Mutación/genética , Estudios Prospectivos , Riesgo , Proteínas Supresoras de Tumor/genética , Ultrasonografía Mamaria/métodosRESUMEN
AIM: This retrospective analysis focused on the effect of treatment with EVE/EXE in a real-world population outside of clinical trials. We examined the efficacy of this combination in terms of PFS and RR related to dose intensity (5 mg daily versus 10 mg daily) and tolerability. METHODS: 163 HER2-negative ER+/PgR+ ABC patients, treated with EVE/EXE from May 2011 to March 2016, were included in the analysis. The primary endpoints were the correlation between the daily dose and RR and PFS, as well as an evaluation of the tolerability of the combination. Secondary endpoints were RR, PFS, and OS according to the line of treatment. Patients were classified into three different groups, each with a different dose intensity of everolimus (A, B, C). RESULTS: RR was 29.8% (A), 27.8% (B) (p = 0.953), and not evaluable (C). PFS was 9 months (95% CI 7-11) (A), 10 months (95% CI 9-11) (B), and 5 months (95% CI 2-8) (C), p = 0.956. OS was 38 months (95% CI 24-38) (A), median not reached (B), and 13 months (95% CI 10-25) (C), p = 0.002. Adverse events were stomatitis 57.7% (11.0% grade 3-4), asthenia 46.0% (6.1% grade 3-4), hypercholesterolemia 46.0% (0.6% grade 3-4), and hyperglycemia 35.6% (5.5% grade 3-4). The main reason for discontinuation/interruption was grade 2-3 stomatitis. CONCLUSIONS: No correlation was found between dose intensity (5 vs. 10 mg labeled dose) and efficacy in terms of RR and PFS. The tolerability of the higher dose was poor in our experience, although this had no impact on efficacy.
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Androstadienos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Everolimus/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Italia/epidemiología , Persona de Mediana Edad , Estadificación de Neoplasias , Receptor ErbB-2/genética , Receptores de Estrógenos/genética , Receptores de Progesterona/genética , Estomatitis/inducido químicamente , Estomatitis/genética , Estomatitis/patologíaRESUMEN
OBJECTIVE: To evaluate the effectiveness of transvaginal ultrasound (TVU) and serum CA-125 measurement in women at different risk of developing ovarian cancer/fallopian tube cancer (OC/FTC) and the incidence of primary peritoneal cancer (PPC) after risk-reducing salpingo-oophorectomy (RRSO). METHODS: Between 2002 and 2014, 661 women at different risk of OC/FTC/PPC due to a family history or BRCA1/2 gene mutation were offered TVU and CA-125 measurement or RRSO as prevention strategies. The detection rate of OC/FTC/PPC was evaluated, and the sensitivity and specificity for CA-125 measurement and TVU were calculated. Survival and event analysis was performed for diagnosed patients. RESULTS: After a median follow-up of 112 months, 12 OC/FTC/PPC cases were detected (2.6/1,000 persons/year). The screening sensitivity was 70%, with 73% for BRCA carriers. Six (50%) of 12 cancers were stage I or II. Among 41 women who underwent RRSO, 2 BRCA1 carriers developed a PPC (4.9%). At 61-month follow-up, overall and event-free survival were 75 and 64%, respectively. CONCLUSIONS: The cancer detection rate in women with BRCA mutation or a strong family history supports the effectiveness of our surveillance program for early diagnosis. Screening for women at lower risk of OC/FTC is not recommended. A residual risk of PPC after RRSO remains for BRCA1 carriers.
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Antígeno Ca-125/sangre , Neoplasias Ováricas/sangre , Neoplasias Ováricas/patología , Proteína BRCA1/genética , Proteína BRCA2/genética , Supervivencia sin Enfermedad , Neoplasias de las Trompas Uterinas/sangre , Neoplasias de las Trompas Uterinas/patología , Femenino , Humanos , Incidencia , Persona de Mediana Edad , Mutación/genética , Neoplasias Ováricas/genética , Ovariectomía/métodos , Neoplasias Peritoneales/sangre , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/patología , Estudios Prospectivos , Factores de Riesgo , Salpingooforectomía/métodos , Sensibilidad y Especificidad , Ultrasonografía/métodosAsunto(s)
Neoplasias , Proteína BRCA1/genética , Neoplasias de la Mama , Femenino , Haplotipos/genética , Humanos , Mutación , Neoplasias OváricasRESUMEN
OBJECTIVES: The aim of this exploratory, descriptive study was to characterize the deleterious BRCA1 and BRCA2 variants evaluated by genetic testing in a group of Ovarian cancer patients living in the Salento peninsula (Southern Italy). METHODS: From June 2014 to July 2023, patients with histologically confirmed high-grade serous carcinoma, fallopian tube, or primary peritoneal cancer who were referred to Lecce Familial Cancer Clinic were considered. BRCA-mutation genetic testing was performed on these patients. Socio-demographic data and cancer epidemiology were assessed, and Next Generation Sequencing and Sanger DNA sequencing were performed. RESULTS: The median age at the diagnosis of 332 ovarian cancer patients collected was 57 years. The pedigree analyses showed that 28.6% had familial cases and 39.7% had sporadic cases. Of the 319 patients submitted to genetic testing, 29.8% were carriers of BRCA1/2 mutation, 75.8% at BRCA1 and 24.2% at BRCA2 gene. Of the 21 BRCA1 mutations, the variant c.5266dupC was the most frequent alteration (28.4%). With respect to BRCA2, 13 mutations were found and the variant c.9676delT was the most frequently recorded (6.3%). CONCLUSIONS: This study reveals that the prevalence of germline mutations in the BRCA1 and BRCA2 genes was higher than reported by other studies. A broader understanding of the prevalence and role of BRCA mutations in development, response to treatment, and prognosis represents an exciting and developing area of ovarian cancer treatment and prevention.
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Genes BRCA2 , Neoplasias Ováricas , Femenino , Humanos , Persona de Mediana Edad , Proteína BRCA2/genética , Prevalencia , Proteína BRCA1/genética , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/genética , Servicios Preventivos de Salud , Italia/epidemiología , Células GerminativasRESUMEN
Chemoprevention for women at risk for breast cancer has been shown to be effective, but in actual practice, women's uptake of chemoprevention has been poor. We explored factors that influence acceptability, adherence, and dropout in the International Breast (Prevention) Intervention Study during our first 3 years of activity at the Modena Familial Breast and Ovarian Cancer Center. We evaluated socio-demographic characteristics, health status, adherence, and side effect intensity. Semi-structured interviews analyzed reasons for accepting/refusing/stopping the trial. A total of 471 postmenopausal women were invited to participate, of which 319 declined to participate (68%), 137 accepted to participate (29%), and 15 participants did not make a final decision (3%). Breast cancer-related worries and trust in our preventive and surveillance programs were the most frequent reasons for accepting. Side effect-related worry was the most frequent reason for refusing. General practitioners' and family members' opinions played an important role in the decision-making process. Adherence significantly decreased after a 12-month follow-up, but it remained unchanged after 24- and 36-month follow-ups. Mild/moderate side effects reported by women did not change after 12 months of treatment. Forty percent of women withdrew from the study due to complaints of side effects. We concluded that chemoprevention trials are difficult medical experiments and that the process of deciding about whether or not to participate is based mainly on beliefs and values. This study has important clinical implications. During counselling with prospective participants, it is important to emphasize the potential benefits and to promote an informed choice. How participants make decisions, their belief systems, and their perception of risk are all factors that should be investigated in future research.
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Anticarcinógenos/uso terapéutico , Neoplasias de la Mama/prevención & control , Cumplimiento de la Medicación , Nitrilos/uso terapéutico , Negativa del Paciente al Tratamiento , Triazoles/uso terapéutico , Adulto , Anciano , Análisis de Varianza , Anastrozol , Anticarcinógenos/efectos adversos , Artralgia/inducido químicamente , Distribución de Chi-Cuadrado , Toma de Decisiones , Método Doble Ciego , Oftalmopatías/inducido químicamente , Femenino , Estudios de Seguimiento , Sofocos/inducido químicamente , Humanos , Italia , Persona de Mediana Edad , Nitrilos/efectos adversos , Pacientes Desistentes del Tratamiento , Triazoles/efectos adversos , Enfermedades Vaginales/inducido químicamenteRESUMEN
The study of the ovarian proteomic profile represents a new frontier in ovarian cancer research, since this approach is able to enlighten the wide variety of post-translational events (such as glycosylation and phosphorylation). Due to the possibility of analyzing thousands of proteins, which could be simultaneously altered, comparative proteomics represent a promising model of possible biomarker discovery for ovarian cancer detection and monitoring. Moreover, defining signaling pathways in ovarian cancer cells through proteomic analysis offers the opportunity to design novel drugs and to optimize the use of molecularly targeted agents against crucial and biologically active pathways. Proteomic techniques provide more information about different histological types of ovarian cancer, cell growth and progression, genes related to tumor microenvironment and specific molecular targets predictive of response to chemotherapy than sequencing or microarrays. Estimates of specificity with proteomics are less consistent, but suggest a new role for combinations of biomarkers in early ovarian cancer diagnosis, such as the OVA1 test. Finally, the definition of the proteomic profiles in ovarian cancer would be accurate and effective in identifying which pathways are differentially altered, defining the most effective therapeutic regimen and eventually improving health outcomes.
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Neoplasias Ováricas/metabolismo , Proteómica/métodos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Electroforesis en Gel Bidimensional , Femenino , Genes BRCA1 , Genes BRCA2 , Humanos , Espectrometría de Masas , Terapia Molecular Dirigida , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/terapia , Análisis por Matrices de Proteínas , Procesamiento Proteico-Postraduccional , Proteoma/metabolismo , Proteómica/tendencias , Transducción de SeñalRESUMEN
BACKGROUND AND OBJECTIVES: Non-melanoma skin cancers (NMSCs) include basal cell carcinoma (BCC) and squamous-cell carcinoma (SCC), as well as a wide range of rare skin tumors. NMSCs is the most frequently diagnosed type of tumor among Caucasians. We aimed at estimating the incidence and mortality of NMSCs in the Salento area (Lecce province, Southern Italy), whose population is assumed to experience heavy and frequent sun exposure due to climatic/environmental factors, both for working and leisure activities. MATERIALS AND METHODS: We computed the incidence of NMSCs in the Province of Lecce by examining the comprehensive real-world data collected by the local cancer registry, which covers all the 830,000 inhabitants, over a period of fifteen years (from 2003 to 2017), with a focus on the latest 5 years (2013-2017) for the analysis of the different histologic morphologies of these tumors. The incidence of NMSCs has been described in terms of absolute frequencies, crude rates and age-adjusted direct standardized rates (DSR). Joinpoint analysis was used to examine temporal trends in the incidence of NMSCs and estimate annual percent changes (APCs). RESULTS: During the period of 2003-2017, the incidence of NMSCs reached a direct standardized rate (DSR) of 162.62 per 100,000 in men (mortality 1.57 per 100,000) and 89.36 per 100,000 in women (mortality 0.52 per 100,000), respectively. The incidence significantly increased among both men and women across the entire period. Basal cell carcinoma (BCC), with its different morphologies, represented about 67.6% of the NMSCs in men (n = 2139 out of a total of 3161 tumors observed between 2013 and 2017) and about 75.8% of the NMSCs in women (n = 1718 out of a total of 2264 tumors from 2013 to 2017), thus accounting for the vast majority of NMSCs. The results are consistent with the literature data carried out both at national and international level. CONCLUSIONS: Proper monitoring of this phenomenon through timely reporting and recording of all new NMSC cases is necessary to develop new preventive strategies.
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Individuals that attend cancer genetic counseling may experience test-related psychosocial problems that deserve clinical attention. In order to provide a reliable and valid first-line screening tool for these issues, Eijzenga and coworkers developed the Psychosocial Aspects of Hereditary Cancer (PAHC) questionnaire. The aim of this work was to develop an Italian adaptation of the PAHC (I-PACH). This prospective multicenter observational study included three stages: (1) development of a provisional version of the I-PAHC; (2) pilot studies aimed at testing item readability and revising the questionnaire; and (3) a main study aimed at testing the reliability and validity of the final version of the I-PAHC with the administration of a battery comprising measures of depression, anxiety, worry, stress, and life problems to 271 counselees from four cancer genetic clinics. Adapting the original PAHC to the Italian context involved adding two further domains and expanding the emotions domain to include positive emotions. While most of the items were found to be easy to understand and score, some required revision to improve comprehensibility; others were considered irrelevant or redundant and therefore deleted. The final version showed adequate reliability and validity. The I-PAHC provides comprehensive content coverage of cancer genetic-specific psychosocial problems, is well accepted by counselees, and can be considered a sound assessment tool for psychosocial issues related to cancer genetic counseling and risk assessment in Italy.
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BRCA1/2-associated hereditary breast and ovarian cancer is the most common form of hereditary breast and ovarian cancer and occurs in all ethnicities and racial populations. Different BRCA1/BRCA2 pathogenic variants (PVs) have been reported with a wide variety among populations. In this study, we retrospectively analyzed prevalence and geographic distribution of pathogenic germline BRCA1/2 variants in families from Apulia in southern Italy and evaluated the genotype-phenotype correlations. Data were collected from Oncogenetic Services present in Apulian hospitals and a shared database was built containing Apulian native probands (n = 2026) that had undergone genetic testing from 2004 to 2019. PVs were detected in 499 of 2026 (24.6%) probands and 68.5% of them (342 of 499) were in the BRCA1 gene. We found 65 different PVs in BRCA1 and 46 in BRCA2. There were 10 most recurrent PVs and their geographical distribution appears to be significantly specific for each province. We have assumed that these PVs are related to the historical and geopolitical changes that occurred in Apulia over time and/or to a "founder effect". Broader knowledge of BRCA1/2 prevalence and recurring PVs in specific geographic areas could help establish more flexible genetic testing strategies that may enhance our ability to detect high-risk subjects.
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Genomic testing expansion is accompanied by an increasing need for genetic counselling and intrafamilial communication. Genetic counselling can play an important role in facilitating intrafamilial communication and relationships. We conducted a cross-sectional, multicenter study including 252 Italian women, using a questionnaire divided in two sections, the first one to be filled after the pre-test counselling and the second after receiving BRCA test results. We assessed the factors influencing intrafamilial disclosure of genetic information for hereditary breast and ovarian cancer, family members with whom probands are more prone to share genetic information, and the perceived understanding of information received by counselees during genetic counselling. Women were accompanied to the counselling more often by their husband/partner. Among those with a positive BRCA test result, 49% intended to communicate it to their offspring and 27% to their husband/partner. Younger women, those living with their husband/partner, and those who described family communication as open/profound and spontaneous/sincere had a higher probability of being accompanied during genetic counselling and discuss about it with relatives. Spontaneous/sincere or open/profound family communication and joyful/happy familial relationships were associated with the decision to undergo genetic testing as a responsibility towards relatives. Women had a good understanding of counselling contents (mean score 9.27 in a scale 1-10). Genetic counselling providers should consider that genetic information disclosure does not depend only on the clarity of the information provided, but also on pre-existing intrafamilial communication and relationships, family structure and marital status, indicating the need for a personalised approach accounting for these factors.
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Neoplasias de la Mama/genética , Comunicación , Asesoramiento Genético , Neoplasias Ováricas/genética , Adulto , Estudios Transversales , Revelación , Familia , Femenino , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Humanos , Italia , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
An attempt for the identification of potential biomarkers predictive of response to chemotherapy (CHT) in breast cancer patients has been performed by the use of two-dimensional electrophoresis and mass spectrometry analysis. Since growth and progression of tumor cells depend also on stromal factors in the microenvironment, we choose to investigate the proteins secreted in Tumor Interstitial Fluid (TIF) and in Normal Interstitial Fluids (NIF). One-hundred and twenty-two proteins have been analyzed and a comparison was also made between the proteomic profile of responders versus nonresponders to CHT. At baseline, proteins isolated in TIF and NIF of all the 28 patients show significant differences in expression. Two clusters of proteins, differentially expressed in TIF with respect to NIF were found. Most significant is the decreased expression in TIF of CRYAB. In the protein metabolism group, also FIBB was found decreased. Some proteins involved in energy pathways were overexpressed (PGAM-1, ALDO A, PGK1, G3Pcn), while some other were down-regulated (CAH2, G3Pdx, PRDX6, TPIS). The same trend was observed for signal transduction proteins, with 14-3-3-Z overexpressed, and ANXA2 and PEBP 1 down-regulated. Moreover, an analysis has been conducted comparing protein expression in interstitial fluids of responders and nonresponders, irrespective of TIF or NIF source. This analysis lead us to identify two clusters of proteins with a modified expression, which might be predictive of response to CHT. In responders, an increase in expression of LDHA, G3Pdx, PGK1sx (energy pathways), VIME (cell growth and maintenance) and 14-3-3-Z (signal transduction), coupled with a decreased expression of TPIS, CAH 2, G3Psx, PGK 1dx (energy pathways), TBB5 (cell growth and maintenance), LDHB and FIBB (protein metabolism), was found. We observed that CHT modifies the expression of these cluster proteins since, after treatment, their expression in TIF of responder is generally decreased. Patients not responding to CHT show an unchanged expression pattern in TIF, with the exception of protein 14-3-3-Z, which is overexpressed, and a decreased expression in NIF of several cluster proteins. In conclusion, the identification of protein clusters associated with response to CHT might be important for predicting the efficacy of a specific antineoplastic drug and for the development of less empiric strategies in choosing the therapy to be prescribed to the single patient.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/análisis , Neoplasias de la Mama , Líquido Extracelular/química , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Análisis por Conglomerados , Electroforesis en Gel Bidimensional/métodos , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Datos de Secuencia Molecular , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
INTRODUCTION: The aim of this study was to investigate the incidence of second primary tumors in patients with breast cancer (BC), with particular regard to bidirectional risk for endometrial cancer (EC). METHODS: A total of 7512 and 343 patients with first and second primary BC, respectively, were referenced to the expected number of cases calculated using the standardized incidence ratio (SIR) over the same period, to evaluate the observed and expected ratio between the groups. Data on tamoxifen use were also considered. RESULTS: A total of 499 women with primary BC developed a second tumor. The total SIR, that is, the ratio between observed second primary cancer among patients with BC and the expected primary cancers in the general population, was significantly higher (SIR = 1.23; 95% confidence interval, 1.12-1.34; P = 0.007), particularly for melanoma (2.25), EC (2.15), ovarian cancer (1.74), hematologic malignancies (1.36), and bilateral BC (1.25). A greater risk of BC after thyroid (2.22) and EC (1.62) was also observed. Furthermore, the risk of developing EC was higher in patients treated with tamoxifen (SIR = 2.50 vs 1.34). CONCLUSIONS: Bidirectional risk of endometrial cancer was not exclusively related to tamoxifen use.
Asunto(s)
Neoplasias de la Mama/epidemiología , Neoplasias Endometriales/epidemiología , Neoplasias Primarias Secundarias/inducido químicamente , Antineoplásicos Hormonales/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Carcinoma Adenoescamoso/tratamiento farmacológico , Carcinoma Adenoescamoso/epidemiología , Carcinoma Adenoescamoso/patología , Carcinoma Papilar/tratamiento farmacológico , Carcinoma Papilar/epidemiología , Carcinoma Papilar/patología , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/epidemiología , Cistadenocarcinoma Seroso/patología , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Femenino , Humanos , Incidencia , Italia/epidemiología , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Primarias Secundarias/patología , Pronóstico , Sistema de Registros , Factores de Riesgo , Tasa de Supervivencia , Tamoxifeno/efectos adversosRESUMEN
The identification of BRCA mutations plays a crucial role in the management of hereditary cancer prevention and treatment. Nonetheless, BRCA-testing in pancreatic cancer (PC) patients is not universally introduced in clinical practice. A retrospective analysis was conducted, firstly, to evaluate the rate of BRCA-positive families among those presenting a family history of PC besides breast and/or ovarian cancer. Secondly, the relationship between BRCA pathogenic variants and PC risk was evaluated. Finally, the characteristics of PC developed in BRCA families were described. Among 5143 family trees reporting breast and/or ovarian cancer cases, 392 showed a family history of PC. A total of 35 families (24.5% selected by the Modena Criteria and 21.3% by the NCCN Criteria) were positive to BRCA testing. Among the BRCA1 mutations, 36.8% were found within a region defined by c.3239â»c.3917, whilst 43.7% of BRCA2 mutations were located within c.7180â»c.8248. This study confirmed that an increase in the rate of positive tests in families with PC when associated to breast and/or ovarian tumors. Moreover, this analysis indicated two possible Pancreatic Cancer Cluster Regions that should be verified in future research. Finally, PC in families with breast and/or ovarian cancer history, particularly in BRCA families, were diagnosed at younger age and showed better one-year overall survival.
RESUMEN
Reproductive history and exogenous hormonal exposures are acknowledged risk factors for breast cancer in the general population. In women at increased breast cancer risk for genetic predisposition or positive family history, data regarding these risk factors are limited or conflicting, and recommendations for these categories are unclear. We evaluated the characteristics of reproductive life in 2522 women at increased genetic or familial breast cancer risk attending our Family Cancer Center. Breast cancers in BRCA mutation carriers were more likely to be hormone receptor negative, diagnosed at 35 years or before and multiple during the lifetime than tumors in women at increased familial risk, while the distribution of invasive cancers and HER2 positive tumors was similar in the different risk groups. At least one full-term pregnancy (HR 0.27; 95% CI 0.12-0.58; p = 0.001), breastfeeding either less (HR 0.24; 95% CI 0.09-0.66; p = 0.005) or more (HR 0.25; 95% IC 0.08-0.82; p = 0.022) than one year and late age at menopause (HR 0.10; 95% CI 0.01-0.82; p = 0.033) showed to be protective factors in BRCA mutation carriers, while in women at increased familial risk early age at first full-term pregnancy (HR 0.62; 95% IC 0.38-0.99; p = 0.048) and late menarche (HR 0.61; 95% CI 0.42-0.85; p = 0.004) showed to be the main protective factors. Finally, for the entire population, combined hormonal contraceptives demonstrated to do not increase breast cancer risk. The results of our study suggest that women at high familial risk and mutation carries develop tumors with different clinical-pathological characteristics and, consequently, are influenced by different protective and risk factors.
Asunto(s)
Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Fertilidad , Mutación , Salud Reproductiva , Adulto , Anciano , Lactancia Materna , Neoplasias de la Mama/terapia , Distribución de Chi-Cuadrado , Anticonceptivos Secuenciales Orales/efectos adversos , Femenino , Predisposición Genética a la Enfermedad , Herencia , Humanos , Italia , Menarquia , Menopausia , Persona de Mediana Edad , Paridad , Linaje , Fenotipo , Embarazo , Modelos de Riesgos Proporcionales , Factores de Riesgo , Factores de TiempoRESUMEN
PURPOSE: We conducted a study to evaluate the relationship between body mass index (BMI) and the risk of breast cancer (BC) and outcome in a population of 14,684 women aged 55 to 69 years eligible to participate in the Mammography Screening Program (MSP) in the Province of Modena, Italy. METHODS: The study population was drawn from women who underwent mammography screening between 2004 and 2006 in the Province of Modena. Women were subdivided into obese, overweight, and normal-weight categories according to BMI and followed until July 31, 2010, to evaluate the BC incidence. The clinicopathological characteristics of BC were also evaluated in different groups of patients classified according to BMI. After BC diagnosis, patients were followed for a median period of 65 (range, 2-104) months. Second events (recurrences and second tumors) were recorded, and the 5-year event-free survival (EFS) was calculated. RESULTS: After a period of 73 months, 366 cases of BC were diagnosed. Compared with normal-weight women, obese women had a significantly higher incidence of BC (relative risk [RR], 1.32; p=0.040) (RR=1), larger tumors (27% of tumors were larger than T2 size), and more nodal involvement (38.5% of tumors were node-positive). Furthermore, a significantly higher rate of total events was seen in obese women compared with overweight and normal-weight patients, respectively (17.9% vs. 11.4% vs. 10.8%, p=0.032). The 5-year EFS was 89.0%, 89.0%, and 80.0% for normal-weight, overweight, and obese patients, respectively. CONCLUSION: We observed a significantly higher risk of BC in obese women among those eligible to participate in the MSP in the Province of Modena. Finally, obese women had more second events and poorer EFS compared to nono bese women.