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BACKGROUND: Combining PARP inhibitors (PARPis) with immune checkpoint inhibitors may improve clinical outcomes in selected cancers. We evaluated rucaparib and atezolizumab in advanced gynaecological or triple-negative breast cancer (TNBC). METHODS: After identifying the recommended dose, patients with PARPi-naive BRCA-mutated or homologous recombination-deficient/loss-of-heterozygosity-high platinum-sensitive ovarian cancer or TNBC received rucaparib plus atezolizumab. Tumour biopsies were collected pre-treatment, during single-agent rucaparib run-in, and after starting combination therapy. RESULTS: The most common adverse events with rucaparib 600 mg twice daily and atezolizumab 1200 mg on Day 1 every 3 weeks were gastrointestinal effects, fatigue, liver enzyme elevations, and anaemia. Responding patients typically had BRCA-mutated tumours and higher pre-treatment tumour levels of PD-L1 and CD8 + T cells. Markers of DNA damage repair decreased during rucaparib run-in and combination treatment in responders, but typically increased in non-responders. Apoptosis signature expression showed the reverse. CD8 + T-cell activity and STING pathway activation increased during rucaparib run-in, increasing further with atezolizumab. CONCLUSIONS: In this small study, rucaparib plus atezolizumab demonstrated acceptable safety and activity in BRCA-mutated tumours. Increasing anti-tumour immunity and inflammation might be a key mechanism of action for clinical benefit from the combination, potentially guiding more targeted development of such regimens. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT03101280).
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Neoplasias das Tubas Uterinas , Neoplasias Ovarianas , Neoplasias Peritoneais , Humanos , Feminino , Neoplasias Peritoneais/terapia , Neoplasias Peritoneais/diagnóstico , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/diagnóstico , Neoplasias das Tubas Uterinas/terapia , Neoplasias das Tubas Uterinas/diagnóstico , Reino Unido , Sociedades MédicasRESUMO
BACKGROUND: Menopausal hormone therapy (MHT) can alleviate menopausal symptoms but has been associated with an increased risk of breast cancer. MHT prescription should be preceded by individualised risk/benefit evaluation; however, data outlining the impact of family history alongside different MHT therapeutic approaches are lacking. AIM: To quantify the risks associated with MHT use in women with varying breast cancer family histories of developing and dying from breast cancer. DESIGN AND SETTING: An epidemiological modelling study for women in England using the BOADICEA breast cancer prediction model and data relating to MHT use and breast cancer risk taken from research by the Collaborative Group on Hormonal Factors in Breast Cancer. METHOD: The risk of developing and dying from breast cancer between the ages of 50 and 80 years was modelled in women with four different breast cancer family history profiles: 'average', 'modest', 'intermediate', and 'strong' by using 1) background risks of breast cancer by age and family history, 2) relative risks for breast cancer associated with MHT use, and 3) 10-year breast cancer-specific net mortality rates. This study modelled use of combined oestrogen-progestogen MHT (cyclical or continuous) and oestrogen-only MHT. RESULTS: For a woman of 'average' family history taking no MHT, the cumulative breast cancer risk (age 50-80 years) is 9.8%, and the risk of dying from the breast cancer is 1.7%. In this model, 5 years' exposure to combined-cyclical MHT (age 50-55 years) was calculated to increase these risks to 11.0% and 1.8%, respectively. For a woman with a 'strong' family history taking no MHT, the cumulative breast cancer risk is 19.6% (age 50-80 years), and the risk of dying from the breast cancer is 3.2%. With 5 years' exposure to MHT (age 50-55 years), this model showed that these risks increase to 22.4% and 3.5%, respectively. CONCLUSION: In this model, both family history and MHT are associated with increased risk of breast cancer. Estimates of the risks of breast cancer associated with MHT for women with different family histories can be used to support decision making around MHT prescription for women experiencing menopausal symptoms.
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Neoplasias da Mama , Menopausa , Humanos , Feminino , Neoplasias da Mama/epidemiologia , Pessoa de Meia-Idade , Medição de Risco , Idoso , Inglaterra/epidemiologia , Idoso de 80 Anos ou mais , Terapia de Reposição de Estrogênios/efeitos adversos , Fatores de RiscoRESUMO
BACKGROUND: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease caused by inherited or de novo germline pathogenic variants in TP53. Individuals with LFS have a 70-100% lifetime risk of developing cancer. The current standard of care involves annual surveillance with whole-body and brain MRI (WB-MRI) and clinical review; however, there are no chemoprevention agents licensed for individuals with LFS. Preclinical studies in LFS murine models show that the anti-diabetic drug metformin is chemopreventive and, in a pilot intervention trial, short-term use of metformin was well-tolerated in adults with LFS. However, metformin's mechanism of anticancer activity in this context is unclear. METHODS: Metformin in adults with Li-Fraumeni syndrome (MILI) is a Precision-Prevention phase II open-labelled unblinded randomised clinical trial in which 224 adults aged ≥ 16 years with LFS are randomised 1:1 to oral metformin (up to 2 mg daily) plus annual MRI surveillance or annual MRI surveillance alone for up to 5 years. The primary endpoint is to compare cumulative cancer-free survival up to 5 years (60 months) from randomisation between the intervention (metformin) and control (no metformin) arms. Secondary endpoints include a comparison of cumulative tumour-free survival at 5 years, overall survival at 5 years and clinical characteristics of emerging cancers between trial arms. Safety, toxicity and acceptability of metformin; impact of metformin on quality of life; and impact of baseline lifestyle risk factors on cancer incidence will be assessed. Exploratory end-points will evaluate the mechanism of action of metformin as a cancer preventative, identify biomarkers of response or carcinogenesis and assess WB-MRI performance as a diagnostic tool for detecting cancers in participants with LFS by assessing yield and diagnostic accuracy of WB-MRI. DISCUSSION: Alongside a parallel MILI study being conducted by collaborators at the National Cancer Institute (NCI), MILI is the first prevention trial to be conducted in this high-risk group. The MILI study provides a unique opportunity to evaluate the efficacy of metformin as a chemopreventive alongside exploring its mechanism of anticancer action and the biological process of mutated P53-driven tumourigenesis. TRIAL REGISTRATION: ISRCTN16699730. Registered on 28 November 2022. URL: https://www.isrctn.com/ EudraCT/CTIS number 2022-000165-41.
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Síndrome de Li-Fraumeni , Metformina , Adulto , Humanos , Camundongos , Animais , Síndrome de Li-Fraumeni/diagnóstico por imagem , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/prevenção & controle , Metformina/efeitos adversos , Qualidade de Vida , Mutação em Linhagem Germinativa , Imageamento por Ressonância Magnética , Predisposição Genética para Doença , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase II como AssuntoRESUMO
OBJECTIVE: The peritoneal cancer index quantitatively assesses cancer distribution and tumor burden in the peritoneal cavity. The aim of this study is to evaluate the association between the peritoneal cancer index and completeness of surgical cytoreduction for ovarian cancer and to identify a cut-off above which complete cytoreduction is unlikely. METHODS: This is a single-center prospective cohort observational study. A total of 100 consecutive patients who underwent ovarian cancer surgery were included. Peritoneal cancer index scores prior to and after surgery were calculated, and a cut-off value for incomplete cytoreduction was identified using a receiver operator characteristic (ROC) curve. Surgical complexity, blood loss, length of surgery, and complications were analyzed and associations with the peritoneal cancer index score were evaluated. RESULTS: The overall median peritoneal cancer index score was 9.5 (range 0-36). The median age of the patients was 61 years (range 24-85). The most common stage was III (13% stage II, 53% stage III, 34% stage IV) and the most common histologic sub-type was high-grade serous (76% high-grade serous, 8% low-grade serous, 5% clear cell, 4% serous borderline, 2% endometrioid, 2% adult granulosa cell, 2% adenocarcinoma, 1% carcinosarcoma). Complete cytoreduction was achieved in 82% of patients, with a median score of 9 (range 0-30). The remaining 18% had a median score of 28.5 (range 0-36). The best predictor of incomplete cytoreduction was the peritoneal cancer index score, with an area under the curve (AUC) of 0.928 (95% CI 0.85 to 1.00). ROC curve analysis determined a peritoneal cancer index cut-off score of 20. Major complications occurred in 15% of patients with peritoneal cancer index scores >20 and in 2.5% of patients with scores ≤20, which was statistically significant (p=0.014). CONCLUSIONS: In our study we found that a peritoneal cancer index score of ≤20 was associated with a high likelihood of complete cytoreduction. Incorporating the peritoneal cancer index into routine surgical practice and research may impact treatment plans.
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Neoplasias Ovarianas , Neoplasias Peritoneais , Adulto , Humanos , Feminino , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Procedimentos Cirúrgicos de Citorredução , Estudos Prospectivos , Neoplasias Peritoneais/cirurgia , Estudos Retrospectivos , Carcinoma Epitelial do Ovário/cirurgia , Neoplasias Ovarianas/patologiaRESUMO
OBJECTIVE: Olaparib plus bevacizumab maintenance therapy improves survival outcomes in women with newly diagnosed, advanced, high-grade ovarian cancer with a deficiency in homologous recombination. We report data from the first year of routine homologous recombination deficiency testing in the National Health Service (NHS) in England, Wales, and Northern Ireland between April 2021 and April 2022. METHODS: The Myriad myChoice companion diagnostic was used to test DNA extracted from formalin-fixed, paraffin-embedded tumor tissue in women with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Tumors with homologous recombination deficiency were those with a BRCA1/2 mutation and/or a Genomic Instability Score (GIS) ≥42. Testing was coordinated by the NHS Genomic Laboratory Hub network. RESULTS: The myChoice assay was performed on 2829 tumors. Of these, 2474 (87%) and 2178 (77%) successfully underwent BRCA1/2 and GIS testing, respectively. All complete and partial assay failures occurred due to low tumor cellularity and/or low tumor DNA yield. 385 tumors (16%) contained a BRCA1/2 mutation and 814 (37%) had a GIS ≥42. Tumors with a GIS ≥42 were more likely to be BRCA1/2 wild-type (n=510) than BRCA1/2 mutant (n=304). The distribution of GIS was bimodal, with BRCA1/2 mutant tumors having a higher mean score than BRCA1/2 wild-type tumors (61 vs 33, respectively, χ2 test p<0.0001). CONCLUSION: This is the largest real-world evaluation of homologous recombination deficiency testing in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. It is important to select tumor tissue with adequate tumor content and quality to reduce the risk of assay failure. The rapid uptake of testing across England, Wales, and Northern Ireland demonstrates the power of centralized NHS funding, center specialization, and the NHS Genomic Laboratory Hub network.
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Proteína BRCA1 , Neoplasias Ovarianas , Feminino , Humanos , Carcinoma Epitelial do Ovário/genética , Proteína BRCA1/genética , Neoplasias Ovarianas/patologia , Medicina Estatal , Proteína BRCA2/genética , Instabilidade Genômica , Recombinação Homóloga , MutaçãoRESUMO
Importance: Patients with platinum-resistant or refractory ovarian high-grade serous carcinoma (PR-HGSC) have a poor prognosis and few therapeutic options. Preclinical studies support targeting PI3K/AKT/mTOR signaling in this setting, and a phase 1 study of the dual mTORC1/mTORC2 inhibitor vistusertib with weekly paclitaxel showed activity. Objective: To evaluate whether the addition of vistusertib to weekly paclitaxel improves clinical outcomes in patients with PR-HGSC. Design, Setting, and Participants: This phase 2, double-blind, placebo-controlled multicenter randomized clinical trial recruited patients from UK cancer centers between January 2016 and March 2018. Patients with PR-HGSC of ovarian, fallopian tube, or primary peritoneal origin and with measurable or evaluable disease (Response Evaluation Criteria in Solid Tumors version 1.1 and/or Gynecological Cancer Intergroup cancer antigen 125 criteria) were eligible. There were no restrictions on number of lines of prior therapy. Data analysis was performed from May 2019 to January 2022. Interventions: Patients were randomized (1:1) to weekly paclitaxel (80 mg/m2 days 1, 8, and 15 of a 28-day cycle) plus oral vistusertib (50 mg twice daily) or placebo. Main Outcomes and Measures: The primary end point was progression-free survival in the intention-to-treat population. Secondary end points included response rate, overall survival, and quality of life. Results: A total of 140 patients (median [range] age, 63 [36-86] years; 17.9% with platinum-refractory disease; 53.6% with ≥3 prior therapies) were randomized. In the paclitaxel plus vistusertib vs paclitaxel plus placebo groups, there was no difference in progression-free survival (median, 4.5 vs 4.1 months; hazard ratio [HR], 0.84; 80% CI, 0.67-1.07; 1-sided P = .18), overall survival (median, 9.7 vs 11.1 months; HR, 1.21; 80% CI, 0.91-1.60) or response rate (odds ratio, 0.86; 80% CI, 0.55-1.36). Grade 3 to 4 adverse events were 41.2% (weekly paclitaxel plus vistusertib) vs 36.7% (weekly paclitaxel plus placebo), and there was no difference in quality of life. Conclusions and Relevance: In this randomized clinical trial of weekly paclitaxel and dual mTORC1/2 inhibition in patients with PR-HGSC, vistusertib did not improve clinical activity of weekly paclitaxel. Trial Registration: isrctn.org Identifier: ISRCTN16426935.
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Neoplasias Ovarianas , Paclitaxel , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases/uso terapêutico , Qualidade de Vida , Carcinoma Epitelial do Ovário/tratamento farmacológico , Alvo Mecanístico do Complexo 1 de Rapamicina , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
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
In the Republic of Ireland (ROI), BRCA1/BRCA2 genetic testing has been traditionally undertaken in eligible individuals, after pre-test counselling by a Clinical Geneticist/Genetic Counsellor. Clinical Genetics services in ROI are poorly resourced, with routine waiting times for appointments at the time of this pilot often extending beyond a year. The consequent prolonged waiting times are unacceptable where therapeutic decision-making depends on the patient's BRCA status. "Mainstreaming" BRCA1/BRCA2 testing through routine oncology/surgical clinics has been implemented successfully in other centres in the UK and internationally. We aimed to pilot this pathway in three Irish tertiary centres. A service evaluation project was undertaken over a 6-month period between January and July 2017. Eligible patients, fulfilling pathology and age-based inclusion criteria defined by TGL clinical, were identified, and offered constitutional BRCA1/BRCA2 testing after pre-test counselling by treating clinicians. Tests were undertaken by TGL Clinical. Results were returned to clinicians by secure email. Onward referrals of patients with uncertain/pathogenic results, or suspicious family histories, to Clinical Genetics were made by the treating team. Surveys assessing patient and clinician satisfaction were sent to participating clinicians and a sample of participating patients. Data was collected with respect to diagnostic yield, turnaround time, onward referral rates, and patient and clinician feedback. A total of 101 patients underwent diagnostic germline BRCA1/BRCA2 tests through this pathway. Pathogenic variants were identified in 12 patients (12%). All patients in whom variants were identified were appropriately referred to Clinical Genetics. At least 12 additional patients with uninformative BRCA1/BRCA2 tests were also referred for formal assessment by Clinical Geneticist or Genetic Counsellor. Issues were noted in terms of time pressures and communication of results to patients. Results from a representative sample of participants completing the satisfaction survey indicated that the pathway was acceptable to patients and clinicians. Mainstreaming of constitutional BRCA1/BRCA2 testing guided by age- and pathology-based criteria is potentially feasible for patients with breast cancer as well as patients with ovarian cancer in Ireland.
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Neoplasias da Mama , Neoplasias Ovarianas , Humanos , Feminino , Testes Genéticos , Projetos Piloto , Irlanda , Estudos de Viabilidade , Proteína BRCA2/genética , Proteína BRCA1/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Predisposição Genética para Doença , Mutação em Linhagem GerminativaRESUMO
BACKGROUND: Germline genetic testing affords multiple opportunities for women with breast cancer, however, current UK NHS models for delivery of germline genetic testing are clinician-intensive and only a minority of breast cancer cases access testing. METHODS: We designed a rapid, digital pathway, supported by a genetics specialist hotline, for delivery of germline testing of BRCA1/BRCA2/PALB2 (BRCA-testing), integrated into routine UK NHS breast cancer care. We piloted the pathway, as part of the larger BRCA-DIRECT study, in 130 unselected patients with breast cancer and gathered preliminary data from a randomised comparison of delivery of pretest information digitally (fully digital pathway) or via telephone consultation with a genetics professional (partially digital pathway). RESULTS: Uptake of genetic testing was 98.4%, with good satisfaction reported for both the fully and partially digital pathways. Similar outcomes were observed in both arms regarding patient knowledge score and anxiety, with <5% of patients contacting the genetics specialist hotline. All progression criteria established for continuation of the study were met. CONCLUSION: Pilot data indicate preliminary demonstration of feasibility and acceptability of a fully digital pathway for BRCA-testing and support proceeding to a full powered study for evaluation of non-inferiority of the fully digital pathway, detailed quantitative assessment of outcomes and operational economic analyses. TRIAL REGISTRATION NUMBER: ISRCTN87845055.
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Neoplasias da Mama , Encaminhamento e Consulta , Humanos , Feminino , Medicina Estatal , Telefone , Testes Genéticos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Reino UnidoRESUMO
INTRODUCTION: The diagnostic pathway for lung cancer can be long. Availability of front-line targeted therapies for NSCLC demands access to good quality tissue for genomic sequencing and rapid reporting of results. Diagnosis of lung cancer and availability of tissue was delayed during the COVID-19 pandemic. METHODS: A pilot study assessing Guardant360™ cfDNA-NGS in patients with radiological-suspected advanced-stage lung cancer was performed at an academic cancer centre during COVID-19. Variants were tiered using AMP/ASCO/CAP guidelines and discussed at a tumour molecular board. The primary endpoint was the proportion of patients who commenced targeted treatment based on cfDNA-NGS results without tissue molecular results, predicted to be ≥ 10%. RESULTS: Between April 2020-May 2021, 51 patients were enrolled; 49 were evaluable. The median age was 71 years, 43% were never-smokers, 86% had stage IV disease. 80% of evaluable cfDNA-NGS were informative (tumour-derived cfDNA detected). cfDNA-NGS detected 30 (61%) AMP/ASCO/CAP tier 1 variants, including 20 additional tier 1 variants compared to tissue testing. Three patients with non-informative cfDNA-NGS had tier 1 variants identified on tissue testing. Eleven (22%; 95%CI 12%-27%) patients commenced targeted therapy based on cfDNA-NGS results without tissue molecular results, meeting the primary endpoint. Median time to results was shorter for cfDNA-NGS compared to standard-of-care tissue tests (9 versus 25 days, P < 0.0001). CONCLUSION: Blood-first cfDNA-NGS in NSCLC patients increased the breadth and rapidity of detection of actionable variants with high tissue concordance and led to timely treatment decisions. A blood-first approach should be considered to improve the speed and accuracy of therapeutic decision-making.
RESUMO
The British Gynecological Cancer Society and the British Association of Gynecological Pathologists established a multidisciplinary consensus group comprising experts in surgical gynecological oncology, medical oncology, genetics, and laboratory science, and clinical nurse specialists to identify the optimal pathways to BRCA germline and tumor testing in patients with ovarian cancer in routine clinical practice. In particular, the group explored models of consent, quality standards identified at pathology laboratories, and experience and data from pioneering cancer centers. The group liaised with representatives from ovarian cancer charities to also identify patient perspectives that would be important to implementation. Recommendations from these consensus group deliberations are presented in this manuscript.
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Proteína BRCA1 , Proteína BRCA2 , Carcinoma Epitelial do Ovário/genética , Neoplasias Ovarianas/genética , Consenso , Feminino , Predisposição Genética para Doença , Testes Genéticos/normas , Mutação em Linhagem Germinativa , Humanos , Reino UnidoRESUMO
As patients are now routinely having large somatic genomic testing panels undertaken as part of routine management, there is the rising likelihood of uncovering the presence of a germline pathogenic variant. This may be found on testing undertaken on plasma (ctDNA) or tissue. This has led to the need for clear guidelines for oncologists about how to manage such results, including which variants require validation, how this should be undertaken, and what potential problems may arise. This requires an understanding of the limits of testing, and the pitfalls that may be encountered. In this review, we assess the frequency of detecting germline variants through tumor-only sequencing, the necessary considerations for such information to be analyzed and the role of the molecular tumor board in considering results. We assess the additional considerations for interpretation of the underlying tumor, use of ctDNA or tissue for testing, clonal hematopoiesis, and hypermutation.
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Testes Genéticos/métodos , Mutação em Linhagem Germinativa , Neoplasias/genética , Análise de Sequência de DNA/métodos , Testes Genéticos/normas , Humanos , Neoplasias/diagnóstico , Neoplasias/terapia , Guias de Prática Clínica como Assunto , Análise de Sequência de DNA/normasRESUMO
Poly (ADP-ribose) polymerase (PARP) inhibitors have transformed the management of recurrent ovarian cancer in patients with BRCA-mutations and beyond. Olaparib was the first PARP inhibitor to gain approval as maintenance therapy for patients with newly diagnosed, advanced BRCA-mutated ovarian cancer establishing a new standard of care. At the end of 2020, as a result of the SOLO1, PRIMA, and PAOLA-1 phase III trials, we are now in an era where three maintenance PARP inhibitor strategies have FDA and European Medicines Agency approval in the first-line setting. In this review, we provide an overview of the key PARP inhibitor trials that have changed clinical practice, discuss directing therapy according to biomarker status (BRCA and homologous recombination deficiency) and future strategies in ovarian cancer and other gynecological malignancies.
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Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Ensaios Clínicos como Assunto , Feminino , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Guias de Prática Clínica como AssuntoRESUMO
As the treatment of epithelial ovarian cancer (OC) moves further into personalised medicine, the importance of determining the presence or absence of inherited mutations in cancer susceptibility genes has grown. It is now becoming routine to test for germline mutations in the BRCA1 and BRCA2 genes, which are responsible for a significant proportion of hereditary epithelial OC and are established predictive biomarkers of potential benefit from poly ADP ribose polymerase (PARP) inhibitors. The identification of patients with hereditary OC allows the patient to benefit from personalised treatment, while allowing family members to undergo cascade testing, where identification of unaffected carriers can allow early detection, risk-reduction or prevention for both breast and OC, and ultimately improve long-term outcomes. Other susceptibility genes, include the Lynch Syndrome (mismatch repair) genes and several other genes involved in the homologous recombination pathway (HRD genes), are implicated in OC genesis, and are also becoming of increasing interest as therapeutic options grow for these patients. This review will highlight the importance of the early detection of a germline gene pathogenic variant, which informs on the clinical course of disease in a particular patient, and therefore, guides therapeutic management including risk reducing and personalised treatment.
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Carcinoma Epitelial do Ovário/genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Neoplasias Ovarianas/genética , Carcinoma Epitelial do Ovário/diagnóstico , Feminino , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Humanos , Neoplasias Ovarianas/diagnósticoRESUMO
Although guidelines recommend BRCA testing for all women with non-mucinous epithelial ovarian cancer, there is significant variability in access to testing across the UK. A germline BRCA mutation (BRCAm) in ovarian cancer patients provides prognostic and predictive information and influences clinical management, such as the use of PARP inhibitors, which have demonstrated a progression-free survival benefit in the BRCAm cohort. Additionally, the finding of a BRCAm has significant implications for patients and their families in terms of cancer risk and prevention. We studied the impact of a newly-formed, oncologist-led 'mainstreaming' germline BRCA testing pathway in 255 ovarian cancer patients at Imperial College NHS Trust. Prior to the establishment of 'mainstreaming', uptake of germline BRCA testing was 14% with a mean turnaround time of 148.2 calendar days. The 'mainstreaming' approach led to a 95% uptake of germline BRCA testing and a mean turnaround time of 20.6 days. Thirty-four (13.33%) BRCAm patients were identified. At the time of data collection nine BRCAm patients had received a PARP inhibitor off-trial, three had entered a PARP inhibitor trial and 5 were receiving platinum-based chemotherapy with a plan to receive PARP inhibitor maintenance. This study provides further evidence of the impact of oncologist-led 'mainstreaming' programs.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Tomada de Decisões , Feminino , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Platina/uso terapêutico , Prognóstico , Reino UnidoRESUMO
Background For patients with early breast cancer, knowledge of germline BRCA1/2 status increasingly influences management as well as informing future cancer risk for patients and their families. As access to germline testing expands, it is important that this benefit is extended to survivors as well as to the newly diagnosed. Methods In collaboration with our breast unit colleagues and by embedding a Senior Genetic Counsellor in the virtual multidisciplinary meeting, we identified patients suitable for genetics review 5 years after their breast cancer diagnosis. Results Between May 2015 and December 2018, 2044 patients were discussed, of whom 769 patients were identified for notes review by Genetics. Of these, 275 had already undergone testing and 47 had confirmed germline pathogenic variants in BRCA1/2 A further 463 were recommended for referral. One hundred and eighty patients were subsequently offered testing with 161 accepting (161/180, 89%). Nine patients were found to harbour pathogenic variants in either BRCA1 or BRCA2 (9/161, 6%). Of the initial 2044 patients reviewed, 2.7% (56/2044) are now known to carry germline pathogenic variants. Conclusion The survivorship setting provides an opportunity for genetic review underpinned by collaborative working between cancer specialists and the genetics team.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Adulto , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Sobreviventes de Câncer , Feminino , Testes Genéticos , Mutação em Linhagem Germinativa/genética , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Molecular aberrations in cancer may represent therapeutic targets, and, if arising from the germline, may impact further cancer risk management in patients and their blood relatives. Annually, 600-700 patients are referred for consideration of experimental drug trials in the Drug Development Unit (DDU) in our institution. A proportion of patients may merit germline genetic testing because of suspicious personal/family history or findings of tumour-based testing. We aimed to assess the impact of different multidisciplinary interventions on family history taking and referral rates from DDU to Cancer Genetics Unit (CGU). METHODS: Over 42 months, three interventions were undertaken at different intervals: (1) embedding a genetics provider in the DDU review clinic, (2) 'traffic light' system flagging cancers with a heritable component and (3) virtual multidisciplinary meeting (MDM). Comparative analyses between intervals were undertaken, including referral rates to CGU, investigations and patient outcomes. Family history taking in a sample of 20 patients managed in each interval was assessed by a retrospective chart review. RESULTS: Frequency of family history taking and referral to CGU, increased with each intervention, particularly, the virtual MDM (40% vs 85%). Referral rates increased over the study period, from 0.1 referral/week (5/year, 0.36% total referrals) to 1.2/week (projected 63/year, 3.81%). Forty-four (52%) patients referred required germline testing; in three of whom, variants were identified. Non-attendance rates were low (6, 7%). CONCLUSION: Patients in the DDU are unique, with long cancer histories and often short estimated life expectancy. Multidisciplinary working between CGU and DDU facilitates germline testing of those patients who may otherwise miss the opportunity.
Assuntos
Desenvolvimento de Medicamentos/métodos , Aconselhamento Genético/métodos , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Anamnese/normas , Neoplasias/genética , Feminino , Humanos , Masculino , Encaminhamento e Consulta , Estudos RetrospectivosRESUMO
Importance: Increasing BRCA1 and BRCA2 (collectively termed herein as BRCA) gene testing is required to improve cancer management and prevent BRCA-related cancers. Objective: To evaluate mainstream genetic testing using cancer-based criteria in patients with cancer. Design, Setting, and Participants: A quality improvement study and cost-effectiveness analysis of different BRCA testing selection criteria and access procedures to evaluate feasibility, acceptability, and mutation detection performance was conducted at the Royal Marsden National Health Service Foundation Trust as part of the Mainstreaming Cancer Genetics (MCG) Programme. Participants included 1184 patients with cancer who were undergoing genetic testing between September 1, 2013, and February 28, 2017. Main Outcomes and Measures: Mutation rates, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios were the primary outcomes. Results: Of the 1184 patients (1158 women [97.8%]) meeting simple cancer-based criteria, 117 had a BRCA mutation (9.9%). The mutation rate was similar in retrospective United Kingdom (10.2% [235 of 2294]) and prospective Malaysian (9.7% [103 of 1061]) breast cancer studies. If traditional family history criteria had been used, more than 50% of the mutation-positive individuals would have been missed. Of the 117 mutation-positive individuals, 115 people (98.3%) attended their genetics appointment and cascade to relatives is underway in all appropriate families (85 of 85). Combining with the equivalent ovarian cancer study provides 5 simple cancer-based criteria for BRCA testing with a 10% mutation rate: (1) ovarian cancer; (2) breast cancer diagnosed when patients are 45 years or younger; (3) 2 primary breast cancers, both diagnosed when patients are 60 years or younger; (4) triple-negative breast cancer; and (5) male breast cancer. A sixth criterion-breast cancer plus a parent, sibling, or child with any of the other criteria-can be added to address family history. Criteria 1 through 5 are considered the MCG criteria, and criteria 1 through 6 are considered the MCGplus criteria. Testing using MCG or MCGplus criteria is cost-effective with cost-effectiveness ratios of $1330 per discounted QALYs and $1225 per discounted QALYs, respectively, and appears to lead to cancer and mortality reductions (MCG: 804 cancers, 161 deaths; MCGplus: 1020 cancers, 204 deaths per year over 50 years). Use of MCG or MCGplus criteria might allow detection of all BRCA mutations in patients with breast cancer in the United Kingdom through testing one-third of patients. Feedback questionnaires from 259 patients and 23 cancer team members (12 oncologists, 8 surgeons, and 3 nurse specialists) showed acceptability of the process with 100% of patients pleased they had genetic testing and 100% of cancer team members confident to approve patients for genetic testing. Use of MCGplus criteria also appeared to be time and resource efficient, requiring 95% fewer genetic consultations than the traditional process. Conclusions and Relevance: This study suggests that mainstream testing using simple, cancer-based criteria might be able to efficiently deliver consistent, cost-effective, patient-centered BRCA testing.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Detecção Precoce de Câncer/normas , Predisposição Genética para Doença , Testes Genéticos/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Custo-Benefício/estatística & dados numéricos , Feminino , Humanos , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Estudos Prospectivos , Estudos Retrospectivos , Medicina Estatal/normas , Reino UnidoRESUMO
INTRODUCTION: Despite treatment strategies which include both surgery and chemotherapy, epithelial ovarian cancer often relapses and survival rates remain poor. There is therefore a need to identify novel treatment targets and develop approaches that improve outcomes. The role of both germ line and somatic mutations in BRCA1 and BRCA2 in the development of ovarian cancer is well established, with mutation in either gene resulting in deficiencies in homologous recombination. Olaparib is an orally active inhibitor of poly(ADP-ribose) polymerase (PARP) which has demonstrated anti-tumor activity in ovarian cancer. Areas covered: This review focuses on the rationale for olaparib therapy in the context of relapsed epithelial ovarian cancer associated with a BRCA1 or BRCA2 mutation and summarizes the existing efficacy and safety data in this context. Ongoing phase III trials will be discussed. Expert commentary: Research regarding the optimal use of olaparib in the context of relapsed epithelial ovarian cancer associated with a BRCA mutation continues, with evidence for its use as maintenance therapy, treatment as a single agent and in combination with other targeted agents. The mechanisms of resistance require further exploration and it remains to be established whether retreatment or combination with other agents are viable treatment strategies.