A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.
A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.
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DOI：
10.1016/s1470-2045(21)00522-2
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Eeles RA
中科院分区：
文献类型：
--
作者：
Bancroft EK;Page EC;Brook MN;Thomas S;Taylor N;Pope J;McHugh J;Jones AB;Karlsson Q;Merson S;Ong KR;Hoffman J;Huber C;Maehle L;Grindedal EM;Stormorken A;Evans DG;Rothwell J;Lalloo F;Brady AF;Bartlett M;Snape K;Hanson H;James P;McKinley J;Mascarenhas L;Syngal S;Ukaegbu C;Side L;Thomas T;Barwell J;Teixeira MR;Izatt L;Suri M;Macrae FA;Poplawski N;Chen-Shtoyerman R;Ahmed M;Musgrave H;Nicolai N;Greenhalgh L;Brewer C;Pachter N;Spigelman AD;Azzabi A;Helfand BT;Halliday D;Buys S;Ramon Y Cajal T;Donaldson A;Cooney KA;Harris M;McGrath J;Davidson R;Taylor A;Cooke P;Myhill K;Hogben M;Aaronson NK;Ardern-Jones A;Bangma CH;Castro E;Dearnaley D;Dias A;Dudderidge T;Eccles DM;Green K;Eyfjord J;Falconer A;Foster CS;Gronberg H;Hamdy FC;Johannsson O;Khoo V;Lilja H;Lindeman GJ;Lubinski J;Axcrona K;Mikropoulos C;Mitra AV;Moynihan C;Ni Raghallaigh H;Rennert G;Collier R;IMPACT Study Collaborators;Offman J;Kote-Jarai Z;Eeles RA
Lynch综合征是一种罕见的家族性癌症综合征，由错配修复基因MLH 1、MSH 2、MSH 6或PMS 2中的致病性变体引起，其导致易患各种癌症，主要是结直肠癌和子宫内膜癌。数据显示，错配修复基因的致病性变异增加了早发性侵袭性前列腺癌的风险。IMPACT研究是前瞻性评估前列腺特异性抗原（PSA）筛查与生殖系错配修复致病性变异的男性。在这里，我们报告PSA筛查的有用性，前列腺癌的发病率，以及在第一轮筛查后的肿瘤特征，在男性和没有这些生殖系致病性变异。IMPACT研究是一项国际前瞻性研究。从8个国家的34个遗传和泌尿科诊所招募了40-69岁的男性，既往无前列腺癌诊断，MLH 1、MSH 2或MSH 6基因中存在已知的生殖系致病性变异，年龄匹配的男性对照，这些基因中的家族性致病性变异检测为阴性，并进行了基线PSA筛查。PSA水平高于3.0 ng/mL的男性接受经直肠超声引导下前列腺活检，并进行组织病理学分析。所有参与者都将接受至少5年的年度筛查。主要终点是确定与非携带者对照组相比，病原性变异携带者中筛查检测到的前列腺癌的发生率、分期和病理。我们使用Fisher精确检验来比较携带者和非携带者之间的病例数、癌症发病率和PSA截止值和活检的阳性预测值以及疾病类型之间的差异（即癌症与非癌症，临床显著癌症与非癌症）。我们通过致病性变异状态评估筛查结果和肿瘤特征。在这里，我们介绍了IMPACT研究中第一轮PSA筛查的结果。本研究注册于ClinicalTrials.gov，NCT 00261456，现已停止招募。在2012年9月28日至2020年3月1日期间，招募了828名男性，（644名错配修复致病性变体携带者[204名MLH 1携带者、305名MSH 2携带者和135名MSH 6携带者]和184名非携带者对照[65名MLH 1非携带者、76名MSH 2非携带者和43名MSH 6非携带者]），为了增加非携带者对照组的样本量，我们从IMPACT研究的BRCA 1和BRCA 2队列中随机选择了134名非携带者，他们被纳入所有三个非携带者队列。男性主要为欧洲血统（953例中有899例[93%]有可用数据），平均年龄为52.8岁（SD 8.3）。在第一轮筛查中，56名（6%）男性的PSA浓度超过3.0 ng/mL，35名（4%）进行了活检。前列腺癌的总发病率为1.9%（18/962; 95%CI 1.1 - 2.9）。MSH 2携带者的发病率为4.3%（13/305; 95%CI 2.3 - 7.2），MSH 2非携带者对照组为0.5%（1/210; 0.0 - 2.6），MSH 6携带者为3.0%（4/135; 0.8 - 7.4），MLH 1携带者、MLH 1非携带者对照组和MSH 6非携带者对照组均未检出。前列腺癌的发病率，使用PSA阈值高于3.0 ng/mL，在MSH 2携带者中高于MSH 2非携带者对照组（4.3% vs 0.5%; p= 0.011），MSH 6携带者高于MSH 6非携带者对照组（3.0% vs 0%; p= 0.034）。使用PSA阈值3.0 ng/mL进行活检的总体阳性预测值为51.4%（95%CI 34.0 - 68.6），PSA阈值3.0 ng/mL的总体阳性预测值为32.1%（20.3 - 46.0）。在第一轮筛查后，与年龄匹配的非携带者对照组相比，MSH 2和MSH 6致病性变体携带者的前列腺癌发病率更高。这些发现支持在这些男性中使用靶向PSA筛查来识别具有临床意义的前列腺癌。需要进一步的年度筛查来确认这些发现。英国癌症研究中心、罗纳德和丽塔·麦考利基金会、国家健康研究所对生物医学研究中心的支持（牛津大学癌症研究所和皇家马斯登NHS基金会信托基金;曼彻斯特和剑桥临床研究中心），杰克贝克先生和夫人，塔斯马尼亚癌症理事会，澳大利亚癌症，澳大利亚前列腺癌基金会，维多利亚癌症理事会，南澳癌症理事会、维多利亚州癌症机构、澳大利亚癌症协会、澳大利亚前列腺癌基金会、西班牙反癌症协会、卡洛斯三世健康研究所、欧洲区域发展基金、加泰罗尼亚健康研究所、加泰罗尼亚自治政府、科学和技术基金会、美国国立卫生研究院国家癌症研究所、瑞典癌症协会、马尔默总医院抗击癌症基金会。
Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. The IMPACT study is an international, prospective study. Men aged 40–69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1–2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3–7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0–2·6), MSH6 carriers was 3·0% (four of 135; 0·8–7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0–68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3–46·0). After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.
影响因子：
2.2
作者：
Bauer, Christina M.;Ray, Anna M.;Halstead-Nussloch, Bronwen A.;Dekker, Robert G.;Raymond, Victoria M.;Gruber, Stephen B.;Cooney, Kathleen A.
通讯作者：
Cooney, Kathleen A.