Oncogenetics Team, Institute of Cancer Research, London, UK; Cancer Genetics Unit & Academic Urology Unit, Royal Marsden NHS Foundation Trust, London, UK.
Oncogenetics Team, Institute of Cancer Research, London, UK.
Lancet Oncol. 2021 Nov;22(11):1618-1631. doi: 10.1016/S1470-2045(21)00522-2. Epub 2021 Oct 19.
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.
林奇综合征是一种罕见的家族性癌症综合征，由错配修复基因 MLH1、MSH2、MSH6 或 PMS2 中的致病性变异引起，导致各种癌症易感性增加，主要是结直肠癌和子宫内膜癌。有数据表明，错配修复基因中的致病性变异会增加早发性侵袭性前列腺癌的风险。IMPACT 研究正在前瞻性评估携带种系错配修复致病性变异男性的前列腺特异性抗原（PSA）筛查。在此，我们报告了 PSA 筛查的有用性、携带和不携带这些种系致病性变异男性的前列腺癌发病率以及肿瘤特征。
IMPACT 研究是一项国际性的前瞻性研究。从 8 个国家的 34 个遗传和泌尿科诊所招募了年龄在 40-69 岁之间、无前列腺癌既往史、MLH1、MSH2 或 MSH6 基因中已知种系致病性变异且这些基因中无家族致病性变异的男性对照，并进行了基线 PSA 筛查。PSA 水平高于 3.0ng/ml 的男性接受经直肠、超声引导的前列腺活检，并进行组织病理学分析。所有参与者均进行至少 5 年的年度筛查。主要终点是比较携带致病性变异和非携带者的筛查发现的前列腺癌的发病率、分期和病理学。我们使用 Fisher 精确检验比较携带者和非携带者的 PSA 截止值和活检的病例数、癌症发病率和阳性预测值，以及疾病类型之间的差异（即癌症与非癌症、有临床意义的癌症与非癌症）。我们根据致病性变异状态评估筛查结果和肿瘤特征。在此，我们展示了 IMPACT 研究中首次 PSA 筛查的结果。这项研究在 ClinicalTrials.gov 上注册，编号为 NCT00261456，现已关闭入组。
2012 年 9 月 28 日至 2020 年 3 月 1 日期间，共招募了 828 名男性（644 名携带错配修复致病性变异[204 名 MLH1 携带者、305 名 MSH2 携带者和 135 名 MSH6 携带者]和 184 名非携带者对照[65 名非 MLH1 携带者、76 名非 MSH2 携带者和 43 名非 MSH6 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 BRCA1 和 BRCA2 队列中随机选择了 134 名非携带者，他们被纳入了所有三个非携带者队列。男性主要为欧洲血统（953 名有可用数据的男性中，93%为 93%），平均年龄为 52.8 岁（标准差 8.3）。在首轮筛查中，56 名（6%）男性 PSA 浓度超过 3.0ng/ml，35 名（4%）接受了活检。前列腺癌总发病率为 1.9%（962 例中的 18 例；95%CI 1.1-2.9）。MSH2 携带者的发病率为 4.3%（305 例中的 13 例；95%CI 2.3-7.2），MSH2 非携带者对照为 0.5%（210 例中的 1 例；0.0-2.6），MSH6 携带者为 3.0%（135 例中的 4 例；0.8-7.4），MLH1 携带者、MLH1 非携带者对照和 MSH6 非携带者对照均未检出。使用 PSA 阈值大于 3.0ng/ml，MSH2 携带者的前列腺癌发病率高于 MSH2 非携带者对照（4.3%比 0.5%；p=0.011）和 MSH6 携带者高于 MSH6 非携带者对照（3.0%比 0%；p=0.034）。使用 PSA 阈值 3.0ng/ml 的活检的总阳性预测值为 51.4%（95%CI 34.0-68.6），PSA 阈值 3.0ng/ml 的总阳性预测值为 32.1%（20.3-46.0）。
在首轮筛查后，MSH2 和 MSH6 致病性变异携带者的前列腺癌发病率高于年龄匹配的非携带者对照。这些发现支持对这些男性进行靶向 PSA 筛查，以发现具有临床意义的前列腺癌患者。进一步的年度筛查需要证实这些发现。
英国癌症研究中心、Ronald 和 Rita McAulay 基金会、国家卫生研究院支持的生物医学研究中心（癌症研究所和皇家马斯登 NHS 基金会信托基金；牛津；曼彻斯特和剑桥临床研究中心）、杰克先生和夫人、塔斯马尼亚癌症协会、澳大利亚前列腺癌基金会、澳大利亚癌症协会、维多利亚癌症协会、南澳大利亚癌症协会、维多利亚癌症机构、澳大利亚癌症协会、前列腺癌基金会、西班牙癌症协会、西班牙卡洛斯三世卫生研究所、欧洲区域发展基金（FEDER）、加泰罗尼亚健康研究所、加泰罗尼亚自治政府、西班牙癌症研究基金会、美国国立卫生研究院国家癌症研究所、瑞典癌症协会、马尔默综合医院癌症基金会。
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