Clinical Management of Patients at Risk for Hereditary Breast Cancer with Variants of Uncertain Significance in the Era of Multigene Panel Testing
Clinical Management of Patients at Risk for Hereditary Breast Cancer with Variants of Uncertain Significance in the Era of Multigene Panel Testing
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DOI：
10.1245/s10434-019-07595-2
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发表时间：
2019-10-01
影响因子：
3.7
通讯作者：
Lum, Sharon S.
中科院分区：
文献类型：
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作者：
Chang, Jenny;Seng, Sirivan;Lum, Sharon S.
背景多基因检测的使用增加导致了对不确定意义变异（VUS）的识别。共识指南指出，临床医生不应根据VUS结果做出医疗管理决策。我们试图分析VUS如何影响遗传性乳腺癌风险患者的管理。方法回顾了2015年至2018年来自单个三级医疗机构的遗传性乳腺癌风险适应症的所有基因检测报告。根据致病性（良性/可能良性、VUS或致病性/可能致病性[P/LP]）和乳腺癌易感性（高、中度或无）对变异体进行分组。患者和管理特点进行了比较变异致病性和乳腺癌的风险。结果563例患者接受了乳腺癌风险基因检测; 228例（40.5%）患者中发现336个VUS，其中26.4%为高或中度突变基因。在61例（10.8%）患者中发现P/LP结果，其中61.2%在乳腺特异性中、高等位基因中发现，38.7%在非乳腺特异性基因中发现。在高危基因中发现的变异中，54.5%为P/LP，45.5%为VUS。多变量分析显示，预防性乳房切除术与年轻年龄和个人癌症史相关，但与变异致病性或转移率无关。基于不同的发现或年龄，在测试后成像、卵巢切除术或结肠镜检查的使用方面没有差异。结论在这个多基因检测的时代，遗传因素有助于为遗传性乳腺癌风险患者的监测和管理提供信息，而不是决定复杂的决策。
Background Rising use of multigene panel testing has led to increased identification of variants of uncertain significance (VUS). Consensus guidelines state that clinicians should not make medical management decisions based on VUS findings. We sought to analyze how VUS affect management of patients at risk for hereditary breast cancer. Methods All genetic testing reports for indications of hereditary breast cancer risk from a single tertiary-care institution from 2015 to 2018 were reviewed. Variants were grouped by pathogenicity (benign/likely benign, VUS, or pathogenic/likely pathogenic [P/LP]) and by breast cancer susceptibility (high, moderate, or none). Patient and management characteristics were compared by variant pathogenicity and breast cancer risk. Results Overall, 563 patients underwent genetic testing for breast cancer risk; 336 VUS were identified in 228 (40.5%) of patients of which 26.4% were in high or moderate penetrance genes. P/LP results were found in 61 (10.8%) patients, of which 61.2% were identified in breast-specific moderate and high penetrance genes, and 38.7% were found in non-breast specific genes. Of variants found in high-risk genes, 54.5% were P/LP and 45.5% were VUS. On multivariable analysis, prophylactic mastectomy was associated with younger age and personal history of cancer, but not variant pathogenicity or penetrance. There were no differences in the use of post-test imaging, oophorectomy, or colonoscopy based on variant findings or age. Conclusions In this era of multigene panel testing, genetic factors help to inform, but not dictate, complex decision-making in surveillance and management of patients at risk for hereditary breast cancer.