乳腺癌确诊后，对癌症易感基因致病变异进行生殖细胞基因检测，可以为癌症治疗、预防、亲属遗传风险检测提供信息。是否应该进行检测，部分取决于致病变异现患率，普通女性人群的现患率可能较低，而具有风险因素（例如确诊时年龄较轻、有家族史）女性人群的现患率较高。对于特征最明确的乳腺癌易感基因BRCA，推荐检测的致病变异现患率至少2.5%～10%。不过，对于检测所有乳腺癌患者还是仅仅检测具有遗传风险特征患者，各家指南推荐意见各不相同。由于缺乏无遗传风险因素绝经后女性致病变异现患率数据，大多数检测指南并未针对此类最常见的乳腺癌患者。
2020年3月10日，国际四大医学期刊之一《美国医学会杂志》正刊发表斯坦福大学、万基遗传、圣迭戈加利福尼亚大学、纽约州立布法罗大学的研究报告，利用女性健康倡议（WHI）大数据，对绝经后有或无乳腺癌女性乳腺癌易感基因致病变异背景现患率进行了调查。
女性健康倡议（WHI）是关于发病率和死亡率的前瞻研究，1993～1998年从美国40个地区入组年龄50～79岁绝经后女性16万1808例。本文对入组时无乳腺癌个人史、截至2017年9月20日被诊断为乳腺浸润癌（病例组2195例）或仍然无癌（对照组2322例）共计4517例女性进行嵌套病例对照分析。病例组与对照组未配对，从所有采集过DNA样本的WHI参与者随机选择。由万基遗传对28个基因进行大规模并行测序和大片段重排分析，其中BRCA1、BRCA2、ATM、BARD1、CDH1、CHEK2、NBN、PALB2、STK11、TP53已知与乳腺癌相关。变异被分为致病、可能致病、意义不确定、良性、可能良性。基因变异现患率为病例组和对照组的比例，通过精确二元法和卡方检验对95%置信区间和P值进行计算。对符合国家综合癌症网络（NCCN）2019年检测指南（与肿瘤学实践最相关并且主要根据诊断时年龄和家族史）致病变异携带者百比例及其与年龄的关系进行分析。根据不同年龄，对BRCA以及其他乳腺癌相关基因致病变异现患率进行卡方检验（双侧P<0.05被认为具有统计学意义）。
结果，病例组乳腺癌诊断时中位年龄73岁、白人占66.3%，对照组末次随访时中位年龄81岁、白人占84.9%。
241例女性检出致病变异，病例组显著多于对照组（P<0.001）
病例组：148例（6.74%，95%置信区间：5.73%～7.87%）
对照组： 93例（4.01%，95%置信区间：3.24%～4.88%）
108例女性检出乳腺癌相关基因致病变异，病例组显著多于对照组（P<0.001）
病例组：78例（3.55%，95%置信区间：2.82%～4.42%）
对照组：30例（1.29%，95%置信区间：0.87%～1.84%）
31例女性检出BRCA致病变异，其中符合检测指南比例：
病例组：30.8%
对照组：20.0%
78例女性检出其他乳腺癌相关基因致病变异，其中符合检测指南比例：
病例组：34.0%
对照组：16.0%
病例组的BRCA致病变异现患率：
诊断时年龄<65岁：2.21%（95%置信区间：0.82%～4.76%）
诊断时年龄≥65岁：1.09%（95%置信区间：0.67%～1.68%）
不同年龄的BRCA（P=0.34）或其他乳腺癌相关基因（P=0.54）致病变异现患率相似。
因此，该研究结果表明，3.55%的绝经后乳腺癌患者携带乳腺癌相关基因致病变异，将近无癌对照组的3倍，并且未随年龄增长而减少。乳腺癌诊断时年龄<65岁女性的BRCA致病变异现患率（2.21%）较高，与德裔犹太人群（≈2.5%）相似。这些关于绝经后女性乳腺癌易感基因致病变异现患率数据能够为检测指南的制定和更新提供参考。对于绝经后乳腺癌患者，即使诊断时年龄不小或无家族史，致病变异现患率也较高，故有必要进行检测。
JAMA. 2020 Mar 10;323(10):995-997.
Prevalence of Pathogenic Variants in Cancer Susceptibility Genes Among Women With Postmenopausal Breast Cancer.
Allison W. Kurian; Ryan Bernhisel; Katie Larson; Jennifer L. Caswell-Jin; Aladdin H. Shadyab; Heather Ochs-Balcom; Marcia L. Stefanick.
Stanford University, Stanford, California; Myriad Genetics, Salt Lake City, Utah; University of California, San Diego School of Medicine, La Jolla; The State University of New York, Buffalo.
This study uses Women's Health Initiative data to compare the prevalence of pathogenic variants (PVs) in breast cancer susceptibility genes in postmenopausal women with vs without breast cancer to guide decisions about who should undergo PV testing.
Germline genetic testing for pathogenic variants (PVs) in cancer susceptibility genes after breast cancer diagnosis may inform cancer treatment, prevention, and testing of relatives. Whether testing should be performed depends partly on PV prevalence, which may be low in the general population but higher in women with risk factors (eg, young diagnosis age, family history). For the best-characterized breast cancer susceptibility genes, BRCA1, BRCA2, or both (BRCA1/2), a minimum PV prevalence of 2.5% to 10% has been recommended for testing. However, guidelines vary in testing all breast cancer patients vs only those with features suggestive of hereditary risk. Most guidelines do not address testing among postmenopausal women without hereditary risk factors, the most common subgroup of breast cancer patients, as PV prevalence data are lacking. This study's purpose was to determine PV prevalence among women diagnosed with breast cancer after menopause vs the background prevalence among cancer-free postmenopausal women.
METHODS
The Women's Health Initiative (WHI) is a prospective study of morbidity and mortality that enrolled 161808 postmenopausal women aged 50 to 79 years at 40 US sites from 1993 through 1998. Research was approved by each institution's review board, and all participants provided written informed consent. We performed a nested case-control study of women without personal history of breast cancer at WHI enrollment who were diagnosed with invasive breast cancer (case participants) or remained cancer free (control participants) as of September 20, 2017. Case and control participants were unmatched and randomly selected from all WHI participants having banked DNA samples.
Next-generation sequencing and large rearrangement analysis was performed by Myriad Genetics using a panel of 28 genes; among these, BRCA1/2, ATM, BARD1, CDH1, CHEK2, NBN, PALB2, STK11, and TP53 were considered breast cancer associated. Variants were classified as pathogenic or likely pathogenic, of uncertain significance, or benign or likely benign.
Gene-specific prevalence was reported as a percentage for case and control participants with 95% CIs and P values calculated using the exact binomial method for CIs and χ2 tests for P values. The percentages of PV carriers meeting National Comprehensive Cancer Network 2019 testing guidelines (most relevant to oncology practice and relying primarily on diagnosis age and family history) were analyzed. Association with age was examined. Tests for PV prevalence trend by age among BRCA1/2 and other breast cancer-associated genes were performed using χ2 tests (R version 3.5.3) (2-sided P<0.05 was considered statistically significant).
RESULTS
Among 4517 women, the median age at breast cancer diagnosis was 73 years for case participants (n=2195) and 81 years at last follow-up for control participants (n=2322). In the case group, 66.3% were white vs 84.9% in the control group. PVs were detected in 241 women (148 case participants [6.74%; 95% CI, 5.73%-7.87%] and 93 control participants [4.01%; 95% CI, 3.24%-4.88%]; P<0.001). A PV was detected in any breast cancer-associated gene in 3.55% (95% CI, 2.82%-4.42%) of case participants and 1.29% (95% CI, 0.87%-1.84%) of control participants (P<0.001). Of women with BRCA1/2 PVs, 30.8% of case participants and 20% of control participants met testing guidelines; of women with PVs in other breast cancer-associated genes, 34% of case participants and 16% of control participants met testing guidelines.
For BRCA1/2, PV prevalence was 2.21% (95% CI, 0.82%-4.76%) among case participants diagnosed when younger than 65 years and 1.09% (95% CI, 0.67%-1.68%) among case participants diagnosed at 65 years or older. There was no trend by age for PV prevalence in BRCA1/2 (P=0.34) or other breast cancer-associated genes (P=0.54).
DISCUSSION
In this study, 3.55% of unselected, postmenopausal patients with breast cancer carried PVs in breast cancer-associated genes, a 3-fold higher prevalence than among cancer-free control participants and without decrease by age. Women diagnosed when younger than 65 years had similar probability of BRCA1/2 PVs as Ashkenazi Jewish individuals (≈2.5%), for whom testing is supported. Limitations: women chose to participate in WHI so the study may not represent all US women, a small number of PVs, and wide CIs in some subgroups.
These data on the prevalence of PVs in breast cancer susceptibility genes among postmenopausal women should inform testing guidelines. Among postmenopausal patients with breast cancer, PV prevalence may be high enough to warrant testing even in the absence of early diagnosis age or family history.
DOI: 10.1001/jama.2020.0229
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