Key Points

• Ninety‐two percent of the study participants “never,” “rarely,” or only “sometimes” reacted negatively to multigene panel results.
• Carriers of high‐ and moderate‐risk pathogenic variants (PVs) had higher levels of uncertainty and distress regarding the panels, whereas patients with a variant of uncertain significance (VUS) or negative findings had lower levels of uncertainty and distress regarding the panels.

Dr. Idos says that one concern raised by critics of multigene panels is the high VUS rate and the potential for distress and uncertainty among these variant carriers. “However, our study showed that the psychologic response of VUS carriers matched the response of the patients testing negative.”

With the increased use of germline multigene panel testing for assessing inherited cancer risk, little is known about the acceptance of these tests—or the fear of them—by patients of ethnically diverse and economically disadvantaged groups who are known or possible carriers of mutations in cancer‐related genes. A new study conducted at multiple academic sites in California reported broad approval of the tests by patients. That study appears in Cancer (published online December 15, 2020. doi:10.1002/cncr.33357).

“We found that multigene panel testing is psychologically safe to use among a diverse population of patients undergoing genetic counseling,” says lead study author Julie O. Culver, MS, CGC, a clinical instructor of medical oncology at the University of Southern California (USC) Norris Comprehensive Cancer Center in Los Angeles.

Culver says that what prompted the study were concerns that the use of multigene panels would lead to confusion, uncertainty, and psychological distress in patients. “Our study … refutes some of the apprehension surrounding the use of multigene panels.”

According to study coauthor Gregory E. Idos, MD, MS, associate clinical professor at the Center for Precision Medicine at the City of Hope National Medical Center in Duarte, California, this study is also one of the first to measure the psychological response to genetic testing among moderate‐risk mutation carriers. “We found that the vast majority of moderate‐risk mutation carriers rarely feel uncertainty or distress about the tests,” he said.

Study coauthor Charité Ricker, MS, CGC, clinical instructor of medicine in medical oncology at USC, who practices at the Los Angeles County–USC Medical Center, added that most studies of psychological responses to testing have been conducted among college‐educated, mostly White or Ashkenazi Jewish individuals. “Our study included a mix of diverse backgrounds including non‐English speaking, Hispanic, and Asian individuals as well as many with a high school education or less.”

Study Details

The 1264 participants in the study were drawn from 3 genetics clinics: the USC Norris Comprehensive Cancer Center, the Los Angeles County–USC Medical Center, and the Stanford University Cancer Institute. All were patients of one of the clinics between July 2014 and November 2016. Participants were deemed eligible if statistical models indicated that either 1) they had at least a 2.5% probability of PVs in genes related to hereditary cancer or 2) they met National Comprehensive Cancer Network (NCCN) guideline criteria for genetic testing.

The participants received counseling by board‐certified genetic counselors or an advanced practice genetics nurse practitioner. Approximately a third of the subjects also met with a physician specializing in cancer genetics. Each participant was tested with a Myriad myRisk 25‐ or 28‐gene panel and completed a result survey, including the Multidimensional Impact of Cancer Risk Assessment (MICRA), at the baseline and after 3 months.

The study participants were predominantly female (79.8%) and had a mean age of 52.2 years; 70% of the participants had cancer. Non‐Hispanic Whites were the largest group at 44.9%. In addition, 37.3% identified as Hispanic, 9.7% identified as Asian, 3.2% identified as Black, and 4.9% identified themselves as “another race or ethnicity” or had mixed ancestry. Approximately 27.7% had an educational attainment of less than a high school diploma, and 22.7% were non–English‐speaking.

Study Results

The researchers found the following:

• 7.4% of the subjects had a high‐risk PV.
• 5.5% of the subjects had a moderate‐risk PV (moderate‐risk genes included those that presented a 2‐ to 5‐fold relative risk of cancer when altered by a PV).
• 35.0% of the subjects had a VUS.
• 52.1% of the subjects tested negative.

They also discovered that 92.4% of the participants had a total MICRA score of no greater than 38. This, they reported, meant that the vast majority of patients “never,” “rarely,” or only “sometimes” reacted negatively to the multigene panel findings. “Because the MICRA scale does not have recognizable thresholds for identifying psychologic distress,” says Culver. “We developed a green‐amber‐red scale that corresponds to MICRA responses to improve the interpretation of the original MICRA scale.”

As expected, the study reported that participants with a high‐ or moderate‐risk PV had much higher uncertainty, distress, and total MICRA scores coupled with significantly fewer positive experiences than did participants with a VUS or negative result. Specifically, using a multivariate analysis, the researchers reported that mean total MICRA scores were significantly higher, which meant greater uncertainty and distress, for high‐risk PV carriers (90 patients; mean MICRA score, 29.7) and moderate‐risk PV carriers (68 patients; mean MICRA, score 24.8) than they were for carriers of a VUS (424 patients; mean MICRA score, 17.4) or for patients who had negative results (623 patients; mean MICRA score, 16.1). These results agree with previous studies, with high‐risk PV carriers having higher total MICRA scores.

The researchers also found that having a cancer diagnosis or less formal education was associated with a significantly higher total MICRA score, whereas race and/or ethnicity was not related to total MICRA scores.

Dr. Idos says that one concern raised by critics of multigene panels is the high VUS rate and the potential confusion among these gene carriers. “However, our study showed that the psychologic response of VUS carriers matched the response of the patients testing negative.” He added, “Because the MICRA scale does not have recognizable thresholds for identifying psychologic distress, we developed a green‐amber‐red scale that corresponds to MICRA responses to improve the interpretation of the original MICRA scale.”

Study Analysis

“This study breaks new ground,” says Tuya Pal, MD, associate director for cancer health disparities and the Ingram Professor of Cancer Research at the Vanderbilt‐Ingram Cancer Canter in Nashville. “While we have a lot of data on the BRCA1 and BRCA2 and what we consider the regular high‐penetrance genes, we don't know as much about the psychosocial outcomes of individuals who have moderate penetrance risk genes.”

Dr. Pal says a key strength of the study was the diversity of its participants, who received counseling by professionals, which she says no doubt helped with the high acceptance rates. “Often, when we think about genetic testing studies, particularly for ones that are clinic‐based, we're not seeing diversity in the patient population,” she says. “Here, they had pretty good representation of Hispanics and Asians, which is not common in US‐based studies.” Dr. Pal did note that there was a fairly low number of African American patients, which is a study limitation. “Additionally, while these results are encouraging for those who receive genetic counseling through a genetics professional prior to testing, it should be recognized that that vast majority (~80%) of patients are tested out in the community without interfacing with someone with expertise in genetics. Consequently, it is critical to evaluate outcomes when patients are tested out in the community without the involvement of a genetics professional.”

“The reason we do genetic testing is so that we can positively influence care,” says Dr. Pal. “While we know that genetics is only one piece of healthy outcomes, if we roll genetic testing out more broadly but we don't address disparities across diverse populations and the ability to pay, we're just going to widen the divide between those who have access to great care and those who don't … we're going to increase those disparities.”

Culver agrees. “Further research would help clarify whether the same results would be found among patients who receive genetic testing from other types of health care providers and in community settings.”

Dr. Pal is also the vice‐chair of the panel for the NCCN Guidelines for Genetic/Familial High‐Risk Assessment: Breast, Ovarian and Pancreatic Panel and encourages clinicians looking for guidance on this topic to use these guidelines as a resource. Anyone can access these guidelines by creating a free account through the NCCN website (nccn.org/store/Login).

Another recommended resource, hosted by the National Cancer Institute and for which Dr. Pal will be the incoming editor‐in‐chief, is PDQ Cancer Information Summaries: Genetics (cancer.gov/publications/pdq/information‐summaries/genetics). “This is a resource that is updated on a monthly basis as new information relevant to the field of inherited cancer predisposition is published,” says Dr. Pal.

中文翻译：

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多基因面板获得患者广泛的心理接受

关键点

• 92% 的研究参与者“从不”、“很少”或“有时”对多基因面板结果产生负面反应。
• 高风险和中等风险致病变异 (PV) 的携带者对面板具有较高的不确定性和困扰，而具有不确定意义的变异 (VUS) 或阴性结果的患者对面板具有较低的不确定性和困扰。

Idos 博士说，多基因组的批评者提出的一个担忧是高 VUS 率以及这些变异携带者之间的痛苦和不确定性的可能性。“然而，我们的研究表明，VUS 携带者的心理反应与检测结果呈阴性的患者的反应相匹配。”

随着生殖系多基因面板检测用于评估遗传性癌症风险的增加，人们对这些检测的接受程度或恐惧程度知之甚少，这些检测被已知或可能携带癌症突变的种族多样化和经济弱势群体的患者所接受相关基因。在加利福尼亚州的多个学术场所进行的一项新研究报告称，患者广泛认可了这些测试。该研究发表在癌症杂志上（2020 年 12 月 15 日在线发表。doi:10.1002/cncr.33357）。

“我们发现，在接受遗传咨询的不同人群中使用多基因面板检测在心理上是安全的，”主要研究作者、南加州大学 (USC) 医学肿瘤学临床讲师 Julie O. Culver, MS, CGC 说。 ) 洛杉矶诺里斯综合癌症中心。

Culver 说，促使这项研究的原因是担心使用多基因面板会导致患者的困惑、不确定性和心理困扰。“我们的研究……驳斥了围绕使用多基因面板的一些担忧。”

根据该研究的合著者、加利福尼亚州杜阿尔特希望之城国家医疗中心精准医学中心临床副教授 Gregory E. Idos 医学博士的说法，这项研究也是最早测量对遗传的心理反应的研究之一。在中等风险突变携带者中进行检测。“我们发现绝大多数中等风险的突变携带者很少对测试感到不确定或痛苦，”他说。

研究合著者 Charité Ricker, MS, CGC, USC 医学肿瘤学临床讲师，在洛杉矶县 - 南加州大学医学中心执业，他补充说，大多数关于测试心理反应的研究都是在受过大学教育的人中进行的，主要是白人或德系犹太人。“我们的研究包括不同背景的人，包括不会说英语的、西班牙裔和亚洲人，以及许多高中或以下学历的人。”

学习详情

该研究的 1264 名参与者来自 3 个遗传学诊所：南加州大学诺里斯综合癌症中心、洛杉矶县-南加州大学医学中心和斯坦福大学癌症研究所。所有人都是 2014 年 7 月至 2016 年 11 月期间其中一家诊所的患者。如果统计模型表明 1) 他们在与遗传性癌症相关的基因中有至少 2.5% 的 PV 概率或 2) 他们符合国家综合癌症网络 (NCCN) 基因检测指南标准。

参与者接受了委员会认证的遗传顾问或高级实践遗传学护士的咨询。大约三分之一的受试者还与专门研究癌症遗传学的医生会面。每个参与者都接受了 Myriad myRisk 25 或 28 基因面板的测试，并在基线和 3 个月后完成了结果调查，包括癌症风险评估的多维影响 (MICRA)。

研究参与者主要是女性 (79.8%)，平均年龄为 52.2 岁；70% 的参与者患有癌症。非西班牙裔白人是最大的群体，占 44.9%。此外，37.3% 被认定为西班牙裔，9.7% 被认定为亚裔，3.2% 被认定为黑人，4.9% 将自己认定为“另一个种族或民族”或具有混血血统。大约 27.7% 的受教育程度低于高中文凭，22.7% 不会说英语。

研究结果

研究人员发现了以下几点：

• 7.4% 的受试者有高危 PV。
• 5.5% 的受试者具有中度风险 PV（中度风险基因包括那些在被 PV 改变时呈现出 2 到 5 倍癌症相对风险的基因）。
• 35.0% 的受试者有 VUS。
• 52.1% 的受试者测试结果为阴性。

他们还发现 92.4% 的参与者的 MICRA 总分不超过 38。他们报告说，这意味着绝大多数患者“从不”、“很少”或“有时”对多基因产生负面反应。小组调查结果。“因为 MICRA 量表没有识别心理困扰的可识别阈值，”卡尔弗说。“我们开发了一种与 MICRA 反应相对应的绿色-琥珀色-红色量表，以改进对原始 MICRA 量表的解释。”

正如预期的那样，该研究报告称，与具有 VUS 或阴性结果的参与者相比，具有高风险或中等风险 PV 的参与者具有更高的不确定性、痛苦和总 MICRA 分数以及显着更少的积极体验。具体而言，使用多变量分析，研究人员报告说，对于高风险 PV 携带者（90 名患者；平均 MICRA 评分为 29.7）和中度风险 PV 携带者（68患者；平均 MICRA，得分 24.8）与 VUS 携带者（424 名患者；平均 MICRA 得分，17.4）或阴性结果的患者（623 名患者；平均 MICRA 得分，16.1）相比。这些结果与之前的研究一致，高风险 PV 携带者的 MICRA 总分更高。

研究人员还发现，癌症诊断或较少的正规教育与显着较高的 MICRA 总分有关，而种族和/或民族与 MICRA 总分无关。

Idos 博士说，多基因面板的批评者提出的一个担忧是高 VUS 率和这些基因携带者之间的潜在混淆。“然而，我们的研究表明，VUS 携带者的心理反应与检测结果呈阴性的患者的反应相匹配。” 他补充说，“因为 MICRA 量表没有识别心理困扰的可识别阈值，我们开发了一个与 MICRA 反应相对应的绿色-琥珀色-红色量表，以改善对原始 MICRA 量表的解释。”

研究分析

“这项研究开辟了新天地，”纳什维尔范德比尔特-英格拉姆癌症中心癌症健康差异副主任、癌症研究英格拉姆教授 Tuya Pal 说。“虽然我们有大量关于 BRCA1 和 BRCA2 以及我们认为的常规高外显率基因的数据，但我们对具有中等外显率风险基因的个体的心理社会结果知之甚少。”

Pal 博士说，这项研究的一个关键优势是参与者的多样性，他们接受了专业人士的咨询，她说这无疑有助于提高接受率。“通常，当我们考虑基因检测研究时，尤其是基于临床的研究时，我们没有看到患者群体的多样性，”她说。“在这里，他们对西班牙裔和亚洲人有很好的代表性，这在美国的研究中并不常见。” Pal 博士确实注意到非裔美国患者的数量相当少，这是研究的局限性。“此外，虽然这些结果对那些在测试前通过遗传学专业人士接受遗传咨询的人来说是令人鼓舞的，应该认识到，绝大多数（约 80%）的患者在社区中进行了测试，而没有与具有遗传学专业知识的人接触。因此，在没有遗传学专业人士参与的情况下，在社区中对患者进行测试时，评估结果至关重要。”

“我们进行基因检测的原因是为了对护理产生积极影响，”帕尔博士说。“虽然我们知道基因只是健康结果的一部分，但如果我们更广泛地开展基因检测，但我们不解决不同人群和支付能力之间的差异，我们只会扩大那些可以得到很好的照顾，而那些没有得到很好的照顾……我们将扩大这些差距。”

卡尔弗同意。“进一步的研究将有助于澄清在接受其他类型医疗保健提供者和社区环境中的基因检测的患者中是否会发现相同的结果。”

Pal 博士还是 NCCN 遗传/家族高危评估指南：乳腺、卵巢和胰腺专家组的副主席，并鼓励寻求该主题指导的临床医生将这些指南用作资源。任何人都可以通过 NCCN 网站 (nccn.org/store/Login) 创建一个免费帐户来访问这些指南。

另一个由国家癌症研究所主办且 Pal 博士将担任主编的推荐资源是 PDQ 癌症信息摘要：遗传学 (cancer.gov/publications/pdq/information-summaries/genetics)。“随着与遗传性癌症易感性领域相关的新信息的发布，这是一个每月更新的资源，”Pal 博士说。