肺癌分子诊断指南：建议所有肺腺癌患者都应接受基因检查

    肺癌在美国和世界其他地区都是致死率最高的癌症。目前，在肺癌生物标志物检验诞生十年后，一种检验EGFR基因突变和ALK基因重排的标准方法以及靶向治疗为肺癌患者提供了改善生存时间和生活质量的机会。日前，美国病理学会(CAP)、国际肺癌研究学会(IASLC)和美国分子病理学学会(AMP)三大权威学术机构发布了一项基于证据的肺癌分子学检测指南，建议所有肺腺癌患者接受基因检测，以便选择靶向治疗药物，例如表皮生长因子受体（EGFR）抑制剂（如厄洛替尼和吉非替尼）和间变性淋巴瘤激酶（ALK）酪氨酸激酶抑制剂（例如克里唑蒂尼）。这一指南于2013年4 月3 日发表于Arch Pathol Lab Med、JMol Diagn以及J Thorac Oncol杂志在线版。
    “指南的关键性推荐，同时也是对肺癌患者最有意义的部分，是指出所有晚期肺腺癌患者均应检查EGFR和ALK基因异常，检验结果可判断患者是否适于接受酪氨酸激素抑制剂治疗。” Marc Ladanyi博士在纽约纪念Sloan-Kettering癌症中心召开的分子诊断服务会议上指出，他是一名病理学家，同时也是IASLC会员。
    循证医学证据提示，肺癌患者如果进行基因检测并选择合适的靶向治疗药物，其预后会明显改善。因此，指南建议，所有肺腺癌患者不论性别、种族、是否吸 烟或伴其他临床危险因素，均应接受基因检测，其中EGFR突变和ALK 融合是首选检测项目。指南强调，原发肿瘤和转移病变同样适合检测EGFR 和ALK 状态。EGFR 和ALK 检测不适用于非腺癌肺癌患者，包括单纯鳞状细胞癌、单纯小细胞癌和免疫组织化学检测缺乏腺癌分化证据的大细胞肺癌患者。EGFR 和ALK 状态检测时机为：适    合治疗的晚期肺癌患者确诊时；既往肺癌分期较早但未接受基因检测的患者疾病复发或进展时。
    其他指南内容包括：
- 检测对原发性和转移性癌症都同样适用。
- 检测结果应该在10天内可以拿到，如果检验科不能达到这个时间线，则需要做出必要的改变来保证此标准。
– 可以是内部的改进或者选择其他标准实验室。（一致意见）
- KRAS检测不能被单独用作确定患者是否符合抗EGFR治疗指征的唯一标准。
- 对于EGFR抑制剂产生了获得性抵抗的患者，可以用最少5%的样本细胞来进行EGFR T790M次级染色体突变检测。
- 并不推荐PCR法用以取代荧光原位杂交法（FISH）来确定患者是否适用ALK抑制剂治疗。
- 如果是全肺切除的患者样本，EGFR和ALK检测并不推荐用于缺少腺癌特征的肺癌上，例如“单纯性”肺鳞癌，“单纯性”小细胞肺癌，或者是没有免疫组化证明有腺癌分化特征的大细胞肺癌。
作者指出，社区基层医院的观点倾向于，吸烟的肺腺癌患者进行基因检查是一种浪费。事实上，这种观点是错误的，5%~10%的吸烟肺腺癌患者基因检测阳性，因此能从靶向治疗中获益。
美国国家犹太健康医院James Jett 指出，该指南会改善大量肺癌患者的预后。肺腺癌是肺癌中最常见的类型，占60%~70%。约15% 的肺腺癌患者为EGFR 突变患者，5% 为ALK 突变患者。Jett 强调，该指南很适合Ⅳ期肺癌这一类“能治疗但不能治愈的疾病”。在不治疗的情况下，晚期肺癌患者的中位生存期仅4~5 个月，标准化疗可将生存期延长至9 个月，而EGFR 抑制剂能将生存期延长至2 年。此外，靶向治疗药物通常是口服药，其毒性低于化疗药物，因此接受该类药物治疗的患者的生活质量更佳。他认为，肺癌患者常规检测基因会在不久的将来实 现。美国国家肺癌伙伴关系执行董事ReginaVidaver 也表示，检测基因异常正成为肺癌标准治疗的一部分。
    与乳腺癌领域展开的分子检验相似，针对癌症患者的靶向治疗相关的分子绘图有助于为患者提供个体化治疗选择。这一指南解释了一些重要的问题，其中包括：

• 什么时候进行分子检验？
• 如何进行分子检验？
• 肺癌其他基因是否也应进行常规检查？
• 肺癌分子检难应如何实现？

    “在美国，多达20%的肺腺癌患者（最常见的肺癌类型）进行此二种生物标志物检验将呈现阳性，” Philip T. Cagle博士说，他是德克萨斯州Methodist医院病理学和基因组学研究室主任，APLM编辑，以及CAP会员。“这对于鉴别适应症人群至关重要，与传统化疗相比，新靶向药物会使适应症患者获益更多，而副作用更小。”
    肺癌患者Richard Heimler的分子诊断检验报告显示他还有5年的生存时间，在2004年初始诊断后，Richard Heimler接受了肺部和脑手术以切除肿瘤灶。然而，2008年，他的体内又出现了多个病灶，Richard Heimler参加了一项临床试验以明确自己是否适合靶向治疗。“结果我的ALK基因异常性检验结果呈现阳性，我开始服用一种靶向药物片剂，” Richard Heimler说，“奇妙的是治疗并没有引起化疗常见的致虚弱等副作用。这一科学进步的结晶带给我希望，我可以有更多的时间与家人分享，看着我的孩子们长大。”
    在精确医学的时代，这项指南可为病理学家，肿瘤学家，以及其他癌症健康专家提供有关肺癌分子检验的现今最高水准的医学推荐。“在关于相关基因突变检验应如何实施的问题上，三家组织达成了共识，”Brigham 妇女医院分子诊断主任Neal I. Lindeman博士表示，他是AMP会员。“专注于分子诊断和肺癌研究的专家紧密合作制定指南，以最大程度地消除分歧，为患者治疗提供了更精确的推荐。”
    CAP病理学和实验室质量中心是制定循证指南和共识推荐的权威机构，它领衔了此次指南的制定工作。制定推荐的专家组由相关领域的世界知名学者组成。“指南是保证患者从肺癌最新分子科学进展中获益的重要一步，” Ladanyi医生说。“随着新研究引导进一步的循证推荐的制定，我们希望看到关于肺癌生物标志物的其它指南出现。”
    指南发表后，CAP, IASLC, 和AMP相继为病理学家和临床医生推出临床工具和相关资料，以综述这些发现和推荐。此外，这些机构还为患者推出了便于加深理解的指南，其中包括常见的患者求助于医生的问题。CAP, IASLC, 和AMP还在YouTube网站上投放了一系列关于指南的视频，供医生和患者了解。

指南下载：肺腺癌分子检测指南.pdf

与肺癌相关的拓展阅读：

• J Clin Oncol：多摄入豆制品可提高肺癌生存率
• Chest：上海肺癌死亡率最高
• Lung Cancer：吉非替尼一线治疗肺癌有效、持久
• JCO：提高豆类摄入延长肺癌女性生存
• JNCI：Ran表达或影响乳腺癌和肺癌患者的生存期
• 吴一龙：肺癌筛查三大疑问有待解决
  
• 更多信息请点击：有关肺癌更多资讯

原始文献：

Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M.Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology.J Thorac Oncol. 2013 Apr 2. [Epub ahead of print]

Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M.Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology.J Mol Diagn. 2013 Apr 4. doi:pii: S1525-1578(13)00041-X.

Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M.Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology.Arch Pathol Lab Med. 2013 Apr 3

Advances in Molecular Testing Offer New Hope for Lung Cancer Patients
Apr. 3, 2013 — The emergence of molecular diagnostic testing in lung cancer offers new hope for patients battling the number one cancer killer in the United States and abroad. Now, for the first time after a decade of biomarker testing in lung cancer, a uniform approach for testing for the EGFR mutation and ALK rearrangement along with the availability of targeted therapies offer lung cancer patients the chance for improved quality of life and more time with their loved ones.
The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) have developed an evidence-based guideline, "Molecular Testing Guideline for the Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors," which establishes recommendations for EGFR and ALK testing, helping to guide targeted therapies. The guideline was released on April 3, 2013, in Archives of Pathology & Laboratory Medicine (APLM), Journal of Thoracic Oncology, and The Journal of Molecular Diagnostics.
"The key recommendation of the guideline, and perhaps most important to lung cancer patients, is that all patients with advanced lung adenocarcinoma should be tested for EGFR and ALK abnormalities, that would qualify them for tyrosine kinase inhibitor therapy, regardless of their clinical variables, such as smoking history, gender, or ethnicity," said Marc Ladanyi, MD, attending pathologist in the Molecular Diagnostics Service at Memorial Sloan-Kettering Cancer Center in New York, and IASLC member. {nextpage}
Similar to the testing done in breast cancer, matching a cancer patient's molecular profile with the appropriate targeted therapy provides individualized treatment options. The guideline answers important clinical questions, including:
•When should testing be performed?
•How should testing be performed?
•Should other genes be routinely tested in lung cancer?
•How should molecular testing of lung cancer be implemented?
"In the U.S. up to 20 percent of patients with lung adenocarcinoma, the most common type of lung cancer, will test positive for one of the two biomarkers," said Philip T. Cagle, MD, FCAP, medical director of Pulmonary Pathology in the Department of Pathology and Genomic Medicine at The Methodist Hospital in Houston, Texas, APLM editor, and CAP member. "It is critical to identify these patients because they stand to benefit more from new targeted drugs than from conventional chemotherapy, and with fewer side effects."
For lung cancer survivor Richard Heimler, molecular diagnostic testing has meant five additional years with his family, including his daughter and son. After his initial diagnosis in 2004, Heimler had surgery to remove cancer tumors in his lungs and brain. When multiple tumors returned in 2008, Heimler participated in a clinical trial to determine if he was a candidate for targeted therapies.
"After testing positive for the abnormal ALK gene, I began taking a targeted drug in the form of a pill," said Heimler. "It was wonderful to not experience the debilitating side effects that I had with chemotherapy. This new world of science has given me hope that I will have more time to create memories with my children and watch them grow up."
In an era of precision medicine, the guideline provides recommendations for pathologists, oncologists, and other cancer health professionals on the current state-of-the-art recommendations for the molecular testing of lung cancer.
"The three organizations came together to address the variance in practice around the world about how this testing should performed," said Neal I. Lindeman, MD, director of Molecular Diagnostics at Brigham and Women's Hospital and associate professor of Pathology at Harvard Medical School in Boston, and AMP member. "Pathologists who specialize in molecular diagnostics and lung cancer collaborated to create the guideline to minimize variation and provide greater precision in the care of patients."
The CAP Pathology & Laboratory Quality Center (the Center), a forum for developing evidence-based guidelines and consensus recommendations, provided the process for creating the guideline. Expert panels made up of renowned worldwide leaders in the field collaborated to develop the recommendations.
"The guideline is an important step in making sure that patients benefit from the new molecular understanding of lung cancer," said Dr. Ladanyi. "As new studies lead to further evidence-based recommendations, we hope to develop additional guidelines for other biomarkers related to this disease."
In conjunction with the publishing of the guideline, CAP, IASLC, and AMP have developed clinical tools and resources for pathologists and oncologists that summarize the findings and recommendations. In addition, the organizations have developed a patient guide for further understanding, including questions for patients to ask their physicians. A series of videos featuring three of the guideline authors and a lung cancer survivor can be found on the CAP, IASLC, and AMP YouTube Channels.