Heather Wakelee, MD
引言
肺癌是全球癌症死亡的首要原因，每年导致大约160万人死亡[1]。烟草烟雾暴露是肺癌的主要病因，在美国，肺癌的发病率和死亡率随着吸烟的减少而下降，这就说明了烟草烟雾暴露的重要性[2,3]。
尽管推测吸烟是肺癌的主要病因，但肺癌也是无吸烟史个体的重大健康问题[4,5]。越来越多的信息支持以下观点：从流行病学及生物学角度来看，从不吸烟者肺癌的区别足以使其被视为一种独立的疾病[6-9]。此外，随着美国和其他国家从不吸烟者人数的增加，这一群体中肺癌的问题变得更加重要。
从不吸烟者肺癌的流行病学、危险因素、生物学差异，以及治疗的潜在意义将总结在此。
流行病学一般而言，术语“从不吸烟者”是指在一生中吸食少于100支香烟的个体。很难确定从不吸烟者肺癌发病率的准确数据，因为大多数基于人群的癌症注册登记，包括美国国家癌症研究所的监测、流行病学和最终结果(Surveillance, Epidemiology and End Results,SEER)数据，并未收集患者的吸烟信息。SEER数据库已经链接了基于人群的烟草使用信息[10,11]，但这仅可用于估计广泛地理区域内从不吸烟者的肺癌。
发病率 — 在世界范围内，从不吸烟者肺癌在男性肺癌中占大约15%-20%，而在女性中超过50%[12]。其发病存在显著的地域差异，特别是在亚洲，亚洲60%-80%的肺癌女性患者从不吸烟[4]。从不吸烟者的小细胞肺癌发病率极低[13]，因此本文将集中讨论非小细胞肺癌(non-small cell lung cancer,NSCLC)。
美国的一项分析显示，估计19%的肺癌女性患者从不吸烟，相比之下，男性肺癌患者中这一比例约为9%[14]。这些结果是基于对美国5项大型队列研究中患者数据的分析[15-20]。40-79岁从不吸烟者中，年龄调整后肺癌的发病率男性为11.2-13.7/100,000人年，女性为15.2-20.8/100,000人年。这些发病率与美国男性骨髓瘤或女性宫颈癌的发病率相近[21]。相比之下，在相同的队列中，当前吸烟者的年龄调整后肺癌发病率增加至大约12-30倍。
一项针对1991-2005年间在加利福尼亚州南部诊断的肺癌患者的分析，根据地区癌症注册的电子病历摘要，采用一种新型文本挖掘程序算法来评估这些患者的吸烟状态。这项研究确定，在25,000多例已知吸烟状态的肺癌患者中，从不吸烟者有8.9%，其中男性有6%，女性有14%[22,23]。
然而，针对13个队列和22项注册登记的另一项分析发现，总体来说，从不吸烟者肺癌的发病率无明显的性别差异，但在40-59岁从不吸烟者中，女性发病率高于男性[24]。在这一项多国家分析中，女性年龄标准化后肺癌的发病率(每100,000例，使用2000年世界人口年龄标准)方面，欧洲血统女性为12.4/100,000、亚洲女性为15.0/100,000，而非洲裔美国女性为19.4/100,000。相比之下，欧洲、亚洲和非洲裔美国男性的肺癌发病率分别为11.2/100,000、12.9/100,000和12.3/100,000。
从不吸烟者肺癌的发病率是否正发生改变尚不清楚，各相关研究得出的结果不一致：
●一项针对瑞典建筑工人医疗保健计划(与他们的国家癌症注册关联)的研究显示，在年龄调整后从不吸烟者肺癌的发病率方面，1991-1995年间比1976-1980年间有大幅增加(1.5/100,000 vs 5.4/100,000)[25]。
●两个美国癌症学会预防研究队列发现，与1959-1972年相比，1982-2000年女性不吸烟相关肺癌所致的死亡率出现具有统计学意义的增加，但幅度较小(12.3/100,000 vs 14.7/100,000)[26]。对于男性患者，这一死亡率未随时间发生改变。
●针对加利福尼亚州南部近12,000例肺癌患者的一项病例系列研究提供了间接证据[27]。相比于1995-1999年间，1999-2003年间细支气管肺泡癌中的从不吸烟者比例从19%上升到26%，而其他类型肺癌中不吸烟者比例从8.6%上升到9.4%。
●从日本和加利福尼亚州南部癌症注册(包括吸烟信息)收集的数据主要针对于两个时间段(即，1991-1996年间和1997-2001年间)中从不吸烟者的肺癌，该数据显示，这两个时间段内，从不吸烟肺癌患者所占比例无显著改变(日本及加利福尼亚州南部癌症注册登记中，较早时间段和较晚时间段的从不吸烟者肺癌比例分别为28% vs 31%和7.2% vs 7.4%)[28]。
●英国现有的数据并不支持从不吸烟者肺癌发病率增加。在1950年和1990年相同医院和社区环境中进行的两项病例对照研究的对比显示，男性肺癌患者中从不吸烟者的比例并未改变，但对照组中从不吸烟者的比例从4.5%增加至19%[29]。在这一时间段内，女性从不吸烟者肺癌的比例显著下降，而对照组中吸烟率的下降程度没那么显著。
●日本的一项单机构评估发现，在1974-2004年的30年间，早期NSCLC的中不吸烟者比例大约从16%增加至33%[6]。对13项队列的大型汇总分析，比较了美国康涅狄格州近期观察到的肺癌发病率与20世纪30年代(女性吸烟非常罕见)时的发病率，结果发现肺癌发病率并没有随时间而显著改变[24]。
需要癌症注册数据收集患者吸烟状态相关信息，以便仔细检测从不吸烟者中肺癌发病率的趋势。得到自述吸烟状态信息存在困难，但若干研究已经验证了这一方法的有效性，这些研究中吸烟者分类错误率较小[30,31]。
性别 — 尽管一些分析报道显示，相比于男性，女性肺癌患者中从不吸烟者的比例更高[4,12,14,32]，但两个美国癌症学会癌症预防研究队列显示，在从不吸烟者中年龄调整后的肺癌死亡率方面，男性高于女性[26]。一项汇总分析纳入了13项队列研究和多个癌症注册研究，且这一汇总分析的大部分欧洲裔患者来源于上述两个队列，结果显示，在年龄标准化后的肺癌死亡率方面，从不吸烟欧洲裔男性为12.0/100,000，从不吸烟欧洲裔女性为9.5/100,000。在亚洲患者中，男性和女性死亡率分别为26.0/100,000和16.1/100,000[24]。女性肺癌患者存活时间比男性更长，但尚不确定这能在多大程度上解释肺癌发病率和死亡率间的差异[33]。
相比之下，日本的一项研究表明，33%的男性肺癌死亡和85%的女性肺癌死亡并不是由吸烟所致。在日本，女性从不吸烟肺癌患者比例要高得多[34,35]。
族群 — 吸烟相关肺癌风险存在种族/民族差异。基于种族或民族的从不吸烟者肺癌发病率差异的准确数据极为有限。
●加利福尼亚南部一项针对20,000多例患者的分析发现，亚洲太平洋岛民所有女性肺癌患者中46%为从不吸烟者，而西班牙裔肺癌女性患者中这一比例25%，非洲裔美国女性这一比例11%，非西班牙裔白人女性这一比例为10%[23]。
●加利福利尼北部一项针对1998-2008年间诊断的肺癌病例的分析发现，在所识别的所有肺癌病例中，亚洲太平洋岛民肺癌女性患者中从不吸烟者占71%，而西班牙裔女性肺癌患者这一比例为35%，非西班牙裔白人女性这一比例为40%[36]。这项研究还观察到了这些患者组间存在生存差异。
●这一内容进一步的数据来自于一项针对队列和注册数据的大型汇总分析，结果显示，从不吸烟者中肺癌的发病率和死亡率具有很大差异，甚至在某些亚洲国家间也是如此，包括中国和泰国，但非洲裔美国人的肺癌发病率和死亡率总体上比其他种族群体高[24]。
为更好地了解这种疾病的种族/民族差异，还需要开展更多的研究。
年龄 — 虽然推测从不吸烟者中肺癌发生的年龄更小[37]，但这仅在部分[32](不是所有)的近期针对西方人群的队列分析中被证实[14]。然而，来自亚洲的研究显示，诊断时年龄更小是从不吸烟者肺癌的特征[38]。
危险因素
从不吸烟者肺癌的致病因素尚不完全清楚。被视为从不吸烟者肺癌最重要的危险因素将讨论在此。
二手烟 — 二手烟(secondhand smoke, SHS)是从不吸烟者中肺癌的重要危险因素[30,39-41]。然而，这个问题的严重程度并不明确。
一些研究表明，在从不吸烟者中，大约15%-35%的肺癌归因于二手烟[42-46]，在25岁前就暴露于二手烟的人群中，这一风险可能会增加[47]。
●法国一项针对1493例肺癌患者的研究发现，79%的从不吸烟女性肺癌患者和21%的从不吸烟男性肺癌患者有二手烟暴露[46]。
●加拿大一项纳入445例患者和948例对照者的基于人群病例对照研究发现，在家中或工作场所的二手烟暴露与肺癌的发生无关[32]。
●日本一项基于人群的前瞻性研究报道，相比于配偶为不吸烟者的从不吸烟女性，和吸烟丈夫生活的从不吸烟女性发生腺癌的风险比(hazard ratio,HR)为2.03(95%CI 1.07-3.86)[48]。
●美国一项病例对照研究报告，在儿童期有二手烟暴露的从不吸烟者发生肺癌的风险增加(OR 2.5，95%CI 1.04-4.90)[49]。
●对欧洲一项纳入520,000人的病例对照研究数据(样本量最大)的分析显示，在非吸烟者中，与二手烟有关的肺癌比例为16%-24%[45]。而从不吸烟者的肺癌中，另外5%-7%被认为是空气污染引起。
●一项纳入55项国际研究的meta分析显示，配偶吸烟可增加从不吸烟者发生肺癌的风险(RR 1.27，95%CI 1.17-1.37)[50]。
●对近500,000人进行癌症风险评估的EPIC研究显示，暴露于二手烟的从不吸烟者肺癌风险显著升高(HR 1.65，95%CI 1.04-2.63)[51]。
较近期的数据显示，证明二手烟是从不吸烟者发生肺癌的真正致病因素存在困难。
●妇女健康行动(Women’s Health Initiative, WHI)观察性研究纳入了76,000多例有完整吸烟史的女性[52]。在平均随访10.5年时，识别了901例肺癌病例。在从不吸烟者中，肺癌的发生与被动吸烟暴露总体上来说无相关性(HR 0.88，95%CI 0.52-1.49)，但具有成年期家庭二手烟暴露的从不吸烟女性存在肺癌升高的趋势(HR 1.61，95%CI 1.00-2.58)。
二手烟可能与亚洲从不吸烟者中较高的肺癌发生率有关，这一假说受到了“对有和无吸烟史的亚洲患者进行肺癌全基因组测序的结果”的质疑。亚洲从不吸烟者肺癌的突变特征与欧洲从不吸烟者肺癌非常相似，但两组均不同于吸烟者的肺癌突变模式。[53]。
氡 — 氡是铀-238和镭-226的一种气态衰变产物，它能通过发射α粒子来损坏呼吸道上皮。现在已经更加明确地证实了铀矿工人的肺癌风险增加，这被认为是由氡辐射所致[54]。
氡存在于土壤、岩石和地下水中，其可在住所蓄积。对于从不吸烟者，家中氡暴露可能对肺癌的发生有一定作用[55-57]，但这存在争议[58]。
环境暴露 — 其他职业暴露已知可增加吸烟者的肺癌风险，也可较小程度地增加从不吸烟者的肺癌发病风险。
●常与肺癌发生相关的毒素包括石棉、铬和砷[59-62]。有研究显示，职业暴露于有机粉尘是肺癌的危险因素[63]。荷兰一项针对职业性石棉暴露的分析发现，在调整了年龄、吸烟和其他因素后，职业性石棉暴露引起肺癌的相对危险度(relative risk, RR)为3.5[62]。法国一项针对1493例患者的研究发现，在从不吸烟者肺癌中，9.4%的女性和48.6%的男性有一些职业暴露[46]。加拿大一项病例对照研究显示，从不吸烟者中职业暴露引起肺癌风险的比值比(odds ratio, OR)为2.1(95%CI 1.3-3.3)，对于溶剂、涂料或稀释剂的暴露，其比值比更高(OR 2.8，95%CI 1.6-5.0)[32]。一篇meta分析评估了油漆工的肺癌风险，分析显示：油漆工整体的肺癌RR为1.35(95%CI 1.29-1.41)，但从不吸烟的油漆工为2.0(95%CI 1.09-3.67)[64]。
●在饮水受到砷污染的地方，如中国台湾和智利的某些地区，砷为肺癌的一个病因[65,66]。对具有砷暴露的从不吸烟患者肺癌的全基因组测序，结果显示出不同于其他肺癌患者的突变模式，包括罕见的TP53突变[67]。
●目前已研究了多种膳食因素可能是肺癌的病因，但尚没有一种膳食因素明确与肺癌有关。较多地摄入水果和蔬菜可能是肺癌的保护性因素[34,68,69]。意大利一项病例对照研究发现，从不吸烟者中，相对于红肉摄入量最低四分位区间，摄入量最高四分位区间者肺癌的RR为2.4(95%CI 1.4-4.0)[70]，另一项报道显示，对于从不吸烟者，较多的摄入鱼可能是肺癌的保护性因素[71]。美国近期一项仅针对从不吸烟者的研究报道，采用“最健康的”膳食模式(即，多摄入水果和蔬菜和低脂食品)的从不吸烟者肺癌风险降低[72]。
●室内空气污染物，如食用油的蒸汽和燃烧煤的烟雾等与肺癌有关，尤其是在亚洲[73-76]，但关于这些因素的重要性仍存在一些争议[77-79]。
●室外空气污染也与肺癌风险相关。癌症预防研究(Cancer Prevention Study, CPS)-Ⅱ使用平均长期环境细颗粒物(PM2.5)作为空气污染的一个指标，结果发现，对于从不吸烟者，PM2.5浓度每增加10μg/m3，肺癌死亡率就增加15%-27%[80]。纳入上述研究和其他17项研究的一项meta分析得出结论，PM2.5相关肺癌的RR为1.09(95%CI 1.04-1.14)，这在从不吸烟者中更明显(RR 1.18，95%CI 1.00-1.39)[81]。针对11项研究的一项汇总分析显示，柴油机废气暴露可增加肺癌风险(OR 1.31，95%CI 1.19-1.43)，但对从不吸烟者没有特异性[82]。日本一项针对14,000余例老年居民的分析显示，交通相关的空气污染(使用升高的二氧化氮水平作为暴露标志)与肺癌死亡有关(HR 1.2，95%CI 1.03-1.40)[83]。
肺部疾病 — 对于不吸烟者，既往因基础肺病或暴露于放射或化疗导致肺损伤者，肺癌风险增加[32,84-87]。这种风险的大小目前还不清楚，因为绝大多数肺部疾病都与吸烟有关。就特发性肺纤维化与肺癌的相关性而言，文献结果不一致，但似乎大多数研究都支持两者相关[88,89]。
致癌病毒 — 目前正在研究部分肺癌的病毒性病因，尤其着重于人乳头瘤病毒(human papillomavirus,HPV)的作用[90,91]。
中国台湾一项纳入141例肺癌患者和60例非癌症对照者的病例对照研究发现，HPV16和18血清型在肺癌患者中显著更常见(55% vs 27%)[92]。这一相关性在年龄较大的非吸烟女性中最明显。然而，一项针对白种人患者的病例系列研究并未观察到HPV较高的阳性率[93]，随后的一项meta分析也不确定HPV在从不吸烟者肺癌病因中的潜在作用[94]。对334例肺肿瘤标本进行详细的病理评估和HPV基因分型，识别到10%的标本有HPV DNA，但未识别到病毒来源的癌基因，因此不支持HPV与肺癌的因果关系[95]。
遗传因素 — 多项研究显示，从不吸烟者肺癌与肺癌家族史相关，这提示存在遗传因素作用[32,40,96-100]。
例如，一项纳入257例从不吸烟肺癌患者和257例从不吸烟对照者的病例对照研究显示，在有肺癌阳性家族史的受试者中肺癌显著更常见(OR 7.2)[99]。另一项病例对照研究纳入了316例从不吸烟肺癌患者的2400余名亲属，分析发现，肺癌患者的一级亲属患任意类型肺癌的风险比对照高25%，其中吸烟的一级亲属患早发型肺癌(<50岁)的风险尤其高[100]。来自肺癌环境和遗传学病因(Environment And Genetics in Lung cancer Etiology,EAGLE)研究的一项分析显示，在调整年龄、性别、居住情况、教育和吸烟情况后，肺癌阳性家族史相关的肺癌RR为1.57(95%CI 1.25-1.98)[101]。环境暴露指数可帮助识别从不吸烟者肺癌发生的家族史和环境暴露之间的相互作用，而这一环境暴露指数是针对中国从不吸烟者中这些问题而进行开发的。同时具有家族史和高度环境暴露的男性相比于那些这两者都没有的男性，肺癌发病的OR为30.6(95%CI 9.4-99.9)，但在女性中这一相关性没有如此强烈[102]。一项关于从不吸烟者的病例对照研究显示，DNA修复能力较差，通过宿主细胞再激活分析检测得出，可使肺癌风险几乎增加一倍(RR 1.92，95%CI 1.3-2.9)[103]。
一些研究表明，从不吸烟者肺癌易感基因位点位于不同的部位，包括染色体6q[104]、5p15.33(TERT)[105-107]、13q31.3(GPC5)[108]、15q25和6p21[109]，以及在韩国人群中的18p11.22[110]。然而，全基因组关联研究(genome-wide association study,GWAS)的结果并不一致[111]。对中国种族患者的14项研究(n=5510例从不吸烟女性肺癌患者和4544例对照者)的汇总数据，报道了3个新的易感位点(10q25.2、6q22.2和6p21.32)，并证实了5p15.33、3q28和17q24.3位点[112]。然而，该分析包括有最初用于识别某些基因位点的部分试验。
其他研究证实了细胞色素p450酶CYP1A1和CYP1B1多态性相关的易感性[113-115]，以及MLH1和MSH2、DNA错配修复基因[116,117]、其他DNA修复基因[118]，以及谷胱甘肽-S-转移酶多态性相关的易感性[119,120]。
针对来自美国两个大型学术中心和中国台湾一个验证队列的从不吸烟肺癌患者进行的一项大型GWAS发现，两个潜在位点与从不吸烟肺癌患者生存率降低有关，但这两个位点与其他研究团体所识别的位点不同，后者可能与肺癌易感性相关[121]。韩国的一项分析纳入了181例从不吸烟女性肺癌患者和179例对照者，识别到集落刺激因子1受体(colony-stimulating factor 1 receptor,CSF1R)是这一人群中引起人们关注的肺癌易感性候选基因[122]。
在数目有限的从不吸烟者NSCLC发病率高的家族中，发现了特定的生殖系突变。了解最多的是表皮生长因子受体(epidermal growth factor receptor,EGFR)的生殖系突变[123-126]。已有报道显示少数其他生殖系突变与从不吸烟者肺癌风险增加有关，但在一个有9名家庭成员患病的日本家庭中，发现了一种新型的Her2生殖系突变[127]。
雌激素 — 无论吸烟状态如何，雌激素和其他女性激素在女性肺癌风险中的作用还不确定。多项研究发现，大多数NSCLC表达雌激素受体β[128-130]，同时也发现相比于吸烟者，这一受体的表达更常见于从不吸烟者[131]。
这些实验室研究的临床意义还不清楚。已有多项研究探讨了肺癌发病率与绝经期提前[132,133]、使用激素治疗[134,135]、第1次生育的年龄[136]、子女的数目[137]，以及使用他莫昔芬[138]的关系。然而，在确立相关性方面的结果不一致。来自WHI随机试验的数据表明，相比于分配至安慰剂组的女性，分配至绝经后雌激素和黄体酮治疗的女性具有更高的肺癌死亡风险，但肺癌发病率并不比前者高[139]。然而，随机分配到单纯雌激素组的女性，其肺癌死亡率和发病率较安慰剂组均无增加[140]。对WHI试验的进一步分析表明，对于从不吸烟女性，应用激素与否对肺癌发病率和死亡率无影响，但应用雌激素加黄体酮的吸烟女性的肺癌死亡率比未使用这些激素的吸烟女性显著更高[141]。
生物学差异
病理 — 腺癌在从不吸烟者、轻度吸烟者和既往吸烟者中更常见，而鳞状细胞癌和小细胞肺癌在重度吸烟者中更常见[4,5]。对已发表的关于肺癌组织学报告(含有吸烟数据)进行的一项综述发现，在不吸烟者中，腺癌比鳞状细胞癌更常见(62% vs 18%，基于5144例病例)。相反，腺癌在吸烟者中更少见(19% vs 53%，21,853例病例)[4]。最近关于从不吸烟者肺癌的病例系列研究仍显示，腺癌是此类患者最常见的组织学类型[14,35,38]。
分子生物学 — 随着当代对肺癌分子生物学了解的进展，已确定了从不吸烟者肺癌与吸烟者肺癌间的巨大差异。这些因素可能比任何临床差异更重要。
从不吸烟者肺癌与当前和既往吸烟者肺癌间最明显的差异之一是EGFR基因的表达和突变。从不吸烟者肺癌比吸烟者肺癌EGFR基因突变更常见[142-147]。针对具有EGFR基因最常见激活性突变(主要为外显子19缺失突变和外显子21的L858R突变)的患者的若干分析报道，无论男性还是女性，从不吸烟者中突变的发生频率，尤其是外显子19和21突变，远高于曾经吸烟者(P<0.001)[148,149]。此外，即使无EGFR突变，从不吸烟者与当前吸烟者的EGFR通路免疫组织化学特征也明显不同[150]。
香烟烟雾的二手烟暴露似乎促成EGFR突变发生率降低。韩国一项纳入179例从不吸烟NSCLC患者的研究发现，有二手烟暴露史的患者中，EGFR突变频率显著更低(39% vs 61%)，并且随着二手烟暴露的增加，EGFR突变率进行性降低[151]。这与日本一项关于126例从不吸烟NSCLC患者的报道相反，该报道显示，EGFR的激活性突变随二手烟暴露的增加而增加[152]。
KRAS基因突变被认为更常见于曾经吸烟的肺癌患者[147,153]。然而，一项纳入482例肺腺癌患者的分析发现，密码子12和13中的KRAS突变率在从不吸烟者(15%)、既往吸烟者(22%)和当前吸烟者(25%)中无显著差异[154]。但突变的性质显著不同，不吸烟者的肿瘤更多为转换突变(G到A)，而有吸烟史的患者的肿瘤则更多为颠换突变(G到T或G到C)。
在3%-7%的NSCLC中发现了棘皮动物微管样蛋白4(echinoderm microtubule-associated protein-like 4, EML4)基因和间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)基因组成部分的一种融合基因，该融合基因似乎与EGFR和KRAS突变互不相容[155]。这一融合基因出现的频率在从不吸烟的肺癌患者中更高[155-157]。中国的一项研究显示，NSCLC中ALK融合癌基因的阳性率接近20%，而在已知EGFR和KRAS为野生型的患者中，该阳性率为42%[158]。
比较从不吸烟者和吸烟者时，也已观察到了其他基因在表达模式和突变方面的差异。例如p53[153,159]、NER家族蛋白(包括参与DNA修复的ERCC1)[160]、p38[丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)的下游][161]、毛细血管扩张性共济失调突变(ataxia telangiectasia mutated,ATM)[162]、硝基酪氨酸(一氧化氮蛋白质损伤的一种标志物)[153]、其他染色体异常[163,164]和p16的甲基化[165,166]。不吸烟肺癌患者中，微小RNA-21(miR-21)似乎是增加的，尤其是在具有EGFR突变的患者中[167]，并且微小RNA-21在肺癌变中可能发挥重要的作用。此外，已有报道称，呼吸链复合物-Ⅰ线粒体DNA突变在从不吸烟者肺癌和吸烟者肺癌之间是不同的[168]。
对17例早期NSCLC患者的肿瘤(16例为腺癌和1例为大细胞癌)和邻近组织进行全基因组和转录组测序，结果发现，有吸烟史患者的NSCLC平均突变频率显著高于从不吸烟者(n=5例不吸烟者加1例既往轻度吸烟患者)[169]。吸烟者肿瘤的每Mb的突变数(中位值10.5)显著高于从不吸烟者(每Mb突变数中位值为0.6)和一例既往轻度吸烟者(每Mb突变数为0.3)。这项工作也证实了在原始克隆中存在EGFR和KRAS基因突变，这支持当发现存在这些突变时它们是真正的“驱动(driver)”突变的假说，并且这项工作还发现了DNA修复和细胞周期途径中的新基因变化。从吸烟者和不吸烟者的肿瘤均具有异质性，有多个亚克隆。另一项针对6例韩国从不吸烟女性的研究中，对肺腺癌肿瘤和邻近正常组织的高通量多维测序发现了多个基因突变，但仅一例患者具有公认的“驱动”突变，即CCDC6-RET融合基因[170]。
多个协作组织正在致力于确定NSCLC中已知“驱动”突变(即，那些似乎是癌症形成的驱动力的突变)的出现频率。美国国家癌症研究所的肺癌突变联盟最初是在美国临床肿瘤学会(American Society of Clinical Oncology,ASCO)2011年年度会议上首次发布了数据，报道了大约前800例患者的检测结果，其中KRAS突变率为25%；EGFR突变率为23%；ALK重排为6%；BRAF、PIK3CA、MET扩增、HER2、MEK1、NRAS的突变率均等于或小于3%[171]。尽管那些结果一般是针对腺癌的，但在超过60%的样本中发现此类突变，以及大部分这些突变互不相容的性质表明了我们对腺癌(从不吸烟者肺癌最常见的组织学类型)的生物学理解程度。
进一步的更新已证实了这些突变的相对百分比，癌症基因组图谱(The Cancer Genome Atlas,TCGA)也对其进行了研究[172]。其他的突变，如ROS1和RET，从不吸烟者通常更常见，并且已被快速证实[173,174]。
韩国一项针对从不吸烟者的229例肿瘤的分析发现，EGFR突变、ALK基因重排和KRAS突变分别占48%、8%及4%[175]。中国一项关于349例从不吸烟肺腺癌女性患者的外科病例系列研究，在接近90%的病例中识别到已知驱动突变，主要是EGFR突变(76%)，HER2、EML4-ALK、KRAS和BRAF的突变均不到5%[176]。对中国已知从不吸烟肺癌高发率可能与煤使用相关的某地区的一项较小型的研究发现，在从不吸烟肺癌患者中，其他研究中较少见的EGFR突变G719X在该地区的发生率非常高，且KRAS突变率为15%[177]。美国一项分析纳入了800多例晚期NSCLC患者，其中1/3是从不吸烟者，结果发现从不吸烟者KRAS突变率仅4%，但EGFR突变率是49%；相比之下，在吸烟包年数最多为15的患者中，KRAS基因突变率为15%，EGFR突变率大约30%；而在吸烟包年数至少为15的患者中，KRAS基因突变率为40%，而EGFR突变率仅11%[178]。这进一步支持了以下主张：在大部分从不吸烟的肺腺癌患者中，目前可以识别可靶向的致癌突变激酶，尤其是在东亚患者中。
治疗及预后与具有吸烟史的NSCLC患者相比，从不吸烟的NSCLC患者采用标准治疗是否具有更好的疗效和/或具有更好的预后尚不明确。一些观察性研究已显示了其具有更好的结局[27,179-183]，但并不是所有研究都得到这样的结果[184-186]。
例如，一项对加利福尼亚州12,000例患者的分析显示，吸烟者比从不吸烟者的生存期更短(死亡HR 1.09，95%CI 1.00-1.18)[27]。类似地，另一项研究比较了132例从不吸烟者与522例当前吸烟者的肺腺癌，研究发现，从不吸烟者的5年生存率明显更好(23% vs 16%)，这一差异在多变量分析时有统计学意义[179]。相比之下，另一项针对254例肺癌患者的研究中，从不吸烟者与吸烟者的5年生存率差异无统计学意义(分别为27% vs 31%)[184]。最近，一项大得多的肺癌注册试验纳入了15,000多例日本患者和13,000多例来自加利福利亚南部的白种人患者，结果显示，无吸烟史的患者的生存率具有统计学意义的改善[28]。日本一项对26,957例NSCLC患者进行的扩大分析显示，不吸烟者的中位总生存期比既往吸烟者明显更长(30个月 vs 19个月)[187]。
EGFR抑制剂 — 采用EGFR酪氨酸激酶抑制剂(tyrosine kinase inhibitor, TKI)(厄洛替尼和吉非替尼)治疗时，疗效存在临床上重要的差异。已报道，采用这些药物时，从不吸烟者比目前或既往吸烟者的缓解率更高，且生存情况更好[144,188,189]。
一项比较吉非替尼和支持治疗作为晚期NSCLC患者的二线治疗的Ⅲ期试验发现，与支持治疗相比，从不吸烟肺癌患者应用吉非替尼具有统计学意义的生存获益(HR为0.67)，而在既往吸烟者中的生存率差异无统计学意义(HR为0.92)[188]。同样，一项比较厄洛替尼和支持治疗的Ⅲ期试验显示，从不吸烟史是厄洛替尼治疗改善患者生存情况的有统计学意义的独立预测因子[189]。这些试验将单独作更详细的讨论。
然而，从不吸烟状态很可能是EGFR激活性突变的替代指标，后者是EGFR-TKI治疗有效的强烈预测指标。比较吉非替尼与化疗作为亚洲从不吸烟晚期NSCLC患者一线治疗疗效的IPASS和First-Signal试验强调了上述观点[190,191]。这两项研究均在从不吸烟患者中发现有较高的EGFR基因突变率，吉非替尼治疗获得了总体的无进展生存(progression-free survival,PFS)益处。在上述两项研究中，将患者分为有和没有EGFR激活突变时，只有基因突变患者采用EGFR-TKI治疗才有PFS获益，而没有突变的患者采用一线化疗效果更好。
总结
●虽然大多数肺癌病例是由吸烟所致，但不吸烟者的肺癌也值得关注，校正年龄因素后，40-79岁从不吸烟者的肺癌发病率为男性11.2-13.7/100,000人年、女性15.2-20.8/100,000人年。
●虽然从不吸烟者的肺癌病因不一定明显，但危险因素包括二手烟、氡和其他环境暴露。
●腺癌是从不吸烟者肺癌最常见的病理类型，在从不吸烟患者中比曾经吸烟患者中更常见。
●从不吸烟者肺癌与吸烟者肺癌在分子水平上存在重要差异。其中了解最多的是表皮生长因子受体(EGFR)通路异常。不吸烟肺癌患者中的这些EGFR通路异常与采用抑制EGFR酪氨酸激酶的药物厄洛替尼和吉非替尼治疗特别有效相关。间变性淋巴瘤激酶(ALK)融合基因是非小细胞肺癌(NSCLC)的另一种分子变异，更常见于从不吸烟者，目前已有针对此基因的靶向治疗。
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