NCCN-遺傳性/家族性乳腺癌卵巢癌高風險評估2018V1

遺傳性乳腺或乳腺/卵巢癌綜合征

乳腺癌是全球最常見的癌症，也是導致女性癌症死亡的主要原因[84]。據ACS估計，2017年將有255180名美國人確診侵潤型乳腺癌，其中有141070名將死於該疾病[85]。高達10%的乳腺癌是由於家族中存在特定的單個基因突變造成[6,8,66,86]。遺傳性乳腺癌/卵巢癌的特殊遺傳模式與BRCA1/2基因的突變相關[87,88]。此外，還有兩種非常罕見的遺傳性癌症綜合征也會增加乳腺癌的風險，分別為與TP53基因相關的李法美尼症候群（Li-Fraumeni syndrome, LFS）和與PTEN基因相關的Cowden綜合征[89.90]。與BRCA1/2基因類似，TP53和PTEN基因也編碼參與腫瘤抑制相關過程（如DNA修復和細胞周期調控）的蛋白。

另一種罕見的遺傳性綜合征是遺傳性瀰漫型胃癌（Hereditary diffusegastric cancer, HDGC），也與小葉乳腺癌的發生相關。這種綜合征是由編碼腫瘤抑制基因產物的CDH1基因突變導致的[91]。在對4個來自紐芬蘭並具有特定CDH1突變的胃癌家系分析中發現，到75歲女性患小葉乳腺癌的累計風險高達52%[92,93]。此外，在不存在瀰漫型胃癌的情況下，CDH1的胚系突變可能與小葉乳腺癌相關[94]。關於HDGC的更多信息可參考NCCN胃癌指南(www.NCCN.org)。

除增加乳腺癌風險之外，這些遺傳性綜合征還有其他共同特徵。這些綜合征都來源於與伴性基因無關的胚系基因突變，因此，這些突變可以從雙親中任意一方遺傳。這些綜合征與乳腺癌發病年齡早以及其他癌症的發生相關，且呈現為常染色體顯性遺傳模式。對35409名接受多基因檢測的乳腺癌女性進行數據分析顯示，40歲以前確診乳腺癌的女性攜帶致病突變的比例最高，而59歲後確診乳腺癌的女性攜帶致病突變的比例最低[66]。具有這些遺傳綜合征之一的個體的後代攜帶遺傳性突變的概率為50%。此外，患有這些遺傳綜合征的個體其多發性早發疾病與雙側疾病的風險也均會增加。儘管基因在沒有遺傳性突變時，第二個拷貝的改變或沉默對癌症的啟動是必需的（二次打擊假說），但是與這些遺傳綜合征相關的基因突變仍被認為是高外顯的[95,96]。另外，這些遺傳性綜合征在同一家族個體間的的臨床表現常常不同（如發病年齡，腫瘤部位，原發性腫瘤個數）。患有這些遺傳綜合征的個體的患癌風險取決於包括性別和年齡在內的諸多變數。

BRCA相關的乳腺癌/卵巢癌綜合征

BRCA1和BRCA2基因都編碼參與腫瘤抑制的蛋白。BRCA1基因位於17號染色體，被認為參與DNA損傷應答過程中的DNA修復和細胞周期檢驗點的調節。然而，BRCA1通過何種分子機制保持基因組穩定性尚不清楚[97]。BRCA2基因位於13號染色體，主要參與複製介導的雙鏈DNA斷裂的修復[98,99]。與BRCA1/2基因突變相關的疾病總發病率分別為1/300和1/800[100,101]。目前，已經在BRCA1和BRCA2基因中鑒定出數百個獨特的突變。然而，也在某些特定特定人群中發現了許多始祖變異（見表1），其中在多個表面上不相關的家庭中發現了相同的突變，並可追溯到共同的祖先。在德系猶太人中，BRCA1基因發生187delAG和5385insC突變的頻率與BRCA2基因發生6174delT突變的頻率約為1/40[6,102]。某些始祖突變也已經在其他人群中被鑒定[100,103-108]。

在488例非轉移性乳腺癌女性中，6.1%攜帶BRCA1/2基因突變，突變頻率隨著年齡的增加而下降（即45歲及其以下的女性中突變率為12%，而46歲以上的女性中突變率為3%）[109]。據估計90%以上具有乳腺癌和卵巢癌的遺傳性家族都是由BRCA1/2基因突變導致的[110]。因此，同時患乳腺癌和卵巢癌的個體和具有乳腺癌和卵巢癌家族史的個體攜帶BRCA突變的可疑程度非常高。

儘管BRCA1/2突變攜帶者發生癌症的可能性是可變的，即使在攜帶相同突變的家族中[37-39]，但是BRCA1/2基因的突變仍具有高外顯率（定義見表1）[111-113]。乳腺癌終生風險的外顯率估計範圍是41%- 90%，且對側乳腺癌的風險也增高[114-121]。此外，人群研究表明這些基因的女性攜帶者患卵巢癌的終生風險為8%-62%[115,54,116-120,122, 123]。2007年對已發表的評估BRCA1/2外顯率的數據的薈萃分析中，BRCA1突變攜帶者到70歲時乳腺癌和卵巢癌的平均累積風險分別為57%和40%[116]。BRCA2突變攜帶者的相應評估值分別為49%和18%。在對英國BRCA1/2突變個體(N=1887)風險評估的前瞻性分析中，BRCA1突變攜帶者到70歲時乳腺癌和卵巢癌的平均累積風險分別為60%和59%[119]。BRCA2突變攜帶者的相應評估值分別為55%和16.5%。一項包括9856例未受累的BRCA1/2攜帶者的前瞻性隊列研究表明，BRCA1突變攜帶者到80歲時乳腺癌的累積風險為72%，BRCA2突變攜帶者為69%[124]。在被確診患有單側乳腺癌的患者中（N=651），BRCA1突變攜帶者到70歲時對側乳腺癌的平均累積風險為83%，而BRCA2攜帶者為62%[119]。在乳腺癌確診20年後對側乳腺癌的累積風險評估中，BRCA1突變攜帶者為40%，BRCA2突變攜帶者為26%[124]。一項包括19581例BRCA1突變攜帶者和11900例BRCA2突變攜帶者的國際研究中，46%的BRCA1突變攜帶者和52%的BRCA2突變攜帶者最終發展為乳腺癌，12%的BRCA1突變攜帶者和6%的BRCA2突變攜帶者最終發展為卵巢癌[125]。目前，外顯率是否僅與家族中特定突變有關，或者有額外因素，或基因或環境影響疾病的發生都尚不清楚。然而普遍認為BRCA1/2基因突變攜帶者患乳腺癌和卵巢癌的風險增加，應考慮進行更頻繁的篩查和預防策略。報道，在以BRCA1/2突變為特徵的乳腺癌中，若干組織病理學特徵頻繁出現。

例如，一些研究表明，BRCA1乳腺癌可能具有ER-/PR-陰性和HER2-陰性（即三陰乳腺癌）[126-131]。有研究報道7%-28%的三陰乳腺癌患者攜帶BRCA1突變[66,109,131-137]。一項包含12個研究的，對2533例乳腺癌患者進行的薈萃分析顯示，三陰乳腺癌女性患者比非三陰乳腺癌患者攜帶BRCA1突變的可能性更大(相對風險[RR]=5.65,95%CI=4.15-7.69)[138]。一些報道也提示BRCA2突變在三陰乳腺癌中的作用。在未選擇年齡和家族史的三陰乳腺癌病例中，BRCA2突變的發生率為1%-17%[109,132,137,139]。在396名40歲以下確診為HER2陽性的乳腺癌女性中，4%的患者攜帶BRCA1或BRCA2突變[140]。

在來自風險人群的三陰乳腺癌病例報道中，BRCA1/2突變的發生率增加。在未選擇家族史的德系猶太乳腺癌女性中（N=451），14%的患者為三陰性疾病，11%的患者發現BRCA始祖突變[141]。在三陰乳腺癌的亞組中（N=65），BRCA突變的發生率為39%（BRCA1為30%，BRCA2為9%）[141]。其他包括被確診患有任何乳腺癌的猶太女性的研究顯示，BRCA1/2突變檢出率為11%-18%[109,142]。

在三陰患者中，BRCA突變攜帶者的確診年齡較非攜帶者更小[134,143]。一項針對三陰乳腺癌患者（N=403）的大型研究中，BRCA1突變攜帶者（N=65）的平均確診年齡為39歲[133]。這項以人群為基礎的研究中，並未對患者的家族史和年齡進行選擇。早髮型（確診年齡＜40歲）三陰乳腺癌患者中（N=106），BRCA1突變率為36%；50歲以前確診的患者中，突變率為27%。在有乳腺癌和/或卵巢癌家族史的三陰乳腺癌患者中（N=105），BRCA1的突變率為48%[133]。

BRCA1/2突變的男性攜帶者也具有較高的癌症易感風險[144]。在一項針對26個至少有一例男性乳腺癌的高風險家庭的研究中，77%的患者攜帶BRCA2突變[110]。在21401個符合德國遺傳性乳腺癌和卵巢癌聯盟BRCA1 / 2突變檢測標準的家族樣本中，在至少有一例男性乳腺癌且至少有一例女性乳腺癌或卵巢癌的家族中，35.8%檢測到存在突變[145]。在未對家族史進行選擇的男性乳腺癌患者中，4%-14%的患者BRCA2突變檢測為陽性[146-149]。在一系列男性乳腺癌病例(N = 115；主要來自癌症登記數據)中，16%的病例中檢測到BRCA2突變；在具有乳腺癌家族史的患者中BRCA2的突變率為40%，在未對乳腺癌家族史進行選擇的患者中BRCA2突變率為13%[148]。對於BRCA2突變的男性，其乳腺癌的終生累積風險為7%-8%[150,151]，BRCA1突變攜帶者的終生累積風險為1.2%[151]。相反，對未BRCA1/2突變的男性，其乳腺癌的終生風險約為0.1%[148,152]。

在黑人女性中BRCA1/2突變率的檢測研究相對較少。一項觀察性研究包括396名50歲以前確診為浸潤性乳腺癌的黑人女性，其中12.4%攜帶BRCA1/2突變[153]。BRCA1/2突變攜帶者也有顯著的可能性是三陰性疾病（P

BRCA1/2基因突變與乳腺癌低生存率相關的證據有爭議[154,155]。一項包含13個研究的薈萃分析結果顯示，BRCA1突變的乳腺癌攜帶者的中生存率較無BRCA突變患者的低（HR,1.50；95%CI,1.11-2.04），然而BRCA2突變與低生存率無顯著相關性[156]。一項近期的包含60個研究105220例乳腺癌患者的薈萃分析也發現，與非攜帶者相比，BRCA1突變攜帶者的總生存率更低（HR,1.30；95%CI,1.11-1.52;P=0.001）[157]。與非攜帶者相比，BRCA2突變攜帶者的總生存率沒有顯著差異，但乳腺癌特異性生存率更低（HR,1.29；95%CI,1.03-1.62;P=0.03）。該項薈萃分析也顯示，在三陰乳腺癌患者中，BRCA1/2突變的患者有更好的生存率（HR,0.49；95%CI,0.26-0.92;P=0.03）。然而這個亞組僅包含兩項研究。第三個包含66個研究的薈萃分析也顯示，BRCA2突變與乳腺癌特異性生存率低具有相關性（HR,1.57；95%CI,1.29-1.86），但研究結果過於混雜以至於分析無法得出結論[158]。一項對119名確診為早髮乳腺癌的瑞典女性的研究顯示，在BRCA2突變攜帶者中，未接受化療的患者生存率更低（HR,3.0；95%CI,1.2-7.7;P=0.014）[159]。攜帶BRCA1/2突變與淋巴結轉移無顯著相關性[160]。

BRCA1/2突變與早髮型乳腺癌具有相關性。在21401個符合德國遺傳性乳腺癌和卵巢癌聯合會BRCA1/2檢測標準的家族中，13.7%的確診年齡小於36歲的單例乳腺癌家族中檢測到突變[145]。對6478例50歲以前確診乳腺癌的患者進行分析，結果顯示與無突變的患者相比，BRCA1突變攜帶者的總生存率更低（HR,1.28；95%CI,1.05-1.57;P=0.01），但考慮到疾病和治療特徵，這種關聯性不具有統計學意義（HR, 1.20; 95% CI, 0.97–1.47; P =0.09）[161]。除了前5年的隨訪（HR, 1.56; 95% CI, 1.06–2.28; P =0.02），在本次分析中BRCA2突變與總生存率之間無顯著相關性。這可能存在遺傳預期效應，攜帶BRCA1/2突變的人群隨著時間的推移，發病年齡越來越小[162]。然而，對已知攜帶BRCA1/2突變，且有多於2個連續代家族成員罹患乳腺癌或卵巢癌的176個家族進行分析，結果表明新一代發病年齡的降低可能是由於群體效應，尤其是生活方式和環境因素，例如口服避孕藥的使用增加和肥胖率的增加等[163]。

BRCA1/2突變攜帶者患卵巢癌，輸卵管癌和腹膜癌的風險也會增加[164,165]。至少10%上皮性卵巢癌是由BRCA1/2胚系突變導致的[166,167]。對2222例上皮性卵巢癌患者的分析表明，11%的高等級漿液型疾病患者攜帶BRCA1/2突變[168]。在被確診為浸潤性卵巢癌的患者中，多達13%-20%的女性攜帶BRCA1/2突變[120,169-171]。在對符合德國遺傳性乳腺癌和卵巢癌聯合會BRCA1/2檢測標準的家族分析中（N=21401），在41.9%的至少有2例卵巢癌病例的家族中發現突變[145]。然而，據報道約半數顯示卵巢癌遺傳易感性的家庭並不攜帶BRCA1/2突變[172]。因此，可能存在其他導致卵巢癌發生的基因突變[173]。一項包括9856例未受累BRCA1/2攜帶者的前瞻性隊列研究顯示，BRCA1突變攜帶者到80歲的卵巢癌累積風險為44%，BRCA2突變攜帶者為17%[124]。

一些研究報道表明，與BRCA1/2突變的非攜帶者相比，攜帶突變的卵巢癌患者其生存率更高[174-180]。在一項對患上皮浸潤性卵巢癌的猶太病人(N=779)的大規模對照研究中，與非攜帶者相比，攜帶BRCA1/2突變的患者的中位生存期顯著延長(54個月vs. 38個月; P =0 .002) [177]。通過對26項浸潤性上皮卵巢癌病例（BRCA1/2突變攜帶者1213例，突變非攜帶者2666例）的觀察性研究進行匯總分析結果顯示，攜帶BRCA1/2突變的患者其生存預後良好[175]。非攜帶者、BRCA1突變攜帶者、BRCA2突變攜帶者的5年生存率分別是36%、44%和52%。與非攜帶者相比，BRCA1突變攜帶者(HR = 0.78; 95% CI, 0.68-0.89; P < .001)、BRCA2突變攜帶者(HR = 0.61; 95% CI, 0.50-0.76; P

BRCA2突變攜帶者的生存結果似乎是最好的，研究中攜帶BRCA2突變的患者(n = 53)，其中位生存期是70個月[174]。一項對高級別漿液性卵巢癌患者(N = 316)的觀察性研究表明，攜帶BRCA2突變的患者的生存結果顯著優於非攜帶者（BRCA野生型）(HR=0.33;95% CI, 0.16-0.69; P=0.003; 5年生存率: 61% vs. 25%)，無進展生存期(HR = 0.40; 95% CI, 0.22-0.74; P =0.004; 3年生存率: 44% vs. 16%)[179]。一項包括1345例卵巢癌女性的來自婦科腫瘤組臨床試驗的觀察性研究結果顯示，與非攜帶者相比，BRCA2突變攜帶者的無進展生存期顯著延長（HR, 0.60; 95% CI,0.45–0.79; P < 0.001)，總生存期也顯著延長(HR, 0.39; 95% CI,0.25–0.60; P < 0.001）[167]。此外，BRCA2突變對初始化療的高應答率相關(相比於BRCA野生型患者或BRCA1突變攜帶者)。相反，BRCA1突變與預後或高應答率化療無關[179]。

攜帶BRCA1/2突變的卵巢癌的組織學特徵更多表現為漿液性腺癌和高級別癌症，儘管在前人群研究中也報道了子宮內膜樣和透明細胞型卵巢癌[166,170,184-187]。突變也與非粘液性卵巢癌相關，而不是粘液性[169,171]。粘液性上皮性卵巢癌可能與其他基因突變相關，如KRAS和TP53基因突變[188]，TP53突變與李法美尼症候群相關（見下文）。非上皮性卵巢癌（如生殖細胞和性索間質腫瘤）與BRCA1/2突變並非顯著相關[189]，但它可能與其他癌症遺傳綜合征相關，例如性索瘤可能與黑斑息肉綜合征相關（見下文），Sertoli-Leydig腫瘤與黑斑息肉綜合征和DICER-1相關疾病有關[190-195]。目前數據顯示，低度惡性潛能卵巢腫瘤（即交界性上皮性卵巢腫瘤）也和BRCA1/2突變無關[169]。因此，專家組並未將低度惡性潛能卵巢腫瘤作為基因檢測的標準。有趣的是，一項前瞻性研究結果表明，來自遺傳性乳腺癌風險增加家族的，但未檢出BRCA突變的女性，其卵巢癌風險並不高。然而這些結果可能受限於研究人群的種族特徵和研究規模[196]。

在對攜帶BRCA1/2突變並接受高風險輸卵管-卵巢切除術(RRSO)的患者研究中發現，基於對卵巢和輸卵管的嚴格病理檢查，在4.5% - 9%的病例中發現婦科惡性腫瘤[197-199]。輸卵管上皮內癌(TIC)被認為是漿液性卵巢癌的早期癌前病變，同時在5%-8%攜帶BRCA1/2突變並接受RRSO的病例中檢測到TIC（帶有或沒有其他病變）[197,200,201]。據報道，在攜帶BRCA1/2突變的患者中發現，纖毛或遠端管是早期惡性腫瘤的起源部位[197,201,202]。儘管BRCA1/2突變攜帶者中出現TIC的頻率高於接受RRSO的非攜帶者[201,202]，但TIC也被記錄在未經家族史或BRCA突變狀態篩選的漿液性腫瘤患者中[203]。由於TIC是在接受降低風險手術(BRCA1/2突變攜帶者)或出於其他婦科指標而進行了手術的個體中被發現的，所以在普通人群中這些早期病變的發生率和意義尚不清楚。因此，目前在婦科指標的病理評估期間，僅依據TIC的發現作為BRCA檢測的依據是不合理的。

在攜帶BRCA1/2基因突變的家族中，其他惡性腫瘤的發病率也有所增加[117,144,204]。大量報道顯示BRCA1/2的胚系突變與前列腺癌風險的增加相關[117,144,204-210]。具體有BRCA2突變導致個體患前列腺癌的風險增高2-6倍[205-207,210-212]，而一些研究表明在BRCA1突變攜帶者中沒有觀察到風險的增加[205-207,211,212]。一項對1,522位接受前列腺特異抗原(PSA)檢測的攜帶BRC1A/2突變的男性進行分析，2.3%的BRCA1攜帶者和3.3%的BRCA2攜帶者活檢結果顯示為前列腺癌[213]。

前列腺癌與BRCA1/2的相關性在轉移性前列腺癌中表現最為強烈。與未攜帶突變的腫瘤患者相比，攜帶BRCA胚系突變的前列腺癌侵襲性更強（例如，更常見於Gleason評分≥8的腫瘤）[214,215]。一項來自西班牙的大型前列腺癌患者的隊列研究(N = 2019)表明，BRCA1/2突變的患者組中，侵襲性前列腺癌（Gleason評分≥8）發生率、淋巴結轉移和遠端轉移發生率顯著高於非攜帶者組[214]。此外，BRCA1/2突變攜帶者的原因特異性生存結果比非攜帶者明顯更差(中位生存期為8.6年vs 15.7年; P =0.015)。

突變類型的亞組分析顯示，BRCA2突變患者的預後不良(n=61)；BRCA1突變尚不明確，這可能與患者規模(n=18)及該亞組有限的隨訪有關[214]。在其他研究中，BRCA2突變的前列腺癌患者有更高的組織學分級[205,206]。在692例轉移性前列腺癌患者樣本中（未對家族史或確診年齡進行選擇），5.3%攜帶BRCA2突變，0.9%攜帶BRCA1突變[216]。此外，從癌症登記處與治療中心資料庫獲得的數據分析顯示，與BRCA1突變攜帶者或非攜帶者相比，攜帶BRCA2突變的前列腺癌患者具有更強的侵襲性和更快的疾病進展[217-220]。一項來源於冰島，並以人群為基礎的癌症登記處的前列腺癌患者的研究中，與非攜帶者（野生型BRCA2患者）相比，BRCA2突變攜帶者的中位生存期顯著縮短（2年vs 12年; P

據報道BRCA2突變攜帶者患胰腺癌和黑色素瘤的風險更高[144,204,210,212,221,222]。對攜帶BRCA1/2突變的490個家庭的分析顯示，BRCA2攜帶者眼部黑色素瘤的風險增加(RR=99.4;95% CI為11.1- 359.8) [211]。BRCA1和BRCA2突變都會與胰腺癌的發生傾向相關[210,222-227]。對來自具有家族性胰腺癌患者（家系中有≥3個家庭成員患有胰腺癌，且至少兩位是一級親屬）的樣本分析，在17%的患者樣本中檢測到BRCA2突變[225]。最近的一項包括727例無胰腺癌家族史的先證者分析中發現，1.2%BRCA1突變陽性，3.7%BRCA2突變陽性[228]。

對159例胰腺癌患者的分析顯示，8%的患者攜帶BRCA2基因突變[226]。但是，值得注意的是，該項研究的參與者不是未被選擇的胰腺癌患者。他們是具有強大家族史的進行遺傳諮詢的群體，且其中56%的樣本是德裔猶太人。具有德裔猶太人血統的胰腺癌患者其BRCA1/2突變陽性的可能性更大，該類人群突變率為5.5%-19%，且BRCA2突變更為常見[221,226,227,229]。在211個具有胰腺癌家族史的德系猶太人乳腺癌患者中，6.6%攜帶BRCA1突變，7.6%攜帶BRCA2突變[230]。

BRCA1/2突變攜帶者在除乳腺/卵巢以外的其他部位的相關患癌風險數據是矛盾的[231]。例如，有人提出在部分BRCA1/2突變攜帶者中觀察到子宮內膜癌風險的增加主要歸因於他莫西芬的治療而非基因突變的存在[232]。在一項多中心前瞻性隊列研究分析中，共包括1083名攜帶BRCA1基因突變的女性，這些女性已接受RRSO手術，未進行子宮切除術，顯示為漿液性子宮內膜癌和/或漿液性子宮內膜樣癌風險增加[233]。另有一項研究顯示，具有BRCA2基因突變的女性白血病風險增加（標準發病率[SIR] 4.76; 95% CI,1.21–12.96; P =0.03），尤其是接受過化療的女性（SIR, 8.11; 95% CI,2.06–22.07; P =0.007）[234]。

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