急速增加的台灣年輕女性乳癌:臨床病理及腫瘤生物學研究

Abstract

乳癌是全世界女性癌症發生率的第一名，高發生率地區主要是高加索(Caucasians)居住的地區如美洲及歐洲，而亞洲及非洲則屬於低發生率地區。雖然目前乳癌在亞洲女性的發生率仍低明顯於西方國家，然而在亞洲部分國家如新加坡、韓國、日本及台灣乳癌發生率卻急速增加中。過去的流行病學分析顯示台灣、新加坡及日本女性乳癌的發生率有一很強的出生世代效應(birth cohort effect)，在1960年後出生的台灣年輕女性(小於50歲)乳癌發生率急速增加，這強烈暗示台灣過去幾十年來環境因素的改變與乳癌的發生有密切的相關。 雖然西方化生活方式(Westernized lifestyle)是最被廣泛認為造成發展中國家乳癌發生的環境因子，西方化生活方式包括高熱量飲食、肥胖、少運動、生育年齡延後及低生育胎數等項。我們的第一個研究就是挑戰這個假說，如果西方化生活方式是唯一的原因，則台灣年輕乳癌的分子分類應該接近同年齡西方國家乳癌的特徵，我們的研究是以在2004-2006年於台大醫院新診斷的1028個乳癌檢體進行，以estrogen receptor (ER)、progesterone receptor (PR)、human epidermal growth factor receptor type 2 (HER2)、cytokeratin 5/6 (CK 5/6)及epidermal growth factor receptor (EGFR)將乳癌分成luminal A、luminal B、HER2+/ER-、basal-like及unclassfied五種分子型態，結果顯示台灣的年老(大於50歲)的分子型態與西方年老乳癌相近，而台灣年輕乳癌的分子型態與西方年輕乳癌有顯著的不同，luminal A分類的比率在年輕台灣乳癌為66%，高於年輕的非裔(36%)與非非裔美國人(51%)，而basal-like分類的比率在年輕台灣乳癌為9%，低於年輕的非裔(39%)與非非裔美國人(16%)。另外，台灣年輕乳癌病理組織高惡性度(grade III)的比率比年老乳癌來的少，這點也是與西方乳癌相反的。Luminal A分類主要涵蓋的是雌激素受體(estrogen receptor, ER)陽性的乳癌，台灣年輕乳癌明顯較高的luminal A分子分類，這暗示急速增加的年輕乳癌的成因與過多的雌激素的曝露有關，而與西方病理特徵及分子分類比率的差異也推翻過去以單純西方化生活方式做為解釋急速增加年輕乳癌的說法。 為了進一步佐證台灣急速增加的乳癌是與過多的雌激素的曝露有關，我們分析自1979年來台灣乳癌及三大婦癌(包括子宮頸癌、子宮內膜癌及卵巢癌)內的年齡發生率消長情形，與美國的做比較，並進一步將各癌的組織次分類，在分析其年齡發生率消長情形。整體發生率方面，我們是用全癌症(所有癌症總和)及惡性腦瘤當作對照，我們的研究結果顯示台灣全癌症及惡性腦瘤自1979年逐年上升，到2003年後發生率則持平，與美國相同的其主要增加的癌症族群主要是發生於大於60歲的老年人。然而台灣乳癌、子宮體癌自1979年起呈現急速且持續的增加，卵巢癌雖然也是逐漸增加但是增加的幅度較小，而子宮頸癌自1998年已逐漸減少，而美國的乳癌、子宮體癌及卵巢癌則與其全癌症相同在1983年後即達到飽和。 對於台灣乳癌及三大婦癌的組織型態方面，我們將International Classification of Diseases for Oncology (ICD-O)的腫瘤組織型態碼依據WHO的分類方式，加以分門別類。我們發現這四個癌症在1979-2007年中小於55歲的台灣女性增加最明顯的組織型態包括-乳癌中的乳管癌(ductal carcinoma)及乳葉癌( lobular carcinoma)、子宮體癌中的類内膜腺癌(endometriod adenocarcinoma)及卵巢癌中的類内膜癌(endometriod carcinoma)，這幾個類型的腫瘤都是荷爾蒙受體(hormone receptor)高表現率的腫瘤，其中子宮體癌的類内膜腺癌，又稱為第一型子宮內膜癌(type I endometrial cancer)，這是與荷爾蒙明顯相關的腫瘤。在大於60歲的女性主要增加的組織型態是子宮體癌中的漿液性癌(serous carcinoma)與透明細胞癌(clear cell carcinoma)，也是所謂的第二型子宮內膜癌(type II endometrial cancer)，這是與荷爾蒙無明顯相關的腫瘤。除了組織型態分類之外，我們藉由台灣癌症資料庫(TCDB)來分析不同年齡群的乳癌的ER及PR表現，TCDB在2005-2006共收案12,436例，發現小於50歲年輕乳癌的ER及PR陽性率均較大於50歲乳癌來的高，這是與美國所完全相反的，也是過去未曾有的報告。這些證據顯示荷爾蒙相關的癌症在台灣年輕女性急速增加中。 在西方國家小於35歲的乳癌特徵是高比率的ER陰性，在台灣這個最年輕的族群卻有比大於50歲女性更高比率的ER及PR陽性率。我們的第三個研究是分析台灣小於35歲的乳癌病人的預後因子，結果顯示在小於35歲女性第I-III期乳癌高Ki67表現、HER2過度表現及TP53突變是預測不良預後的獨立因子。ER表現在單變項分析顯示與較長整體存活期有關，但是在多變項分析並非獨立預測因子，PR及PIK3CA突變則與病人預後無顯著相關。過去某些西方國家的最年輕乳癌的研究顯示ER陽性是較差的預後因子，本研究顯示在台灣最年輕乳癌ER有相對較好的預後趨勢(雖然並非獨立預後因子)，這族群的預後可能存在種族差異，這部分未來仍須大規模研究證實。 綜合以上研究結果，我們推論過去數十年間台灣年輕女性乳癌的快速增加是因為過多的雌激素曝露，而所造成的年輕乳癌與西方年輕乳癌的分子分類是不同的，因此並不能單純用西方化生活方式來解釋台灣年輕乳癌的快速增加。哪些環境曝露與台灣乳癌的發生有關目前並不清楚，且是一項挑戰性高的問題，然而許多具有雌激素活性的環境汙染物是特別值得研究的，過去環境衛生的研究顯示台灣人體內塑化劑(包括nonylphenol及DEHP等)的濃度遠高於西方國家，且在2011年5月在台灣爆發眾多食品遭違法添加DEHP事件，更顯出台灣是個嚴重塑化劑汙染的國家。除了環境差異之外，基因差異也是一個解釋台灣年輕乳癌病理特徵異於西方乳癌的原因，過去研究發現大多數與雌激素生成或代謝相關基因的多樣性在亞洲人與西方人是有很大差異的。

Although the incidence of invasive breast cancer in women is lower in Asian countries than in Western countries, it has been rapidly increasing in parts of Asia, including Singapore, Korea, Japan, and Taiwan. Similar to findings in Japan, the previous showed a significantly stronger birth cohort effect on the incidence trend of breast cancer in Taiwanese than in Caucasian Americans. This strong birth cohort effect suggests that a change in environmental exposure might have had a great impact on the pathogenesis of breast cancer in these countries. The most widely cited environmental factor responsible for increasing the incidence of breast cancer in developing countries is the Westernized lifestyle. However, evidence for this hypothesis remained to be explored. A reasonable first step to test this hypothesis is to compare the molecular subtypes between the two populations. Our first study included 1028 breast cancer diagnosed between 2004 and 2006. Estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), cytokeratin 5/6, and epidermal growth factor receptor expressions were used to define the molecular subtypes. Our result showed that younger (≤50 years) breast cancer patients had a higher prevalence of luminal A and a lower prevalence of basal-like subtype compared with older (>50 years) patients. The frequency of luminal A subtype was even more prevalent in younger (≤50 years) Taiwanese patients (66%) than premenopausal African Americans (36%) and non-African Americans (51%). Furthermore, the basal-like breast cancer was less prevalent in younger Taiwanese (9%) than in premenopausal African Americans (39%) and non-African Americans (16%). We conclude that young breast cancer patients in Taiwan are characterized by a high prevalence of luminal A subtype, and low prevalence basal-like subtype. These features are distinct from young breast cancer patients in Western countries and suggest that westernized lifestyle may not be the only reason for the rapid increasing breast cancer in young Taiwanese women. Our second study analyzed the age-spcific trends of histopathological subtypes of female breast and three major genital tract cancers (cervical, uterine and ovarian cancers) in Taiwane. We used a descriptive epidemiological method and data from the Taiwan Cancer Registry (1979- 2007) to examine secular trends in their age-specific incidences and histopathological subtypes. During the period of 1998–2007 in Taiwan, the incidence of breast and uterine cancers was found to increase to a much greater extent than that of the reference controls. The greatest increases in breast and uterine cancer rates occurred in young Taiwanese women. Uniquely bell-shaped age-specific incidence curves were observed which differed significantly from those for Caucasian American women. The main subtypes significantly increasing in incidence were: for women aged ≤55 years, ductal carcinoma and lobular carcinoma (breast cancer), endometrioid adenocarcinoma (uterine cancer), and endometrioid carcinoma (ovarian cancer); for women aged >60 years, serous and clear cell adenocarcinomas (uterine cancer). The endometrioid carcinoma of uterine (type I endometrial cancer) is an estrogen dependent tumor. In contrast, type II endometrial cancer including serous and clear cell carcinomas is estrogen unrelated. For breast cancers, we analyzed the data obtained from the TCDB in 2005–2006 (n = 12,436) and found that both ER+ and PR+ rates were uniquely higher in younger, as compared to older, Taiwanese women. These findings provide strong support for a rapid increase in the incidence of estrogen-related malignancies in young women in Taiwan. Our third study analyzed the prognostic factors in 116 very young breast cancer in Taiwan. The result showed that high Ki67 expression, HER2 overexpression, and TP53 mutations were independent predictors of poor prognosis in women aged ≤35 years with breast cancer. ER expression was associated with longer overall survival in the univariate analysis but not in the multivariate analysis. PR and PIK3CA mutations were not associated with survival in this population. Further studies are mandatory to answer whether there is ethnic difference in this population. Etiologies of young female breast cancer in Taiwan may involve excess estrogen from either endogenous or exogenous sources. Beyond endogenous estrogens, certain industrial environmental pollutants with estrogenic effects may also be causative and deserve further investigation. For example, the urinary concentration of plasticizer- Bis(2-ethylhexyl)- phthalate (DEHP) in Taiwanese was extraordinarily high. In May 2011, it was disclosed that hundreds of food ingredients were contaminated by the DEHP in Taiwan. The investigation on this case suggests that DEHP contamination in Taiwan had existed for more than two decades. In the plasticizer highly polluted areas such as Taiwan and parts of Asia, the association of these plasticizer exposure and emerging young female breast deserves the priority of investigation. In addition, genetic components, particularly those genes involving estrogen synthesis or metabolism, may also play a role. Determining the responsible environmental factors or gene-environment interactions leading to carcinogenesis in younger women with estrogen-related malignancies in Taiwan and other rapidly developing countries in Asia represents a challenging and important objective.