2019-01-012024-05-16https://scholars.lib.ntu.edu.tw/handle/123456789/666900摘要：本院延續第一、二期計畫，由「癌症卓越研究中心」以二個癌症研究團隊及癌症生物標記整合中心CBCC為架構，從事跨領域、整合性的癌症創新與轉譯研究，將成果匯集轉譯為癌症之新治療藥物或技術；發展出癌症早期預防、診斷與治療之方法，提昇癌症的診療成效，以期降低國人的癌症的死亡率。乳癌團隊：過去40年東亞國家乳癌發生率急速增加中，且年輕族群增加的速度尤其快速。我們一系列的研究指出台灣年輕乳癌的分子分類、臨床病理特徵及預後都異於西方年輕乳癌，有顯著較高的荷爾蒙受體陽性的乳癌且預後較佳。第一及第二期癌症研究計畫支持下，進一步發現東亞年輕乳癌特有的與脂肪代謝相關的基因變異，也發現腫瘤浸潤免疫細胞在東西方乳癌有顯著差異，提供更強的證據顯示東亞乳癌的特殊性。針對治療，我們發現可以藉由TP53突變加上IHC4的檢測篩選出預後特別好的年輕病人可以免除輔助性化學治療，並針對原位癌發現MAP3K1及 CD10與病人復發有關。我們第三期計畫的一部分是延伸過去研究的結果，Theme1-1探討脂肪代謝異常為年輕乳癌的重要病因，並藉由介入性研究嘗試減少乳房發炎; Theme1-2發展新穎評分法來預測乳房原位癌之復發風險，並設計隨機第三期臨床試驗來探討低風險性乳管原位癌病人經乳房保留手術後是否須接受放射治療等研究。本計劃另一部分是針對轉移性乳癌發展精準醫療，轉移性乳癌目前仍無法治癒且標靶藥物昂貴，因此我們提出三個子計畫來開發適合的精準治療:Theme1-3是利用cell-free DNA來偵測ESR1基因突變，我們發現Y537C這個突變型在東亞轉移性乳癌發生率特別高，且導致較高的細胞侵襲性，因此我們計畫研究此有此突變病人後續應接受何種標靶治療;Theme1-4是利用檢驗血液tumor-derived exosome來研究腫瘤進展的機轉，腫瘤惡化或轉移前會截由exome內的分子或miRNA進行腫瘤細胞間交通或改變微環境，我們也會分析tumor-derived exosome的分子或miRNA是否可以當作好的腫瘤標記。食道癌團隊：主題為『食道癌生物標記相關治療策略與癌化因子進行探討』食道癌為亞洲地區（包含台灣）重要的惡性腫瘤，但過去的幾十年來食道癌的早期診斷及治療一直沒有明顯的進展。針對早期食道癌，內視鏡下處置、常規手術或合併化放療(chemoradiotherapy or CRT)均是治療的選項; 然而，如何為病人選擇最合適的治療策略仍有待進一步釐清。針對局部嚴重期食道癌，可預測新輔助化放療(neoadjuvant CRT)病理反應的生物標記有助於幫助個別患者選擇最佳治療方式，但目前最佳的生物標記仍未有定論。至於復發或轉移的食道癌，目前的研究重點則著重於免疫檢查站抑制劑(immune checkpoint inhibitor)所扮演的角色，以及如何提高其在食道癌的治療療效。為了解決以上有關食道癌治療上的重要需求，我們提出了本研究計畫，以將探討以下4個主題：（1）熱傷害相關因子於食道癌癌化與轉移之角色與機轉探討；（2）應用血液中腫瘤相關的生物標記以改善局部嚴重型食道上皮癌病人多科整合治療預後的轉譯醫學研究；（3）免疫檢查站抑制劑治療食道癌: 著重於發現療效不佳之生物標記以探討抗藥性機轉及其反轉策略；（4）分析早期食道癌復發之臨床與基因特徵以發展風險分層策略以治療早期食道癌。癌症生物標記整合中心CBCC：建置完整之生物標記檢測系統，提供社區服務，促成個人化治療之實現。整合台大醫院及台大醫學院現有的癌症相關部科、醫療核心設施與臨床檢驗部門。開發、持續研究及推廣多項重要癌症生物標記。架設網頁以推廣癌症生物標記(cancer biomarkers)，聘請專人負責聯繫以接受院外檢體。辦理癌症生物標記檢測之實驗室認證及單項目之PT認證(proficiency test)。辦理研討會、訓練課程，以培育人才。<br> Abstract: In the next period project (2018-2021), we set our goals to enhance the level of cancer research, to solve the mystery of special endemic cancers in Taiwan (young female breast cancer), to develope new and effective methods of diagnosis and treatment (esophageal cancer), and to realize the personalized therapy (CBCC).Breast Cancer Team：In the past four decades, the breast cancer has been rapidly increasing in young women in East Asia. A series of our prior studies showed the major discrepancy of clinicopathological features, and prognosis in young breast cancer between Asian and Western countries. With the support from Ministry of Health and Welfare, we identified unique lipid metabolizing related genes as a unique genetic alteration of Asian breast cancer, and found significant differences in the composition of tumor-infiltrating immune cells between Asian and Western counties. Regarding treatments, we found that incorporation of TP53 mutation, and MAP3K1 and CD10 expressions could improve the prediction accuracy of recurrence, and these help clinicians in selecting patients free from toxic adjuvant treatment. One part of this program is to expand from our ongoing studies to identify the etiology and to prevent overtreatment. In Theme1-1, the case-control study aims to evaluate whether lipid deregulation is an important etiology of young breast cancer. The pilot intervention study will evaluate whether exercise with and without diet modification can reduce the inflammation in premenopausal patients. In Theme 1-2, we will develop novel DCIS scores to predict risk of recurrence of these patients and design a randomized phase III trial of radiotherapy or observation following breast conserving surgery for low-risk DCIS of breast. Another part of our program will focus on the precision medicine. In Theme 1-3, we aim to understand prevalence of unique ESR1 mutation variants (Y537C) in Asian women, and correlate with treatment efficacy. In Theme 1-4, we aim to provide insightful information for tumor-derived exosomal proteins/miRNAs in cancer progression, and translate them to biomarkers for cancer monitoring and therapeutic targets.Esophageal Cancer Team will focus on the “Study of the biomarker-based therapeutic strategies and carcinogenesis factors of esophageal cancer”. Esophageal cancer, an important malignant disease in Taiwan and Asian countries, is a cancer type lack of significant advances in early detection and treatment over the past decades. For early-stage, endoscopic procedures and conventional surgery or chemoradiotherapy (CRT) are treatments of choice; however, the appropriate use of each treatment option remains to be defined. For locally advanced stage, biomarkers predictive of pathological responses to neoadjuvant CRT are warranted to help individualize patients for optimal approaches. For recurrent/metastatic disease, the current research interests have been focusing on the role of immune checkpoint inhibitors and how to improve their efficacy in esophageal cancer. To address the above-mentioned unmet need for esophageal cancer, we propose this program project covering the following 4 themes: (1) The roles of thermal damage associated factors in the carcinogenesis and metastasis of esophageal cancer; (2) Translational research of circulating tumor markers to improve the therapeutic effect on locally advanced esophageal squamous cell carcinoma patients undergoing combined modality therapy; (3) Immune checkpoint inhibitors in the treatment of esophageal cancer, with the emphasis on identifying negative predictive biomarkers to exploring drug resistance mechanisms and reversal strategies; (4) Investigation of the clinicopathological and genetic characteristics associated with the recurrence of early-stage esophageal cancer and establishment of a risk-stratified treatment algorithm for early-stage esophageal cancer.Cancer Biomarker Coordinating Center (CBCC) ：To integrated the current existing core units and facilities of National Taiwan University Hospital (NTUH) and NTU College of Medicine (NTUCM). To develop the determination of novel cancer biomarkers, and serving as coordinating and service center, NTUH. Most biomarkers are qualified through laboratory accreditation (TAF, TAF-PT, etc.), and open for routine service. In the forthcoming years, We will develop the potential novel cancer biomarkers, such as: genomics, proteomics, epigenetics, etc.乳癌食道癌癌症生物標記Breast cancerEsophageal cancerCancer biomarker