發展早期肺腺癌復發標記與尋找樹幹異物抗原
Development of biomarkers for predicting recurrence and identification of clonal neoantigens in early lung adenocarcinoma
Precision medicine holds tremendous promise for paradigm shift in biomedical research and industry development. Due to the orderless of traditional genomics analysis the development of new generations of precision medicine should focus on the establishment of high-quality and large-scale genomics databases of patients. This will not only advance understanding the causes of cancer specificity in Taiwan, but also accelerate development of precision detection and treatment strategies. In addition, it can enhance the competitiveness of our biomedical industry in the precision diagnosis and high-end market for new drug research and development.
Lung cancer is the leading cause of cancer death worldwide and in Taiwan. In the targeted therapy for advanced lung cancer patients, the medical decision can be made by gene testing of molecular biomarkers. In non small cell lung cancer (NSCLC), the deletions in exon 19 and exon 21 L858R mutation exist in more than 50% of non-smoker in East Asia, which response quite well to EGFR tyrosine-kinase inhibitors (TKIs) therapy. The mutational subtypes of lung adenocarcinoma including receptor tyrosine kinases and RAS pathway members, and translocations involving ALK, ROS1 and RET have been reported in 55% of lung adenocarcinomas. Other about 45% of patients did not know the mutations yet. In clinical setting, only around 30% of NSCLC patients can benefit from gene testing to predict target therapy response because of the risk and difficulty in obtaining adequate tissues from the primary lung tumors by biopsy. The newest way to treat lung cancer is immunotherapy. Targeted immunotherapies involving the blockade of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and/or PD-1/ programmed death ligand 1 (PD-L1) checkpoint have shown promising efficacy for patients with various cancers, such as melanoma, renal cell carcinoma, and NSCLC. The antibody against CTLA-4 ipilimumab was approved in 2011, two antibodies against PD-1 (pembrolizumab and nivolumab) were approved in 2014 by the U.S. FDA and atezolizumab, another PD-1/PD-L1 checkpoint inhibitor, was approved by FDA in 2016 for the treatment of platinum-resistant metastatic NSCLC. Recently, the promising results of PD-1/PDL1 axis blockade in NSCLC clinical trial are KEYNOTE-024 and KEYNOTE-001 that ORR reached 44.8% and 51.9% in PD-L1 positive patients (TC≧50%), respectively.
Given the promising advances of targeting therapy and immunotherapy the five-year survival of late stage NSCLC is around 16% worldwide but the five-year survival of early stage NSCLC is more than 90%. We might consider controlling cancer in as early as possible. How to identify the early lung cancer patients who received resection but will recur eventually is an important unmet need. In this study, we first establish the SOP of specimen collection and optimize the process of NGS data. Next we identified that the mutations of 5 pathways are enriched in early stage lung cancers. The clinical relationship between these pathways and early metastasis and recurrence needs further investigation.
Summary of somatic mutations in early lung cancer patients
「精準醫療」無論在研究或是生技產業發展上都帶來巨大的衝擊。由於傳統基因體研究系統上的雜亂使得新一代的基因體研究首重建立高品質與大規模的簡體基因庫資料，這不僅有助了解台灣癌症族群特異性之成因，進而發展精準檢測及治療策略，並可提升我國生醫產業在精準診斷及新藥研發高端市場上更強競爭力。
肺癌不論在全世界或是台灣都是造成癌症死亡人數的首位，對於末期肺癌的治療，基因檢測可以決定是否標靶藥物。在東亞不抽菸病患中，對EGFR 標靶藥物有效EGFR 外顯子19 突變與外顯子21 L858R 突變佔病人數50%以上，結合其他RAS 突變，和ALK, ROS1 與RET 融合突變共佔肺腺癌55%，而仍有45%病患仍不知其突變。
總括而言，扣除採檢不易等因素，約略只有30% 的非小細胞肺癌病人可以獲益於基因檢測與標靶藥物治療。目前最新的癌症治療方式為免疫治療，其中以CTLA4 與PD1/PDL1 檢查點阻斷法的進展最快，在黑色素瘤，腎細胞癌，非小細胞肺癌都獲得不錯的療效。CTLA-4 阻斷劑，ipilimumab，於2011 獲FDA 核可上市, 兩個 PD-1阻斷劑，pembrolizumab and nivolumab，於2014 上市，atezolizumab, 另一隻 PD-1/PD-L1 阻斷劑針對順鉑抗藥性的非小細胞肺癌藥證也於2016 獲FDA 通過。最近針對非小細胞肺癌的兩個大型臨床試驗，KEYNOTE-024 與KEYNOTE-001，發現對於PD-1 高於50%表現的病人的反應率達 44.8%與51.9%。
然而，且不論在免疫治療與標靶藥物的快速進展，末期非小細胞肺癌的五年存活率依舊僅有16%，而初期病人的五年存活率卻超過90%。所以，我們應該儘早進行癌症的診治，如何”找出”那些經手術切除後仍會發生早發性復發與轉移的病人是一個重要的臨床上未滿足需求。在這個計畫中，我們首先建立了肺癌檢體收集的標準流程與優化了次世代定序資料處理的程序。最後，我們發現了早期肺癌的突變會富集於五個訊息傳遞途徑，而這五個訊息途徑與早期肺癌的早期復發與早發性轉移的相關性仍須進一步的研究。
Summary of somatic mutations in early lung cancer patients