非小細胞肺癌腸道微生態失調與具有表皮生長因子接受體的晚期肺癌病人預後影響因子之探討

Gut Dysbiosis and Factors Associated with Outcomes in Advanced EGFR-mutant Non-Small Cell Lung Cancer

魏裕峰(Yu-Feng Wei)

指導教授 ： 洪志勳

義守大學/工學院/化學工程學系暨生物技術與化學工程研究所/博士(2023年)

摘要

肺癌高居惡性腫瘤死亡率的第一位，如何找出肺癌的風險因子並降低其發生，以及發展更有效的治療方式，是肺癌相關研究重要的課題。
肺癌的發生機轉複雜且因素眾多，除了眾所皆知的內在基因及抽菸等外在環境因子外，腸道微菌叢(microbiota)及微生態失調(dysbiosis)與肺癌的相關性在近幾年也是大家研究的熱門主題。在肺癌治療方面，隨著標靶藥物的問世，為晚期肺癌病人開啟一扇大門，除了可以精準地對抗腫瘤，且相較於傳統化療藥物，已大幅減少副作用所帶來的不適，並讓這些肺癌病人活得更久更好。標靶藥物如表皮生長因子接受體-酪胺酸激酶抑制劑(EGFR-TKIs)為治療具有EGFR突變之晚期肺癌之標準第一線治療。然而，臨床上仍有許多標靶治療的重要問題無法依賴大型臨床試驗獲得解答。
本研究第一部分分析比較34位非小細胞肺癌病人與268位非肺癌健康人的腸道微菌叢，結果發現，肺癌病人有較高的Anaerotruncus spp.及Bacteroides caccae菌叢，這些微生態失調是否跟肺癌發生的致病機轉相關，有待未來更多的研究來驗證。研究結果也可以提供利用益生菌或糞便移植來改變腸道微菌叢作為預防或治療肺癌的方式之一。
第二部分的研究是針對具有EGFR基因突變的晚期非小細胞肺癌病人，做預後影響因子之分析探討。在這些具有EGFR基因突變的晚期非小細胞肺癌病人，腫瘤細胞上的PDL1表現量，是否會影響病人治療的預後，並無一致性結果。我們收錄了114位病人，分析結果發現，腫瘤細胞上的PDL1表現量高低，並不影響EGFR-TKI的治療效果，包含無惡化存活期(PFS)、以及整體存活期(OS)，皆無明顯差異。此研究結果提供臨床醫師不需因PDL1表現量高低而改變這些病人的治療方針。
Afatinib是一種第二代EGFR-TKI藥物，臨床上常作為具有EGFR基因突變的晚期非小細胞肺癌的第一線治療藥物。Afatinib在臨床上常因藥物副作用而需要調降劑量。先前的研究顯示，調降藥物劑量可減低與治療相關的不良反應，但不會影響藥物的有效性。然而，調降藥物劑量是否會影響肺癌合併腦轉移病人的顱內治療效果，卻未被探討研究。我們收錄了74位晚期非小細胞肺癌合併腦轉移的病人且接受afatinib做為第一線治療。分結果發現，接受第一線afatinib不同的起始劑量及平均劑量，無論單獨使用或合併局部治療，皆不會不影響顱內腫瘤的治療效果。此研究結果指出臨床醫師不需擔心因藥物副作用調降劑量會影響這些病人的治療預後。
年紀過大或體能狀態較差的晚期肺癌病人，因為預後較差，常常被排除在臨床試驗之外。我們研究探討老年(大於等於65歲)包含體能狀態較差(ECOG-PS=2-4)的病人，對於標靶藥物治療是否有相同的效益。我們收錄237位接受EGFR-TKI做為標準第一線治療的病人，分析這些病人的預後影響因子。分析後發現，較好的體能狀態(ECOG-PS=0-1)、小於三處的轉移部位、以及第一線使用第二代afatinib作為治療藥物，有較佳的PFS。年紀在老年裡相對年輕、較好的體能狀態(ECOG-PS=0-1)、小於三處的轉移部位、以及診斷時無腦部轉移，有較佳的OS。此研究結果可以補足大型臨床試驗中，幾乎排除了體能狀態較差的病人族群，並提供臨床醫師作為治療這些病人族群的參考。

關鍵字

腸道微菌叢 ； 微生態失調 ； 肺癌 ； 標靶藥物 ； 表皮生長因子接受體-酪胺酸激酶抑制劑 ； 預後影響因子

並列摘要

Lung cancer is the leading cause of cancer deaths in most countries, including Taiwan. The imbalance of gut microbiome, dysbiosis, is associated with various chronic diseases, including lung cancer. Understanding the pathways and risk factors associated with lung cancer is crucial to make an early diagnosis and improve treatment strategies and outcomes in those patients.
The first part of the current study tried to identify gut microbiota characteristics in non-small cell lung cancer (NSCLC) patients and healthy individuals to investigate the gut dysbiosis in NSCLC patients. A total of 34 NSCLC patients and 268 healthy individuals were enrolled for analysis. Our results indicated fecal Anaerotruncus spp. and Bacteroides caccae were prominently enrichment in NSCLC patients after adjusting for potential confounding factors. Further large-scale studies to validate gut dysbiosis and the association with NSCLC are warranted.
Clinically, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard first-line treatment for advanced EGFR-mutated NSCLC patients. The second part of this study focused on the clinical factors associated with outcomes in the treatment of advanced EGFR-mutated NSCLC patients. Afatinib, a commonly used second-generation EGFR-TKI, that frequently required dose adjustment due to intolerable adverse events in previous studies. Dose reduction may result in an insufficient concentration of afatinib in the cerebrospinal fluid and lead to a low efficacy against brain metastases. The effect of dose reduction for afatinib against brain metastasis was seldom investigated. Eighty-four NSCLC patients with brain metastases at diagnosis who received first-line afatinib therapy were enrolled for analyses. The results indicated no significant differences in intracranial treatment responses between patients treated with afatinib monotherapy or afatinib combined local treatments. In addition, dose reduction of afatinib did not affect intracranial treatment response, either alone or combined with local treatments.
Several immune checkpoint inhibitors have been introduced to cancer treatment and successful in improving patient outcomes, including lung cancer. The role of programmed cell death-ligand 1 (PD-L1) expression in lung tumors with EGFR mutation and its effect on clinical outcomes remain controversial. One hundred and fourteen patients with advanced NSCLC who received EGFR-TKIs as the first-line treatment were enrolled for analyses. PD-L1 expression levels were assessed in these patients for outcome analysis. Our results indicated advanced NSCLC patients with EGFR mutation, PD-L1 expression is not uncommon, but no significant impact on clinical outcomes in patients receiving standard first-line EGFR-TKI treatment.
The efficacy of EGFR-TKIs in older patients including poor Eastern Cooperative Oncology Group (ECOG) performance status (PS) was seldom investigated. We enrolled EGFR-mutant advanced NSCLC patients 65 years or older and evaluated the efficacy and prognosis of first-line EGFR-TKI treatment. The results indicated a good PS and < 3 metastatic sites at diagnosis were associated with a longer PFS and OS. Additionally, afatinib as the first-line treatment was associated with a longer PFS, whereas a relatively younger age, and no brain metastasis at diagnosis were associated with better OS. These findings may provide insights into the improved clinical care of those older, including poor ECOG-PS patients treated with EGFR-TKIs.

並列關鍵字

afatinib ； dysbiosis ； EGFR-TKI ； lung cancer ； microbiota ； PD-L1

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