Circulating tumor DNA predicts recurrence and splits disease into two subgroups in Stanford Medicine-led study of Hodgkin lymphoma. New drug targets or changes in treatments may reduce toxicity.
在美國史丹佛大學醫學院領導的霍奇金淋巴瘤研究中，循環的腫瘤DNA預測了，復發且將此種疾病分為兩個亞群。新的藥物標的或在治療上的改變，可能降低毒性。
圖1. Ash Alizadeh宣稱：「進行了與其他癌腫的比較，尋找霍奇金淋巴瘤癌細胞或癌腫DNA，來進行研究，就如同海底撈針。」
“Compared with other cancers, finding Hodgkin lymphoma cancer cells or cancer DNA to study is like searching for a needle in a haystack,” Ash Alizadeh said.
A Stanford Medicine-led, international study of hundreds of samples from patients with Hodgkin lymphoma has shown that levels of tumor DNA circulating in their blood can identify who is responding well to treatment and others who are likely to experience a disease recurrence — potentially letting some patients who are predicted to have favorable outcomes forgo lengthy treatment.
一項由史丹佛大學醫學院所領導，來自罹患霍奇金淋巴瘤病人之數百樣本的國際研究證實，於其血液中循環的腫瘤DNA水平，能確認誰對治療作出適切反應，其他的誰可能經歷疾病復發。潛在上，這能使一些被預測具有良好結果的病人，放棄漫長的治療。
Surprisingly, the study also revealed that Hodgkin lymphoma, a cancer of the lymph nodes, can be divided into two groups, each with distinct genetic changes and slightly different prognoses. These changes hint at weaknesses in the cancer’s growth mechanisms that could be targeted by new, less toxic therapies.
令人驚訝的是，該項研究也揭露了，霍奇金淋巴瘤(一種淋巴結癌)能被分成兩群，每群具有不同的基因改變，及稍有不同的預後(預測疾病發作後的可能結果)。這些改變透露了，於癌腫生長機制中，可能被毒性較小之新療法鎖定的諸多弱點。
The idea of establishing molecular profiles of tumors is not new. But unlike other cancers, Hodgkin lymphoma has resisted these types of analyses. That’s because Hodgkin lymphoma cells are relatively scarce — even within a large tumor.
建立腫瘤分子分析(一種尋找癌細胞內，異常基因改變的基因體分析)並非新構想。不過，不像其他癌腫，霍奇金淋巴瘤一直耐得住，此些類型的分析。那是因為，霍奇金淋巴瘤細胞相對上稀少，即使在大腫瘤內。
“This approach offers our first significant look at the genetics of classical Hodgkin lymphoma,” said professor of medicine Ash Alizadeh, MD, PhD. “Compared with other cancers, finding Hodgkin lymphoma cancer cells or cancer DNA to study is like searching for a needle in a haystack. A patient can have a football-sized tumor in their chest, but only about 1% of the cells in the mass are cancer cells, with the remainder representing an inflammatory response to the tumor. This has made it very difficult to find the smoking guns that drive the disease.”
醫學教授，Ash Alizadeh醫學博士、哲學博士宣稱：「此方法為我們提供了，有關古典霍奇金淋巴瘤之遺傳學，首次意義深遠的探究。與其他癌腫相較下，尋找霍奇金淋巴瘤癌細胞或癌腫DNA來進行研究，就如同海底撈針。於患者胸腔會有一個足球大小的腫瘤，不過於此腫塊中，包括對該腫瘤呈現發炎反應之其餘細胞在內的此些細胞，約僅1%是癌細胞。這一直使得很難找到，驅動該種疾病的確鑿證據。」
Alizadeh, who is the Moghadam Family Professor, and Maximilian Diehn, MD, PhD, professor of radiation oncology and the Jack, Lulu, and Sam Willson Professor, are the senior authors of the research, which published Dec. 11 in Nature. Former postdoctoral scholar Stefan Alig, MD; instructor of medicine Mohammad Shahrokh Esfahani, PhD; and graduate student Andrea Garofalo are the lead authors, as is graduate student Michael Yu Li at British Columbia Cancer.
屬於Moghadam Family教授的Alizadeh，及放射腫瘤學教授Maximilian Diehn醫學博士、哲學博士，及Jack、Lulu與Sam Willson教授，是該項2023年12月11日，發表於《自然》期刊的研究資深撰文人，前博士後學者Stefan Alig醫學博士；醫學講師Mohammad Shahrokh Esfahani哲學博士；及研究生 Andrea Garofalo是首要撰文人，英屬哥倫比亞省癌症中心研究生，Michael Yu Li也是。
About 8,500 people are diagnosed with Hodgkin lymphoma each year in the United States. The disease primarily affects people between the ages of 15 and 35, and people older than 55.
在美國，每年約有8,500人，被診斷罹患霍奇金淋巴瘤。此疾病主要侵襲15至35歲之間的人，及55歲以上的人。
Just over 60 years ago, Stanford radiologist Henry Kaplan, MD, pioneered the use of targeted radiation to treat Hodgkin lymphoma. The new therapy, delivered by a high-energy linear accelerator Kaplan developed in the 1950s for medical use, was the first step in a Stanford-driven effort to turn the once fatal cancer of the lymph nodes into one that is now highly curable.
就在60多年前，史丹佛大學放射學家，Henry Kaplan醫學博士率先使用了，標靶放射療法，來治療霍奇金淋巴瘤。這種由Kaplan於1950年代所開發，供醫療使用之高能量線性加速器遞送的新療法，是在一項史丹佛大學推動，來將曾經是致命的淋巴結癌轉變成，目前高度可治癒之嘗試中的第一步。
Soon thereafter, Kaplan was joined by medical oncologist Saul Rosenberg, MD, and the two worked out ways to combine radiation therapy with chemotherapy regimens, including one known simply as the Stanford 5 (named because it was the fifth in a series of gradually less toxic treatments).
此後不久，醫學腫瘤學家Saul Rosenberg 醫學博士加入了Kaplan行列。之後兩人想出了，結合放射療法與化學療法之療程的方法。包括一種被簡稱為史丹佛5的療程(因為在一系列逐較少毒性治療的過程中，這是第五次）。
During the subsequent decades, however, the genetic changes that cause the cancer have remained mysterious. That’s because, unlike many other cancers, Hodgkin lymphoma tumors are made up primarily of immune cells that have infiltrated the cancer, making it difficult to isolate the diseased cells for study.
然而，在其後的幾十年間，導致癌腫的基因改變，一直依然難以理解。那是因為，不像諸多其他癌腫，霍奇金淋巴瘤腫瘤，主要是由已經浸潤該種癌腫的免疫細胞組成。因此，使其難以分離出，供研究的不健全細胞。
Today, patients are treated with chemotherapy, radiation or a combination of both; about 89% of patients survive five years or more after their initial diagnosis.
目前，接受化學療法、放射療法或結合兩者治療的病患。在初次診斷後，約89%病患，存活五年或更長時間。
Alizadeh, Diehn and their colleagues used an optimized DNA sequencing technique called PhasED-Seq, or phased variant enrichment and detection sequencing, they developed at Stanford Medicine in 2021 to home in on vanishingly rare bits of DNA in a patient’s bloodstream to identify genetic changes that drive the growth of Hodgkin lymphoma.
Alizadeh、Diehn及其同僚們使用了一種，經最佳化，被稱為PhasED-Seq，也就是，相控之變異強化及檢測排序的DNA排序技術。這是於2021年，他們在史丹佛大學醫學院所開發，來瞄準病患血液中，難以察覺之稀少DNA片段，以確認驅動霍奇金淋巴瘤生長的遺傳改變。
PhasED-Seq builds upon a technique called CAPP-Seq, or cancer personalized profiling by deep sequencing, developed in 2014 by Alizadeh and Diehn to assess lung cancer levels and response to treatment. But PhasED-Seq is much more sensitive.
PhasED-Seq以一種，被稱為CAPP-Seq的技術。也就是，於2014年由Alizadeh及Diehn所開發，來評估肺癌程度及對治療反應之藉由深度排序的癌腫個人化分析為基礎。不過，PhasED-Seq更靈敏的得多。
“CAPP-Seq could detect as few as one cancer DNA sequence in 10,000 non-cancer DNA sequences,” Diehn said. “But PhasED-Seq can detect less than one cancer DNA sequence in 1 million non-cancer DNA sequences.”
Diehn宣稱：「在1萬個非癌腫DNA序列中，CAPP-Seq可能檢測少至一個癌腫DNA序列。不過，PhasED-Seq能檢測，1百萬個非癌腫DNA序列中，不及一個癌腫DNA序列。」
Their goal was to learn more about what drives the cancer and how to make successful treatments even easier for patients.
他們的目標是，獲悉更多有關什麼驅動癌腫，及如何使病患更容易獲得成功的治療。
“We typically can cure most patients with one line of therapy,” Alizadeh said. “But we are always trying to figure out less toxic chemotherapeutic agents that are gentler to the bone marrow, lungs and other organs, and ways to more precisely target radiation therapy. And a small minority of patients experience a recurrence that can be challenging to treat successfully.”
Alizadeh宣稱：「通常，我們能使用一種療法，治癒大多數病患。不過，我們一直在試圖想出，對骨髓、肺臟及其他器官，較溫和之毒性較小的化療藥劑，及更精確鎖定放射治療的方法。此外尚有少數病患經歷，對成功治療會是一種挑戰的復發。」
The researchers used CAPP-Seq and PhasED-Seq to analyze blood samples from 366 people treated for Hodgkin lymphoma at three medical centers including Stanford Medicine. The technique was remarkably sensitive.
此些研究人員使用了，CAPP-Seq及PhasED-Seq來分析，來自366名因為霍奇金淋巴瘤，於包括史丹佛大學醫學院等，三個醫療中心接受治療者的血液樣本。此技術非常靈敏。
“Surprisingly, we detected more cancer DNA in the blood than in the cancer tissue itself,” Alizadeh said. “That seemed hard to believe until we had analyzed enough samples to show that it was reproducible.”
Alizadeh宣稱：「令人驚訝的是，在血液中，我們檢測到比癌腫組織本身還要多的癌腫DNA。那似乎令人難以置信，直到我們已經分析足夠的樣本，來證實這可再現。」
The researchers used machine learning techniques to categorize the different types of genetic changes present in the cancer cells. They found that patients could be separated into two groups:
此些研究人員使用了，機器學習技術來分類，存在於癌細胞中，不同類型的基因改變。他們發現，病患能被分成兩群：
one that predominantly has mutations in several cancer-associated genes implicated in cellular survival, growth and inflammation, and another with a type of genetic change called copy number alterations that affects larger swathes of the genome, subbing in or excising regions of DNA that influence cell growth and cancer.
一種主要在與細胞存活、成長及發炎有關聯之若干與癌腫相關的基因中，具有諸多突變體，另一種具有一種，影響基因體較大區域，被稱為複製數改變的遺傳改變，這會替換或剔除，影響細胞生長及癌腫的DNA區域。
“We adapted a method from natural language processing to find these two Hodgkin subtypes, and then used a variety of methods to identify key biological and clinical features and to confirm that the subtypes are also seen in other groups of patients,” Esfahani said.
Esfahani宣稱：「我們採用了一種，來自自然語言處理的方法，來找尋這兩種霍奇金淋巴瘤亞型，然後使用多種方法，來確認關鍵的生物學與臨床特徵，及證實這兩亞型，也在其他病患群體中被發現。」
The first group, which makes up about one-half to two-thirds of patients, occurs primarily in younger patients and has a comparatively more favorable outcome. About 85-90% of these people survive for three years without disease recurrence.
構成大約二分之一到三分之二病患的第一群，主要發生於較年輕的病患中，且具有相對上較良好的結果。此些人中，大約85-90%沒有疾病復發，存活下來達三年。
The second, which makes up about one-half to one-third of the total, occurs in both younger and older patients and has a less favorable, although still good outcome. About 75% of these people live for at least three years without recurrence.
構成大約總數二分之一到三分之一的第二群，發生於較年輕及較老長的病患中，且具有雖然仍然不錯的結果，不過較不良。此些人，大約75%沒有復發，存活下來至少達三年。
Critically, a subset of both groups contained a unique mutation in a gene for the receptor for cellular signaling proteins called interleukin 4 and interleukin 13.
至關重要的是，這兩群體的一個子群，在被稱為白細胞介素4及白細胞介素13之細胞發信號蛋白受體的一個基因中，具有一種獨特的突變體。
“We discovered a new class of mutations in the interleukin 4 receptor gene that enhance a key pathway characteristic to Hodgkin lymphoma,” Alig said. “These mutations may be indicative of unique vulnerabilities of the tumor that can be exploited therapeutically.”
Alig宣稱：「在增強對霍奇金淋巴瘤之一種關鍵途徑特性的白血球介素4受體基因中，我們發現了一類新的突變體。此些突變體可能是，能有療效地被加以利用之該種腫瘤，獨特易受攻擊的顯示物。」
The researchers also showed that patients who had no detectable circulating tumor DNA in their blood shortly after starting treatment were much less likely to have disease recurrence than those who had even small amounts of residual circulating cancer DNA at the same time point — a distinction researchers had hoped to see, but were unsure about being able to detect even with PhasED-Seq.
此些研究人員也證實，在開始治療後不久，於血液中，沒有可檢測到之循環腫瘤DNA的病患，比那些在相同時間點，即使有少量殘留之循環腫瘤DNA的病患，更不可能有疾病復發。這是研究人員們，曾期盼發現的一個差異。不過，在能檢測方面，縱然使用PhasED-Seq也是不確定。
“I was surprised that we could predict which patients would recur,” Diehn said. “Even with our ultrasensitive assay there was a significant chance that the signal from the cancer DNA could become undetectable after treatment, even in patients who eventually recurred. But this didn’t happen.”
Diehn宣稱：「令我感到驚訝，我們可能預測哪些病患會復發。即使採用我們超靈敏的檢測，來自癌腫DNA的訊號，有顯著改變。在治療後也可能變成無法檢測到，即使在最終復發的病患中。不過，這並沒發生。」
The researchers seeking to understand more about the biology of Hodgkin lymphoma have one key goal: the improvement of care for patients.
此些尋求瞭解更多有關霍奇金淋巴瘤生物學的研究人員們，有一個重要目標：改善病患的照護。
“The number of people who experience recurrence is small, but, like Henry Kaplan and Saul Rosenberg, we want to save every one of them,” Diehn said. “They would have been amazed and gratified by these findings, which build upon their important work from decades ago. We look forward to an era in which we can cure every patient with no toxicity.”
Diehn宣稱：「經歷復發的人數很少。不過，如同Henry Kaplan及Saul Rosenberg，我們想拯救此少數的每一個人。他們會，因此些以其來自幾十年前之重要研究為基礎的發現，感到驚訝和欣慰。我們期待一個，能使用無毒性，來治癒每一病患的時代。」
網址：https://med.stanford.edu/news/all-news/2023/12/hodgkin-lymphoma-prognosis.html?microsite=news&tab=news
翻譯：許東榮
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