生物標記對於卵巢癌的早期介入沒有充分準確度
作者：Roxanne Nelson
出處：WebMD醫學新聞
December 30, 2009 — 卵巢癌往往會致命，造成此一令人悲傷結果的其中一個原因是，它常常在末期階段才被診斷出來。及早發現有助於降低相關的死亡率，但是目前沒有特定且敏感的篩檢方法。可能的卵巢癌生物標記包括癌症抗原CA125、第4人類副睪蛋白質(HE4)、mesothelin、B7-H4、第3誘餌蛋白質(DcR3)、spondin-2蛋白質。研究者現在報告指出，血清的CA125、HE4與mesothelin濃度可以在臨床診斷卵巢癌前三年提供證據。
不過，根據即將登載於2010年1月6日美國國家癌症研究院期刊(Journal of the National Cancer Institute)的研究發現，這些生物標記只有在診斷前一年明顯上升。
然而，研究者解釋，雖然這些生物標記在現有篩檢協定中之準確度尚不足以促成提早介入，但是確定了和CA125、HE4與mesothelin有關之適度但統計上顯著的風險上升。此發現和許多卵巢癌流行病學風險因素研究一致。
第一作者、Garnet Anderson博士向Medscape Oncology表示，我仍然認為生物標記在具有成本效益的篩檢計畫中有其功能，但目前的準度似乎不足以支持它們單獨使用或併用於這些一般風險的婦女。
參與Fred Hutchinson癌症研究中心公共健康科學小組的Anderson醫師表示，我不知道目前是否有其他生物標記比這些更有效，但是在過去幾年間，有許多關於找到可能標記的嘗試，不過，並不是每個都有充分研究。
Anderson醫師引述，問題之一在於鑑別可能的生物標記所用的方法，她解釋，迄今，多數研究工作是在有末期疾病的婦女進行，然後和健康婦女比較，如果是和我們所用的樣本一樣，是在末期診斷前幾個月到幾年所蒐集的樣本，有較佳機會發現惡化疾病的早期徵兆。
她指出，改善篩檢和早期診斷的其他機會在於影像檢查。Anderson醫師表示，目前最常使用、且唯一可負擔作為例行性篩檢的影像檢查方式是經陰道超音波，但是在確認有和沒有卵巢癌婦女的準確度不佳，此一領域若有明顯改善，將是令人振奮的事情。
【診斷前不久達到偵測程度】
該研究中，Anderson醫師等人分析診斷前的血清樣本，以及「Carotene and Retinol Efficacy Trial」的病患資料，那是一個評估β-胡蘿蔔素和A醇對於高風險族群肺癌發生率之影響的隨機化療預防試驗。
在34個病患(15 個有末期漿液性癌)診斷有卵巢癌前0-18年取得血清樣本，並且對70名相仿的對照組在相當的期間內取得對照樣本。進行免疫分析，以確認樣本中的CA125、HE4、mesothelin、B7-H4、DcR3與spondin-2濃度。
結果顯示，在診斷前將近三年時，相較於對照組，CA125、HE4與mesothelin的濃度在卵巢癌病患中略為升高，不過，這些生物標記只有在診斷前一年達到可偵測的升高程度，因此，研究者指出，這些標記的識別能力有限，因為準確度只有在診斷前不久時增加。
【尚未定論】
國家癌症研究院癌症流行病學與基因小組的Patricia Hartge博士在編輯評論中指出，對於沒有症狀的卵巢癌婦女，建立成功的篩檢計畫是相當相當困難的。
不過，Hartge博士寫道，研究作者們在這類篩檢計畫邁出了成功的一步，顯示出根據某標記或一些標記的篩檢方式何以失敗的原因。
她指出，這些結果對於血清標記或併用標記來說並非最後定論，反之，將前置時間和其他參數納入考量時，血清標記可能是任何篩檢計畫的關鍵元素。
Hartge博士解釋，但是，就現階段來說，沒有經證實可以妥善運作的生物標記、或一組生物標記、或整體篩檢計畫，現在的報告有其重大涵義，讓我們更加瞭解設計卵巢癌之有效偵測計畫的決定性元素。
國家癌症研究院資助本研究。Anderson醫師宣告沒有相關財務關係，共同作者、Lieling Wu目前受雇於Baxter Healthcare公司，且擁有該公司的股權，但是未參與和卵巢癌有關的計畫。
Biomarkers Not Sufficiently Accurate for Early Intervention in Ovarian Cancer
By Roxanne Nelson
Medscape Medical News
December 30, 2009 — Ovarian cancer is often a lethal disease, and one reason for this dismal prognosis is that it is usually not diagnosed until it has reached an advanced stage. Early detection could help reduce the associated mortality rate, but currently there are no specific and sensitive screening methods. Potential ovarian cancer biomarkers include cancer antigen CA125, human epididymis protein 4 (HE4), mesothelin, B7-H4, decoy receptor 3 (DcR3), and spondin-2 proteins. Researchers now report that serum concentrations of CA125, HE4, and mesothelin may provide evidence of ovarian cancer 3 years before a clinical diagnosis is made.
However, these biomarkers only become substantially elevated in the last year before diagnosis, according to findings published in the January 6, 2010, issue of the Journal of the National Cancer Institute.
However, although these markers are not accurate enough to prompt early intervention in existing screening protocols, the study authors explain, modest but statistically significant increases in risk associated with CA125, HE4, and mesothelin were identified. This finding is consistent with many of the established epidemiologic risk factors for ovarian cancer.
"I still think biomarkers may play a role in a cost-effective screening program, although none of these seem accurate enough either alone or together to justify their use in average-risk women," lead author Garnet Anderson, PhD, told Medscape Oncology.
"I do not know of any other currently identified biomarkers that hold more promise than these, but there has been a massive effort over the last few years to identify candidates and not all have been thoroughly vetted," said Dr. Anderson, who is with the Division of Public Health Sciences at the Fred Hutchinson Cancer Research Center in Seattle, Washington.
One problem, cites Dr. Anderson, may lie in the approach used in identifying candidate biomarkers. "Most of the discovery work done so far has been conducted in women with advanced-stage disease and compared them to healthy women," she explained. "If discovery work were done in samples like the ones we used here, representing specimens collected months to years prior to the advanced stage diagnosis, we might have a better chance of finding earlier signals of aggressive disease."
Another opportunity for improving screening and early diagnosis lies in imaging, she adds. "Currently the most common and only affordable imaging option that could be considered for routine screening is transvaginal ultrasound, but it performs poorly in terms of accurately determining those women [who] have ovarian cancer from those who do not," said Dr. Anderson. "A substantial improvement in this area would be very exciting."
Detectable Levels Reached Shortly Before Diagnosis
In this study, Dr. Anderson and colleagues analyzed prediagnostic serum samples and patient data from the Carotene and Retinol Efficacy Trial, a randomized chemoprevention trial that evaluated the effects of beta-carotene and retinol on the incidence of lung cancer among individuals at high risk for the disease.
The serum samples were obtained 0 to 18 years before a diagnosis of ovarian cancer was made in 34 patients (15 with advanced-stage serous carcinoma) and during a comparable interval before the reference date from 70 matched control subjects. Immunoassays were conducted to determine concentrations of CA125, HE4, mesothelin, B7-H4, DcR3, and spondin-2 proteins in the samples.
Results showed that concentrations of CA125, HE4, and mesothelin became slightly elevated in patients with ovarian cancer vs the control subjects approximately 3 years before their diagnosis. However, these biomarkers only reached detectable elevations within the final year before diagnosis. Thus, the discriminatory power of the markers was limited, the study authors note, because accuracy only increased shortly before diagnosis.
Not the Last Word
In an accompanying editorial, Patricia Hartge, ScD, of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, Bethesda, Maryland, notes that it has been "surprisingly difficult" to create a successful screening program for asymptomatic women with ovarian cancer.
However, the authors of this study have taken a "valuable step toward the successful design of such a screening program by demonstrating one reason why screening regimens that are based on markers, or panels of markers, can fail," writes Dr.?Hartge.
She points out that these results are "not the last word in serum markers or in combinations of markers." Instead, serum markers are likely to form a key element in any screening regimen, with the lead time and other parameters being taken into account.
not the last word in serum markers or in combinations of markers.
However, for right now, there are no proven biomarkers, panel of biomarkers, or overall screening program that works well, explained Dr. Hartge. "The current report, with its sobering implications, brings us closer to understanding the crucial elements in designing any effective early detection program for ovarian cancer."
The National Cancer Institute funded the study. Dr. Anderson has disclosed no relevant financial relationships. Coauthor Lieling Wu is currently employed by Baxter Healthcare, Inc, and holds stock in this company but is not involved in projects related to ovarian cancer.
J Natl Cancer Inst. 2010;102:1-3, 26-38.
