乳癌的「新地圖」確認了10種疾病亞型


  【24drs.com】研究者表示,乳癌的「新地圖」根據基因活性確認了10種獨特的基因亞型,將為此疾病的診斷與治療帶來革命。
  
  這些線上刊載於4月18日自然期刊的研究結果,來自一篇迄今全球規模最大的乳癌基因研究。
  
  全球聞名的乳癌專家、比利時Jules Bordet Institut的Martine Piccart博士表示,這確實是篇石破天驚的研究,目前的乳癌分類過於簡單化,導致我們的病患沒有最佳治療選項。
  
  Piccart博士表示,對於乳癌有至少10種亞型,不只現有的4種,我並不感到驚訝,我相信這個發現將為病患帶來更好的處置,雖然可能還需要再10年才可確認。
  
  英國和加拿大的研究者分析了取自5-10年前診斷乳癌之婦女的近2,000例腫瘤樣本,他們整合了腫瘤樣本的拷貝數和基因表現及長期臨床結果資料,結論認為可以根據和存活有關的一般基因特徵將樣本至少分成10個獨特的亞型。
  
  英國劍橋大學腫瘤科、英國劍橋研究中心癌症研究資深小組領導人Carlos Caldas醫師表示,下個步驟是以臨床試驗確認,但是最終目標是對每個腫瘤類型之基因指紋進行標靶治療。
  
  他表示,我們的研究結果在未來將成為醫師診斷婦女乳癌類型的方法、確認哪些藥物有用、哪些沒用,比目前的方法更加精準。
  
  根據提供此次研究資金的英國癌症研究中心,這個慈善機構在英國倫敦舉辦的記者會中強調,這項指標性研究將完全改變我們對乳癌的看法。
  
  Caldas醫師解釋,目前乳癌分類為4種亞型,這是根據雌激素受體(ER)檢測結果,陽性表示對荷爾蒙治療有反應,如果是HER2陽性則表示對trastuzumab (Herceptin)有反應。
  
  到目前為止,大部分的乳癌(70%)是ER陽性/HER2陰性,約7.5%是ER陽性/HER2陽性,約7.5%是ER陰性/HER2陽性,其他是所謂的三重陰性乳癌(ER陰性/黃體素受體陰性/HER2陰性),這類型最具侵犯性,任何標靶治療都無效,需進行化療。
  
  不過,分類為ER陽性/HER2陰性的這70%乳癌中,有相當大的異質性,有些病患的預後優於其他人。
  
  研究者發現,新確認的10種疾病亞型中,有7種屬於此類別;各亞型的預後有相當大的差異;15年時,存活率最好的達到80%,最差的不到40%。Caldas 醫師在媒體簡報中表示,我們在比率最高的乳癌亞型發現更多亞型,這相當重要,我們一直為這組病患找尋更佳的標記。
  
  他指出,新分類確認了相當多的HER2陽性腫瘤,不論是ER陽性或ER陰性。以前全部的分子檢測都無法適當做到這一點,這或許增加了病患被分類為HER2陽性的機會,可以從trastuzumab治療獲益。
  
  Caldas醫師表示,另一個新的亞型,稱之為cluster 10,相當符合三重陰性亞型,但並不全然是。他表示,新亞型中最多的是cluster 4這型,約佔總數的16%,相當有趣的是,這個亞型的拷貝數增減不多,有明顯的浸潤或發炎細胞,表示免疫系統活化;這亞型包括了ER陽性、ER陰性與三重陰性腫瘤病患,在仰賴基因定序的其他分類系統很可能被忽略。
  
  他表示,研究者也發現許多新基因。其中如激酶和磷酸酶,是新藥研發的重要標靶。
  
  Caldas醫師表示,我們帶來全新的乳癌分類法,且因為我們的樣本數夠大,這結果相當有意義。
  
  這個新的乳癌分子分類法如何與現有的其他檢測,如Oncotype DX和MammaPrint配套?Caldas醫師解釋,證據認為,這些檢測對於各亞型都比不上高品質病理檢測確認方式。他表示,英國在病理學方面領先全球,特別是乳癌這方面。在這個領域,Oncotype DX和MammaPrint都沒能增加許多資訊,事實上,全國臨床精進研究中心認為兩種都不符合成本效益。
  
  資料來源:http://www.24drs.com/professional/list/content.asp?x_logon=W&x_idno=6792&x_classno=0
  

New Map of Breast Cancer Identifies 10 Disease Subtypes

By Zosia Chustecka
Medscape Medical News

April 18, 2012 — A "new map" of breast cancer, which identifies 10 distinct disease subtypes based on gene activity, will revolutionize the diagnosis and treatment of this disease, say researchers.

The findings, published online April 18 in Nature, come from the largest global gene study of breast cancer tissue ever performed.

"This research is 'ground-breaking' indeed," said world-renowned breast cancer expert Martine Piccart, MD, PhD, from the Jules Bordet Institut in Brussels, Belgium. "The current classification of breast cancer is overly simplistic and results in suboptimal treatment selections for our patients," she told Medscape Medical News.

"I am not at all surprised that breast cancer is not 4 diseases but at least 10…and I do believe that this discovery will lead to the better management of patients…although this will probably take another 10 years," Dr. Piccart said.

Researchers in the United Kingdom and Canada analyzed nearly 2000 tumor samples taken from women diagnosed with breast cancer 5 to 10 years ago. They integrated tumor-sample copy numbers and gene expression with data on long-term clinical outcomes. They concluded that the samples could be divided into at least 10 distinct subtypes on the basis of common genetic features that correlate with survival.

The next step is validation in clinical trials, but the ultimate aim is to target treatment to the precise "genetic fingerprint" of each tumor type, said colead author Carlos Caldas, MD, FMedSci, from the Department of Oncology at Cambridge University, United Kingdom, and senior group leader at Cancer Research UK's Cambridge Research Institute.

"Our results will pave the way for doctors in the future to diagnose the type of breast cancer a woman has, the type of drugs that will work, and those that won't, in a much more precise way than is currently possible," he said.

"This landmark study will completely change the way we look at breast cancer," according to Cancer Research UK, which provided much of the funding for the study. The charity highlighted the study at a press conference held in London, United Kingdom.

Current Pathology Subtypes

Currently, breast cancer is classified by pathologists into 4 subtypes, Dr. Caldas explained. This is based on testing for the estrogen receptor (ER), which if positive indicates responsiveness to hormonal therapies, and for HER2, which if positive indicates responsiveness to trastuzumab (Herceptin).

By far the largest proportion of breast cancers (70%) are ER-positive/HER2-negative, about 7.5% are ER-positive/HER2-positive, and about 7.5% are ER-negative/HER2-positive. The remainder are the so-called triple-negative breast cancers (ER-negative/progesterone-receptor-negative/HER2-negative), which are aggressive, do not benefit from any targeted therapy, and are treated with chemotherapy, he said.

However, in the 70% of breast cancers that are classified as ER-positive/HER2-negative, there is a tremendous heterogeneity, Dr. Caldas explained, with some patients having a much better prognosis than others.

The researchers found that 7 of the 10 newly identified disease subtypes are in this category. There is a wide variation in prognosis by subtype; at 15 years, the best shows 80% survival and the worst shows less than 40% survival. "We are getting more separation in this largest subgroup of breast cancer. This is very important. We have been on a quest to find better markers in this group of patients," Dr. Caldas said at the press briefing.

The new classification identifies very robust HER2-positive tumors, whether they are ER-positive or ER-negative, he noted. "All previous molecular tests have failed to do this properly," he added. This might increase the number of patients classified as HER2-positive, who could benefit from treatment with trastuzumab, the researchers write.

Another of the new subtypes, known as cluster 10, coincides fairly closely with the triple-negative subtype, although not exactly, Dr. Caldas said.

The largest of the new subtypes identified, known as cluster 4, accounts for about 16% of the total and is "very interesting," he continued. This subtype has fewer copy number gains and losses, and shows a significant infiltration of inflammatory cells, suggesting an activation of the immune system. This subtype comprises patients with ER-positive, with ER-negative, and with triple-negative tumors, and "would be missed in any other classification system that relies on sequencing," he said.

The researchers also discovered several new genes. Some of these, such as kinases and phosphatases, are very attractive targets for new drug development, he said.

"We have produced a completely new way of looking at breast cancer," Dr. Caldas said. "It is very robust because of the number of samples that we looked at," he explained.

When asked by Medscape Medical News how this novel molecular stratification of breast cancer fits with other tests that are already available, such as Oncotype DX and MammaPrint, Dr. Caldas explained that the evidence suggests that neither of those tests add much to the subtypes that are identified by high-quality pathology. "The United Kingdom leads the world with regard to pathology, especially in breast cancer," he said. In this setting, neither Oncotype DX nor MammaPrint add much information, he said. In fact, the National Institute of Clinical Excellence deemed that both are not cost effective, he added.

Nature. Published online April 18, 2012.

    
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