NCCN指引:先NSCLC病理學檢驗而後突變測試


  【24drs.com】國家整合型癌症網絡(NCCN)更新的非小細胞肺癌(NSCLC)指引有許多變更,包括再發或轉移疾病患者接受全身治療的評估流程。
  
  NSCLC小組主席、馬里蘭巴爾的摩約翰霍普金斯悉尼金梅爾整合型癌症中心成員David Ettinger醫師表示,該評估流程現在需要在表皮生長因子受體(EGFR)檢測之前確定疾病的病理亞型。
  
  病理學檢查是重要的!
  
  在再發與轉移疾病的情況下,EGFR檢測對三種病理疾病亞型是第一類建議:腺瘤、巨細胞惡性腫瘤與其他未被確認的NSCLC。扁平細胞惡性腫瘤不建議接受該檢測;新指引指出,該疾病患者的EGFR突變發生率不到3.6%,這樣的發生率並不需要檢測。
  
  Erlotinib(Tarceva;Genentech/OSI藥廠)建議作為這三種相關病理且EGFR基因突變患者的第一線全身性治療。這項新指引釐清了erlotinib適用於表現狀態0到4的患者;且新建議是,geftinib能使用於可取得該藥物之相同患者的第一線藥物。
  
  指引中指出,腺瘤的EGFR突變大約出現在10%的西方患者以及50%的亞洲患者,大部分是女性、非吸菸者以及非黏液性腫瘤。
  
  指引指出,NSCLC患者應該接受KRAS突變檢查,因為他們與內在TKI(酪胺酸磷酸酶抑制劑)抗藥性有關,這些TKI包括gefitinib與erlotinib,有KRAS基因突變代表TKI類藥物將不會有效。
  
  有KRAS基因突變的患者也比較不會發生未分化性淋巴瘤磷酸酶(ALK)重整,因此,並非研究中新藥crizotinib(輝瑞藥廠)的良好標的。指引指出,部分NSCLC患者有棘皮微小管相關類蛋白4(EML4)與ALK融合的現象。
  
  有趣的是,有EML4-ALK的NSCLC患者也比較可能帶有EGFR基因突變。
  
  Ettinger醫師總結,簡言之,臨床醫師們應該醫囑EGFR與KRAS檢查,且如果有EGFR基因突變,應該醫囑EML4-ALK檢驗。他表示,你所要做的是通知病理科醫師,並且寄送EGFR與KRAS檢驗所需樣本給他們。
  
  不過,這樣的檢驗訊息並未傳遞給許多醫師。他指出,在約翰霍普金斯大學附設醫院的NSCLC患者來自五個州,包括馬里蘭,這些患者都沒有接受分子測試。
  
  另一位NCCN會議參與者表示,臨床醫師並不是對分子檢驗訊息聰而不聞。奧爾巴尼紐約血液腫瘤科的Michael Kolodziej醫師表示,這項檢驗目前並沒有良好的證據基礎,而且還不是很實際。
  
  他指出,分子檢驗的價值尚未證實, 分子檢驗的潛力目前並沒有因其實用性說服社區醫師;舉例來說,一位被診斷NSCLC的女性非吸菸患者,因為她符合EML4-ALK NSCLC的條件,且因此可能因使用crizotinib受益,該名患者適合接受肺腫瘤組織基因定型。
  
  Kolodziej醫師表示,要取得組織需要好幾個星期,他解釋邏輯上的困難,包括全國只有一、兩個商業實驗室進行EML4-ALK檢驗。
  
  EGFR檢驗實際上也存有時間上的問題,這個問題之前由Medscape醫療新聞報告過。
  
  過去一年在肺癌領域最大的新聞可能是國家肺癌篩檢試驗(NLST)這項指標性的研究結果。
  
  NLST從2002年開始,在美國33個地區進行,共有53,454位過去或目前為重度吸菸患者,該項研究因為療效結果而提早結束。NLST研究是第一項提供篩檢可以顯著降低肺癌死亡率的隨機分派研究。
  
  Ettinger醫師表示,相較於胸部X光攝影檢查,電腦斷層掃描(CT)篩檢可以顯著降低20%的肺癌死亡率。
  
  Ettinger醫師提醒NCCN年會參與者,該組織尚未建議以CT進行常規篩檢;其風險與好處需要來自臨床研究數據的進一步確認,包括NLST。
  
  然而,對篩檢有興趣的高風險患者應該參加臨床試驗。如果這不可行,接著患者們應該與卓越中心討論好處與風險,且在有CT篩檢時遵循已建立好的計畫。
  
  資料來源:

NSCLC Histology First, Then Mutation Testing, Says NCCN Guideline

By Nick Mulcahy
Medscape Medical News

March 18, 2011 (Hollywood, Florida) — There are a host of changes in the updated guideline for nonsmall-cell lung cancer (NSCLC) from the National Comprehensive Cancer Network (NCCN).

Some of the most notable changes, presented here at the NCCN 16th Annual Conference, involve the evaluation process for potential systemic therapy in patients with recurrent or metastatic disease.

The evaluation process now calls for the histologic subtype of the disease to be established before proceeding with epidermal growth-factor receptor (EGFR) testing, said David Ettinger, MD, the NCSLC panel chair and a member of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland.

"Histology matters!," Dr. Ettinger told the NCCN audience.

In the setting of recurrent and metastatic disease, EGFR testing is a category 1 recommendation for 3 histologies: adenocarcinoma, large cell carcinoma, and NSCLC not otherwise specified. The testing is not recommended for squamous cell carcinoma; the guideline newly notes that patients with this form of the disease have an incidence of EGFR mutations of "less than 3.6%" and that this frequency does not justify the testing.

Erlotinib (Tarceva, Genentech/OSI Pharmaceuticals) is recommended as the first-line systemic therapy in patients with the 3 relevant histologies and a positive EGFR mutation. New to the guideline is the clarification that erlotinib is for patients with a performance status of 0 to 4. Also new is the recommendation that gefitinib can be used as first-line therapy in these same patients in "areas of the world where it is available."

EGFR mutations are present in adenocarcinomas in about 10% of Western patients and in about 50% of Asian patients, most frequently in women, nonsmokers, and nonmucinous tumors, says the guideline.

NSCLC patients should also be tested for KRAS mutations, because they are "associated with intrinsic TKI [tyrosine kinase inhibitor] resistance," says the guideline, referring to the TKIs gefitinib and erlotinib. KRAS gene sequencing could be useful in selecting patients for TKI therapy, the guideline notes, meaning that having the KRAS mutation indicates that TKIs will not be effective.

Patients who are positive for KRAS mutation are also unlikely to have anaplastic lymphoma kinase (ALK) rearrangements and, thus, are not good candidates for the investigational agent crizotinib (Pfizer), said Dr. Ettinger. The fusion of echinoderm microtubule-associated protein-like 4 (EML4) and ALK occurs in a subset of NSCLCs, the guideline points out.

Interestingly, the subset of patients with EML4-ALK NSCLC are also "likely to harbor EGFR mutations," says the guideline.

In short, clinicians should order EGFR and KRAS testing and, if EGFR mutation is present, order EML4-ALK testing, summarized Dr. Ettinger. "All you have to do is to call up the pathologist and send the material over for EGFR and KRAS testing," he told the audience.

But the testing message is not getting through to many clinicians, Dr. Ettinger reported. He told the audience that he routinely sees NSCLC patients at Johns Hopkins from the "5-state area," including Maryland, who have not received molecular testing.

However, another NCCN meeting attendee suggested that clinicians are not deaf to the molecular testing message. Michael Kolodziej, MD, from New York Oncology Hematology in Albany, said that the testing is not yet well-founded on evidence and has not yet become practical.

"The value of molecular testing has yet to be proven," he told Medscape Medical News.

He also said that the promise of molecular testing currently does not jive well with its practicalities for community-based clinicians.

He offered the example of one of his patients — a female nonsmoker diagnosed with NSCLC. Because she fit the profile of patients with EML4-ALK NSCLC, and therefore might benefit from crizotinib, the woman was a candidate for genotyping of her lung tumor tissue.

"It took weeks to get [her testing] sorted out," said Dr. Kolodziej, explaining that the logistical difficulties included the fact that there are "only 1 or 2 commercial labs in the whole country that do the test" for EML4-ALK.

Practical problems with timing also exist for EGFR testing, a problem that Medscape Medical News has reported in the past.

No Routine Screening With CT Yet

The biggest news in lung cancer in the past year might be the results from the landmark National Lung Screening Trial (NLST).

The NLST, which was started in 2002, was conducted at 33 American sites with a cohort of 53,454 former and current heavy smokers, and was stopped early because of efficacy findings. The NLST represents the first time that a screening test has been shown to provide a significant reduction in lung cancer mortality in a randomized controlled clinical trial.

Screening with computed tomography (CT) provided a statistically significant 20% reduction in lung cancer mortality, compared with screening with chest x-ray, said Dr. Ettinger.

Dr. Ettinger reminded the NCCN audience that the organization does not yet recommend routine screening with CT; the risks and benefits need further definition from clinical trial data, including those of the NLST.

However, high-risk patients who are interested in screening should participate in a clinical trial, says the guideline. If that's not possible, then the patient should go to a center of excellence, discuss benefits and risks, and follow an established protocol when having a CT screening.

Dr. Ettinger reports being a consultant to Boehringer Ingelheim, Daiichi- Sankyo, Eli Lilly, Genentech, Merck, Biodesix, Poniard Pharmaceuticals, Prometheus, Shin Nippon Biomedical Labs, and Telik.

National Comprehensive Cancer Network (NCCN) 16th Annual Conference. Presented March 10, 2011.

    
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