【汤森路透会议报道】ASCO 2014“肿瘤基因组分析：未来出路或TMI？”

【汤森路透会议报道】ASCO 2014“肿瘤基因组分析：未来出路或TMI？”

2014-06-04 汤森路透生命科学与制药

                               
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内容来源：汤森路透旗下BioWorld对“2014美国临床肿瘤学会（ASCO）年会”的跟踪报道。希望为国内关注肿瘤领域的药物工作者带来此重大会议报告中的最新消息。后续还有系列报道推出，敬请关注。

编译：生命科学研究快报 游文娟

说明：译文后附英文原文，若翻译有不明之处，请参见英文原文。

ASCO 2014“肿瘤基因组分析：未来出路或TMI？”

作者：汤森路透科学编辑Anette Breindl

是否值得投入大量金钱进行癌症靶向治疗是争议最多的内容之一。ASCO 2014将此列为今年年会的主题之一以阐明癌症靶向治疗的价值。与会过程中，研究人员就此进行了讨论，包括靶向治疗的复杂性，基因组分析以期靶向药物可以在第一时间靶向靶点等。

癌症基因组测试已经应用临床。美国MemorialSloan-Kettering Cancer Center的CharlesRudin表示其所在癌症中心在治疗腺癌时已经将其作为腺癌的标准治疗方案，而针对肺癌的其他亚类的治疗，测序方法指导临床治疗正在试验中。另外，测序技术的应用反过来促进了腺癌分类的改变，进而影响治疗结果。肺癌的常见突变为KRAS基因的突变，目前还无直接针对这一突变的药物。然而肿瘤往往同时激活EGFR突变，邻近的ALK出现大量重排现象，而目前已经有药物阻抑（或阻止一段时间）这类突变导致的生长。而实际操作过程中发现，与那些没法确定突变靶点的疗法、或已知靶点但没有采用靶向疗法治疗方法相比，靶向治疗的效果更好。

但是在“Tumor genomeprofiling: Field of dreams or ethical minefield（肿瘤基因测序：梦想之区还是伦理雷区）”分会场，来自美国宾夕法尼亚大学的Angela Bradbury提醒大家，肿瘤基因组测序同样有利有弊。AngelaBradbury认为肿瘤基因测序是有益的说法只是一种推测，并不是一种板上钉钉的既成事实，希望大家考虑周全，找到合适利用基因测序的手段，让病患、病患家庭及全社会都能从中获益。

美国MayoClinic的Jennifer McCormick担心全体肿瘤研究人员过分的推崇肿瘤测序，从而陷入一些误区，她建议至少应该考虑全基因组测序和外显子测序。而实际上，DNA测序目前已经相当便宜，民众选择全基因测序将形成趋势。因而，测序结果指导治疗决策必然经历这样一个过程，从某些基因，到gene panels到整个外显子和基因组测序。不过测序越多，信息量越大。到时候就不是测序本身这件事了，还要决定哪些测序结果值得投入更多时间、精力去分析。

来自MemorialSloan Kettering Cancer Center 的MarkRobson认为，目前对于临床医生是否有义务研究基因组测序过程中发现的附带信息，还是将相关信息转达给病患本身由其自行处理，还未形成统一意见。比如，临床医生通过测序结果发现其治疗的癌症病患同样具有罹患心脏病或阿尔茨海默病的风险。如果临床医生深入研究测序过程中发现的其他信息，显然临床医生精力不够。同样，这些发现对于病患来说也是一种负担，他们一旦知道他们的测序结果，他们要根据那些还未表征出疾病的基因测序结果来决定是否选择临床试验并且花费大量的费用请基因咨询师帮助全面分析很多测序中获得的不相关的信息。

就以上观点，AngelaBradbury认为测序本身并无价值，测序的价值在于如何改变病患的治疗方案。例如，发现某个突变在临床上可应用的，也就是说有针对性药物的才有价值。说到底，还在于病患本身另外，测序结果的价值还在于揭示了测试个体的遗传倾向，这样，病患可以将其测序结果与其家属共享。其他突变结果目前可能还缺乏应用性，但是随着更多新的风险基因的确定，更多新药的开发，这一现状或发生改变。

JenniferMcCormick表示，当下病患有的参加的是临床测序有的参加的是研究测序，现状并不令人满意，但是人们可以在争论中创新，在争论中获得新知识。而关于某一测试何时可以进入到临床应用阶段，她认为，需要一个上层管理框架，“不要抑制创新，但是必须要有证据证明，我们是在向前发展，而不是在重蹈覆辙”。

英文原文

ASCO 2014: Tumor genome profiling: the way of the future or TMI?

By Anette Breindl, ScienceEditor

CHICAGO – The most frequentargument about whether targeted therapies are worth it is about money – in thecrudest terms whether the slim survival benefit of such drugs justifies theirfat price tag. The American Society of Clinical Oncology (ASCO) 2014 hasdeclared value to be one theme of this year’s annual meeting.

But at the meeting, researcherswere also discussing the value, in all its complexity, of the genome profilingthat makes it possible to select targeted drugs in the first place.

Tumorgenome sequencing has made profound inroads into clinical practice already. MemorialSloan-Kettering Cancer Center’s Charles Rudin told the audience at a session on“Tumor Genomic Profiling and its Application to Personalized Medicine: Lookingto the Future” that sequencing is now the standard of care at his institutionfor adenocarcinoma – the most common subtype of lung cancer – and othersubtypes are catching up.

That, inturn, has led to a sea change in how adenocarcinoma is categorized,with consequences for treatment. The most frequent mutation in lung cancer, inthe gene KRAS, still has no targeted agents directed against it. But tumorswith both activating EGFR mutations and, more recently ALK rearrangements, havedrugs that can forestall their growth, at least for a time.

And patients treated withtargeted therapies, overall, do better than those where no driver mutations canbe identified (around a quarter to a third of all sequenced patients) or whereno targeted therapies exist against the driver mutations that can beidentified.

But in a session on “Tumorgenome profiling: Field of dreams or ethical minefield?” the University ofPennsylvania’s Angela Bradbury warned the audience that in tumor profiling, too,there can be too much of a good thing.

The ideathat such profiling is broadly beneficial “is not a foregone conclusion,”she said. “This is a hypothesis. I don’t say this to take away the promise …but rather to say, we need to think about how we’re going to harness this sothat it benefits our patients, their families and society.”

The MayoClinic’s Jennifer McCormick echoed those concerns, worrying that theoncology community is collectively “slipping into thisframework of over adoption,” at least as far as whole genome andwhole exome sequencing are concerned.

Several factors contribute tothis over adoption. For one thing, compared to just a few years ago, DNAsequencing is now, to put it bluntly, dirt cheap. As the price of sequencinghas come down, the tendency to sequence more genes has crept up.

As a result, the use ofsequencing to guide treatment decisions is moving from single genes to genepanels, and to whole exome and whole genome sequencing.

But with all that sequence datacomes extra information – and determining whether that information is worth theextra price, not just for the sequencing itself, but for the time, money andenergy that goes into conveying that information.

For now, Memorial SloanKettering Cancer Center’s Mark Robson told the audience, there is no agreementon whether clinicians have a duty to seek incidental information, or convey itto their patients.

If they do, the process is adrain on the resources of the oncologist, who could suddenly know something abouttheir cancer patient’s risk for heart disease or dementia. But it can also be aburden for the patients, who might get their genomes sequenced to determinetheir eligibility for clinical trials only to find themselves hustled off to agenetic counselor to ponder completely unrelated matters unearthed by thesequencing.

Bradbury noted that a testitself has no inherent value – it has value only if its results change apatient’s treatment. For that to occur, a mutation hasto be found that is reasonably clinically actionable – that is, a drug has toexist that can be accessed. That, in turn, can depend on the individualpatient. A clinical trial thatis being conducted at a medical center several states away, for example, mightnot make a practical difference for a patient even if it does target his or hermutation.

On the other hand, some resultscan have value because they uncover genetic predispositions, which the patientsmay want to share with their families.

Other mutations might not beactionable in the present, but might become so as new risk genes arediscovered, and new drugs developed – or more sadly, ifpatients relapse on their first-line treatment.

Thenotion of future value casts light on another conundrum of tumor genomeprofiling – namely, that the lines between research and clinical sequencing canbe fluid.

Currently, McCormick said, somepatients are sequenced clinically and others as research, leaving the procedure“sitting in a somewhat uncomfortable space … it’s tangled with much discoveryand generation of new knowledge.”

The question of whena test can be said to have clinical utility, she argued, needs an oversightframework “not to inhibit or stymie innovation, but to make sure we arecollecting evidence that can move us forward … without constantly re-inventingthe wheel.”

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