分子谱有助发现原发灶不明癌的治疗靶点

阿姆斯特丹——在欧洲多科学癌症大会上，Caris Life Sciences公司执行医学总监Zoran Gatalica博士报告称，在1,400多例原发灶不明癌(CUP)患者中，分子谱分析发现了77%病例可作为治疗靶点的基因谱改变。而且，在较高比例的病例中，分子谱分析指导临床医生使用了非CUP传统治疗的一些药物。

这项研究总共涉及50,000多例来自30个国家的患者，其中1,459 例为CUP病例，占一般人群的3%左右。这是迄今为止接受了肿瘤生物标志物特征分析的最大规模的患者组。


Zoran Gatalica博士

研究采用了多平台分析方法，包括基于Sanger测序、下一代测序和聚合酶链反应(PCR)检测的突变分析；基于荧光或显色原位杂交分析法获得基因拷贝数；基于PCR的O6-甲基鸟嘌呤- DNA甲基转移酶甲基化分析；以及基于免疫组化法的蛋白质表达分析。

Gatalica博士称，与预想的不同，CUP在女性患者中更常见(55%，或822/1,459)，年龄没有保护作用，最年轻的11岁，最年长的92岁(平均年龄61岁)。

最常见的癌症部位是肝脏(24%)，其次是其他部位(30%)和淋巴结(16%)。不出所料，腺癌是最常见的组织学类型(45.3%)，但是基于组织学亚型，在生物标志物上还是存在一些差异。例如，7%的癌症存在雄激素受体表达，而3.3%属于未分化和神经内分泌肿瘤。

Gatalica博士报告称，"top performers"包括TP53 (33%)、KRAS (17.5%)、PIK3CA (7.4%)、APC (3.6%)、BRAF (3%)和表皮生长因子受体(EGFR) (1.1%)的改变。

Gatalica博士还列举了几个典型病例。一名肝转移患者，由于分子谱分析显示DNA拓扑异构酶1表达过度和胸苷酸合成酶表达不足，于是采用了伊立替康(开普拓)/5-氟尿嘧啶治疗，治疗后肿瘤显著减灭。另一个病例是一名64岁的广泛骨病女性患者，由于表达谱分析显示她携带了EGFR突变，于是接受EGFR激酶抑制剂厄洛替尼(特罗凯)治疗，治疗后这名患者获得了近完全缓解。

作为特邀评论员，美国耶鲁癌症中心遗传学与基因组学项目负责人之一Lajos Pusztai博士称这些病例“令人鼓舞”，这些研究结果可谓是“数据宝库”。不过，仍然存在一些问题，包括异常表达谱的分布情况，作者如何定义“可作为治疗靶点”，以及是否确实遵循了治疗推荐意见。他问道：“那么你提出了基于分子学靶点的治疗推荐意见，但是临床医生是否一定会遵循这些意见呢？这是在临床实践中评估这种检测方法的一种很好的途径。到底获益率有多高？”

与会者还对检测费用提出了疑问。一名未知姓名的Caris公司发言人在人群中站起来说，全套检测的成本大约是4,900欧元(约合6,650美元)，不过目前正在想办法降低检测费用。

Gatalica博士说，在少数病例中，分子谱分析“可能确实有助于推进原发灶的诊断。” Sarah Cannon 研究所最近开展的一项研究显示，只采用92种基因反转录酶PCR检测的分子谱分析帮助临床医生预测了289例CUP患者的原发灶并且指导了病灶特异性治疗，使中位总生存期从以前的9个月延长到了12.5个月，即总生存期延长3个多月 (J. Clin. Oncol. 2013;31:217-23)。

Pusztai博士指出，虽然分子谱分析通过关注肿瘤的生物学特征而非原发灶使CUP的治疗有了“概念上的飞跃”，但“问题在于我们目前还没有足够多的好药”。

Gatalica博士声明其拥有Caris Life Sciences公司的所有权和股权，Caris Life Sciences公司资助了这项研究并且提供了分子检测服务。Pusztai博士声明无相关经济利益冲突。

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By: PATRICE WENDLING, Oncology Practice

AMSTERDAM – Molecular profiling of cancers with an unknown primary site identified a targetable alteration in 77% of more than 1,400 cases.

Moreover, in a high proportion of cases, profiling directed clinicians to drugs not traditionally considered for cancers of unknown primary site (CUP), Dr. Zoran Gatalica said at the multidisciplinary European cancer congresses.

The study involved 1,459 CUPs, or about 3% of what is expected in the general population, and more than 50,000 patients from 30 countries. This makes it the largest group of patients to date to have their tumor biomarker profiles characterized, said Dr. Gatalica, executive medical director of Caris Life Sciences, Phoenix, Ariz.

A multiplatform approach was used that included mutational analysis by Sanger sequencing, next-generation sequencing, and polymerase chain reaction (PCR) testing; gene copy number by fluorescent or chromogenic in situ hybridization; O6-methylguanine DNA methyltransferase methylation by PCR; and protein expression analysis by immunohistochemistry.

Contrary to expectations, CUP was more prevalent in women (55%, or 822/1,459), and age offered no protection, with patients as young as 11 years and as old as 92 (average, 61 years), Dr. Gatalica said.

The most common site affected by cancer was the liver (24%), followed by other (30%) and lymph nodes (16%).

Not surprisingly, adenocarcinoma was the most common histology (45.3%), but there were also several differences in biomarkers based on histologic subtype, he said. For example, 7% of carcinomas had androgen receptor expression versus 3.3% of undifferentiated and neuroendocrine tumors.

The top "performers" were alterations in TP53 (33%), KRAS (17.5%), PIK3CA (7.4%), APC (3.6%), BRAF (3%), and epidermal growth factor receptor (EGFR) (1.1%), Dr. Gatalica said.

Dr. Gatalica also presented a few illustrative cases including a patient with liver metastases who had significant tumor reduction after being put on irinotecan (Camptostar)/5-fluorouracil on the basis of molecular profiling showing DNA topoisomerase 1 overexpression and thymidylate synthase underexpression.

A second case involved a 64-year-old woman with extensive bone disease who had a near-complete response after being directed to the EGFR-kinase inhibitor erlotinib (Tarceva) because profiling showed she carried an EGFR mutation.

Invited discussant Dr. Lajos Pusztai, codirector of the Yale Cancer Center genetics and genomics program, New Haven, Conn., described the cases as "inspiring" and said the results represent "a treasure trove of data."

Several questions remain, however, including the distribution of anomalies, how the authors defined "targetable," and whether treatment recommendations were actually followed.

"So you give a molecularly targeted treatment recommendation, but how often do physicians follow that?" he asked. "That would be a good way of gauging the test in practicality. What is the benefit rate?"

Audience members also questioned the cost of the test. An unidentified Caris spokesperson rose from the overflow crowd to say the full panel costs about €4,900 Euros (about $6,650 US), but that efforts are underway to bring the price down.

Dr. Gatalica said that in rare instances, molecular profiling "may actually improve the diagnosis of the primary site."

A recent study from the Sarah Cannon Research Institute showed that molecular profiling, using only a 92-gene reverse transcriptase PCR assay, allowed clinicians to predict the site of origin and direct site-specific therapy in 289 CUP patients, resulting in a 3-month gain in overall survival from the historic median of 9 months to 12.5 months (J. Clin. Oncol. 2013;31:217-23).

While molecular profiling represents a "conceptual leap" in the approach to CUP by emphasizing the biology of the tumor and not the primary site, "the problem is we don’t have enough good drugs," Dr. Pusztai observed.

Dr. Gatalica reported ownership and stock options in Caris Life Sciences, which sponsored the study and provided the molecular panel. Dr. Pusztai reported no relevant financial conflicts of interest.