ASCO侯任主席：乳腺癌循环肿瘤细胞检测进展

检验之星

Daniel F. Hayes, MD, FASCOElected ASCO President for 2016-2017. Professor of Internal Medicine, the Stuart B. Padnos Professor in Breast Cancer, and the Clinical Director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center. He is a breast cancer specialist.

我是 Daniel F. Hayes，是密歇根大学癌症综合研究中心的临床肿瘤学医师，也是美国临床肿瘤学会侯任主席。

过去 30 年来我一直致力于血清肿瘤标志物的研究，最初我着重研究蛋白质，过去10年开始研究循环肿瘤细胞，令我们大为振奋的是，我们能够捕获循环肿瘤细胞。过去3至5年，我们可利用循环肿瘤细胞的表型特征来发现它们的动态变化，正如我们在组织中所做的那样。因此我们可以检测雌激素受体，可以检测HER2，还可以检测许多不同的蛋白质，我的实验室一直致力于这方面的工作。其次是捕获这些细胞，从这些细胞中提取 DNA，这样我们便可以判断基因突变，进而为癌患者提供个体化癌症护理。

我们对西南肿瘤小组过去 15 年所进行的 CTC 研究感到很振奋，我的同事Massimo Cristofanilli 在新英格兰医学期刊上首次介绍了 CTC，其中指出，转移性乳腺癌患者的循环肿瘤细胞为其预后因素。

我在密歇根大学的同事Jeffrey Smerage 博士进行了一项前瞻性试验，对转移性乳腺癌且接受新的一线化疗方案的患者进行了分析。若患者无循环肿瘤细胞，则接受其应进行的任何化疗。若循环肿瘤细胞增强，则接受一个周期化疗，如果再次检测循环肿瘤细胞消失，则继续接受这种化疗；但若患者循环肿瘤细胞没有消失，则被随机分配立即转换治疗方案，或者继续接受这种化疗，直至出现证明此化疗有效的征兆。令人遗憾的是，改变患者的治疗方案并未起效。更可悲的是，那些患者的预后变得很差，也就是说如果经过一个周期的化疗后没有清除循环肿瘤细胞，那么总生存期约为一年，75% 的患者在 18 个月内死亡。令我们失望的是，改变治疗方案没有起到任何帮助。但我们从这项研究中学到了不少东西，现在我们正在尝试的是，应如何治疗经过一个周期的化疗后仍未清除其循环肿瘤细胞的患者。

我们一直在做的第二件事是，鉴定雌激素受体阳性转移性乳腺癌患者是否能够检测出其中不会从抗雌激素受体治疗中获益的 15% 或 20%，这些患者应继续接受化疗，而非用不可能有效的治疗方法。我们鉴定了四种标志物，其中有雌激素受体表达、与对内分泌治疗敏感性相关的Bcl-2，以及HER2 和Ki67，后者与抗药性相关。我们制定了循环肿瘤细胞内分泌治疗指数，由我们实验室中从事临床癌症研究的同事Costanza Paoletti 于今年发布。现在我们已将此指数应用于目前进行的一个前瞻性试验——COMETI 试验，目前为止该试验已招募了 100 多例患者。此次试验主要针对循环肿瘤细胞内分泌治疗指数较高的患者，尽管他们肿瘤中的雌激素受体阳性无法从内分泌治疗中获益。

最后，我们正在尝试将循环肿瘤细胞从乳腺癌患者的血液中分离出来，分离各个细胞，提取 DNA，查看那些细胞的突变状态，这项工作尚处于早期。我们将此与循环血浆游离DNA 进行比较，后者是目前全球兴起的一个非常激动人心的研究领域，我们为此感到很激动。我们认为在接下来的2到5年，将循环肿瘤细胞的表型、循环肿瘤细胞的基因型和循环血浆游离肿瘤 DNA 的基因型结合起来，帮助我们更好地为患有转移性乳腺癌和其他癌症的患者提供个体化治疗。

I’m Daniel F. Hayes. I’m a medical oncologist from the University of Michigan Comprehensive Cancer Center in Ann Arbor, Michigan and I’m the president elect of the American Society of Clinical Oncology.

The first question I was asked is what will I be speaking about tomorrow. And I have been very much involved in the issueof circulating tumor markers, these are biomarkers we can find in blood, for now over 30 years, first looking at proteins and now more recently over the last decade studying circulating tumor cells. We’ve been very excited about theability to capture circulating tumor cells, and then more recently in the last three to five years to phenotype those circulating tumor cells to discover what they are making, just like we do in tissue. So we can do estrogen receptor, we can do HER2, we can also do many, many different proteins, and we’ve been working on that in my laboratory. And then the second is to actually capture those cells and harvest the DNA from the cells, so that we can see what sort of genetic mutations that we can determine, and lead that into further personalizing cancer care for patients with metastatic epithelial cancers.

We’ve been very excited about CTCs overagain the last 15 years within the Southwest Oncology Group based on ourinitial presentation in the New England Journal of Medicine by my colleague Massimo Cristofanilli, when we showed that CTCs in metastatic breast cancer were clearly prognostic.

Doctor Jeffrey Smerage, my colleague at the University of Michigan, ran a prospective trial in which patients who had metastatic breast cancer and were starting a new first line chemotherapy all were profiled. If they didn’t have cells, they got what ever chemotherapy their doctor thought they should get. But if they had elevated circulating tumorcells, then they receive one cycle of chemotherapy. If their CTCs disappeared,then they stayed on that. But if their CTCs didn’t disappear, they were randomly assigned to either switching therapy right away with the feeling that they must have been started on the wrong chemotherapy or staying on that chemotherapy until classic evidence of progression. Sadly, changing therapy in that group of patients didn’t make a difference. And even more sadly, those patients had aterrible prognosis, meaning over all survival if you didn’t clear yourselves after one cycle of chemotherapy was roughly 1 year. And 75% of those patients were dead within 18 months. So we were disappointed that changing therapy didn’t help. But we’ve learned a lot from that study. And what we are now trying to determine is what we should do with patients who have not cleared their CTCs by one cycle of chemotherapy, because those patients appeared to have cancer that’s fundamentally resistant to chemotherapy in general.

The second thing we’ve been doing is trying to identify patients who have estrogen receptor positive metastatic breastcancer, and see if we can detect the 15% or 20% of patients who will not benefit from anti-estrogen receptor therapy and who should go on to getting chemotherapy, instead of being treated with therapy unlikely to work. We worked very hard on identifying four markers that we think will be helpful, obviously the expression of estrogen receptor, also Bcl-2 which is associated with sensitivity to endocrine therapy, and HER2 and Ki67 which should be associated with resistance. We’ve developed a circulating tumor cell endocrine therapy index,this was published by my colleague in my laboratory, Costanza Paoletti in Clinical Cancer Research this year. And now we’ve taken this into a prospective trial, the so-called COMETI trial, which is ongoing. We’ve recruited well over 100 patients now. And we are specifically asking to patients who have a high CTC endocrine therapy index even though their estrogen receptor positive intheir tumor not benefit from endocrine therapy.

Finally, we’ve begun to prove now that wecan isolate circulating tumor cells from the blood of patients with breastcancer, isolate individual cells, harvest the DNA, and look at the mutationalstatus of those cells. This work is very early. We are comparing this to circulating cell-free plasma DNA which is a very exciting area of research of course going on right now in the world. And we are very excited. We think in the next two to three years, maybe five years, combining the phenotype of CTCs, the genotype of CTCs, and the genotype of circulating cell-free plasma tumor DNA will help us better personalize therapy for patients with metastatic breast cancer and other cancers as well.

来源：肿瘤评论