What we did here is to address the question of the choice between hormone therapy or chemotherapy in patients with endocrine sensitive, HER2 negative metastatic breast cancer patients. We know that these patients can be treated with hormone therapy, which is the preferred treatment option because of its lower toxicity, or chemotherapy which is usually chosen by clinicians in cases of unfavourable prognostic profile. Then the key issue with that choice is that it is poorly reproducible from one clinician to another or one country to another so there is a huge discrepancy between the treatment options that are proposed to the same patient. The idea is to use the circulating tumour cell count test as an objective and reproducible biomarker to guide that choice.

So what we did here, it’s a phase III trial, so we had two arms, randomised arms. In the first arm patients were treated according to clinician choice and the circulating tumour cell count was obtained but not disclosed to the clinician. In the other arm the treatment that was proposed by the clinician was simply dismissed and patients were treated according to the CTC count. So low CTC means a good prognosis so means treatment by hormone therapy; high CTC count, more than 5, means a worse prognosis and these patients had to be treated with front line chemotherapy. In both arms patients treated with chemotherapy were allowed to have maintenance hormone therapy after the first chemotherapy cycle.
First we compared the two arms in the overall study population and what we found, this was a non-inferiority trial because the idea is to compare a single biomarker versus a very multiparametric clinical estimate, so we aimed at demonstrating non-interiority of the CTC test. We showed that basically the results we can get in terms of progression free survival and overall survival show that the CTC test is non-inferior and is, therefore, reliable as a tool to choose treatment between hormone therapy or chemotherapy in this patient population.

Can you tell us more about the results in terms of subgroups?

After analysing the study results in the whole study population we then compared the results in the two arms by subgroups. First we found that patients that have a low CTC count have an excellent progression free survival in both arms when treated with hormone therapy. This hormone therapy did not include CDK4/6 inhibitors but the PFS we observed was about 18 months which is really good. So it means that that test is able to tell really which patients may achieve a very long PFS and excellent survival without using CDK4/6 inhibitors in first line. Then also we had patients with a more unfavourable profile, so with a lot of concerning characteristics such as a high CTC count. What we are showing, to our great surprise, is that in these patients when they were randomised between hormone therapy and chemotherapy we observed not only a better progression free survival with front line chemo but also a better overall survival. Obtaining a difference in overall survival is something that is difficult in first line trials but this really shows you that patients with a high CTC count, for these patients clinicians should consider administering front line chemotherapy.

What are the implications of the study?

Currently CDK4/6 inhibitors are becoming mainstream in combination with endocrine therapy and in our study patients did not receive these CDK4/6 inhibitors as first line therapy but most of them were treated with these inhibitors in the subsequent line of therapy. So these patients were not under-treated according to the current guidelines, yet if we are to consider that CDK4/6 inhibitors have to be put in first line then the two main consequences for trials would be, first, patients with a low CTC count and, for example, limited financial resources or in countries where the financial burden of CDK4/6 inhibitors is an issue, then this test might be used to pick a population that is about half of the total population that have excellent PFS in first line without CDK4/6 inhibitors. Then, on the other side, we do have half of the population with a worse prognosis and in the future we’ll have to try to increase the results and to develop new drugs that we have to increase the outcome of these high risk patients. But what our study showed is that to define in a reproducible way the high risk patients, rather than to define presence of liver metastases or such clinical variables, we should use circulating tumour cell count to define patients with a high risk. These patients may deserve to be included in trials that will challenge the current standards.