Reacción a "A therapeutic target has been identified that brings us closer to the goal of preventing brain metastases and avoiding relapses"

Does the article accurately reflect the study?

“It’s fairly accurate, although there are a couple of sentences that strike me as overstated, particularly with regard to the therapeutic implications.”

Is it a high-quality study? Do the data support the conclusions?

“It’s an excellent piece of work that addresses a biological question that is very difficult to tackle. The authors draw on a wide variety of techniques and samples, both in vitro and in vivo, from both animal models and human samples. The level of coordination achieved by the PI [principal investigator] across several clinical centres to obtain these samples is remarkable, particularly the autopsy cohort, which is especially valuable for this study. The data provide strong support for the existence of a ‘pause’ that helps metastatic cells survive in the brain. I find the findings robust regarding the mechanism controlling this pause in metastatic cells and the potential pharmacological and genetic modulators. I find the parallel drawn with the mechanism of tumour reactivation following surgical removal somewhat weaker; I believe that aspect requires further studies to be confirmed.”

How does this fit in with existing evidence?

“Both Dr Valiente’s group and other groups had already described the initial mechanisms of extravasation and the onset of metastasis, although this study now goes a step further and describes an intermediate step which, to my knowledge, had not previously been described.”

Confounding factors and limitations

“The authors honestly describe some of their scientific and technical limitations in the discussion. The main one would be the translational application, as there are no biomarkers that allow the detection of patients with micrometastases. Apart from those they describe, it strikes me as a limitation that the study begins with samples from patients with the same tumour type, and that the tissues from the British cohort are all from lung cancer. Given that these samples form the basis of the work, this poses a risk to its extrapolation to other types of metastasis, although it is true that they also carry out several experiments on samples from the RENACE cohort, which do indeed comprise various tumour types. Another significant limitation is that the two main molecular targets described in detail, MYC and MXD4, have no known pharmacological inhibitors; the authors therefore suggest downstream mechanisms that could be modulated by these proteins. They present results consistent with this line of thinking, but this is perhaps the weakest aspect from a mechanistic perspective.”

Implications for real-world practice

“I agree with Dr Valiente that this study lays the foundations for avenues of research aimed at halting micrometastases and, therefore, preventing them from developing into aggressive tumours in the brain. As it is inconceivable to treat all cancer patients with drugs preventively, we would need, in parallel, to characterise biomarkers (in blood or radiological) that can distinguish the early onset of micrometastases. Furthermore, further research is needed to determine whether this mechanism applies to tumour growth following surgery. It is true that such an application is more feasible in the short to medium term, but in my opinion, it requires more thorough validation.

Another implication that the authors do not explore is that this mechanism might also be relevant to understanding the resistance of these micrometastases to the stress induced by radiotherapy, which patients receive following surgery.

The study opens up a promising avenue, but it does not yet enable the prevention of metastases in patients. To achieve this, we would first need to identify those with micrometastases and validate the efficacy and safety of the treatments. It would also be interesting to investigate whether this pause influences their response to radiotherapy.”