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This article by Himisha Beltran, M.D., appeared in Science - Translational Medicine. Read the original, and the Nature study it references, here.

Himisha Beltran, M.D. Understanding whether one or more tumor clones contribute to metastasis has important clinical implications. For instance, if all metastases share driver alterations that can be traced back to a common ancestor, then targeting those alterations would be expected to be an effective therapeutic approach. On the other hand, if multiple independent tumor clones are capable of metastasis or drive heterogeneous disease progression—for example, by homing to specific metastatic sites—then this would lead to an overall higher genomic diversity among metastatic sites and would likely render the cancer more difficult to treat.

Now, Kumar et al. attempt to get at this question by studying the molecular heterogeneity of 173 prostate cancer lesions obtained from 63 men at the time of autopsy. Through integrative genomic analysis, the investigators report that in all cases, metastatic lesions share common truncal alterations. Early genomic alterations in prostate cancer pathogenesis (such as theTMPRSS2-ERG rearrangement) showed 100% concordance across metastases. Importantly, even later events that typically evolve during the course of treatment and drive resistance, including AR gene copy number gain or mutations, were also concordant among sites in most patients. In this study, the majority of spatially distinct castration-resistant tumors in individual patients showed reactivated androgen receptor signaling through congruent mechanisms. These findings suggest either that resistance occurred early or, more likely, that the vulnerabilities of the tumor were maintained among sites due to shared molecular features, leading to the acquisition of shared and possibly even simultaneously acquired resistance mechanisms. Although “private” subclonal alterations were also present within sites, known recurrent driver mutations were shared. The authors therefore conclude that the molecular composition of a single metastatic site provides a reasonable assessment of the major oncogenic drivers of the other dispersed metastases in an individual prostate cancer patient.

In an era of precision oncology and with an increased number of single-site metastatic biopsies now being performed for clinical or research purposes, these findings may aid in the clinical interpretation of emerging molecular markers for advanced prostate cancer and highlight the utility of autopsy studies in understanding intrapatient heterogeneity. Elucidating shared versus private events and the clonality of lesions, relevant not just to prostate cancer but to all malignancies, will influence further study of mechanisms underlying the observed clinical heterogeneity of treatment responses among patients and potentially among metastatic sites (observed on imaging) and the interpretation of genomic lesions detected in circulating tumor DNA. Such studies will advance our understanding of the evolution of tumors and the drug-resistant state.