Tumor heterogeneity in the clinic: is it a real problem?

Abstract

Tumor heterogeneity is one of the major problems limiting the efficacy of targeted therapies and compromising treatment outcomes. A better understanding of tumor biology has advanced our knowledge of the molecular landscape of cancer to an unprecedented level. However, most patients with advanced cancers treated with appropriately selected targeted therapies become resistant to the therapy, ultimately developing disease progression and succumbing to metastatic disease. Multiple factors account for therapeutic failures, which include cancer cells accumulating new molecular aberrations as a consequence of tumor progression and selection pressure of cancer therapies. Therefore, single agent targeted therapies, often administered in advanced stages, are unlikely to have a sufficiently lethal effect in most cancers. Finally, the molecular profile of cancer can change over time, which we are not able to monitor with existing strategies using tumor tissue biopsies as the gold standard for molecular diagnostics. Novel technologies focusing on testing low-risk, easily obtainable material, such as molecular cell-free DNA from plasma, can fill that gap and allow personalized therapy to be delivered in real time.

Keywords: molecular aberrations; targeted therapies; tumor heterogeneity.

Figure 1.

A 59-year-old patient with heavily pretreated advanced ovarian cancer experiencing a mixed response to treatment with an mTORC1 inhibitor reflecting heterogeneous PIK3CA mutation status.

Figure 2.

Concept of tumor-derived cell-free DNA released to the circulation.