Challenges with intratumor heterogeneity in renal cancer

Clear cell renal cell carcinoma (CCRCC) is the most common type of renal cancer, and it is often resistant to chemotherapy and radiation. Promising new targeted therapies have yielded only disappointing results, due in part to intratumor heterogeneity (ITH), a common finding in malignant neoplasms.

Jose I. López, MD, from the Biocruces Research Institute at the University of the Basque Country in Barakaldo, Spain, along with Javier C Angula, MD, PhD, of the Universidad Europea de Madrid, provided an overview of the complexity of ITH in CCRCC with a focus on the clinical implications, including current practices and challenges.

In the review, published in Current Urology Reports, investigators from Spain explained that CCRCC is a model example of a heterogeneous neoplasm.

“Next-generation sequencing has demonstrated that intratumor heterogeneity encompasses genetic, epigenetic, and microenvironmental variability,” the authors wrote. “Currently accepted protocols of tumor sampling seem insufficient in unveiling intratumor heterogeneity with reliability and need to be updated.”

Carcinogenesis includes the development of malignant clones and sub-clones of cells that evolve over time. The relationship between tumor cells and the microenvironment plays an important role in metastasis, and has been analyzed both with computer models and in vivo.

CCRCC follows a branched pattern of evolution, whereby clones arise from a common ancestor, and multiple clones can evolve together at once, leading to tumors with various sub-regions within regions, all competing for resources.

Pathologists have the difficult task of unveiling ITH. Unfortunately, while many CCRCC appear homogeneous to the naked eye, they are actually heterogeneous when viewed under a microscope.

Protocols of tumor sampling currently in use around the world were designed before targeted therapy, when ITH was not an important issue. Although oncologists have urgently requested updates, the authors feel that tumor sampling is done in a quasi-blind fashion and encourage multidisciplinary cooperation to overcome current deficiencies to improve outcomes for CCRCC patients.

“ITH severely affects the identification of effective tumor markers in CCRCC and tumor adaptation to system therapies,” they concluded. “For these reasons, pathologists, radiologists, surgeons, and clinicians must acknowledge that present practice is not appropriately solving the problem. Designing new strategies to accomplish this is likely the next frontier in oncology.”

To read more about this study, click here.