Tumor heterogeneity: does it matter?

ABSTRACT

Introduction: It has long been recognized that tumors are composed of a mosaic of cells and numerous methods have been developed to detect tumor heterogeneity, including in situ hybridization, multi-regional sampling, cytological assays, and whole genome and single cell sequencing. Using these methods, heterogeneity has been observed at the genetic, epigenetic, and phenotypic level in numerous cancers. With the advent of deep sequencing technology, we now appreciate a greater complexity of distinct genotypes and phenotypes that drive the biological behavior of cancer. Despite decades of progress in detecting tumor heterogeneity, the question remains: to what extent does it matter?

Areas covered: This review explores the evidence for and against the importance of tumor heterogeneity in three main areas: prognostication, development of targeted therapeutics and tumor resistance; summarizing current understanding before evaluating ongoing experimental and clinical developments.

Expert opinion: Theoretical understanding and in vitro detection of intratumour heterogeneity promises much but is yet to translate into meaningful clinical benefit. However, the recent emergence of a host of technological innovations and upcoming clinical trials may soon change the landscape of this field.

KEYWORDS:

• Cancer stem cell
• drug resistance
• liquid biopsy
• tumor evolution
• tumor heterogeneity

Article highlights

• Much progress has been made in our ability to detect tumor heterogeneity and current methods now include in situ hybridization, multi-regional sampling, cytological assays, and whole genome and single cell sequencing.

• Two major explanations have been proposed to explain the origin of tumor heterogeneity including the clonal evolution and the cancer stem cell model.

• Heterogeneity can provide a barrier to reliable prognosis due to biopsy sampling bias.

• Whether the degree of heterogeneity is a prognostic indicator remains actively debated and is likely highly tumor-type dependent.

• While intertumour heterogeneity has been an important consideration in the selection of targeted therapeutics, intratumour and metastatic heterogeneity is rarely considered.

• ‘Liquid biopsies’ based on circulating cell free DNA, circulating tumor DNA, and circulating tumor cells provide a new approach to alleviate the challenges of spatial heterogeneity.

• Underestimation of heterogeneity of tumor resistance mechanisms may explain the failure of most cancer treatments. To address this, an ‘adaptive therapy model’ to anticipate drug resistance has been employed successfully in a mouse model study.

• Several ongoing clinical trials using longitudinal tumor sampling and sequencing in space and time will be important for assessing whether treatment approaches that capture tumor heterogeneity in real-time will be beneficial for patient outcomes.

Declaration of interest

Casmir Turnquist is supported by the Foulkes Foundation Fellowship and University of Oxford Baber Scholarship. Robert A Watson is funded by the National Institute for Health Research (NIHR) Academic Clinical Fellowship (ACF). Andrew Protheroe has received honoraria from Astellas, BMS, Merck, Ipsen, Pfizer, and has received research funding from Merck. Clare Verrill is supported by the NIHR Oxford Biomedical Research Center (BRC). Shivan Sivakumar is supported by the NIHR Academic Clinical Lectureship Grant. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.