Tumor Heterogeneity and Implications for Clinical Practice

Since the late 1890s, when morphologic tumor heterogeneity was first described by pathologists, tumor heterogeneity has been recognized as an important and relevant clinical problem. From the discovery of tumor heterogeneity over 100 years ago until quite recently, we relied almost solely on the histologic review of tumor specimens by our pathology colleagues to inform us of the different subtypes present within a particular tumor type. It was Peter Nowell who, in his landmark 1976 Science paper, proposed an evolutionary perspective on cancer heterogeneity in which the stepwise acquisition of various genetic mutations, along with multiple environmental pressures, resulted in the selective advantage that enabled certain clones to survive, resulting in tumorigenic growth and progression. With the tremendous advances in molecular technologies, such as next-generation and whole-exome sequencing, it is now possible to more precisely identify the different subtypes of tumors at a molecular level, providing important prognostic as well as predictive information.

In this issue of ONCOLOGY, Drs. Allison and Sledge present a nice review of the molecular and clinical/translational studies that have focused on tumor heterogeneity. They also provide a timely perspective on the potential therapeutic implications of tumor heterogeneity. The concept of intertumor heterogeneity has been well appreciated, and this difference in tumor profiles between patients has provided the rational basis for personalized medicine in cancer therapy. However, what has not been as well understood is the relative contribution of intratumor heterogeneity. In 2012, Gerlinger and colleagues reported in the New England Journal of Medicine on the tremendous heterogeneity that exists within a given tumor. Using renal cell cancer as their model, they found that approximately 66% of the mutations present in single biopsies of patients with renal cell cancer were not uniformly detected throughout all of the sampled regions of the same patient’s tumor.[1] While further studies are needed to confirm these findings in other tumor types, it is highly likely that such a high degree of intratumor heterogeneity exists in most, if not all, other cancers.

What are the practical implications of intratumor heterogeneity as it relates to everyday clinical practice? The first thing to consider is that a single tumor biopsy should not be viewed as providing information representative of the entire landscape of molecular abnormalities present within a given tumor. A single biopsy would appear to provide only limited insight regarding the number of genetic alterations that may be present. When dealing with patients who present with metastatic disease, another important question is whether the primary or metastatic tumor should be analyzed. Until recently, the general approach has been to analyze the primary tumor so as to avoid biopsy of a metastatic site. This strategy was based on the widely held belief that high concordance exists between primary and metastatic tumors and that mutations present in advanced disease are already present in the primary tumor. Recent studies suggest that this may not be the case. There is also growing evidence that different treatments may alter the level of heterogeneity present within a given metastatic lesion, a phenomenon that would add an extra level of complexity to treatment decision making. In my own clinical practice, I believe that it is important to biopsy a new metastatic lesion at the time of initial recurrence and/or at the time of disease progression while the patient is on therapy, so as to obtain as accurate a “read” as possible on the current molecular status of the disease.

In their review, Allison and Sledge also discuss the issue of repeat tumor biopsy, and they suggest that re-testing metastatic sites is a logical approach. On a practical level, a couple of important issues need to be factored in when deciding whether to rebiopsy. First, while tumor biopsies are relatively safe, they can be associated with a certain level of morbidity, depending on the particular tumor site involved and its accessibility for biopsy, which then mandates a thoughtful discussion with the patient as to the clinical need for obtaining such a biopsy. Second, there are financial costs associated with tumor biopsies, and given the ever-changing reimbursement landscape, it is not entirely clear that repeat biopsies will be covered by third-party payers. To avoid the real challenges relating to percutaneous tumor biopsies, serious efforts have now focused on using peripheral blood as a “liquid biopsy” to determine the presence of circulating mutated tumor DNA prior to and during therapy. This approach should greatly facilitate the real-time monitoring of the molecular status of metastatic disease. One potential limitation of liquid biopsies, however, is the assumption that the heterogeneity present in metastatic lesions is accurately reflected in peripheral blood. Further studies are needed to determine whether this assumption is truly correct.

In conclusion, the issue of tumor heterogeneity is real, and it is present on several different levels. Without question, the presence of tumor heterogeneity has important clinical implications, and at this time, it represents a significant challenge to the success of cancer therapy. While advanced sequencing analyses will continue to play a key role in characterizing the level of heterogeneity within a given tumor, the presence or absence of genetic mutations should not be viewed as providing a complete picture of the tumor’s molecular status. It will be critically important to work closely with our molecular diagnostic colleagues to perform additional molecular tests-which would include epigenetic profiling, gene expression profiling, and proteomic profiling-to obtain a more comprehensive overview of the molecular landscape of an individual tumor. The hope is that these tremendous advances in molecular tumor profiling will provide a more in-depth understanding of the extent of tumor heterogeneity, which should eventually allow us to prescribe cancer therapy-whether it be cytotoxic chemotherapy, targeted therapy, biologic therapy, or immunotherapy-to our cancer patients in a truly personalized manner.

Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1.Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883-92.