Molecular Insights: Tumor Analysis Providing Answers to Clinically Relevant Biological Questions

Maurie Markman, MD

Editor-in-Chief of OncologyLive

Senior vice president for Clinical Affairs and National Director for Medical Oncology Cancer Treatment Centers of America, Eastern Regional Medical Center

It is increasingly recognized that the era of treating individual advanced or metastatic cancers based essentially on the anatomic site of origin or histologic subtype as determined by light microscopic evaluation is rapidly coming to a close.

Today, no well-trained oncologist would consider it appropriate to treat all patients with newly diagnosed or recurrent metastatic adenocarcinoma of the breast, lung, or colon with an identical antineoplastic drug regimen based only on knowledge of the primary site and the tumor cell type. Instead, the physician would require additional data related to the tumor’s molecular profile that would help define the optimal systemic regimen. Examples include the use of anti-HER2 therapy in breast cancer with HER2 overexpression, administration of a tyrosine kinase EGFR inhibitor in lung cancer with specific documented EGFR mutations, and nonuse of EGFR-antibody therapy in the presence of a KRAS mutation in metastatic colon cancer.

In addition to defining treatment for a population of patients based on phase III trial data (if it exists), molecular studies are increasingly utilized to develop an individual therapeutic approach based on abnormalities present in the setting of uncommon/rare cancers or in specific clinical situations where it is virtually certain formal regulatory-based trials will never be undertaken.

These so-called “N-of-1” experiences are highly likely to become a dominant component of the clinical research paradigm in the oncology arena in the future.

Considering the speed at which these striking advances are being reported in the medical literature and the enthusiasm for the utility of individual patient molecular testing in directly impacting clinical cancer management, it is perhaps understandable that the oncology community may be slow to appreciate the relevance of molecular observations of a more basic nature that may critically confirm or refute fundamental concepts upon which current treatment decisions are based.

Profiling at a Deeper Level

Consider, for example, a recent report in Nature about how laboratory investigators employing a highly novel technique were able to examine in exquisite detail the molecular profile of individual cells within breast tumors from two patients, one with estrogen receptor—positive disease and the other with triple-negative breast cancer.¹ Through this analysis, Wang et al identified three classes of mutations—clonal, subclonal, and de novo—with many of the mutations found in the tumor mass occurring at low frequencies (>10%).

As anticipated, essentially all of the cells contained a number of identical molecular abnormalities indicating their clonal origin. However, what was perhaps most striking was the observation that within a single tumor mass a substantial percentage of the individual cells possessed “subclonal mutations” present in at least two, but not the majority of cells examined, or a specific mutation that was documented in only a single cell among the large number of cells evaluated.

“Our data clearly show that no two single tumor cells are genetically identical, calling into question the strict definition of a clone,” the investigators wrote.

These data are highly relevant to the long-standing, continuous, and often rather contentious debate within the oncology community related to the critical issue of whether chemotherapy-resistant clones found to be present in a cancer are: (a) induced by the administration of cytotoxic chemotherapy; or (b) likely present at the time of initiation of such treatment and are able to survive, grow, and spread because the sensitive cell population has been suppressed or eliminated.

The experience reported in this research paper provides strong support for the latter interpretation with evidence that multiple mutations, including some or perhaps many that may enhance chemotherapy resistance mechanisms, exist within a cancer prior to the administration of cytotoxic agents.

There are even broader implications for these findings—which, of course, will have to be confirmed by other independent investigators. The presence of such a high rate of unique subclones and individual mutations present within the individual cells of a given tumor mass, and the potential presence of large numbers of those cells with preexisting mechanisms to overcome the cytotoxic effects of chemotherapy, provide a powerful explanation for the inability of even the most effective cytotoxic drug regimens against solid tumors to possess genuine curative potential. Even the presence of a small population of cells with mutations that prevent cell death may be capable of surviving and subsequently thriving when the chemosensitive population has been eliminated or reduced in volume.

Finally, these data suggest that perhaps the most effective strategy to optimize the chances for long-term “control” (rather than “cure”) of the growth and spread of a given patient’s cancer will require a detailed understanding of the dominant resistance mechanism(s) operative at any given time in the natural history of the individual cancer. It is reasonable to speculate that the ability to frequently “molecularly” monitor the cancer (eg, liquid tumor biopsy) will ultimately be shown to enhance the opportunity to favorably impact clinical outcomes.

Maurie Markman, MD, editor-in-chief, is president of Medicine & Science at Cancer Treatment Centers of America, and clinical professor of Medicine, Drexel University College of Medicine. maurie.markman@ctca-hope.com.

Reference

1. Wang Y, Waters J, Leung ML, et al. Clonal evolution in breast cancer revealed by single nucleus genome sequencing [published online July 30, 2014]. Nature. 2014;512(7513):155-160.