The Genetic Giant in the Room

Maurie Markman, MD

In the era of molecular signature-based precision cancer medicine, there may be a truly profound role to be played by the detailed knowledge of the normal genetic polymorphisms of an individual patient with cancer. How much more evidence will be required before this still largely unrecognized giant in the room becomes a fully accepted standard or routine component within the general framework of the revolutionary changes taking place these days?

Perhaps the most interesting aspect of normal genetic polymorphisms is the unique role they may play in cancer management. When a tumor is analyzed at the molecular level, the goal is to search for the presence of somatic mutations or other abnormalities that might be targeted with a specific antineoplastic agent based on the presence of that target, such as a small-molecule inhibitor of EGFR with a documented EGFR mutation in non—small cell lung cancer or a BRAF inhibitor with a demonstrated BRAF mutation in metastatic melanoma. Conversely, a finding may suggest a particular drug should not be delivered based on the finding of that target, as is the case with using an anti-EGFR antibody in the presence of a KRAS mutation in colon cancer.

In contrast, the focus of an examination of normal genetic polymorphisms has not been on defining the efficacy of a particular antineoplastic against a target but rather on two alternative highly clinically relevant issues. The first is the statistical probability or “risk” that an individual will experience recognized toxicity, either short term or long term, following the delivery of a particular therapeutic strategy. The second is the potential that specific polymorphisms may be associated with an overall superior or inferior outcome, independent of other recognized factors such as tumor stage or grade.

The hypothesis here is that a patient’s unique genetic background may substantially influence the biological activity of a variety of normal physiologic pathways. The result may be, for example, an increase or a decrease in the risk of a particular side effect due to an unfavorable or favorable effect on the metabolism, detoxification, or elimination of established antineoplastic agents. In addition, one can hypothesize an influence that enhances or interferes with the delivery of specific drugs to the site of tumor involvement.

Research Examples Mount

Once validated as being clinically relevant, knowledge of this information before a patient is scheduled to receive therapy or during the course of treatment may provide the oncology team with data that would permit the selection of a different treatment or result in the modification or discontinuation of a particular approach earlier than planned. Alternatively, in certain clinical settings one might consider careful surveillance to reduce the risk of observing a serious toxic event (eg, neuropathy) or preventive strategies might be undertaken in patients with recognized genetically defined high risks.Consider, for example, recent reports published in high-impact journals that demonstrate the potential for how examination of normal polymorphisms may favorably influence cancer management. Several studies have examined the effects of genetic polymorphisms on neurological function in individuals with malignant disease. In one analysis of patients with gliomas, specific genes relevant to inflammation, DNA repair, and metabolism were found to have a major influence on neurocognitive function,¹ while a second study of children undergoing treatment for acute lymphoblastic leukemia noted the impact of genes known to be involved in both inflammation and oxidative stress.² Of course, the critical next step will be to inquire whether there are strategies that might be employed in patients at greatest risk for impairment that could favorably impact the outcome.

Two recently reported prospective analyses also conducted in children with acute lymphoblastic leukemia found strong associations between specific polymorphisms and the risk of toxicity from two commonly employed antineoplastic agents. Intolerance to mercaptopurine was found to be strongly associated with a particular germline variant of NUDT15,³ while specific normal polymorphisms within the asparaginase pathway were found to correlate with toxicities observed with this agent.⁴ In the realm of adult cancers, investigators examining 514 patients who received fluoropyrimidine chemotherapy found that a specific genetic variant of dihydropyrimidine dehydrogenase was strongly associated with the risk of experiencing severe toxicity when patients possessing these variants were administered this class of antineoplastics.⁵ Finally, two provocative reports suggested normal genetic polymorphisms may substantially impact the outcome of patients with osteosarcoma⁶ and metastatic colon cancer.⁷

The intent of listing these studies is not to suggest they are unique in their findings, but rather to emphasize that the oncology community needs to move beyond the mere reporting of such results in the peer-reviewed literature and begin to seriously consider including such evaluations or testing in relevant populations as a component of routine oncologic care.

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.

References

1. Liu Y, Zhou R, Sulman EP, et al. Genetic modulation of neurocognitive function in glioma patients [published online April 22, 2015]. Clin Cancer Res. 2015;21(14):3340-3346.
2. Cole PD, Finkelstein Y, Stevenson KE, et al. Polymorphisms in genes related to oxidative stress are associated with inferior cognitive function after therapy for childhood acute lymphoblastic leukemia [published online May 18, 2015]. J Clin Oncol. 2015;33(19):2205-2211.
3. Yang JJ, Landier W, Yang W, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia [published online January 26, 2015]. J Clin Oncol. 2015;33(11):1235-1242.
4. Ben Tanfous M, Sharif-Askari B, Ceppi F, et al. Polymorphisms of asparaginase pathway and asparaginase-related complications in children with acute lymphoblastic leukemia [published online June 6, 2014]. Clin Cancer Res. 2014;21(2):329-334.
5. Amstutz U, Offer SM, Sistonen J, et al. Polymorphisms in MIR27A associated with early-onset toxicity in fluoropyrimidine-based chemotherapy [published online February 5, 2015]. Clin Cancer Res. 2015;21(9):2038-2044.
6. Hagleitner MM, Coenen MJ, Gelderblom H, et al. A first step toward personalized medicine in osteosarcoma: pharmacogenetics as predictive marker of outcome after chemotherapy-based treatment [published online March 31, 2015]. Clin Cancer Res. 2015;21(15):3436-3441.
7. Smith CG, Fisher D, Harris R, et al. Analysis of 7,635 patients with colorectal cancer using independent training and validation cohorts show that rs9929218 in CDH1 is a prognostic marker of survival [published online April 14, 2015]. Clin Cancer Res. 2015;21(15):3453-3461.