1. Xu, Jianfeng MD, DRPH
  2. Brendler, Charles B. MD
  3. Conran, Carly BS

Article Content

Genomic-based personalized cancer care strategies are being developed to better assess one's inherited risk for various types of cancer, a development that could lead to more effective ways to screen for, prevent, and treat the disease, all critical to reducing cancer mortality.

Genomics. Genomics... - Click to enlarge in new windowGenomics. Genomics

Currently, inherited cancer risk assessment is based primarily on family history. For a small subset of patients with an exceptionally strong family history of a cancer, or cancers, genetic testing of inherited (germline) impactful alterations in high-penetrance genes (HPGs) such as BRCA1/2 may be performed to further assess inherited risk. However, this current standard of care is insufficient because most individuals are either unaware or possess an incomplete understanding of their family history.


Indeed, about 50 percent of individuals who harbor mutations in HPGs do not have a known family history of the associated disease, and, similarly, many individuals without a known family history or HPG mutations may still have an increased inherited cancer risk.


Genetic Risk Score

The NorthShore University HealthSystem (NorthShore) Genetic Risk Score (GRS) is a novel tool for measuring inherited risk beyond HPGs and can identify additional subjects in the general population who have an elevated risk of developing specific types of cancer. The GRS is based on cancer risk-associated single nucleotide polymorphisms (SNPs) that have been discovered from genome-wide association studies. For example, more than 100 risk-associated SNPs have been associated with prostate cancer risk. Unlike HPGs, the individual effect of each of these SNPs on cancer risk is modest, but they have a strong cumulative effect that is expressed numerically as a single GRS value.


The GRS is objective and easy to interpret; a GRS equal to 1.0 represents population average risk for a given disease, and a GRS higher or lower than 1.0 indicates elevated or decreased inherited risk compared with general population risk, respectively. For example, a GRS of 1.4 for a specific type of cancer indicates the individual has 1.4-fold increased risk for developing that cancer compared to the average individual in the general population.


The clinical validity of the GRS for identifying subjects at elevated disease risk has been well established in multiple cancers. For example, we have been able to validate our GRS using available data from the Prostate Cancer Prevention Trial (PCPT), a large randomized clinical trial of 4,528 men in the placebo arm who did not have a diagnosis of prostate cancer. We recently demonstrated that adding the GRS gathered from the PCPT to family history information identified twice as many high-risk men (36% in the cohort) for prostate cancer than family history alone (17% in the cohort). Approximately 31 percent of high-risk men defined by high GRS and a positive FH of prostate cancer were diagnosed with prostate cancer during the 7 years of trial follow-up, whereas only 29 percent of men with a positive family history alone were diagnosed with prostate cancer during the trial.


Based on these findings, along with evidence obtained from applying the GRS to other cancers including breast cancer, researchers in the Program for Personalized Cancer Care at NorthShore have concluded that comprehensive inherited cancer risk assessment should ideally include all three components: family history, HPGs, and GRS.


To facilitate the clinical implementation of this risk assessment model, we have developed a next-generation sequencing panel that includes both cancer-associated HPGs and SNPs. This panel, called the NorthShore Inherited Cancer Panel (ICP), eliminates the need to perform two separate assays for HPGs and GRS. In this way, it is both simple and cost-effective. A potential clinical utility of the ICP may include inherited risk assessment among asymptomatic subjects for developing targeted cancer prevention and screening strategies. The ICP may also be used among known cancer patients for predicting prognosis and personalizing treatment strategies.


Testing With Clinical Trials

To evaluate the clinical utility of our inherited cancer risk assessment strategy, we have recently initiated two clinical trials at NorthShore. The first trial is a study of our GRS for breast, prostate, and colorectal cancers. We are currently recruiting 250 men and 250 women who have no personal history of breast, prostate, or colorectal cancer. All study participants will receive a GRS for breast and colorectal or prostate and colorectal cancers through their primary care physicians.


The goals of this trial are: 1) to evaluate the clinical utility of the genetic risk score for targeted risk assessment and intervention in colorectal and breast or prostate cancer; 2) to evaluate the experience of physicians in ordering and interpreting the GRS; and 3) to evaluate the interest of patients in the GRS and the impact of GRS results upon cancer screening behavior.


Our second trial will incorporate 600 patients, including 100 newly diagnosed patients with six major types of cancer: breast, prostate, colorectal, thyroid, pancreatic, or lung cancer. This study will utilize the ICP to generate data on HPGs as well as our GRS. The specific aims of this study are: 1) to determine the frequencies of mutations in HPGs among newly diagnosed patients with these six cancers; 2) to assess whether knowing that a patient has (or does not have) a mutation affects clinical outcomes or care; and 3) to gauge whether family members of patients who have mutations in HPGs will be motivated to undergo genetic testing.


Results from these trials will provide critical information that will hopefully result in a paradigm shift in current cancer care. By identifying high-risk individuals at the time of diagnosis, or even before, physicians will be able to more appropriately screen and treat patients. This type of testing (of hundreds of HPGs and SNPs) can be performed on every man and woman, regardless of disease status, at a cost of only several hundred dollars.


Furthermore, since the ICP is based upon inherited (germline) DNA, it needs to be performed only once in an individual's lifetime. At NorthShore, we have already begun to incorporate this information into clinical care at the primary care level, with a goal to seamlessly provide personalized, genomic-based, cancer care to all patients from screening and prevention to diagnosis and treatment.


JIANFENG XU, MD, DRPH, is Vice President of Translational Research & Director, Program for Personalized Cancer Care, NorthShore University HealthSystem. CHARLES B. BRENDLER, MD, is Vice Chairman of Surgery & Executive Research Director, Program for Personalized Cancer Care, NorthShore University HealthSystem. CARLY CONRAN, BS, is Research Coordinator, Program for Personalized Cancer Care, NorthShore University HealthSystem.

Jianfeng Xu, MD, DrP... - Click to enlarge in new windowJianfeng Xu, MD, DrPH. Jianfeng Xu, MD, DrPH
Charles B. Brendler,... - Click to enlarge in new windowCharles B. Brendler, MD. Charles B. Brendler, MD
Carly Conran, BS. Ca... - Click to enlarge in new windowCarly Conran, BS. Carly Conran, BS