ASCO published its first statement on genetic testing and its impact on oncology practice over 2 decades ago. Since then, ASCO has revised the statement three times, the most recent in 2015, in response to advances propelled by the sequencing and mapping of the human genome and the identification of the genetic basis of hereditary cancer syndromes.¹

According to the National Cancer Institute, inherited genetic mutations are a major factor in about 5% to 10% of all cancers, and more than 50 hereditary cancer syndromes have been identified.² And although genetic testing has become integral in oncology care, providing information regarding potential subsequent cancer risks for patients and family members, the technology has also introduced additional complexity into clinical care. The field of cancer genetics was used to focus solely on hereditary risk through germline mutations, but it has now expanded to include the implications of tumor genetics in influencing treatment responses.

To provide oncologists with the resources they need to effectively integrate hereditary cancer risk assessment into their practices, ASCO has developed a genetics toolkit, which includes online learning courses and links to other educational resources related to hereditary genetic cancer risk assessment. ASCO has also published recommendations in five areas of cancer-related genetic and genomic testing in its updated policy statement on genetic and genomic testing for cancer susceptibility.¹ They include:

• Germline implications of somatic mutation profiling, which calls for additional research in best practices for the delivery of incidental and secondary germline findings
• Multigene panel testing for cancer susceptibility, which recommends that providers with expertise in cancer risk assessment be involved in ordering and interpreting multigene panels that include genes of uncertain clinical utility and genes not suggested by the patient’s personal and/or family history
• Quality assurance in genetic testing, which recommends appropriate regulation of tests that detect inherited genetic variants and support a risk-based approach to U.S. Food and Drug Administration regulation for laboratory-developed tests and commercial tests that do not compromise innovation or limit patient access to testing
• Education for oncology professionals, which recommends continued instruction in cancer risk assessment and management of people with an inherited predisposition to cancer
• Access to cancer genetics services, which calls for insurance coverage of cancer risk assessment and prevention services for people with a suspected increased risk for developing cancer.

To learn more about the intricacy of assessing individuals for inherited cancer risk as well as the potential harms and benefits associated with genetic and genomic testing, The ASCO Post talked with Charité N. Ricker, MS, LCGC, Instructor of Clinical Medicine at the Keck School of Medicine of the University of Southern California, genetic counselor with the University of Southern California Norris Comprehensive Cancer Center, and member of ASCO’s Cancer Prevention Committee and Cancer Genetics Subcommittee.

Charité N. Ricker, MS, LCGC

‘Constantly Changing Field of Genetics’

Please talk about some new initiatives being planned by ASCO’s Cancer Genetics Subcommittee to help oncologists determine the appropriate type of genetic testing for their patients and when it should be ordered.

The ASCO Genetics Toolkit has recently been updated to reflect the constantly changing field of genetics. We are exploring development of risk assessment tools that will be incorporated into the toolkit to provide education about cancer susceptibility genes to ensure its relevance. We are also examining how to make the information more accessible to oncologists.

Achieving an accurate cancer risk assessment involves not only ordering an appropriate genetic test, but also interpreting that test in the context of a patient’s personal and family histories. Cancer is a complex disease, and our current genetic tests are focused on known high-risk and, increasingly, moderate-risk cancer predisposition genes. However, there are other genetic and nongenetic factors at play in families that are not well understood, and currently not quantifiable, that can influence risk. This is why capturing a thorough family history remains so important. In the ASCO Cancer Genetics Subcommittee, we are discussing how to develop better tools for collecting this information that can be integrated into the clinical setting.

ASCO published a terrific article, “Assessing and Managing Your Patient’s Hereditary Cancer Risk,” which recommends taking a family cancer history at the first office visit and provides guidance on hereditary risk assessment.³ National Comprehensive Cancer Network^® (NCCN) Clinical Practice Guidelines in Oncology for the management of specific cancer syndromes, such as hereditary breast and ovarian cancer syndrome, can also be found on ASCO’s website.

“Oncologists, and other oncology providers, are in a prime position to identify their patients who qualify for hereditary cancer risk assessment and advise them on the importance of considering genetic testing.”

— Charité N. Ricker, MS, LCGC

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Assessing Genetic Risk Factors for Developing Cancer

Which individuals are at highest risk for developing a hereditary cancer?

Multiple guidelines exist to identify individuals who merit assessment for hereditary cancer syndromes, with specifics based on cancer type. However, there are principles that can be more broadly applied, such as early age at cancer diagnosis, more than one primary cancer diagnosis, multiple family members with the same or related cancer diagnosis, as well as the presence of rare tumors or certain tumor characteristics.

It is also important to note that there are patients who qualify for assessment based on their own cancer diagnosis, regardless of family history, including those with epithelial ovarian cancer, pancreatic adenocarcinoma, metastatic prostate cancer, or triple-negative breast cancer (younger than age 60). The growing use of somatic tumor analysis has contributed to our understanding of the prevalence of mutations in some of these patient populations.

The individuals who often benefit most from the potential preventive power of genetic testing are those who have never had cancer, because there is an opportunity to prevent cancer or find it at an earlier stage with timely surveillance and risk-reducing interventions. However, the individuals who provide the clearest assessment in families are those who have developed a cancer, in which case, oncologists are uniquely poised to assure that access to testing is made available to the most appropriate patients.

For example, if I see the sister of a woman diagnosed with ovarian cancer for genetic counseling and her genetic test is negative, I don’t know if that is because her sister carries a mutation, which my patient did not inherit (a true negative), or because her sister is among the approximately 75% of women with ovarian cancer whose cancer was not caused by a mutation in a cancer predisposition gene, such as BRCA1/2.

In addition to providing crucial information to family members, the results from genetic testing may impact an oncology patient’s treatment decision-making and screening surveillance for the prevention of potential second cancers.

What are the skills required to provide an accurate cancer risk assessment?

Jennifer A. Ligibel, MD

The skills necessary to provide cancer risk assessment incorporate elements from oncology, genetics, genetic counseling, and education, among other fields. They also take into account an understanding and knowledge about germline genetic tests, their implications, and how to interpret them.

Oncologists, and other oncology providers, are in a prime position to identify their patients who qualify for hereditary cancer risk assessment and advise them on the importance of considering genetic testing.

Understanding the Potential Harms of Genetic Screening

Sequencing more genes in patients with a genetic risk factor for cancer with next-generation sequencing technology increases the chance of finding a pathogenic mutation and/or a variant of uncertain significance. What are the potential harms to patients of multiplex testing for cancer risk assessment?

Not much is known about the potential negative impact of multiplex testing, such as unwarranted surgery or adverse psychological effects on individuals at risk for cancer. However, a prospective cohort study we recently conducted provided some interesting clues on the aftereffects of testing.⁴

The study included 2,000 ethnically and economically diverse patients, with and without a personal history of cancer, who underwent genetic counseling; 25 genes related to different hereditary cancer conditions were analyzed. We found that rates of preventive surgery were low, and most patients never or rarely had thoughts of cancer affecting their daily activities, never regretted undergoing tested, and wanted to know all their test results. In addition, patients who tested positive usually advised relatives to undergo genetic testing.⁴

We also found that over one-third of the positive results were clinically unanticipated. With broader multigene panels, an increasing number of individuals will have unexpected findings. For example, a mutation in a colorectal predisposition gene may be identified in a patient with personal and family histories that are more consistent with a hereditary breast cancer condition. Although this information may be beneficial to patients and family members, it does introduce complexities into cancer risk assessment. Still, this is an exciting time to be in cancer genetics, as our tools to define and refine risk expand.

Our goal continues to be how to better determine who is at elevated cancer risk, so individuals can take proactive steps for preventive care and screening.

Managing Patients’ Expectations

How can oncologists counsel their patients to manage their expectations on the benefits and limitations of genetic testing?

“As part of the informed consent process, oncologists should have a conversation with their patients about the reason for the test and the likelihood of a positive result.”

— Charité N. Ricker, MS, LCGC

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As part of the informed consent process, oncologists should have a conversation with their patients about the reason for the test and the likelihood of a positive result. Before undergoing genetic testing, I discuss with patients the different outcomes that might be expected, not just a negative or positive result, but also the potential for finding variants of uncertain significance. I also review the limitations of our current understanding and technologies in genetic testing, as well as the meaning of an uninformative result. I then review patients’ expectations and motivations for the test and their potential emotional impact, both for them and their family.

Once patients understand the pros and cons of genetic testing, they can make an informed decision about whether they want to proceed with the testing process. ■

DISCLOSURE: Ms. Ricker has received institutional research funding from Myriad Genetics.

REFERENCES

1. Robson ME, Bradbury AR, Arun B, et al: American Society of Clinical Oncology policy statement update: Genetic and genomic testing for cancer susceptibility. J Clin Oncol 33:3660-3667, 2015.

2. National Cancer Institute: The genetics of cancer. Available at www.cancer.gov/about-cancer/causes-prevention/genetics. Accessed July 22, 2019.

3. American Society of Clinical Oncology: Assessing and managing your patient’s hereditary cancer risk. Available at www.asco.org/practice-guidelines/cancer-care-initiatives/genetics-toolkit/assessing-managing-your-patients. Accessed July 22, 2019.

4. Idos GE, Kurian AW, Ricker C, et al: Multicenter prospective cohort study of the diagnostic yield and patient experience of multiplex gene panel testing for hereditary cancer risk. JCO Precis Oncol 3:1-12; 2019.