Hereditary cancer syndromes are caused by a pathogenic variant in cancer susceptibility genes, which overall account for approximately 10% of all cancers. Carriers of pathogenic variants are at an increased risk of developing cancer during their lifetime. Genomic cancer risk assessment makes it possible to identify candidates for genetic testing to enable targeted therapy, appropriate risk-reducing recommendations, and cascade testing in family members. However, older patients are often excluded from genomic cancer risk assessment based on their age and characterization, and management of hereditary cancer syndromes information in this group of patients is limited.
In 2020, approximately 10 million older adults (aged 65 and older) were diagnosed with cancer. As the population ages, the risk of cancer increases, and currently more than 50% of people who have cancer are older adults.1
Genomic Cancer Risk Assessment: Don’t Forget Older Patients
Aging is a risk factor for adult cancers, which is the opposite of what is expected when a hereditary cancer syndrome is suspected, since cancer diagnosis is frequently made at a younger age. However, recent research in molecular genetics have shown that not only young patients are at risk of harboring a pathogenic variant in susceptibility cancer genes, especially in moderate-penetrance genes, and that the spectrum of hereditary cancer syndromes and expression is variable, which might depend on the molecular defect, affected genes, as well as other individual factors. Previous studies have reported that between 5% and 10% of older patients referred for genomic cancer risk assessment carry a pathogenic variant in a cancer predisposition gene.2 Therefore, the burden of older patients with hereditary cancer syndromes is higher than initially thought, and it is very important to improve our understanding of how to take care of these individuals.
“Hereditary cancer syndromes are caused by a pathogenic variant in cancer susceptibility genes, which overall account for approximately 10% of all cancers.”— YANIN CHAVARRI-GUERRA, MD, MSc
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Moreover, the most recent cancer management guidelines have increased the scope of indications of genomic cancer risk assessment and genetic testing based on therapeutic implications.3 For example, all patients with metastatic HER2-negative breast cancer are candidates for genetic testing, since a germline pathogenic variant in BRCA genes is a predictor of response to poly (ADP-ribose) polymerase (PARP) inhibitors as well as platin-based chemotherapy. Recently, PARP inhibitors have also yielded responses in those germline pathogenic variants in PALB2.
For patients with early-stage breast cancer, genetic testing prior to surgery can also be used to guide surgical decisions, such as on bilateral mastectomies, to reduce the risk of new breast cancer in patients with a pathogenic variant. Moreover, cancer genetic testing can be used to guide treatment decisions for those with other neoplasms, including certain gastrointestinal and genitourinary cancers. For these reasons, germline genetic testing will be increasingly part of clinical practice for patients at any age with cancer, which will lead to the identification of more older patients with pathogenic variants in cancer susceptibility genes.
Clinical Trial Findings With Genetic Testing for Older Individuals
At the 2022 International Society of Geriatric Oncology (SIOG) Annual Meeting, we presented findings from a study aimed to review clinical characteristics, genetic testing outcomes, and follow-up care for older patients referred for genomic cancer risk assessment.4 It included patients who met the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) criteria for genomic cancer risk assessment and genetic testing. In this study, we focused on patients aged 65 and older at enrollment. Information on the prevalence of cancer susceptibility pathogenic variants, the use of a geriatric screening tool (G8), the use of risk-reducing surgeries, and results from a genetic cancer knowledge questionnaire (KnowGene) were reported.
A total of 1,629 individuals met the inclusion criteria, of whom 271 (16.6%) were aged 65 or older. Median age of older patients who met the criteria was 73 (range, 65–94 years), and 63% were male. More than three-quarters of patients (78%) had a history of cancer, and 9% harbored a pathogenic variant in the following cancer susceptibility genes: BRCA2 (22%), CHEK2 (17%), ATM (17%), BRIP1 (9%), BRCA1 (9%), NF1 (9%), CDKN2A (4%), MLH1 (4%), and PALB2 (2%).
At a median follow-up of 24 months, five patients (2%) died, and one had a new cancer. Just 1% of patients with pathogenic variants had risk-reducing surgery, and 45 family members had cascade testing. Regarding geriatric screening results, the median G8 score was 15 points (range = 11–17), and 25% of patients had an abnormal score. Polypharmacy and nutritional intake were the most common affected domains.
Clinical Implications
Like previous reports, our findings showed that a significant proportion of older patients harbored a genomic alteration in cancer susceptibility genes. About one-third of the mutations were found in moderate-penetrance genes, which might be expressed later in life. The most common single gene found was BRCA2, which is also known to cause a late onset of breast cancer when compared with BRCA1.5,6
It is important to highlight that even though risk-reducing strategies are recommended when a pathogenic variant is found—and our study patients were fit with a good functional status based on the results of the G8 geriatric screening questionnaire—few patients have had such risk-reducing surgery. Geriatric assessment has been widely adopted in the oncology field to identify patients with cancer who are frail and at increased risk of morbidity and mortality, as a tool to aid in treatment decisions. Domains that are recommended by the SIOG to be explored include comorbidity, functional status, physical performance, nutritional status, polypharmacy, social support, cognition, and psychological status.7 However, geriatric assessment has not been used as a tool in older patients with hereditary cancer syndromes, but it might be useful to select older candidates with pathogenic variants for risk-reducing procedures. Although risk-reducing procedures were not common in our cohort, we observed that the number of family members who underwent genetic testing was high, which implies that communication of results to the family was effective.
“Germline genetic testing will be increasingly part of clinical practice for patients at any age with cancer.”— YANIN CHAVARRI-GUERRA, MD, MSc
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As genetic testing criteria broaden, and the population ages, more and more older adults will be candidates for genomic cancer risk assessment and genetic testing. It is important to be aware of some challenges and opportunities in the care of the geriatric population: interpreting genetic testing (clonal hematopoiesis is more common with aging),8 incorporating geriatric assessment into clinical practice recommendations including risk-reducing strategies and treatment recommendations, and sharing how important cascade testing is in family members.
DISCLOSURE: Dr. Chavarri-Guerra has been a member of the speakers bureau for Invitae; has received research funding from Roche; and has been reimbursed for travel, accommodations, and expenses from Pfizer, Roche, and Asofarma.
REFERENCES
1. Ferlay J, Ervik M, Lam F, et al: Global Cancer Observatory: Cancer Today. Lyon, France; International Agency for Research on Cancer. Available at https://gco.iarc.fr/today. Accessed March 30, 2023.
2. Chavarri-Guerra Y, Slavin TP, Longoria-Lozano O, et al: Genetic cancer predisposition syndromes among older adults. J Geriatr Oncol 11:1054-1060, 2020.
3. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology on Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic version 3.2023. Available at https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf. Accessed March 30, 2023.
4. Chavarri-Guerra Y, Araceli CB, Andrea MA, et al: Cancer susceptibility germline pathogenic variants (PVs) and follow up care among older patients (pts). J Geriatr Oncol 13(suppl 1):SIOG2022-0088, 2022.
5. Chavarri-Guerra Y, Hendricks CB, Brown S, et al: The burden of breast cancer predisposition variants across the age spectrum among 10,000 patients. J Am Geriatr Soc 67:884-888, 2019.
6. Chavarri-Guerra Y, Marcum CA, Hendricks CB, et al: Breast cancer associated pathogenic variants among women 61 years and older with triple negative breast cancer. J Geriatr Oncol 12:749-751, 2021.
7. International Society of Geriatric Oncology (SIOG): Comprehensive Geriatric Assessment. Available at https://siog.org/educational-resources/comprehensive-geriatric-assessment. Assessed April 5, 2023.
8. Slavin TP, Sun CL, Chavarri-Guerra Y, et al: Older breast cancer survivors may harbor hereditary cancer predisposition pathogenic variants and are at risk for clonal hematopoiesis. J Geriatr Oncol 11:316-319, 2020.
Dr. Chavarri-Guerra is Associate Professor of Medical Oncology at the Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán in Mexico City.
