Hereditary Cancer Testing Around the World: Challenges and Proposed Solutions

In recent years, the importance of heredity in cancer has received increasing attention, driven by the emergence of treatments based on genetic mutations . While 40-50% of cancer risk can be attributed to environmental and lifestyle factors, at least 16% of cancers may be hereditary , accounting for 3 million of the approximately 20 million cancer cases diagnosed worldwide each year.

At least two-thirds of hereditary cancers are likely to be diagnosed in low- and middle-income countries (LMICs). Diagnosis at an early age is a distinctive feature of cancer in LMICs, potentially indicating a higher proportion of hereditary cancers than elsewhere in the world.

For example, two-thirds of breast cancers in LMICs are diagnosed before age 54, compared with one-third in high-income countries (HICs). In sub-Saharan Africa, Black patients with breast cancer are also three times more likely than White patients to have the triple-negative subtype . These features may signal inherited forms of cancer. Genetic testing of Nigerian patients with breast cancer has identified pathogenic changes in the tumor suppressor genes BRCA1 and BRCA2. Among women with BRCA1 or BRCA2 variants that were inherited and pathogenic (harmful), cancer incidence was higher than in the White population. This creates new opportunities for prevention, early detection and, more recently, treatment. However, numerous barriers limit the ability to address gene mutations in cancer clinics worldwide.

The Referral Challenge

The era of clinical cancer genetics began with the discovery of BRCA1/2 in the mid-1990s. Since then, most HICs have developed multidisciplinary teams to manage genetic counseling and testing for high- and moderate-risk cancer predisposition genes. Even in HICs, however, access to cancer genetics services is unequal. For example, a population-based study in two US states found that Black women were 40% less likely than White women to undergo BRCA1/2 testing. Once appropriately referred, acceptance of genetic counseling did not differ significantly by ethnicity. Racial disparities in referral may reflect several factors: associating pathogenic cancer-related genetic changes with particular populations, such as Ashkenazi Jews; communication barriers rooted in cultural norms; differences in patient awareness and willingness across ethnic groups; or racial bias in discussing communities' genetic heritage. Financial implications pose another ethical challenge, particularly for physicians considering referral for treatment purposes. For example, when patients with pancreatic cancer cannot access poly(ADP)-ribose polymerase (PARP) inhibitors, it can be very difficult to discuss genetic testing and potential benefits for relatives while also describing a treatment they cannot afford and therefore cannot obtain.

The Growing Importance and Complexity of Hereditary Cancer

Guidelines for identifying patients to refer for genetic testing are continually updated and becoming more complex. This adds to the burden on busy physicians who must keep up with changes and check them for each patient. In addition to BRCA1/2, other genes have recently been recognized for which management guidelines are recommended or being developed. The ability to test multiple genes simultaneously has made panel testing more logical than sequential single-gene tests. Panels address both the genetic diversity of inherited cancer syndromes and similarities in clinical features among carriers of different mutations.

For example, breast cancer is common among women with pathogenic variants in BRCA1/2, PALB2, TP53, ATM or CHEK2. Understanding the available tools and personalizing test selection during pretest counseling are therefore important when requesting an individual's genetic test. For decades, Sanger sequencing was the main method for DNA sequencing, before being largely replaced by newer high-throughput technologies such as NGS (next-generation parallel sequencing) .

High-throughput parallel sequencing determines the nucleotide sequence of an individual's genome or a portion of it. It uses DNA sequencing technologies that can analyze many DNA sequences simultaneously. Also called next-generation sequencing, it is often used to examine a set of genes known as a panel. Access is limited in LMICs, further complicating testing and adding to financial difficulties.

Given this complexity, some advocate broad panel testing for all patients with cancer. Many clinically important genetic changes are not detected by history- or syndrome-directed testing. In particular, multigene panel testing of 2,984 selectively high-risk patients identified inherited variants in 13.3%, more than half of which would have been missed under current testing guidelines. This suggests that half of patients with potentially actionable inherited variants did not meet NCCN testing criteria and therefore missed treatment opportunities.

The potential impact of expanded genetic testing on patients and physicians cannot be ignored. Identifying variants of uncertain significance (VUS) may cause unnecessary anxiety. An incidental inherited variant unrelated to the condition of a patient who already has cancer can also be difficult to manage. Explaining these findings and recommending additional tests for relatives may be challenging. Physicians should recognize these issues and focus on minimizing VUS rates by limiting tests to genes clinically relevant to the patient's diagnosis. There is no short-term solution to existing gaps in genetic counseling, and oncologists will continue to need education to discuss inherited findings and their implications.

To help address the complexity of genetic testing referrals when no genetic counselor is available, integrating a standardized tool into oncology visits could reduce physicians' workload. This may be a practical way to increase testing among individuals identified as at risk by guidelines.

Challenges in Acceptance

The obvious difficulty of referral is compounded by attitudes shaped by social, cultural and religious barriers to genetic testing. Some patients consider it unimportant because they have no children or perceive little benefit, which also limits discussions with relatives. One study found that patients regarded testing as unimportant or unhelpful because they lacked information about its rationale and benefits. Patients preoccupied with their cancer diagnosis may miss genetic counseling appointments. Making counseling and molecular testing more widely available during oncology outpatient visits could reduce this loss to follow-up. When these services, whether delivered by oncologists or on-site genetic counselors, were integrated into already scheduled appointments such as chemotherapy sessions, the proportion lost to follow-up fell to 4%. This was much lower than the reported 19.6% who did not attend after referral from oncology services when no genetic counselor was available in the clinic.

Some patients understand the value of testing but worry about finding variants and their potential effects on future generations, including children and grandchildren. Information about risk-reduction strategies may encourage testing and disclosure to relatives. However, even when support for informing relatives and free testing for familial variants were offered, uptake of cascade testing was only 17.6%. This is consistent even with low estimates, generally 20-30%. Low uptake, including among patients identified through family history, limits the potential benefits of inherited-variant testing for early detection and prevention. It raises questions about the clinical usefulness of these tests for promoting early detection at a population level.

Genetic discrimination (GD), particularly in insurance, employment and social relationships, is a concern across cultures. Some countries prohibit it by law, but many, especially those with limited resources, do not. A recent study examined public policy approaches to preventing genetic discrimination worldwide. It identified regions with extensive policy development (North America and Europe), moderate activity (Australia, Asia and South America) and minimal activity (the Middle East and Africa). These laws do not seem to eliminate concerns entirely. For example, the US Genetic Information Nondiscrimination Act covers employers and health insurers but not life or disability insurers. Perceptions of GD also vary across ethnic groups and are often linked to the use of genetic information in marriage and family formation, unlike the patterns seen in North America and Europe. In a Japanese survey, most respondents reported concerns about genetic discrimination in marriage and pregnancy (41.0%), employment (37.6%) and insurance (43.8%).

Fear also appears to be shaped by past experiences of coping with the social consequences of a condition occurring in a family. Concerns about interpersonal discrimination seem particularly high. Such discrimination is often subtle and indirect, taking the form of spontaneous stigma or disrespect, and can be decisive in choosing whether to undergo testing.

The Interpretation Challenge

During interpretation, genetic variants are assigned to five categories:

1. Pathogenic,
2. Likely pathogenic,
3. Uncertain significance (VUS: Variant of Uncertain Significance),
4. Likely benign (harmless), and
5. Benign.

Pathogenic and likely pathogenic variants are considered positive results and are often called mutations, although the American College of Medical Genetics and Genomics no longer recommends that term. Benign and likely benign variants are considered negative results. VUS are variants for which insufficient information is available for classification. Clinical decisions should not be based on them, since 80-90% are reclassified as benign or likely benign. They pose a particular problem in populations underrepresented or absent in large public databases, where VUS rates are higher. For example, Hispanic patients with glioblastoma account for only 2% of the total patient population in The Cancer Genome Atlas. This makes it harder to understand genetic diversity fully in underrepresented populations.

Adequate information about the pathogenicity and clinical actionability of new variants is important for interpreting them in clinical practice. This requires detailed characterization. Higher VUS rates in less-studied populations are therefore expected until these variants are fully characterized.

Data diversity is critical to the success of these efforts. When genetic and genomic studies use datasets that exclude ethnically diverse populations, they cannot be optimally translated into clinical tests. Including diverse populations is essential to discovering useful genomic information and applying it clinically. This broadens the genetic knowledge base and supports more effective, personalized medical care.

Manrai and colleagues noted that developing genetic tests using only White populations could cause misdiagnoses affecting both majority and minority populations. Teo and colleagues showed that multiethnic studies can provide new insights into the genetic basis of human disease because of Africa's distinctive genetic structure. Genomic studies based on African populations can be generalizable to other world populations as a result of Africa's unique genomic architecture.

The design and sample-size calculations of genomic studies therefore depend heavily on accurate information about allele and genotype frequencies. A lack of diversity can limit discovery and clinical translation of genomic knowledge, preventing all populations from benefiting.

The Counseling Challenge

Genetic counselors have expertise in genetics and, more recently, genomics, together with counseling skills.

Their roles include assessing genetic disease risk, preparing people for testing, obtaining consent, communicating results, helping patients manage genetic findings and supporting ongoing testing of relatives. However, the financial burden of inherited genetic testing and its treatment and prevention implications is among their greatest challenges.

Although inherited genetic testing costs have fallen substantially in recent years, they remain unaffordable in most LMICs. A recent study documented that panel testing costs exceeded annual income per person in these countries. Tests cost between 1,500 and 6,040 US dollars. The costs of medicines for prevention, early detection or treatment, particularly PARP inhibitors , add to this burden.

The Challenge of Obtaining Consent

Obtaining consent is complex. It should cover the types of laboratory results that may arise, namely pathogenic, uncertain or benign; their implications for future risk and disease management; and subsequent handling of genomic data. The process involves not only counseling-related education but also psychosocial support throughout testing.

As germline (inherited) testing becomes more widespread and genetic counselors remain scarce, physicians have begun delivering counseling and testing. This approach was successful in a study integrating germline testing counseling by urologists or medical oncologists into routine care for patients with prostate cancer. Most patients (98%) were satisfied with pretest counseling, and 74% chose genetic testing. Educating oncologists may therefore broaden access to hereditary cancer testing. Post-test counseling, however, is still best delivered by a professional counselor and remains a challenge.

Some researchers have developed an online algorithm, or chatbot, to guide patients through testing. Such systems can provide information about tests and possible results, but they cannot replace the psychosocial support patients need to interpret new information and adapt and integrate it into their lives. Cultural competence enhances this support. Counselors must understand social and cultural influences on healthcare decisions and behavior, particularly among minority groups. This competence is important for supporting autonomy and informed choices. Decisions are shaped not only by medical information but also by personal, social and even religious backgrounds, making cultural competence critical to increasing uptake of genetic testing and counseling. Counseling minority individuals in a multiethnic society poses an additional challenge for counselors from the majority ethnic group.

The shortage of genetic counselors is a global problem. The US has only 12 counselors per million people, and the UK only 5 per million. The rate is 20 times lower in the Arab region, at just 0.1 per million. Some countries are now establishing genetic counseling training programs. However, these programs need substantial expansion to train enough local healthcare professionals to meet growing demand.

The Surgeon's Perspective

From the surgeon's perspective, germline molecular testing plays an important role in determining the extent and rationale of surgery in patients with particular variants. For example, patients with a genetic condition such as Lynch syndrome and early-stage colon cancer may choose total colectomy, removal of the entire colon, rather than segmental surgery because of the risk of recurrent cancer.

These practices are generally guided by organizations such as the US National Comprehensive Cancer Network (NCCN) and the UK's National Institute for Health and Care Excellence (NICE). Their guidelines address processes specific to each health system. In LMICs, however, various recommendations may be impractical or unaffordable. A lack of local guidelines may compromise patients' rights and access.

Data on risk factors for different variants, particularly the models used to estimate cancer risk, are also largely based on North American and European populations. LMICs lack sufficient information about the disease-causing potential or penetrance of variants. These uncertainties, together with a shortage of expertise to communicate risks and the benefits of risk-reduction options, can complicate informed consent.

Decisions about the extent of surgery and surveillance are particularly complex. They depend not only on mutation status but also on patient and system factors. Age, education, family, culture, community and sometimes religious beliefs may all influence decisions. Risk-reducing surgery, for instance, remains taboo in some communities. Even when people at risk choose surgery, local availability and cost of breast reconstruction can pose further difficulties. Surgical expertise and reconstructive facilities vary greatly across LMICs and may differ even between private and public sectors, making healthcare inequalities more complex and multidimensional.

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Conclusion

The World Health Organization states that genomics can contribute to global health equity, but only if the genomic health divide is contained and ultimately bridged through equitable economic investment, clinical research, and access to genomic services and technologies worldwide. It is therefore important to recognize and support collaboration and the exchange of knowledge and expertise to bridge gaps between HICs and LMICs and facilitate implementation. In a policy statement, ASCO similarly emphasized optimal deployment of new cancer genetics technologies in clinical practice. It recommended quality assurance in genetic testing, education for oncology professionals and access to clinical cancer genetics services. While such facilities are expanding in HICs, they remain at an early stage in LMICs. Existing guidelines must be adapted to local needs, with resource-based prioritization and sustainable capacity building. Broader, more globally distributed genomic data could provide more reliable information for practice and policy. Only when healthcare systems have the capacity and structures to deliver genetic and genomic services can such testing become an integrated part of healthcare throughout every person's life.