ASCO-SSO new guidelines for germline testing in patients with hereditary breast cancer

Introduction to hereditary breast cancer

starts when the healthy breast cells become cancerous and multiply uncontrollably, forming a tumour mass. It is one of the most common types of cancer worldwide and it can affect both females and males (). If breast cancer is diagnosed at an early stage, the chances of survival are high. Up to 10% of all breast cancer cases are due to hereditary genetic changes, known as germline mutations, which can be passed down from parents to children. These mutations can increase the risk of developing hereditary breast cancer or a hereditary cancer syndrome associated with breast cancer in the future ().

Different genes have been linked with breast cancer development. The most frequently mutated genes in breast cancer patients are . These two genes are tumour suppressors, which can inhibit tumour development. However, mutations in these genes stop this function, leading to tumour development (). Aside from BRCA1/2, Other genes linked to breast cancer include PTEN, TP53, CDH1, STK11, ATM, and CHEK2 (). Identifying the genes that lead to hereditary breast cancer and hereditary breast cancer syndromes is vital and can aid early diagnosis and effective treatment.

Different clinical management approaches are used to treat breast cancer. Surgery to remove the tumour is the primary treatment method for breast cancer. It is the most effective method if the tumour is detected early and it is feasible to remove it (). Other treatment approaches include radiotherapy and chemotherapy in which the cancer cells are destroyed (). Targeted therapy using drugs that can target specific mutated genes responsible for breast cancer development, is another method to treat breast cancer. Examples of targeted therapy drugs include trastuzumab for the ERBB2 gene and talazoparib for genes such as BRCA (, , ).

The importance of hereditary breast cancer genetic testing

Although some people are cautious about whether they want to know their risk of hereditary breast cancer, genetic testing is essential. Having a gene that is linked to breast cancer does not necessarily mean that cancer will develop. Environmental factors such as bad lifestyle habits increase the risk of cancer and contribute to its development. Therefore, genetic testing can help patients make important decisions about prevention, changing lifestyle habits, and taking prophylactic measures such as regular screenings.

Professional bodies and societies such as the (ESMO), , and (NCCN) have published guidelines and recommendations for genetic testing of hereditary breast cancer. These recommendations include testing methods and techniques used, clinical management approaches, diagnosis, testing for key genes linked with breast cancer, and identify who could benefit from hereditary genetic testing. Therefore, healthcare providers can make the best decisions that would benefit the patients and guide them toward the best available clinical management plan.

The purpose and the background of this initiative

Recently, ASCO together with SSO published new guidelines and recommendations for hereditary breast cancer which highlight the importance of genetic testing (). The purpose of this initiative is to develop recommendations that will help in identifying people who would benefit from genetic testing for hereditary breast cancer. The primary audience of these recommendations includes breast cancer patients and their families.

An expert panel comprised of oncologists from different disciplines, genetic counsellors, patient representatives, geneticists, and others created a list of recommendations based on a systematic review of the current literature. Articles published between 2012 and 2023 were critically reviewed, assessed, and used in combination with the experts’ opinion and a formal consensus process to develop the clinical practice recommendations. For each recommendation to be approved it had to reach at least 75% agreement between the panel members, with the highest being 97.5% agreement for the recommendation urging BRCA1/2 testing for patients with recurrent breast cancer who are candidates for PARP inhibitor therapy, irrespective of their family history (see below recommendation 2.1).

Recommendations based on five clinical questions:

The recommendations developed address five clinical questions:

1. Should all newly diagnosed breast cancer patients be tested for BRCA1/2?

1.1 All newly diagnosed patients with stage I-III or de novo stage IV/metastatic stage breast cancer who are 65 years old or younger should be tested for BRCA1/2.

1.2 All newly diagnosed patients with stage I-III or de novo stage IV/metastatic stage breast cancer who are older than 65 years old should be tested for BRCA1/2 if they meet any of the criteria below:

• they are candidates for poly(ADP–ribose) polymerase (PARP) inhibitor therapy for early-stage or metastatic disease
• they have triple negative breast cancer
• they have a personal or family history that might suggest a pathogenic variant
• they are male
• they are of Ashkenazi Jewish ancestry or belong to a group that has high prevalence of a pathogenic mutation.

1.3 Patients who are tested for BRCA1/2 germline mutations should also be offered genetic testing for other predisposing genes according to their personal or family history. Consultation should also be available if needed.

2. Should BRCA1/2 testing be offered for patients with recurrent local, or metastatic disease or with a second breast primary tumour?

2.1 All patients with recurrent breast cancer who are candidates for PARP inhibitors should be offered BRCA1/2 genetic testing regardless of family history.

2.2 Breast cancer patients with a second primary cancer in the ipsilateral or contralateral breast should be offered BRCA1/2 genetic testing.

3. Should people with a personal history of breast cancer but with no active disease be tested for BRCA1/2?

3.1 People who were diagnosed with breast cancer at ≤65 years but have no active disease should be offered BRCA1/2 genetic testing if the results will inform personal risk management or risk assessment for the family.

3.2 Patients with a personal history of breast cancer who were diagnosed at ≥65 age and have no active disease should be offered BRCA1/2 genetic testing if they meet one of the following criteria:

• they had triple-negative breast cancer
• they have a personal or family history that might suggest a pathogenic mutation
• they are male
• they are of Ashkenazi Jewish ancestry or belong to a group that has high prevalence of a pathogenic mutation.

4. What is the importance of genetic testing for genes other than BRCA1/2 for breast cancer patients?

4.1 Testing for genes other than BRCA1/2, such as PALB2, TP53, PTEN, STK11 and CDH1, can improve clinical management, surgical decision making, inform the risk for other family members, and estimate the risk for a second primary cancer.

4.2 Although testing for moderate penetrance breast cancer genes currently does not have a direct association with a treatment, it can be offered in patients that undergo BRCA1/2 testing and can help in informing risk assessment of family members or risk for a second primary cancer.

4.3 Genetic testing with a multigene panel should be considered after taking into account the personal or family history of a patient.

5. How can breast cancer patients benefit from genetic counselling?

5.1 Sufficient information should be given to patients before genetic testing to provide informed consent.

5.2 Post-test genetic counselling should be given to patients with findings of pathogenic mutations.

5.3 Patients with variants of uncertain significance identified should be aware that periodic follow up is necessary since the variants could be reclassified as pathogenic in the future. Genetic counselling is also recommended and should be available to patients when needed.

5.4 Patients with no pathogenic variant detected can benefit from genetic counselling if there is a family history.

Similarities and differences with recommendations and guidelines from other societies and professional bodies

Other societies and professional bodies published guidelines and recommendations for hereditary breast cancer. Although the data studied by each body and society were different, the recommendations developed are similar between them. For example,

• Genes such as BRCA1/2 are recommended for hereditary breast cancer genetic testing by most societies (, , , , ).
• In addition, many societies suggest that people who belong to specific ethnic groups such as Ashkenazi Jewish are encouraged to be tested for hereditary breast cancer since they have an increased risk of having an inherited mutation in breast cancer associated genes (, , ).
• Furthermore, many societies agree that a family history of breast cancer, especially at a young age, can be a sign of breast cancer running in the family, and genetic testing for breast cancer can be highly informative ().
• The   also recommends genetic testing for people with a personal history of breast cancer similar to the ASCO-SSO recommendations (). The testing should include BRCA1/2, PALB2 genes and other genes depending on the case and the family history. In addition, family members might benefit from genetic testing.
• Another common recommendation is genetic counselling, which is advised before and after the genetic test ().

More information about the current guidelines of other societies and bodies can be found in the corresponding websites (, , , , )

It is also important to highlight one difference between the new recommendations from ASCO-SSO and the other published recommendations from other professional bodies. Interestingly, the current ASCO-SSO recommendations suggest genetic testing for people either below or above 65 years old depending on the case and if they fulfil specific criteria. However, recommendations from NCCN suggest germline testing for hereditary breast cancer predisposing genes for people ≤50 years if they meet certain criteria (). Therefore, the current ASCO-SSO recommendations maximises the number of people who can benefit from hereditary genetic testing for breast cancer, leading to potentially better clinical outcomes.

Conclusion

Hereditary breast cancer remains one of the most commonly diagnosed cancer worldwide. The current recommendations from ASCO-SSO empower healthcare providers to identify the best clinical management plan for people who might benefit from hereditary breast cancer genetic testing. Undoubtedly, genetic testing for germline mutations can be a strong weapon against cancer for early diagnosis and better clinical outcomes.