1. Yadav Siddharta, Prof. Dr., Identification and selection of patients for genetic testing, Update in women´s cancer, CMC 2024 Distilled, Berlin, 13. April 2024.
In hereditary breast or ovarian cancer, mutations in the BRCA1 and BRCA2 genes are looked for. The pathogenic variants of these tumour suppressor genes are responsible for the majority of hereditary breast carcinomas. By means of genetic testing, targeted therapy regimens can be used for the affected individuals in the presence of a HER2-negative breast carcinoma with a BRCA1/2 germline mutation, for example. This can also provide clarity for relatives or descendants regarding a positive BRCA1/2 status. However, there are currently still some challenges in correctly selecting patients for germline analysis when it comes to early detection or predisposition to a tumour with a BRCA1/2 germline mutation.1
At the International Charité Mayo Conference 2024, Prof Dr Siddhartha Yadav spoke about the selection and identification of suitable patients for germline analysis. He addressed the challenges posed by the sometimes conflicting country-specific guidelines on germline analysis and showed that some of the patients concerned may fall through the cracks if the procedure conforms to the guidelines.1
Depending on the guideline used, there are various recommendations regarding the indication for germline analysis. The country-specific differences in the guidelines pose a global challenge. These include the ASCO guideline on HER2-negative metastatic breast cancer, renewed in 2022. This also includes the recently updated guideline of the National Comprehensive Cancer Network (NCCN). Also included are the ESMO Clinical Practice Guideline which contains important recommendations and algorithms for the treatment of metastatic breast cancer. And finally added are the guidelines developed by the American Society of Breast Surgeons (ASBrS). Some of them contradict each other with regard to the recommendations on germline analysis. Patient-specific factors such as ethnicity, individual treatment decisions and different healthcare systems also make it difficult to standardise recommendations on germline analysis across countries.1
According to the NCCN guideline, the following factors play a role in the recommendation of a germline analysis for breast cancer:
The ASBrS guideline, on the other hand, recommends germline analysis for all women with breast cancer regardless of other parameters.1
In addition to these differences, however, there are already points on which doctors and scientists around the world agree. In the case of hereditary breast and ovarian cancer, a germline analysis should be carried out for the following aspects:
The guideline-compliant approach to patient selection for germline analysis means that some patients with a predisposition to breast cancer fall through the cracks. Prof Yadav and his research team published a study on this problem in 2020. Between 2000 and 2016, patients with breast cancer were included in a breast cancer registry at a tertiary cancer centre. This cohort was tested for the presence of pathogenic germline variants in the 9 breast cancer predisposition genes ATM, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN and TP53.
Prof Yadav and his team used this cohort to evaluate the specificity and sensitivity of the National Comprehensive Cancer Network (NCCN) recommendations for hereditary cancer testing. 47.9 per cent of affected women who met the NCCN criteria were more likely to carry a pathogenic variant in 9 predisposition genes compared to women who did not meet the criteria. 9 per cent of women did not meet the NCCN criteria. Of these, 0.7 per cent had pathogenic variants in BRCA1 or BRCA2. The sensitivity of the NCCN criteria was therefore 70 per cent for 9 predisposition genes and 87 per cent for BRCA1 and BRCA2. The specificity was 53 per cent. Yadav and his team concluded from this that a significant proportion of women with breast cancer who carry pathogenic germline variants in predisposition genes are not eligible for testing according to the NCCN criteria.1
ASCO and SSO are publishing a new guideline on germline analysis for breast cancer this year. According to the guideline, a test to detect a BRCA1/2 germline mutation should be offered to all women < 65 years of age at the time of newly diagnosed stage I-III or de novo stage IV/metastatic breast cancer. Women > 65 years of age should be recommended for BRCA1/2 germline mutation testing if they are eligible for PARP inhibitor therapy, have triple-negative breast cancer or have a positive family history of oncology.1
1. Yadav Siddharta, Prof. Dr., Identification and selection of patients for genetic testing, Update in women´s cancer, CMC 2024 Distilled, Berlin, 13. April 2024.