Barcelona, Spain ( The field of germline testing to understand baseline cancer risk, as well as therapy response, is exploding, and Dr. Eeles relates this expansion in knowledge to learning how to give immunotherapy after giving chemotherapy for many years. In this educational session, she discussed important genes that if altered in the tumor should trigger germline testing, provided key caveats about genetic tests, and emphasized the importance of taking a family history.

The ESMO Precision Medicine working group has created a list of recommendations for genes that should be included at a minimum in germline testing analysis both in general and for specific tumor types, and genes that if found to be altered in a tumor should trigger germline testing1. The most important genes in this list at present are the mismatch repair genes and BRCA 1 and 2.

Multiple caveats are important to keep in mind when thinking about genetic testing. Variant context matters. For example, some genes such as MUTYH are commonly altered in specific populations such as Celtic people, but are not pathogenic unless the variant is present in both alleles. Second, just because a tumor contains a variant in a gene that is associated with germline cancer risk overall does not mean it is relevant for that patient. Dr. Eeles provides the example of a BRCA1 mutation that would be considered relevant for a breast cancer patient, but of unknown significant for a germ cell tumor.

There are certain variants that if detected in the tumor should prompt a quick but detailed family history. The key example for this is TP53 mutation. These mutations are incredibly rare in the germline, but very common in advanced cancers. However, if present in the germline, this is indicative of Li-Fraumeni syndrome. This diagnosis requires extensive family sreening and ongoing cancer screening with specialized MRI protocols, and therefore should not be missed.

Finally, Dr. Eeles discussed how germline testing is changing prostate cancer screening paradigms on an ongoing basis. She described the example of the IMPACT study2, which showed that the detection of BRCA2 germline mutation was associated with an increased incidence rate in prostate cancer, significantly increased the positive predictive value of prostate biopsy, and ultimately identified higher-risk prostate cancers

While the expansion of germline testing can be daunting, there are many online resources to help understand this field, including ESMO online e-learning courses.


1. Mandelker, D et al. 2019. “Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group”. Annals of Oncology 30 (8): 1221-1231. Oxford University Press (OUP). doi:10.1093/annonc/mdz136.
2. Page, Elizabeth C. et al. 2019. “Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers”. European Urology. Elsevier BV. doi:10.1016/j.eururo.2019.08.019.

Presented by: Rosalind Eeles, MD, PhD, Professor at the Institute for Cancer Research and The Royal Marsden Hospital, London, United Kingdom

Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept – 1 Oct 2019 in Barcelona, Spain