Study: XRAYS Follow Up: Does expanded genetic testing benefit Jewish women with breast cancer?

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This study is about:

Experts who have different conclusions on the same set of data examining expanded genetic testing in Jewish people who test negative for a BRCA founder mutation.

Why is this important?

Data from research studies can be interpreted from multiple perspectives, and debate and discussion are standard within the scientific community. Respectful discussions add to our understanding of the information and its context. However, disagreement by experts on interpretation of research results can lead to conflicting clinical recommendations. This can be confusing to patients.


In this XRAYS follow-up, we update our 9/13/17 XRAYS review of the study by Walsh and colleagues on genetic testing in Jewish women with breast cancer. The original study was published in JAMA Oncology in July of 2017.

The original research team asked if there was benefit of additional genetic testing for Jewish women with breast cancer beyond testing for the 3 founder mutations. They found that 4.2% of the Jewish women tested had mutations that would go undetected if they had only had testing for the 3 Jewish founder mutations. Walsh et al. suggested that Ashkenazi Jewish women consider expanded panel testing to provide the most complete information about cancer-causing mutations.

Different perspectives on the same data

In a recent issue of JAMA Oncology published on May 3, 2018, genetics experts Dr. Steven Narod and colleagues suggested a different interpretation of the study data. They suggest that complete testing of BRCA1 and BRCA2 is sufficient in the Ashkenazi Jewish population and that sequencing other genes adds little value.

Two of the original study authors, Drs. Tom Walsh and Mary-Claire King, responded to this alternative interpretation. They replied to Narod and colleagues by stating that sequencing additional genes provides the opportunity for increased surveillance and preventive options for women who test positive for mutations outside of BRCA1 and BRCA2.

At the center of these differing perspectives are three types of mutations:

  1. Mutations in BRCA1 and BRCA2.
    • Both groups of researchers agree that full sequencing of BRCA1 and BRCA2 is warranted for Jewish women. Narod et al. note that this is now standard practice in Canada. However, this is not always standard in the United States.
  2. Mutations in genes outside of BRCA that confer increased breast cancer risk (e.g. PALB2, CHEK2, ATM and others).
    • In the original study, the majority of mutations outside BRCA identified were in CHEK2 (29 in CHEK2 and 1 each in NBN and BRIP1). Narod et al. suggest that it may not be advantageous to sequence genes other than BRCA because of the lack of data on benefits of additional medical interventions for these individuals.
    • Walsh and King counter this argument by suggesting that women who carry mutations in other genes may be offered different options for managing their risk for a new cancer diagnosis. 
    • Of note, no mutations in PALB2 or other high risk genes were detected in this study. While this may be due to any number of factors, it does not eliminate the possibility of a mutation in another high risk gene.
  3. Mutations of unknown significance for breast cancer risk.
    • Some of the mutations detected by Walsh et al. are of unknown significance, Narod et al. suggest that sequencing these genes is not useful or actionable because it is unclear whether these mutations will predispose women to breast cancer or how to alter surveillance or treatment. Walsh and King agree that only "unambiguous, loss-of-function" mutations in genes with clear effects on cancer risk should be reported back to the doctor who ordered testing and their patient.
    • Some of these mutations will end up being benign variants which do not increase cancer risk; others may predispose people to cancer. Additional research will be required to clarify which mutations of unknown significance warrant altered surveillance or treatment.

Our understanding of scientific data changes with time

Science is a process we use to better understand our world, not a static set of information. New information is constantly being accumulated and incorporated into the knowledge base. As more information is gathered we will have a better more complete understanding of which mutations are the most deleterious and which have more benign effects.

These two groups of researchers do not disagree with the data; the number and type of mutations found within the genes evaluated is not in question. They do disagree about the significance of the mutations and whether detecting them is useful, actionable knowledge that will improve the outcomes of patients.

What does this mean for me?

It is important for people with breast cancer to know:

  • which genetic tests were ordered
  • what the results mean for their current treatment
  • what the results mean for their risk of future cancer
  • what the results mean for their relatives

While detection of a mutation is now straightforward, it is less clear how to interpret the impact of some mutations on breast cancer risk. The original research study and accompanying commentaries highlight the importance of speaking with a genetics expert before and after genetic testing.

Questions to ask your health care provider

  • I had genetic testing in the past, how can I find out which tests were ordered?
  • How can I get a copy of my genetic test results?
  • I previously tested negative for the BRCA Ashkenazi Jewish founder mutations. Should I be tested for other BRCA mutations?
  • Should I be tested for mutations in other, non-BRCA breast cancer genes?
  • Can you refer me to a genetic counselor?
  • If I test positive for a mutation in another breast cancer gene, what does that mean for me and my family as far as screening, cancer prevention, and treatment choices?

Share your thoughts on this XRAYS article by taking our brief survey

Posted 6/7/18


Walsh T, Mandell JB, Norquist BM, et al. “Genetic Predisposition to Breast Cancer Due to Mutations Other Than BRCA1 and BRCA2 Founder Alleles Among Ashkenazi Jewish Women.JAMA Oncology. 2017; 3(12):1647-1653. 

Narod S, Sopik V, Cybulski C. “Testing Ashkenazi Jewish Women for Mutations Predisposing to Breast Cancer in Genes Other Than BRCA1 and BRCA2.JAMA Oncology. Published online May 3, 2018. doi:10.1001/jamaoncol.2018.0595

Walsh T and King M-C. “Testing Ashkenazi Jewish Women for Mutations Predisposing to Breast Cancer in Genes Other Than BRCA1 and BRCA2—Reply.JAMA Oncology. Published online May 3, 2018. doi:10.1001/jamaoncol.2018.0616

This article is relevant for:

This article is also relevant for:

Breast cancer survivors

Women under 45

Women over 45


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