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Study: Inherited mutations in metastatic breast cancer patients

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Contents

At a glance                  Questions for your doctor
Findings               In-depth                
Clinical trials Limitations
Guidelines Resources


STUDY AT A GLANCE

This study is about:

Genetic testing of breast cancer (MBC) patients to learn the frequency of inherited mutations and whether it may be useful to test all MBC patients for mutations.

Why is this study important?

Genetic testing for germline (inherited) mutations such as , , can help people with breast cancer understand their risk and medical options. For a breast cancer patient, knowing if they have an inherited mutation may affect their treatment decisions. Some treatments work best for people with inherited mutations.  The frequency of germline mutations among breast cancer patients is unclear. 

Study findings: 

In this study, participants were tested for mutations in 30 genes that are associated with increased risk of breast cancer:

  • 14 of 100 patients (14%) had a mutation in a repair or cancer gene.
    • 8 of 100 patients (8%) had a mutation in a known breast cancer gene (BRCA1/2, , )
      • 6 of 100 patients (6%) had a mutation in or .
    • 21 of 100 patients (21%) had a result known as a variant of unknown significance ().

The study authors concluded that all patients with breast cancer may benefit from genetic testing for germline mutations.

What does this mean for me?

If you have breast cancer and you have not had genetic testing, you may want to consider getting tested or having additional testing. If you have a mutation in or , you and your health care provider may want to consider BRCA-targeted treatments such as PARP inhibitors. People with breast cancer who test positive for a mutation associated with may benefit from the agent pembrolizumab (Keytruda).

At this time it is unknown whether approved treatments for people with mutations will also benefit individuals who have mutations in other breast cancer-associated genes. If you test positive for a different mutation than , you may qualify for a clinical trial looking at targeted therapies for people with your gene mutation.

More data is required to resolve the impact of a variant of unknown significance.

If you are a person living with breast cancer and you had genetic testing which was done before 2014 with negative test results, you may want to speak with a genetic counselor to learn if you may benefit from additional genetic testing.

Regardless of your genetic test results, it’s important to speak with a genetics expert to understand the meaning of your test results for you and your family.

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

Posted 9/26/19
 

References

Stuttgen K, Croessmann S, Fetting J, et al. “Pathogenic germline variants in patients with breast cancer.” JAMA Oncology. Published online August 29, 2019. doi:10.1001/jamaoncol.2019.3116

Pritchard CC, Mateo J, Walsh MF, et al. “Inherited DNA-Repair Gene Mutations in Men with Prostate Cancer.” New England Journal of Medicine. 2016; 375: 443-453.
 

Disclosure

FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

This article is relevant for:

People with metastatic breast cancer

This article is also relevant for:

Men with breast cancer

Triple negative breast cancer

ER/PR +

Her2+ breast cancer

People with a genetic mutation linked to cancer risk

Breast cancer survivors

Women under 45

Women over 45

Metastatic cancer

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IN-DEPTH REVIEW OF RESEARCH

Study background:

Genetic testing can inform people about breast cancer risk and impact health care decisions. For people with some gene mutations, such as those in and , the recommendations are clear regarding increased surveillance, considering preventive options and weighing treatment choices that target pathways. With recent approval of several PARP inhibitors, clinically actionable information is now available for people with BRCA1/2 mutations who have advanced or cancer.

It is unclear how much some inherited mutations increase risk. Experts debate whether it is beneficial to test for rarer mutations, and if identified, what course of clinical treatment to recommend. NCCN guidelines have been developed to provide guidance for who should be tested. However, most participants in studies used to develop NCCN guidelines had breast cancer. It is unclear whether the frequency of inherited mutations would be different among breast cancer patients.

A 2016 study by Pritchard and colleagues found that 11.8% of patients with prostate cancer had a pathogenic or likely pathogenic mutation. Nearly 10% of these mutations were in genes associated with breast cancer risk (BRCA1/2, , , and ). Based on this and similar data, NCCN guidelines were changed to recommend germline genetic testing for all patients with prostate cancer.

Researchers of this study wanted to know:

the frequency of inherited mutations among breast cancer patients and whether it may be useful to test all MBC patients for germline mutations.

Populations looked at in this study:

This study involved 100 breast cancer patients who were selected only on the criteria that they had breast cancer, rather than a particular family history or breast cancer risk. Individuals were excluded if they had already been tested for more than 10 breast cancer genes.

On average, participants were 49 years old when they were diagnosed with breast cancer, 56 years old when they were diagnosed with breast cancer and 59 years old when they consented to participate in this study. Participants were 76% non-Hispanic white, 12% black, 6% Asian and 3% Hispanic. Two participants were male.

Study design:

Participants were tested for mutations in 30 genes that are associated with increased risk of breast cancer.

Study findings:  

  • 14 of 100 patients (14%) had a pathogenic or likely pathogenic mutation (P/LP)
    • The mutations found were
      • 3 in APC
      • 1 in
      • 1 in
      • 5 in
      • 1 in
      • 1 in
      • 1 in MITF
      • 1 in MUTYH
    • 2 of 6 patients (33%) with a BRCA1/2 mutation had never had genetic testing.
    • Among the mutations deemed pathogenic or likely pathogenic:
      • 8 of 100 patients (8%) had a mutation in a gene that has clear evidence of increased breast cancer risk according to the NCCN (1 in , 5 in , 1 in and 1 in CHEK1).
      • 6 of 100 patients (6%) had a mutation in a gene in which the evidence of increased breast cancer risk is less clear (3 in APC, a gene that is more traditionally associated with colorectal cancer; 1 in , in which evidence of breast cancer risk is currently insufficient by NCCN guidelines; 1 in MITF and 1 in MUTYH).
      • 6 of 14 patients (6%) with a pathogenic or likely pathogenic mutation did not meet NCCN guidelines (i.e., may not have otherwise been tested), including 3 in APC, 1 in , 1 in and 1 in CHEK1.
  • 21 of 100 patients (21%) had a variant of unknown significance.

Study authors concluded that all patients with breast cancer may benefit from genetic testing for germline mutations.

Limitations:

  • This is a relatively small study. Additional research involving a larger group of participants is needed to validate this result.
     
  • Experts debate whether some of the mutations listed by this study as pathogenic or likely pathogenic are truly associated with increased breast cancer risk.
    • 8 of the observed mutations listed by the authors as pathogenic/likely pathogenic are listed by the NCCN as having increased breast cancer risk and warranting genetic testing in family members (1 mutation each in the , and genes and 5 mutations in ).
    • 6 mutations are in genes in which the evidence of breast cancer association is less clear (3 in APC, a gene associated with colorectal cancer; 1 in , which NCCN guidelines say have insufficient evidence; 1 in MITF and 1 in MUTYH).
       
  • This study had no controls. Ideally, researchers use age-matched controls from the same population who do not have breast cancer to identify the frequency of these mutations in the general population and determine how that compares to the frequency among breast cancer patients. Not having controls is a major limitation of this study.
     
  • Some patients who had prior genetic testing (of more than 10 genes) were excluded from the study. Additionally, for some genes, genetic testing in this study did not evaluate the entire gene. As a result, these numbers may underestimate the rate of genetic mutation among breast cancer patients.

Conclusions:

The study authors concluded that all patients with breast cancer may benefit from genetic testing for germline mutations. Of all MBC patients tested, 8% had inherited mutations that are clearly associated with breast cancer, including 6% of MBC patients with mutations in BRCA1/2, which are clinically actionable.

Due to the small sample size and lack of population controls, additional research on a larger population is needed to confirm this study’s result. Furthermore, we do not know whether patients with non-BRCA mutations benefit from BRCA-targeted treatments for breast cancer. It is also unclear whether knowledge of genetic status for patients with non-BRCA mutations would be helpful in making decisions about MBC.

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

Posted 9/26/19

Expert Guidelines
Expert Guidelines

The National Comprehensive Cancer Network has guidelines on who should undergo genetic counseling and testing. If you have been diagnosed with breast cancer, you should speak with a genetics expert about genetic testing if any of the following apply to you:     

  • You have a blood relative who has tested positive for an inherited mutation 
  • You have any of the following:  
    • Breast cancer at age 50 or younger  
    • Male breast cancer at any age
    • Ovarian cancer at any age  
    • at any age 
    • Two separate breast cancer diagnoses
    • Eastern European Jewish ancestry and breast cancer at any age 
    • breast cancer 
    • Testing of your tumor shows a mutation in a gene that is associated with
    • breast cancer and high risk for recurrence
    • Lobular breast cancer and a family history of diffuse gastric cancer

OR 

  • You have one or more close family members who have had:  
    • Young-onset or rare cancers 
    • Breast cancer at age 50 or younger
    • Male breast cancer, ovarian cancer, pancreatic cancer, or   cancer at any age
    • Two separate cancer diagnoses 
    • cancer at age 55 or younger or prostate cancer 

The American Society of Breast Cancer Surgeons (ASBrS) released guidelines in 2019 that recommend all women diagnosed with breast cancer have access to genetic testing for inherited mutations in breast cancer genes. 

If you are uncertain whether you meet the guidelines above and you are interested in or considering genetic testing, you should speak with a cancer genetics expert

 

Updated: 11/22/2021

Expert Guidelines
Expert Guidelines

The National Comprehensive Cancer Network (NCCN) indicates that tumor testing can help determine if a person with breast cancer would benefit from .

  • For tumors that are hormone receptor-positive, , testing for PIK3CA mutations is recommended to help identify patients who would benefit from a known as a PI3K inhibitor.
  • For tumors that are hormone receptor-negative, , testing for PDL-1 is recommended to help identify patients who might benefit from .
  • For  breast tumor types, testing for MSI-H/dMMR may help identify patients who would benefit from

Updated: 12/09/2021

Questions To Ask Your Doctor
Questions To Ask Your Doctor

  • I have breast cancer; should I have genetic testing?
  • Who should I contact to have genetic testing?
  • If I have a mutation in a gene that is associated with increased breast cancer risk, how might that change my treatment for breast cancer?
  • What are the risks and benefits of genetic testing for me and my family?

Open Clinical Trials
Open Clinical Trials

The following studies involve genetic testing in people with advanced cancers:

Updated: 11/11/2021

Peer Support
Peer Support

The following organizations offer peer support services for people with, or at high risk for breast cancer:

Updated: 09/02/2022

Who covered this study?

Cancer Therapy Advisor

Germline Testing Should Be Routinely Conducted in Patients with Metastatic Breast Cancer This article rates 3.0 out of 5 stars

News-Medical.Net

Genetic testing may help patients with metastatic breast cancer This article rates 2.5 out of 5 stars

American Journal of Managed Care

Also published in:

The Weather Hearld

All Patients with Metastatic Breast Cancer Should Undergo Germline Testing, Study Finds This article rates 2.5 out of 5 stars

How we rated the media

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