Study: Inherited mutations In metastatic breast cancer patients


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People with metastatic breast cancer

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Checked Breast cancer survivors

Checked ER/PR +

Checked Her2+ breast cancer

Checked Men with breast cancer

Checked Metastatic cancer

Checked People with a genetic mutation linked to cancer risk

Checked Triple negative breast cancer

Checked Women under 45

Checked Women over 45

Checked Special populations: People with metastatic breast cancer


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Recent research shows that a significant portion of patients with metastatic breast cancer have harmful mutations in a gene associated with hereditary breast cancer and increased breast cancer risk. (9/26/19)

Contents

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


STUDY AT A GLANCE

This study is about:

Genetic testing of metastatic 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 BRCA, PALB2, ATM can help people with breast cancer understand their risk and medical options. For a metastatic 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 metastatic 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 DNA repair or cancer gene.
    • 8 of 100 patients (8%) had a mutation in a known breast cancer gene (BRCA1/2, CHEK2, ATM)
      • 6 of 100 patients (6%) had a mutation in BRCA1 or BRCA2.
    • 21 of 100 patients (21%) had a result known as a variant of unknown significance (VUS).

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

What does this mean for me?

If you have metastatic 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 BRCA1 or BRCA2, you and your health care provider may want to consider BRCA-targeted treatments such as PARP inhibitors. People with metastatic breast cancer who test positive for a mutation associated with Lynch Syndrome may benefit from the immunotherapy agent pembrolizumab (Keytruda).

At this time it is unknown whether approved treatments for people with BRCA mutations will also benefit individuals who have mutations in other breast cancer-associated genes. If you test positive for a different mutation than BRCA, 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 metastatic 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.

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Expert Guidelines

The National Comprehensive Cancer Network (NCCN) is a consortium of cancer and genetics experts that publishes consensus guidelines for genetic testing for inherited mutations that increase cancer risk.

NCCN guidelines for genetic testing for people who are diagnosed with breast cancer include: 

  • Breast cancer of any type (including ductal carcinoma in situ or DCIS) diagnosed before age 50.  
  • Breast cancer in both breasts or a second breast cancer in the same breast.
  • Triple-negative (ER-/PR-/Her2-) breast cancer before age 60.
  • Ashkenazi (Eastern European) Jewish ethnicity. 
  • Relatives with breast, ovarian, pancreatic, prostate or melanoma cancer. 
  • Men with breast cancer. 
  • HER2-negative, metastatic breast cancer. The NCCN recommends BRCA testing before starting chemotherapy, to determine whether a patient might benefit from treatment with a PARP inhibitor. 

The NCCN highly recommends cancer risk assessment and genetic counseling before genetic testing (pre-test counseling) is offered and after results are disclosed (posttest counseling). A genetic counselor, medical geneticist, oncologist, surgeon, oncology nurse or other health professional with expertise and experience in cancer genetics should be involved early in the patient counseling process. 

Questions To Ask Your Health Care Provider

  • I have metastatic 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 metastatic breast cancer?
  • What are the risks and benefits of genetic testing for me and my family?

Open Clinical Trials

Clinical trials

The following trial focuses on genetic testing in metastatic breast cancer patients:

NCT03983577: Efficacy of Point Of Service Testing in MBC (EPOST MBC)

Soon to be enrolling patients with HER2-negative metastatic breast cancer who did not have BRCA testing after 2013. This study will look at the usefulness of a genetics counseling delivery model for metastatic breast cancer patients who are referred for hereditary cancer genetic counseling and testing.

The following trial focuses on genetic testing in various cancers:

NCT00579514: Germline Alterations of Tumor Susceptibility Genes in New York Cancer Patients. This study at Memorial Sloan Kettering in New York is designed to determine  whether there are associations between certain germline mutations and various cancers. Patients with a diagnosis of colon, bladder, breast, testicular, prostate, ovarian, kidney, lung, lymphoid or head and neck cancer may be eligible.

The following trials focus on understanding whether PARP inhibitors are useful for people with non-BRCA mutations:

NCT03344965: Olaparib Expanded. The trial looks at whetehr olaparib ( ) is useful for people with either 1) BRCA1/2 mutations in their tumor that were not inherited mutations and 2) people with mutations in genes that function to repair DNA damage  (i.e. ATM, CHEK2, NBN, PALB2, RAD50, RAD51C/D).

NCT02401347: Talazoparib Beyond BRCA (TBB) Trial. This trial looks at whether talazoparibis useful for 1) people with a non-BRCA inherited mutations or 2) people with triple-negative breast cancer and a tumor test that shows homologous recombination deficiency (HRD).

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 BRCA1 and BRCA2, the recommendations are clear regarding increased surveillance, considering preventive options and weighing treatment choices that target BRCA pathways. With recent approval of several PARP inhibitors, clinically actionable information is now available for people with BRCA1/2 mutations who have advanced or metastatic 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 early-stage breast cancer. It is unclear whether the frequency of inherited mutations would be different among metastatic breast cancer patients.

A 2016 study by Pritchard and colleagues found that 11.8% of patients with metastatic prostate cancer had a pathogenic or likely pathogenic mutation. Nearly 10% of these mutations were in genes associated with breast cancer risk (BRCA1/2, CHEK2, ATM, RAD51D and PALB2). Based on this and similar data, NCCN guidelines were changed to recommend germline genetic testing for all patients with metastatic prostate cancer.

Researchers of this study wanted to know:

the frequency of inherited mutations among metastatic 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 metastatic breast cancer patients who were selected only on the criteria that they had metastatic 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 metastatic 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 ATM
      • 1 in BRCA1
      • 5 in BRCA2
      • 1 in BRIP1
      • 1 in CHEK2
      • 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 BRCA1, 5 in BRCA2, 1 in ATM 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 BRIP1, 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 ATM, 1 in BRIP1 and 1 in CHEK1.
  • 21 of 100 patients (21%) had a variant of unknown significance.

Study authors concluded that all patients with metastatic 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 ATM, BRCA1 and CHEK2 genes and 5 mutations in BRCA2).
    • 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 BRIP1, 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 metastatic breast cancer to identify the frequency of these mutations in the general population and determine how that compares to the frequency among metastatic 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 metastatic breast cancer patients.

Conclusions:

The study authors concluded that all patients with metastatic 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 metastatic 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

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