Study: Inherited mutations in metastatic breast cancer patients

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.

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Posted 9/26/19