Small Study Finds High Rate of Gene Mutations in People Diagnosed With Metastatic Breast Cancer

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Of 100 people diagnosed with metastatic breast cancer, 14 had a genetic mutation linked to the disease and 21 had a variant of unknown significance, according to a small Johns Hopkins study.

The research was published online on Aug. 29, 2019, by JAMA Oncology. Read the abstract of “Pathogenic Germline Variants in Patients With Metastatic Breast Cancer.”

Gene mutations linked to breast cancer

A germline variant is a change, or mutation, in a gene that is inherited from your parents and is in all your DNA. “Pathogenic” means the mutation is linked to a higher risk of disease — in this case, breast cancer.

A variant of unknown significance means that there is a mutation in the gene, but researchers haven’t confirmed whether this mutation is a harmless change or a risk factor for disease.

Two of the most well-known genes that can mutate and raise the risk of breast and/or ovarian cancer are BRCA1 and BRCA2. Women who inherit a mutation in either of these genes — from their mothers or their fathers — have a much higher-than-average risk of developing breast cancer and/or ovarian cancer.

Men with these mutations also have an increased risk of breast cancer, especially if the BRCA2 gene is affected, and possibly of prostate cancer.

About 5% to 10% of breast cancers are thought to be hereditary, meaning the cancer is linked to germline mutations passed from parent to child.

You are substantially more likely to have a genetic mutation linked to breast cancer if:

  • You have blood relatives (grandmothers, mother, sisters, aunts) on either your mother's or father's side of the family who had breast cancer diagnosed before age 50.
  • There is both breast and ovarian cancer on the same side of the family or in a single individual.
  • You have a relative(s) with triple-negative breast cancer.
  • There are other cancers in your family in addition to breast, such as prostate, melanoma, pancreatic, stomach, uterine, thyroid, colon, and/or sarcoma.
  • Women in your family have had cancer in both breasts.
  • You are of Ashkenazi Jewish (Eastern European) heritage.
  • You are African American and have been diagnosed with breast cancer at age 35 or younger.
  • A man in your family has had breast cancer.
  • There is a known breast cancer gene mutation in your family.

About this study

The study included 100 people diagnosed with metastatic breast cancer; 98 were women and two were men. The metastatic disease could be metastatic at first diagnosis, called de novo, or a metastatic recurrence of previously diagnosed early-stage breast cancer.

The people were about 56 years old when diagnosed with metastatic breast cancer:

  • 76% were white
  • 12% were black
  • 6% were Asian
  • 3% were Hispanic
  • 3% were other ethnicities/races

The characteristics of the metastatic breast cancers:

  • 66% were hormone-receptor-positive and HER2-negative
  • 13% were estrogen-receptor-negative, progesterone-receptor-negative, and HER2-negative (triple-negative)
  • 13% were hormone-receptor-positive and HER2-positive
  • 8% were hormone-receptor-negative and HER2-positive

All the participants had genetic testing using a panel test from Color Genomics that looked for mutations in 30 genes, including BRCA1 and BRCA2.

The genetic testing results showed:

  • 14 people had a mutation linked to cancer
  • 21 people had a variant of unknown significance

Of the 14 people with a mutation linked to cancer, six of them (43%) did not meet National Comprehensive Cancer Network (NCCN) criteria for genetic testing, though none of these six people had a BRCA mutation.

Six people were found to have a BRCA mutation. Of these six, two people had never had genetic testing before, even though they met NCCN criteria for genetic testing.

“Our results provide additional support for testing patients with metastatic breast cancer based on their relatively high prevalence of pathogenic or likely pathogenic variants, including a 6% frequency of [pathogenic] variants in BRCA,” the researchers wrote. “Furthermore, given that many of the genes included on the multigene panel are involved in DNA repair, there is scientific rationale that some of these [pathogenic] variants (ATM, BRIP1, CHEK2) may also be predictive for response to PARP inhibitors, a hypothesis currently being tested in clinical trials. Consequently, our results provide evidence to support genetic testing for inherited cancer predisposition among all patients with metastatic breast cancer because this group represents a population with a high prevalence of [pathogenic] variants that could have therapeutic implications.”

What this means for you

If you have been diagnosed with metastatic breast cancer and have never had genetic testing, it’s a good idea to talk to your doctor about it. Currently, there are two PARP inhibitors:

  • Talzenna (chemical name: talazoparib)
  • Lynparza (chemical name: olaparib)

that can be used to treat metastatic HER2-negative breast cancer in people with a BRCA mutation.

DNA carries genetic information in both healthy cells and cancer cells. Cells can develop DNA damage spontaneously or from exposure to specific things in the environment (too much sun, for example) that make DNA damage more likely to happen. But cells can detect and repair damage to DNA. When DNA is damaged in a healthy cell and the damage isn't fixed, that cell can become cancerous. The function of the BRCA genes is to keep breast cells growing normally and prevent any cancer growth. But if there is a mutation in the BRCA1 or BRCA2 gene, it increases the risk of breast and other cancers because these gene mutations interfere with cells' ability to repair damaged DNA.

The poly ADP-ribose polymerase (PARP) enzyme fixes DNA damage in both healthy and cancer cells. Research has shown that PARP inhibitor medicines, which interfere with (inhibit) the PARP enzyme, make it even harder for cancer cells with a BRCA1 or BRCA2 mutation to fix DNA damage. This makes it harder for the cancer cells to survive. In other words, a PARP inhibitor makes some cancer cells less likely to survive their DNA damage.

If you have metastatic disease and don’t have genetic testing, you may be missing out on treatment options that could benefit you.

If you had genetic testing a number of years ago, when the tests only looked for mutations in the BRCA1 and BRCA2 genes, it makes sense to talk to your doctor about having a newer panel test that looks for mutations in a number of genes linked to breast cancer, including ATM, BRIP1, and CHEK2. As the researchers pointed out, mutations in these other genes also may mean that a breast cancer is susceptible to a PARP inhibitor.

For more information on genetic testing, including types of genetic tests and how results are reported, visit the Breastcancer.org Genetic Testing pages.

To connect with others who have been diagnosed with metastatic breast cancer, visit the Breastcancer.org Stage IV/Metastatic Breast Cancer ONLY forum.

Written by: Jamie DePolo, senior editor

Reviewed by: Brian Wojciechowski, M.D., medical adviser


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