Gene Testing in Triple-Negative Breast Cancer Patients

Liam Davenport

December 04, 2014

A study of nearly 2000 patients with triple-negative breast cancer has found that nearly 15% carry deleterious genetic mutations, lending support to current guidelines that recommend genetic testing in this patient population, say the researchers.

The study was published online December 1 in the Journal of Clinical Oncology.

The findings support current practice guidelines in the United States for genetic testing for triple-negative breast cancer. This form of breast cancer, which has little or no expression of estrogen receptor, progesterone receptor, and human epidermal growth-factor 2 receptor, is associated with a worse prognosis than other types of breast cancer.

This study has important implications for clinical practice, said lead author Fergus J. Couch, PhD, professor of laboratory medicine and pathology at the Mayo Clinic in Rochester, Minnesota. This is "a confirmatory study so large that it really does give fairly accurate probability estimates for these patients," Dr Couch told Medscape Medical News.

"It ended up actually confirming a lot of what we already had in place, but it's important to do that. Hopefully, going forward, it will strengthen those guidelines and people will actually follow those now for testing of patients," he added. "Where I see the benefit is that it will convince people to follow the guidelines."

Deleterious Mutations Found in Nearly 15%

Dr Couch and colleagues analyzed data on 1824 women with triple-negative breast cancer from 12 studies in the United States and Europe. The average age at diagnosis was 51 years. In this cohort, 34% of patients had at least one first- or second-degree relative with breast cancer, and 4% had a relative with ovarian cancer.

Germline DNA samples were obtained from each women and tested for mutations in 122 DNA repair genes, including 17 known to be predisposing to breast cancer.

In all, 271 deleterious mutations were identified in 267 (14.6%) of the women; 8.5% were in the BRCA1 gene, 2.7% were in the BRCA2 gene, and 3.7% were in the remaining 15 genes (the majority of which were in the PALB2, BARD1, RAD51D, RAD51D, and BRIP1 genes).

Patients with deleterious gene mutations were significantly younger at diagnosis than those with no mutations (45 vs 51 years). Nevertheless, 10.0% of mutation carriers were diagnosed when they were 60 years or older, whereas 5.5% of all patients with triple-negative disease were.

Mutation carriers also presented with higher-grade tumors than patients without mutations (P < .001). Associations between the presence of mutations and a family history of breast or ovarian cancer were less consistent, however.

Improvements in Care

Dr Couch said he hopes that the findings will increase genetic testing in patients with triple-negative breast cancer, and believes that this will ultimately improve care for the patient population.

He noted that the National Comprehensive Cancer Network (NCCN) guidelines recommend that all patients younger than 60 years with triple-negative breast cancer, whether or not they have a family history of the disease, undergo genetic testing. "Unfortunately, in the clinics that tends to get ignored, and many people do not get tested," he said.

"As we've shown, there's a fairly large number of mutation carriers embedded in that population," he said.

Knowing that a genetic mutation is involved could lead to a change in therapy, he suggested, noting that drugs acting as poly(ADP-ribose) polymerase (PARP) inhibitors have shown promise in the treatment of BRCA cancers. In fact, the first ever drug in this class, olaparib (Lynparza, AstraZeneca), has just been recommended for approval in ovarian cancer in patients with BRCA mutations in the European Union, although it was not recommended for that indication in the United States.

Dr Couch suggested that once patients are known to have a BRCA mutation, they could be enrolled in a clinical trial with PARP inhibitors. "That's a new development that is of benefit to these people," he said.

A further benefit of identifying mutations in triple-negative patients, Dr Couch explained, is that they can inform their family members, who can be tested and learn whether or not they are at risk.

Comparison of American and British Guidelines

As part of their analysis, Dr Couch and colleagues applied the findings to both the NCCN guidelines, which recommend testing all patients diagnosed with triple-negative breast cancer before the age of 60 years, and the National Institute for Health and Care Excellence (NICE) guidelines in the United Kingdom, which do not recommend testing patients diagnosed when they are older than 40 years if they do not have a family history of cancer.

"In the UK, the NICE guidelines select people for testing based on a probability model. You have to have a likelihood greater than 10% of having a BRCA1 or BRCA2 mutation in order to get tested," Dr Couch explained.

"That generally ends up being a cut-point of about 40 years of age for diagnosis, and anyone under 40 years or with a family history ends up getting tested," he added.

"Everybody thought that was a reasonable approach, but in our study we've basically shown that up to 20% of patients are missed by that cut-off, which is a very large proportion," he pointed out. "We looked at the numbers and the ages at diagnosis, and we found that, of those diagnosed between the ages of 40 and 50 without a family history, 8.6% have mutations, and between the ages of 50 and 60, 7.5% have mutations."

"That's not very far off 20%, and perhaps the UK NICE group would want to reconsider their cut-point and, in fact, extend it up to 50 or 60 years of age for testing, just like they do in the United States," he said.

An interesting question remains. Why, in the absence of the findings from this study, was the cutoff of 60 years chosen for the NCCN guidelines? "There really weren't a lot of data to support that," Dr Couch noted.

"I think a lot of it was just a number of genetic counselors or physicians who saw a lot of these types of patients and just had a general feeling that this was the right way to go," he explained. "It was sort of a 'safe zone' where they wouldn't miss very many patients."

"There were really not a lot of data in the literature to support that number prior to our study, so I don't really know how they came up with it. I think there was a lot off guesswork involved," he added.

This study was funded by the National Institutes of Health, the Breast Cancer Research Foundation, and the David F. and Margaret T. Grohne Family Foundation. Dr Couch reports owning a patent with Myriad Genetics.

J Clin Oncol. Published online December 1, 2014. Abstract

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