Another Gene Mutation Increases Breast Cancer Risk

Alexander Castellino, PhD

August 06, 2014

There is now evidence that mutations in the PALB2 gene are associated with a significantly increased risk for breast cancer in women. In fact, the risk of developing breast cancer at the age of 70 is 35% higher in women with PALB2 mutations than in those without, according to a report published in the August 6 issue of the New England Journal of Medicine.

"Although PALB2 was discovered in 2006 and its association with breast cancer was reported in 2007, this is the first study providing clear risk estimates for PALB2 mutation carriers based on their family history," said lead investigator Marc Tischkowitz, MD, from the Department of Medical Genetics at the University of Cambridge, United Kingdom.

The study shows that the breast cancer risk increases when women with PALB2 mutations also have strong family history of breast cancer, he told Medscape Medical News.

"There is a 20% range in risk, depending on one's family history of breast cancer," coauthor William D. Foulkes, MBBS, PhD, from McGill University in Montreal, told Medscape Medical News. After BRCA1 and BRCA2, PALB2 is the next important gene that will define risk for breast cancer, he added.

This is a first step in understanding the polygenic nature of breast cancer.

"This is a first step in understanding the polygenic nature of breast cancer," according to Michele K. Evans, MD, from the Laboratory of Epidemiology and Populations Sciences, National Institute on Aging, National Institutes of Health, Baltimore, Maryland. She coauthored, along with her colleague Dan L. Longo, MD, an accompanying editorial.

"While we know the risks associated with BRCA1 and BRCA2, we do not know the risk for breast cancer associated with other genes," Dr. Evans told Medscape Medical News. However, because of the homogenous nature of the women in this study, we need to study PALB2 mutations in a broader group of women who are at high risk for breast cancer, she explained.

Clinical Relevance of PALB2

Since the discovery of PALB2, the challenge has been to determine its clinical relevance. The PALB2 Interest Group, which comprises 14 research groups from 8 countries (including Australia, Canada, the United States, and some in Europe), was formed in 2009 to address the issue.

The collaboration resulted in a study of 154 families, in which 311 women and 51 men had PALB2 mutations. Risks were determined from family trees and modeling studies.

"PALB2 is a potential candidate to be 'BRCA3'. As mutations in this gene are uncommon, obtaining accurate risk figures is only possible through large international collaborations like this," Dr. Tischkowitz said in a press release.

PALB2 Mutations in Clinical Practice

Although PALB2 mutations are not as frequent as BRCA mutations and associated risks for breast cancer are lower, the risks identified in this study are important enough to warrant clinical use, Dr. Foulkes told Medscape Medical News.

It is important to provide women with PALB2 mutations a clear estimate of risk for breast cancer. Dr. Tischkowitz said he supports surveillance for these patients that is similar to the way women with BRCA mutations are managed.

"The study is a paradigm of how to gather the kind of information that clinicians need to advise their patients about the meaning of mutations in these genes," Mark E. Robson, MD, told Medscape Medical News. As clinical director of the clinical genetics service at the Memorial Sloan Kettering Cancer Center in New York City, he helps patients with cancer incorporate genetic information into treatment decisions.

PALB2 is already present in all the panels that offer BRCA1 and BRCA2 testing; however, until now, the significance of PALB2 and other genes in these panels was not known, according to Dr. Robson and Dr. Tischkowitz.

"If a woman with a strong family history of breast cancer tested negative for mutations in BRCA1 and BRCA2 in the past, there may be value in revisiting the case and determining the status of PALB2," explained Dr. Foulkes.

Surveillance for breast cancer should be increased for women with PALB2 mutations and their families, said Dr. Tischkowitz. Although genetic counseling is appropriate for these women, the role of preventive surgery requires further studies, he added.

Dr. Robson agrees that this study has no immediate therapeutic implications. The year-to-year risk in these patients is not dissimilar to that associated with atypical hyperplasia of the breast or lobular carcinoma in situ — situations not routinely appropriate for preventive surgery, he explained.

The association between PALB2 and BRCA2 provides an indication of the way cancer patients with these mutations might be treated. Because poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors can be effective in treating cancers with BRCA1 and BRCA2 mutations, women with PALB2 cancers might also be appropriate candidates for therapy with PARP inhibitors.

The results of this study provide an argument for including these women in clinical trials evaluating PARP inhibitors, Dr. Tischkowitz said.

The authors have disclosed no relevant financial relationships.

N Engl J Med. 2014;371:497-506, 566-568. Abstract, Editorial


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