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PALB2 mutations may increase risk for breast cancer mortality
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Women harboring a PALB2 mutation face an increased risk for breast cancer and a potentially increased risk for breast cancer mortality compared with non-carriers, according to the results of a prospective cohort study.
Previous research has indicated PALB2 mutations predispose women for breast cancer. However, the effect of PALB2 mutations on disease prognosis remained unknown, according to study background.
Steven A. Narod, MD, FRCPC, FRCS, professor of medicine at the University of Toronto and director of the familial breast cancer research unit at the Women’s College Research Institute in Toronto, Ontario, and colleagues initiated a prospective cohort study to determine the influence of PALB2 mutations on breast cancer incidence and outcomes.
Steven A. Narod
The analysis included data from 12,529 Polish women (mean age, 53.5 years; range, 18-92) who received treatment for breast cancer between 1996 and 2012. The researchers also evaluated data from a control group (n = 4,702) of women from a population study, women recruited following mammography or colonoscopy screening, and randomly selected women.
The researchers obtained blood samples from all patients and controls to perform DNA extraction and genotyping for two deleterious PALB2 mutations (509_510delGA and 172_175delTTGT). Researchers obtained disease-related relevant information — including age at diagnosis, tumor size, lymph node status, ER status, HER-2 status and bilaterality — from medical records.
Further, patients provided family histories, including the proportion of first- and second-degree relatives with breast and ovarian cancers.
Death from any cause served as the primary endpoint. Among patients with breast cancer, the researchers calculated 10-year survival rates of PALB2 carriers compared with non-carriers.
Median follow-up was 53.5 months.
A greater proportion of women with breast cancer than controls harbored a PALB2 mutation (0.93% vs. 0.21%; OR for breast cancer among PALB2 mutation carriers = 4.39; 95% CI, 2.3-8.37). The 509_510delGA mutation occurred in 76 women with cancer (0.61%) and seven women in the control arm (0.15%), whereas the 172_175delTTGT mutation occurred in 40 women with cancer (0.32%) and three controls (0.06%).
The researchers also found BRCA1 mutations in 435 patients with breast cancer (3.47%) and 22 controls (0.47%; OR for breast cancer among BRCA1 mutation carriers = 7.65; 95% CI, 4.98-11.75). No patient harbored both mutation types.
Ninety-five percent of the breast cancer cohort (n = 11,978) harbored no mutations.
A significantly higher proportion of women with breast cancer harboring PALB2 mutations vs. women with breast cancer without the mutation died during follow-up (33% vs. 15%; P < .0001) and significantly fewer achieved 10-year survival (48% vs. 74.7%; P < .0001). A significantly greater proportion of women with a BRCA1 mutation also achieved 10-year survival compared with women with a PALB2 mutation (72%; P < .0001).
Adjusted analyses indicate PALB2 mutations significantly increased the risk for death among women with breast cancer (HR = 2.27; 95% CI, 1.64-3.15).
In a multivariate analysis of women with breast cancer who harbored PALB2 mutations, the strongest predictor for death was tumor size (2 cm-4.9 cm; HR = 3.94; 95% CI, 1.3-11.9; ≥ 5 cm; HR = 14.3; 95% CI, 3.36-60.6).
The researchers identified their inability to confirm causes of death as a limitation of their study.
“Our estimates are based on small numbers of patients and deaths, and data for the effects of different treatments for PALB2 carriers are too small to support clinical recommendations,” Narod and colleagues concluded. “We did not evaluate specific chemotherapy regimens among PALB2 carriers, because the subgroup who received chemotherapy was too small, and this analysis will be done in a future study.”
These data may suggest surveillance is appropriate for women who harbor PALB2 mutations, Suzette Delaloge, MD, of the department of breast oncology at the Gustave Roussy Institute in Villejuif, France, and colleagues wrote in an accompanying editorial.
“Altogether, the information currently available on prognosis of breast cancer in PALB2 carriers does not seem mature enough to prompt specific prevention and treatment recommendations, particularly with respect to preventive surgery,” Delaloge and colleagues wrote. “Careful breast surveillance should, however, be recommended, using currently available techniques. Although Cybulski and colleagues brought some new pieces to the puzzle, more studies are needed to provide evidence for individual and familial management of PALB2 carriers.”– by Cameron Kelsal
Disclosure: The Polish National Science Centre provided funding for this study. The researchers report no relevant financial disclosures.
Perspective
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Charles L. Shapiro
PALB2 gene plays a key role in DNA repair and several studies suggest that the lifetime (up to 75 years old) risk for developing breast cancer in germline mutation carriers is between 24% and 40%. Germline mutation carriers also have higher risks for developing triple-negative breast cancers than those who are not mutation carriers. The frequency of PALB2 mutations in the population is about 0.5% to 1%.
Cybulski and colleagues performed genotyping in over 12,000 women with breast cancer, as well as in over 4,000 women without breast cancer who served as controls in a prospective nested case–control trial. The major findings were the 10-year survival of breast cancer with a germline mutation was 48% vs. 75% for those without the mutation, a highly statistically significant result (adjusted HR for death = 2.27 95% CI 1.64-3.15). In addition, 34% of the mutation carriers had triple-negative breast cancer vs. 14% of the non-mutation carriers (P < 0.0001).
PALB2 adds to a growing list of rare germline mutations associated with increased risks for breast cancer beyond the BRCA genes, including the highly penetrant PTEN, p53, CDH11, STK11, and moderately penetrant CHEK2, BRIP and ATM. That rarer gene mutations increase the risk for breast has led to the more frequent use of gene panel testing. However, many of the mutations detected on these panels are of unknown significance; so, in my view, panel testing is a mixed blessing.
The study from Cybulski and colleagues of PALB2 mutations adds much to the literature. But is having a PALB2 mutation enough to make clinical decisions on prophylactic surgery? I don’t know the answer, but in the accompanying editorial by Delaloge and colleagues, their conclusions was “not yet” and additional studies are needed. However, they recommended careful breast surveillance for PALB2 mutation carriers. Women need to have the most up to date, though incomplete, information to make the best decisions.
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