Judy E. Garber, MD
mutations have been intensely studied in breast cancer for more than a decade, researchers are still seeking to determine which patient populations should be screened for abnormalities and how best to integrate that information into treatment protocols.
Two abstracts presented at the 2015 ASCO Annual Meeting explored those questions. In one study, researchers found evidence to support mutation testing of women 45 years or younger who have been diagnosed with any type of breast cancer.1
In another study, investigators correlated clinical outcomes among patients with triplenegative breast cancer (TNBC) with an assay that offers a more comprehensive DNA repair pathway analysis than BRCA1/2
testing alone.2Screening Younger Women
Platinum agents and PARP inhibitors are increasingly under study in women with TNBC, particularly among patients who harbor BRCA1/2
mutations. Yet focusing mutation testing on that population may bypass other patients who also might benefit from these therapies, according to Judy E. Garber, MD.
In a small study, Garber and colleagues found that BRCA
and other mutations occurred in more than 10% of estrogen-receptor (ER)–positive/ HER2-negative invasive breast cancers in a cohort of women younger than 50 years.1
Overall, 11 of 106 patients (10.4%) had a deleterious mutation. These included seven patients (6.6%) with BRCA1
mutations. Other genes related to breast cancer identified through the analysis were ATM
, and PALB2
. One patient had a mutation in both BRCA2
“Neither age at diagnosis nor family history distinguished carriers in this relatively small cohort of women diagnosed before age 50,” said Garber, director of the Cancer Risk and Prevention Clinic at Dana-Farber Cancer Institute in Boston. “National Comprehensive Cancer Network [NCCN] guidelines call for testing women with breast cancer diagnosed at age 45 years or younger, regardless of subtype. These data are a reminder to extend testing beyond patients with triple-negative breast cancer.”
Among women with newly diagnosed TNBC
mutations typically occur in about 25% of tumors diagnosed at age 50 years or earlier and in 10% to 15% of tumors diagnosed at age 60 years or earlier. Epidemiologic data have shown that BRCA
mutation carriers who are younger than 50 years at diagnosis are more likely to have higher-grade ER-positive tumors.
Given the NCCN recommendation for genetic testing of women 45 years or younger, “We wondered whether we are missing patients who might benefit from targeted therapies if only those with triple-negative breast cancer are tested,” said Garber. “We looked beyond BRCA
to begin to contribute to that epidemiology.”
Investigators obtained blood samples from consenting patients with invasive breast cancer. All patients were younger than 50 years at diagnosis, had ER-positive/HER2-negative breast cancer, grade 3 (poorly differentiated) disease, and invasive cancer only. After exclusions for incorrect grade, insufficient DNA, and other factors, 106 patients remained for testing and data analysis.
The patient specimens were assessed by means of a next-generation sequence-based panel that identified mutations in 25 cancer predisposition genes. Investigators classified germline sequence variations and large rearrangements for pathogenicity.
The test panel identified deleterious mutations in 11 patients. BRCA1
mutations were detected in four patients and BRCA2
in three patients. Other cancer-predisposition genes identified in the study were ATM
in two patients (including one BRCA2
in one patient, and PALB2
in two patients.
Gunter von Minckwitz, MD
Investigators found one or more variants of unknown significance (VUS) in any gene in 47 of 106 patients. The VUS occurred alone in 39 cases and with a mutation in eight cases. Mutation frequencies were higher among women of Ashkenazi Jewish ethnicity (3 of 11 mutations, 27.3%; P
= .02), progesterone-receptor– negative tumors (27.3% vs 5.3% of women without mutations; P
<.01), and women who previously had undergone genetic testing (81.8% vs 42.1% of women without mutations; P