P1-09-03: Prevalence of Germline TP53 Mutations in Young Women with HER2−Positive Breast Cancer.
Authors: Dick MG , Masciari S , Miron A , Miron P , Foley K , Gelman R , Dillon DA , Richardson AL , Verselis SJ , Lypas G , Krop IE , Garber JE 
Published: June 2012

Abstract
Background: Li Fraumeni syndrome is a rare inherited cancer susceptibility condition associated with germline mutations in the TP53 gene, in which breast cancer (BC) is the most frequent tumor. The prevalence of TP53 mutations in population-based series of very young onset BC (&lt;30 years at diagnosis) ranges from &lt;1% to approximately 7%1-4. Recent data show that BC in patients carrying a germline TP53 mutation are commonly HER2 amplified (63-83%)5-7. In this study, we assessed the prevalence of germline TP53 mutations in women with HER2 positive BC diagnosed age ≤ 50 years.
Material & Methods: We identified 347 women with invasive HER2 positive BC diagnosed at age ≤ 50 years using the Clinical Operations and Research Information System (CORIS) at the Dana Farber Cancer Institute. Information on age at diagnosis, histology, hormone receptor and HER2 status as well as personal and family cancer history was confirmed from medical records. 129 patients were excluded for various reasons, including a cancer diagnosis prior to the BC and a documented BRCA1/2 mutation. A combination of Exon Grouping Analysis (EGAN) and Sanger sequencing for detection of TP53 mutations in exons 2–11 including surrounding intronic sequence was performed on 218 germline DNA samples. Multiplex Ligation-dependent Probe Amplification (MLPA) analysis for the detection of TP53 deletions or duplications is ongoing.
Results: A germline TP53 mutation was identified in 4 women diagnosed at age ≤ 50 years (1.8%, 95%CI 0.5−4.6). At BC diagnosis, they were 23, 32, 44 and 50 years. Two BC were ER+/PR+, HER2+ and 2 were ER-/PR-, HER2+. Estimate of prevalence of germline TP53 mutations by age at BC diagnosis are: age ≤ 35, 2/41 (4.9%, 95%CI 0.6−16.6), and age ≤ 45 3/168 (1.8%, 95%CI 0.4−5.1). Among the women with germline TP53 mutations, 2 met the Chompret criteria8 and none the classic LFS criteria.
Discussion: TP53 mutations were identified in a cohort of women with HER2+ BC at young age. As expected, the frequency is higher in younger women, but mutations were seen in all age groups that were evaluated. None of these women met classic LFS criteria by family history. Consideration of TP53 testing should be given to women diagnosed below age 35 who are negative for BRCA1/2 mutations regardless of family history. Analysis of other series will be helpful in reaching more stable estimates of the prevalence of mutation carriers among patients with HER2+ BC at young age.
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Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-09-03.