Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort

Abstract

Background Breast cancer is the most common tumor in women with Li Fraumeni Syndrome (LFS), an inherited cancer syndrome associated with germline mutations in the TP53 tumor suppressor gene. Their lifetime breast cancer risk is 49% by age 60. Breast cancers in TP53 carriers have recently been reported to more often be hormone receptor and HER-2 positive by immunohistochemistry and FISH in small series. We seek to expand this small literature with this report of a histopathologic analysis of breast cancers from women with documented LFS. Methods Unstained slides and paraffin-embedded tumor blocks from breast cancers from 39 germline TP53 mutations carriers were assembled from investigators in the LFS consortium. Central histology review was performed on 93% of the specimens by a single breast pathologist from a major university hospital. Histology, grade and hormone receptor status was assessed by immunohistochemistry; HER-2 status was defined by immunohistochemistry and/or FISH. Results The 43 tumors from 39 women comprise 32 invasive ductal carcinomas and 11 ductal carcinomas in situ (DCIS). No other histologies were observed. The median age at diagnosis was 32 years (range 22–46). Of the invasive cancers, 84% were positive for ER and/or PR; 81% were high grade. Sixty three percent of invasive and 73% of in situ carcinomas were positive for Her2/neu (IHC 3+ or FISH amplified). Of the invasive tumors, 53% were positive for both ER, and HER2+; other ER/PR/HER2 combinations were observed. The DCIS were positive for ER and HER2 in 27% of the cases. Conclusions This report of the phenotype of breast cancers from women with Li Fraumeni syndrome nearly doubles the literature on this topic. Most DCIS and invasive ductal carcinomas in Li Fraumeni syndrome are hormone receptor positive and/or HER-2 positive. These findings suggest that modern treatments may improve outcomes for women with LFS-associated breast cancer.

Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells

“…The majority of LFS patients carry germ line mutations in TP53, the gene that encodes p53, with affected individuals having an increased risk of hormone receptor-positive breast cancer (16,19,20). This suggests an important causal role for p53 inactivation in breast carcinogenesis.…”

“…Germ line mutations in the TP53 gene, which encodes p53, lead to Li-Fraumeni Syndrome (LFS). Among women with LFS, the most common cancer is breast cancer, with the majority of breast cancers being hormone receptor-positive (19,20). Aromatase expression has been shown to be increased in breast adipose stromal cells from LFS patients compared with non-LFS breast tissue (16).…”

Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes

“…Early-onset breast cancer is one of the canonical tumours of the LFS spectrum and the lifetime breast cancer risk of germline TP53 mutations has been estimated to be 49%. 33 TP53 mutation detection rate in women with breast cancer before 36 years of age and without detectable BRCA1 or BRCA2 mutation has been estimated to be 7%. 29,34 Our TP53 mutation detection rate in this series of 468 patients analyzed for TP53 was lower (B1%), which can easily be explained by the fact that our patients had not been selected on an early age of breast cancer onset.…”

Síndrome de Li-Fraumeni

“…Una característica interesante del cáncer de mama asociado a mutaciones en el gen TP53 es que su fenotipo es positivo para los receptores hormonales y para el gen Her2 (16)(17)(18). En el estudio de Mascari, et al, 84 % de los tumores de mama asociados al síndrome de Li Fraumeni fueron positivos para los receptores hormonales de estrógenos y progesterona, y 63 % de los tumores invasivos lo fueron para el gen Her2/neu (16).…”

“…En el estudio de Mascari, et al, 84 % de los tumores de mama asociados al síndrome de Li Fraumeni fueron positivos para los receptores hormonales de estrógenos y progesterona, y 63 % de los tumores invasivos lo fueron para el gen Her2/neu (16). En otro estudio presentado en el 2012 por Melhem-Bertrand, et al, en el que se estudiaron mujeres con estudio genético del gen TP53 ante la sospecha del síndrome de Li-Fraumeni, 67 % de los casos de cáncer de mama con mutaciones en dicho gen fueron positivos también para el gen Her2, comparado con 25 % de las pacientes de control con cáncer de mama cuyo resultado fue negativo para las mutaciones en el gen TP53 (18).…”