Breast cancer is the most common malignancy in female patients with Li–Fraumeni syndrome (LFS), a rare autosomal dominant hereditary syndrome characterized by germline TP53 mutations. Recent studies have shown that the majority of these tumors are estrogen receptor (ER) positive with frequent HER2 co-expression. However, the morphologic features of these tumors have not been as well studied as other germline-associated breast cancers. We evaluated the pathologic features of 27 invasive and in situ carcinomas from patients with known germline TP53 mutations collected through the Li–Fraumeni Consortium. Overall, 60% of cases were HER2 positive and 44% showed ER co-expression. Most DCIS was high nuclear grade with central necrosis and associated periductal fibrosis and lymphocytic response. Invasive carcinomas were mostly of ductal type (NOS), modified Scarff–Bloom–Richardson (mSBR) high grade, with marked nuclear atypia and high mitotic rate. Prominent tumor infiltrating lymphocytes, syncytial growth pattern, or pushing borders were not seen in these tumors. High p53 IHC expression was seen in tumors from individuals with germline TP53 missense mutations whereas little or no protein expression (<1% nuclear expression, null pattern) was seen in tumors from carriers of non-missense mutations. In this study, we report in detail the morphologic features of invasive and in situ carcinomas in LFS. We found that these tumors share features with cancers harboring somatic TP53 mutations but are distinct from BRCA-associated breast cancers.
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WHO Classification of Tumours Editorial Board. Breast tumours. 5th ed. Lyon: IARC; 2019.
Masciari S, Dillon DA, Rath M, Robson M, Weitzel JN, Balmana J, et al. Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast Cancer Res Treat. 2012;133:1125–30.
Verdial FC, Etzioni R, Duggan C, Anderson BO. Demographic changes in breast cancer incidence, stage at diagnosis and age associated with population-based mammographic screening. J Surg Oncol. 2017;115:517–22.
Kamihara J, Rana HQ, Garber JE. Germline TP53 mutations and the changing landscape of Li-Fraumeni syndrome. Hum Mutat. 2014;35:654–62.
AlHarbi M, Mubarak N, AlMubarak L, Aljelaify R, AlSaeed M, Almutairi A, et al. Rare TP53 variant associated with Li-Fraumeni syndrome exhibits variable penetrance in a Saudi family. NPJ Genom Med. 2018;3:35.
Mai PL, Best AF, Peters JA, DeCastro RM, Khincha PP, Loud JT, et al. Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer. 2016;122:3673–81.
Wilson JRF, Bateman AC, Hanson H, An Q, Evans G, Rahman N, et al. A novel HER2-positive breast cancer phenotype arising from germline TP53 mutations. J Med Genet. 2010;47:771–4.
Melhem-Bertrandt A, Bojadzieva J, Ready KJ, Obeid E, Liu DD, Gutierrez-Barrera AM, et al. Early onset HER2-positive breast cancer is associated with germline TP53 mutations. Cancer. 2012;118:908–13.
Lakhani SR, Easton DF, Stratton MR, Breast Cancer Linkage Consortium. Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Lancet. 1997;349:1505–10.
Honrado E, Benitez J, Palacios J. The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications. Mod Pathol. 2005;18:1305–20.
Mai PL, Malkin D, Garber JE, Schiffman JD, Weitzel JN, Strong LC, et al. Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium. Cancer Genet. 2012;205:479–87.
Moore OS Jr, Foote FW Jr. The relatively favorable prognosis of medullary carcinoma of the breast. Cancer. 1949;2:635–42.
Ridolfi RL, Rosen PP, Port A, Kinne D, Miké V. Medullary carcinoma of the breast: a clinicopathologic study with 10 year follow-up. Cancer. 1977;40:1365–85.
Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26:259–71.
Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28:2784–95.
Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Arch Pathol Lab Med. 2018;142:1364–82.
Schrader KA, Masciari S, Boyd N, Wiyrick S, Kaurah P, Senz J, et al. Hereditary diffuse gastric cancer: association with lobular breast cancer. Fam Cancer. 2008;7:73–82.
Bane AL, Beck JC, Bleiweiss I, Buys SS, Catalano E, Daly MB, et al. BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays. Am J Surg Pathol. 2007;31:121–8.
Banneau G, Guedj M, MacGrogan G, de Mascarel I, Velasco V, Schiappa R, et al. Molecular apocrine differentiation is a common feature of breast cancer in patients with germline PTEN mutations. Breast Cancer Res. 2010;12:R63.
Muranen TA, Blomqvist C, Dork T, Jakubowska A, Heikkilä P, Fagerholm R, et al. Patient survival and tumor characteristics associated with CHEK2:p.I157T—findings from the Breast Cancer Association Consortium. Breast Cancer Res. 2016;18:98.
Silwal-Pandit L, Vollan HK, Chin SF, Rueda OM, McKinney S, Osako T, et al. TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance. Clin Cancer Res. 2014;20:3569–80.
Done SJ, Arneson CR, Ozcelik H, Redson M, Andrulis IL. P53 protein accumulation in non-invasive lesions surrounding p53 mutation positive invasive breast cancers. Breast Cancer Res Treat. 2001;65:111–8.
O’Malley FP, Vnencak-Jones CL, Dupont WD, Parl F, Manning S, Page DL. p53 mutations are confined to the comedo type ductal carcinoma in situ of the breast. Immunohistochemical and sequencing data. Lab Investig. 1994;71:67–72.
Lakhani SR, Jacquemier J, Sloane JP, Gusterson BA, Anderson TJ, van de Vijver MJ, et al. Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst. 1998;90:1138–45.
Packwood K, Martland G, Sommerlad M, Shaw E, Moutasim K, Thomas G, et al. Breast cancer in patients with germline TP53 pathogenic variants have typical tumour characteristics: the Cohort study of TP53 carrier early onset breast cancer (COPE study). J Pathol Clin Res. 2019;5:189–98.
Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LA, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst 2014;106:dju055.
Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S, Aguilar Z, et al. Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst. 2003;95:142–53.
Lee HJ, Park IA, Park SY, Seo AN, Lim B, Chai Y, et al. Two histopathologically different diseases: hormone receptor-positive and hormone receptor-negative tumors in HER2-positive breast cancer. Breast Cancer Res Treat. 2014;145:615–23.
Bhargava R, Beriwal S, Striebel JM, Dabbs DJ. Breast cancer molecular class ERBB2: preponderance of tumors with apocrine differentiation and expression of basal phenotype markers CK5, CK5/6, and EGFR. Appl Immunohistochem Mol Morphol. 2010;18:113–8.
Kleihues P, Schauble B, zur Hausen A, Esteve J, Ohgaki H. Tumors associated with p53 germline mutations: a synopsis of 91 families. Am J Pathol. 1997;150:1–13.
Olivier M, Goldgar DE, Sodha N, Ohgaki H, Kleihues P, Hainaut P, et al. Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res. 2003;63:6643–50.
Alsner J, Jensen V, Kyndi M, Offersen BV, Vu P, Borresen-Dale AL, et al. A comparison between p53 accumulation determined by immunohistochemistry and TP53 mutations as prognostic variables in tumours from breast cancer patients. Acta Oncol. 2008;47:600–7.
Goh AM, Coffill CR, Lane DP. The role of mutant p53 in human cancer. J Pathol. 2011;223:116–26.
Rath MG, Masciari S, Gelman R, Miron A, Miron P, Foley K, et al. Prevalence of germline TP53 mutations in HER2+ breast cancer patients. Breast Cancer Res Treat. 2013;139:193–8.
Mao X, Fan C, Wei J, Yao F, Jin F. Genetic mutations and expression of p53 in non-invasive breast lesions. Mol Med Rep. 2010;3:929–34.
Keohavong P, Gao WM, Mady HH, Kanbour-Shakir A, Melhem MF. Analysis of p53 mutations in cells taken from paraffin-embedded tissue sections of ductal carcinoma in situ and atypical ductal hyperplasia of the breast. Cancer Lett. 2004;212:121–30.
We thank the following: Li–Fraumeni Syndrome Consortium members for the contribution of cases for this study: Mark Robson, Jeffrey N. Weitzel, Judith Balmana, Stephen B. Gruber, James M. Ford, David Euhus, Melinda Telli, and Stephen M. Pochebit.
Conflict of interest
DAD consults for Novartis and is on the Advisory Board for Oncology Analytics, Inc. JEG receives research support from Myriad Genetics, Ambry Genetics, Invitae Genetics, is leading two clinical trials for Astra-Zeneca, consults for Helix Genetics, is on the Scientific Advisory Board of Konica Minolta, and has received speaker’s honorarium from Clinical Care Options, LLC. The other authors declare no conflict of interest.
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Kuba, M.G., Lester, S.C., Bowman, T. et al. Histopathologic features of breast cancer in Li–Fraumeni syndrome. Mod Pathol (2020). https://doi.org/10.1038/s41379-020-0610-4
Breast Cancer Research and Treatment (2020)