GATA3 mutations define a unique subtype of luminal‐like breast cancer with improved survival

Abstract

BACKGROUND:The GATA3 gene (GATA-binding protein 3) is one of the most frequently mutated genes in breast cancer. The objective of the current study was to determine the clinicopathologic characteristics of patients with breast cancer harboring GATA3 mutations. METHODS: The authors examined the somatic mutation status of GATA3 and performed survival analysis in The Cancer Genome Atlas (TCGA) cohort (n 5 934) and the Fudan University Shanghai Cancer Center (FUSCC) cohort (n 5 308). Patient characteristics, including age; menopausal status; tumor laterality; tumor size; lymph node status; tumor grade; molecular subtypes; adjuvant radiotherapy, chemotherapy, and endocrine therapy; and prognosis, together with PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) and TP53 (tumor protein p53) mutation status, were collected. RESULTS: GATA3 mutations were detected in 8.8% of patients (82 of 934 patients) in the TCGA cohort and 14.9% of patients (46 of 308 patients) in the FUSCC cohort. GATA3 mutations were found to be significantly associated with luminal-like breast cancer (P 5.002 in the TCGA cohort and P <.001 in the FUSCC cohort), and were highly mutually exclusive to PIK3CA mutations (P 5.001 in the TCGA cohort and P 5.003 in the FUSCC cohort) and TP53 mutations (P <.001 in both cohorts). Furthermore, GATA3 mutations were correlated with improved overall survival in the entire population (P 5.025 in the TCGA cohort and P 5.043 in the FUSCC cohort) as well as in patients with luminal-like disease who received adjuvant endocrine therapy. CONCLUSIONS: GATA3 mutations mainly occur in patients with luminal-like breast cancer and have identifiable clinicopathologic and genetic characteristics, highlighting a subgroup of patients with breast cancer in whom limited therapy may be appropriate.

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

“…5,42 Only one case had both GATA3 and TP53 mutations, reflecting a pattern reported in invasive breast tumors where mutations of these two genes rarely co-exist. 42 Four DCIS cases had both GATA3 and PIK3CA mutations, in contrast to invasive carcinomas in which mutations of these two genes are almost mutually exclusive. 1,42 In one case the allele frequencies suggest that the GATA3 and PIK3CA mutations could be present in different clones.…”

“…If the prevalence of GATA3 mutations observed in the current cohort is truly reflective of the general DCIS population, the high prevalence of GATA3 mutations in DCIS compared with invasive carcinomas suggests that GATA3 mutations, like HER2 amplification, are not selected for during the transition to invasive disease and perhaps may indicate better prognosis, similar to that observed in invasive carcinomas. 42 Our extended cohort did not have sufficient invasive recurrences to be able to test this hypothesis.…”

“…42 Four DCIS cases had both GATA3 and PIK3CA mutations, in contrast to invasive carcinomas in which mutations of these two genes are almost mutually exclusive. 1,42 In one case the allele frequencies suggest that the GATA3 and PIK3CA mutations could be present in different clones.…”

Immunohistochemical Surrogates for Molecular Classification of Breast Carcinoma: A 2015 Update

“…[13][14][15]75 The GATA3 mutation mainly occurs in this subtype and is associated with better prognosis. 76 Morphologically, most luminal A tumors are well differentiated carcinomas of no special type, tubular carcinomas, classical lobular carcinomas, mucinous carcinomas, and neuroendocrine carcinomas. 77 The 2013 St Gallen guidelines propose that a low recurrence score from the Oncotype DX test also suggests a luminal A subtype.…”

Role of steroid receptor and coregulator mutations in hormone-dependent cancers

“…However, the prognostic value of GATA3 mutations is still a matter of debate. Improved disease-free and overall survival were significantly correlated with GATA3 mutations in one study (130), whereas only marginal significance was seen for improved overall survival in ER-positive patients in the TCGA and METABRIC cohorts (130,131). Therefore, not only the functional role of GATA3 mutations but also the interpretation of their clinical role requires further study.…”