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Aug 3, 2020 11:07AM
Survival Outcomes by TP53
Mutation Status in Metastatic Breast Cancer
To determine the significant genomic alterations in patients with metastatic breast cancer (MBC) and survival outcomes in common genotypes.
Patients and Methods
High-depth next-generation sequencing was performed for 202 genes in tumor and normal DNA from 257 patients with MBC, including 165 with estrogen receptor/progesterone receptor–positive and human epidermal growth factor receptor 2 (HER2 [hormone receptor positive (HR+)])–positive, 32 with HER2-positive, and 60 with triple-negative (estrogen receptor/progesterone receptor–negative and HER2-negative) disease. Kaplan-Meier survival analysis was performed in the discovery set, in patients with breast cancer analyzed in The Cancer Genome Atlas, and in a separate cohort of 98 patients with MBC who underwent clinical genomic testing.
Significantly mutated genes (SMGs) varied by histology and tumor subtype, but TP53 was an SMG in all three subtypes. The most SMGs in patients with HR+ cancer were PIK3CA (32%), TP53 (29%), GATA3 (15%), CDH1 (8%), MAP3K1 (8%), PTEN (5%), TGFBR2 (4%), AKT1 (4%), and MAP2K4 (4%). TP53 mutations were associated with shorter recurrence-free survival (P = .004), progression-free survival (P < .001), and overall survival (P = .003). Furthermore, TP53 status was prognostic among patients with HR+ cancer with PIK3CA mutations. TP53 mutations were associated with poorer overall survival in the 442 patients with HR+ breast cancer analyzed in The Cancer Genome Atlas (P = .042) and in an independent set of 96 patients with HR+ MBC who underwent clinical sequencing (P < .001).
Significantly mutated genes (SMGs) differ by tumor subtype, but TP53 is significantly mutated in all three breast cancer subtypes. TP53 mutations are associated with poor prognosis in HR+ breast cancer and should be considered in the design and interpretation of precision oncology trials.
Other points of interest:
GATA3 alterations were mutually exclusive with TP53 alterations.
The authors concluded that HR+ tumors with TP53 mutations are mostly aromatase inhibitor resistant and would be more appropriately treated with other modalities. However, we do not know whether other regimens would be more effective for these tumors or whether TP53 mutations would equally confer resistance to other agents.
DOI: 10.1200/PO.17.00245 JCO Precision Oncology - published online April 25, 2018
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2015, DCIS/IDC, Right, 3cm, Stage IIA, Grade 3, 0/1 nodes, ER-/PR-, HER2+ (IHC)
1/14/2016 Cytoxan (cyclophosphamide), Taxotere (docetaxel)
1/14/2016 Herceptin (trastuzumab)
2017, IDC, Stage IV, metastasized to liver, ER-/PR-, HER2+