Funda Meric-Bernstam1,2,3, Xiaofeng Zheng4, Maryam Shariati2, Senthil Damodaran2,5, Chetna Wathoo1, Lauren Brusco1,2, Mehmet Esat Demirhan2, Coya Tapia2,6, Agda Karina Eterovic7, Reva K Basho8,9, Naoto T Ueno5, Filip Janku2, Aysegul Sahin10, Jordi Rodon1,2, Russell Broaddus10, Tae-Beom Kim4, John Mendelsohn1,11, Kenna R Mills Shaw1, Debu Tripathy5, Gordon B Mills1,7, Ken Chen4. 1. The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. 2. Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. 3. Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. 4. Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. 5. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. 6. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. 7. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. 8. Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX 77030. 9. current address: Cedars-Sinai, Los Angeles, CA 90048. 10. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. 11. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Abstract
PURPOSE: We sought 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 patients with ER/PR+ HER2- (hormone receptor positive, HR+ positive), 32 patients with HER2+ and 60 patients with triple negative (ER/PR/HER2-) cancer. Kaplan Meier survival analysis was performed in our discovery set, in breast cancer patients analyzed in The Cancer Genome Atlas, and in a separate cohort of 98 patients with MBC who underwent clinical genomic testing. RESULTS: Significantly mutated genes (SMGs) varied by histology and tumor subtype, but TP53 was a SMG in all three subtypes. The most SMGs in HR+ patients included 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=0.004), progression-free survival (P=0.00057) and overall survival (P=0.003). Further, TP53 status was prognostic among HR+ patients with PIK3CA mutations. TP53 mutations were also associated with poorer overall survival in the 442 HR+ breast cancer patients in the TCGA (P=0.042) and in an independent set of 96 HR+ MBC who underwent clinical sequencing (P=0.0004). CONCLUSIONS: 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. TP53 mutations should be considered in the design and interpretation of precision oncology trials.
PURPOSE: We sought 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 patients with ER/PR+ HER2- (hormone receptor positive, HR+ positive), 32 patients with HER2+ and 60 patients with triple negative (ER/PR/HER2-) cancer. Kaplan Meier survival analysis was performed in our discovery set, in breast cancer patients analyzed in The Cancer Genome Atlas, and in a separate cohort of 98 patients with MBC who underwent clinical genomic testing. RESULTS: Significantly mutated genes (SMGs) varied by histology and tumor subtype, but TP53 was a SMG in all three subtypes. The most SMGs in HR+ patients included 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=0.004), progression-free survival (P=0.00057) and overall survival (P=0.003). Further, TP53 status was prognostic among HR+ patients with PIK3CA mutations. TP53 mutations were also associated with poorer overall survival in the 442 HR+ breast cancer patients in the TCGA (P=0.042) and in an independent set of 96 HR+ MBC who underwent clinical sequencing (P=0.0004). CONCLUSIONS: 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. TP53 mutations should be considered in the design and interpretation of precision oncology trials.
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