<i>PIK3CA</i> Mutation in the ShortHER Randomized Adjuvant Trial for Patients with Early HER2<sup>+</sup> Breast Cancer: Association with Prognosis and Integration with PAM50 Subtype.
prospective_cohort · Level II
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- Record sourced from PubMed, PMID 32843527.
- Also identified by DOI 10.1158/1078-0432.CCR-20-1731.
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Abstract
We explored the prognostic effect of <i>PIK3CA</i> mutation in HER2<sup>+</sup> patients enrolled in the ShortHER trial. The ShortHER trial randomized 1,253 patients with HER2<sup>+</sup> breast cancer to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. <i>PIK3CA</i> hotspot mutations in exon 9 and 20 were analyzed by pyrosequencing. Expression of 60 genes, including PAM50 genes was measured using the nCounter platform. A mutation of the <i>PIK3CA</i> gene was detected in 21.7% of the 803 genotyped tumors. At a median follow-up of 7.7 years, 5-year disease-free survival (DFS) rates were 90.6% for <i>PIK3CA</i> mutated and 86.2% for <i>PIK3CA</i> wild-type tumors [HR, 0.84; 95% confidence interval (CI), 0.56-1.27; <i>P</i> = 0.417]. <i>PIK3CA</i> mutation showed a favorable prognostic impact in the PAM50 HER2-enriched subtype (<i>n</i> = 232): 5-year DFS 91.8% versus 76.1% (log-rank <i>P</i> = 0.049; HR, 0.46; 95% CI, 0.21-1.02). HER2-enriched/<i>PIK3CA</i> mutated versus wild-type tumors showed numerically higher tumor-infiltrating lymphocytes (TIL) and significant upregulation of immune-related genes (including <i>CD8A, CD274, PDCD1,</i> and <i>MYBL2</i>, a proliferation gene involved in immune processes). High TILs as well as the upregulation of <i>PDCD1</i> and <i>MYBL2</i> were associated with a significant DFS improvement within the HER2-enriched subtype (HR, 0.82; 95% CI, 0.68-0.99; <i>P</i> = 0.039 for 10% TILs increment; HR, 0.81; 95% CI, 0.65-0.99; <i>P</i> = 0.049 for <i>PDCD1</i> expression; HR, 0.72; 95% CI, 0.53-0.99; <i>P</i> = 0.042 for <i>MYBL2</i> expression). <i>PIK3CA</i> mutation showed no prognostic impact in the ShortHER trial. Within the HER2-enriched molecular subtype, patients with <i>PIK3CA</i> mutated tumors showed better DFS versus <i>PIK3CA</i> wild-type, which may be partly explained by upregulation of immune-related genes.
Medical subject headings
- Breast Neoplasms
- Class I Phosphatidylinositol 3-Kinases
- Erb-b2 Receptor Tyrosine Kinases
- Trastuzumab