TP53 Mutations Predict Molecular Response to Chemotherapy in HER2-Positive Breast Cancer

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TP53 mutation, but not PIK3CA status, predicts treatment response in HER2-positive breast cancer.
TP53 mutation, but not PIK3CA status, predicts treatment response in HER2-positive breast cancer.

SAN ANTONIO—TP53 mutation, but not PIK3CA status, predicts treatment response in HER2-positive breast cancer, according to mutational analysis of data from the neoadjuvant phase 3 CALGB 40601 trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer. The findings were presented at the 2014 San Antonio Breast Cancer Symposium.

“TP53 mutation is a frequent, clinically important event in HER2-positive disease and predicts pCR [pathologic complete response] to chemotherapy plus HER2-targeting,” reported lead study author Katherine A. Hoadley, PhD, of the University of North Carolina, Chapel Hill, NC. “Frequency and type of mutation was dependent on molecular subtype within this clinically HER2-positive cohort.”

Previous analyses from CALGB 40601 found that HER2-enriched molecular subtype tumors had significantly better pathologic complete response pCR rates regardless of treatment, Dr. Hoadley noted. “Mutational analysis is now available for this sample set.”

 “We examined the association of mutations with in-breast pCR, molecular subtypes, and gene expression signatures,” she said. In this subset, there were 82 HER2-enriched, 80 Luminal A, and 80 Luminal B tumors, she said.  HER2-enriched subtype was associated with elevated pCR rates, she reported.

As expected, HER2-enriched subtype tumors were associated with significantly higher pCR rates compared with other subtypes, Dr. Hoadley reported. “HER2-enriched were almost two times the pCR rate” of Luminal A and B subtypes, she said.

“TP53 was the most frequently mutated gene (56% overall),” she reported. TP53 mutations were “significantly associated with achieving pCR” and were correlated with a higher overall somatic mutation rate, she reported

In contrast, mutations in PIK3CA and lower-frequency mutations such as GATA3, MALAT1, ERBB2, TRPS1, MPA3K1, AKT1, and MAP2K4, were not associated with pCR, she reported.

Studies that will simultaneously analyze genomic signatures, somatic mutations and clinical variables to predict pCR, are underway, she said.

The study was funded partly by GSK and the Breast Cancer Research Foundation.

Reference

  1. Hoadley KA, Barry WT, Pitcher BN et al. S3-06. Presented at: San Antonio Breast Cancer Symposium 2014. Dec. 9-13, 2014; San Antonio, TX.

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