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PIK3CA mutations rarely demonstrate genotypic intratumoral heterogeneity and are selected for in breast cancer progression

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Abstract

PIK3CA gene mutations are the most common activating mutations in human breast cancer. Its association with hormone receptor-positive breast cancer makes it a prime target for clinical therapeutic advances to maintain anti-estrogen responsiveness. In anticipation of this therapeutic approach, we have evaluated intratumoral heterogeneity in primary breast cancers with regard to PIK3CA mutation status. In addition, we have assessed for the presence of the mutation in paired pre-invasive breast cancer and metastases. To assess for intratumoral heterogeneity, separate tumor blocks from primary breast cancers (n = 63) were genotyped for PIK3CA mutations. Available paired tissue samples from breast tumors known to harbor mutations underwent massARRAY genotyping (n = 70) to identify PIK3CA and AKT1(E17K) mutations. Cores were macro-dissected from matched tissue, including normal breast, benign lymph nodes (LN), ductal carcinoma in situ, regional LN metastases, and distant metastases. Matched samples underwent genetic fingerprinting by multiple SNP genotyping to confirm genetic identity. Intratumoral heterogeneity is minimal with a concordance rate of 95.2% between two different blocks from primary breast cancers. Complete concordance of PIK3CA mutations is noted between primary breast cancer and DCIS. PIK3CA mutations in primary breast cancer are detected in matched regional LNs (91.7%) and distant metastases (100%). Mutation detection by massARRAY genotyping is sensitive but may be affected by sample quality. Intratumoral heterogeneity as measured by PIK3CA genotype is rare; PIK3CA mutations occur early and are selected for in breast cancer progression. HapMap analysis is an essential control for paired sample analysis. This data is clinically important, particularly, for the design of therapies targeting the PI3K/AKT pathway, as it offers confidence that the detection of PIK3CA mutations in the invasive primary tumor will accurately reflect breast cancer biology.

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Acknowledgments

This study was funded by the Geoffrey Beene Cancer Research Center at MSKCC. We would like to acknowledge the following contributors for completion of the study, Marina Drobnjak from the Pathology Core Facility for sample procurement and Sabrena Thomas, Kety Huberman, and Olga Amin from the Geoffrey Beene Translational Core Facility for Sequenom mutation detection.

Conflict of interest

The authors have no conflict of interest to report.

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Authors and Affiliations

  1. Department of Medicine and the Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA

    Kevin Kalinsky

  2. Geoffrey Beene Translational Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Adriana Heguy

  3. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Adriana Heguy

  4. Pathology Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Umeshkumar K. Bhanot

  5. Departments of Biostatistics and Epidemiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Sujata Patil

  6. Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 381, New York, NY, 10065, USA

    Mary Ellen Moynahan

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  1. Kevin Kalinsky
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  2. Adriana Heguy
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  3. Umeshkumar K. Bhanot
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  4. Sujata Patil
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  5. Mary Ellen Moynahan
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Correspondence to Mary Ellen Moynahan.

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Kalinsky, K., Heguy, A., Bhanot, U.K. et al. PIK3CA mutations rarely demonstrate genotypic intratumoral heterogeneity and are selected for in breast cancer progression. Breast Cancer Res Treat 129, 635–643 (2011). https://doi.org/10.1007/s10549-011-1601-4

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  • DOI: https://doi.org/10.1007/s10549-011-1601-4

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