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

  • Kevin Kalinsky
  • Adriana Heguy
  • Umeshkumar K. Bhanot
  • Sujata Patil
  • Mary Ellen Moynahan
Brief Report

DOI: 10.1007/s10549-011-1601-4

Cite this article as:
Kalinsky, K., Heguy, A., Bhanot, U.K. et al. Breast Cancer Res Treat (2011) 129: 635. doi:10.1007/s10549-011-1601-4


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.


PIK3CA mutation Intratumoral heterogeneity Ductal carcinoma in situ Metastatic breast cancer Genetic fingerprinting 

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Kevin Kalinsky
    • 1
  • Adriana Heguy
    • 2
    • 3
  • Umeshkumar K. Bhanot
    • 4
  • Sujata Patil
    • 5
  • Mary Ellen Moynahan
    • 6
  1. 1.Department of Medicine and the Herbert Irving Comprehensive Cancer CenterColumbia University Medical CenterNew YorkUSA
  2. 2.Geoffrey Beene Translational Core FacilityMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  3. 3.Human Oncology and Pathogenesis ProgramMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  4. 4.Pathology Core FacilityMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  5. 5.Departments of Biostatistics and EpidemiologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  6. 6.Breast Cancer Medicine ServiceMemorial Sloan-Kettering Cancer CenterNew YorkUSA

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