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


Authors: Kalinsky, K.; Heguy, A.; Bhanot, U. K.; Patil, S.; Moynahan, M. E.
Article Title: PIK3CA mutations rarely demonstrate genotypic intratumoral heterogeneity and are selected for in breast cancer progression
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. © 2011 Springer Science+Business Media, LLC.
Keywords: controlled study; human tissue; gene mutation; major clinical study; single nucleotide polymorphism; cancer growth; lymph node metastasis; gene; metastasis; breast cancer; genotype; lymph node; dna fingerprinting; cancer tissue; metastatic breast cancer; intraductal carcinoma; pik3ca gene; genetic heterogeneity; ductal carcinoma in situ; akt1 gene; pik3ca mutation; intratumoral heterogeneity; genetic fingerprinting; haplotype map
Journal Title: Breast Cancer Research and Treatment
Volume: 129
Issue: 2
ISSN: 0167-6806
Publisher: Springer  
Date Published: 2011-09-01
Start Page: 635
End Page: 643
Language: English
DOI: 10.1007/s10549-011-1601-4
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 9 December 2011" - "CODEN: BCTRD" - "Source: Scopus"
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MSK Authors
  1. Sujata Patil
    497 Patil
  2. Adriana Heguy
    88 Heguy
  3. Mary Ellen Moynahan
    105 Moynahan
  4. Umeshkumar Kapaldev Bhanot
    65 Bhanot