Intratumor Heterogeneity of Homologous Recombination Deficiency in Primary Breast Cancer.
Purpose:The 3-biomarker homologous recombination deficiency (HRD) assay measures the number of telomeric allelic imbalances, loss of heterozygosity, and large-scale state transitions in tumor DNA and combines these metrics into a single score that reflects DNA repair deficiency. The goal of this study is to assess the consistency of these HRD measures in different biopsies from distinct areas of the same cancer.Experimental Design:HRD scores, BRCA mutation status, andBRCA1promoter methylation were assessed in 99 samples from 33 surgically resected, stage I-III breast cancers; each cancer was biopsied in three distinct areas. Homologous recombination repair (HR) deficiency was defined as either high HRD score (≥42) or tumor BRCA mutation.Results:Eighty-one biopsies from 32 cancers were analyzed. Tumor BRCA status was available for all samples, HRD scores for 70, andBRCA1methylation values for 76 samples. TheBRCA1/2mutation and promoter methylation status and HR category showed perfect concordance across all biopsies from the same cancer. All tumors withBRCA1/2mutations or promoter methylation had high HRD scores, as did 17% (4/24) of theBRCA1/2wild-type and nonmethylated tumors. The HRD scores were also highly consistent between different biopsies from the same tumor with an intraclass correlation coefficient of 0.977, indicating that only 2.3% of the variance is attributed to within-tumor biopsy-to-biopsy variation.Conclusions:These results indicate that within-tumor spatial heterogeneity for HRD metrics and the technical noise in the assay are small and do not influence HRD scores and HR status.Clin Cancer Res; 23(5); 1193-9. ©2016 AACR.
Yale University School of Medicine and Yale Cancer Center, New Haven, Connecticut. Marie-Kristin.vonWahlde@ukmuenster.de lajos.pusztai@yale.edu.|Department of Obstetrics and Gynecology, University Hospital Münster, Germany.
Marie-Kristin
MK
von Wahlde
Myriad Genetics Inc., Salt Lake City, Utah.
Kirsten M
KM
Timms
Yale University School of Medicine and Yale Cancer Center, New Haven, Connecticut.
Anees
A
Chagpar
Yale University School of Medicine and Yale Cancer Center, New Haven, Connecticut.
Vikram B
VB
Wali
Yale University School of Medicine and Yale Cancer Center, New Haven, Connecticut.
Tingting
T
Jiang
Yale University School of Medicine and Yale Cancer Center, New Haven, Connecticut.
Veerle
V
Bossuyt
Yale University School of Medicine and Yale Cancer Center, New Haven, Connecticut.
Ozlen
O
Saglam
Myriad Genetics Inc., Salt Lake City, Utah.
Julia
J
Reid
Myriad Genetics Inc., Salt Lake City, Utah.
Alexander
A
Gutin
Myriad Genetics Inc., Salt Lake City, Utah.
Chris
C
Neff
Myriad Genetics Inc., Salt Lake City, Utah.
Jerry S
JS
Lanchbury
Yale University School of Medicine and Yale Cancer Center, New Haven, Connecticut.
Christos
C
Hatzis
Yale University School of Medicine and Yale Cancer Center, New Haven, Connecticut.
Erin
E
Hofstatter
Yale University School of Medicine and Yale Cancer Center, New Haven, Connecticut. Marie-Kristin.vonWahlde@ukmuenster.de lajos.pusztai@yale.edu.
Lajos
L
Pusztai
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D022981:Allelic Imbalance / Q000235:genetics; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D059767:Recombinational DNA Repair / Q000235:genetics*; D016615:Telomere / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D018719:Erb-b2 Receptor Tyrosine Kinases; C492913:BRCA1 protein, human