Limits...
Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes.

Timms KM, Abkevich V, Hughes E, Neff C, Reid J, Morris B, Kalva S, Potter J, Tran TV, Chen J, Iliev D, Sangale Z, Tikishvili E, Perry M, Zharkikh A, Gutin A, Lanchbury JS - Breast Cancer Res. (2014)

Bottom Line: All three HRD scores were highly associated with BRCA1/2 deficiency (HRD-LOH: P = 1.3 × 10(-17); HRD-TAI: P = 1.5 × 10(-19); HRD-LST: P = 3.5 × 10(-18)).In multivariable analyses the HRD-mean score captured significant BRCA1/2 deficiency information not captured by the three individual scores, or by clinical variables (P values for HRD-Mean adjusted for HRD-LOH: P = 1.4 × 10(-8); HRD-TAI: P = 2.9 × 10(-7); HRD-LST: P = 2.8 × 10(-8); clinical variables: P = 1.2 × 10(-16)).The HRD scores can be combined to produce a more robust predictor of HRD.

View Article: PubMed Central - PubMed

Affiliation: Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA. ktimms@myriad.com.

ABSTRACT

Introduction: Homologous recombination (HR) DNA repair is of clinical relevance in breast cancer. Three DNA-based homologous recombination deficiency (HRD) scores (HRD-loss of heterozygosity score (LOH), HRD-telomeric allelic imbalance score (TAI), and HRD-large-scale state transition score (LST)) have been developed that are highly correlated with defects in BRCA1/2, and are associated with response to platinum therapy in triple negative breast and ovarian cancer. This study examines the frequency of BRCA1/2 defects among different breast cancer subtypes, and the ability of the HRD scores to identify breast tumors with defects in the homologous recombination DNA repair pathway.

Methods: 215 breast tumors representing all ER/HER2 subtypes were obtained from commercial vendors. Next-generation sequencing based assays were used to generate genome wide SNP profiles, BRCA1/2 mutation screening, and BRCA1 promoter methylation data.

Results: BRCA1/2 deleterious mutations were observed in all breast cancer subtypes. BRCA1 promoter methylation was observed almost exclusively in triple negative breast cancer. BRCA1/2 deficient tumors were identified with BRCA1/2 mutations, or BRCA1 promoter methylation, and loss of the second allele of the affected gene. All three HRD scores were highly associated with BRCA1/2 deficiency (HRD-LOH: P = 1.3 × 10(-17); HRD-TAI: P = 1.5 × 10(-19); HRD-LST: P = 3.5 × 10(-18)). A combined score (HRD-mean) was calculated using the arithmetic mean of the three scores. In multivariable analyses the HRD-mean score captured significant BRCA1/2 deficiency information not captured by the three individual scores, or by clinical variables (P values for HRD-Mean adjusted for HRD-LOH: P = 1.4 × 10(-8); HRD-TAI: P = 2.9 × 10(-7); HRD-LST: P = 2.8 × 10(-8); clinical variables: P = 1.2 × 10(-16)).

Conclusions: The HRD scores showed strong correlation with BRCA1/2 deficiency regardless of breast cancer subtype. The frequency of elevated scores suggests that a significant proportion of all breast tumor subtypes may carry defects in the homologous recombination DNA repair pathway. The HRD scores can be combined to produce a more robust predictor of HRD. The combination of a robust score, and the FFPE compatible assay described in this study, may facilitate use of agents targeting homologous recombination DNA repair in the clinical setting.

Show MeSH

Related in: MedlinePlus

Association of clinical variables with the HRD-Mean score. Upper left panel: tumor grade; upper right panel: tumor stage; lower left panel: tumor IHC subtype; lower right panel: age at diagnosis. Mean of the homologous recombination deficiency-loss of heterozygosity, homologous recombination deficiency-large-scale state transition, and homologous recombination deficiency-telomeric allelic imbalance scores (HRD-Mean score). ER, estrogen receptor; HER2, tyrosine kinase-type cell surface receptor HER2; HRD, homologous recombination deficiency; TNBC, triple-negative breast cancer.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4308910&req=5

Fig3: Association of clinical variables with the HRD-Mean score. Upper left panel: tumor grade; upper right panel: tumor stage; lower left panel: tumor IHC subtype; lower right panel: age at diagnosis. Mean of the homologous recombination deficiency-loss of heterozygosity, homologous recombination deficiency-large-scale state transition, and homologous recombination deficiency-telomeric allelic imbalance scores (HRD-Mean score). ER, estrogen receptor; HER2, tyrosine kinase-type cell surface receptor HER2; HRD, homologous recombination deficiency; TNBC, triple-negative breast cancer.

Mentions: Data for tumor stage and grade and for age at diagnosis were available for the majority of samples (Table S1 in Additional file 1). Associations of these clinical variables with the HRD-Mean score are shown in Figure 3. The HRD-Mean score was not significantly correlated with tumor stage or age at diagnosis at the 5% confidence level, but there was significant correlation with tumor grade (Spearman correlation 0.23, P = 0.0017). The HRD-Mean score also differed significantly among breast cancer subtypes (P = 1.6 × 10-5) according to a Kruskal–Wallis one-way analysis of variance test.Figure 3


Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes.

Timms KM, Abkevich V, Hughes E, Neff C, Reid J, Morris B, Kalva S, Potter J, Tran TV, Chen J, Iliev D, Sangale Z, Tikishvili E, Perry M, Zharkikh A, Gutin A, Lanchbury JS - Breast Cancer Res. (2014)

Association of clinical variables with the HRD-Mean score. Upper left panel: tumor grade; upper right panel: tumor stage; lower left panel: tumor IHC subtype; lower right panel: age at diagnosis. Mean of the homologous recombination deficiency-loss of heterozygosity, homologous recombination deficiency-large-scale state transition, and homologous recombination deficiency-telomeric allelic imbalance scores (HRD-Mean score). ER, estrogen receptor; HER2, tyrosine kinase-type cell surface receptor HER2; HRD, homologous recombination deficiency; TNBC, triple-negative breast cancer.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4308910&req=5

Fig3: Association of clinical variables with the HRD-Mean score. Upper left panel: tumor grade; upper right panel: tumor stage; lower left panel: tumor IHC subtype; lower right panel: age at diagnosis. Mean of the homologous recombination deficiency-loss of heterozygosity, homologous recombination deficiency-large-scale state transition, and homologous recombination deficiency-telomeric allelic imbalance scores (HRD-Mean score). ER, estrogen receptor; HER2, tyrosine kinase-type cell surface receptor HER2; HRD, homologous recombination deficiency; TNBC, triple-negative breast cancer.
Mentions: Data for tumor stage and grade and for age at diagnosis were available for the majority of samples (Table S1 in Additional file 1). Associations of these clinical variables with the HRD-Mean score are shown in Figure 3. The HRD-Mean score was not significantly correlated with tumor stage or age at diagnosis at the 5% confidence level, but there was significant correlation with tumor grade (Spearman correlation 0.23, P = 0.0017). The HRD-Mean score also differed significantly among breast cancer subtypes (P = 1.6 × 10-5) according to a Kruskal–Wallis one-way analysis of variance test.Figure 3

Bottom Line: All three HRD scores were highly associated with BRCA1/2 deficiency (HRD-LOH: P = 1.3 × 10(-17); HRD-TAI: P = 1.5 × 10(-19); HRD-LST: P = 3.5 × 10(-18)).In multivariable analyses the HRD-mean score captured significant BRCA1/2 deficiency information not captured by the three individual scores, or by clinical variables (P values for HRD-Mean adjusted for HRD-LOH: P = 1.4 × 10(-8); HRD-TAI: P = 2.9 × 10(-7); HRD-LST: P = 2.8 × 10(-8); clinical variables: P = 1.2 × 10(-16)).The HRD scores can be combined to produce a more robust predictor of HRD.

View Article: PubMed Central - PubMed

Affiliation: Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA. ktimms@myriad.com.

ABSTRACT

Introduction: Homologous recombination (HR) DNA repair is of clinical relevance in breast cancer. Three DNA-based homologous recombination deficiency (HRD) scores (HRD-loss of heterozygosity score (LOH), HRD-telomeric allelic imbalance score (TAI), and HRD-large-scale state transition score (LST)) have been developed that are highly correlated with defects in BRCA1/2, and are associated with response to platinum therapy in triple negative breast and ovarian cancer. This study examines the frequency of BRCA1/2 defects among different breast cancer subtypes, and the ability of the HRD scores to identify breast tumors with defects in the homologous recombination DNA repair pathway.

Methods: 215 breast tumors representing all ER/HER2 subtypes were obtained from commercial vendors. Next-generation sequencing based assays were used to generate genome wide SNP profiles, BRCA1/2 mutation screening, and BRCA1 promoter methylation data.

Results: BRCA1/2 deleterious mutations were observed in all breast cancer subtypes. BRCA1 promoter methylation was observed almost exclusively in triple negative breast cancer. BRCA1/2 deficient tumors were identified with BRCA1/2 mutations, or BRCA1 promoter methylation, and loss of the second allele of the affected gene. All three HRD scores were highly associated with BRCA1/2 deficiency (HRD-LOH: P = 1.3 × 10(-17); HRD-TAI: P = 1.5 × 10(-19); HRD-LST: P = 3.5 × 10(-18)). A combined score (HRD-mean) was calculated using the arithmetic mean of the three scores. In multivariable analyses the HRD-mean score captured significant BRCA1/2 deficiency information not captured by the three individual scores, or by clinical variables (P values for HRD-Mean adjusted for HRD-LOH: P = 1.4 × 10(-8); HRD-TAI: P = 2.9 × 10(-7); HRD-LST: P = 2.8 × 10(-8); clinical variables: P = 1.2 × 10(-16)).

Conclusions: The HRD scores showed strong correlation with BRCA1/2 deficiency regardless of breast cancer subtype. The frequency of elevated scores suggests that a significant proportion of all breast tumor subtypes may carry defects in the homologous recombination DNA repair pathway. The HRD scores can be combined to produce a more robust predictor of HRD. The combination of a robust score, and the FFPE compatible assay described in this study, may facilitate use of agents targeting homologous recombination DNA repair in the clinical setting.

Show MeSH
Related in: MedlinePlus