Genomic signatures predict the immunogenicity of BRCA-deficient breast cancer

Adam A. Kraya, Kara N. Maxwell, Bradley Wubbenhorst, Brandon M. Wenz, John Pluta, Andrew J. Rech, Liza M. Dorfman, Nicole Lunceford, Amanda Barrett, Nandita Mitra, Jennifer J.D. Morrissette, Michael Feldman, Anupma Nayak, Susan M. Domchek, Robert H. Vonderheide, Katherine L. Nathanson

Research output: Contribution to journalArticle

Abstract

Purpose: Breast cancers with BRCA1/2 alterations have a in BRCA1/2 mutant breast cancers. Further, absence of relatively high mutational load, suggesting that immune allele-specific loss of heterozygosity (LOH negative; P ¼ checkpoint blockade may be a potential treatment option. 0.01) or subclonality (P ¼ 0.003) of germline and somatic However, the degree of immune cell infiltration varies widely, BRCA1/2 mutations, respectively, predicted for heightened and molecular features contributing to this variability remain cytolytic activity. Gene set analysis found that multiple unknown. innate and adaptive immune pathways that converge on Experimental Design: We hypothesized that genomic sig-NF-kB may contribute to this heightened immunogenicity. natures might predict immunogenicity in BRCA1/2 breast IHC of Penn breast cancers demonstrated increased CD45þ cancers. Using The Cancer Genome Atlas (TCGA) genomic (P ¼ 0.039) and CD8þ infiltrates (P ¼ 0.037) and increased data, we compared breast cancers with (89) and without (770) PDL1 expression (P ¼ 0.012) in HRD-low or LOH-negative either germline or somatic BRCA1/2 alterations. We also cancers. Triple-negative cancers with low HRD had far studied 35 breast cancers with germline BRCA1/2 mutations greater CD8þ T cells (P ¼ 0.0011) and Perforin 1 expression from Penn using WES and IHC. (P ¼ 0.014) compared with hormone receptor-positive Results: We found that homologous recombination defi-HRD-high cancers. ciency (HRD) scores were negatively associated with expression-Conclusions: HRD scores and hormone receptor subtype based immune indices [cytolytic index (P ¼ 0.04), immune are predictive of immunogenicity in BRCA1/2 breast cancers ESTIMATE (P ¼ 0.002), type II IFN signaling (P ¼ 0.002)] despite and may inform the design of optimal immune therapeutic being associated with a higher mutational/neoantigen burden, strategies.

Original languageEnglish (US)
Pages (from-to)4363-4374
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number14
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

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Breast Neoplasms
Neoplasms
Hormones
Perforin
Mutation
NF-kappa B
Atlases
Loss of Heterozygosity
Homologous Recombination
Breast
Research Design
Alleles
Genome
T-Lymphocytes
Genes
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kraya, A. A., Maxwell, K. N., Wubbenhorst, B., Wenz, B. M., Pluta, J., Rech, A. J., ... Nathanson, K. L. (2019). Genomic signatures predict the immunogenicity of BRCA-deficient breast cancer. Clinical Cancer Research, 25(14), 4363-4374. https://doi.org/10.1158/1078-0432.CCR-18-0468

Genomic signatures predict the immunogenicity of BRCA-deficient breast cancer. / Kraya, Adam A.; Maxwell, Kara N.; Wubbenhorst, Bradley; Wenz, Brandon M.; Pluta, John; Rech, Andrew J.; Dorfman, Liza M.; Lunceford, Nicole; Barrett, Amanda; Mitra, Nandita; Morrissette, Jennifer J.D.; Feldman, Michael; Nayak, Anupma; Domchek, Susan M.; Vonderheide, Robert H.; Nathanson, Katherine L.

In: Clinical Cancer Research, Vol. 25, No. 14, 01.01.2019, p. 4363-4374.

Research output: Contribution to journalArticle

Kraya, AA, Maxwell, KN, Wubbenhorst, B, Wenz, BM, Pluta, J, Rech, AJ, Dorfman, LM, Lunceford, N, Barrett, A, Mitra, N, Morrissette, JJD, Feldman, M, Nayak, A, Domchek, SM, Vonderheide, RH & Nathanson, KL 2019, 'Genomic signatures predict the immunogenicity of BRCA-deficient breast cancer', Clinical Cancer Research, vol. 25, no. 14, pp. 4363-4374. https://doi.org/10.1158/1078-0432.CCR-18-0468
Kraya AA, Maxwell KN, Wubbenhorst B, Wenz BM, Pluta J, Rech AJ et al. Genomic signatures predict the immunogenicity of BRCA-deficient breast cancer. Clinical Cancer Research. 2019 Jan 1;25(14):4363-4374. https://doi.org/10.1158/1078-0432.CCR-18-0468
Kraya, Adam A. ; Maxwell, Kara N. ; Wubbenhorst, Bradley ; Wenz, Brandon M. ; Pluta, John ; Rech, Andrew J. ; Dorfman, Liza M. ; Lunceford, Nicole ; Barrett, Amanda ; Mitra, Nandita ; Morrissette, Jennifer J.D. ; Feldman, Michael ; Nayak, Anupma ; Domchek, Susan M. ; Vonderheide, Robert H. ; Nathanson, Katherine L. / Genomic signatures predict the immunogenicity of BRCA-deficient breast cancer. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 14. pp. 4363-4374.
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AU - Kraya, Adam A.

AU - Maxwell, Kara N.

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AU - Pluta, John

AU - Rech, Andrew J.

AU - Dorfman, Liza M.

AU - Lunceford, Nicole

AU - Barrett, Amanda

AU - Mitra, Nandita

AU - Morrissette, Jennifer J.D.

AU - Feldman, Michael

AU - Nayak, Anupma

AU - Domchek, Susan M.

AU - Vonderheide, Robert H.

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N2 - Purpose: Breast cancers with BRCA1/2 alterations have a in BRCA1/2 mutant breast cancers. Further, absence of relatively high mutational load, suggesting that immune allele-specific loss of heterozygosity (LOH negative; P ¼ checkpoint blockade may be a potential treatment option. 0.01) or subclonality (P ¼ 0.003) of germline and somatic However, the degree of immune cell infiltration varies widely, BRCA1/2 mutations, respectively, predicted for heightened and molecular features contributing to this variability remain cytolytic activity. Gene set analysis found that multiple unknown. innate and adaptive immune pathways that converge on Experimental Design: We hypothesized that genomic sig-NF-kB may contribute to this heightened immunogenicity. natures might predict immunogenicity in BRCA1/2 breast IHC of Penn breast cancers demonstrated increased CD45þ cancers. Using The Cancer Genome Atlas (TCGA) genomic (P ¼ 0.039) and CD8þ infiltrates (P ¼ 0.037) and increased data, we compared breast cancers with (89) and without (770) PDL1 expression (P ¼ 0.012) in HRD-low or LOH-negative either germline or somatic BRCA1/2 alterations. We also cancers. Triple-negative cancers with low HRD had far studied 35 breast cancers with germline BRCA1/2 mutations greater CD8þ T cells (P ¼ 0.0011) and Perforin 1 expression from Penn using WES and IHC. (P ¼ 0.014) compared with hormone receptor-positive Results: We found that homologous recombination defi-HRD-high cancers. ciency (HRD) scores were negatively associated with expression-Conclusions: HRD scores and hormone receptor subtype based immune indices [cytolytic index (P ¼ 0.04), immune are predictive of immunogenicity in BRCA1/2 breast cancers ESTIMATE (P ¼ 0.002), type II IFN signaling (P ¼ 0.002)] despite and may inform the design of optimal immune therapeutic being associated with a higher mutational/neoantigen burden, strategies.

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