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Genomic evaluation of tumor mutational burden-high (TMB-H) versus TMB-low (TMB-L) metastatic breast cancer to reveal unique mutational features.

Publication ,  Conference
Sammons, S; Elliott, A; Force, JM; DeVito, NC; Marcom, PK; Swain, SM; Tan, AR; Roussos Torres, ET; Zeng, J; Khasraw, M; Balko, JM; Korn, WM ...
Published in: Journal of Clinical Oncology
May 20, 2021

1091 Background: Tumor mutational burden (TMB) has emerged as an imperfect biomarker of immune checkpoint inhibition (ICI) outcomes in solid tumors. Despite the approval for pembrolizumab in all TMB-high (TMB-H) solid tumors, the optimal clinical approach to TMB-H or hypermutated advanced/metastatic breast cancer (MBC) is unknown with sparse prospective data. We hypothesize that TMB-H MBC will have unique genomic alterations compared to TMB-low (TMB-L) breast cancer that could inform novel therapeutic approaches. Methods: Tumor samples (N = 5621) obtained from patients with MBC were analyzed by next-generation sequencing (NGS) of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) at Caris Life Sciences (Phoenix, AZ). TMB was calculated based on recommendations from the Friends of Cancer Research TMB Harmonization Project (Merino et al., 2020), with the TMB-H threshold set to ≥ 10 muts/Mb. IHC was performed for PD-L1 (Ventana SP142 ≥1% immune cells). Deficient mismatch repair (dMMR)/high microsatellite instability (MSI-H) was tested by IHC and NGS, respectively. Results: TMB-H was identified in 8.2% (n = 461) of MBC samples, with similar frequencies observed across molecular subtypes (7.8-8.6%, p = 0.85): HR+/HER2- (n = 3087) 7.8%, HR+/HER2+ (n = 266) 8.3%, HR-/HER2+ (n = 179) 7.8%, TNBC (n = 1476) 8.6%. The frequency of TMB-H was significantly increased in lobular (16%) versus ductal (5%) MBC (p < 0.01). TMB-H samples were enriched in genitourinary (42%), soft tissue (20%), and gastrointestinal non-liver (16%) biopsy specimens. Compared to TMB-L tumors, TMB-H tumors exhibited significantly higher mutation rates for TP53 (60 v 52%), PIK3CA (55 vs 31%), ARID1A (34 vs 11%), CDH1 (27 vs 11%), NF1 (22 vs 9%), RB1 (14 vs 5%), KMT2C (12 vs 7%), PTEN (12 vs 7%), ERBB2 (7 vs 2.9%), and PALB2 (3.3 vs 1%) genes (p < 0.05 each). Copy number alteration and fusion rates did not differ between TMB-H and TMB-L breast cancers. PI3K/AKT/MTOR, TP53, Histone/Chromatin remodeling, DNA damage repair (DDR), RAS, and cell cycle pathway alterations were detected in > 25% TMB-H MBCs (p < 0.05 each). dMMR/MSI-High (7.2 vs 0.3%, p < 0.01) and PD-L1 positivity (36 vs 28%, p < 0.05) frequencies were significantly increased in TMB-H tumors. DNA signature analyses including APOBEC and homologous recombination repair deficiency, as well as gene expression profiling to assess immune-related signatures and tumor microenvironment are underway. Conclusions: TMB-H breast cancers contain a unique genomic profile enriched with targetable mutations such as PIK3CA, ARID1A, NF1, PTEN, ERBB2, and PALB2. Concurrent predictive biomarkers of response to immune checkpoint inhibition such as MSI-H and PDL-1 positivity are also more prevalent in TMB-H MBC. These findings suggest novel combination strategies within TMB-H MBC could be explored.

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Published In

Journal of Clinical Oncology

DOI

EISSN

1527-7755

ISSN

0732-183X

Publication Date

May 20, 2021

Volume

39

Issue

15_suppl

Start / End Page

1091 / 1091

Publisher

American Society of Clinical Oncology (ASCO)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 1112 Oncology and Carcinogenesis
  • 1103 Clinical Sciences
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Sammons, S., Elliott, A., Force, J. M., DeVito, N. C., Marcom, P. K., Swain, S. M., … Anders, C. K. (2021). Genomic evaluation of tumor mutational burden-high (TMB-H) versus TMB-low (TMB-L) metastatic breast cancer to reveal unique mutational features. In Journal of Clinical Oncology (Vol. 39, pp. 1091–1091). American Society of Clinical Oncology (ASCO). https://doi.org/10.1200/jco.2021.39.15_suppl.1091
Sammons, Sarah, Andrew Elliott, Jeremy Meyer Force, Nicholas C. DeVito, Paul Kelly Marcom, Sandra M. Swain, Antoinette R. Tan, et al. “Genomic evaluation of tumor mutational burden-high (TMB-H) versus TMB-low (TMB-L) metastatic breast cancer to reveal unique mutational features.” In Journal of Clinical Oncology, 39:1091–1091. American Society of Clinical Oncology (ASCO), 2021. https://doi.org/10.1200/jco.2021.39.15_suppl.1091.
Sammons S, Elliott A, Force JM, DeVito NC, Marcom PK, Swain SM, et al. Genomic evaluation of tumor mutational burden-high (TMB-H) versus TMB-low (TMB-L) metastatic breast cancer to reveal unique mutational features. In: Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO); 2021. p. 1091–1091.
Sammons, Sarah, et al. “Genomic evaluation of tumor mutational burden-high (TMB-H) versus TMB-low (TMB-L) metastatic breast cancer to reveal unique mutational features.Journal of Clinical Oncology, vol. 39, no. 15_suppl, American Society of Clinical Oncology (ASCO), 2021, pp. 1091–1091. Crossref, doi:10.1200/jco.2021.39.15_suppl.1091.
Sammons S, Elliott A, Force JM, DeVito NC, Marcom PK, Swain SM, Tan AR, Roussos Torres ET, Zeng J, Khasraw M, Balko JM, Korn WM, Anders CK. Genomic evaluation of tumor mutational burden-high (TMB-H) versus TMB-low (TMB-L) metastatic breast cancer to reveal unique mutational features. Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO); 2021. p. 1091–1091.

Published In

Journal of Clinical Oncology

DOI

EISSN

1527-7755

ISSN

0732-183X

Publication Date

May 20, 2021

Volume

39

Issue

15_suppl

Start / End Page

1091 / 1091

Publisher

American Society of Clinical Oncology (ASCO)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 1112 Oncology and Carcinogenesis
  • 1103 Clinical Sciences