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Discordance of PIK3CA and TP53 mutations between breast cancer brain metastases and matched primary tumors.

ABSTRACT: There is limited knowledge of the biology of breast cancer (BC) brain metastasis (BM). We primarily aimed to determine the mutations in BCBM and to compare the mutational pattern with the matched primary breast cancer (BC). Secondary aims were to determine mutations in each subgroup (Luminal A-/B-like, HER2+ and TNBC) of BCBM, and to determine survival according to specific mutations. We investigated 57 BCBMs, including 46 cases with matched primary tumors (PT) by targeted Next Generation Sequencing (NGS) using the Cancer Hotspot Panel v2 (ThermoFisher Scientific) covering 207 targeted regions in 50 cancer related genes. Subtype according to immunohistochemistry was re-evaluated. NGS results fulfilling sequencing quality criteria were obtained from 52 BM and 41 PT, out of which 37 were matched pairs. Pathogenic mutations were detected in 66% of PTs (27/41), and 62% of BMs (32/52). TP53 mutations were most frequent; 49% (20/41) of PTs and 48% (25/52) in BMs, followed by PIK3CA mutations; 22% (9/42) in PTs and 25% (13/52) in BMs. Mutations in CDH1, EGFR, HRAS, RB1 CDKN2A and PTEN were detected in single pairs or single samples. Mutational pattern was discordant in 24% of matched pairs. We show a discordance of PIK3CA and TP53 mutations of roughly 25% indicating the need to develop methods to assess mutational status in brain metastasis where analysis of cell-free DNA from cerebrospinal fluid (CSF) has shown promising results.

SUBMITTER: Thulin A

PROVIDER: S-EPMC8651781 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Discordance of PIK3CA and TP53 mutations between breast cancer brain metastases and matched primary tumors.

Thulin Anna A Andersson Carola C Werner Rönnerman Elisabeth E De Lara Shahin S Chamalidou Chaido C Schoenfeld Arnd A Kovács Anikó A Fagman Henrik H Enlund Fredrik F Linderholm Barbro K BK

Scientific reports 20211207 1

There is limited knowledge of the biology of breast cancer (BC) brain metastasis (BM). We primarily aimed to determine the mutations in BCBM and to compare the mutational pattern with the matched primary breast cancer (BC). Secondary aims were to determine mutations in each subgroup (Luminal A-/B-like, HER2+ and TNBC) of BCBM, and to determine survival according to specific mutations. We investigated 57 BCBMs, including 46 cases with matched primary tumors (PT) by targeted Next Generation Sequen ...[more]

PMID: 34876602

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Project description:BackgroundTumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) have increasingly been reported to impact the brain metastatic process of solid tumors. However, data on intra-individual differences between primary tumor and brain metastasis (BM), as well as their correlation with clinical outcome parameters, is scarce.MethodsWe retrospectively identified patients who received resection of the primary tumor and BM between 01/1990 and 10/2022. Density quantification of TAMs (CD68+, CD163+) and TILs (CD3+, CD8+, CD45RO+, FOXP3+) was performed by immunohistochemical staining of matched tumor tissue samples. Images were processed with QuPath software and heterogeneity of generated heatmaps was measured by Shannon Entropy. Time-to-BM (TTBM) was defined as the time from diagnosis of the primary tumor until the first diagnosis of BM.ResultsIn total, 104 patients (46.2% female; median age 57.3 years at BM diagnosis) were included: 78/104 (75%) non-small cell lung cancer, 18/104 (17%) breast cancer, 8/104 (8%) renal cell carcinomas. Densities of CD3+ (p < 0.001) and CD8+-TILs (p < 0.001) were higher in primary tumor samples, while CD68+ (p = 0.035) and CD163+-TAM densities (p < 0.001) were higher in the matched BM. Higher CD3+, CD8+-TILs and CD163+-TAMs densities in primary tumors were associated with shorter TTBM (p = 0.005, p = 0.015 and p = 0.006, respectively). Higher entropies of CD3+ (p < 0.001) and FOXP3+ (p = 0.011) TILs were observed in primary tumors compared to BM. Longer TTBM was associated with higher entropy of FOXP3+ TILs (p = 0.024) and lower entropy in CD163+ TAMs (p = 0.039). No significant associations of immune cell densities or entropies with OS after BM diagnosis were found.DiscussionBy utilizing a unique cohort of matched primary tumor and BM tissue samples, we could demonstrate higher TIL densities in primary tumors and higher TAM densities in BM, respectively. Higher cell densities of CD3+, CD8+-TILs and CD163+-TAMs in primary tumors were associated with shorter TTBM, while a larger difference between CD3+ and CD8+ densities between primary tumor and BM was associated with longer TTBM. These findings highlight the potential of targeting TAMs as a therapeutic strategy to mitigate the development of brain metastases.

Dataset Information

Discordance of PIK3CA and TP53 mutations between breast cancer brain metastases and matched primary tumors.

Publications

Discordance of PIK3CA and TP53 mutations between breast cancer brain metastases and matched primary tumors.

Similar Datasets

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