Targeted next-generation sequencing detects a high frequency of potentially actionable mutations in metastatic breast cancers

Muller, Kristen E.; Marotti, Jonathan D.; Abreu, Francine B. de; Peterson, Julie; Miller, Todd W.; Chamberlin, Mary D.; Tsongalis, Gregory J.; Tafe, Laura J.

doi:10.1016/j.yexmp.2016.04.002

“…Even if metastatic tumor spread is a very complex process consisting of many different events, the mutational spectrum of our BM specimens was surprisingly simple, which is consistent with the findings of Beltrame et al, who reported that the genomic architecture of relapsed disease was less heterogenous than that of the primary disease [ 26 ]. Nevertheless, no two BM shared an identical genetic profile, which is similar to published data about metastatic breast cancer [ 27 , 28 ].…”

Section: Discussionsupporting

confidence: 85%

Next-Generation Sequencing-based genomic profiling of brain metastases of primary ovarian cancer identifies high number of BRCA-mutations

Balendran

¹

,

Liebmann-Reindl

²

,

Berghoff

³

et al. 2017

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Ovarian cancer represents the most common gynaecological malignancy and has the highest mortality of all female reproductive cancers. It has a rare predilection to develop brain metastases (BM). In this study, we evaluated the mutational profile of ovarian cancer metastases through Next-Generation Sequencing (NGS) with the aim of identifying potential clinically actionable genetic alterations with options for small molecule targeted therapy. Library preparation was conducted using Illumina TruSight Rapid Capture Kit in combination with a cancer specific enrichment kit covering 94 genes. BRCA-mutations were confirmed by using TruSeq Custom Amplicon Low Input Kit in combination with a custom-designed BRCA gene panel. In our cohort all eight sequenced BM samples exhibited a multitude of variant alterations, each with unique molecular profiles. The 37 identified variants were distributed over 22 cancer-related genes (23.4%). The number of mutated genes per sample ranged from 3 to 7 with a median of 4.5. The most commonly altered genes were BRCA1/2, TP53, and ATM. In total, 7 out of 8 samples revealed either a BRCA1 or a BRCA2 pathogenic mutation. Furthermore, all eight BM samples showed mutations in at least one DNA repair gene. Our NGS study of BM of ovarian carcinoma revealed a significant number of BRCA-mutations beside TP53, ATM and CHEK2 mutations. These findings strongly suggest the implication of BRCA and DNA repair malfunction in ovarian cancer metastasizing to the brain. Based on these findings, pharmacological PARP inhibition could be one potential targeted therapeutic for brain metastatic ovarian cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s11060-017-2459-z) contains supplementary material, which is available to authorized users.

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“…The present study with only 93 genes analyzed showed actionable mutations or CNVs in 73% (8/11) of recurrent/metastatic breast cancer lesions. This is comparable to the ndings of previous studies including MSK-IMPACT (61%), the study by Vasan et al (84%), and the study by Muller et al (45%) [12,13,40].…”

Section: Discussionsupporting

confidence: 90%

Targeted next-generation sequencing assays using triplet samples of normal breast tissue, primary breast cancer, and recurrent/metastatic lesions

Akahane

¹

,

Kanomata

²

,

Harada

³

et al. 2020

Preprint

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Background: Next-generation sequencing (NGS) has shown that recurrent/metastatic breast cancer lesions may have additional genetic changes compared with the primary tumor. These additional changes may be related to tumor progression and/or drug resistance. However, breast cancer-targeted NGS is not still widely used in clinical practice to compare the genomic profiles of primary breast cancer and recurrent/metastatic lesions.Methods: Triplet samples of genomic DNA were extracted from each patient’s normal breast tissue, primary breast cancer, and recurrent/metastatic lesion(s). A DNA library was constructed using the QIAseq Human Breast Cancer Panel (93 genes, Qiagen) and then sequenced using MiSeq (Illumina). The Qiagen web portal was utilized for data analysis.Results: Successful results for three or four samples (normal breast tissue, primary tumor, and at least one metastatic/recurrent lesion) were obtained for 11 of 35 breast cancer patients with recurrence/metastases (36 samples). We detected shared somatic mutations in all but one patient, who had a germline mutation in TP53. Additional mutations that were detected in recurrent/metastatic lesions compared with primary tumor were in genes including TP53 (three patients) and one case each of ATR, BLM, CBFB, EP300, ERBB2, MUC16, PBRM1, and PIK3CA. Actionable mutations and/or copy number variations (CNVs) were detected in 73% (8/11) of recurrent/metastatic breast cancer lesions.Conclusions: The QIAseq Human Breast Cancer Panel assay showed that recurrent/metastatic breast cancers sometimes acquired additional mutations and CNV. Such additional genomic changes could provide therapeutic target.

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“…This is comparable to the ndings of previous studies including MSK-IMPACT (61%), the study byVasan et al. (84%), and the study by Muller et al (45%)[12,13,40].…”

supporting

confidence: 90%

“…Vasan et al reported that 84% (43/51) of metastatic breast cancers showed at least one genomic alteration that could be targeted by currently available drugs [12]. In 2016, Muller et al reported that 45% (10/22) of metastatic breast cancers contained molecular targets for currently available therapies, including for off-label use [13]. In these studies, comprehensive cancer panels that were not breast cancer speci c were used.…”

Section: Introductionmentioning

confidence: 99%

Targeted next-generation sequencing assays using triplet samples of normal breast tissue, primary breast cancer, and recurrent/metastatic lesions

Akahane

¹

,

Kanomata

²

,

Harada

³

et al. 2020

Preprint

0

View full text Add to dashboard Cite

Background: Next-generation sequencing (NGS) has shown that recurrent/metastatic breast cancer lesions may have additional genetic changes compared with the primary tumor. These additional changes may be related to tumor progression and/or drug resistance. However, breast cancer-targeted NGS is not still widely used in clinical practice to compare the genomic profiles of primary breast cancer and recurrent/metastatic lesions.Methods: Triplet samples of genomic DNA were extracted from each patient’s normal breast tissue, primary breast cancer, and recurrent/metastatic lesion(s). A DNA library was constructed using the QIAseq Human Breast Cancer Panel (93 genes, Qiagen) and then sequenced using MiSeq (Illumina). The Qiagen web portal was utilized for data analysis.Results: Successful results for three or four samples (normal breast tissue, primary tumor, and at least one metastatic/recurrent lesion) were obtained for 11 of 35 breast cancer patients with recurrence/metastases (36 samples). We detected shared somatic mutations in all but one patient, who had a germline mutation in TP53. Additional mutations that were detected in recurrent/metastatic lesions compared with primary tumor were in genes including TP53 (three patients) and one case each of ATR, BLM, CBFB, EP300, ERBB2, MUC16, PBRM1, and PIK3CA. Actionable mutations and/or copy number variations (CNVs) were detected in 73% (8/11) of recurrent/metastatic breast cancer lesions.Conclusions: The QIAseq Human Breast Cancer Panel assay showed that recurrent/metastatic breast cancers sometimes acquired additional mutations and CNV. Such additional genomic changes could provide therapeutic target.

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Targeted next-generation sequencing detects a high frequency of potentially actionable mutations in metastatic breast cancers

Cited by 36 publications

References 17 publications

Next-Generation Sequencing-based genomic profiling of brain metastases of primary ovarian cancer identifies high number of BRCA-mutations

Next-Generation Sequencing-based genomic profiling of brain metastases of primary ovarian cancer identifies high number of BRCA-mutations

Targeted next-generation sequencing assays using triplet samples of normal breast tissue, primary breast cancer, and recurrent/metastatic lesions

Targeted next-generation sequencing assays using triplet samples of normal breast tissue, primary breast cancer, and recurrent/metastatic lesions

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