Genome-wide copy number analysis of cell-free DNA from patients with chemotherapy-resistant metastatic triple-negative breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1092-1092
Author(s):  
Daniel G. Stover ◽  
Heather Anne Parsons ◽  
Gavin Ha ◽  
Samuel Freeman ◽  
William Thomas Barry ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Copy Number ◽  
Triple Negative ◽  
Plasma Samples ◽  
Copy Number Alterations ◽  
Copy Number Analysis ◽  
Blood Draw ◽  
Genome Wide ◽  
Line Of Therapy ◽  
Low Coverage

1092 Background: Triple-negative breast cancer (TNBC) is a poor prognosis breast cancer subset characterized by relatively few mutations but extensive copy number alterations (CNAs). Cell-free DNA (cfDNA) offers the potential to overcome infrequent tumor biopsies in metastatic TNBC (mTNBC) and interrogate the genomics of chemotherapy resistance. Methods: 506 archival or fresh plasma samples were identified from 164 patients with mTNBC who had previously received chemotherapy. We performed low coverage sequencing to determine genome-wide copy number and estimate ‘tumor fraction’ of cfDNA (TFx). In patient samples with TFx >10%, we identified regions that were significantly gained or lost using GISTIC2.0. We compared CNAs of mTNBCs with primary TNBCs from a publicly-available dataset, METABRIC (TNBC n=277). Results: We successfully obtained high quality, low coverage whole genome sequencing data for 478 (94.5%) plasma samples from 158 patients, with 1 to 14 samples per patient. Archival samples had significantly higher average cfDNA per mL plasma and TFx than fresh samples, potentially due to later average line of therapy. Average TFx of first blood draw was significantly higher in patients with liver metastases (TFx 28.3% vs. 14.4%, p=1.1e-7). 101/158 patients (63.9%) had at least one sample with TFx >10%, our threshold for high confidence CNA calls. Most alterations significantly enriched in chemotherapy-resistant mTNBCs were chromosomal gains, including NOTCH2 and ERCC1. Median overall survival from time of first blood draw was 9 months, and TFx was highly correlated independent of metastatic line of therapy, age at metastatic diagnosis, BRCA status, and primary stage: adjusted hazard ratio between 4th and 1stquartiles = 4.29 (95% CI 1.66-11.1; p=0.0008). Conclusions: It is feasible to perform genome-level copy number analysis from cfDNA in both archival and fresh samples from patients with mTNBC. Copy number alterations enriched in mTNBC may have implications in the understanding of metastasis, therapeutic resistance, and novel therapeutic targets. ‘Tumor fraction’ of cfDNA is correlated with overall survival and may be an independent prognostic marker in mTNBC.

scholarly journals Association of Cell-Free DNA Tumor Fraction and Somatic Copy Number Alterations With Survival in Metastatic Triple-Negative Breast Cancer

2018 ◽  
Vol 36 (6) ◽  
pp. 543-553 ◽  
Author(s):  
Daniel G. Stover ◽  
Heather A. Parsons ◽  
Gavin Ha ◽  
Samuel S. Freeman ◽  
William T. Barry ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Copy Number ◽  
Triple Negative ◽  
Copy Number Alterations ◽  
Cell Free Dna ◽  
Primary Tumors ◽  
Free Dna ◽  
Genome Wide ◽  
Somatic Copy Number Alterations

Purpose Cell-free DNA (cfDNA) offers the potential for minimally invasive genome-wide profiling of tumor alterations without tumor biopsy and may be associated with patient prognosis. Triple-negative breast cancer (TNBC) is characterized by few mutations but extensive somatic copy number alterations (SCNAs), yet little is known regarding SCNAs in metastatic TNBC. We sought to evaluate SCNAs in metastatic TNBC exclusively via cfDNA and determine if cfDNA tumor fraction is associated with overall survival in metastatic TNBC. Patients and Methods In this retrospective cohort study, we identified 164 patients with biopsy-proven metastatic TNBC at a single tertiary care institution who received prior chemotherapy in the (neo)adjuvant or metastatic setting. We performed low-coverage genome-wide sequencing of cfDNA from plasma. Results Without prior knowledge of tumor mutations, we determined tumor fraction of cfDNA for 96.3% of patients and SCNAs for 63.9% of patients. Copy number profiles and percent genome altered were remarkably similar between metastatic and primary TNBCs. Certain SCNAs were more frequent in metastatic TNBCs relative to paired primary tumors and primary TNBCs in publicly available data sets The Cancer Genome Atlas and METABRIC, including chromosomal gains in drivers NOTCH2, AKT2, and AKT3. Prespecified cfDNA tumor fraction threshold of ≥ 10% was associated with significantly worse metastatic survival (median, 6.4 v 15.9 months) and remained significant independent of clinicopathologic factors (hazard ratio, 2.14; 95% CI, 1.4 to 3.8; P < .001). Conclusion We present the largest genomic characterization of metastatic TNBC to our knowledge, exclusively from cfDNA. Evaluation of cfDNA tumor fraction was feasible for nearly all patients, and tumor fraction ≥ 10% is associated with significantly worse survival in this large metastatic TNBC cohort. Specific SCNAs are enriched and prognostic in metastatic TNBC, with implications for metastasis, resistance, and novel therapeutic approaches.

DNA copy number alterations and expression of relevant genes in triple-negative breast cancer

2008 ◽  
Vol 47 (6) ◽  
pp. 490-499 ◽  
Author(s):  
Wonshik Han ◽  
Eun-Mi Jung ◽  
Jihyoung Cho ◽  
Jong Won Lee ◽  
Ki-Tae Hwang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Copy Number ◽  
Triple Negative ◽  
Copy Number Alterations ◽  
Dna Copy Number ◽  
Dna Copy Number Alterations

scholarly journals Importance of Copy Number Alterations of FGFR1 and C-MYC Genes in Triple Negative Breast Cancer

2018 ◽  
Vol 0 (0) ◽  
Author(s):  
Milica Nedeljković ◽  
Nikola Tanić ◽  
Tatjana Dramićanin ◽  
Zorka Milovanović ◽  
Snežana Šušnjar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prognostic Marker ◽  
Triple Negative Breast Cancer ◽  
Copy Number ◽  
Triple Negative ◽  
Clinical Course ◽  
Copy Number Gain ◽  
Gene Copy ◽  
Copy Number Alterations ◽  
The Impact

Summary Background: Triple negative breast cancer (TNBC) is characterized by aggressive clinical course and is unresponsive to anti-HER2 and endocrine therapy. TNBC is difficult to treat and is often lethal. Given the need to find new targets for therapy we explored clinicopathological significance of copy number gain of FGFR1 and c-MYC. Our aim was to determine the impact of FGFR1 and c-MYC copy number gain on clinical course and outcome of TNBC. Methods: FGFR1 and c-MYC gene copy number alterations were evaluated in 78 archive TNBC samples using TaqMan based quantitative real time PCR assays. Results: 50% of samples had increased c-MYC copy number. c-MYC copy number gain was associated with TNBC in contrast to ER positive cancers. Our results showed significant correlation between c-MYC copy number gain and high grade of TNBCs. This suggests that c-MYC copy number could be an useful prognostic marker for TNBC patients. c-MYC copy number gain was associated with high pTNM stage as well as lobular and medullary tumor subtypes. 43% of samples had increased FGFR1 copy number. No correlations between FGFR1 copy number gain and clinicopathological variables were observed. Conclusions: We identified c-MYC copy number gain as a prognostic marker for TNBC. Our results indicate that c- MYC may contribute to TNBC progression. We observed no significant association between c-MYC and/or FGFR1 copy number status and patient survival.

scholarly journals 1q21.3 amplification modulates therapy sensitivity in Triple Negative Breast Cancer

2020 ◽  
Author(s):  
Ramakanth Chirravuri-Venkata ◽  
Dario Ghersi ◽  
Apar K. Ganti ◽  
Imayavaramban Lakshmanan ◽  
Sanjib Chaudary ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Risk Stratification ◽  
Genetic Marker ◽  
Triple Negative Breast Cancer ◽  
Copy Number ◽  
Triple Negative ◽  
Copy Number Alterations ◽  
Copy Number Status ◽  
Cytotoxic Therapies

AbstractThe contrast in therapy sensitivity and response across triple negative breast cancer (TNBC) patients suggest underlying genotypic heterogeneity. Using publicly available data, we found significant associations between DNA-level copy number alterations of 1q21.3 locus and therapy sensitivity. We show that in spite of their aggressive nature, 1q21.3 amplified tumors are more responsive to commonly used cytotoxic therapies, highlighting the relevance of 1q21.3 copy number status as a genetic marker for risk stratification, therapy selection and response.

Measuring on-treatment genome-wide tumor copy number alterations in cell-free DNA (cfDNA) in plasma is highly prognostic in metastatic breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1097-1097
Author(s):  
Adriana Aguilar ◽  
Josiane Lafleur ◽  
Susie Brousse ◽  
Cristiano Ferrario ◽  
Graham McLennan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Copy Number ◽  
Tumor Response ◽  
Treatment Time ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Copy Number Alterations ◽  
Genome Wide ◽  
Metastatic Setting

1097 Background: The clinical management of metastatic breast cancer depends on the measurement of tumor response to successive drugs by serial imaging and changes in blood tumor markers, which remain the standard of care despite poor sensitivity and specificity. Highly sensitive and specific cfDNA secreted from the tumor can detect the changes in tumor-specific aberrations that have been shown to be associated with patient response in the metastatic setting. However, most approaches require prior sequencing of the tumor to target specific known mutations. Methods: Using low coverage genomic sequencing, a genomic instability number (GIN) was measured in cfDNA based on the detection of genome-wide tumor-specific DNA copy number alterations for 27 patients with metastatic breast cancer. The GIN value and its variation from baseline before treatment, as well as within 10 days and 3 weeks after start of therapy were compared with tumor response, progression free survival (PFS) and overall survival (OS) of the patients. Patients were followed for a median of 22 months and we used a previously published GIN threshold at 170 for high vs low GIN values. Sequencing was performed blinded to the clinical results. Results: Baseline GIN values were not associated with tumor response at 3or 6 months, but showed a trend towards lower OS with higher GIN (p = 0.12). GIN values fell by an average of 28% in responders (stable disease or response) and 23% in those with progression (p = 0.85), but remained lower at 3 weeks only in the responders. High GIN values within 10 days and 3 weeks were associated with markedly worse OS (p = 0.014 and p = 0.009 respectively) and those at 3 weeks with worse PFS (p = 0.017). Hence the median survival of patients with high GIN at 10 days or 3 weeks was 12 months vs not reached for those with low GIN. The percentage drop of GIN at 10 days but not at 3 weeks was significantly associated with PFS (p = 0.016). Conclusions: These results demonstrate that GIN values of cfDNA measured at early on-treatment time points can predict PFS and OS with a high degree of accuracy. These findings deserve further study in a larger cohort but hold the promise of early prediction of clinical outcomes in a tumor-independent genome-wide approach.

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