Genetic alterations of triple negative breast cancer (TNBC) in women from Northeastern Mexico

541 Background: Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that is markedly heterogeneous and lacks specific targets. The aim of this study is to explore potential predictors and therapeutic targets based on clinical and genetic characteristics. Methods: 138 patients with triple-negative breast cancer after surgical treatment were 1:1 randomly assigned to the paclitaxel combined with carboplatin (TCb) group or the epirubicin combined with cyclophosphamide sequential paclitaxel (EC-T) adjuvant chemotherapy group. PD-L1 was retrospectively analyzed by surgically resected specimens, and 733 cancer-related genes were detected by NGS. Pathway enrichment analysis was performed using DAVID for functional enrichment genetic alterations. Cox regression models and Kaplan-Meier were used to evaluate disease-free survival (DFS). Results: In this study, there was no significant difference in DFS between the TCb and EC-T groups. 31 (22.5%) of 138 TNBC patients were positive for PD-L1 expression, including 15 (10.9%) patients positive for PD-L1 in tumor cells (TCs) and 29 (21.0%) patients positive for PD-L1 in tumor-infiltrating immune cells (TICs). Patients with positive PD-L1 expression, either in TCs or TICs, achieved better DFS [HR=0.13 (95% CI: 0.02-0.93), p=0.016], the difference was also shown in the EC-T group [HR=0 (95% CI: 0- inf), p=0.037], but not in the TCb group [HR=0 (95% CI: 0.04-2.1), p=0.189]. In addition, we identified 7 patients with mutations in DNA topoisomerase IIIα(TOP3A), a homologous recombination (HR)-related gene, and patients with mutations in this gene had worse DFS than those without mutations [HR=4]. However, there was no statistically significant association between BRCA mutation and response to either therapeutic regimens. Conclusions: In this TNBC patient population, immunohistochemistry (IHC) and NGS analyses identified potential prognostic markers. PD-L1 positive and TOP3A mutation were significantly associated with early triple-negative breast cancer prognosis.

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Optimizing Chemotherapy in Triple-Negative Breast Cancer: The Role of Platinum

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2014.34.e37 ◽

2014 ◽

pp. e37-e42 ◽

Cited By ~ 13

Author(s):

Melinda Telli

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Randomized Clinical Trials ◽

Triple Negative ◽

Early Stage ◽

Breast Cancer Subtype ◽

Brca2 Mutation ◽

Genetic Alterations ◽

Brca1 And Brca2 ◽

Repair Capacity

Although characterization of triple-negative breast cancer (TNBC) using mRNA gene expression profiling has certainly provided important insights, the concept of targeting DNA repair defects with DNA damaging therapeutics such as platinum in TNBC has been advanced from studies focusing on both germline and somatic genetic alterations associated with this breast cancer subtype. A growing body of preclinical and clinical data suggests that platinum chemotherapy has a potential role to play in the treatment of both early-stage and advanced TNBC, though results are not yet definitive. Randomized clinical trials that incorporate biomarkers of response, including germline BRCA1 and BRCA2 mutation status as well as tumor-based measures of genomic “scarring” resulting from the accumulation of DNA damage in tumors with deficient repair capacity, will help to clarify the optimal use and activity of platinum in TNBC.

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Immunohistological Expression of SOX-10 in Triple-Negative Breast Cancer: A Descriptive Analysis of 113 Samples

International Journal of Molecular Sciences ◽

10.3390/ijms21176407 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6407 ◽

Cited By ~ 1

Author(s):

Katharina Kriegsmann ◽

Christa Flechtenmacher ◽

Jörg Heil ◽

Jörg Kriegsmann ◽

Gunhild Mechtersheimer ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Descriptive Analysis ◽

Biological Significance ◽

Genetic Alterations ◽

Prognostic Impact ◽

Cancer Genes ◽

Sequencing Data ◽

Disease Free

Background: SRY-related HMG-box 10 (SOX-10) is commonly expressed in triple negative breast cancer (TNBC). However, data on the biological significance of SOX-10 expression is limited. Therefore, we investigated immunhistological SOX-10 expression in TNBC and correlated the results with genetic alterations and clinical data. Methods: A tissue microarray including 113 TNBC cases was stained by SOX-10. Immunohistological data of AR, BCL2, CD117, p53 and Vimentin was available from a previous study. Semiconductor-based panel sequencing data including commonly altered breast cancer genes was also available from a previous investigation. SOX-10 expression was correlated with clinicopathological, immunohistochemical and genetic data. Results: SOX-10 was significantly associated with CD117 and Vimentin, but not with AR expression. An association of SOX-10 with BCL2, EGFR or p53 staining was not observed. SOX-10-positive tumors harbored more often TP53 mutations but less frequent mutations of PIK3CA or alterations of the PIK3K pathway. SOX-10 expression had no prognostic impact either on disease-free, distant disease-free, or overall survival. Conclusions: While there might be a value of SOX-10 as a differential diagnostic marker to identify metastases of TNBC, its biological role remains to be investigated.

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Next generation sequencing reveals CCNE1 amplification as an independent prognostic factor for triple negative breast cancer (TNBC) patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.558 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 558-558

Author(s):

Xin Huang ◽

Huanwen M. Wu ◽

Changbin Zhu ◽

Di Shao ◽

Dan Guo ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Copy Number ◽

Triple Negative ◽

Genetic Data ◽

Genetic Alterations ◽

Clinicopathological Parameters ◽

Genomic Profiling ◽

Cyclin E1 ◽

Comprehensive Genomic Profiling

558 Background: Triple negative breast cancer (TNBC) has the worst prognosis among breast cancer due to the heterogeneity as well as lack of better therapeutic approach. It remains controversial whether BRCA status is the predictor of survival in TNBC. Besides, both germline and somatic mutation may contribute to the prognosis. This study is to explore the potential predictors and therapeutic targets based on genetic data and clinicopathological parameters. Methods: Seventy-five TNBC patients were enrolled with approximately 2:1 based on BRCA status. Genetic data was analysed by comprehensive genomic profiling 508 key cancer related genes. DAVID was applied to perform pathway enrichment analysis of significant enriched genetic alterations. Cox regression model was applied to evaluate disease-free survival (DFS) and overall survival (OS). Immuno-chemistry (IHC) was used to validate clinically meaningful genetic alteration. Results: In this study, 27 germline mutations were detected, including 26 homologous recombination repair (HRR) pathway gene mutations and 1 mismatch repair gene mutation among them 16 BRCA1 mutations and 5 BRCA2 mutations were found. Germline HRR including BRCA1/2 mutation marginally affected DFS ( p = 0.0624 and 0.15, respectively). We found 480 somatic genetic alterations including 110 copy number variations (CNV). The median value of TMB was determined to be 4.1 Muts/Mb which divided 74 TNBC patients into TMB-low (TMB-l) and TMB-high (TMB-h) group. TMB-l group had inferior DFS to TMB-h ( p = 0.0457). CCNE1 (with 5% frequency) copy number gain was specifically enriched in TMB-l group but mutually exclusive with BRCA1/2 mutation. TNBC with CCNE1 gain displayed worse DFS ( p< 0.0001). Cox multivariate regression analysis indicated CCNE1 gain was an independent risk factors for DFS [HR = 13.48 (95% CI 2.62-69.23), p= 0.002)]. Pathway analysis indicated CCNE1 harmed prognosis through regulation of transcription in G1/S phase. Expression of cyclin E1 was validated by IHC, which would be presented later. Conclusions: Comprehensive genomic profiling disclosed various potential prognostic markers for TNBC by integrating clinical characters. Especially, amplified CCNE1 may be a potential prognostic marker and therapeutic target. [Table: see text]

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Abstract 2023: Whole exome and RNA sequencing reveals genetic alterations in DNA damage and homologous recombination pathways in triple negative breast cancer.

10.1158/1538-7445.am2013-2023 ◽

2013 ◽

Author(s):

Shukmei Wong ◽

Joyce A. O'Shaughnessy ◽

Patricia LoRusso ◽

Jessica Aldrich ◽

Ahmet Kurdoglu ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Homologous Recombination ◽

Rna Sequencing ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Genetic Alterations ◽

Whole Exome

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Genetic alterations in sporadic triple negative breast cancer

The Breast ◽

10.1016/j.breast.2017.11.006 ◽

2018 ◽

Vol 38 ◽

pp. 30-38 ◽

Cited By ~ 9

Author(s):

Laura-Ancuta Pop ◽

Roxana-Maria Cojocneanu-Petric ◽

Valentina Pileczki ◽

Gabriela Morar-Bolba ◽

Alexandru Irimie ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Genetic Alterations

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Patterns of mutation enrichment in metastatic triple-negative breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e12596 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e12596-e12596

Author(s):

Cesar H. Saravia ◽

Claudio J. Flores ◽

Luis Jesus Schwarz ◽

Leny Bravo ◽

Jenny Zavaleta ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Multiple Testing ◽

Triple Negative ◽

Metastatic Breast ◽

Genetic Alterations ◽

Breast Cancers ◽

Number Variation ◽

Cancer Project ◽

Chisquare Test

e12596 Background: Triple-Negative breast cancer (TNBC) is a group of heterogeneous tumors with aggressive biology. The purpose of this research was to evaluate enrichment patterns of genomic alterations in metastatic TNBC (mTNBC). Methods: We retrieved genomic data (mutations and copy number variation) from 550 primaries TNBC (pTNBC) from the projects METABRIC and TCGA and 58 mTNBC from the projects “Mutational Profile of Metastatic Breast Cancers” and “The metastatic Breast Cancer Project”. Differences in the proportions of mutations between primary vs. metastatic tumors were evaluated by the Chisquare test and the percentage of enrichment in mTNBC was estimated. Pvalues were adjusted for multiple testing with the Benjamini-Hochberg method with and a FDR < 0.05. In addition we conducted an analysis of the hallmarks of cancers enriched in mTNBC. Results: In total, mutations in eight genes were significantly enriched in mTNBC after correcting for multiple testing. These genes included TTN, HMCN1, RELN, PKHD1L1, DMD, FRAS1 and RYR3. In the other hand, only amplification of RPS6KB2 was enriched in mTNBC. Deletions were enriched more frequently in the genes TET1, RHOA, EPHA5, SET, KCNJ5, ABCG4, NKX3-1, SDHB, IGF2, BRCA1, among others. The hallmark of “genetic instability and mutation” was over represented while the hallmark “activating immune destruction” was the least represented between the enriched genetic alterations in mTNBC. Conclusions: Despite the study limitations, we identified that deletions are the aberrations more commonly enriched in mTNBC while some biological processes could be targetable in order to improve the therapeutic opportunities in TNBC.

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Differences in prognosis by p53 expression after neoadjuvant chemotherapy in triple-negative breast cancer.

Journal of Global Oncology ◽

10.1200/jgo.2019.5.suppl.119 ◽

2019 ◽

Vol 5 (suppl) ◽

pp. 119-119

Author(s):

Seung Pil Jung ◽

Soo Youn Bae ◽

Jeong Hyeon Lee ◽

Joung Won Bae

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Pathologic Complete Response ◽

Genetic Alterations ◽

Residual Cancer ◽

P53 Expression ◽

Significant Difference ◽

Response To Neoadjuvant Chemotherapy

119 Background: Triple negative breast cancer (TNBC) exhibits a higher rate of early recurrence and more aggressive behavior. Despite unfavorable prognoses, TNBCs are known to be highly reactive to chemotherapy and show higher pathologic complete response rates after neoadjuvant chemotherapy. However, TNBC patients with residual cancer have significantly worse prognoses than patients with non-TNBC associated residual cancer. TP53 mutations are the most common genetic alterations in breast cancer and are highly linked to basal subtype carcinomas. Past studies have investigated if TP53 mutation can predict the response of cancer to chemotherapy or affect a difference in prognosis; however, the lack of consistent results has hampered clinical applications. Because immunostaining studies can be easily performed, those results may be more useful until Next generation sequencing results are clinically applicable. The aim of this study was to determine whether p53 expression in TNBC could predict the response to neoadjuvant chemotherapy and the resulting prognosis. Methods: From 2009 to 2017, TNBC patients who underwent neoadjuvant chemotherapy were reviewed, including a total of 31 TNBC patients who had clinical lymph node metastasis. The status of p53 expression in patients before and after chemotherapy was evaluated. Results: Two patients (22.2%, 2/9) achieved pCR in p53(+) TNBC and four patients (50%, 5/10) achieved pCR in p53(-) TNBC. There was no correlation between pCR rate and p53 expression ( P= 0.350). Based on pre-chemotherapy p53 expression, there was no significant difference in DFS between p53(+) TNBC and p53(-) TNBC ( P= 0.335) . However, after chemotherapy, p53(+) TNBC had shown higher DFS than p53(-) TBNC ( P= 0.099). Based on pre-chemotherapy p53 expression, p53(+) TNBC had better OS than p53(-) TNBC, but the difference was not statistically significant ( P= 0.082). After chemotherapy, p53(+) TNBC showed significantly better OS than p53(-) TNBC ( P = 0.018). Conclusions: Immunohistochemically detected p53 expression in TNBC could not predict the response to neoadjuvant chemotherapy. However, p53 (+) TNBC had a better OS than p53 (-) TNBC in patients who underwent neoadjuvant chemotherapy.

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The Evolution of Clinically Aggressive Triple-Negative Breast Cancer Shows a Large Mutational Diversity and Early Metastasis to Lymph Nodes

Cancers ◽

10.3390/cancers13205091 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5091

Author(s):

Héctor Martínez-Gregorio ◽

Ernesto Rojas-Jiménez ◽

Javier César Mejía-Gómez ◽

Clara Díaz-Velásquez ◽

Rosalía Quezada-Urban ◽

...

Keyword(s):

Breast Cancer ◽

Lymph Nodes ◽

Triple Negative Breast Cancer ◽

Genetic Heterogeneity ◽

Triple Negative ◽

Early Stage ◽

Genetic Alterations ◽

Evolutionary Development ◽

Tumor Evolution ◽

Skin Metastases

In triple-negative breast cancer (TNBC), only 30% of patients treated with neoadjuvant chemotherapy achieve a pathological complete response after treatment and more than 90% die due to metastasis formation. The diverse clinical responses and metastatic developments are attributed to extensive intrapatient genetic heterogeneity and tumor evolution acting on this neoplasm. In this work, we aimed to evaluate genomic alterations and tumor evolution in TNBC patients with aggressive disease. We sequenced the whole exome of 16 lesions from four patients who did not respond to therapy, and took several follow-up samples, including samples from tumors before and after treatment, as well as from the lymph nodes and skin metastases. We found substantial intrapatient genetic heterogeneity, with a variable tumor mutational composition. Early truncal events were MCL1 amplifications. Metastatic lesions had deletions in RB1 and PTEN, along with TERT, AKT2, and CCNE1 amplifications. Mutational signatures 06 and 12 were mainly detected in skin metastases and lymph nodes. According to phylogenetic analysis, the lymph node metastases occurred at an early stage of TNBC development. Finally, each patient had three to eight candidate driving mutations for targeted treatments. This study delves into the genomic complexity and the phylogenetic and evolutionary development of aggressive TNBC, supporting early metastatic development, and identifies specific genetic alterations associated with a response to targeted therapies.

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Circulating Tumor DNA and Biomarker Analyses From the LOTUS Randomized Trial of First-Line Ipatasertib and Paclitaxel for Metastatic Triple-Negative Breast Cancer

JCO Precision Oncology ◽

10.1200/po.19.00396 ◽

2020 ◽

pp. 1012-1024

Author(s):

Matthew J. Wongchenko ◽

Sung-Bae Kim ◽

Cristina Saura ◽

Mafalda Oliveira ◽

Doron Lipson ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Objective Response ◽

Circulating Tumor Dna ◽

Genetic Alterations ◽

Longitudinal Analyses ◽

Akt Inhibitor ◽

First Line ◽

Tumor Dna

PURPOSE Combining the oral AKT inhibitor ipatasertib with paclitaxel as first-line therapy for metastatic triple-negative breast cancer significantly improved progression-free survival (PFS) in the placebo-controlled, randomized, phase II LOTUS trial, with a more pronounced effect in patients with PIK3CA/AKT1/PTEN-altered tumors. We report findings from the extensive translational research program. PATIENTS AND METHODS Pretreatment plasma and tumor samples were evaluated for genetic alterations using FoundationACT and FoundationOne (Foundation Medicine, Cambridge, MA) hybrid capture next-generation sequencing assays, respectively. Prevalences of the most common mutations and PIK3CA/AKT1 mutation status were determined using both assays, and concordance was assessed. In longitudinal analyses, circulating tumor DNA (ctDNA) mutations were quantified in baseline and on-treatment (cycle 3, day 1 [C3D1]) samples. The relationship between outcomes and ctDNA fraction (CTF; highest variant allele frequency) and CTF ratio (C3D1 CTF to baseline CTF) was explored. RESULTS Among 89 patients evaluable for ctDNA sequencing, 81 patients (91%) had 149 detectable mutations. There was high agreement between plasma- and tissue-based sequencing for known or likely short variant mutations but not amplifications. There was 100% concordance between ctDNA and tissue sequencing in patients with activating PIK3CA or AKT1 mutations. High baseline CTF was associated with shorter PFS in both treatment arms. Longitudinal analyses showed more favorable outcomes with lower absolute CTF at C3D1 and, to a lesser extent, greater CTF decreases. CONCLUSION These results suggest that plasma ctDNA sequencing may allow reliable and convenient assessment of prognosis and identification of genetic markers associated with increased benefit from ipatasertib. On-treatment CTF showed a meaningful association with objective response and PFS.

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