Genomic Profiling Comparison of Germline BRCA and Non-BRCA Carriers Reveals CCNE1 Amplification as a Risk Factor for Non-BRCA Carriers in Patients With Triple-Negative Breast Cancer

28 Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) with unique clinical-pathological & prognostic characteristics. Studies have shown obesity to be risk factor for TNBC. Furthermore, patients (pts) with BC and overweight/obesity have a worse prognosis. Here we investigate body mass index (BMI) & weight trends among BC survivors. Methods: A retrospective review BC pts at Cancer Treatment Centers of America Atlanta from 2012-10/27/17. Definition of a survivor: pts who have completed definitive therapy with no evidence of disease. Survivor BMI & weight gain (kg) calculated from chart review. Weight gain in kg was recorded post chemotherapy, at 3, 6, 9, 12 month follow up. Inclusion: Pts with ER-PR-HER2- (TNBC), adults > 18 yo, pts who completed chemo (neoadjuvant or adjuvant) & surgery +/- radiation. Exclusion: Pts who died, had relapsed local disease or metastatic disease; missing BMI data; currently on chemotherapy; who did not receive chemotherapy; missing continuous BMI data or pathology report; lost to follow up. Results: 1756 BC pts with stage IA-IIIC identified, 300 pts identified as TNBC. A total of 134 patients met full inclusion/exclusion survivorship criteria. Average age of survivors = 52 (range 25-76). Stage: I = 38%; II = 50%, III = 12%. BMI categories: 0% underweight (BMI < 18.5 kg/m2), 15% normal weight (BMI 18.5 to < 25 kg/m2), 18% overweight (BMI 25 to < 30 kg/m2), 55% obese (BMI ≤30 kg/m2), 12% morbid obesity (BMI ≤ 40 kg/m2). Average BMI for all survivors = 32.23 +/-0.59 kg/m2 (range 19-52 kg/m2); post chemotherapy weight change = 0.53 +/-0.41 kg; at 3 month follow up = -0.16 +/-0.51 kg; at 6 month = -0.02 +/-0.54 kg; at 9 month follow up 1.20 +/-0.59 kg; at 12 month follow up = 2.25 +/-0.61 kg. BMI by stage: I = 32.81 +/- 1.00 kg/m2; II = 32.12 +/- 0.91 kg/m2; III = 32.44 +/- 1.27 kg/m2. Conclusions: In our study, female survivors with TNBC present with obesity and gain weight after chemotherapy. Also, weight gain continues at 9 & 12 months post definitive treatment. Survivors with TNBC should be treated with intensive weight loss interventions given that overweight/obesity is a risk factor for recurrence, worse prognosis, & cardiovascular events.

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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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Integration of genomic profiling and functional screening identifies potential driver somatic copy number alterations in triple-negative breast cancer

European Journal of Cancer ◽

10.1016/s0959-8049(20)30725-5 ◽

2020 ◽

Vol 138 ◽

pp. S74

Author(s):

G. Xie ◽

X. Xu

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Copy Number ◽

Triple Negative ◽

Functional Screening ◽

Genomic Profiling ◽

Copy Number Alterations ◽

Somatic Copy Number Alterations

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Genomic Profiling in Triple-Negative Breast Cancer

Breast Care ◽

10.1159/000357534 ◽

2013 ◽

Vol 8 (6) ◽

pp. 408-413 ◽

Cited By ~ 14

Author(s):

Cornelia Liedtke ◽

Christof Bernemann ◽

Ludwig Kiesel ◽

Achim Rody

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Genomic Profiling

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Comprehensive Genomic Profiling-Guided Niraparib Treatment of Triple-Negative Breast Cancer in a Patient With Extensive Brain Metastasis: Case Report and Literature Review

Journal of Immunotherapy and Precision Oncology ◽

10.36401/jipo-20-24 ◽

2021 ◽

Vol 4 (1) ◽

pp. 16-20

Author(s):

Tai-Chung Lam

Keyword(s):

Breast Cancer ◽

Clinical Response ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Single Agent ◽

Gene Mutations ◽

Central Nervous System Tumor ◽

Genomic Profiling ◽

Wild Type ◽

Comprehensive Genomic Profiling

ABSTRACT Homologous recombination deficiency (HRD) is a common phenotypic alteration that is highly druggable with poly (ADP-ribose) polymerase inhibitors (PARPi). Although BRCA1/2 gene mutations are among the commonest genomic aberrations associated with HRD, defects in other DNA damage repair (DDR) genes also may influence clinical response to PARPi. Here, we report the case of a 51-year-old Chinese woman with extensive symptomatic brain metastases from metastatic BRCA1/2 wild-type triple-negative breast cancer (TNBC). Comprehensive genomic profiling (CGP) of resected central nervous system tumor revealed mutations in TP53 and multiple DDR pathway genes, suggesting an HRD phenotype. The patient showed a rapid and remarkable response to single-agent niraparib, and her improved condition remained stable for > 8 weeks. To the best of our knowledge, this is the first report of the use of CGP for guiding targeted therapy with PARPi in patients with TNBC, for which options have been limited. CGP may have an increasingly impactful role to predict clinical response of PARPi in patients with BRCA1/2 wild-type TNBC.

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