scholarly journals Genetic Variants and Tumor Immune Microenvironment: Clues for Targeted Therapies in Inflammatory Breast Cancer (IBC)

2021 ◽  
Vol 22 (16) ◽  
pp. 8924
Author(s):  
Yulan Gong ◽  
Rajeswari Nagarathinam ◽  
Maria F. Arisi ◽  
Lorenzo Gerratana ◽  
Jennifer S. Winn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Inflammatory Breast Cancer ◽  
Tumor Tissue ◽  
Tumor Infiltrating Lymphocytes ◽  
Parp Inhibitors ◽  
Targeted Next Generation Sequencing ◽  
Increased Risk ◽  
Brca1 Brca2 ◽  
Genetic Profiles ◽  
Next Generation Sequencing Ngs

To better understand the etiology of inflammatory breast cancer (IBC) and identify potential therapies, we studied genomic alterations in IBC patients. Targeted, next-generation sequencing (NGS) was performed on cell-free DNA (cfDNA) (n = 33) and paired DNA from tumor tissues (n = 29) from 32 IBC patients. We confirmed complementarity between cfDNA and tumor tissue genetic profiles. We found a high incidence of germline variants in IBC patients that could be associated with an increased risk of developing the disease. Furthermore, 31% of IBC patients showed deficiencies in the homologous recombination repair (HRR) pathway (BRCA1, BRCA2, PALB2, RAD51C, ATM, BARD1) making them sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. We also characterized the tumor-infiltrating lymphocytes (TILs) in tumor tissue biopsies by studying several markers (CD4, CD8, FoxP3, CD20, PD-1, and PD-L1) through immunohistochemistry (IHC) staining. In 7 of 24 (29%) patients, tumor biopsies were positive for PD-L1 and PD-1 expression on TILs, making them sensitive to PD-1/PD-L1 blocking therapies. Our results provide a rationale for considering PARP inhibitors and PD-1/PDL1 blocking immunotherapy in qualifying IBC patients.

scholarly journals Genetic Variants Detected Using Cell-Free DNA from Blood and Tumor Samples in Patients with Inflammatory Breast Cancer

2020 ◽  
Vol 21 (4) ◽  
pp. 1290
Author(s):  
Jennifer S. Winn ◽  
Zachary Hasse ◽  
Michael Slifker ◽  
Jianming Pei ◽  
Sebastian M. Arisi-Fernandez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Inflammatory Breast Cancer ◽  
Triple Negative ◽  
Genetic Profile ◽  
Cell Free Dna ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Free Dna ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

We studied genomic alterations in 19 inflammatory breast cancer (IBC) patients with advanced disease using samples of tissue and paired blood serum or plasma (cell-free DNA, cfDNA) by targeted next generation sequencing (NGS). At diagnosis, the disease was triple negative (TN) in eleven patients (57.8%), ER+ Her2- IBC in six patients (31.6%), ER+ Her2+ IBC in one patient (5.3%), and ER- Her2+ IBC in one other patient (5.3%). Pathogenic or likely pathogenic variants were frequently detected in TP53 (47.3%), PMS2 (26.3%), MRE11 (26.3%), RB1 (10.5%), BRCA1 (10.5%), PTEN (10.5%) and AR (10.5%); other affected genes included PMS1, KMT2C, BRCA2, PALB2, MUTYH, MEN1, MSH2, CHEK2, NCOR1, PIK3CA, ESR1 and MAP2K4. In 15 of the 19 patients in which tissue and paired blood were collected at the same time point, 80% of the variants detected in tissue were also detected in the paired cfDNA. Higher concordance between tissue and cfDNA was found for variants with higher allele fraction in tissue (AFtissue ≥ 5%). Furthermore, 86% of the variants detected in cfDNA were also detected in paired tissue. Our study suggests that the genetic profile measured in blood cfDNA is complementary to that of tumor tissue in IBC patients.

scholarly journals Poly(ADP-Ribose) Polymerase Inhibitors (PARPi) for Patients With Advanced Breast Cancer: a Meta-analysis of Randomized Controlled Trials

2020 ◽  
Author(s):  
YongCheng Su ◽  
XiaoGang Zheng
Keyword(s):  
Breast Cancer ◽  
Randomized Controlled Trials ◽  
Fixed Effects ◽  
Meta Analysis ◽  
Parp Inhibitors ◽  
Cochrane Library ◽  
Controlled Trials ◽  
Randomized Controlled ◽  
Increased Risk ◽  
Grade 3

Abstract BACKGROUND: Poly(ADP–ribose) polymerase (PARP) inhibitors are new class of drugs that are currently being studied in several malignancies. However, datas about the efficacy and safety of the PARP inhibitors are limited. Therefore, we conducted a meta-analysis of randomized controlled trials (RCT) in patients with breast cancer.METHODS: Pubmed/Medline, Embase, Cochrane Library, and abstracts presented at the annual meeting of the American Society of Clinical Oncology (ASCO) were searched for articles published from 2000 to June 2018.Summary incidences and the RR, HR with 95% confidence intervals, were calculated by using a random-effects or fixed-effects model.RESULTS: The summary HR indicated PARPi was not associated with OS (HR=0.83, 95%CI 0.66–1.06, Z=1.49, P=0.14), while it could significantly improve PFS ande time to deterioration (TTD) of global health status/quality of life(GHS/QoL) as compared with traditional standard therapy, the HR was 0.60(95%CI 0.50-0.72; Z=5.52, P＜0.00001) and 0.4 (95%CI 0.29–0.54,z=5.80 ,p=0.000),respectively.The RR of grade 3 or more anemia ,fatigue and headache was 3.02 (95% CI, 0.69–13.17;p = 0.14,,I2=90%),0.77 (95%CI, 0.34–1.73;p=0.52,I2=7%) and 1.13 (95% CI,0.30–4.18;p=0.86,I2=0%),respectively.CONCLUSION: The findings of this meta-analysis showed that PARPi has no significant effect on OS, while it could significantly improve in PFS and TTD of GHS/QoL for patients with advanced or metastatic breast cancer.Furthermore,our findings also demonstrated that the PARPi treatment is connected with an increased risk of grade 3 or more anemia adverse events.

Targeted Resequencing of Putative Growth-Related Genes Using Whole Exome Sequencing in Patients with Severe Primary IGF-I Deficiency

2017 ◽  
Vol 88 (6) ◽  
pp. 408-417 ◽  
Author(s):  
Greta Grosse ◽  
Alina Hilger ◽  
Michael Ludwig ◽  
Heiko Reutter ◽  
Franziska Lorenzen ◽  
...  
Keyword(s):  
Large Scale ◽  
De Novo ◽  
Targeted Resequencing ◽  
Targeted Next Generation Sequencing ◽  
Increased Risk ◽  
Igf I ◽  
Novel Variant ◽  
Unaffected Parent ◽  
Next Generation Sequencing Ngs ◽  
Clinical Phenotyping

Background/Aims: To elucidate the genetic causes of severe primary insulin-like growth factor-I deficiency (SPIGFD) by systematic, targeted, next-generation sequencing (NGS)-based resequencing of growth-related genes. Methods: Clinical phenotyping followed by NGS in 17 families including 6 affected sib pairs. Results: We identified disease-causing, heterozygous, de novo variants in HRAS (p.Gly13Cys) and FAM111A (p.Arg569His) in 2 male patients with syndromic SPIGFD. A previously described homozygous GHR nonsense variant was detected in 2 siblings of a consanguineous family (p.Glu198*). Furthermore, we identified an inherited novel variant in the IGF2 gene (p.Arg156Cys) of a maternally imprinted gene in a less severely affected father and his affected daughter. We detected 2 other novel missense variants in SH2B1 and SOCS2, both were inherited from an unaffected parent. Conclusions: Screening of growth-related genes using NGS-based, large-scale, targeted resequencing identified disease-causing variants in HRAS, FAM111A, and GHR. Considering the increased risk of subjects with HRAS mutations for neoplasms, close clinical monitoring and a thorough discussion of the risk/benefit ratio of the treatment with recombinant IGF-I is mandatory. Segregation analysis proved to be critical in the interpretation of potential SPIGFD-associated gene variations.

Inflammatory breast cancer and body mass index.

1998 ◽  
Vol 16 (12) ◽  
pp. 3731-3735 ◽  
Author(s):  
S Chang ◽  
A U Buzdar ◽  
S D Hursting
Keyword(s):  
Breast Cancer ◽  
Body Mass Index ◽  
Cancer Patients ◽  
Body Mass ◽  
Inflammatory Breast Cancer ◽  
Menopausal Status ◽  
Control Group ◽  
Breast Cancer Patients ◽  
Increased Risk ◽  
High Bmi

PURPOSE No studies have investigated the etiology of inflammatory breast cancer (IBC), the most lethal form of breast cancer. Because high body mass index (BMI) is associated with decreased risk of premenopausal breast cancer but increased risk of postmenopausal breast cancer, we evaluated whether high BMI was a risk factor for IBC. PATIENTS AND METHODS In a case-comparison study, we matched by ethnicity and registration date 68 IBC patients treated at The University of Texas M.D. Anderson Cancer Center from 1985 to 1996 with 143 patients with non-IBC and 134 patients with cancer at sites other than the breast or reproductive tract (non-breast cancer). The non-breast cancer group was used in lieu of a population-based, healthy control group, which was not available. RESULTS IBC patients were younger at menarche and the time of their first live birth than non-IBC and non-breast cancer patients. The proportion of premenopausal IBC patients was higher than the proportion of premenopausal women in the comparison groups, although differences were not significant. There were no differences in height, but IBC patients were heavier (77.6 kg) than non-IBC (70.0 kg) and non-breast cancer patients (68.0 kg). After adjusting for other factors, women in the highest BMI tertile (BMI > 26.65 kg/m2) relative to the lowest tertile (BMI < 22.27) had significantly increased IBC risk (IBC v non-IBC, odds ratio [OR] = 2.45, 95% confidence interval [CI] = 1.05 to 5.73; IBC v non-breast cancer, OR = 4.52, 95% CI = 1.85 to 11.04). This association was not significantly modified by menopausal status and was independent of age at menarche, family history of breast cancer, gravidity, smoking status, and alcohol use. CONCLUSION Our investigation showed that high BMI was significantly associated with an increased risk of IBC. This association did not vary by menopausal status, although IBC patients were more likely to be premenopausal. Confirming our findings and identifying other IBC risk factors may provide directions for future research on the aggressive nature of IBC.

scholarly journals Clinical Relevance of Immune Checkpoints on Circulating Tumor Cells in Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 376 ◽  
Author(s):  
Maria A. Papadaki ◽  
Anastasios V. Koutsopoulos ◽  
Panormitis G. Tsoulfas ◽  
Eleni Lagoudaki ◽  
Despoina Aggouraki ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Peripheral Blood ◽  
Tumor Tissue ◽  
Mononuclear Cells ◽  
Immune Checkpoints ◽  
Peripheral Blood Mononuclear ◽  
Increased Risk

The role of CD47 and PD-L1 expression on circulating tumor cells (CTCs) remains unclear, and it is currently unknown whether their distribution varies between the blood and tumor tissue in breast cancer (BC). In this study, CD47 and PD-L1 expression was investigated a) on peripheral blood mononuclear cell (PBMC) cytospins from early (n = 100) and metastatic (n = 98) BC patients, by triple immunofluorescence for CD47/PD-L1/Cytokeratins, and b) on matched primary and/or metastatic tumor tissue from CTC-positive patients using immunohistochemistry. CD47+and/orPD-L1+ CTCs were detected in 11%, 16.9%, and 29.6% of early, recurrent, and de novo metastatic patients (p = 0.016). In metastatic disease, CD47highand/orPD-L1high CTCs were associated with disease progression (p = 0.005) and shorter progression-free survival (PFS) (p = 0.010), and independently predicted for an increased risk of relapse (HR: 2.719; p = 0.008) and death (HR: 2.398; p = 0.034). PD-L1 expression rates differed between CTCs and tissue tumor cells and between peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) (positive concordance of 3.8% and 4%, respectively). CD47 expression also differed between CTCs and tumor cells (positive concordance of 11.5%). In conclusion, CTCs expressing CD47 and PD-L1 have independent poor prognostic implications in metastatic BC, indicating a potential role of innate and adaptive immune evasion mechanisms in their metastatic potential. The clinical value of the parallel assessment of the peripheral and local immune response merits further evaluation in BC.

scholarly journals Genetically associated breast cancer. Prevention and treatment

2019 ◽  
pp. 3-9
Author(s):  
А.Д. Зикиряходжаев ◽  
Э.К. Сарибекян ◽  
А.С. Сухотько ◽  
А.В. Трегубова
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cumulative Risk ◽  
Brca2 Gene ◽  
Contralateral Breast ◽  
Malignant Neoplasms ◽  
Female Population ◽  
Increased Risk ◽  
Incidence And Mortality ◽  
Brca1 Brca2

Рак молочной железы (РМЖ) занимает первое место в структуре онкологической заболеваемости и смертности от злокачественных новообразований среди женского населения Российской Федерации. Согласно последним статистическим данным, отмечается неуклонный рост заболеваемости РМЖ, что требует более тщательного изучения возможных мер профилактики его развития. Одним из современных методов обследования при подозрении на РМЖ является выполнение генетического исследования на наличие мутаций, увеличивающих риски развития заболевания. Так, на сегодняшний день известно большое количество генов, ассоциированных с повышенным риском развития РМЖ, к таким генам относятся: BRCA1, BRCA2, CHEK2, TP53, STK-11 и многие другие. При выявлении той или иной мутации у пациентки повышаются риски развития РМЖ, а если заболевание уже реализовано, то риски развития рака контрлатеральной молочной железы. По данным литературы, кумулятивный риск развития РМЖ у носителей мутации в гене BRCA1 к 80 годам составляет 72%, при этом риск развития рака яичников составляет 44% и 40% риск развития рака контралатеральной молочной железы. Для носителей мутации в гене BRCA2 кумулятивный риск развития РМЖ составляет 69%, риск развития рака яичников составляет 17% и 26% риск развития рака контралатеральной молочной железы. Учитывая значительное повышение рисков развития РМЖ при носительстве мутации в том или ином гене, актуальным, на сегодняшний день, является вопрос о внедрении в широкую практику профилактических операций, которые позволяют значительно снизить риски развития РМЖ. В данном обзоре литературы представлены наиболее актуальные статьи, затрагивающие данную тематику. Breast cancer (BC) occupies the first place in the structure of cancer incidence and mortality from malignant neoplasms among the female population of the Russian Federation. According to the latest statistics, there has been a steady increase in the incidence of breast cancer, which requires a more thorough study of possible measures to prevent its development. One of the modern methods of examination for suspected breast cancer is to carry out a genetic study for mutations that increase the risk of developing breast cancer compared with a group of patients with sporadic breast cancer. So, today a large number of genes are known that are associated with an increased risk of developing breast cancer, these genes include: BRCA1, BRCA2, CHEK2, TP53, STK-11 etc. If one or another mutation is detected in a patient, the risks of developing breast cancer increase, and if the disease has already been realized, then the risks of developing cancer of the contralateral breast. Thus, the cumulative risk of developing breast cancer in carriers of mutations in the BRCA1 gene to 80 years old is 72%, while the risk of developing ovarian cancer is 44% and 40% the risk of developing cancer of the contralateral breast. For carriers of mutations in the BRCA2 gene, the cumulative risk of developing breast cancer is 69%, the risk of developing ovarian cancer is 17% and 26% is the risk of developing cancer of the contralateral breast. Given the significant increase in the risks of developing breast cancer with carriage of a mutation in a particular gene, today, the urgent issue is the introduction of preventive surgery into widespread practice, since it is the implementation of preventive mastectomy that can significantly reduce the risks of developing breast cancer. This literature review presents the most relevant articles affecting this topic.

Sign in / Sign up

Export Citation Format

Share Document