Biomarker data from KATHERINE: A phase III study of adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab (H) in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 502-502 ◽  
Author(s):  
Carsten Denkert ◽  
Chiara Lambertini ◽  
Peter A. Fasching ◽  
Katherine L. Pogue-Geile ◽  
Max S. Mano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Targeted Therapy ◽  
Checkpoint Inhibitor ◽  
Invasive Disease ◽  
Phase Iii ◽  
Expression Levels ◽  
Rna Analysis ◽  
Pre Treatment ◽  
The Relationship

502 Background: The phase 3 KATHERINE study (NCT01772472) compared adjuvant T-DM1 versus H in patients with residual invasive breast cancer after neoadjuvant chemotherapy plus HER2-targeted therapy. Here we report exploratory analyses of the relationship between invasive disease-free survival (IDFS) and biomarkers potentially related to response. Methods: Formalin fixed paraffin-embedded tissue samples were collected before neoadjuvant treatment and/or at surgery. Surgical samples were used for analyses, except when only pre-treatment samples were available (~20% of cases). DNA was derived to identify PIK3CA hotspot mutations and gene expression (RNA) analysis was used to detect HER2, PD-L1, CD8 and predefined immune signatures including 3-gene, 5-gene, Teffector, chemokine signaling, and checkpoint inhibitor signatures. RNA analysis was adjusted for tumor content and expression levels were dichotomized at the median into low (≤) and high (>) groups. The effect of treatment and biomarkers on IDFS was assessed. Results: PIK3CA mutation (mut) status was available from 1363 (91.7%) patients. T-DM1 IDFS benefit was independent of PIK3CA mut status (mut: HR 0.54; 95%CI 0.23–0.90; non-mut: HR 0.48; 95%CI 0.35–0.65) and no impact of PIK3CA mut was observed within either treatment arm. Gene expression data were available from 1059 (71.3%) patients. Similar gene expression levels were observed between treatment arms, but, unlike the surgical samples (n = 815), the pre-treatment samples (n = 244) were not representative of the ITT population. Thus, subsequent analyses were based on surgical samples (H n = 398; T-DM1 n = 417). Consistent treatment benefit with T-DM1 vs H was observed across the single-gene and immune gene-signature subgroups as in the ITT population. High vs low HER2 expression was associated with worse outcome (HR 2.02; 95% CI 1.32–3.11) within the H arm, but not within the T-DM1 arm (HR 1.01; 95% CI 0.56–1.83). High vs low PD-L1 expression was associated with better outcome within the H arm (HR 0.66; 95% CI 0.44–1.00) but not within the T-DM1 arm (HR 1.05; 95% CI 0.59–1.87). Similar trends were observed in the checkpoint inhibitor subgroups. Conclusions: These exploratory analyses provide the first data on the relationship between biomarker expression in residual disease after HER2-targeted therapy and outcomes. PIK3CA mut status did not influence outcomes with H or T-DM1. T-DM1 benefit appeared to be independent of all biomarkers assessed. Clinical trial information: NCT01772472 .

Folate pathway gene expression in metastatic colorectal cancer patients treated with arfolitixorin/5-FU-based chemotherapy.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 99-99
Author(s):  
Roger Tell ◽  
Alessandro Di Cara ◽  
Elisabeth Odin ◽  
Göran Ulf Carlsson ◽  
Yvonne Wettergren
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Phase I ◽  
Metastatic Colorectal Cancer ◽  
Clinical Benefit ◽  
Phase Iii ◽  
Expression Levels ◽  
Folate Pathway ◽  
Drug Clinical Trial ◽  
Pre Treatment

99 Background: Arfolitixorin is the natural, biologically active form of the marketed folates and is expected to be efficacious in a larger proportion of patients with less inter- and intra-individual variability compared with e.g. leucovorin. We have previously found a positive correlation between survival and expression of folate pathway genes in stage III/IV CRC treated with 5-fluorouracil/leucovorin (5-FU/LV). Low expression of folate-related genes may lead to poor response to 5-FU/LV-based treatment, since suboptimal transport and metabolization of LV yield insufficient active [6R]-5,10-methylenetetrahydrofolate and weak inhibition of the target enzyme thymidylate synthase (TYMS). The aim of the present study was to investigate possible confounders and biomarkers of arfolitixorin/5-FU-based treatment in relation to safety and response in a phase I/IIa metastatic colorectal cancer (mCRC) trial. Methods: ISO-CC-005 is a multi-center, phase I/IIa study in mCRC patients eligible for 5-FU/folate therapy alone or in combination with irinotecan or oxaliplatin ± bevacizumab. Patients were also treated with different doses of arfolitixorin as a single or double bolus. The study investigated safety and tolerability of arfolitixorin, and anti-tumor activity was evaluated by overall response rate (ORR) per RECIST v1.1 after 4 cycles of chemotherapy. RNA was prepared from FFPE tumor tissue, reverse transcribed and used for gene expression profiling. The following genes of interest were evaluated: ABCC3, MTHFD2, SLC46A1, SLC19A1, SLC25A32 and TYMS. An ANOVA test was used to rule out potential biases in the baseline expression levels of the genes and to assess the potential association with clinical response. Results: Eighty-one (77.1%) of 105 patients provided material for this analysis. A lower pre-treatment expression of TYMS was associated with clinical benefit (PR and SD; p = 0.021). No clear association was identified between the gene expression markers and the number of adverse events. Gender was not significantly associated with differences in gene expression. Conclusions: Low pre-treatment expression levels of TYMS were associated with clinical benefit (PR and SD) following treatment. Given the role of this gene in the folate metabolic pathways we plan to further assess its predictive potential on a larger cohort during our ongoing global phase III AGENT study. In parallel an assessment of the expression of the other candidate genes on specific patient sub-groups is currently ongoing. These studies will provide additional cues on the use of these genes as predictive markers for treatment outcome and their role in the mode of action of the drug. Clinical trial information: NCT02244632.

scholarly journals Developing ZNF Gene Signatures Predicting Radiosensitivity of Patients with Breast Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Derui Yan ◽  
Mingjing Shen ◽  
Zixuan Du ◽  
Jianping Cao ◽  
Ye Tian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Patients ◽  
Cox Regression ◽  
Molecular Taxonomy ◽  
Gene Signature ◽  
The Cancer Genome Atlas ◽  
Breast Cancer Patients ◽  
Expression Levels ◽  
The Relationship

Adjuvant radiotherapy is one of the main treatment methods for breast cancer, but its clinical benefit depends largely on the characteristics of the patient. This study aimed to explore the relationship between the expression of zinc finger (ZNF) gene family proteins and the radiosensitivity of breast cancer patients. Clinical and gene expression data on a total of 976 breast cancer samples were obtained from The Cancer Genome Atlas (TCGA) database. ZNF gene expression was dichotomized into groups with a higher or lower level than the median level of expression. Univariate and multivariate Cox regression analyses were used to evaluate the relationship between ZNF gene expression levels and radiosensitivity. The Molecular Taxonomy Data of the International Federation of Breast Cancer (METABRIC) database was used for validation. The results revealed that 4 ZNF genes were possible radiosensitivity markers. High expression of ZNF644 and low expression levels of the other 3 genes (ZNF341, ZNF541, and ZNF653) were related to the radiosensitivity of breast cancer. Hierarchical cluster, Cox, and CoxBoost analysis based on these 4 ZNF genes indicated that patients with a favorable 4-gene signature had better overall survival on radiotherapy. Thus, this 4-gene signature may have value for selecting those patients most likely to benefit from radiotherapy. ZNF gene clusters could act as radiosensitivity signatures for breast cancer patients and may be involved in determining the radiosensitivity of cancer.

scholarly journals Endolysosomal Cation Channels and MITF in Melanocytes and Melanoma

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1021
Author(s):  
Carla Abrahamian ◽  
Christian Grimm
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Transcription Factor ◽  
Convincing Evidence ◽  
Signaling Cascades ◽  
Cation Channels ◽  
Pore Channel ◽  
Different Types ◽  
Canonical Wnt ◽  
The Relationship

Microphthalmia-associated transcription factor (MITF) is the principal transcription factor regulating pivotal processes in melanoma cell development, growth, survival, proliferation, differentiation and invasion. In recent years, convincing evidence has been provided attesting key roles of endolysosomal cation channels, specifically TPCs and TRPMLs, in cancer, including breast cancer, glioblastoma, bladder cancer, hepatocellular carcinoma and melanoma. In this review, we provide a gene expression profile of these channels in different types of cancers and decipher their roles, in particular the roles of two-pore channel 2 (TPC2) and TRPML1 in melanocytes and melanoma. We specifically discuss the signaling cascades regulating MITF and the relationship between endolysosomal cation channels, MAPK, canonical Wnt/GSK3 pathways and MITF.

scholarly journals The BIRC Family Genes Expression in Patients with Triple Negative Breast Cancer

2021 ◽  
Vol 22 (4) ◽  
pp. 1820
Author(s):  
Anna Makuch-Kocka ◽  
Janusz Kocki ◽  
Anna Brzozowska ◽  
Jacek Bogucki ◽  
Przemysław Kołodziej ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Clinical Data ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Lymphatic Vessels ◽  
The Cancer Genome Atlas ◽  
Expression Level ◽  
Cancer Tissue ◽  
Expression Levels

The BIRC (baculoviral IAP repeat-containing; BIRC) family genes encode for Inhibitor of Apoptosis (IAP) proteins. The dysregulation of the expression levels of the genes in question in cancer tissue as compared to normal tissue suggests that the apoptosis process in cancer cells was disturbed, which may be associated with the development and chemoresistance of triple negative breast cancer (TNBC). In our study, we determined the expression level of eight genes from the BIRC family using the Real-Time PCR method in patients with TNBC and compared the obtained results with clinical data. Additionally, using bioinformatics tools (Ualcan and The Breast Cancer Gene-Expression Miner v4.5 (bc-GenExMiner v4.5)), we compared our data with the data in the Cancer Genome Atlas (TCGA) database. We observed diverse expression pattern among the studied genes in breast cancer tissue. Comparing the expression level of the studied genes with the clinical data, we found that in patients diagnosed with breast cancer under the age of 50, the expression levels of all studied genes were higher compared to patients diagnosed after the age of 50. We observed that in patients with invasion of neoplastic cells into lymphatic vessels and fat tissue, the expression levels of BIRC family genes were lower compared to patients in whom these features were not noted. Statistically significant differences in gene expression were also noted in patients classified into three groups depending on the basis of the Scarff-Bloom and Richardson (SBR) Grading System.

scholarly journals Using cfRNA as a tool to evaluate clinical treatment outcomes in patients with metastatic lung cancers and other tumors

2021 ◽  
Author(s):  
Luis E. Raez ◽  
Kathleen Danenberg ◽  
Daniel Sumarriva ◽  
Joshua Usher ◽  
Jacob Sands ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Response To Therapy ◽  
Liquid Biopsies ◽  
Blood Samples ◽  
Lung Cancers ◽  
Metastatic Lung ◽  
Clinical Responses ◽  
Pre Treatment ◽  
Actin Expression

Aim: We report an exploratory analysis of cfRNA as a biomarker to monitor clinical responses in non-small cell lung cancer (NSCLC), breast cancer, and colorectal cancer (CRC). An analysis of cfRNA as a method for measuring PD-L1 expression with comparison to clinical responses was also performed in the NSCLC cohort. Methods: Blood samples were collected from 127 patients with metastatic disease that were undergoing therapy, 52 with NSCLC, 50 with breast cancer, and 25 with CRC. cfRNA was purified from fractionated plasma, and following reverse transcription (RT), total cfRNA and gene expression of PD-L1were analyzed by real-time polymerase chain reaction (qPCR) using beta-actin expression as a surrogate for relative amounts of cfDNA and cfRNA. For the concordance study of liquid biopsies and tissue biopsies, the isolated RNA was analyzed by RNAseq for the expressions of 13 genes. We had to close the study early due to a lack of follow-up during the Covid-19 pandemic. Results: We collected a total of 373 blood samples. Mean cfRNA PCR signals after RT were about 50-fold higher than those of cfDNA. cfRNA was detected in all patients, while cfDNA was detected in 88% of them. A high concordance was found for the expression levels of 13 genes between blood and solid tumor tissue. Changes in cfRNA levels followed over the course of treatments were associated with response to therapy, increasing in progressive disease (PD) and falling when a partial response (PR) occurred. The expression of PD-L1 over time in patients treated with immunotherapy decreased with PR but increased with PD. Pre-treatment levels of PD-L1 were predictive of response in patients treated with immunotherapy. Conclusion: Changes in cfRNA correlate with clinical response to the therapy. Total cfRNA may be useful in predicting clinical outcomes. PD-L1 gene expression may provide a biomarker to predict response to PD-L1 inhibition.

scholarly journals Network analysis reveals the relationship among wood properties, gene expression levels and genotypes of naturalPopulus trichocarpaaccessions

2013 ◽  
Vol 200 (3) ◽  
pp. 727-742 ◽  
Author(s):  
Ilga Porth ◽  
Jaroslav Klápště ◽  
Oleksandr Skyba ◽  
Michael C. Friedmann ◽  
Jan Hannemann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Network Analysis ◽  
Wood Properties ◽  
Expression Levels ◽  
The Relationship ◽  
Gene Expression Levels
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