HER2 activity in solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23121-e23121
Author(s):  
Lara Ann Kujtan ◽  
Scott Morris ◽  
Janakiraman Subramanian
Keyword(s):  
Breast Cancer ◽  
Mrna Expression ◽  
Solid Tumors ◽  
Copy Number ◽  
Significant Proportion ◽  
Copy Number Gain ◽  
Tumor Type ◽  
Breast Cancers ◽  
Distinctive Pattern ◽  
Tumor Types

e23121 Background: ERBB2 is a member of the human epidermal growth factor receptor family. HER2 expression that is immunohistochemistry (IHC) 3+ or IHC 2+ with copy number gain is an effective predictor for treatment with trastuzumab in breast and gastroesophageal cancers. Here we present an analysis on HER2 activity measured by IHC, mRNA expression and copy number variation (CNV) across a variety of solid tumors. Methods: The study population consists of patients diagnosed with solid tumors (n = 856) that underwent a Paradigm Diagnostic Cancer Test during 2016. We then analyzed tumor types that tested positive for HER2 by IHC (3+), CNV and/or mRNA expression. Results: We identified 365 (43%) patients positive for HER2 by IHC, 258 (30%) had high HER2mRNA expression and 41 (5%) had amplification by CNV. Seventy-five patients were HER2 IHC 3+ or 2+/CNV positive. The proportion of HER2 IHC 3+ or 2+/CNV positive tumors in each tumor type was as follows: breast cancer 41 (18.5%), NSCLC 10 (8.1%), colorectal 6 (6.7%), esophago-gastric 3 (10%,) urothelial/bladder 3 (16%), biliary 2 (28.6%), ovarian cancer 2 (5.1%) and pancreas 1 (3.1%). Using copy number gain as the gold standard, across all tumor types, an IHC of 3+ had a 90.2% sensitivity and a 95.6% specificity. In the same analysis with breast cancers omitted, the sensitivity was 75%, and specificity 96.8%. Whereas high mRNA expression had a sensitivity of 97.6% and specificity of 73.3%, omitting breast cancers, the sensitivity was 93.8% and specificity 73.2%. Conclusions: HER2 activity was identified in a wide variety of solid tumors and a small but significant proportion of these tumors maybe candidates for treatment with HER2 inhibitors such as trastuzumab. Our analysis also identified that HER2 activity in breast cancers has a distinctive pattern which was not seen in other tumor types. HER2 IHC 3+ expression was much less sensitive among other tumor types compared to breast cancer. mRNA expression, while remaining sensitive among other tumor types, is not specific, even among breast cancer patients. Our analysis also identified that HER2 activity in breast cancers has a distinctive pattern which was not seen in other tumor types.

scholarly journals GPCRs show widespread differential mRNA expression and frequent mutation and copy number variation in solid tumors

2019 ◽  
Author(s):  
Krishna Sriram ◽  
Kevin Moyung ◽  
Ross Corriden ◽  
Hannah Carter ◽  
Paul A. Insel
Keyword(s):  
Copy Number Variation ◽  
Mrna Expression ◽  
Solid Tumors ◽  
Copy Number ◽  
Driver Mutations ◽  
Specific Tumor ◽  
Elevated Expression ◽  
Number Variation ◽  
Approved Drugs ◽  
Tumor Types

AbstractG protein-coupled receptors (GPCRs) are the most widely targeted gene family for FDA-approved drugs. To assess possible roles for GPCRs in cancer, we analyzed Cancer Genome Atlas data for mRNA expression, mutations, and copy number variation (CNV) in 20 categories/45 sub-types of solid tumors and quantified differential expression of GPCRs by comparing tumors against normal tissue from the GTEx database. GPCRs are over-represented among coding genes with elevated expression in solid tumors; most tumor types differentially express >50 GPCRs, including many targets for approved drugs, hitherto largely unrecognized as targets of interest in cancer. GPCR mRNA signatures characterize specific tumor types, indicate survival and correlate with expression of cancer-related pathways. Tumor GPCR mRNA signatures have prognostic relevance for survival and correlate with expression of numerous cancer-related genes and pathways. GPCR expression in tumors is largely independent of staging/grading/metastasis/driver mutations and GPCRs expressed in cancer cell lines parallels that measured in tumors. Certain GPCRs are frequently mutated and appear to be hotspots, serving as bellwethers of accumulated genomic damage. CNV of GPCRs while common, does not generally correlate with mRNA expression. We suggest a previously under-appreciated role for GPCRs in cancer, perhaps as functional oncogenes, biomarkers, surface antigens and pharmacological targets.

Scotin expression and survival in breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22006-e22006
Author(s):  
J. Bourdon ◽  
A. Diot ◽  
B. Vojtesek ◽  
S. Bray ◽  
L. Jordan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mrna Expression ◽  
Significant Proportion ◽  
Normal Breast ◽  
Breast Cancers ◽  
Wild Type ◽  
Poor Survival ◽  
Breast Epithelium ◽  
Normal Breast Epithelium ◽  
Cytoplasmic Staining

e22006 Background: The Scotin gene (3p21.3) is directly trans-activated by p53 in response to ionising radiation and produces a 25kD trans-membrane protein located in the endoplasmic reticulum and nuclear membrane which induces a caspase- dependent apoptosis. This study examines the expression of scotin and scotin isoforms in breast cancer in relation to clinical and pathological parameters. Methods: Scotin was examined in 145 breast cancers by DNA sequencing, nested PCR for mRNA expression and using novel antibodies to scotin (pantropic), the C-terminal or N-terminal domain, and the scotin-5 isoform with western blotting and immunohistochemistry on a tissue microarray of breast cancers. Results: Scotin was mutated in 10% of cancers and mRNA expression lost in a further 10%. Moreover, Scotin-5 was expressed in 40% of cancers, while it was not detectable in normal breast epithelium. We established that Scotin-5 is anti-apoptotic and inhibits scotin-mediated apoptosis. Cytoplasmic staining of scotin on TMAs demonstrated that loss of scotin expression was associated with earlier relapse (Mantel-Cox log rank p<0.01) and poor survival (Mantel-Cox log rank p<0.002). Furthermore, loss of Scotin expression identified 50% of the WTp53 patients or 50% of the ER+ patients who also had a poor survival. Conclusions: Scotin may be used as an independent biomarker in breast cancer. Loss of Scotin function may account for a significant proportion of p53 malfunction even in the presence of wild type p53 in breast cancer and adds a further level of complexity to p53 directed therapy in breast cancer. No significant financial relationships to disclose.

Centromere 17 Copy Number Alteration: Negative Prognostic Factor in Invasive Breast Cancer?

2012 ◽  
Vol 136 (9) ◽  
pp. 993-1000 ◽  
Author(s):  
Stella Petroni ◽  
Teresa Addati ◽  
Eliseo Mattioli ◽  
Maria Angela Caponio ◽  
Carmela Quero ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Invasive Breast Cancer ◽  
Copy Number ◽  
Growth Factor Receptor ◽  
Copy Number Gain ◽  
Chromosome 17 ◽  
Proliferation Index ◽  
Fish Analysis ◽  
Breast Cancers ◽  
Ki 67

Context.—Chromosome 17 polysomy has been identified in 5% to 50% of invasive breast cancers; even though a relationship with human epidermal growth factor receptor 2 (HER2/neu) status has been reported, other studies have shown that coincident centromere 17 (Cep17) amplification may be the cause of an overestimation of chromosome 17 polysomy in fluorescence in situ hybridization (FISH) testing. Objective.—To evaluate polysomy/amplification of Cep17 in invasive breast cancer with relation to proliferative activity (Ki-67), estrogen receptor, progesterone receptor, and HER2/neu status, in an attempt to identify a subgroup of patients with a worse prognosis. Design.—A total of 647 cases of invasive ductal breast cancer were collected and subjected to FISH analysis for HER2/neu gene and centromere 17 alteration, HercepTest for HER2/neu protein expression, and routine immunohistochemistry for Ki-67 and hormone receptor status. Results.—Copy number gain of Cep17 was observed in 27.3% of cases. Within this group, HER2/neu gene amplification was detected in 14.1% of cases, whereas HER2/neu expression was scored 3+ in 20.1% of cases; about half of the HER2/neu overexpressing cases (9.8%) did not show amplification by FISH. Moreover, 69% of polysomic cases showed high Ki-67 index. Conclusions.—(1) Centromere 17–altered cases are frequently HER2/neu overexpressing but not amplified, resulting in HercepTest/FISH disagreement; (2) HER2/neu amplification is seen at a higher incidence in cases without Cep17 copy number alterations, which are therefore not necessarily due to chromosome 17 disorder; (3) proliferation index is significantly higher in aneusomic tumors. These data suggest that the presence of Cep17 alterations could identify a subset of breast cancers with more aggressive biological and clinical behavior, which may show nonresponsiveness to conventional therapy independently of HER2/neu amplification status.

scholarly journals Association between ultrasound findings, tumor type, grade, and biological markers in patients with breast cancer

2019 ◽  
Vol 50 (1) ◽  
Author(s):  
Yasmine Mohamed Elsaeid ◽  
Dina Elmetwally ◽  
Salwa Mohamed Eteba
Keyword(s):  
Breast Cancer ◽  
Biological Markers ◽  
Tumor Grade ◽  
The State ◽  
Tumor Type ◽  
Breast Cancers ◽  
Duct Carcinoma ◽  
Ultrasound Findings ◽  
Her 2 ◽  
And Biological Markers

Abstract Background This prospective study included 65 female patients with primary breast cancer. Ultrasound was performed for all patients. Ultrasound findings were analyzed according to the ACR BI-RADS lexicon 5th edition and correlated with tumor type, grade, and biological markers (ER, PR, HER-2/neu, and Ki67). The purpose of this study is to assess the association between ultrasound findings, tumor type, grade, and the state of biological markers in patients with breast cancer. Results Irregular shape and speculated margins are more frequently associated with invasive duct carcinoma than DCIS (p value < 0.001). There were no association between the ultrasound findings (shape, margin, orientation, echopattern, and posterior features) and the tumor grade (p value 1.0, 0, 0.544, 1.0, and 1.0), respectively. Irregular shape is more frequently seen in ER and PR positive breast cancers (p value = 0.036 and 0.026, respectively). Non-circumscribed margins were frequently seen in PR positive breast cancers (p value = 0.068). No statistically significant difference between US descriptors and HER-2/neu-positive cases. Conclusion Irregularly shaped tumors with speculated margins are frequently seen in invasive duct carcinoma and also more frequently seen in ER-, PR-, and Ki67-positive cases. No relation between ultrasound descriptors and the tumor grade of invasive duct carcinoma. Also, there were no relation between ultrasound descriptors and the state of HER-2/neu.

scholarly journals Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
L. E. Anselmino ◽  
M. V. Baglioni ◽  
F. Malizia ◽  
N. Cesatti Laluce ◽  
C. Borini Etichetti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Drug Repositioning ◽  
Combined Treatment ◽  
Alternative Therapy ◽  
Breast Cancers ◽  
Mesenchymal Transition ◽  
Tumor Types

AbstractDrug repositioning refers to new uses for existing drugs outside the scope of the original medical indications. This approach fastens the process of drug development allowing finding effective drugs with reduced side effects and lower costs. Colorectal cancer (CRC) is often diagnosed at advanced stages, when the probability of chemotherapy resistance is higher. Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, highly metastatic and difficult to treat. For both tumor types, available treatments are generally associated to severe side effects. In our work, we explored the effect of combining metformin and propranolol, two repositioned drugs, in both tumor types. We demonstrate that treatment affects viability, epithelial-mesenchymal transition and migratory potential of CRC cells as we described before for TNBC. We show that combined treatment affects different steps leading to metastasis in TNBC. Moreover, combined treatment is also effective preventing the development of 5-FU resistant CRC. Our data suggest that combination of metformin and propranolol could be useful as a putative adjuvant treatment for both TNBC and CRC and an alternative for chemo-resistant CRC, providing a low-cost alternative therapy without associated toxicity.

scholarly journals Centromere 17 copy number gain reflects chromosomal instability in breast cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kyoungyul Lee ◽  
Hyun Jeong Kim ◽  
Min Hye Jang ◽  
Sejoon Lee ◽  
Soomin Ahn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Copy Number ◽  
Chromosomal Instability ◽  
Copy Number Gain ◽  
Next Generation Sequencing Data ◽  
Her2 Status ◽  
Sequencing Data ◽  
Her2 Positive ◽  
Ki 67 ◽  
Positive Linear Correlation

AbstractChromosomal instability (CIN) is known to be associated with prognosis and treatment response in breast cancer. This study was conducted to determine whether copy number gain of centromere 17 (CEP17) reflects CIN, and to evaluate the prognostic and predictive value of CIN in breast cancer. CIN status was determined by summing copy number gains of four centromeric probes (CEP1, CEP8, CEP11, and CEP16) based on fluorescence in situ hybridization and CIN scores were calculated using next generation sequencing data. High CIN was associated with adverse clinicopatholgical parameters of breast cancer. Among them, positive HER2 status, high Ki-67 index and CEP17 copy number gain were found to be independent predictors of high CIN. High CIN was associated with poor clinical outcome of the patients in the whole group, as well as in luminal/HER2-negative and HER2-positive subtypes. CEP17 copy number was significantly higher in the high-CIN-score group than in the low-CIN-score group. A positive linear correlation between the mean CEP17 copy number and the CIN score was found. In conclusion, CEP17 copy number was confirmed as a useful predictor for CIN in breast cancer, and high CIN was revealed as an indicator of poor prognosis in breast cancer.

scholarly journals Checkpoint Inhibitors and Their Application in Breast Cancer

Breast Care ◽  
2016 ◽  
Vol 11 (2) ◽  
pp. 108-115 ◽  
Author(s):  
Davide Bedognetti ◽  
Cristina Maccalli ◽  
Salha B.J. Al Bader ◽  
Francesco M. Marincola ◽  
Barbara Seliger
Keyword(s):  
Breast Cancer ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Immune Surveillance ◽  
Significant Proportion ◽  
Immune Checkpoints ◽  
Immune Recognition ◽  
Breast Cancers ◽  
Inhibitory Molecules

Immune checkpoints are crucial for the maintenance of self-tolerance and for the modulation of immune responses in order to minimize tissue damage. Tumor cells take advantage of these mechanisms to evade immune recognition. A significant proportion of tumors, including breast cancers, can express co-inhibitory molecules that are important formediating the escape from T cell-mediated immune surveillance. The interaction of inhibitory receptors with their ligands can be blocked by specific molecules. Monoclonal antibodies (mAbs) directed against the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and, more recently, against the programmed cell death protein 1 (PD1), have been approved for the therapy of melanoma (anti-CTLA4 and anti-PD1 mAbs) and non-small cell lung cancer (anti-PD1 mAbs). Moreover, inhibition of PD1 signaling has shown extremely promising signs of activity in breast cancer. An increasing number of molecules directed against other immune checkpoints are currently under clinical development. In this review, we summarize the evidence supporting the implementation of checkpoint inhibition in breast cancer by reviewing in detail data on PD-L1 expression and its regulation. In addition, opportunities to boost anti-tumor immunity in breast cancer with checkpoint inhibitor-based immunotherapies alone and in combination with other treatment options will be discussed.

scholarly journals Mammography in Symptomatic Women Attending a Rapid Diagnosis Breast Clinic: A Prospective Study

2006 ◽  
Vol 88 (3) ◽  
pp. 306-308 ◽  
Author(s):  
MJP Biggs ◽  
D Ravichandran
Keyword(s):  
Breast Cancer ◽  
Significant Proportion ◽  
Management Plan ◽  
Clinical Findings ◽  
Rapid Diagnosis ◽  
Breast Cancers ◽  
Breast Clinic ◽  
Breast Radiologist ◽  
A Prospective Study ◽  
Symptomatic Breast

INTRODUCTION We determined whether it is safe to avoid mammograms in a group of symptomatic women with a non-suspicious history and clinical examination. PATIENTS AND METHODS Symptomatic women aged 35 years or over newly referred to a rapid-diagnosis breast clinic underwent mammography on arrival in the clinic. A breast radiologist reported on the mammograms. An experienced clinician who was unaware of the mammogram findings examined patients and decided whether a mammogram was indicated or not. If not, a management plan was formulated. Mammogram findings were then provided to the clinician and any change to the original management plan as a result of mammography was recorded. RESULTS In two-thirds (67%) of 218 patients, the clinician felt a mammogram was indicated. Half (46%) of these mammograms showed an abnormality; of these abnormal mammograms, 41% were breast cancer. Among the third (n = 71) of mammograms felt not to be indicated, 3 showed abnormalities of which 2 were breast cancer. One cancer was not suspected clinically or mammographically but was diagnosed on cyto/histopathological assessment. CONCLUSIONS A significant proportion of patients attending a symptomatic breast clinic have a non-suspicious history and normal clinical findings on examination. However, even in this group avoiding mammograms risks missing clinically occult breast cancers. It would appear sensible to offer mammograms to all symptomatic women over 35 years of age.

scholarly journals Linear and non-linear dependencies between copy number aberrations and mRNA expression reveal distinct molecular pathways in breast cancer

2011 ◽  
Vol 12 (1) ◽  
Author(s):  
Hiroko K Solvang ◽  
Ole Christian Lingjærde ◽  
Arnoldo Frigessi ◽  
Anne-Lise Børresen-Dale ◽  
Vessela N Kristensen
Keyword(s):  
Breast Cancer ◽  
Mrna Expression ◽  
Copy Number ◽  
Molecular Pathways ◽  
Copy Number Aberrations ◽  
Non Linear

Pathologic characteristics of breast cancer with special emphasis on prevalence of triple-negative breast cancer from Kenya: A 4-year experience.

2011 ◽  
Vol 29 (27_suppl) ◽  
pp. 35-35
Author(s):  
S. Sayed ◽  
Z. Moloo ◽  
S. Mukono ◽  
R. Wasike ◽  
R. R. Chauhan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Ductal Carcinoma ◽  
Significant Proportion ◽  
Small Sample ◽  
University Hospital ◽  
Breast Cancers ◽  
Grade 3

35 Background: Previous sub classification of breast cancer in Kenya has been fraught by small sample size, non uniform staining methodology and lack of independent review. Triple Negative Breast Cancer (TNBC) is a “special interest” cancer since it represents a significant proportion of breast cancer patients and is associated with a poorer prognosis. We aimed to determine the estrogen receptor (ER), progesterone receptor (PR) and Her2/neu receptor characteristics of breast cancers and the prevalence of TNBC diagnosed at Aga Khan University Hospital, Nairobi (AKUHN) between 2007 to date. Methods: Slides and blocks of archived invasive breast cancers diagnosed at AKUHN were identified, retrieved and reviewed by two independent pathologists. Histological type, grade and pathological stage were documented. Representative sections from available blocks were stained for ER, PR, Her2 with appropriate internal controls. Scores for ER/PR were interpreted based on the ALLRED system, Her2 /neu scoring followed CAP guidelines. The initial 111 cases were validated and confirmed at Sunnybrook Health Sciences Centre, Toronto. Results: 456 cases of invasive breast cancers were diagnosed at AKUHN during the study period. 91% of cases were invasive ductal carcinomas (NOS).The rest were special types. 37% of the tumors were grade 3 and 63% were grade 2. Blocks for 318 of 456 cases were available for receptor analysis. 54% were ER and/or PR positive, with 52% of these in women < 50 yrs. 86% of the ER and/or PR positive tumors were grade 2. Only 12% were Her2/neu positive. Of the 318 cases studied, 111 (32%) were identified as TNBC. Median age was 53 yrs. 88% were grade 3. Conclusions: Invasive ductal carcinoma (NOS) was the most common breast cancer in our study. Nearly half of our cases were ER and/or PR positive and a third were TNBC. Both occurred predominantly in women less than 50 yrs. This represents the largest validated pathologic sub classification of breast cancer from a tertiary academic hospital in Kenya. Expansion of this study to encompass all breast cancers diagnosed in Kenya is underway.

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