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H&E staining, HER2 immunohistochemistry and ERBB2 FISH analysis of tumors with ERBB2 amplification. Case 1 shows homogeneous strong membranous staining by immunohistochemistry. Corresponding FISH demonstrates ERBB2 amplification. The tumor cells exhibit clusters of orange signals (up to 50 per blue stained nucleus) indicating the ERBB2 gene. The green signals (1–2 per nucleus) represent the centromeric region of chromosome 17. Cases 4 and 8 show strong staining by immunohistochemistry only in a fraction of tumor cells. Corresponding FISH analyses display clusters of orange signals (ERBB2 gene) only in some tumor cells, while other tumor cells exhibit 1–3 orange signals, demonstrating heterogeneous gene amplification. The green signals (1–3 per nucleus) again represent the centromeric region of chromosome 17.
Source publication
The HER2 protein, encoded by the ERBB2 gene, is a molecular target for the treatment of breast and gastric cancer by monoclonal antibodies or tyrosine kinase inhibitors. While intratumoral heterogeneity of ERBB2 amplification is rare in breast cancer it is reported to be frequent in bladder and colorectal cancer. To address the potential heterogene...
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Citations
... ERBB2 heterogeneity is one of the factors affecting diagnosis; it is characterized by differential expression or amplification within the same tumor (intratumoral) or in cancers from various sites or time points in the same patient (intertumoral) [72]. The phenomenon has been described in literature on breast and lung cancer [73][74][75][76]. A retrospective study showed a significant degree of discordance between matched pairs of primary tumors and metastases, with an HER2-positivity rate of 11.2%, 10.1%, and 31.8% in primary CRC tumors, matched positive lymph nodes, and corresponding metastases, respectively [50]. ...
Despite recent improvements in the comprehensive therapy of malignancy, metastatic colorectal cancer (mCRC) continues to have a poor prognosis. Notably, 5% of mCRC cases harbor Erb-B2 receptor tyrosine kinase 2 (ERBB2) alterations. ERBB2, commonly referred to as human epidermal growth factor receptor 2, is a member of the human epidermal growth factor receptor family of protein tyrosine kinases. In addition to being a recognized therapeutic target in the treatment of gastric and breast malignancies, it is considered crucial in the management of CRC. In this review, we describe the molecular biology of ERBB2 from the perspective of biomarkers for mCRC-targeted therapy, including receptor structures, signaling pathways, gene alterations, and their detection methods. We also discuss the relationship between ERBB2 aberrations and the underlying mechanisms of resistance to anti-EGFR therapy and immunotherapy tolerance in these patients with a focus on novel targeted therapeutics and ongoing clinical trials. This may aid the development of a new standard of care in patients with ERBB2-positive mCRC.
... Collectively, the percentage of ctDNA-specific mutated genes, tissue DNAspecific mutated genes, and mutated genes detected by both Table S4). All of the results were consistent with previous studies that the genetic heterogeneity of LUSC is more complex than that in LUAD (47,48). In short, our data indicated that ctDNA analysis is more feasible as an alternative for genomic profiling of LUAD than that of LUSC by comparing the consistency between ctDNA analysis and tumor DNA analysis. ...
Background
Circulating tumor DNA (ctDNA) sequence analysis shows great potential in the management of non-small cell lung cancer (NSCLC) and the prediction of drug sensitivity or resistance in many cancers. Here, we drew and compared the somatic mutational profile using ctDNA and tumor tissue sequence analysis in lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), and assess its potential clinical value.
Methods
In this study, 221 tumor tissues and 174 plasma samples from NSCLC patients were analyzed by hybridization capture-based next-generation sequencing (NGS) panel including 95 cancer-associated genes. Tumor response assessments were applied to 137 patients with advanced-stage (III and IV) NSCLC who first received targeted agents.
Results
Twenty significantly mutated genes were identified such as TP53, EGFR, RB1, KRAS, PIK3CA, CD3EAP, CTNNB1, ERBB2, APC, BRAF, TERT, FBXW7 , and HRAS . Among them, TP53 was the most frequently mutated gene and had a higher mutation probability in male (p = 0.00124) and smoking (p < 0.0001) patients. A total of 48.35% (191/395) of NSCLC patients possessed at least one actionable alteration according to the OncoKB database. Although the sensitivity of genomic profiling from ctDNA was lower than that from tumor tissue DNA, the mutational landscape of target genes from ctDNA is similar to that from tumor tissue DNA, which led to 61.22% (30/49) of mutational concordance in NSCLC. Additionally, the mutational concordance between tissue DNA and ctDNA in LUAD differs from that in LUSC, which is 63.83% versus 46.67%, indicating that NSCLC subtypes influence the specificity of mutation detection in plasma-derived ctDNA. Lastly, patients with EGFR and TP53 co-alterations showed similar responses to Gefitinib and Icotinib, and the co-occurring TP53 mutation was most likely to be a poor prognostic factor for patients receiving Gefitinib, indicating that the distributions and types of TP53 mutations may contribute to the efficacy and prognosis of molecular targeted therapy.
Conclusions
As a promising alternative for tumor genomic profiling, ctDNA analysis is more credible in LUAD than in LUSC. Genomic subtyping has strong potential in prognostication and therapeutic decision-making for NSCLC patients, which indicated the necessity for the utility of target NGS in guiding clinical management.
... Larger number of patients (12) showed HER2 overexpression after the use of Hercep Test Dako, in comparison to only four patients in whom protein overexpression was detected after the use of Ventana anti-HER2/neu (4B5) antibodies. By analysing the percentage-wise prevalence of HER2 overexpression in lung adenocarcinoma in studies that used HercepTest Dako and studies that used Ventana anti-HER2/neu (4B5) antibodies, we observed a higher prevalence when using Hercep Test Dako as compared to Ventana anti-HER2/neu (4B5) antibodies, which is also the case in our study [6,20,[22][23][24][25]. By using the non-parametric Fisher's test, the obtained value P = 0.001 indicates a high statistical correlation between the results obtained by applying these two types of antibodies. ...
... The Phi coefficient value indicates a high correlation of the results obtained through these two tests (Phi = 0.546). Other authors have also reported a significant correlation between HER2 gene amplification and HER2 expression obtained through the use of HercepTest Dako [20,23]. On a sample of 243 lung adenocarcinomas and using Hercep Test Dako, Yoshizawa et al. detected HER2 overexpression in 37 patients (score 2+ and 3+), among whom HER2 gene amplification was found in four patients using "Dual ISH, Ventana Medical Systems" [20]. ...
Background
Discordant results exist about the role of human epidermal growth factor receptor 2 (HER2) overexpression and/or HER2 amplification in lung adenocarcinoma. We aimed to compare the performance of HercepTest and PATHWAY anti-HER2 (4B5) by correlating immunohistochemistry (IHC) results with silver in situ hybridization (SISH) in adenocarcinoma lung specimens.
Methods
A total of 148 surgically resected adenocarcinoma lung specimens were included.
Results
HER2 overexpression was found in 7.4% patients for HercepTest Dako and in 2.7% patients for 4B5 antibody. The overall coincidence between these two types of antibodies equals 93.9%. The incidence of HER2 amplification in lung adenocarcinoma was 17.6%, of which in 2.7% of the cases high-grade amplification was present. HER2 amplification was present in 90.9% of patients with overexpression of HER2, obtained by using HercepTest Dako and 75% patients using 4B5 antibody. A significant correlation between overexpression of HER2 receptors obtained by HercepTest Dako and 4B5 antibody and HER2 amplification was shown.
Conclusion
The research of the efficiency of targeted molecular therapies with an HER2 antibody may serve as a basis for the introduction of routine HER2 status determination in lung adenocarcinoma, dictating the need for the standardized protocol for HER2 status determination in such pathology.
... In colorectal cancer cell lines with different levels of HER2 protein expression (without HER2/neu gene amplification), Takegawa et al., observed that HER2-overexpressing cells were sensitive to T-DXd, but not to other anti-HER2 agents [19]. This specific feature of T-DXd might potentially increase its therapeutic effect in those tumors harboring heterogeneous HER2 expression, as NSCLC and colorectal cancer [20,21]. T-DXd was specifically designed to improve on the characteristics of other anti-ADC. ...
... In colo cancer cell lines with different levels of HER2 protein expression (without HER2/neu amplification), Takegawa et al., observed that HER2-overexpressing cells were sen to T-DXd, but not to other anti-HER2 agents [19]. This specific feature of T-DXd m potentially increase its therapeutic effect in those tumors harboring heterogeneous H expression, as NSCLC and colorectal cancer [20,21]. ...
HER2 targeted therapies have significantly improved prognosis of HER2-positive breast and gastric cancer. HER2 overexpression and mutation is the pathogenic driver in non-small cell lung cancer (NSCLC) and colorectal cancer, however, to date, there are no approved HER2-targeted therapies with these indications. Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed antibody drug conjugate showing significant anti-tumor activity in heavily pre-treated HER2-positive breast and gastric cancer patients. Preliminary data have shown promising objective response rates in patients with HER2-positive NSCLC and colorectal cancer. T-DXd has an acceptable safety profile, however with concerns regarding potentially serious treatment-emergent adverse events. In this review we focus on the pharmacologic characteristics and toxicity profile of T-Dxd, and provide an update on the most recent results of clinical trials of T-DXd in solid tumors. The referenced papers were selected through a PubMed search performed on 16 March 2021 with the following searching terms: T-DXd and breast cancer, or gastric cancer, or non-small cell lung cancer (NSCLC), or colorectal cancer. Oral presentation, abstracts, and posters presented at the American Society of Clinical Oncology (ASCO, Alexandria, VA, USA) 2020 and the European Society for Medical Oncology (ESMO, Lugano, Switzerland) 2020 annual meetings were retrieved for data on T-DXd. We also overview ongoing research and data of combination therapies currently under investigation, which will impact on future therapeutic strategies. Clinicaltrials.gov was searched to identify ongoing clinical trials of T-DXd alone or in combination in solid tumors.
... The predictive and prognostic significance of this subclonal amplification in USC is unknown. Heterogeneous HER2 expression has been documented in a number of tumor types; while unusual in breast carcinoma [58][59][60], heterogeneity is more common in gastric [61][62][63], bladder [64], and lung [65] tumors with ERBB2 amplification. Intratumoral heterogeneity may be a relatively common phenomenon in USC as well, ranging from 11% of cases in this cohort to 31% of cases in a previous report [21]. ...
Uterine serous carcinoma is an aggressive subtype of endometrial cancer that accounts for fewer than 10% of endometrial carcinomas but is responsible for about half of deaths. A subset of cases has HER2 overexpression secondary to ERBB2 gene amplification, and these patients may benefit from anti-HER2 therapies, such as trastuzumab. HER2 protein overexpression is currently assessed by immunohistochemistry (IHC) and ERBB2 gene amplification by fluorescence in situ hybridization (FISH). Targeted next-generation sequencing (NGS) is increasingly used to routinely identify predictive and prognostic molecular abnormalities in endometrial carcinoma. To investigate the ability of a targeted NGS panel to detect ERBB2 amplification, we identified cases of uterine serous carcinoma (n = 93) and compared HER2 expression by IHC and copy number assessed by FISH with copy number status assessed by NGS. ERBB2 copy number status using a combination of IHC and FISH was interpreted using the 2018 ASCO/CAP guidelines for breast carcinoma. ERBB2 amplification by NGS was determined by the relative number of reads mapping to ERBB2 in tumor DNA compared to control nonneoplastic DNA. Cases with copy number ≥6 were considered amplified and copy number <6 were non-amplified. By IHC, 70 specimens were classified as negative (0 or 1+), 19 were classified as equivocal (2+), and 4 were classified as positive (3+). Using combined IHC/FISH, ERBB2 amplification was observed in 8 of 93 cases (9%). NGS identified the same 8 cases with copy number ≥6; all 85 others had copy number <6. In this series, NGS had 100% concordance with combined IHC/FISH in identifying ERBB2 amplification. NGS is highly accurate in detecting ERBB2 amplification in uterine serous carcinoma and provides an alternative to measurement by IHC and FISH.
... The released payload is membrane-permeable, allowing it to exhibit a cytotoxic effect on neighboring tumor cells in close proximity to the targeted cell, regardless of their HER2 expression levels (i.e., a cytotoxic bystander effect; ref. 15). The high DAR and the cytotoxic bystander effect may be of particular importance in targeting tumors with heterogeneous HER2 expression, such as NSCLC and colorectal cancer (16,17). In preclinical studies, T-DXd showed antitumor activity across a wide range of HER2-expressing tumor types (13,15). ...
HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2-targeted antibody–drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with pretreated, HER2-expressing (IHC ≥ 1+), non-breast/non-gastric or HER2-mutant solid tumors from a phase I trial (NCT02564900). Most common (>50%) treatment-emergent adverse events (TEAE) were nausea, decreased appetite, and vomiting. Two drug-related TEAEs were associated with fatal outcomes. The confirmed objective response rate (ORR) was 28.3% (17/60). Median progression-free survival (PFS) was 7.2 [95% confidence interval (CI), 4.8–11.1] months. In HER2-mutant non–small cell lung cancer (NSCLC), ORR was 72.7% (8/11), and median PFS was 11.3 (95% CI, 8.1–14.3) months. Confirmed responses were observed in six tumor types, including HER2-expressing NSCLC, colorectal cancer, salivary gland cancer, biliary tract cancer, endometrial cancer, and HER2-mutant NSCLC and breast cancer. Results suggest T-DXd holds promise for HER2-expressing/mutant solid tumors.
Significance
T-DXd demonstrated promising activity in a heterogeneous patient population with heavily pretreated HER2-expressing or HER2-mutant solid tumors, especially HER2-mutant NSCLC. The safety profile was generally acceptable. Interstitial lung disease can be severe and requires prompt monitoring and intervention. Further research of T-DXd is warranted to address these unmet medical needs.
See related commentary by Rolfo and Russo, p. 643.
This article is highlighted in the In This Issue feature, p. 627
... BRAF mutations have been identified in 2% of patients with NSCLC, half of whom have the BRAF V600E mutation [7]. Additional molecular targets of clinical interest include ERBB2 amplification [8] and inactivation of tumor suppressor genes (eg, TP53 [p53] and phosphatase and tensin homolog [PTEN]) [9]. Immunotherapies targeting programmed cell death 1 (PD-1) and/or PD-1 ligand 1 (PD-L1) may also become important therapeutic modalities in this patient group [10]. ...
... For example, PD-L1 expression in malignant cells can be regulated by oncogenic signaling pathways (eg, PTEN loss) with consequent PI3KCA activation [19], thus stimulating cancer cell proliferation. Furthermore, the expression of PD-L1 in lung cancer tissues is heterogeneous because of EMT [20] and ErbB family receptors [8]. In fact, we found that PD-L1 overexpression was also associated with overexpression of other proteins such as EGFR, BRAF, ERBB2, and KRAS, as well as mutated genes (AXL, CTLA4, PDCD1LG2, p53, VEGFA, and VIM), which may influence a therapeutic response to anti-PD-L1 as recently demonstrated by Kim et al [20] and Catacchio et al [21]. ...
... Epigenetic regulation of the miR-200-ZEB axis is responsible for EMT induction by TGF-β1 in PC9 cells as reported by Zhang et al [32], who demonstrated that decitabine inhibits EMT in NSCLC PC9 cells through its epigenetic therapeutic activity. In agreement with Grob et al [8], ERBB2 mutation was found in 6% of acinar ADCs, 8% of SqCCs, and 5% of null LCCs, thus prioritizing investigation of HER2-targeting therapy in these tumors. ...
To demonstrate the usefulness of complementary next-generation sequencing (NGS) and immunohistochemistry (IHC) counting, we analyzed 196 patients with non-small cell lung cancer (NSCLC) who underwent surgical resection and adjuvant chemotherapy. Formalin-fixed paraffin-embedded samples of adenocarcinoma (ADC), squamous cell carcinoma (SqCC), and large-cell carcinoma (LCC) were used to prepare tissue microarrays and were examined by protein H-score IHC image analysis and NGS for oncogenes and proto-oncogenes and genes of tumor suppressors, immune checkpoints, epithelial-mesenchymal transition factors, tyrosine kinase receptors, and vascular endothelial growth factors (VEGFs). In patients with brain metastases, primary tumors expressed lower PIK3CA protein levels. Overexpression of TP53 and a higher PD-L1 protein H-score were detected in patients that underwent surgical treatment followed by chemotherapy as compared to those that underwent only surgical treatment The absence of brain metastases was associated with wild-type sequences of genes EGFR, CD267, CTLA-4, and ZEB1. The combination of protein overexpression according to IHC and mutation according to NGS was rare (i.e., represented by a very low percentage of concordant cases), except for TP53 and VEGF. Our data suggest that protein levels detected by IHC may be a useful complementary tool when mutations are not detected by NGS and also support the idea to expand this approach beyond ADC to include SqCC and even LCC, particularly for patients with unusual clinical characteristics. Conversely, well-pronounced immunogenotypic features appeared to predict the clinical outcome after univariate and multivariate analyses. Patients with a solid ADC subtype and mutated genes EGFR, CTLA4, PDCD1LG2, or ZEB1 complemented with PD-L1 or TP53 protein lower expression that only underwent surgical treatment, who develop brain metastases, may have the worst prognosis.
... Data from all eligible studies (19)(20)(21)(22)(23)(24)(25) were extracted by 2 independent authors and included the following: the first author's name, year of publication, study location, antibody clone and manufacturer, cutoff value, ISH method, number of patients analyzed, and histological type of NSCLC. For the meta-analysis we extracted all data associated with IHC results (scores 0, 1+, 2+ and 3+) and ISH results (numbers of amplification and non-amplification). ...
... The correlation between HER2 IHC and ISH has not been fully elucidated for NSCLC cases. Previous studies have used the diagnostic flow of breast and gastric cancers (19)(20)(21)(22)(23)(24)(25). To the best of our knowledge, the present study is the first to show the concordance between HER2 IHC and ISH and the first to assess the diagnostic accuracy of HER2 IHC in NSCLC. ...
... In a previous meta-analysis, HER2 IHC overexpression, but not HER2 amplification in ISH, was significantly correlated with worse prognosis (3). In another study, although there was no association between HER2 amplification and tumor stage or metastasis, HER2 amplification was significantly correlated with worse prognosis (21). ...
Purpose:
This study aimed to elucidate the concordance between human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) and in situ hybridization (ISH) and the diagnostic accuracy of HER2 IHC in non-small cell lung cancer (NSCLC) through a meta-analysis and diagnostic test accuracy review.
Methods:
Seven eligible studies and 1,217 patients with NSCLC were included in the review. The concordance between HER2 IHC and ISH was analyzed. To confirm the diagnostic accuracy of HER2 IHC, the sensitivity and specificity were analyzed and the area under the curve (AUC) in the summary receiver operating characteristic (SROC) curve was calculated.
Results:
The concordance rate between HER2 IHC and ISH was 0.795 (95% confidence interval [CI] 0.534-0.929). In the HER2 IHC-negative (score 0/1+) subgroup, the concordance rate was 0.975 (95% CI 0.854-0.996). The concordance rates of the HER2 IHC score 2+ and 3+ subgroups were 0.091 (95% CI 0.039-0.197) and 0.665 (95% CI 0.446-0.830), respectively. In diagnostic test accuracy review, the pooled sensitivity and specificity were 0.67 (95% CI 0.54-0.78) and 0.89 (95% CI 0.87-0.91), respectively. The AUC in the SROC curve was 0.891 and the diagnostic odds ratio was 16.99 (95% CI 5.08-56.76).
Conclusions:
HER2 IHC was largely in agreement with ISH in cases of HER2 IHC score 0/1+. Because the concordance rates of HER2 IHC score 2/3+ cases were lower than that of HER2 IHC score 0/1+ cases, further studies for detailed analysis criteria for HER2 IHC score 2+ or 3+ are required.
... NSCLC with HER-2 mutation (mainly exon 20 insertion) responds to HER-2 targeted agent (such as trastuzumab, afatinib). HER-2 gene amplification occurs in 3.2-7.4% of pulmonary adenocarcinoma (AC) [1,2]. However, efficacy of HER-2 targeted agent in this group of patients remains unknown. ...
... HER-2 is a member of the HER family of proteins containing four receptor tyrosine kinases that mediates proliferation and differentiation of normal epithelial cells. The overexpression of HER-2 and its gene amplification occur in a minority of patients with NSCLC [1][2][3], contribute to tumor growth and predict a worse survival [4,5]. Overexpression of HER-2 determined by immunohistochemistry (IHC) was reported in 9.0% of AC [1]. ...
... Gene amplification, prevalent in many tumors, is a copy number increase of a restricted region of a chromosome arm, and is associated with overexpression of the relevant genes. HER-2 gene amplification detected by fluorescence in situ hybridization (FISH) or NGS was observed in 3.2-7.4% of AC [1,2]. Some studies showed that gene amplification detected by FISH was more specific than IHC [10,11]. ...
HER-2 amplification is a rare mutation and potential target in the treatment of pulmonary adenocarcinoma (AC). Clinical efficacy of HER-2 targeted agent has been reported for AC with HER-2 exon 20 insertions; however it remains unknown for those with HER-2 amplification. Here we report a case of advanced AC harboring HER-2 amplification treated with afatinib, and objective response and symptom improvement were observed.
... In addition, six different prognosis TMAs were analyzed, representing 697 urinary bladder cancers (694 with clinical follow-up data), 1711 colon cancers (1709 with clinical follow-up data), 343 esophageal adenocarcinomas (300 with clinical follow-up data), 251 esophageal squamous cell cancers (244 with clinical follow-up data), 673 lung cancers (269 with clinical followup data), 275 pancreatic cancers (219 with clinical follow-up data), and 230 stomach cancers (146 with clinical follow-up data). The composition of these TMAs has been described before (29)(30)(31)(32)(33). No informed consent was obtained in accordance with the local law (HmbkHG, §12,1). ...
IMP3 is an RNA binding protein required for ribosomal RNA processing, which has been suggested to be a prognostic marker in a large variety of human types of cancer. However, available data on the prevalence of IMP3 expression are largely discrepant. To systematically investigate the epidemiology and clinical relevance of IMP3 expression in human cancers we employed a two-step tissue microarrays (TMAs) approach. First, a normal tissue TMA and a multi-tumor TMA were analyzed for immunohistochemically detectable expression of IMP3 in 76 different normal tissue types and 3889 cancer samples from 95 different tumor categories. In a second step, we searched for associations between IMP3 expression and tumor phenotype and patient prognosis in TMAs containing 697 urinary bladder cancers, 1711 colon cancers, 343 esophageal adenocarcinomas, 251 esophageal squamous cell cancers, 673 lung cancers), 275 pancreatic cancers and 230 stomach cancers. In normal tissues, unequivocal IMP3 expression was found in placenta, lymphocytes and some types of glandular epithelial cells. In cancers, at least one case with weak expression could be found in 76 out of 95 (80%) different tumor types and 64 entities (67%) had at least one tumor with strong positivity. IMP3 expression was most frequently found in testicular cancer (including 71% seminomas and 96% non-seminomas), neuroblastoma (88%), and squamous cell cancer of various origins. Significant associations were found between IMP3 and adverse tumor features in esophageal adenocarcinomas and cancers of the urinary bladder, lung, stomach, and pancreas. In summary, IMP3 was frequently expressed in many different tumor types, and was typically associated with aggressive tumor features.
