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HER2/ERBB2 immunoreactivity in human retinoblastoma.

ABSTRACT: Retinoblastoma (RB) is an ocular malignancy of early childhood. Although mutations in the Rb1 gene and expression of stem cell markers have been identified in RB, additional information on RB-specific alterations in signaling pathways and protein expression would be useful for the design of targeted RB therapies. Here we have evaluated the expression of HER2 (ERBB2) in RB. HER2 is a member of the epidermal growth factor family, which is overexpressed in breast, ovarian, gastric, colorectal, pancreatic, and endometrial cancers in a stratified manner. Overexpression and gene amplification of HER2 is associated with aggressive malignancies, accompanied by chemoresistance and poor outcomes. In this study, we present the first evidence of HER2 immunoreactivity in retinoblastoma, as shown by immunocytochemistry, flow cytometry, and western immunoblot, with validation by reverse transcription PCR (RT-PCR) in both RB cell lines and clinical RB tumors. Our results suggest that the HER2 protein expressed in RB is a truncated version that spares the trastuzumab binding site, while HER2 is not detected in normal ocular tissues. Our discovery of HER2 expression in RB may lead to innovative and targeted drug treatment options designed to spare the eye and preserve vision in RB patients.

SUBMITTER: Seigel GM

PROVIDER: S-EPMC4875886 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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HER2/ERBB2 immunoreactivity in human retinoblastoma.

Seigel G M GM Sharma S S Hackam A S AS Shah Dhaval K DK

Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 20151127 5

Retinoblastoma (RB) is an ocular malignancy of early childhood. Although mutations in the Rb1 gene and expression of stem cell markers have been identified in RB, additional information on RB-specific alterations in signaling pathways and protein expression would be useful for the design of targeted RB therapies. Here we have evaluated the expression of HER2 (ERBB2) in RB. HER2 is a member of the epidermal growth factor family, which is overexpressed in breast, ovarian, gastric, colorectal, panc ...[more]

PMID: 26614428

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Project description:BackgroundIdentification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy.MethodsA research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24 weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated.ResultsA total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab, the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest (44.5%, 95% confidence interval [CI] = 35.4% to 53.9% vs 11.6%, 95% CI = 6.9% to 18.0%; adjusted odds ratio [OR] = 6.05, 95% CI = 3.10 to 11.80, P < .001). Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI = 22.3% to 95.7% vs 14.7% in others, 95% CI = 4.9% to 31.1%; adjusted OR = 11.60, 95% CI = 1.66 to 81.10, P = .01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR] = 0.52, 95% CI = 0.35 to 0.79, P < .001); higher ORR (16.3%, 95% CI = 8.9% to 26.2% vs 3.7%, 95% CI = 0.8% to 10.3%, P = .02); and longer OS (HR = 0.66, 95% CI = 0.44 to 0.97, P = .01).ConclusionsCombining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer.

Project description:ImportanceThe 2013/2014 American Society of Clinical Oncology and College of American Pathologists (ASCO-CAP) guidelines for HER2 testing by fluorescence in situ hybridization (FISH) designated an "equivocal" category (average HER2 copies per tumor cell ≥4-6 with HER2/CEP17 ratio <2.0) to be resolved as negative or positive by assessments with alternative control probes. Approximately 4% to 12% of all invasive breast cancers are characterized as HER2-equivocal based on FISH.ObjectiveTo evaluate the following hypotheses: (1) genetic loci used as alternative controls are heterozygously deleted in a substantial proportion of breast cancers; (2) use of these loci for assessment of HER2 by FISH leads to false-positive assessments; and (3) these HER2 false-positive breast cancer patients have outcomes that do not differ from clinical outcomes for patients with HER2-negative breast cancer.Design, setting, and participantsWe retrospectively assessed the use of chromosome 17 p-arm and q-arm alternative control genomic sites (TP53, D17S122, SMS, RARA, TOP2A), as recommended by the 2013/2014 ASCO-CAP guidelines for HER2 testing, in patients whose data were available through Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and whose tissues were available through the Breast Cancer International Research Group clinical trials. We used data from an international cohort database of invasive breast cancers (1980 participants) and international clinical trial of adjuvant chemotherapy in invasive, node-positive breast cancer patients.Main outcomes and measuresThe primary objectives were to (1) assess frequency of heterozygous deletions in chromosome 17 genomic sites used as FISH internal controls for evaluation of HER2 status among HER2-equivocal cancers; (2) characterize impact of using deleted sites for determination of HER2-to-internal-control-gene ratios; (3) assess HER2 protein expression in each subgroup; and (4) compare clinical outcomes for each subgroup.ResultsOf the 1980 patients in METABRIC,1915 patients were fully evaluated. In addition, 100 HER2-equivocal breast cancers by FISH and 100 comparator FISH-negative breast cancers from the BCIRG-005 trial were analyzed. Heterozygous deletions, particularly in specific p-arm sites, were common in both HER2-amplified and HER2-not-amplified breast cancers. Use of alternative control probes from these regions to assess HER2 by FISH in HER2-equivocal as well as HER2-not-amplified breast cancers resulted in high rates of false-positive ratios (HER2-to-alternative control ratio ≥2.0) owing to heterozygous deletions of control p-arm genomic sites used in ratio denominators. Misclassification of HER2 status was observed not only in breast cancers with ASCO-CAP equivocal status but also in breast cancers with an average of fewer than 4.0 HER2 copies per tumor cell when using alternative control probes.Conclusions and relevanceThe indiscriminate use of alternative control probes to calculate HER2 FISH ratios in HER2-equivocal breast cancers may lead to false-positive interpretations of HER2 status resulting from unrecognized heterozygous deletions in 1 or more of these alternative control genomic sites and incorrect HER2 ratio determinations.

Dataset Information

HER2/ERBB2 immunoreactivity in human retinoblastoma.

Publications

HER2/ERBB2 immunoreactivity in human retinoblastoma.

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