Determining True <i>HER2</i> Gene Status in Breast Cancers With Polysomy by Using Alternative Chromosome 17 Reference Genes: Implications for Anti-<i>HER2</i>  Targeted Therapy

Tse, Chun Hing; Hwang, Harry C.; Goldstein, Lynn C.; Kandalaft, Patricia L.; Wiley, Jesse C.; Kussick, Steven J.; Gown, Allen M.

doi:10.1200/jco.2011.36.0107

Cited by 113 publications

(108 citation statements)

References 36 publications

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“…There was no single tumor with CN gains for all 14 genes, further supporting the rarity of chr17 polysomy, i.e., increased copies of the entire chromosome, as also shown with array-based comparative genomic hybridization (aCGH) [4], [6], [7], alternative FISH approaches [11] and MLPA [25]. In order to compare the present data on gene dosage with relevant literature findings, however, we need to consider technical characteristics of the methods applied for this purpose.…”

Section: Discussionsupporting

confidence: 62%

“…In addition, chr17 may be unstable without increased HER2 copies [4]–[8], or chr17 may not be intact [5], [9]. The above aspects of chr17 instability may be relevant to breast cancer patient outcome, at various disease stages and treatment settings, but are missed with the currently used FISH assays and their interpretation, as shown with the use of distinct evaluation of CEN17 signals [10] and application of multiple FISH assays for chr17 [11].…”

Section: Introductionmentioning

confidence: 99%

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Adjusting Breast Cancer Patient Prognosis with Non-HER2-Gene Patterns on Chromosome 17

Kotoula

Bobos

Alexopoulou³

et al. 2014

PLoS ONE

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Background HER2 and TOP2A gene status are assessed for diagnostic and research purposes in breast cancer with fluorescence in situ hybridization (FISH). However, FISH probes do not target only the annotated gene, while chromosome 17 (chr17) is among the most unstable chromosomes in breast cancer. Here we asked whether the status of specifically targeted genes on chr17 might help in refining prognosis of early high-risk breast cancer patients.MethodsCopy numbers (CN) for 14 genes on chr17, 4 of which were within and 10 outside the core HER2 amplicon (HER2- and non-HER2-genes, respectively) were assessed with qPCR in 485 paraffin-embedded tumor tissue samples from breast cancer patients treated with adjuvant chemotherapy in the frame of two randomized phase III trials.Principal Findings HER2-genes CN strongly correlated to each other (Spearman’s rho >0.6) and were concordant with FISH HER2 status (Kappa 0.6697 for ERBB2 CN). TOP2A CN were not concordant with TOP2A FISH status (Kappa 0.1154). CN hierarchical clustering revealed distinct patterns of gains, losses and complex alterations in HER2- and non-HER2-genes associated with IHC4 breast cancer subtypes. Upon multivariate analysis, non-HER2-gene gains independently predicted for shorter disease-free survival (DFS) and overall survival (OS) in patients with triple-negative cancer, as compared to luminal and HER2-positive tumors (interaction p = 0.007 for DFS and p = 0.011 for OS). Similarly, non-HER2-gene gains were associated with worse prognosis in patients who had undergone breast-conserving surgery as compared to modified radical mastectomy (p = 0.004 for both DFS and OS). Non-HER2-gene losses were unfavorable prognosticators in patients with 1–3 metastatic nodes, as compared to those with 4 or more nodes (p = 0.017 for DFS and p = 0.001 for OS).Conclusions TOP2A FISH and qPCR may not identify the same pathology on chr17q. Non-HER2 chr17 CN patterns may further predict outcome in breast cancer patients with known favorable and unfavorable prognosis.

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Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Adjusting Breast Cancer Patient Prognosis with Non-HER2-Gene Patterns on Chromosome 17

Kotoula

Bobos

Alexopoulou³

et al. 2014

PLoS ONE

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“…Recent reports question the existence of true chromosome 17 polysomy in breast cancer. Many molecular techniques suggest that true chromosome 17 polysomy is a rare event in breast cancer and most of the elevated CEP17 signals detected by dual probe ISH HER2 testing are local gain/amplification in the peri-centromeric region of chromosome 17 [27][28][29][30]. It is not entirely clear how HER2 non-amplified and chromosome 17 polysomy predict the response to HER2-targeted therapy.…”

Section: Discussionmentioning

confidence: 96%

Updated 2013 College of American Pathologists/American Society of Clinical Oncology (CAP/ASCO) guideline recommendations for human epidermal growth factor receptor 2 (HER2) fluorescent in situ hybridization (FISH) testing increase HER2 positive and HER2 equivocal breast cancer cases; retrospective study of HER2 FISH results of 836 invasive breast cancers

Singh

Tantravahi

Lomme

et al. 2016

Breast Cancer Res Treat

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For dual probe HER2 FISH assay, the 2013 CAP/ASCO guideline recommendations lowered the HER2/CEP17 ratio cut off for HER2 amplification to ≥2.0 and introduced an average HER2 copy number criterion for HER2 amplification (≥6.0/cell) and HER2 equivocal categories (≥4 and <6/cell). The HER2/CEP17 equivocal category is eliminated. The aim of this study is to assess the impact of 2013 HER2 FISH testing guideline recommendations update on the assignment of HER2 status with dual probe HER2 FISH assay. Dual probe HER2 FISH assay results on breast cancers from 09/2009 to 07/2015 that underwent reflex HER2 FISH testing after equivocal HER2 (2+) immunohistochemistry (IHC) were reviewed. HER2 copy number, CEP17 signals, and HER2/CEP ratios were noted. HER2 status was assigned as HER2 negative (HER2-), HER2 equivocal (HER2e), and HER2 amplified (HER2+) by applying both 2007 and 2013 CAP/ASCO HER2 FISH guideline recommendations and results were compared. New guidelines reclassified HER2 FISH status in a significant proportion of cases (8.3 %, 69/836; p = .021). There were 22 (2.6 %) more HER2+, 17 (2.1 %) more HER2e, and 39 (4.1 %) fewer HER2- tumors. Change of HER2 status correlated significantly with ≥3 CEP17 signals (38 vs. 2 %; p < .001). The 2013 CAP/ASCO guideline recommendations for HER2 FISH testing by dual probe assay increased the HER2 amplified and HER2 equivocal tumors. Increase in HER2 equivocal tumors would potentially increase the frequency of repeat HER2 testing. Tumors with ≥3 CEP17 signals, so-called chromosome 17 polysomy, are more likely to be impacted and classified as HER2 equivocal.

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“…FISH analysis frequently misinterprets increased counts from both HER2 and CEP17 probes as a polysomy-like pattern. Several reports have attempted to use FISH analysis to distinguish co-amplification of HER2 and the pericentromeric region of chromosome 17 from true polysomy 17 using multiple probes on chromosome 17 (tumor protein p53 [ TP53 ], topoisomerase II alpha [ TOP2A ], and retinoic acid receptor alpha [ RARA ]) and probes on other chromosomes [37, 38]. Some probes such as TOP2A in 17q21-q22, near the HER2 locus at 17q12, may provide information about molecular targets for anticancer therapy; however, confirming aneusomy 17 via multiple FISH probes is challenging without using comparative genomic hybridization or single-nucleotide polymorphism microarray.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide copy number aberrations and HER2 and FGFR1 alterations in primary breast cancer by molecular inversion probe microarray

Chen

Singh

et al. 2017

Oncotarget

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Breast cancer remains the second leading cause of cancer-related death in women despite stratification based on standard hormonal receptor (HR) and HER2 testing. Additional prognostic markers are needed to improve breast cancer treatment. Chromothripsis, a catastrophic genome rearrangement, has been described recently in various cancer genomes and affects cancer progression and prognosis. However, little is known about chromothripsis in breast cancer. To identify novel prognostic biomarkers in breast cancer, we used molecular inversion probe (MIP) microarray to explore genome-wide copy number aberrations (CNA) and breast cancer-related gene alterations in DNA extracted from formalin-fixed paraffin-embedded tissue. We examined 42 primary breast cancers with known HR and HER2 status assessed via immunohistochemistry and FISH and analyzed MIP microarray results for correlation with standard tests and survival outcomes. Global genome-wide CNA ranged from 0.2% to 65.7%. Chromothripsis-like patterns were observed in 23/38 (61%) cases and were more prevalent in cases with =10% CNA (20/26, 77%) than in cases with <10% CNA (3/12, 25%; p<0.01). Most frequently involved chromosomal segment was 17q12-q21, the HER2 locus. Chromothripsis-like patterns involving 17q12 were observed in 8/19 (42%) of HER2-amplified tumors but not in any of the tumors without HER2 amplification (0/19; p<0.01). HER2 amplification detected by MIP microarray was 95% concordant with conventional testing (39/41). Interestingly, 21% of patients (9/42) had fibroblast growth factor receptor 1 (FGFR1)amplification and had a 460% higher risk for mortality than those without FGFR1 amplification (p<0.01). In summary, MIP microarray provided a robust assessment of genomic CNA of breast cancer.

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Determining True HER2 Gene Status in Breast Cancers With Polysomy by Using Alternative Chromosome 17 Reference Genes: Implications for Anti-HER2 Targeted Therapy

Cited by 113 publications

References 36 publications

Adjusting Breast Cancer Patient Prognosis with Non-HER2-Gene Patterns on Chromosome 17

Adjusting Breast Cancer Patient Prognosis with Non-HER2-Gene Patterns on Chromosome 17

Genome-wide copy number aberrations and HER2 and FGFR1 alterations in primary breast cancer by molecular inversion probe microarray

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