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Polysomy 17 and impact on Her2 testing
Polysomy 17 in Breast Cancer: Clinicopathologic Significance and Impact on HER-2 Testing
J Clin Oncol. 2008 Oct 20;26(30):4869-4874, I Vanden Bempt, P Van Loo, M Drijkoningen, P Neven, A Smeets, MR Christiaens, R Paridaens, C De Wolf-Peeters
"Overexpression or amplification of the HER2 oncogene, located on the long arm of chromosome 17 (c17), is associated with poor clinical outcomes in women with breast cancer. The HER2 biomarker is predictive of response to anthracyclines, paclitaxel, and HER2-targeted therapy (ie, trastuzumab). However, moderate to high levels of HER2 expression do not always correlate with trastuzumab activity. Because trastuzumab is costly and is associated with cardiac toxicity, proper patient selection is important.
Immunohistochemical (IHC) detection and fluorescent in situ hybridization (FISH) are standard methods for determining HER2 expression in tumors. Guidelines for HER2 testing require that tumors be categorized as positive, negative, or equivocal. HER2-equivocal tumors are defined as those with an IHC score of 2+ or a modest increase in HER2 gene copy number via FISH analysis. HER2-equivocal status has been linked to polysomy of c17, which would indicate a higher HER2 gene copy number and potentially increased HER2 expression. Investigators from Katholieke University in Leuven, Belgium, postulated that the presence of polysomy 17 may obscure interpretation of HER2 test results. Their study investigated the impact of polysomy 17 on HER2 testing and sought to determine whether polysomy 17 tumors share clinicopathologic features with true HER2-positive tumors.
The analysis was conducted in breast tumors from 226 women who underwent mastectomy, surgical excision, or axillary lymph node dissection for treatment of primary breast tumors. HER2 status was ascertained by IHC and FISH. FISH results were combined from scores for absolute gene copy number and HER2/c17 ratio. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis of tumor HER2 mRNA expression was carried out in 157 of 226 tumors for which frozen tissue was available.
FISH results showed HER2-equivocal status in 44 tumors (19.5%) based on absolute gene copy number and in 3 patients (1.3%) using the HER2/c17 ratio. None of these equivocal tumors was HER2 positive based on IHC. Interestingly, polysomy 17 was present in all tumors with equivocal or discordant HER2 FISH test results. Polysomy 17 was detected in 104 patients (46%). Of these, 42 cases (40%) were HER2 positive.
The presence of polysomy 17 had no effect on HER2 results in the FISH analysis in cases where HER2 gene amplification was detected. Most of these patients (78.6%) were HER2 positive via IHC. However, none of the tumors for which polysomy 17 was not accompanied by HER2 amplification was scored as HER2 positive via IHC. In addition, HER2 scoring was obscured in tumors with polysomy 17 and HER2 absolute gene copy number >3. All 44 samples deemed equivocal via FISH using absolute gene copy number scoring were later deemed HER2 negative via FISH using HER2/c17 ratio scoring. In 5 tumors, the 2 FISH scoring methods had discordant results (ie, diagnosed as HER2 positive using absolute copy number vs equivocal or HER2 negative with HER2/c17 ratio).
Using RT-PCR analysis, tumors were classified as HER2 negative (n = 67), polysomy 17 with no HER2 amplification (n = 62), or HER2 positive based on HER2/c17 ratio (n = 97). HER2 mRNA expression levels in polysomy 17 tumors were much lower than levels in HER2-positive tumors and were comparable to those in HER2-negative tumors. In contrast, HER2-positive tumors had mean HER2 mRNA expression levels that were typically 5-fold those of normal tissue.
The clinicopathologic features of polysomy 17 tumors and HER2-negative tumors were very similar. In contrast, HER2-positive tumors were associated with higher tumor grade (P < 10-8) and higher Nottingham Prognostic Index risk group (P = .030), and they were more frequently estrogen receptor–negative (P < .001) and progesterone receptor–negative (P = .0062). As expected, HER2-positive tumors were associated with shorter disease-free survival (DFS) than were HER2-negative tumors. Polysomy 17 tumors were associated with DFS that was intermediate between that of HER2-negative and HER2-positive tumors.
The findings of this study show that polysomy 17 is associated with HER2-equivocal FISH test results. In addition, polysomy 17 breast tumors are clinically and pathologically distinct from HER2-positive breast cancers. Polysomy 17 is not directly indicative of HER2 overexpression. In contrast to HER2 overexpression, polysomy 17 is not associated with a poor prognosis. However, although polysomy 17 tumors behave more like HER2-negative tumors, the former show a trend toward shorter DFS. Dual-color detection systems for FISH analysis should be utilized for HER2 testing. Further study investigating the effect of HER2-targeted therapy in polysomy 17 breast tumors is warranted."
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