Examination of Low ERBB2 Protein Expression in Breast Cancer Tissue

Fernandez, Aileen I.; Liu, Matthew; Bellizzi, Andrew M.; Brock, Jane E.; Fadare, Oluwole; Hanley, Krisztina; Harigopal, Malini; Jorns, Julie M.; Kuba, María G.; Ly, Amy; Podoll, Mirna; Rabe, Kimmie; Sanders, Mary Ann; Singh, Kamaljeet; Snir, Olivia L.; Soong, Thing Rinda; Wei, Shi; Wen, Hannah Y.; Wong, Serena; Yoon, Esther; Pusztai, Lajos; Reisenbichler, Emily; Rimm, David L.

doi:10.1001/jamaoncol.2021.7239

Cited by 199 publications

(157 citation statements)

References 7 publications

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“…With the development of HER2-targeted ADCs, they have shown promising antitumor efficacy in HER2-low expression tumors. However, the optimal assays for HER2-low tumors need to be further studied due to their low concordance rate between HER2 0 and HER2 1+ status evaluation [ 16 ]. In this study, a large number of HR-positive HER2-negative patients were included with known HER2 mRNA levels.…”

Section: Discussionmentioning

confidence: 99%

“…With the development of these novel HER2-targeted ADCs, there is an urgent need to precisely define HER2 expression level. However, as the HER2 testing assays were initially developed for their accurate positivity or negativity definition [ 16 , 37 , 38 ], there is no certain definition for HER2-low tumors. Although the upper boundary of HER2-low as HER2 2+ with FISH-negative is clear, whether HER2 1+ can be the lower boundary lacks a gold standard [ 39 ], as high heterogeneity of HER2 IHC staining exists in HER2 1+ cases [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…Lambein et al reported that 85% of local HER2 IHC 0 cases were scored as 1+ at a central laboratory [ 15 ]. Fernandez et al also reported a low concordance rate of 26% between HER2 0 and 1+ tumors when these cases were evaluated by different pathologists [ 16 ]. Thus, IHC may not be the optimal assay to assess HER2-low expression.…”

Section: Introductionmentioning

confidence: 99%

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Can HER2 1+ Breast Cancer Be Considered as HER2-Low Tumor? A Comparison of Clinicopathological Features, Quantitative HER2 mRNA Levels, and Prognosis among HER2-Negative Breast Cancer

Shu

Tong

et al. 2022

Cancers

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Background: Human epidermal growth factor receptor 2 (HER2)-low tumor is a new entity defined as HER2 immunohistochemistry (IHC) 1+ or 2+/fluorescence in situ hybridization (FISH)-negative. We aimed to evaluate whether HER2 mRNA levels tested by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) could better define HER2-low tumors. Patients and methods: Consecutive breast cancer patients with hormonal receptor-positive, HER2-negative diseases, and HER2 mRNA results were included. Clinicopathologic features, HER2 mRNA expression level, and prognosis were compared among HER2 0, 1+ and 2+/FISH− groups. Concordance of the HER2 category between qRT-PCR and IHC/FISH was analyzed for each group. Results: 2296 patients were included: 368 (16.0%) HER2 0, 911 (39.7%) 1+, and 1017 (44.3%) 2+/FISH− tumors. HER2 1+ cases shared similarities with HER2 0 tumors in terms of clinicopathologic features (all p > 0.05), whereas IHC 2+/FISH− cases were less often non-IDC (p = 0.045), node-negative (p = 0.044), and Ki-67 < 14% (p <0.001). The mRNA expression was similar between HER2 0 and 1+ cases (p = 0.063), and both were lower than 2+/FISH− cases (p < 0.001). A poor concordance rate was found between IHC/FISH and qRT-PCR for HER2 0 and HER2-low cases (Cohen’s kappa 0.126, p < 0.001). No survival difference was observed among these groups, whether stratified by HER2 IHC/FISH status or mRNA level (all p > 0.05). Conclusions: HER2 1+ cases had similar clinicopathological features to HER2 0 breast cancers, and both were different from HER2 2+/FISH− cases. HER2 mRNA levels were comparable between HER2 0 and 1+ tumors, and both were significantly lower than IHC 2+/FISH− tumors. Neither IHC nor qRT-PCR may be optimal to quantify HER2-low expression, especially for HER2 1+ patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Can HER2 1+ Breast Cancer Be Considered as HER2-Low Tumor? A Comparison of Clinicopathological Features, Quantitative HER2 mRNA Levels, and Prognosis among HER2-Negative Breast Cancer

Shu

Tong

et al. 2022

Cancers

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“…The lowest IHC agreement was found between HER2 0 vs HER2 1+ (less than 70% agreement). An interobserver analysis of 92 cases graded as IHC 0 or IHC 1, resulted in a 90% agreement (17 out of 18 pathologists) in only 26% of the cases (24 out of 92) 19 .…”

Section: Introductionmentioning

confidence: 98%

“…Previous studies have evaluated the HER2 IHC interobserver reproducibility using the 2013 and 2018 versions of the ASCO/CAP guidelines with inconsistent results [16][17][18][19] . In a recent study by Fernandez et al, data from around 1400 laboratories around the world were collected 19 . The lowest IHC agreement was found between HER2 0 vs HER2 1+ (less than 70% agreement).…”

Section: Introductionmentioning

confidence: 99%

Interobserver variation in the assessment of HER2 low expression in breast cancer: can we improve by adjusting criteria? An international interobserver study.

Navarro

Bockstal

Nawawi³

et al. 2022

Preprint

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The classification of Human Epidermal Growth Factor Receptor 2 (HER2) expression is optimized to detect HER2-amplified breast cancer (BC). However, novel HER2-targeting agents are also effective for BCs with low levels of HER2. This raises the question whether the current guidelines for HER2-testing are sufficiently reproducible to identify HER2 low BC. The aim of this multicenter international study was to assess the interobserver agreement of HER2 low scoring according to the current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. Furthermore, we evaluated whether the agreement improved by redefining immunohistochemistry (IHC) scoring criteria, or by adding fluorescent in situ hybridization (FISH). We performed a two-round study of 105 non-amplified BCs. During the first assessment, sixteen pathologists used the latest version of the ASCO/CAP guidelines. After a consensus meeting, the same pathologists scored the same digital slides using modified IHC scoring criteria based on the 2007 ASCO/CAP guideline, and an extra ‘ultralow’ category was added. Overall, the interobserver agreement was limited (4.7% of cases with 100% agreement) in the first round, but this improved by clustering IHC categories. In the second round, the highest reproducibility was seen when comparing IHC 0 versus the grouped cluster of ultralow/1+/2+ (74.3% of cases with 100% agreement). FISH results were not statistically different between HER2 0 and HER2 low cases, regardless of the IHC criteria used. In conclusion, our study suggests that the modified 2007 ASCO/CAP criteria were more reproducible to distinguish HER2 0 from HER2 low cases as compared to the 2018 ASCO/CAP criteria. However, the reproducibility was still moderate, which was not improved by adding FISH. This could lead to suboptimal selection of patients eligible for novel HER2-targeting agents. There is a need for clearer, more reproducible IHC definitions, training and/or development of more accurate methods to detect HER2 low BC.

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Comparison of Management and Outcomes in ERBB2-Low vs ERBB2-Zero Metastatic Breast Cancer in France

et al. 2022

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IMPORTANCE ERBB2-low (ie, ERBB2 immunohistochemistry score of 1+ or 2+ in the absence of ERBB2 gene amplification) breast cancer (BC) is a new entity, with emerging dedicated treatments. Little is known about its prognosis and response to conventional therapy compared with ERBB2-zero breast tumors (ie, those with an immunohistochemistry score of 0). OBJECTIVE To compare the outcomes for patients with ERBB2-low metastatic BC (MBC) with those of patients with ERBB2-zero MBC. DESIGN, SETTING, AND PARTICIPANTS This cohort study was conducted from the Epidemiological Strategy and Medical Economics MBC platform and included patients with MBC

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Examination of Low ERBB2 Protein Expression in Breast Cancer Tissue

Cited by 199 publications

References 7 publications

Can HER2 1+ Breast Cancer Be Considered as HER2-Low Tumor? A Comparison of Clinicopathological Features, Quantitative HER2 mRNA Levels, and Prognosis among HER2-Negative Breast Cancer

Can HER2 1+ Breast Cancer Be Considered as HER2-Low Tumor? A Comparison of Clinicopathological Features, Quantitative HER2 mRNA Levels, and Prognosis among HER2-Negative Breast Cancer

Interobserver variation in the assessment of HER2 low expression in breast cancer: can we improve by adjusting criteria? An international interobserver study.

Comparison of Management and Outcomes in ERBB2-Low vs ERBB2-Zero Metastatic Breast Cancer in France

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