Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials

Denkert, Carsten; Seither, Fenja; Schneeweiß, Andreas; Link, Theresa; Blohmer, Jens-Uwe; Just, Marianne; Wimberger, Pauline; Forberger, A; Tesch, Hans; Jackisch, Christian; Schmatloch, Sabine; Reinisch, Mattea; Solomayer, Erich; Schmitt, Wolfgang; Hanusch, Claus; Fasching, Peter A.; Lübbe, Kristina; Solbach, Christine; Huober, Jens; Rhiem, Kerstin; Marmé, Frederik; Reimer, Toralf; Schmidt, Marcus; Sinn, Bruno Valentin; Janni, Wolfgang; Stickeler, Elmar; Michel, Laura L.; Stötzer, Oliver; Hahnen, Eric; Furlanetto, Jenny; Seiler, Sabine; Nekljudova, Valentina; Untch, Michael; Loibl, Sibylle

doi:10.1016/s1470-2045(21)00301-6

Cited by 283 publications

(410 citation statements)

References 27 publications

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“…In the present study we applied IHC and ISH to define HER2-low tumors, which represent the only standardized and established procedures to assess HER2 status. Accordingly, HER2-low tumors were defined as HER2 1+ and 2+ scores by IHC in the absence of gene amplification by ISH, consistently with previous studies1 11 – 13 , 20 , 21 , 24 , 31 . However, the analytical reliability of both IHC and ISH techniques are suboptimal.…”

Section: Discussionsupporting

confidence: 77%

“…Although results from this survival analysis should be interpreted with caution given the mere exploratory nature, they appear consistent with available scattered retrospective data supporting a possible negative prognostic impact of HER2-low expression in early breast cancer patients 24,[27][28][29] , especially when considering the HR-positive subset 28 . However, a prognostic association in the opposite direction has been reported as well 30,31 , thus precluding the possibility to draw definitive conclusions in this regard. In addition, it should be noted that in the abovementioned studies heterogeneous definitions for the identification of HER2-low expressing tumors were adopted, thus further complicating the interpretation of results.…”

Section: Discussionmentioning

confidence: 99%

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Evolution of HER2-low expression from primary to recurrent breast cancer

et al. 2021

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About a half of HER2-negative breast cancer (BC) show HER2-low expression that can be targeted by new antibody-drug conjugates. The main aim of this study is to describe the evolution of HER2 expression from primary BC to relapse by including HER2-low category in both primary and recurrent BC samples. Patients with matched primary and relapse BC samples were included. HER2 was evaluated according to ASCO/CAP recommendations in place at the time of diagnosis. A cutoff of >10% cells staining for HER2-positivity was applied. HER2-negative cases were sub-classified as HER2-low (IHC = 1 + /2+ and ISH not amplified), or HER2-0 (IHC-0). 547 patients were included. The proportion of HER2-low cases was 34.2% on the primary tumor and 37.3% on the relapse samples. Among HER2-negative cases, HER2-low status was more frequent in HR-positive vs triple-negative tumors (47.3% vs 35.4% on primary tumor samples, 53.8% vs 36.2% on relapse samples). The overall rate of HER2 discordance was 38.0%, mostly represented by HER2-0 switching to HER2-low (15%) and HER2-low switching to HER2-0 (14%). Among patients with a primary HER2-negative tumor, the rate of HER2 discordance was higher in HR-positive/HER2-negative vs triple-negative cases (45.5% vs 36.7% p = 0.170). This difference was mostly driven by cases switching from HER2-0 to HER2-low. HER2-low expression is highly unstable during disease evolution. Relapse biopsy in case of a primary HER2-0 tumor may open new therapeutic opportunities in a relevant proportion of patients.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Evolution of HER2-low expression from primary to recurrent breast cancer

et al. 2021

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“…The efficacy of anti-HER2 agents in HER2-low tumors has not been demonstrated yet [ 8 , 9 ], and this breast cancer subgroup is thought to have a poorer prognosis compared with HER2 0 tumors, based on retrospective studies. However, the published evidence shows conflicting results from one clinical setting to another one, and depending on hormone receptor status [ 8 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Prognostic Value of HER2-Low Expression in Non-Metastatic Triple-Negative Breast Cancer and Correlation with Other Biomarkers

Jacot

Maran-Gonzalez

Massol

et al. 2021

Cancers

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HER2-low breast cancer (i.e., HER 1+ or 2+, without gene amplification) is an emerging subtype for which very few data are available, especially within the triple-negative breast cancer (TNBC) group. Our aim was to evaluate HER2 expression and its prognostic value in a large retrospective series of patients with non-metastatic TNBC (median age: 57.7 years; range: 28.5–98.6). Among the 296 TNBC samples, 83.8% were HER2 0, 13.5% were HER2 1+, and 2.7% were HER2 2+ (HercepTestTM and 2018 ASCO/CAP guidelines for HER2 scoring). CK5/6 and/or EGFR-expressing androgen receptors and FOXA1-expressing tumors were classified as basal-like (63.8%) and molecular apocrine-like (MA, 40.2%), respectively. Compared with HER2 0 tumors, HER2 1+/2+ tumors exhibited a lower histological grade (1/2) (35.4% vs. 18.2%, p = 0.007) and MA profile (57.5% vs. 36.7%, p = 0.008). Moreover, patients with HER2 1+/2+ tumors were older (p = 0.047). After a median follow-up of 9.7 years, HER2 2+ tumors (compared with HER2 0/1+ tumors) were associated with worse relapse-free survival (RFS) (HR = 3.16, 95% CI [1.27; 7.85], p = 0.034) in a univariate analysis. Overall survival (OS) and RFS were not different in the HER2 0 and 1+/2+ groups. HER2 levels were not significantly associated with OS or RFS in a multivariate analysis.

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“…Importantly, previous analysis suggested that the difference between HER2 low expression and HER2 negativity had more clinical impact in HR + breast cancer than in triple negative breast cancer 17 . In the past two decades, the 21-gene recurrence-score (RS) 18 has provided prognostic information for HR+/HER2-patients in clinical practice, including HER2-low tumors.…”

Section: Introductionmentioning

confidence: 98%

“…Approximately 50-80% of traditional HER2-negative breast cancer were HR-positive simultaneously 11,17 .…”

Section: Introductionmentioning

confidence: 99%

Clinical Significance and Genetic Characteristics in HER2 Low Expression Tumors of Hormone Receptor Positive Breast Cancer Patients

Chen

Liu

Chen

et al. 2021

Preprint

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BackgroundHuman epidermal growth factor receptor 2 (HER2) low expressed breast cancer was considered as a distinct subtype different from HER2 negative tumors. We investigated the clinicopathological features and recurrence score (RS) of HER2-low and HER2- patients and their prognostic value in hormone receptor (HR) positive breast cancer.MethodsA total of 2,099 HR-positive primary female breast cancer patients between Jan 2009 and Jan 2019 were collected and tumors with immunohistochemistry 1 + or 2 + with negative in situ hybridization results was defined as HER2 low. We retrospectively compared the clinical and genetical features of HER2-low (n = 1,732) and HER2- (n = 367) breast cancer and theirs impacts on disease-free survival (DFS).ResultsThe HER2 low tumors had a higher ratio of concurrent estrogen receptor (ER) high expression than HER2- patients both at protein level (ER > 90%: 78.2% vs 58.6%, p < 0.01) and mRNA level (Spearman R = 0.5 vs 0.3). Analysis about DFS showed no significant difference between HER2 negative and low subgroups (5-year DFS: 92.3% vs 93.3%, p = 0.83). However, RS range (cut-off: 18 and 30) didn’t maintain its predictive value in HER2 low patients (p = 0.11) unlike that in HER2- group (p = 0.003). Further research for respective gene suggested that proliferation related genes performed well in predicting DFS in HER2- patients but lost its value in HER2 low group (p for interaction < 0.01). Contrarily, higher HER2 module was associated with worse DFS only in HER2 low patients (p = 0.04).ConclusionOur study found that HER2 low expression couldn’t be a prognostic factor in HR + patients. HER2-low patients had a higher proportion of ER high expressed tumors than HER2- ones did. The 21-gene assay and its proliferation module might be less applicable to HER2-low patients compared with HER2- patients.

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Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials

Cited by 283 publications

References 27 publications

Evolution of HER2-low expression from primary to recurrent breast cancer

Evolution of HER2-low expression from primary to recurrent breast cancer

Prognostic Value of HER2-Low Expression in Non-Metastatic Triple-Negative Breast Cancer and Correlation with Other Biomarkers

Clinical Significance and Genetic Characteristics in HER2 Low Expression Tumors of Hormone Receptor Positive Breast Cancer Patients

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