HER2-Low Breast Cancer: Molecular Characteristics and Prognosis

Agostinetto, Elisa; Rediti, Mattia; Fimereli, Danai; Debien, Véronique; Piccart, Martine; Aftimos, Philippe; Sotiriou, Christos; Azambuja, Evandro de

doi:10.3390/cancers13112824

Cited by 165 publications

(191 citation statements)

References 42 publications

Supporting

Mentioning

163

Contrasting

Unclassified

Order By: Relevance

“…This finding was also confirmed in a following study were we showed a significant positive correlation between ERBB2 mRNA levels and HER2 protein levels (Spearman Correlation ¼ 0.531, p < 0.001) [109]. Finally, we found no survival differences between HER2-low vs 0 tumors, however the large biological heterogeneity observed, confirmed by a following study based on TCGA data, might have potential therapeutic implications [108,110]. An exemplification of the correlation between HER2 protein and mRNA levels is reported in Fig.…”

Section: Beyond Her2 Overexpression: Her2-low Breast Tumors and Her2 Heterogeneitysupporting

confidence: 86%

Dissecting the biological heterogeneity of HER2-positive breast cancer

Schettini

Prat

2021

The Breast

View full text Add to dashboard Cite

HER2-positive (HER2+) breast cancer (BC) is a heterogenous and multifaceted disease, with interesting therapeutic implications. First, all intrinsic molecular subtypes can be identified in HER2+ tumors, with the HER2-enriched being the most frequent. Such subtypes do not differ much from their counterparts in HER2-negative disease, apart for the high expression of genes in/near the HER2 amplicon on chromosome 17. Intrinsic subtyping, along with the quantification of ERBB2 mRNA levels, is associated with higher rates of pathologic complete response across neoadjuvant trials of dual HER2 blockade and might help select patients for de-escalation and escalation treatment strategies. Secondly, HER2+ tumors have a broad range of DNA alterations. ERBB2 mutations and alterations in the PI3K/Akt/mTOR pathway are among the most frequent and might predict benefit from potent pan-HER, PI3K and mTOR inhibitors. Moreover, HER2+ tumors are usually infiltrated by lymphocytes. These tumor infiltrating-lymphocytes (TILs) predict response to neoadjuvant anti-HER2-based treatment and exert a prognostic role. PD-L1, detected in ∼42 % of HER2+ BC, might also be useful to define patients responding to novel anti-PD1/PD-L1 immunotherapies. New multiparametric clinicopathologic and genomic tools accounting for this complexity, such as HER2DX, are under development to define more tailored treatment approaches. Finally, HER2-targeted antibody-drug conjugates (ADC) such as trastuzumab deruxtecan might be active in tumors with low expression of HER2. Overall, there is a need to molecularly characterize and develop novel targeted therapies for HER2+ disease.

show abstract

Section: Beyond Her2 Overexpression: Her2-low Breast Tumors and Her2 Heterogeneitysupporting

confidence: 86%

Dissecting the biological heterogeneity of HER2-positive breast cancer

Schettini

Prat

2021

The Breast

View full text Add to dashboard Cite

show abstract

“…Recently, Agostinetto et al evaluated the transcriptomic profile of the HER2-low group using the PAM50 intrinsic subtype classification and data on 804 primary breast cancers (n = 410 HER2 1+/2+ tumors, among which 74 were TNBC) from the TCGA dataset [ 12 ]. They found that the percentage of HER2-enriched tumors (i.e., hormone receptor-negative and HER2-positive) was higher in the HER2 1+/2+ TNBC group (13.7% versus 1.6% in the HER2 0 TNBC population), unlike the study by Schettini et al (9% of HER2-enriched tumors in the HER2 0 TNBC population vs. 7.1% in the HER2 1+/2+ TNBC population) [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…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

View full text Add to dashboard Cite

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.

show abstract

“…Two recent studies also discovered that HER2-low/HR + patients had similar survival outcomes compared with HER2-/HR + patients. Furthermore, a recent research based on PAM50 subtype demonstrated that instead of low HER2 expression, it was hormone receptor and its related genes expression that might be the actually dominated oncological driver for HER2-low/HR + breast cancer 10 . This subtype was found to make up for a dominated proportion of luminal A/B breast cancer in current data.…”

Section: Discussionmentioning

confidence: 99%

“…So far, studies about these tumors were insu cient for clinicians to differentiate them from other traditional subtypes. Previous evidence also contradicted with each other when investigating the survival outcomes of these patients [9][10][11][12] . The result of NASBP B-47 suggested that HER2-targeted therapy didn't produce effect on HER2 low breast cancer 13 and this subset was treated as luminal-like or triple negative subtype according to the hormone receptor (HR) status.…”

Section: Introductionmentioning

confidence: 91%

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

Chen

Liu

Chen

et al. 2021

Preprint

View full text Add to dashboard Cite

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.

show abstract

HER2-Low Breast Cancer: Molecular Characteristics and Prognosis

Cited by 165 publications

References 42 publications

Dissecting the biological heterogeneity of HER2-positive breast cancer

Dissecting the biological heterogeneity of HER2-positive 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

Contact Info

Product

Resources

About