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

Jacot, William; Maran-Gonzalez, Aurélie; Massol, Océane; Sorbs, Charlotte; Mollévi, Caroline; Guiu, Séverine; Boissière, Florence; Ramos, Jeanne

doi:10.3390/cancers13236059

Cited by 77 publications

(70 citation statements)

References 32 publications

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“…Previous literature is inconsistent with respect to outcome. In line with our findings, various studies reported no difference in overall survival www.nature.com/scientificreports/ between HER2-and HER2low breast cancer patients 5,15,29 . Denkert et al reported that ER+/HER2low breast cancers have a lower pathological complete response rate after neoadjuvant chemotherapy compared to ER+/ HER2-cancers 14 .…”

Section: Discussionsupporting

confidence: 92%

HER2-low breast cancer shows a lower immune response compared to HER2-negative cases

Ende

Smid

Timmermans

et al. 2022

Sci Rep

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Currently, the human epidermal growth factor receptor 2 (HER2) status of breast cancer is classified dichotomously as negative or positive to select patients for HER2-targeted therapy. However, with the introduction of novel treatment options, it is important to get more insight in the biology of cancers with low HER2 expression. Therefore, we studied several clinicopathologic characteristics in relation to the level of HER2 expression (HER2- versus HER2low). We used a well-documented cohort of breast cancer patients (n = 529), with available tissue microarrays and Affymetrix mRNA expression data. HER2 status was scored as negative (immunohistochemistry 0) or low (immunohistochemistry 1 + or 2 + without amplification). We associated HER2 status with several clinicopathologic characteristics, gene-expression data and survival, stratified for estrogen receptor (ER) status. Overall, breast cancers were scored as HER2- (n = 429) or HER2low (n = 100). Within the ER+ cohort (n = 305), no significant associations were found between the HER2 groups and clinicopathologic features. However, HER2low tumors showed several differentially expressed genes compared to HER2- cases, including genes that are associated with worse outcome and depletion of immunity. In ER- cases (n = 224), HER2low status was significantly associated with increased regional nodal positivity, lower density of tumor infiltrating lymphocyte and a lower protein expression of Ki-67 and EGFR compared to HER2- cases. After multivariate analysis, only density of tumor infiltrating lymphocytes remained significantly associated with HER2low status (P = 0.035). No difference in survival was observed between HER2low and HER2- patients, neither in the ER+ nor ER- cohort. In conclusion, our data suggests that HER2low breast cancer is associated with a lower immune response compared to HER2- breast cancer.

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Section: Discussionsupporting

confidence: 92%

HER2-low breast cancer shows a lower immune response compared to HER2-negative cases

Ende

Smid

Timmermans

et al. 2022

Sci Rep

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“…Nevertheless, while patients with HR-positive had a similar DFS regardless the expression of HER2, those with HR-negative has a worse outcome when HER2 was low instead of zero (Supplementary Figure S1). Our finding is in line with the recently reported analysis of triple negative breast cancer cases outcome with respect to HER2 expression which found a worse relapse-free survival among HER2-low than HER2-0 cases (Jacot et al, 2021;U.S. National Library of Medicine, 2022).…”

Section: Figuresupporting

confidence: 92%

Moving HER2-low breast cancer predictive and prognostic data from clinical trials into the real world

Cosimo

Rocca

Ljevar

et al. 2022

Front. Mol. Biosci.

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Background: Previous data, mostly from clinical trials, reported that HER2-low status is associated with low pathological complete response (pCR), and favourable prognosis. Since these findings suggest the existence of an additional breast cancer subtype, we questioned if the predictive/prognostic value of HER2-low was also relevant in the real world.Methods: Data from non-metastatic breast cancer patients treated with neoadjuvant chemotherapy and surgery (2009–2020) were retrieved from our institutional prospectively-maintained registry. Univariable and multivariable logistic models were implemented to study the association between pCR and baseline HER2 status. Univariable analysis of disease-free survival (DFS) was performed through Kaplan-Meier survival curves and log-rank tests.Results: Starting from a total of 790 consecutive cases, we identified 444 newly-diagnosed breast cancer patients featuring HER2 immunohistochemistry (IHC) 0 (HER2-0, n = 109), and 1 + or IHC 2+/in situ hybridization negative (HER2-low, n = 335) receiving anthracycline and taxane-based regimens in 88.9% of cases. Most of the patients were diagnosed with stage II (67.3%) and there was no difference of disease presentation according to HER2-status. pCR was attained by 71 (16.0%) patients and was significantly associated with increased DFS (p = 0.031). Compared to HER2-0, HER2-low cases were more likely hormone receptor-positive (81.2% vs. 43.1%, p < 0.001), well-differentiated (47.5% vs. 26.6%, p = 0.001), less proliferative (21.5% vs. 8.3%, p = 0.001) and less responsive to treatment (pCR 11.6% vs. 29.4%, p < 0.0001). There was no difference in DFS according to HER2 status, though hormone-receptor (HR) negative/HER2-low cases tended to have a worse prognosis compared to HR-negative/HER2-0. By pCR achievement, 3-years DFS was 87.5.% (75.1–100%) vs. 71.6% (65.9–77.8%) (p = 0.161) in HER2-low and 89.1% (75.8–100%) vs. 72.1% (59.7–87.0%) (p = 0.092) in HER2-0.Conclusion: Our real-world data show that HER2-low breast cancer patients represent roughly a half of the cases treated with neoadjuvant therapy, and have poor treatment response. In absence of pCR, HER2-low breast cancer patients have a dismal prognosis, especially when primary tumor hormone receptor status is negative. Studies are therefore needed to define the biology of these tumors for new therapeutic targets and to incorporate HER2-targeting agents in early-stage treatment.

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“…93 It is interesting to note that triplenegative HER2-low cancers were associated with lower grade and the AR(+)FOXA1(+) phenotype, features associated with the LAR subtype. 94 This clincopathological association could have a therapeutic implication for the anti-HER2 ADC in TNBC.…”

Section: A N T I B O D Y -D R U G C O N J U G a T E Smentioning

confidence: 93%

Update on triple‐negative breast cancers – highlighting subtyping update and treatment implication

Tsang

Tse

2022

Histopathology

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Triple‐negative breast cancer (TNBC) remains a major challenge in breast cancer management. Continuing research in the past years aimed at understanding the biology of this tumour and developing more effective therapeutic options. It is now clear that TNBC is vastly heterogeneous with diverse histological, molecular, immunological profiles and clinical differences. Current evidence suggested the existence of at least four predominant subtypes based on expression profiling across studies. These subtypes exhibited specific genomic alterations and tumour microenvironment. Subtype‐specific therapeutic strategies were identified. Recognising these subtypes allows not only an improved prognostication but also a better treatment decision. Herein, we provide an overview of the recent findings on TNBC heterogeneity at different levels and corresponding subtyping. The characteristic of subtypes and the implication of these subtypings in therapeutic approaches are also discussed.

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

Cited by 77 publications

References 32 publications

HER2-low breast cancer shows a lower immune response compared to HER2-negative cases

HER2-low breast cancer shows a lower immune response compared to HER2-negative cases

Moving HER2-low breast cancer predictive and prognostic data from clinical trials into the real world

Update on triple‐negative breast cancers – highlighting subtyping update and treatment implication

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