The Association of <i>ERBB2</i>-Low Expression With the Efficacy of Cyclin-Dependent Kinase 4/6 Inhibitor in Hormone Receptor–Positive, <i>ERBB2</i>-Negative Metastatic Breast Cancer

Bao, Kelvin K H; Sutanto, Leone; Tse, Shirley S. W.; Cheung, Ka Man; Chan, Jeffrey

doi:10.1001/jamanetworkopen.2021.33132

Cited by 39 publications

(63 citation statements)

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“…HLBC-2E also showed an increase in CDK4 , PTEN , and RB1 signatures. Bao et al [ 30 ] have recently investigated the association between low levels of ERBB2 expression and clinical outcomes among patients with ER-positive/HER2-negative metastatic breast cancer patients treated with CDK4/6 inhibitors and described ERBB2-low expression as an independent predictor of inferior progression-free survival.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, in the advanced setting, response rates to ADCs targeting HER2 are observed in about 30-50% of patients [ 4 – 6 ]. Furthermore, CDK4/6 inhibitors and PIK3CA inhibitors are standard of care for advanced luminal carcinomas, and as mentioned above, ERBB2 -low expression has been recently reported as an independent predictor of inferior progression-free survival [ 30 ]. Data on PIK3CA mutational status were not available for further stratification in this study.…”

Section: Discussionmentioning

confidence: 99%

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Integrative genomic and transcriptomic analyses illuminate the ontology of HER2-low breast carcinomas

et al. 2022

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Background The “HER2-low” nomenclature identifies breast carcinomas (BCs) displaying a HER2 score of 1+/2+ in immunohistochemistry and lacking ERBB2 amplification. Whether HER2-low BCs (HLBCs) constitute a distinct entity is debated. Methods We performed DNA and RNA high-throughput analysis on 99 HLBC samples (n = 34 cases with HER2 score 1+/HLBC-1, n = 15 cases with HER2 score 2+ and ERBB2 not amplified/HLBC-2N, and n = 50 cases with score 2+ and ERBB2 copy number in the equivocal range/HLBC-2E). We compared the mutation rates with data from 1317 samples in the Memorial Sloan-Kettering Cancer Center (MSKCC) BC cohort and gene expression data with those from an internal cohort of HER2-negative and HER2-positive BCs. Results The most represented mutations affected PIK3CA (31/99, 31%), GATA3 (18/99, 18%), TP53 (17/99, 17%), and ERBB2 (8/99, 8%, private to HLBC-2E). Tumor mutational burden was significantly higher in HLBC-1 compared to HLBC-2E/N (P = 0.04). Comparison of mutation spectra revealed that HLBCs were different from both HER2-negative and HER2-positive BCs, with HLBC-1 resembling more HER2-negative tumors and HLBC-2 mutationally related to HER2-addicted tumors. Potentially actionable alterations (annotated by using OncoKB/ESCAT classes) affected 52 patients. Intra-group gene expression revealed overlapping features between HLBC-1 and control HER2-negative BCs, whereas the HLBC-2E tumors showed the highest diversity overall. The RNA-based class discovery analysis unveiled four subsets of tumors with (i) lymphocyte activation, (ii) unique enrichment in HER2-related features, (iii) stromal remodeling alterations, and (iv) actionability of PIK3CA mutations (LAURA classification). Conclusions HLBCs harbor distinct genomic features when compared with HER2-positive and HER2-negative BCs; however, differences across IHC classes were also unveiled thus dissecting the full picture of heterogeneity across HER2-low disease. The HLBC-2E category harbors most distinctive features, whereas HLBC-1 seems superimposable to HER2-negative disease. Further studies are needed to ascertain whether the four genomic-driver classes of the LAURA classification hold prognostic and/or predictive implications.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Integrative genomic and transcriptomic analyses illuminate the ontology of HER2-low breast carcinomas

et al. 2022

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“…In addition, some scholars believe that bidirectional crosstalk between members of the human epidermal growth factor receptor family (HER) and the estrogen receptor (ER) is the basis of drug resistance; that is, high expression and amplification of HER2 drive the occurrence of endocrine resistance [ 150 ]. Kelvin et al investigated the relationship between HER2 expression levels and the efficacy of CDK4/6i combined with letrozole or fulvestrant therapy in ER+/HER2-negative BC patients [ 151 ]. In HER2-low BC, the PFS was significantly shorter than in HER2-0 (8.9 months vs. 18.8 months, p = 0.014) [ 151 ].…”

Section: Other Therapiesmentioning

confidence: 99%

“…Kelvin et al investigated the relationship between HER2 expression levels and the efficacy of CDK4/6i combined with letrozole or fulvestrant therapy in ER+/HER2-negative BC patients [ 151 ]. In HER2-low BC, the PFS was significantly shorter than in HER2-0 (8.9 months vs. 18.8 months, p = 0.014) [ 151 ]. HER2 upregulation is responsible for endocrine resistance, resulting in reduced PFS and pCR rates with overall endocrine therapy.…”

Section: Other Therapiesmentioning

confidence: 99%

Targeted Approaches to HER2-Low Breast Cancer: Current Practice and Future Directions

Lai

Han

et al. 2022

Cancers

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HER2-low breast cancer (BC) has a poor prognosis, making the development of more suitable treatment an unmet clinical need. While chemotherapy is the main method of treatment for HER2-low BC, not all patients benefit from it. Antineoplastic therapy without chemotherapy has shown promise in clinical trials and is being explored further. As quantitative detection techniques become more advanced, they assist in better defining the expression level of HER2 and in guiding the development of targeted therapies, which include directly targeting HER2 receptors on the cell surface, targeting HER2-related intracellular signaling pathways and targeting the immune microenvironment. A new anti-HER2 antibody-drug conjugate called T-DM1 has been successfully tested and found to be highly effective in clinical trials. With this progress, it could eventually be transformed from a disease without a defined therapeutic target into a disease with a defined therapeutic molecular target. Furthermore, efforts are being made to compare the sequencing and combination of chemotherapy, endocrine therapy, and HER2-targeted therapy to improve prognosis to customize the subtype of HER2 low expression precision treatment regimens. In this review, we summarize the current and upcoming treatment strategies, to achieve accurate management of HER2-low BC.

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“…A recent study analysed the association of HER2 low expression determined by immunohistochemistry score in HR positive and HER2 negative metastatic breast cancer subjects treated with CDK4/6 inhibitors. They found that the low expression of HER2 is associated with inferior progression-free survival [ 2 ] . However, not all patients achieve the expected survival outcome and become resistant to treatment regimens.…”

Section: Introductionmentioning

confidence: 99%

Molecular vulnerabilities and therapeutic resistance in hormone receptor positive and HER2 dependent breast cancer tumours

Velaga¹,

Tanaka²,

Toi³

2022

Cancer Drug Resist

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Over the past two decades, high sensitivity to HER2-amplified primary breast cancers has been achieved with HER2-targeted therapies. CDK4/6 inhibitors have long been identified as a potential treatment option for advanced breast cancer patients. However, acquired HER2 heterogeneity leading to resistance during the treatment has been identified as a bottleneck. This review focuses on the recent resistance mechanisms identified and potential therapeutic targets for conventional and combination endocrine therapies with CDK4/6 inhibitors by various breast cancer clinical trials and research groups in HER amplified and/or mutated breast cancer tumour. Activating HER2 alterations, JNK pathway, hyperactivated TORC1, co-mutations in HER2 and HER3, phenotypic changes of HER2, and few other advanced findings are identified as potential therapeutic targets in treating current HER2 endocrine therapy-resistant tumour. Along with the HER2-focused resistance mechanisms, we also describe how the microbiome may play a role in breast cancer therapy and its potential for new therapeutic strategies to overcome drug resistance in breast cancers.

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The Association of ERBB2-Low Expression With the Efficacy of Cyclin-Dependent Kinase 4/6 Inhibitor in Hormone Receptor–Positive, ERBB2-Negative Metastatic Breast Cancer

Cited by 39 publications

References 5 publications

Integrative genomic and transcriptomic analyses illuminate the ontology of HER2-low breast carcinomas

Integrative genomic and transcriptomic analyses illuminate the ontology of HER2-low breast carcinomas

Targeted Approaches to HER2-Low Breast Cancer: Current Practice and Future Directions

Molecular vulnerabilities and therapeutic resistance in hormone receptor positive and HER2 dependent breast cancer tumours

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