Evolving standards of care and new challenges in the management of HER2‐positive breast cancer

Choong, Grace; Cullen, Grace; O’Sullivan, Ciara C.

doi:10.3322/caac.21634

Cited by 117 publications

(87 citation statements)

References 144 publications

(197 reference statements)

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“…The human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase cell membrane receptor and an important biomarker of breast cancer (BC) molecular subtypes. HER2-positive (HER2+) BC accounts for 15%–20% of total BC and exhibits aggressive behavior and poor prognosis ( 1 ). HER2 testing is performed via immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of Anti-HER2 Agents in Combination With Chemotherapy for Metastatic HER2-Positive Breast Cancer Patient: A Network Meta-Analysis

et al. 2021

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BackgroundThe presence of anti-HER2 agents, such as trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1), significantly improved the prognosis of metastatic HER2-positive (HER2+) breast cancers (BC). However, drug resistance and disease progression are still common. In order to further improve the treatment efficacy, new clinical trials about anti-HER2 agents in combination with chemotherapy are growing rapidly. We conducted the network meta-analysis to synthesize evidences of clinical trials to identify the best therapy for metastatic HER2+ BC.MethodsA systematic search of randomized controlled trials regarding anti-HER2 agents in combination with chemotherapy for advanced or metastatic breast cancers up to May 2020 was conducted in Embase, PubMed, and the Cochrane Library. The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS), objective response rate (ORR), and safety. Bayesian network meta-analysis was conducted to synthesize the results and rank the therapies.ResultsTwenty-six studies, including 16 studies for first-line treatments and 10 studies for second- or later-line treatments were included in the network meta-analysis. For first-line studies, the THP (taxanes + trastuzumab + pertuzumab) regimen exhibited the highest probability to be the optimal treatment in all efficacy outcomes and moderate safety. For second- or later-line studies, the T-DM1 and XHTuC (capecitabine + trastuzumab + tucatinib) regimens ranked top two in all efficacy outcomes according to the surface under the cumulative ranking (SUCRA) results. T-DM1 ranked first in PFS and OS whereas XHTuC ranked first in ORR. The safety outcomes of T-DM1 and XHTuC were acceptable.ConclusionsTHP was still the optimal first-line treatment for metastatic HER2+ BC. T-DM1 and XHTuC were recommended for second-line treatments.Systematic Review RegistrationINPLASY.com, identifier (INPLASY202090086).

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Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of Anti-HER2 Agents in Combination With Chemotherapy for Metastatic HER2-Positive Breast Cancer Patient: A Network Meta-Analysis

et al. 2021

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“…If a patient is classified as HER2 positive (HER2 +) then HER2 targeted therapies are prescribed and can be administered in tandem with chemotherapeutics, surgery and endocrine treatment (Cardoso et al 2018). Standard-of-care treatments include combinations of the monoclonal antibodies trastuzumab and pertuzumab which target distinct extracellular regions of the HER2 protein (Choong et al 2020). These block receptor-activated cell signalling and induce an immune response (Nami et al 2019).…”

Section: Introductionmentioning

confidence: 99%

HER2-PI9 and HER2-I12: two novel and functionally active splice variants of the oncogene HER2 in breast cancer

Hart

Silipo

Satam

et al. 2021

J Cancer Res Clin Oncol

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In this study, two novel alternative splice variants of HER2, named HER2-PI9 and HER2-I12, were identified in breast cancer cell lines and breast tumour tissues. Whilst HER2-P19 arises from the inclusion of an 117 bp cassette-exon of intron 9 of HER2, HER2-I12 results from intron 12 inclusion. In silico analyses were performed to predict the amino acid sequences of these two HER2 novel variants. To confirm their protein expression, plasmid vectors were generated and transfected into the HER2 negative breast cancer cell line, MCF-7. Additionally, their functional properties in oncogenic signalling were confirmed. Expression of HER2-PI9 and HER2-I12 was successful and matched the in silico predictions. Importantly, these splice variants can modulate the phosphorylation levels of extracellular signal-related kinase 1/2 (ERK1/2) and Akt/protein kinase B (Akt) signalling in MCF-7 breast cancer cells. Enhanced cellular proliferation, migration and invasion were observed in the case of the HER2-I12 expressing model. In human tissues and breast carcinoma tumours both variants were present. This study reveals two novel splice variants of HER2. Additionally, the potential biological activity for HER2-PI9 and HER2-I12 in breast cancer cells is also reported..

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“…As there are now at least seven FDA-approved HER2 inhibitors 26 , we wanted to corroborate our findings with some of the newer HER2 inhibitors. Tucatinib is a novel, FDA-approved agent that has demonstrated more than 1000-fold selectivity for HER2 over EGFR in in vitro assays 27 and significant efficacy in clinical trials for the treatment of metastatic HER2-positive breast cancer (NCT02614794) [28][29][30][31][32] .…”

Section: Dinaciclib Sensitizes Her2-amplified Breast Cancer Cells To mentioning

confidence: 86%

Targeting transcription of MCL-1 sensitizes HER2-amplified breast cancers to HER2 inhibitors

et al. 2021

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Human epidermal growth factor receptor 2 gene (HER2) is focally amplified in approximately 20% of breast cancers. HER2 inhibitors alone are not effective, and sensitizing agents will be necessary to move away from a reliance on heavily toxic chemotherapeutics. We recently demonstrated that the efficacy of HER2 inhibitors is mitigated by uniformly low levels of the myeloid cell leukemia 1 (MCL-1) endogenous inhibitor, NOXA. Emerging clinical data have demonstrated that clinically advanced cyclin-dependent kinase (CDK) inhibitors are effective MCL-1 inhibitors in patients, and, importantly, well tolerated. We, therefore, tested whether the CDK inhibitor, dinaciclib, could block MCL-1 in preclinical HER2-amplified breast cancer models and therefore sensitize these cancers to dual HER2/EGFR inhibitors neratinib and lapatinib, as well as to the novel selective HER2 inhibitor tucatinib. Indeed, we found dinaciclib suppresses MCL-1 RNA and is highly effective at sensitizing HER2 inhibitors both in vitro and in vivo. This combination was tolerable in vivo. Mechanistically, liberating the effector BCL-2 protein, BAK, from MCL-1 results in robust apoptosis. Thus, clinically advanced CDK inhibitors may effectively combine with HER2 inhibitors and present a chemotherapy-free therapeutic strategy in HER2-amplified breast cancer, which can be tested immediately in the clinic.

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Evolving standards of care and new challenges in the management of HER2‐positive breast cancer

Cited by 117 publications

References 144 publications

Efficacy and Safety of Anti-HER2 Agents in Combination With Chemotherapy for Metastatic HER2-Positive Breast Cancer Patient: A Network Meta-Analysis

Efficacy and Safety of Anti-HER2 Agents in Combination With Chemotherapy for Metastatic HER2-Positive Breast Cancer Patient: A Network Meta-Analysis

HER2-PI9 and HER2-I12: two novel and functionally active splice variants of the oncogene HER2 in breast cancer

Targeting transcription of MCL-1 sensitizes HER2-amplified breast cancers to HER2 inhibitors

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