Newly Approved and Emerging Agents in HER2-Positive Metastatic Breast Cancer

Graff, Stephanie L.; Yan, Fengting; Abdou, Yara

doi:10.1016/j.clbc.2023.05.003

Cited by 12 publications

(5 citation statements)

References 79 publications

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“…Our analysis included 8.8% Her2+ BC, lower than the 15-20% prevalence of Her2+ BC typically reported. This discrepancy may reflect patterns of genomic profiling utilization in clinical practice [25]. Conversely, rarer BC subtypes, such as malignant breast adenomyoepithelioma, are known to be driven by the MAP kinase pathway alterations, such as HRAS Q61 recurrent hotspot mutations [26].…”

Section: Discussionmentioning

confidence: 99%

The Genomic, Transcriptomic, and Immunologic Landscape of HRAS Mutations in Solid Tumors

Kareff,

Trabolsi,

Krause

et al. 2024

Cancers

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Tipifarnib is the only targeted therapy breakthrough for HRAS-mutant (HRASmt) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The molecular profiles of HRASmt cancers are difficult to explore given the low frequency of HRASmt. This study aims to understand the molecular co-alterations, immune profiles, and clinical outcomes of 524 HRASmt solid tumors including urothelial carcinoma (UC), breast cancer (BC), non-small-cell lung cancer (NSCLC), melanoma, and HNSCC. HRASmt was most common in UC (3.0%), followed by HNSCC (2.82%), melanoma (1.05%), BC (0.45%), and NSCLC (0.44%). HRASmt was absent in Her2+ BC regardless of hormone receptor status. HRASmt was more frequently associated with squamous compared to non-squamous NSCLC (60% vs. 40% in HRASwt, p = 0.002). The tumor microenvironment (TME) of HRASmt demonstrated increased M1 macrophages in triple-negative BC (TNBC), HNSCC, squamous NSCLC, and UC; increased M2 macrophages in TNBC; and increased CD8+ T-cells in HNSCC (all p < 0.05). Finally, HRASmt was associated with shorter overall survival in HNSCC (HR: 1.564, CI: 1.16–2.11, p = 0.003) but not in the other cancer types examined. In conclusion, this study provides new insights into the unique molecular profiles of HRASmt tumors that may help to identify new targets and guide future clinical trial design.

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Section: Discussionmentioning

confidence: 99%

The Genomic, Transcriptomic, and Immunologic Landscape of HRAS Mutations in Solid Tumors

Kareff,

Trabolsi,

Krause

et al. 2024

Cancers

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“…Trastuzumab is a key part of contemporary treatment regimens in HER2+ breast cancer patients (46), but up to 70% exhibit resistance to the drug (9,12,47). Consequently, having identified key components of the αVβ6 integrin adhesome in HER2+ breast cancer cells (Fig.…”

Section: Trastuzumab Regulates Recruitment Of Rab5/rab7a/gdi2 Traffic...mentioning

confidence: 99%

A trafficking regulatory subnetwork governs αVβ6 Integrin-HER2 crosstalk to control breast cancer invasion and drug resistance

Maldonado,

Dreger,

Wolanska

et al. 2023

Preprint

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HER2 and αVβ6 integrin are independent predictors of breast cancer survival and metastasis. We investigated αVβ6 signalling and identified an αVβ6/HER2 crosstalk mechanism, which drives invasion and is dysregulated in drug resistant HER2+ breast cancer cells. Proteomic approaches revealed ligand-bound αVβ6 recruits HER2 and a trafficking regulatory subnetwork comprising the small GTPases RAB5 and RAB7A, and the Rab regulator GDI2. We show that the RAB5/RAB7A/GDI2 functional module mediates direct crosstalk between αVβ6 and HER2, impacting receptor trafficking and signalling. Acute exposure to trastuzumab increases recruitment of the RAB5/RAB7A/GDI2 subnetwork to αVβ6, but trastuzumab resistance decouples GDI2 recruitment from this trafficking module. Consequently, GDI2, RAB5 and RAB7A cooperate to regulate migration and TGFβ activation to promote tumour cell invasion and dissemination. However, these mechanisms are dysregulated following acquired trastuzumab resistance. In patients, RAB5, RAB7A & GDI2 expression correlates with patient survival and αVβ6 expression predicts therapeutic response following breast cancer relapse. Thus, the RAB5/RAB7A/GDI2 subnetwork regulates αVβ6-HER2 crosstalk to drive breast cancer invasion, but is subverted in trastuzumab resistant cells to drive αVβ6- and HER2-independent tumour progression.

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“…The mAbs pertuzumab, trastuzumab, and margetuximab were approved by US Food and Drug Administration (FDA) in 1998, 2012, and 2020, respectively ( 6 ). Lapatinib was the first-generation TKI approved in 2007, after which neratinib and tucatinib were approved in 2020, showing an improvement in combination with capecitabine ( 7 ). Trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd; DS-8201) were the ADCs approved by the FDA for the treatment of HER2+ mBC in 2013 and 2022 ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

“…As first-line treatment, dual HER2-targeted mAbs, pertuzumab + trastuzumab, in combination with a taxane has a favorable therapeutic effect in a large proportion of patients ( 7 ). In second-line treatment, nowadays, T-DXd is found to be the preferred option compared with T-DM1 ( 8 , 9 ).…”

Section: Introductionmentioning

confidence: 99%

Economic evaluation of third-line neratinib plus capecitabine versus lapatinib plus capecitabine with HER2+ metastatic breast cancer

Ren

Zheng

et al. 2023

Front. Oncol.

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BackgroundBreast cancer (BC) is one of the most common malignant tumors in women. In addition, human epidermal growth factor receptor 2-positive (HER2+) BC is overexpressed in 25% of BC patients, resulting in the predicament of poor prognosis. Although first- and second-line treatments have been established, optimum third-line treatment is still mired in controversies for HER2+ metastatic BC (mBC). Therefore, this study analyzes the cost-effectiveness of neratinib plus capecitabine (N+C) and lapatinib plus capecitabine (L+C) over a 5-year time horizon from a payer perspective.MethodsA half-cycle corrected four-state Markov model was established to simulate the course of BC events and deaths in N+C and L+C armed patients. The data of this model were derived from NCT01808573 trail and other published literatures. One-way deterministic sensitivity analysis (DSA) was conducted to investigate the impact of variables and probabilistic sensitivity analysis (PSA) was performed based on second-order Monte Carlo simulation. In addition, subgroup analysis was performed to verify its cost-effectiveness in China.ResultThe base-case results found that N+C was in dominant position in 82.70% of the generation scenarios, providing an improvement of 0.17 quality-adjusted life-years (QALYs) and a reduction of $1,861.28 compared with L+C. The ICER was $-1,3294.86/QALY, which did not exceed the willingness to pay (WTP) threshold, while in subgroup, the ICER decreased to $-2,448.17/QALY.ConclusionThis analysis indicated that the combination of neratinib plus capecitabine is likely to be cost-effective in comparison with lapatinib plus capecitabine in patients with HER2+ mBC who continues to progress during or after second-line HER2-targeted therapy. So neratinib plus capecitabine can become a third-line treatment option.

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Newly Approved and Emerging Agents in HER2-Positive Metastatic Breast Cancer

Cited by 12 publications

References 79 publications

The Genomic, Transcriptomic, and Immunologic Landscape of HRAS Mutations in Solid Tumors

The Genomic, Transcriptomic, and Immunologic Landscape of HRAS Mutations in Solid Tumors

A trafficking regulatory subnetwork governs αVβ6 Integrin-HER2 crosstalk to control breast cancer invasion and drug resistance

Economic evaluation of third-line neratinib plus capecitabine versus lapatinib plus capecitabine with HER2+ metastatic breast cancer

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