Post-CDK 4/6 Inhibitor Therapy: Current Agents and Novel Targets

Ashai, Nadia; Swain, Sandra M.

doi:10.3390/cancers15061855

Cited by 5 publications

(2 citation statements)

References 76 publications

(77 reference statements)

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“…Trials with novel agents designed to overcome CDK4/6i-resistance are urgently needed ( 27 ). However, the population of patients with disease progression under CDK4/6i significantly exceeds the population eligible for most clinical trials ( 5 , 8 , 11 , 12 ).…”

Section: Discussionmentioning

confidence: 99%

Tailoring advanced breast cancer treatment after cyclin-dependent kinase 4/6 inhibitors progression - real-world data analysis

Kubeczko,

Polakiewicz-Gilowska,

Świderska

et al. 2024

Front. Oncol.

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BackgroundCyclin-dependent kinase 4/6 inhibitors (CDK4/6i) represent the gold standard of the hormone receptor positive human epidermal growth factor receptor 2 (HER-2) negative advanced breast cancer. However, optimal treatment after disease progression is a matter of debate. We aimed to assess predictive and prognostic factors associated with the treatment outcome following CDK4/6i progression.MethodsWe retrospectively analyzed patients who progressed on CDK4/6i treatment between 2018 and 2024. Treatment based on molecular findings (PIK3CA mutation), genetic findings (BRCA1/2 germline mutation), or adapted to the change in the tumor phenotype in rebiopsy (anti-HER2 therapy in the transformation to HER-2-positive disease) was grouped into tailored treatment and compared to the endocrine-based therapy and chemotherapy alone.ResultsFive hundred twelve patients were treated with CDK4/6i. Two hundred patients with disease progression were enrolled in the study. Duration of response to CDK4/6i was not predictive of the response to subsequent treatment, whereas the progression in the central nervous system was the worst prognostic factor. Thirty patients were ineligible for subsequent treatment. Survival after CDK4/6i progression was significantly longer in patients eligible for tailored treatment. The median PFS in patients with tailored treatment (n=19) was 13.5 months vs. 4.9 months in patients with non-tailored therapy (n=151; p=0.045). 12-month PFS was 54.1% with tailored treatment [95% CI 24.1–76.7%] compared to 18.5% with non-tailored therapy [95% CI 11.6–26.6%]. The median OS for patients treated with a tailored approach was not reached compared to 11.5 months with non-tailored treatment (p=0.016). The 24-month OS for patients treated with a tailored approach was 80.2% [95% CI 40.3–94.8%] compared to 21.1% [95% CI 12.2–31.7%] for patients with non-tailored treatment.ConclusionsTailoring of subsequent treatment strategy seems to be essential for achieving long-term benefit. Further studies are required, as the prognosis after CDK4/6i progression remains dismal, especially in cases affecting the central nervous system.

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Section: Discussionmentioning

confidence: 99%

Tailoring advanced breast cancer treatment after cyclin-dependent kinase 4/6 inhibitors progression - real-world data analysis

Kubeczko,

Polakiewicz-Gilowska,

Świderska

et al. 2024

Front. Oncol.

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“…It is important to note that CDK4/6 is considered a downstream effector for both estrogen- and RTK-triggered pathways. Many additional first- and second-generation CDK4/6 inhibitors are in clinical trials and have been reviewed recently in multiple publications [ 58 , 59 , 60 ]. Despite promising results, resistance to CDK4/6 inhibitors also seems to be inevitable and seems to involve a variety of mechanisms, including abnormal activation of CDK4/6, loss of retinoblastoma protein (pRb), cyclin E activation, loss of PTEN, and activation of alternative pathways including Ras, fibroblast growth factor receptor 1 (FGFR1), and/or PI3K/AKT pathways [ 61 , 62 ].…”

Section: The Familiarmentioning

confidence: 99%

Targeting Breast Cancer: The Familiar, the Emerging, and the Uncharted Territories

Montazeri Aliabadi,

Manda,

Sidgal

et al. 2023

Biomolecules

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Breast cancer became the most diagnosed cancer in the world in 2020. Chemotherapy is still the leading clinical strategy in breast cancer treatment, followed by hormone therapy (mostly used in hormone receptor-positive types). However, with our ever-expanding knowledge of signaling pathways in cancer biology, new molecular targets are identified for potential novel molecularly targeted drugs in breast cancer treatment. While this has resulted in the approval of a few molecularly targeted drugs by the FDA (including drugs targeting immune checkpoints), a wide array of signaling pathways seem to be still underexplored. Also, while combinatorial treatments have become common practice in clinics, the majority of these approaches seem to combine molecularly targeted drugs with chemotherapeutic agents. In this manuscript, we start by analyzing the list of FDA-approved molecularly targeted drugs for breast cancer to evaluate where molecular targeting stands in breast cancer treatment today. We will then provide an overview of other options currently under clinical trial or being investigated in pre-clinical studies.

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Oral SERDs changing the scenery in hormone receptor positive breast cancer, a comprehensive review

Gheysen,

Punie,

Wildiers

et al. 2024

Cancer Treatment Reviews

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Post-CDK 4/6 Inhibitor Therapy: Current Agents and Novel Targets

Cited by 5 publications

References 76 publications

Tailoring advanced breast cancer treatment after cyclin-dependent kinase 4/6 inhibitors progression - real-world data analysis

Tailoring advanced breast cancer treatment after cyclin-dependent kinase 4/6 inhibitors progression - real-world data analysis

Targeting Breast Cancer: The Familiar, the Emerging, and the Uncharted Territories

Oral SERDs changing the scenery in hormone receptor positive breast cancer, a comprehensive review

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