Resistance Mechanisms to Combined CDK4/6 Inhibitors and Endocrine Therapy in ER+/HER2− Advanced Breast Cancer: Biomarkers and Potential Novel Treatment Strategies

Al-Qasem, Abeer J.; Alves, Carla L.; Ditzel, Henrik J.

doi:10.3390/cancers13215397

Cited by 12 publications

(9 citation statements)

References 92 publications

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“…However, different CDK activities and cyclins in driving cancer cell cycles are highly heterogeneous and can explain why some metastatic breast cancer patients can initially express high estrogen receptors, during which time they can turn into different expressions of estrogen/progesterone features, thus transforming from Luminal A to Luminal B. [25,26].…”

Section: Resultsmentioning

confidence: 99%

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Real-World Outcomes of CDK4/6 Inhibitors Treatment in Metastatic Breast Cancer in Romania

Miron,

Anghel,

Barnonschi

et al. 2023

Diagnostics

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The introduction in clinical practice of selective cyclin-dependent kinase (CDK) 4/6 inhibitors improves the outcome of patients with hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC). In Romania, the three available CDK 4/6 inhibitors (Palbociclib, Ribociclib and Ademaciclib) have been approved by the National Agency for Medicines (ANM) in 2019, 2020 and 2021. We conducted a retrospective study from 2019 to 2022 on 107 patients with metastatic breast cancer HR+ that have been treated with CDK 4/6 inhibitors in addition to hormone therapy in the Oncology Department of Colțea Clinical Hospital in Bucharest. The purpose of this study is to calculate the median progression-free survival (PFS) and to compare it with the median PFS from other randomized clinical trials. A key difference from other studies is that our study evaluated both patients with non-visceral mBC and patients with visceral mBC, as these two groups often have different outcomes. A total of 79.4% were postmenopausal patients and 20.6% were premenopausal; 42,1% had different stages at the beginning of disease and 57.9% presented newly metastatic disease. Median PFS was 17 months, unlike randomized clinical trials which reported a median PFS of 25.3 months. The combination of CDK 4/6 inhibitors with endocrine therapy is the golden standard treatment in HR-positive, HER2-negative metastatic breast cancer, bringing a prolongation of survival for these patients. Our results show no major differences compared to randomized clinical trials, despite the smaller patient group. In order to have a picture of the efficacy of the treatment as close as possible to the real-world data, we believe that it would be very useful to have a collaboration between several oncology departments in different institutions to carry out a multi-center study on large groups of patients.

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Section: Resultsmentioning

confidence: 99%

“…13, x FOR PEER REVIEW 6 of 17 breast cancer patients can initially express high estrogen receptors, during which time they can turn into different expressions of estrogen/progesterone features, thus transforming from Luminal A to Luminal B [25,26]…”

mentioning

confidence: 99%

Real-World Outcomes of CDK4/6 Inhibitors Treatment in Metastatic Breast Cancer in Romania

Miron,

Anghel,

Barnonschi

et al. 2023

Diagnostics

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“…Nevertheless, many current studies attach importance to improving the resistance of breast cancer cells to CDK 4/6 inhibitors. It is hoped that these inhibitors can be further used in the treatment of breast cancer (157,158).…”

Section: Discussionmentioning

confidence: 99%

New Advances in Targeted Therapy of HER2-Negative Breast Cancer

Peng

Xie

et al. 2022

Front. Oncol.

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Breast cancer has an extremely high incidence in women, and its morbidity and mortality rank first among female tumors. With the increasing development of molecular biology and genomics, molecular targeted therapy has become one of the most active areas in breast cancer treatment research and has also achieved remarkable achievements. However, molecular targeted therapy is mainly aimed at HER2-positive breast cancer and has not yet achieved satisfactory curative effect on HER2-negative breast cancer. This article describes the potential targets that may be used for breast cancer treatment from the aspects of PI3K/AKT signaling pathway, DDR, angiogenesis, the cell cycle, breast cancer stem cells, etc., and explores possible inhibitors for the treatment of HER2-negative breast cancer, such as PI3K inhibitors, AKT inhibitors and m-TOR inhibitors that inhibit the PI3K/AKT signaling pathway, small molecule tyrosine kinase inhibitors that restrain angiogenesis, CDK inhibitors, aurora kinase inhibitors and HDAC inhibitors that block cell cycle, as well as the drugs targeting breast cancer stem cells which have been a hit, aiming to provide a new idea and strategy for the treatment of HER2-negative breast cancer.

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“…CE maintenance treatment after chemo is frequently given although not recommended by current guidelines because of an insufficient database [23]. Although CE treatment is associated with prolonged progression-free survival and even OS, resistance inevitably develops in almost all patients [24, 25]. A number of resistance mechanisms have been described including mutation/activation of the ESR1 gene and a variety of signal transduction pathways and transcription factor alterations, which have been detected in biopsies of metastases [8, 26, 27] and ctDNA [14, 28].…”

Section: Discussionmentioning

confidence: 99%

Clonal Evolution in Patients with Hormone Receptor Positive, HER-2 Negative Breast Cancer Treated with Chemotherapy or CDK4/6 Inhibitors

et al. 2022

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Introduction Somatic evolution of the cancer genome resulting in genetically different subclones is thought to be involved in the development of treatment resistance but might also offer new therapeutic opportunities in metastatic breast cancer. No data are available if clonal evolution differs in patients treated with chemotherapy or CDK4/6 inhibitors given with endocrine treatment (CE treatment). Methods We performed a prospective analysis of circulating tumor DNA(ctDNA) by targeted next generation sequencing in 46 patients before the beginning of a systemic firstline (n=37) or second-line (n=9) treatment. Ct DNA was analyzed again upon disease progression. Results New mutations in ctDNA of patients with progressive disease were detected in 1/11 patients who started chemotherapy, in 4/9 patients treated with chemotherapy followed by CE maintenance treatment and in 9/26 patients receiving CE therapy. The number of acquired new mutations did not differ significantly between the three therapy cohorts (all p-values >0.05). However, in patients classified as secondary resistant (n=37), occurrence of new mutations significantly differed between patients who started chemotherapy (0/9) compared to patients treated with chemotherapy followed by CE (4/11; p=0.041) and patients receiving CE therapy (8/19; p=0.024), respectively. Conclusion Clonal evolution might differ significantly between metastatic breast cancer patients with HR positive and HER-2 negative disease treated with chemotherapy or CDK4/6 inhibitors. These results should be confirmed in larger patient cohorts.

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Resistance Mechanisms to Combined CDK4/6 Inhibitors and Endocrine Therapy in ER+/HER2− Advanced Breast Cancer: Biomarkers and Potential Novel Treatment Strategies

Cited by 12 publications

References 92 publications

Real-World Outcomes of CDK4/6 Inhibitors Treatment in Metastatic Breast Cancer in Romania

Real-World Outcomes of CDK4/6 Inhibitors Treatment in Metastatic Breast Cancer in Romania

New Advances in Targeted Therapy of HER2-Negative Breast Cancer

Clonal Evolution in Patients with Hormone Receptor Positive, HER-2 Negative Breast Cancer Treated with Chemotherapy or CDK4/6 Inhibitors

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