Adjuvant CDK4/6 inhibitors combined with endocrine therapy in HR-positive, HER2-negative early breast cancer: A meta-analysis of randomized clinical trials

Gao, Hong‐Fei; Lin, Yi-Cheng; Zhu, Teng; Ji, Fei; Zhang, Liulu; Yang, Ciqiu; Yang, Mei; Li, Jieqing; Cheng, Minyi; Wang, Kun

doi:10.1016/j.breast.2021.07.002

Cited by 11 publications

(21 citation statements)

References 47 publications

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“…Additionally, rates of grade 3/4 AEs were significantly higher with the combination therapy (RR 4.14, 95% CI 3.33–5.15, p<0.00001) with significantly higher treatment discontinuation rate due to AEs (RR 19.16, 95% CI 9.27–39.61, p < 0.00001). 57 …”

Section: Discussionmentioning

confidence: 99%

Expanding the Clinical Use of CDK4/6 Inhibitors in the Treatment of Hormone Receptor-Positive, HER2-Negative Breast Cancer from Metastatic Setting to Adjuvant Setting

Abdel‐Razeq¹,

Sharaf²

2022

DDDT

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More than two-thirds of patients with breast cancer present with hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative disease at their initial diagnosis. HR-positive breast cancer’s growth depends on Cyclin D1, a direct transcriptional target of estrogen receptors (ER). The recent introduction of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors (palbociclib, ribociclib, and abemaciclib) has revolutionized the treatment of metastatic HR-positive, HER2-negative breast cancer in both endocrine-sensitive and endocrine-resistant settings and in both pre-and post-menopausal women. Multiple large randomized clinical trials had demonstrated improvement in progression-free survival (PFS) and, more recently, in overall survival (OS). Adjuvant endocrine therapy (ET) significantly reduces the risk of recurrence and death among patients with HR-positive early-stage breast cancer (EBC). However, up to 20% of these patients will experience local, regional or distal recurrences in the first ten years. Such resistance to ET motivated researchers to try CDK4/6 inhibitors in EBC, both in adjuvant and neoadjuvant settings. While many clinical trials are still ongoing, at least one study and two meta-analyses had shown beneficial results, based on which the US Food and Drug Administration had recently approved the use of one of these agents, abemaciclib, in combination with ET for the adjuvant therapy of patients with high-risk EBC. In this paper, we review the recently published and ongoing landmark clinical trials attempting to expand the use of CDK4/6 inhibitors, in combination with ET, in the adjuvant setting of EBC.

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Section: Discussionmentioning

confidence: 99%

Expanding the Clinical Use of CDK4/6 Inhibitors in the Treatment of Hormone Receptor-Positive, HER2-Negative Breast Cancer from Metastatic Setting to Adjuvant Setting

Abdel‐Razeq¹,

Sharaf²

2022

DDDT

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“…For postmenopausal women, the initial 5 years of adjuvant endocrine therapies primarily consisted of TAM, AIs, and TAM followed by an AI. Moreover, recent explorations of CDK4/6 inhibitors in adjuvant setting suggested that the addition of CDK4/6 inhibitors to standard endocrine therapy significantly improved the prognosis ( Johnston et al, 2020 ; Gao et al, 2021 ). Therefore, in the era of CDK4/6 inhibitors, it seemed necessary to standardize the basic endocrine therapy and thereby reduce the discrepancy in outcomes resulted from drug differences.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Initial 5 Years of Adjuvant Endocrine Therapy in Postmenopausal Hormone Receptor-Positive Breast Cancer: A Systematic Review and Network Meta-Analysis

et al. 2022

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Purpose: To identify the optimal initial 5 years of adjuvant endocrine therapy for hormone receptor-positive postmenopausal early breast cancer (EBC) patients.Methods: We conducted a systematic search of the PubMed, Web of Science, and EMBASE to obtain relevant studies published between January 2000 and January 2022. Randomized clinical trials assessing the efficacy and safety of initial 5 years of adjuvant endocrine therapy were included. The primary outcomes were disease-free survival and overall survival and the secondary outcome was severe adverse effects (SAEs). A Bayesian network meta-analysis was carried out to indirectly compare all regimens and the value of surface under the cumulative ranking curve (SUCRA) was used to obtain rankings.Results: Eleven studies with 49,987 subjects were included. For DFS, exemestane (EXE) [hazard ratio (HR) 0.91, 95% confidence interval (95%CI) 0.87–0.96], anastrozole (ANA) (0.94, 0.90–0.97), letrozole (LET) (0.93, 0.89–0.97), tamoxifen (TAM) followed by EXE (0.91, 0.87–0.96), and TAM followed by ANA (0.92, 0.87–0.98) were more favorable than TAM, with TAM followed by EXE ranking as the first of SUCRA. For OS, only TAM followed by ANA showed significant superiority than TAM (HR 0.91, 95%CI 0.86–0.97) and ranked as the first of SUCRA. For SAEs, EXE (HR 1.72, 95%CI 1.04–2.98), ANA (1.58, 1.03–2.43), and LET (1.63, 1.02–2.57) showed greater associations with bone fracture than TAM. However, no significant difference in the incidences of cardiac events, thromboembolic events, and cerebrovascular events was found among all comparisons.Conclusion: The sequential use of aromatase inhibitors, which has the best curative effects and relatively mild side effects, may be the optimal treatment mode for hormone receptor-positive postmenopausal EBC patients. In addition, the three kinds of aromatase inhibitors achieved roughly equal efficacy, but caused different types of SAEs.Systematic Review Registration: [website], identifier [registration number].

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“…At present, studies involving the engineering of stem cell therapies may ultimately induce the development of new agents employed for clinical practice. The sites specific for cancer growth may be useful for initial clinical trials that remain to be developed and evaluated [ 96 ]. While research of CSCs has exploded during the last few years, its development towards clinical practice is still at a preliminary stage [ 36 , 97 ].…”

Section: Progress In Clinical Medicinementioning

confidence: 99%

“…A form of medical practice, often employed for non-cancer diseases, is regenerative medicine, which is based on affected tissues including the brain, the blood vessels, and other organs (for details see [ 75 , 99 ]). In case of cancers, this approach is employed, however not frequently [ 88 , 96 ]. In the field of cancer, ongoing research is about personalized medicine [ 12 , 20 , 100 ].…”

Section: Progress In Clinical Medicinementioning

confidence: 99%

“…Protocols for EV loading, modification, and isolation need to be standardized for large-scale production. Careful evaluation of the findings concerning qualification, characterization, and production of the methods employed, include pharmacokinetics, targeting and transfer of drugs to appropriate sites; assessment of safety profiles; and others [ 95 , 96 , 97 , 98 , 100 , 101 , 102 ].…”

Section: Progress In Clinical Medicinementioning

confidence: 99%

See 1 more Smart Citation

Cancer Stem Cells and Their Vesicles, Together with Other Stem and Non-Stem Cells, Govern Critical Cancer Processes: Perspectives for Medical Development

Meldolesi

2022

IJMS

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Stem cells, identified several decades ago, started to attract interest at the end of the nineties when families of mesenchymal stem cells (MSCs), concentrated in the stroma of most organs, were found to participate in the therapy of many diseases. In cancer, however, stem cells of high importance are specific to another family, the cancer stem cells (CSCs). This comprehensive review is focused on the role and the mechanisms of CSCs and of their specific extracellular vesicles (EVs), which are composed of both exosomes and ectosomes. Compared to non-stem (normal) cancer cells, CSCs exist in small populations that are preferentially distributed to the niches, such as minor specific tissue sites corresponding to the stroma of non-cancer tissues. At niches and marginal sites of other cancer masses, the tissue exhibits peculiar properties that are typical of the tumor microenvironment (TME) of cancers. The extracellular matrix (ECM) includes components different from non-cancer tissues. CSCs and their EVs, in addition to effects analogous to those of MSCs/EVs, participate in processes of key importance, specific to cancer: generation of distinct cell subtypes, proliferation, differentiation, progression, formation of metastases, immune and therapy resistance, cancer relapse. Many of these, and other, effects require CSC cooperation with surrounding cells, especially MSCs. Filtered non-cancer cells, especially macrophages and fibroblasts, contribute to collaborative cancer transition/integration processes. Therapy developments are mentioned as ongoing preclinical initiatives. The preliminary state of clinical medicine is presented in terms of both industrial development and future treatments. The latter will be administered to specific patients together with known drugs, with the aim of eradicating their tumor growth and metastases.

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Adjuvant CDK4/6 inhibitors combined with endocrine therapy in HR-positive, HER2-negative early breast cancer: A meta-analysis of randomized clinical trials

Cited by 11 publications

References 47 publications

Expanding the Clinical Use of CDK4/6 Inhibitors in the Treatment of Hormone Receptor-Positive, HER2-Negative Breast Cancer from Metastatic Setting to Adjuvant Setting

Expanding the Clinical Use of CDK4/6 Inhibitors in the Treatment of Hormone Receptor-Positive, HER2-Negative Breast Cancer from Metastatic Setting to Adjuvant Setting

Efficacy and Safety of Initial 5 Years of Adjuvant Endocrine Therapy in Postmenopausal Hormone Receptor-Positive Breast Cancer: A Systematic Review and Network Meta-Analysis

Cancer Stem Cells and Their Vesicles, Together with Other Stem and Non-Stem Cells, Govern Critical Cancer Processes: Perspectives for Medical Development

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