bims-cyhorp 2022-09-04 papers

Issue of 2022–09–04
six papers selected by
Piotr Okupski,

Breast Cancer Res Treat. 2022 Aug 31.

Clinical management of metastatic hormone receptor-positive, HER2-negative breast cancer (MBC) after CDK 4/6 inhibitors: a retrospective single-institution study.

Grace M Choong, Savannah Liddell, Roberto A Leon Ferre, Ciara C O'Sullivan, Kathryn J Ruddy, Tufia C Haddad, Timothy J Hobday, Prema P Peethambaram, Minetta C Liu, Matthew P Goetz, Karthik V Giridhar.

PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), in combination with endocrine therapy (ET), are standard either in the first (1L) or second-line (2L) setting for the treatment of hormone receptor (HR) positive, HER2-negative metastatic breast cancer (MBC). However, the optimal sequencing of treatments after progression on CDK4/6i remains unknown. We performed a single-institution analysis to identify treatments and outcomes after progression on a CDK4/6i.
METHODS: We identified patients with HR-positive, HER2-negative MBC prescribed a CDK4/6i in the 1L or 2L settings from December 2014 to February 2018 at Mayo Clinic in Rochester, Minnesota. Outcomes were collected through September 30, 2020.
RESULTS: Palbociclib, in combination with letrozole or fulvestrant, was the most prescribed CDK4/6i. The 1L and 2L CDK4/6i cohorts exhibited comparable overall survival (OS), but progression-free survival (PFS) was longer in the 1L than the 2L cohort [28.2 months (95% CI 19.6-34.9) vs 19.8 months (95% CI 15.7-29.6)]. The most common post-CDK4/6i treatments were PI3K/mTOR inhibitors (PI3K/mTORi), single-agent ET, or chemotherapy. PFS in the 1L CDK4/6i cohort following PI3K/mTORi was 8.5 months (95% CI 5.5 months-NE), single-agent ET was 6.0 months (95% CI 3.3-14.0 months), and chemotherapy PFS was 5.4 months (95% CI 3.3 months-NE).
CONCLUSIONS: Following progression on a CDK 4/6i, mPFS was short, with similar PFS times comparing chemotherapy and ET, with slightly longer PFS for targeted strategies (PI3K/mTOR). These results highlight a major need to better understand the mechanisms of CDK4/6i resistance and identify new therapeutic strategies for these patients.

Keywords: CDK 4/6 inhibitor; Metastatic breast cancer; PI3K/mTOR inhibitor; Subsequent lines of therapy

DOI: https://doi.org/10.1007/s10549-022-06713-1

J Breast Cancer. 2022 Aug;25(4): 296-306

Time to Chemotherapy for Patients With Estrogen Receptor-Positive Breast Cancer and Cyclin-Dependent Kinase 4 and 6 Inhibitor Use.

Yuka Endo, Akiyo Yoshimura, Masataka Sawaki, Masaya Hattori, Haruru Kotani, Ayumi Kataoka, Nanae Horisawa, Yuri Ozaki, Kazuki Nozawa, Daiki Takatsuka, Ayaka Isogai, Hiroji Iwata.

PURPOSE: Safely postponing the use of chemotherapy is important for quality of life maintenance in patients with hormone receptor-positive advanced breast cancer. In previous studies, a combination of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) and fulvestrant prolonged the time to chemotherapy (TTC). In this study, we used real-world data to evaluate TTC in the context of CDK4/6i therapy.
METHODS: We performed a retrospective chart review of women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treated at the Aichi Cancer Center Hospital. The patients were categorized into having received CDK4/6i therapy first (n = 41), second (n = 33), and none at all (n = 67). The change in TTC among the groups was examined.
RESULTS: The median follow-up time was 13.8, 27.5, and 30.3 months in the CDK4/6i (first), CDK4/6i (second), and non-CDK4/6i groups, respectively. The median progression-free survival (PFS) with first-line therapy for metastasis was 30.0, 11.9, and 13.0 months, respectively (CDK4/6i [first] vs. non-CDK4/6i; p = 0.018, CDK4/6i [second] vs. non-CDK4/6i; p = 0.383). The median TTC was not reached in the CDK4/6i (first) group, was 39.1 months in the CDK4/6i (second) group, and was 44.2 months in the non-CDK4/6i group (CDK4/6i [first] vs. non-CDK4/6i; p = 0.880; CDK4/6i [second] vs. non-CDK4/6i; p = 0.407). The non-CDK4/6i group with TTC ≥ 60 months included more cases of secondary endocrine therapy resistance (p = 0.017), no perioperative chemotherapy (p = 0.021), and a longer disease-free interval (p = 0.093).
CONCLUSION: Although PFS was significantly longer in the CDK4/6i (first) group than in the non-CDK4/6i group, TTC did not significantly differ among the three groups in real-world data. The non-CDK4/6i group showed a long TTC in patients with late recurrence and low risk at the primary lesion site, who benefited greatly from hormone monotherapy.

Keywords: Breast Neoplasms; Cyclin-Dependent Kinases; Neoplasm Metastasis; Receptors, Estrogen

DOI: https://doi.org/10.4048/jbc.2022.25.e34

Int J Mol Med. 2022 Oct;pii: 128. [Epub ahead of print]50(4):

CDK4/6 inhibitor resistance mechanisms and treatment strategies (Review).

Jinyao Huang, Liang Zheng, Zicheng Sun, Jie Li.

In recent years, the incidence rate of breast cancer has increased year by year, and it has become a major threat to the health of women globally. Among all breast cancer subtypes, the hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)‑ luminal subtype breast cancer is the most common form of breast cancer. Cyclin‑dependent kinase 4 and 6 (CDK4/6) inhibitors, the hotspots in the field of targeted therapy for breast cancer, have proved to exhibit a good effect on patients with HR+/HER2‑ breast cancer in a number of clinical trials, but the problem of drug resistance is inevitable. At present, three specific CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) have been approved by the USA Food and Drug Administration for the first‑line treatment of HR+/HER2‑ breast cancer. The drug resistance mechanisms of CDK4/6 inhibitors can be divided into cell cycle‑specific resistance and cell cycle non‑specific resistance. With the discovery of the drug resistance mechanism of CDK4/6 inhibitors, various targeted strategies have been proposed. The present review mainly discusses the mechanism of CDK4/6 inhibitors, drug resistance mechanisms and treatment strategies after resistance.

Keywords: CDK4/6; breast cancer; drug resistance; mechanisms; strategies

DOI: https://doi.org/10.3892/ijmm.2022.5184

Biochim Biophys Acta Mol Cell Res. 2022 Aug 24. pii: S0167-4889(22)00138-0. [Epub ahead of print]1869(12): 119346

Resistance to CDK4/6 inhibition: Mechanisms and strategies to overcome a therapeutic problem in the treatment of hormone receptor-positive metastatic breast cancer.

Marios C Papadimitriou, Anastasia Pazaiti, Konstantinos Iliakopoulos, Mariam Markouli, Vasiliki Michalaki, Christos A Papadimitriou.

Selective CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, have been approved in combination with hormone therapy for the treatment of patients with HR+, HER2-negative advanced or metastatic breast cancer (mBC). Despite their promising activity, approximately 10 % of patients have de novo resistance, while the rest of them will develop acquired resistance after 24-28 months when used as first-line therapy and after a shorter period when used as second-line therapy. Various mechanisms of resistance to CDK4/6 inhibitors have been described, including cell cycle-related mechanisms, such as RB loss, p16 amplification, CDK6 or CDK4 amplification, and cyclin E-CDK2 amplification. Other bypass mechanisms involve the activation of FGFR or PI3K/AKT/mTOR pathways. Identifying the different mechanisms by which resistance to CDK4/6 inhibitors occurs may help to design new treatment strategies to improve patient outcomes. This review presents the currently available knowledge on the mechanisms of resistance to CDK4/6 inhibitors, explores possible treatment strategies that could overcome this therapeutic problem, and summarizes relevant recent clinical trials.

Keywords: CDK4/6 inhibitors; Clinical trials; Endocrine resistance; Hormone receptor-positive; Metastatic breast cancer; Resistance mechanisms

DOI: https://doi.org/10.1016/j.bbamcr.2022.119346

Mol Cancer. 2022 Aug 30. 21(1): 171

S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c-Myc pathway in patients with estrogen receptor-positive breast cancer.

Hongnan Mo, Xuefeng Liu, Yu Xue, Hongyan Chen, Shichao Guo, Zhangfu Li, Shuang Wang, Caiming Li, Jiashu Han, Ming Fu, Yongmei Song, Dan Li, Fei Ma.

BACKGROUND: CDK4/6 inhibitors combined with endocrine therapy has become the preferred treatment approach for patients with estrogen receptor-positive metastatic breast cancer. However, the predictive biomarkers and mechanisms of innate resistance to CDK4/6 inhibitors remain largely unknown. We sought to elucidate the molecular hallmarks and therapeutically actionable features of patients with resistance to CDK4/6 inhibitors.
METHODS: A total of 36 patients received palbociclib and endocrine therapy were included in this study as the discovery cohort. Next-generation sequencing of circulating tumour DNA in these patients was performed to evaluate somatic alterations associated with innate resistance to palbociclib. Then the candidate biomarker was validated in another independent cohort of 104 patients and publicly available datasets. The resistance was verified in parental MCF-7 and T47D cells, as well as their derivatives with small interfering RNA transfection and lentivirus infection. The relevant mechanism was examined by RNA sequencing, chromatin immunoprecipitation and luciferase assay. Patient-derived organoid and patient-derived xenografts studies were utilized to evaluated the antitumor activity of rational combinations.
RESULTS: In the discovery cohort, S6K1 amplification (3/35, 9%) was identified as an important reason for innate resistance to CDK4/6 inhibitors. In the independent cohort, S6K1 was overexpressed in 15/104 (14%) patients. In those who had received palbociclib treatment, patients with high-expressed S6K1 had significantly worse progression free survival than those with low S6K1 expression (hazard ratio = 3.0, P = 0.0072). Meta-analysis of public data revealed that patients with S6K1 amplification accounted for 12% of breast cancers. Breast cancer patients with high S6K1 expression had significantly worse relapse-free survival (hazard ratio = 1.31, P < 0.0001). In breast cancer cells, S6K1 overexpression, caused by gene amplification, was sufficient to promote resistance to palbociclib. Mechanistically, S6K1 overexpression increased the expression levels of G1/S transition-related proteins and the phosphorylation of Rb, mainly through the activation of c-Myc pathway. Notably, this resistance could be abrogated by the addition of mTOR inhibitor, which blocked the upstream of S6K1, in vitro and in vivo.
CONCLUSIONS: S6K1 amplification is an important mechanism of innate resistance to palbociclib in breast cancers. Breast cancers with S6K1 amplification could be considered for combinations of CDK4/6 and S6K1 antagonists.

Keywords: Breast cancer; CDK4/6 inhibitors; Circulating tumour DNA; Drug resistance; S6K1

DOI: https://doi.org/10.1186/s12943-022-01642-5

Genes Cancer. 2022 ;13 21-45

CDK4: a master regulator of the cell cycle and its role in cancer.

Stacey J Baker, Poulikos I Poulikakos, Hanna Y Irie, Samir Parekh, E Premkumar Reddy.

The cell cycle is regulated in part by cyclins and their associated serine/threonine cyclin-dependent kinases, or CDKs. CDK4, in conjunction with the D-type cyclins, mediates progression through the G1 phase when the cell prepares to initiate DNA synthesis. Although Cdk4-null mutant mice are viable and cell proliferation is not significantly affected in vitro due to compensatory roles played by other CDKs, this gene plays a key role in mammalian development and cancer. This review discusses the role that CDK4 plays in cell cycle control, normal development and tumorigenesis as well as the current status and utility of approved small molecule CDK4/6 inhibitors that are currently being used as cancer therapeutics.

Keywords: CDK4/6; cancer; cell cycle; checkpoint inhibitor; targeted therapy

DOI: https://doi.org/10.18632/genesandcancer.221