bims-cyhorp 2022-03-06 papers

bims-cyhorp

Biomed News

on Cyclin-dependent kinases in hormone receptor positive breast cancer

Issue of 2022‒03‒06
eight papers selected by
Piotr Okupski,

The Role of the CDK4/6 Inhibitor Ribociclib in Locally Advanced and Oligometastatic Hormone Receptor Positive, Her2 Negative, Advanced Breast Cancer: Case Series and Review of the Literature.
Abemaciclib in Combination With Endocrine Therapy for Patients With Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: A Phase 1b Study.
Interstitial lung disease in patients treated with Cyclin-Dependent Kinase 4/6 inhibitors: A systematic review and meta-analysis of randomized controlled trials.
Cyclin-Dependent Kinase 4/6 Inhibitor Outcomes in Patients With Advanced Breast Cancer Carrying Germline Pathogenic Variants in DNA Repair-Related Genes.
Cyclin dependent kinase 4/6 inhibitors in early breast cancer: what is the role of Ki-67?
Clonal Evolution in Patients with Hormone Receptor (HR) Positive, HER-2 Negative Breast Cancer Treated with Chemotherapy or CDK4/6 Inhibitors.
Randomised, open-label, multicentric phase III trial to evaluate the safety and efficacy of palbociclib in combination with endocrine therapy, guided by ESR1 mutation monitoring in oestrogen receptor-positive, HER2-negative metastatic breast cancer patients: study design of PADA-1.
CDK/cyclin dependencies define extreme cancer cell-cycle heterogeneity and collateral vulnerabilities.

Front Oncol. 2022 ;12 797157

The Role of the CDK4/6 Inhibitor Ribociclib in Locally Advanced and Oligometastatic Hormone Receptor Positive, Her2 Negative, Advanced Breast Cancer: Case Series and Review of the Literature.

Andrea Botticelli, Agnese Fabbri, Michela Roberto, Daniele Alesini, Alessio Cirillo, Giuliana D'Auria, Eriseld Krasniqi, Eleonora Marrucci, Margherita Muratore, Francesco Pantano, Laura Pizzuti, Ilaria Portarena, Rosalina Rossi, Simone Scagnoli, Paolo Marchetti.

  The recent addition of cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors to endocrine therapy has remarkably improved the outcome of patients affected with hormone receptor positive (HR+), human epidermal grow factor receptor 2 negative (HER2 -) advanced breast cancer (ABC). Ribociclib showed to be effective across most subgroups, regardless of the number and the site of metastasis. Up to 10% of patients with ABC, reported an oligometastatic condition, recently defined as a slow-volume metastatic disease with limited number and size of metastatic lesions (up to 5 and not necessarily in the same organ), potentially amenable for local treatment, aimed at achieving a complete remission status. Despite the wide use of CDK4/6 inhibitors in HR+, HER2-, ABC treatment, data regarding both locally advanced, inoperable disease and oligometastatic conditions are still poor. We reported a review and case series of HR+, HER2-, ABC patients treated with ribociclib as first-line therapy, for a locally advanced and oligometastatic conditions, reporting an impressive response and good safety profile.

Keywords:  CDK4/6 inhibitor; case report; locally advanced breast cancer (LABC); oligometastatic; ribociclib

DOI:  https://doi.org/10.3389/fonc.2022.797157
Front Oncol. 2021 ;11 810023

Abemaciclib in Combination With Endocrine Therapy for Patients With Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: A Phase 1b Study.

Sara M Tolaney, Muralidhar Beeram, J Thaddeus Beck, Alison Conlin, E Claire Dees, Shannon L Puhalla, Brent N Rexer, Howard A Burris, Komal Jhaveri, Teresa Helsten, Carlos Becerra, Kevin Kalinsky, Kathleen N Moore, Allison M Manuel, Andrew Lithio, Gregory L Price, Sonya C Chapman, Lacey M Litchfield, Matthew P Goetz.

  Background: Cyclin-dependent kinases (CDK) 4 and 6 regulate G1 to S cell cycle progression and are often altered in cancers. Abemaciclib is a selective inhibitor of CDK4 and CDK6 approved for administration on a continuous dosing schedule as monotherapy or as combination therapy with an aromatase inhibitor or fulvestrant in patients with advanced or metastatic breast cancer. This Phase 1b study evaluated the safety and tolerability, pharmacokinetics, and antitumor activity of abemaciclib in combination with endocrine therapy for metastatic breast cancer (MBC), including aromatase inhibitors (letrozole, anastrozole, or exemestane) or tamoxifen.Patients and Methods: Women ≥18 years old with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) MBC were eligible for enrollment. Eligibility included measurable disease or non-measurable but evaluable bone disease by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, Eastern Cooperative Oncology Group performance status 0-1, and no prior chemotherapy for metastatic disease. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 and tumor response were assessed by RECIST v1.1.
Results: Sixty-seven patients were enrolled and received abemaciclib 200 mg every 12 hours in combination with letrozole (Part A, n=20), anastrozole (Part B, n=16), tamoxifen (Part C, n=16), or exemestane (Part D, n=15). The most common treatment-emergent adverse events (TEAE) were diarrhea, fatigue, nausea, and abdominal pain. Grade 4 TEAEs were reported in five patients (one each with hyperglycemia, hypertension, neutropenia, procedural hemorrhage, and sepsis). There was no effect of abemaciclib or endocrine therapy on the pharmacokinetics of any combination study drug. Across all treated patients, the median progression-free survival was 25.4 months (95% confidence interval: 18.0, 35.8). The objective response rate was 38.9% in 36 patients with measurable disease.
Conclusions: Abemaciclib in combination with multiple endocrine therapy options exhibited manageable safety and promising antitumor activity in patients with HR+, HER2- MBC.
Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT02057133.

Keywords:  CDK4; CDK6; abemaciclib; endocrine therapy; metastatic breast cancer

DOI:  https://doi.org/10.3389/fonc.2021.810023
Breast. 2022 Feb 22. pii: S0960-9776(22)00038-8. [Epub ahead of print]62 162-169

Interstitial lung disease in patients treated with Cyclin-Dependent Kinase 4/6 inhibitors: A systematic review and meta-analysis of randomized controlled trials.

Yi Zhang, Zhuo Ma, Ximu Sun, Xin Feng, Zhuoling An.

  BACKGROUND: Cyclin-Dependent Kinase (CDK) 4/6 inhibitors have shown significant clinical activity in cancer patients. However, some concerns regarding rare adverse events (AEs) have occurred including interstitial lung disease (ILD)/pneumonitis, for which data are deficient. The aim of this study was to evaluate the overall incidence and risk of ILD/pneumonitis related to CDK4/6 inhibitors in randomized controlled trials (RCTs).METHODS: Electronic databases and ClinicalTrials.gov were searched from inception to October 1, 2021 for RCTs reporting the occurrence of LD/pneumonitis in cancer patients treated with CDK4/6 inhibitors. Peto odds ratios (Peto ORs) and 95% confidence intervals (CIs) were used to pool the study.
RESULTS: 12 RCTs with a total of 16,060 patients were eligible. The overall incidence of all-grade ILD/pneumonitis was 1.6% (131/8407) in the treatment group compared with 0.7% (50/7349) in the control group. CDK4/6 inhibitors significantly increased the risk of all-grade ILD/pneumonitis with a pooled Peto OR of 2.12 (95% CI [1.57, 2.86], P < 0.00001) with no heterogeneity (I2 = 0%, χ2 P = 0.98). A higher incidence of grade 3 or higher ILD/pneumonitis was also observed in the treatment group (0.2%, 16/7087) compared with the control group (0.05%, 3/6617) with a Peto OR of 3.22 (95% CI [1.28, 8.09], P = 0.01) with no heterogeneity (I2 = 0%, χ2 P = 0.62). Two grade 5 pneumonitis were reported in the included studies. Subgroup analyses did not show any significant difference.
CONCLUSIONS: The risk of all-grade and grade 3 or higher ILD/pneumonitis was higher in patients treated with CDK4/6 inhibitors compared to controls. The awareness for these rare AEs in the application of CDK4/6 inhibitors should be enhanced. Further studies are required to validate the mechanisms and the risk factors of ILD/pneumonitis with CDK4/6 inhibitors.

Keywords:  Cyclin-dependent kinase (CDK) 4/6 inhibitors; ILD; Meta-analysis; Pneumonitis; Randomized controlled trials

DOI:  https://doi.org/10.1016/j.breast.2022.02.011
JCO Precis Oncol. 2022 Mar;6 e2100140

Cyclin-Dependent Kinase 4/6 Inhibitor Outcomes in Patients With Advanced Breast Cancer Carrying Germline Pathogenic Variants in DNA Repair-Related Genes.

Luisina Bruno, Alexis Ostinelli, Federico Waisberg, Diego Enrico, Carolina Ponce, Sergio Rivero, Albano Blanco, Martín Zarba, Martín Loza, Verónica Fabiano, Mora Amat, María Teresa Pombo, Laura Noro, Matías Chacón, Federico Coló, Reinaldo Chacón, Jorge Nadal, Adrián Nervo, Victoria Costanzo.

PURPOSE: In recent years, unprecedented benefits have been observed with the development of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. However, there is scarce evidence of their value in specific populations, such as patients carrying germline pathogenic variants in DNA repair-related genes.PATIENTS AND METHODS: We retrospectively studied the efficacy of CDK 4/6 inhibitors plus endocrine therapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Three cohorts were compared, including patients harboring germline pathogenic variants in DNA repair-related genes (gBRCA1/2-ATM-CHEK2 mutated), those tested without these mutations (wild type [WT]), and the nontested subgroup. Relevant prognostic factors including age, metastatic site (visceral v nonvisceral), Eastern Cooperative Oncology Group, and prior treatment with CDK 4/6 inhibitors were stratified by univariate and multivariate Cox regression models.
RESULTS: Among the total population (n = 217), 15 (6.9%) patients carried gBRCA1/2 (n = 10)-ATM (n = 4)-CHEK2 (n = 1) pathogenic variants, 45 (20.7%) were WT, and 157 (72.4%) were nontested. Gene pathogenic variant carriers were younger (P < .001). Most patients (164, 75.6%) had not received prior endocrine therapy in the advanced setting. Median progression-free survival was shorter in patients with evaluated germline pathogenic variants (10.2 months [95% CI, 5.7 to 14.7]), compared with WT and nontested patients (15.6 months [95% CI, 7.8 to 23.4], and (17.6 months [95% CI, 12.9 to 22.2]; P = .002). Consistently, a worse median overall survival was observed in the subgroup with germline pathogenic variants than in the WT group (P = .006). Multivariable analysis showed that mutation status was an independent prognostic factor of progression-free survival (P = .020) and overall survival (P = .012).
CONCLUSION: In this retrospective real-world study, gBRCA1/2-ATM-CHEK2 pathogenic variants were independently associated with poor outcomes in patients with advanced breast cancer treated with CDK4/6 inhibitors.

DOI: https://doi.org/10.1200/PO.21.00140
Lancet Oncol. 2022 03;pii: S1470-2045(21)00756-7. [Epub ahead of print]23(3): 325-328

Cyclin dependent kinase 4/6 inhibitors in early breast cancer: what is the role of Ki-67?

Gabriele Antonarelli, Carmine Valenza, Erica L Mayer, Sibylle Loibl, Giuseppe Curigliano.

DOI: https://doi.org/10.1016/S1470-2045(21)00756-7
Oncol Res Treat. 2022 Feb 25.

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

Thomas Decker, Matthias Bichler, Andrea Birtel, Gerhard Fischer, Kathrin Geiger, Stella Gaenger, Christoph Nonnenbroich, Tobias Dechow, Axel Muendlein.

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.

DOI: https://doi.org/10.1159/000523758
BMJ Open. 2022 Mar 03. 12(3): e055821

Randomised, open-label, multicentric phase III trial to evaluate the safety and efficacy of palbociclib in combination with endocrine therapy, guided by ESR1 mutation monitoring in oestrogen receptor-positive, HER2-negative metastatic breast cancer patients: study design of PADA-1.

PADA-1 investigators

  INTRODUCTION: The combination of a CDK4/6 inhibitor with an aromatase inhibitor (AI) has recently become the gold standard for AI-sensitive first line treatment of oestrogen receptor-positive (ER+) HER2-negative (HER2-) advanced breast cancer. However, most patients receiving this combination will ultimately progress and require further therapies.Several studies have demonstrated that the onset of a ESR1 gene mutation lead to AIs resistance in the advanced setting. ESR1 mutations can be detected in circulating tumour DNA (ctDNA) using a digital PCR assay. Our study aims to prove the clinical efficacy of periodic monitoring for emerging or rise of ESR1 mutations in ctDNA to trigger an early change from AI plus palbociclib to fulvestrant plus palbociclib treatment while assessing global safety.METHODS: PADA-1 is a randomised, open-label, multicentric, phase III trial conducted in patients receiving AI and palbociclib as first line therapy for metastatic ER +HER2- breast cancer. 1000 patients will be included and treated with palbociclib in combination with an AI. Patients will be screened for circulating blood ESR1 mutation detection at regular intervals. Patients for whom a rising circulating ESR1 mutation is detected without tumour progression (up to N=200) will be randomised (1:1) between (1) Arm A: no modification of therapy; and (2) Arm B: palbociclib in combination with fulvestrant, a selective ER down-regulator. At tumour progression, an optional crossover will be offered to patients randomised in arm A. The coprimary endpoints are (1) Grade ≥3 haematological toxicities and their associations with baseline characteristics and (2) progression-free survival in randomised patients.
ETHICS AND DISSEMINATION: The study has been approved by the French medicines agency (ANSM) and by an ethics committee (ref 01/17_1 CPP Ouest-IV Nantes) in January 2017. The trial results will be published in academic conference presentations and international peer-reviewed journals.
TRIAL REGISTRATION NUMBERS: EudraCT: 2016-004360-18; NCT03079011.

Keywords:  breast tumours; clinical trials; oncology

DOI:  https://doi.org/10.1136/bmjopen-2021-055821
Cell Rep. 2022 Mar 01. pii: S2211-1247(22)00175-9. [Epub ahead of print]38(9): 110448

CDK/cyclin dependencies define extreme cancer cell-cycle heterogeneity and collateral vulnerabilities.

Erik S Knudsen, Vishnu Kumarasamy, Ram Nambiar, Joel D Pearson, Paris Vail, Hanna Rosenheck, Jianxin Wang, Kevin Eng, Rod Bremner, Daniel Schramek, Seth M Rubin, Alana L Welm, Agnieszka K Witkiewicz.

  Progression through G1/S phase of the cell cycle is coordinated by cyclin-dependent kinase (CDK) activities. Here, we find that the requirement for different CDK activities and cyclins in driving cancer cell cycles is highly heterogeneous. The differential gene requirements associate with tumor origin and genetic alterations. We define multiple mechanisms for G1/S progression in RB-proficient models, which are CDK4/6 independent and elicit resistance to FDA-approved inhibitors. Conversely, RB-deficient models are intrinsically CDK4/6 independent, but exhibit differential requirements for cyclin E. These dependencies for CDK and cyclins associate with gene expression programs that denote intrinsically different cell-cycle states. Mining therapeutic sensitivities shows that there are reciprocal vulnerabilities associated with RB1 or CCND1 expression versus CCNE1 or CDKN2A. Together, these findings illustrate the complex nature of cancer cell cycles and the relevance for precision therapeutic intervention.

Keywords:  CDK; E2F; RB; cyclin; cyclin D1; cyclin E; p16; p27

DOI:  https://doi.org/10.1016/j.celrep.2022.110448