bims-cyhorp 2023-01-29 papers

Issue of 2023‒01‒29
six papers selected by
Piotr Okupski

Front Oncol. 2022 ;12 1022913

Hormone receptor-positive, HER2-negative, metastatic breast cancer responded well to abemaciclib and exemestane after palbociclib and fulvestrant failure: A case report and literature review.

Yan Mao, Meng Lv, Yongmei Wang, Weihong Cao, Wenfeng Li.

There is uncertainty regarding the usefulness of CDK4/6-inhibitor-based therapy for hormone receptor positive (HR+), human epidermal grow factor receptor 2 negative (HER2-), metastatic breast cancer (MBC), when CDK4/6 inhibitor treatment had previously failed. Furthermore, a biomarker for abemaciclib resistance has not been identified. Herein, we reported outcomes for an HR+/HER2- MBC patient diagnosed with multiple myeloma and treated with abemaciclib and exemestane, who had cancer progression after treatment with palbociclib and fulvestrant. Thalidomide was used in conjunction with all treatments. The patient had a good response to abemaciclib and exemestane, with progression-free survival much longer than previously reported. PIK3CA and TP53 mutations were identified after cancer progression following abemaciclib treatment. It is unclear whether thalidomide increased the effectiveness of abemaciclib. Whether benefit can be derived by the use of PI3K inhibitors, after cancer progression, requires further investigation, and this may be best accomplished by the use of next-generation sequencing.

Keywords: CDK4/6 inhibitor; abemaciclib; breast cancer; case report; metastatic

DOI: https://doi.org/10.3389/fonc.2022.1022913

J Thromb Haemost. 2022 Dec 22. pii: S1538-7836(22)07823-0. [Epub ahead of print]

Cyclin-dependent kinase 4/6 inhibitor-associated thromboembolism: a critical evaluation of the current evidence.

Nathan W Watson, Joseph J Shatzel, Hanny Al-Samkari.

Cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors are an essential treatment modality for hormone receptor-positive breast cancer. As the rates of breast cancer continue to rise globally and the indications for CDK 4/6 inhibitors now extend beyond metastatic disease, more patients than ever are receiving these agents. Thrombosis is an emerging clinical concern with this class of agents, particularly venous thromboembolism. Although venous thromboembolism initially emerged as an adverse effect of interest in early trials, more recent studies have demonstrated even higher incidences of thrombosis in real-world clinical practice. In this review, we summarize the evidence to date that has informed the thrombosis risk for these agents both in clinical trials and real-world studies. We review data describing the venous and arterial thromboembolic risks in clinical trials of CDK 4/6 inhibitors as well as the now rather extensive real-world evidence available, including a comparison of risk for each of the 3 agents approved for use in breast cancer: palcociclib, ribociclib, and abemaciclib. As the role of prophylactic anticoagulation continues to remain unknown in women receiving CDK 4/6 inhibitors, future efforts directed at carefully investigating the risks and benefits of thromboprophylaxis may lead to improved outcomes in these patients.

Keywords: breast cancer; cardiovascular diseases; thromboembolism; thrombosis; venous thromboembolism

DOI: https://doi.org/10.1016/j.jtha.2022.12.001

Endokrynol Pol. 2023 Jan 27.

The effect and safety of CDK4/6 inhibitors combined endocrine therapy on HR+, HER2-breast cancer: a meta-analysis of randomized controlled trials.

Tongmin Huang, Yujing He, Chiyuan Yu, Feiyan Mao, Yuexiu Si.

INTRODUCTION: The purpose of this meta-analysis is to evaluate the efficacy and safety of cyclin-dependent kinase4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) on hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC).MATERIAL AND METHODS: A search was conducted in the PubMed, Embase, Web of Science, and Cochrane Library databases before July 2022.
RESULTS: A total of 19 studies comprising 19,004 patients were eligible for this meta-analysis. This meta-analysis found that for unresectable locally advanced or metastatic HR+, HER2- BC, CDK4/6i combined with ET can significantly improve the progression-free survival (PFS) (hazard ratio = 0.59, p < 0.001), overall survival (OS) (hazard ratio = 0.77, p < 0.001), objective response rate (ORR) [risk ratio (RR) = 1.32, p = 0.001)], disease control rate (DCR) (RR = 1.10, p < 0.001), and clinical benefit response (CBR) (RR = 1.15, p = 0.001). For early HR+, HER2- BC, CDK4/6i combined with ET improved ORR (RR = 1.14, p = 0.05) and invasive disease free survival (iDFS) (hazard ratio = 0.87, p = 0.045) but had no effect on pathologic complete response (pCR) (RR = 1.75, p = 0.33), distant recurrence free survival (DRFS) (hazard ratio = 0.83, p = 0.311), and OS (hazard ratio = 1.08, p = 0.705).
CONCLUSION: CDK4/6i combined with ET can improve the prognosis of patients with unresectable locally advanced or metastatic HR+, HER2- BC, but it has no obvious effect on patients with early HR+, HER2- BC. It is generally safe and manageable.

Keywords: breast cancer; cyclin-dependent kinase4/6 inhibitors; endocrine therapy; hormone receptor-positive; human epidermal growth factor receptor 2-negative; meta-analysis

DOI: https://doi.org/10.5603/EP.a2023.0007

Clin Cancer Res. 2023 Jan 24. pii: CCR-22-2177. [Epub ahead of print]

Genomic complexity predicts resistance to endocrine therapy and CDK4/6 inhibition in hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer.

PURPOSE: Clinical biomarkers to identify patients unlikely to benefit from CDK4/6 inhibition (CDK4/6i) in combination with endocrine therapy (ET) are lacking. We implemented a comprehensive circulating tumor DNA (ctDNA) analysis to identify genomic features for predicting and monitoring treatment resistance.EXPERIMENTAL DESIGN: ctDNA was isolated from 216 plasma samples collected from 51 patients with hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) on a phase II trial of palbociclib combined with letrozole or fulvestrant (NCT03007979). Boosted whole exome sequencing (WES) was performed at baseline and clinical progression to evaluate genomic alterations, mutational signatures, and blood tumor mutational burden (bTMB). Low-pass whole-genome sequencing was performed at baseline and serial timepoints to assess blood copy number burden (bCNB).
RESULTS: High bTMB and bCNB were associated with lack of clinical benefit and significantly shorter progression-free survival (PFS) compared to patients with low bTMB or low bCNB (all P<0.05). Dominant APOBEC signatures were detected at baseline exclusively in cases with high bTMB (5/13, 38.5%) vs. low bTMB (0/37, 0%) (P=0.0006). Alterations in ESR1 were enriched in samples with high bTMB (P=0.0005). There was a high correlation between bTMB determined by WES and bTMB determined using a 600-gene panel (R=0.98). During serial monitoring, an increase in bCNB scores preceded radiographic progression in 12/18 (66.7%) patients.
CONCLUSIONS: Genomic complexity detected by non-invasive profiling of bTMB and bCNB predicted poor outcomes in patients treated with ET and CDK4/6i and identified early disease progression before imaging. Novel treatment strategies including immunotherapy-based combinations should be investigated in this population.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-2177

J Exp Med. 2023 Apr 03. pii: e20220729. [Epub ahead of print]220(4):

PD-1 blockade and CDK4/6 inhibition augment nonoverlapping features of T cell activation in cancer.

Lestat R Ali, Ana C Garrido-Castro, Patrick J Lenehan, Naima Bollenrucher, Courtney T Stump, Michael Dougan, Shom Goel, Geoffrey I Shapiro, Sara M Tolaney, Stephanie K Dougan.

We performed single-cell RNA-sequencing and T cell receptor clonotype tracking of breast and ovarian cancer patients treated with the CDK4/6 inhibitor ribociclib and PD-1 blockade. We highlight evidence of two orthogonal treatment-associated phenomena: expansion of T cell effector populations and promotion of T cell memory formation. Augmentation of the antitumor memory pool by ribociclib boosts the efficacy of subsequent PD-1 blockade in mouse models of melanoma and breast cancer, pointing toward sequential therapy as a potentially safe and synergistic strategy in patients.

DOI: https://doi.org/10.1084/jem.20220729

RSC Adv. 2023 Jan 06. 13(3): 1617-1626

Carrier-free nanomedicines self-assembled from palbociclib dimers and Ce6 for enhanced combined chemo-photodynamic therapy of breast cancer.

Zheng Huang, Huaisong Hu, Tong Xian, Zhigang Xu, Dianyong Tang, Bochu Wang, Yimei Zhang.

Palbociclib is the world's first CDK4/6 kinase inhibitor to be marketed. However, it is not effective in the treatment of triple negative breast cancer (TNBC) due to the loss of retinoblastoma protein expression. Thus, combinatorial chemotherapy is indispensable for TNBC treatment. Herein, a carrier-free nanomedicine self-assembled from palbociclib dimers and Ce6 for enhanced combined chemo-photodynamic therapy of breast cancer is reported. The dimeric prodrug (Palb-TK-Palb) was synthesized by conjugating two palbociclib molecules to the connecting skeleton containing a ROS-responsive cleavable thioketal bond. The Palb-TK-Palb/Ce6 NP co-delivery nanoplatform was prepared through the self-assembly of Palb-TK-Palb, Ce6 and DSPE-PEG2000. This novel carrier-free formulation as an efficient therapeutic agent showed efficient therapeutic agent loading capacity, high cellular uptake and huge therapeutic performance against breast cancer cells. The results of in vitro antitumor activity and cell apoptosis demonstrated that Palb-TK-Palb/Ce6 NPs presented a better inhibitory effect on the growth of cancer cells due to the palbociclib and Ce6 co-delivery nanomedicine-mediated synergistic chemo-photodynamic therapy. The IC50 values of Palb-TK-Palb/Ce6 NPs in MDA-MB-231 cells were around 1-2 μM and 2 μM and the Palb-TK-Palb/Ce6 NPs showed an increase in apoptosis up to 91.9%. In general, the carrier-free nanomedicine self-assembled from palbociclib dimers and Ce6 provides options for combinatorial chemo-photodynamic therapy.

DOI: https://doi.org/10.1039/d2ra05932k