bims-cyhorp Biomed News
on Cyclin-dependent kinases in hormone receptor positive breast cancer
Issue of 2023–01–15
eight papers selected by
Piotr Okupski,

  1. On-treatment derived neutrophil-to-lymphocyte ratio and survival with palbociclib and endocrine treatment: analysis of a multicenter retrospective cohort and the PALOMA-2/3 study with immune correlates.
  2. Efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, advanced breast cancer: a systematic review and meta-analysis.
  3. Case report: 18F-FES PET/CT predicted treatment responses of second-line and third-line CDK4/6 inhibitors after disease progression on first-line CDK4/6 inhibitor in a HR+/HER2- metastatic breast cancer patient.
  4. Impact of CDK4/6 inhibitors on chemotherapy utilization in earlier therapy lines for HR+/HER2- metastatic breast cancer in the United States.
  5. Adherence to the CDK 4/6 Inhibitor Palbociclib and Omission of Dose Management Supported by Pharmacometric Modelling as Part of the OpTAT Study.
  6. A phase II study of palbociclib plus letrozole plus trastuzumab as neoadjuvant treatment for clinical stages II and III ER+ HER2+ breast cancer (PALTAN).
  7. SETDB1 modulates degradation of phosphorylated RB and anti-cancer efficacy of CDK4/6 inhibitors.
  8. A Phase II Single-arm Study of Palbociclib in Patients With HER2-positive Breast Cancer With Brain Metastases and Analysis of ctDNA in Patients With Active Brain Metastases.
  1. Breast Cancer Res. 2023 Jan 12. 25(1): 4
    On-treatment derived neutrophil-to-lymphocyte ratio and survival with palbociclib and endocrine treatment: analysis of a multicenter retrospective cohort and the PALOMA-2/3 study with immune correlates.
    Chang Gon Kim, Min Hwan Kim, Jee Hung Kim, Seul-Gi Kim, Gun Min Kim, Tae Yeong Kim, Won-Ji Ryu, Jee Ye Kim, Hyung Seok Park, Seho Park, Young Up Cho, Byeong Woo Park, Seung Il Kim, Joon Jeong, Joohyuk Sohn.
       BACKGROUND: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have been established as a standard treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC); however, predictive biomarkers with translational relevance have not yet been elucidated.
    METHODS: Data from postmenopausal women who received the CDK4/6 inhibitor palbociclib and letrozole for HR-positive, HER2-negative ABC from tertiary referral centers were analyzed (N = 221; exploratory cohort). Pre- and on-treatment neutrophil-to-lymphocyte ratio (NLR) and derived NLR (dNLR; neutrophil/[leukocyte-neutrophil]) were correlated with survival outcomes. Data from the PALOMA-2 (NCT01740427) and PALOMA-3 studies (NCT01942135) involving patients treated with endocrine treatment with or without palbociclib were also analyzed (validation cohort). Prospectively enrolled patients (N = 20) were subjected to immunophenotyping with circulating immune cells to explore the biological implications of immune cell dynamics.
    RESULTS: In the exploratory cohort, palbociclib administration significantly reduced leukocyte, neutrophil, and lymphocyte counts on day 1 of cycle 2. Although the baseline dNLR was not significantly associated with progression-free survival (PFS), higher on-treatment dNLRs were associated with worse PFS (hazard ratio = 3.337, P < 0.001). In the PALOMA-2 validation cohort, higher on-treatment dNLRs were associated with inferior PFS in patients treated with palbociclib and letrozole (hazard ratio = 1.498, P = 0.009), and reduction in the dNLR after treatment was predictive of a survival benefit (hazard ratio = 1.555, P = 0.026). On-treatment dNLRs were also predictive of PFS following palbociclib and fulvestrant treatment in the PALOMA-3 validation cohort. Using flow cytometry analysis, we found that the CDK4/6 inhibitor prevented T cell exhaustion and diminished myeloid-derived suppressor cell frequency.
    CONCLUSIONS: On-treatment dNLR significantly predicted PFS in patients with HR-positive, HER2-negative ABC receiving palbociclib and endocrine treatment. Additionally, we observed putative systemic immune responses elicited by palbociclib, suggesting immunologic changes upon CDK4/6 inhibitor treatment.
    Keywords:  Advanced breast cancer; CDK4/6 inhibitor; Neutrophil-to-lymphocyte ratio; Palbociclib
    DOI:  https://doi.org/10.1186/s13058-022-01601-4
  2. Ann Palliat Med. 2022 Dec;11(12): 3727-3742
    Efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, advanced breast cancer: a systematic review and meta-analysis.
    Qiuying Dai, Yongling Wang, Mingjuan Liao, Hongfeng Chen.
       BACKGROUND: In previous studies on the application of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy in advanced breast cancer, the outcomes of overall survival (OS) were inconsistent. This systematic review and meta-analysis aimed to further evaluate the clinical efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy on patients with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer.
    METHODS: Randomized controlled trials (RCTs) comparing CDK4/6 inhibitors plus endocrine therapy and endocrine therapy alone in patients with HR-positive and HER2-negative advanced breast cancer were searched in the databases of PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), WANFANG and China Science and Technology Journal Database (VIP) up to November 2022. Hazard ratios (HRs) and confidence intervals (CI) of OS, progression-free survival (PFS), the time from randomization to the first recorded disease progression while the patient was receiving next-line therapy or death from any cause (PFS2), time to first subsequent chemotherapy after discontinuation (TTC), and objective response rate (ORR), clinical benefit rate (CBR), safety indicators were extracted. Stata 14.0 software was used for meta analysis and the Cochrane risk-of-bias tool 2.0 was used to evaluate the bias risk.
    RESULTS: A total of 9 RCTs with 4,920 participants were included. The addition of CDK4/6 inhibitors to endocrine therapy significantly prolonged OS (HR 0.76; 95% CI: 0.69-0.84; P<0.001), regardless of the application in first-line and second-line treatment, compared with endocrine therapy alone. Similar benefit was observed in PFS (HR 0.56; 95% CI: 0.52-0.60; P<0.001). Moreover, the CDK4/6 inhibitors group improved results of ORR [relative risk (RR) 1.43; 95% CI: 1.27-1.62; P<0.001], CBR (RR 1.24; 95% CI: 1.08-1.41; P<0.01 and RR 1.11; 95% CI: 1.06-1.18; P<0.001), PFS2 (HR 0.68; 95% CI: 0.60-0.76; P<0.001) and TTC (HR 0.65; 95% CI: 0.58-0.72; P<0.001). One of the included RCTs had performance bias. Publication bias was not significant.
    CONCLUSIONS: CDK4/6 inhibitors combined with endocrine therapy effectively prolong OS, PFS, PFS2, and TTC, and also improve ORR and CBR in patients with HR-positive, HER2-negative advanced breast cancer, and the safety was within the controllable range.
    Keywords:  Advanced breast cancer; CDK4/6 inhibitors; endocrine therapy; meta-analysis
    DOI:  https://doi.org/10.21037/apm-22-1306
  3. Front Oncol. 2022 ;12 1095779
    Case report: 18F-FES PET/CT predicted treatment responses of second-line and third-line CDK4/6 inhibitors after disease progression on first-line CDK4/6 inhibitor in a HR+/HER2- metastatic breast cancer patient.
    Bo Pan, Zhixin Hao, Ying Xu, Zhe Wang, Ru Yao, Xuefei Wang, Chao Ren, Yidong Zhou, Qiang Sun, Li Huo.
       Background: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) has become the commonest first-line treatment of hormonal receptor positive and human epidermal growth factor receptor 2 negative (HR+/HER2-) metastatic breast cancer (MBC). However, therapy is quite individualized after progression of disease (PD) when CDK4/6i fails. Estrogen receptor (ER) status of metastatic lesions of bone, lung or liver might be different from the primary tumor and biopsy of metastatic lesions was invasive and not always available. Prediction of treatment response after PD of CDK4/6i remains unsolved. 18F-fluoroestradiol (FES) PET/CT could non-invasively reveal ER expression both in primary and metastatic breast cancer and recognize heterogeneity of ER status.
    Case presentation: A 70-year-old woman with Parkinson's disease, osteoporosis and cardiovascular co-morbidity was diagnosed with HR+/HER2- breast cancer (pT2N2M0, stage IIIa). Three years later, she developed metastases in right lung and pleura with pleural effusion and received palbociclib + letrozole. After 8 months the disease progressed, and 18F-FES PET/CT revealed multiple ER-positive pleural lesions and ER-negative pulmonary nodules after PD and the progression-free survival (PFS) of first-line CDK4/6i was 8 months. Since most of the metastatic lesions were ER-positive, abemaciclib + fulvestrant were chosen as the second-line CDK4/6i treatment and the PFS was 15 months. Another 18F-FES PET/CT showed a new ER-positive pleural mass with multiple ER-negative pulmonary nodules. Since 18F-FES PET/CT revealed that the dominant lesions were still ER-positive, dalpiciclib + exemestane + fulvestrant were prescribed as the third-line CDK4/6i treatment. Currently the patient's disease had been stable for 2 months.
    Conclusion: This case demonstrated that 18F-FES PET/CT could show ER heterogeneity non-invasively and reveal the treatment responses a predictive imaging tool of serial second- and third-line of CDK4/6i treatments when first-line CDK4/6i failed in HR+/HER2- MBC. So long as the dominant or newly-developed metastatic lesion was ER-positive on 18F-FES PET after first-line CDK4/6i, the patient might show certain therapeutic response towards endocrine-based treatment including second- and third-line of CDK4/6i, and thus increased the time to chemotherapy (TTC).
    Keywords:  CDK4/6 inhibitor; FES PET/CT; estrogen receptor (ER); metastatic breast cancer; treatment response
    DOI:  https://doi.org/10.3389/fonc.2022.1095779
  4. Breast Cancer Res Treat. 2023 Jan 07.
    Impact of CDK4/6 inhibitors on chemotherapy utilization in earlier therapy lines for HR+/HER2- metastatic breast cancer in the United States.
    Ravi K Goyal, Holly M Holmes, Hua Chen, Susan Abughosh, Sean D Candrilli, Michael L Johnson.
       PURPOSE: Delaying chemotherapy remains a vital goal in therapeutic management of HR+/HER2- metastatic breast cancer (MBC). However, recent reports continue to highlight substantially high chemotherapy utilization in earlier therapy lines. In this study, we explored the impact of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy class, introduced in 2015, on early chemotherapy utilization in an older population of patients with HR+/HER2- MBC in the United States (US).
    METHODS: Using an interrupted time series design, patients with a confirmed diagnosis of MBC aged ≥ 65 years initiating systemic therapy during 2010-2019 were selected from the SEER-Medicare database. The proportion of chemotherapy use was summarized quarterly based on the date of treatment initiation separately in the first, second, and third lines. Segmented regression models adjusted for autocorrelation over time were fitted to estimate trends before and after the availability of CDK4/6 inhibitors in the first quarter of 2015.
    RESULTS: Of the 3244 eligible women (median age at diagnosis: 74 years), all initiated first-line therapy; 47.9% (n = 1581) initiated second-line therapy, and 50.1% (n = 792) initiated third-line therapy. Overall utilization of chemotherapy (alone or in combination) during the study period was 15.7% for the first line, 19.6% for the second line, and 24.8% for the third line. Chemotherapy utilization in the period immediately after introduction of CDK4/6 inhibitor therapy decline by estimated 2.5% in the first line (P = 0.408), 15.5% in the second line (P = 0.005), and 16.3% in the third line (P = 0.003).
    CONCLUSIONS: This population-based study illustrates that chemotherapy utilization in earlier therapy lines for HR+/HER2- MBC declined steadily between 2010 and 2019. These declines were significantly accelerated by the introduction of CDK4/6 therapy class in 2015, notably in the second- and third-line settings.
    Keywords:  Abemaciclib; CDK4/6 inhibitors; Chemotherapy; Metastatic breast cancer; Palbociclib; Real-world evidence; Ribociclib; SEER-medicare; Treatment trends
    DOI:  https://doi.org/10.1007/s10549-022-06845-4
  5. Cancers (Basel). 2023 Jan 03. pii: 316. [Epub ahead of print]15(1):
    Adherence to the CDK 4/6 Inhibitor Palbociclib and Omission of Dose Management Supported by Pharmacometric Modelling as Part of the OpTAT Study.
    Carole Bandiera, Isabella Locatelli, Perrine Courlet, Evelina Cardoso, Khalil Zaman, Athina Stravodimou, Ana Dolcan, Apostolos Sarivalasis, Jean-Philippe Zurcher, Veronica Aedo-Lopez, Jennifer Dotta-Celio, Solange Peters, Monia Guidi, Anna Dorothea Wagner, Chantal Csajka, Marie P Schneider.
      The cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib is administered orally and cyclically, causing medication adherence challenges. We evaluated components of adherence to palbociclib, its relationship with pharmacokinetics (PK), and drug-induced neutropenia. Patients with metastatic breast cancer (MBC) receiving palbociclib, delivered in electronic monitors (EM), were randomized 1:1 to an intervention and a control group. The intervention was a 12-month interprofessional medication adherence program (IMAP) along with monthly motivational interviews by a pharmacist. Implementation adherence was compared between groups using generalized estimating equation models, in which covariates were included. Model-based palbociclib PK and neutrophil profiles were simulated under real-life implementation scenarios: (1) optimal, (2) 2 doses omitted and caught up at cycle end. At 6 months, implementation was slightly higher and more stable in the intervention (n = 19) than in the control (n = 19) group, 99.2% and 97.3% (Δ1.95%, 95% CI 1.1-2.9%), respectively. The impact of the intervention was larger in patients diagnosed with MBC for &gt;2 years (Δ3.6%, 95% CI 2.1-5.4%), patients who received &gt;4 cycles before inclusion (Δ3.1%, 95% CI 1.7-4.8%) and patients &gt;65 (Δ2.3%, 95% CI 0.8-3.6%). Simulations showed that 25% of patients had neutropenia grade ≥3 during the next cycle in scenario 1 versus 30% in scenario 2. Education and monitoring of patient CDK4/6i cycle management and adherence along with therapeutic drug monitoring can help clinicians improve prescription and decrease toxicity.
    Keywords:  CDK4/6 inhibitor; electronic adherence monitoring; interprofessionality; medication adherence; motivational interviewing; neutropenia; oral anticancer therapy; palbociclib; pharmacists
    DOI:  https://doi.org/10.3390/cancers15010316
  6. NPJ Breast Cancer. 2023 Jan 06. 9(1): 1
    A phase II study of palbociclib plus letrozole plus trastuzumab as neoadjuvant treatment for clinical stages II and III ER+ HER2+ breast cancer (PALTAN).
    Foluso O Ademuyiwa, Donald W Northfelt, Tracey O'Connor, Ellis Levine, Jingqin Luo, Yu Tao, Jeremy Hoog, Marie L Laury, Tracy Summa, Trish Hammerschmidt, Zhanfang Guo, Ashley Frith, Katherine Weilbaecher, Mateusz Opyrchal, Rebecca Aft, Katherine Clifton, Rama Suresh, Nusayba Bagegni, Ian S Hagemann, Michael D Iglesia, Cynthia X Ma.
      Patients with ER+/HER2+ breast cancer (BC) are less likely to achieve pathological complete response (pCR) after chemotherapy with dual HER2 blockade than ER-/HER2+ BC. Endocrine therapy plus trastuzumab is effective in advanced ER+/HER2+ BC. Inhibition of CDK4/6 and HER2 results in synergistic cell proliferation reduction. We combined palbociclib, letrozole, and trastuzumab (PLT) as a chemotherapy-sparing regimen. We evaluated neoadjuvant PLT in early ER+/HER2+ BC. Primary endpoint was pCR after 16 weeks. Research biopsies were performed for whole exome and RNA sequencing, PAM50 subtyping, and Ki67 assessment for complete cell cycle arrest (CCCA: Ki67 ≤ 2.7%). After 26 patients, accrual stopped due to futility. pCR (residual cancer burden-RCB 0) was 7.7%, RCB 0/I was 38.5%. Grade (G) 3/4 treatment-emergent adverse events occurred in 19. Among these, G3/4 neutropenia was 50%, hypertension 26.9%, and leucopenia 7.7%. Analysis indicated CCCA in 85% at C1 day 15 (C1D15), compared to 27% at surgery after palbociclib was discontinued. Baseline PAM50 subtyping identified 31.2% HER2-E, 43.8% Luminal B, and 25% Luminal A. 161 genes were differentially expressed comparing C1D15 to baseline. MKI67, TK1, CCNB1, AURKB, and PLK1 were among the genes downregulated, consistent with CCCA at C1D15. Molecular Signatures Database gene-sets analyses demonstrated downregulated processes involved in proliferation, ER and mTORC1 signaling, and DNA damage repair at C1D15, consistent with the study drug's mechanisms of action. Neoadjuvant PLT showed a pCR of 7.7% and an RCB 0/I rate of 38.5%. RNA sequencing and Ki67 data indicated potent anti-proliferative effects of study treatments. ClinicalTrials.gov- NCT02907918.
    DOI:  https://doi.org/10.1038/s41523-022-00504-z
  7. Cancer Res. 2023 Jan 13. pii: CAN-22-0264. [Epub ahead of print]
    SETDB1 modulates degradation of phosphorylated RB and anti-cancer efficacy of CDK4/6 inhibitors.
    Zhenlin Huang, Xiang Li, Bo Tang, Hao Li, Jianong Zhang, Rui Sun, Jian Ma, Yunqian Pan, Binyuan Yan, Yingke Zhou, Dongling Ding, Yuqian Yan, Rafael Jimenez, Jacob J Orme, Xin Jin, Jinjian Yang, Haojie Huang, Zhankui Jia.
      Retinoblastoma (RB) protein can exert tumor suppressor functions even when it becomes phosphorylated. It is thus essential to understand how phosphorylated RB (p-RB) expression and function are regulated. Here we demonstrated that RING finger domain protein TRIM28 bound and promoted ubiquitination and degradation of CDK4/6-phosphorylated RB protein. SETDB1, a known TRIM28 binding partner, protected p-RB from degradation through the binding of methylated RB by its Tudor domain independent of its methyltransferase activity. SETDB1 was found to be frequently overexpressed due to gene amplification and positively correlated with p-RB in prostate cancer patient specimens. Inhibition of SETDB1 expression using a gene-specific antisense oligonucleotide (ASO) reduced tumor growth but accelerated RB protein degradation, limiting the therapeutic efficacy. However, co-administration of CDK4/6 inhibitor palbociclib blocked ASO-induced RB degradation and resulted in a much greater cancer-inhibitory effect than each inhibitor alone both in vitro and in vivo. This study identified CDK4/6-dependent, TRIM28-mediated proteasomal degradation as a mechanism of RB inactivation and reveals SETDB1 as a key inhibitor of this process. Our findings suggest that combined targeting of SETDB1 and CDK4/6 represents a viable approach for treatment of cancers with SETDB1 gene amplification or overexpression.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0264
  8. Clin Breast Cancer. 2022 Dec 15. pii: S1526-8209(22)00283-X. [Epub ahead of print]
    A Phase II Single-arm Study of Palbociclib in Patients With HER2-positive Breast Cancer With Brain Metastases and Analysis of ctDNA in Patients With Active Brain Metastases.
    Ami N Shah, Cesar A Santa-Maria, Dhruvika Mukhija, Nikita Shah, Anthony K Kang, Priya Kumthekar, Kirsten Burdett, Shruti Chandra, Jenny Chang, Dean Tsarwhas, Jill Woodman, Borko Jovanovic, Lorenzo Gerratana, William Gradishar, Massimo Cristofanilli.
       INTRODUCTION: Palbociclib is highly efficacious and well tolerated in hormone-receptor positive (HR+) metastatic breast cancer (BC) but its activity for HER2+ BC with brain metastases (BM) is unknown.
    METHODS: In a single-arm phase II study we evaluated palbociclib with trastuzumab for patients with HER2+ MBC and BM. The primary endpoint was BM response rate. Circulating tumor DNA (ctDNA) was evaluated at baseline, and in a subset of patients at cycle 3 and progression. We also retrospectively identified additional patients with metastatic BC, active BM, and a ctDNA assessment prior to therapy for BM.
    RESULTS: Twelve patients with HER2+ MBC were enrolled, 4 with HR+ and 8 with HR- disease. No responses were seen. Best response was stable disease for 6 patients and progressive disease for 6 patients. The median PFS was 2.2 months, interquartile range (IQR) was 1.56 to 3.63 months. The median OS was 13.1 months and IQR was 9.4 to 23.8 months The CNS was the primary site of progression for all patients. The median variant allele fraction (VAF) of the dominant variant in each patient was 0.18% (interquartile range [IQR] 0.12%-0.47%) with a median number of somatic alterations of 1. We additionally evaluated ctDNA results from 26 patients with BC and active BM, among whom the median VAF was 11.8% (IQR 3.9%-27.3%) with a median number of alterations was 6 (IQR 4-9). Notably, progressive systemic disease was significantly less frequent in the trial cohort compared with additional retrospectively identified patients (8% vs. 81%).
    CONCLUSION: Palbociclib did not demonstrate activity in HER2+ MBC with BM. Patients with progressive BM but stable, responding, or absent systemic disease have low VAF and number of alterations detected by ctDNA analysis from blood.
    Keywords:  CDK4/6i; CNS metastases; Liquid biopsy; Metastatic breast cancer
    DOI:  https://doi.org/10.1016/j.clbc.2022.12.006
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