bims-cyhorp Biomed News
on Cyclin-dependent kinases in hormone receptor positive breast cancer
Issue of 2022–02–27
six papers selected by
Piotr Okupski,

  1. PALVEN: phase 1b trial of palbociclib, letrozole and venetoclax in estrogen receptor- and BCL2-positive advanced breast cancer.
  2. Ribociclib plus letrozole in male patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: subgroup analysis of the phase IIIb CompLEEment-1 trial.
  3. Real-World Treatment Patterns and Clinical Effectiveness of Palbociclib Plus an Aromatase Inhibitor as First-Line Therapy in Advanced/Metastatic Breast Cancer: Analysis from the US Syapse Learning Health Network.
  4. Serial circulating tumor DNA monitoring of CDK4/6 inhibitors response in metastatic breast cancer.
  5. Real-world effectiveness of palbociclib plus fulvestrant in advanced breast cancer: Results from a population-based cohort study.
  6. Inhibition of Cytochrome P450 Enzyme and Drug‑Drug Interaction Potential of Acid Reducing Agents Used in Management of CDK inhibitors for Breast Cancer Chemotherapy.
  1. Future Oncol. 2022 Feb 21.
    PALVEN: phase 1b trial of palbociclib, letrozole and venetoclax in estrogen receptor- and BCL2-positive advanced breast cancer.
    Christine Muttiah, James R Whittle, Catherine Oakman, Geoffrey J Lindeman.
      The addition of a CDK4/6 inhibitor to endocrine therapy improves progression-free and overall survival in women with metastatic estrogen receptor-positive breast cancer. In that setting, CDK4/6 inhibitors induce a potent cell-cycle arrest (which may be accompanied by tumor senescence) but fail to induce apoptotic cell death. Venetoclax is a potent inhibitor of BCL2, a pro-survival protein overexpressed in the majority of estrogen receptor-positive cancers. Pre-clinical findings indicate that venetoclax augments tumor response to the CDK4/6 inhibitor palbociclib by triggering apoptosis, including in senescent cells. The PALVEN phase 1b trial will further examine this finding. The primary objective is to identify the maximum tolerated dose and determine the recommended phase 2 dose for palbociclib, letrozole and venetoclax combination therapy. Clinical Trial Registration: NCT03900884 (ClinicalTrials.gov).
    Keywords:  BCL-XL; BCL2; BH3 mimetic; CDK4/6 inhibitor; apoptosis; breast cancer; estrogen receptor; senescence; senolysis; venetoclax
    DOI:  https://doi.org/10.2217/fon-2021-1450
  2. Breast Cancer Res Treat. 2022 Feb 25.
    Ribociclib plus letrozole in male patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: subgroup analysis of the phase IIIb CompLEEment-1 trial.
    Mario Campone, Michelino De Laurentiis, Claudio Zamagni, Igor Kudryavcev, Mariëtte Agterof, Ursa Brown-Glaberman, Markéta Palácová, Sanjoy Chatterjee, Lakshmi Menon-Singh, Jiwen Wu, Miguel Martín.
       PURPOSE: CompLEEment-1 (NCT02941926) is a single-arm, open-label, multicentre phase IIIb study investigating the safety and efficacy of ribociclib plus letrozole (RIB + LET) in a large, diverse cohort who have not received prior endocrine therapy (ET) for advanced disease. We present an exploratory analysis of male patients.
    METHODS: Eligible patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), who had no prior ET and ≤ 1 line of prior chemotherapy for advanced disease, received RIB + LET. Male patients also received goserelin or leuprolide. Primary endpoint was safety and tolerability; efficacy was a secondary endpoint.
    RESULTS: In total, 39/3246 patients were male. Baseline characteristics were similar to the overall population. Male patients experienced fewer treatment-related adverse events (AEs) and treatment-related serious AEs compared with the overall population; fewer male patients had treatment-related AEs leading to discontinuation, adjustment/interruption, or additional therapy. One male patient died as a result of a serious AE that was not considered to be treatment-related. The most common AE was neutropenia; the incidence of grade ≥ 3 neutropenia in males (41.0%) was lower than in the overall population (57.2%). Median follow-up was 25.4 months; median time to progression was not reached in males versus 27.1 months for the overall population.
    CONCLUSION: The clinical benefit and overall response rates in males were consistent with the overall population. This analysis demonstrates the safety and efficacy of ribociclib in a close-to-real-world setting, supporting the use of RIB + LET in male patients with HR+, HER2- ABC.
    TRIAL REGISTRATION NUMBER: NCT02941926 (Registered 2016).
    Keywords:  Advanced breast cancer; Male breast cancer; Men; Real-world evidence; Ribociclib
    DOI:  https://doi.org/10.1007/s10549-022-06543-1
  3. Curr Oncol. 2022 Feb 12. 29(2): 1047-1061
    Real-World Treatment Patterns and Clinical Effectiveness of Palbociclib Plus an Aromatase Inhibitor as First-Line Therapy in Advanced/Metastatic Breast Cancer: Analysis from the US Syapse Learning Health Network.
    Jeanna Wallenta Law, Debanjali Mitra, Henry G Kaplan, Tamuno Alfred, Adam M Brufsky, Birol Emir, Haley McCracken, Xianchen Liu, Ronda G Broome, Chenan Zhang, Caroline DiCristo, Connie Chen.
      This retrospective single-arm study assessed real-world treatment patterns and clinical outcomes in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced/metastatic breast cancer (A/MBC) who received palbociclib plus an aromatase inhibitor as first-line therapy in US community health systems. Using electronic health records from the Syapse Learning Health Network, 242 patients were identified as having received first-line palbociclib plus an aromatase inhibitor between 3 February 2015, and 31 July 2019 (data cutoff 1 February 2020) resulting in a minimum potential 6-month follow-up period. In total, 56.6% of patients had de novo A/MBC at initial breast cancer diagnosis, 50.8% had bone-only disease, and 32.2% had visceral disease. Median follow-up was 22.4 months. Disease progression (26.4%) and intolerance/toxicity (14.9%) were the main reasons for treatment discontinuation. The median (95% CI) real-world progression-free survival was 31.7 (27.9-not estimable (NE)) months and 2-year estimated overall survival (OS) rate was 78.0%. In total, 25.6% of patients died; however, OS data are limited by the small population size and insufficient follow-up time. These real-world effectiveness outcomes complement findings from other real-world studies and randomized controlled trials and support palbociclib plus an aromatase inhibitor as first-line therapy for HR+/HER2- A/MBC.
    Keywords:  HR+/HER2−; aromatase inhibitor; metastatic breast cancer; palbociclib; real-world data
    DOI:  https://doi.org/10.3390/curroncol29020089
  4. Cancer Sci. 2022 Feb 24.
    Serial circulating tumor DNA monitoring of CDK4/6 inhibitors response in metastatic breast cancer.
    Yoon Ming Chin, Tomoko Shibayama, Hiu Ting Chan, Masumi Otaki, Fumikata Hara, Takayuki Kobayashi, Kokoro Kobayashi, Mari Hosonaga, Ippei Fukada, Lina Inagaki, Makiko Ono, Yoshinori Ito, Shunji Takahashi, Shinji Ohno, Takayuki Ueno, Yusuke Nakamura, Siew-Kee Low.
      CDK4/6 inhibitors (CDK4/6i) significantly improve progression-free survival (PFS) and have become the standard therapy for ER+/HER2- metastatic breast cancer patients. Treatment surveillance by radiological imaging has some limitations in detection while repeated biopsy genomic profiling is not clinically feasible. Serial ctDNA analysis may provide insights into treatment response. Here we performed serial ctDNA analysis (n=178) on 33 patients. Serial ctDNA analysis identified disease progression with sensitivity of 75% and specificity of 92%. In eight of twelve patients (61%) responding to CDK4/6i but eventually developed progressive disease, serial sampling every 3 or 6 months captured the initial rise of ctDNA with average lead time of 3 months. In three of eight patients that did not respond to CDK4/6i (PD at first radiological assessment- 3 months), biweekly sequencing within the first cycle of CDK4/6i treatment (1 month) detected sustained ctDNA levels (≥0.2% VAF), with lead time of 2 months. Serial ctDNA analysis tracked RECIST response, including clinically challenging scenarios (bone metastases or small-sized target lesions) as well as detect acquired genetic alterations linked to CDK4/6i resistance in the G1 to S transition phase. ctDNA analysis was more sensitive than CEA and CA 15-3 serum tumor markers at monitoring tumor response to CDK4/6i treatment. Our findings demonstrated the possible clinical utility of serial ctDNA analysis for earlier progressive disease detection and real-time monitoring of CDK4/6i response.
    Keywords:  Breast cancer; CDK4/6 inhibitor; Circulating tumor DNA; Liquid biopsy; targeted NGS
    DOI:  https://doi.org/10.1111/cas.15304
  5. Breast. 2022 Feb 08. pii: S0960-9776(22)00032-7. [Epub ahead of print]62 135-143
    Real-world effectiveness of palbociclib plus fulvestrant in advanced breast cancer: Results from a population-based cohort study.
    Fábio Cardoso Borges, Filipa Alves da Costa, Adriana Ramos, Catarina Ramos, Catarina Bernardo, Cláudia Brito, Alexandra Mayer-da-Silva, Cláudia Furtado, Arlindo R Ferreira, Diogo Martins-Branco, Ana Miranda, António Lourenço.
       BACKGROUND: Real-world (RW) data may provide valuable information on the effectiveness and safety of medicines, which is particularly relevant for clinicians, patients and third-party payers. Evidence on the effectiveness of palbociclib plus fulvestrant is scarce, which highlights the need of additional studies. The aim of this study was to evaluate the effectiveness of palbociclib plus fulvestrant in advanced breast cancer (ABC).
    MATERIALS AND METHODS: We conducted a population-based retrospective cohort study and cases of interest were identified through the Portuguese National Cancer Registry database and additional data sources. Patients aged≥18 years, diagnosed with ABC and exposed to palbociclib plus fulvestrant between May 31, 2017 and March 31, 2019 were included. Patients were followed-up until death or cut-off date (February 28, 2021). Primary outcome was rw-progression-free survival (rwPFS). Secondary outcomes were rw-overall survival (rwOS), rw-time to palbociclib failure (rwTPF) and rw-time to next treatment (rwTTNT).
    RESULTS: A total of 210 patients were included. Median age was 58 years (range 29-83) and 99.05% were female. Median follow-up time was 23.22 months and, at cut-off date, treatment had been discontinued in 189 patients, mainly due to disease progression (n = 152). Median rwPFS was 7.43 months (95% confidence interval [CI] 6.28-9.05) and 2-year rwPFS was 16.65% (95%CI 11.97-22.00). Median rwOS was 24.70 months (95%CI 21.58-29.27), median rwTPF was 7.5 months (95%CI 6.51-9.08) and median rwTTNT was 11.74 months (95%CI 10.33-14.08).
    CONCLUSION: Palbociclib plus fulvestrant seems an effective treatment for ABC in real-world context. Compared to registrations studies, rwPFS and rwOS were shorter in real-life setting.
    Keywords:  Advanced breast cancer; Cancer registries; Effectiveness; Fulvestrant; Palbociclib; Real-world data
    DOI:  https://doi.org/10.1016/j.breast.2022.02.005
  6. Curr Drug Metab. 2022 Feb 18.
    Inhibition of Cytochrome P450 Enzyme and Drug‑Drug Interaction Potential of Acid Reducing Agents Used in Management of CDK inhibitors for Breast Cancer Chemotherapy.
    Prajakta Harish Patil, Jagadish P C, Fajeelath Fatima, Sumit Birangal, G Gautham Shenoy, Mahadev Rao, Junaid Farooqui, Himanshu Rastogi, Tarun Sharma, Jakir Pinjari.
       BACKGROUND AND OBJECTIVE: Concurrent usage of proton pump inhibitors and their effect on survival and medication termination has been found in individuals receiving protein kinase inhibitor chemotherapy. To investigate the drug-drug interaction mechanism between CDK inhibitors and proton pump inhibitors, the in-silico docking approach was designed by applying computer simulation modules to predict the binding and inhibitory potential.
    METHOD: The interaction potential of proton pump inhibitors and CDK inhibitors was predicted utilising molecular docking techniques that employed Schrödinger algorithms to capture the dynamics of the CYP450 enzyme-inhibitor interaction between PPIs and CDK inhibitors. Additionally, the human liver microsomes assay was used to determine the in vitro half-maximal inhibitory concentration (IC50) of proton pump inhibitors and the inactivation of CDK inhibitors via CYP3A4.
    RESULTS: Proton pump inhibitors alter the conformation of the CYP3A4 and CYP2C19 enzymes and interact with the heme prosthetic group, as determined by docking studies. It may result in the suppression of CDK inhibitors' metabolism via competitive inhibition at the binding site of an enzyme. Omeprazole and rabeprazole both significantly block midazolam's 1'-hydroxylation by CYP3A4 in vitro, with IC50 values of 9.86µM and 9.71µM, respectively. When omeprazole and rabeprazole are co-incubated in human liver microsomes at a 30µM concentration equivalent to the Cmax of omeprazole and rabeprazole, rabeprazole significantly prolongs the metabolic clearance of palbociclib, whereas omeprazole affects the ribociclib CYP3A4-mediated metabolism.
    CONCLUSION: Using dynamic models, we determined that proton pump inhibitors such as rabeprazole and omeprazole indeed have the potential to cause clinically significant drug-drug interactions with CDK inhibitors in the treatment of estrogen receptor (ER) positive and HER2-positive breast cancer. As a result, it is suggested to use caution when prescribing proton pump inhibitors to these individuals.
    Keywords:  CDK inhibitors; CYP450; drug-drug interactions; HER2-positive breast cancer; Ligand-based docking; Proton pump inhibitors; Human liver microsomes; metabolic stability
    DOI:  https://doi.org/10.2174/1389200223666220218090948
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