bims-cyhorp 2021-10-31 papers

Issue of 2021‒10‒31
five papers selected by
Piotr Okupski,

Int J Clin Oncol. 2021 Oct 26.

Palbociclib as an early-line treatment for Japanese patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: a review of clinical trial and real-world data.

Norikazu Masuda, Nobuyoshi Kosaka, Hiroji Iwata, Masakazu Toi.

Breast cancer is the most common type of cancer among women worldwide and in Japan. The majority of breast cancers are hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2‒), and endocrine therapy is an effective therapy for this type of breast cancer. However, recent substantial advances have been made in the management of HR+/HER2‒ advanced breast cancer (ABC) with the advent of targeted therapies, such as cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, resulting in significant improvements in survival outcomes versus endocrine therapy alone. To evaluate the optimal use of palbociclib, a CDK4/6 inhibitor, in HR+/HER2- ABC, this review summarizes clinical trial and real-world data for palbociclib. In addition, current biomarker studies in palbociclib clinical research are reviewed. In Japanese patients, palbociclib was shown to be effective with a manageable safety profile, although differences were observed in the frequency of adverse event and dosing parameters. Current evidence supporting palbociclib as a first-line treatment strategy for patients with HR+/HER2‒ ABC in Asia, and specifically japan, is also discussed.

Keywords: Advanced breast cancer; Clinical trial; HR+/HER2–; Palbociclib; Real-world

DOI: https://doi.org/10.1007/s10147-021-02013-8

Am J Clin Dermatol. 2021 Oct 26.

Skin Toxicities with Cyclin-Dependent Kinase 4/6 Inhibitors in Breast Cancer: Signals from Disproportionality Analysis of the FDA Adverse Event Reporting System.

Emanuel Raschi, Michele Fusaroli, Michelangelo La Placa, Andrea Ardizzoni, Claudio Zamagni, Elisabetta Poluzzi, Fabrizio De Ponti.

BACKGROUND: Cyclin-dependent kinase (CDK)-4/6 inhibitors have been associated with dermatologic reactions, especially alopecia, in pivotal trials.OBJECTIVE: We aimed to comprehensively describe skin toxicities with CDK4/6 inhibitors reported in the real world through the US FDA Adverse Event Reporting System (FAERS).
METHODS: Cutaneous adverse events (AEs) were characterized in terms of spectrum and clinical features, including seriousness (with fatality proportion), latency, and discontinuation. Disproportionality analyses were performed through the reporting odds ratio (ROR) and 95% confidence interval (CI) by comparing CDK4/6 inhibitors with other anticancer drugs used in breast cancer.
RESULTS: As of December 2020, a total of 7986 cutaneous events were reported with CDK4/6 inhibitors (15% of total AEs with CDK4/6 inhibitors), mainly by consumers (39.6%), with 43.5% classified as serious and 25% requiring discontinuation. In 49% of the cases, five or more noncutaneous events were co-reported. The most frequently reported cutaneous events were alopecia (N = 3528), rash (N = 1493), and pruritus (N = 1211): rashes were recorded in the first month (median onset 28 days), whereas alopecia and nail alterations were recorded after a median of 67 and 112 days, respectively. Several cutaneous AEs were associated with increased reporting, including vitiligo (N = 6; ROR 8.88; 95% CI 2.95-22.46) and bullous dermatitis with ribociclib (N = 7; ROR 2.90; 95% CI 1.13-6.27); erythema multiforme with abemaciclib (N = 9; ROR 5.80; 95% CI 2.57-11.48); onychoclasis (N = 142, ROR 2.27; 95% CI 1.83-2.79) and trichorrhexis (N = 22; ROR 3.27; 95% CI 1.78-5.93) with palbociclib.
CONCLUSIONS: Although causality cannot be demonstrated, a diverse reporting pattern of cutaneous AEs emerged from FAERS, including dermal/epidermal conditions, hair/nail disorders, and serious bullous conditions, with variable onsets and a remarkable proportion of discontinuations. The potential differential reporting among CDK4/6 inhibitors deserves further investigation.

DOI: https://doi.org/10.1007/s40257-021-00645-0

Pharmacol Res. 2021 Oct 23. pii: S1043-6618(21)00538-7. [Epub ahead of print] 105954

ABCB1 and ABCG2 limit brain penetration and, together with CYP3A4, total plasma exposure of abemaciclib and its active metabolites.

Alejandra Martínez-Chávez, Nancy H C Loos, Maria C Lebre, Matthijs M Tibben, Hilde Rosing, Jos H Beijnen, Alfred H Schinkel.

Abemaciclib is the third cyclin-dependent kinase (CDK) 4/6 inhibitor approved for the treatment of breast cancer and currently under investigation for other malignancies, including brain cancer. Primarily CYP3A4 metabolizes abemaciclib, forming three active metabolites (M2, M20 and M18) that are likely relevant for abemaciclib efficacy and toxicity. We investigated the impact of ABCB1 (P-gp), ABCG2 (BCRP) and CYP3A on the pharmacokinetics and tissue distribution of abemaciclib and its metabolites using genetically modified mice. In vitro, abemaciclib was efficiently transported by hABCB1 and mAbcg2, and slightly by hABCG2, but the active metabolites were transported even better. Upon oral administration of 10mg/kg abemaciclib, absence of Abcg2 and especially Abcb1a/1b significantly increased the plasma AUC0-24h and Cmax of M2 and M18. Furthermore, the relative brain penetration of abemaciclib, M2 and M20 was dramatically increased by 25-, 4- and 60-fold, respectively, in Abcb1a/1b;Abcg2-/- mice, and to a lesser extent in single Abcb1a/1b- or Abcg2-deficient mice. The recovery of all active compounds in the small intestine content was profoundly reduced in Abcb1a/1b;Abcg2-/- mice, with smaller effects in single Abcb1a/1b-/- and Abcg2-/- mice. Our results indicate that Abcb1a/1b and Abcg2 cooperatively and profoundly limit the brain penetration of abemaciclib and its active metabolites, and likely also participate in their hepatobiliary or direct intestinal elimination. Moreover, transgenic human CYP3A4 drastically reduced the abemaciclib plasma AUC0-24h and Cmax by 7.5- and 5.6-fold, respectively, relative to Cyp3a-/- mice. These insights may help to optimize the clinical development of abemaciclib, especially for the treatment of brain malignancies.

Keywords: Abemaciclib; Abemaciclib (PubChem CID: 46220502); Abemaciclib metabolite M18; Abemaciclib metabolite M2 (PubChem CID: 59376686); Abemaciclib metabolite M20 (PubChem CID: 139600311); BCRP/ABCG2; CYP3A; P-glycoprotein/ABCB1; active metabolites; brain penetration; pharmacokinetics

DOI: https://doi.org/10.1016/j.phrs.2021.105954

Nat Cancer. 2021 Jun;2(6): 658-671

Serial single-cell genomics reveals convergent subclonal evolution of resistance as early-stage breast cancer patients progress on endocrine plus CDK4/6 therapy.

Jason I Griffiths, Jinfeng Chen, Patrick A Cosgrove, Anne O'Dea, Priyanka Sharma, Cynthia Ma, Meghna Trivedi, Kevin Kalinsky, Kari B Wisinski, Ruth O'Regan, Issam Makhoul, Laura M Spring, Aditya Bardia, Frederick R Adler, Adam L Cohen, Jeffrey T Chang, Qamar J Khan, Andrea H Bild.

Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for metastatic estrogen receptor positive (ER+) breast cancer patients but its value in earlier stage patients is unclear. We examined evolutionary trajectories of early-stage breast cancer tumors, using single cell RNA sequencing (scRNAseq) of serial biopsies from the FELINE clinical trial (#NCT02712723) of endocrine therapy (letrozole) alone or combined with the CDK inhibitor ribociclib. Despite differences in subclonal diversity evolution across patients and treatments, common resistance phenotypes emerged. Resistant tumors treated with combination therapy showed accelerated loss of estrogen signaling with convergent up-regulation of JNK signaling through growth factor receptors. In contrast, cancer cells maintaining estrogen signaling during mono- or combination therapy showed potentiation of CDK4/6 activation and ERK upregulation through ERBB4 signaling. These results indicate that combination therapy in early-stage ER+ breast cancer leads to emergence of resistance through a shift from estrogen to alternative growth signal-mediated proliferation.

DOI: https://doi.org/10.1038/s43018-021-00215-7

Int J Radiat Oncol Biol Phys. 2021 Nov 01. pii: S0360-3016(21)01013-0. [Epub ahead of print]111(3S): S55-S56

CDK4/6 Inhibition and Radiation as a Treatment Strategy to Improve Local Disease Control in Breast Cancers With Poor Prognoses.

A Pesch, N Hirsh, A R Michmerhuizen, B Chandler, K Wilder-Romans, L Lerner, M Liu, D F Hayes, E Cobain, L J Pierce, J Rae, C Speers.

PURPOSE/OBJECTIVE(S): Locoregional control remains an issue in women with multi-node positive estrogen receptor-positive (ER+) breast cancer and many women with triple-negative breast cancer (TNBC). There is growing evidence that CDK4/6 inhibition (CDK4/6i) sensitizes breast cancer cells to ionizing radiation (RT) by suppressing the DNA damage response, but the role of RB is currently unclear. We sought to understand the role of RB and the implications of RB loss in ER+ and TNBC.MATERIALS/METHODS: Clonogenic survival assays were used to calculate radiosensitivity and calculate enhancement ratios (rER). Cellular viability was quantified 72 hours after drug addition to calculate half-maximal inhibitory concentrations (IC50s). Phospho- and total RB expression levels were assessed by immunoblotting. DNA repair was assessed with γH2AX and RAD51 immunofluorescence. GFP-based plasmid reporter systems were used to assess homologous recombination (HR) and non-homologous end joining (NHEJ) competency. Isogenic RB1 knockout cells were generated with CRISPR-Cas9, and siRNA was used for transient RB1 knockdown. G1 cell cycle arrest was quantified using propidium iodide-based flow cytometry. In vivo efficacy of CDK4/6 inhibition + RT was assessed using MDA-MB-231 xenografts.
RESULTS: Four TNBC cell lines with intact RB expression were radiosensitized (rER 1.08 - 2.22) after CDK4/6i with palbociclib, ribociclib, or abemaciclib, but two RB null TNBC models were not radiosensitized with combination treatment (rER: 0.84 - 1.00). In ER+ and TNBC cell lines, response to CDK4/6i + RT was accurately predicted by the presence or absence of RB protein, and higher RB expression led to increased radiosensitization of breast cancer cell lines at lower doses. In addition, pRB expression decreased in wild type TNBC cell lines treated with CDK4/6i + RT. HR was suppressed with CDK4/6i in RB wild type - but not mutant - cell lines. NHEJ efficiency in RB wild type TNBC was unchanged with CDK4/6i. Genetic knockdown of RB1 led to the loss of radiosensitization in ER+ and TNBC cell lines (rER: 0.84 - 1.13) as well as a decrease in sensitivity to CDK4/6i monotherapy. Parental and Cas9 control TNBC cells arrested in G1 24 hours after CDK4/6i and remained arrested at 48 hours, but RB1 CRISPR TNBC cells did not arrest after drug treatment. In a TNBC xenograft model with wild type RB expression (MDA-MB-231), CDK4/6i + RT led to significant radiosensitization in vivo and delayed time to tumor doubling.
CONCLUSION: RB loss mitigates CDK4/6 inhibitor-mediated radiosensitization of both ER+ and TNBC cells. Loss of RB expression prevents CDK4/6i-mediated radiosensitization, suggesting that RB expression may be a valuable clinical biomarker to predict efficacy of CDK4/6i + RT in future clinical trials. Our data also provide the preclinical rationale for CDK4/6i with RT not just in ER+ BC, but also in women with TNBC that express RB.

DOI: https://doi.org/10.1016/j.ijrobp.2021.07.143