bims-cyhorp 2022-12-04 papers

Issue of 2022‒12‒04
four papers selected by
Piotr Okupski

Oxf Med Case Reports. 2022 Nov;2022(11): omac116

Ribociclib and palbociclib-induced erythema multiforme: a case report.

Eleni Vrana, Stella Mylona, Mattheos Bobos, Loukas Kontovinis, Konstantinos Papazisis.

Cyclin-dependent kinase 4/6 inhibitors (CKIs), ribociclib, palbocilb and abemaciclib, have been approved in combination with endocrine therapy for the treatment of hormone receptor-positive and human epidermal growth factor 2-negative advanced or metastatic breast cancer. Severe dermatological adverse events are rare with these agents; however, they require direct recognition and management in order not to become life-threatening. Erythema multiforme (EM) belongs to a dermatopathic spectrum that includes immune-mediated, widespread hypersensitivity reaction, which occurs with varying degrees of severity and affects the skin and/or the mucosa. We hereby present a case of ribociclib- and palbociclib-related EM. We sought to report this case given the implication of two agents from the same drug class in EM onset. We also aim to emphasize the breadth of mechanisms of actions of CKIs, with an impingement in the immune system as well, and the importance of promptly identifying and handling such skin toxicities.

DOI: https://doi.org/10.1093/omcr/omac116

NPJ Breast Cancer. 2022 Nov 29. 8(1): 126

Crystal structure of active CDK4-cyclin D and mechanistic basis for abemaciclib efficacy.

Despite the biological and therapeutic relevance of CDK4/6 for the treatment of HR+, HER2- advanced breast cancer, the detailed mode of action of CDK4/6 inhibitors is not completely understood. Of particular interest, phosphorylation of CDK4 at T172 (pT172) is critical for generating the active conformation, yet no such crystal structure has been reported to date. We describe here the x-ray structure of active CDK4-cyclin D3 bound to the CDK4/6 inhibitor abemaciclib and discuss the key aspects of the catalytically-competent complex. Furthermore, the effect of CDK4/6 inhibitors on CDK4 T172 phosphorylation has not been explored, despite its role as a potential biomarker of CDK4/6 inhibitor response. We show mechanistically that CDK4/6i stabilize primed (pT172) CDK4-cyclin D complex and selectively displace p21 in responsive tumor cells. Stabilization of active CDK4-cyclin D1 complex can lead to pathway reactivation following alternate dosing regimen. Consequently, sustained binding of abemaciclib to CDK4 leads to potent cell cycle inhibition in breast cancer cell lines and prevents rebound activation of downstream signaling. Overall, our study provides key insights demonstrating that prolonged treatment with CDK4/6 inhibitors and composition of the CDK4/6-cyclin D complex are both critical determinants of abemaciclib efficacy, with implications for this class of anticancer therapy.

DOI: https://doi.org/10.1038/s41523-022-00494-y

Clin Ther. 2022 Nov 28. pii: S0149-2918(22)00379-4. [Epub ahead of print]

Real-World Treatment Patterns and Clinical Outcomes Associated With Palbociclib Combination Therapy: A Multinational, Pooled Analysis From the Ibrance Real World Insights Study.

Katie Mycock, Kent A Hanson, Gavin Taylor-Stokes, Gary Milligan, Christian Atkinson, Debanjali Mitra, Salena Preciado, Ernest H Law.

PURPOSE: Palbociclib was the first cyclin-dependent kinase 4/6 inhibitor approved by the US Food and Drug Administration for use in combination with aromatase inhibitors (AIs) as initial endocrine-based therapy or with fulvestrant in postmenopausal women who previously received endocrine therapy based on data from randomized clinical trials. Real-world studies examining the effectiveness of palbociclib in large, diverse patient populations in routine clinical practice were needed.PATIENTS AND METHODS: Ibrance Real World Insights (IRIS) was a retrospective medical record review study of women with confirmed hormone receptor-positive, HER2-negative advanced/metastatic breast cancer treated with palbociclib plus an AI or with palbociclib plus fulvestrant according to approved indications. Participating physicians reviewed medical records of up to 16 sequentially presenting patients, collecting demographic and clinical data. Outcomes included objective response rates, progression-free rates, and survival rates overall and in patients stratified according to age, race and ethnicity, Eastern Cooperative Oncology Group (ECOG) performance status (PS), disease-free interval, visceral disease, liver metastases, bone-only metastases, and previous lines of therapy.
FINDINGS: Data were abstracted by 417 physicians for 2954 patients in 13 countries; 1415 patients (47.9%) were ≥65 years of age, 369 patients (12.5%) had an ECOG PS ≥2 at initiation, and 835 patients (28.3%) were races other than White. The 12-month progression-free rate was 88% for palbociclib plus an AI and 79% for palbociclib plus fulvestrant; the 12-month survival rate was 96% in both groups. The objective response rates were 80% for palbociclib plus an AI and 75% for palbociclib plus fulvestrant. Palbociclib was similarly effective in most subgroups examined.
IMPLICATIONS: Data from IRIS provide in-depth, real-world evidence for the use of palbociclib in a range of breast cancer populations in multiple countries. These data support the findings of the randomized PALOMA-2 and PALOMA-3 studies.

Keywords: breast cancer; effectiveness; palbociclib; real-world evidence

DOI: https://doi.org/10.1016/j.clinthera.2022.11.004

Anticancer Res. 2022 Dec;42(12): 6027-6035

Risk of Abemaciclib-induced Liver Injury in Hormone Receptor-positive, HER2-negative Metastatic Breast Cancer: A Retrospective Analysis.

Azusa Taniguchi, Nobuyoshi Kittaka, Haruka Kanaoka, Satomi Nakajima, Yuri Oyama, Yukiko Seto, A I Soma, Hiroki Kusama, Noriyuki Watanabe, Saki Matsui, Minako Nishio, Fumie Fujisawa, Takahiro Nakayama.

BACKGROUND/AIM: The efficacy of endocrine therapy combined with abemaciclib for hormone receptor-positive, HER2-negative metastatic breast cancer has been established through pivotal clinical trials. However, abemaciclib-induced liver injury (AILI) can be a cause for dose reduction or discontinuation. Therefore, it is critical to understand the risk factors for AILI.PATIENTS AND METHODS: This retrospective study analyzed data from patients who had received abemaciclib combined with endocrine therapy for metastatic breast cancer as first- or second-line therapy at our hospital between December 2018 and October 2021. Relevant data were extracted from their medical records. Logistic regression analysis was performed to identify characteristics associated with AILI.
RESULTS: Of the 52 eligible patients, 12 (23%) received an aromatase inhibitor (AI), and 40 (77%) received fulvestrant, concomitantly with abemaciclib. Fifteen (29%) of the patients developed liver injury after starting abemaciclib. Univariate analysis revealed the following risk factors for AILI: age ≥65 years (p=0.047), fatty liver disease (p=0.047), and concomitant use of an AI (p=0.002). Concomitant use of an AI was identified by multivariate analysis as an independent risk factor for AILI [odds ratio (OR)=10.23, 95% confidence interval (CI)=2.02-51.91, p=0.005].
CONCLUSION: Concomitant use of an AI could be the most significant factor associated with increased risk of AILI. Future research on the mechanism by which the use of an AI plus abemaciclib can cause liver injury, and prospective studies to validate our findings regarding AILI risk factors, are warranted.

Keywords: Abemaciclib; aromatase inhibitor; breast cancer; liver injury; risk factor

DOI: https://doi.org/10.21873/anticanres.16114