bims-cyhorp 2023-04-16 papers

Issue of 2023–04–16
five papers selected by
Piotr Okupski,

Front Cell Dev Biol. 2023 ;11 1148792

CDK4/6 inhibitor resistance in estrogen receptor positive breast cancer, a 2023 perspective.

Fiona H Zhou, Teesha Downton, Allegra Freelander, Joshua Hurwitz, C Elizabeth Caldon, Elgene Lim.

CDK4/6 inhibitors have become game-changers in the treatment of estrogen receptor-positive (ER+) breast cancer, and in combination with endocrine therapy are the standard of care first-line treatment for ER+/HER2-negative advanced breast cancer. Although CDK4/6 inhibitors prolong survival for these patients, resistance is inevitable and there is currently no clear standard next-line treatment. There is an urgent unmet need to dissect the mechanisms which drive intrinsic and acquired resistance to CDK4/6 inhibitors and endocrine therapy to guide the subsequent therapeutic decisions. We will review the insights gained from preclinical studies and clinical cohorts into the diverse mechanisms of CDK4/6 inhibitor action and resistance, and highlight potential therapeutic strategies in the context of CDK4/6 inhibitor resistance.

Keywords: CDK4/6 inhibitor; breast cancer; endocrine therapy; estrogen receptor; resistance

DOI: https://doi.org/10.3389/fcell.2023.1148792

Expert Opin Pharmacother. 2023 Apr 12. 1-14

Advances in pharmacotherapies that target the cell cycle for treatment of breast cancer: where are we at today?

Martina Perrone, Francesco Giuliani, Valeria Sanna, Stefania Bruno, Assunta Melaccio, Anna Natalizia Santoro, Carmelo Laface, Felicia Maria Maselli, Maria Laura Iaia, Chiara Guarini, Alessandro Fancellu, Palma Fedele.

INTRODUCTION: Advances in pharmacotherapies that target cell cycle in breast cancer have transformed the therapeutic armamentarium of breast oncology leading to the approval of CDK4/6 inhibitors plus endocrine therapy as the upfront treatment in the HR+/HER2- metastatic setting. The current challenge is to evaluate the efficacy of these drugs in the early setting. The current challenge is to evaluate the efficacy of these drugs in the early setting. Research is also making progress for other breast cancer subtypes (triple negative and HER 2+ breast cancer).
AREAS COVERED: The aim of this review is to summarize the recent therapeutic updates regarding the efficacy of CDK4/6 inhibitors in the metastatic and early setting for the treatment of HR+/HER2- breast cancer. The review also presents data regarding the clinical role of CDK4/6 inhibitors in HER2+, triple negative breast cancer, and on therapeutic sequences in resistant tumors. A comprehensive search for the literature was conducted using MEDLINE, ASCO, ESMO, and SABCS databases.
EXPERT OPINION: The therapeutic paradigm of breast cancer involving CDK4/6 inhibitors presents some still open discussion points. Further evidence regarding the best treatment strategy in HR+ HER2- metastatic breast cancer and the efficacy of CDK 4/6is in the early stage will be necessary in the next future. Predictive biomarkers of response or resistance need to be validated.

Keywords: Abemaciclib; CDK4/6 Inhibitors; HR+ breast cancer; Palbociclib; Ribociclib; cell cycle; targeted treatment

DOI: https://doi.org/10.1080/14656566.2023.2201373

Cancers (Basel). 2023 Mar 28. pii: 2015. [Epub ahead of print]15(7):

Filling the Gap after CDK4/6 Inhibitors: Novel Endocrine and Biologic Treatment Options for Metastatic Hormone Receptor Positive Breast Cancer.

Abhenil Mittal, Consolacion Molto Valiente, Faris Tamimi, Ilana Schlam, Sarah Sammons, Sara M Tolaney, Paolo Tarantino.

The rise of cyclin-dependent kinase (CDK)4/6 inhibitors has rapidly reshaped treatment algorithms for hormone receptor (HR)-positive metastatic breast cancer, with endocrine treatment (ET) plus a CDK4/6-inhibitor currently representing the standard of care in the first line setting. However, treatment selection for those patients experiencing progression while on ET + CDK4/6-inhibitors remains challenging due to the suboptimal activity or significant toxicities of the currently available options. There is also a paucity of data regarding the efficacy of older regimens, such as everolimus + exemestane, post-CDK4/6 inhibition. In this setting of high unmet need, several clinical trials of novel drugs have recently reported encouraging results: the addition of the AKT-inhibitor capivasertib to fulvestrant demonstrated a significant improvement in progression-free survival (PFS); the oral selective estrogen receptor degrader (SERD) elacestrant prolonged PFS compared to traditional ET in a phase 3 trial, particularly among patients with detectable ESR1 mutations; finally, PARP inhibitors are available treatment options for patients with pathogenic BRCA1/2 germline mutations. Overall, a plethora of novel endocrine and biologic treatment options are finally filling the gap between first-line ET and later line chemotherapy. In this review article, we recapitulate the activity of these novel treatment options and their potential role in future treatment algorithms.

Keywords: CDK4/6-inhibitors; SERD; breast cancer; camizestrant; capivasertib; elacestrant

DOI: https://doi.org/10.3390/cancers15072015

Rev Esp Med Nucl Imagen Mol (Engl Ed). 2023 Apr 06. pii: S2253-8089(23)00030-7. [Epub ahead of print]

Comparison of prognostic value of different metabolic response criteria determined by PET/CT in patients with metastatic breast cancer under CDK 4/6 inhibitor treatment.

Hasan Önner, Orhan Önder Eren, Muslu Kazım Körez, Farise Yilmaz, Gonca Kara Gedik.

PURPOSE: This study evaluates the prognostic role of different [18F]FDG PET/CT metabolic response criteria in metastatic breast cancer (MBC) patients treated with cyclin-dependent kinase 4/6 inhibitors (CDK 4/6).
MATERIALS AND METHODS: We retrospectively evaluated the data of MBC patients treated with CDK 4/6 inhibitors who underwent an [18F]FDG PET/CT scan before starting and during treatment. [18F]FDG PET/CT response was assessed with the European Organization for Research and Treatment of Cancer (EORTC), PET Response Criteria in Solid Tumors (PERCIST), and whole-body total lesion glycolysis (WBTLG) criteria. Fleiss kappa was computed to assess the agreement between metabolic response criteria. The endpoint of the study was progression-free survival (PFS). PFS data were analyzed by the Kaplan-Meier method and compared using the log-rank test.
RESULTS: The study included sixteen MBC patients who received CDK 4/6 inhibitors therapy. According to PERCIST, partial metabolic response (PMR) was found in seven patients, stable metabolic disease (SMD) in seven patients, and progressive metabolic disease (PMD) in two patients. According to EORTC, PMR was detected in eight patients, SMD in seven patients, and PMD in one patient. According to WBTLG, PMR was found in 10 patients, SMD in four patients, and PMD in two patients. There was a fair agreement between the three criteria. While progression was detected in seven of the patients during follow-up, no progression was detected in nine of them. Kaplan-Meier analysis revealed that the responders according to WBTLG showed significantly longer PFS than non-responders.
CONCLUSION: Treatment response according to WBTLG criteria during treatment appears to be associated with prolonged PFS in patients treated with CDK 4/6 inhibitors for MBC.

Keywords: Breast cancer; Cyclin-dependent 4/6 kinase therapy; Cáncer de mama; Evaluación de la respuesta; Fluorodeoxyglucose; Fluorodesoxiglucosa; Positron emission tomography; Response assessment; Terapia con quinasa 4/6 dependiente de ciclina; Tomografía de emisión de positrones

DOI: https://doi.org/10.1016/j.remnie.2023.04.001

Cancer Res Treat. 2023 Apr 11.

Efficacy of Limited Dose Modifications for Palbociclib-Related Grade 3 Neutropenia in Hormone Receptor-Positive Metastatic Breast Cancer.

Seul-Gi Kim, Min Hwan Kim, Sejung Park, Gun Min Kim, Jee Hung Kim, Jee Ye Kim, Hyung Seok Park, Seho Park, Byeong Woo Park, Seung Il Kim, Jung Hwan Ji, Joon Jeong, Kabsoo Shin, Jieun Lee, Hyung-Don Kim, Kyung Hae Jung, Joohyuk Sohn.

Purpose: Frequent neutropenia hinders uninterrupted palbociclib treatment in patients with hormone receptor (HR)-positive breast cancer. We compared the efficacy outcomes in multicenter cohorts of patients with metastatic breast cancer receiving palbociclib following conventional dose modification or limited modified schemes for afebrile grade 3 neutropenia.
Materials and Methods: Patients with HR-positive, human epidermal growth factor receptor 2-negative mBC (n=434) receiving palbociclib with letrozole as first-line therapy were analyzed and classified based on neutropenia grade and afebrile grade 3 neutropenia management as follows: Group 1 (maintained palbociclib dose, limited scheme), Group 2 (dose delay or reduction, conventional scheme), Group 3 (no afebrile grade 3 neutropenia event), and Group 4 (grade 4 neutropenia event). The primary and secondary endpoints were progression-free survival (PFS) between Groups 1 and 2 and PFS, overall survival, and safety profiles among all groups.
Results: During follow-up (median 23.7 months), Group 1 (2-year PFS, 67.9%) showed significantly longer PFS than did Group 2 (2-year PFS, 55.3%; p=0.036), maintained across all subgroups, and upon adjustment of the factors. Febrile neutropenia occurred in one and two patients of Group 1 and Group 2, respectively, without mortality.
Conclusion: Limited dose modification for palbociclib-related grade 3 neutropenia may lead to longer PFS, without increasing toxicity, than the conventional dose scheme.

Keywords: Afebrile neutropenia; Limited dose modification; Metastatic breast cancer; Palbociclib; Progression-free survival

DOI: https://doi.org/10.4143/crt.2022.1543