bims-cyhorp 2021-11-14 papers

bims-cyhorp

Biomed News

on Cyclin-dependent kinases in hormone receptor positive breast cancer

Issue of 2021–11–14
ten papers selected by
Piotr Okupski,

Resistance Mechanisms to Combined CDK4/6 Inhibitors and Endocrine Therapy in ER+/HER2- Advanced Breast Cancer: Biomarkers and Potential Novel Treatment Strategies.
Matching-Adjusted Indirect Comparison of Ribociclib Plus Fulvestrant versus Palbociclib Plus Letrozole as First-Line Treatment of HR+/HER2- Advanced Breast Cancer.
Tolerability of palbociclib in younger and older patients with advanced breast cancer.
Which Clinicopathologic Parameters Suggest Primary Resistance to Palbociclib in Combination With Letrozole as the First-Line Treatment for Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer?
Palbociclib versus abemaciclib in HR+/HER2- advanced breast cancer: an indirect comparison of patient-reported end points.
Treatment Experiences with CDK4&6 Inhibitors Among Women with Metastatic Breast Cancer: A Qualitative Study.
CDK4/6 inhibitors in breast cancer: spotting the difference.
Correction to: Purification of Cyclin-Dependent Kinase Fusion Complexes for In Vitro Analysis.
Protective role of cytoplasmic p21Cip1/Waf1 in apoptosis of CDK4/6 inhibitor-induced senescence in breast cancer cells.
Implications of TGFβ Signaling and CDK Inhibition for the Treatment of Breast Cancer.

Cancers (Basel). 2021 Oct 27. pii: 5397. [Epub ahead of print]13(21):

Resistance Mechanisms to Combined CDK4/6 Inhibitors and Endocrine Therapy in ER+/HER2- Advanced Breast Cancer: Biomarkers and Potential Novel Treatment Strategies.

Abeer J Al-Qasem, Carla L Alves, Henrik J Ditzel.

  The introduction of CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) has revolutionized the treatment landscape for patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC) and has become the new standard treatment. However, resistance to this combined therapy inevitably develops and represents a major clinical challenge in the management of ER+ ABC. Currently, elucidation of the resistance mechanisms, identification of predictive biomarkers, and development of novel effective combined targeted treatments to overcome the resistance are active areas of research. Given the heterogeneity of the resistance mechanisms towards combined CDK4/6i and ET, identification of a single universal predictive biomarker of resistance is unlikely. Novel approaches are being explored, including examination of multiple genetic alterations in circulating cell-free tumor DNA in liquid biopsies from ABC patients with disease progression on combined CDK4/6i and ET treatment. Here, we review the molecular basis of the main known resistance mechanisms towards combined CDK4/6i and ET and associated potential biomarkers. As inhibiting key molecules in the pathways driving resistance may play an important role in the selection of therapeutic strategies for patients who experience disease progression on combined CDK4/6i and ET, we also review preclinical and early phase clinical data on novel combination therapies for these patients.

Keywords:  CDK4/6 inhibitor; biomarkers; breast cancer; liquid biopsy; resistance mechanisms

DOI:  https://doi.org/10.3390/cancers13215397
Cancer Manag Res. 2021 ;13 8179-8189

Matching-Adjusted Indirect Comparison of Ribociclib Plus Fulvestrant versus Palbociclib Plus Letrozole as First-Line Treatment of HR+/HER2- Advanced Breast Cancer.

Peter A Fasching, Thomas E Delea, Yen-Shen Lu, Richard De Boer, Sara A Hurvitz, Aaron Moynahan, David Chandiwana, Brad Lanoue, Huilin Hu, Astrid Thuerigen, Joyce O'Shaughnessy.

   Purpose: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) plus endocrine therapy are recommended for first-line treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). However, not all CDK4/6i trials have reported significant overall survival (OS) benefit, and there have been no head-to-head trials. Two trials have reported OS outcomes in first-line patients: MONALEESA-3 reported significant OS benefit with first- or second-line ribociclib plus fulvestrant (RIB+FUL) versus placebo plus fulvestrant (PBO+FUL), while PALOMA-1 reported no significant OS benefit for palbociclib plus letrozole (PAL+LET) versus LET in first-line postmenopausal patients. Matched-adjusted indirect comparisons (MAICs) are an established method for comparing efficacy of treatments from different trials. We used an MAIC to compare first-line patients from MONALEESA-3 and PALOMA-1.
Patients and Methods: An unanchored MAIC of progression-free survival (PFS) and OS in first-line patients with HR+/HER2- ABC treated with RIB+FUL versus PAL+LET was conducted using individual patient data from MONALEESA-3 and aggregated data from PALOMA-1. To match patients in PALOMA-1, patients in MONALEESA-3 were limited to those with no prior endocrine therapy for ABC and no (neo) adjuvant LET ≤12 months before enrollment. PFS and OS were compared using Kaplan-Meier estimators and Cox regression.
Results: A total of 329 and 178 patients from RIB+FUL and PBO+FUL arms, respectively, of MONALEESA-3 were matched to 84 and 81 patients from PAL+LET and LET arms of PALOMA-1. After weighting, OS was significantly longer for RIB+FUL versus PAL+LET (hazard ratio [HR], 0.50; 95% CI, 0.32-0.77; p = 0.0020). PFS favored RIB+FUL versus PAL+LET, although the difference was not statistically significant (HR, 0.77; 95% CI, 0.54-1.10; p = 0.1553).
Conclusion: Using MAIC to adjust for trial differences, OS comparisons favored RIB+FUL over PAL+LET as first-line treatment in postmenopausal patients with HR+/HER2- ABC. These exploratory results suggest a significant increase in OS benefit with RIB treatment compared with PAL.

Keywords:  CDK4/6 inhibitor; MONALEESA-3; PALOMA-1; overall survival

DOI:  https://doi.org/10.2147/CMAR.S325043
J Oncol Pharm Pract. 2021 Nov 09. 10781552211053639

Tolerability of palbociclib in younger and older patients with advanced breast cancer.

Taylor Dennison, Hillary Heiling, Allison Deal, Kelly Brunk, Ryan Kemper, Daniel J Crona, Aimee Faso.

   INTRODUCTION: Palbociclib is a small-molecule cyclin-dependent kinase 4/6 inhibitor used to treat hormone receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer. Patient-specific factors impacting dose reductions or discontinuations are unknown.
METHODS: The primary objective was to evaluate the association of age (<60 vs. ≥60 years) with palbociclib dose reductions or discontinuations secondary to neutropenia. This single-center, retrospective chart review included hormone receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer patients ≥18 years treated with palbociclib between April 2015 and May 2020. Patients <60 years at the time of palbociclib initiation were in the younger group and patients ≥60 years were in the older group.
RESULTS: Among the 107 patients included, younger patients were less likely than older patients to have a palbociclib starting dose <125 mg (0% vs. 11.9%, p = 0.02). Differences in palbociclib dose reductions or treatment discontinuations secondary to neutropenia were not detected (35.4% vs. 42.4%, p = 0.55). Neither the total number of palbociclib dose reductions (none: 54.2% vs. 49.1%, one: 33.3% vs. 42.4%, two: 12.5% vs. 8.5%, p = 0.61), nor the final dose of palbociclib (125 mg: 54.2% vs. 40.7%, 100 mg: 29.2% vs. 27.1%, 75 mg: 16.7% vs. 32.2%, p = 0.17) differed between younger and older patients.
CONCLUSIONS: Age (<60 vs. ≥60 years) was not associated with the rate of palbociclib dose reductions or discontinuations secondary to neutropenia. Older (≥60 years) patients were more likely to start palbociclib at lower doses which may impact neutropenia and non-neutropenic intolerance.

Keywords:  Palbociclib; advanced breast cancer; age; cyclin-dependent kinase 4/6 inhibitor; neutropenia

DOI:  https://doi.org/10.1177/10781552211053639
Front Oncol. 2021 ;11 759150

Which Clinicopathologic Parameters Suggest Primary Resistance to Palbociclib in Combination With Letrozole as the First-Line Treatment for Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer?

Ji-Yeon Kim, Jung Min Oh, Yeon Hee Park, Jin Seok Ahn, Young-Hyuck Im.

  In this study, we evaluated clinical parameters to predict the primary resistance of palbociclib in combination with endocrine therapy as the first-line treatment in patients with hormone receptor (HR)+, human epidermal growth factor receptor 2 (HER2)- metastatic breast cancer (MBC). We performed a data analysis of patients diagnosed with HR+, HER2-MBC who received palbociclib plus letrozole as the first-line treatment in the metastatic setting from the clinical data warehouse in Samsung Medical Center. In this study, 305 patients were included in the final data analysis. The median follow-up duration was 31 months, and we observed 123 cases of disease progression. The median progression-free survival (PFS) was 28.7 months, and 38 patients (12.5%) had less than a 6-month PFS. The multivariate analysis suggested that primary resistance to adjuvant endocrine therapy (ET) (hazard ratio: 1.91), presence of liver metastasis (hazard ratio: 2.17), initial elevation of serum CA-15-3 (hazard ratio: 1.99), weak positivity of estrogen receptor (ER) (hazard ratio: 2.28), Ki-67 3+ or 4+ (hazard ratios: 2.58 and 10.28), and presence of mutation (hazard ratio: 9.59) were associated with a short PFS duration. A further prediction model was developed with data from 256 patients and 33 cases of disease progression in 6 months. This model included five factors-primary resistance to adjuvant ET (odds ratio, OR: 1.14), liver metastasis (OR: 1.56), initial CA-15-3 elevation (OR: 1.51), weak ER expression (OR: 2.22), and BRCA2 mutation (OR: 2.85)-and the area under the receiver operating characteristic curve was 0.842 (95% CI: 0.775, 0.909; p < 0.001). Finally, we divided them into four risk groups according to the prediction model with the five risk factors. These four groups had different PFS (p < 0.001) and primary resistance of palbociclib with letrozole [OR of group 2 vs. group 1 (ref): 2.18 (p = 0.002), OR of group 3: 3.91 (p < 0.001), and OR of group 4: 4.25 (p < 0.001)]. We developed a prediction model of primary resistance to palbociclib with letrozole as the first-line treatment for HR+, HER2-MBC. Our prediction model might be helpful for considering the first-line treatment strategies. Further well-designed clinical trials would be warranted to validate our prediction model.

Keywords:  CDK4/6 inhibitor; first line; hormone receptor positive (HR+); metastatic breast cancer (MBC); primary resistance

DOI:  https://doi.org/10.3389/fonc.2021.759150
J Comp Eff Res. 2021 Nov 09.

Palbociclib versus abemaciclib in HR+/HER2- advanced breast cancer: an indirect comparison of patient-reported end points.

Ernest Law, Roya Gavanji, Sarah Walsh, Anja Haltner, Rebecca McTavish, Chris Cameron.

  Aim: To assess the relative impact of palbociclib plus fulvestrant (PAL + FUL) and abemaciclib plus fulvestrant (ABEM + FUL) on patient-reported outcomes in patients with hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer. Patients & methods: Anchored matching-adjusted indirect comparisons were conducted using individual patient data from PALOMA-3 (PAL + FUL) and summary-level data from MONARCH-2 (ABEM + FUL). Outcomes included the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items (EORTC QLQ-C30) and its breast cancer-specific module (QLQ-BR23). Results: Significantly different changes from baseline favoring PAL + FUL compared with ABEM + FUL were observed in global quality of life (6.95 [95% CI: 2.19-11.71]; p = 0.004) and several functional/symptom scales, including emotional functioning, nausea/vomiting, appetite loss, diarrhea and systemic therapy side effects. Conclusion: PAL + FUL was associated with more favorable patient-reported outcomes than ABEM + FUL in patients with HR+/HER2- advanced breast cancer.

Keywords:  HER2-negative; abemaciclib; advanced breast cancer; health-related quality of life; hormone receptor-positive; indirect treatment comparison; matching-adjusted indirect comparison; palbociclib; patient-reported outcomes; quality of life

DOI:  https://doi.org/10.2217/cer-2021-0221
Patient Prefer Adherence. 2021 ;15 2417-2429

Treatment Experiences with CDK4&6 Inhibitors Among Women with Metastatic Breast Cancer: A Qualitative Study.

Judith J Stephenson, Jonathon Colby Gable, Rebekah Zincavage, Gregory L Price, Collin Churchill, Emily Zhu, Keri Stenger, Mukul Singhal, Bal Nepal, Michael Grabner, Michael J Fisch, David Debono, Amy R Geschwender, Gebra Cuyun Carter.

   Purpose: To describe patients' perspectives on the use of and potential challenges and barriers with adherence/persistence to cyclin-dependent kinase 4 and 6 inhibitors (CDK4&6i's) to treat metastatic breast cancer (MBC).
Methods: This qualitative study consisted of 60-minute semi-structured telephone interviews with patients with MBC in the US who were either current or recent CDK4&6i users, identified from administrative claims of survey-eligible commercial and Medicare Advantage patients in the HealthCore Integrated Research Database between November 1, 2018 and November 1, 2019. Patients were recruited by email and/or mailed letter. The 60-minute telephone interviews were conducted by a trained facilitator using a study-developed interview discussion guide that included topics impacting treatment choice and adherence/persistence. Interviews were audio-recorded, transcribed, and thematically analyzed.
Results: All 462 eligible patients were sent a recruitment email and/or letter to which 36 patients responded, consented to participate, and met study inclusion criteria; 25 patients scheduled interviews, and 24 completed them. Study participants were predominately white, non-Hispanic (96%) with a mean age of 59.5 years. Participants reported a largely positive experience and mentioned very few adherence/persistence issues. They further reported appreciating the ease and convenience of oral oncolytics, coped with side effects, had strong medical and social support, and experienced few cost issues.
Conclusion: The few adherence/persistence issues reported by participants contrasts with other findings of suboptimal oral oncolytic use. Interview themes indicated several factors that likely contributed to the lack of adherence/persistence issues: trusted relationship with oncologist, belief in importance of medication, positive medication views, strong medical and social support, and minimal personal drug cost. Future research should focus on whether and how much these factors impact adherence/persistence in more diverse populations. If adherence/persistence issues are identified in these populations, then it would be appropriate to study the development of interventions that target factors associated with better adherence/persistence.

Keywords:  CDK4&6i users; adherence; oral oncolytics; patient perspective; persistence; semi-structured interviews

DOI:  https://doi.org/10.2147/PPA.S319239
Nat Med. 2021 Nov 08.

CDK4/6 inhibitors in breast cancer: spotting the difference.

Jose Manuel Perez-Garcia, Javier Cortes, Antonio Llombart-Cussac.

DOI: https://doi.org/10.1038/s41591-021-01570-9
Methods Mol Biol. 2021 ;2329 C1

Correction to: Purification of Cyclin-Dependent Kinase Fusion Complexes for In Vitro Analysis.

Mardo Kõivomägi.

DOI: https://doi.org/10.1007/978-1-0716-1538-6_24
Cancer Med. 2021 Nov 11.

Protective role of cytoplasmic p21Cip1/Waf1 in apoptosis of CDK4/6 inhibitor-induced senescence in breast cancer cells.

Irna D Kartika, Hitoshi Kotani, Yuichi Iida, Akira Koyanagi, Ryosuke Tanino, Mamoru Harada.

  Inhibition of CDK4/6 slows the cell cycle and induces senescence in breast cancer cells. However, senescent cancer cells promote invasion and metastasis. Several drugs reportedly target senescent cells, including ABT-263 (navitoclax). We examined the effects of the CDK4/6 inhibitor abemaciclib and ABT-263 on two human breast cancer cell lines. The abemaciclib and ABT-263 combination additively decreased the viability of MDA-MB-231 cells, but not MCF-7 cells. Also, the combination therapy-induced caspase-dependent apoptosis in MDA-MB-231 cells. Combination therapy with abemaciclib and ABT-737, an ABT-263 analog, significantly suppressed the in vivo growth of MDA-MB-231 with transient body-weight loss. Given that p16Ink4a and p21Cip1/Waf1 are key factors in senescence and that both cell lines were negative for p16, the role of p21 in apoptosis of treated breast cancer cells was investigated. Although abemaciclib increased the cytoplasmic p21 level in both cell lines as a hallmark of senescence, the abemaciclib and ABT-263 combination decreased it only in MDA-MB-231 cells. This decrease of p21 expression was relieved by caspase inhibition, and p21 was colocalized with caspase-3 in the cytoplasm of MDA-MB-231 cells. Alternatively, small interfering RNA-mediated knockdown of p21 rendered caspase-3-negative MCF-7 cells susceptible to abemaciclib and ABT-263, as well as TNF-related apoptosis-inducing ligand. Furthermore, a clinical database analysis showed that p21high breast cancer patients had a poorer prognosis compared to p21low patients. These results suggest that cytoplasmic p21 plays a protective role in apoptosis of CDK4/6 inhibitor-induced senescent breast cancer cells.

Keywords:  ABT-263; abemaciclib; breast cancer; p21; senescence

DOI:  https://doi.org/10.1002/cam4.4410
Cancers (Basel). 2021 Oct 25. pii: 5343. [Epub ahead of print]13(21):

Implications of TGFβ Signaling and CDK Inhibition for the Treatment of Breast Cancer.

Joseph T Decker, Jeffrey A Ma, Lonnie D Shea, Jacqueline S Jeruss.

  TGFβ signaling enacts tumor-suppressive functions in normal cells through promotion of several cell regulatory actions including cell-cycle control and apoptosis. Canonical TGFβ signaling proceeds through phosphorylation of the transcription factor, SMAD3, at the C-terminus of the protein. During oncogenic progression, this tumor suppressant phosphorylation of SMAD3 can be inhibited. Overexpression of cyclins D and E, and subsequent hyperactivation of cyclin-dependent kinases 2/4 (CDKs), are often observed in breast cancer, and have been associated with poor prognosis. The noncanonical phosphorylation of SMAD3 by CDKs 2 and 4 leads to the inhibition of tumor-suppressive function of SMAD3. As a result, CDK overactivation drives oncogenic progression, and can be targeted to improve clinical outcomes. This review focuses on breast cancer, and highlights advances in the understanding of CDK-mediated noncanonical SMAD3 phosphorylation. Specifically, the role of aberrant TGFβ signaling in oncogenic progression and treatment response will be examined to illustrate the potential for therapeutic discovery in the context of cyclins/CDKs and SMAD3.

Keywords:  CDK inhibitor; SMAD3; TGFβ; breast cancer

DOI:  https://doi.org/10.3390/cancers13215343