bims-cyhorp 2023-02-12 papers

bims-cyhorp

Biomed News

on Cyclin-dependent kinases in hormone receptor positive breast cancer

Issue of 2023–02–12
thirteen papers selected by
Piotr Okupski,

Ribociclib-induced hepatotoxicity.
Pretreatment neutrophil to lymphocyte ratio as prognostic factor in metastatic breast cancer treated with cyclin dependent kinase 4/6 inhibitors.
Vitiligo-like lesions associated with ribociclib in a woman with metastatic breast cancer.
Efficacy and safety results by menopausal status in monarchE: adjuvant abemaciclib combined with endocrine therapy in patients with HR+, HER2-, node-positive, high-risk early breast cancer.
Overall survival associated with CDK4/6 inhibitors in patients with HR+/HER2- metastatic breast cancer in the United States: A SEER-Medicare population-based study.
Safety and Feasibility of Radiation Therapy Combined with CDK 4/6 Inhibitors in the Management of Advanced Breast Cancer.
Cellular senescence in the response of HR+ breast cancer to radiotherapy and CDK4/6 inhibitors.
The BET inhibitor/degrader ARV-825 prolongs the growth arrest response to Fulvestrant + Palbociclib and suppresses proliferative recovery in ER-positive breast cancer.
What's the reality for CDK4/6 inhibitors: Clinical trials or real-world evidence?
Quality of life with palbociclib plus fulvestrant versus placebo plus fulvestrant in postmenopausal women with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer: patient-reported outcomes from the FLIPPER trial.
Deciphering the Immunomodulatory Role of Cyclin-Dependent Kinase 4/6 Inhibitors in the Tumor Microenvironment.
Efficacy of subsequent treatments in patients with hormone-positive advanced breast cancer who had disease progression under CDK 4/6 inhibitor therapy.
CCNE1 and PLK1 mediates resistance to palbociclib in HR+/HER2- metastatic breast cancer.

J Oncol Pharm Pract. 2023 Feb 10. 10781552231154009

Ribociclib-induced hepatotoxicity.

Muhammed Muhiddin Er, Murat Araz, Engin Hendem, Melek Karakurt Eryılmaz, Mehmet Artaç.

   INTRODUCTION: Cyclin-dependent kinase (CDK) 4/6 inhibitors have shown a different adverse effect. In this case, persistent grade 3 hepatoxicity was observed after ribociclib. Therefore, ribociclib therapy was stopped, and then palbociclib was introduced. Transaminase levels returned to normal by switching to palbociclib therapy.
CASE REPORT: 71-year-old postmenopausal female patient with luminal subtypes of metastatic breast cancer treated with ribociclib.
MANAGEMENT & OUTCOME: Grade 3 hepatotoxicity secondary to ribociclib developed. She was successfully treated with palbociclib 125 mg.
DISCUSSION: In our case, palbociclib was started with a full dose, to increase treatment success. Starting with a 125 mg dose was not cause any toxicity. Nevertheless, laboratory follow-up is required in terms of neutropenia and increased transaminases.

Keywords:  hepatotoxicity; metastatic breast cancer; ribociclib

DOI:  https://doi.org/10.1177/10781552231154009
Front Oncol. 2022 ;12 1105587

Pretreatment neutrophil to lymphocyte ratio as prognostic factor in metastatic breast cancer treated with cyclin dependent kinase 4/6 inhibitors.

Pauline Rottier, George Emile, Alison Johnson, Christelle Levy, Djelila Allouache, Ioana Hrab, Carine Segura, Adeline Morel, Maud Villemin, Coraline Dubot-Poitelon, Louis Boismoreau, François Cherifi, Justine Lequesne, Angélique Da Silva.

   Background: Cyclin dependent kinase inhibitors (CdK4/6i) changed the course of hormone receptor positive (HR+) HER2 negative (HER2-) metastatic breast cancer (mBC). To date, no factors have been shown to predict response to CdK4/6i. Neutrophil-to-lymphocyte ratio (NLR), an indicator of the host systemic inflammatory response, is an independent prognostic factor for survival in cancers. We conducted this study to evaluate the impact of NLR on survival in mBC patients treated with first line CdK4/6i.
Methods: All mBC patients treated with first line CdK4/6i between November 2015 and December 2019 were retrospectively included. The biomarker threshold was defined using ROC curves. We analyzed progression free survival (PFS), overall survival (OS), 12-month PFS and response rate according to NLR in univariable and multivariable analysis.
Results: A total of 126 patients treated with palbociclib (n=101), ribociclib (n=18) or abemaciclib (n=7) were included, with a median follow-up of 33 months [range: 2.9-57]. Median age was 65 years [29-86], 40% patients had good performance status (ECOG-PS 0). Most patients (71%) were included at the metastatic relapse stage and 29% had only bone metastases. Median PFS and median OS were 27 and 51 months, respectively. High NLR (≥ 2.53) was significantly associated with worse PFS (Hazard Ratio (HR)=0.50, CI95% = [0.32-0.79]) and worse OS (HR=0.45, [CI95%: 0.23-0.87]). In multivariable analysis, NLR and ECOG PS were independently factors associated with PFS (p=0.016 and p=0.001, respectively).
Conclusion: High NLR was associated with worse PFS and OS in HR+ HER2- mBC patients treated with first line CdK4/6i. NLR is a reliable and inexpensive prognostic marker, easily accessible in routine clinical practice, which could help optimize the therapeutic strategy. These results need to be confirmed in larger prospective studies.

Keywords:  NLR; cyclin dependent kinase inhibitor; hormone dependent cancer; metastatic breast cancer; prognostic factor

DOI:  https://doi.org/10.3389/fonc.2022.1105587
J Oncol Pharm Pract. 2023 Feb 09. 10781552231156521

Vitiligo-like lesions associated with ribociclib in a woman with metastatic breast cancer.

Alper Türkel, Cengiz Karaçin, İrem Öner, Erdoğan Şeyran, Berna Öksüzoğlu.

   INTRODUCTION: Cyclin-dependent kinase 4/6 inhibitors are new generation drugs that have recently been used in patients with hormone receptor-positive and human epidermal growth factor receptor 2-negativenegative metastatic breast cancer. Recent studies have shown that the use of cyclin-dependent kinase 4/6 inhibitors significantly improves the outcomes of these patients. The most common side effects of cyclin-dependent kinase 4/6 inhibitors are hematological toxicity, gastrointestinal side effects, and fatigue. We aimed to present a case of metastatic breast cancer who was treated with ribociclib and developed vitiligo-like lesions after treatment.
CASE REPORT: A 56-year-old female patient was diagnosed with locally advanced hormone receptor (+)/human epidermal growth factor receptor 2 (-) breast cancer in May 2000. She was followed up with hormonal therapy after adjuvant chemotherapy and radiotherapy. The patient progressed with lung metastases in 2012. Ribociclib, anastrozole, and leuprolide acetate were started in November 2021 after multiple-line chemotherapy. After six cycles of ribociclib, vitiligo-like lesions that developed in the last 1 month were detected on the upper extremities, both hands, neck, chest, and upper back.
MANAGEMENT AND OUTCOME: The patient was referred to dermatology. Topical immunosuppressive therapy and oral corticosteroids were recommended. At the first and third-month follow-up examinations, vitiligo-like lesions were observed to persist.
DISCUSSION: Vitiligo-like lesions are not a life-threatening side effect. However, it significantly affects the quality of life and disrupts the patient's compliance with treatment. Cyclin-dependent kinase 4/6 inhibitors can inhibit cell division or cause premature cell death by acting on the melanocyte cell cycle.

Keywords:  Ribociclib; cyclin-dependent kinase 4/6; metastatic breast cancer; vitiligo-like lesions

DOI:  https://doi.org/10.1177/10781552231156521
Ther Adv Med Oncol. 2023 ;15 17588359231151840

Efficacy and safety results by menopausal status in monarchE: adjuvant abemaciclib combined with endocrine therapy in patients with HR+, HER2-, node-positive, high-risk early breast cancer.

Shani Paluch-Shimon, Patrick Neven, Jens Huober, Irfan Cicin, Matthew P Goetz, Chikako Shimizu, Chiun-Sheng Huang, Hans Joachim Lueck, Jane Beith, Eriko Tokunaga, Jessica Reyes Contreras, Rosane Oliveira de Sant'Ana, Ran Wei, Ashwin Shahir, Sarah C Nabinger, Tammy Forrester, Stephen R D Johnston, Nadia Harbeck.

   Background: Abemaciclib is the first and only cyclin-dependent kinases 4 and 6 inhibitor approved for adjuvant treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), node-positive, and high-risk early breast cancer (EBC), with indications varying by geography. Premenopausal patients with HR+, HER2- tumors may have different tumor biology and treatment response compared to postmenopausal patients.
Objectives: We describe the efficacy and safety of abemaciclib plus endocrine therapy (ET) for the large subgroup of premenopausal patients with HR+, HER2- EBC in monarchE.
Design: Randomized patients (1:1) received adjuvant ET with or without abemaciclib for 2 years plus at least 3 additional years of ET as clinically indicated.
Methods: Patients were stratified by menopausal status (premenopausal versus postmenopausal) at diagnosis. Standard ET (tamoxifen or aromatase inhibitor) with or without gonadotropin-releasing hormone agonist was determined by physician's choice. Invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) by menopausal status were assessed at data cutoff on 1 April 2021 (median follow-up of 27 months).
Results: Among randomized patients, 2451 (43.5%) were premenopausal and 3181 (56.4%) were postmenopausal. The choice of ET for premenopausal patients varied considerably between countries. Treatment benefit was consistent across menopausal status, with a numerically greater effect size in premenopausal patients. For premenopausal patients, abemaciclib with ET resulted in a 42.2% and 40.3% reduction in the risk of developing IDFS and DRFS events, respectively. Absolute improvement at 3 years was 5.7% for IDFS and 4.4% for DRFS rates. Safety profile for premenopausal patients was consistent with the overall safety population.
Conclusion: Abemaciclib with ET demonstrated clinically meaningful treatment benefit for IDFS and DRFS versus ET alone regardless of menopausal status and first ET, with a numerically greater benefit in the premenopausal compared to the postmenopausal population. Safety data in premenopausal patients are consistent with the overall safety profile of abemaciclib.

Keywords:  abemaciclib; early breast cancer; high risk; monarchE; premenopausal

DOI:  https://doi.org/10.1177/17588359231151840
Cancer. 2023 Feb 09.

Overall survival associated with CDK4/6 inhibitors in patients with HR+/HER2- metastatic breast cancer in the United States: A SEER-Medicare population-based study.

Ravi K Goyal, Hua Chen, Susan M Abughosh, Holly M Holmes, Sean D Candrilli, Michael L Johnson.

   BACKGROUND: Evidence on overall survival (OS) with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors is generally limited to data from clinical trials or a few observational studies with limited generalizability to Medicare population. The aim of this study was to determine OS benefits associated with CDK4/6 inhibitors in older Medicare patients with hormone receptor (HR)-positive and human epidermal growth factor receptor-2 overexpressing (HER2-) metastatic breast cancer (MBC).
METHODS: In a retrospective cohort design, female patients aged ≥65 years with diagnosis of HR+/HER2- MBC from 2015 to 2017 who initiated first-line systemic therapy within 12 months of MBC diagnosis were selected from the Survey Epidemiology and End Results-Medicare database. The effect of treatment type (endocrine therapy [ET]+CDK4/6 inhibitor vs. ET alone) on OS was analyzed using Kaplan-Meier methods and multivariable Cox regression models. Adjusted hazard ratio (aHR) and 95% CIs were estimated.
RESULTS: A total of 630 eligible patients were identified (169 patients treated with ET+CDK4/6 inhibitor and 461 patients treated with ET alone). In the Kaplan-Meier analysis, OS rate at 3 years after first-line treatment initiation was 73.0% for ET+CDK4/6 inhibitor versus 49.1% for ET alone (log-rank p < .0001). In Cox regression analysis, first-line ET+CDK4/6 inhibitor therapy was associated with 41% lower rate of mortality versus ET alone (aHR, 0.590; 95% CI, 0.423-0.823).
CONCLUSIONS: The findings of this real-world study demonstrate significant OS benefit associated with ET+CDK4/6 inhibitor therapy over ET alone in an older Medicare population of patients with HR+/HER2- MBC, largely consistent with the evidence from clinical trials.

Keywords:  CDK4/6 inhibitors; SEER Medicare; metastatic breast cancer; overall survival; palbociclib

DOI:  https://doi.org/10.1002/cncr.34675
Cancers (Basel). 2023 Jan 22. pii: 690. [Epub ahead of print]15(3):

Safety and Feasibility of Radiation Therapy Combined with CDK 4/6 Inhibitors in the Management of Advanced Breast Cancer.

Marcin Kubeczko, Dorota Gabryś, Marzena Gawkowska, Anna Polakiewicz-Gilowska, Alexander J Cortez, Aleksandra Krzywon, Grzegorz Woźniak, Tomasz Latusek, Aleksandra Leśniak, Katarzyna Świderska, Marta Mianowska-Malec, Barbara Łanoszka, Konstanty Chomik, Mateusz Gajek, Anna Michalik, Elżbieta Nowicka, Rafał Tarnawski, Tomasz Rutkowski, Michał Jarząb.

  The addition of CDK4/6 inhibitors to endocrine therapy in advanced hormone receptor-positive HER2-negative breast cancer has led to practice-changing improvements in overall survival. However, data concerning the safety of CDK4/6i combination with radiotherapy (RT) are conflicting. A retrospective evaluation of 288 advanced breast cancer patients (pts) treated with CDK4/6i was performed, and 100 pts also received RT. Forty-six pts received 63 RT courses concurrently and fifty-four sequentially before CDK4/6i initiation (76 RT courses). Neutropenia was common (79%) and more frequent during and after concurrent RT than sequential RT (86% vs. 76%); however, CDK4/6i dose reduction rates were similar. In patients treated with CDK4/6i alone, the dose reduction rate was 42% (79 pts) versus 38% with combined therapy, and 5% discontinued treatment due to toxicity in the combined group. The risk of CDK4/6i dose reduction was correlated with neutropenia grade, RT performed within the first two CDK4/6i cycles, and more than one concurrent RT; a tendency was observed in concurrent bone irradiation. However, on multivariate regression analysis, only ECOG 1 performance status and severe neutropenia at the beginning of the second cycle were found to be associated with a higher risk of CDK4/6i dose reduction. This largest single-center experience published to date confirmed the acceptable safety profile of the CDK4/6i and RT combination without a significantly increased toxicity compared with CDK4/6i alone. However, one might delay RT for the first two CDK4/6i cycles, when myelotoxic AE are most common.

Keywords:  CDK 4/6 inhibitors; abemaciclib; advanced breast cancer; palbociclib; radiotherapy; ribociclib

DOI:  https://doi.org/10.3390/cancers15030690
J Transl Med. 2023 Feb 10. 21(1): 110

Cellular senescence in the response of HR+ breast cancer to radiotherapy and CDK4/6 inhibitors.

Vanessa Klapp, Aitziber Buqué, Norma Bloy, Ai Sato, Takahiro Yamazaki, Xi Kathy Zhou, Silvia C Formenti, Lorenzo Galluzzi, Giulia Petroni.

   BACKGROUND: Preclinical evidence from us and others demonstrates that the anticancer effects of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors can be enhanced with focal radiation therapy (RT), but only when RT is delivered prior to (rather than after) CDK4/6 inhibition. Depending on tumor model, cellular senescence (an irreversible proliferative arrest that is associated with the secretion of numerous bioactive factors) has been attributed beneficial or detrimental effects on response to treatment. As both RT and CDK4/6 inhibitors elicit cellular senescence, we hypothesized that a differential accumulation of senescent cells in the tumor microenvironment could explain such an observation, i.e., the inferiority of CDK4/6 inhibition with palbociclib (P) followed by RT (P→RT) as compared to RT followed by palbociclib (RT→P).
METHODS: The impact of cellular senescence on the interaction between RT and P was assessed by harnessing female INK-ATTAC mice, which express a dimerizable form of caspase 8 (CASP8) under the promoter of cyclin dependent kinase inhibitor 2A (Cdkn2a, coding for p16Ink4), as host for endogenous mammary tumors induced by the subcutaneous implantation of medroxyprogesterone acetate (MPA, M) pellets combined with the subsequent oral administration of 7,12-dimethylbenz[a]anthracene (DMBA, D). This endogenous mouse model of HR+ mammary carcinogenesis recapitulates key immunobiological aspects of human HR+ breast cancer. Mice bearing M/D-driven tumors were allocated to RT, P or their combination in the optional presence of the CASP8 dimerizer AP20187, and monitored for tumor growth, progression-free survival and overall survival. In parallel, induction of senescence in vitro, in cultured human mammary hormone receptor (HR)+ adenocarcinoma MCF7 cells, triple negative breast carcinoma MDA-MB-231 cells and mouse HR+ mammary carcinoma TS/A cells treated with RT, P or their combination, was determined by colorimetric assessment of senescence-associated β-galactosidase activity after 3 or 7 days of treatment.
RESULTS: In vivo depletion of p16Ink4-expressing (senescent) cells ameliorated the efficacy of P→RT (but not that of RT→P) in the M/D-driven model of HR+ mammary carcinogenesis. Accordingly, P→RT induced higher levels of cellular senescence than R→TP in cultured human and mouse breast cancer cell lines.
CONCLUSIONS: Pending validation in other experimental systems, these findings suggest that a program of cellular senescence in malignant cells may explain (at least partially) the inferiority of P→RT versus RT→P in preclinical models of HR+ breast cancer.

Keywords:  INK-ATTAC mice; MCF7 cells; MDA-MB-231 cells; MPA/DMBA-driven mammary carcinogenesis; TS/A cells; β-galactosidase

DOI:  https://doi.org/10.1186/s12967-023-03964-4
Front Oncol. 2022 ;12 966441

The BET inhibitor/degrader ARV-825 prolongs the growth arrest response to Fulvestrant + Palbociclib and suppresses proliferative recovery in ER-positive breast cancer.

Ryan M Finnegan, Ahmed M Elshazly, Nipa H Patel, Liliya Tyutyunyk-Massey, Tammy H Tran, Vishnu Kumarasamy, Erik S Knudsen, David A Gewirtz.

  Anti-estrogens or aromatase inhibitors in combination with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are the current standard of care for estrogen receptor-positive (ER+) Her-2 negative metastatic breast cancer. Although these combination therapies prolong progression-free survival compared to endocrine therapy alone, the growth-arrested state of residual tumor cells is clearly transient. Tumor cells that escape what might be considered a dormant or quiescent state and regain proliferative capacity often acquire resistance to further therapies. Our studies are based upon the observation that breast tumor cells arrested by Fulvestrant + Palbociclib enter into states of both autophagy and senescence from which a subpopulation ultimately escapes, potentially contributing to recurrent disease. Autophagy inhibition utilizing pharmacologic or genetic approaches only moderately enhanced the response to Fulvestrant + Palbociclib in ER+ MCF-7 breast tumor cells, slightly delaying proliferative recovery. In contrast, the BET inhibitor/degrader, ARV-825, prolonged the growth arrested state in both p53 wild type MCF-7 cells and p53 mutant T-47D cells and significantly delayed proliferative recovery. In addition, ARV-825 added after the Fulvestrant + Palbociclib combination promoted apoptosis and demonstrated efficacy in resistant RB deficient cell lines. These studies indicate that administration of BET inhibitors/degraders, which are currently being investigated in multiple clinical trials, may potentially improve standard of care therapy in metastatic ER+ breast cancer patients and may further prolong progression-free survival.

Keywords:  ARV-825; Palbociclib; autophagy; cancer; fulvestrant; senescence

DOI:  https://doi.org/10.3389/fonc.2022.966441
Cancer. 2023 Feb 09.

What's the reality for CDK4/6 inhibitors: Clinical trials or real-world evidence?

Dario Trapani, Erica L Mayer.



Keywords:  CDK4/6 inhibitor; breast cancer; geriatric oncology; metastatic; real world evidence

DOI:  https://doi.org/10.1002/cncr.34672
Ther Adv Med Oncol. 2023 ;15 17588359221148921

Quality of life with palbociclib plus fulvestrant versus placebo plus fulvestrant in postmenopausal women with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer: patient-reported outcomes from the FLIPPER trial.

Ariadna Tibau, M Teresa Martínez, Manuel Ramos, Luis De La Cruz-Merino, Ana Santaballa, Miriam O'Connor, Noelia Martínez-Jañez, Fernando Moreno, Isaura Fernández, Juan Antonio Virizuela, Jesús Alarcón, Juan de La Haba-Rodríguez, Pedro Sánchez-Rovira, Cinta Rosa Albacar, Coralia Bueno Muiño, Catherine Kelly, Maribel Casas, Susana Bezares, Libertad Rosell, Joan Albanell.

   Background: In the FLIPPER trial, palbociclib/fulvestrant significantly improved progression-free survival (PFS) compared with placebo/fulvestrant in postmenopausal women with HR+/HER2- advanced breast cancer (ABC).
Objective: We assessed health-related quality of life (QoL) using patient-reported outcomes (PROs).
Design and methods: In this phase II double-blinded study, PROs were assessed at baseline after every three cycles and at the end of the treatment using the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23. Time to deterioration (TTD) in global health status (GHS)/QoL was defined as a decrease of ⩾10 points. Changes from baseline (CFB) and TTD were analysed using linear mixed-effect and Cox regression models, respectively.
Results: Of the 189 randomised (1:1) patients, 178 (94%) completed ⩾1 post-baseline assessment; 50% received ⩾22 cycles of study treatment, with a questionnaire compliance >90%. Mean baseline scores were comparable between arms. GHS/QoL scores were maintained throughout the palbociclib/fulvestrant treatment. CFB showed significant differences for GHS/QoL, appetite loss, constipation and systemic therapy side effect scores favouring placebo/fulvestrant. TTD in GHS/QoL was delayed in placebo/fulvestrant versus palbociclib/fulvestrant [30.3 versus 11.1 months; adjusted hazard ratio (aHR): 1.57, 95% CI: 1.03-2.39, p = 0.036]; this difference was not significant in patients with progressive disease (aHR: 1.2, 95% CI: 0.6-2.2, p = 0.658). No statistically significant differences in TTD were found for the other QLQ-C30 and QLQ-BR23 scales.
Conclusions: Although TTD in GHS/QoL was prolonged with placebo/fulvestrant, no differences were observed on other functional or symptom scales. This finding and the improvement in PFS support the combination of palbociclib/fulvestrant as a beneficial therapeutic option for HR+/HER2- ABC.
Trial registration number: Sponsor Study Code: GEICAM/2014-12EudraCT Number: 2015-002437-21ClinTrials.gov reference: NCT02690480.

Keywords:  CDK4/6 inhibitor; advanced breast cancer; fulvestrant; palbociclib; patient-reported outcomes; quality of life

DOI:  https://doi.org/10.1177/17588359221148921
Int J Mol Sci. 2023 Jan 23. pii: 2236. [Epub ahead of print]24(3):

Deciphering the Immunomodulatory Role of Cyclin-Dependent Kinase 4/6 Inhibitors in the Tumor Microenvironment.

Pratibha Pandey, Fahad Khan, Tarun Kumar Upadhyay, Amit Baran Sharangi.

  Cancer is characterized by persistent cell proliferation driven by aberrant cell cycle regulation and stimulation of cyclin-dependent kinases (CDKs). A very intriguing and potential approach for the development of antitumor medicines is the suppression of CDKs that lead to induction of apoptosis and cell cycle arrest. The shift of the cell cycle from the G0/G1 phase to the S phase, which is characterized by active transcription and synthesis, depends on the development of the cyclin D-CDK4/6 complex. A precise balance between anticancer activity and general toxicity is demonstrated by CDK inhibitors, which can specifically block CDK4/6 and control the cell cycle by reducing the G1 to S phase transition. CDK4/6 inhibitors have recently been reported to exhibit significant cell growth inhibition via modulating the tumour microenvironment in cancerous cells. One significant new understanding is that these inhibitors serve important functions in the interaction among tumour cells and the host immune system in addition to being cytostatic. Herein, we discuss the biological significance of CDK4/6 inhibitors in cancer therapeutics, as well as their biological impact on T cells and other important immune cells. Furthermore, we explore the integration of preclinical findings of these pharmaceuticals' ability to enhance antitumor immunity.

Keywords:  CDK4; CDK6; cancer therapy; cell cycle; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms24032236
BMC Cancer. 2023 Feb 10. 23(1): 136

Efficacy of subsequent treatments in patients with hormone-positive advanced breast cancer who had disease progression under CDK 4/6 inhibitor therapy.

Cengiz Karacin, Berna Oksuzoglu, Ayşe Demirci, Merve Keskinkılıç, Naziyet Köse Baytemür, Funda Yılmaz, Oğuzhan Selvi, Dilek Erdem, Esin Avşar, Nail Paksoy, Necla Demir, Sema Sezgin Göksu, Sema Türker, Ertuğrul Bayram, Abdüssamet Çelebi, Hatice Yılmaz, Ömer Faruk Kuzu, Seda Kahraman, İvo Gökmen, Abdullah Sakin, Ali Alkan, Erdinç Nayır, Muzaffer Uğraklı, Ömer Acar, İsmail Ertürk, Hacer Demir, Ferit Aslan, Özlem Sönmez, Taner Korkmaz, Özde Melisa Celayir, İbrahim Karadağ, Erkan Kayıkçıoğlu, Teoman Şakalar, İlker Nihat Öktem, Tülay Eren, Enes Urul, Eda Eylemer Mocan, Ziya Kalkan, Nilgün Yıldırım, Yakup Ergün, Baran Akagündüz, Serdar Karakaya, Engin Kut, Fatih Teker, Burçin Çakan Demirel, Kubilay Karaboyun, Elvina Almuradova, Olçun Ümit Ünal, Abdilkerim Oyman, Deniz Işık, Kerem Okutur, Buğra Öztosun, Burcu Belen Gülbağcı, Mehmet Emin Kalender, Elif Şahin, Mustafa Seyyar, Özlem Özdemir, Fatih Selçukbiricik, Metin Kanıtez, İsa Dede, Mahmut Gümüş, Erhan Gökmen, Arzu Yaren, Serkan Menekşe, Senar Ebinç, Sercan Aksoy, Gökşen İnanç İmamoğlu, Mustafa Altınbaş, Bülent Çetin, Başak Oyan Uluç, Özlem Er, Nuri Karadurmuş, Atike Pınar Erdoğan, Mehmet Artaç, Özgür Tanrıverdi, İrfan Çiçin, Mehmet Ali Nahit Şendur, Esin Oktay, İbrahim Vedat Bayoğlu, Semra Paydaş, Adnan Aydıner, Derya Kıvrak Salim, Çağlayan Geredeli, Tuğba Yavuzşen, Mutlu Doğan, İlhan Hacıbekiroğlu.

   BACKGROUND: There is no standard treatment recommended at category 1 level in international guidelines for subsequent therapy after cyclin-dependent kinase 4/6 inhibitor (CDK4/6) based therapy. We aimed to evaluate which subsequent treatment oncologists prefer in patients with disease progression under CDKi. In addition, we aimed to show the effectiveness of systemic treatments after CDKi and whether there is a survival difference between hormonal treatments (monotherapy vs. mTOR-based).
METHODS: A total of 609 patients from 53 centers were included in the study. Progression-free-survivals (PFS) of subsequent treatments (chemotherapy (CT, n:434) or endocrine therapy (ET, n:175)) after CDKi were calculated. Patients were evaluated in three groups as those who received CDKi in first-line (group A, n:202), second-line (group B, n: 153) and ≥ 3rd-line (group C, n: 254). PFS was compared according to the use of ET and CT. In addition, ET was compared as monotherapy versus everolimus-based combination therapy.
RESULTS: The median duration of CDKi in the ET arms of Group A, B, and C was 17.0, 11.0, and 8.5 months in respectively; it was 9.0, 7.0, and 5.0 months in the CT arm. Median PFS after CDKi was 9.5 (5.0-14.0) months in the ET arm of group A, and 5.3 (3.9-6.8) months in the CT arm (p = 0.073). It was 6.7 (5.8-7.7) months in the ET arm of group B, and 5.7 (4.6-6.7) months in the CT arm (p = 0.311). It was 5.3 (2.5-8.0) months in the ET arm of group C and 4.0 (3.5-4.6) months in the CT arm (p = 0.434). Patients who received ET after CDKi were compared as those who received everolimus-based combination therapy versus those who received monotherapy ET: the median PFS in group A, B, and C was 11.0 vs. 5.9 (p = 0.047), 6.7 vs. 5.0 (p = 0.164), 6.7 vs. 3.9 (p = 0.763) months.
CONCLUSION: Physicians preferred CT rather than ET in patients with early progression under CDKi. It has been shown that subsequent ET after CDKi can be as effective as CT. It was also observed that better PFS could be achieved with the subsequent everolimus-based treatments after first-line CDKi compared to monotherapy ET.

Keywords:  Advanced breast cancer; Cyclin-dependent kinase; Endocrine treatment; Everolimus; Fulvestrant; Hormonotherapy; Palbociclib; Ribociclib

DOI:  https://doi.org/10.1186/s12885-023-10609-8
Clin Cancer Res. 2023 Feb 07. pii: CCR-22-2206. [Epub ahead of print]

CCNE1 and PLK1 mediates resistance to palbociclib in HR+/HER2- metastatic breast cancer.

Ángel Guerrero-Zotano, Stefania Belli, Christoph Zielinski, Miguel Gil-Gil, Antonio Fernandez-Serra, Manuel Ruiz-Borrego, Eva Maria Ciruelos Gil, Javier Pascual, Montserrat Muñoz-Mateu, Begoña Bermejo, Mireia Margeli Vila, Antonio Antón, Laura Murillo, Bella Nisenbaum, Yuan Liu, Jesus Herranz, Daniel Fernandez Garcia, Rosalía Caballero, José A López-Guerrero, Roberto Bianco, Luigi Formisano, Nicholas Turner, Miguel Martín.

PURPOSE: In HR+/HER2- metastatic breast cancer (MBC) is imperative to identify patients who respond poorly to CDK4/6i and to discover therapeutic targets to reverse this resistance. Non-luminal breast cancer subtype and high levels of CCNE1 are candidate biomarkers in this setting but further validation is needed.
EXPERIMENTAL DESIGN: We performed mRNA gene expression profiling and correlation with progression-free-survival (PFS) on 455 tumor samples included in the phase III PEARL study, that assigned HR+/HER2- MBC patients to receive palbociclib+ET vs capecitabine. ER+/HER2- breast cancer cell lines were used to generate and characterize resistance to palbociclib+ET.
RESULTS: Non-luminal subtype was more prevalent in metastatic (14%) than in primary tumor samples (4%). Patients with non-luminal tumors had median PFS of 2.4months (m) with palbociclib+ET and 9.3m with capecitabine; HR:4.16, adjusted p-value<0.0001. Tumors with high CCNE1 expression (above median) had also worse median PFS with palbociclib+ET (6.2m) than with capecitabine (9.3m); HR:1.55, adjusted p-value=0.0036. In patients refractory to palbociclib+ET (PFS in the lower quartile) we found higher levels of Polo Like Kinase 1 (PLK1). In an independent data set (PALOMA3), tumors with high PLK1 show worse median PFS than those with low PLK1 expression under palbociclib+ET treatment. In ER+/HER2- cell line models we show that PLK1 inhibition reverses resistance to palbociclib+ET.
CONCLUSIONS: We confirm the association of non-luminal subtype and CCNE1 with resistance to CDK4/6i+ET in HR+ MBC. High levels of PLK1 mRNA identify patients with poor response to palbociclib, suggesting PLK1 could also play a role in the setting of resistance to CDK4/6i.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-2206