Cancer Research and Treatment

Original Articles

Pre-treatment Ki-67 Index for Everolimus Efficacy in Patients with Hormone Receptor–Positive and Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: A Multicenter Cohort Study: Yujing Tan, Hanfang Jiang, Fei Ma, Bo Lan, Yang Luo, Jiayu Wang, Pin Zhang, Binghe Xu, Weihong Zhao, Ying Fan; Received May 12, 2025 Accepted January 11, 2026 Published online January 14, 2026; DOI: https://doi.org/10.4143/crt.2025.506 [Epub ahead of print]

Abstract PDF Supplementary Material: Purpose
The study aims to explore the predictive value of the Ki-67 index for everolimus efficacy in patients with hormone receptor–positive and human epidermal growth factor receptor 2–negative (HR+/HER2–) advanced breast cancer (ABC).
Materials and Methods
We collected data on 2,518 cancer patients who received everolimus treatment from three cancer centers in China. Their clinicopathologic characteristics were retrospectively collected. A training cohort and a validation cohort were developed.
Results
A total of 300 patients with HR+/HER2– ABC were included in the study, with 200 patients in the training cohort and 100 patients in the validation cohort. When analyzing the Ki-67 index from 14% to 50%, only the Ki-67 cutoff of 40% was found to be significantly correlated with progression-free survival for patients in the training cohort. Multivariate Cox analyses further showed that Ki-67 index of 40% (p=0.03) was significantly associated with progression-free survival (PFS) in patients treated with everolimus. Patients with Ki-67 less than 40% had an improved PFS of 7.0 months, significantly better than 4.6 months for patients with Ki-67 more than 40% (p=0.03; hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.46 to 0.97). In the validation cohort, patients with a Ki-67 index of less than 40% had a significantly longer PFS of 4.3 months (2.1 vs. 4.3 months, p < 0.001; HR, 0.29; 95% CI, 0.17 to 0.51).
Conclusion
The Ki-67 cutoff value of 40% was identified as an optimal index for predicting the efficacy of everolimus, which may help with the management of everolimus in Chinese patients with HR+/HER2– ABC.

863 View
51 Download

Genitourinary cancer

Efficacy and Safety of Lenvatinib Plus Everolimus in Metastatic Renal Cell Carcinoma after Immune Checkpoint and VEGFR Tyrosine Kinase Inhibitors Treatment: So Heun Lee, Inkeun Park, Shinkyo Yoon, Jae Lyun Lee; Cancer Res Treat. 2026;58(3):897-905. Published online August 13, 2025; DOI: https://doi.org/10.4143/crt.2025.628

Abstract PDF Supplementary Material PubReader ePub

Purpose
Real-world data on the efficacy and safety of lenvatinib plus everolimus in metastatic renal cell carcinoma (RCC) after failure of immune checkpoint inhibitors (ICIs) and/or vascular endothelial growth factor receptor (VEGFR)–targeted tyrosine kinase inhibitors (TKIs) remain limited.
Materials and Methods
This single-center retrospective study included patients with metastatic RCC treated with lenvatinib plus everolimus as second-line or later therapy at Asan Medical Center, Korea, between September 2017 and June 2024. Data on dose adjustments, treatment response, survival, and adverse events were collected from electronic medical records. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS); secondary endpoints included overall survival (OS), time to progression, adverse events, and prognostic factors.
Results
A total of 83 patients were included, predominantly with clear cell histology (90.4%). The median number of prior therapies was four (range, 1 to 7), with 80.7% receiving the combination as fourth-line or beyond. All had prior anti-angiogenic TKI exposure, 86.7% had received ICIs, and 37.3% had prior mTOR inhibitor therapy. The ORR was 40.0%, with disease control at 81.3%. Median PFS and OS were 5.4 months (95% confidence intervals [CI], 4.4 to 6.8) and 8.5 months (95% CI, 6.3 to 12.1), respectively. Efficacy was consistent across key subgroups. During the treatment, lenvatinib dose reductions were required in 55.4% of patients, and 26.5% experienced treatment interruptions. Grade ≥ 3 proteinuria occurred in 22.9%.
Conclusion
Lenvatinib plus everolimus demonstrated promising efficacy in heavily pretreated patients with metastatic RCC, including those previously exposed to VEGFR-targeted TKIs and/or ICIs. Further studies are warranted to optimize treatment strategies in this patient population.

Citations

Citations to this article as recorded by

Diosmetin alleviates the immunosuppressive tumor microenvironment in esophageal squamous cell carcinoma by dually inhibiting angiogenesis and promoting CD8+T cell cytotoxicity
Xiaoxuan Duan, Xiaoshuo Dai, Xiaoya Li, Yingfei Wang, Kai Zhang, Wei Chen, Yihuan Chen, Jimin Zhao, Yan Qiao, Xiang Li, Saijun Mo, Fang Tian, Ziming Dong, Kangdong Liu, Jing Lu
Phytomedicine.2026; : 158036. CrossRef

2,334 View
122 Download
1 Crossref

Breast cancer

Comparison of the Effectiveness and Clinical Outcome of Everolimus Followed by CDK4/6 Inhibitors with the Opposite Treatment Sequence in Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: Hyehyun Jeong, Jae Ho Jeong, Jeong Eun Kim, Jin-Hee Ahn, Kyung Hae Jung, Sung-Bae Kim; Cancer Res Treat. 2022;54(2):469-477. Published online June 23, 2021; DOI: https://doi.org/10.4143/crt.2021.205

Abstract PDF Supplementary Material PubReader ePub

Purpose
In hormone receptor-positive, human epidermal growth factor receptor 2–negative metastatic breast cancer (HR+ HER2–MBC), the mainstay treatment options include cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and everolimus (EVE) in combination with endocrine treatment. This study aims to compare the outcomes of the following treatment sequences: CDK4/6i followed by EVE and EVE followed by CDK4/6i.
Materials and Methods
Data from HR+ HER2– MBC patients treated between January 2014 and November 2020 with both CDK4/6i and EVE were retrospectively analyzed.
Results
Among the 88 patients included in the study, 51 received CDK4/6i before EVE (C→E group), and 37 received EVE before CDK4/6i (E→C group) with endocrine treatment. More patients in the E→C group had endocrine resistance (13.7% vs. 40.5%), experienced palliative chemotherapy (7.8% vs. 40.5%), and were heavily treated (treated as ≥ 3rd line, 5.9% vs. 40.5%). Median overall survival was 46.8 months in the C→E group and 38.9 months in the E→C group (p=0.151). Median composite progression-free survival (PFS), defined as the time from the start of the preceding regimen to disease progression on the following regimen or death, was 24.8 months in the C→E group vs. 21.8 months in the E→C group (p=0.681). Median PFS2/PFS1 ratio did not differ significantly between groups (0.5 in the C→E group, 0.6 in the E→C group; p=0.775). Ten patients (11.4%) discontinued EVE, and two patients (2.3%) discontinued CDK4/6i during treatment.
Conclusion
Although the CDK4/6i-based regimen should be considered as an earlier line of treatment, CDK4/6i- and EVE-based treatments can be valid options in circumstances where the other treatment had been already given.

Citations

Citations to this article as recorded by

CDK4/6 inhibitors for metastatic breast cancer in routine clinical practice in Spain: survey of patterns of use and oncologists’ perceptions
F. Moreno, V. Iranzo, I. Álvarez, A. Antón, J. I. Chacón, J. Gavilá, M. Martín, P. Sánchez Rovira, P. Gratal, M. J. Fernández González, R. López
Clinical and Translational Oncology.2025; 27(9): 3819. CrossRef
The Growth Modulation Index (GMI) as an Efficacy Outcome in Cancer Clinical Trials: A Scoping Review with Suggested Reporting Guidelines
Kilian Trin, Cynthia Dalleau, Simone Mathoulin-Pelissier, Christophe Le Tourneau, Derek Dinart, Carine Bellera
Current Oncology Reports.2025; 27(5): 516. CrossRef
The different sequences of CDK4/6 inhibitor and mTOR inhibitor in HR+/HER2-advanced breast cancer: A multicenter real-world study
Yuqian Liao, Yujing Tan, Yipeng Li, Fei Ma, Jiayu Wang, Pin Zhang, Qing Li, Qiao Li, Yang Luo, Bo Lan, Shanshan Chen, Binghe Xu, Hanfang Jiang, Weihong Zhao, Ying Fan
Heliyon.2024; 10(19): e38147. CrossRef
Long-Term Results with Everolimus in Advanced Hormone Receptor Positive Breast Cancer in a Multicenter National Real-World Observational Study
Hélène François-Martin, Audrey Lardy-Cléaud, Barbara Pistilli, Christelle Levy, Véronique Diéras, Jean-Sébastien Frenel, Séverine Guiu, Marie-Ange Mouret-Reynier, Audrey Mailliez, Jean-Christophe Eymard, Thierry Petit, Mony Ung, Isabelle Desmoulins, Paule
Cancers.2023; 15(4): 1191. CrossRef
Selective protection of normal cells from chemotherapy, while killing drug-resistant cancer cells
Mikhail V. Blagosklonny
Oncotarget.2023; 14(1): 193. CrossRef
A systematic review of computational approaches to understand cancer biology for informed drug repurposing
Faheem Ahmed, Anupama Samantasinghar, Afaque Manzoor Soomro, Sejong Kim, Kyung Hyun Choi
Journal of Biomedical Informatics.2023; 142: 104373. CrossRef
Tetraspanin 1 (TSPAN1) promotes growth and transferation of breast cancer cells via mediating PI3K/Akt pathway
Yange Wu, Wenxiu Chen, Yufeng Gong, Hongxia Liu, Bo Zhang
Bioengineered.2021; 12(2): 10761. CrossRef

9,570 View
225 Download
9 Web of Science
7 Crossref

Review Article

Systemic Treatment of Advanced Gastroenteropancreatic Neuroendocrine Tumors in Korea: Literature Review and Expert Opinion: Changhoon Yoo, Chung Ryul Oh, Seung-Tae Kim, Woo Kyun Bae, Hye-Jin Choi, Do-Youn Oh, Myung-Ah Lee, Baek-Yeol Ryoo; Cancer Res Treat. 2021;53(2):291-300. Published online December 29, 2020; DOI: https://doi.org/10.4143/crt.2020.1233

Abstract PDF PubReader ePub

Neuroendocrine tumors (NETs) are a group of malignancies arising from neuroendocrine cells and frequently originate in the gastrointestinal tract and pancreas. Although curative resection is the main treatment for localized disease, systemic therapy is needed for relapsed or metastatic/unresectable gastroenteropancreatic NETs (GEP-NETs). Although there are several NET treatment guidelines from various countries, the geographical discrepancies between patient clinical characteristics, the regulatory approval status for therapeutic agents, and medical practices necessitate specific guidelines for Korean patients. We here provide a consensus review of the diagnosis, staging and systemic treatment of Korean GEP-NET patients. Systemic therapy options and the current Korean expert consensus on these treatments, including somatostatin analogs, targeted therapies such as everolimus and sunitinib, peptide receptor radionuclide treatments, and cytotoxic chemotherapies are addressed.

Citations

Citations to this article as recorded by

First Real-World Evidence on the Safety and Effectiveness of LutatheraTM for Treating Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs): Insights from Post-Marketing Surveillance
Yong-il Kim, Hoon Young Suh, Yehrim Kang, Hojin Cho, Seung Hyup Hyun, Yoo Sung Song, Seunggyun Ha, Keon Wook Kang
Cancers.2025; 17(18): 2992. CrossRef
Lanreotide acetate subcutaneous injection-induced granulomatous inflammation after surgery for neuroendocrine tumor of unknown primary origin
Susumu Saigusa, Hiroyuki Sakurai, Hiroyuki Fujikawa, Shuyo Watanabe, Kosuke Fukumochi, Yo Uchiyama, Tomomi Mohri, Yoshifumi Hirokawa, Koji Tanaka
International Cancer Conference Journal.2025; 15(1): 80. CrossRef
Efficacy and Safety of Lu-177 DOTATATE Peptide Receptor Radionuclide Therapy in Patients with Unresectable or Metastatic Neuroendocrine Tumors in Korea
Yeokyeong Shin, Bo Hyun Moon, Baek-Yeol Ryoo, Heung-Moon Chang, Kyu-pyo Kim, Yong Sang Hong, Tae Won Kim, Jin-Sook Ryu, Yong-il Kim, Changhoon Yoo
Targeted Oncology.2024; 19(1): 41. CrossRef
Effectiveness and Safety of Retreatment with177Lu-DOTATATE in Patients with Progressive Neuroendocrine Tumors: A Retrospective Real-World Study in the United States
Ebrahim S. Delpassand, Soheil M. Yazdi, Shashank Ghantoji, Antonio Nakasato, Corinne Strickland, Rodolfo Nunez, Afshin Shafie, Susan Cork, Clare Byrne, Jackson Tang, Jeetvan Patel
Journal of Nuclear Medicine.2024; 65(5): 746. CrossRef
Advances in hydrogel materials applied to pancreatic-related diseases
Yuan Zhou, Maoen Pan, Ronggui Lin, Heguang Huang
Journal of Pancreatology.2024; 7(3): 222. CrossRef
Prognostic value of interim [68Ga]Ga-DOTA-TOC PET/CT in patients with neuroendocrine tumour who underwent peptide receptor radionuclide therapy
Eonwoo Shin, Yong-il Kim, Changhoon Yoo, Yeokyeong Shin, Baek-Yeol Ryoo, Dong Yun Lee, Jin-Sook Ryu
European Radiology.2024; 35(5): 2559. CrossRef
Consideration of quality of life in the treatment decision-making for patients with advanced gastroenteropancreatic neuroendocrine tumors
Boris G. Naraev, Josh Mailman, Thorvardur R. Halfdanarson, Heloisa P. Soares, Erik S. Mittra, Julie Hallet
Expert Review of Anticancer Therapy.2023; 23(6): 601. CrossRef
KSNM60 in Nuclear Endocrinology: from the Beginning to the Future
Chae Moon Hong, Young Jin Jeong, Hae Won Kim, Byeong-Cheol Ahn
Nuclear Medicine and Molecular Imaging.2022; 56(1): 17. CrossRef
Efficacy of Immune Checkpoint Inhibitors against Advanced or Metastatic Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis
Eun-Joo Park, Hyo-Jung Park, Kyung-Won Kim, Chong-Hyun Suh, Changhoon Yoo, Young-Kwang Chae, Sree Harsha Tirumani, Nikhil H. Ramaiya
Cancers.2022; 14(3): 794. CrossRef
Advances in the Diagnosis and Therapeutic Management of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs)
Krzysztof Kaliszewski, Maksymilian Ludwig, Maria Greniuk, Agnieszka Mikuła, Karol Zagórski, Jerzy Rudnicki
Cancers.2022; 14(8): 2028. CrossRef
Capecitabine plus temozolomide in patients with grade 3 unresectable or metastatic gastroenteropancreatic neuroendocrine neoplasms with Ki-67 index <55%: single-arm phase II study
H. Jeong, J. Shin, J.H. Jeong, K.-p. Kim, S.-M. Hong, Y.-i. Kim, J.-S. Ryu, B.-Y. Ryoo, C. Yoo
ESMO Open.2021; 6(3): 100119. CrossRef

14,143 View
410 Download
12 Web of Science
11 Crossref

Original Articles

Everolimus Plus Ku0063794 Regimen Promotes Anticancer Effects against Hepatocellular Carcinoma Cells through the Paradoxical Inhibition of Autophagy: Sang Chul Lee, Kee-Hwan Kim, Ok-Hee Kim, Sang Kuon Lee, Ha-Eun Hong, Byung Jo Choi, Wonjun Jeong, Say-June Kim; Cancer Res Treat. 2018;50(3):1023-1038. Published online November 9, 2017; DOI: https://doi.org/10.4143/crt.2017.085; Retraction in: Cancer Res Treat 2026;58(3):1024

12,474 View
210 Download
7 Web of Science
9 Crossref

Crizotinib in Combination with Everolimus Synergistically Inhibits Proliferation of Anaplastic Lymphoma Kinase‒Positive Anaplastic Large Cell Lymphoma: Wendan Xu, Ji-Won Kim, Woo June Jung, Youngil Koh, Sung-Soo Yoon; Cancer Res Treat. 2018;50(2):599-613. Published online June 19, 2017; DOI: https://doi.org/10.4143/crt.2016.357

Abstract PDF Supplementary Material PubReader ePub

Purpose
Anaplastic large cell lymphoma (ALCL) is a rare aggresive non-Hodgkin lymphoma, of which over 50% of cases have an aberrant nucleophosmin (NPM)‒anaplastic lymphoma kinase (ALK) fusion protein. Both mechanistic target of rapamycin (mTOR) inhibitor everolimus and ALK inhibitor crizotinib have shown promising antitumor activity in ALK-positive cancer cell lines. However, their combined effect has not yet been investigated.
Materials and Methods
We evaluated the anti-proliferative effects of everolimus and/or crizotinib in ALK-positive ALCL cell lines, Karpas 299 and SU-DHL-1, and lung adenocarcinoma cell line, NCI-H2228.
Results
We found that individually, both everolimus and crizotinib potently inhibited cell growth in a dose-dependent manner in both Karpas 299 and SU-DHL-1 cells. A combination of these agents synergistically inhibited proliferation in the two cell lines. Crizotinib down-regulated aberrant AKT and ERK phosphorylation induced by everolimus. Combination treatment also significantly increased G0/G1 cell-cycle arrest, DNA damage, and apoptosis compared with everolimus or crizotinib alone in ALK-positive ALCL cells. In the Karpas 299 xenograft model, the combination treatment exerted a stronger antitumor effect than monotherapies, without significant change in body weight. The synergistic effect of everolimus and crizotinib was also reproduced in the ALK-positive lung adenocarcinoma cell line NCI-H2228. The combination treatment abrogated phosphoinositide 3-kinase/AKT and mTOR signaling pathways with little effect on the Ras/ERK pathway in NCI-H2228 cells.
Conclusion
Crizotinib combinedwith everolimus synergistically inhibits proliferation of ALK-positive ALCL cells. Our results suggest that this novel combination is worthy of further clinical development in patients with ALK-positive ALCL.

Citations

Citations to this article as recorded by

Enhanced Efficacy and Safety of 177Lu-Anti-CD25 Radioimmunotherapy by Combination with Targeted Anticancer Agents
Jung Lim Kim, Choong Mo Kang, Kyung-Ho Jung, Mina Kim, Giro Kim, Hyunjong Lee, Kyung-Han Lee
Molecular Pharmaceutics.2026; 23(4): 2659. CrossRef
The PI3K signaling pathway; from normal lymphopoiesis to lymphoid malignancies
Bahareh Kashani, Zahra Zandi, Atieh Pourbagheri‑Sigaroodi, Amir-Mohammad Yousefi, Seyed H. Ghaffari, Davood Bashash
Expert Review of Anticancer Therapy.2024; 24(7): 493. CrossRef
Holistic View of ALK TKI Resistance in ALK-Positive Anaplastic Large Cell Lymphoma
Yuan Wang, Jing He, Manyu Xu, Qingfeng Xue, Cindy Zhu, Juan Liu, Yaping Zhang, Wenyu Shi
Frontiers in Oncology.2022;[Epub] CrossRef
Inhibiting ALK-TOPK signaling pathway promotes cell apoptosis of ALK-positive NSCLC
Juanjuan Xiao, Lu Zhang, Huijun Yi, Ling Zou, Jianmei Mo, Feng Xue, Jinhua Zheng, Yingze Huang, Hui Lu, Hansheng Wu, Peipei Xue, Xin Zhang, Lifei He, Zhaoxin Li, Shigui Pang, Guibin Qiao, Qiuhong Duan, Feng Zhu
Cell Death & Disease.2022;[Epub] CrossRef
CORR Insights®: Identification of a Novel MAN1A1-ROS1 Fusion Gene Through mRNA-based Screening for Tyrosine Kinase Gene Aberrations in a Patient with Leiomyosarcoma
Xiaodong Tang
Clinical Orthopaedics & Related Research.2021; 479(4): 853. CrossRef
Combined crizotinib and endocrine drugs inhibit proliferation, migration, and colony formation of breast cancer cells via downregulation of MET and estrogen receptor
Nehad M. Ayoub, Amer E. Alkhalifa, Dalia R. Ibrahim, Ahmed Alhusban
Medical Oncology.2021;[Epub] CrossRef
The Dual Role of Autophagy in Crizotinib-Treated ALK+ ALCL: From the Lymphoma Cells Drug Resistance to Their Demise
Estelle Espinos, Raymond Lai, Sylvie Giuriato
Cells.2021; 10(10): 2517. CrossRef
Hexokinases II‐mediated glycolysis governs susceptibility to crizotinib in ALK‐positive non‐small cell lung cancer
Caiyu Lin, Hengyi Chen, Rui Han, Li Li, Conghua Lu, Shuai Hao, Yubo Wang, Yong He
Thoracic Cancer.2021; 12(23): 3184. CrossRef

15,488 View
408 Download
9 Web of Science
8 Crossref

First
Prev
Page of 1
Next
Last

Search