Lis Victoria Ravani, Zahra Bagheri, Adam M Brufsky, Isabella Michellon, Ruth O'Regan, Maryam Lustberg, Hyo Han, Ming Wang, Seth A Wander
{"title":"一线与二线CDK4/6抑制在激素受体阳性、her2阴性转移性乳腺癌中的比较疗效","authors":"Lis Victoria Ravani, Zahra Bagheri, Adam M Brufsky, Isabella Michellon, Ruth O'Regan, Maryam Lustberg, Hyo Han, Ming Wang, Seth A Wander","doi":"10.1186/s13058-025-02095-6","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>The greater progression-free survival (PFS) improvements observed in first-line (1L) versus second-line (2L) CDK4/6 inhibitor (CDK4/6i) trials underpin current guideline recommendations establishing these agents as standard 1L therapy in hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (mBC). While earlier CDK4/6i use is associated with increased cumulative toxicity and costs, comparative survival data of earlier versus deferred use remain scarce.</p><p><strong>Methods: </strong>We performed a systematic review and meta-analysis, searching PubMed, Embase, Cochrane, and conference proceedings for observational studies and randomized clinical trials (RCTs) including patients treated with first- and/or 2L CDK4/6i. Patients who received CDK4/6 inhibition as part of 1L therapy were included in the 1 L group, while those who did not receive CDK4/6i in the 1L setting and deferred it until the 2L setting were assigned to the 2 L group. Pooled analysis of Kaplan-Meier-derived individual patient data was conducted for PFS2, defined as time from randomization to progression on 2L therapy, and overall survival (OS). Both outcomes were measured from the start of 1L treatment to progression on 2L treatment for both 1L and 2L groups. Sensitivity analysis by study design was also conducted.</p><p><strong>Results: </strong>Nine studies (5 RCTs and 4 observational studies) comprising 7,602 patients with mBC were included. Of these, 6,475 (85.1%) received CDK4/6i in 1L, and 1,127 (14.8%) in the 2 L setting. Overall, 1L CDK4/6i therapy was associated with significantly longer PFS2 compared to 2L treatment (HR 2.08; 95%CI 1.90-2.27), a trend not observed in sensitivity analysis of RCTs alone (HR 1.10; 95%CI 0.94-1.30). No significant differences in OS were observed between 1L and 2L CDK4/6i regimens (HR 1.09; 95%CI 1.00-1.18), or in sensitivity analysis of only RCTs (HR 1.03; 95%CI 0.84-1.26).</p><p><strong>Conclusion: </strong>This extensive data pool suggests that deferring CDK4/6is to 2L may be associated with worse PFS2 but comparable OS when compared to early use in 1L, challenging the assumption that shifting therapies from 2L to 1L universally improves outcomes despite increased toxicity and costs.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"146"},"PeriodicalIF":5.6000,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12351955/pdf/","citationCount":"0","resultStr":"{\"title\":\"Comparative efficacy of first- versus second-line CDK4/6 inhibition in hormone receptor-positive, HER2-negative metastatic breast cancer.\",\"authors\":\"Lis Victoria Ravani, Zahra Bagheri, Adam M Brufsky, Isabella Michellon, Ruth O'Regan, Maryam Lustberg, Hyo Han, Ming Wang, Seth A Wander\",\"doi\":\"10.1186/s13058-025-02095-6\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>The greater progression-free survival (PFS) improvements observed in first-line (1L) versus second-line (2L) CDK4/6 inhibitor (CDK4/6i) trials underpin current guideline recommendations establishing these agents as standard 1L therapy in hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (mBC). While earlier CDK4/6i use is associated with increased cumulative toxicity and costs, comparative survival data of earlier versus deferred use remain scarce.</p><p><strong>Methods: </strong>We performed a systematic review and meta-analysis, searching PubMed, Embase, Cochrane, and conference proceedings for observational studies and randomized clinical trials (RCTs) including patients treated with first- and/or 2L CDK4/6i. Patients who received CDK4/6 inhibition as part of 1L therapy were included in the 1 L group, while those who did not receive CDK4/6i in the 1L setting and deferred it until the 2L setting were assigned to the 2 L group. Pooled analysis of Kaplan-Meier-derived individual patient data was conducted for PFS2, defined as time from randomization to progression on 2L therapy, and overall survival (OS). Both outcomes were measured from the start of 1L treatment to progression on 2L treatment for both 1L and 2L groups. Sensitivity analysis by study design was also conducted.</p><p><strong>Results: </strong>Nine studies (5 RCTs and 4 observational studies) comprising 7,602 patients with mBC were included. Of these, 6,475 (85.1%) received CDK4/6i in 1L, and 1,127 (14.8%) in the 2 L setting. Overall, 1L CDK4/6i therapy was associated with significantly longer PFS2 compared to 2L treatment (HR 2.08; 95%CI 1.90-2.27), a trend not observed in sensitivity analysis of RCTs alone (HR 1.10; 95%CI 0.94-1.30). No significant differences in OS were observed between 1L and 2L CDK4/6i regimens (HR 1.09; 95%CI 1.00-1.18), or in sensitivity analysis of only RCTs (HR 1.03; 95%CI 0.84-1.26).</p><p><strong>Conclusion: </strong>This extensive data pool suggests that deferring CDK4/6is to 2L may be associated with worse PFS2 but comparable OS when compared to early use in 1L, challenging the assumption that shifting therapies from 2L to 1L universally improves outcomes despite increased toxicity and costs.</p>\",\"PeriodicalId\":49227,\"journal\":{\"name\":\"Breast Cancer Research\",\"volume\":\"27 1\",\"pages\":\"146\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2025-08-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12351955/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Breast Cancer Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s13058-025-02095-6\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Breast Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13058-025-02095-6","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Medicine","Score":null,"Total":0}
Comparative efficacy of first- versus second-line CDK4/6 inhibition in hormone receptor-positive, HER2-negative metastatic breast cancer.
Purpose: The greater progression-free survival (PFS) improvements observed in first-line (1L) versus second-line (2L) CDK4/6 inhibitor (CDK4/6i) trials underpin current guideline recommendations establishing these agents as standard 1L therapy in hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (mBC). While earlier CDK4/6i use is associated with increased cumulative toxicity and costs, comparative survival data of earlier versus deferred use remain scarce.
Methods: We performed a systematic review and meta-analysis, searching PubMed, Embase, Cochrane, and conference proceedings for observational studies and randomized clinical trials (RCTs) including patients treated with first- and/or 2L CDK4/6i. Patients who received CDK4/6 inhibition as part of 1L therapy were included in the 1 L group, while those who did not receive CDK4/6i in the 1L setting and deferred it until the 2L setting were assigned to the 2 L group. Pooled analysis of Kaplan-Meier-derived individual patient data was conducted for PFS2, defined as time from randomization to progression on 2L therapy, and overall survival (OS). Both outcomes were measured from the start of 1L treatment to progression on 2L treatment for both 1L and 2L groups. Sensitivity analysis by study design was also conducted.
Results: Nine studies (5 RCTs and 4 observational studies) comprising 7,602 patients with mBC were included. Of these, 6,475 (85.1%) received CDK4/6i in 1L, and 1,127 (14.8%) in the 2 L setting. Overall, 1L CDK4/6i therapy was associated with significantly longer PFS2 compared to 2L treatment (HR 2.08; 95%CI 1.90-2.27), a trend not observed in sensitivity analysis of RCTs alone (HR 1.10; 95%CI 0.94-1.30). No significant differences in OS were observed between 1L and 2L CDK4/6i regimens (HR 1.09; 95%CI 1.00-1.18), or in sensitivity analysis of only RCTs (HR 1.03; 95%CI 0.84-1.26).
Conclusion: This extensive data pool suggests that deferring CDK4/6is to 2L may be associated with worse PFS2 but comparable OS when compared to early use in 1L, challenging the assumption that shifting therapies from 2L to 1L universally improves outcomes despite increased toxicity and costs.
期刊介绍：
Breast Cancer Research, an international, peer-reviewed online journal, publishes original research, reviews, editorials, and reports. It features open-access research articles of exceptional interest across all areas of biology and medicine relevant to breast cancer. This includes normal mammary gland biology, with a special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal covers preclinical, translational, and clinical studies with a biological basis, including Phase I and Phase II trials.
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