对于早期三阴性乳腺癌，病理完全缓解可有效预测术前新辅助化疗的长期结局。不过，仅三分之一的早期三阴性乳腺癌术前患者接受紫杉类→蒽环类＋环磷酰胺标准化疗方案可获得病理完全缓解。8年前，癌症与白血病协作组B（CALGB）40603研究初步结果表明，卡铂或贝伐珠单抗可显著提高早期三阴性乳腺癌术前新辅助化疗的病理完全缓解率。不过，病理完全缓解率能否有效预测卡铂或贝伐珠单抗的长期结局？
CALGB 40603 (NCT00861705): Randomized Phase II 2 x 2 Factorial Trial of the Addition of Carboplatin /- Bevacizumab to Neoadjuvant Weekly Paclitaxel Followed by Dose-Dense AC in Hormone Receptor-Poor/HER2-Negative Resectable Breast Cancer
2022年1月19日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表北卡罗来纳大学莱恩伯格综合癌症中心、梅奥医学中心、芝加哥大学、量子生物、生命编辑、怀特普莱恩斯医院、哈佛大学达纳法伯癌症研究所、希望之城综合癌症中心、纽约西奈山医疗中心、圣路易斯华盛顿大学、桑福德肿瘤医院、佛罗里达大学奥兰多癌症中心、耶鲁大学医学院癌症中心、纽约纪念医院斯隆凯特林癌症中心、杜克大学、布朗大学沃伦阿尔珀特医学院罗德岛妇婴医院的研究报告，探讨了卡铂或贝伐珠单抗能否改善三阴性乳腺癌新辅助化疗患者的长期生存结局及其临床和分子特征。
该多中心非盲随机对照二期临床研究于2009年5月～2012年8月入组II～III期三阴性乳腺癌术前患者443例，按1∶1∶1∶1的比例随机分为四组进行新辅助化疗：
新辅助化疗组115例：每周紫杉醇×12→每2周多柔比星＋环磷酰胺×4
新辅助化疗＋贝伐珠单抗组113例：每周紫杉醇×12＋每2周贝伐珠单抗×9→每2周多柔比星＋环磷酰胺×4
新辅助化疗＋卡铂组113例：每周紫杉醇×12＋每3周卡铂×4→每2周多柔比星＋环磷酰胺×4
新辅助化疗＋卡铂＋贝伐珠单抗组113例：每周紫杉醇×12＋每3周卡铂×4＋每2周贝伐珠单抗×9→每2周多柔比星＋环磷酰胺×4
采用生存曲线法推算开始研究治疗患者的长期生存结局。通过对数秩检验和多因素比例风险模型评估临床特征、病理缓解、残癌患者的残癌负荷、治疗分配、每周紫杉醇剂量对无事件生存等长期结局的影响。对治疗前肿瘤标本进行信使核糖核酸测序，评定治疗效果和结局的基因组预测因素。
结果，在治疗前特征中，仅临床分期与长期结局相关。
中位随访7.9年时，卡铂或贝伐珠单抗与标准化疗方案相比，全部患者或基底样亚型患者的长期结局均未显著改善。
不过，病理完全缓解患者（205例，46.3%）与残癌患者（即使残癌负荷I级）相比：
5年无事件生存率显著较高：85.5%比56.6%（对数秩P<0.0001）
5年总生存率显著较高：87.9%比63.4%（对数秩P<0.0001）
在临床和基因组特征中，免疫激活证据（包括肿瘤浸润淋巴细胞和B淋巴细胞受体均匀度较低）与病理完全缓解和无事件生存改善显著相关。
因此，该研究长期随访结果表明，对于早期三阴性乳腺癌术前患者，卡铂或贝伐珠单抗虽然可以显著提高新辅助化疗的术后病理完全缓解率，但是似乎均未改善长期结局，尽管该研究次要终点尚未达到中位。不过，病理完全缓解即使与最小残癌相比，长期结局也显著较好。治疗前肿瘤活检标本的免疫激活标志物与病理完全缓解率和无事件生存率改善独立相关。目前，卡铂＋帕博利珠单抗已经成为早期三阴性乳腺癌术前新辅助化疗的新标准，将来的研究应侧重优化化疗＋免疫检查点抑制，将免疫激活测定作为预测和预后生物标志物可能有助于对早期三阴性乳腺癌采用更个体化的新辅助治疗方案。
J Clin Oncol. 2022 Jan 19. Online ahead of print.
CALGB 40603 (Alliance): Long-Term Outcomes and Genomic Correlates of Response and Survival After Neoadjuvant Chemotherapy With or Without Carboplatin and Bevacizumab in Triple-Negative Breast Cancer.
Jonathan H. Shepherd, Karla Ballman, Mei-Yin C. Polley, Jordan D. Campbell, Cheng Fan, Sara Selitsky, Aranzazu Fernandez-Martinez, Joel S. Parker, Katherine A. Hoadley, Zhiyuan Hu, Yan Li, Matthew G. Soloway, Patricia A. Spears, Baljit Singh, Sara M. Tolaney, George Somlo, Elisa R. Port, Cynthia Ma, Charles Kuzma, Eleftherios Mamounas, Mehra Golshan, Jennifer R. Bellon, Deborah Collyar, Olwen M. Hahn, Clifford A. Hudis, Eric P. Winer, Ann Partridge, Terry Hyslop, Lisa A. Carey, Charles M. Perou, William M. Sikov.
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC; Mayo Clinic, Rochester, MN; University of Chicago, Chicago, IL; QuantBio LLC, Durham, NC; Life Edit Therapeutics, RTP, NC; White Plains Hospital, White Plains, NY; Dana-Farber/Partners CancerCare, Boston, MA; City of Hope Comprehensive Cancer Center, Duarte, CA; Mount Sinai Medical Center, New York, NY; Washington University School of Medicine, St Louis, MO; FirstHealth Sanford Hematology and Oncology, Sanford, NC; UF Health Cancer Center Orlando, Orlando, FL; Yale Cancer Center, Yale School of Medicine, New Haven, CT; Patient Advocates In Research, Danville, CA; University of Chicago Medical Center, Chicago, IL; Memorial Sloan Kettering Cancer Center, New York, NY; Duke University, Durham, NC; Women and Infants Hospital of Rhode Island and Warren Alpert Medical School of Brown University, Providence, RI.
PURPOSE: CALGB 40603 (NCT00861705), a 2 × 2 randomized phase II trial, demonstrated that adding carboplatin or bevacizumab to weekly paclitaxel (wP) followed by doxorubicin and cyclophosphamide significantly increased the pathologic complete response (pCR) rate in stage II-III triple-negative breast cancer. We now report long-term outcomes (LTOs) and correlative science end points.
PATIENTS AND METHODS: The Kaplan-Meier method was used to estimate LTOs in 443 patients who initiated study treatment. Log-rank tests and Cox proportional hazards models evaluated the impact of clinical characteristics, pathologic response, calculated residual cancer burden (RCB) in patients with residual disease (RD), treatment assignment, and dose delivery during wP on LTOs, including event-free survival (EFS). Genomic predictors of treatment response and outcomes were assessed on pretreatment tumor samples by mRNA sequencing.
RESULTS: Among baseline characteristics, only the clinical stage was associated with LTOs. At a median follow-up of 7.9 years, LTOs were not significantly improved with either carboplatin or bevacizumab, overall or in patients with basal-like subtype cancers by genomic analysis. Patients with pCR (n = 205, 46.3%) had significantly higher 5-year EFS (85.5% v 56.6%, log-rank P < .0001) and overall survival (87.9% v 63.4%, P < .0001) rates compared with patients with RD, even those with RCB class I. Among clinical and genomic features, evidence of immune activation, including tumor-infiltrating lymphocytes and low B-cell receptor evenness, was associated with pCR and improved EFS.
CONCLUSION: Despite higher pCR rates, neither carboplatin nor bevacizumab appeared to improve LTOs although the study was not powered to assess these secondary end points. pCR was associated with superior LTOs even when compared with minimal RD. Markers of immune activation in pretreatment tumor biopsies were independently associated with higher pCR rates and improved survival.
KEY OBJECTIVE: This analysis assesses whether adding bevacizumab or carboplatin to anthracycline- and taxane-based neoadjuvant chemotherapy (NACT) in triple-negative breast cancer (TNBC) improves long-term outcomes (LTOs) and evaluates clinical and molecular features for predictors of response and survival.
KNOWLEDGE GENERATED: Achievement of pathologic complete response correlated with better event-free survival (EFS) and overall survival, with even minimal residual invasive disease associated with worse outcomes. Although both bevacizumab and carboplatin significantly increased pCRs, neither improved LTOs. From gene expression analyses, evidence of an active tumoral immune response correlated with increased pCRs and improved EFS.
RELEVANCE: Addition of bevacizumab or carboplatin to TNBC NACT increased pCRs, but did not appear to improve LTOs. However, standard of care is now NACT including carboplatin with pembrolizumab; future studies should focus on optimizing chemotherapy plus immune checkpoint inhibition. Identification of immune activation as a predictive and prognostic biomarker may allow more tailored neoadjuvant approaches in nonmetastatic TNBC.
PMID: 35044810
DOI: 10.1200/JCO.21.01506
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