预测老年早期乳腺癌化疗毒性风险

　　对于老年早期乳腺癌患者，预测化疗毒性风险的工具极少。

　　2021年1月14日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表希望之城国家医学中心、罗彻斯特大学、耶鲁大学、纽约纪念医院斯隆凯特林癌症中心、维克森林大学、圣路易斯华盛顿大学、北卡罗来纳大学莱恩伯格综合癌症中心、福克斯蔡斯癌症中心、哈佛大学达纳法伯癌症研究所、罗斯威尔帕克癌症研究所、杜克大学的HOPE研究报告，开发并验证了一种预测老年早期乳腺癌化疗严重毒性风险的工具。

HOPE (The Hurria Older PatiEnts with Breast Cancer Cohort Study): Clinical and Biological Predictors of Chemotherapy Toxicity in Older Adults (NCT01472094)

　　该多中心前瞻队列研究于2011年9月～2017年5月从全国16家医院入组年龄≥65岁的I～III期乳腺癌术前或术后化疗患者473例，对可预测3～5级化疗毒性的老年特征和临床特征进行分析。通过逻辑回归和最佳亚组选择确定化疗毒性的独立预测因素，建立加权变量评分模型。根据预测与实际发生率曲线下面积和拟合优势度统计，判断该评分模型的性能。随后对该模型进行内部和外部验证。

　　结果，473例患者（建模队列283例、验证队列190例）其中46%发生3～5级化疗毒性。

　　8个独立预测因素被确定并按权重评分：

• 蒽环类化疗（1分）

• 二期或三期（3分）

• 计划治疗时间>3个月（4分）

• 肝功能异常（3分）

• 低血红蛋白（3分）

• 跌倒（4分）

• 步行受限（3分）

• 缺乏社会支持（3分）

　　对每例患者的风险评分进行计算并定义了3个风险组：

• 低风险（0～5分）

• 中风险（6～11分）

• 高风险（≥12分）

　　低、中、高风险组的3～5级化疗毒性发生率：

• 建模队列：19%、54%、87%（P<0.01）

• 验证队列：27%、45%、76%

　　预测与实际发生率曲线下面积：

• 建模队列：0.75（95%置信区间：0.70～0.81）

• 验证队列：0.69（95%置信区间：0.62～0.77）

　　高风险组与中低风险组相比，住院、用药减少、用药延迟、早期治疗中断、用药强度降低比例显著较高（P<0.01）。

　　因此，该研究结果表明，该评分可预测老年早期乳腺癌3～5级化疗毒性，有助于临床医师个体化预测老年早期乳腺癌化疗毒性风险并指导治疗，强化支持治疗和制定改良治疗方案可能适用于被确定为易受毒性影响较大的亚组患者。

J Clin Oncol. 2021 Jan 14. Online ahead of print.

Development and Validation of a Risk Tool for Predicting Severe Toxicity in Older Adults Receiving Chemotherapy for Early-Stage Breast Cancer.

Magnuson A, Sedrak MS, Gross CP, Tew WP, Klepin HD, Wildes TM, Muss HB, Dotan E, Freedman RA, O'Connor T, Dale W, Cohen HJ, Katheria V, Arsenyan A, Levi A, Kim H, Mohile S, Hurria A, Sun CL.

University of Rochester, Rochester, NY; City of Hope, Duarte, CA; Yale School of Medicine, New Haven, CT; Memorial Sloan Kettering Cancer Center, New York, NY; Wake Forest School of Medicine, Winston-Salem, NC; Washington University School of Medicine, St. Louis, MO; UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Fox Chase Cancer Center, Philadelphia, PA; Dana-Farber Cancer Institute, Boston, MA; Roswell Park Cancer Institute, Buffalo, NY; Duke University Medical Center, Durham, NC.

KEY OBJECTIVE: To develop and validate a model that can predict grade 3-5 chemotherapy toxicity in patients of age 65 years or older with early-stage breast cancer.

KNOWLEDGE GENERATED: The Cancer and Aging Research Group-Breast Cancer (CARG-BC) score, derived by combining eight clinical and geriatric variables, was developed to classify older patients with early-stage breast cancer into low, intermediate, and high risk for grade 3-5 chemotherapy toxicity. The score was externally validated; demonstrated to better predict toxicity compared with prior models and physician-rated performance status; and was strongly associated with dose reductions, dose delays, early treatment discontinuation, reduced dose intensity, and hospitalizations.

RELEVANCE: These findings may be useful to clinicians for predicting individual probability of chemotherapy toxicity and directing therapy in older adults with early-stage breast cancer. Intensifying supportive care and developing modified treatment regimens may be appropriate for subgroups identified as being vulnerable to greater toxicity.

PURPOSE: Limited tools exist to predict the risk of chemotherapy toxicity in older adults with early-stage breast cancer.

METHODS: Patients of age ≥ 65 years with stage I-III breast cancer from 16 institutions treated with neoadjuvant or adjuvant chemotherapy were prospectively evaluated for geriatric and clinical features predictive of grade 3-5 chemotherapy toxicity. Logistic regression with best-subsets selection was used to identify and incorporate independent predictors of toxicity into a model with weighted variable scoring. Model performance was evaluated using area under the ROC curve (AUC) and goodness-of-fit statistics. The model was internally and externally validated.

RESULTS: In 473 patients (283 in development and 190 in validation cohort), 46% developed grade 3-5 chemotherapy toxicities. Eight independent predictors were identified (each assigned weighted points): anthracycline use (1 point), stage II or III (3 points), planned treatment duration > 3 months (4 points), abnormal liver function (3 points), low hemoglobin (3 points), falls (4 points), limited walking (3 points), and lack of social support (3 points). We calculated risk scores for each patient and defined three risk groups: low (0-5 points), intermediate (6-11 points), or high (≥ 12 points). In the development cohort, the rates of grade 3-5 chemotherapy toxicity for these three groups were 19%, 54%, and 87%, respectively (P < .01). In the validation cohort, the corresponding toxicity rates were 27%, 45%, and 76%. The AUC was 0.75 (95% CI, 0.70 to 0.81) in the development cohort and 0.69 (95% CI, 0.62 to 0.77) in the validation cohort. Risk groups were also associated with hospitalizations and reduced dose intensity (P < .01).

CONCLUSION: The Cancer and Aging Research Group-Breast Cancer (CARG-BC) score was developed and validated to predict grade 3-5 chemotherapy toxicity in older adults with early-stage breast cancer.

PMID: 33444080

DOI: 10.1200/JCO.20.02063