精准预测乳腺癌长期疗效的新指标
对于肿瘤较大难以手术或复发风险较高的早期乳腺癌，术前新辅助治疗可缩小肿瘤，有助于提高手术的可行性和成功率、减少术后复发风险、加速新药临床开发、实现精准治疗。不过，该方法的优势取决于短期疗效指标能否预测长期生存获益。目前的短期疗效指标为病理完全缓解，代表手术切除标本病理检查未发现残癌，可预测复发风险，但是作为预测长期生存获益的替代指标仍然存在争议。
残癌负荷提供了一种标准化的病理定量方法，由病理科医师根据残留浸润癌二维面积、浸润癌面积比例、受累淋巴结数量和转移淋巴结最大尺寸计算得出，可对新辅助治疗后乳房或区域淋巴结残留浸润癌的程度进行定性评估和定量分析。因此，残癌负荷提供了对残癌程度的连续测量，残癌负荷分布可能提高对乳腺癌术前新辅助疗效的预测水平。
2021年9月16日，《美国医学会杂志》肿瘤学分册在线发表德克萨斯大学MD安德森癌症中心、旧金山加利福尼亚大学、明尼苏达大学、耶鲁大学、芝加哥大学、圣迭戈加利福尼亚大学、伯明翰阿拉巴马大学、宾夕法尼亚大学、芝加哥洛约拉大学、梅奥医学中心、莫菲特癌症中心、乔治城大学、科罗拉多大学安舒茨医学中心、南加利福尼亚大学、西雅图华盛顿大学、德克萨斯大学西南医学中心、梅奥医学中心亚利桑那分院、堪萨斯大学、费尔法克斯医院、亚利桑那大学、俄勒冈医科大学、西雅图瑞典癌症研究所、阿维拉癌症研究所、量子飞跃医疗联盟、毕瑞咨询、双子集团的I-SPY2研究数据分析报告，比较了不同亚型高风险早期乳腺癌随机对照组和新药治疗组的残癌负荷分布，并探讨其对无复发生存的预测作用。
I-SPY2 TRIAL (NCT01042379): Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis 2)
I-SPY研究平台采用了多快好省的创新思路和方法，将4000多例乳腺癌患者随机分入27个新药联合标准治疗组和1个标准治疗对照组，可大大减少对照组患者数量、提高新药临床开发效率。
该全国多中心随机对照二期临床研究I-SPY2于2010年3月～2016年入组早期复发风险较高的2～3期乳腺癌术前成年女性938例（平均年龄49±11岁，其中亚裔66例、黑人103例、白人750例，分别占7%、11%、80%）随机分入10个新药联合标准化疗组（740例）和1个标准化疗对照组（198例）给予新辅助治疗（紫杉醇±1种新药12周→环磷酰胺＋多柔比星化疗12周）随后手术并随访至2020年9月9日，根据激素受体（HR）和HER2状态对不同亚型进行比较。若某一新药用于预先指定亚型的病理学完全缓解率≥85%，则定义为毕业。分析计划包括对不同亚型的残癌负荷进行建模，并将对照组与已毕业和未毕业的研究组进行比较。主要结局指标为残癌负荷和无复发生存。
结果，中位随访52个月（四分位间距29个月）期间，残癌负荷每增加1个单位：
HR阳性HER2阴性：复发死亡风险高75%（风险比：1.75，95%置信区间：1.45～2.16）
HR阳性HER2阳性：复发死亡风险高55%（风险比：1.55，95%置信区间：1.18～2.05）
HR阴性HER2阳性：复发死亡风险高139%（风险比：2.39，95%置信区间：1.64～3.49）
HR阴性HER2阴性：复发死亡风险高99%（风险比：1.99，95%置信区间：1.71～2.31）
根据多因素比例风险回归模型分析，残癌负荷每增加1个单位：
已毕业：复发死亡风险高100%（风险比：2.00，95%置信区间：1.57～2.55，254例，占27%）
未毕业：复发死亡风险高87%（风险比：1.87，95%置信区间：1.61～2.17，486例，占52%）
对照组：复发死亡风险高79%（风险比：1.79，95%置信区间：1.42～2.26，198例，占21%）
根据探索性分析，新药治疗显著降低HR阴性HER2阴性（已毕业和非毕业）和HER2阳性（已毕业）亚型的残癌负荷，复发死亡风险低39%（风险比：0.61，95%置信区间：0.41～0.93）
因此，该随机对照研究结果表明，无论乳腺癌亚型和新辅助治疗方案如何，残癌负荷的预后意义都一致。有效的新药治疗不仅提高了病理完全缓解率，还改变了残癌负荷分布、提高了无复发生存率。采用标准化的定量方法对短期疗效进行分析，将有助于预测长期生存获益，有望成为可靠的临床疗效衡量标准。
该研究报告第一作者和通信作者访谈录音（34分49秒）
JAMA Oncol. 2021 Sep 16. Online ahead of print.
Assessment of Residual Cancer Burden and Event-Free Survival in Neoadjuvant Treatment for High-risk Breast Cancer: An Analysis of Data From the I-SPY2 Randomized Clinical Trial.
W. Fraser Symmans; Christina Yau; Yunn-Yi Chen; Ron Balassanian; Molly E. Klein; Lajos Pusztai; Rita Nanda; Barbara A. Parker; Brian Datnow; Gregor Krings; Shi Wei; Michael D. Feldman; Xiuzhen Duan; Beiyun Chen; Husain Sattar; Laila Khazai; Jay C. Zeck; Sharon Sams; Paulette Mhawech-Fauceglia; Mara Rendi; Sunati Sahoo; Idris Tolgay Ocal; Fang Fan; Lauren Grasso LeBeau; Tuyethoa Vinh; Megan L. Troxell; A. Jo Chien; Anne M. Wallace; Andres Forero-Torres; Erin Ellis; Kathy S. Albain; Rashmi K. Murthy; Judy C. Boughey; Minetta C. Liu; Barbara B. Haley; Anthony D. Elias; Amy S. Clark; Kathleen Kemmer; Claudine Isaacs; Julie E. Lang; Hyo S. Han; Kirsten Edmiston; Rebecca K. Viscusi; Donald W. Northfelt; Qamar J. Khan; Brian Leyland-Jones; Sara J. Venters; Sonal Shad, BS; Jeffrey B. Matthews; Smita M. Asare, BS; Meredith Buxton; Adam L. Asare; Hope S. Rugo; Richard B. Schwab; Teresa Helsten; Nola M. Hylton; Laura van 't Veer; Jane Perlmutter; Angela M. DeMichele; Douglas Yee; Donald A. Berry; Laura J. Esserman.
The University of Texas MD Anderson Cancer Center, Houston, Texas; University of California, San Francisco; University of Minnesota, Minneapolis; Yale University, New Haven, Connecticut; University of Chicago, Chicago, Illinois; University of California, San Diego, La Jolla; University of Alabama at Birmingham; University of Pennsylvania, Philadelphia; Loyola University, Chicago, Illinois; Mayo Clinic, Rochester, Minnesota; Moffitt Cancer Center, Tampa, Florida; Georgetown University, Washington, DC; University of Colorado Anschutz Medical Center, Aurora; University of Southern California, Los Angeles; University of Washington, Seattle; University of Texas Southwestern Medical Center, Dallas, Texas; Mayo Clinic, Scottsdale, Arizona; University of Kansas Medical Center, Kansas City; University of Arizona Health Sciences, Tucson, Arizona; Inova Health System, Fairfax, Virginia; Oregon Health and Science University, Portland; Swedish Cancer Institute, Seattle, Washington; Inova Schar Cancer Institute, Fairfax, Virginia; Avera Cancer Institute, Sioux Falls, South Dakota; Quantum Leap Healthcare Collaborative, San Francisco, California; Berry Consultants, LLC, Houston, Texas; Gemini Group, Ann Arbor, Michigan.
This randomized clinical trial examines the distribution and prognosis of residual cancer burden across high-risk phenotypic subtypes of breast cancer and by different treatment groups.
QUESTION: Does the pattern of and prognosis for residual cancer burden (RCB) after neoadjuvant chemotherapy for breast cancer vary by subtype and treatment?
FINDINGS: In this analysis of data from the I-SPY2 randomized clinical trial including 938 women with breast cancer, RCB was consistently prognostic within subtypes of breast cancer and across investigational and control treatments. Some investigational treatments reduced residual cancer burden and also improved event-free survival in an exploratory analysis.
MEANING: The results suggest that RCB after neoadjuvant chemotherapy is a robust prognostic response measure across treatments and within subtypes and, when compared between randomized treatments, is likely to be a clinically useful measure of efficacy.
IMPORTANCE: Residual cancer burden (RCB) distributions may improve the interpretation of efficacy in neoadjuvant breast cancer trials.
OBJECTIVE: To compare RCB distributions between randomized control and investigational treatments within subtypes of breast cancer and explore the relationship with survival.
DESIGN, SETTING, AND PARTICIPANTS: The I-SPY2 is a multicenter, platform adaptive, randomized clinical trial in the US that compares, by subtype, investigational agents in combination with chemotherapy vs chemotherapy alone in adult women with stage 2/3 breast cancer at high risk of early recurrence. Investigational treatments graduated in a prespecified subtype if there was 85% or greater predicted probability of higher rate of pathologic complete response (pCR) in a confirmatory, 300-patient, 1:1 randomized, neoadjuvant trial in that subtype. Evaluation of a secondary end point was reported from the 10 investigational agents tested in the I-SPY2 trial from March 2010 through 2016, and analyzed as of September 9, 2020. The analysis plan included modeling of RCB within subtypes defined by hormone receptor (HR) and ERBB2 status and compared control treatments with investigational treatments that graduated and those that did not graduate.
INTERVENTIONS: Neoadjuvant paclitaxel plus/minus 1 of several investigational agents for 12 weeks, then 12 weeks of cyclophosphamide/doxorubicin chemotherapy followed by surgery.
MAIN OUTCOMES AND MEASURES: Residual cancer burden (pathological measure of residual disease) and event-free survival (EFS).
RESULTS: A total of 938 women (mean [SD] age, 49 [11] years; 66 [7%] Asian, 103 [11%] Black, and 750 [80%] White individuals) from the first 10 investigational agents were included, with a median follow-up of 52 months (IQR, 29 months). Event-free survival worsened significantly per unit of RCB in every subtype of breast cancer (HR-positive/ERBB2-negative: hazard ratio [HZR], 1.75; 95% CI, 1.45-2.16; HR-positive/ERBB2-positive: HZR, 1.55; 95% CI, 1.18-2.05; HR-negative/ERBB2-positive: HZR, 2.39; 95% CI, 1.64-3.49; HR-negative/ERBB2-negative: HZR, 1.99; 95% CI, 1.71-2.31). Prognostic information from RCB was similar from treatments that graduated (HZR, 2.00; 95% CI, 1.57-2.55; 254 [27%]), did not graduate (HZR, 1.87; 95% CI, 1.61-2.17; 486 [52%]), or were control (HZR, 1.79; 95% CI, 1.42-2.26; 198 [21%]). Investigational treatments significantly lowered RCB in HR-negative/ERBB2-negative (graduated and nongraduated treatments) and ERBB2-positive subtypes (graduated treatments), with improved EFS (HZR, 0.61; 95% CI, 0.41-0.93) in the exploratory analysis.
CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the prognostic significance of RCB was consistent regardless of subtype and treatment. Effective neoadjuvant treatments shifted the distribution of RCB in addition to increasing pCR rate and appeared to improve EFS. Using a standardized quantitative method to measure response advances the interpretation of efficacy.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01042379
DOI: 10.1001/jamaoncol.2021.3690