乳腺癌基因突变者铂类化疗不可一刀切
对于生殖细胞乳腺癌易感基因BRCA突变携带者，三阴性乳腺癌的铂类化疗活性较高。不过，雌激素受体阳性HER2阴性乳腺癌的铂类化疗活性尚不明确。
2020年5月10日，美国临床肿瘤学会《临床肿瘤学杂志》正式发表哈佛大学贝斯以色列医院和新英格兰女执事医院、麻省总医院、达纳法伯癌症研究所、德克萨斯大学MD安德森癌症中心、耶鲁大学癌症中心、罗格斯大学新泽西癌症研究所、科罗拉多大学癌症中心、布朗大学罗德岛妇婴医院、乔治城大学兰巴迪综合癌症中心、霍普金斯大学坎摩尔癌症中心、杜克大学医学中心的乳腺癌转化研究联盟TBCRC 031 / INFORM研究报告，对顺铂单药与两药联合治疗携带BRCA突变的HER2阴性乳腺癌术前患者进行了比较。
TBCRC 031 / INFORM (Cisplatin vs. Doxorubicin / Cyclophosphamide in BrCa): A Randomized Phase II Trial of Neoadjuvant Cisplatin vs. Doxorubicin / Cyclophosphamide (AC) in Women With Newly Diagnosed Breast Cancer and Germline BrCa Mutations (NCT01670500)
该多中心随机对照二期临床研究于2012年1月～2019年1月从13家医学中心入组I～III期（cT1-3、≥1.5cm、cN0-3）HER2阴性乳腺癌BRCA突变携带者，按1∶1的比例随机分入两组进行术前新辅助化疗：顺铂单药组（每3周每平方米体表面积75毫克×4次）58例、两药联合组（每2～3周每平方米体表面积多柔比星60毫克＋环磷酰胺600毫克×4次）60例，随后进行手术。主要目标为顺铂单药与多柔比星＋环磷酰胺相比，病理完全缓解（ypT0/is、N0）比例提高至少20%，次要目标包括残癌负荷评分0～1分和毒性反应。病理缓解经过集中复核确认。
结果，入组患者118例，年龄24～73岁、平均42岁，其中BRCA1突变阳性81例、BRCA2突变阳性35例、BRCA1和BRCA2同时突变2例，临床分期：I期占19%、II期占63%、III期占18%，入组时淋巴结转移占45%，三阴性乳腺癌占70%。两组患者的临床和肿瘤特征相似。
顺铂单药组1例患者从未开始治疗方案，其余57例顺铂单药与60例两药联合相比：
病理完全缓解率：18%比26%（风险比：0.70，90%置信区间：0.39～1.2）
低残癌负荷比例：33%比46%（风险比：0.73，90%置信区间：0.50～1.1）
耐受性总体良好，无意外毒性反应
因此，该研究结果表明，对于早期HER2阴性乳腺癌BRCA突变携带者，无论三阴性乳腺癌，还是雌激素受体阳性HER2阴性乳腺癌，顺铂单药术前新辅助化疗的病理完全缓解或残癌负荷评分并未显著高于多柔比星＋环磷酰胺，不可一刀切。
J Clin Oncol. 2020 May 10;38(14):1539-1548.
TBCRC 031: Randomized Phase II Study of Neoadjuvant Cisplatin Versus Doxorubicin-Cyclophosphamide in Germline BRCA Carriers With HER2-Negative Breast Cancer (the INFORM trial).
Tung N, Arun B, Hacker MR, Hofstatter E, Toppmeyer DL, Isakoff SJ, Borges V, Legare RD, Isaacs C, Wolff AC, Marcom PK, Mayer EL, Lange PB, Goss AJ, Jenkins C, Krop IE, Winer EP, Schnitt SJ, Garber JE.
Beth Israel Deaconess Medical Center, Boston, MA; The University of Texas MD Anderson Cancer Center, Houston, TX; Yale Cancer Center, New Haven, CT; Rutgers Cancer Institute of New Jersey, Rutgers, NJ; Massachusetts General Hospital, Boston, MA; University of Colorado Cancer Center, Denver, CO; Women and Infants Hospital, Providence, RI; Lombardi Comprehensive Cancer Center, Washington DC; Johns Hopkins Kimmel Cancer Center, Baltimore, MD; Duke Medical Center, Durham, NC; Dana-Farber Cancer Institute, Boston, MA.
PURPOSE: Platinum compounds have activity in triple-negative breast cancer (TNBC) in germline BRCA mutation carriers (BRCA carriers). Limited data exist for estrogen receptor (ER)-positive (+) breast cancer among BRCA carriers. INFORM is a randomized, multicenter, phase II trial comparing pathologic complete response (pCR) rates (ypT0/is, N0) after neoadjuvant single-agent cisplatin (CDDP) versus doxorubicin-cyclophosphamide (AC) in BRCA carriers with stage I-III human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Secondary objectives included residual cancer burden scores (RCB) of 0 or 1 (combined) and toxicity. The goal was to determine whether pCR was ≥ 20% higher with CDDP than AC.
PATIENTS AND METHODS: BRCA carriers with cT1-3 (≥ 1.5 cm), cN0-3 HER2-negative breast cancer were randomly assigned to preoperative CDDP (75 mg/m2 every 3 weeks × 4 doses) or AC (doxorubicin 60 mg/m2; cyclophosphamide 600 mg/m2 every 2-3 weeks × 4 doses) followed by surgery. Pathologic responses were confirmed by central review.
RESULTS: A total of 118 patients were randomly assigned; 117 were included in outcome analyses. Mean age was 42 years (range, 24-73 years); 69% were BRCA1+, 30% were BRCA2+, and 2% had both mutations. Clinical stage was I for 19%, II for 63%, and III for 18%; 45% had nodal involvement at baseline. Seventy percent had TNBC. Clinical and tumor characteristics were well matched between treatment arms. The pCR rate was 18% with CDDP and 26% with AC, yielding a risk ratio (RR) of 0.70 (90% CI, 0.39 to 1.2). The risk of RCB 0 or 1 (RCB 0/1) was 33% with CDDP and 46% with AC (RR, 0.73; 90% CI, 0.50 to 1.1). Both regimens were generally well tolerated without unexpected toxicities.
CONCLUSION: pCR or RCB 0/1 is not significantly higher with CDDP than with AC in BRCA carriers with stage I-III HER2-negative breast cancer for both TNBC and ER+/HER2-negative disease.
PMID: 32097092
DOI: 10.1200/JCO.19.03292