奥拉帕利对其他基因突变乳腺癌也有效
乳腺癌易感基因BRCA1和BRCA2是重要的抑癌基因，对于染色体DNA损伤的同源重组修复至关重要，如果发生致病突变，容易引起乳腺癌等恶性肿瘤，尤其HER2阴性或三阴性等难治型乳腺癌。OlympiAD研究已经证实，多腺苷二磷酸核糖聚合酶PARP抑制剂奥拉帕利（旧称奥拉帕尼）可显著改善性细胞（又称种系、胚系、生殖系、可遗传、先天性）BRCA突变晚期乳腺癌患者的生存，已于2018年8月22日获批进入中国内陆（商品名：利普卓）。不过，奥拉帕利对体细胞（又称获得性）BRCA或其他基因突变晚期乳腺癌患者是否有效？
2020年10月29日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表哈佛大学医学院、贝斯以色列医院和新英格兰女执事医院、达纳法伯癌症研究院、纽约纪念医院斯隆凯特林癌症中心、霍普金斯大学悉德尼金梅尔综合癌症中心、芝加哥大学、杜克大学、宾夕法尼亚大学、印第安那大学、伯明翰阿拉巴马大学、华盛顿大学、弗雷德哈钦森癌症研究中心、西雅图抗癌联盟、旧金山加利福尼亚大学海伦迪勒家族综合癌症中心、匹兹堡大学、教堂山北卡罗来纳大学的乳腺癌转化研究联盟（TBCRC）048研究报告，探讨了奥拉帕利对性细胞或体细胞BRCA或其他同源重组相关基因突变晚期乳腺癌的有效性。
TBCRC 048 (Olaparib Expanded): A Phase 2 Study of Olaparib Monotherapy in Metastatic Breast Cancer Patients With Germline or Somatic Mutations in DNA Repair Genes (NCT03344965)
该多中心单组两阶段二期临床研究于2018年3月～2020年1月入组晚期乳腺癌病变可测量的性细胞非BRCA同源重组相关基因突变（性细胞基因突变队列）或体细胞BRCA或非BRCA同源重组相关基因突变（体细胞基因突变队列）患者各27例，其中雌激素受体阳性HER2阴性占76%，性细胞PALB2、体细胞BRCA1或ATM或CHEK2突变占87%。用过PARP抑制剂、铂类难治型或转移后超过两种化疗方案失败的患者已被剔除。患者每天口服两次奥拉帕利300毫克，直至疾病进展。主要终点为客观缓解率，次要终点包括临床获益率和无进展生存。
结果，客观缓解率：
性细胞基因突变队列：33%（90%置信区间：19%～51%）
体细胞基因突变队列：31%（90%置信区间：15%～49%）
性细胞PALB2突变患者：82%
体细胞BRCA突变患者：50%
中位无进展生存：
性细胞PALB2突变患者：13.3个月（90%置信区间：12个月～尚未进展或死亡）
体细胞BRCA突变患者：6.3个月（90%置信区间：4.4个月～尚未进展或死亡）
ATM或CHEK2突变患者未见缓解。
因此，该初步研究结果表明，奥拉帕利对于性细胞PALB2或体细胞BRCA突变晚期乳腺癌患者也有效，将进一步扩大对奥拉帕利可能获益的乳腺癌乳腺癌患者人群。这些结果再次突显分子特征分析对于晚期乳腺癌治疗决策的价值。
相关链接
J Clin Oncol. 2020 Oct 29. Online ahead of print.
TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes.
Tung NM, Robson ME, Ventz S, Santa-Maria CA, Nanda R, Marcom PK, Shah PD, Ballinger TJ, Yang ES, Vinayak S, Melisko M, Brufsky A, DeMeo M, Jenkins C, Domchek S, D'Andrea A, Lin NU, Hughes ME, Carey LA, Wagle N, Wulf GM, Krop IE, Wolff AC, Winer EP, Garber JE.
Beth Israel Deaconess Medical Center, Boston, MA; Harvard Medical School, Boston, MA; Memorial Sloan Kettering Cancer Center, New York, NY; Dana-Farber Cancer Institute, Boston, MA; Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; The University of Chicago, Chicago, IL; Duke University Medical Center, Durham, NC; University of Pennsylvania, Philadelphia, PA; Indiana University School of Medicine, Indianapolis, IN; University of Alabama at Birmingham, Birmingham, AL; University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA; University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; University of Pittsburgh Medical Center, Pittsburgh, PA; University of North Carolina, Chapel Hill, NC.
PURPOSE: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in germline (g)BRCA1/2 mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s)BRCA1/2 mutations or g/s mutations in homologous recombination (HR)-related genes other than BRCA1/2.
METHODS: Eligible patients had MBC with measurable disease and germline mutations in non-BRCA1/2 HR-related genes (cohort 1) or somatic mutations in these genes or BRCA1/2 (cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (≤ 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS).
RESULTS: Fifty-four patients enrolled. Seventy-six percent had estrogen receptor-positive HER2-negative disease. Eighty-seven percent had mutations in PALB2, sBRCA1/2, ATM, or CHEK2. In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with gPALB2 (ORR, 82%) and sBRCA1/2 (ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable [NA]) for gPALB2 and 6.3 months (90% CI, 4.4 months to NA) for sBRCA1/2 mutation carriers. No responses were observed with ATM or CHEK2 mutations alone.
CONCLUSION: PARP inhibition is an effective treatment for patients with MBC and gPALB2 or sBRCA1/2 mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond gBRCA1/2 mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC.
PMID: 33119476
DOI: 10.1200/JCO.20.02151