乳腺癌易感基因BRCA1和BRCA2是重要的抑癌基因，對(duì)于染色體DNA損傷的同源重組修復(fù)至關(guān)重要，如果發(fā)生致病突變，容易引起乳腺癌等惡性腫瘤，尤其HER2陰性或三陰性等難治型乳腺癌。OlympiAD研究已經(jīng)證實(shí)，多腺苷二磷酸核糖聚合酶PARP抑制劑奧拉帕利（舊稱奧拉帕尼）可顯著改善性細(xì)胞（又稱種系、胚系、生殖系、可遺傳、先天性）BRCA突變晚期乳腺癌患者的生存，已于2018年8月22日獲批進(jìn)入中國(guó)內(nèi)陸（商品名：利普卓）。不過，奧拉帕利對(duì)體細(xì)胞（又稱獲得性）BRCA或其他基因突變晚期乳腺癌患者是否有效？

　　2020年10月29日，美國(guó)臨床腫瘤學(xué)會(huì)《臨床腫瘤學(xué)雜志》在線發(fā)表哈佛大學(xué)醫(yī)學(xué)院、貝斯以色列醫(yī)院和新英格蘭女執(zhí)事醫(yī)院、達(dá)納法伯癌癥研究院、紐約紀(jì)念醫(yī)院斯隆凱特林癌癥中心、霍普金斯大學(xué)悉德尼金梅爾綜合癌癥中心、芝加哥大學(xué)、杜克大學(xué)、賓夕法尼亞大學(xué)、印第安那大學(xué)、伯明翰阿拉巴馬大學(xué)、華盛頓大學(xué)、弗雷德哈欽森癌癥研究中心、西雅圖抗癌聯(lián)盟、舊金山加利福尼亞大學(xué)海倫迪勒家族綜合癌癥中心、匹茲堡大學(xué)、教堂山北卡羅來納大學(xué)的乳腺癌轉(zhuǎn)化研究聯(lián)盟（TBCRC）048研究報(bào)告，探討了奧拉帕利對(duì)性細(xì)胞或體細(xì)胞BRCA或其他同源重組相關(guān)基因突變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)

　　該多中心單組兩階段二期臨床研究于2018年3月～2020年1月入組晚期乳腺癌病變可測(cè)量的性細(xì)胞非BRCA同源重組相關(guān)基因突變（性細(xì)胞基因突變隊(duì)列）或體細(xì)胞BRCA或非BRCA同源重組相關(guān)基因突變（體細(xì)胞基因突變隊(duì)列）患者各27例，其中雌激素受體陽性HER2陰性占76%，性細(xì)胞PALB2、體細(xì)胞BRCA1或ATM或CHEK2突變占87%。用過PARP抑制劑、鉑類難治型或轉(zhuǎn)移后超過兩種化療方案失敗的患者已被剔除?；颊呙刻炜诜纱螉W拉帕利300毫克，直至疾病進(jìn)展。主要終點(diǎn)為客觀緩解率，次要終點(diǎn)包括臨床獲益率和無進(jìn)展生存。

　　結(jié)果，客觀緩解率：

• 性細(xì)胞基因突變隊(duì)列：33%（90%置信區(qū)間：19%～51%）

• 體細(xì)胞基因突變隊(duì)列：31%（90%置信區(qū)間：15%～49%）

• 性細(xì)胞PALB2突變患者：82%

• 體細(xì)胞BRCA突變患者：50%

　　中位無進(jìn)展生存：

• 性細(xì)胞PALB2突變患者：13.3個(gè)月（90%置信區(qū)間：12個(gè)月～尚未進(jìn)展或死亡）

• 體細(xì)胞BRCA突變患者：6.3個(gè)月（90%置信區(qū)間：4.4個(gè)月～尚未進(jìn)展或死亡）

　　ATM或CHEK2突變患者未見緩解。

　　因此，該初步研究結(jié)果表明，奧拉帕利對(duì)于性細(xì)胞PALB2或體細(xì)胞BRCA突變晚期乳腺癌患者也有效，將進(jìn)一步擴(kuò)大對(duì)奧拉帕利可能獲益的乳腺癌乳腺癌患者人群。這些結(jié)果再次突顯分子特征分析對(duì)于晚期乳腺癌治療決策的價(jià)值。

相關(guān)鏈接

• 奧利帕利對(duì)晚期乳腺癌基因突變患者優(yōu)于標(biāo)準(zhǔn)化療

• 奧拉帕利可改善晚期乳腺癌基因突變患者生存結(jié)局
  

• 奧拉帕利治療晚期乳腺癌的患者自評(píng)生活質(zhì)量結(jié)局

• 基因突變晚期乳腺癌：利普卓＋英飛凡

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