我要搞搞 调整性去势敏锐性前哨腺癌精确全程诊疗案例
作家简介:我要搞搞
樊连城 训导
上海交通大学医学院附属仁济病院泌尿外科
2020年获国度当然科学基金资助;
2020年获上海市东谈主才打算-扬帆打算资助;
以第一作家身份发表SCI论文十余篇,总影响因子>100,包括NCCN官方杂志:JNCCN论文1篇,好意思国泌尿外科协会官方杂志Journal of urology论文4篇,2017年获BJU international年度中国最好论文;并屡次受邀于欧洲泌尿外科年会、好意思国泌尿外科年会等国际会议进行会议发言及交流。
欧美色病例选录:
调整性激素敏锐性前哨腺癌预后较差,且个体预后相配关于治愈决策的疗效各异极大,现在尚无最好决策的定论。跟着二代测序的逾越,让基于基因检测从而衔尾肿瘤患者精确治愈成为了可能。本篇著作先容了一例我院诊治的基于年青的,初诊时肿瘤负荷极高的患者,基于基因检测末端制定了基于新式抗雄集合多西他赛化疗三联决策治愈,取得了极佳的临床疗效,且治愈期间耐受度尚可。
患者,男,54岁,因发现PSA升高8月余(155.0ng/ml)于我院就诊,直肠指检:前哨腺III度增大,双侧叶质硬,名义不光滑。遂于2022-01-24于我院行前哨腺穿刺,穿刺病理指示: 12针均阳性,1(90%),2(90%),3(90%),4(100%),5(90%),6(90%),7(90%),8(90%),9(90%),10(80%),11(60%),12(50%):前哨腺腺癌,Gleason评分4+5=9分。查MRI指示:前哨腺占位性病变,侵略双侧精囊,盆腔多发骨调整可能。骨扫描指示全身多发骨调整。字据以上病史,磋议患者会诊为:调整性去势敏锐性前哨腺癌(mCSPC) (T3b N0 M1b)。
磋议到患者年齿较轻,且治愈意愿比较积极,经我院MDT扣问后,提出患者先行基因检测,指定精确治愈决策。基因检测末端如下:患者检出高频的CDK12无益突变(13.15%),这一突变时时预示患者关于单纯内分泌治愈耐药快,预后欠安。磋议患者年齿较轻,但肿瘤恶性度极高,且肿瘤负荷极大,同期伴有指示预后时时欠安的CDK12突变,因此我院MDT扣问后提出患者收受新式抗雄治愈治愈+多西他赛化疗+药物去势治愈。同期多西他赛化疗期间最常见的反作用为粒缺伴发烧,因此治愈期间防护性使用长效升白针保护,并加强治愈期间血老例监测保护。
患者三联决策治愈后一月,PSA快速着落至1.5ng/mL,治愈后三月后逐渐着落<0.01 ng/mL,同期化疗期间未出现粒缺,化疗耐受佳。治愈后6月复查盆腔MRI指示:“前哨腺癌内分泌治愈后”,前哨腺内病灶较前(2022-1-13)消弱、信号搀杂;左侧精囊腺雀斑状弥漫受限灶;上次所见“右侧髂血管旁肿大淋恭维及骶前增大淋恭维”本次未见。复查PSMA-PET-MRI:1.前哨腺癌详细治愈后,前哨腺PSMA摄取轻度增高,双侧髂血管旁及腹膜后散在淋恭维、PSMA摄取未见明白极端,全身骨骼多发成骨性编削伴部分PSMA摄取轻度增高,磋议肿瘤活性大部分扼制。前哨腺钙化灶,左侧精囊腺出血。患者治愈后半年再次行外周血轮回肿瘤DNA靶向基因检测,指示上次所见CDK12突变本次未见,指示联系高度耐药潜能细胞治愈后终了明白。现在患者化疗已暂停,收受保管药物去势治愈集合达罗他胺口服治愈。扫数治愈经过中,患者耐受度极佳,无明白不良反应。
病例扣问:
雄激素褫夺治愈(ADT)是mCSPC最粗拙使用的基础治愈步调。比年来,跟着新的临床查验的开展、新的药物走向临床、PCa基因突变图谱的揭示以及基因检测在临床的普及,mCSPC的诊疗旅途发生了一些积极的变化。跟着ARASENS、CHAARTED、STAMPEDE、LATITUDE等推敲末端的公布,mCSPC患者在ADT基础之上集合达罗他胺、阿比特龙,恩杂鲁胺或多西他赛不错显赫的裁汰患者的逝世风险,延迟总生计[4-6]。尽管跟着治愈决策的不断开拓,关于mCSPC的治愈现在仍不存在一个最好尺度治愈决策。此外,mCSPC存在显赫的肿瘤异质性,PCa在基因组序列、表不雅遗传学均分子水平上也存在纷乱各异,这种各异径直导致了调换病理类型的PCa患者对治愈药物的反应也不尽调换。若何精确选拔药物,让患者的生计时辰最大化,是临床大夫濒临的又一个挑战。
跟着二代测序(Next-generation sequencing,NGS)技能的快速发展,PCa仍是投入精确/个体化诊疗时间。以分子分型判断PCa患者预后与衔尾治愈成为热门和趋势。推敲泄露,约莫90%的mCRPC患者佩带临床可滋扰的基因突变,触及的通路包括AR通路、DNA挫伤开拓通路、细胞周期信号通路、PI3K信号通路及Wnt信号通路等[8]。在DNA挫伤开拓通路中,CDK12突变的患者,其无生化复发生计期更短,更快发生调整进展,预后较差,且更能从免疫观望点扼制剂治愈获益[15-18]。现在我国对PCa基因流行病学的判辨主要来自西方东谈主群的数据,中国东谈主mPCa的基因突变情况、以及在实在寰宇中与老例药物治愈疗效的联系性推敲还较少。咱们中心牵头发起的一项纳入316例中国PCa患者的推敲泄露,中国mPCa患者中胚系DNA开拓基因突变率为12%,除BRCA1/2、ATM外,还检出2例GEN1(0.63%)、1例CHEK2(0.32%)及1例FANCA(0.32%)基因胚系致病变异,指示中国调整性PCa患者胚系基因突变谱与国际东谈主群存在各异[24,25]。咱们中心也对mPCa的基因突变情况及与药物疗效的联系性进行了总结性分析,末端发现中国mPCa患者存在高频率突变的基因,包括AR(34.6%)、FOXA1(21.1%)、TP53(19.5%)、CDK12(15.4%)、BRCA2(13%)等,其中CDK12基因的突变频率明白高于西方东谈主群的5%-7%[27]。在药物疗效方面,咱们发现中国东谈主群佩带CDK12基因体系突变的患者接受阿比特龙治愈的成果较差,佩带TP53或RB1基因突变的患者,接受阿比特龙或多西他赛疗效均欠安,佩带DNA挫伤开拓通路联系基因突变,极度是佩带BRCA2基因突变的患者对奥拉帕利或铂类化疗的反应更佳,无疾病进展的生计期更长[27,30]。由于每个治愈亚组的样本量较小,特定基因的药物疗效测度价值及ctDNA检测的临床益处还需要更大样本量的前瞻性临床推敲的进一步考证。该例患者年齿较轻,但肿瘤恶性度极高,且肿瘤负荷极大,同期伴有指示预后时时欠安的CDK12突变,因此该患者未提出收受新式内分泌治愈集合去势治愈,收受了基于达罗他胺以及多西他赛化疗的三联决策,兼顾了内分泌治愈依赖或相悖的癌细胞亚群,患者治愈期间取得了极好的治愈成果,且不良反应小。同期患者治愈后半年再次行外周血轮回肿瘤DNA靶向基因检测,指示上次所见CDK12突变本次未见,指示联系高度耐药潜能细胞治愈后终了明白。
多西他赛是调整性前哨腺癌一线治愈的紧迫药物,其治愈成果显赫,决策及不良反应的把控及防护亦然极其紧迫的。CHAARTED和STAMPEDE推敲均阐述,在雄激素褫夺治愈(ADT)基础上集合多西他赛化疗可显赫延迟调整性去势敏锐性前哨腺癌(mCSPC)患者的总生计期[4,5]。但是,多西他赛最常见的不良反应是骨髓扼制,极度是中性粒细胞减少症(CIN)。为了保证化疗的剂量强度和治愈成果,防护性使用粒细胞集落刺激因子(G-CSF)可灵验裁汰CIN的发生风险和严重进程[31]。在G-CSF制剂中,聚乙二醇化重组东谈主粒细胞集落刺激因子(PEG-rhG-CSF)比较短效G-CSF具有更优厚的药代能源学特质和临床成果。推敲标明,长效G-CSF可显赫裁汰中重度CIN和发烧性中性粒细胞减少症(FN)的发生率,为化疗提供更好的保护[32]。在多西他赛化疗中,PEG-rhG-CSF每3周仅需一次打针,可握续进展作用2周,大大擢升了患者的盲从性和生活质料[33]。本例患者收受多西他赛集合新式抗雄治愈,防护性使用PEG-rhG-CSF,不仅取得了很好的治愈成果,何况耐受性高超。这种治愈战术充分体现了个体化治愈的理念,既最大化了多西他赛的抗肿瘤成果,又通过长效升白针的哄骗灵验防护和处置了骨髓扼制这一主要不良反应,使患者约略按期完成既定的化疗决策,从而获取最好的治愈获益。这种详细治愈决策的得胜实施,为调整性前哨腺癌患者的处置提供了贵重的临床教学,值得在今后的推行中进一步执行和优化。
参考文件(文件重新编号)
[1].The Global Cancer Observatory - All Rights Reserved, December, 2020
[2].陈万青,等,2011年中国恶性肿瘤发病和逝世分析. 中国肿瘤,2015,24(1):1-10.
[3].叶定伟,等,中国前哨腺癌的流行病学概述和启示. 中华外科杂志,2015,53(4):249-252.
[4].Kyriakopoulos CE, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial. Journal of Clinical Oncology, 2018,36(11), 1080–1087.
[5].Parker CC. et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet 2018 12 01;392(10162).
[6].Fizazi K. et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol 2019 05;20(5).
[7].De Bono NO J, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med, 2020, 382(22): 2091-2102.
[8].Sheng-Yu Ku, MartinE.et al. Towards precision oncology in advanced prostate cancer. Nature reviews. Urology.201911;1611(11).
[9].Adams EJ, et al. FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes. Nature 2019;571(7765).
[10].ABIDA W, et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci U S A, 2019, 116(23): 11428-11436.
[11].CHEN WS, et al. Genomic Drivers of Poor Prognosis and Enzalutamide Resistance in Metastatic Castration-resistant Prostate Cancer. Eur Urol, 2019,76(5): 562-571.
[12].Na R, Zheng SL, et al. Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death. Eur Urol 2017 05;71(5).
[13].Annala M, Vandekerkhove G, et al. Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer. Cancer Discov 2018 04;8(4).
[14].Cheng HH, Pritchard CC, et al. Biallelic Inactivation of BRCA2 in Platinum-sensitive Metastatic Castration-resistant Prostate Cancer. Eur Urol 2016 06;69(6).
[15].Reimers MA, Yip SM, et al. Clinical Outcomes in Cyclin-dependent Kinase 12 Mutant Advanced Prostate Cancer: Clinical Outcomes in Cyclin-dependent Kinase 12 Mutant Advanced Prostate Cancer. Eur Urol 2020 03;77(3).
[16].Wu YM, Cieślik M, et al. Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer. Cell 2018 06 14;173(7).
[17].Antonarakis ES, et al. Cyclin-Dependent Kinase 12, Immunity, and Prostate Cancer. N Engl J Med 2018 09 13;379(11).
[18].Nguyen B, Mota JM, et al. Pan-cancer Analysis of CDK12 Alterations Identifies a Subset of Prostate Cancers with Distinct Genomic and Clinical Characteristics. Eur Urol 2020 11;78(5).
[19].MATEOJ,et al. DNA-repair defects and Olaparib in metastatic prostate cancer. N Engl J Med, 2015, 373(18): 1697-1708.
[20].ABIDAW,et al. Preliminary results from TRITON2: a phase 2 study of rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination repair (HRR) gene alterations. Ann Oncol, 2018, 29(suppl_8): Ⅷ271-Ⅷ302.
[21]. MATEO J, et. al. Olaparib in patients with metastatic castration-resistant prostate cancer with dna repair gene aberrations(TOPARP-B):a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol, 2020, 21(1):162-174.
[22].ROBINSON D, et al. IntegrativeClinical genomics of advanced prostate cancer. Cell, 2015,161(5): 1215-1228.
[23].LE D T, DURHAM J N, et al. Mismatch repairdeficiency predicts response of solid tumors to PD-1 blockade. Science, 2017, 357(6349):409-413.
[24].WEI Y, WU J, et al. Germline DNA repair gene mutationlandscape in Chinese prostate cancer patient. Eur Urol, 2019, 76(3): 280-283.
[25].WEI Y, WU J L, et al. Prognostic value of germline DNA repair gene mutations in de novo metastatic and castration-sensitive prostate cancer. Oncologist, 2020,25(7):e1042-e1050.
[26].LI J, XU C, et al. A genomic and epigenomic atlas of prostate cancer in Asian populations. Nature, 2020, 580(7801):93-99.
[27].Dong B. et al. Use of Circulating Tumor DNA for the Clinical Management of Metastatic Castration-Resistant Prostate Cancer: A Multicenter, Real-World Study. J Natl Compr Canc Netw. 2021 May 14:1-10.
[28].Gong Y, Fan L. et al. Targeted Next-Generation Sequencing Reveals Heterogenous Genomic Features in Viscerally Metastatic Prostate Cancer. J Urol 2021 Aug;206(2).
[29].Fan L, Fei X. et al. Comparative Analysis of Genomic Alterations across Castration Sensitive and Castration Resistant Prostate Cancer via Circulating Tumor DNA Sequencing. J Urol 2021 02;205(2).
[30]. Fan L, Fei X. et al. Distinct Response to Platinum-Based Chemotherapy among Patients with Metastatic Castration-Resistant Prostate Cancer Harboring Alterations in Genes Involved in Homologous Recombination. J Urol 2021 Apr 27.
[31].Crawford J, et al. Pegfilgrastim administered once per cycle reduces incidence of chemotherapy-induced neutropenia. J Clin Oncol. 2005;23(15):3215-3220.
[32].Vogel CL, et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol. 2005;23(6):1178-1184.
[33].Yang BB我要搞搞, et al. Pharmacokinetics and pharmacodynamics of pegfilgrastim in patients with non-small cell lung cancer. Clin Pharmacol Ther. 2003;73(6):558-569.
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