Genetic Testing in Ovarian Cancer
The “Dream” Test
Olaparib Maintenance Therapy
in Platinum-Sensitive Relapsed Ovarian Cancer
N Engl J Med 2012;366:1382-92.
n The patients had recurrent ovarian or fallopiantube cancer or primary peritoneal cancer with high grade serous features or a serous component, which was platinum-sensitive.
n BRCA1/2 mutation status was not required.
Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer
1.0
N Engl J Med 2012;366:1382-92.
Maintenance Olaparib in Platinum-Sensitive Recurrent Ovarian Cancer: Phase II
n Known BRCA
mstatus was not required for eligibility, but was established via case report forms documenting previous local germline BRCA testing, or via retrospective germline BRCA testing
Lancet Oncol 2016; 17: 1579–89
BRCAm BRCAwt
Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer
N Engl J Med 2016;375:2154-64.DOI: 10.1056/NEJMoa1611310
n We enrolled two independent cohorts on the basis of the presence or absence of a
germline BRCA mutation (gBRCA cohort and non-gBRCA cohort), as determined on
BRACAnalysis testing (Myriad Genetics).
Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer
N Engl J Med 2016;375:2154-64.DOI: 10.1056/NEJMoa1611310N Engl J Med 2016;375:2154-64.DOI: 10.1056/NEJMoa1611310
FDA-Approved PARP Inhibitors in Ovarian Cancer
n Olaparib (Dec 19, 2014)
• >3rd line, germline BRCA, treatment n Rucaparib (Dec 19, 2016)
• >2nd line, germline and somatic BRCA, treatment n Niraparib (March 27, 2017)
• >2nd line, no biomarker, maintenance
Olaparib for Metastatic Breast Cancer
in Patients with a Germline BRCA Mutation
n The patients had HER2-negative metastatic breast cancer that was hormone-receptor positive or was triple negative.
n Patients had a confirmed deleterious or suspected deleterious germline BRCA mutation; the mutation was detected by central testing with BRACAnalysis (Myriad Genetics) in 297 patients and by local testing in 167 patients.
n Patients had received no more than two previous chemotherapy regimens for metastatic disease,
N Engl J Med 2017;377:523-33. DOI: 10.1056/NEJMoa1706450
Olaparib for Metastatic Breast Cancer
in Patients with a Germline BRCA Mutation
N Engl J Med 2017;377:523-33. DOI: 10.1056/NEJMoa1706450
Genetic Testing in Ovarian Cancer
n NCCN Guidelines Version 1.20171
• [Any] patients with a personal history of invasive
[non-mucinous] epitherail cancer [including fallopian, peritoneal]
diagnosed at any age
n ASCO Expert Statement
• Epithelial ovarian, fallopian, or peritoneal cancer…. Even in the absence of family history
n SGO Clinical Practice Statement October 2014
• …. All women with ovarian, fallopian, and peritoneal carcinoma
National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Ovarian Cancer. Version 1.2017. 2. Lu KH et al.J Clin Oncol.
2014;32:833-840. 3. https://www.sgo.org/clinical-practice/guidelines/genetic-testing-for-ovarian-cancer/. Accessed May 24, 2017.
~1 in 4 ovarian cancer patients harbor a hereditary mutation
乳癌に対するPARP阻害薬の対象患者の選択？
BRCA1/2変異を伴う正常細胞
n Germ line mutation
BRCA1/2変異を伴う癌細胞
n Somatic mutation
Development of Oncology Drugs
Category Breast Gastric CRC NSCLC Ovary Melanoma
Chemotherapy Anthracyclines Taxanes
Fluorpyrimidines Cyclophosphamide Eribulin
Gemcitabin Vinorelbine
Fluoropyrimidines Platinum
Taxanes
Anthracyclines
Fluorpyrimidines Oxaliplatin
Irinotecan Trifluridine/
tipiracil
Platinum Taxanes
Fluoropyrimidines Irinotecan
Pemetrexed Gemcitabine Vinorelbine
Platinum Taxanes
Camptothecins Liposomal-Dox Gemcitabine
Dacarbazine
Hormonetherapy
enhancer Everolimus Palbociclib Targeted:
Antibody Trastuzumab Pertuzumab Bevacizumab T-DM1
Trastuzumab
Ramucirumab Bevacizumab Cetuximab/
Panitumumab Ramucirumab
Bevacizumab
Ramucirumab Bevacizumab
Targeted: TKI Lapatinib Regorafenib Gefitinib/Erlotinib
Afatinib Osimeritinib
Crizotinib/Alectinib Targeted:
PARP-I Olaparib Olaparib
Rucaparib Niraparib
Immuno-oncology Nivolumab/
Pembrolizumab Nivolumab/
Pembrolizumab Ipirimumab
Nivolumab/
Pembrolizumab
がん免疫のメカニズム
n
腫瘍に対する免疫反応はリンパ節において T 細胞が腫瘍抗原を認識し活性化され、その 後、活性化されたT細胞が゙腫瘍部位に到達して腫瘍細胞の排除に働く事で成⽴する。n
ヒトには免疫反応の調節メカニズムとして、もともと⾃⼰に対する過剰な免疫反応や正 常組織への障害を抑えるための免疫チェックポイント機構が備わっており、T 細胞が活 性化する と細胞膜上に発現される CTLA-4 や PD-1 が、抗原提⽰細胞上の CD28 リガンドファミリーと結合する事で、免疫反応が鎮静化される。
n
腫瘍環境ではこの免疫チェックポイント機構が増強しており、腫瘍細胞上の CD28 リガンドファミリ ーと活性化リンパ球の CTLA-4 や PD-1 が結合する事で腫瘍免疫の抑制反 応が起こり、免疫反応による抗腫瘍効果からの回避が可能となっている。
東みゆき 医学の歩み 2013年3⽉2⽇ p.809-815 京都⼤学医学研究科 呼吸器内科/腫瘍薬物治療学講座 永井 宏樹先⽣の総説を改変
Immune Checkpoints and Inhibitors
NATURE 497, 7 Nov.
京都⼤学 本庶 佑 教授