Inherited breast and ovarian cancer

Transcription

1 Inherited breast and ovarian cancer Pr François Duhoux Medical Oncology and Center for Human Genetics Breast Incidence - Mortality.be: Life9me risk : 12% IARC EUCAN Fact Sheets 2 1

2 Breast cancer in Belgium according to age Belgian Cancer Registry 3 Breast cancer: risk factors Sex 1 M / 100 F Age the risk increases with age but 15-20% before the age of 50 Family history Personal history Environmental factors (geographic migra9on) Prolonged exposure to estrogens: Early menarche Late menopause Late first pregnancy, few pregnancies Lack of breast- feeding Other breast lesions (in situ carcinoma, atypical hyperplasia, radial scar,...) Controversies: endocrine treatment for menopausal status, weight, alcohol, tobacco, 4 2

3 Introduc5on Breast cancer gene9c risk 15% of healthy women have at least one 1 st degree rela9ve with breast cancer! risk x 2 Breast cancer risk increases with the number of 1 st degree rela9ves with breast cancer 1: x 1.8 2: x 2.9 3: x 3.9 BRCA1 and BRCA2 germline muta9ons are responsible for 20-25% of familial breast cancer cases, but < 5% of all breast cancers > 50% of the gene9c predisposi9on to familial breast cancer remains unexplained 5 Ovary Incidence - Mortality.be: Life9me risk : 1.3% IARC EUCAN Fact Sheets 6 3

4 Ovarian cancer: risk factors Age Obesity Reproduc9ve history Birth control Family history of breast, ovarian and colorectal cancer Personal history of breast cancer 7 Introduc5on Breast and ovarian cancer : mul9disciplinary team surgeon / gynaecologist medical oncologist radia9on oncologist radiologist pathologist gene5cist 8 4

5 Gene5c predisposi5on to breast and ovarian cancer 9 Defini5ons Penetrance = the likelihood a given gene will result in disease High penetrance genes : rare muta9ons very high risk of disease independently of other risk factors Low penetrance genes frequent gene9c variants interact with exogenous factors to cause the diseases 10 5

6 High- risk breast cancer suscep5bility genes/alleles 20x BRCA1, BRCA2, TP53, PTEN, STK11 Multiple risk alleles Population frequency <0,1% Relative risk fold Disease Risk 10x 5x 0,1% 5% 50% Allele frequency 11 Moderate- risk breast cancer suscep5bility genes/alleles 20x BRCA1, BRCA2, TP53, PTEN, STK11 Multiple risk alleles Population frequency <0,1% Relative risk fold Disease Risk 10x 5x ATM, BRIP1, CHEK2, PALB2 Multiple risk alleles Population frequency <0,6% Relative risk 2 4 fold 0,1% 5% 50% Allele frequency 12 6

7 Low- risk breast cancer suscep5bility genes/alleles 20x BRCA1, BRCA2, TP53, PTEN, STK11 Multiple risk alleles Population frequency <0,1% Relative risk fold Disease Risk 10x 5x ATM, BRIP1, CHEK2, PALB2 Multiple risk alleles in each gene Population frequency <0,7% Relative risk 2 4 fold rs (FGFR2), rs (TNRC9), rs (MAP3K1), rs (LSP1), rs (8q), rs (2q), rs (CASP8) Population frequency 10-50% Relative risk 1,25-1,65 fold 0,1% 5% 50% Allele frequency 13 BRCA1 and BRCA2 BRCA1 : chr 17q21 BRCA2 : chr 13q

8 BRCA1 and BRCA2 Genes BRCA1 BRCA2 81 kbp 22 exons 84 kbp 26 exons Proteins 15 BRCA1 and BRCA2 Encode proteins that are mainly involved in DNA repair : Loss of fonc9on! genomic instability! tumor development 16 8

9 Acquired (soma5c) loss of the second allele Breast T, 54 BRCA1/2 mutation Breast T, 34 Germline Tumor Smith et al, 1992 Collins et al, BRCA1 and BRCA2 Exact pathophysiology remains unknown; tumor progression arises from different cellular subtypes : BRCA1 mainly triple nega9ve (ER-, PgR-, HER2- ) basal- like subtype BRCA2 mainly ER+ luminal subtype 18 9

10 BRCA1 and BRCA2 Thousands of different sequence variants have been iden9fied : 1) muta9ons that are known or likely to be deleterious and disease- associated 2) variants of unknown func9on = UV : unclassified variants 3) gene9c variants that are likely to be neutral and without clinical importance EMQN Best Practice Guidelines BRCA1 and BRCA2: High penetrance : high risk of disease if muta5on is found But risk also depends on: Sex 1 M / 100 F Age the risk increases with age but 15-20% before the age of 50 Personal history Environmental factors (geographic migra9on) Prolonged exposure to estrogens: Early menarche Late menopause Late first pregnancy, few pregnancies Lack of breast- feeding Other breast lesions (in situ carcinoma, atypical hyperplasia, radial scar,...) Controversies: endocrine treatment for menopausal status, weight, alcohol, tobacco, 20 10

11 BRCA1 and BRCA2 High penetrance : BRCA1 : breast (women) : young age, 82% cumula9ve risk at age 80 years ovary : 54% cumula9ve risk at age 80 years colon prostate BRCA2 : breast (women) : cumula9ve risk same as BRCA1 ovary : lower cumula9ve risk than BRCA1 (23% at age 80 years) breast (men) : increased risk (10% of breast cancers in males have a BRCA2 muta9on) pancreas colon prostate larynx BJMO (4), pp Future risks of developing cancer for a female carrier at a range of ages in the next 10- year interval, 20- year interval, and so on Breast BRCA1 Breast BRCA2 Ovary BRCA1 Ovary BRCA2 Chen, S. et al. J Clin Oncol; 24:

12 Annual Ovarian, Fallopian Tube and Peritoneal Cancer Finch, A. et al. J Clin Oncol; PALB2 Increased risk of developing breast cancer: 14% by age 50 35% by age 70 Risk varies with age: 8 to 9 9mes higher than average in women ages 20 to 39 6 to 8 9mes higher than average in women ages 40 to mes higher than average in women older than 60 Risk varies with family history by age 70, if PALB2 muta9on: no family history of breast cancer: 33% risk of developing breast cancer 2 or more first- degree rela9ves with breast cancer: 58% risk of developing the disease Antoniou AC et al, NEJM

13 TP53 Li- Fraumeni syndrome : prevalence : 1-9/100,000 due to TP53 germline muta9on associa9on : breast cancer sarcoma leukemia brain tumor occurence at a young age Eur J Hum Genet Jun;17(6): Li- Fraumeni syndrome: heterozygous TP53 muta5on Brain T, 35 Sarcoma, 39 Br. T, 38 Br. T, 39 Sarcoma, 15 Br T, 41 Lung T, y.o. 21 y.o. Brain T, 6 Brain T,

14 J Clin Oncol Sep 10;27(26):e Rare syndromes Peutz Jeghers syndrome : frequency : 1-9/100,000 heterozygous germline muta9ons of STK11 (tumor suppressor gene) associa9on : gastro- intes9nal polyps (hamartomas) abnormal pigmenta9on of the skin and mucosa increased risk of various cancers (including breast cancer : 45% risk at age 70 years) Eur J Hum Genet Jun;17(6):

15 Rare syndromes Cowden syndrome frequency : 1-9/1,000,000 germline muta9ons of PTEN (tumor suppressor gene) associa9on : mul9ple hamartomas (skin, breast, thyroid, gastro- intes9nal tract, endometrium, brain) increased risk of various cancers (including breast cancer : 30-50% at age 70 years) Eur J Hum Genet Jun;17(6): Rare syndromes CDH1 muta9ons (tumor suppressor gene) : associa9on : diffuse gastric cancer lobular breast cancer (52% risk at age 75 years for 2398delC muta9on) Eur J Hum Genet Jun;17(6):

16 Rare syndromes Type 1 neurofibromatosis : von Recklinghausen disease frequency : 1-5/10,000 autosomal dominant transmission NF1 germline muta9ons (tumor suppressor gene) associa9on : cafe au lait spots neurofibromas len9gines Lisch nodules (=hamartomas of the iris) bone problems increased risk of breast cancer standardized incidence ra9o : 3.5 Eur J Hum Genet Jun;17(6): Panel tes5ng for breast cancer: who should be tested? Panel tes9ng: expensive in terms of manpower and material! define a sub- popula9on in which the muta9ons are frequent! improvement of the cost / benefit ra9o Criteria to take into account : family history (family tree up to 3 rd genera9on) age at onset triple nega9ve breast cancer male case in the family Ashkenazi Jewish origin other types of cancer in the same pa9ent or in the family 32 16

17 Propor5on of ovarian cancer pa5ents with an inherited muta5on! test all pa5ents with epithelial ovarian cancer Walsh et al, PNAS Br. T, 54 Br. T, 42 Br. T, 45 Br. T, 56? Br. T, 36 Br. T, 34 aged 39 Br. T,

18 BRCA1 and BRCA2: how to interpret the results? Many muta9ons, different from one family to another A clearly deleterious muta9on cannot be iden9fied in all cases! 2- step process : Index case (usually a family member treated for cancer at a young age) then analyze the rela5ves, if appropriate (usually asymptoma9c) If no muta5on could be iden9fied aner the analysis of the index case, the test should be considered as non informa5ve, because the presence of a deleterious muta9on cannot be excluded, and no presymptoma9c test can be offered to the rela9ves If a muta5on is iden9fied, a predisposi5on test can be offered to the rela9ves : if it is nega9ve, it can be concluded that the rela9ve has not inherited the familial predisposi9on factor Minors : no indica9on to test 35 BRCA1 and BRCA2 Sonware for risk assessment e.g. BOADICEA

19 Br. T, 54 Br. T, 42 Br. T, 45 Br. T, 56? Br. T, 36 Br. T, 34 aged 39 Br. T, Br. T, 54 Br. T, 42 Br. T, 45 Br. T, 56? Br. T, 36 Br. T, 34 INDEX CASE aged 39 Br. T,

20 Hypothesis 1 Br. T, 54 Br. T, 42 Br. T, 45 Br. T, 56? Br. T, 36 Br. T, 34 INDEX CASE: BRCA1 mt aged 39 Br. T, Hypothesis 1- a Br. T, 54 Br. T, 42 Br. T, 45 Br. T, 56? Br. T, 36 Br. T, 34 INDEX CASE: BRCA1 mt aged 39 BRCA1 mt Br. T,

21 Hypothesis 1- b Br. T, 54 Br. T, 42 Br. T, 45 Br. T, 56? Br. T, 36 Br. T, 34 INDEX CASE: BRCA1 mt aged 39 BRCA1 wt Br. T, Hypothesis 2 Br. T, 54 Br. T, 42 Br. T, 45 Br. T, 56? Br. T, 36 Br. T, 34 INDEX CASE: BRCA wt aged 39 Br. T,

22 Hypothesis 2 - phenocopy Br. T, 54 Br. T, 42 Br. T, 45 Br. T, 56? Br. T, 36 Br. T, 34 2 nd INDEX CASE: BRCA1 mt BRCA1 wt aged 39 Br. T, 40 Hypothesis 2 really wt Br. T, 54 Br. T, 42 Br. T, 45 Br. T, 56? Br. T, 36 Br. T, 34 2 nd INDEX CASE: BRCA1 wt BRCA1 wt aged 39 Br. T, 40 22

23 BRCA1 and BRCA2 Sonware for risk assessment e.g. BOADICEA 45 Management of pa5ents with a gene5c predisposi5on 46 23

24 In case of BRCA1 / BRCA2 muta5on Breast cancer screening: From 20 y.o.: Physical examina9on every 6 months From 25 y.o. : Physical examina9on every 6 months MRI 1x/year Ultrasound (+/- mammogramm) 1x/year 47 In case of BRCA1 / BRCA2 muta5on Alterna9ve to breast cancer screening Prophylac9c mastectomy 48 24

25 In case of BRCA1 / BRCA2 muta5on Ovarian cancer preven9on No screening technique is effec9ve Preven9ve removal of the ovaries never if childbearing wish not before 35 y.o. ideally at the latest " at 40 y.o. if BRCA1 " at 45 y.o. if BRCA2 indica9on validated by a mul9disciplinary team consulta9on with the team s psychologist clinical and psychological follow- up 49 The benefics of prophylac5c salpyngo- oophorectomy Kauff et al, NEJM

26 BRCAtool hqp://brcatool.stanford.edu/ 51 Novel therapies tailored for pa5ents with a gene5c predisposi5on 52 26

27 Systemic treatment: targeted therapies new targets: focus on PARP Poly (ADP-Ribose) Polymerase (PARP) 53 27

28 Shah GM et al, Front Oncol. 2013; 3: Shah GM et al, Front Oncol. 2013; 3:

29 BRCA1 -/- and BRCA2 -/- are extremely sensitive to PARP inhibition Targeted inhibition of -/- cells! selective, less toxic treatment Farmer et al. Nature 2005; 434: PARP inhibitors in 2018 With PARP trapping ac9vity: Olaparib Niraparib Rucaparib Talazoparib! Single agent Without PARP trapping ac9vity: Veliparib! In combina9on with chemotherapy 58 29

30 59 OLYMPIAD study results 7.0 months 4.2 months Robson et al. NEJM

31 Phase II study of maintenance olaparib in ovarian cancer: study 19 Pa5ents Pla9num- sensi9ve high- grade serous ovarian cancer 2 previous pla9num regimens Maintained PR or CR following last pla9num regimen Olaparib 400mg bid, orally (n=136) Randomized 1:1 Placebo (n=129) Primary endpoint PFS by RECIST Secondary endpoints TTP by CA- 125 (GCIG criteria) or RECIST, OS, safety 82 sites in 16 countries Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003); N Engl J Med Apr 12;366(15): Study 19: progression- free survival Propor5on of pa5ents progression free At risk (n) Olaparib Placebo 0 0 Randomized treatment Placebo Olaparib 400 mg bid No. of events: Total pa5ents (%) Median PFS (months) Olaparib Placebo 60:136 (44.1) 93:129 (72.1) Time from randomiza5on (months) Hazard ra5o 0.35 (95% CI, ) P< Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003); N Engl J Med Apr 12;366(15):

32 Study 19: common adverse events* Olaparib 400 mg bid (n=136) Percentage of Pa5ents Placebo (n=128) Adverse event Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4 Any event Nausea Fa5gue Vomi5ng Diarrhea Headache Decreased appe5te Abdominal pain Anemia Dyspepsia *Adverse events graded according to maximum CTCAE version 3.0 grade, experienced by >15% of pa9ents in either treatment group. Ledermann et al. J Clin Oncol 2011;29 (suppl; abstr 5003); N Engl J Med Apr 12;366(15): Study 19: PFS by BRCAm status Propor5on of pa5ents progression- free Olaparib BRCAm Placebo BRCAm BRCAm (n=136) Olaparib Placebo Events: total pts (%) 26:74 (35.1) 46:62 (74.2) Median PFS, months HR= % CI (0.11, 0.31); P< Time from randomiza5on (months) Number at risk Olaparib BRCAm Placebo BRCAm % reduc9on in risk of disease progression or death with olaparib Presented by: Jonathan Ledermann et al at ASCO

33 Study 19: PFS by BRCAm status Propor5on of pa5ents progression- free BRCAm (n=136) BRCAwt (n=118) Olaparib Placebo Olaparib Placebo Events: total pts (%) 26:74 (35.1) 46:62 (74.2) 32:57 (56.1) 44:61 (72.1) Median PFS, months HR= % CI (0.11, 0.31); P< Olaparib BRCAm 0.2 Placebo BRCAm 0.1 Olaparib BRCAwt Placebo BRCAwt Time from randomiza5on (months) Number at risk Olaparib BRCAm Placebo BRCAm Olaparib BRCAwt Placebo BRCAwt HR= % CI (0.33, 0.84); P=0.007 BRCAwt, wild type (includes pa5ents with no known BRCAm or a muta5on of unknown significance) Presented by: Jonathan Ledermann et al at ASCO Systemic treatment: targeted therapies new targets TCGA, Nature

34 Conclusions BRCA1 and BRCA2 Breast cancer is frequent ovarian cancer is rare Gene9c predisposi9on is only par9ally explained by BRCA1/2 muta9ons +/- 10% of breast cancers are due to a gene9c predisposi9on < 5% are due to BRCA1 or BRCA2 germline muta9ons BRCA1 and BRCA2 muta9ons are rare in the general popula9on (<1/800) But they have a high penetrance Mul9ple different muta9ons exist Only pa9ents with a high probability of muta9on should be tested Other, rare gene9c anomalies exist PARP inhibitors are promising treatment op9ons for BRCAm breast and ovarian cancer pa9ents Future breast and ovarian cancer treatments will take into account cons9tu9onal and soma9c GENETIC altera9ons 67 Cliniques universitaires Saint- Luc Ins9tut Roi Albert II Francois Duhoux Thank you for your ahen5on francois.duhoux@uclouvain.be 68 Cliniques universitaires Saint- Luc Ins9tut Roi Albert II Francois Duhoux 34