Prevalence and clinical implications of BRCA1/2 germline mutations in Chinese women with breast cancer Yuntao Xie M.D., Ph.D.

Transcription

1 Prevalence and clinical implications of BRCA1/2 germline mutations in Chinese women with breast cancer Yuntao Xie M.D., Ph.D. Hereditary Cancer Center, Peking University Cancer Hospital 1

2 Breast cancer is the most common cancer in Chinese women Chen W, et al. National cancer incidence and mortality in China, Chin J Cancer Res 2016;28(1):

3 Breast Cancer in Beijing, China (/100,000) 7.5%/per year 1998: 25/100, : 61/100,000 Familial breast cancer 5%-10% The incidence of breast cancer in Beijing between 1998 to

4 Breast Cancer susceptibility genes BRCA2 BRCA1 Science 2014,(343):

5 BRCA1/2 Genes High penetrance breast cancer susceptibility genes Germline mutations in BRCA1/ % in Caucasian women Roukos et al. Nat Clin Pract Oncol. 2007;4:

6 The current status of BRCA1/2 mutations in Chinese women Most studies with small samples The frequency of BRCA1/2 mutations is not fully elucidated The phenotype of BRCA1/2 carriers is unclear 6

7 Study Population From October 2003 to September 2012 Breast Cancer: 5931 cases Familial breast cancer (9.2%) Early-onset breast cancer (17.4%) Triple-negative breast cancer (16.7%) Sporadic breast cancer (56.7%) (>40y) 7

8 BRCA1 deleterious mutation + + BC 42y,43y + BC 32y,35y ID: 5455, BRCA1 exon11,nt3478 delttaat, codon 1130 stop

9 BRCA2 deleterious mutation ID:4599 :BRCA2 exon23,nt9269 C >A, codon 3014stop

10 BRCA1/2 mutations in 5931 cases based on family history of breast cancer Age of Onset Familial (n=543) Non-familial (n=5388) BRCA1/2 BRCA1/2 No. of carrier No. of carrier Patients Patients No. % No. % Total

11 Recurrent mutations of BRCA1/2 Gene Exon Nucleotide change Effect on protein Frequency(%) References BRCA del TT Stop1328 (4/634) 0.6% BIC BRCA C>T Q1525X (2/634) 0.3% Novel BRCA C>A S611X (3/634) 0.5% BIC BRCA del AG Stop1725 (2/634) 0.3% BIC BRCA C>G S1955X (2/634) 0.3% Novel BRCA del TG Stop2201 (4/634) 0.6% BIC BRCA del4ins5 Stop2811 (4/634) 0.6% BIC BRCA insA Stop3042 (3/634) 0.5% BIC BIC: The Breast Cancer Information Core 11

12 Spectrum of BRCA1/2 mutations BRCA1 (%) BRCA2 (%) Total Total Mutation type Frameshift 73 (66.4) 93 (76.2) 166 (71.6) Non-sense 30 (27.3) 24 (19.7) 54 (23.3) Splice 2 (1.8) 4 (3.3) 6 (2.6) Missense 4 (3.6) 0 (0.0) 4 (1.7) Synonymous 1 (0.9) 1 (0.8) 2 (0.9) BIC report Yes 66 (60.0) 70 (57.4) 136 (58.6) No 44 (40.0) 52 (42.6) 96 (41.4) 12

13 13

14 Triple-negative Breast Cancer(TNBC) Estrogen receptor (ER), Progesterone receptor (PR), and HER2 are negative. Accounted for 12%-17% of all breast cancer patients Lack of targeted therapy and endocrine therapy and poor survival Foulkes W D. et al. N Engl J Med 2010; 363(20):

15 Objectives 965 Triple-negative Breast Cancer Patients The frequency of BRCA1 germline mutations among Chinese women with TNBC BRCA1 mutations and response to neoadjuvant chemotherapy in women with TNBC BRCA1 mutation status and Survival 15

16 BRCA1 mutation rate in 956 Chinese women with TNBC Age of Onset No. of Patients Total TNBC BRCA1 carrier No. % Abbreviation: TNBC, triple-negative breast cancer. 16

17 Treatment of 956 TNBC patients Anthracycline with or without taxanebased regimen (n=477) TNBC (n=956) Neoadjuvant chemotherapy (n=652) Non-neoadjuvant chemotherapy (n=304) Taxane-based regimen (n=133) Others (n=16) 17

18 BRCA1 carriers and response to Anthracycline in the patients with triple-negative breast cancer pcr Anthracycline with or without taxane(n=477) n n % P Carriers <.001 Non-carriers

19 BRCA1 carriers and response to Taxane in the patients with triple-negative breast cancer pcr Taxane(n=159) n n % P Carriers Non-carriers

20 Annals of Oncology 2015 BRCA1 mutation among TNBC patients who were diagnosed at or before the age of 50 years was 10.5%. BRCA1-mutated TNBC patients are more sensitive to anthracycline-based neoadjuvant chemotherapy. 20

21 Breast cancer risk in Chinese women with BRCA1 or BRCA2 mutations 21

22 研究方案 Research process A total of 4420 consecutive breast cancer patients were tested for germline mutations of BRCA1 and BRCA2 genes from 2007 to 2012 The current age or age at death, and site of any cancer were ascertained for all female first-degree relatives of the participants A total of 1816 families (1816 probands,5549 first-degree female relatives) The breast cancer risk among female carriers of BRCA1 and BRCA2 mutations was estimated using the kincohort study Yao, L., et al. Breast Cancer Res Treat, ,

23 Breast cancer risk in Chinese women with BRCA1 or BRCA2 mutations Breast cacner risk by age of 70 BRCA1:37.9% BRCA2:36.5% General population:3.6% Yao, L., et al. Breast Cancer Res Treat, ,

24 Implications of this study Genetic counseling, regular surveillance and individualized prevention should be provided for Chinese women carrying BRCA1/2 mutations Yao, L., et al. Breast Cancer Res Treat, ,

25 Searching for potential breast cancer susceptibility genes by whole-exome sequencing 9 index cases were negative for BRCA1/2 mutations 35, 1) diagnosed with at or before the age of 2) had at least one first-degree relative affected with breast cancer finding potential breast cancer susceptibility gene-recql 13 novel mutations in the RECQL gene in 439 unrelated familial breast cancer patients 25

26 RECQL is a novel breast cancer susceptibility gene Mutation rate of RECQL is 2.0% (9/448) in non-brca mutation patients

27 Sun, J. et al. PLoS Genet 11, e (2015).

28 Multiple breast cancer susceptibility genes panel is available for routine clinical practice Kurian AW et al. J Clin Oncol women without BRCA1/2 mutation underwent multiple-gene sequencing Identified potentially pathogenic mutations in other genes (ATM, CDH1, CDKN2A etc.), mutation rate is 11.4%

29 Multiple-gene panel in our large series 8085 unselected breast cancer patients 62-gene panel Sun J et al, Clin Cancer Res 2017

30 Germline mutations in cancer susceptibility genes in the 8085 cases

31 Distribution of mutations (N=743)

32 Mutations in other genes (N=315) Sun J et al, Clinical cancer research 2017

33 BRCA1/2mutations in the cohort of 8085 cases No. BRCA1 BRCA2 Total n % n % n %

34 Frequencies of mutations in this cohort of 8085 cases No. Of patients Mutation Cases (Prevalence, %) BRCA1/2 (%) Other mutation (%) Total mutation (%) (5.3%) 315 (3.9%) 743 (9.2%) 34

35 Science, 2014, March BRCA1 20 Years 35

36 Challenges 1. Interpretation of multiple-gene panel data 2. Precision treatment of patients with mutations 3. Selection of optimal surgery and adjuvant therapy for patients with mutation 4. Optimal risk-reducing medications and / or surgery procedures for high-risk women 36

37 Acknowledgements