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第三十屆醫學圖書館工作人員研討會

第三十屆醫學圖書館工作人員研討會. 乳癌的發生與治療 沈志陽 中央研究院生命科學圖書館 9, 18, 2008, 成功大學. Breast Cancer in Asia: Low incidence. Breast Cancer Incidence in the World, 2000. Parkin et al., 2001. Breast Cancer in Asia: Low incidence. Asian countries.

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第三十屆醫學圖書館工作人員研討會

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  1. 第三十屆醫學圖書館工作人員研討會 乳癌的發生與治療 沈志陽 中央研究院生命科學圖書館 9, 18, 2008,成功大學

  2. Breast Cancer in Asia: Low incidence Breast Cancer Incidence in the World, 2000 Parkin et al., 2001

  3. Breast Cancer in Asia: Low incidence Asian countries

  4. Breast Cancer in Asia: The leading cause of cancer incidence in women

  5. Breast Cancer in Asia: The leading cause of cancer incidence in women Cumulative Incidence of Female Cancer in the World, 2005 http://ganjoho.ncc.go.jp/public/statistics/backnumber/2005_en.html

  6. Breast Cancer in Asia: Significantly increasing Age-specific incidence of breast cancer in Japanese (Osaka) (Matsuno, et al, CEBP 2007) Longitudinal Cross-sectional

  7. Breast Cancer in Asia: Significantly increasing Age-Adjusted Incidence of Common Female Cancers in Taiwan, 1979-2002 per 100,000 60.00 50.00 Breast 40.00 Colon/ Rectum 30.00 Liver Lung 20.00 Cervix 10.00 0.00 1980 1985 1990 2000 1995

  8. The change of age-adjusted cancer incidence of the ten leading causes of cancer in women in Taiwan, 2001-2005 Breast Ca Uterus Ca Colon/Rectum Ca Thyroid Ca Lung Ca Ovarian Ca Skin Ca Liver Ca Stomach Ca Cervical Ca Total % of change, 2001-2005 Bureau of Health Promotion, 2008

  9. High-fat diet Cholesterol Estrogen as a Promoter to Trigger Cell Proliferation, Leading to Cancer Formation

  10. Cancer = Molecular defects + Cell proliferation Apoptosis Cancer Molecular defects Estrogen Over-proliferation Pregnancy Differentiation

  11. Ages at Menarche in Different Birth Cohorts in Taiwan Age at Menarche [You SL, Unpublished data] Birth Cohort

  12. Secular Trend of Ages at First Full-Term Pregnancy and Numbers of Parity in Taiwan. Ages at First Full-TermPregnancy (years) Numbers of Parity Calendar year Ministry of Interior: Demographic Facts, 1976-2002, Taiwan

  13. Age-Adjusted Incidence of Common Female Cancers in Taiwan, 1979-2002 per 100,000 60.00 Western dietary pattern (more fat/cholesterol intake) Changing attitude about pregnancy 50.00 Breast 40.00 Colon/ Rectum 30.00 Liver Lung 20.00 Cervix 10.00 0.00 1980 1985 1990 2000 1995

  14. Breast Cancer in Asia: Early-Onset 600 400 200 0 “Early-onset” of breast cancer in Taiwan Median ages at tumor onset of breast cancer Taiwan UK White 64 Black 57 JAHI 62 Osaka 51 (SEER, 1978-97) Taiwanese 48(1997) 50(2005) Rate per 100,000 population Early-onset 0 70 80 10 20 30 40 50 60 Age at diagnosis

  15. 600 400 200 0 Breast Cancer in Asia: Early-Onset “Early-onset” of breast cancer in Taiwan 50% of breast cancers in Taiwan occur during the premenopausal ages Taiwan UK Rate per 100,000 population Early-onset 0 70 80 10 20 30 40 50 60 Age at diagnosis

  16. 600 400 200 Cohort effect 0 “Early-onset” and Cohort effect of breast cancer in Taiwan Taiwan UK Rate per 100,000 population Early-onset 0 70 80 10 20 30 40 50 60 Age at diagnosis

  17. Matsuno et al., CEBP 2007

  18. Cohort Effect: More postmenopausal and older breast cancers are seen in Taiwan per 100,000 Incidence American Caucasian Taiwanese 2005 2002 1998 1994

  19. Breast Cancer in Asia Low incidence Leading cause of cancer incidence Significantly increasing Early tumor onset

  20. Genetic Susceptibility to Breast Cancer

  21. What kinds of genes determine genetic predisposition to breast cancer? High-penetrance Single/Few Low-penetrance Multiple BRCA1, BRCA2

  22. Breast cancer susceptibility genes (i.e. BRCA1, BRCA2) Linkage Analysis The combined effect of a large number of co-dominant alleles, each of which is associated with a small increase in risk. BRCA3?

  23. Genotyping Candidate Gene Approach Vt/Vt Vt/Wt Wt/Wt DNA C A B F D E Association Study Disease Case Control Non- Disease Risk [Odds Ratio] of Vt/Vt = A/C / D/F = AF/CD Risk [Odds Ratio] of Vt/Wt= B/C / E/F = BF/CE Rvt/vt>Rvt/wt>1,Test of significance (P value)

  24. Estimated odds ratio of breast cancer development associated with number of high-risk genotypes of estrogen-metabolizing genes. No. of high-risk genotypes CYP17 CYP1A1 COMTCase(%) Contol(%) OR(95%CI) No putative high-risk genotype 1.00(ref) A1/A1, A1/A2 wt/wt, wt/vt H/H, H/L 47(44.3) 69(58.0) One putative high-risk genotype 1.47(0.81-2.66) A2/A2 wt/wt, wt/vt H/H, H/L 27(25.5) 30(25.2) A1/A1, A1/A2 vt/vt H/H, H/L 4(3.8) 3(2.5) A1/A1, A1/A2 wt/wt, wt/vt L/L 14(13.2) 12(10.1) Two putative high-risk genotypes 3.25(1.06-12.4) A2/A2 vt/vt H/H, H/L 2(1.9) 0(0) A2/A2 wt/wt, wt/vt L/L 7(6.6) 5(4.2) A1/A1, A1/A2 vt/vt L/L 3(2.8) 0(0) All three putative high-risk genotypes ------ A2/A2 vt/vt L/L 2(1.9) 0(0) P test for trend=0.006

  25. Risk factor Multivariate-aOR(95%CI) Estrogen-metabolizing genes CYP17 (HH vs. HL, LL) 1.23(0.67-2.28) CYP1A1 (HH vs. HL, LL) 1.79(0.86-3.78) COMT(LL vs. HL, HH) 4.02(1.12-19.1) Family history of breast CA Yes vs. No 1.39(0.34-5.61) Age at menarche <=13 vs. >13 yrs 1.93(1.05-3.58) Age at FFTP >=30 or nulliparity vs.<30 yrs 2.39(1.13-5.24) History of HRT Yes vs. No 4.47(1.58-14.8) Huang et al., Cancer Res 1999

  26. The frequency of variant (low-activity) allele of COMT in different populations. Asian Caucasian

  27. Vt/Vt Vt/Wt Wt/Wt DNA C A B F D E Association Study Genotyping Genome-wide Approach Disease Case Control Non- Disease Risk [Odds Ratio] of Vt/Vt = A/C / D/F = AF/CD Risk [Odds Ratio] of Vt/Wt= B/C / E/F = BF/CE Rvt/vt>Rvt/wt>1,Test of significance (P value)

  28. 408 familial Br CA/400 CN 266,722 SNPs P<0.01 3990 European Br CA/3916 CN 12,711 SNPs P<0.00002 22,714 Euro+Asian Br CA/23,369 CN 31SNPs 6 SNPs

  29. FGFR2 10q rs2981582 Easton et al., Nature 2007

  30. Breast Cancer Susceptibility Genes identified by GWAS, and Risk (OR)/Population Attributable Proportion (PAR) Associated with Variant Alleles of These Genes GENE FGFR2 TNRC9 MAP3K1 8q24 LSP1 CASP8 2q35 SNP rs17468277 rs1982073 rs2981582 rs13281615 rs3817198 rs889312 rs13387042 OR per allele 1.24 1.21 1.11 1.10 1.08 1.08 1.14 PAR(%) 16 11 6 6 7 17 11

  31. How important of these variant alleles are in determining the risk of breast cancer in Asia? Population Attributable Proportion (PAR) (族群可歸因比率)(%) = Risk associated with variant allele (這個因子對疾病發生有多麼重要?) X Proportion of population carrying variant allele (這個因子在族群中有多麼盛行?)

  32. Breast Cancer Sub-typing

  33. Knowing cancer's HER2 status is important. • HER2+ cancers grow faster and spread faster than other cancer cells. • (B)HER2 cancers need to be treated differently. Allows doctor to rule out some treatments that do not work as effectively on HER2 cancers.

  34. Breast cancer subtypes predict progression.

  35. Breast cancer subtypes influence treatment. ER-, PR- HER2+ ER-, PR-, HER2- CK5/6+ and/or HER1+ ER+ and/or PR+ HER2+ ER+ and/or PR+ HER2-

  36. Time Magazine Oct, 2007 Hormone-responsive breast cancers are less frequent in Asian women compared to Caucasians?

  37. Letrozole Tamoxifen Aromatase Pacitaxel E2 ER Cholesterol Rapamycin PI3K/AKT/mTOR VEGF VEGFR HER3/EGFR ligand Angiogenesis Bevacizumab Trastuzumab HER2 Selected Chemotherapeutic Strategies used in Breast Cancer Treatment 標靶治療 Target Therapy Proliferation Anti-apoptosis

  38. (postmenopausal) CYP19 Letrozole CYP2D6

  39. Among patients who are wild-type for CYP2D6, adjuvant treatment with tamoxifen appears to provide 5-year disease-free survival outcomes that are similar or perhaps even superior to those achieved with aromatase inhibitors. Aromatase inhibitor Tamoxifen in the CYP2D6 wt/wt Tamoxifen Tamoxifen in the CYP2D6 wt/vt Tamoxifen in the CYP2D6 vt/vt Punglia et al., JNCI 2008

  40. Personalized Medicine 個人化的醫學 預防與治療

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