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Epidemiology

Epidemiology. Definition Biology. The “Triple Negative” Breast Cancer. Estrogen Receptor ( ER ) negative Progesterone receptor ( PR ) negative Her2neu ( HER2 ) negative. ER/PR/HER2 -. “Basal-Like” . Clinical features.

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Epidemiology

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  1. Epidemiology

  2. DefinitionBiology

  3. The “Triple Negative” Breast Cancer Estrogen Receptor (ER) negative Progesterone receptor (PR) negative Her2neu (HER2) negative ER/PR/HER2 - “Basal-Like”

  4. Clinical features

  5. “Triple-Negative” Breast Cancer: Clinical Features and Patterns of Recurrence • HBBC database (1987-1997) • 1601 (80%) of patients had details on hormone receptors/HER2 and were eligible for the study • 180 (12%) of the 1601 patients were defined as “triple negative” breast cancers • Mean follow up was 8.1 years Dent, R. et al. Clin Cancer Res 2007

  6. Characteristics of “Triple Negative” vs. Other Breast Cancers * p values were calculated with the use of the chi-square test Dent, R. et al. Clin Cancer Res 2007

  7. Tumor Size by Nodal Status according to “Basal-Like” Group * p values were calculated with the use of the chi-square test Dent, R. et al. Clin Cancer Res 2007

  8. “Triple-negative” (61 of 180) Other (290 of 1421) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Distant Recurrence 1.0 0.9 0.8 0.7 0.6 0.5 Probability of being recurrence-free p<0.0001 (log-Rank test) 0.4 0.3 0.2 0.1 0.0 Years after diagnosis Dent, R. et al. Clin Cancer Res 2007;13:4429-4434

  9. “Triple-negative” (62 of 180) Other (261 of 1420) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Overall Survival 1.0 0.9 0.8 0.7 0.6 0.5 Probability of survival p<0.0001 (log-Rank test) 0.4 0.3 0.2 0.1 0.0 Years after diagnosis Dent, R. et al. Clin Cancer Res 2007;13:4429-4434

  10. X² statistic 42.78 p  0.0003 Non-random distribution Subtype Smid et al, Cancer Res, in press

  11. Patterns of Metastatic Spread • More likely to spread to brain, lung and possibly liver and less likely to spread to bone and soft tissues • Tsuda et al. 2000 Am J of Surgical Pathology • Rodriguez-Pinilla et al. Clinical Cancer Research 2006 • Fulford et al. Breast Cancer Research and Treatment 2007 • Hicks et al. 2006 Am J of Surgical Pathology • More likely to present with visceral metastases versus bone metastases as first site of metastases • 70% vs 37%, p < 0.001 (Dent et al. SABCS 2007)

  12. Median Time from Distant Relapse to Death “Triple Negative” Breast CA 9 months Other Breast CA 22 months Dent R, Trudeau M, Pritchard K, Hana W, Narod S. et al. Clinical Cancer Res 2007

  13. Treatment

  14. Response of Brca1/p53Mammary Tumors to Doxorubicin or Cisplatin/Carboplatin in vivo

  15. Characteristics of retrieved studies - I Gennari et al, JNCI 2008

  16. Characteristics of studies - II Gennari et al, JNCI 2008

  17. Adjuvant Anthracyclines and HER2:Disease Free Survival Anthra better Non anthra better Study HER2 status HR (95% CI) + 0.60 (0.44 to 0.82) NSABP B11 - 0.96 (0.75 to 1.23) + 0.84 (0.65 to 1.08) NSABP B15 - 1.02 (0.86 to 1.20) + 0.65 (0.34 to 1.26) Belgian - 1.35 (0.93 to 1.97) + 0.83 (0.46 to 1.49) Milan - 1.22 (0.91 to 1.64) + 0.75 (0.53 to 1.06) DBCG 89D - 0.79 (0.60 to 1.05) + 0.52 (0.34 to 0.80) NCIC MA5 - 0.91 (0.71 to 1.17) Overall 0.90 (0.82 to 0.98) + 0.71 (0.61 to 0.83) HER2 specific - 1.00 (0.90 to 1.11) 0.00 0.50 1.00 1.50 2.00 Test for interaction: 2 13.7, p< .001 Gennari A. et al. JNCI 2008

  18. Adjuvant Anthracyclines and HER2 :Overall Survival Anthra better Non anthra better Study HER2 status HR (95% CI) + 0.66 (0.42 to 1.01) NSABP B11 - 0.90 (0.69 to 1.18) + 0.82 (0.63 to 1.06) NSABP B15 - 1.07 (0.88 to 1.30) + 0.85 (0.27 to 2.69) GUN - 1.64 (0.85 to 3.15) + 0.61 (0.32 to1.16) Milan - 1.26 (0.89 to 1.79) + 0.73 (0.50 to 1.05) DBCG 89D - 0.82 (0.59 to 1.13) + 0.65 (0.42 to 1.01) NCIC MA5 - 1.06 (0.80 to1.40) + 0.71 (0.32 to 1.55) GOIRC - 1.25 (0.58 to 2.67) Overall 0.91 (0.79 to 1.04) + 0.73 (0.62 to 0.85) HER2 specific - 1.03 (0.92 to 1.16) 0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 Test for interaction: 2 12.6, p< .001 Gennari A. et al. JNCI 2008

  19. Efficacy summary • Risk of relapse 29% HR 0.71 (0.61-0.83) • Risk of death 27% HR 0.73 (0.62-0.85) HER2 negative HER2 positive Risk of relapse anthra ≈ non anthra HR 1.00 (0.90-1.11) Risk of death anthra ≈ non anthra HR 1.03 (0.92-1.16) p <0.001 p <0.001 Gennari et al, JNCI 2008

  20. Highly hormon-sensitive Moderately hormon-sensitive HER-2 amplified Triple negative

  21. Pathological Complete Response to Chemotherapy Differs by Subtipes

  22. Neoadjuvant Chemotherapy in Triple Negative Patients. MD Anderson Experience • The largest date set available (1118 pts) 23% TNBC, pCR 15% Liedtke, M. et al. J Clin Oncol; aheadof print on Febr 4, 2008

  23. Neoadjuvant Chemotherapy in TNBCSurvival by Pathological Response Liedtke, M. et al. J Clin Oncol; aheadof print on Febr 4, 2008

  24. Ixabepilone + Capecitabine N = 375 Metastaticbreast cancer N = 752 Capecitabine N = 377 Ixabepilone+Capecitabine a Phase III Trial Previous Anthra Taxane Resistant Vahdat LT et al: ASCO2007

  25. 1.0 0.8 Ixabepilone + Capecitabine Median 95 % Cl 0.6 Proportion Progression Free 5.8 mo 4.2 mo (5.5 - 7.0) (3.8 - 4.5) 0.4 HR: 0.75 (0.64-0.88) p = 0.0003 0.2 Capecitabine 0.0 0 4 8 12 16 20 24 28 32 36 Months Ixabepilone+Capecitabine a Phase III Trial Vahdat LT et al: ASCO2007

  26. Ixabepilone+Capecitabine a Phase III Trial Rugo et al: SABCS 2007

  27. Perspectives

  28. Basal-like Breast Cancer and BRCA1 = BRCA1+ Sorlie T et al. PNAS 03

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