Gene Profiling of Traditionele Pathologie?

1. 50 jaar VVOG: Nieuwigheden Adj. Hormonale Therapie Operabele ER+ borstkanker CT + HT of HT? Gene Profilingof Traditionele Pathologie? Each row is a tumour / each column a single gene.

2. Gene Expression Profiling of Breast Cancer (Arrays for mRNA transcripts) • Molecular Classification of Breast Cancer: • Prognostic value and many possible approaches • Top down / Bottom up/ …prognostic signatures • Four main molecular classes of breast cancer have been distinguished! • Luminal A, Luminal B, HER-2, Basal Like

3. There is a large concordance between all gene-expression based predictors Profiles do quantify mainly tumor proliferation. • intrinsic subtypes (4…) • 70-gene profile, • 76-gene profile, • (wound response) • recurrencescore, • (two-gene ratio) • … 100% agreement Basal like (ER-PR-HER-2-HER-1-CK5,6+ ER-negative, HER-2 positive Veridex 80% concordance between Mammaprint & CellSearch & Oncotype Dx They track different gene sets but the significant agreement in the outcome predictions for individualpatients means they track a common set of biologicphenotypes. All include cell-cycle and proliferation-related genes N Engl J Med. 2009 Feb 19;360(8):790-800. Review.

4. Mindact-GuidedTherapy In Mindact: 71% in stead of 87% will get chemotherapy! RASTER Lancet Oncol Please look for other markers 30% chemo UZ Leuven: 573 ER+, Grade 2, node negative: 9% had chemotherapy At 5.5 yrs FU 4.3% distant relapse

6. II. Zijn AIs beter dantamoxifen? 50 jaar VVOG: Nieuwigheden Adj. Hormonale Therapie Operabele borstkanker Postmenopausal Update latest trials BIG 1-98: Letrozole IES: Switch to Exemestane TEAM: Upfront Exem vs Switch

7. BIG 1-98: Letrozole or Tamoxifen or Switch at Year 2 (NEJM 2009)

8. Switch is Not Inferior to 5 yrs Letrozole

9. BIG 1-98: A very high Ki 67: Let>Tam

10. 2008/9 Highlights in Adjuvant Tamoxifen versus AI ASCO 2009 • Risk-stratification factors are helpful in making treatment decisions • Patients with "higher"-risk tumors -- node-positive breast cancers, tumors that are HER-2 positive and/or lack high levels of ER or PR, or that have high Ki67 scores or bad Mammaprint / Oncotype DX signature may be advised to start with an AI. • For lower-risk, node-negative tumors with other favorable prognostic features, ANY treatment strategy yields a good prognosis. • Patients intolerant to either tamoxifen or an AI can be reassured that the long-term differences between these antiestrogen options remain very small. • If you consider an AI, there might be an additional benefit on DFS when adding a bisphosfonate

11. QoL: AI versus TAM Against AI • Bone • Joints, CTS • Sexual Health • Cardio-Vascular! Elderly! • Cognitive Function • Gastro-Intestinal Upset • Uterus • DVT • Flashes Against TAM

12. III. Improving Anti-Estrogen Therapy ER+ Tumors Utilize Different Signaling Pathways Cross Talk between ER and many Growth Pathways Growth Factor Receptors ER-positive The Future GFR Luminal SRC IRS1 PI3Kp85 Frequent PI3K/AKT mutations PI3Kp110 Rictor RAS De Novo Acquired Torc1 PTEN PDK2/mTOR PDK1 RAF AKT Basal ER-negative TSC2 Erk Mek TSC1 More HER-2 signaling if ER+ tumours are PR-negative. HJ Huang et al. BCRT/JCP Stemke-Hale, et al., Can Res 68, 2008

13. MABs and NIBS: Interfering with Oestrogen Receptor- Mediated Signalling Pathways in Breast Cancer

14. PFS: Letrozole vs Letrozole + Lapatinib: HER2+ Population 14

15. Future of Adjuvant anti-E • Who is resistant to tamoxifen? • Gene profiles • Pharmacogenetics • Bisphosfonates if AI for efficacy: Needs Validation? • Extended anti-E beyond 5 years if high risk? • Continuous / Interrupted • AI / Tam / AI versus Tam / AI / Tam • Combining anti-E with targetted therapy in adjuvant? • Tam + Iressa • Anastrozole + Herceptin • Letrozole + Lapatinib • Letrozole + Everolimus* * Neo-adjuvant setting/ 4 months setting

16. Correspondence between Molecular Class and Clinicopathological Features of Breast Cancer When including Clinico-Pathological Features … N Engl J Med 2009;360:790-800

17. Prognosis by ER, PR, HER-2All UZ Leuven Consecutive Cases (n=2059) Disease Free Survival (months) 5.4 years after primary operation for breast cancer

18. IGF-1R, EGFR • Preclinical data show that long term estrogen deprivation (LTED) MCF7 cells exhibit upregulation of ErbB2/MAPK, p-Akt/ p-S6K1/ p-4E-BP1. mTOR pathway plays the primary role in mediating the proliferation of LTED cells. • Combination mTOR inhibition and hormonal therapy↓ cell proliferation and ↑ apoptosis in BC cells to a greater extent than either agent alone4 • mTOR inhibition reverses resistance to hormonal therapy in BC5,6 with synergistic antitumor effects with hormonal therapy7 • Objective responses and stable disease in patients with BC treated with mTOR inhibitors alone1-3 ER RAS PI3K AKT RAF ER TSC1 TSC2 MEK mTOR ERK Cell Growth Metabolism Angiogenesis Cell Proliferation ER 1. Chan et al. J Clin Oncol. 2005;23:5314-5322. 2. Tabernero et al. J Clin Oncol. 2008;26:1603-110.3. Ellard et al. J Clin Oncol. 2007;25(18s):141s. Abstract 3513. 4. Boulay et al. Clin Cancer Res. 2005;11:5319-5328. 5. deGraffenreid et al. Clin Cancer Res. 2004;10:8059-8067. 6. Ghayad et al. Cancer Sci. 2008;99:1992-2003.7. Lisztwan et al. Breast Cancer Res. 2008;10:R56.