1. Gene Profiling of Traditionele Pathologie?
50 jaar VVOG: Nieuwigheden Adj. Hormonale Therapie
Operabele ER+ borstkanker
CT + HT of HT?
Gene Profiling of 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. intrinsic subtypes (4…) 70-gene profile, 76-gene profile,
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)
recurrence score,
(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 individual patients
means they track a common set of biologic phenotypes.
All include cell-cycle and proliferation-related genes
N Engl J Med Feb 19;360(8): Review.

4. Mindact- Guided Therapy
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 dan tamoxifen?
50 jaar VVOG: Nieuwigheden Adj. Hormonale Therapie
Operabele borstkanker
II. Zijn AIs beter dan tamoxifen?
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 Bone Joints, CTS Sexual Health
Cardio-Vascular! Elderly!
Cognitive Function
Gastro-Intestinal Upset
Uterus
DVT
Flashes
Against AI
Against TAM

12. The Future 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
Torc1
De Novo
Acquired
PTEN
PDK2/mTOR
PDK1
RAF
AKT
ER-negative
Basal
Erk
TSC2
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
Letrozole + Lapatinib (N = 111)
Progressed or died
89 (82%)
88 (79%)
Median PFS, mo
3.0
8.2
Hazard ratio (95% CI)
0.71 (0.53, 0.96)
p-value
0.019 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. Clinico-Pathological
Correspondence between Molecular Class and Clinicopathological Features of Breast Cancer
When including
Clinico-Pathological
Features …
Figure 1. Correspondence between Molecular Class and Clinicopathological Features of Breast Cancer. Data are from Sorlie et al.,3 Hu et al.,5 Rouzier et al.,28 and van de Vijver et al.29 HER2 status, as determined by immunohistochemical (IHC) analysis, was available for only 82 of 535 patients in the combined studies. ER denotes estrogen receptor, and Ki-67 nuclear antigen Ki-67.
N Engl J Med 2009;360:

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

18. 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
IGF-1R, EGFR ER
RAS
PI3K ER
AKT
RAF
TSC2
TSC1
MEK
mTOR
ERK
Cell Growth
Metabolism
Angiogenesis
Cell Proliferation ER
1. Chan et al. J Clin Oncol. 2005;23: Tabernero et al. J Clin Oncol. 2008;26: Ellard et al. J Clin Oncol. 2007;25(18s):141s. Abstract Boulay et al. Clin Cancer Res. 2005;11:
5. deGraffenreid et al. Clin Cancer Res. 2004;10: Ghayad et al. Cancer Sci. 2008;99: Lisztwan et al. Breast Cancer Res. 2008;10:R56.