Der St. Gallen Consensus 2009 aus der Sicht eines Panelisten

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1 Der St. Gallen Consensus 2009 aus der Sicht eines Panelisten Michael Gnant Medizinische Universität Wien Austrian Breast & Colorectal Cancer Study Group Daten Fakten - Konsequenzen Palais Ferstl, 25. März

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3 Besucher St. Gallen Consensus Conferences (3)

4 TeilnehmerInnen St. Gallen (4)

5 Hans-Jörg Senn: There is hardly any major breast cancer conference today in any part of the world where there is no reference to the latest St. Gallen Consensus. Which does not mean at all, that our international Panel s critical work in setting general recommendations on the basis of mostly clinico-pathological parameters are just applauded. But they are recognized, either as a standard of care for countries and societies, or they serve as a challenge to compete with for science, in developing new, hopefully even better ways to realistically select breast cancer patients for optimal and curative initial treatment. (5)

6 St. Gallen 2009 Recommendations Consensus & Controversy

7 International Consensus Panel James N. Ingle, USA & Aron Goldhirsch, CH/I (Chairmen) Matti Aapro (CH) Kathy Albain (USA) Jonas Bergh (S) Harold Burstein (USA) Robert Carlson (USA) Monica Castiglione-Gertsch (CH) Alan S. Coates (AUS) Marco Colleoni (I) Alberto Costa (I) Jack Cuzick (UK) Nancy Davidson (USA) Angelo Di Leo (I) John F. Forbes (AUS) Richard D. Gelber (USA) John H. Glick (USA) Joseph Gligorov (F) Michael Gnant (A) Paul E. Goss (USA) Jay R. Harris (USA) Jacek Jassem (PL) Per Karlsson (S) Manfred Kaufmann (D) Stella Kyriakides (CY) Louis Mauriac (F) Gunter von Minckwitz (D) Monica Morrow (USA) Henning Mouridsen (DK) Moise Namer (F) Larry Norton (USA) Soonmyung Paik (USA) Martine Piccart-Gebhart (B) Kurt Possinger (D) Kathy Pritchard (CAN) Emiel J.T. Rutgers (NL) Vladimir Semiglazov (RUS) Ian E. Smith (UK) Beat Thürlimann (CH) Giuseppe Viale (I) Toru Watanabe (JPN) Eric P. Winer (USA) William C. Wood (USA) (7)

8 Areas of controversy - Need for debate Areas which do not require discussion because evidence is accepted by most / all Controversies deserve stated opinion for Debated arguments & definitive resolution Debate leading to a range of resolutions (because need a different approach in different environments / countries) (8)

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10 Areas of controversy - Need for debate Clinical trials are useful for defining whether one treatment is better than another useful for defining the average improved treatment outcome not useful for defining how to treat an individual patient Interpretation on what evidence means for treating an individual patient is a matter of debate (10)

11 Consider 10 Areas of Controversy Surgery: Axilla, Margins Radiation: DCIS, Accelerated, Post Mx Pathology:, ER, PgR, Ki67, Grade Multi-gene signatures, AOL Endocrine therapies Chemotherapies Targeted therapies Neo-Adjuvant systemic therapy Fertility Male breast cancer (11)

12 Surgery: Axilla Should SN biopsy be considered a standard in invasive breast cancer with cno (not T4d)? 1 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Can AND be avoided with low risk of residual axillary disease (i.e., micromets or ILT in SN)? All patients? Selected patients?

13 Consider 10 Areas of Controversy Surgery: Axilla, Margins Radiation: DCIS, Accelerated, Post Mx Pathology:, ER, PgR, Ki67, Grade Multi-gene signatures, AOL Endocrine therapies Chemotherapies Targeted therapies Neo-Adjuvant systemic therapy Fertility Male breast cancer (13)

14 Pathology: ER Should percent ER stained be reported? Should an ER score be reported? Should the definition of highly endocrine responsive require ER > 50% stained cells?

15 Pathology: PgR Should PgR be considered when evaluating prognosis? Should PgR be used to predict response to Tam? Does low or absent PgR predict response to AIs?

16 Pathology Should Oncotype DX be used to predict CT response in an endocrine-responsive cohort? Should Mammaprint be used to predict CT responsiveness? Does Adjuvant! Online (AOL) provide a reasonable estimate of CT effectiveness? Can AOL be used as a communication tool? Can AOL be used for clinical decision making?

17 Primary Consideration (must be agreed on by majority of participants) Primary goals - treatment choice for women with early breast cancer: * Integrate tumor biology and tumor extent into an estimate of responsiveness to treatment and risk of relapse Utilize tumor biology, host biology and risk to obtain an optimal management strategy (17)

18 St. Gallen Panel Conclusions 2007: Significant Number Patients in Uncertain Category Re: Use of Chemotherapy Highly Endocrine Responsive Incompletely Endocrine Responsive Endocrine Non- Responsive HER2 negative CT HER2 positive ET + Trastuzumab + CT ET + Trastuzumab + CT Trastuzumab + CT Ann Oncol 2007 (18)

19 Top-Ten Questions (1-5) Identification of molecular signatures to select patients who could be spared chemotherapy (643 points). 2. Identify molecular features which indicate the optimal chemotherapy regimen (eg combination or sequential, anthracycline or not, taxane or not) (450). 3. Determine the factors in DCIS and/or ADH leading to progression into invasive carcinoma (406). 4. Determine the role of stem cells in breast cancer development, progression and treatment sensitivity (404). 5. Identify response/resistance mechanisms and thereby therapeutic targets for triple negative breast cancer (369). Dowsett, et al. Breast Cancer Res 2007 (19)

20 Commercially Available Genomic Assays for the Prediction of Clinical Outcome in Patients with Breast Cancer* *Driven by proliferation, HER2, ER genes Sotiriou C and Pusztai L. NEJM 2009 (20)

21 21-gene recurrence score Oncotype Dx 16 Cancer and 5 Reference Genes From 3 Studies PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 INVASION Stromolysin 3 Cathepsin L2 HER2 GRB7 HER2 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC ESTROGEN ER PR Bcl2 SCUBE2 CD68 GSTM1 BAG1 Category RS (0 100) Low risk RS < 18 Intermediate RS risk High risk RS 31 Paik et al, NEJM 2004 Habel et al, BCRT 2006

22 Prognosis and Prediction from 21-Gene RS Assay (Oncotype DX ) Recurrence Score in N-, ER+ if 5 Years Tamoxifen Lower RS Less likelihood of recurrence Greater tamoxifen benefit No to minimal chemotherapy benefit 1) Paik et al NEJM 2004, 2) Habel et al Breast Cancer Research ) Paik et al JCO 2006, 4) Gianni et al JCO

23 21 Gene Recurrence Score Assay: Strongly Predicts CMF Benefit (NSABP B-20) Recurrence Score Recurrence Score Minimal, if any, Chemo Benefit Clear Chemo Benefit Sparano, TBCI San Antonio, 2005 Paik JCO 2006 (23)

24 Combined Non-Randomized 70-Gene Dataset CET vs ET in High and Low Risk Pooled, single patient data; n=1,637 5-year Breast Cancer Specific Survival - Low 99% vs 96% HR 0.54, p= High 94% vs 76% HR 0.17, p= year Distant Disease-Free Survival - Low 99% vs 92% HR 0.22, p= High 88% vs 69% HR 0.28, p<0.01* *Cox model HR = 0.39, p=0.03 adjusted for age, T size, nodes, grade, ER, and HER2 Knauer, et al. St. Gallen 2009, Abstr 73 (24)

25 Relevance of Multigene Assays in the Clinical Practice Setting Study N Setting Type Change in Treatment Decision* Oratz, et al. 32 Community, USA Asad, et al. 85 Community, USA Kamal, et al. 80 Academic, USA Lo, et al. 89 Academic + Community, USA Bueno-de Mequita, et al. 427 Community, Dutch Retrospective, 21 gene Retrospective, 21 gene Retrospective, 21 gene Prospective, 21 gene Prospective, 70 gene *Most frequent decision change in all studies was from CHT HT 25% 44% 18% 32% 26% (25)

26 Adjuvant! High/ 70-Gene Low Risk (34% of cases) Excellent Survival Adjuvant! High Risk Patients (n=209) 93% 72% 70-gene good profile (n=72) 70-gene poor profile (n=137) HR 3.9 (95%CI ), p=0.004 Mook, et al. PSABCS 2007; Breast Cancer Res Treat 2008 (26)

27 St. Gallen 2009 Expert Panel A Proposed Revision Adding Chemotherapy to Endocrine-Based Adjuvant Therapy The Panel accepts molecularly-based tools (such as the 21-gene recurrence score assay) or gene expression profiling (such as by the 70-gene assay) as an adjunct to high-quality standard histopathologic assessment to refine risk categories. The Panel recognizes in many cases this may provide more optimal individual risk allocation for making a decision to add chemotherapy or not. DO YOU AGREE? 27

28 Pathology Should a validated multi-gene assay when available - be considered in addition to expert classical pathology in situations von patients and doctors are uncertain? Is UPAI/PAI1 useful?

29 Self-renewal and differentiation pathways in breast stem cells Karakala M, Wicha M. J Clin Oncol 2008; 26: (29)

30 Stammzellcharakteristika in DTC Glinsky G, et.al. J Clin Oncol 2008; 26: (30)

31 Stammzellcharakteristika in DTC Glinsky G, et.al. J Clin Oncol 2008; 26: (31)

32 Stammzellcharakteristika in Primary Tumor (Prostate) Glinsky G, et.al. J Clin Oncol 2008; 26: (32)

33 Stem Cell charasteristics in Primary Tumors breast Prostate lung ovarian Glinsky G, et.al. J Clin Oncol 2008; 26: (33)

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35 The Lancet, March 23,

36 Metastatic Niches in Bone Marrow Endosteal niche Vascular niche Hematopoietic stem cells (HSCs) Homing Quiesce nce Mobilizat Stem Cell ion Sanctuary Shiozawa Y, et al. Leukemia. 2008;22:

37 Principle of adjuvant therapy Surgery Number of cells critical for Cure (37)

38 Austria ABCSG Science from the heart (of Europe) (38)

39 Das Portfolio der ABCSG DCIS ABCSG-15 IBIS-2 offen Neoadjuvante Therapie ABCSG-24/24H abgeschlossen Low Risk - HR+ ABCSG-18 offen Intermed Risk N+ ABCSG-23 FACE abgeschlossen HR+ / Long Term ABCSG-16 SALSA offen High Risk - N+ ABCSG-25 PANTHER offen High Risk - triple neg ABCSG-27 Beatrice offen Prämenopausal HR+ ABCSG-22R offen OP bei M1 Patientinnen ABCSG-28 Bisphosphonate nach NeoadjTh ABCSG-29 NATAN offen Adj Th bei HER-2+++ ABCSG-30 BETH offen Adj Th bei HER-2+++ ABCSG-31 ALTTO offen Neoadjuvante Th bei HER-2+++ ABCSG-32 Neoadjuvante chemofreeth ABCSG-33 Neoadjuvante Th mit Sunitinib ABCSG-34 (39)

40 Klinische Studien retten Leben. Klinische Studien schaffen Lebensqualität. Klinische Studien sparen Geld. (40)

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