Is Gene Expression Profiling the Best Method for Selecting Systemic Therapy in EBC? Norman Wolmark Miami March 8, 2013

Transcription

1 Is Gene Expression Profiling the Best Method for Selecting Systemic Therapy in EBC? Norman Wolmark Miami March 8, 2013

2 Changing Phases claudin low Lum A Lum B Basal Her2

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4 NIH Consensus Development Panel, 2001 JNCI Monographs 2001: 30: 5-15 It is accepted practice to offer cytotoxic chemotherapy to node negative women with primary breast cancers larger than 1 cm in diameter For women with lymph node-negative cancers smaller than 1 cm in diameter, the decision to consider chemotherapy should be individualized.

5 21 Gene Recurrence Score N-, ER+

6 Dec 2003 >

7 The 21 Gene RS assay can accurately quantify the likelihood of recurrence in node negative (N+), ER positive, tamoxifen (and AI) treated patients. The 21 Gene recurrence score performance exceeds standard measures, such as age, tumor size, tumor grade and A!OL.

8 The assay is practical and clinically applicable since it utilizes sections from standard fixed paraffinembedded tissue using RT-PCR The 21 Gene RS assay is predictive of chemotherapy benefit 350,000 patients have been tested in the U.S. ASCO, NCCN Guidelines, St Gallen, ESMO

9 NICE Guidance Recommendations (UK) The draft guidance published today (Feb 18, 2013) recommends the use of Oncotype DX in ER+, LN- and Her2- EBC. The draft guidance also highlights that it has not been able to support the routine use of the IHC4, MammaPrint or Mammostrat tests NHS National Institute for Health and Clinical Excellence

10 250 Candidate Genes, 3 Studies, 447 Pts, 16 Gene Recurrence Score Assay PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 INVASION Stromelysin 3 Cathepsin L2 ESTROGEN ER PR Bcl2 SCUBE2 HER2 GRB7 HER2 Category RS Low risk RS < 18 Intermed RS High risk RS 31 GSTM1 CD68 BAG1 REFERENCE GENES Beta-actin, GAPDH, RPLPO GUS, TFRC

11 Prospective validation B-14 ER Positive, Node Negative Placebo TAM NEJM ( 82-88, 14 yrs MTS) 668 of 2617

12 B-14 Overall 10yr TAM 82% Plac 75% Δ7% NEJM Feb 89

13 DRFS B-14 DRFS N Lo 338 Int % Hi 181 p< v 69% Δ 24% NEJM

14 In multivariate analyses recurrence score was superior to age tumor size, tumor grade and A!OL

15 An instrument formerly used for the characterization of breast cancer

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17 Recurrence Score is used as a continuous variable to estimate individual patient risk

18 50% 45% Likelihood of 10 Year Distant Recurrence Cox PH Model (Time Varying Coefficients) B-14 DR Lo Int Hi 40% 35% 30% 25% 20% 15% 10% 5% 0% RS

19 Does recurrence score predict the benefit of chemotherapy?

20 of 2326 NSABP B-20 Pre and Post Menopausal Node Negative Receptor Positive TAM M F CMF (227) (203) (221) (424)

21 B-20 All 10yr TAM 87% CT 92% Δ5% p = 0.02 JNCI Nov 97

22 B-20 Low RS < 18 B-20 Int RS JCO 8 06

23 B-20 High RS 31 10yr TAM 60% CT 88% Δ 28% N Events p = JCO 8 06

24 B-20 CT benefit (absolute) Low RS<18 Int RS18-30 High RS 31 n = 353 n = 134 p (interaction) = n = % 20% 30% 40% % Increase in DRFS at 10 Yrs (mean ± SE)

25 Distribution of Recurrence Score (N-) in US n=200,000 High RS 15% 35% 50% Intermediate RS Low RS

26 70 Chemo Usage v ODX Usage (US, N- ER+) % Quarters

27 [21Gene RS] is being used this year by 50,000 women And that s saving our health-care system $100 million this year. Francis Collins, Newsweek

28 TAILORx (PACT1) Trial Trial Assigning IndividuaLized Options for Treatment Node Negative E/PR+, HER2 negative 21 Gene RS Assay RS < 11 No Chemo (29%) Started 4-06 Accrual >10,000 Closed: RS Chemo vs No Chemo (44%) N=7000 RS > 25 Chemo (27%) Choice of therapy at investigator discretion all receive hormonal Rx Results 2015

29 yr DR (%) RS and Number of Positive Nodes Recurrence Score >3 N+ 1-3 N+ N N+ S8814 Dowsett., SABCS 2008

30 Rxsponder Schema (S1007) N 1-3 ER-pos, HER2-neg (N= 8,800) RS > 25 (N= 3,800) alternative trials for high risk patients RS < 25 ACCEPT RANDOMIZATION Rx N= 4,000 stratified 1. RS 0-13 vs Menopausal status 3. AND vs. SNB Activated Jan 21, 2011 Randomized~1200 N= 2,000 Chemotherapy N= 2,000 No Chemotherapy

31 Recurrence Score Distribution B28 N+ ER+ High RS 30% 34% Intermediate RS 36% Low RS RS distribution was not significantly different according the number of positive nodes

32 NSABP B-28 AC vs. AC T* N+; n=1,065 / 3,060 ER+ Subset % Distant Recurrence 65% 56% 46% DRFI P<.001 Δ 28% 12% *concom tam

33 B-28 BCSS Proportion of Alive w/o Disease N+ >4 N+ RS Low RS Intermedidate RS High P< Time in years 98% 83% 76% Proportion of Alive w/o Disease RS Low RS Intermedidate RS High P< Time in years 88% 70% 54%

34 250 Candidate Genes, 3 Studies, 447 Pts, 16 Gene Recurrence Score Assay PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 INVASION Stromelysin 3 Cathepsin L2 ESTROGEN ER PR Bcl2 SCUBE2 HER2 GRB7 HER2 Category RS Low risk RS < 18 Intermed RS High risk RS 31 GSTM1 CD68 BAG1 REFERENCE GENES Beta-actin, GAPDH, RPLPO GUS, TFRC

35 Genome-wide somatic mutations: Increased Mutations AI-Resistant Tumors (P=.02) AI Sensitive AI Sensitive Circos plots: outside ring represents chromosomes with cytoband information Inner ring represents copy number at a given locus; lines represent translocations Trend for more somatic structural variations in the AI-resistant group Ellis M, et al. Nature 2012;486:353

36 An Anachronism in His Own Time