The Use of Genomics in Early Stage Breast Cancer Hope S. Rugo, MD Professor of Medicine Director, Breast Oncology and Clin...
Goals of Individualized/Personalized Treatment <ul><li>Understand the biology of each specific tumor </li></ul><ul><ul><li...
“ Conventional” Wisdom of Yesterday… <ul><li>Breast cancer is one disease </li></ul><ul><li>One-size-fits-all treatment ap...
“ Conventional Wisdom” of Today… <ul><li>Breast cancer is a heterogeneous disease comprised of different molecular subtype...
Prognostic & predictive markers utilized in breast cancer management <ul><li>Prognostic (recurrence risk) </li></ul><ul><l...
70 Gene-Expression Signature (Mammaprint ® )  Prognostic for  Survival in Early Breast Cancer* Good signature Poor signatu...
Recurrence Score <ul><li>Invent methods for quantifying gene expression in FPET </li></ul><ul><li>Select candidate genes f...
<ul><li>Recurrence Score in N-, ER+ if 5 Years Tamoxifen </li></ul>Prognosis and Prediction from  21-Gene RS Assay 1) Paik...
Recurrence Score Clinical Validation:   NSABP B-14,  Distant Recurrence Distant Recurrence Over Time 10-Year rate of recur...
<ul><li>Low Risk (RS < 18) </li></ul>p = 0.76 N  Events 218  11 135  5  10 yr 96 % 95% Paik S, et al: JCO 2006 p = 0.71 N ...
NSABP B-20: Many Younger Patients Have Low Recurrence Score ®  Results NSABP B-20: Many Small Tumors Have Intermediate to ...
Onco type  DX ®  and Patient Age:  Distribution of RS Risk Groups by Age Group Shak S, et al.  SABCS 2010. Poster P3-10-01...
S8814 N+ ER+ Single Gene Analyses might “Misclassify”Dominant Biology of Tumor Example: Some High ER (by either Allred Sco...
Summary of Key Differences Between  Genomic Assays 1.  Paik S, et al.  N Engl J Med.  2004;351:2817; 2. Paik S, et al.  J ...
Summary of Practical Differences Between MammaPrint ®  and the Onco type  DX ® Assay 1.  Paik S, et al.  N Engl J Med.  20...
What about Node-Positive Disease?
Recurrence Score Clinical Validation in  Node-Positive Patients Superior disease-free survival  and overall survival over ...
Recurrence Score ®  Result Is Prognostic  for Node-Positive Patients  (Tamoxifen Arm) 0 2 4 6 8 10 0 2 4 6 8 10 1.00 0.75 ...
S8814 CAFT vs T  Breast Cancer Specific Survival by RS   S8814 S8814 S8814 Albain, et al. Lancet Oncology 12/10/09 epub In...
Exploratory Neoadjuvant Studies  Are Consistent with Adjuvant Studies Paik S, et al.  N Engl J Med.  2004;351:2817. Paik S...
Relevance of Multigene Assays in the Clinical Practice Setting *Most frequent decision change in all studies was from CHT ...
Meta-Analysis: Overall Impact of RS on Treatment Decisions Treatment plan prior to Onco type  DX® Treatment plan after RS ...
Discordance between Risk Level Assigned by Clinical-Pathologic Factors vs Multigene Assay Occurs in 30%-35% of Cases <ul><...
Proportion of Node-Negative Patients Classified as Low, Intermediate and High Risk by RS and RSPC:  RSPC has Prognostic Va...
Prediction of Chemotherapy Benefit in NSABP B-20: RS Is Most Significant P-value for interaction  with chemotherapy treatm...
TAILORx SCHEMA PI: Sparano 21-Gene RS Assay  N= 6906 Closed 8/20/10, N=11233 Closed 10/6/10,  N=10259 N=1624 N=1729
S1007: A Phase III, Randomized Clinical Trial of Standard Adjuvant Endocrine Therapy +/- Chemotherapy in Patients with 1-3...
Schema and Patient Flow Node-positive (1-3 nodes) HR-positive and HER2-negative breast cancer (N= 600) RS already Availabl...
Plan B Study schema  West German Study Group Prospective study of >2,500 patients  As of11/2010, 2094 pts registered , 158...
Evaluate Clinical-Pathological risk  and  70-gene signature risk EORTC-BIG MINDACT TRIAL DESIGN 6,000 Node negative women ...
Incorporation into Clinical Practice <ul><li>ASCO, NCCN and St. Gallen guidelines endorse consideration of assays: </li></...
Case Presentation <ul><li>40 year old premenopausal woman </li></ul><ul><li>0.7 cm node negative invasive ductal cancer </...
Adjuvantonline 10 yr mortality 10 yr recurrence
Results <ul><li>Recurrence score 50! </li></ul><ul><ul><li>36% distant recurrence risk at 10 years with 5 yrs of tamoxifen...
Case <ul><li>67 year old Chinese woman </li></ul><ul><ul><li>2.4-cm grade 2 invasive ductal carcinoma, associated 2.6 cm h...
 
Past Medical History and Treatment Plan <ul><li>Chronic anemia </li></ul><ul><li>Tuberculosis with bilobe lung resection i...
64 yo woman: mammographically detected, 1.3 cm grade 2 IDCA, no LVI, SNL neg, ER+++PR+, HER2 neg by FISH. RX: TC x 4 and AI
47 yo woman, self exam detected 0.8 cm grade I IDC, 1 SNL + 0.9 cm CA with focal extranodal extension, 12 additional nodes...
Copyright  © American Society of Clinical Oncology Walgren, R. A. et al. J Clin Oncol; 23:7342-7349 2005 Personalized Medi...
Patient is on Study Randomize Randomize Surgery Surgery Learn, Adapt from each patient as we go along * Or equivalent Clos...
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Gene Profiling in Clinical Oncology - Slide 10 - H. Rugo - Why genomic tools in endocrine-responsive tumours: a US perspective

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  • Main point: A host of factors are utilized in the management of patients with breast cancer. Many of these factors are prognostic; some are predictive. Some are both predictive and prognostic. Prognosis refers to the risk of disease recurrence if untreated. Prediction refers how well a patient will respond to a given therapy. ER, HER2, and the Onco type DX ® assay test are examples of factors that are both prognostic and predictive. Cianfrocca and Goldstein. Oncologist . 2004;9(6):606-616; Lonning PE. Ann Oncol . 2007;18(suppl 8):viii3-viii7.
  • The Recurrence Score is comprised of the expression of 21 genes, 5 reference genes and 16 cancer-related genes. Note: among the genes are ER, PR, and HER2. All genes are important in determining the Recurrence Score
  • The Recurrence Score has been correlated with Distant recurrence rate at 10 years assuming 5 years of tamoxifen treatment (the higher the score, the higher the distant recurrence rate) Hormone therapy benefit (the lower the score, the greater the impact of tamoxifen (given for 5) years on 10 year distant recurrence-free survival) Chemotherapy benefit (the higher the score, the greater the impact of chemotherapy on 10 year distant recurrence-free survival)
  • Main point: The Oncotype DX® assay is clinically validated to predict the risk of distant recurrence at 10 years in patients with ER+, node-negative breast cancer treated with tamoxifen. The Recurrence Score ® result was calculated for each patient: 51% of the patient population fell into the low-risk group (n = 338), 22% fell into the intermediate-risk group (n = 149), and 27% fell into the high-risk group (n = 181). 1 This graph demonstrates the difference in distant relapse-free survival (DRFS) over time for the different risk categories. The DRFS for the high- and low-risk groups were statistically significantly different; the 10-year distant relapse-free survival for the low-risk category was 93% compared to 69% for the high-risk category. 1 Paik S, Shak S, Tang G, et al. Use of an RT-PCR assay to predict the likelihood of breast cancer recurrence in node-negative, estrogen receptor–positive, tamoxifen-treated patients. In preparation.
  • A wide range of Recurrence Score ® biology was observed across all age groups. Younger patients had a slightly higher distribution of Recurrence Scores (as measured by low, intermediate, and high Recurrence Scores), and older patients had a slightly lower distribution, but it is notable that there is a range of Recurrence Scores within each age group.
  • Main point: Key differences between the Onco type DX ® assay, MammaPrint ® , Mammostrat ® , and Insight ® Dx are summarized here.
  • Main point: This table shows how MammaPrint ® and the Onco type DX ® assay compare, in terms of practical differences in routine clinical practice.
  • Main point: The Onco type DX ® assay was first validated and adopted in ER-positive, node-negative breast cancer. Can the Onco type DX assay identify patients who are at low, intermediate and high risk of recurrence and predict differential chemotherapy benefit in node-positive patients – a group that has traditionally been thought to be at high risk and to unequivocally require chemotherapy?
  • Main point: The prognostic utility of the Onco type DX® assay in node-positive patients was validated in several studies, including the SWOG 8814 study. The sequential CAF –tamoxifen arm turned out to have superior disease-free survival and overall survival over 10 years Thus comparisons in this genomic study utilized this sequential arm rather than the concurrent arm, since it represents the most effective way to give CAF and tamoxifen Albain KS, et al. Lancet Oncol . 2009; [Epub ahead of print].
  • Main point: The Recurrence Score ® result was shown to be prognostic for patients with node-positive disease. Among these node positive patients, the Recurrence Score result was able to separate out a group with a better and a group with a worse prognosis. These patients were treated with tamoxifen alone and thus these results are prognostic in the sense that they do not include any chemotherapy effect (though tamoxifen effect is included). There was a wide gap between the 10-year DFS (disease-free survival) in those patients on this study with a low Recurrence Score result (40% 10-year DFS) and those with a high Recurrence Score result (57% 10-year DFS) Here, DFS was used, as opposed to DRFS (distant recurrence-free survival) which was used in the NSABP B-14 and B-20 analyses with node negative patients. Thus, the event rate would be expected to be higher here. Albain KS, et al. Lancet Oncol . 2009; [Epub ahead of print].
  • Main point: Results of neoadjuvant studies are consistent with those of adjuvant studies, in terms of predicting likelihood of response to chemotherapy and endocrine therapy. In both the adjuvant setting and neoadjuvant setting: Endocrine therapy benefit: the lower the score, the greater the benefit of endocrine therapy. Chemotherapy benefit: the higher the score, the greater the benefit of chemotherapy. Paik S, et al. N Engl J Med . 2004;351:2817. Paik S, et al. J Clin Oncol . 2006;24:3726. Gianni L, et al. J Clin Oncol . 2005;23:7265. Chang JC, et al. Breast Cancer Res Treat . 2008;108 (2):233.
  • This decision tree shows the breakdown of patients initially recommended to adjuvant chemo-hormonal therapy or hormonal therapy alone, and how the use of the Recurrence Score ® guided their treatment. Use of the Recurrence Score led to a 52% switch in patients recommended chemo-hormonal therapy to hormonal therapy alone and a 12% switch in patients recommended hormonal therapy alone to chemo-hormonal therapy. Both arms combined, the Recurrence Score led to a treatment decision change in 37% of all patients studied: 33% from chemo-hormonal therapy to hormonal therapy alone and 4% from hormonal therapy alone to chemo-hormonal therapy.
  • This slide looks at the relative contribution of the Recurrence Score ® , which integrates the contribution of all 21 genes, compared to individual genes and gene groups, and their value in the prediction of chemotherapy benefit. The RS is the most significant predictor of chemotherapy benefit when compared to individual genes or gene groups. As shown here, it is likely that the proliferation genes and hormone receptor genes contribute to the predictive value of the Recurrence Score, as the proliferation gene group trended to benefit with higher expression, and the ER and PR gene expression trended to benefit with lower expression.
  • Gene Profiling in Clinical Oncology - Slide 10 - H. Rugo - Why genomic tools in endocrine-responsive tumours: a US perspective

    1. 1. The Use of Genomics in Early Stage Breast Cancer Hope S. Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA
    2. 2. Goals of Individualized/Personalized Treatment <ul><li>Understand the biology of each specific tumor </li></ul><ul><ul><li>Risk of recurrence </li></ul></ul><ul><ul><li>Pathways that drive growth and resistance </li></ul></ul><ul><ul><li>Potential targets for therapy </li></ul></ul><ul><li>Goals </li></ul><ul><ul><li>Identify patients who need treatment due to adverse tumor biology in addition to traditional tumor characteristics </li></ul></ul><ul><ul><li>Identify benefits of a specific therapy, or type of therapy </li></ul></ul><ul><ul><li>Avoid ineffective therapy </li></ul></ul><ul><li>Current tools allow: </li></ul><ul><ul><li>Assessment of risk </li></ul></ul><ul><ul><li>Assessment of chemotherapy benefit </li></ul></ul>
    3. 3. “ Conventional” Wisdom of Yesterday… <ul><li>Breast cancer is one disease </li></ul><ul><li>One-size-fits-all treatment approach </li></ul><ul><ul><li>By stage, nodal status, and hormone receptor status </li></ul></ul>
    4. 4. “ Conventional Wisdom” of Today… <ul><li>Breast cancer is a heterogeneous disease comprised of different molecular subtypes based on gene/protein expression profiling </li></ul>
    5. 5. Prognostic & predictive markers utilized in breast cancer management <ul><li>Prognostic (recurrence risk) </li></ul><ul><li>Axillary node status </li></ul><ul><li>Histologic type/grade </li></ul><ul><li>Tumor size </li></ul><ul><li>Patient age </li></ul><ul><li>Lymphatic/Vascular invasion </li></ul><ul><li>ER/PR status </li></ul><ul><li>HER2 neu status </li></ul><ul><li>Mammaprint ® </li></ul><ul><li>Onco type DX ® </li></ul><ul><li>Predictive (treatment benefit) </li></ul><ul><li>ER status </li></ul><ul><li>HER2 neu status </li></ul><ul><li>Onco type DX ® test </li></ul>Cianfrocca and Goldstein. Oncologist . 2004;9(6):606-616; Lonning PE. Ann Oncol . 2007;18(suppl 8):viii3-viii7. These markers can be used to predict treatment benefit These markers can be used to estimate the risk of disease recurrence
    6. 6. 70 Gene-Expression Signature (Mammaprint ® ) Prognostic for Survival in Early Breast Cancer* Good signature Poor signature Probability of Remaining Metastasis-free St. Gallen, High Risk St. Gallen, Low Risk Probability of Remaining Metastasis-free NEJM 347 (25), 2002 Validated Prognostic Tool in Several Additional Independent Data Sets
    7. 7. Recurrence Score <ul><li>Invent methods for quantifying gene expression in FPET </li></ul><ul><li>Select candidate genes from human genome </li></ul><ul><li>Test candidate genes in three independent breast cancer studies to identify an optimal gene panel for clinical validation </li></ul><ul><li>Prospectively validate 21-gene panel in large multicenter clinical trial </li></ul>
    8. 8. <ul><li>Recurrence Score in N-, ER+ if 5 Years Tamoxifen </li></ul>Prognosis and Prediction from 21-Gene RS Assay 1) Paik et al NEJM 2004, 2) Habel et al Breast Cancer Research 2006 3) Paik et al JCO 2006, 4) Gianni et al JCO 2005 <ul><li>Lower RS </li></ul><ul><li>Less likelihood of recurrence </li></ul><ul><li>Greater tamoxifen benefit </li></ul><ul><li>No to minimal chemotherapy benefit </li></ul><ul><li>Higher RS </li></ul><ul><li>Greater likelihood of recurrence </li></ul><ul><li>Less tamoxifen benefit </li></ul><ul><li>Clear chemotherapy benefit </li></ul>
    9. 9. Recurrence Score Clinical Validation: NSABP B-14, Distant Recurrence Distant Recurrence Over Time 10-Year rate of recurrence = 6.8%* 95% CI: 4.0%, 9.6% 0 2 4 6 8 10 12 14 16 Years Paik S, et al. N Engl J Med. 2004;351:2817-2826. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Proportion without distant recurrence RS < 18, n = 338 RS 18-30, n = 149 RS ≥ 31, n = 181 All Patients, n = 668 P < 0.001 10-Year rate of recurrence = 14.3% 95% CI: 8.3%, 20.3% 10-Year rate of recurrence = 30.5%* 95% CI: 23.6%, 37.4% *10-Year distant recurrence comparison between low- and high-risk groups: P < 0.001 RS, Recurrence Score ® result
    10. 10. <ul><li>Low Risk (RS < 18) </li></ul>p = 0.76 N Events 218 11 135 5 10 yr 96 % 95% Paik S, et al: JCO 2006 p = 0.71 N Events 89 9 45 8 89% 90% Interm. Risk (RS 18–30) p = 0.001 N Events 117 13 47 18 60% 88% High Risk (RS ≥ 31) Interaction p = 0.0368 21 Gene Recurrence Score Assay: Strongly Predicts CMF Benefit (NSABP B-20)
    11. 11. NSABP B-20: Many Younger Patients Have Low Recurrence Score ® Results NSABP B-20: Many Small Tumors Have Intermediate to High Recurrence Score ® Values NSABP B-20: Significant Proportion of High-Grade Tumors Have Low Recurrence Score ® Values Paik S, et al. J Clin Oncol . 2006;24:3726-3734.
    12. 12. Onco type DX ® and Patient Age: Distribution of RS Risk Groups by Age Group Shak S, et al. SABCS 2010. Poster P3-10-01 . n 145,240 5,794 117,744 21,702 RS (mean) 18.6 21.3 18.6 18.2
    13. 13. S8814 N+ ER+ Single Gene Analyses might “Misclassify”Dominant Biology of Tumor Example: Some High ER (by either Allred Score or RT-PCR) have High RS Albain, et al, 2009
    14. 14. Summary of Key Differences Between Genomic Assays 1. Paik S, et al. N Engl J Med. 2004;351:2817; 2. Paik S, et al. J Clin Oncol. 2006;24:3726. 3. Bueno-de-Mesquita JM, et al. Lancet Oncol . 2007; 8:1079-1087; 4. Mook S, et al. Breast Cancer Res Treat . 2009;116:295-302. ASCO is a trademark of the American Society of Clinical Oncology. ASCO does not endorse any therapy or product. NCCN is a trademark of the National Comprehensive Cancer Network .   Onco type DX ® (Genomic Health) MammaPrint ® (Agendia) Mammostrat ® (Clarient) Insight ® Dx (Clarient) Does the test strongly predict recurrence risk? YES YES NO YES Is the test clinically validated in uniform patient populations? YES NO YES NO Can the test be performed in a clinically practical manner? FFPE (failure < 3% 1,2 ) Fresh tissue (failure 27% 3,4 ) FFPE (failure rate unpublished) FFPE (failure rate unpublished) What types of samples does the test accept? Surgical excisions, core biopsies Surgical excisions, core biopsies Surgical excisions Surgical excisions Does the test supply a result on a continuous scale or a risk category? Continuous; individualized risk assessment Group risk assessment (low, high) Group risk assessment (low, intermediate, high) Continuous Does the test predict chemotherapy benefit? YES NO NO NO What platform does the test use? RT-PCR Microarray IHC IHC/FISH What type of regulatory clearance does the test have? CLIA CLIA/FDA CLIA CLIA Is the test recommended in published treatment guidelines of ASCO ® and NCCN ® ? YES NO NO NO Is the test widely reimbursed? Medicare & > 95% of US privately insured lives Medicare & private insurance with signed Assignment of Benefits form No public information available Test uses CPT codes No public information available Test uses CPT codes
    15. 15. Summary of Practical Differences Between MammaPrint ® and the Onco type DX ® Assay 1. Paik S, et al. N Engl J Med. 2004;351:2817; 2. Paik S, et al. J Clin Oncol. 2006;24:3726. 3. Bueno-de-Mesquita JM, et al. Lancet Oncol . 2007; 8:1079-1087; 4. Mook S, et al. Breast Cancer Res Treat . 2009;116:295-302. ASCO is a trademark of the American Society of Clinical Oncology. ASCO does not endorse any therapy or product. NCCN is a trademark of the National Comprehensive Cancer Network .   Onco type DX ® (Genomic Health) MammaPrint ® (Agendia) Does the test strongly predict recurrence risk? YES YES Is the test clinically validated in uniform patient populations? YES NO Can the test be performed in a clinically practical manner? FFPE (failure < 3% 1,2 ) Fresh tissue (failure 27% 3,4 ) What types of samples does the test accept? Surgical excisions, core biopsies Surgical excisions, core biopsies Does the test supply a result on a continuous scale or a risk category? Continuous; individualized risk assessment Group risk assessment (low, high) Does the test predict chemotherapy benefit? YES NO What platform does the test use? RT-PCR Microarray What type of regulatory clearance does the test have? CLIA CLIA/FDA Is the test recommended in published treatment guidelines of ASCO ® and NCCN ® ? YES NO Is the test widely reimbursed? Medicare & > 95% of US privately insured lives Medicare & private insurance with signed Assignment of Benefits form
    16. 16. What about Node-Positive Disease?
    17. 17. Recurrence Score Clinical Validation in Node-Positive Patients Superior disease-free survival and overall survival over 10 years Albain KS, et al. Lancet Oncol . 2009; [Epub ahead of print]. SWOG 8814 SUB ANALYSIS Tamoxifen × 5 yrs n = 361 CAF × 6  tamoxifen n = 566 CAF × 6 + tamoxifen n = 550 <ul><li>Patients with samples (n = 666) </li></ul><ul><li>RT-PCR obtained (n = 601) </li></ul><ul><li>Tamoxifen alone (n = 148) </li></ul><ul><li>CAF + T (n = 243) </li></ul><ul><li>CAF  T (n = 219) </li></ul><ul><ul><li>Sample for primary analysis </li></ul></ul><ul><ul><li>148 + 219 = 367 (40% of parent trial) </li></ul></ul>
    18. 18. Recurrence Score ® Result Is Prognostic for Node-Positive Patients (Tamoxifen Arm) 0 2 4 6 8 10 0 2 4 6 8 10 1.00 0.75 0.50 0.25 0.00 1.00 0.75 0.50 0.25 0.00 RS < 18 (n = 55) RS 18-30 (n = 46) RS ≥ 31 (n = 47) Stratified log-rank P = 0.017 at 10 years RS < 18 (n = 55) RS 18-30 (n = 46) RS ≥ 31 (n = 47) Stratified log-rank P = 0.003 at 10 years DFS by risk group (tamoxifen-alone arm) OS by risk group (tamoxifen-alone arm) Years since registration Years since registration Albain KS, et al. Lancet Oncol . 2009; [Epub ahead of print]. RS, Recurrence Score result 10-Year DFS : 60%, 49%, 43% 10-Year OS : 77%, 68%, 51%
    19. 19. S8814 CAFT vs T Breast Cancer Specific Survival by RS S8814 S8814 S8814 Albain, et al. Lancet Oncology 12/10/09 epub Interaction p = 0.021 10 yr BCSS T: 92% vs CAF-T: 87% 10 yr BCSS T: 70% vs CAF-T: 81% 10 yr BCSS T: 54% vs CAF-T: 73%
    20. 20. Exploratory Neoadjuvant Studies Are Consistent with Adjuvant Studies Paik S, et al. N Engl J Med. 2004;351:2817. Paik S, et al. J Clin Oncol. 2006;24:3726. Gianni L, et al. J Clin Oncol . 2005;23(29):7265-7277. Chang JC, et al. Breast Cancer Res Treat . 2008;108 (2):233-240. <ul><li>The lower the Recurrence Score: </li></ul><ul><li>The lower the benefit of chemotherapy </li></ul><ul><li>The greater the benefit of endocrine therapy </li></ul><ul><li>The higher the Recurrence Score: </li></ul><ul><li>The greater the benefit of chemotherapy </li></ul><ul><li>The lower the benefit of endocrine therapy </li></ul>Distant Recurrence at 10 Years Recurrence Score ® In both the adjuvant AND neoadjuvant settings: 4 0 % 3 5 % 3 0 % 2 5 % 2 0 % 1 5 % 1 0 % 5 % 0 % 0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0
    21. 21. Relevance of Multigene Assays in the Clinical Practice Setting *Most frequent decision change in all studies was from CHT -> HT Study N Setting Type Change in Treatment Decision* Oratz, et al. 74 Community, USA Retrospective, 21 gene 25% Asad, et al. 85 Community, USA Retrospective, 21 gene 44% Kamal, et al. 80 Academic, USA Retrospective, 21 gene 18% Lo, et al. 89 Academic + Community, USA Prospective, 21 gene 32% Bueno-de Mequita, et al. 427 Community, Dutch Prospective, 70 gene 26%
    22. 22. Meta-Analysis: Overall Impact of RS on Treatment Decisions Treatment plan prior to Onco type DX® Treatment plan after RS Treatment plan after RS CT + HT HT 4% change 33% change Hornberger J, et al. SABCS 2010. Poster P2-09-06. <ul><li>Overall, the RS led to a 37% change in treatment decisions </li></ul><ul><li>33% from CT+HT  HT </li></ul><ul><li>4% from HT  CT+HT </li></ul>
    23. 23. Discordance between Risk Level Assigned by Clinical-Pathologic Factors vs Multigene Assay Occurs in 30%-35% of Cases <ul><li>21-gene assay adds independent prognostic information to clinical-pathologic risk assessed by Adjuvant! in randomized and non-randomized data sets (Paik, Goldstein, Tang) </li></ul><ul><li>Multigene assays may be more accurate predictor of outcome in the individual patient </li></ul><ul><li>“ Both genomic and clinical variables should be included in a common algorithm to yield the most accurate prediction model.” Sotiriou and Pusztai, NEJM 2009 </li></ul>
    24. 24. Proportion of Node-Negative Patients Classified as Low, Intermediate and High Risk by RS and RSPC: RSPC has Prognostic Value BUT Does Not Add Predictive Value to RS – B14 and B20 n=1444 RSPC RS RSPC Classifies Fewer Patients as Having Intermediate Risk Tang et al, ASCO and SA 2010 54.2% 26.7% 19.1% 63.8% 17.8% 18.4% Low Risk Intermediate Risk High Risk 2010
    25. 25. Prediction of Chemotherapy Benefit in NSABP B-20: RS Is Most Significant P-value for interaction with chemotherapy treatment Trended to benefit with higher expression Trended to benefit with lower expression Greater benefit with higher RS Not predictive of benefit Paik S, et al. J Clin Oncol . 2006;24:3726-3734. Recurrence Score 0.037 Proliferation Gene Group Score by RT-PCR 0.133 PR Gene by RT-PCR 0.190 ER Gene by RT-PCR 0.393 HER2 Gene by RT-PCR 0.925
    26. 26. TAILORx SCHEMA PI: Sparano 21-Gene RS Assay N= 6906 Closed 8/20/10, N=11233 Closed 10/6/10, N=10259 N=1624 N=1729
    27. 27. S1007: A Phase III, Randomized Clinical Trial of Standard Adjuvant Endocrine Therapy +/- Chemotherapy in Patients with 1-3 Positive Nodes, Hormone Receptor-Positive and HER2-Negative Breast Cancer with Recurrence Score of 25 or Less Ana M. Gonzalez-Angulo, M.D.
    28. 28. Schema and Patient Flow Node-positive (1-3 nodes) HR-positive and HER2-negative breast cancer (N= 600) RS already Available Physician and patients discuss randomization knowing the RS (N= 8,800) Patients consent to study-sponsored RS testing, discussion of potential trials, tumor tissue submission and linkage to cancer registry data RECURRENCE SCORE (N= 3,800) Discuss alternative trials for high risk patients N= 5,600 Physician and patients discuss randomization knowing the RS N= 1,600 Record chosen therapy and followed for vital status through cancer registry N= 2,000 Chemotherapy; appropriate endocrine therapy N= 2,000 No Chemotherapy; appropriate endocrine therapy STEP 2 REGISTRATION/ RANDOMIZATION N= 4,000 Randomization stratified by 1. RS 0-13 vs. 14-25 2. Menopausal status 3. Axillary node dissection vs. Sentinel node biopsy RS > 25 RS < 25 Accept Refuse STEP 1 REGISTRATION Tumor tissue submission for RS STEP 2 RANDOMIZATION
    29. 29. Plan B Study schema West German Study Group Prospective study of >2,500 patients As of11/2010, 2094 pts registered , 1586 randomized Unable to predict RS with tumor grade or Ki67
    30. 30. Evaluate Clinical-Pathological risk and 70-gene signature risk EORTC-BIG MINDACT TRIAL DESIGN 6,000 Node negative women Clinical-pathological and 70-gene both HIGH risk Clinical-pathological and 70-gene both LOW risk Use Clin-Path risk to decide Chemo or not Use 70-gene risk to decide Chemo or not R1 55% 32% 13% N=1920 30% 288 Clin-Path Low 70-gene High: Ctx Clin-Path High 70-gene Low: CTx 70% 672 Clin-Path Low 70-gene High: no CTx 30% 288 Clin-Path High 70-gene Low: no Ctx 70% 672 Supported by the EU framework VI programme BIG-TRANSBIG Secretariat – Used with permission H 0 : 5y DMFS >92% (80% power) Discordant Clin-Path HIGH 70-gene LOW 70% N=1344 Clin-Path LOW 70-gene HIGH 30% N=576
    31. 31. Incorporation into Clinical Practice <ul><li>ASCO, NCCN and St. Gallen guidelines endorse consideration of assays: </li></ul><ul><ul><li>To predict benefit from chemotherapy in patients for whom the benefit of adding chemotherapy to hormone therapy is unclear </li></ul></ul><ul><ul><li>To predict risk of recurrence in patients considering tamoxifen </li></ul></ul><ul><li>Considerations </li></ul><ul><ul><li>Sample required (fresh vs paraffin embedded) </li></ul></ul><ul><ul><li>Prognostic vs predictive </li></ul></ul><ul><li>Who should we order testing on? </li></ul><ul><ul><li>Patients for whom choice of treatment is unclear </li></ul></ul><ul><ul><ul><li>Intermediate grade </li></ul></ul></ul><ul><ul><ul><li>Disparity in pathologic information </li></ul></ul></ul><ul><ul><ul><li>To confirm ER/PR and HER2 </li></ul></ul></ul><ul><ul><li>Allows both appropriate use of chemotherapy when beneficial, and avoidance when not necessary </li></ul></ul><ul><li>Disparities between clinical/pathologic and genomic testing unusual </li></ul>
    32. 32. Case Presentation <ul><li>40 year old premenopausal woman </li></ul><ul><li>0.7 cm node negative invasive ductal cancer </li></ul><ul><ul><li>Well differentiated </li></ul></ul><ul><ul><li>ER + >90%, PR + >50% </li></ul></ul><ul><ul><li>Ki67 > 20% </li></ul></ul><ul><ul><li>HER2 3+, FISH ratio 6.0 </li></ul></ul><ul><li>Treatment? </li></ul>
    33. 33. Adjuvantonline 10 yr mortality 10 yr recurrence
    34. 34. Results <ul><li>Recurrence score 50! </li></ul><ul><ul><li>36% distant recurrence risk at 10 years with 5 yrs of tamoxifen </li></ul></ul><ul><li>Recommendation for treatment: </li></ul><ul><ul><li>Adjuvant chemotherapy and Herceptın </li></ul></ul><ul><ul><li>Hormonal therapy </li></ul></ul>
    35. 35. Case <ul><li>67 year old Chinese woman </li></ul><ul><ul><li>2.4-cm grade 2 invasive ductal carcinoma, associated 2.6 cm high-grade DCIS </li></ul></ul><ul><ul><li>2 SNL negative </li></ul></ul><ul><ul><li>No LVI </li></ul></ul><ul><ul><li>ER 3+ in 95% of cells, PR 1+ in 5% of cells </li></ul></ul><ul><ul><li>HER-2/neu testing was positive at 3+ by IHC </li></ul></ul><ul><ul><li>FISH </li></ul></ul><ul><ul><ul><li>Mean ERBB2 signals: 6.4 </li></ul></ul></ul><ul><ul><ul><li>Mean Centromere 17 signals: 2.4 </li></ul></ul></ul><ul><ul><ul><li>Avg. Ratio: 2.7 </li></ul></ul></ul>
    36. 37. Past Medical History and Treatment Plan <ul><li>Chronic anemia </li></ul><ul><li>Tuberculosis with bilobe lung resection in 1967 </li></ul><ul><li>Dermal plasmacytoses </li></ul><ul><li>Vocal cord dysfunction </li></ul><ul><li>Plan: </li></ul><ul><ul><li>Hormone therapy +/- one year of trastuzumab </li></ul></ul>
    37. 38. 64 yo woman: mammographically detected, 1.3 cm grade 2 IDCA, no LVI, SNL neg, ER+++PR+, HER2 neg by FISH. RX: TC x 4 and AI
    38. 39. 47 yo woman, self exam detected 0.8 cm grade I IDC, 1 SNL + 0.9 cm CA with focal extranodal extension, 12 additional nodes negative. RX: tamoxifen
    39. 40. Copyright © American Society of Clinical Oncology Walgren, R. A. et al. J Clin Oncol; 23:7342-7349 2005 Personalized Medicine
    40. 41. Patient is on Study Randomize Randomize Surgery Surgery Learn, Adapt from each patient as we go along * Or equivalent Closed 8/20/10 Paclitaxel + Trastuzumab* + New Agent A Paclitaxel + New Agent C Paclitaxel + Trastuzumab Paclitaxel + Trastuzumab* + New Agent B Paclitaxel Paclitaxel + New Agent E AC AC HER 2 (+) HER 2 (–) Paclitaxel + New Agent F Paclitaxel + Trastuzumab* + New Agent C Paclitaxel + New Agent D Paclitaxel + New Agent GH Paclitaxel + Trastuzumab* + New Agent F MRI Residual Disease (Pathology) Key

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