The Oncotype DX Breast Cancer Assay helps you find an answer

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1 CHEMO? NO CHEMO? The Oncotype DX Breast Cancer Assay helps you find an answer Oncotype DX helps clarify one of the most difficult treatment questions by providing an individualized Recurrence Score result that assesses the benefit of chemotherapy and the likelihood of breast cancer recurrence. 1,2

2 Do all patients have the same magnitude of benefit from chemotherapy? CHEMO? Landmark NSABP B-2 trial of 651 estrogen receptor positive (ER-positive), node-negative breast cancer patients found 1 : The addition of chemotherapy provided only a 4% absolute benefit, measured as the proportion of patients free of distant recurrence at 1 years Proportion of all patients free of distant recurrence at 1 years 1 Proportion without distant recurrence 1. 92% P =.2 n Events Tam + chemo Tam % 4% ABSOLUTE BENEFIT FROM TAM + CHEMO The Oncotype DX Breast Cancer Assay is the only test that provides patients with an individual score validated to predict chemotherapy benefit and the likelihood of distant recurrence

3 Providing predictive and prognostic information for a broad range of patients The Oncotype DX Breast Cancer Assay 1,2 : Analyzes the expression of 21 genes Predicts chemotherapy benefit Indicates the 1-year risk of distant recurrence NO CHEMO? Eligible ER-positive breast cancer patients extend along a biologic continuum 1,2,4-7 ER-positive, tamoxifen-treated, or AI-treated 4 stage i pt1, N pt2-3, N included in asco and nccn guidelines 5,6 stage ii pt1-3, N1mi* included in nccn guidelines 6 stage iii pt-2, N1 pt3, N1 certain node-positive patients 4,7 AI=aromatase inhibitor; ASCO=American Society of Clinical Oncology; NCCN=National Comprehensive Cancer Network. Cancer Network. ASCO and NCCN do not endorse any product or therapy. *T1b moderate/poorly differentiated or unfavorable features/1c/2/3, N1mi, M; HER2-negative. Consider patients from a subset of stage IIIa as indicated; not all stage III patients. The Oncotype DX Breast Cancer Assay is the only multigene expression assay incorporated in both the ASCO and NCCN guidelines. 5,6 3

4 Accurate, precise, and reproducible CHEMO? Why RT-PCR was chosen for the Oncotype DX Breast Cancer Assay 3 : Precise, accurate, and highly reproducible over a wide dynamic range Minimizes variability that may result from: Tissue preparation method, type of fixative, and fixation time Tumor block age, storage, and variability in preparation Sample heterogeneity Can be assayed using fixed tissue from core biopsy or surgical excision samples Genomic Health s surgical pathologists take additional steps to ensure accuracy 3 Perform manual microdissection Clear sample contaminants Enrich for invasive tumor tissue Fixed paraffin-embedded tumor sample. With a success rate >97% in generating an accurate result, you can feel confident in the Oncotype DX Breast Cancer Assay. 8 4

5 Helping you find an individualized answer with genomics 21 genes identified through a rigorous selection process 2 NO CHEMO? 447 patients with ER-positive and ER-negative, and node-positive and node-negative breast cancer were examined 25 breast cancer associated genes were analyzed 21-gene panel used to develop the Recurrence Score algorithm 2 PROLIFERATION INVASION HER2 Ki-67 STK15 Stromelysin 3 GRB7 Survivin Cathepsin L2 HER2 Cyclin B1 MYBL2 ESTROGEN OTHER ER PR Bcl-2 SCUBE2 GSTM1 CD68 BAG1 16 cancer genes Several identified with a consistent and strong statistical association to breast cancer recurrence Others with robust predictive power for chemotherapy benefit REFERENCE Beta-actin GAPDH RPLPO GUS TFRC 5 reference genes Normalize gene expression Provide quality control Gene expression levels determine the Recurrence Score (RS) result 2 RS = +.47 HER2 group score.34 Estrogen group score +1.4 Proliferation group score +.1 Invasion group score +.5 CD68.8 GSTM1.7 BAG1 5

6 The proven prognostic utility of the Oncotype DX Breast Cancer Assay CHEMO? Validated in NSABP B-14 Prospective analysis on archived tissue patients treated with tamoxifen 2 ER-positive, node-negative 2 1-year rate of distant recurrence was significantly lower for patients with low Recurrence Score values 2 Rate of distant recurrence at 1 years (%) % 95% Cl 4%-9.6% RECURRENCE SCORE VALUE <18 LOW RISK 14.3% 95% Cl 8.3%-2.3% RECURRENCE SCORE VALUE 18-3 INTERMEDIATE RISK 3.5% 95% Cl 23.6%-37.4% RECURRENCE SCORE VALUE 31 HIGH RISK CI=confidence interval. ALL PATIENTS 15%= IN STUDY (n=668) The majority of patients had low Recurrence Score values 2 51% RS <18 27% RS 31 22% RS Prognostic: any measurement available at the time of diagnosis or surgery associated with clinical outcome in the absence of systemic adjuvant therapy or following the standard of care treatment. 3

7 Adding critical information to your treatment decision Provides significant information about recurrence risk, independent of age and tumor size (P<.1) 2 NO CHEMO? Multivariate COX analysis 2 VARIABLE HAZARD RATIO 95% CI P-VALUE Age at surgery.71 (.48, 1.5).8 Clinical tumor size 1.26 (.86, 1.86).23 Recurrence Score 3.21* (2.23, 4.61) <.1 * The hazard ratio for the Recurrence Score is calculated relative to an increment of 5 units. May predict the magnitude of tamoxifen benefit, as shown in a follow-up study to NSABP B-14 (n=645) 9 Proportion without distant recurrence LOW RECURRENCE SCORE VALUE (<18) P =.39 n Proportion without distant recurrence % 86% P =.82 n Placebo 99 Tam 79 INTERMEDIATE RECURRENCE SCORE VALUE (18-3) Proportion without distant recurrence Placebo Placebo 85 Tam 142 Tam HIGH RECURRENCE SCORE VALUE ( 31) % 69% P = n 8% 62% Results should not be used to indicate that tamoxifen should not be given to the high-risk group. 3 Patients with high ER scores (and low Recurrence Score values) saw the largest benefit from treatment with tamoxifen 9 7

8 The proven predictive utility of the Oncotype DX Breast Cancer Assay CHEMO? Validated in NSABP B-2 Prospective analysis on archived tissue patients treated with tamoxifen or tamoxifen plus CMF/MF 1 ER-positive, node-negative 1 Low Recurrence Score value (<18); little to no chemotherapy benefit 1 Proportion without distant recurrence P =.61 n Events Tam + chemo Tam % 96% Intermediate Recurrence Score value (18-3); no substantial chemotherapy benefit 1 * Proportion without distant recurrence P =.39 n Events Tam + chemo 89 9 Tam % 89% *Clinically important benefit cannot be excluded.

9 Helping you predict the benefit of chemotherapy in node-negative patients NO CHEMO? High Recurrence Score value ( 31); large chemotherapy benefit 1 Proportion without distant recurrence P<.1 n Events Tam + chemo Tam % 6% % ABSOLUTE BENEFIT FROM TAM + CHEMO Large reduction in 1-year distant recurrence for high-risk patients treated with chemotherapy 1 Absolute increase in proportion free of distant recurrence (mean ± SE) 4% 3% 2% 1% -1% RECURRENCE SCORE VALUE <18 (n=353) RECURRENCE SCORE VALUE 18-3 (n=134) RECURRENCE SCORE VALUE 31 (n=164) Predictive: any measurement associated with benefit or lack of benefit from a particular therapy. 3 9

10 Additional insight may help guide your treatment decision CHEMO? NSABP B-2 trial (n=651) 1 Recurrence Score value % 14% 44% <4 (n=63) 24% 21% 55% 4-49 (n=226) 28% 22% 5% 5-59 (n=166) 19% 21% 6% 6 (n=196) Recurrence Score value < Patient age P=.18 1 Younger patients can have low Recurrence Score values 1 Older patients can have high Recurrence Score values 1 NSABP B-2 trial (n=651) 1 Recurrence Score value % 25% 3% 33% 2% 19% 23% 21% 64% 56% 46% 46% 1 cm (n=11) cm (n=318) cm (n=196) >4 cm (n=24) Clinical tumor size P=.1 Patients with larger tumors can have low Recurrence Score values 1 Patients with smaller tumors can have high Recurrence Score values 1 1

11 Providing independent, significant data beyond traditional measures NO CHEMO? NSABP B-2 trial (n=651) 1 Recurrence Score value grading by pathologist at local hospital 12% 16% 73% WELL (n=77) 22% 22% 56% MODERATE (n=339) 42% 22% 36% POOR (n=163) Recurrence Score value < Tumor grade (site) P<.1 1 grading by pathologist at central lab Recurrence Score value % 12% 83% WELL (n=119) 12% 24% 64% MODERATE (n=34) 61% 19% 19% POOR (n=19) Tumor grade (central) P<.1 Significant proportions of high-grade tumors have low Recurrence Score values 1 Even low-grade tumors can have high Recurrence Score values 1 Nearly 1 in 3 adjuvant treatment recommendations were changed based on the Recurrence Score results in a decision impact study. 1 11

12 Providing independent recurrence risk information across a biologic continuum CHEMO? Validated in Trans ATAC Prospective analysis on archived tissue 4 1,231 postmenopausal patients treated with tamoxifen or Al 4 1,178 ER-positive, node-positive, and node-negative 4 Comparative risks were seen in node-negative patients and patients with 1 to 3 nodes who had low Recurrence Score values 3,4 9-year risk of distant recurrence (%) Mean 95% Cl 4+ POSITIVE NODES n=63 (31 EVENTS) 1-3 POSITIVE NODES n=243 (43 EVENTS) NODE- NEGATIVE n=872 (72 EVENTS) Recurrence Score value Oncotype DX is the only multigene expression assay incorporated in the NCCN guidelines to help guide chemotherapy treatment decisions in patients with micrometastases. 6 12

13 Helping you predict the benefit of chemotherapy in node-positive patients Validated in SWOG 8814 Prospective analysis on archived tissue postmenopausal patients treated with tamoxifen or tamoxifen plus CAF 7 HR-positive, node-positive 7 NO CHEMO? Strong chemotherapy benefit seen only in the high Recurrence Score value group 7 No substantial benefit in Breast Cancer Specific Survival from anthracycline based chemotherapy for node-positive patients with lower Recurrence Score values Breast cancer specific survival LOW RECURRENCE SCORE VALUE (<18) P =.56 n Events 92% 87% INTERMEDIATE RECURRENCE SCORE VALUE (18-3) Breast cancer specific survival P =.89 Tam only Tam only CAF-T 91 1 CAF-T HIGH RECURRENCE SCORE VALUE ( 31) 1. Breast cancer specific survival P =.33 n Events Tam only 47 2 CAF-T % 54% n Events 81% 7% Half of adjuvant treatment recommendations for node-positive patients were changed based on the Recurrence Score result in a decision impact survey 11 For 33.3% of patients tested with Oncotype DX, their treatment was changed from chemotherapy plus hormonal therapy to hormonal therapy alone For 9.4% of patients tested with Oncotype DX, their treatment was changed from hormonal therapy alone to chemotherapy plus hormonal therapy 13

14 The Oncotype DX Breast Cancer report CHEMO? Page 1 of 3 Genomic Health, Inc. 31 Penobscot Drive Redwood City, CA 9463 USA Toll Free Tel 866-ONCOTYPE ( ) Worldwide Tel The first page of the report contains the individualized Recurrence Score result between and 1. Estimate of the likelihood of distant recurrence at 1 years. PATIENT REPORT Patient/ID: Doe, Jane Sex: Female DOB: 1/1/195 Medical Record/Patient #: Date of Surgery: 9/25/28 Specimen Type/ID: Breast/SURG-1 Requisition: R3G Order Received: 1/15/28 Date Reported: 1/23/28 Client: Community Medical Center Ordering Physician: Dr. Harry D Smith Submitting Pathologist: Dr. John P Williams Submitting Pathologist: Dr. Sally M Jones BREAST CANCER ASSAY DESCRIPTION Oncotype DX Breast Cancer Assay uses RT-PCR to determine the expression of a panel of 21 genes in tumor tissue. The Recurrence Score is calculated from the gene expression results. The Recurrence Score range is from -1. RESULTS Breast Cancer Recurrence Score = 6 The findings summarized in the Clinical Experience sections of this report are applicable to the patient populations defined in each section. It is unknown whether the findings apply to patients outside these criteria. CLINICAL EXPERIENCE: PROGNOSIS FOR NODE NEGATIVE, ER-POSITIVE PATIENTS The Clinical Validation study included female patients with Stage I or II, Node Negative, ER-Positive breast cancer treated with 5 years of tamoxifen. Those patients who had a Recurrence Score of 6 had an Average Rate of Distant Recurrence of 5% (95% CI: 3%-7%) The following results are from a clinical validation study of 668 patients from the NSABP B-14 study. N Engl J Med 24; 351: Recurrence Score vs Distant Recurrence in Node Negative, ER-Positive Breast Cancer Prognosis Laboratory Director: Patrick Joseph, MD CLIA Number 5D This test was developed and its performance characteristics determined by Genomic Health, Inc. The laboratory is regulated under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) as qualified to perform high-complexity clinical testing. This test is used for clinical purposes. It should not be regarded as investigational or for research. These results are adjunctive to the ordering physician's workup. Online Ordering and Reports Available Please contact Customer Service at customerservice@genomichealth.com Genomic Health, Inc. All rights reserved. Oncotype DX and Recurrence Score are registered trademarks of Genomic Health, Inc. GHI4 Rev17 The report also contains predictive information about chemotherapy benefit, validated in the NSABP B-2 study 1 For node-positive patients, the report also includes both predictive and prognostic information, as validated in the SWOG 8814 study 7 14

15 Helping to make a more informed decision with quantitative data Page 3 of 3 Genomic Health, Inc. 31 Penobscot Drive Redwood City, CA 9463 USA Toll Free Tel 866-ONCOTYPE ( ) Worldwide Tel NO CHEMO? PATIENT REPORT Patient/ID: Doe, Jane Sex: Female DOB: 1/1/195 QUANTITATIVE SINGLE GENE REPORT Requisition: R3G Order Received: 1/15/28 Date Reported: 1/23/28 The Oncotype DX assay uses RT-PCR to determine the RNA expression of the genes below. These results may differ from ER, PR, or HER2 results reported using other methods or reported by other laboratories. 1 The ER, PR, and HER2 Scores are also included in the calculation of the Recurrence Score. ER Score = Positive The ER Score positive/negative cut-off of 6.5 units was validated from a study of 761 samples using the 1D5 antibody (immunohistochemistry) and 67 samples using the SP1 antibody (immunohistochemistry). The standard deviation for the ER Score is less than.5 units. 2 Clinical Experience: For ER positive breast cancer, the magnitude of tamoxifen benefit increases as the ER Score increases from 6.5 to Please note: The Average Rate of Distant Recurrence reported on Page 1 based on the Recurrence Score was determined in patients who received 5 years of tamoxifen treatment and takes into account the magnitude of tamoxifen benefit indicated by the ER Score. PR Score = Positive Quantitative ER, PR, and HER2 scores, which are highly concordant with IHC and FISH 3,12,13 The PR Score positive/negative cut-off of 5.5 units was validated from a study of 761 samples using the PR636 antibody (immunohistochemistry) and another study of 67 samples using the PR636 antibody (immunohistochemistry). The standard deviation for the PR Score is less than.5 units. 2 HER2 Score = Negative The HER2 positive cut-off of 11.5 units, equivocal range from 1.7 to 11.4 units, and negative cut-off of < 1.7 units were validated from concordance studies of 755 samples using the HercepTest assay (immunohistochemistry) and another study of 568 samples using the PathVysion assay (FISH). The standard deviation for the HER2 score is less than.5 units. 4 Genomic Health accepts all early-stage breast cancer samples to help confirm or clarify ER status References: 1. ER Score based on quantitative ESR1 expression (estrogen receptor); PR Score based on quantitative PGR expression (progesterone receptor); HER2 Score based on quantitative ERBB2 expression. 2. ASCO Breast Cancer Symposium 27 Abstracts #87 by S.S. Badve et al., and #88 by F.L. Baehner et al. 3. ASCO Annual Meeting 25 Abstract #51 by S. Paik et al. 4. ASCO Breast Cancer Symposium 28 Abstracts #13 by F.L. Baehner et al., and #41 by F.L. Baehner et al. Laboratory Director: Patrick Joseph, MD CLIA Number 5D This test was developed and its performance characteristics determined by Genomic Health, Inc. The laboratory is regulated under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) as qualified to perform high-complexity clinical testing. This test is used for clinical purposes. It should not be regarded as investigational or for research. These results are adjunctive to the ordering physician's workup. Online Ordering and Reports Available Please contact Customer Service at customerservice@genomichealth.com Genomic Health, Inc. All rights reserved. Oncotype DX and Recurrence Score are registered trademarks of Genomic Health, Inc. GHI4 Rev17 Sign up now for the Customer Portal at Online ordering Online results Important customer information postings Call Customer Service at 866-ONCOTYPE to open an account. 15

16 CHEMO? NO CHEMO? The Oncotype DX Breast Cancer Assay helps you find an answer A personalized approach to breast cancer treatment Validated through an extensive suite of studies, across a continuum of more than 4, ER-positive patients in 13 clinical studies 1,2,4,7 Only test incorporated in both the ASCO and NCCN guidelines to help guide chemotherapy treatment decisions 5,6 Clinical utility in node-negative and certain node-positive, ER-positive breast cancer patients 1,2,4-7 Changed adjuvant treatment recommendations for a significant proportion of both node-negative and node-positive patients 1,11 Genomic Health is committed to making Oncotype DX available to your patients 3 Extensively reimbursed, with more than 95% of privately insured lives and Medicare beneficiaries covered for the test, as well as expanding coverage in node-positive patients Provides numerous services to ease the reimbursement process for you, your staff, and your patients through the Genomic Access Program (GAP) Genomic Health is a CLIA-certified, CAP-accredited reference laboratory Oncotype DX is now available for patients with stage II colon cancer, expanding Genomic Health s technology to other cancer types. For Customer Service, please contact 866-ONCOTYPE ( ) or customerservice@genomichealth.com within the United States, and or international@genomichealth.com outside the United States. References: 1. Paik S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor positive breast cancer. J Clin Oncol. 26;24(23): Paik S, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 24;351(27): Data on file. Genomic Health, Redwood City, CA. 4. Dowsett M, et al. Risk of distant recurrence using Oncotype DX in postmenopausal primary breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study. Abstract presented at: 31st Annual San Antonio Breast Cancer Symposium; December 1-14, 28; San Antonio, TX. Abstract Harris L, et al. American Society of Clinical Oncology 27 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 27;25(33): National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology : breast cancer: V Published December 2, 28. Accessed December 22, Albain KS, et al; for The Breast Cancer Intergroup of North America. Prognostic and predictive value of the 21-gene Recurrence Score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol. 21;11(1): Anderson JM, et al. Molecular characterization of breast cancer core biopsy specimens by gene expression analysis using standardized quantitative RT-PCR. Poster presented at: 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 29; San Antonio, TX. Poster Paik S, et al. Expression of the 21 genes in the Recurrence Score assay and tamoxifen clinical benefit in the NSABP study B-14 of node negative, estrogen receptor positive breast cancer. J Clin Oncol. 25;23(16S)(suppl). Abstract Lo SS, et al. Prospective multicenter study of the impact of the 21-gene Recurrence Score assay on medical oncologist and patient adjuvant breast cancer treatment selection [published online ahead of print January 11, 21]. J Clin Oncol. doi:1.12/jco Oratz R, et al. Effect of a 21-gene reverse-transcriptase polymerase chain reaction assay on treatment recommendations for patients with lymph node positive and estrogen receptor positive breast cancer. Poster presented at: 32nd Annual San Antonio Breast Cancer Symposium; December 9-13, 29; San Antonio, TX. Poster Badve SS, et al. Estrogen- and progesterone-receptor status in ECOG 2197: comparison of immunohistochemistry by local and central laboratories and quantitative reverse transcription polymerase chain reaction by central laboratory. J Clin Oncol. 28;26(15): Baehner FL, et al. A Kaiser-Permanente populationbased study of ER and PR expression by the standard method, immunohistochemistry (IHC), compared to a new method, quantitative reverse transcription polymerase chain reaction (RT-PCR). Presented at: 27 American Society of Clinical Oncology Breast Cancer Symposium; September 7-8, 27; San Francisco, CA. Abstract 88. American Society of Clinical Oncology (ASCO) and ASCO are registered trademarks of ASCO; National Comprehensive Cancer Network (NCCN) and NCCN are registered trademarks of NCCN. ASCO and NCCN do not endorse any product or therapy. Genomic Health, Oncotype DX, and Recurrence Score are registered trademarks of Genomic Health, Inc. 21 Genomic Health, Inc. All rights reserved. GHI21 12/1