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| ASCO 2011 Abstract on CALGB 9581 |
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Validation of a 12-gene colon cancer recurrence score (RS) in patients (pts) with stage II colon cancer (CC)
from CALGB 9581.
Author(s): A. P. Venook, D. Niedzwiecki, M. Lopatin, M. Lee, P. N. Friedman, W. Frankel, K. Clark-Langone, C. Yoshizawa, C. Millward, S. Shak, R. M. Goldberg, N. N. Mahmoud, R. L. Schilsky, M. M. Bertagnolli, Cancer and Leukemia Group B; University of California, San Francisco, San Francisco, CA; Duke University, Durham, NC; Genomic Health, Redwood City, CA; Cancer and Leukemia Group B, Chicago, IL; The Ohio State University, Columbus, OH; University of North Carolina at Chapel Hill, Chapel Hill, NC; University of Pennsylvania, Philadelphia, PA; The University of Chicago, Chicago, IL; Brigham and Women's Hospital, Boston, MA.
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| Background: |
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| The 12-gene RS (Genomic Health, Inc.) has been shown to predict risk of recurrence in stage II colon cancer (CC) pts in QUASAR. We conducted a validation study in tumor specimens from pts enrolled in CALGB 9581, which found no difference for edrecolomab (MoAb 17-1A) v. observation in 1672 pts with, on average, low risk stage II CC (14% 5-yr recurrence.) |
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| Methods: |
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| Cohort sampling included all pts with available tissue and recurrence and random pts w/o recurrence (3:1 ratio). Gene expression was analyzed by RT-PCR using FFPE from primary tumor. Mismatch repair (MMR) protein status (D= Deficient; I= Intact) was assessed by IHC for MLH1 and MSH2. Primary aim: prognostic value of continuous RS alone and in presence of MMR and traditional clinical/pathologic prognostic variables. A weighted Cox proportional hazards model was used to test the association between RS and recurrence-free interval (RFI) based on a Wald-type test statistic constructed using a weighted partial likelihood estimate and robust variance estimate. |
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| Results: |
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Tumor was available for 1361/1672 (81%) pts. RT-PCR was successful in 690 (162 recurrences) of 736 pts (21% MMR-D, 35%
≥ 70 yrs old, 47% < 12 nodes.) The continuous RS was significantly associated with RFI in univariate analysis (hazard ratio (HR)/ 25 units, 1.52; 95% CI, 1.09-2.12; p=0.01). MMR-D was also associated with RFI (HR, 0.62; 95%CI, 0.39-0.99; p=0.04); # nodes examined and lymphovascular invasion (LVI) were borderline significant (both p=0.06). In a pre-specified multivariate analysis w/ MMR, T-stage, nodes examined, grade, and LVI, RS was the only significant predictor of recurrence (HR/25 units=1.68, 95%CI 1.18-2.38; p=0.004). Recurrence risk at 5 yrs increased as RS increased and among subgroups defined by T-stage and MMR. In pts with T3, MMR-I tumors (n=488) pre-specified low (44% of pts RS < 29), intermediate (33%), and high (22% w/ RS > 39) RS groups had average 5-yr recurrence risks of 13%, 16%, and 21%, respectively. |
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| Conclusions: |
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| In 9581, RS improves the ability to discriminate higher from lower recurrence risk stage II CC pts beyond known prognostic factors, particularly in T3, MMR-I pts where traditional factors like grade and LVI were not prognostic. |
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| A PDF version of the CALGB 9581 poster is available here. |
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| CALGB 9581 Summary |
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| CALGB 9581: Second Successful Prospectively-Designed Validation Study: |
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- Confirms the performance of the Oncotype DX Colon Cancer Assay, previously validated in QUASAR as a predictor of recurrence risk in stage II colon cancer
- In CALGB 9581, a phase III prospectively-designed US cooperative group clinical trial, the continuous 12-gene RS was significantly associated with the risk of recurrence, providing value beyond conventional markers
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| CALGB 9581: A Unique Opportunity to Test in Low/Standard Risk Stage II Colon Cancer |
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- Sampling design with 690 evaluable patients, including 162 recurrence events, representative of 1672 stage II colon cancer patients from CALGB 9581
- Age and nodal sampling reflective of contemporary clinical practice
- Low/standard recurrence risk population; excluded patients with pT4b stage, perforation, obstruction, positive margins
- A population where risk discrimination is challenging with conventional clinical and pathologic factors
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CALGB 9581: RS Predicts Risk of Recurrence Beyond Traditional Clinical and Pathologic Covariates |
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| CALGB 9581: Improving the Ability to Discriminate High vs. Low risk of Recurrence in Standard Risk Stage II Colon Cancer |
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- For standard risk patients with T3, N0, MMR-P tumors, a high Recurrence Score can reveal an underlying biology indicative of more aggressive disease for which adjuvant therapy may be more appropriate
- The Oncotype DX Colon Cancer Assay identified 22% of patients with average risk of recurrence at 5 years above 20%, thus improving the ability to discriminate high from low recurrence risk stage II colon cancer patients beyond known prognostic factors
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| A PDF summary of the CALGB 9581 study is available here. |
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| To listen to Dr. Steve Shak review the ASCO 2011 data on the CALGB 9581 study, please click here. |
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| To download the slides from the post ASCO review, please click here. |
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| QUASAR Multivariate Analysis Spotlight |
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| Interpreting results of a model with multiple variables |
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| When a new tumor marker such as Recurrence Score is introduced, it is important to know whether it predicts clinical outcome such as risk of recurrence. However, it is also critical to know if it offers additional value beyond that provided by traditional clinical and pathological characteristics such as number of nodes examined or tumor (T) stage. Multivariate analysis (i.e. analysis of multiple explanatory variables) is a powerful statistical technique which evaluates the importance of a marker after the information from all other variables in a model has been taken into account. This evaluation is performed by comparing the model with all the variables, including the new marker, to a model without that specific marker. If the model including the new marker fits the data much better, this marker provides statistically significant additional information. On the other hand, if the information provided by a new marker is already captured by other variables, its inclusion will not improve the fit of the model. It is important to pre-specify which variables will be included in the model prior to study conduct to avoid post-hoc ‘data dredging’ and minimize the chances of false positive findings.
This concept is well-illustrated by the pre-specified Cox proportional hazards regression of six covariates on risk of recurrence in stage II colon cancer patients treated with surgery alone in the QUASAR validation study (Table 1). When MMR status, T stage, number of nodes examined, tumor grade and lymphovascular invasion (LVI) were included in the model, the continuous Recurrence Score provided significant additional information on recurrence risk beyond these conventional markers (p=0.008). T stage and MMR status were also highly significant predictors of recurrence risk in this analysis, underlining the importance of these two tumor characteristics for a relatively small proportion of stage II colon cancer patients (13% of patients had MMR deficient tumors and 15% had T4 disease). Tumor grade and nodes examined were significant, albeit with less significant p-values (p = 0.026 and 0.040, respectively) while LVI was not a significant predictor of recurrence risk in the context of these other factors (p=0.175).
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| Table 1. Multivariate analysis of clinical and pathologic covariates and risk of recurrence in stage II colon cancer patients treated with surgery alone in the QUASAR study (n=605 patients). |
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Variable |
Categories |
HR |
95% CI |
p value |
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MMR |
13% Deficient vs. 87% Proficient |
0.32 |
(0.15,0.69) |
<.001 |
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T Stage |
15% T4 vs. 85% T3 |
1.83 |
(1.23,2.75) |
0.005 |
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Tumor Grade |
29% High vs. 71% Low |
0.62 |
(0.40,0.96) |
0.026 |
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# Nodes Examined |
62% <12 vs. 38% ≥12 |
1.47 |
(1.01,2.14) |
0.040 |
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LVI |
13% Present vs. 87% Absent |
1.40 |
(0.88,2.23) |
0.175 |
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Recurrence Score |
Continuous, per 25 units |
1.61 |
(1.13,2.29) |
0.008 |
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| Why is Analytical Validation Important? |
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| Analytical validation is the assessment of assay performance characteristics and the optimal conditions to ensure consistent and reliable test results for patients. Analytical validation involves testing sensitivity, precision, linear dynamic range, and reproducibility of the finalized assay. The Oncotype DX Colon Cancer Assay has been analytically validated to give accurate, precise and reproducible Recurrence Score results across different reagent lots, operators, days of the week and patient samples. Standardization of the assay is critical to ensuring that the Oncotype DX Colon Cancer Assay will yield results which clinicians can use in informing patient treatment decision-making. |
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Publication on Analytical Validation and the Oncotype DX Colon Cancer Assay |
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| An article by Clark-Langone et al. in BMC Cancer entitled “Translating Tumor Biology into Personalized Treatment Planning: Analytical Performance Characteristics of the Oncotype DX Colon Cancer Assay” shows the applicability, reproducibility, and sensitivity of RT-PCR technology to quantify gene expression in fixed paraffin-embedded colon cancer tissue. The studies described in this paper demonstrate the precision and reproducibility of the standardized and highly controlled Oncotype DX Assay process. The results of the analytical validation studies reported in the Clark-Langone paper illustrate how the analytical capability of the Oncotype DX Colon Cancer Assay has enabled clinical validation of a test to determine individualized recurrence risk after colon cancer surgery. |
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| Analytical performance characteristics shown for both individual genes and gene groups in the Oncotype DX Colon Cancer Assay demonstrate consistent translation of individual tumor biology into clinically useful diagnostic information.The high precision of the individual genes translates into a similarly high level of precision for the stromal gene group score (SD≤0.04), the cell cycle gene group scores (SD≤0.05) and the RS (SD≤1.38). These estimates are for variance of the components of the RS (stromal gene group and cell cycle gene group scores) as well as the RS, for the same sample run through the process on different days, and with different equipment, operators, and reagent lots. These results give confidence that the Oncotype DX results can be reliably obtained for individual patients and thus appropriately applied in treatment planning for stage II colon cancer patients. |
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| To read more about the analytical validation of the Oncotype DX Colon Cancer Assay, click here. |
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| Clark-Langone et al. Translating Tumor Biology into Personalized Treatment Planning: Analytical Performance Characteristics of the Oncotype DX Colon Cancer Assay. BMC Cancer 2010, 10:691 |
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| Spotlight on Oncotype DX Colon Cancer Assay Genes: Cell Cycle and Ki67 |
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| Cell Cycle Gene Group: |
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| In contrast to the Oncotype DX Breast Cancer Assay, where higher expression of cell cycle genes (STK15, MYBL2, Ki-67 and CCNB1) is associated with increased risk of recurrence [1-2], higher expression of the colon cell cycle genes (cMYC and Ki-67 and MYBL2) is associated with a lower risk of recurrence [3-4]. This is consistent with other reported evidence that cell cycle gene expression correlates with a good prognosis in colon cancer [5-8]. Increased expression of these cell cycle genes in colon cancer may thus represent a different biological property than cell cycle gene expression in breast cancer, where it has been associated with proliferation. In colon cancer, increased expression of these genes may instead represent tightened control of various stages of the cell cycle in response to DNA damage or misalignment of chromosomes during mitosis. With tighter cell cycle control, a tumor could reduce the likelihood of chromosomal instability and aneuploidy [9], which are associated with poor outcome [10-13]. |
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Ki-67 (MK167; Antigen identified by monoclonal antibody Ki-67) |
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| The Ki-67 gene encodes a protein which is synthesized from late G1 through M phase of the cell cycle, and is localized to the nucleus. There are several reports where high expression of Ki-67 in colon cancer is correlated with a lower risk of recurrence [6-8]. Although the Ki-67 antigen is the classic IHC marker for cell proliferation, Garrity et al. reported only a weak correlation in colon cancer between Ki-67 levels and S-phase (the standard measure of proliferation) [6]. Consequently, in colon cancer, expression of this gene may not actually signify rapidly dividing tumors, but rather represent part of an important cell cycle control mechanism. |
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| 1. |
Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL, Walker MG, Watson D, Park T, Hiller W, Fisher ER, Wickerham DL, Bryant J, Wolmark N: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N. Engl. J. Med 2004, 351:2817-2826. |
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| 2. |
Paik S, Tang G, Shak S, Kim C, Baker J, Kim W, Cronin M, Baehner FL, Watson D, Bryant J, Costantino JP, Geyer CE, Wickerham DL, Wolmark N: Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J. Clin. Oncol 2006, 24:3726-3734. |
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| 3. |
O'Connell M, Lavery I, Yothers G, Paik S, Clark-Langone KM, Lopatin M, Watson D, Baehner FL, Shak S, Baker J, Cowens J, Wolmark N: Relationship between tumor gene expression and recurrence in four independent studies of stage II/II colon cancer patients treated with surgery alone and surgery plus 5-FU/LV. J Clin Oncol 2010, 28:3937-3944. |
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| 4. |
Validation of a 12-gene colon cancer recurrence score (RS) in stage II colon cancer (CC) patients (pts) from CALGB 9581. A. P. Venook, D. Niedzwiecki, M. Lopatin, M. Lee, P. N. Friedman, W. Frankel, K. Clark-Langone, C. Yoshizawa, C. Millward, S. Shak, R. M. Goldberg, N. N. Mahmoud, R. L. Schilsky, M. M. Bertagnolli. American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago IL, 2011: Abstract # 77737. |
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| 5. |
Anjomshoaa A, Lin Y, Black MA, McCall JL, Humar B, Song S, Fukuzawa R, Yoon H, Holzmann B, Friederichs J, van Rij A, Thompson-Fawcett M, Reeve AE: Reduced expression of a gene proliferation signature is associated with enhanced malignancy in colon cancer. Br. J. Caner 2008, 99:966-973. |
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| 6. |
Garrity MM, Burgart LJ, Mahoney MR, Windschitl HE, Salim M, Wiesenfeld M, Krook JE, Michalak JC, Goldberg RM, O'Connell MJ, Furth AF, Sargent DJ, Murphy LM, Hill E, Riehle DL, Meyers CH, Witzig TE: Prognostic value of proliferation, apoptosis, defective DNA mismatch repair, and p53 overexpression in patients with resected Dukes' B2 or C colon cancer: a North Central Cancer Treatment Group Study. J. Clin. Oncol 2004, 22:1572-1582. |
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| 7. |
Salminen E, Palmu S, Vahlberg T, Roberts P, Söderström K: Increased proliferation activity measured by immunoreactive Ki67 is associated with survival improvement in rectal/recto sigmoid cancer. World J. Gastroenterol 2005, 11:3245-3249. |
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| 8. |
Allegra CJ, Paik S, Colangelo LH, Parr AL, Kirsch I, Kim G, Klein P, Johnston PG, Wolmark N, Wieand HS: Prognostic value of thymidylate synthase, Ki-67, and p53 in patients with Dukes' B and C colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project collaborative study. J. Clin. Oncol 2003, 21:241-250 . |
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| 9. |
Kops GJPL, Weaver BAA, Cleveland DW: On the road to cancer: aneuploidy and the mitotic checkpoint. Nat. Rev. Cancer 2005, 5:773-785. |
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| 10. |
Jen J, Kim H, Piantadosi S, Liu ZF, Levitt RC, Sistonen P, Kinzler KW, Vogelstein B, Hamilton SR: Allelic loss of chromosome 18q and prognosis in colorectal cancer. N. Engl. J. Med 1994, 331:213-221. |
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| 11. |
Choi S, Lee KJ, Bae Y, Min K, Kwon M, Kim K, Rhyu M: Genetic classification of colorectal cancer based on chromosomal loss and microsatellite instability predicts survival. Clin. Cancer Res 2002, 8:2311-2322. |
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| 12. |
Chang S, Lin J, Lin T, Liang W: Loss of heterozygosity: an independent prognostic factor of colorectal cancer. World J. Gastroenterol 2005, 11:778-784. |
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| 13. |
Sinicrope FA, Rego RL, Halling KC, Foster N, Sargent DJ, La Plant B, French AJ, Laurie JA, Goldberg RM, Thibodeau SN, Witzig TE: Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients. Gastroenterology 2006, 131:729-737. |
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| Intro to Patient Ambassador |
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| Hearing from a Patient Ambassador |
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| Dan’s Story, Dan C. |
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A sergeant in the police force and father of four, Dan always considered himself to be in good health. But in 2010 when he attempted to train for a local bike race, one that he had easily completed the year before, he found his energy levels weren't the same. After a series of tests his medical team discovered that Dan was bleeding internally. Dan will never forget what his doctor told him when he entered the exam room. He said, "This could be something as small as an ulcer or something very serious." Following this visit, his physician scheduled Dan to meet with the gastrointestinal doctor, but he believed it was most likely an ulcer, because otherwise Dan felt fine. After his endoscopy came back clear they set up a colonoscopy for the following day and this is when the doctor discovered cancer in Dan's ascending colon.
"Being diagnosed with colon cancer was an absolute kick in the stomach, but I was relieved to learn that the cancer had not spread to my liver." After an operation to remove Dan's tumor, his surgeon, Dr. Ian Lavery at the Cleveland Clinic described how the Oncotype DX colon cancer test could be used to determine his risk of recurrence, based on the underlying biology of his individual colon tumor. Dan was impressed that the Oncotype DX test could measure the aggressiveness of his individual disease and when his test result came back low, he and his physician had the confidence to decide to forgo chemotherapy. Dan's entire family was elated, and he was able to return to his life as a policeman, dad and husband. "Having cancer gave me a new perspective on life and I'm ready to live it to the fullest." |
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| About Genomic Health’s Ambassador Program |
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| How to get involved! |
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| Genomic Health is proud to work with a passionate group of volunteer patient “ambassadors”, to help spread the word about personalized colon cancer treatment & genomic tests. The ambassador program is set up to engage participants in various ways, and to meet the comfort level of each ambassador. From visiting with local colon cancer support groups to sharing their treatment stories with the media, there are many ways Genomic Health and their ambassadors work together to help educate newly diagnosed patients. Ambassadors are also invited to visit the Genomic Health campus, and tour the labs where the Oncotype DX test is run. If you have a patient who may be interested in participating in this program, please send an email to: advocacy@genomichealth.com. |
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| What’s to Come/Future Products |
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With the 12-gene Oncotype DX Colon Cancer Assay as the foundation of our Colon Cancer program, Genomic Health is committed to conducting further research to build on our understanding of the underlying biology in colon cancer. Together with our collaborators , Genomic Health is pursuing studies to characterize the impact of the Colon Cancer Assay on clinical practice and to evaluate the 12-gene Recurrence Score as a predictor of recurrence risk in new clinical settings. Based on data from the QUASAR and CALGB studies, which support a paradigm incorporating Recurrence Score, T stage, and MMR for recurrence risk assessment in stage II colon cancer, Genomic Health will begin providing MMR testing for recurrence risk assessment as part of the Oncotype DX service in late 2011. Our next major development effort is focused on the identification of molecular markers predictive of sensitivity and resistance to oxaliplatin given in the adjuvant setting for stage II and stage III colon cancer. Although oxaliplatin is likely to benefit only a small minority of patients, oxaliplatin is widely used in practice, and many patients face the risk of toxicity, including the potential for debilitating, long-term neuropathy. The development and validation of a genomic assay which identifies patients most likely to benefit from the addition of oxaliplatin to fluoropyrimidine-based adjuvant chemotherapy would significantly improve the quality of care for colon cancer patients.
This newsletter contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including the Company’s planned launch of testing for mismatch repair status; the ability of the company to develop additional tests in the future; the ability of any tests the company may develop to optimize cancer treatment and the scope, success or results of clinical trials and the timing of such activities. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially. These risks and uncertainties include, but are not limited to: the risks and uncertainties associated with possible additional regulation of our tests; the applicability of clinical study results to actual outcomes; the risks and potential delays associated with such studies; and the other risks set forth in the company's filings with the Securities and Exchange Commission, including the risks set forth in the company's Quarterly Report on Form 10-Q for the quarter ended June 30, 2011.
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| An Interview with Dr. Sullivan |
| Dr. James Sullivan, a colorectal surgeon at St. Francis Hospital in Great Neck, New York, recently sat down with Genomic Health to talk about his experiences with the Oncotype DX Colon Cancer Assay. |
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| Why do you order the Oncotype DX Colon Cancer Assay? |
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| Since we are seeing a rise in stage II colon cancer patients as a result of improved screening over the past 10 years, it becomes increasingly important to make sure that we are treating the right patients. I have witnessed firsthand the overtreatment that has been happening for years for stage II colon cancer patients. Fortunately, we are now in an era where we don’t have to treat the many to benefit the few. With a test like the Oncotype DX Colon Cancer Assay, I can be more confident that I am personalizing treatment recommendations for my stage II colon cancer patients. This gives both me and my patients a peace of mind that we didn’t have before this test. The test gives the patient something objective to put their finger on, and it really helps them make their decision. Without it, we are guessing at the right treatment. Since I follow my patients for years, I am often struck by the extent of chemotherapy induced neuropathies that I see in my clinic and this toxicity should not be discounted as a minor issue. Oncotype helps better weigh the benefit and risks of chemotherapy for these patients. |
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| Who should be ordering the Oncotype DX Colon Cancer Assay? |
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| If the surgeon is in the business of treating cancer, then it should be the surgeon who orders the test. In doing so, it expedites the whole process and is ultimately the best thing for the patient. I order the test for all my stage II colon cancer patients who are T3, N0 and MMR-Proficient. I bring it up at tumor boards if we are discussing an appropriate patient who hasn’t had an Oncotype test. I explain that this is a validated test that helps stratify risk better than the markers we currently have. |
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| Does your institution routinely order MMR? |
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| Yes, we routinely order MMR on our stage II colon cancer patients as a prognostic tool. There definitely seems to be a lot of misunderstanding in the community. It is so important to understand the differences between MMR-Proficient and MMR-Deficient due to the implications for the patient. Regarding ordering MMR, I understand that Genomic Health will be offering MMR testing by the end of this year which will streamline the ordering process for both MMR and Oncotype. |
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