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Gene Profiling in Clinical Oncology - Slide 6 - A. Sobrero - Is T4, fewer than 12 lymph nodes and absence of MMR-D the standard to decide adjuvant chemotherapy in Stage II CRC?
 

Gene Profiling in Clinical Oncology - Slide 6 - A. Sobrero - Is T4, fewer than 12 lymph nodes and absence of MMR-D the standard to decide adjuvant chemotherapy in Stage II CRC?

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  • A defective DNA mismatch repair (MMR) mechanism is a key biologic characteristic of ~15% of stage II colon cancer patients. This biological characteristic, also called MMR deficiency, represents one of two distinct mechanisms for producing colon tumors, with the other mechanism being chromosomal instability – both mechanisms lead to accumulation of genetic changes in tumors which ultimately drive tumor formation. In normal cells, the presence of a multi-protein “machine” (panel at left) allows for repair of routinely encountered errors in DNA replication. This machine ceases to function if any of its components (e.g. MLH1, MSH2 or the other proteins depicted) is missing. Loss of expression of MMR proteins in tumor, especially MLH1 and MSH2 (accounting for >95% of patients with this characteristic), results in an inability to faithfully replicate DNA, which in turn leads to accumulation of mutations which drive tumorigenesis. One readily detectable manifestation of tumor MMR deficiency is an inability to faithfully replicate microsatellite DNA sequences (short stretches of repetitive sequence DNA found throughout the genome), such that the length of these microsatellites in tumor DNA is not faithfully preserved. Differences in the lengths of microsatellite DNA sequences observed in MMR deficient tumors relative to normal tissue has thus been termed microsatellite instability (MSI). Colon tumors with MMR deficiency can be identified either by (1) IHC for the MMR proteins (top right panel) – MMR proficient = both MLH1 and MSH2 staining positive and MMR deficient = either MLH1 or MSH2 staining negative, or (2) PCR assessment of DNA markers for MSI, where high-grade MSI (MSI-H) demonstrates lack of faithful replication of DNA in tumor relative to normal tissue. In tumors exhibiting the MSI-H phenotype (bottom right panel), tumor DNA is of different lengths compared to normal tissue. MMR deficiency (MMR-D) directly results in the MSI-H phenotype. Thus, MMR-D is considered synonymous with MSI-H. It is worth noting that concordance studies of MMR status assessment by IHC for MMR proteins vs PCR for MSI have shown that the two methods have >90% concordance overall. A very recent study by CALGB, involving ~700 colon cancer patients from CALGB 89803, rigorously demonstrated that IHC for MLH1 and MSH2 had >97% concordance with PCR for MSI (using a 10 marker panel) (Bertagnolli et al JCO 2009). References: Bertagnolli MM, Niedzwiecki D, Compton CC, et al: Microsatellite Instability Predicts Improved Response to Adjuvant Therapy with Irinotecan, Fluorouracil, and Leucovorin in Stage III Colon Cancer: Cancer and Leukemia Group B Protocol 89803. J Clin Oncol . 2009; 27:1814-1821. Imai and Yamamoto. Carcinogenesis 2008 Umetani, Annals of Surgical Oncology 2000 Rosen et al. Modern Pathology (2006) 19, 1414-1420
  • Can genomic and molecular markers stratify colon cancer patients by prognosis and predict response to therapy? The pooled dataset provides in total 1027 patients from 6 clinical trials. Again, approximately 50% of the patients are stage II, and the overall proportion of patients with dMMR tumors is 16%.
  • On this slide, survival curves are shown for MMR-D vs MMR-P patients from a combined set of stage II and stage III colon cancer patients who received surgery without adjuvant chemotherapy. Clinical relevance of the MMR/MSI biology: multiple series, including the depicted data from Ribic et al NEJM 2003, demonstrated that patients with MMR-D or MSI-H have significantly better outcome, particularly for stage II colon cancer. There has been remarkable consistency in the literature on this point. A recent PETACC-3 analysis of MMR/MSI in a large dataset of stage II and stage III colon cancer has also reported a markedly improved outcome for stage II colon cancer patients with MMR-D tumors. MMR/MSI is not yet standardized in clinical practice, and its use for adjuvant treatment decision making is not yet specified by guidelines. References: Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N. Engl. J. Med . 2003;349(3):247-257. Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J. Clin. Oncol . 2005;23(3):609-618. Lanza G, Gafà R, Santini A, et al. Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients. J. Clin. Oncol . 2006;24(15):2359-2367. Kim GP, Colangelo LH, Wieand HS, et al. Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study. J. Clin. Oncol . 2007;25(7):767-772. Sargent DJ, Marsoni S, Thibodeau SN, et al. Confirmation of deficient mismatch repair (dMMR) as a predictive marker for lack of benefit from 5-FU based chemotherapy in stage II and III colon cancer (CC): A pooled molecular reanalysis of randomized chemotherapy trials. J Clin Oncol (Meeting Abstracts) . 2008;26(15_suppl):4008. Roth A 2009 ASCO Abstract # Tejpar S 2009 ASCO Abstract #
  • Can genomic and molecular markers stratify colon cancer patients by prognosis and predict response to therapy? First, looking the prognostic ability of MMR status, we see that in the 512 treated patients, there is no difference in outcomes between patients with proficient versus deficient MMR. However, in the 515 untreated patients, MMR status is a clear prognostic factor, with the 5 year disease free survival increasing from 56% in patients with pMMR tumors to 80% in patients with dMMR tumors, p = 0.009, with a hazard ratio of 0.51.
  • Figure 2. Kaplan-Meier Estimates of Overall Survival among Patients with Stage II or Stage III Colon Cancer According to Treatment Status. Patients with tumors exhibiting microsatellite stability or low-frequency microsatellite instability who received adjuvant chemotherapy had a significant increase in overall survival as compared with patients who received no adjuvant chemotherapy (hazard ratio for death, 0.69 [95 percent confidence interval, 0.50 to 0.94]; P=0.02) (Panel A). Among patients with tumors exhibiting high-frequency microsatellite instability, there was no significant difference in the duration of overall survival between patients who received adjuvant chemotherapy and those who did not (hazard ratio for death, 2.17 [95 percent confidence interval, 0.84 to 5.55]; P=0.10) (Panel B). The analysis included data for eight years from the date of randomization.
  • Based on this data, we feel that in a patient being considered for 5-FU based therapy (predominately stage II patients), MMR status should be tested by either MSI or IHC to determine whom not to treat, with treatment not offered for patients with dMMR tumors based on their favorable prognosis in the absence of chemotherapy, and their lack of benefit from 5-FU based chemotherapy.
  • Based on this data, we feel that in a patient being considered for 5-FU based therapy (predominately stage II patients), MMR status should be tested by either MSI or IHC to determine whom not to treat, with treatment not offered for patients with dMMR tumors based on their favorable prognosis in the absence of chemotherapy, and their lack of benefit from 5-FU based chemotherapy.
  • Based on this data, we feel that in a patient being considered for 5-FU based therapy (predominately stage II patients), MMR status should be tested by either MSI or IHC to determine whom not to treat, with treatment not offered for patients with dMMR tumors based on their favorable prognosis in the absence of chemotherapy, and their lack of benefit from 5-FU based chemotherapy.
  • How are stage II colon cancer patients being assessed for their recurrence risk today? There are a limited set of clinical and pathologic markers that are in current practice and recommended by guidelines: obstruction or perforation, T stage, the number of nodes examined, tumor grade, lymphatic vascular invasion, and margin status. Conspicuously, on the right-hand side, with respect to markers that predict treatment benefit, there are none. According to the current guidelines, it’s quite striking that unlike in breast cancer where we’ve had decades of use of molecular markers (e.g. ER, PR, HER2) to guide treatment decisions, there are no molecular markers that are established for stage II colon cancer. There are no markers in stage II colon cancer that identify patients specifically with very high or very low proportional risk reduction with chemotherapy. These are limitations to the system that we have today.
  • Based on this data, we feel that in a patient being considered for 5-FU based therapy (predominately stage II patients), MMR status should be tested by either MSI or IHC to determine whom not to treat, with treatment not offered for patients with dMMR tumors based on their favorable prognosis in the absence of chemotherapy, and their lack of benefit from 5-FU based chemotherapy.
  • How are stage II colon cancer patients being assessed for their recurrence risk today? There are a limited set of clinical and pathologic markers that are in current practice and recommended by guidelines: obstruction or perforation, T stage, the number of nodes examined, tumor grade, lymphatic vascular invasion, and margin status. Conspicuously, on the right-hand side, with respect to markers that predict treatment benefit, there are none. According to the current guidelines, it’s quite striking that unlike in breast cancer where we’ve had decades of use of molecular markers (e.g. ER, PR, HER2) to guide treatment decisions, there are no molecular markers that are established for stage II colon cancer. There are no markers in stage II colon cancer that identify patients specifically with very high or very low proportional risk reduction with chemotherapy. These are limitations to the system that we have today.

Gene Profiling in Clinical Oncology - Slide 6 - A. Sobrero - Is T4, fewer than 12 lymph nodes and absence of MMR-D the standard to decide adjuvant chemotherapy in Stage II CRC? Gene Profiling in Clinical Oncology - Slide 6 - A. Sobrero - Is T4, fewer than 12 lymph nodes and absence of MMR-D the standard to decide adjuvant chemotherapy in Stage II CRC? Presentation Transcript

  • Is T4 ,fewer than 12 lymph nodes and absence of MMR-D the standard to decide adjuvant chemotherapy in Stage II CRC? Alberto Sobrero Ospedale San Martino Genova
  • Colon Cancer: adjuvant STAGE II III Fluoropyrimidine Folfox - FLOX HIGH RISK LOW RISK Fluoropyrimidine No Rx Folfox - FLOX + 3-4 % + 10-11% + 10-15% + 17-22%
  • ACCENT pooled analysis: benefit of adjuvant therapy in stage II colon cancer Sargent, D. et al. J Clin Oncol; 2009 N = ~7000 5% benefit at 8 years
  • Efficacy of adjuvant chemotherapy in stage II colon cancer: 5-year RFS
    • Trials Study Patients Risk Reduction p value Absolute gain
    • 1 Mayo 318 31% NO 8%
    • 5 IMPACT 1016 17% NO 3%
    • 1 CKVO 468 26%* NA 8%
    • 3 Japan 2295 22% NO 5%
    • 7 Pooled 1440 17% YES 4%
    • 1 Quasar 3238 22% YES 4%
  • Mosaic: 5-YR DFS
    • Stage HR Δ
    • III .78 .005 7.5%
    • II high risk .74 ns 7.2%
    • II and III .80 .003 5.9%
    • II .84 ns 3.8%
  • A Common Assumption
    • The risk reduction associated with adjuvant therapy is consistent across the spectrum of risk
    Risk Relapse No Rx Adj Rx
  • Mismatch Repair Deficiency (MMR-D): Unique Biological Subgroup of Colon Cancer Imai and Yamamoto. Carcinogenesis 2008 Umetani, Annals of Surgical Oncology 2000 Rosen et al. Modern Pathology (2006) 19, 1414-1420 PCR on tumor DNA for MSI (microsatellite instability) IHC for MMR protein status MLH1+ MSH2+ MLH1- MSH2-
    • Thus, IHC for MMR proteins and PCR for MSI detect two manifestations of the same tumor biology:
    • MMR-D is synonymous with MSI-H
    • MMR-P is synonymous with MSI-L/MSS
  • Pooled data (N=1027) Trial Treatment N % Stage II % dMMR 784852 5FU/LEV 117 30% 14% INT 0035 5FU/LEV 215 50% 18% 874651 5FU/LV 66 19% 12% GIVIO 5FU/LV 183 52% 16% FFCD 5FU/LV 154 66% 19% NCIC 5FU/LV 292 61% 15% Total 1027 52% 16%
  • MMR-D Identifies Resected Colon Cancer Patients With Low Recurrence Risk Ribic, NEJM, 2003
    • Multiple studies have consistently demonstrated that the ~15% patients with MMR-D have markedly lower recurrence risk than the average stage II colon cancer patient
    • MMR not yet a standardized marker in clinical practice
    No adjuvant chemotherapy n=287 MMR-D MMR-P
  • DFS by MMR status, stage II Untreated (N=515) HR: 0.51 (0.29-0.89) p=0.009 dMMR 80% pMMR 56% 5 yr DFS
  • Ribic C et al. N Engl J Med 2003;349:247-257 Overall Survival Stage II MMR-D pts According to Treatment Status
  • Sargent 2008 DFS in MMR-D patients HR: 2.80 (0.98-8.97) p=0.05 Stage II (N=102) Untreated 87% Treated 72% 5 yr DFS
  • Take Home Message
    • MMR prognostic for stage II: MMR-D = good
    • dMMR predict for detrimental effect of FU stage II
    • When considering a Stage II patient for 5-FU-based therapy, MMR should be used to determine whom not to treat
  • Predicted % 5-Year DFS Estimates by T stage ( N= 2657 T3 ; 201 T4) T3 73 77 65 70 T4 60 66 51 57 Low grade high grade control CT control CT
  • Predicted % 5-Year OS Estimates by T stage ( N= 2657 T3 ; 201 T4) T3 83 85 78 81 T4 76 79 69 72 Low grade high grade control CT control CT
  • Take Home Message
    • T4 means 12 to 15 % higher chances of relapse
    • Prognostic effect independent from treatment and grade
  • THE LYMPH NODE WORLD OF THE SURGEON & PATHOLOGIST
    • Surgeon “ What do you mean there were only 4 l.-nodes in the rectal cancer specimen?”
    • Pathologist “ That is all I could find “
    • Surgeon “Perhaps you ought to look harder “
    • Pathologist “Perhaps you ought to work harder at surgery”
  • Node evaluation and survival N= 61371 in 17 studies INT 0089 N =3411 (5yr data on 648 stage II)
    • N OS CSS DFS
    • <11 73 80 72
    • 11-20 80 85 79
    • >20 87 92 83
    Chang JNCI 2007
  • RATIO OF METASTATIC /EXAMINED LYMPH NODES Colon Cancer Berger , J Clin Oncol,2005 Gastric Cancer Inoue , Ann Surg Oncol, 2002 Pancreatic Cancer Slidell, SEER database Rectal Cancer Meyers JCO 2007
  • DFS according to LNR ( N= 3411) INT 0089 Berger JCO 2005
  • Take Home Message
    • Inadequate node dissection / recovery ( <11) means 10% fewer chances of relapsing compared to optimal conditions ( > 20)
    • Ratio equally important
  • Recurrence Risk & Treatment Benefit Markers Currently Used for Stage II Colon Cancer
    • Recurrence Risk
    • Bowel obstruction or perforation
    • T-Stage
    • # of nodes assessed
    • Tumor grade
    • Lymphatic/vascular invasion
    • Margin status
    • Treatment Benefit
    • None
    * NCCN Clinical Practice Guidelines for Oncology: Colon Cancer v3.2009 ASCO Recommendations on Adjuvant Chemotherapy for Stage II Colon Cancer, JCO, 2004 .
    • According to current guidelines*:
    • Unlike in breast cancer, there are no molecular markers established in clinical practice for stage II colon cancer
    • No markers in stage II colon cancer identify patients with disproportionately high or low benefit from chemotherapy
  • Predicted % 5-Year DFS Estimates by T stage ( N= 2657 T3 ; 201 T4) T3 73 77 65 70 T4 60 66 51 57 Low grade high grade control CT control CT
  • Predicted % 5-Year OS Estimates by T stage ( N= 2657 T3 ; 201 T4) T3 83 85 78 81 T4 76 79 69 72 Low grade high grade control CT control CT
  • Take Home Message
    • G3 means 8-9 % higher chances of relapse
  • Proposed Stage II Algorithm Today MMR Clinical Risk No Adjuvant Deficient Intact Not High High No Adjuvant Or Adjuvant Adjuvant *all decisions require discussion with patient
  • Proposed Stage II Algorithm Soon MMR Clinical & Molecular Risk No Adjuvant Deficient Intact Very small benefit from adjuvant therapy ?<3% No Adjuvant Or Adjuvant No Adjuvant *all decisions require discussion with patient More than very small benefit from adjuvant therapy ?3+%
  • CONCLUSIONS Is T4 ,fewer than 12 lymph nodes and absence of MMR-D the standard to decide adjuvant chemotherapy in Stage II CRC? NO
  • Recurrence Risk & Treatment Benefit Markers Currently Used for Stage II Colon Cancer
    • Recurrence Risk
    • Bowel obstruction or perforation
    • T-Stage
    • # of nodes assessed
    • Tumor grade
    • Lymphatic/vascular invasion
    • Margin status
    • Treatment Benefit
    • None
    * NCCN Clinical Practice Guidelines for Oncology: Colon Cancer v3.2009 ASCO Recommendations on Adjuvant Chemotherapy for Stage II Colon Cancer, JCO, 2004 .
    • According to current guidelines*:
    • Unlike in breast cancer, there are no molecular markers established in clinical practice for stage II colon cancer
    • No markers in stage II colon cancer identify patients with disproportionately high or low benefit from chemotherapy