Stage II Colon Cancer

1. Stage II Colon Cancer Parvin F. Peddi February 24, 2012

2. 20% of colon cancers have no evidence of lymph node metastasis at time of surgery but are advanced locally. About 20% of these patients recur in 5 yrs Can we identify the 20%? Can we overcome their poor prognosis with adjuvant chemotherapy? The Problem

3. Staging Evidence for/against adjuvant therapy 5-FU Oxaliplatin High risk group by clinicopathologic data NCCN guidelines Molecular testing Microsatellite instability Oncotype Dx GCC testing Outline

4. Dukes� Classification

5. Dukes� Classification

6. Stage II IIA: T3N0 -> 5 yr survival 85% IIB: T4N0 -> 5 yr survival 72% TNM Staging

7. 1990: 5-FU based adjuvant therapy reduced overall death rate by 33% over placebo in Dukes� C patients. 2004: MOSAIC Trial FL vs FL + Oxaliplatin Cancer related events 21.1% vs 26.1% (P=0.002) DFS at three years 78.2% vs 72.9% (P=0.002) Stage III 1990 study: 296 patients with stage C or B. Results for stage B patients were equivocal. Initially 1 yr of therapy then 6 months shown to be as good. MOSAIC: European study. 2246 patients. 1990 study: 296 patients with stage C or B. Results for stage B patients were equivocal. Initially 1 yr of therapy then 6 months shown to be as good. MOSAIC: European study. 2246 patients.

8. 5-FU/Leucovorin vs observation post surgery QUASAR study: Quick and Simple and Reliable 3239 patients; Stage II colon or rectal cancer Relative risk of recurrence: 0�78 (95% CI 0�66�0�93; p=0�004) OS benefit: borderline significance Wilkinson study: Meta-analysis of 5 NSABP trials; ~ 3000 patients with stage II or III 5 yr OS for stage II improved with chemotherapy (HR = 0.58, 95% CI = 0.48�0.71) How about stage II? The relative risk of recurrence with chemotherapy compared with observation alone in patients with stage II cancer was 0�78 (95% CI 0�66�0�93; p=0�004) Did include rectal cancer The relative risk of recurrence with chemotherapy compared with observation alone in patients with stage II cancer was 0�78 (95% CI 0�66�0�93; p=0�004) Did include rectal cancer

9. 5-FU/Leucovorin vs observation post surgery IMPACT: Pooled analysis of 3 trials; 1526 patients with Dukes� B or C Significant OS benefit in Dukes� C patients but not B IMPACT B2: Pooled analysis of 5 trials; 1016 patients with Dukes� B2 Trend toward EFS benefit (76% vs 73%) and OS (82% vs 80%) but not significant. Mayo clinic study: Pooled analysis of 7 trials; 3302 patients with stage II or III 5 yr DFS improved in node negative patients (72 vs 76%; P=0.049) but no benefit in OS. And The Negative Trials�. Mayo clinic online calculator, does not have an option for negative lymph nodes. Mayo clinic online calculator, does not have an option for negative lymph nodes.

10. MOSAIC stage II subset: ~ 60% stage III, 40% stage II How about adding oxaliplatin?

11. Exploratory analysis: T4, perforation, bowel obstruction, poorly differentiated tumor, venous invasion, or less than 10 lymph nodes examined. DFS at 5yr: 82.3% vs 74.6% (HR 0.72, 95% CI 0.5-1.02) OS at 6 yr: 85.0% vs 83.3% (HR 0.91, 95% CI 0.61-1.36; P 0.648) High risk group?

12. Consider adjuvant chemotherapy for: T4 tumors Grade 3 or 4 pathology Lymphovascular invasion Perineural invasion Bowel obstruction Perforation Close or positive margins Fewer than 12 lymph nodes sampled NCCN

13. Data from National Cancer Data Base (NCDB) 35,787 patients with T3N0 colon cancer reviewed 5 yr OS significantly different based on number of LNs examined. Where did 12 come from? 49.8% for 1 to 7 lymph nodes, 56.2% for 8 to 12 lymph nodes, and 63.4% for 13 lymph nodes (P .0001). Only 7% got chemotherapy. 49.8% for 1 to 7 lymph nodes, 56.2% for 8 to 12 lymph nodes, and 63.4% for 13 lymph nodes (P .0001). Only 7% got chemotherapy.

14. Any studies confirming poor prognosis with characteristics outlined in NCCN guidelines? Does poor prognosis translate to benefit from chemotherapy? Questions:

15. Retrospective study of 43,032 Medicare beneficiaries who had: Primary colon cancer dx from 1992 to 2005 Underwent colectomy for stage II or III disease 24,847 patients with stage II cancer, 75% had one or more poor prognostic features (per NCCN guidelines) Adjuvant chemotherapy received by 20% of patients with stage II disease and 57% of patients with stage III disease Poor prognostic features identified from Medicare data included diagnosis in the setting of intestinal obstruction or perforation, emergent admission for surgery, T4 stage, poor/undifferentiated histology, and fewer than 12 lymph nodes examined.12,14,16,17 Other reported poor prognostic features (preoperative CEA level and peritumoral lymphatic/venous invasion) were not available in the SEER-Medicare data set.Poor prognostic features identified from Medicare data included diagnosis in the setting of intestinal obstruction or perforation, emergent admission for surgery, T4 stage, poor/undifferentiated histology, and fewer than 12 lymph nodes examined.12,14,16,17 Other reported poor prognostic features (preoperative CEA level and peritumoral lymphatic/venous invasion) were not available in the SEER-Medicare data set.

16. Overall Survival

17. Predictive of Response?

18. Predictive of Response?

19. Predictive of Response?

20. Large but retrospective study Age > 65 (but more real world: average age at dx 70) Involved time period before use of oxaliplatin. Interesting that did show benefit in stage III patients. So it doesn�t really work? Poor prognostic features did separate a group with poor prognosis but did not show benefit with chemotherapy. Poor prognostic features did separate a group with poor prognosis but did not show benefit with chemotherapy.

21. Microsatellite instability Oncotype Dx GCC testing Molecular Testing

22. Microsatellite instability Oncotype Dx GCC testing Molecular Testing

23. Microsatellite Instability Can get short of long CA is the most common repeat. Can get short of long CA is the most common repeat.

24. Germline or somatic mutations in DNA mismatch repair genes Germline: Lynch syndrome (2-4% of colon cancers) Somatic: 15% of colorectal tumors High microsatellite instability: Sign of good prognosis. Microsatellite Instability

25. Pooled data from 5 phase III randomized trials of adjuvant 5-FU vs observation More than 50% were Stage II

26. 16% had high microsatellite instability (instability in >30% of loci screened) Population with MSI-H, MSI-L or stable were similar in Stage distribution Age Sex Patient Population

27. Results Regardless of stageRegardless of stage

28. Microsatellite stable/low instability tumors benefit from adjuvant chemotherapy. Caveat: Stage II and III combined in analysis. Another retrospective study confirmed benefit from 5-FU in microsatellite stable tumors. In patients with stage II disease and with dMMR tumors, treatment was associated with reduced overall survival (HR, 2.95; 95% CI, 1.02 to 8.54;P�= .04). However, several negative studies. Re-analysis of patients from QUASAR study showed prognostic but no predictive value in MSI testing. NCCN recommendation: Consider testing for patients with stage II for whom you are planning adjuvant therapy with 5-FU alone. What does this mean?

29. Microsatellite instability Oncotype Dx GCC testing Molecular Testing

30. 12 gene panel (7 cancer-related genes and 5 reference genes) Developed from pool of four studies (1851 patients) Validated in setting of QUASAR study patients RS high-risk group were more likely than those in the low-risk group to have stage T4 disease (20% [ie, 81 of 400] v 14% [ie, 86 of 601]; P = .014), to be MMR deficient (15% [ie, 52 of 336] v 11% [ie, 62 of 569]; P = .034), to have right-sided tumors (41% [ie, 166 of 403] v 33% [ie, 199 of 606]; P = .007), and to have high-grade tumors (44% [ie, 178 of 403] v 23% [ie, 137 of 606]; P < .001). Recurrence risk genes: BGN, FAP, INHBA, Ki-67, C-MYC, MYBL2, and GADD45B Reference genes: ATP5E, GPX1, PGK1, UBB, and VDAC2 Treatment related genes: EFNB2, BIK, MAD2L1, RUNX1, AXIN2, and HSPE1RS high-risk group were more likely than those in the low-risk group to have stage T4 disease (20% [ie, 81 of 400] v 14% [ie, 86 of 601]; P = .014), to be MMR deficient (15% [ie, 52 of 336] v 11% [ie, 62 of 569]; P = .034), to have right-sided tumors (41% [ie, 166 of 403] v 33% [ie, 199 of 606]; P = .007), and to have high-grade tumors (44% [ie, 178 of 403] v 23% [ie, 137 of 606]; P < .001). Recurrence risk genes: BGN, FAP, INHBA, Ki-67, C-MYC, MYBL2, and GADD45B Reference genes: ATP5E, GPX1, PGK1, UBB, and VDAC2 Treatment related genes: EFNB2, BIK, MAD2L1, RUNX1, AXIN2, and HSPE1

31. But Dr. Tan doesn�t order this! A separate treatment score failed to predict response from treatment. Another DNA microarray assay (634 probe) also identified high risk patients in same JCO issue. ColoPrint developed in the Netherlands, uses an 18 gene set to also predict high vs low recurrence risk patients. Requires fresh frozen samples. Both published December of 2011. Both published December of 2011.

32. Microsatellite instability Oncotype Dx GCC testing Molecular Testing

33. Guanylyl cyclase C Also called GUCY2C Brush border membrane protein, present from the duodenum down to rectum Receptor for the paracrine hormones guanylin and uroguanylin � involved in chloride/water secretion GCC �Enterotoxigenic�Escherichia coli� also binds to GCC�Enterotoxigenic�Escherichia coli� also binds to GCC

34. Preserved expression after malignant transformation in colon cancer. => Tissue-specific protein useful for identifying metastatic colorectal cancer cells in extraintestinal tissues. Preserved expression after malignant transformation in colon cancer. => Tissue-specific protein useful for identifying metastatic colorectal cancer cells in extraintestinal tissues.

35. Expression retained in tubular adenomas Primary and metastatic adenocarcinomas of the colon Metastatic disease in lymph nodes and liver Peripheral blood of patients with Dukes� C and D GCC-specific amplification products with specimens from normal intestine and primary and metastatic colorectal tumors, but not from extraintestinal tissues or tumors. PCR of GCC detected tumor cells in blood from some patients with Dukes B colorectal cancer and all patients examined with Dukes C and D colorectal cancer, but not in that from normal subjects or patients with Dukes A colon carcinoma or other nonmalignant intestinal pathologies. Confirmation of detection in Duke class C and not Class A. In some people in Class B. GCC-specific amplification products with specimens from normal intestine and primary and metastatic colorectal tumors, but not from extraintestinal tissues or tumors. PCR of GCC detected tumor cells in blood from some patients with Dukes B colorectal cancer and all patients examined with Dukes C and D colorectal cancer, but not in that from normal subjects or patients with Dukes A colon carcinoma or other nonmalignant intestinal pathologies. Confirmation of detection in Duke class C and not Class A. In some people in Class B.

36. Prospective study of 257 patients with pN0 colon or rectal cancer. 87 patient with stage III enrolled for comparison. Chemotherapy at discretion of oncologist Adjuvant 5-FU based chemotherapy was received by 22.2% of patients with stage II. Patients followed for median of 24 months Can it detect occult LN met? Adjuvant 5-fluorouracil�based chemotherapy, delivered at the discretion of treating physicians, was received by 22.2% of patients with pN0 colorectal Cancer. Similar percentage in Mol + and � patients. Adjuvant 5-fluorouracil�based chemotherapy, delivered at the discretion of treating physicians, was received by 22.2% of patients with pN0 colorectal Cancer. Similar percentage in Mol + and � patients.

37. GCC expression detected in 87.5% of patients. Can it detect occult LN met?

38. T, grade, number of lymph nodes examined, did not matter T, grade, number of lymph nodes examined, did not matter

39. Stage II patients who had not received adjuvant therapy Patients separated into high and low risk based on GCC positive lymph node/total ratio: High risk: LNR >0.1 Low risk: LNR 0-0.1 Can the results be replicated? Multi-instituitional, presented at GI ASCO then published last year Multi-instituitional, presented at GI ASCO then published last year

41. Developed in 2008 by DiagnoCure, now in partnership with Signal Genetics Patented worldwide

42. �Poor prognostic� characteristics in current guidelines have not been reproducible in predicting response to chemotherapy. High microsatellite instability does identify a low risk group patient. -> can use to exclude patients from chemotherapy. Oncotype Dx may be prognostic but does not help in directing care. -> no current use GCC testing needs predictive data but has potential. -> ? Future use In conclusion�