1. Time-dependent patterns of treatment effect and failure as an explanation for the predictive role of deficient mismatch repair (dMMR) in stage II and III colon cancer
GP Kim, S Marsoni, G Monges, SN Thibodeau, R Labianca, SR Hamilton, B Kabat, F Sinicrope, S Gallinger, DJ Sargent

2. Background Adjuvant 5FU based therapy provides survival benefit
Examination of time-dependent patterns of treatment effect details…
Nature and duration of treatment benefit on overall survival (OS), disease free survival (DFS)
Long term recurrence rates

3. Hazard Rates for OS and DFS Sargent et al. JCO 2009
Overall Survival
Disease-Free Survival
Surgery Alone Arms
Surgery Alone Arms
0.0006
0.0006
5-FU Based Rx Arms
5-FU Based Rx Arms
0.0004
0.0004
Hazard Rate
Hazard Rate
For example, Sargent and colleagues using the ACCENT database consisting of over 3,300 stage II and III patients reported that in terms of OS in patients receiving surgery alone, the peak of events occurs at year 2 and diminishes thereafter.
Adjuvant therapy provides a consistent benefit with a constant difference between survival curves in patients with 5FU treatment or surgery alone being observed.
In terms of DFS, surgery alone patients have a high risk of DFS event early on that diminishes with time and in 5FU treated patients a dramatic reduction in DFS risk in the first 2 years that results in the later portion of the curves from the two groups being similar.
0.0002
0.0002
0.0
0.0 2 4 6 8 2 4 6 8
Follow-up Time (Years)
Follow-up Time (Years)

4. Application of time-dependent pattern analyses
Time-dependent patterns may also help understand why certain patient subsets have different clinical outcomes with adjuvant therapy
For example with deficient mismatch repair (dMMR) patients who have a confirmed lack of benefit from 5FU based treatment

5. Sargent et al. dMMR analysis ASCO 2008
Pooled patients from randomized trials of 5-FU based treatment vs. control, not used in previous Ribic analysis
No suggestion of benefit from 5-FU based treatment in dMMR patients
Significant OS decrement to 5-FU based treatment in stage II patients
Validated dMMR as a favorable prognostic marker
New tissue and clinical data from an additional 491 patients from 5 clinical trials conducted in the US and Europe was collected and pooled.
The treatment regimens were either bolus 5-FU and levamisole or leucovorin.

6. Pooled data (N=1027) Total 1027 Trial Treatment N Stage II dMMR 784852
5FU/LEV
117
30%
14%
INT 0035
215
50%
18%
874651
5FU/LV 66
19%
12%
GIVIO
183
52%
16%
FFCD
154
66%
NCIC
292
61%
15%
Total
1027
This is the pooled dataset of 1027 patients from 6 clinical trials.

7. DFS in dMMR patients Pooled data
Stage II (N=102)
Stage III (N=63)
And to review, in terms of DFS, in stage II patients with dMMR tumors, there was a strong trend toward worsened disease free survival with treatment compared to control, with a p-value of 0.05 and a hazard ratio of 2.8.
No benefit from treatment was observed in these patients with stage III disease, with the survival curves essentially overlapping and a p-value of 0.86.

8. Overall Survival by Treatment, stage II dMMR patients
P-value = for treatment
by MMR status interaction
With overall survival, in stage II patients with dMMR tumors, there was a statistically significant decreased OS in patients who were treated, compared to control, with a p-value of 0.03 and a hazard ratio of 3.1.
In addition there is a significant treatment by dMMR status interaction, indicating that the impact of treatment differed for patients with dMMR versus pMMR patients, with a p-value of
5 yr OS
Untreated %
Treated %
HR: 3.15 ( )
p=0.03

9. Application of time-dependent pattern analyses
How can time-dependent patterns help understand these dMMR observations?

10. Hazard Rates for OS and DFS Surgery Alone by MMR status
Disease-Free Survival
Overall Survival
dMMR patients consistently at
lower risk of recurrence
Well, first when we evaluate the OS curves for patients treated with surgery alone, in the pMMR patients, we see similar findings as with the ACCENT data- a peak of events around two years and a subsequent plateau.
In contrast, in the dMMR patients, we see no peak of events at 2 years and observe a consistent declining risk over the entire study period
There is a consistent separation between the two survival curves
With DFS, we have similar findings with a peak of events around two years for pMMR patients and a consistent reduced risk for dMMR individuals

11. Hazard Rates for OS and DFS 5-FU Treated by MMR status
Disease-Free Survival
Overall Survival
No difference between
dMMR and pMMR treated patients
When we look at the time patterns in the context of 5FU based adjuvant treatment, in the dMMR patients, we again see a downward trend consistent with reduced risk over time.
In the pMMR, the patterns is also similar to results seen with the ACCENT analysis with a decrease of events after a 2 year peak. Arguably when comparing the surgery alone vs. 5FU treated curves in the last two slides, a decrease in DFS event risk is seen in the 5FU treated patients (not visible)

12. Hazard Rates for OS and DFS dMMR Patients by Treatment
Overall Survival
Disease-Free Survival
Treated dMMR pts at increased recurrence risk for approximately 4 years
If we look at this from the perspective of dMMR status, with OS, we see that the surgery alone pattern remains favorable relative to the 5FU treated patients but that the curves intersect at around 6 years. The significance of this intersection is unclear. No peak at the 2 year mark is detected.
Likewise with DFS, the patterns are similar with the surgery alone patients experiencing more favorable outcomes.

13. Hazard Rates for OS and DFS pMMR Patients by Treatment
Overall Survival
Disease-Free Survival
Treatment uniformly reduces
recurrence risk in pMMR pts
With the pMMR patients, the peak at 2 years is observed in both the surgery alone and 5FU treated patients. The 5FU treated patients, as expected, have a better outcome. These curves approximate what was seen in unselected patients in the ACCENT dataset.

14. Long-term recurrence rates

15. Long-term recurrence rates
Annualized Risk for recurrence (%)
S = Surgery alone, AT = 5-FU adjuvant
MMR status
dMMR
pMMR
Year 0-2
Years 2-4
Years 4-6
Years 6-8 S AT
7.1
8.5
4.0
6.1
1.4
0.5
2.3
16.8
10.4
6.6
5.4
1.2
And if we look at the data from a more broad perspective, using annualized risk for recurrence, as we would anticipate, while the risk of recurrence is highest in the early years in the pMMR patients (years 0-2 and 2-4), as shown in orange, this is also the period where adjuvant therapy provides a have a significant reduction in risk of recurrence.
On the other hand (as shown in green), adjuvant therapy in the dMMR patients provides no benefit or incremental reduction in recurrence risk at any time.
In both groups, the risk of recurrence at later periods does not increase suggesting that there are no differences by MMR status in long-term recurrence rates.

16. Time from Recurrence to Death Independent of MMR or Treatment
Surgery Alone
5-FU Treated
Finally, we considered whether MMR status impacts time from recurrence to death in patients who recurr. As demonstrated on this slide, for both patient treated with surgery alone and those treated with adjuvant therapy, the survival after relapse did not depend on MMR status.

17. Conclusions: Nature and duration of benefit based on MMR status
Surgery alone
Long term advantage in clinical outcomes- TTR, DFS, OS
recurred at a 2-3 fold lower rate
No trend towards late recurrences
Over the 8-year study period, in patients treated with S alone, dMMR pts maintained a consistent advantage in the clinical endpoints TTR, DFS, OS compared to pMMR pts. dMMR pts treated with S alone recurred at a 2-3 fold lower rate than pMMR in particular during the 0-4 years after treatment. dMMR patients recur less overall, without a trend towards later recurrences.

18. Conclusions: Nature and duration of benefit based on MMR status
5-FU adjuvant therapy
Pronounced reduction in risk of recurrence (years 0-4) in pMMR but not dMMR patients
Long term advantage in pMMR with few long-term events
5-FU based AT provided pMMR pts a pronounced reduction in the risk of recurrence within the first-four years of follow-up that is not observed in dMMR pts, in whom AT was not associated with a reduced recurrence risk. Importantly, this AT benefit persists in pMMR pts with few long-term events.

19. Conclusions: Nature and duration of benefit based on MMR status
Time from Recurrence to Death
Poor prognosis following disease recurrence and independent of MMR status (p=0.87 in S pts, p=0.52 in AT pts).
5-FU based AT provided pMMR pts a pronounced reduction in the risk of recurrence within the first-four years of follow-up that is not observed in dMMR pts, in whom AT was not associated with a reduced recurrence risk. Importantly, this AT benefit persists in pMMR pts with few long-term events.

20. Conclusions
dMMR- consistent favorable prognosis throughout natural course of disease
recurrence risk is low following surgery
No benefit from AT
pMMR- increased risk of recurrence
Risk greatest in first four years post-surgery
Risk significantly reduced with AT
Favorable prognosis and low recurrence risk in dMMR pts is consistent and maintained throughout the natural course of the disease. In particular, in dMMR pts, the recurrence risk is low in all years following surgery, and no benefit from AT is observed at any point.
Conversely, pMMR pts have an increased risk of recurrence during the first four years post-surgery that is significantly reduced with 5-FU based AT.

21. Conclusions
Difference in the time patterns of recurrence and impact of AT may ultimately explain why MMR status is predictive
Continued data mining of large datasets (ie. NSABP trials) may provide confirmation of time-dependent patterns
This difference in the time patterns of recurrence and impact of AT may ultimately explain why MMR is predictive of AT benefit

22. Acknowledgements
NCCTG: B Kabat, N Foster, A French, F Sinicrope, S Alberts, S Thibodeau
NCIC: A Pollett, M Moore, M Redston, R Gryfe, S Gallinger
ECOG: A Benson, P Catalano, Adekunle Raji, B Cundiff, SR Hamilton
GIVIO: S Marsoni, R Labianca
FFCD: P Laurent-Puig, JF Seitz, F Piard, G Monges
I would like to close by acknowledging the many investigators around the world who in addition to the co-authors made this project possible. Thank you very much.