In this webinar, Dr. Azad discusses colorectal cancer recurrence. She addresses things to do to help reduce the risk of recurrence, in addition to what steps should be taken if colon or rectal cancer returns.

1. Recurrence: What now?

2. TODAY’S WEBINAR
 SPEAKER(S)
 Nilofer Azad, MD
 QUESTIONS
 Ask a question in the panel on the RIGHT SIDE of your
screen
 WEBINAR ARCHIVE
 FightCRC.org/webinar
 TWEET ALONG
 Follow along via Twitter – use the hashtag #CRCWebinar

3. RESOURCE
S
TABOO-TY PODCAST MINI MAGAZINES CLINICAL TRIAL FINDER

4. FIGHTCOLORECTALCANCER
DISCLAIMER
The information and services provided
by Fight Colorectal Cancer are for
general informational purposes only.
The information and services are not
intended to be substitutes for
professional medical advice,
diagnoses or treatment.
If you are ill, or suspect that you are
ill, see a doctor immediately. In an
emergency, call 911 or go to the
nearest emergency room.
Fight Colorectal Cancer never
recommends or endorses any specific
physicians, products or treatments for
any condition.

5. NiloferAzad,MD
Dr. Azad is an Associate Professor of Oncology and a member of the
Gastrointestinal Oncology Program within the Sidney Kimmel Comprehensive
Cancer Center (SKCCC). She completed her fellowship in Medical Oncology at the
National Cancer Institute and became a faculty member in July 2008. Since joining
the faculty of the SKCCC at Johns Hopkins, Dr. Azad is the PI of numerous early
phase clinical trials in solid tumors and gastrointestinal cancers. Dr.Azad is a
clinically active medical oncologist and is the co-leader of the NCI funded UM1
Developmental Therapeutics clinical research program at the SKCCC. She is a
member of both the Epigenetics and Colon Cancer Stand Up 2 Cancer Dream
Teams, serving as a Principal on the latter. She is a member of the NCI Colon
Cancer Task Force, the Advisory Board of the Biden Cancer Initiative, and the
Executive Board of The Cholangiocarcinoma Foundation, among others.
Dr. Azad’s laboratory is dedicated to translational research in drug development
that will form the foundation of future clinical trials. Her research focuses on
epigenetic alterations in cancer cells, which are changes in gene expression due to
potentially reversible modifications of DNA. Her lab is currently investigating drugs
that work through epigenetic mechanisms as well as epigenetic molecular
differences in tumors that may change the efficacy of treatment, as well as the
intersection of these agents with immunotherapy. These preclinical studies are
designed to
move directly into early phase clinical trials, with strong laboratory correlates that
will be used to further hone the therapeutic regimens, as a quintessential example
of bench-to-bedside medicine.

6. August 21, 2019
Recurrence: What now?"
Nilofer Azad, MD
Director, Developmental Therapeutics
Sidney Kimmel Comprehensive Cancer Center

7. Standard of care for colon cancer
adjuvant (post-surgery) therapy

8. The many ways to treat rectal
cancer…

9. What if you are metastatic from
the beginning but operable?
• American standard of care is adjuvant
FOLFOX/CAPOX x 6 months
• There is minimal data to support this
– Single trial looked at chemo before and
after surgery vs only surgery and found
equal 5-year survival after initial disease-
free survival benefit
– Adding irinotecan to 5-FU did not do better
than 5-FU alone

10. Surveillance

11. CAN I LOWER MY
RECURRENCE RISK?
8/21/2019 11

12. Association vs causation and
reducing recurrence
• Risk factors for developing colon cancer
may not equal things that are modifiable
to reduce recurrence risk
• Ex: charred meats, alcohol, tobacco,
decreased exercise, high-fructose corn
syrup

13. High-fructose corn syrup
• Recent data that has been examining sugary
beverages/high-fructose corn syrup in formation
of propagation of colon tumors
8/21/2019

14. Fiber
• One major study (JAMA Oncology 2018
Song et al.)
• 1575 CRC patients were examined
• Patients who had greater intake of
cereal fiber or whole grain intake had
lower CRC mortality (not true for
vegetable or fruit fiber)

15. Vitamin D
• Biggest study looked at 5706 CRC pts and 7107 non-
CRC patients
• Low serum vitamin D had increased risk of colon
cancer and the opposite was true as well
• Intervention study: 139 patients with mCRC treated
with high-dose 8000IU a day then 4000 IU vs
standard dose Vitamin D
– No difference in survival but decreased cancer
progression on the first treaemtnt
FOLFOX+bevacizumab
8/21/2019 15

16. Nut intake
• 826 patients observed and found those
who had 2+ servings of tree nuts lived
longer
• Non-tree nuts examined and did not
have this benefit
16

17. Aspirin (ASA) intake
• Lots of conflicting data and uncertainty
around dosing
• Some initially strong data showing
improved survival with ASA, especially
in PIK3K-mutated patients
• More recent studies have not shown
this association and even shown
increased mortality, especially in cancer
patients 17

18. CLINICAL TRIALS FOR STAGE
I-III PATIENTS

19. SU2C trial for patients with +
circulating tumor DNA

20. Adjuvant therapy trial for MSI-
high patients
8/21/2019 20

21. KRAS vaccine + immunotherapy
for patients with high-risk disease

22. IF THERE IS RECURRENCE
8/21/2019 22

23. Basic tenets of metastatic
colorectal cancer treatment
• People live on average for years
• We have multiple, very-effective FDA-
approved therapies with good quality of life
– CLINICAL TRIALS, CLINICAL TRIALS,
CLINICAL TRIALS – LOOK EARLY
• All patients should have testing for KRAS,
BRAF, NRAS, and microsatellite instability
(MSI-high) done on their tumor
• Left vs right-sided colon cancer matters

24. Many exciting areas of research
• Immunotherapy
• Epigenetic therapy
• Molecularly targeted therapy
• New chemotherapies
• Many others
• Combinations of these approaches

25. Immunotherapy is not one thing
8/21/2019 25

26. Epigenetics and genetics interact to
control cell function through proteins

27. Just one example of combination
approaches
MC38
in vitro
Immunodeficient
Untreated
Immunotherapy
anti-PD-1
Harvest tumor
Isolate DNA
Barcode SequenceExpression of tumor
associated mutations
n=1163 ORFs

28. PIK3CA activation confers resistance to PD-
1 blockade
-5
-4
-3
-2
-1
1
2
3
4
5
Fold Change
(log2)
Enrichedinimmune
selectivepressure
Depletedinimmune
selectivepressure
PIK3CA
AKT E17K
PIK3CG R191H
PanCancer mutagenized ORFs (n=836)
PIK3CA
PIK3CA H1047R
PIK3CA H1047Y
-5
-4
-3
-2
-1
0
1
2
3
4
5
Luciferase
(Control)

29. PIK3CA H1047R confers resistance to PD-1
blockade

30. Phase I/Ib of copanlisib +
nivolumab
• Copanlisib is a potent PIK3C a, b, d, g inhibitor (a most potent)
• Phase I: advanced solid tumors patients (prior PD-1 exposure
allowed) will receive dose escalating copanlisib in combination
with fixed dose nivolumab – completed
• Phase II – A) PIK3CA-mutated and b) PIK3CA CRC wild-type
cohorts (21 each) – just opened
– Patients will have biopsies at baseline and 6 weeks with
serial blood draws at the same time points and monthly on
trial

31. Conclusion
• We have very standard paradigms for
treating colorectal cancer around the
world
• Uncertain how much changing lifestyle
factors affects outcomes
• Everyone with recurrence should get a
second opinion at an academic center
early in their diagnosis
• Many exciting new directions in
research

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