0
Welcome!
Pathways and Targets:
How do these affect my treatment
options?
Part of Fight Colorectal Cancer’s Monthly Patient...
Fight Colorectal Cancer
1. Tonight’s speaker: Dr. Gail Eckhardt, MD
2. Archived webinars: Link.FightCRC.org/Webinars
3. Fo...
Fight Colorectal Cancer
Disclaimer
The information and services provided by Fight Colorectal
Cancer are for general inform...
Fight Colorectal Cancer
Up coming webinars
Peripheral Neuropathy: Will it ever go away?
Problems, Causes, Solutions
Octobe...
Fight Colorectal Cancer
www.FightColorectalCancer.org
877-427-2111
Dr. Gail Eckhardt, MD
Professor and Division Head
Unive...
Pathways and Targets: How do
these affect my treatment
options?
S. Gail Eckhardt, M.D.
University of Colorado Cancer Center
CRC: What Have We Learned?
• Patient selective trials are needed earlier in order to
avoid thousands of patients being tre...
Treatment for colorectal cancer has
improved, but . . .
Courtesy of Wells Messersmith, MD
• Solid tumors cannot grow beyond 1-2 mm3 without an increase in blood
supply via new vessel formation
• Angiogenesis is t...
VEGF: A Central Mediator of
Angiogenesis
Binding and activation
of VEGF receptor
Environmental factors
(hypoxia, pH)
Growt...
VEGF
Small-molecule TKIs
Antibodies
VEGFR-2
(KDR/flk-1)
VEGFR-1
(flt-1)
VEGFR-1/2
heterodimer
P
P
P
P
P
P
P
P
P
P
P
P
Solu...
Pivotal Randomized Phase III Trial of 813 Advanced CRC
Patients Comparing IFL Regimen +/- Bevacizumab
Primary Endpoint: Su...
p<.001
Results: Bevacizumab added to IFL significantly
improved overall survival by > 4 months
Hurwitz et al, N Engl J Med...
VEGFR Tyrosine Kinase Inhibitors in CRC:
Over 10,000 CRC Patients Treated on Negative Trials!
Agent AKA mCRC Trials CRC Pa...
Mode of Action of Regorafenib
• Regorafenib inhibits multiple cell-
signaling kinases:
– Angiogenic
• VEGFR1–3, TIE2
– Str...
Toxicity (>10% patients, any grade, related)
Patients D/C treatment due to AEs: 8.2% (R) versus 1.2%(P)
Grothey, GI Sympos...
Regorafenib:
Overall survival (primary endpoint)
Primary endpoint met prespecified stopping criteria at interim analysis
(...
Aflibercept
Another Approach to Targeting Angiogenesis
• Soluble fusion protein
• Consists of portions of the extracellula...
Aflibercept: MOA Comparison
Courtesy of Philip Philip.
Cell membrane
VEGF-A
VEGF-R1
(Flt-1)
Migration
Invasion
Survival
VE...
“VELOUR” trial
Similar Combination Approach as Bev
- Aflibercept (VEGF Trap) in colorectal cancer
- Multiple centers in Au...
VELOUR trial
Safety Population, % of patients Placebo, N = 605 Aflibercept N = 611
PT, SOC, HLT* All Grades Grade 3/4 All ...
“VELOUR” trial: Overall Survival
Cut-off date = February 7, 2011; Median follow-up = 22.28 mos
Van Cutsem et al, 2011.
6 w...
Issues Regarding Angiogenesis Inhibitors
– Most medical oncologists believe that utilization of AIs
is relevant throughout...
Can Biomarkers Help Us Select the
Patients Most Likely to Benefit from
Targeted Therapies ?
Biomarker = Toxicity (mechanism based)
Biological effect
Efficacy
Pharmacodynamic biomarker: Associated with drug
effect
E...
Biomarkers for Bevacizumab in CRC
• Although there are biomarkers associated with the PD
effects of bevacizumab, to date t...
EGFR Antibodies Target Tumor Cell-Bound EGFR
Extracellular
Intracellular
Ligand
EGF-R
PI3K
Akt
Raf
MEK
MAPK
Cell Motility
...
Cetuximab +/- Irinotecan
PFS
p<0.001
Cunningham, NEJM 2004
Note: overall survival curves were nearly identical (likely due...
What About Biomarkers and EGFR Antibodies in
CRC?
Did staining for EGFR matter? NO!
Courtesy of DakoCytomation, 2004
21% 25%
23%
Response Rates
EGFR Signaling Cascade and KRAS
Akt
SOS
FOS Myc
P13K
FKHR
mTOR
PTEN
MEK 1/2
MAPK
BAD
GSK-3
Shc
Grb-2
Ras
Raf
Jun
p27
Cycli...
Randomized Trial Results
Median PFS (Cetux- or Pmab- containing arms)
Study Treatment
Total Pts
MT WT
Amado
2008
P versus ...
Amgen “408” Trial
This trial was important because it had a
placebo arm
Patients had to be “EGFR positive,” defined as >1%...
PFS by treatment overall
Van Cutsem et al. J Clin Oncol; 25(13):1658-1664 2007
Resulted in FDA
approval of
panitumumab
for...
Amado, R. G. et al. J Clin Oncol; 26:1626-1634 2008
PFS by treatment within KRAS groups
Note: The BSC arms look similar in...
KRAS and Panitumumab
Waterfall plot shows
responses (tumor
shrinkage) were
confined to Ras WT
patients
Mut WT
Amado, R. G....
Mechanism-based toxicity:
Skin Rash with EGFR Blockade
This is a pharmacodynamic biomarker- is it predictive?
M Peeters et al, Cancer, 2009
More severe skin toxicity
and associated
symptoms led to
prolonged survival in this
subset a...
Summary and Lessons Learned with EGFR Inhibitors in CRC
• EGFR-targeted antibodies have very modest single-agent activity
...
What About the Combination of
Biologics- is More Better????
PACCE Trial:
Randomized phase III trial of 1000 patients comparing
chemo/Bev with or without panitumumab
Previously
untrea...
PACCE Trial
Progression-Free Survival
Hecht, World GI 2007
Months
413 267 92 21 3
410 298 96 21 1
0 5 10 15 20
Pmab+bev/Ox...
TCGA Data: Many Pathways to Target
Conclusions
• Novel biological agents targeting the EGFR and VEGF pathways
have extended survival and provided new options...
Thank You- Questions?
Fight Colorectal Cancer
CONTACT US
Fight Colorectal Cancer
1414 Prince Street, Suite 204
Alexandria, VA 22314
(703) 548-12...
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Pathways and targets how might these affect my treatment decisions gail eckhardt webinar

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Dr. Gail Eckhardt

Professor and Head of the Division of Medical Oncology at the University of Colorado Denver and Health Sciences Center.

Join us for an exciting webinar about pathways and targets. Dr. Eckhardt will discuss the basic of pathways within a cancer cell, and how (and why) they can affect treatment options for patients. She'll explain how we learn about how new pathways are discovered, and how this information tell us what drugs may work in certain patients and why some drugs don’t.

Dr. Eckhardt will discuss the idea of targeted therapies, and the difference between them and regular chemotherapy. She'll talk about the relationship between pathways and targeted drugs, and how this may impact drug development in the future.

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Transcript of "Pathways and targets how might these affect my treatment decisions gail eckhardt webinar"

  1. 1. Welcome! Pathways and Targets: How do these affect my treatment options? Part of Fight Colorectal Cancer’s Monthly Patient Webinar Series Our webinar will begin shortly www.FightColorectalCancer.org 877-427-2111
  2. 2. Fight Colorectal Cancer 1. Tonight’s speaker: Dr. Gail Eckhardt, MD 2. Archived webinars: Link.FightCRC.org/Webinars 3. Follow up survey to come via email. Get a free Blue Star of Hope pin when you tell us how we did tonight. 4. Ask a question in the panel on the right side of your screen and look for hyperlinks during throughout the presentation. 5. Or call the Fight Colorectal Cancer Answer Line at 877-427-2111 www.FightColorectalCancer.org 877-427-2111
  3. 3. Fight Colorectal Cancer 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, diagnosis, 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. www.FightColorectalCancer.org 877-427-2111
  4. 4. Fight Colorectal Cancer Up coming webinars Peripheral Neuropathy: Will it ever go away? Problems, Causes, Solutions October 16, 2013 8 - 9:30pm EDT Advances in Surgical Treatments for Colon and Rectal Cancer Patients November 20, 2013 8 - 9:30pm EDT
  5. 5. Fight Colorectal Cancer www.FightColorectalCancer.org 877-427-2111 Dr. Gail Eckhardt, MD Professor and Division Head University of Colorado Division of Medical Oncology
  6. 6. Pathways and Targets: How do these affect my treatment options? S. Gail Eckhardt, M.D. University of Colorado Cancer Center
  7. 7. CRC: What Have We Learned? • Patient selective trials are needed earlier in order to avoid thousands of patients being treated with ineffective agents (EGFR Ab/KRAS) • Indiscriminant addition of biological agents to adjuvant therapy is not warranted (bevacizumab/cetuximab) • Dual biological combinations in unselected patients may lead to more toxicity with little benefit (bevacizumab + cetuximab)
  8. 8. Treatment for colorectal cancer has improved, but . . . Courtesy of Wells Messersmith, MD
  9. 9. • Solid tumors cannot grow beyond 1-2 mm3 without an increase in blood supply via new vessel formation • Angiogenesis is thus required for tumor growth and metastasis • Inhibition of tumor angiogenesis leads to tumor cell growth arrest, death of tumor cells, and in some cases, tumor regression Tumor angiogenesis is stimulated… New vessels then facilitate tumor growth Slide Courtesy of Novartis Oncology Targeting Angiogenesis in CRC
  10. 10. VEGF: A Central Mediator of Angiogenesis Binding and activation of VEGF receptor Environmental factors (hypoxia, pH) Growth factors, hormones (EGF, bFGF, PDGF, IGF-1, IL-1 , IL-6, estrogen) Genes involved in tumorigenesis (p53, p73, src, ras, vHL, bcr-abl) P P P P ANGIOGENESIS ProliferationSurvival Migration Endothelial cell activation VEGF 1. Dvorak. J Clin Oncol. 2002;20:4368. 2. Ferrara et al. Nat Med. 2003;9:669. 3. Ebos et al. Mol Cancer Res. 2002;1:89.
  11. 11. VEGF Small-molecule TKIs Antibodies VEGFR-2 (KDR/flk-1) VEGFR-1 (flt-1) VEGFR-1/2 heterodimer P P P P P P P P P P P P Soluble, truncated receptors Targeting VEGF and its receptors Several Approaches Courtesy of Herb Hurwitz
  12. 12. Pivotal Randomized Phase III Trial of 813 Advanced CRC Patients Comparing IFL Regimen +/- Bevacizumab Primary Endpoint: Survival Previously untreated pts with metastatic colorectal cancer Arm A: IFL + Bevacizumab Arm B: IFL + Placebo IFL = Irinotecan / 5-FU / Leucovorin Hurwitz et al, N Engl J Med. 2004 Jun 3;350(23):2335-42.
  13. 13. p<.001 Results: Bevacizumab added to IFL significantly improved overall survival by > 4 months Hurwitz et al, N Engl J Med. 2004 Jun 3;350(23):2335-42. Copyright Mass Med Soc
  14. 14. VEGFR Tyrosine Kinase Inhibitors in CRC: Over 10,000 CRC Patients Treated on Negative Trials! Agent AKA mCRC Trials CRC Patients Cediranib AZD2171 2 Phase III 3,194 Semaxinib SU5416 2 Phase III 2,084 Vatalanib PTK787 2 Phase III 2,050 Sunitinib SU11248 Phase III 1,623 Brivanib BMS-582664 Phase III 926 Sorafenib BAY 43-9006 Phase IIB 814 Vandetanib ZD6474 Phase IIB 356 Axitinib AG-013736 Phase IIB 299 Linifanib ABT-869 Phase IIB 147 Vargateg BIBF 1120 Phase II 166 Tivozanib AV-951 Phase II 80 Motesanib AMG-706 Phase IB 148 Pazopanib GW786034 Phase IB 94 Clinicaltrials.gov; Slide courtesy of Scott Kopetz
  15. 15. Mode of Action of Regorafenib • Regorafenib inhibits multiple cell- signaling kinases: – Angiogenic • VEGFR1–3, TIE2 – Stromal • PDGFR-β, FGFR – Oncogenic • KIT, PDGFR, RET • T1/2 in man: approx. 26-28 hrs – Two major metabolites (M2, M5) are pharmacologically active Wilhelm SM et al. Int J Cancer 2011
  16. 16. Toxicity (>10% patients, any grade, related) Patients D/C treatment due to AEs: 8.2% (R) versus 1.2%(P) Grothey, GI Symposium 2012, J Clin Oncol 30, 2012 (suppl 4; abstr LBA385) Adverse event, % Regorafenib N=500 Placebo N=253 All grades Grade 3 Grade 4 Grade 5 All grades Grade 3 Grade 4 Grade 5 Hand–foot skin reaction 46.6 16.6 0 0 7.5 0.4 0 0 Fatigue 47.4 9.2 0.4 0 28.1 4.7 0.4 0 Hypertension 27.8 7.2 0 0 5.9 0.8 0 0 Diarrhea 33.8 7.0 0.2 0 8.3 0.8 0 0 Rash/desquamation 26.0 5.8 0 0 4.0 0 0 0 Anorexia 30.4 3.2 0 0 15.4 2.8 0 0 Mucositis, oral 27.2 3.0 0 0 3.6 0 0 0 Thrombocytopenia 12.6 2.6 0.2 0 2.0 0.4 0 0 Fever 10.4 0.8 0 0 2.8 0 0 0 Nausea 14.4 0.4 0 0 11.1 0 0 0 Bleeding 11.4 0.4 0 0.4 2.8 0 0 0 Voice changes 29.4 0.2 0 0 5.5 0 0 0 Weight loss 13.8 0 0 0 2.4 0 0 0
  17. 17. Regorafenib: Overall survival (primary endpoint) Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p<0.009279 at approximately 74% of events required for final analysis) 1.00 0.50 0.25 0 0.75 200100500 150 300250 400350 450 Days from randomization Survivaldistributionfunction Placebo N=255 Regorafenib N=505 Median 6.4 mos 5.0 mos 95% CI 5.9–7.3 4.4–5.8 Hazard ratio: 0.77 (95% CI: 0.64–0.94) 1-sided p-value: 0.0052 Regorafenib Placebo Grothey et al, ASCO GI 2012 42 days!
  18. 18. Aflibercept Another Approach to Targeting Angiogenesis • Soluble fusion protein • Consists of portions of the extracellular domains of human VEGFR1 and VEGFR2 fused to a human IgG1 Fc portion • Binds all VEGF-A isoforms, VEGF-B, and PlGF • High affinity: Binds VEGF-A and PlGF more tightly than native receptors • Half-life ~ 17 days Van Cutsem et al, 2011.
  19. 19. Aflibercept: MOA Comparison Courtesy of Philip Philip. Cell membrane VEGF-A VEGF-R1 (Flt-1) Migration Invasion Survival VEGF-R3 (Flt-4) Lymphangio- genesis VEGF-R2 (KDR/Flk-1) Proliferation Survival Permeability PlGF VEGF-B VEGF-C VEGF-D Functions Bevacizumab VGX-100 Ramucirumab CT-322 IMC-18F1 Aflibercept TB403 XXX VEGFR TKIs
  20. 20. “VELOUR” trial Similar Combination Approach as Bev - Aflibercept (VEGF Trap) in colorectal cancer - Multiple centers in Australia, China, Europe, Japan, and North America mCRC after failure of an oxaliplatin-based regimen N=1200 Placebo + FOLFIRI (n=605) R Aflibercept 4 mg/kg IV + FOLFIRI (n=611) Primary Endpoint: Overall Survival (OS) 1:1 Note: 30% had received prior bevacizumab Van Cutsem et al, 2011. (FOLFIRI= infusional 5FU/IRI/LV)
  21. 21. VELOUR trial Safety Population, % of patients Placebo, N = 605 Aflibercept N = 611 PT, SOC, HLT* All Grades Grade 3/4 All Grades Grade 3/4 Diarrhea 56.5 7.8 69.2 19.3 Neutropenia** Complicated neutropenia 56.3 29.5 2.8 67.8 36.7 5.7 Asthenic conditions (HLT) 50.2 10.6 60.4 16.9 Stomatitis & ulceration (HLT) 34.9 5.0 54.8 13.7 Thrombocytopenia** 33.8 1.7 47.4 3.3 Infections (SOC) 32.7 6.9 46.2 12.3 Decrease appetite 23.8 1.8 31.9 3.4 Weight decreased 14.4 0.8 31.9 2.6 Palmar plantar erythrodysaesthesia 4.3 0.5 11.0 2.8 Skin hyperpigmentation 2.8 0 8.2 0 Dehydration 3.0 1.3 9.0 4.3 PL: 12.1% AFL: 26.6% AEs leading to treatment discontinuation Van Cutsem et al, 2011.
  22. 22. “VELOUR” trial: Overall Survival Cut-off date = February 7, 2011; Median follow-up = 22.28 mos Van Cutsem et al, 2011. 6 weeks longer OS Not compared to bevacizumab
  23. 23. Issues Regarding Angiogenesis Inhibitors – Most medical oncologists believe that utilization of AIs is relevant throughout the course of advanced CRC (when risks are acceptable) – Bevacizumab can be used with chemotherapy and the reason aflibercept is not being routinely used is related to unfamiliarity and concerns regarding the toxicity data – For some reason, although regorafenib was active in refractory patients, drugs that are similar have not worked with chemotherapy – Among those involved in clinical research (like me), we are worried that patients will get regorafenib rather than be offered a clinical trial
  24. 24. Can Biomarkers Help Us Select the Patients Most Likely to Benefit from Targeted Therapies ?
  25. 25. Biomarker = Toxicity (mechanism based) Biological effect Efficacy Pharmacodynamic biomarker: Associated with drug effect Example: skin rash with EGFR inhibitor, or inhibition of p-ERK with MEK inhibitor Predictive biomarker: Predicts outcome to therapy Example: Her2/Neu amplification by FISH for trastuzumab Prognostic biomarker: Associated with outcome, independent of therapy Example: VEGF expression Biomarkers: Introduction
  26. 26. Biomarkers for Bevacizumab in CRC • Although there are biomarkers associated with the PD effects of bevacizumab, to date to no predictive biomarkers have been identified • This is likely due to the complex interaction of the tumor and microenvironment • Studies are ongoing to determine whether the PD biomarkers such as high blood pressure and MRI can be used to identify patients deriving clinical benefit
  27. 27. EGFR Antibodies Target Tumor Cell-Bound EGFR Extracellular Intracellular Ligand EGF-R PI3K Akt Raf MEK MAPK Cell Motility MetastasisAngiogenesis Proliferation Cell survival DNA PTEN Ras Slide courtesy of Axel Grothey Targeting the EGFR in CRC
  28. 28. Cetuximab +/- Irinotecan PFS p<0.001 Cunningham, NEJM 2004 Note: overall survival curves were nearly identical (likely due to crossover)
  29. 29. What About Biomarkers and EGFR Antibodies in CRC?
  30. 30. Did staining for EGFR matter? NO! Courtesy of DakoCytomation, 2004 21% 25% 23% Response Rates
  31. 31. EGFR Signaling Cascade and KRAS Akt SOS FOS Myc P13K FKHR mTOR PTEN MEK 1/2 MAPK BAD GSK-3 Shc Grb-2 Ras Raf Jun p27 Cyclin D-1 Ligand Signal Adapters and Enzymes Signal Cascade EGFR dimer Transcription Factors STAT Inhibitors upstream may be ineffective Karapetis WGIC 2008
  32. 32. Randomized Trial Results Median PFS (Cetux- or Pmab- containing arms) Study Treatment Total Pts MT WT Amado 2008 P versus BSC (3rd line) 427 7.4 wks HR 0.99 12.3 wks HR 0.45 Karapetis 2008 C versus BSC (no X-over) 394 1.9 mos 3.7 mos HR 0.40 Van Cutsem 2008 FOLFIRI +/- C (1st line) 540 7.6 mos HR 1.07 9.9 mos HR 0.68 Bokemeyer 2008 FOLFOX +/- C (1st line) 233 5.5 mos HR 1.83 7.7 mos HR 0.57 C = cetuximab; P = panitumumab; BSC = best supportive care
  33. 33. Amgen “408” Trial This trial was important because it had a placebo arm Patients had to be “EGFR positive,” defined as >1% tumor cells staining by IHC Pretreated with 5-FU, oxaliplatin, irinotecan Previously treated metastatic colorectal cancer N=463 Panitumumab 6 mg/kg Q2 weeks Best Supportive Care OptionalCrossover Van Cutsem et al. J Clin Oncol; 25(13):1658-1664 2007
  34. 34. PFS by treatment overall Van Cutsem et al. J Clin Oncol; 25(13):1658-1664 2007 Resulted in FDA approval of panitumumab for use in 3rd line setting
  35. 35. Amado, R. G. et al. J Clin Oncol; 26:1626-1634 2008 PFS by treatment within KRAS groups Note: The BSC arms look similar indicating lack of impact on prognosis KRAS MT KRAS WT BSC BSC
  36. 36. KRAS and Panitumumab Waterfall plot shows responses (tumor shrinkage) were confined to Ras WT patients Mut WT Amado, R. G. et al. J Clin Oncol; 26:1626-1634 2008
  37. 37. Mechanism-based toxicity: Skin Rash with EGFR Blockade This is a pharmacodynamic biomarker- is it predictive?
  38. 38. M Peeters et al, Cancer, 2009 More severe skin toxicity and associated symptoms led to prolonged survival in this subset analysis Grade 2+ skin toxicity Greater skin toxicity symptoms Skin Rash: Maybe necessary but not sufficient for antitumor activity
  39. 39. Summary and Lessons Learned with EGFR Inhibitors in CRC • EGFR-targeted antibodies have very modest single-agent activity in refractory CRC but appear to improve responses to chemotherapy • Biomarker studies have demonstrated that benefit is restricted to KRAS WT patients • Surprisingly, no benefit was observed in the adjuvant studies • Ongoing questions remain regarding the extent to which immune mechanisms contribute to antitumor effects and how to integrate skin rash data in dosing decisions • The EGFR TKIs (oral drugs) have not exhibited activity in CRC
  40. 40. What About the Combination of Biologics- is More Better????
  41. 41. PACCE Trial: Randomized phase III trial of 1000 patients comparing chemo/Bev with or without panitumumab Previously untreated metastatic colorectal cancer N=1000 5-FU/Oxali/Bev N=800 5-FU/Irino/Bev N=200 Hecht, World GI 2007 + panitumumab + panitumumab (alone) (alone)
  42. 42. PACCE Trial Progression-Free Survival Hecht, World GI 2007 Months 413 267 92 21 3 410 298 96 21 1 0 5 10 15 20 Pmab+bev/Ox-CT N bev/Ox-CT N Patients at risk: # PFS events (%) Median (95%CI), mos 206 (50) 9.0 (8.5-10.4) 172 (42) 10.5 (9.7-11.6) Pmab+bev/Ox-CT Bev/Ox-CT HR= 1.29 (95% CI: 1.05-1.58) ProportionProgression-Free 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% ITT set Control group did better!
  43. 43. TCGA Data: Many Pathways to Target
  44. 44. Conclusions • Novel biological agents targeting the EGFR and VEGF pathways have extended survival and provided new options for CRC patients with advanced disease • Unfortunately, these results have not translated to adjuvant therapy and the reasons for this are not well understood • Biomarkers have been instrumental in further defining a potentially responsive patient population • These results, along with the issues of combining “double biologics” in unselected patients, are driving the field forward towards personalized therapy and more rational combinations • Despite the advances in therapy, more effective agents are needed and luckily drug development is robust, but very dependent on clinical trials
  45. 45. Thank You- Questions?
  46. 46. Fight Colorectal Cancer CONTACT US Fight Colorectal Cancer 1414 Prince Street, Suite 204 Alexandria, VA 22314 (703) 548-1225 Toll-Free Answer Line: 1-877-427-2111 www.FightColorectalCancer.org Email us: Info@FightColorectalCancer.org
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