Colorectal Cancer: Lumping or Splitting? Jimmy J. Hwang, MD FACP Levine Cancer Institute Carolinas HealthCare System Charlotte, NC
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Epidemiology Colorectal Cancer is the 2 nd Leading Cause of Cancer-related Mortality in the US. 2017 estimates 1 50, 260 deaths 135, 430 new diagnoses Increasing in pts 40 and younger Second Leading Cause of Cancer-related Mortality, Worldwide, 2015 estimates 2 Estimated 832, 000 deaths Gastric is 3 rd, Liver cancer is 4 th, Esophageal is 6 th, Pancreatic is 7 th Estimated 1.7 million new diagnoses, 3 rd most common overall 1 Siegel et al, CA Cancer J Clin 2017; 67: 7 2 Global Burden of Disease Cancer Collaboration. JAMA Oncology 2016, doi:10.1001/jamaoncol.2016.5688 69
Siegel et al, CA Cancer J Clin, 2017; 7-30
Advances in the Treatment of Metastatic Colorectal Cancer? Agent Year First Approved in US for Colorectal Cancer Median Survival in 1 st line Studies Best Supportive Care N/A 6 months 5-Fluorouracil 1962 9-12 months (with Leucovorin) Capecitabine 2001 12 months (non-inferior to 5FU) Irinotecan 1996 15-16 months Oxaliplatin 2002 18-20 months Bevacizumab 2004 20-24 months Ziv-Aflibercept 2012 Ramucirumab 2015 Cetuximab/Panitumumab (Ras nonmutated) Regorafenib 2012 Trifluridine (TAS 102) 2015 2004/2006 20-24 months Pembrolizumab (MSI-H only) 2017?
Metastatic Colorectal Cancer: CALGB 80405 Venook et al, JAMA 2017; 9/11/17 6 317: 2392-2401
Metastatic Colorectal Cancer: CALGB 80405 9/11/17 7
Rectal vs colon carcinoma Surgery Adjuvant therapy (radiation) Classifying Colorectal Cancer? 2003 (Ribic et al, NEJM), Microsatellite Instability was reported to be a possible negative predictive factor for adjuvant chemotherapy with 5-FU, at least in stage II colon cancer 2007 (Amado et al, JCO), identification of k-ras exon 2 as a negative predictive factor for EGFR inhibitors in colorectal cancer Predictive role may vary with disease K-ras exon 2-4, N-ras exon 2-4 B-raf?
Colon Cancer: Left Versus Right 9/11/17 9
Anatomy Embryology Etiology Clinical Data The Uniformity of Colo(rectal?) Cancer?
Anatomy of Colorectal Cancer Downloaded from Google Images, accessed 7/26/17
Right colon Midgut Blood supply from SMA Left colon, rectum Hindgut Blood Supply from IMA Transverse colon Embryology of Colorectal Cancer
Genetic Other Diet Tobacco Bacteria Bacteroides fragilis Fusobacterium nucleatum Helicobacter pylori? Etiology of Colorectal Cancer
Chromosomal Instability Familial Adenomatous Polyposis Serrated Pathway B-raf/ras Microsatellite Instability Etiology of Colo(rectal?) Cancer Lynch Syndrome Epigenetic Silencing/CpG Methylation
Left Versus Right Colon Cancer: Clinical Differences Right Sided Colon Cancer Tend to be older More often female More often peritoneal metastases More often mucinous More often poorly differentiated Left Sided Colon Cancer More often present with GI bleeding More often liver, lung metastases More often K ras mutated 9/11/17 15
Colon Cancer: Left Versus Right 9/11/17 16 Missiaglia et al, Ann Oncol 2014, 27: 1995-2001
Left versus Right Colon Cancer: Clinical Data Retrospective and registry data suggest that left sided colon cancer has better survival/prognosis than right sided colon cancer Petrelli et al (JAMA Oncology 2017): Meta-Analysis of 66 Studies involving 1, 437, 846 pts: Pooled HR=0.82 However, limited data in stage I-III colon cancer suggests that there is not a significant difference in left versus right colon cancer German study (Benedix et al, 2010) did not demonstrate a significant difference in stage II disease Weiss et al (JCO 2011), from SEER 1992-2005 including 53, 801 pts Schrag et al (ASCO 2016, #3505), from SEER, did not demonstrate a significant difference in early stage disease, but did demonstrate significant difference in stage III and in particular stage IV
Left versus Right Colon Cancer: Clinical Data Unclear if sidedness affects outcomes from treatment with chemotherapy. Oxaliplatin/Capecitabine as 1st line Therapy: No differences in outcomes in 213 pts treated between 2003-2006. Boisen et al, Ann Oncol 2013; 24: 2554-2559
Left Versus Right Colon Cancer: Chemotherapy 9/11/17 19 Boisen et al, Ann Oncol 2013; 24: 2554-2559
Left versus Right Colon Cancer: Anti-VEGF Therapy Data from multiple studies demonstrate that outcomes are better in the left sided colon cancers was better than right sided tumors in bevacizumabbased chemotherapy Combination with chemotherapy in 1 st line AVF2107g and NO16966: Loupakis et al, JNCI 2015; v 107 (3). Similar benefits in R and L sided tumors, but in absolute terms, more benefit in L sided tumors
Left Versus Right Colon Cancer: Anti-VEGF Therapy Loupakis et al, JNCI 2015; 107 (3): dju427 9/11/17 21
Left versus Right Colon Cancer: EGFR Inhibitors Several studies suggest that in ras non-mutated mcrc, anti-egfr therapy has greater effect in Left sided tumors than in Right sided tumors Single agent, 3 rd line in CO17: Brule et al, Eur J Cancer 2015; 51: 1405-1415 Also demonstrated differences in mutations Combination with FOLFIRI, 1 st line: CRYSTAL and FIRE3: Tejpar et al, JAMA Oncol epub October 10 2016; doi.10.1001/jamaoncol.2016.3797
Left versus Right Colon Cancer: EGFR inhibitors Brule et al 9/11/17 Eur J Cancer 23 2015; 51: 1405-1414
Left versus Right Colon Cancer: CRYSTAL Tejpar et al, JAMA Oncol epub Oct 10, 2016 9/11/17 doi: 10.1001/jamaoncool.2016.3797 24
L Vs R Colon Cancer: Overall Survival Arnold et al. Ann Oncol 2017, 28: 1713-1729 9/11/17 25
L Vs R Colon Cancer: Progression Free Survival 9/11/17 26
L Vs R Colon Cancer: Overall Response Rate 9/11/17 27
Left v Right sided Colon Cancer q Venook et al, ASCO 2016, #3504. Unplanned exploration from CALGB 80405 q 732 Left colon, 293 Right Colon, 66 transverse colon, 46 not evaluable Left Colon Right Colon 33.3 months Median Survival (HR=1.55) 19.4 months 31.4 months Bevacizumab 24.2 months 36.0 months Cetuximab 16.7 months 11.7 months Median PFS 8.9 months Bevacizumab (HR=1.28) 12.4 months Cetuximab (HR=0.82) 7.8 months 28
L Vs R Colon Cancer: FIRE 3 9/11/17 29
L v R Colon Cancer: EGFR Inhibitors q Demurtas et al, Br J Cancer 2017; 117: 315-321 q Retrospective evaluation of 88 pts in 2 nd /3 rd line setting who were treated with irinotecan/cetuximab q Pts with left sided tumors did better with regards to survival, PFS, ORR q EGFR Gene copy number and EGFR methylation were also associated with outcomes q In multivariate analysis, EGFR Gene copy number and EGFR methylation were independently associated with outcomes, but tumor sidedness was not 30
Available data Left versus Right Colon: Targeted Therapies Is retrospective and limited, BUT Suggests that anti-egfr therapy may have greater efficacy in left colon cancer than right Uncertain if anti-vegf therapy is more effective in left colon cancer, compared to the right, but the relative benefits seem similar in both sides REALLY LIMITED data from FIRE3, CALGB80405, then could be interpreted as favoring anti-egfr therapy as initial treatment in left sided tumors and anti-vegf therapy in right sided tumors, BUT I think there are too many limitations in the data to truly conclude this Pts who are ras/raf nonmutated are going to receive anti-egfr therapy at some point regardless of initial site of disease The real question, if these differences are real, is WHY?
Colorectal Cancer: Continuum? Yamauchi et al, Gut 2012 9/11/17 32
Colorectal Cancer: Continuum of MSI from Caris COE, Marshall et al Marshall et al, CARIS COE, ASCO 2016, #3552 33
Mutations frequency comparison with right colon Presented by Dr. Mohammed Salem, 2017 GI Cancer Symposium 80% 70% 60% 50% 40% 30% 20% 10% 0% Right Colon Splenic Flexure/Descending Rectum Indicates a significant difference between rectal cancer vs. right sided tumors (p < 0.05)
Colorectal Consensus Classification Guinney et al, Nature Medicine 2015; 21: 1350-1356 35 9/11/17 35
Left v Right sided Colon Cancer q Lee et al, ASCO 2016, #3506 q Analyzed tumors from 440 pts at MDACC from 2010-2013, and noted that left, right sided tumors were biologically different (HR 1.56, p=0.04) q Differences in outcomes R v L: Median PFS 4.7 months to 6.5 months Right Colon Left Colon 49% CMS1 8% 9% CMS2 3% 32% CMS3 61% 10% CMS4 28% 36
CMS at ASCO 2017 Multiple retrospective evaluations of CMS were presented, with some consistent findings, but some discordant results in trying to evaluate outcomes by therapy BUT, generalizability is uncertain because some of the studies were already limited to ras/raf nonmutated disease AND, the determination of CMS is not yet widely available
Stage III disease CMS at ASCO 2017 Marisa et al, abstract 3509, from PETACC 8 prognosis was associated with CMS classification (worst with CMS4) and that CMS1 did worse with cetuximab Kim et al, abstract 3514, from NSABP C-07 Only investigated association with sidedness, but found CMS1, 3 was more frequent on Right side; CMS 2 more frequent on L, and CMS4 was similar in both
Metastatic disease Stintzing et al, abstract 3510, from FIRE3 CMS at ASCO 2017 Prognosis was associated with CMS classification; worst survival with CMS 1, 3, best in CMS2 Outcomes generally reflected the primary analysis, except in CMS 3, where survival was similar in arms, or slightly worse with cetuximab. Differences in outcomes between treatment arms was only sig in CMS4 favoring cetuximab Lenz et al, abstract 3511, from 80405 Prognosis in PFS, OS was associated with CMS classification, worst survival in CMS 1 Worse outcomes in CMS 1 with chemo/cetuximab than chemo/bev, otherwise similar in both
CMS and FIRE 3 (Stintzing et al, ASCO 2017, #3510) CMS1 Immune CMS2 Canonical (wnt/myc) CMS3 Metabolic (ras mut) CMS4 EMT Overall Survival Progression Free Survival Overall Cetuximab Bevacizumab Overall Cetuximab Bevacizumab 13.1 months 20.3 months 11.0 months 6.1 months 5.1 months 6.7 months 31.9 months 38.3 months 30.8 months 12.3 months 12.2 months 12.4 months 18.7 months 16.6 months 18.7 months 7.6 months 7.3 months 10.9 months 25.3 months 41.3 months 22.3 months 9.9 months 10.5 months 9.7 months Based on 385 pts of 592 pts that were enrolled on study
CMS and 80405 (Lenz et al, ASCO 2017, #3511) Overall Survival Progression Free Survival Overall Cetuximab Bevacizumab Overall Cetuximab Bevacizumab CMS1 Immune CMS2 Canonical (wnt/myc) CMS3 Metabolic (ras mut) CMS4 EMT 17.0 months 11.7 months 20.4 months 6.5 months 6.0 months 7.0 months 39.7 months 41.2 months 36.8 months 13.3 months 14.0 months 12.9 months NOT REPORTED, small n because they were excluded 23.7 months 20.0 months 26.7 months 9.6 months 9.5 months 9.9 months 392 primary tumors of pts who were k ras exon 2 nonmutated of 1135 pts overall on study
MOLECULAR PROFILING Classifications of mcrc? CONSENSUS MOLECULAR SUBTYPE q 50% ras mutated q 7-9% b-raf mutated q 2-4% MSI-H/dMMR q 4-5% HER-2 amplified q 1% NTRK q CMS1: 10-17%: MSI/Immune q CMS2: 34-47 (mostly 40)%: Canonical (Wnt/myc) q CMS3: 10-13% in unselected population, 2-4% in all ras wt Metabolic (ras mutated?) q CMS4: 23-45 (mostly 30)%: EMT q Not classified 42
Conclusions The right and left colon could be considered to be different organs, given differences in embryology, anatomy, etiology, and prognosis However, the therapeutic impact of sidedness, per se, is uncertain, and may be a gross reflection of underlying molecular biology Import of differences may be more important for more advanced disease (ie stage III, IV) rather than early stage disease There is no clear evidence for difference in treatment by chemotherapy Uncertain if there is a difference in outcomes with anti-vegf therapy Retrospective studies suggest that the impact of anti-egfr therapy are greater in the left colon Consensus Molecular Subtyping may be prognostic of outcomes, but less predictive ability with targeted therapy is unclear Not commercially or otherwise easily available
9/11/17 44 Vandenbroucke, Lancet 2004; 363: 1728-1731