RIGHT OR LEFT CRC- DOES IT

MATTER?
Anjana Joel
Department of Medical Oncology
CMC, Vellore
18.11.2016
 SCHEMA
• Definition of RSCC (vs) LSCRC
• Differences in:
– Clinical presentation /epidemiology
– Genomic pattern
– Prognosis
– Outcomes with targeted therapy
• Conclusions and take home messages
 DEFINITION OF RIGHT (VS) LEFT COLO-
RECTAL CANCER

DEFINITION USED IN TRIALS:

• CRYSTAL
• FIRE-3
(RSCC) (LSCRC) • PRIME
• PEAK
• CALGB/ SWOG 80405
 DIFFERENCES IN CLINICO-PATHOLOGICAL
FEATURES IN mCRC
CHARACTERISTIC RIGHT SIDED COLON LEFT SIDED COLO-RECTAL
CANCER (RSCC) CANCER (LSCRC)

Age at presentation Higher; 71-74 yrs 66-71 yrs

T Stage at presentation Higher proportion of Lower proportion of
(metastatic setting) p-T3/4 p-T3/4
T size at presentation More Less
(metastatic setting)
Tumour differentiation Poorly diff Mod diff more common
Mucinous histology More Less
Patterns of metastatic Peritoneal carcinomatosis Distant mets (liver/ lung)
disease
 DIFFERENCES IN GENOMIC EXPRESSION PATTERN
CHARACTERISTIC RIGHT SIDED COLON CANCER LEFT SIDED COLO-RECTAL
(RSCC) CANCER (LSCRC)
EGFR/ c- erbB2 expression Less common More common
KRAS mutation • Lower incidence • Higher incidence
• No diff in prognosis between • Associated with poorer
KRAS mut and WT prognosis if present
• ? Association with distant
metastases
NRAS Mutation Less common More common

BRAF mutation (among KRAS Higher incidence in RSCC Less common in LSCRC
WT)
P53 Higher p53 gene mutation Less
Chromosomal instability Less More

Ploidy Generally diploid Aneuploid (CIN PATHWAY)

MSI High (MSI PATHWAY) Low
CpG island methylation (CIMP) High (CIMP PATHWAY) Low
ROLE OF GENDER?
• Overexpression of ER-Beta
receptor only in right colon
• Protective effect of HRT for
RSCC
 DIFFERENCES IN MICRO BIOTA AND
IMMUNOLOGY
DIFFERENCES IN MICRO BIOTA
• Bacterial biofilm in RSCC
• Associated with higher
expression of E-Cadherin, IL-
6 and STAT-3
DIFFERENCES IN IMMUNOLOGY
• Higher concentration of
eosinophils and
intraepithelial T cells in the
RSCC compared to LSCRC

Christaine Deja et al. PNAS 2014

RSCC (vs) LSCRC IN STAGE IV CRC
 DIFFERENCES IN TUMOUR BIOLOGY IN STAGE
II/III DISEASE

Integrated Analysis of Molecular and Clinical Prognostic Factors in Stage II/III Colon Cancer. AD Roth et al. JNCI 2012
 CONSENSUS MOLECULAR SUBTYPE (CMS )
CLASSIFICATION
RSCC

LSCRC
1. The consensus molecular subtypes of colorectal cancer. J Guinney et al. Nat Med.  2015
Nov;21(11):1350-6
2. Michael Lee et al. ASCO 2016
The Cancer Genome Atlas Network Nature 487, 330-337 (2012)
TUMOUR LOCATION (VS) BIOLOGY

“CONTINUUM HYPOTHESIS”
Kimmie Ng ASCO 2016
IMPACT OF TUMOUR LOCATION ON
SURVIVAL OUTCOMES IN m-CRC
1. CALGB/SWOG 80405- ASCO 2016
2. META ANALYSIS FROM JAMA ONC
2016
CALGB/SWOG 80405 TRIAL-ASCO 2014
CALGB/SWOG 80405 TRIAL-ASCO 2016
UPDATE
CALGB/SWOG 80405 TRIAL-ASCO 2016
UPDATE
 CALGB/SWOG 80405 TRIAL-ASCO 2016
UPDATE
CONCLUSIONS FUTURE DIRECTIONS
• PROGNOSTIC: • Practice changing????
– RSCC has worse outcome • Need for stratification in
when compared to LSCRC future trials based on
– Irrespective of biological
tumour location
choice
• PREDICTIVE:
– Different treatment effects of
1st line Cetuximab (vs)
Bevacizumab in diff subgroups
• Sidedness- ? Surrogate for
tumour biology
 META-ANALYSIS – PROGNOSTIC SURVIVAL
ASSOCIATED WITH LSCRC VS RSCC
• Included 1 437 846 patients among 66 studies
• Median follow-up: 65 months.
• Left sided primary tumor location was
associated with a significantly reduced risk of
death (HR, 0.82; 95% CI, 0.79-0.84; P < .001)
• Independent of stage, race, adjuvant
chemotherapy, year of study, number of
participants.
Prognostic Survival Associated With Left-Sided vs Right-Sided Colon Cancer - A Systematic Review and Meta-
analysis. Petrelli F et al. JAMA Oncology Oct 2016
TUMOUR LOCATION IN m-CRC AND
RESPONSE TO TARGETED AGENTS-
UPDATES FROM ESMO 2016
1. Cetuximab (CRYSTAL)
2. Panitumumab (PRIME)
3. Cetuximab / Bevacizumab (FIRE3)
NCI CO 17: EFFECT OF TUMOUR LOCATION VS
OUTCOME (CETUXIMAB+BSC VS BSC)

Brule SY et al. Eur J cancer. 2015

CRYSTAL TRIAL
RETROSPECTIVE ANALYSIS OF THE CRYSTAL
TRIAL- ESMO 2016

Eric van Cutsem et al: ESMO 2016

THERAPEUTIC IMPLICATIONS-
PANITUMUMAB
 CONCLUSIONS- ANTI EGFR THERAPY

PROGNOSTIC PREDICTIVE

RSCC has worse prognosis than 
In LSCRC:
LSCRC: 
Addition of Cetuximab improved

In both 1st- and 2nd-line survival outcomes in LSCRC
settings, regardless of treatment (KRAS WT) (CRYSTAL)
received. 
Panitumumab + chemotherapy

Even after adjusting for BRAF provides better outcomes
status compared with chemotherapy ±
bevacizumab (PRIME/PEAK/101)

Higher incidence of BRAF mutations
in RSCC (30% vs 5%) (Panitumumab

In RSCC:
trials) 
Cetuximab: No significant benefit

Role of further of addition of Cetuximab
biomarkers???? 
Panitumumab: Difficult to
conclude due to small numbers
 FIRE-3 TRIAL

Stintzing S et al. Lancet Oncology 2016

 FIRE-3: primary endpoint

Evaluation of OS* in RAS wt patients N=

= ORR

400

N=400 FOLFIRI + FOLFIRI + OR/ HR P

1. Cet Bev
0 — FOLFIRI + (N=1 (N=2
99) 01)
Cetuximab
— FOLFIRI +
0.7
5 Bevacizumab OS 33.1 25 0.697 0.00
OS estimate

(mo) 59

0.5 ORR, 65.3 58.7 1.33 0.18

0 %

0.2 PFS, 10.3 10.3 0.97 0.77

mo
5

0.
0
12 36 48

60 Stintzing S, et al. Lancet Oncol 2016

*OS evaluated as a
24 72
 FIRE-3: TUMOUR LOCATION
LOCATION NUMBER
(n=400)
Right sided 88(22%)
Left sided 306 (76.5%)
Indeterminate 6 (1.5%)
FIRE 3: LSCRC
FIRE 3: RSCC
 Efficacy results stratified by tumor location
Right-sided Left-sided
Cetux+ FOLFIRI Bev+ FOLFIRI (n=50) Cetux +FOLFIRI Bev+FOLFIRI (n= )
(n=38) (n=)
ORR, % 52.6 50.0 68.8 61.7
Odds Ratio 11.1 1.37
P-value 0.83 0.23

PFS, 7.6 9.0 10.7 10.7

months
Hazard 1.44 0.90
Ratio
P-value 0.11 0.38

OS, months 18.3 23.0 38.3 28.0

Hazard 1.31 0.63
Ratio
P-value 0.28 0.002

1
3
 CONCLUSIONS
• Confirms association of right-sided tumor location with poor
prognosis

• Significant interaction between tumor location and

treatment effects for OS, but not for ORR or PFS

• In LSCRC:

• Cetuximab plus FOLFIRI is superior to bevacizumab plus

FOLFIRI

• In RSCC:

• Numerically (but not statistically) greater benefit from

bevacizumab plus FOLFIRI
1
7
META ANALYSIS OF RCTS- OS ACCORDING TO
SIDE AND TREATMENT
Pignon and Douillard. ESMO 2016
TRIBE TRIAL- ? ROLE OF INTENSIFICATION OF CHEMO (3
VS 2 DRUG )

Loupakis F et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med
2014
 STRENGTHS AND LIMITATIONS
STRENGTHS LIMITATIONS

High RAS/BRAF ascertainment; 
Definition of Right vs Left colorectal
though retrospective cancer

Rectum included as LSCRC- ? Different

Over 80% ascertainment for biology for rectal (vs) left colonic
tumor sidedness; process tumours
blinded to treatment and 
Unplanned, retrospective, exploratory
outcome analyses

Potential imbalances between treatment
subgroups due to lack of randomization

Small numbers of patients with right-
sided tumours

No data on biomarkers beyond RAS and
BRAF

No data on RAS Mut tumours
IMPLICATIONS FOR OUR DAILY
PRATICE?
IMPLICATIONS FOR OUR DAILY PRATICE?
• Practice changing????
– Can guide decisions on choice of therapy- especially in a
resource limited setting
• Reinforces the need for Pan-RAS and RAF testing
• Need future trials to be stratified as per tumour
location
• ? Intensification of therapy based on tumour location
• ? Role of newer agents (demethylating agents in RSCC,
anti Her 2 neu therapy in LSCRC , Immune checkpoint
inhibitors in RSCC)
 TAKE HOME MESSAGES
• Different tumour biology based on tumour location (RSCC vs
LSCRC)
• Prognostic effect: RSCC worse than LSCRC (OS, PFS and ORR)
• Predictive effect:

RSCC LSCRC
• THANK YOU…