impact of tumor location in crc on treatment decision

Colorectal Cancer Advancements“Does tumor location affect treatment choice?” Mohamed Abdulla M.D.

03/11/2017

Member of Advisory Board, Consultant, and Speaker for:

• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag, Merck Serono, Novartis, Pfizer, Mundipharma, MSD, Ely Lilly

Speaker Disclosures:

Egypt Demographics:

Gender Lower Egypt2009 - 2011

Middle Egypt2009

Upper Egypt2008

Males 2.9% 2.1% 2.48%

Females 2.3% 2.3% 2.08%

Incidence Rates/100000 Population: Colon Cancer

Year 2013 2015 2020 2025 2050

Number 2862 3055 3608 4465 8585

Estimated Number of New Cases Over Time:

Ibrahim et al. Journal of Cancer Epidemiology. Volume 2014, Article ID 437971, 18 pages

mCRC:

The Expanding Landscape

mOAS

> 30 months

Efficacy of 1st L

“Biomarker”

Resection/Ablation of Organ Limited Disease

More Subsequent Treatment Options

Treatment Holidays (QoL)

Maintenance Therapy

Re-challenge Beyond Progression

Treatment Intensification

MDT Approach

1ry Tumor Location

Tumor Immunogenicity

Vogel et al. Cancer Treatment Reviews 59 (2017) 54–60

CALGB/SWOG 80405: KRAS wt

1ST LINE

MET / ADVANCED

COLORECTAL

KRAS wtCodons 12 & 13

FOLFIRIor

FOLFOX

MD choice

Chemo + CetuximabOS = 29.9 mosPFS = 10.4 mos

Chemo + BevacizumabOS = 29.0 mosPFS = 10.8 mosN = 1137

PRESENTED AT THE 2014 ASCO ANNUAL MEETING DATA IS THE PROPERTY OF THE AUTHOR

CALGB 80405: OAS

Alan P. Venook, MD et al. JAMA June 20, 2017 Volume 317, Number 23

80405: (KRAS WT) Overall Survival by Sidedness

Presented by:ASCO ANNUAL MEETING ‘16

SideN

(Events)

Median

(95% CI)

HR

(95% CI)p

Left 732 (550)33.3

(31.4-35.7) 1.55

(1.32-1.82)

<

0.0001Right 293 (242)

19.4

(16.7-23.6)

Right versus Left Colon:Evidence from Literature

Outcome Right Sided Colon Left Sided Colon P

5-Y OAS 1990s 56.3% 59.7% < 0.01

5-Y OAS 2000s 67% 71% < 0.01

5-Y PFS 2010 73% 74% > 0.05

5-Y PFS 2014 88.6% 89.4% > 0.05

Median OAS 18.2 ms 29.4 ms < 0.001

Shen etal. World J Gastroenterol 2015 June 7; 21(21): 6470-6478

Right versus Left Colon:Evidence from Literature

King et al. AJHO. 2016;12(10):4-11

Right versus Left Colon:Why different disease entities?

Different:• Blood Supply• LN Drainage

1. Embryologic Origin2. Blood Supply & Nodal Drainage

3. Microbiome Difference

4. Precancerous Lesions.

6. Histopathology & Natural History

5. Consensus Molecular Subtypes.

Stintzing et al. European Journal of Cancer 84 (2017) 69e80

3. Microbiome Difference:

Right Colon Cancer Left Colon Cancer

Prevotella, Pyramido-bacterium, Selenomonas and Peptostreptococcus.

Fusobacterium, Escherichia-Shigellaand Leptotrichia

Escherichia coli phylogroup B2. Helicobacter pylori infection

Dense Bacterial Aggregates

1. E-Cadherin2. IL-63. STAT3

Cellular Proliferation

Invasion of Colonic Mucous LayerProinflammatory Genes

Flemer et al. Tumour-associated and non-tumour- associated microbiota in colorectal cancer. Gut 2017;66(4): 633e43.

4. Pre-Neoplastic Lesions:

Lee et al. JNCCN—Journal of the National Comprehensive Cancer Network. Volume 15 Number 3. March 2017

Lee et al. JNCCN—Journal of the National Comprehensive Cancer Network. Volume 15 Number 3. March 2017

Molecular Alterations in CRC:

Molecular Alterations in CRC:

Stintzing et al. European Journal of Cancer 84 (2017) 69e80

5. Consensus Molecular Subtypes (CMS):

RIG

HT

CO

LON

LEFT

CO

LON

BETTER OUTCOME

WORSE OUTCOME

Guinney et al. Nature Medicine. 21,1350-1356 (2015)Lee et al. JNCCN—Journal of the National Comprehensive Cancer Network. Volume 15 Number 3. March 2017.

Parameter Right Colon Left Colon

Gender Female Male

Age Higher Lower

Grade Higher Lower

Mucoid Activity More Prevalent Less Prevalent

Stage Higher Lowe

Spread Peritoneum Liver & Lung

6.Natural History & Histopathology:

Nitsche et al. Right sided colon cancer as a distinct histopathological subtype with reduced prognosis. Dig Surg 2016;33(2):157e63.

Petrelli et al. Jama Oncology. 2017 Vol 3 Number 2

66 RCT = 1437846 Colon Cancer Patients

Location as an Independent Prognostic Factor:

TEJPAR et al. JAMA Oncology February 2017 Volume 3, Number 2

Right Versus Left Sided Colon Cancer OAS & Anti-EGFR:

Jhonathan et al. Ther Adv Med Oncol 2017, Vol. 9(8) 551–564


Right Versus Left Sided Colon Cancer PFS & Anti-EGFR:

Treatment Platform:


Take Home Message:

• Tumor location in mCRC has prognostic and predictive implication.

• Right colon cancer is doing much worse than left colon across treatment trials.

• Anti-EGFR directed therapies in RAS wild patients should not be used for patients with right sided colon cancer.

• Significant survival benefit was confirmed for both Anti-EGFR and Anti-VEGF directed therapies for left sided lesions.

• Bevacizumab is beneficial in right sided colon cancer particularly if BRAF mutation is present.

Thank You

impact of tumor location in crc on treatment decision

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