PRECISION MEDICINE AND CANCER TREATMENT:

COLORECTAL CANCER AS A MODEL

Aru Sudoyo
Faculty of Medicine Universitas Indonesia (FKUI)
Indonesian Society of Hematology Oncology Internal Medicine
(PERHOMPEDIN)
Indonesian Society of Oncolgy (POI)
Global Cancer Statistics 2018 (GLOBOCAN)

Bray, et al. CA Cancer J Clin. 2018 Nov;68(6):394-424.

KANKER DI INDONESIA
• 25.8 per 100.000
dengan rate
kematian 23,2 per
100.000

• 15.9 per 100.000

dengan rate
kematian 10.8 per
100.000.

• 40.3 per 100.000

dengan rate
kematian 16.6 per
100.000
• 17.3 per 100.000
dengan rate
kematian 8.2 per
100.000.
(Globocan 2012)
•Harith Rajagopalan, Martin A. Nowak, Bert Vogelstein & Christoph Lengauer
Nature Reviews Cancer volume 3, pages695–701(2003)
 COLORECTAL CANCER : TREATMENT
• SURGERY
• CHEMOTHERAPY = “SYSTEMIC THERAPY”
• RADIOTHERAPY

• CYTOSTATICS
• BIOLOGICALS / TARGETED THERAPY
• IMMUNOTHERAPY
• OTHERS
Stage 2 and 3
STAGE 4
Advanced and Metastatic Disease
 Algorithm of mCRC
A 10-15% B 75-90% C

Resectable 1.Initially Non-Resectable Unlikely ever to

disease (potentially) Become resectable
2.Not optimally resectable (no option for resection)

Aim of treatment :
Aim of treatment : Curative Palliative
 Algorithm of mCRC
A 10-15% B 75-90% C

Resectable 1.Initially Non-Resectable Unlikely ever to

disease (potentially) Become resectable
2.Not optimally resectable (no option for resection)

Aim of treatment :
Aim of treatment : Curative Palliative
 In mCRC
Cytotoxics Remain the Nucleus
• First Line:
– 5-FU/capecitabine +/- bevacizumab
– FOLFOX +/- bevacizumab
– FOLFIRI +/- bevacizumab
– FOLFIRINOX +/- bevacizumab
– ? Role for EGFR targeted therapy in first line: 80405
• Second Line
– Reciprocal of first line +/- EGFR monoclonal AB
• Third Line:
– KRAS wt: EGFR monoclonal +/- irinotecan
– KRAS mt: no standard therapy

Marshall, 2012
 Stage 4 Colorectal Cancer is a
Continuum from curable
disease to incurable disease

Incurable
Curable High disease burden
with widespread
Low disease burden, metastatic cancer
generally with a single
solitary site of spread
1st line Palliative Chemotherapy

2nd line Palliative Chemotherapy

Chemotherapy & Surgical

removal of the site of
metastasis with the
intention of achieving cure
3rd line Palliative Chemotherapy
Experimental therapy or stop all
active cancer treatment (@BSC)
Role of Targeted Therapy ?
 CANCER TREATMENT AND PATIENT SAFETY :
CHALLENGES
• STAGE OF CANCER AT PRESENTATION : ADVANCED
• ANTICANCER DRUGS : ONE-FOR-ALL
• EFFECTIVE TREATMENT : MULTIPLE DRUGES (“REGIMEN”)
• SIDE EFFECTS : ALSO MULTIPLE
• THE CHALLENGE : SAFE AND EFFECTIVE CHEMOTHERAPY
CAUSE OF TREATMENT FAILURE :
TUMOR HETEROGENEITY
 Paradigm in CRC treatment

• Inter patient Heterogeneity

Biology • Need to Target biology

• Clinician: aim for the pts you can cure,

Aim based on their characteristics
• Not incremental gain, not ease of use,
but optimal use of anti cancer tools
 Paradigm in CRC treatment

• Inter patient Heterogeneity

Biology • Need to Target biology

• Clinician: aim for the pts you can cure,

Aim based on their characteristics
• Not incremental gain, not ease of use,
but optimal use of anti cancer tools
Treatment strategy in mCRC is becoming more complex

• After initial therapy

• Patient-related
– Resectability after tumour
– Age and comorbidities shrinkage
• Tumour- and treatment-related – Can we stop
– Adjuvant therapy with chemotherapy?
oxaliplatin? – Bevacizumab beyond
progression
– Resectable metastases?
– Neurotoxicity
– Resectable sites?
– KRAS status?
– Prognostic?
⚫ Future biomakers
– Oxaliplatin reintroduction:
stop and go? – ?????
 Ultimate goal of targeted therapy
First-line therapy for patients with metastases

Patient Upfront Borderline

Unresectable
assessment resectable resectable

Treatment Make eligible for Extend survival and

Curative surgery
goal curative surgery maintain quality of life

Treatment Chemotherapy Chemotherapy Chemotherapy

strategy  resection ± biologics ± biologics

Figure modified from Nordlinger, et al. Ann Oncol 2009

 Metastatic Colorectal Cancer
• Stage 3 and 4 : 70 percent
• Stage 4 : more than 42 percent*
• Chemotherapy : Palliative
• Condition of patient : less than ideal
• Important : specific drugs
• Needed : Biomarkers to guide decision
HOW SUCCESSFUL ARE WE?

28
New Paradigm : Personalized Treatment
WHERE ARE WE NOW ?
WHERE ARE WE NOW ?
CHANGE IN PARADIGM
Let’s think of precision medicine !

Adenocarcinoma Adenocarcinoma
Adenocarcinoma Adenocarcinoma

Mutations in : Mutations in :
APC APC
KRAS BRAF
P53 PIK3CA

Morphologically the same - Impersonal

Genetically different - Personal
 Precision Medicine

• Tumours which look similar can be

genetically very different
• The mutation profile may dictate patient
management
• Some mutations will give resistance to
therapy (e.g. KRAS mutations and anti-
EGFR therapy)
• Some mutations will give sensitivity to
therapy (e.g. C-Kit mutations and Glivec)
Adenocarcinoma Adenocarcinoma

Mutations in : Mutations in :
APC APC
KRAS BRAF
P53 PIK3CA

No: Cetuximab Yes: Aspirin

 Precision Medicine
• Based on the tumour profile, the patients
can be stratified into the appropriate
treatment group
• This would apply also to other diseases
(such as inflammatory diseases)
• However ……we are not just treating the
disease, we are treating the patient
• We need to take a holistic approach
APPROACH : INFORMATION

• DISEASE PATIENT

• DISEASE WHICH DRUG TO USE ?

• INFORMATION PATIENT HANDLING OF DISEASE

 Precision Medicine
• Information about the patients:
- may derive from the germline DNA and may
reflect inherited variants or newly acquired
variants
- may derive from the diseased tissue
(tumour tissue, inflamed tissued) and may
reflect somatic events
• The new technologies can give a huge
amount of information and this can be put
into discrete categories
New Paradigm : Right vs Left Sidedness
There are multiple differences between the right
and left colon and their associated tumors
Embryologic origin1 Function2 Microbiome3

Metabolism
Midgut Hindgut Almost inactive
Fermentation Biofilm Biofilm
metabolically
Proteolysis positive negative
Waste reservoir
Degradation
Processing

Epigenetic2,4,5 Genetic4,6

Methylation
MSI-High
BRAF mt See slide notes for references.
43
JNCCN, 2017
Sidedness matters in MCRC1–4

Tumor location – a master prognostic

factor

Right-sided (proximal) KRAS Left-sided (distal)

RAS RAS
colon cancer1 MSI KRAS colon cancer1
BRAF PIK3CA
PIK3CA
• More common in women PTEN APC • More common in men
TP53
• Microsatellite instability • Chromosomal instability
• Derived from mid-gut • Derived from hind-gut
KRAS
HER2
APC
TP53

Figure from Salem ME, e t al. Oncotarget 2017;8:86356 –86368. 5 mCRC, metastatic colorectal cancer.
1. Kim SE, et al. World J Gastroenterol 2015;21:5167–5175; 2. Venook A, et al. ESMO 2016 (Oral Presentation); 3. Dan Aderka. ESMO 2017 (Merck Satellite Symposium); 4.
Venook A, et al. JAMA 2017;317:2392–2401; 5. Salem ME, et al. Oncotarget 2017;8:86356–86368.
Tumor location
A prognostic factor for overall survival
Stage IV

Unadj. HR 95% CI
Right vs. Left 1,32 1,30 – 1,35
Overall survival

Rectal vs. left 1,01 0,99 – 1,03

— Right Colon
— Left Colon
— Rectum

n = 64770
Months

Primary CRC diagnosed 2000-2012 in a SEER region and followed for death through end of 2013,
N=64,770. R-sided 1° = cecum to transverse colon; L-sided 1° = splenic flexure to sigmoid
Schrag D, e t al. ASCO 2016 (Abstr. 3505) descending colon; 1° rectum = rectosigmoid and rectal
Hanahan, 2011
Cancer hallmarks in relation to colorectal cancer

Hagland, et al. Dig Surg 2013;30:12-25

IN PRACTICE ....
CRC Patient

Surgery Chemotherapy Radiation Adjuvant Therapy

Patients with similar

In recent
Treatment decisions years, CRC
are based Recentstudies were focused
Evidences on
clinicopathologic
on : molecular genetic changes which predicted to be harbor a
characteristics
more
• Patients’ clinical accurate markers than clinicopathological
features different genetic biology that
• Clinicopathological features regulates their tumor
features development
Gonzalez. Applied Cancer Research volume 37,
Article number: 13 (2017)
Dienstmann, 2017
Dengan segala kecanggihan dan kemajuan
pengetahuan …..…….

MULTIDISIPLINARY TEAM APPROACH

MEMEGANG PERAN PENTING

 Take Home MessageMARY

• CHANGE IN PARADIGM OF COLORECTAL CANCER TREATMENT

BROUGHT UPON BY ADVANCES IN KNOWLEDGE SHOULD BE
IMPLEMENTED BY THE MEDICAL PROFESSION
• RESECTABILITY EVEN IN METASTATIC COLORECTAL CANCER IS A
REALISTIC GOAL
• A MULTIDISCIPLINARY TEAM APPROACH INCREASES SURVIVAL
• PATIENT-DERIVED INDIVIDUALIZED ASSESSMENT SHOULD BE THE
BASIS OF TREATMENT DECISION
THANK YOU FOR YOUR ATTENTION