Cambridge Cancer CentreLectures in Cancer Biology &

Medicine

Biology and fundamental management of colorectal cancer

Incidence

About 40K cases per

annum (UK)

Mortality

Survival – age standardised 10y

57% survival (5 year)

Sporadic (average risk) (65%–85%)

Familyhistory

(10%–30%)

Hereditary non-polyposis colorectal cancer (HNPCC)

(5%)Familial adenomatous polyposis (FAP)

(1%)

Rare syndromes

(<0.1%)

Aetiology provides biological insights

Sporadic CRC risk factors

• 54% of CRCs are linked to lifestyle and other risk factors

• Red & processed meat (21%)

• Obesity (13%)

• EtOH (12%)

• Smoking (8%)

• Radiation (2%)

• Fibre intake and physical activity are protective

Cell of origin

Cell of origin ctdStem Cell Non-stem cell

Barker et al, Nature. 2009Schwitalla, Cell. 2013

Cell of origin ctd

The Wnt pathway

Classical genetics – the ‘Vogelgram’

Fearon & Vogelstein, Cell. 1990

Classical epigenetic contribution – CIMP & MMR

Toyota et al, PNAS. 1999Eso et al. Journal of Gastroenterology. 2019

Classical CRC sub-types

Contemporary genetics/epigenetics/transcriptome and the proteome: the NGS era

TCGA. Nature. 2012 De Sousa et al. Nat Med. 2013Zhang et al. Nature. 2014

Consensus CRC Classfication

Guinney et al, Nat Med. 2015

Intratumoral heterogeneity?No more Vogelgram

Big Bang or Branched Evolution?

Sottoriva et al, Nat Genetics. 2015

Clinical Management

Presentation

• Bleeding

– Fresh or dark. Mixed with stool.

• Change in bowel habit

– Commonly to looser

• Weight loss & loss of appetite

• Abdominal pain

• Peri-anal symptoms

Investigations – how we make the diagnosis

• History & Examination inc‘the finger’ and rigid sigmoidoscopy

• Blood tests

– Fe def anaemia

– NOT tumour marker (CEA)

• Colonoscopy/Flexible sigmoidoscopy - histology

• CT colography

Polyp management

• Diagnosis made on endoscopy

• Risk factor for developing CRC ... but prolonged (10-15 years)

• Endoscopic removal

• Subsequent surveillance – time course dependant on # and size. High gddysplasia treated as CRC

• FAP managed surgically

Staging – how advanced?

• Colon– CT Chest/Abdomen/Pelvis

• Rectal– CT Chest/Abdomen/Pelvis

– MRI (local staging)

T N Mtumour/node/metastasis

‘Dukes’ StageAJCC – American Joint Committee on

Cancer

Routes of metastasis

Vascular i.e. haematogenous

Lymphatic

Transcoelomic

Treatment – non-metastatic

Colon

• Occasionaly neo-adjuvant chemo (T4)

• Surgery

• Histology

• Adjuvant chemotherapy (path stage)

Rectal

• MRI stage– Straight to surgery (GOOD)

– Short course RT (BAD)

– Long course neo-adjuvant chemoradiotherapy (UGLY)

• Histology

• Adjuvant chemotherapy (path stage)

• Option of total neoadjuvant therapy (TNT): SCRT followed by extended chemotherapy

Treatment metastatic

• If liver mets resectable – resect mets and primary

– ?order

• If not ... ?

– Palliative chemo

– Resection of primary

• Avoidance of local complications

• ?benefit

• Ongoing studies

Principles of surgery

• Macroscopic resection of the primary tumour

• Regional lymph nodes– ?for staging purposes

– ?for oncological benefit

• Avoidance of stomas and restoration of bowel continuity

• Laparoscopic or Open

Halsted & Cady-Fisher theories of cancer progression

Chemotherapy – often combo

• 5-fluorouracil (5-FU)

• Leucovorin (Folinic Acid)

• Capecitabine (Xeloda) – pro-drug converted to 5-FU within tumour

• Irinotecan – topoisomerase inhibitor

• Oxaliplatin – alkylating agent

• Targeted Therapies

– Bevacizumab (Avastin) – monoclonal Ab VEGF

– Cetuximab (Erbitux) – monoclonal Ab EGFR

Chemotherapy

Who gets what and which?

Risks V Benefits

Progression free and overall survival (TCGA)

Follow up

• Generally 3 or 5 years

• Annual clinical assessment & CT (C/A/P)

• Surveillance colonoscopy of remaining colon

Treating recurrence

• Local recurrence

– Surgery

– Radiotherapy

– Chemotherapy

• Metastatic

– Palliative chemotherapy

Summary

• CRC is a heterogeneous disease both between tumours and within tumours

• CRC arises through multiple oncogenic routes

• Fundamental questions about what drives the adenoma-carcinoma transition remain poorly understood

• CRC is potentially curable if diagnosed early

• Treatment is multi-modality

https://www.stemcells.cam.ac.uk/research/pis/dr-buczacki

https://crukcambridgecentre.org.uk/research/programmes/aerodigestive-cancer

@SiBucz

Questions