Post on 11-Jul-2020
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
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