Colorectal Cancer Flashcards
Features of colorectal cancer
> 90% are adenocarcinoma, other histological variants include mucinous and signet cell
3 Types
- Sporadic
- Familial: no associated gene identified
- Hereditary
Hereditary nonpolyposis colorectal cancer (HNPCC)
Familial adenomatous polyposis
- Colorectal carcinogenesis
- Primary tumour location
Colorectal Carcinogenesis
1. Chromosomal Instability (CIN)
- Abnormalities in chromosomal copy number and structure caused by errors during mitosis
- APC/KRAS/TP53 genes
- Tends to occur in DISTAL/LEFT colon (descending), younger men, FAP
- APC = adenomas
- APC/B catenin pathway
Wnt signalling involved in gene transcription. Wnt pathway that causes an accumulation of β-catenin in the cytoplasm and its eventual translocation into the nucleus to act as a transcriptional coactivator. APC usually inactivates B catenin and inhibits gene transcription
APC gene is a tumour suppressor gene
- CpG island methylator phenotype (CIMP)
MLH1 promotor hypermethylation (also associated with BRAF mutations) - Microsatellite Instability (MSI)
- Loss of MMR (MLH1, MSH2) - mismatch repair
- MSI = sessile
- CIMP and MSI are correlated - 70% of MSI-h CRC are also CIMP high
- BRAF mutation is strongly associated with SPORADIC origin
- Tends to occur in PROXIMAL/RIGHT colon (caecum, AC, TC)
MSI high
CIMP high
BRAF mutation
Women, older age, white/black, HNPCC/lynch
Rectum
- Early onset CRC < 50yo
- Asian
Colorectal Cancer Screening
Category 1: near average risk
- No 1st/2nd degree relative with CRC
- One 1st degree relative with CRC >55yo
- One 1st degree and one 2nd degree with CRC >50yo
FOBT every 2 years from age 50-74yo
Category 2: moderately increased risk
- One 1st degree relative with CRC < 55yo
- Two first degree relatives with CRC diagnosed at any age
- One 1st degree relative and at least two 2nd degree relative with CRC at any age
FOBT every 2 years from age 40-49
Colonoscopy every 5 years from age 50-74
Category 3: potentially high risk
- At least 3 1st degree or 2nd degree relatives with CRC, at least 1 diagnosed <55yo
- At least 3 1st degree relatives with CRC at any age
FOB every 2 years from 35-44
Colonoscopy every 5 years from 45yo-74yo
Which tumours are harder to find on endoscopy?
Difference between left sided and right sided tumours
- Serrated adenomas are more common in R side of colon
- CIMP high, associated with MSI
- Flatter and difficult to visualise
- More commonly carry BRAF V600E mutation
Right sided: Less common, MUTYH mutation, mucinous, larger tumours, higher TNM, a/w RAS/BRAF, SESSILE SERRATED POLYPS
Left sided: KRAS, p53, APC, ADENOMAS
Features of Lynch Syndrome/ Hereditary non polyposis colorectal cancer (HNPCC)
- 2-4% of hereditary cancers
- Autosomal dominant with high penetrance
- Predominantly located in PROXIMAL RIGHT SIDED colon
- Mutation in MISMATCH REPAIR GENES - MLH1, MSH2, MSH6, PMS2
MSH2 and MLH1 >90% of cases - Often poorly differentiated, mucinous and infiltrating lymphocytes
Diagnostic Criteria - Amsterdam Criteria 3/2/1 rule
>3 relatives across >2 generations, with one diagnosed <50
- At least 3 relatives with Lynch associated cancer (colorectal, endometrial, small bowel, ureter, renal)
- At least 2 successive generations should be affected
- At least 1 should be diagnosed <50yo
Cancers associated with lynch syndrome
High Risk Of: COURSE
- colorectal cancer
- endometrial cancer - most common
- ovarian
- small bowel
- ureter
- renal pelvis
Surveillance and surgical management for individuals with HNPCC/Lynch
- Surveillance colonoscopy every 1-2 years
- Commence at age 25 or 5 years younger than the youngest affected member if < 30yo
- Extended resection (subtotal colectomy/total colectomy) generally favoured
- Annual surveillance required for residual colorectum
- Role of ASPIRIN chemoprophylaxis for all Lynch associated tumours
What is Muir Torre Syndrome
Muir-Torre syndrome, a variant of Lynch syndrome, is characterized by sebaceous tumors and cutaneous keratoacanthomas, in addition to cancers associated with Lynch syndrome
Phenotypic variant of hereditary nonpolyposis colorectal carcinoma syndrome (Lynch syndrome) caused by mutations in MLH1, MSH2 or MLH6 that are inherited in an autosomal dominant pattern. Causes the formation of several cutaneous tumours (eg: sebaceous adenomas and carcinomas, keratocanthomas) and visceral malignancies (eg: colorectal, endometrial, ovarian, urothelial)
Features of Familial Adenomatous Polyposis (FAP)
FAP
- <1%
- Germline APC mutation - autosomal dominant with high penetrance
APC: tumour suppressor, chromosome 5, frame shift mutations with premature stop codon
- Characterised by development of polyps ++++ in the DISTAL LEFT SIDED COLON, beginning from adolescence
- Risk of CRC reaches 100% by 40yo
Other cancers associated: (APC = GIT)
- papillary thyroid
- gastric cancer
- ileal carcinoid
• Extracolonic features: supernumerary teeth, desmoid/gastric cancers, papillary/follicular thyroid cancers
AFAP - Attenuated FAP
• <100 polyps, CRC 54y.
Surveillance and surgical management for patients with FAP
- Annual Colonoscopy from age of 10 until colectomy considered; screen for duodenal polyps from the age of 25
- In classical FAP, sigmoidoscopy is adequate since adenoma occur simultaneously throughout the colorectum
- Once an adenoma is identified, annual colonoscopy should be performed until colectomy is undertaken
- Colectomy is usually performed between 15-25 year
- NSAID is recommended as chemoprophylaxis where surgery is not indicated
Screening
• Classic FAP – screening colonoscopy at 10 years
• AFAP – screening colonoscopy at 25 years
Colectomy Indications
• Documented/suspected CRC
• Adenoma with High Grade Dysplasia
• Significant Sx related to CRC (GI bleeding)
• Marked increases in polyp number on consecutive exams
• Inability to survey colon due to multiple diminutive polyps
Hamartomatous polyposis syndromes
- Hamartomatous polyps can cause symptoms of bleeding or intussusception and obstruction
- Syndrome characterised by relatively benign appearing polyps of the GI tract, but also an increased risk of cancer.
- Peutz-Jeghers Syndrome
• Autosomal dominant, STK11 mutation
• FRECKLING, multiple hamartomatous polyps in the gastrointestinal tract (jejunum), mucocutaneous pigmentation (pigment laden macrophages), and an increased risk of gastrointestinal and nongastrointestinal cancer (CRC > Gastric > pancreatic > Breast) - Cowden Syndrome
• PTEN mutation, germline,
• Trichilemmomas, oral fibromas, and punctate palmoplantar keratoses, and an increased risk of breast, endometrial, thyroid, kidney and colorectal cancers. Macrocephaly
• Breast cancer is the most common malignancy in Cowden syndrome
• The most frequently reported extracutaneous manifestation of Cowden syndrome is thyroid disease ie thyroid nodules, Hashimoto
3.Juvenile polyposis syndrome
• SMAD4 germline mutation, autosomal dominant
• Polyposis since 10 years of age; 60% risk of CRC by 60 years
Lifestyle RF for CRC
• Excess body weight, low levels of physical activity
40% increase risk of CRC if BMI >30
• High consumption of processed meat and EtOH
• Low fibre consumption
• Cigarette smoking
Diagnosis of CRC
- Colonoscopy + biopsy
- Imaging
Colorectal: CTCAP to exclude distant metastatic disease
Rectal:
MRI rectum to assess local extent of disease
If locally advanced (T3/4, N+) then consider neoadjuvant therapy
Staging of CRC
TNM I: into submucosa II: into muscularis propria III: LN involvement IV: metastatic Common: liver, lung, bone, brain, spinal cord
Treatment for CRC
(A) Stage 1: Surgery
(B) Stage 2:
- Low Risk: surgery
- High Risk: surgery + adjuvant chemo
High Risk defined as:
- T4 disease
- Poorly differentiated histology
- Presence of obstruction, perforation
- Lymphovascular invasion
- Perineural invasion
- Inadequate LN sampling < 12
(C) Stage 3: surgery + adjuvant chemo
Adjuvant Chemo: Involves 5-fluorouracil/capectiabine + oxaliplatin or capectiabine alone
(D) Stage 4: palliative chemo -Liver only: resect if possible - Check for BIOMARKERS - Chemotherapy: 5FU + Oxaliplatin OR 5FU + Irinotecan (SN38- topoisomerase I inhibitor)
Targeted Therapies
- Bevacizumab: VEGF inhibitor (regardless of RAS/RAF status, location)
- EGFR inhibitors: cetuximab/panitumumab - only in KRAS WT tumours, left sided primary
- BRAF V600E mutation:
Encorafenib (BRAF V600E) + Cetuximab (EGFR) + Binimetinib (MEK)
- Checkpoint inhibitor: PD1 inhibitor pembrolizumab for Mismatch Repair Deficiency
RECTAL CANCER: high chance of local recurrence.
- Resect in T1-2 with no nodal disease.
- Resect + neoadjuvant chemoradiotherapy + adjuvant chemotherapy in T3-4 or in nodal disease.
SURVEILLANCE: 3 monthly CEA, 6 monthly CT CAP for 3 years, then annual for the next two years
What happens in BRAF V600E mutation
EGFR –> RAS –> BRAF V600E mutation exon 15 –> MEK ++ –> ERK ++ = stimulation of cancer cell growth
5-fluorouracil (5-FU)
Capecitabine
Are pro-drugs
SE
- Diarrhoea
- Hand/foot syndrome - capecitabine > 5FU
- Mucositis
- Rarely coronary artery spasm and myelosuppression
DPD enzyme is encoded by the DPYD gene
Patients with DPD deficiency who are treated with 5FU or capecitabine are at significantly increased risk of developing severe and potentially fatal mucositis, diarrhea, myelosuppression/neutropenia
Oxaliplatin
- Platinum derivative
- Usually used in combination with 5FU or capecitabine
SE:
- Peripheral neuropathy
- Diarrhoea
- Neutropenia/myelosuppression
- Cold induced pharyngolaryngeal dysethesia
- Hypersensitivity reaction
Irinotecan
- Topoisomerase I inhibitor
- Active as monotherapy or in combination with 5FU
SE:
- Diarrhoea
- Myelosuppression
- Neutropenia
- Early onset diarrhoea due to acute cholinergic syndrome can be treated with atropine
Toxicity can be caused by insufficient deactivation (glucuronidation) or irinotecan active metabolite SN=38 by UGT1A enzyme
- Gilbert Syndrome
- Crigler-Najjar type 1 and 2 syndrome - unable to clear bilirubin
EGFR/RAS Pathway - MAPK Pathway
MAPK Pathway
-EGFR –> KRAS –> BRAF –> MEK –> ERK = normal cascade results in regulated activation of nuclear signalling
- COLORECTAL: EGFR is overexpressed in about 80% –> KRAS WILD TYPE/NOT MUTATD
- LUNG: EGFR MUTATIONS in 10-30%, KRAS pG12c mutations
- MELANOMA - BRAF MUTATIONS
- BREAST: HER2 POSITIVE/AMPLIFIED
(an EGFR domain)
Cetuximab/Panitumumab
Cetuximab/Panitumumab are EGFR inhibitors
- MONOCLONAL ANTIBODY that inhibits EGFR
- Binds to an EXTRACELLULAR PORTION of EGFR protein
- Only treats METASTATIC CRC KRAS WILD TYPE, LEFT SIDE PRIMARY
- Note: EGFR is a TRANSMEMBRANOUS TYROSINE KINASE PROTEIN
SE:
- Acneiform rash - SEVERITY CORRELATES WITH RR + OS
- Diarrhoea
- Pneumonitis
- Hepatotoxicity
- Skin and nail toxicities - xerosis (dry skin), paronychia nail inflammation
- Hypo K/Mg/Ca
What sided CRC do worse?
Right sided
RP RAS WT – lack of response to EGFR inhibitors
EGFR inhibitors - cetuximab and panitumumab only work in LP RAS WT
LEFT SIDED RAS WT TUMOUR:
EGFR INHIBITORS - cetuximab, panitumumab
RIGHT SIDED + RAS MUTANT:
VEGF INHIBITORS - Bevacizumab
EGFR INHIBITORS
- Transmembrane tyrosine kinase protein - has EXTRACELLULAR and CYTOPLASMIC domains
COLORECTAL CANCER (EXTRACELLULAR)
- CetuxiMAB and panitumuMAB
- MONOCLONAL antibody that inhibits EGFR - binds to an EXTRACELLULAR portion of EGFR
- KRAS WILD TYPE
LUNG CANCER (INTRACELLULAR)
- GefitiniIB, ErlotinIB, OsimertinIB
- INTRACELLULAR TYROSINE KINASE INHIBITOR
- Inhibits EGFR by CROSSING THE CELL MEMBRANE and blocking the receptor’s active site
- EGFR MUTATED
Bevacizumab
- VEGF-A Inhibitor
- Inhibits new vessel growth, regression of newly formed tumour vasculature, normalisation of tumour blood flow
- Used in conjunction with chemo
SE
- Hypertension - seen as a PREDICTIVE MARKER
- Proteinuria/nephrotic syndrome
- GI perforation
- Delayed wound healing
- Bleeding/increased risk of haemorrhage: intracranial or pulmonary haemorrhage
- Arterial thromboembolic events - CVA/TIA/AMI
What do you give for BRAF V600E mutation in CRC?
- BRAF mutations are mutually exclusive of KRAS mutation (both are not mutated)
- Associated with shorter overall survival
- Similar to KRAS mutations, do not respond to EGFR inhibitors
Encorafenib (BRAF V600E) + Cetuximab (EGFR) + Binimetinib (MEK)
What is mismatch repair deficient CRC
Mismatch Repair Deficient = MSI microsatellite instability/unstable
- MMRd = 15% CRC
12% sporadic, 3% hereditary
- Lynch Syndrome
Inherited GERMLINE defect in one of the four (MLH1, MSH2, MSH6, PMS2) followed by 2nd inactivating SOMATIC changed in the remaining WT allele - Sporadic MMR deficient tumours
- Both alleles of a mismatch repair gene are INACTIVATED by SOMATIC MUTATIONS or by EPIGENETIC SIGNALLILNG
- 80% of cases caused by methylation of the MLH1 gene promoter
- In sporadic MSI - most common cause of MLH1 gene activation is promotor hypermethylation (epigenetic silencing), BRAF is a surrogate marker!
- Both hereditary and sporadic forms result in the inability of cells to recognise and repair spontaneous mutations resulting in high tumour mutation burden and have high microsatellite instability.
Treated with PD1 inhibitor PEMBROLIZUMAB
Prembolizumab
PD1 blocker
Used in mismatch repair deficient CRC - eg: hereditary (lynch) or sporadic
In Lynch syndrome what is the most typical phenotype?
Right sided
<50yo
Microsatellite instability
What cetuximab SE predicts response? A. Worsening diarrhoea B. Severe mucositis C. Severe N+V D. Acneiform rash E. Neutropenia
D. Acneiform rash
Which is the least likely SE to occur with Bevacizumab? A. Bowel perforation B. Hypertension C. Febrile neutropenia D. Proteinuria E. Myocardial infarct
C. Febrile neutropenia
Remember monoclonal antibodies don’t really cause febrile neutropenia
A man with node positive sporadic CRC was treated 12 months ago with surgery + chemo. He is currently followed up with regular CEA and annual CT scan. Detecting which of the following would be strongest reason for following this patient up in this way?
A. Anastomotic recurrence
B. A separate primary malignancy
C. Minimal residual disease so that chemo can be commenced
D. Pancreatic cancer
E. Resectable secondaries to liver and lung
E. Resectable secondaries to liver and lung
What is KRAS NRAS WT?
NRAS mutations are mutually exclusive from KRAS and NRAS mutation testing should be performed when KRAS is wild-type.
The presence of NRAS mutations is associated with lack of response to cetuximab therapy.
63M has been diagnosed with metastatic CRC with liver and lung mets. He has a ECOG of 1. Mutation analysis shows that he is WT for KRAS but has a mutation in NRAS. He is subsequently commenced on bevacizumab/FOLFIRI. What is false regarding this man’s case
A. Bevacizumab should be used because his tumour’s NRAS mutation makes him unsuitable for EGFR monoclonal antibody inhiitors
B. He is NOT a candidate for curative resection because he has multiple sites of mets
C. Bevacizumab when added to his regimen may extend survival by 2-3 months
D. Bevacizumab SE include hypotension and predisposition to excessive bleeding
E. VTE and increased GIT fistulas are SE of treatment
D. Bevacizumab SE include hypotension and predisposition to excessive bleeding
Should be hypertension
Causes of elevated CEA
- Gastric cancer
- Colorectal Cancer
- Lung cancer
- Breast cancer
C-BGL
Benign conditions which can elevate CEA include:
- smoking
- infections
- inflammatory bowel disease
- pancreatitis,
- cirrhosis of the liver
A colorectal cancer is found to have features of microsatellite instability.
Which of the following would be most suggestive of this being a sporadic, rather than genetically inherited, cancer?
A. Associated BRAF mutation in tumour tissue
B. Associated MLH1 gene mutation
C. Associated MSH2 gene mutation
D. A family history of uterine cancer
E. Diagnosis of colorectal cancer before the age of 50 years
A - Associated BRAF
MS is found classically in lynch syndrome but can also be found in sporadic cancer. When it does occur, it occurs with BRAF
