13 & 14 - Colon Cancer Flashcards
Third most common cancer in the USA
Colon Cancer
Leading cause of cancer death in non-smokers
Colon cancer
Majority of colorectal cancers
Sporadic
Risk in general population of colorectal cancer
6 - 8%
Risk for those with personal history of colorectal neoplasia
15% - 20%
Risk for those with IBD
15% - 40%
Risk for those with Lynch Syndrome
80%
Risk for those with FAP
100%
Strongest risk factor for colorectal cancer in general population
Age
Upswing begins at 50
Other risk factors for CRC
High red meat diet Prior history of adenoma or cancer Family history of adenoma or cancer High fat diet smoking obesity
Protective factors for CRC
High physical activity Aspirin/NSAID use High vegetable/fruit diet High fiber diet High folate/methionine diet High calcium intake postmenopausal hormone therapy
First degree family history of CRC
Shift screening 10 years earlier
Hereditary Colorectal Cancer Syndromes
Familial Adenomatous Polyposis (FAP)
Lynch Syndrome
Both involve germline inheritance of gene mutations
Autosomal dominant
Sporadic Cancer
Tumor initiation 30 - 50 years
Tumor progression 10 - 20 years
Carcinoma 6% risk - mean age 66 years
FAP
Tumor initiation 5 - 20 years
Tumor progression 10 - 20 years
Carcinoma 100% risk - mean age 40 years
Lynch Syndrome
Tumor initiation 30 - 50 years
Tumor progression 1 - 3 years
Carcinoma 80% risk - mean age 40 years
Clinical Features of FAP
1% of all CRC 100 - 1000s of adenomas APC gene mutations Risk of extracolonic tumors (desmoids, duodenal cancer, thyroid, brain) Risk of CRC 100% if untreated
Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE)
Associated with FAP
Desmoid Tumor
Fibrous, non-malignant, obstruction is greatest risk
Surgery increases their risk.
They grow back bigger.
Diagnosis of FAP
APC gene mutations in >90% with classic polyposis
Family history: AD inheritance
Prevalence 1/8000
De novo mutations - 30% of carriers have no family history
Management of FAP
Sigmoidoscopy at 10 - 12 years and every 2 years to assess polyp burden
Colectomy
Upper GI surveillance for adenomas
Genetic counseling
Lynch Syndrome
Most common hereditary CRC syndrome 5% of all CRC Defective DNA mismatch repair Mutations in MLH1, MSH2, MSH3, PMS2 Lifetime risk of CRC = 70 - 80% Risk is markedly lower if we begin colonoscopies early
Lynch Syndrome - Clinical Features
Striking family history (multiple generations) Early (but variable) age at CRC diagnosis (mean 45 years) Multiple primary cancers Extracolonic cancers: Endometrium Ovary Urinary tract Stomach Small bowel Sebaceous carcinomas of skin
Lynch Syndrome - Mechanism
Failure of mismatch repair (MMR) genes
Microsatellite instability
Lynch Syndrome - Amsterdam Criteria
Three or more CRC diagnoses in a family Two or more generations 1 case is a first degree relative of the other two One is affected by age 50 FAP excluded
Lynch Syndrome - Revised Bethesda Guidelines
CRC
Lynch Syndrome Screening Recommendations
Colonoscopy starting at age 20 - 25, repeat every 1 - 2 years
Transvaginal ultrasound & endometrial aspirate annually starting at age 25 - 35
Asymptomatic, no risk factors
Start screening at age 50 Colonoscopy Flexible sigmoidoscopy CT colonography Double contrast barium enema Fecal stool tests (Guaiac-based fecal occult blood test or fecal immunohistochemical test) - Can't detect polyps, though...
Screening for patients risky enough to warrant colonoscopy
History of adenomas History of CRC Family history of adenomas Family history of CRC IBD Hereditary CRC Syndromes
Right colon symptoms
Occult bleeding
Obstruction
Anemia
Abdominal Mass
Left colon symptoms
Gross bleeding Obstruction Anemia Change in bowel habits Pain
Metastatic CRC Spread
Lymphatics:
Mesenteric nodes
Virchow’s nodes
Hematogenous spread:
Liver via portal circulation
Types of polyps
Adenomas
Serrated sessile polyps
Hyperplastic polyps
Adenomas
True pre-malignant lesions that have a risk for developing cancer
Blue means dysplasia
Lack of surface maturation
Proliferation extends to surface
Hyperplastic polyps
Benign Pink Saw tooth shape of surface epithelium Normal surface maturation No dysplasia Proliferation restricted to crypts
Pedunculated Adenomas
Nice stalk
Easier to excise than sessile
Sessile Adenomas
Gotta resect
Polypectomy is effective/curative if
Stalk margin has normal colonic mucosa
No lymphatic/vascular invasion
Tumor is not poorly differentiated
Dysplastic Crypt
Earliest sign of an adenoma/adenocarcinoma to come
Never catch it at this point
If you can catch it (probably via familial setting) you can cure it before ever forming a polyp
WNT Pathway
At rest, WNT is inactive
APC destroys beta catenin
WNT signaling prevents APC’s action and beta catenin remains intact. Proliferation!
FAP - with regard to WNT pathway
Always on!
You don’t even need WNT.
It is a problem with APC
Beta Catenin never gets degraded!!
Key protein in sporadic cases
Always MLH1 - but not due to a mutation
It is epigenetics! The promoter is methylated!
MSH2 deficiency - Sporadic or Lynch?
LYNCH!!!
2 Molecular categories of CRC
Microsatellite Instability
Chromosombal Instability
CRC - Microsatellite Instability
Nucleotide-level mutations
Hypermutated (many at high frequency)
15% of CRC
Leads to HNPCC/Lynch (Germline Mutation of MLH1, MSH2, MHS6, PMS2, MMR genes)
OR
Leads to Sporadic MSI+ (Epigenetic silencing of MLH1 by hypermethylation of its promotor region)
CRC - Chromosomal Instability
More macro genetic mutations
Non-hypermutated (low frequency)
85% of CRC
Leads to FAP (Germline mutation of APC gene)
OR
Leads to Sporadic CIN (Acquired mutations of APC, p53, DCC, KRAS, LOH)
What genetic testing do we do on all cases of CRC?
KRAS BRAF PIK3CA MMR Lynch
TNM Classification (Tumor Node Metastasis) - Tumor
T - Primary Tumor
Tx - Primary tumor cannot be assessed
T0 - No evidence of primary tumor
Tis - Carcinoma in situ (intraepithelial or intramucosal invasion of lamina propria)
T1 - Tumor invades submucosa (start to develop risk of invasive tumor/metastatic invasion)
T2 - Tumor invades muscularis propria
T3 - Tumor invades through muscularis propria into subserosa or into pericolic/perirectal fat
T4 - Tumor directly invades other organs or structures and/or perforates the visceral peritoneum
TNM Classification (Tumor Node Metastasis) - Node
N0 - No regional lymph node metastasis
N1 - Metastasis in 1 to 3 regional lymph nodes
N2 - Metastasis in 4 or more regional lymph nodes
TNM Classification (Tumor Node Metastasis) - Metastasis
M0 - No distant metastasis
M1 - Distant metastasis
Stage 1 Colorectal Cancer
25% of CRC
Cancer has grown through mucosa and invades muscularis
Treatment - Surgery to remove the tumor & some surrounding lymph nodes
5-year Survival 90%
Once you reach 5 years, recurrence is unlikely
Stage 2 Colorectal Cancer
30% of CRC
Cancer grows beyond muscularis of the colon or rectum, but has not spread to lymph nodes
Treatment (colon) - Surgery +/- adjuvant chemo
Treatment (rectal) - Sugery, radiation, chemo
Stage 3 Colorectal Cancer
25% of CRC
Cancer has spread to regional lymph nodes
Treatment (Colon) - Surgery and adjuvant chemo
Treatment (Rectal) - Surgery, radiation & Chemo
Survival - 40% to 80%
Stage 4 Colorectal Cancer
20% of CRC
Cancer has spread to other areas of the obdy
Treatment - Chemotherapy, surgery to remove mets (liver/lung) in carefully-selected patients
Survival - Evolving
CRC Prognosis Depends on
Histo (poor differentiation, vascular invasion)
Depth of invasion
Nodal involvement
Genetic alterations: -18Q LOH (bad), MSI (good)
CRC Treatment
Surgery (Stage 1, 2, 3) - Try to remove isolated mets
Radiation (Rectal cancer) - Prevent local recurrence
Pharmaceuticals (Stage III Node+ and IV)
CRC Pharmaceuticals
5-Fluorouracil
Irinotecan
Oxaliplatin
5-Fluorouracil
Pyrimidine antimetabolite
Irinotecan
Topoisomerase I inhibitor
Prevents re-ligation after cleavage of DNA by Topoisomerase I
Oxaliplatin
Alkylating agent
Causes formation of bulky DNA adducts
Irinotecan - Side Efects
Alopecia
GI toxicity
5-Fluorouracil - Side Effects
Gi toxicity
Oxaliplatin - Side Effects
Neuropathies
Cold tingly
CRC Biologics
Bevacizumab Regorafenib Aflibercept Cetuximab Panitumumab
Bevacizumab
Ab against VEGF-A
May block angiogenesis and also stabilize leaky vasculature
Regorafenib
Multi-targeted TKI
Aflibercept
Binds to circulating VEGF
Costs $11,000/month
Prolongs survival by 1.4 months
Cetuximab
Antibodies against EGFR
KRAS mutation means this drug won’t work!!
Panitumumab
Antibodies against EGFR
KRAS mutation means this drug won’t work!!
Bevacizumab Toxicities
Bleeding Thrombosis Hypertension Wound healing complications Half life of about 3 weeks, wait at least 2 half lives before major surgery
Cetuximab & Panitumumab Toxicities
Horrible rash
Rash predicts better outcome though so haaaayyy
Types of cancers with a LOT of mutations
Melanoma Lung Cancer Bladder Cancer Esophagus Colorectum
Mostly associated with toxins
CTLA4
On T Cells
Brake on the immune system
Prevents T Cells from attacking body
PD1 is another receptor that does the same thing
Who responds to PD1 inhibitors?
Mismatch Repair cancers!
Tumors with a ton of mutations!!
Survival for those with metastatic disease
Systemic chemo - 3 years
Sometimes treat neoadjuvantly
If the metastases are “limited” you can CURE!
Can you resect a liver met? - Criteria
Ability to resect all evident disease
Ability to leave a sufficient hepatic remnant (at least 2 contiguous remaining segments, adequate inflow and outflow, adequate hepatic volume and function) - >20% desirable
