Colorectal Cancer Flashcards
Of the following, which are tumor suppressor genes, which are oncogenes, & which are DNA repair enzymes?
p53, APC, hMSH2, SMAD, ras, MYH, DCC, c-myc, hMLH1
Oncogenes: ras, c-myc
Tumor Suppressor: APC, p53, DCC, SMAD
DNA Repair Genes: hMSH2, hMLH1, MYH
In what test is the K-Ras mutation detectable?
Mutations detectable in stool
Which gene, when inactivated, promotes the formation of other pro-oncotic mutations?
p53 (chromosome 17)
b/c it normally arrests the cell at the G1/S checkpoint, permitting the cell to locate & fix other mutations.
w/out this “repair time”, other mutations accumulate
(thus correlates w/ poor prognosis)
Name the gene defects in each step of the microsatellite instability pathway:
Normal (a) -- DNA hypomethylation -- Early adenoma (b) Advanced Adenoma (c) Invasive cancer (& may lead to metastases)
a) APC
b) K-ras
c) p53
What is the rate-limiting step for initiation of most CRC?
APC mutation
~70% of FAP has what mutation?
APC mutation – 90% of these are a truncated APC protein
other 30% sporadic
What is the central mutational cause of Hereditary Non-Polyposis Colorectal Carcinoma?
Faulty DNA Mismatch Repair
Compare HNPCC & Sporadic Colorectal Carcinoma:
Age at diagnosis?
HNPCC: 45
Sporadic: 67
Compare HNPCC & Sporadic Colorectal Carcinoma:
Frequency of multiple colon cancers?
HNPCC: 35%
Sporadic: 4-11%
Compare HNPCC & Sporadic Colorectal Carcinoma:
Proximal locatin?
HNPCC: 72%
Sporadic: 35%
Compare HNPCC & Sporadic Colorectal Carcinoma:
Excess malignant tumors at other sites? (yes or no)
HNPCC: Yes
Sporadic: No
Compare HNPCC & Sporadic Colorectal Carcinoma:
Prognosis?
HNPCC: Favorable
Sporadic: Variable
What is the Amsterdam Criteria used for?
Used to determine if people have are likely to have Lynch Syndrome (HNPCC)
What are the Amsterdam Criteria?
3 : 2 : 1
3 relatives w/ an HNPCC-ass’d cancer (CRC, endometrial, SB, ureter/renal pelvis)
2 generations spanned
1 at age <50
Are DNA Replication Errors a common theme of:
- HNPCC?
- Sporadic Colorectal Carcinoma?
HNPCC: Yes (79%) (mostly Microsatellite Instability genes)
Sporadic: No (17%)
What is a polyp?
Visible protruding mass covered w/ mucosa
What does it mean to refer to polyps as sessile or pedunculated?
Sessile = Flat
Pedunculated = Stalked
What clinical diagnosis is made that calls for a prophylactic colectomy in young adulthood?
Familial Adenomatous Polyposis (FAP)
What type of gene is BAT26?
Microsatellite Instability gene
Some symptoms of Colorectal Carcinoma?
- Melena/Hematochezia
- Iron Deficiency Anemia
- Change in bowel habits (stool caliber & frequency)
- Abdominal pain
- NO symptoms!
What is Carcinoembryonic Antigen?
Cell Surface Adhesion Glycoprotein that can be elevated in a variety of cancers such as Colorectal, Breast, Lung, & Gastric
- Expressed in 80-85% of Colon Cancers
- It’s also elevated in non-cancer states such as Colitis, Pancreatitis, Cirrhosis, & Smoking
(therefore not useful for screening)
Is Carcinoembryonic Antigen useful for screening?
No, but it may be useful for prognosis & follow-up
What are some poor prognostic factors for Colon Cancer?
- Obstruction or Perforation
- Elevated Carcinoembryonic Antigen pre-op
- Fewer nodes removed at surgery (minimum = 12)
What are some “good” prognostic factors for Colon Cancer?
- Microsatellite Instability
- – ass’d w/ HNPCC
- Lower stage
3 major differences between Colon vs. Rectal cancers?
Colon = Melena Rectal = Hematochezia
Rectal = much HIGHER risk of relapse after surgery
Rectal = usually require local RADIATION b/c of higher risk of relapse post-surgery
General Tx for Stages I-IV: Colon Cancer
Stage I (small tumor, negative nodes) - Surgical resection
Stage II (bigger tumor, negative nodes) - Surgical resection ~~ Post-op Chemo if Stage IIb or perforation / obstruction / lymphovascular invasion
Stage III (positive nodes)
- Surgical resection
- Post-op Chemo
Stage IV (distant metastases)
- Chemotherapy
- Surgery may play role if…
- – Bowel obstruction
- – Bleeding
- – Isolated liver metastases
**note: rectal cancer is same, except add Radiation @ stages 2-3 & definite chemo @ 2
General Tx for Stages I-IV: Rectal Cancer
Stage I (small tumor, neg nodes) - Surgical resection
Stage II (bigger tumor, neg nodes)
- Pre- or post-operative Radiation & Chemo
- Surgical Resection
- Postoperative Chemo
Stage III (positive nodes)
- Pre- or post-operative Radiation & Chemo
- Surgical Resection
- Post-operative Chemo
Stage IV (distant metastases)
- Chemotherapy
- Most will need surgery or radiation for palliation of primary tumor
Fluorouracil- absorption?
Poor oral absorption
(rapidly taken up into cells & phosphorylated)
Capecitabine is oral prodrug
Fluorouracil- MOA?
Interferes w/ DNA
- Inhibits Thymidylate Synthase
- Incorporated into DNA
Interferes w/ RNA
Fluorouracil- Toxicities?
- Myelosuppression
- Mucositis
- Diarrhea
- Photosensitivity
- Hand-foot Syndrome
Uncommon:
- Cardiac Syndrome
- Biliary Fibrosis
A congenital deficiency of Dihydropyrimidine Dehydrogenase in 0.5% of population, puts you at risk for what?
Increased Fluorouracil toxicity
Leucovorin- use/effects?
Augments the cytotoxicity/effectiveness of Fluorouracil
Leucovorin is Reduced Folate
What is Capecitabine?
Oral prodrug of Fluorouracil
b/c Fluorouracil is poorly absorbed
What are the 2 current standard drugs used for adjuvant therapy of Colorectal Cancer?
Fluorouracil
- Capecitabine (oral prodrug)
- Leucovorin (augments effect)
Oxaliplatin
Fluorouracil is a _____ _____ (type of drug)
Halogenated Pyrimidine
Oxaliplatin- MOA?
Mainly forms N7-d(GpG) intrastrand adduct
- blocks DNA replication
- blocks Transcription
*adduct = combo of 2 or more compounds
How is resistance to Oxaliplatin mediated?
Nucleotide Excision Repair Genes
Oxaliplatin- method of delivery?
IV only (undergoes non-enzymatic conversion)
Oxaliplatin- Toxicities?
- Myelosuppression
- Peripheral neuropathy
- Diarrhea
- Mucositis
Metastatic (stage IV) Colorectal Cancer:
- Median Survival?
- Cure?
~2 yrs.
Currently no cure
Colorectal Cancer: Hematogenous & Local metastatic tendencies?
Hematogenous:
- Liver
- Lungs
- Bone, Brain
Local
- Intra-abdominal
- Intra-pelvic
Drugs for Metastatic (stage IV) Colorectal Cancer?
- Fluorouracil
- Oxaliplatin
- Irinotecan
- Bevacizumab
- Cetuximab/Panitumomab
Irinotecan- MOA?
Topoisomerase I inhibitor
Irinotecan- Resistance mechanisms?
- Impaired transport/Enhance efflux
- Topoisomerase mutations
- Enhanced metabolism
Irinotecan- method of delivery?
IV only
Irinotecan- Toxicities?
- Myelosuppression
- Diarrhea
- Mucositis
Bevacizumab- MOA?
Humanized anti-VEGF antibody
Bevacizumab- method of delivery?
Given by vein w/ chemotherapy
Bevacizumab- Toxicities?
- Hypertension
- Thrombosis
- Bleeding
- Infusion rxns
- Inc toxicity of chemotherapy
Cetuximab/Panitumomab- MOA?
- Antibodies directed at extracellular domain of EGFR
- Block binding of EGF to receptor
Cetuximab/Panitumomab- Toxicities?
- Rash
- Diarrhea
- Mucositis
Cetuximab/Panitumomab- Mechs of Resistance?
Activating mutations in K-ras & BRAF render cells resistant to antibodies
(these convey poor natural history)
@ what stage does post-operative Chemotherapy become standard use in Colorectal Cancer?
Stage III
sometimes used in Stage II
@ what stage does Chemotherapy become standard use in Rectal Cancer?
Stages II & III
@ what stage does Radiation become standard use in Rectal Cancer?
Stages II & III
T or F? Stage IV Colorectal Cancer is incurable, but Tx prolongs life.
True
