colorectal cancer treatment Flashcards
colorectal cancer
aka bowel cancer
is a type of cancer that develops in the colon or rectum
more prevalent in people less than 50 yrs old
symptoms of colorectal cancer
Blood in the stool
A change in bowel habits
Unexplained weight loss
Abdominal pain
Fatigue
Low iron levels(anaemia)
has similar symptoms to IBS, Chron’s and colitis so might be difficult to diagnose that it is colorectal cancer
some risk factors of colorectal cancer
age
health history
individuals with diet rich in animal fat and low in fibre
obese individuals
state some of the ways that colorectal cancer can be diagnosed
Colonoscopy with biopsy for initial diagnosis
Digital rectal examination and endoscopy with biopsy
Endoscopic ultrasound (EUS) to differentiate between T1 and T2
MRI is used to stage invasive rectal tumours and assess the effect of chemotherapy
Contrast-enhanced CT to detect distant metastasis
Molecular testing
some of the molecular tests involved are Ras, MSI, B-RAF and Her2
what percentages of CRC affects the colon and the rectum
75% in the colon
25% in the rectum
note that 25% of CRC are metastatic at the time of diagnosis
metastasis
The spread of cancer cells from the place where they first formed to another part of the body
CRS metastases mainly occurs to the liver, lymph node, peritoneum, lungd and brain
what percentage of CRC happens sporadically, and what percentage is caused by genetics(familial history )
65-70%
30-35%
sporadic CRC means that the cancer has no genetic cause and is not inherited
Mismatch repair system(MMR)
a series of steps that corrects errors in DNA replication. It’s essential for maintaining genomic stability and preventing cancer.
the most common form of hereditary CRC
lynch syndrome
causes up to 5% of CRC
what causes lynch syndrome , and what happens in lynch syndrome
caused by germline mutations in genes involved in the mismatch repair system (MMR)
the mutations(hypermethylation of promoter regions) lead to a loss of protein expression, which can be detected through immunohistochemistry (IHC) testing.
The loss of MMR proteins results in microsatellite instability (MSI), a condition where repetitive DNA sequences become unstable.
Carcinogenesis occurs when these MMR defects lead to mismatch errors in tumor suppressor genes, promoting cancer development, particularly in the colon and other organs
Carcinogenesis is the process by which normal cells are transformed into cancer cells
note that in lynch syndrome the MMR is non functional
list some of the genes involved in the mismatch repair system
MLH1, MSH2, MSH6, PMS2, and EPCAM.
name two forms of tumour testing that are to be considered in all cases of CRC
IHC (immunohistochemistry)
MSI(microsatellite instability) testing
what can issues with MMR lead to
microsatellite instability (MSI)
note that the presence of MSI indicates issues with MMR which consequently increases the risk of many cancers, not just CRC
microsatellite instability (MSI)
MSI is a condition where repetitive DNA sequences become prone to errors during DNA replication
Microsatellites are stretches of dinucleotides which are repeated many times. They are prone to mismatch. As they are mostly in the non-coding regions of the DNA
RAS testing in CRC and any important information you know about it
this test in mandatory in all cases of CRC , because RAS gene mutations occur in some CRC cases and can affect the effectiveness of anti-EGFR therapies for CRC
anti-EGFR drugs target epidermal growth factor receptor (EGFR), however, RAS mutations prevent their action
so RAS testing helps in identifying patients not suitable for anti-EGFR treatments, so that other treatment options can be opted for
anti-EGFR drugs target epidermal growth factor receptor (EGFR)
RAS stands for Rat Sarcoma
MSI testing and any important information you know about it
MSI testing identifies tumors with microsatellite instability, a form of genomic instability caused by defective DNA mismatch repair (dMMR).
important for identifying patients at risk of Lynch syndrome
Patients with MSI/dMMR tumors may benefit from immune checkpoint inhibitors (e.g., pembrolizumab, nivolumab), which are more effective in these cases due to the tumor’s heightened immune visibility.
patients with mSI/dMMR tumours may benefit from which type of drugs
immune checkpoint inhibitors
e.g pembrolizumab, nivolumab
HER2 testing and any important information you know about it
this test is used to identify overexpression or amplification of the HER2 gene in mCRC tumors.
testing helps identify patients who may benefit from anti-HER2 treatments, which can improve outcomes in HER2-positive mCRC.
HER2 overexpression is found in a small subset of mCRC(metastatic CRC) cases
BRAF testing and any important information you know about it
BRAF mutations (particularly BRAF V600E) are common in mCRC, especially in tumors that are microsatellite stable (MSS)
BRAF mutations associated with poor prognosis in mCRC
Testing for BRAF mutations helps guide therapy selection, particularly for patients who are BRAF-mutant and may benefit from targeted BRAF inhibitor treatments
patients with BRAF mutations may benefit from BRAF inhibitors (e.g., vemurafenib), often in combination with MEK inhibitors.
BRAF mutations common in tumours that are microsatellite instable, true or false
false,
they are common in tumors that are microsatellite stable (MSS) and wild-type for RAS.
is CRC curable
yes
treatment aimed at cure or palliation, decision on which aim to adopt depends on various factors, including the person’s health and
preferences, as well as the stage of the tumour.
Palliation is the act of reducing the severity of a disease or pain without curing it
some anti-cancer treatments
chemotherapy:drugs affecting fast-dividing cells; these induce DNA damage, inhibit DNA replication or cell division.
targeted therapy: biological therapy – drugs binding to specific proteins in/on cancer cells to block their functions; require molecular testing
immunotherapy: utilise immune system of the patient to help eradicate cancer
cells, e.g. immune checkpoints inhibitors, cancer vaccines, CAR T-cell therapy
(CAR = chimeric antigen receptor)
cancer treatments often used in combination to achieve improved efficacy, example, chemotherapy often used together with targeted therapy.
the two main COMBINATION mCRC(metastatic CRC) treatments
FOLFOX (5-FU+folinic acid+oxaliplatin)
FOLFIRI(5-FU+folinic acid+irinotecan)
5-FU = fluorouracil
can the drugs in the combination therapies for mCRC be used individually in mCRC treatment ?
yes
mechanism of action of 5-FU(fluorouracil)
inibits thymidylate synthase, leading to the inhibition of dTMP which leads to nucleotide imbalance, then to double stranded DNA breaks during replication → apoptosis
folinic acid(Leukovorin) mechanism of action
enhances cytotoxic effects of 5-FU
oxaliplatin mechanism of action
intercalating agent causing DNA crosslinks → accumulation of difficult to repair DNA damage →
apoptosis in all phases of cell cycle
irinotecan mechanism of action
inhibitor of topoisomerase, allows
topoisomerase to cut a single strand of DNA but prevents it from sealing it back → single stranded DNA breaks → accumulation
of damage in cells attempting to replicate DNA → apoptosis.
topoisomerase is an enzyme needed to uncoil double stranded DNA at the start of replication
treatment for CRC with high MSI
Nivolumab + ipilimumab - (after fluoropyrimidine-based combination chemotherapy).
THE STATED DRUGS ARE IMMUNE CHECKPOINTS
nivolumab and Iplimumab mechanisms of action
Nivolumab – anti-PD1 antibody, prevents binding of PDL1(programmed death-ligand 1) to immune cells and suppressing TCR(t cell receptor) activation. this prevents inhibition to immune response
Ipilimumab – anti-CTL4 antibody, prevents inhibitory signal for T cell activation.
nivolumab activates T cells
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) prevents T cells from attacking cancer cells
some examples of anti EGFR antibodies
cetuximab, panitumumab
anti EGFR antibodies only work if EGFR, RAS and BRAF are wild type, meaning they are not mutated
