Neoplasia 4 Flashcards
Incidence
> 14 million new cases of cancer worldwide in 2012
Estimated 9.6 million deaths in 2018 • World’s second most lethal disease
Majority of cancers are diagnosed in people over the age of 65 but only a small proportion in people up to age 24
In children younger than 14, leukaemia’s, central nervous system tumour and lymphomas
Survival rates and mortality
Survival for different cancer types in the UK is very variable
½ of all people diagnosed with cancer in England and Wales survive their disease for 10 years or more
Higher in women
Improving and has doubled in the last 40 years in the UK
Testicular cancer 98%
Melanoma 90%
Pancreatic 1%
Different cancers have improved at different rates
Due to the exposure that breast and testicular cancers have their treatments have excelled and their survival rates have increased
On the flipside, since 1970s improvements and survival rates in lung and pancreas cancer have not seen much increase - why is this? - pancreases is so difficult to treat as its usually diagnosed so late on
Predicting outcome and determing a tumors stage
prediction - Which individual will have a favourable outcome
These are far from exact but a good guide
Factors that will affect the outcome include - Age, general health status, tumour site, tumour type, differentiation, tumour stage
Availability of effective treatments
Determining a Tumour’s stage - Currently we use TNM Staging System
Which is only for Solid Tumours
Standardised across the world
Takes into account 3 factors -
T = size of primary tumour
N = extent of regional lymph node involvement
M = metastatic spread via the blood
Each cancer has its own specific TNM criteria
Tumour stage is a measure of the overall burden of the malignant neoplasm
Converted to a stage 1-4 usually
Vary for each cancer
Stage 1 = early local disease (T1 or T2)
Stage 2 = Advanced local disease (T2 or T3 but N0, M0)
Stage 3 = regional metastasis (T2 and N1 or more with M0)
Stage 4 = advanced disease with distant metastasis (M1)
Ann Arbor staining system
For lymphomas we use a different staging system
Talks about the location of the nodes - bit simpler than above
Their are different ones for different tumor types
Stage 1 lymphoma - means lymphoma is present in a single node region
Stage 2 lymphoma - 2 separate regions involved but they are on the same side of the diaphragm
Stage 3 lymphoma - 2 or more regions involved but they are on separate sides of the diaphragm
Stage 4 lymphoma - diffuse or disseminated involvement of 1 or more of the extra lymphatic organs such as the bone marrow or the lungs
Dukes staging system
A type of staging system that was mainly used for identifying bowel cancers
This highlights how important staging is for predicting survival
Stage then entails potential treatments for that patient
E.g. Stage A - a small tumor that is just infiltration through the mucosa and into the muscle
Stage B - tumor is bigger but it hasn’t breached the outer lining of the bowl wall
Stage C - tumor is bigger and the outer lining has been breached along with local lymph nodes being affecting
Stage D - their is a metastasis - survival rates with this are very low
Grading
Grade describes the degree of differentiation of a neoplasm (how well in represents its tissue of origin
G1 = well-differentiated
G2 = moderately differentiated
G3 = poorly differentiated
G4 = undifferentiated or anaplastic
I.e. if the cell was meant to be Squamous cell, is it still a squamous cell
Grading in breast cancer:
There is an internationally recognised grading system for breast cancer - uses modified Bloom Richardson score - assess 1) tubule/gland formations, 2) nuclear variation and 3) number of mitotic figures
Between grade 1 and grade 3 there is large difference in survival rate - therefore its key to get this right to inform correct prognosis and treatment
Grading in prostate cancer:
Treatment is entirely dependent on the grading of the tumor - using Gleason’s pattern
E.g. if you only have stage 3 Gleason - then you will only be monitored
If then progress to stage 4 - patient is now eligible for all treatment options such as hormone therapy and surgery
Treatments
Surgery Radiotherapy Chemotherapy Hormone Therapy Treatments targeted to specific molecular alterations Immunotherapy
Can never say someone is cured of cancer as we done know about micrometastasis
Adjuvant vs neoadjuvent therapy:
Adjuvant - Treatment is given after surgical removal of a primary tumour to eliminate subclinical disease
Neoadjuvant - Treatment is given prior to surgical excision to reduce the size of the primary tumour
Radiation therapy
Kills proliferating cells by triggering apoptosis or interfering with mitosis
Given in fractionated doses to minimise normal tissue damage
In theory this kills rapidly dividing cells in G2 of the cell cycle
Causes either direct or free-radical induced DNA damage that is detected by cell cycle checkpoints
Which triggers apoptosis
Double stranded DNA breakages causes damaged chromosomes that prevent M phase from completing correctly
Over time we have found that if you give 1 very large dose, the affect radiation has on cancer cells and normal cells isn’t that great especially when you increase the dose
However if you break this up into lots of smaller doses then you give the healthy cells time to recover - so dont get as much damage and theres a bigger differential effect between cancer cells and normal cells
Chemotherapy
Scientist found that cancers with folic acid present excelled - so he decided to try and find a folic acid antagonist to try and null these effects
Folic acid is used in DNA synthesis - so if you interfere with DNA metabolism using the antagonist you can then stop DNA synthesis and stop replication and reduce cancer burden - which created antimetabolites
Antimetabolites
Mimic normal substrates involved in DNA replication
E.g. Fluorouracil
Alkylating and Platinum Based Drugs
Cyclophosphamide and Cisplatin
Cross link the two strands of the DNA helix
Antibiotics
Doxorubicin inhibits DNA topoisomerase needed for DNA synthesis
Bleomycin causes double stranded DNA breaks
Plant derived drugs
Vincristine from Periwinkles
Block microtubules assemble and interferes with mitotic spindle formation
Have to remember if we are effecting DNA replication of the cancer cells, then we are also damaging DNA replication of our normal cells - so any cells that usually undergo rapid DNA replication (GI mucosa, hair, nails) will be effected so there will be toxic side effect of chemotherapy
Hormonal therapy
Selective oestrogen receptor modulators (SERMs)
Tamoxifen – Bind to oestrogen receptors thus preventing oestrogen receptors to prevent oestrogen from binding
Used to treat hormone receptor positive breast cancer
Another example was found in dogs that had testosterone driven enlarged prostate and found that castration led to shrinkage of this prostate and was then size was subsequently rescued with testosterone supplements - can be seen in humans
Targeting Oncogenes
Identifying cancer specific alterations such as oncogene mutations allows us to create targeted drugs specifically at cancer cells
Trastuzumab (Herceptin) - blocks HER2 receptor in breast cancer
Imatinib (Gleevec)
With regards to cancer treatments - its much easier to block an overactive oncogene then it is to replace a Tumor suppressor gene that has been switched off - Targeted drugs are then made
E.g. in breast cancer 1/4 of cases have a gross expansion of the HER2 receptor - this can be blocked by Herceptin
Immunotherapy
Target immune system to help it fight cancer by recognising and attacking cancer cells
Cancer immunity cycle highlights points where immune treatments can be used
Immune checkpoint inhibitors
Tumor markers
Various substances are released by cancer cells into the circulation (and urine and faeces)
They can be measured
Sometimes for diagnosis
Most useful for monitoring tumour burden during treatment and follow-up
Assess recurrence
Examples
Human Chorionic Gonadotrophin - testicular tumours
Alpha fetoprotein -
Cancer screening
Breast screening- Women, 47
