Oncology Flashcards
What is the most common cause of cancer death in 20-34 year olds?
Melanoma.
Australia has highest incidence in the world.
Incidence doubled over last 20y.
4th most common cancer overall. 10%.
Stage IV confers a 10-20% 5yr survival rate.
What is the 5 leading causes of cancer death in Australia?
Lung > bowel > PROSTATE > breast > pancreas
In males: lung > prostate > bowel > pancreas > CUP (unknown primary)
In women: lung > breast > bowel > pancreas > CUP (unknown primary)
Cancer is the second leading cause of mortality
Most common overall: prostate, bowel, breast, melanoma, lung
What are the agents available for metastatic melanoma?
- Targeting the MAP kinase pathway:
note 45% of melanomas have BRAF mutation –> constitutive activation of the MAP kinase pathway –> promotes proliferation, prevents apoptosis
- BRAF INHIBITORS: Vemurafenib, **Dabrafenib
- MEK INHIBITORS: Trametenib, Cobimetenib - Immunotherapy
- Anti-CTLA4 Antibody - **Ipilimumab
- Anti-PD1 Antibody - **Nivolumab, Pembrolizumab
- Anti-PD-L1 Antibody
- Anti Interleukin 2 (not in Australia)
Older agents - Dacarbazine (alkylating agent) and Fotemustine
- Do NOT work, no improvement in overall survival
What are the side effects of the BRAF inhibitors?
SKRAP the Dog says “RAF RAF RAF!” (From Playschool)
Side effects of the BRAFs - Vemurafenib and Dabrafenib:
S - SCCs (20%) treat by excision, well tolerated)
K - keratoacanthoma (10%)
R - Rash
A - Arthralgias
P - Photosensitivity
(Also causes deranged LFTs)
“Dab your forehead - you have a fever!”
Dabrafenib also causes FEVER & alopecia
What is Trametinib?
What are the side effects?
Trametinib is a MEK inhibitor. (MEK is downstream of BRAF in the map kinase pathway)
Improves overall survival in metastatic melanoma.
Side effects: Heart failure - reduced LVEF! Diarrhoea Rash Ocular side effects Peripheral oedema (NO SCCs!)
(Trams in MElbourne make my “Heart-DROP”…..
TRAMetenib = MEK = side effects: Heart-DROP)
Is there a role for combination BRAF/MEK inhibition?
Yes. New data from 2014 supports combination as 1st line for metastatic melanoma (but not PBS approved)
Double inhibition shows progression-free survival, and combination Dabrafenib/Trametinib showed better overall survival,
with
NO significant increase in toxicity and LESS SCCs (1%)
What is the best evidence for the duration of adjuvant tamoxifen therapy for breast cancer?
New data from 2014 shows evidence for 10 YEARS of tamoxifen. Greater benefit than 5 years.
What is Ipilimumab?
What are the side effects?
Ipilimumab is a mab against the inhibitory CTLA-4 Tcell receptor.
Ipilimumab is a CTLA-4 BLOCKER used in metastatic melanoma.
As CTLA-4 usually stops T cell activation and proliferation, Ipilimumab
- -> “inhibits the inhibition”
- -> acts as a T cell agonist
- -> promotes anti-tumour immunity in metastatic melanoma
(Note this is OPPOSITE to the action of Abatacept, which is a fusion Ig for CTLA-4, is used in RA (not as good as the TNFs or infliximab) –> potentiates the inhibitory action of CTLA-4 –> PREVENTS T cell activation and proliferation)
SIDE EFFECTS of CTLA-4 INHIB = “CaPiTaLS”
These IRAEs or Immune-related Adverse Events (75% of patients) are good signs that the drug is working. Side effects are reversible and easily treated with steroids +/- TNF blockade.
C - colitis
P - Pneumonitis, pituitary dysfunction (hypopituitarism)
T - thyroid hyper/hypo
L - liver dysfunction / hepatitis
S - SKIN RASH = ***VITILIGO a good prognostic sign, Pruritis, SJS, TEN.
What is Nivolumab?
What are the side effects?
Nivolumab is an Anti-PD1 antibody, used in metastatic melanoma.
(New evidence for use in NSCLC)
(New agent probably, not in written exam)
** USED IN BRAF NEGATIVE PATIENTS **
Note that PD1 and CTLA4 are both inhibitory receptors.
The PD1 receptor (Programmed Death 1) on Tcells is an immune checkpoint receptor that binds to the PD1 Ligand on tumour cells and makes them “invisible” –> renders them invisible from destruction by CTLs and CD4 Tcells.
Hence Nivolumab BINDS to PD1 receptor on Tcells and inhibits this anti-tumour response –> allows destruction of tumour cells by CTLs and CD4 Tcells.
SIDE EFFECTS:
Immune related adverse events (“CaPiTaLS” = same as for CTLA4 blockers) but also UVEITIS
What cancers do we recommend screening for?
Breast
Colorectal
CERVICAL
Not routinely recommended for- prostate, lung, ovarian, melanoma
Guidelines for breast cancer screening.
Age 50-74 - Mammograms every 2 years
(If patients are under 50 (>40) or over 75, can still have mammograms but these women are not formally invited to the Breast Ca Screening program)
NOT evidence for breast self examination as a stand-alone screening tool. Must use mammograms.
What are the guidelines for Screening for Colorectal Cancer?
Normal people, Age 50-75:
- Annual FOBT
- Colonoscopy every 10 years
- Flexisig every 5 years
MODERATE Risk FHx (1st deg relative younger than 55)
- Colonoscopy every 5 years from age 50,
or 10 years younger than age of relative
SCREENING IN FAMILIAL CANCER SYNDROMES:
1. FAP / Familial Adenomatous Polyposis
(Auto Dom, mutated APC gene, get adenomas in childhood and CRCs by age 45. Prevention of bowel cancer with surgery/Colectomy usually at age 18)
- Sigmoidoscopy/Colonoscopy yearly from ADOLESCENCE, age 12-15!!!
- Endoscopic & Duodenal screening from age 25, or from time of Colectomy (to look for Duodenal adenomas and rectal carcinomas)
- HNPCC (2-4%)
(Auto Dom, mismatch repair gene defect –> CRCs and increased endometrial and GU cancers)
- Colonoscopy ONCE A YEAR from age 25,
or 5 years younger than age of relative
Spinal Cord Compression = Oncological emergency.
What is the most common mechanism of Spinal Cord Compression in Oncology patients?
How do patients present?
What cancers are usually associated?
What is the Mx?
What is the BEST predictor of outcome in these patients?
Most common mechanism is **epidural extension from vertebral body or pedicle.
Other mechanisms are:
- Extension of paravertebral tumour
- Pathological collapse of vertebral body
- Metastasis to meninges or cord.
Most common associated tumours: lung, breast, prostate
Presentation: Back pain (>90%) worse at night and lying down. Motor changes, sensory changes (saddle sensory loss in cauda equina), bowel and bladder dysfunction.
MANAGEMENT:
MRI whole spine
High dose dexamethasone ASAP! 10mg stat then 4mg QID.
Surgery to stabilise spine.
Radiotherapy alone if radio sensitive tumour, or radiotherapy after surgery.
(not chemo)
BEST PREDICTOR of outcome is the neurological status at the START of treatment.
An oncology patient presents with:
- facial and arm swelling (often worse with bending forward / lying)
- headaches / pressure sensation in head
- SOB
- cough
- hoarse voice
- epistaxis
What is the condition?
What are the associations?
Management?
Superior Vena Cava Syndrome = Oncological Emergency!
- partial or complete obstruction of bloodflow from SVC to right atrium due to tumour compression, invasion and/or thrombosis
May develop laryngeal oedema / stridor from airway obstruction, or cerebral oedema / confusion / coma.
Associated with Lung Ca > NHL > other
MANAGEMENT:
- CT Chest to look at SVC - diagnostic.
- remove any central lines if present that may be causing thrombus
- ANTICOAGULATE if thrombus
(No evidence for steroids or diuretics for facial oedema)
- CHEMOTHERAPY for SCLC, NHL, germ cell tumours
- **ENDOLUMINAL STENT!
- -> rapid and sustained symptom improvement
- -> no need to get histology first
- RADIOTHERAPY either alone or after stent
What are the benefits of measuring CEA?
- good indicator of PROGNOSIS (if elevated CEA pre-operatively, then worse prognosis)
- used to monitor for disease RELAPSE post curative surgery
- used to monitor RESPONSE TO TREATMENT of metastatic disease
(But CEA also raised in other cancers- most adenocarcinomas, medullary thyroid Ca, PUD/gastritis, COPD, diabetes, liver disease, SMOKING, inflammation)
Which tumour markers are used to monitor for RELAPSE and RESPONSE TO TREATMENT?
Which tumour markers have PROGNOSTIC value?
Monitors RELAPSE and RESPONSE TO TREATMENT:
CEA in CRC
Ca 19-9 in pancreatic Ca
AFP (also used in screening for HBV/HCV/cirrhosis- high risk patients)
Ca 125 in ovarian Ca
AFP/betaHCG/LDH in testicular cancer
PSA in prostate cancer
ChromograninA (CgA) in neuroendocrine tumours
Thyroglobulin in thyroid Ca
Calcitonin and CEA in medullary thyroid cancer
Monitors RESPONSE TO TREATMENT ONLY:
Ca 15-3 and CEA in breast cancer is only used to monitor response to treatment in metastatic disease
(NO ROLE for measuring for disease relapse)
PROGNOSTIC value: CEA Ca 19-9 AFP/betaHCG/LDH Thyroglobulin! Calcitonin and CEA in medullary thyroid cancer
Germ Cell Tumours / Testicular Cancer.
How do you differentiate Pure Seminomas from Non-Seminomas.
Look at the AFP.
Pure Seminomas:
BetaHCG normal/high
LDH normal/high
AFP NORMAL
Non-seminomatous Germ Cell tumours:
BetaHCG normal/high
LDH normal/high
**AFP INCREASED (in 80%)
What are the benefits of measuring Chromogranin A?
Chromogranin A is more sensitive than Urine 5HIAA for neuroendocrine tumours but it is less specific –> better for monitoring RECURRENCE of disease.
Used to monitor disease progression, relapse, response to treatment.
Benign causes - PPI use, renal and liver dis, atrophied gastritis, IBD
What are the gene characteristics of the BrCa1 and BrCa2 genes?
What is the usual function of the BrCa1 and 2 genes?
BrCa1 gene
- on chromosome 17q/22
> 80% of mutations are truncating
- Higher (female) cancer risk compared with BrCa2
BrCa2 gene
- on chromosome 13q
- 27 exons which include the OCCR Ovarian Cancer Cluster Region on exon 11
- Higher risk of MALE breast cancer, prostate cancer, pancreatic cancer
- BRCA2-associated Prostate cancer is more aggressive, with greater chance of T3/4 disease and node positivity at diagnosis. Gleason score often > 8. –> **High risk therefore need Immediate Radical Prostatectomy!!
GENE FUNCTIONS:
- both have similar roles in dsDNA repair
- function as TUMOUR SUPPRESSOR GENES
- -> inactivation of these genes leaves DNA damage unrepaired –> leads to cancer.
What are the tumour features associated with BRCA 1 and 2 mutations?
Tumours associated with BRCA1 appear to have typical histological features:
- high grade
- hormone receptor NEGATIVE in 75%!!!
- pushing borders
- less DCIS
- medullary or atypical medullary histology
- basal epithelial phenotype
BRCA2 tumours do NOT have any specific phenotypic features
What are the characteristics of Hereditary epithelial ovarian cancer?
These are ovarian cancers that develop in BRCA1 and 2 mutation carriers.
Recent data shows BRCA mutation rate in invasive epithelial ovarian cancers = 14%.
Highest mutation rate is in invasive SEROUS ovarian cancers.
Classically:
- SEROUS PAPILLARY ovarian cancers (85% vs 40% in sporadic ovarian ca’s)
- less common to see other histological subtypes such as clear cell, endometrioid ca.
- MORE RESPONSIVE TO PLATINUM CHEMO (better overall survival) compared with non-BrCa-associated Ovarian ca’s
- ** Guidelines suggest to TEST ALL CASES OF INVASIVE EPITHELIAL CANCERS FOR BRCA MUTATIONS
(Note - mucinous adenocarcinomas are NOT associated)
In which patients is it appropriate to offer Gene Testing for Familial Breast and Ovarian cancer (BRCA gene testing)?
Offered to HIGH RISK families.
High risk includes:
- 3 or more cases of breast/ovarian cancer in 1st or 2nd degree relatives
- 2 or more cases of breast/ovarian cancer in 1st or 2nd degree relatives, PLUS one high risk feature
- bilateral breast cancer
- male breast cancers
- age under 40
- OVARIAN cancer
(There are computer programs that can calculate the patient’s risk of mutation - generally the arbitrary cut off is to offer gene testing if the probability is >10%)
If a BRCA MUTATION IS IDENTIFIED –> can offer other family members predictive gene testing. (If positive in 1st deg relative, the risk of having a mutation is 50% based on auto dominant inheritance)
If someone is a BRCA gene carrier, what are their options for:
- surveillance (watchful waiting)
- prophylactic surgery
- chemoprevention?
- SURVEILLANCE
- YEARLY MAMMOGRAMS AND BREAST MRI from age 25-30,
or 5-10 years before the age of the youngest affected relative.
(Breast MRI highly sensitive in detection but NO proven survival benefit)
(No proven benefit in clinical breast examination, Ca 125 monitoring or yearly transvaginal ultrasounds)
- PROPHYLACTIC SURGERY FOR BREAST OR OVARY
BREAST SURGERY
- bilateral mastectomy (with or without breast reconstruction) offers best protection against breast cancer - leaves a residual risk of 1-3%
- age < 50 years best outcome
- the younger the patient, the higher the relative risk of developing breast cancer
eg. 30yo has 60% lifetime risk, 60yo has 15% lifetime risk.
Also
SECONDARY PREVENTION - if Br Ca before age 40, there is a 50% risk of developing a second primary Bc Ca in the next 25 years.
OVARY / SALPINGO-OOPHRECTOMY
- at age 40-45
- consider at age 35 if patient BRCA1 carrier (as 4% risk of ovarian cancer before age 40)
- reduces risk of ovarian cancer by 80%. Leaves a residual risk of primary peritoneal cancer of 2-5%
- reduces risk of breast cancer if performed before menopause (RR 0.5)
- must follow up BMD and CV health!!
- CHEMOPREVENTION = “Risk Reducing Medication”
- -> TAMOXIFEN (Anti-oestrogen) daily for 5 years, but benefits extend to 10 years. Reduces risk of hormone positive breast cancer by 30-40% but no proven survival benefit)
side effects:
Increased risk endometrial cancer (with Tamoxifen only, in postmenopausal), VTEs.
–> HRT: used after BSO to age 50. Never use if prior breast cancer.
–> OCP: protective against ovarian cancer. Issue of possible increase in breast cancer risk- need balance.
- -> PARP INHIBITORS (OLAPARIB)
- active in breast and ovarian metastatic disease.
- increased response rates and PFS but not overall survival.
polyADP ribose polymerase enzymes are involved in an alternative DNA repair pathway (base excision repair) – tumour cells have defective dsDNA repair (methylation or somatic BRCA mutation) and rely on alternative DNA repair pathways such as PARP.
- -> BLOCKING this repair pathway in BRCA-associated tumours is LETHAL to the cancer.
- -> confers “selective tumour cytotoxicity” because normal tissues have normal BRCA function but cancer tissues have no normal BRCA function
What is Hereditary breast/ovarian cancer syndrome?
What are the risk factors / when would you suspect this syndrome in your patient?
Hereditary breast/ovarian cancer syndrome:
- BrCa genes 1 and 2
- penetrance 50-80% of gene carriers develop cancer
- explains most of high risk breast and ovarian cancer families, and approx 30% of high risk Br Ca families
Suspect in:
- early age
What is the lifetime risk of cancer in:
BRCA1
And
BRCA2?
BRCA1
- Breast cancer –> 40-80%
- Ovarian cancer –> 20-40%
- Prostate cancer in males –> Increased relative risk by 1.5-2
BRCA2
- Breast cancer –> 40-60%
- Ovarian cancer –> 10-20%
- Breast cancer in males –> 6%
- Pancreatic cancer –> 3.5%
- Pancreatic cancer high grade –> Increased RR by 4+
- Melanoma –> Incresed
What is Li Fraumeni Syndrome?
p53 p53 p53!!!!
(“P” Frau”MANY” Cancers!)
CANCERS IN 90% by age 60!!! - BLAGS (see below)
Auto dominant GERMLINE p53 mutation on chromosome 17!
Multiple primary tumours common.
Prevalence 1 in 20,000. Rare.
PRESENTATION: “BLAGS”
Breast > Leukaemia > Adrenal > GBM > Sarcomas
“Breast-sarcoma syndrome”
- often HER2 positive pre-menopausal breast cancer
- SARCOMAS (non Ewing)
- brain tumours - GBM
- leukaemia
- **Paediatric cancers
- **Adrenocortical cancers
