Oncology Flashcards
What are neoantigens
Abnormal proteins expressed by the tumour Recognised by T cells
What are the 2 distinct signals required in T cell activation
TCR + Ag-MHC complex AND Co-stimulatory regulatory binding There are many kinds of co-stimulatory receptors. they can be stimulatory or inhibitory molecules. Activation of immune checkpoints leads to inhibitory signals. Examples of co-stimulatory receptors: CD28, CD27, GITR, CD40L Examples of inhibitory molecules/checkpoints: PDL1, PD1, CTLA4, CD80
CTLA-4 CTLA-4 antibodies
The antigen presenting cell presents the neoantigen to the TCR. B7 binds initially to CD28 and becomes activated. After activation, the CTLA-4 migrates onto the surface of the cell and it has a higher affinity to B7 and replaces CD28. That deactivates the T cell. This process occurs in normal viral infections after a few days. CTLA-4 antibodies will stop the CTLA_4 being activated and keeps the CD8 activated (Ipilimumab is the only PBS approved one)
Ipilimumab
anti-CTLA-4 antibody that keeps CD8+ on Leads to a sustained response
anti PD-1 antibody
The expression of PD-L1 and PDL1-PD1 binding causes the CD8+ cell to recognise the antigen as “self” and switches the CD8+ off e.g Pembrolizumab, nivolumab
What cancers have the highest mutation load
Melanoma Squamous Lung Lung adenocarcinoma Highest success w immunotherapy
Microsatellite instability
The condition of genetic hypermutability (predisposition to mutation) that results from impaired DNA mismatch repair (MMR). Rare May be more susceptible to immunotherapy (but not yet on PBS)
Pembrolizumab
PD-1 inhibitor (PD-1 is an inhibitory signal and will enable lymphocytes to kill cancer cells)
Autoimmune toxicities in immunotherapy - endocrine
hypophysitis thyroiditis type 1 diabetes
Management of checkpoint inhibitor toxicity
Low grade: - Dose delay - Increase monitoring frequency High grade: - Withhold checkpoint inhibitor - Steroids - Can consider adding second agent - e.g. Infliximab or mycophenolate
Melanoma BRAF mutation
BRAF V600 mutation It means the pathway does not require upstream activation of RAS and leads to uncontrolled proliferation of the melanoma. Present in 40% of melanomas BRAF inhibitors e.g. dabrafenib, vemurafenib, sabrafenib, encorafenib
MEK inhibitor
Can be added onto BRAF as combination medication the next step in the ROS-> BRAF -> MEK -> ERK pathway (e.g. TRAMETINIB) used in combination therapy with dabrafenib
Immunotherapy and target therapy for unresectable stage III and IV melanoma.
The evidence is that immunotherapy or target therapy should be first line for unresectable stage III and IV melanoma. BRAF600V mutation must be tested first. First line anti-PD1 immunotherapy in BRAF wild type improves progression-free survival and overall survival compared with ipilimumab (CTLA-4). Combination therapy (nivolumab and ipilimumab) is better than monotherapy with either agent. Available on PBS as combination for metastatic melanoma. Note that toxicity triples Used in brain mets Note that targeted therapy has good response rates but the response is not sustained. The PBS mandates that target therapy (BRAF/MEK inhibitor e.g. dabrafenib + trametinib) be used first if there is a BRAFV600 mutation. However, immunotherapy can be commenced is there is no response or further disease progression. Note that is there is no head to head trial with immunotherapy and target therapy
Melanoma adjuvant therapy
Targeted therapy works - Dabrafenib and trametinib combination therapy cf placebo in resection stage III melanoma increases relapse free survival for 20% Positive study but not PBS listed PD1 - nivolumab vs ipilmumab - nivolumab has 20% improvement in relapse free survival None of the PD1 adjuvant therapy has reported improvement in overall survival
Adjuvant treatment of colon ca
Stage 3 - clear adjavtage - oxaliplatin plus 5FU/capecitadine (3 mo) or single agent of eitehr of the above (6 mo) Stage 2 - not clear if adjuvant offers survival benefit (only consider in high risk stage 2)
Adjuvant treatment of rectal ca
T3 or node positive - neoadj chemoRT or RT Adj chemo if node +ve
Why is adjuvant chemo given
to decrease micrometastasis
What other is HPV associated with aside from cervial
anal and head/neck (oropharyngeal)
bevacizumab SE (and mechanism of action)
VGEF/angiogenesis inhibitor Hypertension and proteinuria
infusion 5FU SE
coronary artery spasm
B7 is expressed by the antigen presenting cell. What are the 2 clinically significant molecules it can bind to and what do they do to the T cell
CTLA-4 is expressed by the CD8+ T cell as an inhibitory molecule. When CTLA-4 and B7 binds, the CD8+is deactivated. CD28 is expressed by the CD8+T cell as a stimulatory molecule. When the CD28 and B7 binds, the CD8+ T cell becomes activated.
How does the immune-permissive vs immunosuppressive tumour microenvironment affect the target therapies chosen?
Immune-permissive TMEs have fewer somatic mutations (e.g. ALL). They have decreased antigen processing/presentation. Therefore, CAR-T-cell therapy that target a specific mutation would be predicted to be the most effective. Immunosuppressive TMEs have a high frequency of somatic mutations and therefore neoantigens. There is a high tumour infiltrating lymphocytes burden. Therefore, immunomodulating nAb therapy that increases lymphocyte activity would be more effective.
Are mismatch repair deficient or mismatch repair proficient colorectal tumours more receptive to PD-1 blockage?
Mismatch repair deficient tumours - because these tumours have more mutations and increased tumour infiltrating lymphocytes. The tumour cells usually upregulate PD-1 inhibition so PD-1 blockages is more effective in mismatch repair deficient tumours
When is sentinel node mapping recommended for melanomas
Clinically negative nodes and a primary melanoma >0.8mm thick or melanomas <0.8mm thick but with ulceration
What is melanoma in situ and how much margin should there be in the excision
Melanoma in situ is melanoma that is limited to the the epidermis. There should be a 5-10mm radial margin but lentigo maligna may require a larger margin
What should the radial excision margins be for invasive melanomas
1-2cms Thickness <1mm -> 1cm 1-4mm -> 1-2cm >4mm -> 2cm
When should sentinel node biopsy be considered for melanomas?
All patients with melanoma >1mm thickness and patients with melanoma >0.75mm with other high risk pathological features
Should melanoma patients with a positive sentinel lymph node biopsy get complete lymph node dissection?
No - no mortality benefit compared with active surveillance over 3 years. There is increased morbidity associated with CLND.
What is lentigo maligna?
A subtype of melanoma in situ characterised by atypical intraepidermal melanocytes that usually occurs in sun damaged skin. Can develop into invasive melanoma - lentigo maligna melanoma.
What initial staging should be performed for asymptomatic stage I and II melanoma patients
Not: - CXR - CT imaging - PET (not commended for stage I-IIB) - MRI PET/CT can be considered for IIC (melanoma >4mm thick with ulceration)
What kind of biopsy can be undertaken to diagnose stage 3 melanoma
Both fine needle aspirate and core biopsy
What investigations should be performed in stage III melanoma
PET/CT is the initial staging for stage II melanoma patients with PALPABLE nodal disease. A brain scan (CT or MRI) should be added to a PET/CT. MRI is more accurate for the brain but less so for everything else. There is very low diagnostic yield is only the sentinel lymph node biopsy is positive without a clinically palpable node and the guidelines say to consider NOT doing a PET/CT.
What investigations should be performed when stage IV melanoma is diagnosed?
- LDH 2. PET or PET/CT (unless it will not change management 3. CT w contrast or MRI 4. Assessment for BRAF mutations
Symptoms with the highest predictive values for colorectal cancer in primary care
Anaemia (5.8-10%) Rectal bleeding (4.8%) Weight loss (3%) Abdo pain (2%) Dypepsia (0.6%)
What family history for colorectal cancer would justify colonoscopy screening?
Category 2 risk (7x general population risk): - One first-degree relative with colorectal cancer diagnosed under 55 years - Two first degree relatives with colorectal cancer diagnosed at any cage - One first-degree relative and at least two second-degree relative with colorectal cancer diagnosed at any age Screening: iFOBT every 2 years from age 40-49. Colonoscopy every 5 years from 50-74 Category 3 risk (7-10x general population risk): - At least three first-degree or second-degree relatives with colorectal cancer, with at least one diagnosed under 55 years - At least three first-degree relatives with colorectal cancer diagnosed at any age Screening: -FOBT every 2 years from age 35-44 - Colonoscopy every 5 years from age 45 to 74
Familial adenomatous polyposis gene mutation and inheritance
APC gene Autosomal dominant
What other malignancies is FAP associated with?
malignancies of the upper gastrointestinal tract (most commonly duodenum), brain, thyroid and liver (hepatoblastoma). There is also an increased risk of desmoid tumours.
Surveillance in familial adenomatous polyposis
commence from age 10 to 15 years or earlier if there are gastrointestinal symptoms (Robays and Poppe, 2014). In families with classical FAP, flexible sigmoidoscopy is adequate since adenomas occur simultaneously throughout the colorectum (Syngal et al., 2015; Stoffel et al., 2015; Robays and Poppe, 2014). Once an adenoma is identified, annual colonoscopy should be performed until colectomy is undertaken.
Management of classical familial adenomatous polyposis
Colectomy between 15-25 years once adenomas have been observed
Lynch syndrome genetic defect and inheritance
Autosomal inheritance. Germline mutations in any one of the mismatch repair genes (MSH2, MLH1, MSH6, PMS2) ) or a deletion of the last few exons of the gene EPCAM that results in epigenetic silencing of MSH2.
Lynch syndrome colorectal cancer tumour location
Proximal colon cancer
Lynch syndrome colorectal cancer surveillance
Surveillance colonoscopy every 1 to 2 years is recommended for individuals carrying a germline mutation or clinically at risk of carrying a mutation but in whom definitive testing is not possible.[1][9][2][3][8] It should commence at age 25 or 5 years younger than the youngest affected family member if < 30 years.
Peutz-Jeghers syndrome clinical features and inheritance
Hamartomatous polyps throughout the GI tract. Most patients also have characteristic mucocutaneous pigmentation. 39% lifetime risk of colorectal cancer and a risk o small bowel intussusception; 45% risk of breast cancer, 18% of gynaecological cancer and 11-25% risk of pancreatic cancer. Autosomal dominant. Over 90% of patients meeting the clinical criteria for Peutz-Jeghers syndrome have an identifiable pathogenic mutation in the STK11 gene
AJCC prognostic stage groups for colorectal cancer
Stage 0 = Caricinoma in situ Stage I = T1 and T2 (up to invasion of the muscularis propria but not subserosal/pericolorectalic tissues) Stage II = Further tumour invasion without any nodal involvement Stage III = Nodal involvement Stage IV = Metastasis
Population based colorectal screening
50-74 years Every 2 years immunochemical faecal blood
Systemic therapy in non-resectable colorectal metastatic disease
EGFR or VEGF antibodies in combination with chemotherapy are first line. EGFR (cetuximab/panitumumab) should be used in patients with RAS wild-type tumours VEGF (bevacizumab) can be used in patients with a BRAF mutation
EGFR lung adenocarcinoma phenotype stereotype
East-Asian, female, non-smoker
What are the 4 most common mutations (in order) in NSCLC adenocarcinoma?
EGFR mutations (10-15%) ALK translocation (5%) Ros1 translocation (1-2%) Braf mutation (1-2%)
What are first line EGFR inhibitors in adenocarcinoma of the lung
Tyrosine kinase inhibitors: Erlotinib, gefitinib, osimertinib Improved progression free survival but not overall survival
What is the monoclonal antibody against EGFR and what is it used in?
Cetuximab Colorectal cancer - unresectable disease
What is the resistance mutation that lung adenocarcinomas can acquire during EGFR TKI treatment?
T790M
Which EGFR TKI has better activity in advanced EGFR mutated NSCLC
Osimertinib - better activity in the brain Not available on the PBS
What ALK inhibitor is used for IIIB or IV NSCLC
ALECTINIB (better CNS penetration vs Crizotinib) On PBS
What target therapy is used for NSCLC Ros1 translocation?
Crizotinib (both ALK, MET and Ros1 inhibitor
What therapy can be used to treat BRAF mutations in NSCLC
dabrafenib + trametinib
What lung cancer patients should be tested for PD-L1 immunohistochemistry?
Everyone with stage IV NSCLC Adeno AND squamous histology
What therapy can be given to PD-L1 (>50%) positive NSCLC?
Pembrolizumab (On PBS since Nov 1st 2018)
Phases I to IV of clinical trials
Phase I - to test a new biomedical intervention for the first time in a small group of people (e.g. 20-80) to evaluate safety (e.g. to determine a safe dosage range and identify side effects). Phase II - to study an intervention in a larger group of people (several hundred) to determine efficacy (that is, whether it works as intended) and to further evaluate its safety. Phase III - to study the efficacy of an intervention in large groups of trial participants (from several hundred to several thousand) by comparing the intervention to other standard or experimental interventions (or to non-interventional standard care). Phase III studies are also used to monitor adverse effects and to collect information that will allow the intervention to be used safely. Phase IV - done after an intervention has been marketed. These studies are designed to monitor the effectiveness of the approved intervention in the general population and to collect information about any adverse effects associated with widespread use over longer periods of time. They may also be used to investigate the potential use of the intervention in a different condition, or in combination with other therapies.
What immunotherapy can be added to chemotherapy in metastatic adenocarcinoma non small cell lung cancer (unselected for PD-L1)
Pembrolizumab Gandhi et al. NJEM 2018
What treatment for metastatic squamous NSCLC?
PD-L1 >50% - pembrolizumab PD-L1<50% - immunotherapy + chemotherapy
MOA of fulvestrant and clinical utilisation
MOA:
- ER antagonist that blocks ER dimerization and DNA binding, increases ER turnover, and inhibits nuclear uptake of the receptor. Because it blocks ER function before estrogen can bind the receptor, fulvestrant can theoretically overcome resistance that is driven by the agonist properties of tamoxifen [34]
Clinical utilisation:
- Hormone receptor positive, HER-2 negative breast cancer
- Not on PBS
PIK3CA-mutant tumors breast cancer treatment
Alpelisib
Background:
- ER positive metastatic cancers should be tested for PIK3CA mutation
- Alpha isoform-selective PI3K inhibitors have demonstrated promising activities in endocrine-resistant, PIK3CA-mutant, advanced, hormone receptor-positive breast cancer
- Not on PBS
- Used in patients who progress with first line treatment
Adverse effects of abiraterone
hypokalemia, hypertension, edema, hepatotoxicity
PSA screening in prostate cancer
<50 years
>50 years
< 50 years: inform risks and benefits. PSA testing 45-69 yr. If <75 centile then suggest no testing until 50yr.
> 50 years: inform risk + benefits, PSA testinf every 2 years further Ix of >3.0 ng/m
What monoclonal antibody causes reversible cardiac dysfunction?
HER2 antibodies: trastuzumab, pertuzumab
What is the gene for hereditary diffuse gastric cancer?
CDH1 gene in 30-50%, autosomal dominant
Staging investigations in gastric cancer
- Endoscopic ultrasound (85% sensitivity for depth/nodal involvement)
- Laparoscopic staging prior to surgical resection
- CT CAP
- PET
Gastric cancer peri-operative management:
1) adenocarcinoma
2) squamous
1) pre-operative neoadjuvant chemo
2) chemo RT
Chemotherapy for cholangiocarcinoma
Gemcitabine/cisplatin combination or gemcitabine/capecitabine
What chemotherapy is used for pancreatic cancer?
fluorouracil (5-FU) irinotecan. oxaliplatin
FOLFIRINOX
Initial treatment for ovarian cancer
- Debulking surgery
- Primary chemotherapy 6x carbo/taxol
- Can also consider intraperitoneal chemotherapy if optimally debulked
- Maintenance olaparib if BRCA1/2 mutant
Risk factors for endometrial cancer
Unopposed estrogen (e.g. nulliparity, early menarche, obesity, tamoxifen, chronic anovulation)
Age
Lynch syndrome
What viruses are responsible for cervix cancer ?
HPV 16 and 18
What kind of genes are BRCA 1 and 2?
Tumour suppressor genes - regulate cell growth and prevent abnormal cell division that might otherwise lead to tumour development
What kind of ovarian cancer is assocaited with BRCA1?
HGSOC
Screening in BRCA1/2 for breast cancer
Start at age 30
Annual MRI + mammogram for age 30-50
Annual mammogran for age 50+
Consider US for pregnant women
What kind of androgen deprivation therapy can cause a flare response?
GnRH agonist - goserelin, leuprolide
Metastatic castration-resistant prostate cancer treatment
- Docetazel or cabazitaxel
- Mitotic arrest and cell death during mitosis/interphase
- Androgen receptor targeted therapies - abiraterone, enzalutamide
- PARP inhbitors
- Radiopharmaceuticals
Important AE of docetaxel
Neutropenic sepsis
Important AE of cabazitaxel
Diarrhoea
What are poor prognostic markers of metastatic renal cell carcinoma?
Poor performance status
High neutrophils
High plts
High calcium
Low Hb
<12 mo between dx and tx
Treatment of stage I and II NSCLC
- Surgical resection or stereotactic ablative body radiotherapy
- Adjuvant chemotherapy for II +/- IB
- Cisplatin based
<5cm and only minor lymph node involvement
Treatment for locally advanced NSCLC (Stage III)
- Resectable
- Adjuvant chemotherapy +/- post operative radiotherapy
- Unresectable
- Concurrent chemoradiotherapy
- 2 drug platinum based combination (e.g. cisplatin + etoposide)
- Immunotherapy - durvalumab (PD-L1 antibody)
When and where to use chemotherapy in metastatic NSCLC
- EGFR and ALk negative disease without major comorbidities and PS 0-2
- Platinum based + third generation cytotoxics
Treatment SCLC
- Limited disease - tumour confinsed to the ipsilateral hemithorax and regional nodes (able to included in a single tolerable radiotherapy field
- Radical intent chemoradiation
- Extensive disease - tumour beyond the boundaries of limited disease
- Chemotherapy alone
- Carboplatin-etoposide
- Palliative radiation as clinically indicated
- Chemotherapy alone
Main purpose of neoadjuvant therapy in breast cancer
Refine prognostic estimates
Where can CDK 4/6 inihibitors be used?
1st and 2nd line setting in combination with endocrine therapy for HR positive, HER2 negative advanced breast cancer
Palbociclib and ribociclib
What are the 2 most important prognostic predictors in melanoma?
- Tumour thickness
- Mitotic rate
When to consider sentinel LN biopsy in melanoma?
>1mm or >0.75mm with high risk features
BRAF and MEK combination toxicity
Fever and photosensitivity
What is the strongest predictor in breat cancer prognosis?
Lymph node involvement
Adjuvant systemic therapy for ER positive disease
- Low risk: endocrine therapy
- High risk: chemotherapy then endocrine therapy
- Bisphosphonate in high risk postM
Premenopausal
- Ovarian function suppressor + AI or TAM
- OFS + AI more toxic but better
- TAM alone - 10 years better than 5years marginally
Post menopausal
- AI slightly better than tamoxifen
Where are SERMs pro-estrogenic?
Bones (partial), uterus
Management of hot flushes with SERMS
- NO estrogenic agents
- SSRIs/SNRIs (NO CYP2D6 INHIBITORS e.g. paroxetine/fluxetine)
- E.g. venlafazine
What chemotherapy is most likely to cause transfusion reactions?
Taxanes
Treatment of metastatic breast cancer with ER positivity
- Endocrine therapy unless high volume visceral disease or highly symptomatic
- Ovarian function suppression preferable surgically or medically
- CDK 4/6 inhibitor
- Stop cell progression from G to S phase
- SE: neutropenia (intermittent), PR prolongation
Treatment of triple-negative metastatic breast cancer
- Atezolizumab (PD-1 inhibitor) with taxane
- Sequential single agent chemotherapy
- PARP inhibitors after chemotherapy if BRCA mutant
What is the role of bone agents in metastatic breast cancer
Improves survival in adjuvant setting but not metastatic breast cancer
- Improves bone pain
- Commenced when evidence of destructive bone metastases
When to use adjuvant chemotherapy in NSCLC?
>4cm and/or positive nodes
Cisplatin (carboplatin is slightly less effective but no ototoxicity) + vinorelbine
Management of unresectable stage III NSCLC
Concurrent chemoradiotherapy
Who to test PD-L1 in NSCLC
Squamous cell carcinoma - test straight away
Adenocarcinoma - test for driver mutation first and if no driver mutation then PD-L1
