Oncology

Question 1

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Of colon & rectal cancer - which is more common?

Answer 1

Colon - 70%; R) sided primaries more common (caecum, ascending colon, hepatic flexure)
Rectum - 30%

Question 2

What is microsatellite instability? Which syndrome is it associated with? What mutations can cause it?

Answer 2

• MSI = genetic hypermutability in large repeat DNA sequences due to mutations in mismatch repair proteins
• can be genetic or sporadic mutations in MMR -> more commonly sporadic (85% = acquired mutations, 15% Lynch syndrome)
• MSI associated with hereditary non-polypoposis colorectal cancer = Lynch Syndrome; which represents 3% of colorectal cancer
• MMR genes are - MLH1, MSH2, MSH 6, PMS2
• PMS2 mutations are the most common; BUT MLH1 and MSH2 are most represented in CRC because they are associated with a higher risk of CRC
• Lifetime risk of developing CRC with HNPCC is 50% - highest with MLH1
• MSI due to sporadic mutations is due to BRAF V600E mutation -> MLH1 methylation -> loss of expression of MLH1 & PMS2 -> microsatellite instability

Question 3

Mutation in what gene is associated with FAP? What is the lifetime risk of CRC with FAP?

Answer 3

FAP = familial adenomatous polyposis
-associated with autosomal dominant mutation in TSG APC (adenomatous polyposis coli) on chromosome 5
-associated with >100 polyps (usually 100-1000s)- 90% risk of developing CRC by age 45
-12% with FAP will also develop duodenal malignancies
-100% penetrance - adenoma mean age 16, carcinoma mean age 39

Question 4

What are the other clinical syndromes associated APC mutations?

Answer 4

• Gardener’s syndrome - osteomas, epidermoid cysts, desmoid tumours
• Turcot’s syndrome - CNS malignancies
• Attenuated FAP - less polyps 10s-100s, presents later in life but 100% penetrance

Question 5

Mutations in the MUTYH gene are also associated with colorectal cancer. What is the underlying mechanism?

Answer 5

MUTYH =base excision repair gene
- autosomal recessive disorder, with 80% penetrance
- associated with >15 adenomas
- accounts for >40% of attenuated FAP without APC mutation
- accounts for <1% of colorectal cancer

Question 6

What is Peutz - Jegher’s syndrome? What is the underlying gene mutation?

Answer 6

• Hamartomatous polyposis syndrome
• LKB1 (STK11) mutation
• manifests with skin & mucosal pigmenttaion, upper & lower GI hamartomatous lesions, small bowel & pancreatic malignancy, colorectal cancer, sex-cord tumours with annular tubules of ovary

Question 7

What are the differences between L) sided & R) sided colorectal cancer?

Answer 7

R) sided more common, worse prognosis, more likely to have RAS / RAF mutations - therefore poorer response to EGFR inhibitors, MSI-H / MMRd more common in R) sided malignancies (again associated with worse prognosis - immunotherapy may have a role)

R) sided colon cancer presents later
- more commonly presents with iron deficiency anaemia, SBP, sometimes PR bleeding not noticed because lesion is more proximal & blood mixes with stool

L) sided colon cancer - often presents with PR bleeding, LBO

Question 8

Most common causes for a positive FOBT

Answer 8

1. Haemorrhoids
2. Diverticular disease

1/29 people with positive FOBT have cancer

Question 9

NHMRC guidelines for population screening for colorectal cCa

Answer 9

Question 10

What are the extra-colonic manifestations of FAP & the screening recommendations for patients with FAP?

Answer 10

• 5% lifetime risk of duodenal cancer
• fundic gland polyps common but rarely progress to cancer
• duodenal adenomas in 45-90%
• increased risk of papillary & follicular thyroid cancer, childhood hepatoblastoma, CNS tumours - but much less common than colonic & duodenal malignancies

Annual sigmoidoscopy from 12-15 yrs till 35; then 3 yearly
Gastroscopy - starting age 30-35 yrs every 1-3 years
If attenuated FAP - for colonoscopy until 65 yrs.
? Thyroid exam / USS, CT brain

Question 11

What are the extra-colonic manifestations of HNPCC?
What are the screening recommendations for patients with HNPCC?

Answer 11

Extracolonic manifestations
- endometrial Ca
- other cancers - ovarian, gastric, genitourinary
- rarely - bile duct, pancreas, small bowel, skin, brain

Screening
Colonoscopy every 2 yrs from age of 25 yrs (or 5 yrs earlier than youngest cancer in family)
Annually in mutation carriers

Pelvic exam + transvaginal USS - annual from age 25-5 yrs.

Gastroscopy every 2 yrs in mutation carriers

Question 12

How do underlying mutations predict treatment response in CRC?

Answer 12

BRAF mutations - both prognostic & predictive (poor prognosis, poor response to EGFR inhibitors)

MSI-H or MMRd
- poor response to adjuvant chemotherapy
- overall poor prognosis
- MMR deficiency - generation of large DNA mutations -> neo-antigen generation -> immonogenic -> immunotherapy (PD-1 inhibitor pembrolizumab) shows benefit (both endometrial & colorectal Ca)

EGFR inhibitors ONLY for KRAS / BRAF / NRAS wildtype AND only for L) sided tumours (not for R sided even if wildtype) - cetuximab and panitumumab

BRAF V600E mutated metastatic colorectal Ca - responds to combination BRAF & EGFR inhibitor therapy (encorafenib + cetuximab)

Question 13

Prognostic factors in CRC

Answer 13

Question 14

Colorectal cancer biomarkers

Answer 14

Question 15

Colorectal cancer - treatment by biomarkers

Answer 15

New KRAS G12C inhibitors for KRAS mutant metastatic colorectal Ca - sotorasib & adagrasib

Question 16

MMR deficiency in colorectal Ca

Answer 16

Question 17

BRAF mutant colorectal Ca

Answer 17

Question 18

Therapies for MMRd colorectal Ca

Answer 18

Pembrolizumab (PD-1 blockade) leads to increased PFS in MSI-H metastatic colorectal Ca
Dostarlimab (PD-1 blockade) effective for MMRd locally advanced rectal Ca

Question 19

What is the most common genetic mutation in pancreatic cancer?

Answer 19

Activating mutations of the KRAS 2 oncogene seen in 90-95% cases

Question 20

Mutation associated with oesophageal squamous cell carcinoma

Answer 20

Amplifications in CCNDI = cyclin D1 (controls progression from G1 to S phase of cell cycle)

Question 21

Mutation see in lower oesophageal cancers

Answer 21

HER2 - human epidermal growth factor receptor 2

Question 22

Risk factors for gastric cancer

Answer 22

• obesity
• smoking
• ETOH
• CDH1 mutation associated with hereditary diffuse gastric cancer (CDH1 encodes E-cadherin) - autosomal dominant
• EBV
• H.pylori
• atrophic gastritis, pernicious anaemia
• high salt intake
• Lynch syndrome
• Polyposis syndromes - e.g. FAP or Peutz-Jeughers

Question 23

What stage is node positive HCC?

Answer 23

Node positive HCC is automatically stage IVA

Question 24

What is the criteria for transplantation for HCC?

Answer 24

Milan criteria
1 x lesion <5cm OR up to 3 lesions all <3cm with NO evidence of gross vascular invasion or nodal / distant mets

Question 25

What are the contraindications for HCC resection?

Answer 25

• usually restricted to tumours 5cm or less
• well-compensated liver disease (i.e. no worse than CPA), NO evidence of portal HTN
• no vascular invasion

Question 26

Who is eligible for ablation (radiofrequency or microwave) for HCC?

Answer 26

Liver targeted therapy - for unresectable disease but confined to liver
Small tumours <3-4cm, 1-2 nodules max, no vascular invasion
Healthy liver - restrict to CPA or CPB

Question 27

What are contraindications to TACE?

Answer 27

Portal hypertension!
Liver is reliant on arterial blood flow if there is portal HTN -> TACE can cut off too much arterial supply & cause decompensation

Main principle behind is TACE is to cut off the blood supply to the tumour

Question 27

What are the ADRs associated with the main systemic therapy options for HCC?

Answer 27

1st line - atezolizumab & bevacizumab (improved OS compared to sorafenib) - can cause variceal bleeding so much band first

2nd line - Lenvatinib - oral multi-kinase inhibitor. Improved PFS but NOT OS compared to sorafenib). Less ADRs then sorafenib.
If you respond to lenvatinib -> can have sorafenib

3rd line - sorafenib
-can only use in CPA compensated, ECOG 0-1
-oral multi-kinase inhibitor
-ADRs - haemorrhage (ensure banding before), hypophosphataemia, hand-foot syndrome

Atez & bev PFS - 6.8 months
Levatinib PFS - 7.4 months
Sorafenib PFS - 4 months

Question 28

Key differences between oesophageal SCC & adenocarcinoma

Answer 28

Adenocarcinoma - early nodal invasion
SCC - early submucosal & nodal invasion

Question 29

Risk factors for oesophageal adenocarcinoma vs SCC

Answer 29

Hereditary RFs
- Peutz-Jegher’s syndrome (STK11 / LKB1) - autosomal dominant
- PTEN tumour suppressor gene mutation (e.g. Cowden’s syndrome)

SCC RFs
>90% attributable to smoking & excess ETOH
Poor nutrition, reduced fruit / veg intake
Hot beveridges
HPV
Underlying oesophageal disease - achalasia, strictures
Prior gastrectomy
Bisphosphonates
Poor oral hygiene

Adenocarcinoma
Barrett’s & GORD
NOT H pylori
Smoking
ETOH
HPV
Obesity / metabolic syndrome
Drugs that reduce lower oesophageal sphincter pressure - benzos ,nitroglycerin, anticholinergics, beta agonists

Protective factors for adenocarcinoma - high fibre diet, NSAIDs

Question 30

What is the role of neoadjuvant therapy in oesophageal Ca?

Answer 30

CROSS protocol for neoadjuvant concurrent chemotherapy radiotherapy - weekly carbo / pacli PLUS RTx
R0 resection rate 92% compared to upfront surgery without neoadjuvant therapy
50% of SCC and 25% of adenocarcinoma patients will have pCR after neoadjuvant therapy

Question 31

What is the role of further systemic therapy after pCR post neoadjuvant CROSS protocol in localised oesophageal Ca?

Answer 31

neoadjuvant CROSS leads to pCR in significant proportion of pts

Can be followed by surveillance alone
OR FOLFOX (improved OS)
OR Nivolumab (improved RFS)

Question 32

What cell type do GISTs originate from?
What antigens do GISTs express?
What are the common underlying mutations / genetic syndromes?

Answer 32

• originate from interstitial cells of Cajal
• universally express the CD117 antigen (not expressed in leiyomyosarcomas, leiyomyomas)
  **- most common mutations are c-KIT (TK) and PDGFR alpha - Imatinib inhibits the ATP-binding site on the c-KIT TK and the PDGFR -> reducing cell proliferation & angiogenesis (advanced GIST very sensitive to imatinib)
  **
  Genetic syndromes
• primary familial GIST syndrome

Neurofibromatosis type 1- high incidence of GIST but usually small intestine

Question 33

Most common sites for GIST

Answer 33

Gastric > jejunum / ileu > colorectum > duodenum > oesophagus

Question 34

Risk factors for breast cancer

Answer 34

1. Endogenous oestrogene exposure - early menarche, late menopause, older at first full-term pregnancy
2. Exogenous oestrogen exposure - OCP associated with slightly increased breast Ca risk but significant reduction in ovarian & endometrial Ca risk; HRT for 6-7 yrs nearly doubles risk of breast Ca, use of HRT in women with Hx of breast Ca increases recurrence rate, eostrogen only replacement not assoicated with increased breast Ca risk but unacceptably high endometrial Ca risk
3. Previous radiation (esp if <30)
4. <10% of breast ca is directly linked to germline mutation

Question 35

What does the BRCA gene encode?

Answer 35

DNA repair enzyme that corrects double stranded DNA breaks by homologous recombination

Tumour suppressor gene

Question 36

What cancers are associated with BRCA mutations?

Answer 36

• Breast - 70% lifetime risk
• Ovarian 20-40% lifetime risk
• Prostate 15% lifetime risk
• Melanoma
• Pancreatic

Question 37

What types of cancers are associated with BRCA1?

Answer 37

On chromosome 17
BRCA1 typically associated with triple negative breast Ca
Higher risk of ovarian Ca than with BRCA 2

Question 38

What types of cancers are associated with BRCA2?

Answer 38

Chromsome 13
Lower risk of ovarian than with BRCA 1 mutations
Small risk of pancreatic
More commonly associated with hormone positive breast Ca

Question 39

Who should get breast conserving surgery vs mastectomy in early stage breast Ca?

Answer 39

WLE + radiotherapy is non-inferior to mastectomy in most cases - RTx reduces recurrence & improves survival
Mastectomy preferred if multifocal tumour, >4cm, previous chest RTx or central tumour, diffuse malignant microcalcifications, pregnancy
Follow mastectomy with RTx if tumour size >5cm, node positive

Question 40

Are late recurrences more common in triple negative breast Ca or hormone receptor positive breast Ca?

Answer 40

HR positive breast Ca has better prognosis BUT late recurrences > 5 yrs can occur
Triple negative -> poor prognosis but late recurrence >5 yrs uncommon

Question 41

What is the utility of adjuvant chemotherapy post curative intent surgery for early stage breast Ca and who should receive it?

Answer 41

Node positivity associated with increased risk of recurrence & death
All node positives = adjuvant therapy
If node negative but >2 cm OR 1-2 cm with poor prognostic features (grade 3, extensive LVI, weak ER / PR expression) -> adjuvant therapy
Always give chemo (doxorubicin + paclitaxel) to pre-menopausal women getting adjuvant therapy - but in post-menopausal HR + or HER2 + can give endocrine / targeted therapy instead of chemo (give chemo if triple neg in post menopausal women)