Medical Oncology Flashcards
Which of the following best describes the mechanism of chemoresistance associated with P-glycoprotein?
A. Induction of mutations in the receptor that binds to cytotoxic agent
B. Induction of angiogenesis
C. Alterations in enzymes involved in DNA repair
D. Recognition of the cytotoxic agent and pumping of the drug to the extra-cellular space
E. Drug inactivation by glycosylation
Answer: D - Recognition of the cytotoxic agent and pumping of the drug to the extra-cellular space
P-glycoprotein is a member of the ATP-binding receptor family and spans the plasma membrane, recognising a broad spectrum of cytotoxic drugs. In the presence of ATP, PGP pumps the drugs to the extra-cellular space so that an effective intracelllular concentration cannot be reached.
Resistance to chemotherapy can result from interference in multiple steps e.g. poor absorption, liver metabolism, decreased blood supply to the target organ, tumour microenvironment (e.g. hypoxia), drug target modifications, and mechanisms which block the intracellular accumulation of the drug.
Which one of the following statements regarding p53 is correct?
A. p53 protein functions by directly repairing DNA molecules
B. Activation of p53 results in DNA mutations
C. p53 protein is an oncogene that is inactivated by hypoxia
D. p53 mutations promote cellular apoptosis
E. Activation of p53 leads to arrest in the G1 phase of the cell cycle
Answer: E - Activation of p53 leads to arrest in the G1 phase of the cell cycle
p53 is a tumour suppressor gene which plays a critical role in the maintenance of the genomic integrity - popular designation as ‘guardian of the genome’.
p53 is normally expressed at low levels in all cells, but genetic injuries (e.g. ionising radiation) trigger the activation. p53 functions as a transcription factor, directing expression of p21 and regulates the cell cycle. Activation leads to arrest in the G1 phase of the cycle, enabling DNA damage repair before proceeding into the S (synthesis) phase with DNA replication. In other cells, p53 leads to apoptosis.
Mutations of p53 are common in human cancers, demonstrable in about 50%, and increased levels of its negative regulators MDM2 and MDM4 (also known as MDMX) downregulate p53 function in many of the rest.
Most mutations result in misfolding and rate of turnover is greatly slowed. This explains the paradox that high levels of p53 are commonly taken as evidence of p53 mutations.
Germline p53 mutations are associated with a familial syndrome of breast cancer, sarcomas and other neoplasms - Li-Fraumeni syndrome
Which one of the following is a good prognostic factor for patients with breast cancer?
A. Oestrogen receptor positivity
B. Age greater than 70 years at time of diagnosis
C. human epidermal growth factor receptor 2 (HER2) overexpression
D. Inflammatory breast cancer
E. BRCA1 gene mutation
Answer: A - Oestrogen receptor positivity
Oestrogen receptor positivity is a good prognostic factor.
Lymph node involvement is the most important adverse/negative prognostic factor. Increasing tumour grade and HER2 overexpression are also associated with poor prognosis.
BRCA1/2 mutations, whilst increasing risk for development are not established as prognostic markers.
2 factors determine local recurrence risk: 1. margin status, 2. presence or absence of in-situ component.
Young age <35yrs and lymphatic invasion are predictors for increased risk of ipsilateral recurrence. Large tumour size >2cm and high histological grade also are consistent with increased recurrence risk.
EMQ
A. p53 B. BRCA1 C. BRCA2 D. Von Hippel Lindau (VHL) E. APC F. KRAS G. MUTYH H. PTEN
- Which gene is frequently mutated in adult renal cell carcinoma?
- Which gene mutation activates the mitogen-activated protein kinase (MAPK) signalling pathway and can lead to the development of colorectal cancers?
- Answer: D - Von Hippel-Lindau
A frequent event during evolution of clear cell RCC is loss of function of the von-Hippel Lindau (VHL) gene on Ch 3p. Inherited defective copies of the VHL gene lead to VHL disease and is the most comomn cause for inherited clear-cell RCC in which a second hit or somatic mutation is presumed to occur in cancer cells. Up to 75% of sporadic clear cell RCC have mutation or silencing by methylation of VHL.
VHL functions in several pathways linked to carcinogenesis, most notably the hypoxia-inducible pathway. In the absence of VHL, hypoxia-inducible factor (HIF) accumulates, producing growth factors incl. VEGF and platelet derived growth factor and glycolysis.
- Answer: F - KRAS
Oncogenic mutations of RAS and BRAF activate the MAPK pathway and occur in 37% and 13% of CRC.
EMQ
A. Direct DNA repair B. Base excision repair C. Nucleotide excision repair D. Mismatch repair E. Non-homologous end joining F. Homologous recombination repair G. Interstrand cross-link H. Single-strand break repair
- Which pathway corrects replication errors that cause the incorporation of the wrong nucleotide and nucleotide deletions and insertions?
2/ Which pathway prevents unwanted mutations by removing ultraviolet-induced DNA damage?
- Answer: D - Mismatch repair
Mismatch repair (MMR) corrects replication erros that cause the incorporation of the wrong nucleotide (a mismatch) and nucleotide deletions and insertions. Defective MMR increases mutation rates up to 1000-fold and results in microsatellite instability –> cancer.
- Answer: C - nucleotide excision repair
NER removes helix-distorting adducts on DNA e.g. those caused by UV radiation and tobacco smoke, and contributes to the repair of intra-strand and inter-strand cross-links.
Hereditary defects in NER cause UV sensitivity and skin cancer.
Which one of the following techniques in radiotherapy for lung cancers is used to counteract the effect of tumour motion due to breathing?
A. Shunting B. Arc technique C. Gating D. Modulation E. Stereotactic
Answer: C - gating
Gating is a system that tracks a patient’s normal respiratory cycle with an infrared camera and a chest/abdomen marker. It is coordinated to only deliver radiation when the tumour is in the treatment field.
Which of the following best describes Bevacizumab in the treatment of metastatic colorectal carcinoma?
A. Monoclonal antibody targeting vascular endothelial growth factor (VEGF)
B. Monoclonal antibody targeting epidermal growth factor receptor (EGFR)
C. Standard monotherapy for metastatic colorectal carcinoma
D. It has no proven survival benefit in patients with metastatic disease
E. It is contraindicated in patients with hypertension
Answer: A - A. Monoclonal antibody targeting vascular endothelial growth factor (VEGF)
Bevacizumab, by targeting the VEGF-VEGFR pathway, prevents new blood vessel formation and tumour growth. It improves survival in metastatic colorectal carcinoma when used in combination with chemotherapy.
It is generally well tolerated. Hypertension is the only consistently observed side-effect that requires treatment.
A 52 year old man presents to hospital complaining of abdominal pain and watery diarrhoea over the past 2 months. He has also been increasingly breathless. He stopped drinking alcohol as he noticed his face becoming red.
On examination, there is pitting oedema of the ankles, raised JVP. He has a pan-systolic murmur in the apex area and tender hepatomegaly.
Which investigation is most likely to be useful diagnostically?
A. Plasma brain natriuretic peptide level
B. Plasma somatostatin level
C. Plasma gastrin level
D. 24-hr urine for 5 hydroxyindoleacetic acid (5-HIAA)
E. 24-hr urine for 4-hydroxymethoxymandelate (VMA)
Answer: D - 24-hr urine for 5 hydroxyindoleacetic acid (5-HIAA)
Carcinoid syndrome
The syndrome of facial flushing, watery diarrhoea, abdominal pain and cardiac abnormalities imply hepatic metastasis. Common sites of carcinoid tumour in the bowel are the terminal ileum, rectum and appendix (25% of all tumours).
Diagnosis is made by the clinical picture and 24-hour collection of urine for 5-HIAA levels - a metabolite of H-HT (serotonin) that is postulated to be responsible for the cardiac manifestations and profuse watery diarrhoea.
Treatment with somatostatin analogues, which inhibit hormone production by several tumours, is useful for carcinoid.
24-hour collection of VMA (catecholamine metabolites) are helpful to diagnose pheochromocytoma.
A 50 year old woman is receiving carboplatin-based combination chemotherapy for ovarian cancer. Which one of the following is the most appropriate therapy to prevent acute emesis?
A. Intravenous NK1 receptor antagonist (aprepitant)
B. Metoclopramide and a 5-HT3 serotonin antagonist
C. Dexamethasone, 5-HT3 serotonin antagonist and aprepitant
D. Metoclopramide and dexamethasone
E. Dexamethasone and aprepitant
Answer: C - Dexamethasone, 5-HT3 serotonin antagonist and aprepitant
3 agent superior to 2 agent for highly emetogenic chemotherapy (i.e. carboplatin based)
Which one of the following describes the role of Denosumab in the treatment of bone metastases of solid tumours?
A. Is superior to zoledronic acid for castration-resistant prostate cancer with bony metastasis
B. Is inferior to zoledronic acid for breast cancer with bony metastasis
C. Is renally cleared and contraindicated in patients with renal failure
D. Does not affect the serum calcium level
E. Is associated frequently with osteonecrosis of the jaw
Answer: A - Is superior to zoledronic acid for castration-resistant prostate cancer with bony metastasis
Denosumab is superior to zoledronic acid in castrate-resistant prostate cancer with bone mets.
It is non-inferior in non-prostate, non-breast bony metastasis. It also has the benefit of being less renally cleared and can be used in renal dysfunction.
Hypocalcaemia can occur with any osteoclast inhibitor, but is more common with Denosumab. ONJ is rare but an important SE for both drugs.
Which one of the following statements is true of prostate cancer bony metastases and their complications?
A. Most fractures occur as the result of trauma
B. Pathological fractures of proximal long bones are more common than vertebral fractures
C. Androgen deprivation therapy for prostate cancer may increase the risk of fracture
D. Bisphosphonates may help reduce bone pain but do not reduce the number of cancer-associated skeletal events
E. Radiotherapy is the most effective way of preventing pathological fractures from bone metastases
Answer: C - Androgen deprivation therapy for prostate cancer may increase the risk of fracture
Androgen deprivation therapy (ADT) with a GnRH) agonist is the standard initial hormonal treatment for metastatic prostate cancer. It causes severe hypogonadism and significantly increases the risk of fracture. Prophylactic orthopaedic surgery may be required to reduce risk for lesions with high risk of fracture.
Pathological fractures may occur without trauma. Vertebral fractures are actually more common than long bone.
A patient is referred for evaluation of a soft-tissue mass on his leg. The histopathology result is consistent with soft-tissue sarcoma. The patient wants to know how you would treat such a tumour. You will inform him that:
A. Chemotherapy is contraindicated for soft-tissue sarcomas
B. Local control of soft-tissue sarcomas consists of surgical resection, often with radiotherapy
C. Localised soft-tissue sarcoma usually only requires radiotherapy
D. Soft-tissue sarcomas are usually well encapsulated and seen to have clear margins on resection
E. The presence of necrosis on MRI suggests a low grade sarcoma
Answer: B - Local control of soft-tissue sarcomas consists of surgical resection, often with radiotherapy
Surgery, often supplemented by adjuvant radiotherapy is often curative for localised sarcoma.
Low grade tumours push aside contiguous structures, whereas high-grade tumours invade adjacent organs and have large areas of necrosis. They are usually pseudo-encapsulated (i.e. microscopic projections extend beyond apparent capsule). Any excision that ‘shells out’ the apparently encapsulated tumour results in recurrence in 80% of cases.
Multimodal therapy is routine for rhadbomyosarcomas and Ewing sarcoma. Adjuvant chemotherapy generally alters the natural history of other sarcomas.
A 72 year old man with unresectable lung cancer presents to ED complaining of back pain. In addition, he reports having difficulty walking the last 1 week (only able to stagger from bed to chair), but denies bladder or bowel difficulty. Examination shows mid-thoracic bony tenderness, 4/5 strength in bilateral legs and normal knee jerks. Which one of the following imaging modalities of the spine and management is recommended?
A. Radionuclide bone scan and NSAIDs
B. CT spine and IV Pamidronate
C. IV Dexmethasone while awaiting plan films/XR thoracic spine
D. IV Pamidronate while awaiting bone scan
E. IV Dexamethasone while awaiting gadolinium-enhanced MRI spine
Answer: E - IV Dexamethasone while awaiting gadolinium-enhanced MRI spine
Most likely spinal cord compression from metastatic disease.
Gad-enhanced MRI is the most sensitive and specific imaging modality.
Surgery followed by radiation is considered for selected patients with a single high-grade lesion caused by a radio-resistant tumour with estimated survival >3 months.
A 63 year old woman with no significant medical history presents with facial swelling. Exmination shows facial swelling, distended jugular veins. She is alert and her vital signs are normal. Contrast CT chest reveals mediastinal lymphadenopathy and external compression of the superior vena cava by an enlarged node. What is the most appropriate next step in management?
A. IV thrombolysis
B. Fine needle aspiration of an enlarged mediastinal lymph node
C. Immediate initiation of mediastinal irradiation
D. Thoracic MRI
E. Initiation of anti-coagulation with warfarin
Answer: B - Fine needle aspiration of an enlarged mediastinal lymph node
Recent reviews have suggested with SVC syndrome is not a true emergency and histological diagnosis should be quickly established first before prompt treatment.
SVC syndrome is most commonly caused by malignant mediastinal massess such as bronchogenic carcinoma (especially small-cell lung cancer) and non-Hodgkin lymphoma.
Emergent mediastinal radiation is only warranted in children and occasionally adults who have life-threatening manifestations e.g. mental status alteration, elevated ICP, cardiovascular collapse.
Which one of the following factors increases the risk of venous thromboembolism in patient with cancer receiving chemotherapy?
A. Use of EPO B. Haemoglobin 120g/L C. Low levels or circulating platelet microparticles D. Neutropenia E. BMI 27kg/m2
Answer: A - Use of erythropoeitin stimulating agents
Relative risk of thromboembolic events is increased in 67% in patients treated with erythropoeitin-stimulating agents compared to placebo.
