Inherited Cancer Part Three

Question 1

Outline von Hippel-Lindau Syndrome (VHL).

Answer 1

von Hippel-Lindau Syndrome (VHL):

• AD
• Birth incidence is 1 in 1000
• Haemangioblastomas (retinal or CNS).
• Renal cell cancer
• Multiple renal cysts
• Phaeochromocytoma
• Multiple pancreatic cysts
• Pancreatic tumours
• There is some recognised evidence based screening - yearly.
• Can’t do prophylactic surgery so need to catch it early.

Question 2

Outline Li-Fraumeni Syndrome.

Answer 2

• Caused by germline mutations in TP53.
• Tumour suppressor gene encoding a transcription factor with a crucial role in regulation of cell cycle and apoptosis.
• Loss of wild-type allele by deletion or mutation.
• Typically presents with young soft tissue sarcomas, young (<45) breast cancers, and adrenocortical cancers.
• Need to be aware that seeing tumours in lots of different organs in a family pedigree does not mean that they are not connected - need to think about these rare conditions.

Question 3

Outline how families with suspected hereditary cancers get triaged.

Answer 3

• Usually the GP will send them to a district general hospital close to them and they will be seen in the family history clinic by a nurse. The nurse will make an assessment, organise some screening, and then if she feels they are high risk they will be sent to clinical genetics.
• Sometimes a GP will refer directly to clinical genetics - that is particularly if you have a mixture of cancers in the family that don’t fit into the breast family history clinic or the bowel family history clinic.
• After being referred to family history clinics the people who are low risk get discharged, those at moderate risk will get some screening and stay at their district general hospital, and the high risk patients will come through to clinical genetics.
• Once the high risks have been assessed by clinical genetics and it has been decided what genetic testing or screening they need they will then go back to their family history clinic for ongoing surveillance.

Question 4

Outline the assessment that is carried out in the family history service or clinical genetics service when patients are referred with suspected hereditary cancer.

Answer 4

• Take pedigree.
• Confirm family history.
• Confirm diagnosis in affected relatives. If affected individual is dead then obtain details from the cancer registry or from patient notes. If no cancer registry information, request death certificate from patient. If affected individual is alive then obtain consent from that individual via the patient you are reviewing to review their hospital records.
• Need to do all of this before we make an assessment.

Question 5

Once we have made an assessment of the risk present in a family with suspected hereditary cancer, what risk modification strategies are available to at risk families?

Answer 5

1) . Surveillance
2) . Prophylactic Surgery and/or chemoprevention
3) . Diagnostic and predictive molecular genetic testing

Question 6

What lifestyle advice may be given to those at risk of hereditary cancers?

Answer 6

• Smoking - 60% of cancers amongst smokers due to smoking. Tobacco causes 1/3 of all cancer deaths in developed countries.
• Alcohol
• Obesity
• Diet
• Can reduce risk by modifying lifestyle - majority of risk will come from inherited factors in hereditary cancer cases.

Question 7

What surveillance is offered in patients with a family history of breast cancer and/or ovarian cancer?

Answer 7

• Mammography from 40-50yrs and NBSP
• MRI scanning from 30-50 if you fall into very high risk category.
• ?ovarian screening by transvaginal USS and CA125 annually. No real evidence that ovarian screening is effective.

Question 8

Outline management in FAP.

Answer 8

• Annual flexible sigmoidoscopy/colonoscopy from 11 years.
• Once polyps identified, discuss prophylactic colectomy.
• Annual rectal stump surveillance if left in situ.
• Upper GI endoscopy from 25, initially every 2-3 years but depends on number of polyps.

Question 9

Outline management in HNPCC?

Answer 9

• 2 yearly colonoscopy from 25 years.
• Endometrial and ovarian surveillance as suggested by local Gynecologist. Screening is suggested from 35 years.
• 2 yearly upper GI endoscopy if there is a family history of gastric cancers.
• Annual urine cytology if there is a family history of transitional cell carcinoma from 30-60.

Question 10

Outline prophylactic surgery and chemoprevention for high risk hereditary cancer families.

Answer 10

Prophylactic surgery in women with BRCA1/2 mutations:

• Prophylactic mastectomy removes around 90% of breast cancer risk.
• Prophylactic Salpingo-oopherectomy - residual risk of peritoneal cancer of 1-4%.
• Reduces/removes risk of fallopian tube malignancies. May reduce risk of breast cancer by 50%.

Chemoprevention in patients with BRCA1/2 mutations:

• Oral contraceptive pill may increase the risk of breast cancer in women over the age of 35. Appears to reduce the risk of ovarian cancer if used for mote than 5 years.
• Tamoxifen - interim results from 2 European trials failed to find any reduction in breast cancer risk.

Question 11

Outline the use of PARP inhibitors for treating BRCA1/2 breast cancers.

Answer 11

• PAPR inhibitors - novel class drugs that target DNA repair mechanisms.
• Poly(ADP-ribose) polymerases - multifactorial enzymes, repair DNA - single stranded breaks.
• Inhibition PARP - accumulation of single strand breaks. During cell division this results in double strand breaks at replication forks.
• PARP inhibitors are selectively toxic to the tumour cells.
• BRCA1 and BRCA2 are essential components of double stranded DNA repair pathway.
• Germline heterozygous BRCA mutation - double stranded DNA repair function retained.
• Loss or WT allele - obligate step in tumour development therefore tumours are deficient in double stranded DNA repair function.
• Standard chemotherapy basically picks out any cells growing quickly.
• Monotherapy - tumours in BRCA mutation carriers - selective toxicity to tumour cells.
• Triple negative tumours (deficient in ds repair mechanisms, poor response to stranded treatment options) - in combination with cytotoxic agents.
• Possible implications for testing - PARP inhibitors offer exciting new treatment option for BRCA associated cancers. This is increasing urgent referrals for BRCA tests as patients go into these trials.

Question 12

Outline treatment for NHPCC.

Answer 12

• Role of NSAIDs on colonic adenomas being investigated.
• Role of progesterone IUD on endometrial cancer being investigated.
• Role of OCP on endometrial and ovarian cancer unproven.
• Prophylactic surgery, colectomy, hysterectomy.

Question 13

Outline the identification of families appropriate for genetic testing. What needs to happen before diagnostic mutation analysis takes place?

Answer 13

• Usually only patients in the high risk category are eligible for molecular genetic testing.
• But not all patients within the high risk category are eligible for testing.
• Algorithms used to identify the patient group suitable for molecular genetic testing.
• Genetic testing carried out by the clinical genetics service.
• Need living affected relative or a DNA sample stored from deceased.
• Detailed discussion with genetic counsellor/consultant.
• Fully informed written consent before blood can be taken for mutation analysis.

Question 14

Inherited cancer part three: conclusions.

Answer 14

• Patients are aware that a family history of cancer may mean the patient is at risk of developing cancer.
• Guidelines for the assessment of cancer risk should be evidence based about the level of risk and effectiveness of interventions and fully integrated with developing structures of networks for cancer.
• Different management strategies have been used, but to be effective all management strategies need to be multi-disciplinary.