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year 4 CDM 2 > Case 16: Inherited cancers > Flashcards

Case 16: Inherited cancers Flashcards

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1
Q

Why do you do population screening

A
  • Large scale screening: Reduce risks or complications of a disease
  • Identify at risk individuals who are more likely to be helped by further tests or treatment
  • Provide individuals with results, further investigation and treatment options
  • Facilitate preventative medicine through early diagnosis of at risk and affected individuals.
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2
Q

Potential benefits of population screening

A
  • Early detection of disease allows for earlier more effective treatment
  • Identifies at risk individuals so preventive measures can be put in place
  • Identification of carriers of heritable conditions allows for informed family planning
  • Increased awareness of own health allowing for lifestyle changes
  • Control of disease at a population level
  • Cost-effective
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3
Q

Potential harms of population screening

A
  • False positive/negative results
  • Test may be invasive
  • Insurance implications
  • Psychological implications
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4
Q

How many cases of breast and bowel cancer are inherited

A

How many cases of breast cancer are genetic: most are sporadic. Less than <10% are caused by a germline mutation

How many cases of bowel cancer are inherited: 1 in 4 have a family history. 5-6% are inherited i.e. Familial adenomatous polyposis (FAP) and Lynch syndrome

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5
Q

The NHS breast cancerscreening Programme

A
  • Population screening programme
  • Offered to women from the age of 50 to 71st birthday every 3 year
  • May be eligible before the age of 50 if individuals are at a higher risk of developing breast cancer
  • Women who are 71 or over are still eligible for screening but must request
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6
Q

The NHS bowel cancer screening

A
  • Population screening programme
  • One-off bowel scope screening test offered at age 55 (if available in the individual’s area)
  • Individuals aged 60-74 offered home testing kit (faecal occult blood test) every 2 years
  • Individuals 75 or over can request a home testing kit every 2 years
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7
Q

Referral for a family history of cancer

A
  • Young age at onset
  • Number/pattern of similar tumours on one side of the family
  • Multiple primaries in one individual
  • Type of cancer e.g. Triple negative breast cancer
  • Ethnicity e.g. – Chinese, Indian, Ashkenazi Jewish ancestry
  • Results of genetic testing
  • Main cancer affected: Breast, Bowel and Ovarian
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8
Q

What do the genetic services do

A
  • Accept referrals of people with a family history of cancer
  • Request family information from patient
  • Compile a family tree
  • Confirm diagnoses in the family: Confirmed through cancer registry or medical records (with consent)
  • Provide a risk assessment for family members and screening recommendations
  • Genetic testing/Predictive testing
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9
Q

Inherited v familial

A
  • Hereditary – Due to a mutation in a cancer gene e.g. BRCA1/ BRCA2
  • Familial – mixture of weaker genetic factors and environment
  • Low risk – family history likely to be sporadic cancer
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10
Q

Surveillance and management breast cancer: low risk

A
  • Discharged back to referrer
  • NHS breast screening programme 50-70 and 70+ (normal)
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11
Q

Surveillance and management breast cancer: Moderate risk

A
  • Seen in clinic/discharged with advice letter
  • annual mammography aged 40-50
  • NHS breast screening programme 50-70 and 70+
  • Chemoprevention advice: i.e. Tamoxifen, Roloxifen, aromatase inhibitors
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12
Q

Breast cancer: surveillance and management High risk

A
  • Seen in clinic
  • Genetic testing may be available
  • Chemoprevention advice
  • Annual mammography aged 40-60
  • NHS breast screening programme 60-70 and 70+
  • Risk reducing surgical options may be discussed
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13
Q

Breast cancer surveillance and management very high risk (known mutation i.e. BRCA)

A
  • Seen in clinic
  • Genetic testing may be available
  • Chemoprevention advice: with BRCA1 alterations its not typically recommended
  • Annual MRI from 30-50 and annual mammography from 40-70
  • NHS breast screening programme 70+
  • Bilateral risk-reducing mastectomy
  • Prophylactic bilateral salpingo-oophorectomy (BSO) offered if high lifetime risk of ovarian cancer: consider if >40 and completed their family
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14
Q

Bowel cancer surveillance and management- Low risk families

A
  • Discharged back to referrer
  • NHS bowel screening programme
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15
Q

Bowel cancer surveillance and management- Moderate families

A
  • Appointment in clinic
  • Surveillance determined – either one off at 55 or 5 yearly (if high/moderate)
  • NHS Bowel screening programme
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16
Q

Bowel cancer surveillance and management- High risk families (Lynch and FAP)

A
  • Appointments in genetic clinic
  • Genetic testing: tumour and germline testing
  • Chemoprevention advice – Aspirin
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17
Q

Bowel cancer surveillance and management- Lynch syndrome

A
  • Colonoscopies are offered every two years, usually starting from the age of 25
  • hysterectomy and oophorectomy offered to women at risk of gynecology cancers once they have completed their families
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18
Q

Bowel cancer surveillance and management- FAP

A

Annual bowel checks, starting between ages 10-13 (sigmoidoscopy can be used to examine the lower part of the bowel, or colonoscopies can be used to examine more of bowel)

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19
Q

BRCA1/2 carrier risk

A
  • BRCA1: increased risk of ovarian cancer and female breast cancer compared to BRCA2. Increased risk of male breast cancer compared to the general population
  • BRCA2: increased risk of Male breast cancer and Prostate cancer compared to BRCA1. Increased risk of ovarian cancer and female breast cancer compared to general population
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20
Q

Percentage risk of cancer in BRCA1/2 mutation

A
  • BRCA1/2 developing contralateral breast cancer after unilateral: 50%
  • BRCA1 breast cancer: up to 90%
  • BRCA2 breast cancer: up to 85%
  • BRCA1 ovarian: up to 60%
  • BRCA2 ovarian: up to 30%
  • BRCA2 male breast cancer: 5-10%
  • BRCA2 prostate: 25%
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21
Q

Genetic testing- BRCA 1/2

A
  • Individuals with a grade 3 triple negative breast cancer <50 should also be offered BRCA testing
  • Testing for the 3 Ashkenazi founder mutations offered to women with breast cancer and Ashkenazi ancestry: Full analysis offered when Manchester Scoring is 15 and above
  • Newer genes such as PALB2 can also be tested
  • P53, Stk11, CDH1, PTEN can also be considered if appropriate
22
Q

Manchester scoring system

A
  • Used to calculate the probability for the presence of a BRCA1/2 mutation in a family suspected to have hereditary breast/ ovarian cancer
  • BRCA1/2 testing is indicated in a person affected with breast cancer where the Manchester Score is >15
  • Manchester Scoring System (MSS): scores are added for each first degree relative. different scores are given for age of diagnosis and type of cancer. A score of 15 is associated with a 10% risk of finding a variant
23
Q

BRCA 1/2 testing: individuals unaffected with breast or ovarian cancer

A
  • BRCA1/2 testing is indicated in an unaffected person where there is no living affected person available for testing. The Manchester score should be >20
  • The individual should have a 1st degree relative affected with a relevant cancer (Breast/ovarian/prostate). Ideally test the individual affected (greater chance of finding the mutation)
  • Testing for the 3 Ashkenazi founder mutations offered to women with breast cancer and Ashkenazi ancestry. Full analysis offered when Manchester Scoring is >20 and first degree family member affected
  • Testing of other genes e.g. PALB2, P53, Stk11, CDH1, PTEN can also be considered
24
Q

Lynch syndrome risk

A
  • Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), is caused by mutations in one of several DNA mismatch repair (MMR) genes; MLH1, MSH2, MSH6 and PMS2.
  • Autosomal Dominant
  • Men: 80% risk of colorectal cancer
  • Women: 70% risk of colorectal and 60% risk of endometrial cancer
25
Q

Management offered to MLH1 and MLH2 carriers

A
  • 25-75: Offered colonoscopy every 2 years
  • One off H.pylori screening
  • NHS cervical screening
  • Hysterectomy: offered >35 once childbearing is complete
  • May have surgery to remove healthy bowel or bilateral salpingectomy
26
Q

Lynch syndrome carriers treatment

A
  • MSH6 carriers and PMS2: Colorectal screening is offered 2 yearly from 35-75 yrs- review at 75.
  • PMS2 carriers in that hysterectomy ALONE is offered, once childbearing is complete but no earlier than 45.
27
Q

Amsterdam criteria: family likely to have Lynch syndrome

A
  • CRC diagnosed <50 years OR
  • CRC diagnosed <60 years with abnormality on IHC already detected OR
  • CRC diagnosed any age and one other Lynch tumour any age OR
  • CRC diagnosed <60 years and one first degree relative with lynch tumour <60 years OR
  • CRC diagnosed <75 years and two or more first/second degree relatives with Lynch tumour <75 years (two cases must be FDR)
  • Lynch tumours= Colorectal cancer, endometrial cancer, ovarian cancer, pancreatic cancer, hepatobiliary tract cancer, certain skin cancers.
28
Q

Lynch syndrome investigations

A
  • Microsatellite instability (MSI)/Immunohistochemically testing (IHC) and BRAF testing is done on tumour tissue or a sample from members of the family in whom Lynch syndrome is most likely
  • MSI high / Abnormal IHC / Negative BRAF: proceed to germline MMR testing
  • If MSI/IHC testing not possible, Amsterdam positive patients can proceed to germline MMR testing
  • Testing should be done on family member diagnosed with Lynch Syndrome Cancer (greatest chance of identifying mutation)
  • Only test when there is a living affected relative. Can test if no relative but MSI/IHC suggest presence of a germline mutation
29
Q

Predictive testing

A
  • Predictive testing for known pathogenic variants should be offered to all families where a pathogenic variant has been identified.
  • This is testing in individuals who are not yet affected by the condition - risk management if positive test
  • Offered from >18: exception is FAP and TP53
  • Offered to first degree relatives of affected, if they test positive predictive testing is offered to their first degree relatives and so on
  • Negative predictive test: when an individual doesn’t carry the mutation. Returned to population screening
30
Q

Insurance and genetic tests

A
  • Insurance companies should not require or pressure you into a predictive or diagnostic genetic test
  • Insurance companies should not ask for or take into account the result of a predictive genetic test if you are applying for insurance (the exception being if you are applying for life insurance over £500,000 and you have had a predictive genetic test for Huntington’s Disease)
  • However companies can ask questions around the subject and make assumptions
  • Advise patients to get life insurance before undergoing the genetic tests
31
Q

Options for genetic testing of hereditary breast/ovarian cancer

A
  • Test for a single mutation if known mutation in family, standard, panel test and bespoke panel test
  • Genes: BRCA1, BRCA2, PALB2
  • A bespoke panel might be carried out if the patients phenotype suggests a different gene at play i.e. TP53, PTEN, STK11
32
Q

Risk factors for breast cancer

A
  • Family history
  • Smoking, Obesity, Alcohol, Lack of exercise
  • Nulliparity or first pregnancy >30
  • Early menarche (<12) and/or late menopause (>55)
  • Current or previous HRT use
  • Previous radiotherapy
  • Previous breast cancer
  • (Prolonged breast feeding is protective)
33
Q

What classifies a patient as moderate risk for breast cancer

A
  • One female FDR with BC <40
  • One male FDR with BC
  • One FDR with bilateral BC at any age
  • One FDR with BC and OC at any age
  • Two female FDR with BC at any age
34
Q

What classifies a patient as high risk for breast cancer

A
  • One FDR with both cancers <50
  • One FDR with BC <50 and then develops OC
  • Two FDR with breast cancer cancers <50 or one <35
35
Q

Types of genes and family history associated with breast cancer

A
  • Hereditary: rare, single gene, high penetrance. For example: BRCA1, BRCA2, PALB2, TP53, PTEN, STK11
  • Family cluster: relatively common, >1 gene, low penetrance, ‘Polygenic risk scores’
  • Sporadic disease: common, multigenic, environment more important
36
Q

Genetic testing in breast cancer

A
  • Single mutation (predictive) test – if known mutation in the family. A yes/no test for the gene i.e. BRCA1
  • Standard panel test – BRCA1/BRCA2/PALB2 – if fhx breast/ovarian cancer meeting testing criteria of 10% chance of finding a mutation (Manchester criteria). When there has been no previous genetic investigations
  • Bespoke panel test – by adding other relevant genes to above panel. If we suspect presence of rarer genes
  • Future: large panel testing, Polygenic risk score (looking for presence of common variants- individually might not confer a lot of risk but do when combined)
37
Q

High penetrance breast cancer genes 1

A
  • Would always test for BRCA1, BRCA2 and PALB2. Might add the others if the phenotype suggests it
  • BRCA1 and BRCA2: most highly associated with ovarian cancer
  • PALB2: may have less ovarian cancer risk
  • TP53 = Li Fraumeni syndrome, saw other early onset cancers like sarcoma, brain cancer, leukaemia. Assoicated with breast cancer
38
Q

High penetrance breast cancer genes 2

A
  • PTEN = Cowden. Associated with Microcephaly, autism, harmatomas (tumour like growths). Other cancers like endometrial cancer, kidney cancer, thyroid cancer. Associated with breast cancer.
  • CDH1 = Hereditary Diffuse Gastric Cancer. Causes lobular breast cancer
  • STK11 = Peutz Jeghers, perioral freckling and young onset bowel cancer. Associated with breast and ovarian cancer
39
Q

BRCA1 and BRCA2 tumour suppressor genes

A
  • Can offer predictive testing to see which members of the family have the gene
  • The most common single gene cause of breast cancer – implications for screening and prevention; associated with ovarian cancer risk (largely preventable with RR BSO)
  • Other cancers are associated – especially with BRCA2, and especially male breast (still low), prostate (occurs younger, is aggressive- get annual PSA for 40), pancreas
  • Lifetime breast and ovarian cancer risks higher with BRCA1 compared with BRCA2
40
Q

Breast cancer screening for at risk populations

A
  • Population: 3 yearly from 50 (standard)
  • Moderate: annual mammogram 40-50 then NHS standard
  • High: annual mammogram 40-60 then NHS standard
  • Very high: annual screening from 30 initially by MRI till 50 then mammogram
41
Q

Breast cancer at risk populations: risk reduction

A
  • Population: lifestyle
  • Moderate: lifestyle, ?Chemoprophylaxis
  • High: Lifestyle, Chemoprophylaxis, ?bRRM (bilateral risk reduction mastectomy- only thing that significantly works) is only suggested for minority in high risk group
  • Very high: lifestyle, chemoprophylaxis, bRRM
42
Q

Breast cancer: Chemoprophylaxis

A
  • Premenopausal: Tamoxifen 5 years. Given to women >35 once complete family as induce menopause. Increases risk of endometrial cancer + VTE.
  • Post menopausal: Aromatase inhibitor i.e. Anastrozole 5 years
43
Q

Breast cancer risk reducing surgery: Pros and cons

A
  • Pros: only effective way to reduce risk (90-95% reduction). Can be combined with cancer surgery if undergoing treatment for primary cancer. No screening needed after
  • Cons: risks of surgery including reconstruction (autologous vs implant), Psychological implications. May be an ‘unnecessary’ major procedure, might not go on to develop breast cancer. Some residual breast cancer risk remains
  • Tends to be patients who have a primary breast cancer and are concerned they will get it again and women who have a strong family history.
44
Q

Risk reducing surgery in breast/ovarian cancer

A
  • bilateral risk reducing mastectomy
  • prophylactic bilateral saplingo-oophorectomy if high lifetime risk of ovarian cancer, over 40 and family completed
  • Will not need screening afterwards
45
Q

What question do you ask in family’s with an increased bowel cancer risk

A

Is there an identifiable single gene disorder

  • If YES - counsel patient and family members appropriately (screening, treatment)
  • If No base recommendations on strength of family history
46
Q

Lynch syndrome

A
  • Accounts for 1/30 colorectal cancer diagnoses: tend to affect the proximal colon, poorly differentiated and highly aggressive
  • Dominantly inherited
  • Due to a mutation in one of four ‘mismatch repair’ genes: MLH1, MSH2, MSH6, PMS2
  • Core Lynch cancers are Bowel and Endometrial. Can also cause gynae, urological and CNS tumours
47
Q

Identifying families with Lynch syndrome

A
  • Clinical (‘Amsterdam’) criteria - 3,2,1 - (3 Lynch tumours, 2 successive generations, 1 diagnosis <50)
  • NICE recommends tumour testing on all Colorectal Tumours to look for evidence of mismatch repair deficiency (evidence of Lynch syndrome) via IHC or MSI
48
Q

How do you test for colorectal cancer gene- step 1

A
  • Mismatch repair tests on tumour:
  • Immunohisto-chemistry (looks for protein expression of Lynch syndrome protein if loss of expression suggests Lynch syndrome): abnormal IHC suggests Lynch
  • Microsatellite instability (repetitive sequences of DNA present in Lynch): High MSI suggests Lynch
49
Q

How do you test for colorectal cancer gene: step 2

A
  • On Tumour
  • Evidence of ‘sporadic’ i.e. non lynch cause.
  • BRAF V600E and/or MLH1 promotor hypermethylation.
  • If positive STOP, lynch unlikely as suggests disease is sporadic
50
Q

How do you test for colorectal cancer gene: step 3

A
  • Blood DNA
  • Germline Lynch gene testing of MLH1/ MSH2/ MSH6/ PMS2. If positive Lynch confirmed

year 4 CDM 2 (39 decks)

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