Cancer Genetics Louise Lynagh and Isabelle Danos Associate Genetic Counsellors Clinic ethos: cancer prevention and early detection
SVH Cancer Genetics team • Clinical Academic – Professor Allan Spigelman • 3 x Genetic Counsellors – Louise Lynagh – Isabelle Danos – Manisha Chauhan • Clinic Coordinator – Sobia Dean
New Referrals 600 545 500 465 400 400 300 203 198 200 133 129 112 112 95 88 100 77 72 61 60 44 18 10 0 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13 14 15
What is genetic counselling? • Genetic counselling is a communication process, which aims to help individuals, couples and families understand and adapt to the medical, psychological, familial and reproductive implications of the genetic contribution to specific health conditions ’
Genetic services in NSW State wide database Kintrak
Process 1. Construct family history (minimum 3 generation) 2. Assess the likelihood of an inherited predisposition to cancer – Types of cancer/ages at diagnosis – Confirm diagnoses: pathology, death certificate or verification through Cancer Institute (deceased 30yrs) – Ancestry – Consanguinity 3. Coordinate genetic testing and gain informed consent 4. Provide risk assessment based on PHx and FHx +/- GT results – Offer surveillance recommendations for risk management 5. Assess risk for relatives and link to cancer genetics
Genetic testing • Targeted single gene tests: – Mutation search – Mutation found – No mutation found – VUS found – Predictive testing – Positive – Negative – Founder mutation testing – Positive – Negative
Genetic Testing • Funding – Cost of genetic testing billed to LHD of patient – Self funded testing • BRCA1/2 currently ≈$1200 • Turnaround time – 4-6 weeks, longer for rarer conditions – Urgent results within 14 working days
Genetic Counselling • People often are interested in knowing… …why did I develop cancer? …can I have a genetic test? …what might it mean for me and my family? …what are the pros and cons of genetic testing? …what can I do about my cancer risk? …what can my relatives do to manage their risk?
Do I want to know? • Potential benefits • Tailor screening advice • Treatment related decisions • Sense of control • Alleviate anxiety • Remove uncertainty • More personalised risk assessment
Do I want to know? • Potential harms • Anxiety/fear/depression • Guilt/blame • Bearer of bad news • Change to family relationships • Insurance issues
Source: Stadler 2010 JCO 28(27):4255-4267.
Breast cancer • Conditions – Hereditary Breast Ovarian Cancer (BRCA1/2) – Li Fraumeni (tp53) – Cowden syndrome (PTEN) – Hereditary diffuse gastric cancer (CDH1) – Peutz-Jegher syndrome (STK11) • Risk assessment – Manchester, BOADICEA
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Colorectal Cancer • Lynch Syndrome (MLH1, MSH2, MSH6, PMS2) • Familial adenomatous polyposis (APC) • MUTYH-associated polyposis (MUTYH) • Sessile serrated polyposis (?)
Case 1 • 31yo female with triple negative breast cancer, undergoing neoadjuvant chemo before surgery • Referred by oncologist for a genetic review
Txt focused genetic testing • Traditional GT done following cancer txt to guide future risk management • TFGT done soon after cancer dx to guide initial cancer txt – Enabled by faster TAT – Inform surgical decisions (breast conservation vs therapeutic mastectomy +/- contralateral RR mastectomy) – Tailoring chemotherapy agents ie. PARP inhibitors and platinum based therapy
Information preferences w/ TFGT • Timing – Most women want to be informed about TFGT close to time of cancer dx, before decisions on cancer management – Some want to be informed at time of diagnosis, despite acknowledging that the time is fraught and emotionally overwhelming • Mode of delivery – No clear preference for which healthcare professional should introduce TFGT (similar numbers for onc, surgeon, genetics professional or cancer care nurse) – But if presented by onc or surgeon, want to be able to discuss test result with genetics professional • Amount and format of information – Face to face consultation plus additional written supporting info – Remain focused on the woman, briefly mention family implications Meiser et al. (2012). Getting to the Point: What Women Newly Diagnosed With Breast Cancer Want to Know About Treatment-Focused Genetic Testing. Oncology Nursing Forum. Vol 39(2)
Case 2 • 37yo female • Referred by GP for genetic assessment
“2 x VUS” 1 in BRCA1 1 in BRCA2
“2 x VUS” 1 in BRCA1 1 in BRCA2 Polymorphism and likely benign VUS
“2 x VUS” 1 in BRCA1 1 in BRCA2 Polymorphism and likely benign VUS Likely benign VUS BRCA2
“2 x VUS” 1 in BRCA1 1 in BRCA2 Polymorphism and likely benign VUS Unaffected full BRCA1/2 sequencing and MLPA = no mutation identified. Variant classified as polymorphism
BRCA1 deletion Unaffected full BRCA1/2 sequencing and MLPA = no mutation identified. Variant classified as polymorphism
Case 3 • 46yo female • Asked for GP referral following receipt of letter from Australasian Colorectal Cancer Family Registry
Case 4 • 65yo female • Referred by GP for predictive BRCA1 testing. Different BRCA1 mutations identified in sister and maternal cousin • HIV dx from blood transfusion 20yrs prior
BRCA1 BRCA1
BRCA1 BRCA1 Negative for both BRCA1 mutations
Case 5 • 36yo female with breast cancer • Referred by radiation oncologist given young age and family history
Case 6 • SDHD • Succinate dehydrogenase complex subunit B • Found in inner mitochondrial membrane • Involved in citric acid cycle • Pts with mutation present with head and neck paragangliomas/pheochromocytomas • Altitude can modify penetrance/avoid smoking
SDHD: c.191_192delTC (p.Leu64ProfsX4)
Case 7 • 55yo male with CRC showing loss of staining for MLH1 and PMS2 on IHC, and BRAF v600E negative • Referred by colorectal surgeon
MLH1+
Case 8 • Lynch like • MMR IHC: loss of MLH1/PMS2 • BRAF molecular – negative • Germline testing MLH1/PMS2 – no mutation identified
Case 9 • 50yo male referred by oncologist for ?Birt- Hogg-Dube assessment • PHx: renal cancer at 50, skin lesions ?fibrofolliculomas
Case 10
Case 11 • 30yo female referred by GP for predictive BRCA2 testing
Case 12 • Died CRC in 2004 • Stored DNA on deceased family member
MLH1+
Case 13 • IVF BRCA mutation
Indicators for referral • Cancer at a young age • Bilateral or multifocal tumours • Multiple cancers in one patient or family • Ethnicity (founder mutations) • Tumour pathology – Triple negative breast cancer – High grade serous ovarian cancer • Rare tumour types (Phaeochromocytoma, paraganglioma, sarcoma, glioblastoma, choroid plexus carcinoma, retinoblastoma)
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