Genetic testing, such as BRCA

Germline vs somatic

Two distinct questions, often conflated
- Germline - inherited, present in every cell; implications for the patient's future cancers and for the family
- Somatic (tumour) - acquired, tumour-only; implications for this cancer's treatment
Somatic testing can incidentally reveal a germline variant - consent must cover this

Class	Meaning	Action
5 Pathogenic / 4 Likely pathogenic	Disease-causing	Act on it - surveillance, risk-reducing surgery, cascade testing
3 Variant of uncertain significance (VUS)	Unknown	*Do NOT act on it* - no surgery, no cascade testing; manage on family history alone; may be reclassified
2 Likely benign / 1 Benign	Not causative	No action

~5% of breast cancer and ~20% of ovarian cancer carry a germline BRCA1/2 variant
~5-10% of all cancers are attributable to a high-penetrance germline mutation
Founder mutations: Ashkenazi Jewish (three BRCA1/2 founder variants, carrier rate ~1 in 40); Icelandic, Polish, French-Canadian
Genetic testing is Medicare-rebated in Australia for eligible patients; BRCA testing is funded for all newly diagnosed high-grade non-mucinous ovarian cancer

BRCA1/2 mediate homologous recombination repair of double-strand DNA breaks
- Loss -> HR deficiency -> error-prone repair -> genomic instability
- -> synthetic lethality with PARP inhibition
Two-hit: germline first hit in every cell + somatic loss of the second allele in the tumour

TP53 (Li-Fraumeni) - sarcoma, breast, brain, adrenocortical; avoid radiotherapy where possible
PTEN (Cowden) - breast, thyroid, endometrial, macrocephaly
CDH1 - lobular breast + hereditary diffuse gastric cancer (prophylactic gastrectomy)
PALB2 - breast risk approaching BRCA2
STK11 (Peutz-Jeghers), MMR genes (Lynch)
Moderate penetrance: ATM, CHEK2 - manage with surveillance, not surgery

Triple-negative breast cancer diagnosed <50 (many centres now <60)
Breast cancer <50, or male breast cancer at any age
Ovarian, fallopian tube or primary peritoneal cancer at ANY age - test everyone
Bilateral or two primary breast cancers, first <50
A first- or second-degree relative with breast or ovarian cancer (particularly young onset)
Known familial pathogenic variant -> targeted single-site testing
Ashkenazi Jewish ancestry with a breast/ovarian cancer diagnosis
>10% probability on a validated risk tool (Manchester score, BOADICEA/CanRisk, BRCAPRO)
Limited family structure (small families, few female relatives, adoption) lowers the threshold
Also: metastatic prostate cancer, pancreatic cancer at any age (test all), high-grade prostate cancer with family history

Pre-test counselling is mandatory - what will be tested, what results are possible (including VUS and incidental findings), implications for relatives, insurance and psychological consequences
Test the affected family member first wherever possible; only if the familial variant is known can an unaffected relative's negative result be interpreted as a true negative
- *An "uninformative negative" in an untested family is not reassurance*
Post-test counselling and cascade testing of at-risk relatives

Life insurance: an industry moratorium restricts use of genetic test results below specified cover thresholds; *income protection and existing policies are treated differently - advise the patient to seek independent advice before testing*

A. This cancer's treatment

PARP inhibitor: adjuvant olaparib in high-risk HER2-negative breast cancer (OlympiA); maintenance olaparib in ovarian cancer (SOLO-1); olaparib/talazoparib in mCRPC and pancreatic cancer
Platinum sensitivity is increased
May influence surgical choice - bilateral rather than unilateral mastectomy

B. Future cancer risk

Risk-reducing bilateral salpingo-oophorectomy: dec ovarian cancer risk ~80%; before age 40 (BRCA1) / 45 (BRCA2)
- Remove the tubes - most high-grade serous cancer arises in fimbrial epithelium
- HRT until the average age of menopause if no prior breast cancer
Risk-reducing bilateral mastectomy: dec breast cancer risk ~90%
Or surveillance: annual breast MRI from age 25-30 (+ mammography from 30-40)
Chemoprevention: tamoxifen or anastrozole
Consider prostate (PSA from 40 in male BRCA2 carriers) and pancreatic surveillance in selected families

C. The family

*Cascade testing of first-degree relatives is the highest-value intervention that follows the result*
Reproductive options: prenatal diagnosis, preimplantation genetic testing
The result belongs clinically to the family, but legally to the patient - facilitate, do not disclose

*Nothing.* Manage on family history. Do not offer risk-reducing surgery. Re-contact if reclassified.

BRCA1/2 - breast, ovarian, fallopian tube, primary peritoneal, prostate, pancreatic, melanoma
PALB2, ATM, CHEK2, RAD51C/D, BRIP1
Li-Fraumeni (TP53), Cowden (PTEN), Peutz-Jeghers (STK11), hereditary diffuse gastric cancer (CDH1)
Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM)
FAP (APC), MUTYH-associated polyposis
Von Hippel-Lindau, MEN1/MEN2, NF1/NF2, retinoblastoma
Fanconi anaemia - biallelic BRCA2 (FANCD1)

Penetrance is incomplete and modified by other genes, reproductive history and environment - a pathogenic variant is a risk, not a diagnosis
Risk-reducing surgery in BRCA carriers is associated with reduced cancer-specific and all-cause mortality
Variant reclassification happens - VUS may be upgraded or downgraded over time; establish a re-contact pathway
Psychosocial sequelae: anxiety, body image after mastectomy, surgical menopause, guilt about transmission to children, family conflict about disclosure
Panel testing generates more VUS and more incidental findings than single-gene testing - broader is not automatically better
Uptake of cascade testing among relatives is only ~30-50%, and this is the main leak in the system

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