Hereditary Breast/Ovarian Cancer Syndromes - Moderate Risk Genes

Week 5

What are the challenges with moderate risk genes?

wide-range of risk estimates for single genes

lack of prospective studies, extrapolating data from other genes/data

members of same family given different recommendations at different clinics

nomenclature/variant classification may vary across laboratories

interaction of mutation + family hx, other risk factors

lack of age-specific recommendations for rarer genes

lifetime risks vs short-term risks

Do other factors impact cancer more in germline pathogenic variants in high penetrance genes or moderate penetrance genes?

moderate penetrance genes

Genes on panels associated with high breast cancer risk (40-60%+ lifetime)…

BRCA1/2

TP53

PTEN

CDH1

STK11

PALB2

Genes on panels associated with moderate breast cancer risk (20-40% lifetime)…

ATM

BARD1

CHEK2

NF1

RAD51C

RAD51D

Genes on panels associated with established epithelial ovarian cancer risk…

BRCA1/2

BRIP1

MLH1

MSH2/EPCAM

MSH6

PALB2

RAD51C/D

ATM? (increased risk, but not to level of recommending surgery)

P/LP variants in which genes warrant recommendation for RRSO?

BRCA1/2

BRIP1

MLH1

MSH2/EPCAM

MSH6

PALB2

RAD51C/D

Is our understanding of CHEK2 evolving? Is CHEK2 still associated with CRC?

Yes

No

True or False: All CHEK2 LP/P variants are managed the SAME at this time.

True

True or False: Most of our knowledge on CHEK2 comes from 1100delC. Risks for other CHEK2 variants are extrapolated from 1100delC.

True

CHEK2 1100delC is found in what population? Increased risk for which cancer?

European; European founder variant

ER positive breast cancer

CHEK2 current established cancer risks per NCCN guidelines includes:

female breast cancer

prostate cancer

ATM is associated with which cancers? What are the recommendations for each?

Breast cancer - mammogram at 40, breast MRI 30-35, little evidence for RRM (based on family hx)

pancreatic cancer - screening

prostate cancer - early prostate cancer screening

ovarian - possible slightly increased risk, but no change in management (little evidence for RRSO, based on family hx)

RAD51C/D is associated with which cancers? what are the recommendations for each?

breast cancer - often BR negative; screening at 40, little evidence for RRM (based on family hx)

ovarian cancer - recommend RRSO

BARD1 is associated with which cancers? What are the recommendations for each?

breast cancer - often triple negative; screening begins at 40, consideration of breast MRI, little evidence for RRM (based on family hx)

NF1 is associated with which cancers? What are the recommendations for each?

breast cancer - screening at 30, association with early onset breast cancer, breast MRI 30-50, little evidence for RRM (based on family hx)

BRIP1 is associated with which cancers? What are the recommendations for each?

ovarian cancer - RRSO

Polygenic risk scores (PRS)? Is ancestral background important for PRS? How do labs use PRS to further define risk?

combination of SNPs and combined association to risk

yes, for understanding which SNPs should/should not be considered in calculating PRS

Combine PRS data with moderate risk gene mutation

Autosomal recessive risk genes?

ATM

BRCA1

BRCA2

BRIP1

MLH1, MSH2, MSH6, PMS2, EPCAM

PALB2

RAD51C

True or false: Management decisions for a person diagnosed with a breast cancer is THE SAME than a person who is unaffected and found to be high-risk based on a genetic test result.

False

management decisions MAY BE DIFFERENT

“personalized risk-assessment is key”

True or false: Knowledge about moderate risk genes evolving. Risks can change over time.

True

What do risk models tell us? Why does this matter?

Provide individualized risk for those with known mutations in certain genes, or those with family history of cancer with negative/declined testing

If lifetime risk high enough, patient can qualify for high-risk cancer screening even with negative genetic test results

Risk factors for breast cancer (other than P/LP variant)?

Age

Family history

Early menarche

late menopause

nulliparity

1st child after age 30

physical inactivity

recent oral contraceptive use

alcohol use

height

high naturals of sex hormones

excess weight/BMI

breast density

biopsy history (atypical hyperplasia, LCIS)

exogenous hormone (estrogen, progesterone)

chest radiation

type 2 diabetes

What risk models exist?

Tyrer-Cuzick

Gail model (Breast cancer risk assessment tool - BCRAT)

CanRisk (BOADICEA)

ASK2ME

Claus Model

BRCAPro

Tyrer Cuzick risk factors included? Exclusion criteria/limitations? Other information?

age at menarche, age at first live birth, age at menopause, parity, height and BMI, breast biopsy history, hormone replacement therapy, mammographic breast density, first-,second-, and third-degree relatives with breast and ovarian cancer, father and/or brother with breast cancer, BRCA1/2 genetic test results; takes into consideration lots of different risk factors

not great for true negative risks (overestimates risks in true negatives), tends to overestimate risk based on biopsy history, especially LCIS; cannot be used if pt has BC

calculates probability of BRCA1/2 mutation, determines eligibility for chemoprevention (10 yr risk >5%)

Gail model risk factors included? Exclusion criteria/limitations? Other information?

age, age at menarche, age at first live birth, breast biopsy history, first-degree female relatives with breast cancer, ethnicity

under age 35, history of breast cancer/DCIS/LCIS, history of mantle radiation, known genetic mutation; doesn’t consider family hx much (2nd or 3rd degree relatives); cannot be used if pt has BC

validated model, determines eligibility for chemoprevention (5 yr risk >1.67%)

CanRisk (Boadicea) risk factors included? Exclusion criteria/limitations? Other information?

age, height and BMI, alcohol use, age at menarhce, oral contraceptive use, menopause, HRT, mammographic breast density, hx of tubal ligation, BC hx, masectomy and oophorectomy hx, extremely detailed family history: first-,second-,third-degree relatives with BC, OC, and PC, genetic test results of pt and family members including moderate risk genes

family hx requires very detailed information such as year of birth for deceased individuals'; time consuming, cumbersome model

calculates probability of BRCA1/2 mutation

ASK2ME risk factors included? exclusion criteria/limitations? other information?

age, sex assigned at birth, genetic mutation, mastectomy, hysterectomy, oophorectomy surgical hx, prior cancer hx

can only use for pts with identified pathogenic mutation, may discuss cancer risks that are not established, data based on limited studies as opposed to meta-analysis

na

Claus model/tables risk factors included? exclusion criteria/limitations? other information?

age, fm hx. of BC and OC in both maternal and paternal lineages

outdated, fm hx of BC is the only risk factor considered

statistical model based on fm hx.

BRCAPro risk factors included? exclusion criteria/limitations? other information?

first-, second-, third-degree relatives with BC and OC

program no longer supported

Bayesian calculation, calculates probability of BRCA1/2 mutation

Blind spots/limitations of risk-models?

two models may give you different risk numbers for same pt

models may over/under-estimate risk

risk perception is pt-specific

risk numbers change with age, consideration for recalculation is 3-5 years