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Genetic Testing for Breast Cancer

Jessica Ordonez, MS, CGC.

Certified Genetic Counselor

Genetic Risk Education & Counseling Service

Outline

• The hereditary basis of breast cancer– BRCA1/2– Additional high- and moderate-risk genes

• Current approach to clinical genetic testing– Single-gene vs. multi-gene panels

• Case vignettes

Breast Cancer Etiology

70%20%

10%

Sporadic

Familial

Hereditary

50%

30%

20%

BRCA1 and

BRCA2

~15 other

genes known

in 2015

Unknown

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Flags for Hereditary Breast Cancer� Early-onset breast cancer diagnosis (≤ 50)

� Bilateral presentation or multiple primary cancers

� Male breast cancer

� Families with 3 or more cases of breast cancer over 2 or more

generations

� Triple negative histopathology (≤ 60)

� Ashkenazi Jewish ancestry

� A history of breast and ovarian cancer in the same individual

� Specific associations of different primary cancers in the same side of

the family

� Breast, ovarian, prostate, pancreatic

� Breast, endometrial, thyroid

� Lobular breast, and stomach

Breast Cancer Etiology

70%20%

10%

Sporadic

Familial

Hereditary

50%

30%

20%

BRCA1 and

BRCA2

~15 other

genes known

in 2015

Unknown

BRCA1 and BRCA2

Hereditary Breast and Ovarian Cancer Syndrome (HBOC)

Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, et

al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266:66–71.

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HBOC >20 years later…• BRCA1/2 are tumor suppressor genes whose mutations are highly

penetrant

• Well-defined, increased lifetimes risks for breast, ovarian, prostate,

pancreatic cancer are associated with BRCA mutations

• Younger ages at cancer diagnosis and increased risks for second primary

cancers are common in HBOC

• There are well-defined cancer risk management strategies

• Founder mutations in specific populations have been reported

• Genotype-phenotype correlations have started emerging

HBOC Lifetime Cancer Risks

www.ambrygen.com

NCCN,v2.2015

www.ambrygen.com

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• Carrier rate among Ashkenazi Jews= 1/40 (2.5%)

• Carrier rate among Ashkenazi Jewish

women with breast cancer at any age= 1/10 (10%)

Ashkenazi Jews (3 founder mutations,

particularly BRCA1,

185delAG)

• Carrier rate among Bahamians=1/35 (2.8%)

• Carrier rate among Bahamian women with

breast cancer at any age= 1/20 (20%)

Bahamians (7 founder mutations,

particularly BRCA1,

IVS13+1G>A)

HBOC More Recent Data

Rebbeck TR, Mitra N, Wan F, et al. Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk

of Breast and Ovarian Cancer. JAMA. 2015;313(13):1347-1361. doi:10.1001/jama.2014.5985.

Genetic testing for BRCA1/2 genes is common practice among general

practitioners, breast/GYN specialists, and cancer genetics centers.

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When to offer BRCA testing? (NCCN v2,2015) (1/2)

• Breast cancer diagnosis and any of the following:– Age at diagnosis ≤ 45

– Age at diagnosis ≤ 50 AND any of the following:

• An additional breast ca primary

• ≥ 1 close relative with BC at any age, pancreatic or prostate ca(Gleason score ≥7)

• Limited family history

– Any age at diagnosis AND any of the following:

• ≥ 2 individuals with BC, pancreatic or prostate ca in the same side of the family

• ≥1 close relative with BC diagnosed ≤50 or ovarian ca at any age

• Ashkenazi Jewish ancestry

• Prior history of ovarian/fallopian tube cancer

– Triple negative histopathology diagnosed at ≤ age 60

– Male breast ca

When to offer BRCA testing? (NCCN v2,2015) (2/2)

• Prostate cancer diagnosis (Gleason score ≥7) AND ≥ 1 close blood relative with any of the following:– Breast cancer ≤ age 50– Invasive ovarian cancer– Pancreatic cancer– Prostate cancer (Gleason score ≥7)

• Pancreatic cancer diagnosis AND any of the following:– Ashkenazi Jewish ancestry– ≥ 1 close blood relative with any of the following:

• Breast cancer ≤ age 50• Invasive ovarian cancer• Pancreatic cancer

Breast Cancer Etiology

70%20%

10%

Sporadic

Familial

Hereditary

50%

30%

20%

BRCA1 and

BRCA2

~15 other

genes known

in 2015

Unknown

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Hereditary Breast Cancer Genes

High-risk

Well-defined increased risks for ≥ 1 type of cancer

Lifetime breast cancer risk ~60-80%

Well-established testing and risk management guidelines

BRCA1.2, TP53, PTEN, CDH1, PALB2(*)

Moderate-risk

Less-defined increased risks for mostly one type of cancer

Lifetime breast cancer risk ~20-40%

No established testing and risk management guidelines

Different health risks associated with heterozygous vs. homozygous status

CHEK2, ATM, STK11, PALB2(*), RAD50, RAD51C, RAD51D, BARD1, BRIP1, MRE11A, NBN, NF1

How does the expanded genetic landscape of hereditary breast cancer reflect into current clinical practice?

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Single-gene Testing

• Scope: One or a number of genes associated with a single hereditary cancer syndrome.

• Technology: Sanger sequencing and MLPA

Multi-gene Panel Testing

• Scope: Multiple genes associated with more than one hereditary cancer syndrome (simultaneous analysis).

• Technology: Next-Generation Sequencing/ Targeted Microarray

Multi-gene Panel Testing

Benefits

• Increased diagnostic yield

• BRCA1/2 only: ~5% vs. Multi-gene panel: ~8-12% (ASCO, 2015)

• Minimized testing fatigue

• Cost effectiveness (*)

Challenges

• Increased likelihood of variants of unknown significance

• Limited clinical information for moderate-risk genes

• Panel variation among testing laboratories

Professional Statements (Multi-gene Panel Testing)

NCCN, v2. 2015:“Multi-gene testing is ideally offered in the context of professional

genetic expertise for pre- and post-test counseling”

ASCO, August 31 2015:“ASCO asserts that providers with particular expertise in cancer risk

assessment should be involved in ordering and interpreting multi-gene

panels that include genes of uncertain clinical utility and genes not

suggested by the patient’s personal and/or family history. Further, ASCO

encourages research to delineate the optimal use of panel-based testing,

development of evidence-based practice guidelines as data emerges, and

education of providers on the challenges of using these tests.”

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Clinical Case Vignette #1

• 54 yo woman with a past history of bilateral breast ca diagnosed at

48 (invasive ductal; ER/PR positive, Her2 negative)

• Treatment consisted of bilateral mastectomy followed by adjuvant

chemotherapy. She was on Tamoxifen for 5 years. Doing well.

• She has no history of colon polyps. Ovaries are in place.

• BRCA1/2 sequencing and deletion/duplication analysis in 2009

revealed two variants of unknown significance in the BRCA1 gene

(P1614L, V1234L). Variants continued to be unclassified by the

testing company in 2015.

• Topics of discussion during pre-test counseling session:

– Availability of multi-gene panel testing

– Differences between high- and moderate-risk gene mutations

– Potential impact of positive test results depending on gene

involved

– Inheritance patterns

– Previously identified BRCA1 variants of unknown significance

and differences in VUS interpretation among testing laboratories

• Test of choice:

– 17-gene hereditary breast cancer panel

Results?

Clinical Case Vignette #1…

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Clinical Case Vignette #2…• Topics of discussion during post-test

counseling session:

– CHEK2 associated cancers risks

– Potential implications for

medical management

– Risk assessment for family

members

– Reproductive risks for CHEK2

carriers (Fanconi anemia)

– Contact information for non-

local genetics professionals to

share with family members

– Need of additional family

history details to review

surveillance recommendations

– PROMPT

Clinical Case Vignette #2

• 38 yo Ashkenazi

Jewish male with a

family history of

breast/ovarian

cancer

• Mother identified

as BRCA1+

through a research

protocol overseas

Clinical Case Vignette #2…

• Topics of discussion during pre-test

counseling session:

– 50% risk for positive results

– BRCA lifetime cancer risks for

men

– Risk management strategies for

men who are BRCA positive

– GINA (benefits and limitations)

– Appropriateness of genetic

testing after age 18 for at-risk

family members

• Test of choice:– BRCA1/2 Ashkenazi Jewish founder

mutation panel

• Results?

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Clinical Case Vignette #2

• 38 yo Ashkenazi

Jewish male with a

family history of

breast/ovarian cancer

• Mother identified as

BRCA1+ through a

research protocol

overseas

• Personal history of

adenomatous colon

polyps since age 25

(>20)

• No family history of

colorectal ca or

polyps Is there room for additional genetic testing?

Clinical Case Vignette #2…• Test of choice:

– 14 gene panel associated with colorectal

cancer

• Result:

– Variant of unknown significance in APC

(APC, p.Ser130Gly)

• Reported in population databases

• Reported in individuals with colon cancer

and one individual with FAP (pathogenic

mutation)

• In-silico tools predict that this variant may

affect mRNA splicing

• Located in a part of the gene that

resembles the patient’s clinical

presentation

– APC codons 1-177 --AFAP

Current and Future Challenges

• Multi-gene panel testing for cancer-free individuals

– Potential of false reassurance by negative results

• Limited availability of clinicians with expertise in genetics

• Increasingly complex genetic testing technologies may

eventually become mainstream in cancer genetics

– Whole-exome sequencing

– Whole-genome sequencing

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Thank you!

References

• Akbari M, Donenberg T, Lunn J, Curling D, Turnquest T, Krill-Jackson E, Zhang S, Narod S, Hurley J."The spectrum of

BRCA1 and BRCA2 mutations in breast cancer patients in the Bahamas." Clin Genet. 2013 Mar 4.

• Bellcross, C. A. "The changing landscape of genetic testing for hereditary breast and ovarian cancer." Current

problems in cancer. 2013; 38(6): 209-15.

• Donenberg T, Lunn J, Curling D, Turnquest T, Krill-Jackson E, Royer R, Narod SA, Hurley J. A high prevalence of

BRCA1 mutations among breast cancer patients from the Bahamas. Breast Cancer Res Treat. 2011 Jan;125(2):591-6

• Kapoor, N. S. et al. Multigene Panel Testing Detects Equal Rates of Pathogenic BRCA1/2 Mutations and has a Higher

Diagnostic Yield Compared to Limited BRCA1/2 Analysis Alone in Patients at Risk for Hereditary Breast Cancer.

Annals of Surgical Oncology 22, 3282–3288 (2015).

• LaDuca, H. et al. Utilization of Multigene Panels in Hereditary Cancer Predisposition Testing. Next Generation

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• Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, et

al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266:66–71.

• Petrucelli N, Daly MB, Feldman GL. BRCA1 and BRCA2 Hereditary Breast and Ovarian Cancer. 1998 Sep 4 [Updated

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10.1007/s11912-013-0371-z.

• Rebbeck TR, Mitra N, Wan F, et al. Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of

Breast and Ovarian Cancer. JAMA. 2015;313(13):1347-1361. doi:10.1001/jama.2014.5985.

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