10/29/2015
Jessica Ordonez, MS, CGC. Certified Genetic Counselor Genetic Risk Education & Counseling Service
Genetic Testing for Breast Cancer
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 10% 20%
70%
Sporadic Familial Hereditary
BRCA1 and BRCA2 20% 50% 30%
~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 10% 20%
70%
Sporadic Familial Hereditary
BRCA1 and BRCA2 20% 50% 30%
~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
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Well-defined, increased lifetimes risks for breast, ovarian, prostate, pancreatic cancer are associated with BRCA mutations
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Younger ages at cancer diagnosis and increased risks for second primary cancers are common in HBOC
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There are well-defined cancer risk management strategies
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Founder mutations in specific populations have been reported
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Genotype-phenotype correlations have started emerging
HBOC Lifetime Cancer Risks
www.ambrygen.com
NCCN,v2.2015
www.ambrygen.com
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Ashkenazi Jews (3 founder mutations, particularly BRCA1, 185delAG)
Bahamians (7 founder mutations, particularly BRCA1, IVS13+1G>A)
• Carrier rate among Ashkenazi Jews= 1/40 (2.5%) • Carrier rate among Ashkenazi Jewish women with breast cancer at any age= 1/10 (10%)
• Carrier rate among Bahamians= 1/35 (2.8%) • Carrier rate among Bahamian women with breast cancer at any age= 1/20 (20%)
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 10% 20%
70%
Sporadic Familial Hereditary
BRCA1 and BRCA2 20% 50% 30%
~15 other genes known in 2015 Unknown
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Well-defined increased risks for ≥ 1 type of cancer Lifetime breast cancer risk ~60-80%
High-risk Hereditary Breast Cancer Genes
Well-established testing and risk management guidelines BRCA1.2, TP53, PTEN, CDH1, PALB2(*) Less-defined increased risks for mostly one type of cancer Lifetime breast cancer risk ~20-40%
Moderaterisk
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: NextGeneration Sequencing/ Targeted Microarray
Multi-gene Panel Testing Benefits
Challenges
• Increased diagnostic yield • BRCA1/2 only: ~5% vs. Multi-gene panel: ~8-12% (ASCO, 2015)
• Minimized testing fatigue • Cost effectiveness (*)
• 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.
Clinical Case Vignette #1… • 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?
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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 nonlocal 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 •
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•
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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… •
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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.
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Bellcross, C. A. "The changing landscape of genetic testing for hereditary breast and ovarian cancer." Current problems in cancer. 2013; 38(6): 209-15.
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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
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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).
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LaDuca, H. et al. Utilization of Multigene Panels in Hereditary Cancer Predisposition Testing. Next Generation Sequencing in Cancer Research, Volume 2 459–482 (2015). doi:10.1007/978-3-319-15811-2_26
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National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial HighRisk Assessment: Breast and Ovarian. V.2.2015. Accessed at www.nccn.org on 10/03/2015.
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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 2013 Sep 26]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1247/
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Rainville I. R., Rana H. Q. Next-generation sequencing for inherited breast cancer risk: counseling through the complexity topical collection on breast cancer. Current Oncology Reports. 2014;16(3, article 371) doi: 10.1007/s11912-013-0371-z.
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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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Riley BD, Culver JO, Skrzynia C et al. (2011) Essential elements of genetic cancer risk assessment, counseling, and testing: Updated recommendations of the National Society of Genetic Counselors. Journal of Genetic Counseling [epub ahead of print]. Available at www.springerlink.com/content/ax33415046874623/.
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Rubinstein WS (2004) Hereditary breast cancer in Jews. Fam Cancer 3:249–257. doi:10.1007/s10689-004-9550-2
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Trottier, M., Lunn, J., Butler, R., Curling, D., Turnquest, T., Francis, W., Halliday, D., Royer, R., Zhang, S., Li, S., Thompson, I., Donenberg, T., Hurley, J., Akbari, M. R. and Narod, S. A. (2015), Prevalence of founder mutations in the BRCA1 and BRCA2 genes among unaffected women from the Bahamas. Clinical Genetics. doi: 10.1111/cge.12602
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Trottier, M. et al. Strategies for recruitment of relatives of BRCA mutation carriers to a genetic testing program in the Bahamas. Clinical Genetics 88, 182–186 (2014).
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