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RISK REDUCTION STRATEGIES FOR WOMEN WITH
PATHOGENIC VARIANTS IN MULTIGENE PANEL TESTS
Hyung Seok Park, MD, PhD Department of Surgery
Yonsei University College of Medicine
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CONFLICT OF INTEREST
• None declared
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SINGLE GENE VS. MULTI-GENE TESTING
Multigene
BRCA1
TP53
PTEN
BRCA2 PALB2 CHEK2
CDH1 MLH1 SKT11
BRIP MUTYH MRE11A
BRCA1
Single gene or limited-gene
BRCA2
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NEXT-GENERATION SEQUENCING(NGS)
• NGS-panel testing for Hereditary cancer syndrome
• High speed and low cost
• WGS, WES - too much
• Target sequencing - target genes of interest
• Simultaneous tests for various mutations
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TRADITIONAL SEQUENCING
Sequencing by terminationTime and Labor
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SANGER VS NGS
TAT: 1mo
TAT: <2wks
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Genomic medicine 2nd edition, Oxford, p149
Point Mutation
Small Insertion/Deletion
Larger Duplication/
Deletion
MLPASouthern Blotting
CGH/SNP Arrarys
FISH
Spectral
Cytogenetics
NGS
bp100 109105
PCR-based
trisomy/ monosomy Altered ploidy
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5-April.-2018
Cancer Predisposition Genes
Rahman, Nature 2014
114 Cancer Predisposition Genes (CPGs)
WHAT WE CAN IDENTIFY
Over 100 Cancer predisposition genes
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5-April.-2018
Cancer Gene Truncation Carrier Frequencies across 12 cancer types (rare variants; MAF ≤0.05%)
Lu et al., Nat Commun 2015
9%
21%OV: ovarian cancerSTAD: stomach adenocarcinomaBRCA: breast adenocarcinomaPRAD: prostate adenocarcinomaLUSC: lung squamous cell carcinomaLGG: low grade gliomaHNSC: head and neck squamous cell carcinomaUCEC: uterine corpus endometrial carcinomaLUAD: lung adenocarcinomaKIRC: kidney renal cell carcinomaGBM: glioma multiformeAML: acute myeloid leukemia
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5-April.-2018
Odds ratio of pathogenic or likely pathogenic variants beyond BRCA
Couch et al., JAMA Oncology 2017; Obeid et al., JAMA Oncol 2017 (editorial)
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LIMITATIONS OF PANEL TESTS
• Validation of this novel techniques
• Selection of candidate susceptibility genes
• Difference in ethnicities (ex. L1780P)
• Lack of robust evidence
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RISK REDUCTION STRATEGY
Close observation Chemoprevention
Risk reduction surgery
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CLOSE OBSERVATION
• Clinical Breast Examination
• Screening mammography
• Screening MRI
• Screening Ultrasound - lack of evidence
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Cancers 2018, 10, 477
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CHEMOPREVENTION
• NSABP-P1, P2, IBIS I-II, NCIC CTG MAP.3 Trials
• SERMS (Tamoxifen, Raloxifene)
• Aromatase Inhibitors
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https://www.onclive.com/web-exclusives/breast-cancer-chemoprevention-targeting-the-estrogen-receptor
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RISK REDUCTION SURGERY
• Risk reduction surgery - prophylactic surgery for breast-cancer risk reduction
• Not 100% effective - more than 90% (mastectomy), about 50% reduction (RRSO)
• Case by case, individualized decision
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COSMETIC OUTCOMES
• NSM provides better cosmesis
NSM Robot-assisted NSMTotal Mastectomy
Park et al, GBCC 2019, Poster presentation
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N Engl J Med 2016; 374:454-468
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LACK OF EVIDENCE FOR PATHOGENIC MUTATION IN OTHER CANCER SUSCEPTIBILITY
GENES
• BRCA1/2 - only have evidence
• Others not
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5-April.-2018
Germline mutations, breast cancer risks, and preventive strategies
Modified from Easton et al., N Engl J Med 2015; NCCN guideline version 1.2018
GeneMagnitude of Relative Risk
associated with Truncating Variants*
Risk associated with Missense
Variants†
Estimated Relative Risk
(90% CI)
Absolute risk by 80
years of AgeOther Associated Cancers Prevention option for breast cancer
in NCCN guidelines
Moderate(2-4 times)
High(>4 times) %
BRCA1 � � � 11.4 75 Ovary § 18y-, Breast awareness§ 25y-, Clinical Breast Exam§ 25-29y, annual Breast MRI§ 30-75y, Annual mammography,
consider tomosynthesis and MRI§ Discuss about RRM; Recommend RRSO, 35-40y
BRCA2 � � � 11.7 76 Ovary, prostate, pancreas
TP53 � � � 105 (62-165)Childhood sarcoma,
adreno-cortical carcinoma, brain tumors
§ 20y-, Clinical Breast Exam§ 20-29y, Annual Breast MRI§ 30-75y, Annual Breast MRI
+ mammography, consider tomosynthesis
§ Discuss about RRM
PTEN Unknown Unknown �follicular > papillary thyroid
endometrial cancer, harmatoma syndrome
§ 25y-, Clinical Breast Exam§ 30-35y ~ 75y or 5-10y before the
earliest known BC family, annual mammography, consider tomosynthesis and breast MRI
§ Discuss about RRM
CDH1 Likely Unknown Unknown 6.6 (2.2-19.9) 53 Diffuse gastric cancer
§ 30y- Annual mammogram, consider breast MRI
§ RRM: evidence insufficient, manage based on family history
PALB2 Likely Unknown Unknown 5.3 (9.0-9.4) 45 Pancreas
§ 40y- Annual mammogram, consider tomosynthesis, breast MRI
§ RRM: evidence insufficient, manage based on family history
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LIMITATION OF RRM IN KOREA
• RRM for pathogenic variants other than BRCA1/2
• No insurance cover in Korea
• Cost-effectiveness has not proven
• No evidence at all for RRM in Korea
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Reject
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KBCS GUIDELINES
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PANEL GENES
• The section of multi-gene panel includes several cancer susceptibility genes • ATM, CDH1, CHEK2, NBN, PALB2, PTEN, and TP53.
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SURVEILLANCE
• Breast screening - Annual mammography (or tomosynthesis) and breast MRI with contrast
• PTEN
• Self examination at age 18
• CBE from at age 25 (6-12monthly) or 5-10 years before the earliest known breast cancer in the family
• Breast screening at age 30-35 or or 5-10 years before the earliest known breast cancer in the family
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SURVEILLANCE
• PALB2, CDH1 - annual breast screening using mammography and breast MRI at age 30
• ATM, CHEK2, NBN - the breast screening at age 40,
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CHEMOPREVENTION
• lack of evidence
I’m so…Sorry
This is not
my fault
http://jjalbang.today/view/%ED%95%B4%EC%9A%94/2549
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RISK REDUCTION SURGERY
• RRM
• PTEN - discuss with women for option of RRM.
• Appropriate counseling should be included.
• Address psycosocial, social, and QoL aspects of undergoing RRM
• insufficient evidence, manage based on family history - ATM, CDH1, CHEK2, NBN, PALB2
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SUMMARY
• Multi-gene panel enables identifying mutations in various cancer susceptibility genes with high speed and low cost compared to the Sanger sequencing.
• Surveillance and risk-reducing surgery can be discussed with women with pathogenic variants in multi-gene panel testing, but risk-reducing surgery should be considered by genetic counseling based on individualized approaches because of lack of evidence.
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ACKNOWLEDGEMENTS
JS Park, MD, PhD Severance Hospital, Yonsei Cancer Center Breast Cancer Center
Breast Surgery: BW Park, YU Cho, SI Kim, S Park, JY Kim, KB Lee, JA Lee, HM Lee Medical Oncology: S Paik, JH Sohn, GM Kim, MH Kim Radiology: EK Kim, MJ Kim, HJ Moon, JH Yoon, Vivian Y Park Radiation Oncology: KC Keum, YB Kim, JS Jang Pathology: JS Koo Plastic Surgery: DH Lew, DW Lee, SY Song Nuclear Medicine: MJ Yoon, HJ Kim Coordinator, RN : JW Jung, JS Park
Cancer Prevention Center JS Park, EJ Nam, JW Han, ST Lee, JR Choi, TI Kim RN (genetic counselor) : YJ Lee, SH Lee
Breast Cancer Translational Research Lab YA Choi, HJ Han, JD Lee, AR Choi