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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
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
CONFLICT OF INTEREST
• None declared
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
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
TRADITIONAL SEQUENCING
Sequencing by terminationTime and Labor
SANGER VS NGS
TAT: 1mo
TAT: <2wks
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
5-April.-2018
Cancer Predisposition Genes
Rahman, Nature 2014
114 Cancer Predisposition Genes (CPGs)
WHAT WE CAN IDENTIFY
Over 100 Cancer predisposition genes
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
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)
LIMITATIONS OF PANEL TESTS
• Validation of this novel techniques
• Selection of candidate susceptibility genes
• Difference in ethnicities (ex. L1780P)
• Lack of robust evidence
RISK REDUCTION STRATEGY
Close observation Chemoprevention
Risk reduction surgery
CLOSE OBSERVATION
• Clinical Breast Examination
• Screening mammography
• Screening MRI
• Screening Ultrasound - lack of evidence
Cancers 2018, 10, 477
CHEMOPREVENTION
• NSABP-P1, P2, IBIS I-II, NCIC CTG MAP.3 Trials
• SERMS (Tamoxifen, Raloxifene)
• Aromatase Inhibitors
https://www.onclive.com/web-exclusives/breast-cancer-chemoprevention-targeting-the-estrogen-receptor
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
COSMETIC OUTCOMES
• NSM provides better cosmesis
NSM Robot-assisted NSMTotal Mastectomy
Park et al, GBCC 2019, Poster presentation
N Engl J Med 2016; 374:454-468
LACK OF EVIDENCE FOR PATHOGENIC MUTATION IN OTHER CANCER SUSCEPTIBILITY
GENES
• BRCA1/2 - only have evidence
• Others not
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
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
Reject
KBCS GUIDELINES
PANEL GENES
• The section of multi-gene panel includes several cancer susceptibility genes • ATM, CDH1, CHEK2, NBN, PALB2, PTEN, and TP53.
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
SURVEILLANCE
• PALB2, CDH1 - annual breast screening using mammography and breast MRI at age 30
• ATM, CHEK2, NBN - the breast screening at age 40,
CHEMOPREVENTION
• lack of evidence
I’m so…Sorry
This is not
my fault
http://jjalbang.today/view/%ED%95%B4%EC%9A%94/2549
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
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.
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
