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

Cancer Genetics Overview (PDQ®)

Hong Kong Med J 2016 Apr;22(2):171–7 | Epub 14 Mar 2016

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