Genetic Counseling & the Woman's Health Patient Family History Is

4/27/2016

Genetic Counseling & the Woman’s Health Patient

MCW Women’s Health Conference Morgan Depas, MS, CGC Samantha Stachowiak, MS, CGC

At the conclusion of this presentation, participants should understand the following: • How to recognize patients and families who may benefits from a prenatal or cancer genetics consult • Understand how a patient’s family history may impact cancer screening recommendations • Understand the benefits and limitations of cell free DNA testing

Family History is Important

• 5–10 % of all cancers are HEREDITARY 70‐80% • 15‐20% of cancers are FAMILIAL 5‐10% • 70‐80% of cancers are SPORADIC 15‐20% • Family history tailors cancer screening recommendations and Hereditary Familial reduces cancer risks Sporadic “The identification of at‐risk individuals can facilitate individualized preventative care and surveillance, which could impact disease morbidity and mortality” Owens et al, 2011

Frezzo et al. 2003; Guttmacher et al. 2004; Yoon et al. 2002; Nagy et al. 2004. 3

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Family History: The Basics

• Who? – Mom, dad, siblings, aunts, uncles, nieces, nephews, children, grandchildren, grandparents, and cousins – Maternal and paternal relatives • What? – Cancer type – Age of diagnosis – Unusual pathological features – Multiple primaries • “Are there other cancers?” • Ancestry?

Who Should Be Referred?

Red Flags for Hereditary Cancer: EMR

Early age at cancers diagnosis (personal or family history) – Pre‐menopausal breast cancer – Colorectal cancer diagnosed <50 years of age Multiple – Individuals with multiple primary cancers • Women with breast and ovarian cancer • Individual with two separate colorectal cancers – Clusters of the same or related types of cancer – Breast & ovarian cancer or colon & endometrial cancer Rare – Rare cancers present in patient and/or family history • Ovarian cancer • Male breast cancer

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What is Genetic Counseling?

• Process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease • Genetic Counselors are specially trained Advanced Practice Providers

What is the Role of a Cancer Genetic Counselor? • Provide risk assessment based on family history • Evaluate for possible hereditary cancer syndromes • Determine appropriate genetic test and testing strategy – Genetic counseling does not always include genetic testing • Aid in test interpretation

3 2 2 3 2 2

Paternal Paternal Great Maternal Maternal Great grandfather grandmother uncle grandfather grandmother aunt

2 1 1 2

Father Aunt Mother Uncle

1 1 3

Brother Proband Sister First cousin (female)

2 2 1 1

Niece Nephew Son Daughter

2 2

Grand‐ Grandson daughter 9

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What is the Role of a Cancer Genetic Counselor? • Explore the psychological impact of genetic testing • Work closely with insurance companies • Address genetic discrimination concerns • Introduce medical management options • Talk about implications for family members • Discuss the option of DNA banking • Acts as a resource for the patient and family

d. 53 y OvCa

d. 45 y BrCa BrCa

d. 56 y OvCa dx 46 y

Laboratories offering genetic testing for hereditary cancer

…and many more.

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Genetic Testing is Multifaceted

• Multiple genes for a syndrome • Different testing methods – Tumor testing – Genetic testing • Single site analysis • Multisite analysis • Sequencing • Deletion/duplication testing • NextGeneration sequencing technologies • New genes become available for testing • Determine most informative family member for testing • Challenges in test interpretation and variants of uncertain significance

Movement away from single gene testing and toward Next Generation Sequencing (NGS) multi‐gene panels

Why? • Efficient sequencing of multiple genes • Many genes implicated in each cancer – Testing multiple genes simultaneously can be more time efficient and more cost effective • Overlapping clinical presentation among different hereditary cancer syndromes – Approximately 9‐10% of BRCA‐negative patients have a causative gene mutation identified via panel testing (Ambry Genetics data)

Genes Associate with Hereditary Breast and Ovarian Cancer

Courtesy of

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Next Generation Sequencing

• Massively parallel sequencing • Create 100’s to 1000’s of reads per base pair • Provided enhanced resolution, throughput and speed • Generates large amounts of data quickly in a cost effective manner • Sequence multiple genes simultaneously • Possible to detect mosaicism

Sequencing Methodology

Sanger Sequencing Next Generation Sequencing • Increased cost • Massively parallel • Longer read lengths sequencing • Primer targeted full coverage of exons

Breast cancer genes

Rare Common High risk genes Moderate risk genes Low risk genes Example: BRCA1/2, PTEN, Examples: ATM, CHEK2, RAD50 TP53, CDH1, PALB2

Increases risk 2x‐4x Increases risk 1‐2x Increases risk 10x‐20x

Lifetime risk of breast cancer Lifetime risk of breast Multiplicative effect up to 20% cancer up to 80%

Often involve family history May account for 13‐16% of of other cancers (e.g., breast cancer ovarian cancer)

Clinical testing available Clinical testing available Clinical testing not available

Nasir, et al., 2009; Ahmed, et al., 2009

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Genetic Testing

• Benefits – Provides more accurate risk of cancer moving forward for individuals and families – Provides information useful for medical management – Leads to cancer PREVENTION and EARLY detection of cancer – May actually relieve anxiety • Risks – Emotional (increased fear/anxiety) – Insurance Discrimination • State and Federal Laws • Limitations – Genetic testing is not able to detect all causes of hereditary cancer – Continued risk for sporadic cancers – Some management strategies not proven effective

Genetic Information Nondiscrimination Act (GINA)

• GINA is a federal law passed in 2008 that protects individuals from genetic discrimination in health insurance and employment – GINA prohibits employers from discriminating against employees and applicants based on genetic tests and genetic information and prohibits health insurers from restricting enrollment or adjusting premiums for health insurance on the basis of genetic information • For additional information: http://ginahelp.org/

Breast Cancer  Most commonly diagnosed  Risk Factors cancer in women  Age  2nd leading cause of cancer  Risk increases with age death in women  Median age at diagnosis is 61 years  Hormonal factors  Early menarche/Late menopause  Nulliparity  Hormone replacement therapy  Lifestyle  Alcohol consumption  Physical inactivity  Obesity

American Cancer Society Breast Cancer Facts & Figures 2011‐2012 21

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How much of breast cancer is hereditary

Breast Cancer Genetics

16% Other*

70‐80% 32% 52% 5‐10% Hereditary BRCA2 BRCA1 15‐20%

*Other Genes: TP53, PTEN, & others Hereditary Familial Sporadic

J Med Genet 2002; 39: 225‐242 Am J Hum Genet 1998; 62: 676‐689 23

Genetic Evaluation Guidelines Personal history: Family history: (any one of the following) • Premenopausal breast cancer (<50 yrs) • Bilateral breast cancer • Ovarian cancer • Male breast cancer • Postmenopausal breast cancer with a family history of any of the above 24 National Comprehensive Cancer Network and US Preventative Services Task Force

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Breast Cancer Risk Models

• Risk assessment models can aid in patient management • Chance of developing breast cancer – Gail model – Claus tables – BRCAPRO – Tyrer‐Cuzick (IBIS) – BOADICEA • Chance of having BRCA gene mutation – BRCAPRO – Tyrer‐Cuzick (IBIS) – BOADICEA

Bellcross Oncology Genetics 2009; 6(8): 373‐382 Saslow et al, Ca Cancer J Clinic 2007;57:75‐89 25

Hereditary Breast and Ovarian Cancer (HBOC) Syndrome • BRCA1 & BRCA2 gene mutations • Autosomal dominant inheritance • Breast cancer – 45‐85% lifetime risk – Risk for a 2nd primary breast cancer • Ovarian cancer – 15‐45% lifetime risk • Other increased cancer risk – Prostate, male breast, pancreatic, melanoma, ocular melanoma

AJHG. 2003:1117‐1130 Science. 2003:643‐646 J Clin Oncol. 2007:1329‐33

HBOC Medical Management

• Change in screening recommendations – National Comprehensive Cancer Network – American Cancer Society – US Preventive Services Task Force – American College of Obstetrics and Gynecology • High risk surveillance – Annual mammogram and breast MRI • Starting at age 25 – Semi‐annual transvaginal ultrasound and CA‐125 • Starting at age 30 • Risk reduction options – Tamoxifen for chemoprevention of breast cancer – Prophylactic mastectomy – Oral contraceptive use for chemoprevention of ovarian cancer – Prophylactic salpingo‐oophorectomy • Decision Tool from Women with BRCA Mutation, http://brcatool.stanford.edu/brca.html • Information for family members

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Patient Resources

• BrightPink –a national non‐profit focused on prevention and early detection in young women • FORCE –a national non‐profit devoted to hereditary breast and ovarian cancer • American Cancer Society • National Cancer Institute

Impact on Your Practice

• 9% of patients in a primary care practice have a considerable family history of breast or ovarian cancer – 63% of these patients (6% of all patients) were likely to be at especially high risk and warranted intensive evaluation • 6.2% of a screening mammography population are considered to be at high risk of a BRCA gene mutation J of Gen Int Med. 2009;24(7):822‐28 Genet in Med. 2009:783‐789 Breast J. 2003:19‐25. The Open Health Services and Policy Journal. 2008;1:4‐37 29

Case Example

d. 80 d. 49 d. 60 d. 73 Breast cancer dx 48

d. 50 70 72 72 74 Ovarian Breast cancer dx cancer dx 49 42

48 38 Breast 42 Breast cancer dx cancer dx 35 47 30

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Case Example

• Lifetime risk of developing breast cancer – 26% based on BRCAPRO Model – 35% based on Tyrer‐Cuzick Model • Include annual breast MRI in medical management recommendations

Case Example

d. 80 d. 49 d. 60 d. 73 Breast cancer dx • Patient is now a 48 TRUE NEGATIVE

• No increased risk for breast or ovarian cancer d. 50 70 72 72 74 Ovarian Breast cancer dx cancer dx • Medical 49 42 management should include only annual mammogram + ‐

48 38 Breast 42 Breast cancer dx BRCA1 Mutation NEGATIVE cancer dx 35 47 BRCA1 Mutation POSITIVE 32

Prenatal Genetics

Samantha Stachowiak, MS, CGC

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Who should be referred for prenatal genetic counseling?

Indications

• Advanced maternal age • Personal history • 35 years or older at delivery • Carrier of genetic condition for singleton pregnancy • Translocation carrier • 33 years or older for multiples • Family history • Fetal ultrasound findings • Genetic condition indicating an increased • Congenital anomaly risk for aneuploidy • Ancestry/Ethnicity • Positive screening result • Carrier screening for aneuploidy • Pregnancy history • Multiple miscarriages • Prior pregnancy with a trisomy

Benefits of Seeing A Prenatal Genetic Counselor • Assess individual risk of having a child with birth defects or a genetic condition – Learn more about birth defect or genetic condition • Have a conversation about testing options • What to expect and to prepare for the birth of a child with special needs and/or genetic condition • Discuss pregnancy options, such as continuation of pregnancy, termination or adoption

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Referrals

Cell free DNA screening

• Also referred to as noninvasive prenatal screening (or testing) • Screening method to identify pregnancies at increased risk for the common trisomies and sex chromosome aneuploidies • Measures circulating cell‐free DNA from maternal serum • Cell‐free DNA from the fetus is http://www.downsyndromeprenataltesting.com/what‐exactly‐is‐maternit21‐harmony‐verifi‐panorama‐testing/ primarily derived from the placenta

Benefits

• Can be done anytime after 10 weeks gestation • Noninvasive • Higher detection rates and lower false positive rates than traditional serum screening

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The NEXT Study

Norton, ME, et al. (2015) NEJM

The NEXT Study

Norton, ME, et al. (2015) NEJM

The NEXT Study

Norton, ME, et al. (2015) NEJM

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Limitations

• Non‐reportable results

• False positives – Positive Predictive Value (PPV)

https://quizlet.com/8226119/blk‐8c‐genetics‐flash‐cards/

ACOG Committee Opinion 640

The NEXT Study

Norton, ME, et al. (2015) NEJM

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Updates in cell free DNA screening

Timeline of cell free DNA screening

Oct. 2011 Feb. 2012 Feb. 2013 Oct. July 2015 Cell free DNA MaterniT screening for T18 & T13 SCAs 2013 Genome T21 available are added available Microdeletio launches ns available

Chromosome Abnormalities

22% Common trisomies (T21, T18, T13) Sex chromosome 10% aneuplodies 68% Other

Norton, ME. (2015) Am J Obstet Gynecol.

Microdeletion syndromes

• Missing piece of • Often have wide range of chromosome symptoms • Common deletions • Rare in general screened: population – 22q11.2 deletion • Most occur sporadically syndrome (DiGeorge) – 1p36 deletion syndrome – Cri‐du‐chat syndrome – Prader‐Willi/Angelman syndrome – Wolf‐Hirschhorn syndrome

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MaterniT Genome

Who should get this testing?

• ACOG and SMFM do not recommend routine screening for deletions or duplications • Clinical validation needed

Carrier screening

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Carrier Screening

• Identifying couples at risk for passing on genetic conditions to their offspring • Depends on prevalence of condition, ancestry • Most conditions are inherited in an autosomal recessive, or X‐linked manner

Ethnicity‐Based Carrier Screening

Guidelines: Carrier Screening

• Cystic Fibrosis (CF): offer to all women of reproductive age/preconception

• Spinal Muscular Atrophy (SMA) – ACOG: only when family history is present – ACMG: offer screening regardless of family history

• Fragile X syndrome: not recommended for population carrier screening – All recommend based on family history – ACOG adds: unexplained ID, developmental delay, autism, or primary ovarian insufficiency

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Guidelines: Carrier Screening

– Hemoglobinopathies • ACOG: African‐American, Mediterranean, Southeast Asian

– Ashkenazi Jewish: • ACOG: Tay‐Sachs disease, CF, Canavan disease, familial dysautonomia • ACMG: same as ACOG as well as Niemann‐Pick disease (type A), Bloom syndrome, Fanconi anemia group C, Mucolipidosis IV, and Gaucher disease

– French Canadian/ Cajun: offer screening for Tay‐Sachs disease(ACOG)

Expanded Carrier Screening

• More comprehensive screening – Advancements in technology allows screening of a large number conditions simultaneously • Same conditions offered to everyone (regardless of race or ethnicity) • Ideally should be offered before conception – Provides couples with information for reproductive decision‐making

Expanded Carrier Screening

• In a study of 23,453 people, 24% were found to be a carrier of at least one non‐mild condition – 5.2% were found to be carriers of two or more conditions – 127 “carrier couples” were identified

Lazarin GA, et al. (2013)Genet Med

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Expanded Carrier Screening

• Take away points from this study: – ACOG & ACMG guidelines would have missed 70% of carriers that were identified – Several severe diseases had higher carrier frequencies than expected • Smith Lemli‐Opitz syndrome carrier frequency was 1 in 68 vs 1 in 123 – Several conditions were present outside their characteristic ethnic group • 26.3% of familial dysautonomia carriers did not report Jewish ancestry

Limitations/Considerations

• Conditions screened for range in severity • Many are rare • Screen negative results reduce likelihood of being a carrier but does not eliminate it • MANY labs to choose from – Different conditions – Detection rates • Genotyping vs Sequencing

How to Find Us

• Main GC phone line: 414‐955‐5899 – Morgan Depas: 414‐805‐9036, [email protected] • Email: [email protected] • Website: http://www.mcw.edu/Human‐and‐Molecular‐Genetics‐ Center‐HMGC/Genetic‐Counseling.htm

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How to Find a Genetic Counselor

• The National Society of Genetic Counselors website: http://www.nsgc.org/

• The Wisconsin Genetics Website: http://www.slh.wisc.edu/genetics/index.dot

• Contact State Genetic Coordinator – 608‐267‐7148 – Contact Us tab of Wisconsin Genetics Website

References

• American College of Obstetricians and Gynecologists. Committee Opinion No. 640: Cell‐free DNA Screening for fetal aneuploidy. Obstet Gynecol. 2015;126:e31‐7. • Edwards JG, Feldman G, Goldberg J, Gregg AR, Norton ME, Rose NC, Schneider A, et al. Expanded carrier screening in reproductive medicine—points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal–Fetal Medicine. Obstet Gynecol. 2015;125:653–62. • Lazarin GA, Haque IS, Nazareth S, Lori K, Patterson AS, Jacobson JL, Marshall JR, et al. An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. Genet Med. 2013 Mar;15(3):178‐86. • Norton ME, Baer RJ, Wapner AJ, Kuppermann M, Jelliffe‐Powlowski LJ, Currier RJ. Cell‐free DNA vs sequential screening for the detection of fetal chromosomal abnormalities. Am J Obstet Gynecol. 2015 Dec 18. • Norton, ME, Jacobsson, B, Swamy, GK, Laurent, LC, Ranzini, AC, Brar, H, Tomlinson, MW, et al. Cell‐free DNA analysis for noninvasive examination of trisomy. New England Journal of Medicine. 2015; 372(17), 1589–1597. • Tomita‐Mitchell A, Mahnke DK, Larson JM, Ghanta S, Feng Y, Simpson PM, Broeckel U, et al. Multiplexed quantitative real‐time PCR to detect 22q11.2 deletion in patients with congenital heart disease. Physiol Genomics. 2010 Sep;42A(1):52‐60. • Yaron Y, Jani J, Schmid M, Oepkes D. Current Status of Testing for Microdeletion Syndromes and Rare Autosomal Trisomies Using Cell‐Free DNA Technology. Obstet Gynecol. 2015 Nov;126(5):1095‐9 • Zhang H, Gao Y, Jiang F, Fu M, Yuan Y, Guo Y, & Wang W. Non‐invasive prenatal testing for trisomies 21, 18 and 13: clinical experience from 146,958 pregnancies. Ultrasound in Obstetrics & Gynecology. 2015; 45(5), 530–538.

Acknowledgements

• Wisconsin Cancer Risk Program Network (WiCRPN)