1/25/2018 1 Cancer genetics in Gynecology Dana Zakalik, M.D. Director, Nancy and James Grosfeld Cancer Genetics Center Professor of Medicine, OUWB Medical School SEMCME Postgraduate Course in OB/GYN January 24 th , 2018 Outline • Introduction • Hereditary Breast and Ovarian Cancer (HBOC) • Multi‐gene panel testing and “other” genes • Hereditary colorectal cancer syndromes – Lynch syndrome • Gyn Cancers – (Polyposis syndromes) • Genetics and the law
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Cancer genetics in Gynecology - SEMCME · Cancer genetics in Gynecology Dana Zakalik, M.D. Director, Nancy and James Grosfeld Cancer Genetics Center Professor of Medicine, OUWB Medical
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Cancer genetics in Gynecology
Dana Zakalik, M.D.
Director, Nancy and James Grosfeld Cancer Genetics Center
Professor of Medicine, OUWB Medical School
SEMCME Postgraduate Course in OB/GYN
January 24th , 2018
Outline
• Introduction
• Hereditary Breast and Ovarian Cancer (HBOC)
• Multi‐gene panel testing and “other” genes
• Hereditary colorectal cancer syndromes
– Lynch syndrome
• Gyn Cancers
– (Polyposis syndromes)
• Genetics and the law
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Impact of Genetics on CancerHereditary Cancer Syndromes
• May be considered starting at age 30‐35 y :• CA‐125• Transvaginal ultrasound
• No data showing that surveillance lowers mortality from ovarian cancer
• Annual gyn screening of BRCA mutation carriers “noteffective.”
Surveillance for Ovarian Cancer
• NCCN 2017 Guidelines:
• For patients who elect not to do RRSO, “ while there may be circumstances where clinicians find screening helpful, data do not support routine ovarian screening. TVUS has not been shown to be sufficiently sensitive/specific to support a positive recommendation… Ca‐125 has similar caveats”
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Screening for Other Cancers
• Prostate (starting at age 45): – BRCA1 Consider prostate screening– BRCA2 Recommend prostate screening
• Male breast: – Breast Self Exam training and education at age 35 – Clinical Breast Exam every 12 mos starting at age 35
• Pancreas – no proven benefit– Consider EUS in high risk families– Screening registry enrollment– Research trials e.g. CAPS‐5
Prophylactic Surgery
Bilateral Mastectomy
Risk‐reducing salpingo‐oophorectomy
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Prophylactic Surgery
• Bilateral Mastectomy
– 90% ‐ 95% reduction of breast cancer risk
– Options of reconstruction varied
• Nipple sparing option
• Risk‐reducing salpingo‐oophorectomy (RRSO)
– 80‐90% reduction of ovarian cancer risk
– Also reduces risk of breast cancer (in patients < 50 y)
– Should be considered upon completion of childbearing or between ages of 35‐40 y
– Occult cancer found in 2‐18% of specimens
– Decreased mortality in BRCA mutation carriers (Domchek et al JAMA 2010)
RRSO
• Counseling re: quality of life, management of menopausal symptoms, possible short‐term HRT, degree of protection
– Short course HRT does not adversely impact cancer risk
– Estrogen therapy alone appeared safe in WHI study
• “Salpingectomy alone is not the standard of care and is discouraged outside a clinical trial” (NCCN 2016)
• Decrease in all cause mortality (Domchek at al JAMA ‘10)
• Removal of uterous not mandated; may be considered if patient opting to take Tamoxifen or HRT
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Chemoprevention
Tamoxifen
Oral Contraceptives
Tamoxifen Chemoprevention
• SERM – Selective estrogen receptor modulator
– Blocks estrogen receptor
• 50% reduction in breast cancer risk in high risk women (NSABP‐P1 Trial)
• Increase in endometrial cancer, DVT, PE (>50y)
• Improved bone density
• Limited data in BRCA mutation carriers
• Prevents ER + breast cancers
– More effective in BRCA2 mutation carriers
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Chemoprevention of Ovarian Cancer
• Up to 60% risk reduction for ovarian cancer in general population
• BRCA+ patients have similar benefit
• Breast Cancer Risk Minimal to none with modern, low dose formulations
d. 60SBreast
d. 8370s d. 56Breastdx 48
4544Breastdx 44
BRCA2+
70s d. 60Cancer
typeunknown
4745Breastdx 35
70s
n
d. 62 79
3
52787870
d. 26
d. 69d. 50Pancreatic
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Family letter template
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The “Other” Breast Cancer Genes
The “Other” Ovarian Cancer Genes
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Gene Panel Testing
• Allows for efficient analysis of multiple genes
• Next generation sequencing (NGS) technology
• Rapid, simultaneous gene analysis
• Made available for multiple tumor types
• Caveat: Variants of uncertain significance (VUS)
– Potential for misinterpretation
– May lead to confusion re: management of risk ? ?
• Clinical utility not proven – which genes are “actionable” ?
• Potential for uncertainty re: optimal management
• Lack of evidence‐based guidelines for many genes
• Genetic evaluation/counseling imperative
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PROMPT
• Prospective Registry of Multiplex Panel Testing
• Data collection research project open to any patient undergoing panel testing
• Goal to collect large numbers of mutation carriers, learn about cancer risks, outcomes, and facilitate classification of uncertain variants
• Will need to input results from large numbers of patients
• Biologic sample collection for translational research
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PALB2 and Cancer Risk
• Breast Cancer Risk (association with triple negative type)
– 14% by age 50
– 35% by age 70
– Impact of family history
• 33%‐58%
• Pancreas Cancer Risk
– Identified in 3‐4% of familial pancreatic cancer cases
• Ovarian Cancer Risk – conflicting results
• Other cancers (?)
Beyond BRCA: Other Hereditary Breast Cancer Syndromes
Gene Syndrome
PTEN Cowden Syndrome
P53 Li Fraumeni Syndrome (LFS)
PALB2 PALB2
CDH1Hereditary Diffuse Gastric Cancer
(HDGC)
STK11 Peutz Jeghers Syndrome (PJS)
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Beyond BRCA: Other Hereditary Breast Cancer Syndromes
Syndrome Key Features
Cowden SyndromeBreast, Uterine, and Thyroid Cancers; Large head
size; Skin findings
Li Fraumeni Syndrome (LFS)Breast, Brain, and Lung Cancers, Sarcomas, and Adrenocortical Carcinoma; very early age at
diagnosis
PALB2 Breast and Pancreatic Cancers
Hereditary Diffuse Gastric Cancer (HDGC)
Breast and Stomach Cancers
Peutz Jeghers Syndrome (PJS)Breast, Colon, Pancreatic, and Stomach Cancers;
freckling of lips in childhood
Cowden’s Syndrome
• PTEN hamartoma syndrome
• Breast (30‐60% lifetme risk), thyroid cancer (3‐10%), endometrial cancer (19‐28%)
• Skin manifestations:
– papillomatous papules
– Trichilemmomas
– Acral keratoses
• Macrocephaly
• Thyroid nodules, goiter
• Uterine fibroids
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3
3
10 9
Two “moles” removed from the
back and head grew back
35Breast dx 35
Papillary thyroid cadx 31
HC 58cm
ADDLearning
disabilities
Melanoma dx 38Pap thyroid ca dx
40Melanoma dx 50
Pap thyroid ca dx 55Multiple lipomas facial fibromas
Possible renal ca
60s 60s55Skin BCC
Benign tumor-BrainBreast fibroadenoma x 2
Kidney-nephrectomy (2000)-benignMultiple moles
TAH 40s
6050-60s
d.70sProstate ca dx 50s
Heart attack
d. 77Breast ca 50-60s
Heart attack
d. 60sLung ca?
Bladder caSmoker
86Thyroidectomy
GoiterBreast mass removedMoles, benign tumors
on back, foot, arm and breast
BreastMelanoma
Benign brain tumor
ColonBenign breast masses
Thyroid caGoiter
Dutch German/English
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Genetics and Personalized Care
• PARP inhibitors ‐ targeted agents
• Novel treatments targeting the defect in DNA repair in BRCA mutation carriers
– Poly ADP ribose polymerase (PARP)
– Olaparib; Veliparib
– Promising treatments – early studies with good results
– Molecularly targeted treatments for cancer
– Clinical trials now open at Beaumont
• Newly diagnosed breast cancer in BRCA mutation carriers
– Personalized Medicine
Targeting DNA Repair
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NSABP B‐55 Clinical Trial
• Inclusion Criteria:
– Triple Negative Breast Cancer (> 2cm or lymph node + )
– ER + expected to open in near future
– BRCA1/2 +
• Chemotherapy given to each patient per standard of care
– Anthracycline, taxane or both
• Olaparib 300mg (vs placebo) orally twice a day for 12 mos
• Patients followed every 3 months for 2 yrs, then every 6 months for 3 years, then annually
• Beaumont enrolls first patient in U.S. (10/14)
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Lynparza (Olaparib)‐ FDA approval
• Oral PARP inhibitor
• Approved 12/19/14 for advanced ov ca in BRCA + women
• 4th line treatment
• Single open label trial of 137 patients
– Overall response rate 34%
– Median duration of response 7.9 months
– Side effects fatigue, nausea, vomiting, headache
• Further studies in progress
• Companion diagnostic test approved
Lynparza (Olaparib)‐ FDA approval
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Colorectal Cancer Genetics
• 3rd most common cancer in the U.S.
– 145,000 new cases per year
• 3rd most common cause of cancer‐related death
• Most common form of hereditary CRC is Lynch Syndrome (LS)
• Stepwise progression
– Benign mucosa polyp cancer
• Effective screening prevention
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Risk Factors for Colorectal Cancer (CRC)
• Aging
• Personal history of CRC or adenomas
• Dietary patterns
• Inflammatory bowel disease
• Family history of CRC
• Hereditary colon cancer syndromes
Epidemiology of Colorectal Cancer
Cancer 1996;78:1149-67Am J Med 1999;107:68-77Gastroenterology 2000;119:837-53Am J Path 2003;162:1545-8
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Risk of Colorectal Cancer
Lynch Syndrome
Hereditary Colorectal Cancer Syndromes
Multiple Polyposis Syndromes:
• FAP– Familial Adenomatous Polyposis
Syndrome
• AFAP– Attenuated Familial Adenomatous
Polyposis
• MYH‐Associated Polyposis (MAP) Syndrome– Similar to AFAP
NonPolyposis Syndromes:
• Lynch syndrome– Also known as: Hereditary
Nonpolyposis Colorectal Cancer = HNPCC
Slides Courtesy of WBH Cancer Genetics Program
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Red Flags for Lynch Syndrome
• Lynch Syndrome
– Colon or endometrial cancer under age 50
– More than one LS‐associated cancer in one individual/family