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G E T T I N G I T R I G H T

THIS COULD BE YOU ONE DAY SOON:

Starting out in your new

OB/Gyn practice

You meet Lori, a new

patient, for her annual

well-woman visit:

LORI:

37-year old Caucasian female

good general health

family history:

mother: HTN, osteopenia dx’ed 65

father: colon polyps dx’ed 68

PGM: breast cancer dx’ed 55

sister: recently dx’ed with breast cancer at 42

FUN FACT #1:F A M I LY H I S T O R Y W A S T H E F I R S T G E N E T I C T E S T.

CASE #1 – LORI’S PEDIGREE

Lifestyle

Genes

Environment

Family histor

y

Cancer

Risk

FUN FACT #2:A L L C A N C E R I S G E N E T I C ,

BUT

F E W C A N C E R S A R E I N H E R I T E D .

STAGES OF CANCER DEVELOPMENTNormal cell

Increased proliferation

Early neoplasia

Progressive neoplasia

Carcinoma

Metastasis

Mutation in Gene A

Mutation in Gene B

Mutation in Gene C

Continuing

cascade of

mutations

ALL CANCERS HAVE GENETIC ORIGINS

Somatic mutations

Occur in non-germline tissues

(breast, colon, lung, blood, etc.)

Not inherited

“sporadic”

90-97% of all cancers

Germline Mutations

Start out in egg and sperm cells

Heritable

Once inherited, mutation is present in

all cells of the body

3-10% of all cancers

THE WORLD OF CANCER GENETIC TESTING

Direct-to-consumer

Tumor testing (somatic-

based)

Germline genetic testing

not every cancer risk gene is known

possibility of unclear results

cannot prevent / screen for all cancer

risks

more questions than answers

anxiety / distress

GERMLINE GENETIC TESTINGWHO?

– DNA sequencing and deletion/duplication

analysis of genes associated with

inherited cancer syndromes

WHY?

– Myriad, Ambry, GeneDx, Prevention, etc.

WHAT?

– To guide screening, prophylaxis, risk

management, and identify at-risk family

members

LIMITATIONS

CASE #1 – LORI’S PEDIGREE

NATIONAL COMPREHENSIVE CANCER NETWORK www.NCCN.org

Mission statement:

“Our mission, as an alliance of leading

cancer centers devoted to patient care,

research, and education, is improve the

quality, effectiveness, and efficiency of

cancer care so that patients can live better

lives.”

Clinical Practice Guidelines in Oncology

Patient Guidelines

CEU programs

NCCN GUIDELINES FOR HEREDITARY BREAST/OVARIAN ASSESSMENT personal history of ovarian cancer at any age

personal history of breast cancer <45

triple negative breast cancer

two primary breast cancers

two or more family members with breast and/or ovarian

cancer, especially <50

CONSIDER GENETIC TESTING……BUT FOR WHO?

Lori ?

Lori’s sister ??

Someone else???

FUN FACT #3:IDEALLY, GENETIC TESTING

SHOULD BE PERFORMED ON

AN AFFECTED INDIVIDUAL.

SO WHAT TESTING DO WE OFFER THIS FAMILY?

Back in the day (<5 years ago), we had only a small handful of cancer genes

we routinely tested for.

Myriad Labs held the patent on the BRCA1 and BRCA2 genes and was the

only lab who could do the testing.

On June 13, 2013, the Supreme Court struck down the patent, ruling that

genes are not patentable.

On June 14, 2013, every genetic testing laboratory was offering BRCA1 / 2.

Introduction of NGS technologies

NGS MULTIGENE PANELS

Benefits

-- assess any number of genes at once (typically anywhere from 15 – 50)

-- clarify patient’s risk (and those of other carriers of familial variant)

-- guide medical management

Challenges

-- turnaround time may be several weeks delayed decision-making

-- limited literature on many genes / variants

-- interpreting results for unaffected family members

-- variants of unknown significance

-- informed consent

-- follow up in the case of variant reclassification

DISTRIBUTION OF PATHOGENIC VARIANTS IN HBOC FAMILIES

Citation: Castera, L. et al. Next-

generation sequencing for the

diagnosis of hereditary breast and

ovarian cancer using genomic capture

targeting multiple candidate

genes. Eur J Hum Genet. 2014 Feb

19

GENES AND CANCER SITES

FUN FACT #4:I T I S V E R Y U N L I K E LY Y O U W I L L E V E R O R D E R

G E N E T I C T E S T I N G F O R A S I N G L E G E N E /

C A N C E R S Y N D R O M E

CASE #2 – COLON POLYPS

57-year old male

first colonoscopy at 56

-- multiple polyps throughout colon

-- pathology: tubular adenomas and

mucosal polyps with muscle overgrowth

follow-up colonoscopy (6 months later)

-- multiple polyps in each colon segment

-- uncountable polyps in transverse colon

-- pathology: tubular adenomas and

hyperplastic polyps

TESTING STRATEGY

genetics evaluation

if >10 adenomas present, test for FAP / MAP

conventional approach:

-- sequencing and rearrangement testing of APC, MUTYH genes

-- if polyp NOT adenomatous, assess whether patient meets NCCN criteria for

less common polyposis syndrome, such as Cowden, Peutz-Jehger, or Juvenile

Polyposis syndrome.

COLORECTAL CANCERSporadic (70%)

Familial (25%)

- Lynch syndrome (3%)

- FAP (1%)

- MAP (1%)

- Rare CRC syndromes (<1%)

juvenile polyposis

Peutz-Jehgers syndrome

serrated polyposis

PTEN-related syndrome

hereditary diffuse gastric

cancer (HDGC)FAP = Familial adenomatous polyposis

MAP= MUTYH-associated polyposis

LIFETIME RISKS FOR COLORECTAL CANCER

0

10

20

30

40

50

60

70

80

90

100

FAP AFAP MAP General

Population

Can

cer

Ris

k (

%)

APC /

MUTYH

negative

NOW

WHAT?

COLONEXT NGS PANEL (AMBRY)Gene Syndrome CRC Risk Polyposis Other Associated

Cancer(s)

STK11 Peutz-Jeghers Up to 40% Yes Breast, pancreas,

GI, uterine,

cervical

CHEK2 Hereditary

Breast/CRC

Increased No Breast

CDH1 Hereditary Diffuse

Gastric Cancer

Increased No Lobular breast,

diffuse gastric

PTEN Cowden Increased Yes Breast, thyroid,

kidney, uterine

TP53 Li-Fraumeni Increased No Breast, sarcoma,

brain, leukemia

MYH MAP Up to 80% Yes Duodenal, thyroid

APC FAP / AFAP Up to 99% Yes Duodenal, thyroid

MLH1

MSH2

MSH6

PMS2

EPCAM

Lynch Up to 80% No

Stomach, brain,

Uterine, ovarian,

Pancreas, ureter

SMAD4

BMPR1A

Juvenile Polyposis Up to 50% Yes Stomach

THINGS TO CONSIDER BEFORE TESTING - CLINICIAN Gene / syndrome-specific testing is still available and MAY be a reasonable

option in some cases and should be discussed with any patient

MSI / IHC should be utilized when Lynch syndrome is suspected

Large gene panels can take several weeks to several months for results

Large panels may not be feasible when making time-sensitive decisions

THINGS TO CONSIDER BEFORE TESTING - PATIENT

Longer turnaround time may delay treatment / surgery

Testing may find variants with unclear cancer implications

Testing may find variants revealing risk for unrelated cancers

Results may have implications for other family members

PTEN HAMARTOMA TUMOR SYNDROME (PHTS)

– Thyroid cancer (35%)

– Kidney cancer (33%)

– Colorectal cancer (9%)

– Melanoma (6%)

– Breast cancer (60%)

– Endometrial cancer (28%)

– Uterine fibroids

– Hamartomatous polyps

– Macrocephaly

– Thyroid nodules, goiter

– Trichilemmomas, papillomatous papules

– Hyperpigmentation

– Overgrowth

– Fibrocystic breast disease

– Autism spectrum disorder

– Mental retardation (IQ<75)

– Lipomas

Includes: Cowden syndrome, Proteus syndrome, Bannayan-Riley-Ruvalcaba syndrome (BRRS)

Lipomas, HC 63.9 cm

Asperger

syndrome

macrocephaly

LDautism

PTEN HAMARTOMA TUMOR SYNDROME (PHTS)

– Thyroid cancer (35%)

– Kidney cancer (33%)

– Colorectal cancer (9%)

– Melanoma (6%)

– Breast cancer (60%)

– Endometrial cancer (28%)

– Uterine fibroids

– Hamartomatous polyps

– Macrocephaly √

– Thyroid nodules, goiter

– Trichilemmomas, papillomatous papules

– Hyperpigmentation

– Overgrowth

– Fibrocystic breast disease

– Autism spectrum disorder √

– Mental retardation (IQ<75)

– Lipomas √

Includes: Cowden syndrome, Proteus syndrome, Bannayan-Riley-Ruvalcaba syndrome (BRRS)

VARIABLE EXPRESSIVITY

PTEN WORKUP - JW Subtotal colectomy with IRA

– path: colon with multiple tubular adenomas and

hamartomatous polyps

Double balloon enteroscopy

-- glycogenic acanthosis, ileal and jejunal polyps

Thyroid ultrasound

– innumerable nodules

Derm exam

– unremarkable

MRI of the abdomen

– unremarkable

Recommendations:

– Yearly physical

– Yearly thyroid ultrasound

– Yearly derm exam

– Continue GI screening based on polyp burden

– Genetic testing for first degree relatives > age 18

CASE #3 - HBOC

46 year old woman with a newly diagnosed left breast cancer

– ER/PR+ invasive ductal carcinoma

Referred for genetic risk assessment by patient request

-- wants risk estimate to help her decide about bilateral

mastectomy

CANCER RISKS IN HBOC

BRCA1

– Breast cancer: 54-90%

– 2nd breast cancer: 27% within 5 years

– Ovarian cancer: 24-40%

BRCA2

– Breast cancer: 41-87%

– 2nd Breast cancer: 12% within 5 years

– Ovarian cancer: 8.4-18%

CANCER RISKS IN HBOC

FUN FACT #5A LWAY S A S K A B O U T B O T H S I D E S O F

T H E FA M I LY W H E N TA K I N G A FA M I LY

H I S T O RY !

CASE #3 – PEDIGREE

MYRISK (MYRIAD) RESULTS

BOOM! POSITIVE TEST!

Deleterious variant

- MUTYH gene c.1187G>A (p.Gly396Asp)

MUTYH GENE involved in base excision repair

germline MUTYH mutations impair DNA repair of somatic APC mutations leading to a phenotype similar to FAP

RECESSIVE inheritance

biallelic carriers are predisposed to:

– Multiple colorectal adenomas

– upper GI manifestations – stomach cancer, duodenal polyps

– Early onset colon caner

– CHRPE

– Risks for other cancers is unclear (possible increased risk for breast cancer, skin cancer, ovarian cancer)

MUTYH-ASSOCIATED POLYPOSIS MUTYH testing classically bundled with APC

accounts for 1% of all CRC

accounts for up to 3% of CRC under age 50

monoallelic carriers:

- studies conflict on whether cancer risk is

increased

- carrier rate: 1-2% of the general US population

SO, IN OTHER WORDS

Does she have a disease-causing

variant? YES.

Does it explain her cancer? NO.

Does this variant, on its own,

affect her risk for cancer?

Probably not.

MYRISK RESULTS

Deleterious variant

- MUTYH gene c.1187G>A (p.Gly396Asp)

Variants of Uncertain Significance (VUS)

- BRCA2 c.8447G>A (p.Gly2816Asp)

- STK11 c.1062C>G (p.Phe354Leu)

FUN FACT #6:

S O M E T I M E S I N O U R Q U E S T F O R A N S W E R S W E

O N LY F I N D M O R E Q U E S T I O N S .

VARIANT INTERPRETATION

Medical mgmt. based on personal &

family hx. Uncertain results do not

influence recommendations for care.

Medical mgmt. based on

guidelines for gene variant and

its associated syndrome(s).

Citation:

Richards, S., Aziz, N.,

Bale, S., Bick, D., Das, S.,

Gastier-Foster, J., ... &

Voelkerding, K. (2015).

Standards and guidelines

for the interpretation of

sequence variants: a joint

consensus

recommendation of the

American College of

Medical Genetics and

Genomics and the

Association for Molecular

Pathology. Genetics in

Medicine.

RATES OF UNCERTAIN VARIANTS

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

35.0%

40.0%

2002 2006 2008 2012

Decline in Rate of BRCA1/2 Variants of Uncertain Significance

All Patients

Middle Eastern

Asian

African

Native American

Latin American

Central European

Western European

Eggington et. al. Current Variant of Uncertain Significance Rates in BRCA1/2 and Lynch Syndrome Testing (MLH1, MSH2,

MSH6, PMS2, EPCAM), March 2012, ACMG Poster Presentation.

CASE #3 – PEDIGREE

MUTYH-positive

VUS – BRCA2

VUS – STK11

NO BRCA2 VUS

STK11 GENE

associated with Peutz-Jehgers syndrome

autosomal dominant

~50% de novo

characteristic hyperpigmentation of the

mucosa

hamartomatous polyps

CANCER RISKS IN PJS

Breast - 50%

Colorectal - 39%

Pancreatic – 11-36%

Gastric - 29%

Small bowel – 13%

Ovarian - 21%

Cervical – 10%

Uterine - 9%

Lung - 15%

Testicular - ?

RECOMMENDATIONS

currently no genetic indication that PR’s risk for a second breast cancer

is significantly increased.

recommended standard breast treatment, screening, and follow-up

care based on physician recommendations and family history

undergo colonoscopy every 5 years

MYH testing recommended for 1st degree relatives

-- to assess for MAP

-- high US carrier rate (1-2%)

THIS CASE ILLUSTRATES…

complex inheritance patterns with some syndromes

significant risk of variants of uncertain significance

- approximately one-third of panel results

- newer genes, less literature, smaller samples

- reclassification of many VUS with time

challenges for clinicians in sorting out the data

challenges for patients trying to make decisions about care

FUN FACT #7:Y O U D O N ’ T N E E D T O K N O W E V E R Y T H I N G .

Y O U D O N E E D T O K N O W W H E N T O R E F E R .

A GENETIC COUNSELOR CAN HELP YOU

RIGHT PATIENT

RIGHT TEST

RIGHT LAB

RIGHT RESULTS

WHEN TO REFER TO GENETICS triple-negative breast cancer

male breast cancer

ovarian cancer

young onset (< 50)

same/related cancer in relatives

autosomal dominant inheritance

– with rare exceptions

aggressive prostate cancer

- Gleason score ≥ 7

multiple primaries

multifocal / bilateral cancers

rare cancers

unusual non-malignant features (i.e.,

“syndromic”)

confirmed mutation in relative

If uncertain, refer anyway!

LAST FUN FACT:

“ G E N E T I C S A N D O U R U N D E R S TA N D I N G O F

M U TAT I O N S I S E V O LV I N G , S O T O D AY ’ S

G E N E T I C R E S U LT M U S T A L W AY S B E

R E A S S E S S E D A N D I N T E R P R E T E D B A S E D O N

C U R R E N T I N F O R M AT I O N A N D S T U D I E S O F

M O D I F I E R S , P R O P H Y L A X I S O P T I O N S , A N D

P R E V E N T I O N . ”

M I C H A E L H A L L , M D

F O X C H A S E C A N C E R C E N T E R

P H I L A D E L P H I A , P A

QUESTIONS?

My contact information:

Carla Bell, MS, LCGC

Wesley Medical Center

Oncology Department

550 North Hillside

Wichita, KS 67214

Direct phone: 316.361.0991

Fax: 501.222.7753

Email: Carla.Bell@WesleyMC.com