Kara J. Milliron, MS, CGC Certified Genetic Counselor Breast and Ovarian Cancer … Annual... ·...

Kara J. Milliron, MS, CGC

Certified Genetic Counselor

Breast and Ovarian Cancer Risk Evaluation Program

University of Michigan Comprehensive Cancer Center

These slides are the property of the presenter. Do not duplicate without express written consent.

I am a contract genetic counselor with Informed Medical

Decisions, Inc.


Introduction to breast cancer pathology

Triple negative breast cancer (TNBC)

TNBC and BRCA1/2

BRCA1/2 genetic testing and the NCCN guidelines

Cases

Other genetic causes of TNBC


Breast profile:

A Ducts

B Lobules

C Dilated section of duct

to hold milk

D Nipple

E Fat

F Pectoralis major muscle

G Chest wall/rib cage

Enlargement

A Normal duct cells

B Basement membrane

C Lumen (center of duct)

Invasive ductal 80%

Invasive lobular 10%


Modified Bloom

Richardson Grade

Based on three

characteristics

o Degree of tubule

formation

o Nuclear pleomorphism

o Mitotic activity

Scored on a scale 1-3

Grade I

Grade II

Grade III



1985: Her2neu discovered by 2 independent labs

1987: Her2neu amplification shown to be a poor prognostic factor in breast cancer

1998: Addition of trastuzumab proven beneficial in Her2neu + metastatic patients


ER negative

PR negative

Her2Neu

negative

15% of all invasive breast cancers

Risk Factors o dx <50 years

o A. American ancestry

o High BMI

o Young age menarche

o High parity

o Young age of FLB

o Lack of breast feeding


Ductal NOS

o Poorly differentiated

o High nuclear grade

o Highly proliferative

Rare histological subtypes

Good Prognosis Poor Prognosis

Medullary Adenoid cystic Metaplastic


Estimated New Female Breast Cancer Cases by Age, US, 2011*

Age In Situ Cases Invasive Cases Est. TNBC (total) cases

(~15%)

< 40 1,780 11,330 1700

< 50 14,240 50,430 7564

50-64 23,360 81,970 12,296

65+ 20,050 98,080 14,712

All ages 57,650 230,480 36,272

*Rounded to the nearest 10.

Source: Total estimated cases are based on 1995-2007 incidence rates from 46 states as reported by the

North American Association for Central Cancer Registries. Total estimated deaths are based on data from

US Mortality Data, 1969-2007, National Center for Health Statistics, Centers for Disease Control and

Prevention. American Cancer Society, Surveillance Research, 2011


ACT dose dense fashion most common

TC every 3 weeks can be utilized in some patients

Platinum agents have recently emerged as drugs of interest

o One trial that treated 28 women with stage II or stage III TNBC with four cycles of neoadjuvant cisplatin resulted in a 22% pCR rate

o CALGB-40603 (NCT00861705), evaluated the benefit of carboplatin added to paclitaxel and adriamycin plus cyclophosphamide chemotherapy in the neoadjuvant setting.

o Triple Negative Trial (NCT00532727), is evaluating carboplatin against docetaxel in the metastatic setting.

o These trials will help to define the role of platinum agents for the treatment of TNBC.

o Currently, there is no established role for adding platinum agents to the treatment of early-stage TNBC outside of a clinical trial.


http://www.cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=636850










African American Non-African American

Pre-menopausal 39% 16%

Post-menopausal 14% 16%

Carolina Breast Cancer Study JAMA 2006


mortality hazard.1 .5 1 5 10

Combined

Crowe

Jatoi 1995-99

Bradley

Polednak

Albain Postmen

Albain Premen

Roetzheim

El Tamer

Yood

Wojcik

Howard

Franzini

Simon (<50 yo)

Simon (>49 yo)

Perkins

Eley

Neale

Ansell

Gordon

Coates

Bassett

AA Mortality Risk: 1.28 (95% CI 1.18-1.38)

(22% excess risk of death) Newman et al, JCO 2006


Higher Mortality

Advanced Stage Distribution

Lower lifetime incidence

Younger age distribution

Increased risk of adverse tumor factors

Higher incidence of male breast cancer

Socioeconomic

disparities

Delivery of Care

Tumor biology

Genetics

Lifestyle &

Reproductive

Experiences

Environmental

exposures

Diet/Nutrition


60% of breast

cancers in Ghanian

women are TNBC

Location of many of

the slave colonies

several hundred

years ago


Parallels between hereditary breast cancer (BRCA1/2) and breast cancer in individuals with African ancestry o younger age distribution

o increased prevalence of ER-neg, aneuploid tumors

o higher risk of male breast cancer

Is African ancestry associated with a heritable marker for high-risk breast cancer subtypes?


How Much Breast and Ovarian

Cancer is Hereditary?


Causes of Hereditary Breast and Ovarian

Cancer Syndrome


BRCA1 BRCA2

Year cloned 1994 1995

Chromosome

location

17q21 13q12

Genomic DNA/coding

exons

5.6 kb/22 exons 10.2 kb/26 exons

# of amino acids 1, 863 3, 418

# of mutations reported >1, 230 >1,380

Inheritance pattern Autosomal

Dominant

Autosomal

Dominant


BRCA1 BRCA2

Breast cancer to age 80 50-85% 50-85%

Ovarian cancer to age 80 20-60% up to 27%

Male breast cancer ~1% ~6%

Prostate cancer Slight ↑ Slight ↑

Pancreatic cancer Slight ↑ 1.5-5%

Melanoma Slight ↑ Slight ↑


Breast cancers in BRCA1 carriers80% Triple negative

Breast cancer in BRCA2 carriers20% Triple negative

o Mutation Carrier frequency in general population 1/300-1/800

o Mutation Carrier frequency in A. Jewish population 1/40


Gonzalez-Angula CCR 2011

o 77 unselected TNBC

o 15% incidence of BRCA1 mutation (one somatic) (12)

o 3.9% incidence of BRCA2 mutation (3)

o 9/14 had no first degree family history of cancer

o However, 22/77 or (30%), DID have a family history of breast

and ovarian cancer

o In addition 12/77 (16%) HAD a first degree relative with

breast cancer

o 6/14 found to be BRCA carriers had not been referred to genetic

counseling


Diagnosed age < 60 y with a TNBC


Estimated New Female Breast Cancer Cases by Age, US, 2011*

Age In Situ Cases Invasive Cases Est. TNBC (total) cases

(~15%)

< 40 1,780 11,330 1700

< 50 14,240 50,430 7564

50-64 23,360 81,970 12,296

65+ 20,050 98,080 14,712

All ages 57,650 230,480 36,272

*Rounded to the nearest 10.

Source: Total estimated cases are based on 1995-2007 incidence rates from 46 states as reported by the

North American Association for Central Cancer Registries. Total estimated deaths are based on data from US

Mortality Data, 1969-2007, National Center for Health Statistics, Centers for Disease Control and Prevention.

American Cancer Society, Surveillance Research, 2011

21,560

potential patients

tested for BRCA1/2

from these cases

alone

Healthcare cost

for testing

$4000 X 21,560

= $86,240, 000.00

~$107,800 to find

1 BRCA1/2

positive individual




46 year old G1P1 Filipino female

s/p L lumpectomy

o 1.8 cm invasive ductal carcinoma

o Triple negative

o 0/3 SLN

Menarche: 11

FLB: 23


s/p 4 cycles AC

s/p 2 cycles T

Carries BRCA2 mutation R3052W

Recorded 8 times in the BIC located in exon 24 of BRCA2

Bilateral mastectomy with reconstruction is scheduled for the near future

Plans on BSO, scheduled with Dr. Pearlman to further discuss options

Scheduled with Dr. El Munzer to discuss risks, benefits, and limitations of pancreatic cancer screening



51 year old G4P3SAB1 Caucasian female

s/p R lumpectomy

o 2 foci 0.3 cm and 0.7 cm invasive ductal carcinoma

o Triple negative

o 0/1 SLN

s/p 3 cycles AC

s/p 1 cycle of Taxol, developed toxicity

s/p 15 weeks of weekly Taxotere

s/p radiotherapy


Patient is adopted with some knowledge about family

history

BRCA1/2 genetic testing-no mutation detected

Based on negative test results, not felt to be at increased

risk for ovarian cancer



59 year old G0 Chinese female

s/p Left breast biopsy

Discrepancy in size of tumor via imaging—u/s 1.5 cm vs

MRI 3 cm

No definitive cancer surgery

Lymph nodes not sampled

Triple negative

Due to NCCN guidelines, requested BRCA1/2 genetic

testing


BRCA1/2 genetic testing revealed a variant of uncertain

significance (VUS) BRCA1 G1157R

1st reported observation of this VUS


41dx 41

49 44

d. 65 CO PD ? Lung cancer Used

tobacco

~ 75 60 69s/p

TAH/ BSO

73d. 53 MI

d. 75 ? Ane ury sm/

CVA/MI

d. 70 Lung

cancer Used

tobacco

dx 60's Colon

cancer d. Alzheimer' s

dx 50's d. Colon cancer

d. 50's MI

3

4 6 20

50'sdx 41 DCIS d. 40's Choked

MR

50's 50's 30


41 year old G2P2 Caucasian female

s/p 4 cycles AC, and 3 cycles T (neo-adjuvant)

R breast cancer 2.1 X 2.4 X 2.6 cm via U/S

Triple negative

0/8 SLN


Patient was found to have BRCA2 VUS N1910S

1st observation


Genetic counseling-what do they mean to the patient?

Does everyone agree on the interpretation?

Inconsistency between DNA diagnostic laboratories and between countries on interpretation and reporting of variants

In US-Myriad Genetic Laboratories alone reports and interprets


BRCA1/2 o ~ 7% of overall test

results

o ~ 15% of test results if of African American descent

o Most seen < 3 times

Few are likely to be associated with a high risk of disease

BUT knowing which ones is difficult to ascertain


Unfortunately, since these were the first observation of

these VUS, and there is no family history of cancer,

additional investigation at this time is not helpful.

Due to rarity of VUS, follow HBOC guidelines

BSO to be considered by both patients in the near future

once they have completed breast cancer treatment


Another Cause of TNBC


Autosomal recessive (i.e.

2 PALB2 mutations)

Characterized by:

o Thumb deformity

o Kidney malformation

o Small stature

o Developmental delay

o Microcephaly

o Bone marrow failure



PALB2 is a low penetrence breast cancer susceptibility gene

Encodes a BRCA2 interacting protein

Rahman et al. 2007

oFound monoallelic truncating mutations in 10/923 (1%) familial breast cancer families and 0/1084 (0%)controls




Carriers are at a 2-3 fold increased risk of

developing breast cancer

May confer a higher RR for male breast

cancer vs. female breast cancer

Ovarian cancer risk not studied

Clinical management for unaffected individuals

is based on family history


Heikkinen et al CCR 2009

2% (19/947) of familial breast cancer patients in S.

Finland had mutations

Tumors of the PALB2 mutation carriers were more often

o triple negative

o basal-like subtype

o higher expression of Ki67

o lower expression of cyclin D1

Increased risk for pancreatic cancer


Is becoming more complex

o age is only a number

We are testing based on cancer pathology (i.e. TNBC)

We may need to test for multiple genes

This will impact

o Integration of genetic testing into diagnostic and treatment flow

o Multiple genes tested (will insurers pay?)

o ? increase the uptake of bilateral mastectomy (patients not

wanting to wait for all information before making a surgical

decision)


Cancer risk management for those with inherited

susceptibility is a challenging and dynamic process

Consistent protocols for counseling/help manage/re-

contact these high risk patients

How to Contact us

Clinic coordinator: Kara J. Milliron, MS, CGC

734.764.0107 or 734.936.6266 pager number 8881


Sofia D.Merajver, MD, PhD Celina Kleer, MD Mark D. Pearlman, MD Kathleen Diehl, MD Breast Care Center Hematology/Oncology Surgical Oncology Radiation Oncology Gynecology Oncology Clinic Radiology Obstetrics and Gynecology Primary Care Clinics


Genes: The Link to Our Past—The Bridge to Our Future:


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Kara J. Milliron, MS, CGC Certified Genetic Counselor Breast and Ovarian Cancer … Annual... ·...

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