kara j. milliron, ms, cgc certified genetic counselor breast and ovarian cancer … annual... ·...
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Kara J. Milliron, MS, CGC
Certified Genetic Counselor
Breast and Ovarian Cancer Risk Evaluation Program
University of Michigan Comprehensive Cancer Center
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I am a contract genetic counselor with Informed Medical
Decisions, Inc.
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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
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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%
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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
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These slides are the property of the presenter. Do not duplicate without express written consent.
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
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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
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Ductal NOS
o Poorly differentiated
o High nuclear grade
o Highly proliferative
Rare histological subtypes
Good Prognosis Poor Prognosis
Medullary Adenoid cystic Metaplastic
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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
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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.
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African American Non-African American
Pre-menopausal 39% 16%
Post-menopausal 14% 16%
Carolina Breast Cancer Study JAMA 2006
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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
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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
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60% of breast
cancers in Ghanian
women are TNBC
Location of many of
the slave colonies
several hundred
years ago
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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?
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How Much Breast and Ovarian
Cancer is Hereditary?
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Causes of Hereditary Breast and Ovarian
Cancer Syndrome
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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
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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 ↑
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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
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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
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Diagnosed age < 60 y with a TNBC
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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
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These slides are the property of the presenter. Do not duplicate without express written consent.
These slides are the property of the presenter. Do not duplicate without express written consent.
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
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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
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These slides are the property of the presenter. Do not duplicate without express written consent.
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
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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
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These slides are the property of the presenter. Do not duplicate without express written consent.
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
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BRCA1/2 genetic testing revealed a variant of uncertain
significance (VUS) BRCA1 G1157R
1st reported observation of this VUS
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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
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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
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Patient was found to have BRCA2 VUS N1910S
1st observation
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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
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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
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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
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Another Cause of TNBC
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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
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These slides are the property of the presenter. Do not duplicate without express written consent.
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
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These slides are the property of the presenter. Do not duplicate without express written consent.
These slides are the property of the presenter. Do not duplicate without express written consent.
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
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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
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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)
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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
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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
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Genes: The Link to Our Past—The Bridge to Our Future:
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