Kara J. Milliron, MS, CGC
Certified Genetic Counselor
Breast and Ovarian Cancer Risk Evaluation Program
University of Michigan Comprehensive Cancer Center
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
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%
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
Ductal NOS
o
Poorly differentiated
o
High nuclear grade
o
Highly proliferative
Rare histological subtypes
Good Prognosis
Poor Prognosis
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
African American
Non-African American
Pre-menopausal
39%
16%
Post-menopausal
14%
16%
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)
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 carriers
80% Triple negative
Breast cancer in BRCA2 carriers
20% 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
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
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,
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
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
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
BRCA1/2 genetic testing revealed a variant of uncertain
significance (VUS) BRCA1 G1157R
41 dx 41 49 44 d. 65 CO PD ? Lung c a nc e r Use d toba cc o ~ 75 60 69 s/p TAH/ BSO 73 d. 53 MI d. 75 ? Ane ury sm / CVA/MI d. 70 Lung c a nc e r Use d toba cc o dx 60's Colon c a nc e r d. Alzheim er' s dx 50's d. Colon c ance r d. 50's MI 3 4 6 20 50's dx 41 DC IS d. 40's Choke d 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
Patient was found to have BRCA2 VUS N1910S
1
st
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
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
Autosomal recessive (i.e.
2 PALB2 mutations)
Characterized by:
o
Thumb deformity
o
Kidney malformation
o
Small stature
o
Developmental delay
o
Microcephaly
PALB2 is a low penetrence breast
cancer susceptibility gene
Encodes a BRCA2 interacting protein
Rahman et al. 2007
o
Found 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
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
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
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
