Carolina Breast Cancer Study:Breast cancer subtypes and race
Robert MillikanUniversity of North Carolina
Chapel Hill, NC
Research Questions
Could breast cancer represent more than one disease?
Can different subtypes of breast cancer help to explain racial disparities?
Research Question #1
A major problem in breast cancer research is tumor heterogeneity:
Patients do not respond uniformly to treatment.
Could breast cancer represent more than one disease?
Clinical and Pathologic Staging of Breast Cancer
Traditional StagingBreast cancer patients receive a clinical
stage at initial diagnosis.
The definitive stage is based upon pathologic information obtained at the time of surgical removal of the primary tumor and regional lymph nodes.
TNM system.
New Paradigm
“Biology trumps staging.” ASCO 2008
Differences in underlying biology of breast tumors determine clinical course and response to therapy.
How do we get at the underlying biology of breast
cancer?How do we apply this knowledge to:
• Prognosis
• Predicting therapeutic response
• Understanding disease causation
• Prevention
Histology TNMStaging
Biology
IHC / TMAs mRNA profiling
Histology
Biology
IHC / TMAs mRNA profiling TNMStaging
TNM staging• T stands for tumor (its size and how far it
has spread within the breast and to nearby organs).
• N stands for spread to lymph nodes (the number of nodes where cancer is detected).
• M is for metastasis (spread to distant organs).
TNM staging
• TNM staging helps understand survival (prognosis).
• It does not tell us how to treat, what drugs to give (predict therapeutic response).
New paradigm:
Use gene expression profiling
and immunohistochemistry to understand the
underlying biology
Histology
Biology
IHC / TMAs mRNA profiling TNMStaging
Identification of Breast Cancer Subtypes
DNA microarray-based gene expression profiling.
Perou and colleagues (UNC Chapel Hill)
8,102 genes →1,753 genes→ 496 genes “intrinsic”
Nature 406: 747-52 (2000).
“Intrinsic” breast cancer subtypes
Basal-like ER- PR- HER2- ck5/6+ and /or HER1+
Luminal A ER+ and/or PR+ HER2-
Luminal B ER+ and/or PR+ HER2+
HER2+ / ER – ER- PR- HER2+
“Unclassified” Negative for all five markers
Histology Clinical Staging
Biology
IHC / TMAs mRNA profiling
Algorithm for breast cancer subtypes
HER2 + HER2 -
EGFR + or CK5/6 +EGFR - CK5/6 –
Unclassified Basal-like
All cases
ER - PR - ER+ or PR +
HER2 - HER2 +
HER2+/ER- Luminal B Luminal A
Carolina Breast Cancer StudyCarolina Breast Cancer Study
The Carolina Breast Cancer Study (CBCS) is an ongoing population-based epidemiologic study examining the causes of breast cancer in African American and white women.
The study began in 1993 and continued enrolling participants until 2001 (Phase 1 and 2).
We are opening the study again from 2008 to 2012 (Phase 3).
Carolina Breast Cancer Study
Distribution of IHC subtypes in invasive breast cancer
(Phase 1 CBCS) Luminal A (ER+ PR+ HER2-)
51%
Luminal B (ER+ PR+ HER2+)
16%
Basal-like (ER- PR- HER2- ck5/6+ and/or HER1+)
20%
HER2+, ER-(HER2+,ER-, PR-)
7%
Unclassified (negative for all five IHC markers)
6%
Basal-like subtype
Increased proliferation (P < 0.0001)Higher grade (P < 0.0001)Poor differentiation (P < 0.003)P53 mutation positive (P< 0.001)
JAMA 2006, 295: 2492-2502.
Breast Cancer Specific Survival
Mean survival Percent (years) survival
Luminal A 7.6 84%Luminal B 7.7 87%Basal-like 4.9 75%HER2+/ER- 6.7 52%
Log-rank test P < 0.0001
Luminal ALuminal BUnclassifiedBasal-likeHER2+/ER-P <0.0001
Breast Cancer Specific Survival Time in YearsNote: Prior to introduction of herceptin.
Basal-like subtype of breast cancer
No proven therapeutic targets
ER negative, PR negative:Can’t use Tamoxifen or anti-estrogens
HER2 negative:Can’t use Herceptin
Tailored Therapy
ER positive ER negative
HORMONALTHERAPY
HERCEPTIN
EGFR C-kitBRCA1 defective
Gefitinib, erlotinibLapatinibCI-1033
DNA damagePARP inhibitors Imatinib/
Gleevec
Luminal A Luminal B HER2 BASAL-LIKE
BASALTHERAPEUTICTARGETS?
Research Question #2:Why is breast cancer mortality higher among African American women compared with white women?
Younger white women6.3 deaths / 100,000 per year
Younger African American women11.0 deaths / 100,000 per year
Basal-like breast cancer is more common in younger African American women.
Our observation may help to explain why breast cancer mortality is higher among younger African American women.
Distribution of subtypes according to race and menopausal status (CBCS
Phase 1)PremenopausalAfrican American
Postmenopausal African American
PremenopausalWhites
Postmenopausal Whites
Luminal A 36% 59% 51% 58%
Luminal B 9% 16% 18% 16%
Basal-like 39% 14% 16% 16%
HER2+ / ER- 9% 7% 6% 6%
UnclassifiedChi square P = 0.0001
6% 4% 10% 4%
Basal-like breast cancer in North Carolina
(Carolina Breast Cancer Study)
05
1015202530354045
AA < 50 AA >= 50 W < 50 W >= 50
Latest CBCS results
Younger African American women have a higher risk of basal-like breast cancer because they have a higher prevalence of risk factors for the disease:
Higher waist hip ratioHigher parityLower breastfeeding
Several of these risk factors are modifiable.
Breast Cancer Res Trt 2008, 109: 123-139
Public Health Significance
These results stand in stark contrast to recent news commentaries (NY Times, AP, Science) suggesting that basal-like breast cancer represents:
The “exclusive property” of a specific age and racial group.
A disease caused solely by “genetic inheritance.”
Summary• Breast cancer appears to be more than
one disease
• Younger African American women have a higher frequency of basal-like breast cancer, which could contribute to higher breast cancer mortality
• Basal-like breast cancer may be preventable