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