Black women experience higher rates of breast cancer and mortality compared to other groups in the US. Some factors that may contribute include less access to screening and treatment, as well as a higher frequency of more aggressive tumor subtypes like triple negative breast cancer. Research has found Black women are also more likely to be diagnosed with breast cancers that have exhausted immune cells surrounding the tumor. Factors like ancestry, a stronger pro-inflammatory response, lower breastfeeding rates, and lower vitamin D levels may all play a role in the increased aggressiveness seen in Black women's breast cancers. Ongoing research aims to better understand and address these disparities.

1. Christine Ambrosone, PhD
Song Yao, PhD
Aggressive Breast Cancers in
Black Women

2. Breast Cancer in Black Women
2
Increase Team Science Project
• Historically, breast cancer rates in the US
were highest in white women, but rates have
been changing, with more breast cancer
experienced by Black women
• More Black women die from breast cancer
than other groups in the US

3. Breast Cancer Incidence and Death in US
3
Increase Team Science Project

4. Breast Cancer in Black Women
4
Increase Team Science Project
• Some of higher mortality may be due to less access to
screening (later stage at diagnosis), and less access to
best possible treatments
• Black women more often diagnosed with tumors that
are more aggressive, and have worse outcomes
– Lack receptors for estrogen (ER), progesterone (PR) and HER2
(Triple Negative Breast Cancer (TNBC))
– No targeted therapies available for TNBC, such as tamoxifen
and aromatase inhibitors

5. Breast Cancer Subtypes in the US
5
Increase Team Science Project

6. 6
Why are these aggressive breast
cancers more common in Black
women??

7. Funded by:
DOD DAMD17-01-1-0334 (2001-2006)
NCI R01 CA 100598 (2003 – 2011)
Breast Cancer Research Foundation
(2008- )
NCI P01 CA151135 (2011 – 2016)
Women’s Circle of Health Study
Christine Ambrosone, PhD
Elisa Bandera, MD, PhD (CINJ)

8. • In the past, majority of studies examined overall breast
cancer risk, not by ER status
• Studies were conducted mainly in populations of older
white women (@90% are ER+) – so ‘known’ risk factors
apply primarily to ER+ disease
• It was unknown if risk factors differed by ER status, or
if there were differing risk factor profiles for Black
women
Risk factors for aggressive breast cancer

9. Increased risk with:
• Family history of breast cancer
• Radiation exposure (atom bomb, radiation treatment to
the chest)
• Hormone replacement therapy
• Alcohol consumption
• Overweight in postmenopausal women
• Sedentary behavior (low physical activity)
What do we know about causes of breast cancer?

10. Reduced risk with:
• Later age at menarche
• Having children (parity)
– Earlier age at first birth
• Early age at menopause
Reproductive Risk Factors

11. Parity and Breast Cancer Subtypes
Case-control
analysis
Luminal A
(ER+)
OR (95% CI)
Basal-like
(TNBC)
OR (95% CI)
No children
1
2
3+
1.0
0.7 (0.5-1.0)
0.7 (0.6-1.0)
0.7 (0.5-0.9)
1.0
1.7 (0.9-3.0)
1.8 (1.1-3.1)
1.9 (1.1-3.3)
Carolina Breast Cancer Study Millikan, Br Ca
Trt Res 2008

12. Breastfeeding and Reduced Risk of TNBC
Millikan, Br Ca Trt Res 2008
Carolina Breast Cancer Study
Luminal A
OR (95% CI)
Basal-like
OR (95% CI)
Parity and
breastfeeding
No children
1-2, never
3+, never
1-2, ever
3+, ever
1.0
0.7 (0.6-0.9)
0.7 (0.5-0.9)
0.7 (0.5-0.9)
0.7 (0.5-0.9)
1.0
1.8 (1.1-3.0)
1.9 (1.1-3.3)
1.1 (0.6-2.0)
1.3 (0.7-2.3)

13. Parity, Breastfeeding and Aggressive Breast Cancer
• Millikan paper received no publicity, people were not
aware of the findings
• Black women more likely to have children at a
younger age, more children, and less likely to
breastfeed
• Important for public health (Black as well as white
women) to reduce risk of poor prognosis breast
cancer through breastfeeding

14. Aggressive Breast Cancer in Black Women
• Subsequent fairly small studies (WCHS, Black
Women’s Health Study (BWHS), others) replicated
findings
• Still not incorporated into thinking about risk factors
for breast cancer subtypes
• Need for large study, pooling data from multiple
studies, to confirm associations and get the word
out

15. Black Women’s
Health Study
(BWHS)
Multi-Ethnic Cohort (MEC)
Carolina Breast
Cancer Study (CBCS)
Women’s Circle of
Health (WCHS)

16. Aggressive Breast Cancer in Black Women
NCI P01 CA151135
Epidemiology of Breast Cancer
Subtypes in African-American Women:
AMBER Consortium
3,698 cases
14,180 controls

17. Parity, Breast Feeding and Aggressive Breast Cancer in AMBER Consortium
Palmer et al, JNCI 2014
ER+ n=2,450
ER- n=1,254
For ER- breast cancer,
highest risk for parous
women who never
breastfed
As in Millikan study,
reduced risk of ER+
disease with parity,
regardless of
breastfeeding

18. Brainstorming Across Disciplines (and over drinks)
Roswell epidemiologists and immunologists
(Kelvin Lee, Kunle Odunsi)

19. Breast Cancer in African-American Women: an evolutionary perspective
• Evolution over millennia - numerous differences between
populations from different continents of origin
• Adaptation to endemic infectious disease (protozoa and helminths)
in sub-Saharan Africa – robust immune/inflammatory responses
• Increases likelihood of surviving reproductive years, but may be
maladaptive in Western, modern society – relationship to cancer –
more aggressive disease?
• Project 4 in AMBER Consortium P01

20. Ancestral Differences in Systemic Immune Responses
Quach et al. Cell
2016
Nédélec et al. Cell
2016
Ye et al. Science 2014
• Immune responses differ by ancestry; A substantial degree of the observed
population differences in immune responses are under genetic control
• Regulatory genetic variants associated with population differences in immune
responses are enriched for recent natural selection signatures of human adaption

21. AMBER: Influence of Ancestry, Environment and
Genetics on Circulating Cytokines
• Measured panel of 14 chemokines and
cytokines in serum from controls from CBCS
and WCHS;
• 914 AA, 855 EA
• After controlling for multiple comparisons
and technical variables, significant differences
• CCL11, CCL2, IL10, IL4 – higher in Blacks
• INFα2, IL1RA, TNFα – higher in Whites
Yao, Hong, et al., Ambrosone. PLoS Genet

22. Influence of Ancestry, Environment and Genetics on
Circulating Cytokines
• Population differences in levels of
cytokines, many accounted for by lifestyle
factors
• Strong ancestral component to serum levels
of CCL2, CCL11 (key chemokines regulating
migration of WBCs, role in inflammation)
• Variant in Duffy antigen receptor
responsible for ancestral differences– null in
Blacks, results in loss of protein on RBC, loss
of buffering function for chemokine levels
Yao, Hong, et al., Ambrosone. PLoS Genet

23. What does this mean for breast cancer?
• Back to key question – could prolonged and
heightened inflammatory response in Blacks lead to
tumors co-evolving in this milieu to evade immune
surveillance, resulting in more aggressive breast
cancer

24. Stronger Immune Cell Presence in Breast Tumors in Black Patients
• Black breast cancer patients have more immune cells present in the
regions surrounding the tumor
# events/total HR (95% CI) p-value
a. All-cause mortality
Per 10% increase in TIL score 104/688 0.86 (0.78-0.95) 0.003
TIL score in categories
<10% 31/197 1.00
10-50% 60/382 0.71 (0.45-1.12) 0.14
50-100% 13/109 0.38 (0.19-0.76) 0.006
b. Breast cancer-specific mortality
Per 10% increase in TIL score 71/688 0.87 (0.78-0.98) 0.02
TIL score in categories
<10% 18/197 1.00
10-50% 44/382 0.84 (0.48-1.49) 0.56
50-100% 9/109 0.43 (0.18-1.00) 0.05
Yao, et al., Ambrosone. JNCI

25. More Exhausted Immune Cells in Breast Tumors in Black Patients
• But the immune cells surround breast tumors in Black patients are
more likely to be “exhausted”
Yao, et al., Ambrosone. JNCI

26. • Immune cell exhaustion associated with poor patient survival
• Black breast cancer patients had the highest rate of tumors surrounded
by exhausted immune cells
Yao, et al., Ambrosone. JNCI
More Exhausted Immune Cells in Breast Tumors in Black Patients

27. • An NCI-funded study to
understand lifestyle,
stress, immunity and
breast cancer outcomes
(PI: Ambrosone)
• Currently enrolling Black
and white breast cancer
patients through New York
Cancer Registry
Ongoing Study to Understand Stress, Tumor Immune Contexture, and
Breast Cancer Disparities

28. What Does This Mean for Patients on Cancer Immunotherapy?

29. A New Nation-Wide Study on Response and Toxicities to Cancer
Immunotherapy between Black and White Patients
• Disparities in REsults of Immune Checkpoint Inhibitor Treatment
(DiRECT) (PIs: Yao [Roswell Park], Kamen [University of Rochester])

30. A New Nation-Wide Study on Response and Toxicities to Cancer
Immunotherapy between Black and White Patients

31. Skin Pigmentation and Vitamin D
Sturm 2009; Hum Mol Genet 18:R9-R17

32. Skin Pigmentation and Vitamin D
Yao et al. Ambrosone. Am J Clin Nutr.
•Project 4 in AMBER Consortium
P01

33. Lower Vitamin D Levels at Diagnosis Associated with Poor Survival
• 3,995 breast cancer patients with a
median of 10-years follow up from the
Pathways Study (PIs: Kushi [Kaiser
Permanente], Ambrosone [Roswell
Park])
• Patients with deficient vitamin D levels
at diagnosis had significantly poorer
survival than those with sufficient
vitamin D levels.

34. Lower Vitamin D Levels in Black Breast Cancer Patients
• Lower vitamin D levels in black breast cancer patients may contribute to
their poorer survival outcomes

35. Key Takeaways
35
Increase Team Science Project
• Black women have more aggressive breast cancer and
higher death rate from the disease
• Breast-feeding lowers the risk of more aggressive
breast cancer
• Stronger pro-inflammatory immune response
contributes to more aggressive breast cancer in Black
women, which may be targeted by immunotherapy
• Maintaining sufficient vitamin D levels may be
beneficial after breast cancer diagnosis, particularly
for Black women

36. Questions
Questions
Thank
You!
36