There are striking disparities in survival rates between Black and white breast cancer patients. Our guest speakers, Christine Ambrosone, PhD, and Song Yao, MD, PhD, have led a team that has done extensive research to understand the causes of why certain cancers are more aggressive in Black women. They have developed a hypothesis that the higher rate of aggressive tumors in Black women when compared with white women might have something to do with their immune systems. We will get updates from their research and how we can work towards eliminating racial gaps in breast cancer survival.

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

2. Breast Cancer in Black Women
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• Historically, breast cancer rates in the US were
highest in White women; but rates have been
changing, leading to more similar breast cancer
rates between the two groups
• More Black women die from breast cancer than
other groups in the US, about 40% higher than
White women

3. Breast Cancer Death Rates by Race/Ethnicity
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Breast Cancer Statistics 2022
CA: Cancer J Clin 2022 Nov;72(6): 524-541

4. Breast Cancer Incidence and Death Rates in US (per 100,000)
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Mortality and incidence rate ratios for Black vs.
White women with breast cancer

5. Breast Cancer in Black Women
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• Black women are more likely than White women to be
diagnosed before age 40; reasons for this are under active
investigation
• Within all age groups, Black women are more likely to die of
breast cancer than White women –
– more than twice as likely to die of their breast cancer if
they are diagnosed younger than age 40

6. Breast Cancer in Black Women
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• Some of higher mortality may be due to less access to
screening (diagnosis at later stages), and less access to
best possible treatments, other social and structural
determinants of health (SSDoH)
– Lack of private insurance
– Receipt of care at low-resourced and/or unaccredited facilities
– Institutional and social contexts
– Neighborhood (social, built and physical environments)

7. Gomez et al 2023, adapted from Warnecke 2008

8. Breast Cancer in Black Women
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• 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

9. Breast Cancer Incidence Rates by Hormone Receptor Status
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Overall Breast Cancer Rates 2000-2019
((average annual percent change)

10. 10
Rates of Triple Negative Breast Cancer by Race

11. 11
Why are these aggressive breast
cancers more common in Black
women??

12. 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?

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

14. • 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

15. Estimating Risk with an Exposure
Odds Ratio: Ratio of risk of disease among those exposed and
risk of disease among those not exposed
Example: Lung cancer and smoking
Lung Cancer
(n=100)
No cancer
(n=100)
Smoking 90 (a) 40 (b)
Non-smoking 10 (c) 60 (d)
Odds Ratio (OR)=a*d/b*c 90*60/40*10 OR=13.5

16. Statistical significance
p values - the probability of having an observed (or more extreme) result if there were
in reality no association at all
(p < 0.05) less than 5% likelihood that the observed association is not true
Doesn’t tell you anything about strength of association
Confidence intervals (CI) - the range in which the true magnitude of an effect lies
with a certain degree of assurance (95% CI = p=.05) “We can say with 95%
confidence that the true risk lays between….
Statistically significant when CI excludes the “null value”; OR =1.00
– width of CI can provide information about sample size; narrow CI reflects less
variability in the estimate of effect and larger sample size
• OR=1.67; 95% CI 1.54-1.71
• wide CI reflects greater variability and small sample size (OR=1.67; 95%
CI 0.65-8.99)

17. 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)

18. 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

19. 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)

20. 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

21. 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

22. Black Women’s
Health Study
(BWHS)
Carolina Breast
Cancer Study (CBCS)
Women’s Circle of
Health (WCHS)
Epidemiology of Breast
Cancer Subtypes in
African-American
Women:
3,698 cases, 14,180
controls
NCI P01 CA151135

23. 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

24. 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

25. Findings from Pathways Heart Study
• Breast cancer survivors experienced elevated risks of diabetes and
hypertension compared with women without breast cancer, depending on
treatments received (chemotherapy, left-sided radiation, endocrine therapy)
and BMI (normal-weight cases at higher risk).

26. Findings from Pathways Heart Study
• Breast cancer survivors had increased incidence of CVD events, CVD-
related mortality, and all-cause mortality compared with women without
breast cancer, and risks varied according to the history of cancer treatment
received (anthracyclines, trastuzumab, radiation therapy, aromatase
inhibitor).

27. • Black women are
at higher risk of
cardiovascular
disease before
breast cancer
diagnosis

28. Black women are at higher risk of cardiovascular disease after breast cancer diagnosis

29. Incident CMD Risk with Race/Ethnicity and Genetic Ancestry
Unadjusted model Adjusted Model Unadjusted model Adjusted Model
sHR (95% CI) P sHR (95% CI) P sHR (95% CI) P sHR (95% CI) P
Black, self-reported African Ancestry, per 25% increment
Any CMD risk factor 1.23 (0.91, 1.65) 0.17 1.25 (0.92, 1.72) 0.16 1.04 (0.94,1.15) 0.42 1.04 (0.94, 1.16) 0.41
Hypertension 1.64 (1.23, 2.20) <0.001 1.69 (1.24, 2.29) <0.001 1.15 (1.05,1.27) 0.003 1.17 (1.06, 1.30) 0.002
Diabetes 2.50 (1.77, 3.53) <0.001 1.74 (1.21, 2.49) 0.003 1.35 (1.22,1.51) <0.001 1.17 (1.05, 1.31) 0.005
Dyslipidemia 0.82 (0.59, 1.13) 0.23 0.83 (0.59, 1.18) 0.30 0.94 (0.85,1.04) 0.25 0.94 (0.84, 1.05) 0.26
Asian, self-reported Asian Ancestry, per 25% increment
Any CMD risk factor 1.01 (0.81, 1.25) 0.94 1.65 (1.30, 2.08) <0.001 0.99 (0.93,1.05) 0.68 1.13 (1.06, 1.20) <0.001
Hypertension 0.83 (0.64, 1.07) 0.15 1.34 (1.02, 1.76) 0.04 0.96 (0.9,1.03) 0.26 1.09 (1.02, 1.18) 0.02
Diabetes 1.97 (1.45, 2.67) <0.001 3.63 (2.59, 5.08) <0.001 1.16 (1.07,1.26) <0.001 1.34 (1.22, 1.47) <0.001
Dyslipidemia 1.05 (0.83, 1.32) 0.70 1.46 (1.14, 1.87) 0.003 1.00 (0.94,1.07) 0.97 1.08 (1.01, 1.16) 0.02
Hispanic, self-reported Native American Ancestry, per 25% increment
Any CMD risk factor 0.88 (0.70, 1.11) 0.28 0.93 (0.73, 1.20) 0.60 0.96 (0.82,1.12) 0.61 0.96 (0.82, 1.13) 0.62
Hypertension 0.92 (0.72, 1.18) 0.51 1.03 (0.79, 1.35) 0.82 0.90 (0.75,1.08) 0.26 0.96 (0.79, 1.16) 0.66
Diabetes 2.15 (1.58, 2.92) <0.001 2.19 (1.58, 3.04) <0.001 1.53 (1.27,1.85) <0.001 1.61 (1.30, 1.99) <0.001
Dyslipidemia 1.00 (0.78, 1.27) 0.97 1.03 (0.79, 1.34) 0.83 1.01 (0.85,1.19) 0.92 1.01 (0.85, 1.21) 0.91

30. Incident CVD Risk with Race/Ethnicity and Genetic Ancestry
Unadjusted model Adjusted Model Unadjusted model Adjusted Model
sHR (95% CI) P sHR (95% CI) P sHR (95% CI) P sHR (95% CI) P
Black, self-reported African Ancestry, per 25% increment
Any CVD 1.33 (1.02, 1.73) 0.04 1.35 (1.02, 1.78) 0.03 1.09 (1.00, 1.19) 0.04 1.09 (1.00, 1.19) 0.05
Serious CVD* 1.17 (0.86, 1.59) 0.31 1.17 (0.85, 1.62) 0.33 1.08 (0.98, 1.18) 0.13 1.06 (0.96, 1.17) 0.27
Arrhythmia 0.97 (0.67, 1.41) 0.89 1.09 (0.74, 1.60) 0.67 0.99 (0.88, 1.12) 0.88 1.01 (0.89, 1.15) 0.85
Heart failure or
cardiomyopathy
1.87 (1.27, 2.77) 0.002 1.57 (1.04, 2.39) 0.03 1.23 (1.09, 1.39) <0.001 1.12 (0.98, 1.28) 0.09
Ischemic heart disease 1.78 (1.12, 2.84) 0.02 1.80 (1.10, 2.94) 0.02 1.25 (1.08, 1.44) 0.002 1.23 (1.06, 1.43) 0.007
Stroke 0.76 (0.33, 1.76) 0.53 0.89 (0.38, 2.09) 0.79 0.98 (0.77, 1.26) 0.90 1.04 (0.81, 1.35) 0.75
Venous thromboembolic
disease
1.76 (1.15, 2.67) 0.008 1.52 (0.97, 2.37) 0.07 1.18 (1.03, 1.35) 0.02 1.11 (0.96, 1.28) 0.16
CVD-related death 0.69 (0.34, 1.42) 0.32 1.69 (1.25, 2.30) <0.001 0.91 (0.73, 1.14) 0.42 0.92 (0.73, 1.16) 0.47

31. 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

32. 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?

33. More Exhausted Immune Cells in Breast Tumors in Black Patients
• Immune cells surround breast tumors in Black patients are more likely
to be “exhausted”
Yao, et al., Ambrosone. JNCI 202

34. • 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 202
More Exhausted Immune Cells in Breast Tumors in Black Patients

35. • 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

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

37. Immune Checkpoint Inhibitors for Breast Cancer
Keynote 355 Trial - metastatic TNBC Keynote 522 Trial - early TNBC

38. Immune Checkpoint Inhibitors for Breast Cancer
Keynote 355 Trial - metastatic TNBC

39. Immune Checkpoint Inhibitors for Breast Cancer
Keynote 522 Trial - early TNBC

40. Better Benefits of Black Patients on ICIs?
• Higher sTILs in Black patients (median
40% vs 15%, P=0.048)
• Higher pCR in Black patients (79% vs.
53%, P=0.049)

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

42. DiRECT Cohort Enrollment

43. DiRECT Cohort Enrollment
Black (n = 209) White (n = 707)
Age at diagnosis, median (range),
years
62 (31-85) 66 (21-93)
Sex, n (%)
Male 78 (38) 345 (49)
Female 129 (62) 352 (51)
Hispanic ethnicity, n (%)
Yes 4 (2) 12 (2)
No 194 (93) 679 (96)
Unknown 11 (5) 16 (2)
Cancer Type, n (%)
Lung 70 (36) 257 (39)
Breast 54 (27) 100 (15)
Kidney/GU 12 (6) 109 (16)
GI 17 (9) 41 (6)
GYN 17 (9) 40 (6)
Liver 10 (5) 42 (6)
Head and Neck 6 (3) 24 (4)
Other 11 (6) 48 (7)

44. Key Takeaways
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• 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
• Black women are at higher risk of cardiovascular
disease before breast cancer diagnosis; the higher
risk continues after breast cancer treatment

45. Questions
Questions
Thank
You!
45