‘Powerful clues’ show tumor biology contributes to racial disparities in mortality

Black individuals with cancer are 25% more likely to die of their disease than white patients.

Although persisting across tumor types, this disparity is particularly evident among black women, whose population-based breast cancer mortality rate is 42% higher than white women, and among black men with prostate cancer, who are more than twice as likely to die as white men.

For decades, researchers attributed higher mortality rates to socioeconomic factors such as inadequate health insurance, fewer years of education and lower income. However, research now supports the hypothesis that tumor biologic differences among blacks could have a greater impact on response to treatment and outcomes.

“I do not dispute that socioeconomic disadvantages are always going to play a huge role in terms of access to care and, ultimately, outcomes from any health threat,” Lisa A. Newman, MD, MPH, FACS, director of the breast oncology program at Henry Ford Health System, told HemOnc Today. “But, when it comes to breast cancer, there are so many powerful clues suggesting the contribution of tumor biology linked to African ancestry that it’s bad science for us to close our eyes to it and not explore it fully.”

Source: Henry Ford Health System.

However, large clinical trials that recruit, retain and follow minorities for extended periods are needed to further explore this association.

“This is not straightforward, but rather a very complex issue we’re dealing with,” John D. Carpten, PhD, professor and chair of translational genomics and director of Institute of Translational Genomics at Keck School of Medicine of University of Southern California, told HemOnc Today. “We’re starting to see that it’s not one size fits all. It’s likely certain cancer disparities will be associated with socioeconomics and some will be associated with biologic differences associated with race and ancestry.

“Perhaps even more interesting, some disparities are a function of environmental stressors influenced by race that affect biology,” Carpten added. “Although we need to disentangle these factors, we also have to consider how they coalesce to drive cancer disparities.”

HemOnc Today spoke with oncologists, researchers and epidemiologists about the biologic differences that may lead to worse outcomes among black patients with breast, prostate, lung or colorectal cancers; efforts to develop precision medicine strategies to identify and treat those mutations; and disparities that exist in the treatment approaches for black patients.

A call to action

Newman was troubled by the number of black women presenting with advanced breast cancer when she began practicing as a general surgeon in Brooklyn in the 1990s.

“What became apparent to me in my daily practice was that my black patients with breast cancer tended to be younger when they were diagnosed, and they had more advanced-stage, aggressive and difficult-to-treat cancers,” Newman said. “That’s what motivated me to become involved with research.”

After 7 years as a general surgeon, Newman completed a surgical oncology fellowship at The University of Texas MD Anderson Cancer Center and received her master’s degree at Harvard School of Public Health, launching a research career dedicated to discovering the genetic connection between black women and triple-negative breast cancer.

“There were certainly others who also speculated that African-American identity and African ancestry were associated with ‘bad-biology’ breast cancers, but it was not widely accepted in the 1990s,” Newman said. “Many emphatically refuted that possibility and expressed the opinion that breast cancer disparities and race/ethnicity-associated differences were exclusively explained by socioeconomic inequities.”

These differences persist today — 2017 SEER data showed the average age at breast cancer diagnosis is 58 years for black women compared with 62 years for white women. Further, between 30% and 40% of black women with breast cancer are diagnosed when aged younger than 50 years compared with 20% of white women.

In a study published this year in Journal of Clinical Oncology, Jemal and colleagues estimated how differences in demographics, comorbidity, insurance, tumor characteristics and treatment impacted the 42% mortality disparity between 78,737 black and 484,760 white nonelderly women with early-stage breast cancer.

Hormone receptor-positive breast cancers — which accounted for 78.5% of all diagnoses — occurred more frequently among white women (80.7% vs. 64.8%). However, black women with this subtype had an increased risk for death in a demographics-matched model (HR = 2.05; 95% CI, 1.94-2.17).

Researchers estimated that differences in insurance — about 22.7% of nonelderly black patients were uninsured or had Medicaid vs. 8.4% of nonelderly white patients — explained about 37% of the excess risk for death among black women. Differences in tumor characteristics represented 23.2% of the excess risk for black women, whereas comorbidities accounted for 11.3% and treatment accounted for 4.8% of excess risk.

“Although death rates are going down for both whites and blacks, that [42%] differential remains,” Julie R. Palmer, ScD, associate director of Boston University’s Slone Epidemiology Center, professor of epidemiology at Boston University School of Public Heath, and associate director for population sciences at the BU-BMC Cancer Center, told HemOnc Today. “Differences in access to care and the type of care people receive make a difference, but that’s only part of the reason for the disparity. Black women are almost twice as likely to be diagnosed with the more aggressive hormone receptor-negative subtype as white women.”

Jemal and colleagues showed that 35.7% of black women diagnosed with breast cancer had the more aggressive hormone receptor-negative subtype, compared with 19.3% of white women.

Environmental factors such as age at menarche, breastfeeding and the number of child births influence risk for ER-negative breast cancer.

“We have shown that women who have more children and do not breastfeed have higher incidences of ER-negative breast cancer,” Palmer said. “Earlier age at menarche also carries increased risk for breast cancer, and age at menarche on average is earlier among black women than white women.”

Increasing the number of women who breastfeed is easily modifiable, Palmer said, but there needs to be an institutional commitment to make it feasible for all women.

“Women in low-wage occupations who need to return to work 4, 8 or 12 weeks after having a baby need to have a room in their workplace that allows them to pump their milk,” Palmer said. “Not all of them are given the space and time to do that.”

Palmer co-authored a 2017 study published in Cancer Research that showed black women with type 2 diabetes had a significantly increased risk for ER-negative breast cancer (HR = 1.42; 95% CI, 1.03-2), but not ER-positive cancer.

“Black women are twice as likely to have type 2 diabetes as white women; if the results are confirmed in future research, improved monitoring of blood sugar levels to identify women with prediabetes could provide opportunities for reduction of the incidence of ER-negative breast cancer,” Palmer said.

Still, Newman believes that, even if socioeconomic disparities were not a factor in the treatment of breast cancer, black women would likely have a 25% greater mortality rate than white women because of tumor biology.

“It certainly wouldn’t be 42%,” she said. “Studies bear this out. Even when adjusting for socioeconomic and treatment factors, you continue to see gaps in survival between blacks and whites.”

Triple-negative breast cancer

Triple-negative breast cancer also is a marker of hereditary susceptibility for breast cancer, regardless of family history.

This subtype occurs disproportionately among younger women, it is more likely to metastasize to the brain, and patients who do not achieve a complete response to neoadjuvant chemotherapy have disproportionately high relapse and mortality rates.

In a 2017 study published in CA: A Cancer Journal for Clinicians, Newman and colleagues reported that black women are twice as likely to be diagnosed with this subypte (24 vs. 12 incidences per 100,000). Researchers also found that black women had lower proportions of localized breast cancers than white women (55% vs. 65%) and higher proportions of regional-stage (34% vs. 27%) and distant (9% vs. 5%) disease.

For the past 14 years, Newman has been principal investigator for an international breast registry — now part of Henry Ford Health System’s International Center for the Study of Breast Cancer Subtypes — through which researchers compare tumor patterns of black and white U.S. women with women from western Africa (Ghana) and eastern Africa (Ethiopia).

Newman and colleagues found the highest frequency of triple-negative breast cancer among Ghanaian women, for whom about half of the tumors were triple negative, and the lowest frequencies — around 15% — among Ethiopians and white Americans. Prevalence of the triple-negative phenotype in their comparison black U.S. patients was about 30%.

“We hypothesize that these variations in distribution of triple-negative breast cancer are related to a germline genetic pattern associated with western, sub-Saharan African ancestry,” Newman said. “African-Americans have more shared ancestry with Ghanaians compared with Ethiopians because the colonial-era trans-Atlantic slave trade resulted in the forced migration of western, sub-Saharan Africans to the Americas. In contrast, the East African slave trade was largely dominated by forced migration further eastward to the Mideast and Asia.”

Newman’s ongoing studies have expanded to involve collaborations with other countries in Africa and the Caribbean, as well as the diverse patient population of metropolitan Detroit.

“We are extremely excited about our planned studies utilizing ancestry-informative markers and gene expression profiling to tease out associations between western, sub-Saharan African ancestry and risk for triple-negative breast cancer,” Newman said.

In 2016, the NCI provided a $12 million grant to launch the largest single study — Breast Cancer Genetic Study in African-Ancestry Populations — to investigate how genetic and biologic factors contribute to the risk for breast cancer among black women. Researchers will pool specimens and data from 18 previous studies representing more than 20,000 black women.

Recruiters ‘have to do better’

Compared with white men, black men are nearly 60% more likely to be diagnosed with prostate cancer and 2.4 times more likely to die of the disease, according to studies published in BioMed Central Urology and Cancer.

Black men also appeared three times more likely than white men to have advanced, aggressive prostate cancer.

In a modeling study published last year in Cancer, Tsodikov and colleagues estimated that 30% to 43% of black men develop asymptomatic prostate cancer by the age of 85 years, compared with 24% to 29% of all men. This difference equated to a 28% to 56% increased risk for preclinical prostate cancer for black men compared with men of other races. Researchers also determined black men were more likely to experience progression to metastatic disease.

Further, data from the American Cancer Society showed one in six black men were diagnosed with prostate cancer in 2016, and one in 23 died of the disease.

“The reasons are unclear but, with time, they will become clearer,” Peter R. Carroll, MD, MPH, professor and chair of urology at University of California, San Francisco, told HemOnc Today. “We’re not there yet but, in this march toward precision medicine, we may be able to look simultaneously at environmental causes and biology. There will come a time when medicine will be so precise that risk will be analyzed more at the biologic and environmental level, including access to and quality and type of care, rather than by broad phenotypic descriptions such as simply black or white.”

It is also important to recognize that there is considerable variation in risk within populations, Carroll added.

Like Newman’s research into the biologic makeup of breast cancer tumors among women living in Africa, Edward M. Schaeffer, MD, PhD, department chair of urology and professor of urology at Northwestern University Feinberg School of Medicine, is studying genomic markers in black men from West Africa with prostate cancer.

In an interview with HemOnc Today last year, Schaeffer said that, unlike white men, black men tend to present with high-grade cancers at the top or anterior region of the prostate — farthest from the rectum — making them increasingly difficult to detect. That, he said, could be one reason more black men present with advanced-stage disease.

Carroll said he has not seen that same phenomenon in his research.

“This is a great example of where we need to pool data from several sources,” Carroll said. “Those same researchers found that African-American men had a higher likelihood of adverse pathology when they underwent surgery for low-risk disease. When we looked at that in two other large cohorts, we did not see that effect. We need a large enough cohort so that we can be sure we are seeing a real effect.”

Certain inherent single nucleotide polymorphisms have been identified in some black populations that may predispose them to prostate cancer, according to Eric A. Klein, MD, chairman of Glickman Urological and Kidney Institute at Cleveland Clinic.

“We haven’t identified the specific genomic differences between some populations, but I’m impressed with our ability to sequence DNA,” Klein said in an interview. “I don’t think there is any clinical actionability yet, but as the power of sequencing technology expands and gets refined, we’re seeing some interesting signals.”

To make prostate cancer research actionable, a study needs to be designed to assess determinants in different subpopulations, Klein said.

“It’s not restricted to African-Americans vs. Caucasians,” he said. “The incidence of prostate cancer in Asia is far lower than it is in the Western world. To me, the question is, are genomic determinants different in subpopulations around the world?”

A major stumbling block in the treatment of prostate cancer is that therapy that helps control disease for white men is not as effective for all black men.

According to a 2016 study by Kovtun and colleagues published in Cancer, black men with low-risk or favorable intermediate-risk prostate cancer who received androgen deprivation therapy had increased risk for all-cause mortality (adjusted HR = 1.77; 95% CI, 1.06-2.94) and other-cause mortality (adjusted HR = 1.86; 95% CI, 1.08-3.19) compared with nonblack men. Because this association did not persist among men who did not receive ADT, the researchers concluded ADT should be reserved for black men with high-risk disease.

In that study, however, black men comprised only 7.3% of the study cohort of 7,252 men.

In an international study assessing the representation of black men in clinical trials, researchers found from 1991 through 2015, only 19% of prostate cancer clinical trials worldwide and 43% of trials in the United States reported the inclusion of black men. Of those trials that included black men, the median percentage of the black study population was 10.5% overall and 12.3% in the United States.

“We have to do better when it comes to recruiting black men,” Carpten said. “There is limited education in many underrepresented communities regarding the risks and benefits of clinical trials. This needs to be addressed.

“But, part of the problem is that the individuals who are running these trials know they’ll get the funding if they accrue to the trial,” Carpten added. “There has been no accountability — and I don’t know if there ever will be — to say that you only get funding if you ensure that the clinical trial cohort is diverse. They should be strategically accruing in a way to ensure they have adequate representation, so we can better understand the importance of these biomarkers across individuals who are more diverse.”

Another issue facing oncologic urologists is the reliability of genomic testing for black men.

The NIH funded a study for which researchers are testing Oncotype DX (Genomic Health) — widely used for breast cancer — to see if its prostate cancer assay performs differently for 100 black men from three institutions than it does for white men.

“In high-level academic circles, clinicians don’t make a decision on chemotherapy for patients with breast cancer without one of those tests,” Klein said. “We’re not there yet in prostate cancer, but I don’t doubt that sometime in the relatively near future, additional genomic testing is going to be useful.”

According to Klein, Genomic Health is expected in 2018 to unveil a circulating tumor cell assay for men with metastatic castration-resistant prostate cancer that can determine whether a patient will respond better to enzalutamide (Xtandi; Astellas, Pfizer) or abiraterone (Zytiga, Janssen Biotech), or whether they may be resistant to those therapies and should be treated with chemotherapy.

“Theoretically, we’ll be able to do dynamic monitoring that tells us if there is a resistant clone, allowing us to switch treatments before the patient has any sign of progression of his cancer,” Klein said. “That’s exciting.”

Although large-scale studies on the biologic makeup of prostate tumors are lacking, studies suggest black men are still treated differently.

A 2017 study by Friedlander and colleagues, published in European Urology, showed 39% of treatment facilities delivered significantly higher rates of definitive therapy to white men, whereas only 1% favored black men. Overall, 83% of white men followed from 2004 through 2013 received definitive therapy, compared with 74% of black men.

In addition, data from the CaPSURE study, published in Journal of Clinical Oncology, showed black men were less likely to receive surgery than white men with similar disease characteristics, less likely to have radical prostatectomy than radiation therapy or ADT, and more likely to have treatment-related side effects.

There are two possible reasons for treatment disparities, according to Carroll.

“One is that physicians may treat black men differently, either by their perceived preference or an actual bias,” Carroll said. “The other is that certain populations of men, whether African-American or others, perceive treatment differently — its effectiveness and also its risks. There may be a preference toward noninvasive treatment based on perceived risks of surgery vs. radiation therapy.”

Carroll said some urologists believe that black men with low-risk prostate cancer should not be offered active surveillance.

“We reject that,” he said. “Ethnicity is one risk factor, but it may not be the only risk factor. The key is not to treat based on race alone. Clinicians need to offer patients, whether white or black, the best evidence on which to base treatment.”

Researchers said they also need more evidence that shows which treatments work better in black men with prostate cancer. Duke University Medical Center is recruiting 50 black men and 50 white men with metastatic castration-resistant prostate to prospectively estimate their median PFS after receiving apalutamide (ARN-509, Janssen), abiraterone and prednisone.

Lung, colorectal cancers

Disparities between white and black patients are not limited to breast and prostate cancers.

Significant mortality disparities also are evident in lung cancer, in which black men are 20% more likely to die than white men, and colorectal cancer, in which death rates are 52% higher among black men and 41% higher among black women.

Although research shows the disparity in lung cancer incidence rates between black and white men has narrowed in recent years, black men were 18% more likely to be diagnosed with cancer of the lung and bronchus between 2008 and 2012, according to ACS data.

Black women appeared 13% less likely to be diagnosed with lung and bronchus cancer than white women, but were less likely to achieve 5-year survival (14.5% vs. 18.3%).

“Although they are diagnosed less often, African-American women still seem to do worse with a lung cancer diagnosis than men,” Carpten said.

Unlike breast and prostate cancers, researchers have shown little evidence of genomic variations between lung cancer tumors in blacks and whites.

A 5-year study by Campbell and colleagues and published in JAMA Oncology showed genomic alterations appeared similar in black and white patients with lung adenocarcinoma and lung squamous cell carcinoma, suggesting that different mutational profiles do not contribute to the increased incidence of lung cancer in black men.

“What we do know is that, in studies looking at the genomic profiles of lung cancer tumors, there do not seem to be significant differences in the key drivers of lung cancer in whites and blacks,” Carpten said. “It could mean the disparities we see in lung cancer are more related to socioeconomics or access to care. But, more research needs to be done to reach that conclusion definitively. Another issue is that we also may have to look beyond the genome and look at other biological and physiological processes across diverse cohorts of patients.”

Researchers have also investigated the role of cotinine, a byproduct of nicotine that remains in the bloodstream after smoking, especially for menthol cigarettes. Black smokers tend to have higher levels of cotinine in their blood than white smokers, possibly because of the way nicotine is metabolized. This could lead to higher exposure to nicotine and other tobacco carcinogens, according to a report by the American Lung Association.

Further, Berg and colleagues found a genetic marker — UGT2B10 haplotype — is associated with cotinine levels and occurs at greater frequency among black individuals.

“There are aspects related to smoking menthol cigarettes and addiction rates among African-Americans and that might have a lot to do with the [survival] disparity, but many of those studies are controversial,” Carpten said.

According to the American Lung Association, money spent by magazines advertising menthol cigarettes aimed toward black patients increased from 13% in 1998 to 49% in 2005. Further, a report from the Substance Abuse and Mental Health Services Administration noted that nearly 83% of black smokers aged 12 years and older choose menthol cigarettes, compared with 24% of white smokers.

However, smoking prevalence has decreased more rapidly among blacks aged 25 to 34 years than among their white counterparts. If those trends continue, researchers believe racial differences in lung cancer mortality among men should be eliminated within 40 to 50 years.

Although white individuals had higher colorectal cancer incidence rates prior to 1989, incidence rates are now 27% higher among black men and 22% higher among black women, according to the ACS.

However, the mortality gap has been narrowing — from 2008 to 2012, annual declines in mortality rates appeared similar among black and white men (2.7% vs. 2.6%), and slightly larger among black women than white women (3.3% vs. 2.9%).

Differences may stem from the use of colonoscopy.

“One of the only screening tools we have that can increase OS is the colonoscopy,” Carpten said. “There is evidence that African-Americans are less likely to get colonoscopies in general, and much less at an earlier age than the recommended 50 years. This could drive the cancers to be diagnosed once they are more aggressive, making them much more difficult to treat.”

In 2017, the United States Multi-Society Task Force on Colorectal Screening released new recommendations, stating that blacks should begin screening at age 45 years, compared with 50 years for other groups.

From a genomic standpoint, research from Guda and colleagues revealed that two predominant genes, ephrin type A receptor 6 (EPHA6) and folliculin (FLCN), have mutations exclusive to colorectal cancer among black individuals, and are highly likely driver genes in black populations.

“In collaboration with University of Illinois Chicago, University of Arizona and Yale University, we have unpublished data that also suggest there are some genomic differences in mutations derived from black and white colorectal cancers,” Carpten said. “However, the overall numbers of tumors profiled from African-American patients, even collectively, remain significantly smaller than cohorts derived from largely European patients. Only with additional focused research will we address these issues once and for all.”

‘Melting pot’ of genomics

Many oncologists believe genomic biomarkers in prostate and breast cancers will determine treatment for individuals and that, in the near future, precision medicine will become standard of care in those two diseases.

“This train has left the station and it’s going to continue to power on,” Klein said. “We now have targeted therapies for disease that traditionally had been resistant to treatment. It’s very clear in clinical practice that by using sequencing information we help some patients — even if it’s 5% to 7% of patients — who we otherwise would not have helped.”

Klein believes that within 5 years, liquid biopsies will determine not only who is most likely to be diagnosed with cancer, but how that cancer will be treated.

“Screening will be deciding the aggressiveness of therapy,” he said. “There are already some gene signatures in prostate cancer that are starting to tell us who’s going to respond to radiation therapy and who’s going to be resistant to radiation therapy. In the near future — I would predict sooner than 5 years — we’ll be using that information to decide who gets radiation and who gets surgery.”

Although socioeconomics may always play a role in the disparity of health care in the United States, if enough research is devoted to genomics, the mortality disparity could close significantly within the next decade.

“I don’t want to paint the picture that everybody completely accepts the correlation between African ancestry and breast cancer biology, because there are many who continue to refute these associations, even though the science clearly demonstrates a correlation,” Newman said. “America is a big melting pot, and so we have genetic admixture when it comes to racial-ethnic backgrounds. This is where the science of genotyping and ancestry-informative markers can be especially valuable in trying to scientifically define geographically based ancestry compared with what may or may not be available in family history information.”

U.S. Census data show the number of Americans who self-identify as biracial more than doubled from 2000 to 2010, suggesting genetic admixture is increasing.

This could impact the accuracy of self-identifcation reporting.

“Self-reported African-American identity tends to correlate well with a predominance of African ancestry, but contributions of non-African heritage — including European and/or Native American — can approach 50% in some individuals who self-identify as being African-American,” Newman said. “Quantified data correlating heritage with cancer susceptibility patterns will, therefore, become increasingly more important than self-identification as one single racial/ethnic profile — which is the way that most cancer registries currently categorize patients.”

There also exists a tremendous amount of heterogeneity in the population genetics of Africa, she added.

“But if we study those diverse genetics and compare them with African-American men and women, we’ll then be able to correlate genetic signatures with cancer patterns,” Newman said. “This should be a key focus for international collaborations, and these research partnerships are also capacity-binding for routine cancer care in under-resourced countries. When we get a handle on disease genetics in diverse populations, we are in a better position to treat biologically aggressive patterns more definitively.” – by Chuck Gormley

Click here to read the , “Should different prostate cancer screening guidelines exist for black men?”

References:

American Cancer Society. Cancer Facts & Figures for African Americans 2016-2018. Available at: www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/cancer-facts-and-figures-for-african-americans/cancer-facts-and-figures-for-african-americans-2016-2018.pdf. Accessed on Dec. 28, 2017.

American Lung Association. Too many cases, too many deaths: Lung cancer in African Americans. Available at: www.lung.org/assets/documents/research/ala-lung-cancer-in-african.pdf. Accessed on Dec. 28, 2017.

Berg JZ, et al. J Pharmacol Exp Ther. 2010;doi:10.1124/jpet.109.159855.

Campbell JD, et al. JAMA Oncol. 2017;doi:10.1001/jamaoncol.2016.6108.

Chen RC, et al. Cancer. 2013;doi:10.1002/cncr.27975.

DeSantis CE, et al. CA Cancer J Clin. 2017;doi:10.3322/caac.21412.

Friedlander DF, et al. Eur Urol. 2017;doi:10.1015/j.euro.2017.07.023.

Guda K, et al. Proc Natl Acad Sci U S A. 2014;doi:10.1073/pnas.1417064112.

Howlader N, et al. SEER Cancer Statistics Review, 1975-2014. NCI. Available at: seer.cancer.gov/csr/1975_2014/. Accessed on Dec. 28, 2017.

Jemal A, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2017.73.7932.

Kovtun KA, et al. Cancer. 2016;doi:10.1002/cncr.30224.

Moses KA, et al. J Clin Oncol. 2010;doi:10.1200/JCO.2009.26.2469.

Palmer JR, et al. Cancer Res. 2017;doi:10.1158/0008-5472.CAN-17-1903.

Rex DK, et al. Am J Gastroenterol. 2017;doi:10.1038/ajg.2017.174.

Shenoy D, et al. BMC Urol. 2016;doi:10.1186/s12894-016-0137-7.

The Journal of Urology. PD09-05 Participation of black men with prostate cancer: A longitudinal assessment of 25 years (1991-2015) of randomized controlled trials. Accessed on Jan. 2, 2018.

Tsodikov A, et al. Cancer. 2017;doi:10.1002/cncr.30687.

For more information:

John D. Carpten, PhD, can be reached at carpten@usc.edu.

Peter R. Carroll, MD, MPH, can be reached at peter.carroll@ucsf.edu.

Eric A. Klein, MD, can be reached at kleine@ccf.org.

Lisa A. Newman, MD, MPH, FACS, can be reached at lnewman1@hfhs.org.

Julie R. Palmer, ScD, can be reached at jpalmer@bu.edu.

Disclosures: Carpten, Carroll, Klein, Newman and Palmer report no relevant financial disclosures.