Feature

Researchers aim to personalize chemotherapy for black patients with breast cancer

Bryan P. Schneider, MD
Bryan P. Schneider

Racial disparities in cancer care and outcomes have been well-documented. However, not all challenges black patients with breast cancer face stem from cultural or socioeconomic factors; some may be inherited.

In an analysis of racial disparity data from a large international treatment study, researchers found that a combination of genetics and taxane-based chemotherapy may be responsible for a significantly higher rate of neuropathy among black women with breast cancer compared with women of other races.

“The taxanes in general cause neuropathy, and there’s a risk for neuropathy for patients of all races,” Bryan P. Schneider, MD, professor of medicine and medical/molecular genetics at Indiana University School of Medicine, said in an interview with Healio. “What we think is that some African American patients have different genetics, setting them up for the damage to be more severe and more common.”

Schneider spoke with Healio about the NCI-sponsored E5103 clinical trial — which was designed and conducted by researchers in the ECOG-ACRIN Cancer Research Group — what it revealed and how this information may help better prevent or treat neuropathy among black women with breast cancer.

Question: What were the main findings of your study?

Answer: E5103 was a very large breast cancer treatment trial of about 5,000 women, of whom just shy of 400 were of African descent or African American. The risk for neuropathy, grade 2 or grade 3, was about double among these women compared with those of other races.

We looked at some of the known risk factors for neuropathy. Older patients get more neuropathy, and patients who are obese have higher rates of neuropathy. BMI and rates of diabetes are a bit higher for African Americans, so those could be contributors; however, by no means do they account for everything. So, we began to explore whether inherited genetic differences may predispose African Americans to neuropathy. We found a few generic variants that seem to increase or predict an increased risk for neuropathy among African American patients.

Within the clinical trial, we used two genomic approaches. We did a genome-wide association study in which we looked at more than a million different common genetic variants across populations. We found that a gene called FCAMR, which is important for immune modulation or immunity, seemed to protect African Americans. We then looked at rare variants using whole-exome sequencing and found that patients who carried variants in a gene called SBF2 had markedly more neuropathy. If you carry two genetic variants in SBF2, you get the most common form of hereditary neuropathy, called Charcot-Marie-Tooth disease. If you carry one variant, you don’t get Charcot-Marie-Tooth, but if you get exposed to a taxane or a drug that can cause neuropathy, you’re predisposed to it. We don’t think this is entirely why African Americans have higher rates of neuropathy. However, complex genetic differences appear to factor into why this happens.

Q: Your study shows neuropathy often causes physicians to reduce the dose of chemotherapy for black patients. Does this impact efficacy?

A: Yes. This was another provocative finding. We had looked at whether there were more dose reductions of chemotherapy, particularly the taxane portion, as one might expect with a doubling of neuropathy risk. African Americans had markedly more reductions, or even early cessation of the drug, in order to maintain quality of life. There also was a substantial difference in DFS or efficacy among African Americans whose doses were reduced vs. those whose doses were not reduced. E5103 is one of the first studies to show that one of the causes of inferior outcomes for patients of African descent with breast cancer is a function of side effects of the drugs. African Americans simply aren’t getting all the doses of this important chemotherapy.

Q: What is the focus of your research?

A: We recognize neuropathy to be a big problem among African Americans. Our current study, EAZ171 — which opened to enrollment last June — is one of the first NCI cooperative-group trials to focus accrual specifically on the population that needs to be targeted. We will enroll 240 African American patients with breast cancer. We’re going to try to prospectively prove that by using the known genetic markers we’ve identified, we can predict which African Americans are likely to get neuropathy, and then show what we can do to lower risk for neuropathy. At the same time, we’re going to compare two types of taxanes. In the curative setting, we will be comparing weekly paclitaxel for four cycles vs. docetaxel every 3 weeks for four cycles. For most patients, specifically Caucasians, weekly paclitaxel will have fewer acute side effects, but for African Americans, the docetaxel regimen may be preferred and result in less neuropathy. What we hope to do ultimately is determine which taxane is right for which African American patient based on their genetic makeup and preferences.

Q: Will the emergence of new targeted therapies improve the way African American patients with breast cancer respond to treatment?

A: Yes. We’ve done a very good job of thinking about the importance of precision medicine in terms of matching up a drug with a target. What we haven’t been great at yet is personalizing it in terms of side effects. I think our research is taking it a step further, where we’re not only asking whether we have a good drug target, but also how it can impact toxicity.

Although this trial is available through ECOG-ACRIN nationally, here at IU School of Medicine, we have partnered with two amazing advocacy groups in the Indianapolis area, the R.E.D. Alliance and Pink 4-Ever. These groups are very committed to minimizing disparities of breast cancer in the African American community. The only way this trial will be successful is for the African American community to become involved and participate in research like this, where we can take these outcomes and make them better. – by Jennifer Byrne

Reference:

Schneider BP, et al. J Oncol Pract. 2017;doi:10.1200/PO.17.00059.

For more information:

Bryan P. Schneider, MD, can be reached at Indiana Cancer Pavilion, Suite 474535 Barnhill Drive, Indianapolis, IN 46202-5289.

Disclosures: Schneider reports no relevant financial disclosures.

Bryan P. Schneider, MD
Bryan P. Schneider

Racial disparities in cancer care and outcomes have been well-documented. However, not all challenges black patients with breast cancer face stem from cultural or socioeconomic factors; some may be inherited.

In an analysis of racial disparity data from a large international treatment study, researchers found that a combination of genetics and taxane-based chemotherapy may be responsible for a significantly higher rate of neuropathy among black women with breast cancer compared with women of other races.

“The taxanes in general cause neuropathy, and there’s a risk for neuropathy for patients of all races,” Bryan P. Schneider, MD, professor of medicine and medical/molecular genetics at Indiana University School of Medicine, said in an interview with Healio. “What we think is that some African American patients have different genetics, setting them up for the damage to be more severe and more common.”

Schneider spoke with Healio about the NCI-sponsored E5103 clinical trial — which was designed and conducted by researchers in the ECOG-ACRIN Cancer Research Group — what it revealed and how this information may help better prevent or treat neuropathy among black women with breast cancer.

Question: What were the main findings of your study?

Answer: E5103 was a very large breast cancer treatment trial of about 5,000 women, of whom just shy of 400 were of African descent or African American. The risk for neuropathy, grade 2 or grade 3, was about double among these women compared with those of other races.

We looked at some of the known risk factors for neuropathy. Older patients get more neuropathy, and patients who are obese have higher rates of neuropathy. BMI and rates of diabetes are a bit higher for African Americans, so those could be contributors; however, by no means do they account for everything. So, we began to explore whether inherited genetic differences may predispose African Americans to neuropathy. We found a few generic variants that seem to increase or predict an increased risk for neuropathy among African American patients.

Within the clinical trial, we used two genomic approaches. We did a genome-wide association study in which we looked at more than a million different common genetic variants across populations. We found that a gene called FCAMR, which is important for immune modulation or immunity, seemed to protect African Americans. We then looked at rare variants using whole-exome sequencing and found that patients who carried variants in a gene called SBF2 had markedly more neuropathy. If you carry two genetic variants in SBF2, you get the most common form of hereditary neuropathy, called Charcot-Marie-Tooth disease. If you carry one variant, you don’t get Charcot-Marie-Tooth, but if you get exposed to a taxane or a drug that can cause neuropathy, you’re predisposed to it. We don’t think this is entirely why African Americans have higher rates of neuropathy. However, complex genetic differences appear to factor into why this happens.

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Q: Your study shows neuropathy often causes physicians to reduce the dose of chemotherapy for black patients. Does this impact efficacy?

A: Yes. This was another provocative finding. We had looked at whether there were more dose reductions of chemotherapy, particularly the taxane portion, as one might expect with a doubling of neuropathy risk. African Americans had markedly more reductions, or even early cessation of the drug, in order to maintain quality of life. There also was a substantial difference in DFS or efficacy among African Americans whose doses were reduced vs. those whose doses were not reduced. E5103 is one of the first studies to show that one of the causes of inferior outcomes for patients of African descent with breast cancer is a function of side effects of the drugs. African Americans simply aren’t getting all the doses of this important chemotherapy.

Q: What is the focus of your research?

A: We recognize neuropathy to be a big problem among African Americans. Our current study, EAZ171 — which opened to enrollment last June — is one of the first NCI cooperative-group trials to focus accrual specifically on the population that needs to be targeted. We will enroll 240 African American patients with breast cancer. We’re going to try to prospectively prove that by using the known genetic markers we’ve identified, we can predict which African Americans are likely to get neuropathy, and then show what we can do to lower risk for neuropathy. At the same time, we’re going to compare two types of taxanes. In the curative setting, we will be comparing weekly paclitaxel for four cycles vs. docetaxel every 3 weeks for four cycles. For most patients, specifically Caucasians, weekly paclitaxel will have fewer acute side effects, but for African Americans, the docetaxel regimen may be preferred and result in less neuropathy. What we hope to do ultimately is determine which taxane is right for which African American patient based on their genetic makeup and preferences.

Q: Will the emergence of new targeted therapies improve the way African American patients with breast cancer respond to treatment?

A: Yes. We’ve done a very good job of thinking about the importance of precision medicine in terms of matching up a drug with a target. What we haven’t been great at yet is personalizing it in terms of side effects. I think our research is taking it a step further, where we’re not only asking whether we have a good drug target, but also how it can impact toxicity.

Although this trial is available through ECOG-ACRIN nationally, here at IU School of Medicine, we have partnered with two amazing advocacy groups in the Indianapolis area, the R.E.D. Alliance and Pink 4-Ever. These groups are very committed to minimizing disparities of breast cancer in the African American community. The only way this trial will be successful is for the African American community to become involved and participate in research like this, where we can take these outcomes and make them better. – by Jennifer Byrne

Reference:

Schneider BP, et al. J Oncol Pract. 2017;doi:10.1200/PO.17.00059.

For more information:

Bryan P. Schneider, MD, can be reached at Indiana Cancer Pavilion, Suite 474535 Barnhill Drive, Indianapolis, IN 46202-5289.

Disclosures: Schneider reports no relevant financial disclosures.