News Release

Black and white women who received neoadjuvant therapy were equally likely to have pathologic complete response

Tumor biology, not race, was a more significant factor in predicting response to clinical trial treatment

Reports and Proceedings

American Association for Cancer Research

SAN ANTONIO – Analysis of data from the I-SPY 2 clinical trial showed that race did not significantly affect several key measures of breast cancer treatment outcomes, including pathologic complete response and event-free survival, according to results presented at the San Antonio Breast Cancer Symposium, held December 7-10, 2021.

“Breast cancer treatment and management is constantly evolving with advancements in immunotherapy leading the way. However, there remains a persistent mortality gap between white and Black women with breast cancer,” said lead author Beverly Kyalwazi, BS, a medical student at the University of Chicago Pritzker School of Medicine. According to recent estimates, Black women with breast cancer are about 40 percent more likely to die of the disease than white women.

Previous research has shown that pathologic complete response is a strong predictor of distant recurrence-free survival. In this study, Kyalwazi, working in conjunction with senior authors Olufunmilayo Olopade, MD, FAACR, director of the University of Chicago Center for Clinical Cancer Genetics and  Laura Esserman, MD, MBA, director of the University of California San Francisco Breast Care Center and the principal investigator of the I-SPY 2 trials, aimed to assess whether racial disparities exist in the achievement of pathologic complete response. As a secondary aim, the researchers studied the association between racial groups and 28 expression signatures related to immune cell types, checkpoint inhibitor targets, and immune signaling pathways.

Final study data included 974 patients; follow-up data was available for 907, with a median follow-up time of 4.4 years. Eighty-one percent of the women were white; 12 percent were Black; and 7 percent were Asian. Study participants came from 10 treatment arms of the I-SPY 2 trial. They had been randomly assigned to either standard neoadjuvant therapy with paclitaxel followed by doxorubicin and cyclophosphamide or an investigational drug (neratinib, veliparib and carboplatin, trebananib, ganitumab, MK2206, pertuzumab, TDM1 and pertuzumab, ganetespib, pexidartinib, or pembrolizumab) with paclitaxel. The researchers analyzed associations of race with pretreatment grade, subtype, and residual burden class, and used logistic regression to evaluate pathologic complete response and event-free survival in all racial groups.

The study showed that pathologic complete response rates did not significantly differ by racial groups. There were also no significant differences in event-free survival or residual cancer burden.

Among women who did not experience pathologic complete response however, HR-positive/HER2-negative breast cancer showed the greatest survival disparity between Black women and white women, with Black women almost twice as likely to experience mortality than white women. This finding was consistent with other recent research on this topic by Olopade and may suggest that biological factors may have resulted in a lack of response to therapy.

“It is critical for us to work to understand and address this underlying disparity and develop interventions to improve outcomes for women who do not experience pathologic complete response. An improved knowledge of how tumor biology predicts response could help researchers develop novel approaches that not only target the tumor and immune microenvironment but also take into account the individual characteristics of the patients to help guide clinical trial design,” said Olopade.

Patients with high-risk Mammaprint gene expression were eligible to participate in the I-SPY 2 trial. Among the 28 expression signatures evaluated, only three were differentially expressed among racial groups for the HR-positive/HER2-negative breast cancer subtype: IFN module, mitotic score, and ER/PR module. Kyalwazi said further research would be necessary to understand how these differences could potentially influence disparities in breast cancer outcomes and design of innovative interventions to close the mortality gap.

Overall, Kyalwazi said the similar outcomes in pathologic complete response and event-free survival for women of all races indicates that tumor molecular subtype is a more significant factor in breast cancer survival than race.

“This is reassuring because it helps us to know that biomarker-informed therapies should work for patients across all racial groups with equal access to quality care,” she said. “These results demonstrate that when women are able to access the appropriate, effective therapies based on their tumor profiles, achievement of pathologic complete response and survival is independent of race.”

The results underscore the importance of enrolling more Black women into breast cancer clinical trials to ensure that they have access to the full range of biomarker-informed cancer therapeutics, she said.

“As long as racial disparities exist, race will continue to be a part of discussions regarding breast cancer,” Kyalwazi said. “Understanding that race is less likely than tumor biology to predict response to therapy places more of a focus on strategies to increase access to quality cancer care among women underrepresented in clinical trials.” 

“We are committed to ensuring access to all women in the I-SPY TRIAL, especially women who are traditionally underrepresented in trials. Our trial sites reflect both the geographic and racial diversity of the country. Women of color have a higher mortality rate from breast cancer, and trials with personalized therapies and full genomic profiling will help us to improve the outcomes for all women,” said Esserman.

A limitation of the study was the relatively small number of self-reported Black and Asian patients. Kyalwazi noted that additional analysis will include 1,000 more I-SPY participants, 12 percent of whom are Black. Also, study data did not capture socioeconomic differences or patient comorbidities that could have influenced response to treatment.

This study was funded by the Breast Cancer Research Fund and the Pritzker/Northshore Fellowship. Kyalwazi declares no conflicts of interest.



Analysis of clinical outcomes and expression-based immune signatures by race in the I-SPY 2 trial

Background: Transcriptomic immune-related gene signatures have been associated with achievement of pathologic complete response (pCR) and prognosis in the neoadjuvant setting. I-SPY 2 is a multicenter, phase 2 platform trial using response-adaptive randomization within subtypes defined by receptor status (HR/HER2) and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk breast cancer. Given racial disparities in mortality from breast cancer and the paucity of racial demographic data from clinical trials, we aimed to evaluate the association between racial groups and baseline characteristics, including expression-based subtypes and immune signatures, treatment response, and prognosis of patients enrolled in the I-SPY 2 TRIAL.

Methods: Our study population included 990 I-SPY 2 patients. 15 patients identified as part of a racial group with <10 patients enrolled in the trial and were excluded from analysis. Pre-treatment expression data was available for 971 patients. Follow-up data was available for 907 patients; median follow-up time of 4.4 yrs. Chi-square test was used to assess associations between racial groups and pre-treatment SBR grade, HR/HER2 defined subtypes, intrinsic subtype (defined by BluePrint 80-gene molecular subtyping) and residual cancer burden (RCB) class. Logistic regression was used to evaluate race association with pCR. Cox proportional hazard modeling was used to assess the association between racial groups and event free survival (EFS) in a univariate setting, adjusting for pCR status. Association between racial groups and 28 expression signatures related to immune, proliferation, ER and HER2 pathway was analyzed using ANOVA with post-hoc Tukey test in the overall population and in each receptor subtype.

Results: Of 975 patients included in our analysis, 787 (81%) were White, 68 (7%) were Asian, and 120 (12%) were Black or African American. No significant associations between race and pre-treatment SBR grade (p=0.49), HR/HER2 defined subtypes (p=0.09), or expression-based subtypes (p=0.25) were observed. pCR rates do not significantly differ by racial groups (Odds ratio of pCR relative to White: 1.00 for Asian and 0.89 for Black or African American); and no significant differences in RCB class distribution by race was observed (p=0.88). Event free survival was not associated with patient racial group in a univariate Cox model (Hazard ratio relative to White: 1.10, p=0.73 for Asian and 1.37, p=0.13 for Black or African American). Among the 28 expression signatures evaluated, four were differentially expressed among racial groups within the overall population (F-test p<0.05): IFN module, B cell signature, Dendritic cell signature, and Mitotic score. Pairwise comparisons between racial groups with post-hoc Tukey test identified significant differences in IFN module expression between Black or African American vs. White (p=0.019) and Dendritic cell signature expression between Asian vs White (p=0.047). Among patients in the TNBC subtype, three signatures (dendritic cell signature, macrophage signature and ERBB2 module) were differentially expressed between Black or African American and White patients (p=0.002, 0.016 and 0.007).

Conclusion: Our analysis demonstrates that among women with high risk breast cancer, race does not affect subtype specific response rates nor event free survival. Distribution of subtypes previously shown to be associated with pCR in the I-SPY2 trial did not significantly differ among racial groups indicating race is less likely than tumor biology to predict response. The decreased expression of immune signatures observed in Black or African American women with TNBC suggests possible differential sensitivity to immunotherapy plus combination chemotherapy. Tumor immune multiplex studies are underway to further investigate.

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