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Multicenter Study
. 2023 Dec 1;6(12):e2349646.
doi: 10.1001/jamanetworkopen.2023.49646.

Race, Gene Expression Signatures, and Clinical Outcomes of Patients With High-Risk Early Breast Cancer

Beverly Kyalwazi  1   2 , Christina Yau  3 , Michael J Campbell  3 , Toshio F Yoshimatsu  1   4 , A Jo Chien  5 , Anne M Wallace  6 , Andres Forero-Torres  7 , Lajos Pusztai  8 , Erin D Ellis  9 , Kathy S Albain  10 , Anne H Blaes  10 , Barbara B Haley  11 , Judy C Boughey  12 , Anthony D Elias  13 , Amy S Clark  14 , Claudine J Isaacs  15 , Rita Nanda  4 , Hyo S Han  16 , Rachel L Yung  17 , Debasish Tripathy  18 , Kristen K Edmiston  19 , Rebecca K Viscusi  20 , Donald W Northfelt  21 , Qamar J Khan  22 , Smita M Asare  23 , Amy Wilson  23 , Gillian L Hirst  3 , Ruixiao Lu  23 , William Fraser Symmans  24 , Douglas Yee  10 , Angela M DeMichele  14 , Laura J van 't Veer  25 , Laura J Esserman  3 , Olufunmilayo I Olopade  1   4
Affiliations
Multicenter Study

Race, Gene Expression Signatures, and Clinical Outcomes of Patients With High-Risk Early Breast Cancer

Beverly Kyalwazi et al. JAMA Netw Open. .

Abstract

Importance: There has been little consideration of genomic risk of recurrence by breast cancer subtype despite evidence of racial disparities in breast cancer outcomes.

Objective: To evaluate associations between clinical trial end points, namely pathologic complete response (pCR) and distant recurrence-free survival (DRFS), and race and examine whether gene expression signatures are associated with outcomes by race.

Design, setting, and participants: This retrospective cohort study used data from the Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2 (I-SPY 2) multicenter clinical trial of neoadjuvant chemotherapy with novel agents and combinations for patients with previously untreated stage II/III breast cancer. Analyses were conducted of associations between race and short- and long-term outcomes, overall and by receptor subtypes, and their association with 28 expression biomarkers. The trial enrolled 990 female patients between March 30, 2010, and November 5, 2016, with a primary tumor size of 2.5 cm or greater and clinical or molecular high risk based on MammaPrint or hormone receptor (HR)-negative/ERBB2 (formerly HER2 or HER2/neu)-positive subtyping across 9 arms. This data analysis was performed between June 10, 2021, and October 20, 2022.

Exposure: Race, tumor receptor subtypes, and genomic biomarker expression of early breast cancer.

Main outcomes and measures: The primary outcomes were pCR and DRFS assessed by race, overall, and by tumor subtype using logistic regression and Cox proportional hazards regression models. The interaction between 28 expression biomarkers and race, considering pCR and DRFS overall and within subtypes, was also evaluated.

Results: The analytic sample included 974 participants (excluding 16 self-reporting as American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or multiple races due to small sample sizes), including 68 Asian (7%), 120 Black (12%), and 786 White (81%) patients. Median (range) age at diagnosis was 47 (25-71) years for Asian, 49 (25-77) for Black, and 49 (23-73) years for White patients. The pCR rates were 32% (n = 22) for Asian, 30% for Black (n = 36), and 32% for White (n = 255) patients (P = .87). Black patients with HR-positive/ERBB2-negative tumors not achieving pCR had significantly worse DRFS than their White counterparts (hazard ratio, 2.28; 95% CI, 1.24-4.21; P = .01), with 5-year DRFS rates of 55% (n = 32) and 77% (n = 247), respectively. Black patients with HR-positive/ERBB2-negative tumors, compared with White patients, had higher expression of an interferon signature (mean [SD], 0.39 [0.87] and -0.10 [0.99]; P = .007) and, compared with Asian patients, had a higher mitotic score (mean [SD], 0.07 [1.08] and -0.69 [1.06]; P = .01) and lower estrogen receptor/progesterone receptor signature (mean [SD], 0.31 [0.90] and 1.08 [0.95]; P = .008). A transforming growth factor β signature had a significant association with race relative to pCR and DRFS, with a higher signature associated with lower pCR and worse DRFS outcomes among Black patients only.

Conclusions and relevance: The findings show that women with early high-risk breast cancer who achieve pCR have similarly good outcomes regardless of race, but Black women with HR-positive/ERBB2-negative tumors without pCR may have worse DRFS than White women, highlighting the need to develop and test novel biomarker-informed therapies in diverse populations.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Yau reported receiving US patent application No. 18/174,191 assigned to her institution. Dr Chien reported receiving research support from Puma, Seagen, Merck, and Amgen to her institution outside the submitted work, and a US patent pending. Dr Wallace reported receiving grants from I-SPY per contract with the University of California, San Francisco during the conduct of the study. Dr Forero-Torres reported employment since 2018 with Seagen outside the submitted work. Dr Albain reported receiving patient care costs to her institution and salary support from Quantum Leap Healthcare Collaborative during the conduct of the study and independent data monitoring committee membership with Seattle Genetics and research support paid to her institution from Seattle Genetics, Daiichi, and AstraZeneca outside the submitted work. Dr Boughey reported receiving grants paid to her institution from Eli Lilly and Quantum Leap Healthcare Collaborative to support I-SPY activities during the conduct of the study and grants paid to her institution from SimBioSys and data monitoring and safety board fees from CairnSurgical outside the submitted work. Dr Clark reported receiving grants paid to her institution from Eli Lilly and Novartis and personal fees from Siemens during the conduct of the study. Dr Isaacs reported receiving grants from Quantum Leap Healthcare Collaborative to support I-SPY activities during the conduct of the study and consulting fees from Genentech, PUMA, Seattle Genetics, AstraZeneca, Novartis, Pfizer, Gilead, and Biotheranostics; grants to her institution from Pfizer; and royalties from Wolters Kluwer and McGraw Hill outside the submitted work. Dr Nanda reported receiving personal fees from AstraZeneca, BeyondSpring, Daiichi Sankyo, Fujifilm, GE, Gilead, Infinity, iTeos, Macrogenics, Merck, Novartis, OBI Pharma, OncoSec, Pfizer, Sanofi, Seagen, and Stemline and grants from Arvinas, AstraZeneca, Celgene, Corcept Therapeutics, Genentech/Roche, Gilead/Immunomedics, Merck, Novartis, OBI Pharma, OncoSec, Pfizer, Relay, Seattle Genetics, Sun Pharma, and Taiho outside the submitted work. Dr Han reported receiving research funding paid to her institution from Quantum Leap Healthcare Collaborative during the conduct of the study; grants from the US Department of Defense; and research funding paid to her institution from AbbVie, Seagen, G1 Therapeutics, Pfizer, Novartis, Marker Therapeutics, Zymeworks, Phoenix, Celcuity, Arvinas, Senhwa Biosciences, and Pionyr outside the submitted work. Dr Tripathy reported receiving research support to his institution from Novartis and Pfizer and personal fees from Novartis, Pfizer, AstraZeneca, AMBRX, Personalis, Roche, Sermonix, and Stemline-Menarini outside the submitted work. Ms Asare reported receiving research support from Quantum Leap Healthcare Collaborative during the conduct of the study. Dr Symmans reported receiving founder equity from Delphi Diagnostics outside the submitted work and a US patent No. 11,459,617 issued to Delphi Diagnostics. Dr Yee reported receiving advisor fees from Martell Diagnostics and clinical trial support from Boehringer Ingelheim and Fusion Pharmaceuticals outside the submitted work. Prof van ’t Veer reported being a part-time employee of and stockholder in Agendia during the conduct of the study. Dr Esserman reported receiving grants from Quantum Leap Healthcare Collaborative during the conduct of the study and being an unpaid member of the board of directors of Quantum Leap Healthcare Collaborative, being a member of a medical advisory panel for and receiving reimbursement for time and travel from Blue Cross/Blue Shield, and receiving grant support from Merck outside the submitted work. Dr Olopade reported serving on the scientific advisory board for Tempus, receiving cofounder equity from CancerIQ, serving on the board of directors of 54gene, and receiving grants from Roche/Genentech and Color Genomics during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flow Diagram
DRFS indicates distant recurrence–free survival; I-SPY 2, Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2; pCR, pathologic complete response.
Figure 2.
Figure 2.. Kaplan-Meier Curves of Distant Recurrence–Free Survival (DRFS) Differences by Race and Pathologic Complete Response (pCR) Status
A, Hazard ratios 1.06 (95% CI, 0.60-1.88; P = .84) and 1.37 (95% CI, 0.90-2.06; P = .14) for Asian and Black patients relative to White patients. B, Hazard ratios 0.00 and 0.93 (95% CI, 0.21-4.07; P = .92) for Asian and Black patients relative to White patients. C, Hazard ratios 1.23 (95% CI, 0.69-2.18; P = .48) and 1.45 (95% CI, 0.95-2.24; P = .09) for Asian and Black patients relative to White patients. D, Hazard ratios 1.26 (95% CI, 0.50-3.17; P = .62) and 2.28 (95% CI, 1.24-4.21; P = .01) for Asian and Black patients relative to White patients. HR indicates hormone receptor.
Figure 3.
Figure 3.. Gene Expression Signatures of Hormone Receptor (HR)–Positive/ERBB-Negative Tumors by Race
Boxes indicate the IQR, with the center line indicating the median and whiskers indicating the lower quartile minus 1.5 times the IQR and upper quartile plus 1.5 times the IQR. ER/PR indicates estrogen receptor/progesterone receptor; IFN, interferon.
See this image and copyright information in PMC

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