Abstract GS4-10: Development and validation of a tool integrating the 21-gene recurrence score and clinicopathlogic features to individualize prognosis for distant recurrence and prediction of absolute chemotherapy benefit in early breast cancer
Authors: Sparano Joseph A , Crager Michael R , Tang Gong , Gray Robert J , Stemmer Salomon M , Shak Steve 
Published: February 2021

Abstract
Background: The 21-gene recurrence score (RS) provides prognostic information for distant recurrence (DR) and predictive information for chemotherapy (CT) benefit in early breast cancer, whereas clinicopathologic features provide only prognostic information. We used patient-specific meta-analysis (PSMA) methods (Crager et al, J Appl Stat 2014 [PMID: 26664111]; Tang et al. J Clin Oncol 2011 [PMID: 22010013]) to develop an online tool that assesses individualized estimates of DR risk and absolute CT benefit. We also externally validated this new tool for estimating DR risk in an independent cohort.Methods: The PSMA included 10,004 women with hormone-receptor positive, HER2-negative, node-negative breast cancer from the NSABP B-14 (n=577) trial receiving endocrine therapy (ET) alone and TAILORx trial receiving ET alone (n=4854) or CT plus ET (n=4573). The baseline risk used TAILORx event rates with ET alone. A patient-specific estimator of absolute CT benefit was computed by combining PSMA of the individualized relative CT effect from the TAILORx and NSABP B-20 (n=550 HER2-negative) trials and risk estimates with ET alone. External validation of DR risk estimation was performed in an independent cohort of 1098 women enrolled in the Clalit Health Service registry who had a 21-gene RS performed, of whom 222 (20%) received CT in addition to ET as per the recommendation of their treating physician guided by the RS. Results: The new tool is more informative for DR risk than RS or clinicopathologic factors alone (p&lt;0.001, likelihood ratio test). The risk estimate was significantly associated with DR risk in the independent Clalit cohort (p&lt;0.001), and closely approximated the observed 10-year DR risk (Lin concordance 0.962). Since the RS strongly influenced CT use, propensity score matching could not appropriately be used for evaluation of CT benefit in Clalit. Using this tool for a 55-year-old woman with a low clinical risk 1.5 cm intermediate grade tumor, the absolute CT benefit estimate ranges from 0% to 15% as RS ranges from 11 to 50; this compares to a range of 2% to 8% if the relative CT benefit were held constant. Over the same RS range for a 55-year-old woman with high clinical risk 2.5 cm poor grade tumor, the tool’s absolute CT benefit estimate ranges from 1% to 33% compared to 4% to 17% if the relative CT benefit were held constant. This indicates that incremental CT benefit observed with higher RS is driven not only by a higher underlying recurrence risk, but also by prediction of relative CT benefit.Conclusions: We describe a validated clinical tool integrating clinicopathologic and genomic features to guide adjuvant chemotherapy of hormone-receptor positive, HER2-negative, axillary node-negative breast cancer with greater precision than using clinicopathologic or genomic data alone. The individualized CT effect prediction provided by the RS, based on contemporary treatments, contributes substantially to the estimate of absolute CT benefit. Support: This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180794, U10CA180820, U10CA180822, U10CA180868, and UG1CA189859. The content is solely the responsibility of the authors. Mention of commercial products does not imply endorsement by the U.S. government. Additional support was provided by the Breast Cancer Research Foundation, the Komen Foundation, and the Breast Cancer Research Stamp (BCRS) issued by the United States Postal Service.
Citation Format: Joseph A Sparano, Michael R Crager, Gong Tang, Robert J Gray, Salomon M Stemmer, Steve Shak. Development and validation of a tool integrating the 21-gene recurrence score and clinicopathlogic features to individualize prognosis for distant recurrence and prediction of absolute chemotherapy benefit in early breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS4-10.