Evaluation of risk-stratification using gene expression assays in patients with breast cancer receiving neoadjuvant chemotherapy.
Authors: Ma Sung Jun , Yu Brian , Serra Lucas M , Bartl Austin , Farrugia Mark , Iovoli Austin , Oladeru Oluwadamilola Temilade , Miccio Joseph , Aljabab Saif , Fung-Kee-Fung Simon , Haas-Kogan Daphne A. , Singh Anurag K. 
Published: June 2021

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Background: Among patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, several prospective studies investigated various gene expression assays, such as 21-gene recurrence score (21 RS) and 70-gene signature (70 GS), to identify a subgroup of patients with pathologic complete response (pCR) from neoadjuvant chemotherapy. However, in the absence of large prospective trials to validate such findings, the National Comprehensive Cancer Network guideline does not recommend the routine adoption of such assays in the setting of neoadjuvant therapies. To address this knowledge gap, we performed an observational cohort study to compare pCR and survival outcomes based on these assays. Methods: The National Cancer Database (NCDB) was queried for female patients diagnosed between 2010 and 2017 with stage I-III breast cancer who underwent neoadjuvant chemotherapy and either 70 GS or 21 RS. Logistic multivariable analysis (MVA) was performed to identify variables associated with pCR. Cox MVA was performed to evaluate overall survival (OS). Subgroup analyses were performed among patients with favorable hormone receptor status (hormone receptor-positive, HER2-negative) and with RS ≥26 instead of RS ≥31. Results: A total of 3,009 patients met our inclusion criteria, with 2,075 (n = 1,287 for RS < 31, n = 788 for RS ≥31) and 934 (n = 175 for low risk, n = 759 for high risk) patients who underwent 21 RS and 70 GS, respectively. The median follow up was 48.0 months (interquartile range 32.2-66.7). On logistic MVA for all patients, those with a high risk from 70 GS or with RS ≥31 were more likely to have pCR. When compared to RS ≥31, a high risk from 70 GS was not associated with pCR. However, among those with favorable hormone receptor status, similar findings were noted, except that those with a high risk group from 70 GS were less likely to have pCR compared to those with RS ≥31. On Cox MVA for all patients, pCR was associated with improved OS. While RS ≥31 was associated with worse mortality, a high risk from 70 GS was not. No interaction was observed between pCR and risk groups for OS in both groups (interaction p = 0.23 for 70 GS, p = 0.66 for 21 RS). When analyses were repeated using a high risk group from 21 RS defined as RS ≥26, similar findings were noted, except that having favorable hormone receptor status and RS ≥26 was not associated with pCR when compared to the high risk from 70 GS. Conclusions: To our knowledge, this is the largest study using a nationwide oncology database suggesting that high recurrence risk groups in both assays were associated with pCR and that pCR was associated with improved survival. For those with favorable hormone receptor status, RS ≥31 may be a more selective prognostic marker. Further studies would be warranted to investigate the role of gene expression assays in the setting of neoadjuvant chemotherapy.