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Transcriptomic and functional pathway features were associated with survival after pathological complete response to neoadjuvant chemotherapy in breast cancer.

ABSTRACT: Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) has been proposed as a surrogate endpoint for the prediction of long-term survival in breast cancer (BC); however, an increased pCR rate has not clearly correlated with improved survival. We hypothesized that some transcriptomic and functional pathway features correlate with survival after pCR in BC. We utilized 2 published NAC cohorts, 105 women with gene expression data before, "Baseline", and that changed during NAC, "Delta", and TCGA database with 1068 BC patients to investigate the relationship between the efficacy of NAC and survival utilizing differentially expressed-mRNAs, construction and analysis of the mRNA-hub gene network, and functional pathway analysis. In mRNA expression profiling, S100A8 was a gene involved in survival after pCR in Baseline and NDP was a gene involved in recurrence after pCR in Delta. In functional pathway analysis, we found multiple pathways involved in survival after pCR. In mRNA-hub gene analysis, HSP90AA1, EEF1A1, APP, and HSPA4 were related to recurrence in BC patients with pCR due to NAC. TP53, EGFR, CTNNB1, ERBB2, and HSPB1 may play a significant role in survival for patients with pCR. Interestingly, high HSP90AA1, HSPA4, S100A8, and TP53, and low EEF1A1, EGFR, and CTNNB1 expressing tumors have significantly worse overall survival in TCGA BC cohort. We demonstrated the genes and functional pathway features associated with pCR and survival utilizing the bioinformatics approach to public BC cohorts. Some genes involved in recurrence after pCR due to NAC also served as prognostic factors in primary BC.

SUBMITTER: Takeshita T

PROVIDER: S-EPMC7471342 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Transcriptomic and functional pathway features were associated with survival after pathological complete response to neoadjuvant chemotherapy in breast cancer.

Takeshita Takashi T Yan Li L Peng Xuan X Kimbung Siker S Hatschek Thomas T Hedenfalk Ingrid A IA Rashid Omar M OM Takabe Kazuaki K

American journal of cancer research 20200801 8

Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) has been proposed as a surrogate endpoint for the prediction of long-term survival in breast cancer (BC); however, an increased pCR rate has not clearly correlated with improved survival. We hypothesized that some transcriptomic and functional pathway features correlate with survival after pCR in BC. We utilized 2 published NAC cohorts, 105 women with gene expression data before, "Baseline", and that changed during NAC, "D ...[more]

PMID: 32905537

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Project description:BackgroundIn the neoadjuvant setting, changes in the proliferation marker Ki67 are associated with primary endocrine treatment efficacy, but its value as a predictor of response to chemotherapy is still controversial.Patients and methodsWe analyzed 262 patients with centralized basal Ki67 immunohistochemical evaluation derived from 4 GEICAM (Spanish Breast Cancer Group) clinical trials of neoadjuvant chemotherapy for breast cancer. The objective was to identify the optimal threshold for Ki67 using the receiver-operating characteristic curve method to maximize its predictive value for chemotherapy benefit. We also evaluated the predictive role of the defined Ki67 cutoffs for molecular subtypes defined by estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2).ResultsA basal Ki67 cutpoint of 50% predicted pathological complete response (pCR). Patients with Ki67 >50% achieved a pCR rate of 40% (36 of 91) versus a pCR rate of 19% in patients with Ki67 ≤ 50% (33 of 171) (p = .0004). Ki67 predictive value was especially relevant in ER-HER2- and ER-HER2+ patients (pCR rates of 42% and 64%, respectively, in patients with Ki67 >50% versus 15% and 45%, respectively, in patients with Ki67 ≤ 50%; p = .0337 and .3238, respectively). Both multivariate analyses confirmed the independent predictive value of the Ki67 cutpoint of 50%.ConclusionBasal Ki67 proliferation index >50% should be considered an independent predictive factor for pCR reached after neoadjuvant chemotherapy, suggesting that cell proliferation is a phenomenon closely related to chemosensitivity. These findings could help to identify a group of patients with a potentially favorable long-term prognosis.Implications for practiceThe use of basal Ki67 status as a predictive factor of chemotherapy benefit could facilitate the identification of a patient subpopulation with high probability of achieving pathological complete response when treated with primary chemotherapy, and thus with a potentially favorable long-term prognosis.

Project description:BackgroundBreast cancer with pathological non-complete response (non-pCR) after neoadjuvant chemotherapy (NAC) has a worse prognosis. Despite Neo-Bioscore has been validated as an independent prognostic model for breast cancer submitted to NAC, non-pCR carcinoma was not assessed in this setting.MethodsThis is a retrospective trial that included women with localized breast cancer who underwent NAC and had non-pCR carcinoma in surgical specimen between 01/01/2013 to 12/31/2015 with a three-year follow-up. Survival analysis was performed by Kaplan-Meier estimator and hazard ratio (HR) set by log-rank test for the primary and secondary endpoints, respectively Disease-Free Survival (DFS) and Overall Survival (OS). According to Neo-Bioscore, the proposed prognostic model named Clustered Neo-Bioscore was classified into low (0-3), low-intermediate (4-5), high-intermediate (6) and high (7) risk. The prognostic accuracy for recurrence risk was assessed by time-dependent receiver operating characteristic (time-ROC) methodology. Multivariate Cox regression assessed the menopausal status, histological grade, Ki-67, estrogen receptor, HER2, tumor subtype, pathological and clinical stages. Confidence interval at 95% (CI95%) and statistical significance at set 2-sided p-value less than 0.05 were adopted.ResultsAmong the 310 women enrolled, 267 patients (86.2%) had non-pCR carcinoma presenting size T3/T4 (63.3%), node-positive axilla (74.9%), stage III (62.9%), Ki-67???20% (71.9%) and non-luminal A (78.3%). Non-pCR carcinoma presented worse DFS-3y (HR?=?3.88, CI95%?=?1.18-11.95) but not OS-3y (HR?=?2.73, CI95%?=?0.66-11.40). Clustered Neo-Bioscore discerned the recurrence risk for non-pCR carcinoma: low (DFS-3y?=?0.86; baseline), low-intermediate (DFS-3y?=?0.70; HR?=?2.61), high-intermediate (DFS-3y?=?0.13, HR?=?14.05), and high (DFS-3y?=?not achieved; HR?=?22.19). The prognostic accuracy was similar between Clustered Neo-Bioscore and Neo-Bioscore (0.76 vs 0.78, p?>?0.05). Triple-negative subtype (HR?=?3.6, CI95%?=?1.19-10.92) and pathological stages II (HR?=?5.35, CI95%?=?1.19-24.01) and III (HR?=?6.56, CI95%?=?1.29-33.32) were prognoses for low-intermediate risk, whereas pathological stage III (HR?=?13.0, CI95%?=?1.60-106.10) was prognosis for low risk.ConclusionsClustered Neo-Bioscore represents a novel prognostic model of non-pCR carcinoma undergoing NAC with a more simplified and appropriate score pattern in the assessment of prognostic factors.

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Transcriptomic and functional pathway features were associated with survival after pathological complete response to neoadjuvant chemotherapy in breast cancer.

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Transcriptomic and functional pathway features were associated with survival after pathological complete response to neoadjuvant chemotherapy in breast cancer.

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