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Tumor-stroma ratio is associated with Miller-Payne score and pathological response to neoadjuvant chemotherapy in HER2-negative early breast cancer.

ABSTRACT: The tumor-stroma ratio (TSR) has proven to be a strong prognostic factor in breast cancer, demonstrating better survival for patients with stroma-low tumors. Since the role of the TSR as a predictive marker for neoadjuvant chemotherapy outcome is yet unknown, this association was evaluated for HER2-negative breast cancer in the prospective DIRECT and NEOZOTAC trials. The TSR was assessed on 375 hematoxylin and eosin-stained sections of pre-treatment biopsies. Associations between the TSR and chemotherapy response according to the Miller-Payne (MP) grading system, and between the TSR and pathological response were examined using Pearson's chi-square, Cochran-Armitage test for trend and regression analyses. A stroma-low tumor prior to neoadjuvant chemotherapy was significantly associated with a higher MP score (P = .005). This relationship remained significant in the estrogen receptor (ER)-negative subgroup (P = .047). The univariable odds ratio (OR) of a stroma-low tumor on pathological complete response (pCR) was 2.46 (95% CI 1.34-4.51, P = .004), which attenuated to 1.90 (95% CI 0.85-4.25, P = .119) after adjustment for relevant prognostic factors. Subgroup analyses revealed an OR of 5.91 in univariable analyses for ER-negativity (95% CI 1.19-29.48, P = .030) and 1.48 for ER-positivity (95% CI 0.73-3.01, P = .281). In conclusion, a low amount of stroma on pre-treatment biopsies is associated with a higher MP score and pCR rate. Therefore, the TSR is a promising biomarker in predicting neoadjuvant treatment outcome. Incorporating this parameter in routine pathological diagnostics could be worthwhile to prevent overtreatment and undertreatment.

SUBMITTER: Hagenaars SC

PROVIDER: S-EPMC8362217 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionHR+/HER2- breast cancer (BC) has a much lower pathological complete response (pCR) rate to neoadjuvant chemotherapy (NAC). Therefore, to better stratify the relapse risk for HR+/HER2- non-pCR populations, it is essential to accurate identification new prognostic markers.Materials and methodsThe study retrospectively analyzed 105 stage II-III patients who were diagnosed with HR+/HER2- BC and received NAC followed by breast and axilla surgery between 2013 and 2019 in Sun Yat-Sen University Cancer Center. The Miller-Payne (MP) grading system was used to evaluate pathological responses to NAC. The 70-gene signature was used to classify the prognosis signatures.ResultsAmong the 105 patients, the study demonstrated that larger tumor size and lower progesterone receptor level at baseline and larger tumor size postoperative were statistically significantly associated with worse disease-free survival (DFS) (p = 0.004, p = 0.021, and p = 0.001, respectively). Among 54 patients who underwent the 70-gene assays, 26 (48.1%) had a low-risk signature; 28 (51.9%) patients had a high-risk signature. Patients with poor response (MP grades 1-2) were more likely to with a high-risk 70-gene signature than those with good response (MP grades 4-5). The final analysis showed that DFS was longer in the low-risk group than in the high-risk group [52.4 vs. 36.1 months of the median DFS, hazard ratio (HR) for recurrence, 0.29; 95% confidence interval (CI), 0.10-0.80; p = 0.018]. DFS was longer in the good response (MP grades 3-4) group than in the poor response (MP grades 1-2) group (94.7% vs. 60% of the patients free from recurrence; HR, 0.16; 95% CI, 0.05-0.47; p = 0.037). When stratified by MP grades combined with the 70-gene signature, subgroup analyses showed the good-response low-risk group with the best DFS, whereas the poor-response high-risk group showed the worst DFS (p = 0.048). Due to the short median follow-up time of 34.5 months (5.9-75.1 months), MP grades and the 70-gene signature did not show significant prognostic value for overall survival.ConclusionThe study showed that analysis of MP grades combined with the 70-gene signature with residual NAC-resistant breast samples has a significant correlation with DFS.

Project description:Determining which patients with early-stage breast cancer should receive chemotherapy is an important clinical issue. Chemotherapy has several adverse side effects, impacting on quality of life, along with significant economic consequences. There are a number of multi-gene prognostic signatures for breast cancer recurrence but there is less evidence that these prognostic signatures are predictive of therapy benefit. Biomarkers that can predict patient response to chemotherapy can help avoid ineffective over-treatment. The aim of this work was to assess if the OncoMasTR prognostic signature can predict pathological complete response (pCR) to neoadjuvant chemotherapy, and to compare its predictive value with other prognostic signatures: EndoPredict, Oncotype DX and Tumor Infiltrating Leukocytes. Gene expression datasets from ER-positive, HER2-negative breast cancer patients that had pre-treatment biopsies, received neoadjuvant chemotherapy and an assessment of pCR were obtained from the Gene Expression Omnibus repository. A total of 813 patients with 66 pCR events were included in the analysis. OncoMasTR, EndoPredict, Oncotype DX and Tumor Infiltrating Leukocytes numeric risk scores were approximated by applying the gene coefficients to the corresponding mean probe expression values. OncoMasTR, EndoPredict and Oncotype DX prognostic scores were moderately well correlated according to the Pearson's correlation coefficient. Association with pCR was estimated using logistic regression. The odds ratio for a 1 standard deviation increase in risk score, adjusted for cohort, were similar in magnitude for all four signatures. Additionally, the four signatures were significant predictors of pCR. OncoMasTR added significant predictive value to EndoPredict, Oncotype DX and Tumor Infiltrating Leukocytes signatures as determined by bivariable and trivariable analysis. In this in silico analysis, OncoMasTR, EndoPredict, Oncotype DX, and Tumor Infiltrating Leukocytes were significantly predictive of pCR to neoadjuvant chemotherapy in ER-positive and HER2-negative breast cancer patients.

Project description:The neoadjuvant setting provides immense opportunities for translational research and drug development. The acceptance of pathological complete response (pCR) as a surrogate endpoint for clinical benefit has led to the widespread use of neoadjuvant treatment. Optimal neoadjuvant therapies are determined based on their ability to achieve the highest rates of pCR. Predicted rates of pCR for triple negative breast cancer (TNBC) treated with sequential taxane/anthracycline regimens range from 35% to 48%. With the addition of a platinum agent pCR rates of 55% are predicted. Further increases have been observed with the addition of immune checkpoint inhibitors to this standard chemotherapy backbone. In the pivotal KEYNOTE-522 clinical trial pCR rates of 65% and 69% were reported for chemotherapy plus pembrolizumab in the overall and PD-L1-positive subgroup respectively. The role of the neoadjuvant chemotherapy is less clear in hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative breast cancer. In general, HR-positive cancers have the least chance of achieving a pCR after neoadjuvant chemotherapy, especially if they are low-grade. If neoadjuvant chemotherapy is given for high-risk HR-positive, HER2-negative breast cancer, standard adjuvant anthracycline/taxane regimens are appropriate. Optimum endocrine therapy is the standard-of-care in the adjuvant setting regardless of pCR. There are several genomic signatures available to guide decisions regarding adjuvant chemotherapy use however these assays are not routinely used in the neoadjuvant setting. For high-risk patients meeting the criteria for the monarchE trial adjuvant abemaciclib in addition to endocrine therapy is associated with an improvement in disease free survival (DFS) at 3 years. Based on the OlympiA trial patients with germline BRCA mutations should be considered for adjuvant olaparib therapy. In this article we review neoadjuvant clinical trials that guide optimum treatment options for TNBC and HR-positive, HER2-negative breast cancer.

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Tumor-stroma ratio is associated with Miller-Payne score and pathological response to neoadjuvant chemotherapy in HER2-negative early breast cancer.

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