Dataset Information

A Prognostic Model Based on Residual Cancer Burden and Tumor-Infiltrating Lymphocytes on Residual Disease after Neoadjuvant Therapy in HER2+ Breast Cancer.

ABSTRACT:

Purpose

We aim to evaluate the prognostic significance of tumor-infiltrating lymphocyte on residual disease (RD-TIL) in HER2+ patients with breast cancer who failed to achieve pathologic complete response (pCR) after anti-HER2+ chemotherapy (CT)-based neoadjuvant treatment (NAT). We assessed the feasibility of combining the prognostic information provided by residual cancer burden (RCB) and RD-TILs into a composite score (RCB+TIL).

Experimental design

HER2+ patients with breast cancer treated with CT+anti-HER2-based NAT at three institutions were retrospectively included. RCB and TIL levels were evaluated on hematoxylin and eosin-stained slides from surgical samples according to available recommendations. Overall survival (OS) was used as an outcome measure.

Results

A total of 295 patients were included, of whom 195 had RD. RCB was significantly associated with OS. Higher RD-TILs were significantly associated with poorer OS as compared with lower RD-TILs (15% cutoff). In multivariate analysis, both RCB and RD-TIL maintained their independent prognostic value. A combined score, RCB+TIL, was calculated from the estimated coefficient of RD-TILs and the RCB index in a bivariate logistic model for OS. The RCB+TIL score was significantly associated with OS. The C-index for OS of the RCB+TIL score was numerically higher than that of RCB and significantly higher than that of RD-TILs.

Conclusions

We have reported an independent prognostic impact of RD-TILs after anti-HER2+CT NAT, which might underlie an imbalance of the RD microenvironment towards immunosuppressive features. We provided a new composite prognostic score based on RCB+TIL, which was significantly associated with OS and proved to be more informative than the isolated evaluation of RCB and RD-TILs.

SUBMITTER: Miglietta F

PROVIDER: S-EPMC10472099 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

A Prognostic Model Based on Residual Cancer Burden and Tumor-Infiltrating Lymphocytes on Residual Disease after Neoadjuvant Therapy in HER2+ Breast Cancer.

Miglietta Federica F Ragazzi Moira M Fernandes Bethania B Griguolo Gaia G Massa Davide D Girardi Fabio F Bottosso Michele M Bisagni Alessandra A Zarrilli Giovanni G Porra Francesca F Iannaccone Daniela D Dore Leocadia L Gaudio Mariangela M Santandrea Giacomo G Fassan Matteo M Lo Mele Marcello M De Sanctis Rita R Zambelli Alberto A Bisagni Giancarlo G Guarneri Valentina V Dieci Maria Vittoria MV

Clinical cancer research : an official journal of the American Association for Cancer Research 20230901 17

<h4>Purpose</h4>We aim to evaluate the prognostic significance of tumor-infiltrating lymphocyte on residual disease (RD-TIL) in HER2+ patients with breast cancer who failed to achieve pathologic complete response (pCR) after anti-HER2+ chemotherapy (CT)-based neoadjuvant treatment (NAT). We assessed the feasibility of combining the prognostic information provided by residual cancer burden (RCB) and RD-TILs into a composite score (RCB+TIL).<h4>Experimental design</h4>HER2+ patients with breast ca ...[more]

PMID: 37417941

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Project description:The residual cancer burden index was developed as a method to quantify residual disease ranging from pathological complete response to extensive residual disease. The aim of this study was to evaluate the inter-Pathologist reproducibility in the residual cancer burden index score and category, and in their long-term prognostic utility. Pathology slides and pathology reports of 100 cases from patients treated in a randomized neoadjuvant trial were reviewed independently by five pathologists. The size of tumor bed, average percent overall tumor cellularity, average percent of the in situ cancer within the tumor bed, size of largest axillary metastasis, and number of involved nodes were assessed separately by each pathologist and residual cancer burden categories were assigned to each case following calculation of the numerical residual cancer burden index score. Inter-Pathologist agreement in the assessment of the continuous residual cancer burden score and its components and agreement in the residual cancer burden category assignments were analyzed. The overall concordance correlation coefficient for the agreement in residual cancer burden score among pathologists was 0.931 (95% confidence interval (CI) 0.908-0.949). Overall accuracy of the residual cancer burden score determination was 0.989. The kappa coefficient for overall agreement in the residual cancer burden category assignments was 0.583 (95% CI 0.539-0.626). The metastatic component of the residual cancer burden index showed stronger concordance between pathologists (overall concordance correlation coefficient=0.980; 95% CI 0.954-0.992), than the primary component (overall concordance correlation coefficient=0.795; 95% CI 0.716-0.853). At a median follow-up of 12 years residual cancer burden determined by each of the pathologists had the same prognostic accuracy for distant recurrence-free and survival (overall concordance correlation coefficient=0.995; 95% CI 0.989-0.998). Residual cancer burden assessment is highly reproducible, with reproducible long-term prognostic significance.

Project description:BackgroundThere is a need to develop surrogates for treatment efficacy in the neoadjuvant setting to speed-up drug development and stratify patients according to outcome. Preclinical studies showed that chemotherapy induces an antitumor immune response. In order to develop new surrogates for drug efficacy, we assessed the prognostic value of tumor-infiltrating lymphocytes (TIL) on residual disease after neoadjuvant chemotherapy (NACT) in patients with triple-negative breast cancer (TNBC).Patients and methodsThree hundred four TNBC patients with residual disease after NACT were retrospectively identified in three different hospitals. Hematoxylin and eosin-stained slides from surgical postchemotherapy specimens were evaluated for intratumoral (It-TIL) and stromal (Str-TIL) TIL. Cases were classified as High-TIL if It-TIL and/or Str-TIL >60%.ResultsTIL were assessable for 278 cases. Continuous It-TIL and Str-TIL variables were strong prognostic factors in the multivariate model, both for metastasis-free [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.77-0.96, P = 0.01 and HR 0.85, 95% CI 0.75-0.98, P = 0.02 for Str-TIL and It-TIL, respectively] and overall survival (HR 0.86, 95% CI 0.77-0.97, P = 0.01 and HR 0.86, 95% CI 0.75-0.99, P = 0.03 for Str-TIL and It-TIL, respectively). The 5-year overall survival rate was 91% (95% CI 68% to 97%) for High-TIL patients (n = 27) and 55% (95% CI 48% to 61%) for Low-TIL patients (HR 0.19, 95% CI 0.06-0.61, log-rank P = 0.0017). The major prognostic impact of TIL was seen for patients with large tumor burden following NACT (residual tumor >2 cm and/or node metastasis). In all but one High-TIL case, It-TIL and Str-TIL values were lower on the prechemotherapy sample.ConclusionsThe presence of TIL in residual disease after NACT is associated with better prognosis in TNBC patients. This parameter may represent a new surrogate of drug efficacy to test investigational agents in the neoadjuvant setting and a new prognostic marker to select patients at high risk of relapse.

Project description:BackgroundThe influence of the tumor microenvironment and tumor-stromal interactions on the heterogeneity of response within breast cancer subtypes have just begun to be explored. This study focuses on patients with estrogen receptor-positive/human epidermal growth factor receptor 2-positive (ER+/HER2+) breast cancer receiving neoadjuvant chemotherapy and HER2-targeted therapy (NAC+H), and was designed to identify novel predictive biomarkers by combining gene expression analysis and immunohistochemistry with pathologic response.MethodsWe performed gene expression profiling on pre-NAC+H tumor samples from responding (no or minimal residual disease at surgery) and non-responding patients. Gene set enrichment analysis identified potentially relevant pathways, and immunohistochemical staining of pre-treatment biopsies was used to measure protein levels of those pathways, which were correlated with pathologic response in both univariate and multivariate analysis.ResultsIncreased expression of genes encoding for stromal collagens, including Col10A1, and reduced expression of immune-associated genes, reflecting lower levels of total tumor-infiltrating lymphocytes (TILs), were strongly associated with poor pathologic response. Lower TILs in tumor biopsies correlated with reduced likelihood of achieving an optimal pathologic response, but increased expression of the Col10A1 gene product, colXα1, had greater predictive value than stromal abundance for poor response (OR = 18.9, p = 0.003), and the combination of increased colXα1 expression and low TILs was significantly associated with poor response in multivariate analysis. ROC analysis suggests strong specificity and sensitivity for this combination in predicting treatment response.ConclusionsIncreased expression of stromal colXα1 and low TILs correlate with poor pathologic response in ER+/HER2+ breast tumors. Further studies are needed to confirm their predictive value and impact on long-term outcomes, and to determine whether this collagen exerts a protective effect on the cancer cells or simply reflects other factors within the tumor microenvironment.

Dataset Information

A Prognostic Model Based on Residual Cancer Burden and Tumor-Infiltrating Lymphocytes on Residual Disease after Neoadjuvant Therapy in HER2+ Breast Cancer.

Purpose

Experimental design

Results

Conclusions

Publications

A Prognostic Model Based on Residual Cancer Burden and Tumor-Infiltrating Lymphocytes on Residual Disease after Neoadjuvant Therapy in HER2+ Breast Cancer.

Similar Datasets

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