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Cell killing and resistance in pre-operative breast cancer chemotherapy.

ABSTRACT: BACKGROUND: Despite the recent development of technologies giving detailed images of tumours in vivo, direct or indirect ways to measure how many cells are actually killed by a treatment or are resistant to it are still beyond our reach. METHODS: We designed a simple model of tumour progression during treatment, based on descriptions of the key phenomena of proliferation, quiescence, cell killing and resistance, and giving as output the macroscopically measurable tumour volume and growth fraction. The model was applied to a database of the time course of volumes of breast cancer in patients undergoing pre-operative chemotherapy, for which the initial estimate of proliferating cells by the measure of the percentage of Ki67-positive cells was available. RESULTS: The analysis recognises different patterns of response to treatment. In one subgroup of patients the fitting implied drug resistance. In another subgroup there was a shift to higher sensitivity during the therapy. In the subgroup of patients where killing of cycling cells had the highest score, the drugs showed variable efficacy against quiescent cells. CONCLUSION: The approach was feasible, providing items of information not otherwise available. Additional data, particularly sequential Ki67 measures, could be added to the system, potentially reducing uncertainty in estimates of parameter values.

SUBMITTER: Ubezio P

PROVIDER: S-EPMC2496916 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The importance of inflammation is increasingly noticed in cancer. The aim of this study was to analyze the prognostic influence of pre-operative serum C-reactive protein (CRP) in a cohort of 148 lymph node-negative breast cancer patients. The prognostic significance of CRP level for disease-free survival (DFS), metastasis-free survival (MFS) and overall survival (OS) was evaluated using univariate and multivariate Cox regression, also including information on age at diagnosis, tumor size, tumor grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, proliferation index (Ki67) and molecular subtype, as well as an assessment of the presence of necrosis and inflammation in the tumor tissue. Univariate analysis showed that CRP, as a continuous variable, was significantly associated with DFS (P = 0.002, hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 1.02-1.07) and OS (P = 0.036, HR= 1.03, 95% CI = 1.00-1.06), whereas a trend was observed for MFS (P = 0.111). In the multivariate analysis, CRP retained its significance for DFS (P = 0.033, HR= 1.01, 95% CI = 1.00-1.07) as well as OS (P = 0.023, HR= 1.03, 95% CI = 1.00-1.06), independent of established prognostic factors. Furthermore, large-scale gene expression analysis by Affymetrix HG-U133A arrays was performed for 72 (48.6%) patients. The correlations between serum CRP and gene expression levels in the corresponding carcinoma of the breast were assessed using Spearman's rank correlation, controlled for false-discovery rate. No significant correlation was observed between CRP level and gene expression indicative of an ongoing local inflammatory process. In summary, pre-operatively elevated CRP levels at the time of diagnosis were associated with shorter DFS and OS independent of established prognostic factors in node-negative breast cancer, supporting a possible link between inflammation and prognosis in breast cancer.

Project description:Peri-operative chemotherapy has been proposed to improve the survival of patients with colorectal cancer hepatic metastases (CRCHM). However, the role of the adjuvant chemotherapy post-metastasectomy for CRCHM patients who have undergone pre-operative chemotherapy is still undetermined. We retrospectively analyzed the role of adjuvant chemotherapy post-metastasectomy on relapse-free survival (RFS) and overall survival (OS) in 163 CRCHM patients who received pre-operative chemotherapy using a Kaplan-Meier curve and univariate/multiple Cox model. Ten patients with rapidly progressing disease were further excluded in a sensitivity analysis. Seven risk factors (metachronous/synchronous metastases, differentiated grade of the primary tumor, number of metastases, size of the max metastasis, duration of pre-operative chemotherapy, radiologic response and pathologic regression) were used to stratify patients and investigate the beneficial features of adjuvant chemotherapy post-metastasectomy. The results indicated that adjuvant chemotherapy post-metastasectomy prolonged both RFS (median RFS: 3.3 vs. 10.2 m, P = 0.002) and OS (median OS: 28.1 vs. 40.7 m, P = 0.005) in CRCHM patients who received pre-operative chemotherapy. After adjusting for other risk factors in a multiple Cox model, the adjuvant chemotherapy group was estimated to have a 54.0 % relapse-free survival (hazard ratio (HR) = 0.46, 95 % confidence interval (CI) 0.31 - 0.69, P < 0.001) and a 55.0 % overall survival (HR [95 % CI]: 0.45 [0.26 - 0.78], P = 0.005) advantage compared to patients without adjuvant chemotherapy. Additionally, the benefit of adjuvant chemotherapy post-liver resection remained in sensitivity analysis. After the risk stratification, patients with synchronous metastases, poor differentiation, ? 3 metastases per patient, size of the maximum metastasis >3 cm, a short duration of pre-operative chemotherapy, radiologic response and poor pathologic regression seem to benefit more from adjuvant chemotherapy. To sum up, adjuvant chemotherapy post-metastasectomy might be considered for CRCHM patients who have received preoperative chemotherapy, especially for those with high-risk factors.

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Cell killing and resistance in pre-operative breast cancer chemotherapy.

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