Prognostic importance of CDK4/6-specific activity as a predictive marker for recurrence in patients with endometrial cancer, with or without adjuvant chemotherapy.
ABSTRACT: Pathologically low-risk endometrial cancer patients do not receive postoperative treatment; however, 10-15% of these patients show recurrence with poor prognosis. We evaluated the clinical importance of cyclin-dependent kinase 4/6 (CDK4/6) activity, and its significance as a novel biomarker for the prognosis and chemo-sensitivity of endometrioid endometrial carcinoma (EEC).Cyclin-dependent kinase 4/6 expression and enzyme activity in 109 tumour samples from patients with EEC were examined with a cell-cycle profiling (C2P) assay. CDK4/6-specific activity (CDK4/6SA) was determined, and its relationship with clinicopathological factors and expression of Ki-67 was analysed.CDK4/6-specific activity was significantly correlated with Ki-67 (P=0.035), but not with any other clinicopathological characteristics. CDK4/6SA was significantly higher (P=0.002) in pathologically low-risk patients (not receiving adjuvant chemotherapy, n=74) than in intermediate- or high-risk patients (receiving adjuvant chemotherapy, n=35). In addition, patients with high CDK4/6SA (>3.0) showed significantly (P=0.024) shorter progression-free survival (PFS) than those with low CDK4/6SA (<3.0). Although Ki-67 expression itself was not a marker for prognosis, the combination of high CDK4/6SA and high Ki-67 expression (>15%) was robustly associated with shorter PFS (P=0.015), and this combination was an independent poor prognostic factor in the low-risk group. Inversely, in the intermediate-/high-risk group, patients with high CDK4/6SA had a tendency of a more favourable prognosis compared with patients with low CDK4/6SA (P=0.063).CDK4/6-specific activity can be used as a biomarker to predict prognosis and, possibly, chemo-sensitivity. The combination of Ki-67 expression might strengthen the clinical usefulness of CDK4/6SA as a biomarker.
Project description:PURPOSE:To investigate whether estrogen receptor (ER), progesterone receptor (PR) and Ki-67 expression discordance before and after neoadjuvant chemotherapy (NAC) correlates with prognosis and treatment of breast cancer patients. METHODS:The study cohort included 482 breast cancer patients at the Zhejiang Cancer Hospital from January 1, 2008, to December 31, 2018. Core needle biopsies and excised tissue biopsies pre- and post-NAC were obtained. Immunohistochemistry was used to determine ER, PR and Ki-67 status. The relationship between biomarker discordance before and after NAC and clinicopathological features was compared retrospectively. RESULTS:ER (n = 482), PR (n = 482) and Ki-67 (n = 448) expression was assessed in the same lesion pre- and post-NAC. Discordance in the three markers pre- and post-NAC was observed in 50 (10.4%), 82 (17.0%) and 373 (77.4%) cases, respectively. Positive-to-negative PR expression changes were the most common type of discordance observed. The risk of death in patients with a PR positive-to-negative conversion was 6.58 times greater than for patients with stable PR expression. The risk of death in patients with increased Ki-67 expression following NAC treatment was 2.05 times greater than for patients with stable Ki-67 expression. CONCLUSION:Breast cancer patients showed changes in ER, PR and/or Ki-67 status throughout NAC, and these changes possibly influenced disease-free survival and overall survival. A switch to negative hormone receptor expression with increased Ki-67 expression following NAC could be indicators of a worse prognosis. Biomarker expression investigations following NAC may potentially improve patient management and survival.
Project description:Thymidine kinase 1 (TK1) is a cell cycle-regulated enzyme with peak expression in the S phase during DNA synthesis, and it is an attractive biomarker of cell proliferation. Serum TK1 activity has demonstrated prognostic value in patients with early-stage breast cancer. Because cyclin-dependent kinase 4/6 (CDK4/6) inhibitors prevent G1/S transition, we hypothesized that serum TK1 could be a biomarker for CDK4/6 inhibitors. We examined the drug-induced change in serum TK1 as well as its correlation with change in tumor Ki-67 levels in patients enrolled in the NeoPalAna trial (ClinicalTrials.gov identifier NCT01723774).Patients with clinical stage II/III estrogen receptor-positive (ER+)/HER2-negative breast cancer enrolled in the NeoPalAna trial received an initial 4 weeks of anastrozole, followed by palbociclib on cycle 1, day 1 (C1D1) for four 28-day cycles, unless C1D15 tumor Ki-67 was?>?10%, in which case patients went off study owing to inadequate response. Surgery occurred following 3-5 weeks of washout from the last dose of palbociclib, except in eight patients who received palbociclib (cycle 5) continuously until surgery. Serum TK1 activity was determined at baseline, C1D1, C1D15, and time of surgery, and we found that it was correlated with tumor Ki-67 and TK1 messenger RNA (mRNA) levels.Despite a significant drop in tumor Ki-67 with anastrozole monotherapy, there was no statistically significant change in TK1 activity. However, a striking reduction in TK1 activity was observed 2 weeks after initiation of palbociclib (C1D15), which then rose significantly with palbociclib washout. At C1D15, TK1 activity was below the detection limit (<20 DiviTum units per liter Du/L) in 92% of patients, indicating a profound effect of palbociclib. There was high concordance, at 89.8% (95% CI: 79.2% -?96.2%), between changes in serum TK1 and tumor Ki-67 in the same direction from C1D1 to C1D15 and from C1D15 to surgery time points. The sensitivity and specificity for the tumor Ki-67-based response by palbociclib-induced decrease in serum TK1 were 94.1% (95% CI 86.2% -?100%) and 84% (95% CI 69.6% -98.4%), respectively. The ?-statistic was 0.76 (p?<?0.001) between TK1 and Ki-67, indicating substantial agreement.Serum TK1 activity is a promising pharmacodynamic marker of palbociclib in ER+ breast cancer, and its value in predicting response to CDK4/6 inhibitors warrants further investigation.ClinicalTrials.gov, NCT01723774. Registered on 6 November 2012.
Project description:Ki-67 protein is a cellular marker for proliferation. The role of Ki-67 as a prognostic biomarker has not been established in gastric cancer. The present study was performed to investigate the significance of Ki-67 expression as a biomarker in early gastric cancer (EGC).With tissue microarray for 320 patients with gastric cancer, we performed immunohistochemical staining for Ki-67. Its clinical significance was analyzed with adjustment via the propensity score-matching. For validation, we performed bootstrap resampling.The median follow-up duration was 72 months (range: 3-120 months). Ki-67-high group showed worse prognosis than Ki-67-low group in EGC (5-YSR, 78.9% vs 92.0%, P? = ?.018), but not in advanced gastric cancer (AGC) (5-YSR, 58.5% vs 59.2%, P? = ?.951). Interestingly, in the patients with well-differentiated histology, prognosis for Ki-67-high group was considerably worse than that for Ki-67-low group (5-YSR, 67.0% vs 94.4%, P? = ?.012), but not in those with moderately differentiated (P? = ?.504) and poorly differentiated histology (P? = ?.905). In this cohort, there was a strong correlation between the proportion of EGC and well-differentiated histology (r? = ?0.215, P? = ?.002). Multivariate analysis also revealed that the high-Ki-67 expression serves as a poor prognostic factor in EGC (HR 4.346, 95% CI 1.397-13.515, P? = ?.011), especially in the well-differentiated histology, but not in all the patients (P? = ?.171). Bootstrap resampling internally validated this result (P? = ?.011).This study suggests that Ki-67 expression may be a good biomarker for prognosis prediction for EGC with well-differentiated histologic type.
Project description:Objective: To elucidate how lncRNA 00668 (LINC00668) influences the development of breast cancer (BC). Materials and methods: Genome-wide expression profile of BC and paracancerous tissues were downloaded from The Cancer Genome Atlas (TCGA) and BC tissues and paracancerous tissues enrolled from our hospital for analyzing the expression level of LINC00668 and its correlation with prognosis. GSEA was conducted to analyze the potential functions of LINC00668. By transfection of sh-LINC00668 in BC cells, proliferation, apoptosis, cell cycle and colony formation of BC cells were accessed. Western blot was conducted to detect protein expressions of Ki-67, CDK4, Bcl-2, p21 and genes in AKT/mTOR pathways after LINC00668 knockdown in BC cells. Finally, tumor-bearing nude mice were administrated with BC cells. We compared the proliferative rate in mice with different administrations. Immunohistochemistry was carried out to access expression levels of Ki-67, CDK4, Bcl-2 and P21 in mice. Results: Both TCGA data and BC tissues harvested from our hospital indicated the higher expression of LINC00668 in BC tissues. LINC00668 expression was negatively correlated to prognosis of BC patients. GSEA pointed out that LINC00668 is enriched in regulations of cell cycle and apoptosis. By transfection of sh-LINC00668 in MDA-MB-231 and MDA-MB-436 cells, the proliferative and colony formation abilities of BC cells decreased. Besides, LINC00668 knockdown in BC cells induced apoptosis and arrested cell cycle. LINC00668 knockdown downregulated Ki-67, CDK4 and Bcl-2, but upregulated p21. The AKT/mTOR pathway was inhibited after LINC00668 silenced. In vivo experiments demonstrated the decreased proliferative rate in tumor-bearing mice administrated with sh-LINC00668 transfected BC cells. Consistently, immunohistochemical results showed lower positive expressions of Ki-67, CDK4 and Bcl-2, but higher positive expression of p21 in sh-LINC00668 group. Conclusion: LINC00668 is highly expressed in BC tissues and can promote the progression of BC by inhibiting apoptosis and accelerating cell cycle progression.
Project description:Ki-67 is an established marker of cell proliferation, and the Ki-67 index correlates with the clinical course of several cancer types, including bladder cancer (BC). However, the clinicopathological and prognostic significance of Ki-67 in bladder cancer remains unclear. Therefore, we performed a systematic review and meta-analysis to clarify this relationship.A comprehensive literature search for relevant studies published up to February 1, 2016, was performed using PubMed, Cochrane Library, Embase and ISI Web of Knowledge. The effects of Ki-67 expression on survival outcome in patients with BC and BC subtypes were evaluated. Furthermore, the relationship between Ki-67 expression and the clinicopathological features of BC were assessed.Thirty-one studies with 5147 bladder cancer patients were selected for evaluation. Ki-67 expression was significantly associated with shorter recurrence-free (HR 1.69, 95% CI: 1.33-2.14), progression-free (HR 1.89, 95% CI: 1.43-2.51), overall (HR 2.03, 95% CI: 1.31-3.16), and cancer-specific (HR 1.69, 95% CI: 1.47-1.95) survival. Moreover, whereas high expression was more common in high tumor stage, recurrence status, tumor size, there was no correlation between high Ki-67 expression and age, gender, smoking habits, and tumor number. Importantly, analysis of the different subgroups of BC suggested that significant correlations between high Ki-67 expression and survival outcome (recurrence-free/progression-free/overall/cancer-specific survival) are present only in European-American patients.The present results indicate that over-expression of Ki-67 is distinctly correlated with poor patient survival. Ki-67 may serve as a valuable biomarker for prognosis in BC patients, particularly in non-Asian BC patients. The results suggest no significant association between Ki-67 expression and BC prognosis in Asian patients. Further efforts are needed to fully clarify this relationship.
Project description:As a cell proliferation biomarker, Ki-67 is principally used in ER+/HER2- breast cancer. However, the importance and the best cutoff point of Ki-67 in triple-negative breast cancer (TNBC) remains unclear and was evaluated in this study.A total of 1800 patients with early invasive TNBC between 2011 and 2016 at Fudan University Shanghai Cancer Center were consecutively recruited for this study. The optimal cutoff for Ki-67 was assessed by Cutoff Finder. Propensity score matching (PSM, ratio?=?1:2) was performed to match the Ki-67low group with the Ki-67high group. Overall survival (OS) and disease-free survival (DFS) were compared between the two groups using the Kaplan-Meier method and Cox regression model. The most relevant cutoff value for Ki-67 for prognosis was 30% (p?=?0.008). At the cutoff point of 30%, worse DFS and OS were observed in the Ki-67high group. In multivariate analyses, N-stage (p?<?0.001), T-stage (p?=?0.038), and Ki-67 at the 30% threshold (p?=?0.020) were independently linked to OS. In subgroup analysis, Ki-67 cutoff at 30% had prognostic and predictive potential for DFS with either tumor size ?2?cm (p?=?0.008) or lymph node-negative (N-) (p?=?0.038) and especially with T1N0M0 (stage I) TNBCs. For 945 N- TNBC patients, adjuvant chemotherapy (CT) was associated with better OS in the Ki-67high group (p?=?0.017) than in the Ki-67low group (p?=?0.875). For stage I/Ki-67low patients, adjuvant CT did not affect DFS (p?=?0.248). Thus, Ki-67 cutoff at 30% had early independent prognostic and predictive potential for OS and DFS in TNBCs, and Ki-67?>?30% was significantly associated with worse prognosis, especially for stage I patients. For stage I/Ki-67low TNBC patients, the advantage of CT is unclear, providing the basis for future de-escalation therapy.
Project description:INTRODUCTION: Ki-67 expression is a biomarker for proliferation. Its prognostic value is recognized in breast cancer (BC) patients with negative axillary nodes, but is less clear in BC patients with positive axillary lymph nodes. METHODS: We retrospectively reviewed the medical records of 1131 Chinese BC patients treated from January 2002 to June 2007 and 450 patients met the inclusion criteria: positive nodes, adjuvant therapy, and complete biomarker profile (estrogen receptor (ER), progesterone receptor (PR), HER2, p53, Ki-67). Univariate and multivariate regression analysis were used to correlate biomarkers and tumor characteristics with metastasis free survival (MFS) and overall survival (OS). RESULTS: Median follow-up time was 46 months (range 5-76 months). The Ki-67 expression was associated significantly with histological grade, ER, PR, HER2, and P53 status (P<0.05). Tumor stage, nodal stage, and ER status were independent prognostic factors for MFS. Ki-67 status was associated significantly with OS but not MFS. To determine whether the extent of LN involvement in the BC patients influenced the role of Ki-67 in survival rates, we compared these variables in patients with 1-3 positive lymph nodes (N1) to those of patients with ? 4 positive lymph nodes. Ki-67 status was an independent prognostic factor for MFS (Hazard Ratio, 3.27, P = 0.026) and overall survival (HR, 10.64, P = 0.007) in patients with 1-3 positive nodes (N1). CONCLUSIONS: The possibility that Ki-67 expression together with clinical factors can improve prediction of the prognosis of BC patients with 1 ? 3 positive axillary lymph nodes warrants further studies.
Project description:Previous studies have elevated the prognostic value of Ki-67 in renal cell carcinoma (RCC), but the reports are controversial and inconsistent. We conducted a systematic review and meta-analysis to clarify the significance of Ki-67 in RCC prognosis. We systematically searched PubMed, Web of Science, and Embase to identify relevant studies until April 2016. Based on the inclusion and exclusion criteria, 20 studies, including 5,398 patients, were eligible for further analysis. Results showed that high Ki-67 expression in RCC was associated with poor OS (HR?=?1.95, 95% CI: 1.44-2.64), CSS (HR?=?1.67, 95% CI: 1.47-1.89), and DFS (HR?=?2.56, 95% CI: 1.79-3.67). In addition, high Ki-67 expression was significantly associated with TNM stage (III/IV vs. I/II: RR?=?2.03, 95% CI: 1.68-2.44), pathological T stage (T3/T4 vs. T1/T2: RR?=?1.67, 95% CI: 1.35-2.06), metastasis (yes vs. no: RR?=?2.15, 95% CI: 1.77-2.62), and Fuhrman grade (III/IV vs. I/II: RR?=?1.77, 95% CI: 1.20-2.60). Our study suggested that Ki-67 was a prognostic marker in RCC. High Ki-67 expression was correlated with poor prognosis and advanced clinicopathological features, and it could serve as a biomarker for disease management.
Project description:The prognostic value and clinicopathologic significance of Ki-67 expression in gastric cancer patients was controversial. This meta-analysis was performed to clarify the prognostic value and clinicopathologic significance of Ki-67 expression in gastric cancer patients.Several electronic databases were searched for eligible studies. The pooled odds ratio (OR), hazard ratios (HR) and 95% confidence interval(CI) were calculated to explore the prognostic value and clinicopathologic significance of Ki-67 expression for disease free survival and overall survival.Totally 5600 gastric cancer patients from 29 studies were included in this study. High Ki-67 expression was significantly related with Lauren's classification (OR = 1.70; P = 0.001; 95%CI: 1.40-2.06) and tumor size(OR = 1.54; P = 0.006; 95%CI: 1.14-2.09). However, high Ki-67 expression was not significantly associated with lymph node metastasis (OR = 1.37; P = 0.138; 95% CI: 0.90-2.08) , tumor stage (OR = 1.31; P = 0.296; 95% CI: 0.79-2.16) and tumor differentiation (OR = 1.03; P = 0.839; 95% CI: 0.78-1.35). The pooled HRs were 1.87(P = 0.001; 95% CI 1.30-2.69) for disease free survival and 1.23(P = 0.005; 95% CI 1.06-1.42) for overall survival.High Ki-67 expression may serve as a predictive biomarker for poor prognosis in gastric cancer patients. Stratification by Ki-67 expression may be a consideration for selection of therapeutic regimen and integrated managements.
Project description:Tumor biomarkers including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki-67 are routinely tested in breast cancer patients and their status guides clinical management and predicts prognosis. A few retrospective studies have suggested that neoadjuvant chemotherapy (NAC) in breast cancer may change the status of biomarker expression, which in turn will affect further management of these patients. In this study we take advantage of a relatively large cohort and aim to study the effect of NAC on biomarker expression and explore the impact of tumor size and lymph node involvement on biomarker status changes. We collected 107 patients with invasive breast cancer who received at least three cycles of NAC. We retrospectively performed and scored the immunohistochemistry (IHC) of ER, PR, HER2 and Ki-67 using both the diagnostic core biopsies before NAC and excisional specimens following NAC. HER2 gene status was assessed by fluorescence in situ hybridization for cases with IHC result of 2+. We demonstrated that there was a significant decrease in expression of PR (P = 0.013) and Ki-67 (P = 0.000) in post-NAC specimens compared to pre-NAC core biopsies. In addition, cases with large tumor size (? 2 cm) and cases with lymph node metastasis were more frequently to have biomarker changes. Finally we studied cases with HER2 status changes after NAC treatments in detail and emphasized the nature of tumor heterogeneity.