Ki-67/MIB-1 as a Prognostic Marker in Cervical Cancer - a Systematic Review with Meta-Analysis

Background: In cervical cancer patients it has been reported that there in a significant Ki-67/MIB-1 expressionis correlated with survival in cervical cancer patients. However, the prognostic value is still not well understood.Materials and Methods: In the present meta-analysis the prognostic value of Ki-67/MIB-1 with regard to overallsurvival (OS) and disease-free survival (DFS) in cervical cancer was investigated. The databases of PubMed, ISIWeb of Science, Cochrane Central Register of Controlled Trials, EMBASE, Science Direct and Wiley OnlineLibrary were used to identify appropriate literature. Results: In order to explore the relationship between Ki-67/MIB-1 and cervical cancer, we have included 13 studies covering 894 patients in the current meta-analysis. Theeffect of Ki-67/MIB-1 on OS for pooled random effects HR estimate was 1.63 (95%confidence interval (CI) 1.09-2.45; P<0.05). The pooled HR for DFS was 1.26 (95%CI 0.58-2.73; P>0.05) and the subgroup analysis indicatedKi-67/MIB1 was associated with DFS (HR=3.67, 95%CI 2.65-5.09) in Asians. Conclusions: According to thismeta-analysis, Ki-67/MIB-1 has prognostic value for OS in patients suffering from cervical cancer. For betterevaluation of the prognostic role of Ki-67/MIB-1 on DFS, studies with larger numbers of patients are needed tovalidate present findings in the future.     

Prognostic value of Ki-67 labeling index in patients with node-negative, triple-negative breast cancer

The aim of this analysis was to investigate the usefulness of Ki-67 labeling index (LI) for the identification of different prognostic subgroups in primary node-negative, triple negative breast cancer (TNBC) patients. From January 1997 to December 2005, 1,053 patients operated for TNBC were identified through the institutional clinical database. The study was performed in accordance with REMARK criteria. The relationship between Ki-67LI and the risk of breast-related deaths was evaluated with a multivariable Cox regression model. Cubic splines were used to model Ki-67LI as a continuous variable. We selected 496 consecutive patients with node-negative TNBC. Median age was 52 years, median Ki-67LI 48% (range 4-95), and median follow up 6 years (range 0.5-13). Total deaths and deaths from BC were 52 (10.5%) and 38 (7.7%), respectively. Ki-67LI increased with decreasing age (P<0.01), increasing tumor size (P<0.01), and grade (P<0.01). When analyzing Ki-67LI as a continuous variable, the risk of death from BC increased steeply with increasing Ki-67LI up to about 35% and remained flat for higher values (adjusted effect of Ki-67 P=0.049; adjusted nonlinear effect P=0.021). Accordingly, when dividing patients into lower (≤35%) and higher (>35%) Ki-67LI subgroups, the 5-year cumulative incidence of breast-related deaths were 2.3 and 9.0%, respectively, with an adjusted HR(>35 vs ≤35) of 2.3 (95% CI 1.0-5.8, P=0.046). Within the group of patients with node-negative TNBC, Ki-67LI was associated with different prognoses subgroups. Ki-67LI might be useful in the design of trials of risk-adapted adjuvant therapies.     

RHAMM, p21 combined phenotype identifies microsatellite instability-high colorectal cancers with a highly adverse prognosis.

PURPOSE: The aim of this study was to identify prognostic subgroups of microsatellite instability-high (MSI-H) colorectal cancers by combined analysis of 10 well-established immunohistochemical tumor markers and 7 clinicopathologic features. EXPERIMENTAL DESIGN: Using a tissue microarray, immunohistochemistry was done on 223 cases of MSI-H cancers for the following protein markers: raf-1 kinase inhibitor protein, receptor for hyaluronic acid-mediated motility, apoptosis protease activating factor-1, mammalian sterile20-like kinase 1, p21, p27, p53, ephrin B2 receptor, Ki-67, and epidermal growth factor receptor. Seven clinicopathologic features and all tumor markers were evaluated in univariate and multivariable analyses. RESULTS: RHAMM overexpression [P < 0.001; hazard ratio [HR; 95% confidence interval (95% CI)], 3.86 (2.19-6.81)], loss of p21 [P = 0.002; 0.33 (0.16-0.67)], and higher N stage [P < 0.001; 3.31 (1.9-5.8)] were independent adverse prognostic factors. RHAMM/p21 combinations were evaluated by N stage. Significant differences in survival were observed with various RHAMM/p21 combinations (P < 0.001). Both node-negative and node-positive patients with RHAMM- tumors survived more than 120 months. Node-positive RHAMM+ patients had a strikingly worse prognosis [16.0 (10.0-63.0) months] and could further be divided into p21- patients [14.0 (9.0-27.0) months] and p21+ patients surviving 47.0 months. RHAMM+/p21- node-negative patients had a significantly shorter survival time than RHAMM+/p21+ tumors (P = 0.021). CONCLUSION: These results suggest that the combined phenotype of RHAMM and p21 expression is an invaluable independent prognostic immunohistochemical profile in MSI-H colorectal cancer. Based on the prognostic subgroups identified in our cohort, node-negative patients overexpressing RHAMM but with loss of p21 may derive a potential benefit from postoperative treatment, whereas adjuvant chemotherapy should be reconsidered for MSI-H node-positive RHAMM- tumors.     

Adjuvant radiotherapy and survival for patients with node-positive head and neck cancer: an analysis by primary site and nodal stage

PURPOSE: Adjuvant radiotherapy (RT) is frequently recommended for node-positive head and neck squamous cell carcinoma (HNSCC) treated with primary surgery. The impact of RT on survival for various subgroups of node-positive HNSCC has not been clearly demonstrated. METHODS AND MATERIALS: Within the Surveillance, Epidemiology, and End Results (SEER) Database, we identified 5297 patients with node-positive (N1 to N3) HNSCC treated with definitive surgery with or without adjuvant RT between 1988 and 2001. The median follow-up was 4.4 years. RESULTS: Adjuvant RT significantly improved 5-year overall survival (46.3%: 95% confidence interval [CI], 44.7-48.0% for surgery + RT, vs. 35.2%: 95% CI, 32.0-38.5% for surgery alone, p < 0.001) and cancer-specific survival (54.8%: 95% CI, 53.2-56.4% for surgery + RT, vs. 46.2% for surgery alone 95% CI, 42.4-50.0%, p < 0.05). Use of adjuvant RT remained a significant predictor of survival on multivariable analysis (hazard ratio [HR], 0.75; 95% CI, 0.68-0.83; p < 0.001). Subset analyses demonstrated that adjuvant RT was associated with significantly improved survival for N1 (HR, 0.78; 95% CI; 0.67-0.90; p = 0.001), N2a (HR, 0.82; 95% CI, 0.67-0.99, p = 0.048) and N2b to N3 nodal disease (HR, 0.62; 95% CI, 0.51-0.75; p < 0.001). Adjuvant RT increased overall survival for node-positive patients with oropharynx (HR, 0.72; 95% CI, 0.57-0.90; p = 0.004), hypopharynx (HR, 0.66; 95% CI, 0.49 to 0.88; p = 0.004), larynx (HR, 0.66; 95% CI, 0.52-0.84; p = 0.001), and oral cavity (HR, 0.84; 95% CI, 0.73-0.98; p = 0.025) primary tumors. CONCLUSIONS: In a large population-based analysis, adjuvant RT significantly improves overall survival for patients with node-positive HNSCC. All nodal stages, including N1, appear to benefit from the addition of RT to definitive surgery.     

The utility of mitotic index, oestrogen receptor and Ki-67 measurements in the creation of novel prognostic indices for node-negative breast cancer.

INTRODUCTION: Prognostic factors can be useful to identify node-negative patients at increased risk of relapse who should receive adjuvant treatment. In the past, oestrogen receptor status and mitotic index have been shown to be significant predictors of prognosis. Different techniques for the measurement of these prognostic factors are available. METHODS: Paraffin-embedded tumour specimens from 441 pre-menopausal patients with node-negative breast cancer who were previously randomized onto a trial comparing peri-operative chemotherapy with no further therapy were studied. Oestrogen receptor status was determined by the classical biochemical assay and by immunohistochemistry (ER-IA). Mitotic index was assessed by counting the number of mitoses and by calculating the percentage of tumour cells positively staining for the antibody Ki-67. RESULTS: There was a good correlation between ER-IA and the biochemical ER-assay (P<0.01), and the percentage of Ki-67 positive tumour cells and mitotic counts (P<0.01) respectively. However, ER-IA significantly predicted disease-free survival (RR=2.67, 95% CI: 1.60-4.44, P<0.01) whereas the biochemical assay was only borderline significant (RR=1.54, 95% CI: 1.00-2.36, P=0.05). Similarly, Ki-67 was a stronger indicator of prognosis (RR=2.84, 95% CI: 1.80-4.48, P<0.01) than mitotic counts (RR=1.56, 95% CI: 1.22-2. 00, P<0.01). CONCLUSIONS: We conclude that ER-IA performs better in predicting prognosis than the classical biochemical oestrogen receptor assay. Ki-67 is a more accurate marker for tumour cell proliferation and predicts prognosis of patients with breast cancer better than do mitotic counts.     

Role of endocrine responsiveness and adjuvant therapy in very young women (below 35 years) with operable breast cancer and node negative disease.

BACKGROUND: There is limited knowledge about prognosis, and treatment effects in young women with node-negative disease. PATIENTS AND METHODS: We evaluated biological features, treatment recommendations and prognosis for 841 premenopausal patients with pT1-3, pN0 and M0, operated from 1997 to 2001. RESULTS: Patients below 35 years (101, 12%) were more likely to have tumors > 2 cm (35.6% versus 24.2%, P = 0.002), grade 3 (48.5% versus 31.9%, P = 0.009) and with elevated Ki-67 expression (62.4% versus 50.7%, P = 0.002). At the multivariate analysis a statistically significant difference in disease-free survival (DFS, HR 4.44; 95% CI 2.53 to 7.78, P < 0.0001), risk of distant metastases (DDFS) (HR 3.23; 95% CI 1.32 to 7.94, P = 0.011) and overall survival (OS) (HR 2.89; 95% CI 1.06 to 7.87, P = 0.038) was observed for younger versus older patients and in the subgroup with endocrine responsive tumors (DFS, HR 5.17, 95% CI 2.72-9.83, P = < 0.0001; DDFS, 3.76, 95% CI 1.33-10.6, P = 0.013; OS, 4.71, 95% CI 1.09-20.4, P = 0.039 ). CONCLUSIONS: Compared with less young, very young patients with endocrine responsive and node-negative breast cancer have a worse prognosis. Tailored treatments should be explored in this cohort of patients.     

Cell proliferation in prostate cancer patients with lymph node metastasis: a marker for progression.

The biological aggressiveness of lymph node-positive prostate cancer is closely linked to cancer volume in nodal metastases. We evaluated MIB-1 (Ki-67) labeling index and bcl-2 expression in primary cancer and matched nodal metastases from 138 node-positive patients treated with radical prostatectomy and bilateral pelvic lymphadenectomy between 1987 and 1992 at the Mayo Clinic. One hundred twenty-eight patients (93%) received androgen deprivation therapy within 90 days after radical prostatectomy. Mean patient age was 66 years (range, 51-78). The median follow-up was 6.7 years (range, 0.03-11). MIB-1 (Ki-67) labeling index was determined by digital image analysis, and nodal cancer volume was determined by the grid method. Systemic progression, defined as the presence of distant metastasis documented by biopsy or radiographic examination, was used as an outcome end point in the Cox proportional hazard models. MIB-1 labeling index in nodal metastases was predictive of systemic progression-free survival (P = 0.001). The 8-year systemic progression-free survival was 100% for those with MIB-1 labeling index <3.5% compared with 78% for those with MIB-1 labeling index > or =7.8%. MIB-1 labeling index correlated with Gleason score, DNA ploidy, and nodal cancer volume (P<0.001, 0.04, and <0.001, respectively). After controlling for nodal cancer volume, MIB-1 labeling index remained significant in predicting systemic progression-free survival (P = 0.047). bcl-2 expression in the primary cancer and lymph node metastasis was associated with systemic progression-free survival in univariate analysis (P = 0.027 and 0.048, respectively) but was not significant after adjusting for nodal cancer volume (P = 0.52 and 0.17, respectively). Our data indicate that assessment of cell proliferation in nodal metastasis is predictive of clinical outcome in prostate cancer patients with regional lymph node metastasis.     

Prognostic importance of c-erbB-2 expression in breast cancer. International (Ludwig) Breast Cancer Study Group.

PURPOSE: To evaluate the prognostic importance of immunocytochemically determined c-erbB-2 overexpression in the primary tumors of patients with breast cancer. PATIENTS AND METHODS: Primary tumors from 1,506 breast cancer patients (760 node-negative and 746 node-positive) who were treated in the International (Ludwig) Breast Cancer Study Group Trial V were studied. Node-negative patients were allocated randomly to either a single cycle of perioperative chemotherapy (PeCT) or no adjuvant treatment, and node-positive patients received either a prolonged chemotherapy (with tamoxifen for postmenopausal patients) or a single perioperative cycle. RESULTS: Tumors from 16% of the node-negative patients and 19% of the node-positive patients were found to be c-erbB-2-positive. In both groups c-erbB-2 positivity correlated with negative progesterone receptors (PR), negative estrogen receptors (ER), and high tumor grade. Lobular carcinomas were all negative, and, thus support the view that such tumors represent a defined subtype of breast carcinoma. The expression of c-erbB-2 was prognostically significant for node-positive but not for node-negative patients. However, in both subgroups, the prognostic significance was greater for patients who had received more adjuvant therapy. For node-positive patients, the effect of prolonged-duration therapy on disease-free survival (DFS) was greater for patients without c-erbB-2 overexpression (hazards ratio [HR], = 0.57; 95% confidence interval [CI], 0.46 to 0.72) than for those with c-erbB-2 overexpression (HR, 0.77; 95% CI, 0.51 to 1.16). Similarly, for node-negative patients, the effect of PeCT on DFS was greater for those without c-erbB-2 overexpression (HR, 0.82; 95% CI, 0.61 to 1.09) than for those with c-erbB-2 overexpression (HR, 1.22; 95% CI, 0.66 to 2.25). CONCLUSION: We conclude that tumors with overexpression of the c-erbB-2 oncogene are less responsive to cyclophosphamide, methotrexate, and fluorouracil (CMF)-containing adjuvant therapy regimens than those with a normal amount of gene product.     

Ki-67 as a Prognostic Marker in Upper Urinary Tract Urothelial Carcinoma: A Systematic Review and Meta-Analysis

Background

We systematically evaluated the prognostic significance of Ki-67 on survival outcomes in patients with upper urinary tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU).

Prognosis in women with small (T1mic,T1a,T1b) node-negative operable breast cancer by immunohistochemically selected subtypes

Knowledge is limited about prognostic significance of breast cancer subtypes among women with small invasive node-negative breast tumours. We explored patterns of recurrence in 1691 women with pT1mic/T1a/T1b, pN0 and M0 breast cancer according to four immunohistochemically defined tumour subtypes: (i) Luminal A (ER-positive, PgR-positive, HER2-negative and Ki-67 < 14%); (ii) Luminal B (ER-positive and/or PgR-positive, HER2-positive and/or Ki-67 ≥ 14%); (iii) HER2-positive, both endocrine receptors absent; and (iv) Triple Negative. At multivariate analysis, women with the Triple Negative breast cancer subtype had an increased risk of loco-regional relapse (LRR) (Hazards Ratio (HR) 3.58; 95%CI: 1.40-9.13) and breast cancer related events (HR 2.18; 95%CI: 1.04-4.57). Overall, Luminal B subtype was not associated with a statistically significant increased risk of recurrence compared with Luminal A, while patients with Luminal B subtype tumours overexpressing HER2 had a 2 fold risk of reduced breast cancer related survival (BCS), but not an increased risk of LRR and distant metastases. Women with HER2 breast cancer subtype had a statistically significant increased risk of LRR (HR 4.53; 95%CI: 1.56-13.1), distant metastases and reduced BCS (HR 3.22; 95%CI: 1.44-7.18) and overall survival (HR 2.87; 95%CI: 1.05-7.89) when compared with the Luminal A subtype, at multivariate analysis. In conclusion, women with small size, node-negative, breast cancer are at higher risk of relapse if with HER2-positive endocrine receptor absent or Triple Negative disease.     

Ki-67 is a Valuable Prognostic Factor in Gliomas: Evidence from a Systematic Review and Meta-analysis

Ki-67 has been widely used as an indicator of cell proliferation in gliomas. However, the role of Ki-67 as aprognostic marker is still undefined. Thus, we conducted a meta-analysis of the published literatures in order toclarify the impact of Ki-67 on survival in glioma cases. Eligible studies were identified in PubMed, EMBASE, ISIWeb of Science, Cochrane Central Register of Controlled Trials, Science Direct and Wiley Online Library withthe last search updated on August 31, 2014. The clinical characteristics, overall survival (OS) and progressionfreesurvival (PFS) together with Ki-67 expression at different time points were extracted. A total of 51 studies,covering 4,307 patients, were included in the current meta-analysis. The results showed that overexpression ofKi-67 can predict poor OS (HR=1.66, 95%CI: 1.53-1.80; Z=11.87; p=0.000) and poor PFS (HR=1.67, 95%CI:1.47-1.91; Z=7.67; p=0.000) in gliomas. Moreover, subgroup analyses also indicated that high level of Ki-67expression was related to poor OS and PFS in glioma patients regardless of region, pathology type, cut-offvalue and statistical method. In conclusion, the current meta-analysis revealed that Ki-67 expression might bea predicative factor for poor prognosis of glioma patients, emphasizing its importance as a predictor.     

Minimal and small size invasive breast cancer with no axillary lymph node involvement: the need for tailored adjuvant therapies.

BACKGROUND: Prognosis of patients with node-negative disease and tumor size <1 cm is a matter of controversy. While data exist to clearly correlate small tumor size to better prognosis, the fact that very small breast cancers may express biological markers of dire prognosis leads many to ignore small tumor size during treatment decision-making. PATIENTS AND METHODS: Data from 425 patients classified as having node-negative pT1mic, pT1a or pT1b after surgery (from April 1997 to December 2001) at the European Institute of Oncology, were analyzed to be described as disease-free according to prognostic variables including: Ki-67 (<20% versus > or =20% of the cells), ER (absent versus positive > or =1% of the cells), PgR (absent versus positive > or =1% of the cells), grade, overexpression or amplification of HER2/neu, presence of peritumoral vascular invasion and age (by decade). The median follow-up for this cohort of patients was 43 months. RESULTS: No local or distant relapse was observed for patients with pT1mic breast cancer; 4-year disease-free survival for pT1a and pT1b was 97.0% and 97.6%, respectively. In both univariate and multivariate analyses the most relevant prognostic factor for this low-risk population was Ki-67 labeling. The 4-year disease-free survival was 99.2% for tumors with low Ki-67 and 93.3% for tumors with high Ki-67 (> or =20%) labeling. The hazard ratio (HR) for patients with high Ki-67 was 12.9 (95% CI 1.5-112.0, P=0.02). CONCLUSIONS: Within the first 4 years, microinvasive breast cancer parallels ductal carcinoma in situ (DCIS) rather than invasive carcinoma. Costs and benefits of adjuvant therapy should be accurately weighted in these patients. Patients with pT1a and pT1b, node-negative disease have a limited but substantial risk of recurrence and therefore adjuvant therapy, according to endocrine responsiveness of the tumor and patient preference, should continue to be offered as a reasonable treatment option.     

Protein expression, survival and docetaxel benefit in node-positive breast cancer treated with adjuvant chemotherapy in the FNCLCC - PACS 01 randomized trial

Introduction

The PACS01 trial has demonstrated that a docetaxel addition to adjuvant anthracycline-based chemotherapy improves disease-free survival (DFS) and overall survival of node-positive early breast cancer (EBC). We searched for prognostic and predictive markers for docetaxel's benefit.

Methods

Tumor samples from 1,099 recruited women were analyzed for the expression of 34 selected proteins using immunohistochemistry. The prognostic and predictive values of each marker and four molecular subtypes (luminal A, luminal B, HER2-overexpressing, and triple-negative) were tested.

Results

Progesterone receptor-negativity (HR = 0.66; 95% CI 0.47 to 0.92, P = 0.013), and Ki67-positivity (HR = 1.53; 95% CI 1.12 to 2.08, P = 0.007) were independent adverse prognostic factors. Out of the 34 proteins, only Ki67-positivity was associated with DFS improvement with docetaxel addition (adjusted HR = 0.51, 95% CI 0.33 to 0.79 for Ki67-positive versus HR = 1.10, 95% CI 0.75 to 1.61 for Ki67-negative tumors, P for interaction = 0.012). Molecular subtyping predicted the docetaxel benefit, but without providing additional information to Ki67 status. The luminal A subtype did not benefit from docetaxel (HR = 1.16, 95% CI 0.73 to 1.84); the reduction in the relapse risk was 53% (HR = 0.47, 95% CI 0.22 to 1.01), 34% (HR = 0.66, 95% CI 0.37 to 1.19), and 12% (HR = 0.88, 95% CI 0.49 to 1.57) in the luminal B, HER2-overexpressing, and triple-negative subtypes, respectively.

Conclusions

In patients with node-positive EBC receiving adjuvant anthracycline-based chemotherapy, the most powerful predictor of docetaxel benefit is Ki67-positivity.     

The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic infiltration and COX-2 expression and survival in patients with transitional cell carcinoma of the urinary bladder

The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic infiltration, and COX-2 expression and survival was examined in patients with transitional cell carcinoma of the urinary bladder (n=103). Sixty-one patients had superficial disease and 42 patients had invasive disease. Cancer-specific survival was shorter in those patients with invasive compared with superficial bladder cancer (P<0.001). On univariate analysis, stratified by stage, increased Ki-67 labelling index (P<0.05), increased COX-2 expression (P<0.05), C-reactive protein (P<0.05) and adjuvant therapy (P<0.01) were associated with poorer cancer-specific survival. On multivariate analysis of these significant factors, stratified by stage, only C-reactive protein (HR 2.89, 95% CI 1.42-5.91, P=0.004) and adjuvant therapy (HR 0.29, 95% CI 0.14-0.62, P=0.001) were independently associated with poorer cancer-specific survival. These results would suggest that tumour-based factors such as grade, COX-2 expression or T-lymphocytic infiltration are subordinate to systemic factors such as C-reactive protein in determining survival in patients with transitional cell carcinoma of the urinary bladder.     

The impact of old age on cancer-specific and non-cancer-related survival following elective potentially curative surgery for Dukes A/B colorectal cancer

Previous studies have suggested that survival following surgery for colorectal cancer is poorer in the elderly. However, the findings were inconsistent and none of the studies adjusted for case mix. The aim of this study was to establish whether there were age-related differences in cancer (colorectal)-specific and non-cancer (colorectal)-related survival in patients undergoing elective potentially curative resection for Dukes stage A/B colorectal cancer. One thousand and forty three patients who underwent elective potentially curative resection for Dukes' A/B colorectal cancer between 1991 and 1994 in 11 hospitals in Scotland were included in the study. Ten year cancer-specific and non-cancer-related survival and the hazard ratios were calculated according to age groups (<64; 65-74/>74 years). On follow-up 273 patients died of their cancer and 328 died of non-cancer-related causes. At 10 years, overall survival was 45%, cancer specific was 70% and non-cancer-related survival was 64%. On multivariate analysis of all factors, age (HR 1.38, 95% CI 1.18-1.62, P<0.001), sex (HR 1.74, 95% CI 1.36-2.23, P<0.001), site (HR 1.42, 95% CI 1.11-1.81, P<0.01) and Dukes' stage (HR 1.71, 1.19-2.47, P<0.01) were independently associated with cancer-specific survival. On multivariate analysis of all factors, age (HR 2.14, 1.84-2.49, P<0.001), sex (HR 1.43, 1.15-1.79, P<0.01) and deprivation (HR 1.30, 1.09-1.55, P<0.01) were independently associated with non-cancer-related survival. The results of this study show that increasing age impacts negatively both on cancer-specific and non-cancer-related survival following elective potentially curative resection for node-negative colorectal cancer. However, the effect of increasing age is greater on the non-cancer-related survival. These results suggest that cancer-specific and non-cancer-related mortality should be considered separately in survival analysis of these cancer patients.     

Prognostic role of the extent of peritumoral vascular invasion in operable breast cancer.

BACKGROUND: The clinical relevance of the degree of peritumoral vascular invasion (PVI) in patients with no or limited involvement of the axillary nodes is unknown. Materials and methods: 2606 consecutive patients with pT1-3, pN0 (1586)-1a (1020) and M0, operated and counseled for medical therapy from 1/2000 to 12/2002, were prospectively classified according to the degree of PVI: absent (2017, 77.4%), focal (368, 14.1%), moderate (51, 2.0%) and extensive (170, 6.5%). RESULTS: Patients with extensive PVI were more likely to be younger, to have larger tumors, high tumor grade, axillary-positive nodes, high Ki-67 expression and HER2/neu over-expression compared with patients having less PVI (P for trend, <0.0001). In patients with node-negative disease a statistically significant difference in disease-free survival (DFS), risk of distant metastases and overall survival (OS) was observed at the multivariate analysis for extensive PVI versus no PVI (hazard ratios: 2.11, 95% CI, 1.02 to 4.34, P = 0.04 for DFS; 4.51, 95% CI, 1.96 to 10.4, P< 0.001 for distant metastases; 3.55, 95% CI, 1.24 to 10.1, P = 0.02 for OS). CONCLUSIONS: The extent of vascular invasion should be considered in the therapeutic algorithm in order to properly select targeted adjuvant treatment.     

Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials

BackgroundTwo recent studies (ABC-02 [UK] and BT22 [Japan]) have demonstrated the superiority of cisplatin and gemcitabine (CisGem) chemotherapy over gemcitabine (Gem) alone for patients with pathologically proven advanced biliary tract cancer (BTC: cholangiocarcinoma, gallbladder and ampullary cancers). This pre-planned analysis evaluates the efficacy of CisGem with increased statistical power.Patients and methodsWe carried out a meta-analysis of individual patient-level data of these studies to establish the effect of CisGem versus Gem on progression-free survival (PFS), overall survival (OS) and carried out exploratory subgroup analyses.ResultsCisGem demonstrates a significant improvement in PFS [hazard ratio (HR) = 0.64, 95% confidence interval (CI) 0.53–0.76, P < 0.001] and OS (HR = 0.65, 95% CI 0.54–0.78, P < 0.001) over Gem. This effect is most marked among patients with good performance status (PS 0–1): HR for PFS is 0.61 (95% CI 0.51–0.74), P < 0.001 and OS HR = 0.64 (95% CI 0.53–0.77), P < 0.001. CisGem resulted in improved PFS and OS for intra- and extra-hepatic cholangiocarcinomas and gallbladder cancer. The treatment effect between UK and Japanese patients was consistent with respect to OS (HR = 0.65, 95% CI 0.53–0.79 and 0.65, 95% CI 0.42–1.03, respectively); with similar OS in the combination arms (median 11.7 and 11.1 months, respectively). Subgroups least likely to benefit included patients with ampullary tumours and poor performance status (PS2).ConclusionsCisGem is the standard of care for the first-line treatment of good-PS patients with advanced BTC regardless of ethnicity. Future studies should aim to enhance the effectiveness of this regimen in the first-line setting, establish the role of subsequent (second-line) therapy and assess the role of rationally developed molecular-targeted therapies.     

Expression of Bcl-2 in node-negative breast cancer is associated with various prognostic factors, but does not predict response to one course of perioperative chemotherapy.

The aim of this study was to assess relationships between Bcl-2 expression, response to chemotherapy and a number of pathological and biological tumour parameters in premenopausal, lymph node-negative breast cancer patients. Expression of Bcl-2 was determined using immunohistochemistry on paraffin-embedded sections in a series of 441 premenopausal, lymph node-negative breast cancers of patients randomised to receive perioperative chemotherapy (5-fluorouracil, doxorubicin, cyclophosphamide) or no perioperative chemotherapy. Immunohistochemistry of Bcl-2 was evaluated by scoring both staining intensity (0-3) and number of positive cells (0-2). Using these scores tumours were grouped into categories 0-6. It was found that 9.2% of the tumours were completely negative (0), 17.2% weakly (1 + 2), 41.6% moderately (3 + 4) and 31.9% strongly positive (5 + 6) for Bcl-2. A positive correlation was found between high Bcl-2 expression and oestrogen (P < 0.001) and progesterone receptor positivity (P < 0.001) and low tumour grade (P < 0.001), whereas high Bcl-2 expression was negatively correlated with p53 (P < 0.001) and c-erb-B-2 positively (P < 0.001), high Ki-67 index (P < 0.001), mitotic index (P < 0.001) and large tumour size (P = 0.006). Patients with tumours expressing high levels of Bcl-2 (overall score 3-6) had a significantly better disease-free (P = 0.004) and overall (P = 0.009) survival. However, in a multivariate model this association no longer remained significant. There was a trend for an effect of adjuvant chemotherapy on disease-free survival both for patients with Bcl-2-positive (HR-0.61, 95% CI 0.35-1.06, P = 0.07) and negative (HR = 0.55, 95% CI 0.27-1.12, P = 0.09) breast tumours at a median follow-up of 49 months. The level of Bcl-2 expression does not seem to predict response to perioperative chemotherapy in premenopausal, lymph node-negative breast cancer patients. High levels of Bcl-2 are preferentially expressed in well-differentiated tumours and are associated with favourable prognosis. However, Bcl-2 expression is not an independent prognostic factor in this patient series.     

Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression

BackgroundTaxane-based adjuvant chemotherapy is standard in node-positive (N+) early breast cancer (BC). The magnitude of benefit in intermediate-risk N+ early BC is still unclear. WSG-AGO epiribicine and cyclophosphamide (EC)-Doc is a large trial evaluating modern taxane-based chemotherapy in patients with 1–3 positive lymph nodes (LNs) only.Patients and methodsA total of 2011 BC patients (18–65 years, pN1) were entered into a randomized phase III trial comparing 4 × E₉₀C₆₀₀ q3w followed by 4 × docetaxel₁₀₀ q3w (n = 1008) with the current standard: 6 × F₅₀₀E₁₀₀C₅₀₀ q3w (n = 828) or C₆₀₀M₄₀F₆₀₀ d1, 8× q4w (n = 175). Primary end point was event-free survival (EFS); secondary end points were overall survival (OS), toxicity, translational research, and quality of life. Central tumor bank samples were evaluable in a representative collective (n = 772; 40%). Ki-67 was assessed centrally in hormone receptor-positive disease as a surrogate marker for the distinction of luminal A/B-like tumors.ResultsBaseline characteristics were well balanced between study arms in both main study and central tumor bank subset. At 59-month median follow-up, superior efficacy of EC-Doc [versus FEC (a combination of 5-fluorouracil, epirubicin, and cyclophosphamide)] was seen in EFS and OS: 5-year EFS: 89.8% versus 87.3% (P = 0.038); 5-year OS: 94.5% versus 92.8% (P = 0.034); both tests one-tailed. EC-Doc caused more toxicity. In hormone receptor-positive (HR)+ disease, only high-Ki-67 tumors (≥20%) derived significant benefit from taxane-based therapy: hazard ratio = 0.39 (95% CI 0.18–0.82) for EC-Doc versus FEC (test for interaction; P = 0.01).ConclusionEC-Doc significantly improved EFS and OS versus FEC in intermediate-risk BC (1–3 LNs) within all subgroups as defined by local pathology. In HR+ disease, patients with luminal A-like tumors may be potentially over-treated by taxane-based chemotherapy.Clinical Trial numberClinicalTrials.gov, NCT02115204.     

Prognostic Significance of Fms-Like Tyrosine Kinase 3 Internal Tandem Duplication Mutation in Non-Transplant Adult Patients with Acute Myeloblastic Leukemia: A Systematic Review and Meta-Analysis

Background: Fms-like tyrosine kinase-3, internal tandem duplication (FLT3-ITD) mutation, is a known predictor for worse outcome in patients with acute myeloblastic leukemia (AML). However, the prognostic significance of FLT3-ITD mutation in adult, non-transplant patients is still unclear therefore we conducted a systematic review and meta-analysis to explain this issue. The main outcome was overall survival (OS), while additional outcomes included event-free survival (EFS). Methods: Seven Databases (ScienceDirect, Scopus, PubMed, Cochrane, SpringerLink, ProQuest, and EBSCOhost) were searched up to August 2020.  Studies investigating the prognostic value of AML in adults with FLT3-ITD mutational status were selected. Studies which patients had received transplantation, diagnosed with acute promyelocytic leukemia (APL) or secondary AML were excluded. The selected studies were divided into subgroups based on their cytogenetic profile. Summary hazard ratios (HR) and 95% confidence intervals (CI) were calculated using fixed-effects models. Heterogeneity tests were conducted and presented in I2 value. Forest plot was presented to facilitate understanding of the results. Publication bias was analyzed by Funnel Plot test. Results: A total of ten studies describing research conducted from 1999 to 2020, met the inclusion criteria for this study. Nine studies reported OS and four studies reported EFS in HR. The highest HR for OS is 6.33 (95% CI, 2.61-15.33; p < 0.001), for EFS is 3.58 (95% CI, 1.59 – 8.05); p = 0.002)., while the lowest for OS is 1.33 (95% CI, 0.88-2.01; P = 0.174) and for EFS is 1.29 (95% CI, 0.75-2.23; p = 0.34). Nine studies were included in meta-analysis with HR for OS 1.91 (95% CI, 1.59–2.30, p < 0.00001), whereas 4 studies were included in meta-analysis for EFS with HR 1.64 (95% CI, 1.25–2.14; p = 0.0003). Conclusion: FLT3-ITD mutation is associated with worse prognosis in adult, non-transplant patients with AML, both for OS and EFS.