Greater Ki-67 Expression Research Articles

Breast Cancer: Evaluation of Response to Neoadjuvant Chemotherapy with 3.0-T MR Imaging

To assess how the molecular biomarker status of a breast cancer, including human epidermal growth factor receptor 2 (HER2), hormone receptors, and the proliferation marker Ki-67 status, affects the diagnosis at 3.0-T magnetic resonance (MR) imaging. This study was approved by the institutional review board and was HIPAA compliant. Fifty patients (age range, 28-82 years; mean age, 49 years) receiving neoadjuvant chemotherapy were monitored with 3.0-T MR imaging. The longest dimension of the residual cancer was measured at MR imaging and correlated with pathologic findings. Patients were further divided into subgroups on the basis of HER2, hormone receptor, and Ki-67 status. Pathologic complete response (pCR) was defined as when there were no residual invasive cancer cells. The Pearson correlation was used to correlate MR imaging-determined and pathologic tumor size, and the unpaired t test was used to compare MR imaging-pathologic size discrepancies. Of the 50 women, 14 achieved pCR. There were seven false-negative diagnoses at MR imaging. The overall sensitivity, specificity, and accuracy for diagnosing invasive residual disease at MR imaging were 81%, 93%, and 84%, respectively. The mean MR imaging-pathologic size discrepancy was 0.5 cm ± 0.9 (standard deviation) for HER2-positive cancer and 2.3 cm ± 3.5 for HER2-negative cancer (P = .009). In the HER2-negative group, the size discrepancy was smaller for hormone receptor-negative than for hormone receptor-positive cancers (1.0 cm ± 1.1 vs 3.0 cm ± 4.0, P = .04). The size discrepancy was smaller in patients with 40% or greater Ki-67 expression (0.8 cm ± 1.1) than in patients with 10% or less Ki-67 expression (3.9 cm ± 5.1, P = .06). The diagnostic accuracy of breast MR imaging is better in more aggressive than in less aggressive cancers. When MR imaging is used for surgical planning, caution should be taken with HER2-negative hormone receptor-positive cancers.

Phase I Study of GSK461364, a Specific and Competitive Polo-like Kinase 1 Inhibitor, in Patients with Advanced Solid Malignancies

GSK461364 is an ATP-competitive inhibitor of polo-like kinase 1 (Plk1). A phase I study of two schedules of intravenous GSK461364 was conducted. GSK461364 was administered in escalating doses to patients with solid malignancies by two schedules, either on days 1, 8, and 15 of 28-day cycles (schedule A) or on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (schedule B). Assessments included pharmacokinetic and pharmacodynamic profiles, as well as marker expression studies in pretreatment tumor biopsies. Forty patients received GSK461364: 23 patients in schedule A and 17 in schedule B. Dose-limiting toxicities (DLT) in schedule A at 300 mg (2 of 7 patients) and 225 mg (1 of 8 patients) cohorts included grade 4 neutropenia and/or grade 3-4 thrombocytopenia. In schedule B, DLTs of grade 4 pulmonary emboli and grade 4 neutropenia occurred at 7 or more days at 100 mg dose level. Venous thrombotic emboli (VTE) and myelosuppression were the most common grade 3-4, drug-related events. Pharmacokinetic data indicated that AUC (area under the curve) and C(max) (maximum concentration) were proportional across doses, with a half-life of 9 to 13 hours. Pharmacodynamic studies in circulating tumor cells revealed an increase in phosphorylated histone H3 (pHH3) following drug administration. A best response of prolonged stable disease of more than 16 weeks occurred in 6 (15%) patients, including 4 esophageal cancer patients. Those with prolonged stable disease had greater expression of Ki-67, pHH3, and Plk1 in archived tumor biopsies. The final recommended phase II dose for GSK461364 was 225 mg administered intravenously in schedule A. Because of the high incidence (20%) of VTE, for further clinical evaluation, GSK461364 should involve coadministration of prophylactic anticoagulation.

Prognosis related to Ki67 in early breast cancer.

e11085 Background: Breast cancer (BC) is the most common tumor in Mexican women. Ki67 is a nuclear antigen considered as a proliferation marker with potential prognostic significance in BC survival. Our objectives are determine the prognosis and correlation between Ki67 and prognostic factors in BC patients (pts). Methods: From January 2000 to December 2008, patients (pts) > 18 yrs old with invasive BC, I to IIB, ductal or lobular, treated with surgery were included. Pts with in situ or inflammatory BC or neoadjuvant chemotherapy were excluded. Age, tumor size, lymph node status, Ki-67, HER2, ER, PR, p53, angiogenesis, adjuvant therapy, recurrence and overall survival were registered. Pts were divided into four groups according to Ki67 levels: 1) Ki67 < 5%, 2) 6 to 20%, 3) 21 to 50%, and 4) > 51%. Descriptive statistical methods and X2, ANOVA tests were applied. Results: 132 pts analyzed. Groups 1 to 4 were integrated by 23 pts (17.4%), 49 (37.1%), 39 (29.5%) and 21 (15.9%); median age 49, 48, 51 and 48 yrs (p > 0.05), respectively. Conservative surgery 56.4%, 30.6%, 25.6% y 42.9%, respectively. In each group, adjuvant chemotherapy was indicated in 82.6%, 83.6%, 89.7% and 90.4%; radiation 47.8%, 36.7%, 43.5% and 42.8%; hormonal therapy 65.2%, 71.4%, 50.9% and 38%. Chemotherapy based in anthracyclines in 36.8%, 34.1%, 31.4% and 31.5%, anthracyclines and taxanes in 57.8%, 53.6%, 62.8% and 68.5%. Ki67 was associated to tumor size > 2 cm (p = 0.02), negative ER (p = 0.000), negative p53 (p= 0.048). A tendency was detected for relationship to negative PR (p = 0.06) and hypodiploid DNA (p = 0.071). We noted higher frequency of triple negative immunophenotype in the groups with greater expression of Ki67 (8.7%, 10.2%, 10.2% y 28.5%) (p > 0.05). In each group, median follow-up time was 49, 37, 41 y 48 mos, (p > 0.05). Recurrence was observed in 18 pts (13.6%), of them 0, 5, 7 y 6 in the groups 1 to 4, respectively. Systemic was more frequent than local recurrence (66.6% vs. 27.4%). Median time to recurrence was 27, 39 and 60 mos in the groups 2 to 4. There were 0, 2 (4%), 4 (10.2%) and 3 (14.2%) deaths in each group, median overall survival 49, 25.5, 38.5 y 36 mos, respectively. Conclusions: High cellular proliferation through Ki67 (> 51%) was related to poor prognostic factors in BC. No significant financial relationships to disclose.

Abstract 829: A panel of three biomarkers for differentiating high from low grade neuroendocrine tumors of the lung: Findings from a Pilot Project

Abstract Background: Distinguishing low/intermediate grade (carcinoid &amp; atypical carcinoid) from high grade neuroendocrine carcinoma [small cell carcinoma &amp; large cell neuroendocrine carcinoma (LCNEC)] of the lung can be difficult, especially in small biopsy specimens. This distinction is important for appropriate planning of a patient's course of treatment. Expression of biomarkers can be used to improve the precision of a differential diagnosis. We evaluated the expression of a panel of 5 biomarkers: CD117, a cytokine receptor, and KOC, a member of the insulin-like growth factor messenger RNA-binding protein family; Ki-67, a proliferation marker; the von Hippel-Lindau gene product (pVHL) and p16, 2 tumor suppresser markers. This panel was chosen because of their biological functions and their differential expression in low/intermediate vs. high grade cacinomas. Method: We studied 42 consecutive cases of carcinoma of the lung (20 small cell carcinomas, 7 large cell neuroendocrine carcinomas, 12 carcinoids and 3 atypical carcinoids). Tissue microarrays were constructed and biomarkers’ expressions were evaluated immunohistochemically. Staining was standardized and scored as “0+” = Negative, “1+” = Focal, “2+” = 30-49% cells staining and “3+” = 50-100% cells staining positively. A specimen scored as “0” / “1+” was classified as negative, while a specimen scored as “2+” / “3+” was considered positive. The likelihood of expression of the panel by histopathologic diagnosis was estimated using two-sided non-parametric statistical techniques. Results: Statistically significant differential expression for KOC, p16, pVHL and Ki-67 between low and high grade tumors was seen, but no significant difference for CD117 was detected. High grade tumors showed greater expression of Ki-67 (OR=13.85, 95% CI 3.34-57.47, p=0.0003), p16 (OR=3.52, 95% CI 1.75-7.11, p=0.0004) and KOC (OR=4.24, 95% CI 1.88-9.56, p=0.0005); while, pVHL expression was lower in high relative to low/intermediate grade tumors (OR=0.31, 95% CI 0.12-0.84, p=.022). We detected a statistically significant probability of the joint over-expression of 3 of the 5 biomarkers [p16 and KOC and Ki-67] in LCNEC relative to atypical carcinoids (OR=2.53, 95% CI 1.24-5.17, p=.011). Conclusion: Findings suggest that Ki-67, KOC and p16 is an effective antibody panel in differentiating high from low/intermediate grade neuroendocrine carcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 829.

Characterization of prostate cancer incidentally detected in radical cystoprostatectomy specimens from Japanese men with bladder cancer

The objective of this study was to investigate and characterize the clinicopathological features of incidentally detected prostate cancer in radical cystoprostatectomy specimens from Japanese men with bladder cancer. We reviewed the pathological reports of 251 male patients who underwent radical cystoprostatectomy for bladder cancer at our institution and identified men with incidentally detected prostate cancer in these specimens. Clinicopathological data of patients with incidental prostate cancer in cystoprostatectomy specimens (group A) were compared with those of 193 patients with clinically detected prostate cancer who underwent radical prostatectomy (group B). Immunohistochemical staining was also performed to measure the expression levels of Ki-67, p53 and androgen receptor (AR) proteins in specimens from both groups A and B. In this series, a total of 31 patients (12.3%; group A) were incidentally diagnosed as having prostate cancer in radical cystoprostatectomy specimens. Clinically significant cancer, defined as any tumor greater than 0.5 cc according to the report by Stamy et al. (Cancer 71:933-938, 1993) was detected in 9 (29.0%) in group A and 170 (88.1%) in group B. Mean age in group A was significantly older than that in group B, while despite the lack of significant difference in the incidence of seminal vesicle invasion between these two groups, other parameters in group A were significantly more favorable than those in group B, including serum prostate-specific antigen, pathological stage, Gleason score, perineural invasion and capsular penetration. None of the patients in group A had biochemical recurrence (median observation period, 82 months); however, biochemical recurrence occurred in 41 (21.2%) in group B (median observation period, 46 months). Furthermore, immunohistochemical study demonstrated the significantly greater expression of Ki-67, p53 and AR proteins in group B than in group A. Clinicopathological features of incidentally detected prostate cancer are markedly more favorable than those of clinically detected prostate cancer, which may reflect less aggressive biological phenotypes of incidental prostate cancer arising in Japanese men.