Zhuang Hg

MYC Expression in Concert with BCL2 and BCL6 Expression Predicts Outcome in Chinese Patients with Diffuse Large B-Cell Lymphoma, Not Otherwise Specified

Recent studies provide convincing evidence that a combined immunohistochemical or fluorescence in situ hybridization (FISH) score of MYC, BCL2, BCL6 proteins and MYC translocations predicted outcome in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, by far, all these researches are based on Western populations. Therefore, we investigate the prognostic relevance of MYC-, BCL2- and BCL6-rearrangements and protein expression by immunohistochemistry and FISH from 336 de novo DLBCL, NOS treated with CHOP or R-CHOP. Breaks in MYC and BCL6, and fusion in IGH/BCL2 were detected in 9.7%, 20.0%, and 11.1% of the cases, respectively, and were not significantly associated with clinical outcomes. Protein overexpression of MYC (≥40%), BCL2 (≥70%) and BCL6 (≥50%) was encountered in 51%, 51% and 36% of the tumors, respectively. On the basis of MYC, BCL2 and BCL6 expression, double-hit scores (DHSs) and triple-hit score (THS) were assigned to all patients with DLBCL. Patients with high MYC/BCL2 DHS, high MYC/BCL6 DHS and high THS had multiple adverse prognostic factors including high LDH level, poor performance status, advanced clinical stage, high International Prognostic Index (IPI) score, and non-germinal center B-cell. In univariate analysis, high MYC/BCL2 DHS, high MYC/BCL6 DHS and high THS were associated with inferior OS and PFS in both CHOP and R-CHOP cohorts (P<0.05). The highly significant correlations with OS and PFS were maintained in multivariate models that controlled for IPI (P<0.05). DLBCLs with high DHSs and high THS share the clinical features and poor prognosis of double-hit lymphoma (P>0.05). These data together suggest that the immunohistochemical DHSs and THS defined a large subset of DLBCLs with double-hit biology and was strongly associated with poor outcome in patients treated with R-CHOP or CHOP.

Justification of the Change From 10% to 30% for the Immunohistochemical HER2 Scoring Criterion in Breast Cancer

We compared the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) immunohistochemical scoring criterion (30%) for determining HER2 status and the Food and Drug Administration criterion (10%) with fluorescence in situ hybridization (FISH), the HER2 gene amplification method in 328 cases of breast cancer. Of 294 tumor samples successfully analyzed simultaneously by FISH and immunohistochemically, 178 of 196 cases scored 3+ using the 10% and the 30% criteria. Using FISH as the reference, the number of false-positives was reduced from 24 to 9 after application of the 30% criterion. The specificity of immunohistochemical analysis was higher with the 30% (92.0%) vs the 10% (78.8%) criterion. The kappa coefficient between FISH and immunohistochemical analysis was increased to 0.850 (almost perfect agreement; P < .001) after application of the 30% criterion vs 0.757 (substantial agreement) for the 10% criterion; the false-positive rate decreased to 5.1% from 12.2%. The chi(2) test showed that immunohistochemical analysis had significantly higher accuracy with the 30% (94.9%) vs the 10% (87.8%; P = .014) criterion. Our results from a large series of Chinese patients with breast cancer support that the ASCO/CAP 30% criterion may offer better results for assessing HER2 status.

Efficacy of intraoperative GeneSearch Breast Lymph Node (BLN) Assay for breast cancer metastasis detection in sentinel lymph node in Chinese patients

Although intraoperative assessment of the sentinel lymph node (SLN) is useful, it has not gained popularity in China as it involves a heavy workload for pathologists. We conducted a prospective clinical feasibility study of the GeneSearch Breast Lymph Node (BLN) Assay performed in 158 SLNs from 97 patients by comparison with postoperative permanent section histopathology, to validate its potential usefulness in China. Every SLN was cut into alternating 1.5 to 3.0 mm slabs. The BLN assay processed 50% of the fresh alternating slabs to detect the presence of cytokeratin 19 and mammaglobin mRNA. Assay results were compared with those for permanent section histopathology and intraoperative imprint cytology. Slides for imprint cytology were prepared from the BLN assay node tissue before it was processed. Full axillary lymph node (ALN) dissections were performed on some patients after a SLN biopsy. The BLN assay was successfully performed on 158 SLNs from 97 patients. Overall performance of the BLN assay compared with permanent section histopathology was sensitivity 83.9% (26/31), specificity 95.5% (63/66), positive predictive value 89.7% (26/29), negative predictive value 92.6% (63/68), and overall agreement 91.8% (89/97). The BLN assay detected about 25% more metastases than imprint cytology. Moreover, the BLN assay correctly identified most of the additional non‐sentinel ALNs metastases (P = 0.005). Our results from a large series of Chinese patients with breast cancer indicate that the BLN assay may be a viable alternative for the standard intraoperative procedures used for metastases detection, especially in early stage breast cancer patients. Name of the trial register: GeneSearch Breast Lymph Node (BLN) Assay China Registration Study. Clinical trial registration number: NCT00869674. (Cancer Sci 2010)

Overexpression of SRC‐3 promotes esophageal squamous cell carcinoma aggressiveness by enhancing cell growth and invasiveness

Steroid receptor coactivator‐3 (SRC‐3), a transcriptional coactivator for nuclear receptors and other transcription factors, plays an important role in the genesis and progression of several cancers. However, studies investigated the role of SRC‐3 in esophageal squamous cell carcinomas (ESCCs) are limited, and the role of SRC‐3 in tumor progression remains unclear. We examined the expression of SRC‐3 in 8 ESCC cell lines and 302 human ESCC tissues by qPCR, Western blot, and immunohistochemistry. In addition, ESCC cell lines were subjected to proliferation and invasion assays, tumorigenicity assay, flow cytometry assay, qPCR, Western blot, and Chromatin Immunoprecipitation assay to investigate the role of SRC‐3 in cancer progression. SRC‐3 was overexpressed in 48% of cases and correlated with poor overall (P = 0.0076) and progression‐free (P = 0.0069) survival of surgically resected ESCC patient. Cox regression analysis revealed that SRC‐3 is an independent prognostic marker. Furthermore, we found that activation of insulin‐like growth factor (IGF)/AKT) was involved in the SRC‐3 on the cell growth and invasiveness in two ESCC cell lines, Eca109 and EC18 cells. SRC‐3 overexpression is clinically and functionally relevant to the progression of human ESCC, and might be a useful molecular target for ESCC prognosis and treatment.

Reply to Span et al.: Mammaglobin RT‐qPCR for breast cancer metastasis detection in sentinel lymph nodes

(Cancer Sci 2010; 101: 2502)