We sought to develop criteria for ERBB2-positivity (HER2) in colorectal cancer to ensure accurate identification of ERBB2-amplified metastatic colorectal cancer patients suitable for enrolment in a phase II trial of ERBB2-targeted therapy (HERACLES trial). A two-step approach was used. In step 1, a consensus panel of pathologists adapted existing protocols for use in colorectal cancer to test ERBB2 expression and amplification. Collegial revision of an archival test cohort of colorectal cancer samples led to specific recommendations for adapting current breast and gastric cancer criteria for scoring ERBB2 in colorectal cancer. In step 2, from September 2012 to January 2015, colorectal-specific ERBB2 testing protocols and ERBB2 scoring criteria were used to centrally screen for ERBB2-positive KRAS wild-type colorectal cancer patients to be enrolled in the HERACLES trial (clinical validation cohort). In both archival test (N = 256) and clinical validation (N = 830) cohorts, a clinically sizeable 5% fraction of KRAS wild-type colorectal cancer patients was found to be ERBB2-positive according to the colorectal cancer-specific ERBB2 scoring criteria. ERBB2-positive tumors showed ERBB2 immunostaining consisting of intense membranous ERBB2 protein expression, corresponding to homogenous ERBB2 amplification, in 450% of cells. None of the immunohistochemistry 0 or 1+ cases was amplified. Concordance between SISH and FISH was 100%. In conclusion, we propose specific criteria for defining ERBB2-positivity in colorectal cancer (HERACLES Diagnostic Criteria). In a phase II trial of trastuzumab and lapatinib in a cetuximabresistant population, HERACLES Diagnostic Criteria shaped the selection of patients and defined ERBB2 as a predictive marker for response to ERBB2-targeted therapy in metastatic colorectal cancer.
Background: To verify the accuracy of applanation tonometry through disposable latex caps used to prevent transmission of infectious diseases. Methods: Tonometry was performed in 80 patients. Each patient underwent two intraocular pressure (IOP) measurements with and without the latex. In group A patients tonometry was performed first without the cap; in group B tonometry was performed first with the cap. Each group was also divided into patients with IOP, ≥20 mm Hg (A1; B1) and patients with IOP <20 mm Hg (A2; B2). Results: The mean difference of tonometry readings was equal to –0.36 ± 1.62 mm Hg in group A, –0.03 ± 1.77 mm Hg in group A1, –0.61 ± 1.45 mm Hg in group A2, 0.23 ± 1.44 in group B, 0.64 ± 1.41 mm Hg in group B1, 0.05 ± 1.42 in group B2. A statistically significant correlation was found in group A, in group A2, B, B1 and B2; a less significant correlation was found in group A1. Conclusions: The use of the latex caps does not alter the reliability of tonometry readings as long as the cap is applied tightly. Measurement variation in our study is comparable to published data on applanation tonometry.
BackgroundPolymorphisms in the excision repair cross-complimentary group 1 (ERCC1) gene have been involved in the prognosis of various cancers. In the present study, we evaluated the prognostic role of the two most common ERCC1 polymorphisms in patients with T4 breast cancer receiving platinum-based chemotherapy.MethodsA total of 47 patients with T4 breast cancer undergoing treatment with a platinum-based regimen were collected and followed up (median 159 months; range, 42–239 months). ERCC1 C8092A (rs3212986) and T19007C (rs11615) polymorphisms were genotyped, using an automated sequencing approach. The same series was screened for BRCA1/2 mutations by DHPLC analysis and DNA sequencing.ResultsAmong the tested patients, 16 (34%) and 25 (53%) presented the 8092A (homo-zygosity A/A or heterozygosity A/C) and the 19007C (homozygosity C/C or heterozygosity C/T) genotypes, respectively. The 8092A and 19007C genotypes in ERCC1 were significantly associated with overall survival in T4 breast cancer patients treated with chemotherapy containing platinum (p-values = 0.036 and 0.004, respectively). Univariate and multivariate Cox regression analyses showed that combination of 8092A and 19007C genotypes acts as a significant prognostic factor in women with T4 breast cancer receiving platinum-based chemotherapy (p-values = 0.022 and 0.049, respectively). Two (4.3%) out of 47 cases were found to carry BRCA1/2 mutations; they presented the highest overall survival rates into the series.ConclusionsThe ERCC1 8092A and 19007C genotypes or their combination may predict a favorable prognosis in T4 breast cancer patients undergoing a platinum-based treatment. Further large-scale, prospective studies are needed to validate our findings.
After completing this course, the reader will be able to:1. Summarize the main risk factors for relapse in patients with T4 breast cancer after neoadjuvant chemotherapy.2. Evaluate the role of hormone receptors and HER-2 as determinants of risk of relapse after neoadjuvant treatment.3. Compare the difference in outcomes between patients who achieve less than pCR in relation to receptor status.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME
ABSTRACTPurpose. Pathological complete response (pCR) to primary chemotherapy is the main determinant for improved disease-free survival (DFS) and overall survival (OS). The primary endpoints of our study were the longterm DFS and OS rates in homogeneously treated stage IIIB breast cancer patients who failed to achieve a pCR (
a large proportion of human tumors show deregulated expression of a variety of proteins that play a crucial role in the execution of the apoptotic program. Survivin belongs to the family of inhibitor of apoptosis proteins which were originally identified in baculoviruses. ectopic expression of survivin conveys resistance to apoptosis to a variety of stimuli, and survivin is one of the most abundantly overexpressed genes in human tumors such as breast cancer. in this study we examined the expression of survivin protein in a series of t4 breast cancers to identify any correlation with long-term patient outcomes. moreover, we investigated the hypothesis of a possible association between p53 and survivin as a factor further complicating the outcome. archival specimens from 53 t4 breast cancer patients were included in the study and treated for the immunohistochemical localization of survivin and p53 using the streptavidin-biotin alkaline phosphatase method. the immunoreactivity was evaluated semiquantitatively according to the percentage of cells stained. Forty percent of tumors were positive for survivin. Statistical analysis revealed that survivin expression negatively influenced the 5-and 10-year disease-free and overall patient survival. in multivariate analysis, survivin expression was a significant independent prognostic indicator of worse outcome in overall survival [hazard ratio (hr)=2.61]. Our results showed that survivin is associated with a worse prognosis in patients with t4 breast cancer, and remarkably its prognostic relevance is maintained even long-term. notably, p53 (hr=3.2) seems to negatively enhance the effect of survivin on survival. departments of 1 medical Oncology, 2 cytomorphology, and 3 public health, university of cagliari, i-09042 monserrato (ca), italy
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