Oncotype DX® in breast cancer patients: clinical experience, outcome and follow-up-a case-control study.

PURPOSE: Breast cancer is the leading cause of death from cancer in women and the most common cancer in the world [1]. To date, many patients with estrogen-receptor-positive (ER+) breast cancer are overtreated with chemotherapy when the rationale for adjuvant chemotherapy is based on clinicopathologic parameters. Different studies were able to demonstrate that a 21-gene expression assay (Oncotype DX® Genomic Health, Redwood City, CA) can predict the benefit from adjuvant chemotherapy in ER+ breast cancers [2, 3] and provide additional prognostic information independent of clinicopathological features [4]. RESULTS: Data from all patients with ER+ Her2neu- breast cancer undergoing Oncotype DX® testing between 2011 and 2014 at a tertiary referral center in Germany were analyzed. Oncotype DX® was performed in 69 cases, in 2 cases data were missing and in 3 cases Oncotype DX® could not be performed by the company. The results showed a low risk in 39 cases, an intermediate risk in 22 cases and a high risk in 3 cases. Based on Oncotype results, treatment recommendations were changed in 39 of 64 patients (61%). Before Oncotype DX® testing, chemotherapy was recommended in 67 patients, afterwards only in 25 patients. Data from 44 of 67 patients were matched to controls for stage, tumor grade, menopausal and hormone receptor status. Within a mean observation time of 19.7 months, cancer recurrence was observed in two patients. CONCLUSIONS: Oncotype DX® testing can be recommended for risk-tailored chemotherapy. Results should be validated in larger prospective studies.

Predictors of Residual Tumor in Breast-Conserving Therapy.

BACKGROUND: Breast-conserving therapy is considered to be the standard treatment for early breast tumors (T1-T2). In up to 82 % of breast-conserving surgery, tumor cells were still found to be present at or near the cut edge of the surgical specimen after surgery. Thus, it is of clinical need to identify tumors at high probability for reexcision in the preoperative setting. METHODS: A total of 686 patients with invasive or in situ breast cancers and primary breast-conserving surgery were included. In 169 cases (24.6 %), breast-conserving therapy was either incomplete or the presence of residual tumor could not be assessed. By univariate analysis, the following parameters were associated with increased probability for reexcision: carcinoma in situ component next to the invasive tumor (p < 0.001), lower age (p = 0.025), premenopausal status (p = 0.033), tumor size (p < 0.001), multifocality (p < 0.001), involved lymph nodes (p = 0.006) and lymphovascular invasion (p < 0.001), differentiation (p = 0.002), and overexpression of the Her2/neu receptor (p = 0.004). The variables with the strongest impact on the reexcision probability in multivariate analyses were tumor size and histology (both p < 0.001), followed by multifocality (p = 0.002) and an accompanying carcinoma in situ (p = 0.004). Lymphovascular invasion (p = 0.016) and age (p = 0.047) also were significantly associated with increased reexcision probability in multivariate analyses. A nomogram for predicting residual tumor in breast-conserving therapy was developed. CONCLUSIONS: The clinical and pathological parameters associated with increased reexcision rates will help to assess an optimized surgical margin, to decrease reexcision rates, and therefore to improve patient care and the quality of life for patients.

Prevalence of germline TP53 mutations in HER2+ breast cancer patients.

Breast cancer is the most frequent tumor in Li-Fraumeni syndrome (LFS), a rare inherited cancer syndrome associated with germline mutations in the TP53 gene. Recent data show that breast cancer in germline TP53 mutation carriers is commonly HER2+ (63-83 %). We assessed the prevalence of germline TP53 mutations in a cohort of women with HER2+ breast cancer diagnosed age ≤50 years. We identified blood specimens from 213 women with primary invasive HER2+ breast cancer age ≤50 years from a single center. Exon grouping analysis sequencing and multiplex ligation-dependent probe amplification techniques were used to screen for germline TP53 mutations. Among 213 women with HER2+ breast cancer age ≤50 years, 3 (ages at diagnosis 23, 32, 44 years) were found to carry a TP53 mutation (1.4 %, 95 % CI 0.3-4.1 %). ER/PR status was not uniform. Two TP53 carriers met Chompret criteria for LFS; none met classic LFS criteria. Although two-thirds of breast cancers in women with TP53 mutations are HER2+, we observed a low prevalence of germline TP53 mutations among unselected young women with HER2+ breast cancer. Given the potential clinical impact, consideration of germline TP53 testing should be given to young women with HER2+ breast cancer, especially if family cancer history is notable.

Molecular and clinical characterization of an in frame deletion of uncertain clinical significance in the BRCA2 gene.

In this study, we analyzed a "variant of uncertain significance" (VUS) located in exon 23 of the BRCA2 gene exhibited by six members of five distinct families with hereditary breast cancer (BC). The variant was identified by DNA sequencing, and cDNA analysis revealed its co-expression with wild-type mRNA. We analyzed co-occurrence with other pathological mutations in BRCA1/2, performed a case-control study, looked for evolutionary data and used in-silico analyses to predict its potential clinical significance. Sequencing revealed an in frame deletion of 126 nucleotides in exon 23, leading to a deletion of 42 amino acids (c.9203_9328del126, p.Pro2992_Thr3033del). All of the VUS-carriers suffered from either BC or ovarian/pancreatic cancer. No other definite pathologic mutation of BRCA genes was found in the five families. The identified deletion could not be observed in a control cohort of 2,652 healthy individuals, but in 5 out of 916 (0.5%) tested BC families without a bona fide pathogenic BRCA1/2 mutation (P = 0.0011). According to these results, the in frame deletion c.9203_9328del126 is a rare mutation strongly associated with familial BC. In summary, our investigations indicate that this BRCA2 deletion is pathogenic.

Predictors of resectability in breast-conserving therapy.

BACKGROUND: Our goal is to identify subgroups of women undergoing breast-conserving therapy (BCT) who are at increased risk for requiring a secondary surgical procedure, and to identify tumor and patient profiles that will allow surgeons to anticipate the need for taking larger margins when removing the tumor. METHODS: One hundred female patients who had palpable, invasive carcinomas of the breast, and had undergone a primary BCT, were included in the study. Of these, all women (n = 25) who had incomplete resections, or questionable margins of resection, had to undergo re-excisions. RESULTS: Patients who had multifocal disease, accompanying ductal carcinoma in situ, involvement of regional lymph nodes, high-grade breast cancer (Grade 3 vs. 1/2), lympho-vascular invasion or negative hormone-receptor-status, were significantly more likely to have undergone incomplete removal of tumor tissue-these patients thus required a secondary surgery. CONCLUSION: The clinical and pathological predictors described above indicate that surgery in breast cancer patients meeting these criteria require larger safety margins to minimize the incidence rate of re-excision at a later date.

I-scan optical enhancement for the in vivo prediction of diminutive colorectal polyp histology: Results from a prospective three-phased multicentre trial.

BACKGROUND AND AIMS: Dye-less chromoendoscopy is an emerging technology for colorectal polyp characterization. Herein, we investigated whether the newly introduced I-scan optical enhancement (OE) can accurately predict polyp histology in vivo in real-time. METHODS: In this prospective three-phased study, 84 patients with 230 diminutive colorectal polyps were included. During the first two study phases, five endoscopists assessed whether analysis of polyp colour, surface and vascular pattern under i-scan OE can differentiate in vivo between adenomatous and hyperplastic polyps. Finally, junior and experienced endoscopists (JE, EE, each n = 4) not involved in the prior study phases made a post hoc diagnosis of polyp histology using a static i-scan OE image database. Histopathology was used as a gold-standard in all study phases. RESULTS: The overall accuracy of i-scan OE for histology prediction was 90% with a sensitivity, specificity, positive (PPV) and negative prediction value (NPV) of 91%, 90%, 86% and 94%, respectively. In high confidence predictions, the diagnostic accuracy increased to 93% with sensitivity, specificity, PPV and NPV of 94%, 91%, 89% and 96%. Colonoscopy surveillance intervals were predicted correctly in ≥ 90% of patients. In the post hoc analysis EE predicted polyp histology under i-scan OE with an overall accuracy of 91%. After a single training session, JE achieved a comparable diagnostic performance for predicting polyp histology with i-scan OE. CONCLUSION: The histology of diminutive colorectal polyps can be accurately predicted with i-scan OE in vivo in real-time. Furthermore, polyp differentiation with i-scan OE appears to require only a short learning curve.