Papers by Christos Markopoulos
Journal of Clinical Oncology, Apr 20, 2011
The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial included a prospectively planned... more The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial included a prospectively planned pathology substudy testing the predictive value of progesterone receptor (PgR) expression for outcome of estrogen receptor-positive (ER-positive) early breast cancer treated with exemestane versus tamoxifen. Patients and Methods Pathology blocks from 4,781 TEAM patients randomly assigned to exemestane versus tamoxifen followed by exemestane for 5 years of total therapy were collected centrally, and tissue microarrays were constructed from samples from 4,598 patients. Quantitative analysis of hormone receptors (ER and PgR) was performed by using image analysis and immunohistochemistry, and the results were linked to outcome data from the main TEAM trial and analyzed relative to disease-free survival and treatment. Results Of 4,325 eligible ER-positive patients, 23% were PgR-poor (Allred Ͻ 4) and 77% were PgRrich (Allred Ն 5). No treatment-by-marker effect for PgR was observed for exemestane versus tamoxifen (PgR-rich hazard ratio [HR], 0.83; 95% CI, 0.65 to 1.05; PgR-poor HR, 0.85; 95% CI, 0.61 to 1.19; P ϭ .88 for interaction). Both PgR and ER expression were associated with patient prognosis in univariate (PgR HR, 0.53; 95% CI, 0.43 to 0.65; P Ͻ .001; ER HR, 0.66; 95% CI, 0.51 to 0.86; P ϭ .002), and multivariate analyses (P Ͻ .001 and P ϭ .001, respectively). A trend toward a treatment-by-marker effect for ER-rich patients was observed. Conclusion Preferential exemestane versus tamoxifen treatment benefit was not predicted by PgR expression; conversely, patients with ER-rich tumors may derive additional benefit from exemestane. Quantitative analysis of ER and PgR expression provides highly significant information on risk of early relapse (within 1 to 3 years) during treatment.
Journal of Clinical Oncology, Jun 20, 2006
... Abstract. Correlation of molecular HLA typing and outcome in high-risk melanoma patients rece... more ... Abstract. Correlation of molecular HLA typing and outcome in high-risk melanoma patients receiving adjuvant interferon. H. Gogas, M. Spyropoulou-Vlachou, U. Dafni, D. Tsoutsos, C. Markopoulos, A. Polyzos, A. Stratigos, D. Pectasides, D. Bafaloukos and G. Fountzilas ...
PubMed, 1999
Four cases of radial scar of the breast, primarily diagnosed as carcinoma are presented; the pati... more Four cases of radial scar of the breast, primarily diagnosed as carcinoma are presented; the patients were found among 858 patients who were operated on at our Breast Unit over the last 4 years. The lesion was revealed on routine mammographic examination in 4 of our patients, while in the fourth it was found by palpation. In two of our patients mammographic examination revealed architectural distortion, in one patient micro-calcifications and in the fourth patient a stellate lesion was found. In the last two patients the lesion was localized before surgery with a hook wire. Diagnosis was established by histopathologic examination in all cases. The surgeon, the radiologist and the pathologist should be aware of this clinical entity which, in spite of its benign character, has the ability to simulate invasive carcinoma clinically, mammographically and histopathologically.
PubMed, 1997
A rare case of metachronous bilateral Paget's disease of the nipple is presented. The occasional ... more A rare case of metachronous bilateral Paget's disease of the nipple is presented. The occasional failure of routine follow-up to detect certain tumours until biologically advanced and the value of patient observations are mentioned.
PubMed, Aug 21, 2003
This phase II trial studied the efficacy and toxicity of docetaxel-epirubicin, supported by granu... more This phase II trial studied the efficacy and toxicity of docetaxel-epirubicin, supported by granulocyte colony-stimulating factor, as first-line chemotherapy in metastatic breast cancer. Patients received epirubicin (60 mg/m2) followed 1 hour later by docetaxel (80 mg/m2) every 3 weeks for a maximum of 8 cycles or until disease progression. Prophylactic granulocyte colony-stimulating factor (5 micrograms/kg) was administered daily for 5 days. Sixty-nine patients were evaluable for efficacy and toxicity. Objective responses occurred in 45 patients (65%; 95% confidence interval: 53-76%), with 11 (16%) complete responses and 34 (49%) partial responses. Responses were observed at all metastatic sites. The median response duration was 8 months (range 4-68), median time to progression was 10 months (range 4-68) and median overall survival was 24 months (range 7-68): neutropenia was dose limiting (46% grade 3-4 toxicity). The left ventricular ejection, fraction measured in 50 patients, fell below normal in 14 patients (28%), 8 patients had grade 1 and 6 grade 2 cardiotoxicity, but none developed congestive cardiac failure. The docetaxel-epirubicin regimen is extremely effective in poor prognosis breast cancer patients with visceral metastases, with significant overall and complete responses, followed by prolonged survival in responders. Although myelosuppression remains the major toxicity, prophylactic GCSF administration was associated with a small percentage of neutropenic fever.
PubMed, Jun 1, 1994
Hamartomas of the breast are rare tumor-like lesions composed of ducts, lobules, fat, and fibrous... more Hamartomas of the breast are rare tumor-like lesions composed of ducts, lobules, fat, and fibrous tissue. The clinical and pathologic findings of six cases of patients ranging in age from 19 to 63 years are reported. Diagnosis is difficult, and we emphasize that fine needle aspiration and cytology of the smears is not diagnostic for hamartomas.
Ejc Supplements, Mar 1, 2010
Background: Recent trials have demonstrated prognostic relevance of CTCs in metastatic BC. The SU... more Background: Recent trials have demonstrated prognostic relevance of CTCs in metastatic BC. The SUCCESS trial evaluates the role of CTCs at primary diagnosis and after chemotherapy as well as two and five years after diagnosis in primary BC patients treated with chemotherapy and zoledronate. Methods: We analyzed 23 ml of peripheral blood in N+ and high risk N− primary BC pts receiving 3×FEC (500/100/500)-3×Doc100 q3w vs. 3×FEC (500/100/500)-3×DocGemcitabine (75/1000 d1+8) chemotherapy
JAMA, Feb 8, 2012
Context In addition to classic tumor-related prognostic factors, patient characteristics may be a... more Context In addition to classic tumor-related prognostic factors, patient characteristics may be associated with breast cancer outcome. Objective To assess the association between age at diagnosis and breast cancer outcome in postmenopausal women with hormone receptor-positive breast cancer. Design, Setting, and Patients Study analysis of 9766 patients enrolled in the TEAM (Tamoxifen Exemestane Adjuvant Multinational) randomized clinical trial between January 2001 and January 2006. Age at diagnosis was categorized as younger than 65 years (n=5349), 65 to 74 years (n=3060), and 75 years or older (n=1357). Main Outcome Measures Primary end point was disease-specific mortality; secondary end points were other-cause mortality and breast cancer relapse. Results During median follow-up of approximately 5.1 years, there were a total of 1043 deaths. Disease-specific mortality, as a proportion of all-cause mortality, decreased with categorical age group (78% [Ͻ65 years], 56% [65-74 years], and 36% [Ն75 years]; PϽ.001). In multivariable analyses, compared with patients younger than 65 years, disease-specific mortality increased with age for patients aged 65 to 74 years (hazard ratio [HR], 1.25; 95% CI, 1.01-1.54); and patients aged 75 years or older (HR, 1.63; 95% CI, 1.23-2.16) (PϽ.001). Similarly, breast cancer relapse increased with age for patients aged 65-74 years (HR, 1.07; 95% CI, 0.91-1.25 and patients aged 75 years or older (HR, 1.29; 95% CI, 1.05-1.60) (P=.06). Other-cause mortality increased with age in patients aged 65 to 74 years (HR, 2.66; 95% CI, 1.96-3.63) and patients aged 75 years or older (HR, 7.30; 95% CI, 5.29-10.07) (PϽ.001). Conclusion Among postmenopausal women with hormone receptor-positive breast cancer, increasing age was associated with a higher disease-specific mortality.
PubMed, 1996
Endometriosis of a surgical scar is rare and occurs mainly when a hysterectomy has been performed... more Endometriosis of a surgical scar is rare and occurs mainly when a hysterectomy has been performed in the past. Development of malignancy in such a lesion is very unusual. A rare case of primary endometrioid carcinoma in the endometriosis of a caesarean scar is described.
Cancer Research, Dec 1, 2012
Background: PIK3CA is mutated in about 26% of breast cancers (BC) and is the most frequently muta... more Background: PIK3CA is mutated in about 26% of breast cancers (BC) and is the most frequently mutated gene in (BC). Almost 95% of mutations occur in exons 9 (E9) or 20 (E20). PIK3CA mutations may be associated with increased survival in endocrine-treated patients; however the impact of mutations in E9 vs E20 is not clear. We assessed 10 common PIK3CA mutations (95% of all mutations), in ER-positive (+ve) samples from the TEAM pathology study (n = ∼4500), and determined the impact of PIK3CA mutations on survival. We report an interim analysis of 1969 TEAM cases. Methods: DNA was extracted from formalin-fixed paraffin embedded sections. Mutational analyses were performed on 25 mutations in 6 genes (PIK3CAx10, Akt1x1, KRASx5, HRASx3, NRASx2 & BRAFx4), using Sequenom MassArray. Results: Mutations were found in PIK3CA: 37.5%; Akt1: 3.3%; KRAS: 0.3%; and BRAF: 0.1% of cases. No mutations were found in HRAS or NRAS (n = 1969). 90% of PIK3CA mutations were located in E9 and E20. Outcome data was available for 1958/1969 patients. Patients whose tumours contained any PIK3CA mutations (n = 739) were at lower risk of distant metastasis, Hazard ratio=0.86 (0.67–1.11), when compared to those without PIK3CA mutations (n = 1219); although this difference was not statistically significant (Cox Regression; p = 0.24). PIK3CA mutations were significantly more frequent in HER2-negative (−ve) (39%) than in HER2+ve samples (25%) (p = 0.001), without evidence that PIK3CA mutations differentially impacted outcome in HER2+ve vs HER2-ve patients. A positive correlation was demonstrated between PIK3CA mutations and PgR Allred score (p = 0.002) but not ER Allred score (p = 0.37). With increasing PgR Allred score increase there is an increased frequency of mutations in E20 but not E9 (Table 1). Discussion: This study indicates a higher percentage of PIK3CA mutations in ER+ve BC samples than previously demonstrated, either for BC as a whole or for ER+ve cases, suggesting that in ER+ve early BC, PIK3CA mutations are more common than previously reported. Furthermore, increased PIK3CA mutation frequency is significantly associated with increasing PgR Allred score and this appears solely due to increased numbers of patients with E20 mutations further complicating the analysis of the impact of PIK3CA mutations in BC. This may explain current uncertainty regarding the impact of PIK3CA mutations in E9 vs E20 with respect to clinical outcome. Whilst we were unable to show a significant impact on outcome in patients whose tumours contained PIK3CA mutations, we believe the complex relationship between PgR expression (good prognosis indicator) and PI3K mutations requires further exploration in the full dataset using interaction techniques adjusting for the impact of PgR on outcome. Mutational analysis and correlation with clinical outcome data for the remaining ∼2500 DNA samples, along with the existing data for 1969 patients, will be presented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-5.
Therapeutic Advances in Medical Oncology, Aug 8, 2012
Evidence-based medicine Breast cancer is the most frequent malignant tumor in women worldwide, wi... more Evidence-based medicine Breast cancer is the most frequent malignant tumor in women worldwide, with almost 1,400,000 new cases in 2008 [Jemal et al. 2011]. In the USA, 41% of these women were 65 years or older at diagnosis [data.gov, Surveillance Epidemiology and End Results, 2011]. As breast cancer incidence increases with age, worldwide changing demographics and increasing life expectancy are expected to further enlarge the absolute number of older women with breast cancer. Several studies have shown that older patients are not treated to the same extent as younger patients; older patients with breast cancer have lower odds of receiving standard care [Yancik et al. 2001; Allemani et al. 2010]. Studies on adherence to breast cancer guidelines have shown that increasing age at diagnosis predicts deviation from guidelines for surgical therapy [
Cancer Research, May 1, 2015
Acta Radiologica, 2003
Purpose: To evaluate of a computer-aided method for differentiating malignant from benign cluster... more Purpose: To evaluate of a computer-aided method for differentiating malignant from benign clustered microcalcifications. Material and Methods: Our material was 350 suspicious microcalcifications on mammograms from 330 female patients who underwent breast biopsy (after hook wire localization and under mammographic guidance). The histologic findings were malignant in 140 cases (40%) and benign in 210 cases (60%). Those clusters were manually detected, computer-aided analyzed and quantitatively estimated. Besides computer analysis, 3 physicians-observers (2 radiologists and 1 breast surgeon) evaluated the malignant or benign nature of the clustered microcalcifications. The performance of the artificial network, each observer and the three observers as a group was evaluated by receiver operating characteristics (ROC) curves. Results: Comparison of the ROC curves revealed the following AUC values (area under the curve): computer À 0.950, physician 1 À 0.815, physician 2 À 0.830, physician 3 À 0.830, and physicians as a group À 0.825. The results, compared by the student t-test for paired data, showed a statistically significant difference between computer analysis and physicians' performance, independently and as a group. Conclusion: Our study showed that computer analysis achieved statistically significantly better performance than that of physicians in the classification of malignant and benign calcifications.
Nature Communications, Nov 12, 2018
Biomarkers lie at the heart of precision medicine. Surprisingly, while rapid genomic profiling is... more Biomarkers lie at the heart of precision medicine. Surprisingly, while rapid genomic profiling is becoming ubiquitous, the development of biomarkers usually involves the application of bespoke techniques that cannot be directly applied to other datasets. There is an urgent need for a systematic methodology to create biologically-interpretable molecular models that robustly predict key phenotypes. Here we present SIMMS (Subnetwork Integration for Multi-Modal Signatures): an algorithm that fragments pathways into functional modules and uses these to predict phenotypes. We apply SIMMS to multiple data types across five diseases, and in each it reproducibly identifies known and novel subtypes, and makes superior predictions to the best bespoke approaches. To demonstrate its ability on a new dataset, we profile 33 genes/nodes of the PI3K pathway in 1734 FFPE breast tumors and create a foursubnetwork prediction model. This model out-performs a clinically-validated molecular test in an independent cohort of 1742 patients. SIMMS is generic and enables systematic data integration for robust biomarker discovery.
Journal of Clinical Psychology in Medical Settings
Cancer patients’ quality of life (QoL) and distress are affected by dispositional factors such as... more Cancer patients’ quality of life (QoL) and distress are affected by dispositional factors such as attachment anxiety or avoidance. In this review, we aimed to provide a thorough overview of the relationship between attachment dimensions and QoL and distress among early-stage breast cancer patients. Following PRISMA guidelines, we conducted a systematic search using PubMed, PsycINFO, Scopus, Cinahl, Google Scholar, and PMC Europe. We reviewed 8 eligible studies describing 1180 patients. Insecure attachment appeared to be related to poorer QoL and higher distress levels. Avoidant attachment was more frequent and was more often associated with more negative outcomes. Healthcare providers should consider investigating modifiable personality traits in the immediate post diagnosis period to identify patients more vulnerable to mental health problems, deliver personalized care, and reduce emotional burden.
Cancer Genomics - Proteomics
Background/Aim: The use of multi-gene panels for germline testing in breast cancer enables the es... more Background/Aim: The use of multi-gene panels for germline testing in breast cancer enables the estimation of cancer risk and guides risk-reducing management options. The aim of this study was to present data that demonstrate the different levels of actionability for multi-gene panels used in genetic testing of breast cancer patients and their family members. Materials and Methods: We performed an analysis in our clinical database to identify breast cancer patients undergoing genetic testing. We reviewed positive results in respect of risk estimation and management, cascade family testing, secondary findings and information for treatment decision-making. Results: A total of 415 positive test reports were identified with 57.1%, 18.1%, 10.8% and 13.5% of individuals having pathogenic/likely pathogenic variants in high, moderate, low and with insufficient evidence for breast cancer risk genes, respectively. Six point seven percent of 60 This article is freely accessible online.
Journal of Endocrinology and Diabetes
Introduction The main hormonal treatment of estrogen sensitive breast cancer includes the use of ... more Introduction The main hormonal treatment of estrogen sensitive breast cancer includes the use of selective estrogen receptor modulators, aromatase inhibitors and GnRH-Analogs. It has been observed that administering aromatase inhibitor to breast cancer patients not only impairs their glucose metabolism but it can even cause frank diabetes mellitus. Moreover, it has been hypothesized that aromatase inhibitors may have an impact on glucose metabolism by their effect on estrogen levels. Therefore, we designed an experiment in order to assess the effect of estrogens on insulin secretion from rat beta pancreatic insulinoma INS-1 cells. Methods Experiments were conducted on an INS-1 cell line, a rodent beta cell line derived from a rat insulinoma induced by X-ray irradiation, which displays high insulin content, production of both proinsulin I and II and responsiveness to glucose and hormones. INS-1 cells were routinely cultured in 75cm2 flasks (T75) containing 10ml of appropriate culture...
European Journal of Surgical Oncology, 2020
The Breast Surgery theoretical and practical knowledge curriculum comprehensively describes the k... more The Breast Surgery theoretical and practical knowledge curriculum comprehensively describes the knowledge and skills expected of a fully trained breast surgeon practicing in the European Union and European Economic Area (EEA). It forms part of a range of factors that contribute to the delivery of high quality cancer care. It has been developed by a panel of experts from across Europe and has been validated by professional breast surgery societies in Europe. The curriculum maps closely to the syllabus of the Union of European Medical Specialists (UEMS) Breast Surgery Exam, the UK FRCS (breast specialist interest) curriculum and other professional standards across Europe and globally (USA Society of Surgical Oncology, SSO). It is envisioned that this will serve as the basis for breast surgery training, examination and accreditation across Europe to harmonise and raise standards as breast surgery develops as a separate discipline from its parent specialties (general surgery, gynaecology, surgical oncology and plastic surgery). The curriculum is not static but will be revised and updated by the curriculum development group of the European Breast Surgical Oncology Certification group (BRESO) every 2 years.
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Papers by Christos Markopoulos