Squamous cell carcinomas (SCCs) are among the most frequent solid tumors in humans. SCCs, related... more Squamous cell carcinomas (SCCs) are among the most frequent solid tumors in humans. SCCs, related or not to the human papillomavirus, share common molecular features. Immunotherapies, and specifically immune checkpoint inhibitors, have been shown to improve overall survival in multiple cancer types, including SCCs. However, only a minority of patients experience a durable response with immunotherapy. Epigenetic modulation plays a major role in escaping tumor immunosurveillance and confers resistance to immune checkpoint inhibitors. Preclinical evidence suggests that modulating the epigenome might improve the efficacy of immunotherapy. We herein review the preclinical and the clinical rationale for combining immunotherapy with an epidrug, and detail the design of PEVOsq, a basket clinical trial combining pembrolizumab with vorinostat, a histone deacetylase inhibitor, in patients with SCCs of different locations. Sequential blood and tumor sampling will be collected in order to identify predictive and pharmacodynamics biomarkers of efficacy of the combination. We also present how clinical and biological data will be managed with the aim to enable the development of a prospective integrative platform to allow secure and controlled access to the project data as well as further exploitations.
In the era of personalized medicine, the introduction of translational studies in clinical trials... more In the era of personalized medicine, the introduction of translational studies in clinical trials has substantially increased their costs, but provides the possibility of improving the productivity of trials with a better selection of recruited patients. With the overall goal of creating a roadmap to improve translational design for future gynecological cancer trials and of defining translational goals, a main discussion was held during a brainstorming day of the Gynecologic Cancer InterGroup (GCIG) Translational Research Committee and overall conclusions are here reported. A particular emphasis was dedicated to the new frontier of the immunoprofiling of gynecological cancers. The discussion pointed out that to maximize patients’ benefit, translational studies should be integral to clinical trial design with standardization and optimization of procedures including a harmonization program of Standard Operating Procedures. Pathology-reviewed sample collection should be mandatory and e...
La degenerescence maligne des kystes dermoides de l'ovaire est rapportee approximativement da... more La degenerescence maligne des kystes dermoides de l'ovaire est rapportee approximativement dans 0,5 a 2 % des cas. Differents types de cancer peuvent survenir, les carcinomes epidermoides etant de loin les plus frequents (75 %). L'âge au moment du diagnostic est superieur a 50 ans. Les techniques chirurgicales a minima se sont beaucoup developpees et la coelioscopie operatoire est devenue un traitement courant des kystes ovariens benins. On se doit de reconnaitre les rares transformations malignes afin d'eviter une effraction kystique per-operatoire. L'envahissement des structures pelviennes voisines et de l'intestin grele represente le mode le plus habituel d'extension. Un depassement de la capsule est de tres mauvais pronostic
The macrophage-colony stimulating factor (M-CSF) has been already shown to affect the function of... more The macrophage-colony stimulating factor (M-CSF) has been already shown to affect the function of dendritic cells (DC). Therefore, the differentiation of dendritic cells into macrophages (MΦ) might represent a pathway which could inhibit the immune response initiated by DC. Because Major Histocompatibility Complex class II molecules (MHC-II) are crucial for DC function, we asked whether M-CSF may influence the intracellular transport of MHC-II in monocyte derived DC. We found that, at early stages, M-CSF induced first a rapid redistribution of MHC-II from the MHC-II containing compartments (MIIC) to the plasma membrane and second an increase in MHC-II synthesis as observed with LPS or TNF-α. These processes were associated with the sorting of MHC-II from lysosomal membranes which underwent a drastic structural reorganization. However, in contrast to tumor necrosis factor (TNF)-α or lipopolysaccharide (LPS), M-CSF neither potentiated the allostimulatory function of DC nor allowed the...
BACKGROUND: Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortali... more BACKGROUND: Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality world wide and constitutes the third most common malignancy in women. The RAIDs consortium (http://www. raids-fp7.eu/) conducted a prospective European study [BioRAIDs (NCT02428842)] with the objective to stratify CC patients for innovative treatments. A "metagene" of genomic markers in the PI3K pathway and epigenetic regulators had been previously associated with poor outcome [2]. METHODS: To detect new, more specific, targets for treatment of patients who resist standard chemo-radiation, a high-dimensional Cox model was applied to define dominant molecular variants, copy number variations, and reverse phase protein arrays (RPPA). FINDINGS: Survival analysis on 89 patients with all omics data available, suggested loss-of-function (LOF) or activating molecular alterations in nine genes to be candidate biomarkers for worse prognosis in patients treated by chemo-radiation while LOF of ATRX, MED13 as well as CASP8 were associated with better prognosis. When protein expression data by RPPA were factored in, the supposedly low molecular weight and nuclear form, of beta-catenin, phosphorylated in Ser552 (pb-Cat552), ranked highest for good prognosis, while pb-Cat675 was associated with worse prognosis. INTERPRETATION: These findings call for molecularly targeted treatments involving p53, Wnt pathway, PI3K pathway, and epigenetic regulator genes. Pb-Cat552 and pb-Cat675 may be useful biomarkers to predict outcome to chemo-radiation, which targets the DNA repair axis. FUNDING: European Union's Seventh Program for research, technological development and demonstration (agreement N°304,810), the Fondation ARC pour la recherche contre le cancer.
BACKGROUND: Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortali... more BACKGROUND: Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality worldwide and constitutes the second most common malignancy in women. CC exhibits differences in clinical behavior; infection by high-risk Human Papilloma Virus (HPV) remains an important initiating event in tumorigenesis and the most important risk factors for CC. As HPV integration types may be specific biomarkers for prediction of clinical outcomes, we analyzed the association between the different viral integration signatures and clinic-pathological parameters in CC patients. EXPERIMENTAL DESIGN: Patients included in this study were enrolled in the EU-funded RAIDs Network (Rational Molecular Assessment and Innovative Drug Selection, www.raids-fp7.eu) prospective CC BioRAIDs study [NCT02428842]. HPV double capture method followed by NGS was used to define the different integration signatures. Correlations between HPV integration signatures and clinical, biological and molecular fea...
The use of neoadjuvant chemotherapy in operable breast cancer may, at least in theory, eliminate ... more The use of neoadjuvant chemotherapy in operable breast cancer may, at least in theory, eliminate early systemic micrometastases, avoid rapid growth of metastases after treatment of the primary site and hopefully prevent emergence of resistant clones (Bhalla and Harris, 1998). The only demonstrated benefit in terms of treatment effects is the achievement of tumour shrinkage, which allows more conservative treatment in some patients (Fisher et al, 1997). Several clinical trials have compared preoperative and postoperative chemotherapy in operable breast cancer, but no significant advantage in terms of long-term survival has been demonstrated to date (
Background: Aiming to enlarge cancer treatment options, large-scale pharmacological screenings of... more Background: Aiming to enlarge cancer treatment options, large-scale pharmacological screenings of cancer cell lines were set up: The NCI-60 DTP human tumor cell panel intended to screen 3000 compounds per year on a set of 60 different human tumor cell lines. The Broad-Novartis Cancer Cell Line Encyclopedia aimed at integrating genomic and pharmacological results on a panel of 673 cancer cell lines. Only 6 cervical cancer cell (CC) lines are included in this Encyclopedia. Methods: We performed pharmacological profiling of a panel of 20 original cervical cancer cell lines and attempt to correlate drug responsiveness with genomic markers. 43 different drugs have been tested, singly or in combination with Paclitaxel and Carboplatin for their ability to induce cell death. Full exome sequencing has been completed on all cell lines. Results: The number of "druggable" mutations detected in each of the 20 cell lines varied between 5 and 21 while the range of genetic variants identified by full exome sequencing was 500 and 2000. Pharmacological profiling showed some cell lines to be highly sensitive and others highly resistant to many drugs. 5 CC cell lines were retested for (a) their sensitivity or resistance to a family of drugs affecting the spindle assembly checkpoint (SAC), as well as (b) a control drug, methotrexate belonging to an independent family of drugs. Focusing on one highly resistant-IC3, and one highly sensitive-IC5 cell line, the comparison with molecular data showed the resistant cell lines to carry 7 relevant mutations. The sensitive cell line had 5 relevant mutations which included BRCA. Similarly, in patient treatment, BRCA mutated tumors are highly sensitive to chemotherapy. The search for correlations between bioinformatics analysis with targeted drug sensitivity as a function of genomic markers is still ongoing. Full exome sequencing from the first 48 BioRAIDs patient tumors (>365 patients included) revealed predominant mutations in several pathways including the PI3K pathway, chromatin remodeling and loss of function mutations of the suppressor gene FBWX7. Using an atlas for cancer signaling network (ACSN), 5 clusters could be defined. All 20 cell lines were contained in clusters 1 and 4, which (according to ingenuity pathway analysis) were enriched in dysfunctions of oxidative phosphorylation and mitochondrial energy production. Discussion: Strategies envisioning to enlarge cancer treatment options will need to take into account: (1) correlations between mutational data and drug response in cell line screening, (2) selection of the patients who need alternative treatment options most (by defining) molecular markers of drug resistance/incomplete response (from BioRAIDs) and (3) drug availability both for laboratory screening and for patient treatment. No conflict of interest.
Drug discovery efforts have focused on the tumor microenvironment in recent years. However, few s... more Drug discovery efforts have focused on the tumor microenvironment in recent years. However, few studies have characterized the stroma component in patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMs). In this study, we characterized the stroma in various models of breast cancer tumors in mice. We performed transcriptomic and flow cytometry analyses on murine populations for a series of 25 PDXs and the two most commonly used GEMs (MMTV-PyMT and MMTV-erBb2). We sorted macrophages from five models. We then profiled gene expression in these cells, which were also subjected to flow cytometry for phenotypic characterization. Hematopoietic cell composition, mostly macrophages and granulocytes, differed between tumors. Macrophages had a specific polarization phenotype related to their M1/M2 classification and associated with the expression of genes involved in the recruitment, invasion and metastasis processes. The heterogeneity of the stroma component of the models studied suggests that tumor cells modify their microenvironment to satisfy their needs. Our observations suggest that such models are of relevance for preclinical studies.
ObjectiveCervical cancer is responsible for more than a quarter of a million deaths globally each... more ObjectiveCervical cancer is responsible for more than a quarter of a million deaths globally each year, mostly in developing countries, making therapeutic advances in all health care settings a top priority. The Gynecologic Cancer InterGroup (GCIG) is a worldwide collaboration of leading national research groups that develops and promotes multinational trials in gynecologic cancer. In recognition of the pressing need for action, the GCIG convened an international meeting with expert representation from the GCIG groups and selected large sites in low- and middle-income countries.MethodsThe focus was to develop a consensus on several concepts for future clinical trials, which would be developed and promoted by the GCIG and launched with major international participation. The first half of the meeting was devoted to a resume of the current state of the knowledge and identifying the gaps in need of new evidence, validating control arms for present and future clinical trials and identify...
Background: Cervical cancer (CC) is-second to breast cancer-a dominant cause of gynecological can... more Background: Cervical cancer (CC) is-second to breast cancer-a dominant cause of gynecological cancer-related deaths worldwide. CC tumor biopsies and blood samples are of easy access and vital for the development of future precision medicine strategies. Design: BIO-RAIDs is a prospective multicenter European study, presently recruiting patients in 6 EU countries. Tumor and liquid biopsies from patients with previously non-treated cervical cancer (stages IB2-IV) are collected at defined time points. Patients receive standard primary treatment according to the stage of their disease. 700 patients are planned to be enrolled. The main objectives are the discovery of-dominant molecular alterations,-signalling pathway activation, and-tumor micro-environment patterns that may predict response or resistance to treatment. An exhaustive molecular analysis is performed using 1°Next generation sequencing, 2°Reverse phase protein arrays and 3°Immuno-histochemistry. Discussion: The clinical study BIO-RAIDs is activated in all planned countries, 170 patients have been recruited till now. This study will make an important contribution towards precision medicine treatments in cervical cancer. The results will support the development of clinical practice guidelines for cervical cancer patients to improve their prognosis and their quality of life.
Infusional 5-fluorouracil in advanced breast cancer has been associated with improved clinical re... more Infusional 5-fluorouracil in advanced breast cancer has been associated with improved clinical response rates when compared with conventional bolus therapy. As a first line of chemotherapy in proven metastatic breast carcinoma, 258 women were randomly assigned to receive FAC consisting of 5-fluorouracil (F) 600 mg m-2 intravenously (i.v.) over 1 h on days 1, 2 and 3, doxorubicin (A) 50 mg m-2 i.v. bolus on day 1 and cyclophosphamide (C), 400 mg m-2 i.v. bolus on days 1, 2 and 3 or 'FULON' consisting of 5-fluorouracil 250 mg m-2 day-1 continuously infused from day 1 to day 22, doxorubicin 15 mg m-2 i.v. bolus on days 1, 8, 15 and 22 and cyclophosphamide 300 mg m-2 i.v. bolus on days 1, 8, 15 and 22. Chemotherapy courses were administered 4-weekly for the bolus regimen and 6-weekly for FULON. Pretreatment characteristics were identical between the two groups. Response rates were 54% in the FAC arm and 53% in the FULON arm. Time to progression was 14 months in the FAC arm and 12 months in the FULON arm. Differences were not statistically significant. Median overall survival duration for all patients was 22 months. Haematological toxicity was more severe in the bolus-treated group (P = 0.05), as were nausea and vomiting (P < 0.01). We conclude that the two regimens appeared equally effective but have different toxicities.
CSF-1 (colony stimulating factor-1), initially considered to be a monocyte specific growth and di... more CSF-1 (colony stimulating factor-1), initially considered to be a monocyte specific growth and differentiation factor [4], has recently been shown to be produced in human endometrium [16], placenta [7], as well as in numerous solid tumors [19-23, 26, 27]. The CSF-1 receptor (a protein product of c-fms) [24] is a member of the tyrosine kinase receptor family and an autocrine or paracrine mechanism of activation has been suggested. Overactivation of this receptor can lead to a malignant phenotype in various cell systems [20, 21]. We review the biology of CSF-1 and fms expression in normal as well as in malignant tissues with particular reference to a potential role for CSF-1 in breast tumour invasion.
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 27, 2015
Background: EGFR is frequently overexpressed in cervical cancer (CC), suggesting EGFR blockade as... more Background: EGFR is frequently overexpressed in cervical cancer (CC), suggesting EGFR blockade as a promising treatment approach. Cetuximab, an anti EGFR antibody, used conjointly with radio-chemotherapy, was feasible in first-line treatment of cervix carcinoma limited to the pelvis. Methods: This randomized phaseII trial enrolled 78 FIGO-stage IB2-IIIB CC patients to either Cisplatin based radio-chemotherapy alone (Arm B, n=38) or conjointly with a 6 week course of weekly Cetuximab (Arm A, n=40). Brachytherapy was given to the pelvic mass. Primary endpoint was disease free survival (DFS) at 2 years. EGFR expression and targeted sequencing were performed in 54/78 patients. Findings: Cetuximab over a 6 week period didn't improve DFS at 24 months. At 31 months median follow-up, DFS was not significantly different (p=0•18). Complete response at 4-6 months was strongly predictive for excellent DFS (Log-Rank test; p<0•001). PIK3CA, KRAS and STK11 mutations were observed in 22%, 4%...
Objectives. The purpose of this retrospective evaluation of advanced-stage ovarian cancer patient... more Objectives. The purpose of this retrospective evaluation of advanced-stage ovarian cancer patients was to compare outcome with published findings from other centers and to discuss future options for the management of advanced ovarian carcinoma patients.Methods. A retrospective series of 340 patients with a mean age of 58 years (range: 17–88) treated for FIGO stage III and IV ovarian cancer between January 1985 and January 2005 was reviewed. All patients had primary cytoreductive surgery, without extensive bowel, peritoneal, or systematic lymph node resection, thereby allowing initiation of chemotherapy without delay. Chemotherapy consisted of cisplatin-based chemotherapy in combination with alkylating agents before 2000, whereas carboplatin and paclitaxel regimes were generally used after 1999-2000. Overall survival and disease-free survival were analyzed by the Kaplan-Meier method and the log-rank test.Results. With a mean followup of 101 months (range: 5 to 203), 280 events (recur...
Squamous cell carcinomas (SCCs) are among the most frequent solid tumors in humans. SCCs, related... more Squamous cell carcinomas (SCCs) are among the most frequent solid tumors in humans. SCCs, related or not to the human papillomavirus, share common molecular features. Immunotherapies, and specifically immune checkpoint inhibitors, have been shown to improve overall survival in multiple cancer types, including SCCs. However, only a minority of patients experience a durable response with immunotherapy. Epigenetic modulation plays a major role in escaping tumor immunosurveillance and confers resistance to immune checkpoint inhibitors. Preclinical evidence suggests that modulating the epigenome might improve the efficacy of immunotherapy. We herein review the preclinical and the clinical rationale for combining immunotherapy with an epidrug, and detail the design of PEVOsq, a basket clinical trial combining pembrolizumab with vorinostat, a histone deacetylase inhibitor, in patients with SCCs of different locations. Sequential blood and tumor sampling will be collected in order to identify predictive and pharmacodynamics biomarkers of efficacy of the combination. We also present how clinical and biological data will be managed with the aim to enable the development of a prospective integrative platform to allow secure and controlled access to the project data as well as further exploitations.
In the era of personalized medicine, the introduction of translational studies in clinical trials... more In the era of personalized medicine, the introduction of translational studies in clinical trials has substantially increased their costs, but provides the possibility of improving the productivity of trials with a better selection of recruited patients. With the overall goal of creating a roadmap to improve translational design for future gynecological cancer trials and of defining translational goals, a main discussion was held during a brainstorming day of the Gynecologic Cancer InterGroup (GCIG) Translational Research Committee and overall conclusions are here reported. A particular emphasis was dedicated to the new frontier of the immunoprofiling of gynecological cancers. The discussion pointed out that to maximize patients’ benefit, translational studies should be integral to clinical trial design with standardization and optimization of procedures including a harmonization program of Standard Operating Procedures. Pathology-reviewed sample collection should be mandatory and e...
La degenerescence maligne des kystes dermoides de l'ovaire est rapportee approximativement da... more La degenerescence maligne des kystes dermoides de l'ovaire est rapportee approximativement dans 0,5 a 2 % des cas. Differents types de cancer peuvent survenir, les carcinomes epidermoides etant de loin les plus frequents (75 %). L'âge au moment du diagnostic est superieur a 50 ans. Les techniques chirurgicales a minima se sont beaucoup developpees et la coelioscopie operatoire est devenue un traitement courant des kystes ovariens benins. On se doit de reconnaitre les rares transformations malignes afin d'eviter une effraction kystique per-operatoire. L'envahissement des structures pelviennes voisines et de l'intestin grele represente le mode le plus habituel d'extension. Un depassement de la capsule est de tres mauvais pronostic
The macrophage-colony stimulating factor (M-CSF) has been already shown to affect the function of... more The macrophage-colony stimulating factor (M-CSF) has been already shown to affect the function of dendritic cells (DC). Therefore, the differentiation of dendritic cells into macrophages (MΦ) might represent a pathway which could inhibit the immune response initiated by DC. Because Major Histocompatibility Complex class II molecules (MHC-II) are crucial for DC function, we asked whether M-CSF may influence the intracellular transport of MHC-II in monocyte derived DC. We found that, at early stages, M-CSF induced first a rapid redistribution of MHC-II from the MHC-II containing compartments (MIIC) to the plasma membrane and second an increase in MHC-II synthesis as observed with LPS or TNF-α. These processes were associated with the sorting of MHC-II from lysosomal membranes which underwent a drastic structural reorganization. However, in contrast to tumor necrosis factor (TNF)-α or lipopolysaccharide (LPS), M-CSF neither potentiated the allostimulatory function of DC nor allowed the...
BACKGROUND: Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortali... more BACKGROUND: Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality world wide and constitutes the third most common malignancy in women. The RAIDs consortium (http://www. raids-fp7.eu/) conducted a prospective European study [BioRAIDs (NCT02428842)] with the objective to stratify CC patients for innovative treatments. A "metagene" of genomic markers in the PI3K pathway and epigenetic regulators had been previously associated with poor outcome [2]. METHODS: To detect new, more specific, targets for treatment of patients who resist standard chemo-radiation, a high-dimensional Cox model was applied to define dominant molecular variants, copy number variations, and reverse phase protein arrays (RPPA). FINDINGS: Survival analysis on 89 patients with all omics data available, suggested loss-of-function (LOF) or activating molecular alterations in nine genes to be candidate biomarkers for worse prognosis in patients treated by chemo-radiation while LOF of ATRX, MED13 as well as CASP8 were associated with better prognosis. When protein expression data by RPPA were factored in, the supposedly low molecular weight and nuclear form, of beta-catenin, phosphorylated in Ser552 (pb-Cat552), ranked highest for good prognosis, while pb-Cat675 was associated with worse prognosis. INTERPRETATION: These findings call for molecularly targeted treatments involving p53, Wnt pathway, PI3K pathway, and epigenetic regulator genes. Pb-Cat552 and pb-Cat675 may be useful biomarkers to predict outcome to chemo-radiation, which targets the DNA repair axis. FUNDING: European Union's Seventh Program for research, technological development and demonstration (agreement N°304,810), the Fondation ARC pour la recherche contre le cancer.
BACKGROUND: Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortali... more BACKGROUND: Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality worldwide and constitutes the second most common malignancy in women. CC exhibits differences in clinical behavior; infection by high-risk Human Papilloma Virus (HPV) remains an important initiating event in tumorigenesis and the most important risk factors for CC. As HPV integration types may be specific biomarkers for prediction of clinical outcomes, we analyzed the association between the different viral integration signatures and clinic-pathological parameters in CC patients. EXPERIMENTAL DESIGN: Patients included in this study were enrolled in the EU-funded RAIDs Network (Rational Molecular Assessment and Innovative Drug Selection, www.raids-fp7.eu) prospective CC BioRAIDs study [NCT02428842]. HPV double capture method followed by NGS was used to define the different integration signatures. Correlations between HPV integration signatures and clinical, biological and molecular fea...
The use of neoadjuvant chemotherapy in operable breast cancer may, at least in theory, eliminate ... more The use of neoadjuvant chemotherapy in operable breast cancer may, at least in theory, eliminate early systemic micrometastases, avoid rapid growth of metastases after treatment of the primary site and hopefully prevent emergence of resistant clones (Bhalla and Harris, 1998). The only demonstrated benefit in terms of treatment effects is the achievement of tumour shrinkage, which allows more conservative treatment in some patients (Fisher et al, 1997). Several clinical trials have compared preoperative and postoperative chemotherapy in operable breast cancer, but no significant advantage in terms of long-term survival has been demonstrated to date (
Background: Aiming to enlarge cancer treatment options, large-scale pharmacological screenings of... more Background: Aiming to enlarge cancer treatment options, large-scale pharmacological screenings of cancer cell lines were set up: The NCI-60 DTP human tumor cell panel intended to screen 3000 compounds per year on a set of 60 different human tumor cell lines. The Broad-Novartis Cancer Cell Line Encyclopedia aimed at integrating genomic and pharmacological results on a panel of 673 cancer cell lines. Only 6 cervical cancer cell (CC) lines are included in this Encyclopedia. Methods: We performed pharmacological profiling of a panel of 20 original cervical cancer cell lines and attempt to correlate drug responsiveness with genomic markers. 43 different drugs have been tested, singly or in combination with Paclitaxel and Carboplatin for their ability to induce cell death. Full exome sequencing has been completed on all cell lines. Results: The number of "druggable" mutations detected in each of the 20 cell lines varied between 5 and 21 while the range of genetic variants identified by full exome sequencing was 500 and 2000. Pharmacological profiling showed some cell lines to be highly sensitive and others highly resistant to many drugs. 5 CC cell lines were retested for (a) their sensitivity or resistance to a family of drugs affecting the spindle assembly checkpoint (SAC), as well as (b) a control drug, methotrexate belonging to an independent family of drugs. Focusing on one highly resistant-IC3, and one highly sensitive-IC5 cell line, the comparison with molecular data showed the resistant cell lines to carry 7 relevant mutations. The sensitive cell line had 5 relevant mutations which included BRCA. Similarly, in patient treatment, BRCA mutated tumors are highly sensitive to chemotherapy. The search for correlations between bioinformatics analysis with targeted drug sensitivity as a function of genomic markers is still ongoing. Full exome sequencing from the first 48 BioRAIDs patient tumors (>365 patients included) revealed predominant mutations in several pathways including the PI3K pathway, chromatin remodeling and loss of function mutations of the suppressor gene FBWX7. Using an atlas for cancer signaling network (ACSN), 5 clusters could be defined. All 20 cell lines were contained in clusters 1 and 4, which (according to ingenuity pathway analysis) were enriched in dysfunctions of oxidative phosphorylation and mitochondrial energy production. Discussion: Strategies envisioning to enlarge cancer treatment options will need to take into account: (1) correlations between mutational data and drug response in cell line screening, (2) selection of the patients who need alternative treatment options most (by defining) molecular markers of drug resistance/incomplete response (from BioRAIDs) and (3) drug availability both for laboratory screening and for patient treatment. No conflict of interest.
Drug discovery efforts have focused on the tumor microenvironment in recent years. However, few s... more Drug discovery efforts have focused on the tumor microenvironment in recent years. However, few studies have characterized the stroma component in patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMs). In this study, we characterized the stroma in various models of breast cancer tumors in mice. We performed transcriptomic and flow cytometry analyses on murine populations for a series of 25 PDXs and the two most commonly used GEMs (MMTV-PyMT and MMTV-erBb2). We sorted macrophages from five models. We then profiled gene expression in these cells, which were also subjected to flow cytometry for phenotypic characterization. Hematopoietic cell composition, mostly macrophages and granulocytes, differed between tumors. Macrophages had a specific polarization phenotype related to their M1/M2 classification and associated with the expression of genes involved in the recruitment, invasion and metastasis processes. The heterogeneity of the stroma component of the models studied suggests that tumor cells modify their microenvironment to satisfy their needs. Our observations suggest that such models are of relevance for preclinical studies.
ObjectiveCervical cancer is responsible for more than a quarter of a million deaths globally each... more ObjectiveCervical cancer is responsible for more than a quarter of a million deaths globally each year, mostly in developing countries, making therapeutic advances in all health care settings a top priority. The Gynecologic Cancer InterGroup (GCIG) is a worldwide collaboration of leading national research groups that develops and promotes multinational trials in gynecologic cancer. In recognition of the pressing need for action, the GCIG convened an international meeting with expert representation from the GCIG groups and selected large sites in low- and middle-income countries.MethodsThe focus was to develop a consensus on several concepts for future clinical trials, which would be developed and promoted by the GCIG and launched with major international participation. The first half of the meeting was devoted to a resume of the current state of the knowledge and identifying the gaps in need of new evidence, validating control arms for present and future clinical trials and identify...
Background: Cervical cancer (CC) is-second to breast cancer-a dominant cause of gynecological can... more Background: Cervical cancer (CC) is-second to breast cancer-a dominant cause of gynecological cancer-related deaths worldwide. CC tumor biopsies and blood samples are of easy access and vital for the development of future precision medicine strategies. Design: BIO-RAIDs is a prospective multicenter European study, presently recruiting patients in 6 EU countries. Tumor and liquid biopsies from patients with previously non-treated cervical cancer (stages IB2-IV) are collected at defined time points. Patients receive standard primary treatment according to the stage of their disease. 700 patients are planned to be enrolled. The main objectives are the discovery of-dominant molecular alterations,-signalling pathway activation, and-tumor micro-environment patterns that may predict response or resistance to treatment. An exhaustive molecular analysis is performed using 1°Next generation sequencing, 2°Reverse phase protein arrays and 3°Immuno-histochemistry. Discussion: The clinical study BIO-RAIDs is activated in all planned countries, 170 patients have been recruited till now. This study will make an important contribution towards precision medicine treatments in cervical cancer. The results will support the development of clinical practice guidelines for cervical cancer patients to improve their prognosis and their quality of life.
Infusional 5-fluorouracil in advanced breast cancer has been associated with improved clinical re... more Infusional 5-fluorouracil in advanced breast cancer has been associated with improved clinical response rates when compared with conventional bolus therapy. As a first line of chemotherapy in proven metastatic breast carcinoma, 258 women were randomly assigned to receive FAC consisting of 5-fluorouracil (F) 600 mg m-2 intravenously (i.v.) over 1 h on days 1, 2 and 3, doxorubicin (A) 50 mg m-2 i.v. bolus on day 1 and cyclophosphamide (C), 400 mg m-2 i.v. bolus on days 1, 2 and 3 or 'FULON' consisting of 5-fluorouracil 250 mg m-2 day-1 continuously infused from day 1 to day 22, doxorubicin 15 mg m-2 i.v. bolus on days 1, 8, 15 and 22 and cyclophosphamide 300 mg m-2 i.v. bolus on days 1, 8, 15 and 22. Chemotherapy courses were administered 4-weekly for the bolus regimen and 6-weekly for FULON. Pretreatment characteristics were identical between the two groups. Response rates were 54% in the FAC arm and 53% in the FULON arm. Time to progression was 14 months in the FAC arm and 12 months in the FULON arm. Differences were not statistically significant. Median overall survival duration for all patients was 22 months. Haematological toxicity was more severe in the bolus-treated group (P = 0.05), as were nausea and vomiting (P < 0.01). We conclude that the two regimens appeared equally effective but have different toxicities.
CSF-1 (colony stimulating factor-1), initially considered to be a monocyte specific growth and di... more CSF-1 (colony stimulating factor-1), initially considered to be a monocyte specific growth and differentiation factor [4], has recently been shown to be produced in human endometrium [16], placenta [7], as well as in numerous solid tumors [19-23, 26, 27]. The CSF-1 receptor (a protein product of c-fms) [24] is a member of the tyrosine kinase receptor family and an autocrine or paracrine mechanism of activation has been suggested. Overactivation of this receptor can lead to a malignant phenotype in various cell systems [20, 21]. We review the biology of CSF-1 and fms expression in normal as well as in malignant tissues with particular reference to a potential role for CSF-1 in breast tumour invasion.
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 27, 2015
Background: EGFR is frequently overexpressed in cervical cancer (CC), suggesting EGFR blockade as... more Background: EGFR is frequently overexpressed in cervical cancer (CC), suggesting EGFR blockade as a promising treatment approach. Cetuximab, an anti EGFR antibody, used conjointly with radio-chemotherapy, was feasible in first-line treatment of cervix carcinoma limited to the pelvis. Methods: This randomized phaseII trial enrolled 78 FIGO-stage IB2-IIIB CC patients to either Cisplatin based radio-chemotherapy alone (Arm B, n=38) or conjointly with a 6 week course of weekly Cetuximab (Arm A, n=40). Brachytherapy was given to the pelvic mass. Primary endpoint was disease free survival (DFS) at 2 years. EGFR expression and targeted sequencing were performed in 54/78 patients. Findings: Cetuximab over a 6 week period didn't improve DFS at 24 months. At 31 months median follow-up, DFS was not significantly different (p=0•18). Complete response at 4-6 months was strongly predictive for excellent DFS (Log-Rank test; p<0•001). PIK3CA, KRAS and STK11 mutations were observed in 22%, 4%...
Objectives. The purpose of this retrospective evaluation of advanced-stage ovarian cancer patient... more Objectives. The purpose of this retrospective evaluation of advanced-stage ovarian cancer patients was to compare outcome with published findings from other centers and to discuss future options for the management of advanced ovarian carcinoma patients.Methods. A retrospective series of 340 patients with a mean age of 58 years (range: 17–88) treated for FIGO stage III and IV ovarian cancer between January 1985 and January 2005 was reviewed. All patients had primary cytoreductive surgery, without extensive bowel, peritoneal, or systematic lymph node resection, thereby allowing initiation of chemotherapy without delay. Chemotherapy consisted of cisplatin-based chemotherapy in combination with alkylating agents before 2000, whereas carboplatin and paclitaxel regimes were generally used after 1999-2000. Overall survival and disease-free survival were analyzed by the Kaplan-Meier method and the log-rank test.Results. With a mean followup of 101 months (range: 5 to 203), 280 events (recur...
Uploads
Papers by Suzy Scholl