The overall survival of patients with high-risk colorectal cancer (CRC) (stages II, III or IV) is improved by adjuvantchemotherapy [ 1 , 2 ]. First-line chemotherapy commonly associates 5-fluorouracil, folinic acid and oxaliplatin in the FOLFOX-4 protocol. However, nearly half the patients receiving adjuvant treatment do not benefit from oxaliplatin [ 2 , 3 ]. Platinum salts (e.g. oxaliplatin) form platinum adducts in DNA double strands, resulting in the inhibition of DNA replication. Consequently, the cellular distribution of platinum salts is considered to be a signif- icant factor determining drug sensitivity [ 4 ]. Membrane transporters of xenobiotics are impor- tant factors involved in the intracellular distribution and efficacy of anticancer drugs [ 4 ]. In vitro studies have demonstrated that organic cation transporters OCT1, OCT2 and OCT3, belonging to the solute carrier family 22 (SLC22a1, SLC22a2 and SLC22a3, respectively), are involved in the cellular uptake of platinum salts, especially for oxaliplatin [ 5 – 7 ]. The Copper Transporter 1 (CTR1), belonging to the solute carrier family 31 (SLC31A1), is also linked to the influx of platinum salts such as oxaliplatin into cells, while its efflux can be linked to the copper transporter, ATPase Cu 2+ transporting beta polypeptide (ATP7B) [ 8 ]. Thus, in the con- text of CRC, the tumor expression of OCT1, OCT2, OCT3, CTR1 and ATP7B may affect response to FOLFOX-4 chemotherapy. However, to this date, very little clinical studies have been done in CRC and no study in the context of adjuvantchemotherapy. In metastatic CRC, a high expression of OCT2 has been associated with a better prognostic and a high expression of ATP7B with a poor prognostic [ 9 – 11 ]. No clinical study has ever assessed the relation between the chemotherapy response and the expression of OCT1, OCT3 and CTR1 in CRC. The aim of this study was to perform a retrospective assessment, in tumor samples after surgery and before chemotherapy, of the relation between the expression of oxaliplatin transporters (OCT1, OCT2, OCT3, CTR1 and ATP7B) and the response to adjuvant FOLFOX-4 chemotherapy, in responder and non-responder patients.
generation prognostic tests (OncotypeDX ™, Mammaprint®) are
now used worldwide to guide decision making regarding adjuvantchemotherapy. These tests were validated initially based on sub- stantial retrospective data and, more recent prospective data [ 3 e5 ]. The most recently developed prognostic signatures add value by integrating clinical parameters to standard characteristics. They have demonstrated independent added value on top of tumor burden, tumor grade, estrogen receptor (ER) and progesterone re- ceptor (PR) status, HER2 status, age and also tumor proliferation. EndoPredict ® (EpClin) is one of such tests. It is based on the reverse
away from the “one shoe fits all” strategy. Here, we have analyzed the expression of 34 selected proteins in a sub- set of 1,099 patients included in the PACS01 trial.
We show that a Ki67-positive status is not only inde- pendently associated with shorter DFS, but also with the benefit of a docetaxel addition in women treated with adjuvant anthracycline-based chemotherapy. Ki67, expressed during the cell cycle, is a well-established cell proliferation marker. Its expression in breast cancer cor- relates with poor prognosis [35,36] and higher response to chemotherapy. In the neo-adjuvant setting, correla- tion between Ki67 positivity and response to taxanes, either as monotherapy  or in association with anthracyclines , has been reported, although the relationship was not observed in other small series [39,40]. We found a prognostic correlation much more important in docetaxel-free patients (P <0.001, log-rank test) than in docetaxel-treated patients (P = 0.048), in relation to the interaction observed with docetaxel bene- fit. Such interaction has been previously studied in ran- domized trials of adjuvantchemotherapy. Higher efficiency of the CMF regimen vs. no chemotherapy (P = 0.16 for interaction) was reported in Ki67-positive ER- positive patients treated in the NSABP-20 trial , whereas Ki67 labeling index was not predictive of better response to adjuvantchemotherapy in endocrine- responsive tumors . Bartlett et al. analyzed data of the UK NEAT/BR9601 trial, which showed benefit for the addition of anthracyclines to CMF regimen, and did not detect any interaction with anthracycline benefit for Ki67 status . The benefit of docetaxel (P = 0.11 for
Preoperative Hyperfractionated Accelerated Radiotherapy (HART) with concomittant CPT-11 immediately followed by surgery and adjuvantchemotherapy. A phase I study (Trial 98-02)
P. A. Coucke 1 , V. Volter 2 , M. Gillet 3 , R. Stupp 2 . Radiation Oncology 1 , Medical Oncology 2 , Surgery 3 , CHUV - Lausanne
PRODIGE-19-FFCD1103-ADCI002 is a prospective multi- centre controlled randomised phase II/III trial comparing current standard of care (2x3 cycles of perioperative Epirubicin, cisplatin, 5-fluorouracil (ECF) chemotherapy) with a strategy of primary surgery followed by adjuvant ECF chemotherapy (6 cycles) in patients with a SRC tumour and eligible for curative surgery. In phase II pa- tients will be randomised using minimisation with stratifi- cation criteria – centre, tumour stage, performance status and tumour localisation. The principal objective will be to determine if the experimental arm (primary surgery followed by adjuvantchemotherapy) has a sufficient inter- est in terms of percentage of living patients at 24 months to be evaluated in a phase III trial. If ≤10% of patients in the experimental arm is alive at 24 months, phase III will not be initiated. Recruitment will be postponed for a 6 month period after the completion of phase II of the study to allow for the interim analysis of data. The primary ob- jective of phase III will be to demonstrate the superiority of the experimental arm in terms of overall survival. The study is planned for a total duration of 10 years and is reg- istered on clinicaltrial.gov website (NCT01717924).
Although identified to be at a higher risk of relapse, no consensus exists on the treatment of breast cancer (BC) patients with no pathological complete response after neoadjuvant che- motherapy (NAC). The benefit of adjuvantchemotherapy (ADJ) in this context has scarcely been studied. We evaluated the benefit of administrating adjuvantchemotherapy in a real life cohort of BC patients with invasive residual disease after NAC. 1199 female BC patients with T1-3NxM0 invasive tumors receiving NAC at Institut Curie from 2002 to 2012 were included in the analysis. 1061 had been treated by NAC only, whereas 138 had received additional adjuvantchemotherapy after NAC (FUN protocol: 5-FU-Vinorelbine). We com- pared disease-free survival (DFS) and overall survival (OS) rates between patients having received NAC only and patients having received NAC+ADJ. To ensure comparability of our populations, we used a propensity score (which defines the probability of treatment assign- ment conditional on observed baseline covariates) and matched each patient having received NAC+ADJ (n = 138) with a patient having received NAC only that had a similar pro- pensity score value. Before propensity score matching, DFS and OS rates were significantly lower in the NAC+ADJ group compared to NAC only, after 3 years, 5 years and 10 years fol- low-up (p < 0.01). After one-to-one PS matching, the two groups were comparable (n = 276 patients; 138 patients in each group). No significant difference was found regarding DFS (p
The first study evaluating the value of
XRCC1-399 as a pharmacogenetic marker was per-
formed in 61 patients with advanced CRC receiving 5FU/oxaliplatin chemotherapy (8). The authors showed that 73% (8/11) of responders had a G/G genotype and 27% (3/11) were G/A, while 66% (33/50) of non-responders showed A/A or G/A gen- otypes (p=0.038) (8). Patients carrying at least one A allele were at a 5.2 fold increased risk to be resistant to oxaliplatin-based chemotherapy (8). More recently, another study reported similar results in 62 patients treated with oxaliplatin-based chemotherapy for metastatic CRC (9). In keeping, we observed in our study that DFS of patients with XRCC1-399 A/A genotype was shorter. However, other studies in- cluding between 61 and 166 patients failed to detect a significant prognostic impact of XRCC1-399 SNP in metastatic setting (11, 22, 24, 29). This indicates that
The global cancer burden is becoming a major threat to many countries. It has been observed in studies mainly carried out in developed countries that the understanding of cancer has improved; And today we have a better knowledge from molecular to biological behavior of tumor cells and it’s characteristics, due to advances in pathological techniques. Natural history of cancer is also changing with increasing life expectancy. We know that risk factors are not completely known even if for breast cancer for example we can categorize in 3 risks groups: environmental, biological and hereditary. Additional factors would include age, gender, reproductive factors, endogenous hormones, exogenous hormones, hormone replacement therapy, breast density, previous breast disease and family history. Exposure to estrogen is a key factor in developed settings and more and more this is now true for developing countries. Much of the data shows that many countries will have to face rising cancer incidence as a public health scorge, unless comprehensive cancer plans are devised around screening, early diagnosis and optimized treatment strategies. The major challenge for developing countries will be setting up of infrastructures and empowering the local human resources and investing in training and software structural developments. One example would be to develop centralized clinics equipped with diagnostic tools, surgical, medical and radiation-therapy units with the specialized staff. What we know is that early detection and treatment improves the overall survival rate. Implementing standardized management strategies is hence simpler and achieving this seems possible within reasonable costs. Even if it appears difficult to predict the cost-effectiveness of developing prevention, screening and treatment strategies; one of the fundamental aspects to optimize cancer care is to have a comprehensive approach based on a multidisciplinary team. We have this vast experience in developed countries and today multidisciplinary approach is a standard. The setting up a centralized specialized clinics covering diagnostic tools, pathology and clinical, medical, surgical and radiation oncology. Also the challenge of clinical research can be met within an organized setting thus facilitating the selection of biologically defined subgroups to optimize research. Research patterns have evolved from horizontal to vertical patterns depending on the quality and accessibility to tumorotheques. This collaborative approach with access to appropriate treatment whether surgical, chemotherapy, hormone and targeted therapies and radiation therapy will have a definitive impact for advances in the management of cancer.
overexpression in PDAC cell lines with GATA6 ChIP-Seq and RNA-Seq data, in order to understand the mechanism of GATA6 functions. We then con ﬁrmed some of our observations in primary patient samples, some of which were included in the ESPAC-3 randomised clinical trial for adjuvant therapy. Results GATA6 inhibits the epithelial –mesenchymal transition (EMT) in vitro and cell dissemination in vivo. GATA6 has a unique proepithelial and antimesenchymal function, and its transcriptional regulation is direct and implies, indirectly, the regulation of other transcription factors involved in EMT. GATA6 is lost in tumours, in association with altered differentiation and the acquisition of a basal-like molecular phenotype, consistent with an epithelial-to-epithelial (ET 2 ) transition. Patients with basal-like GATA6 low tumours have a shorter survival and have a distinctly poor response to adjuvant 5- ﬂuorouracil (5-FU)/leucovorin. However, modulation of GATA6 expression in cultured cells does not directly regulate response to 5-FU.
fractionated focal irradiation at a dose of 2 Gy per fraction given once daily 5 days per week over a period of 6 weeks, for a total dose of 59.4 Gy focal radiotherapy and 13 regimens of temozolomide at a dose of 75 mg per square meter per day, given 7 days per week from the first day of radiotherapy until the last day of radiotherapy. After a 4-week break, the patient received 7 cycles of adjuvantchemotherapy according to the standard 5-day schedule every 28 days. The dose was 150 mg per square meter for the first cycle and was increased to 200 mg per square meter beginning with the second cycle (no hematologic toxic effects were noticed). Because he presented local recurrence, his case was discussed in a multidisciplinary neuro-oncological meeting, and he underwent a third surgical resection. During the procedure, we surprisingly found remains of the partially degraded copolymer of the carmustine wafer (Figure 1b). We obtained the patient’s written consent to analyze and publish anonymously his data. The wafer’s spectrum by 1 H-RMN was compared to BCNU and to an unused copolymer wafer.
Hormone-receptor –positive breast cancer accounts for 60 to 65% of all malignant neoplasms of the breast and the majority of these patients will receive endocrine therapy. Decisions on whether to offer adjuvantchemotherapy are assisted by identifying patients at greater risk of recur- rence. Gene expression profiling augments information provided by traditional histopathologic factors and bio- markers by providing quantitative recurrence risk esti- mates. Today these technologies are frequently used for making treatment decisions in patients with early-stage breast cancer [ 1 – 6 ]. The Oncotype DX® 21-gene Recur- rence Score (RS) assay predicts and quantifies the risk of DR, and overall survival (OS) in node-negative (N-)/node- positive (N+), estrogen receptor-positive (ER+) breast can- cer patients treated with adjuvant endocrine therapy (ET) [ 5 , 7 ]. The assay also predicts the magnitude of chemo- therapy benefit in endocrine therapy treated N −/ER+ and postmenopausal, N+/ER+ patients [ 8 , 9 ]. Additional stud- ies (ECOG E2197, NSABP B-28, and PlanB) have demon- strated that RS results are predictive of the risk of recurrence and survival in patients who received adjuvant chemoendocrine therapy [ 10 – 12 ].
Methods: We conducted a retrospective study from 2004–2011 with 21 male breast cancer patients. We aimed to analyse epidemiological data (age, personal and family history), tumour characteristics (size, histological type, location, TNM stage, receptors), surgery, adjuvantchemotherapy and radiation therapy, hormonal therapy and survival (relapse, follow up, death) of men who were referred to our centre with breast cancer.
scintigraphy showed total tumour resection. To date, no recurrence was found and the patient did not show hematopoietic adverse effects.
Malignant paragangliomas has a 5-year survival rates up to 50%. Malignancy is difficult to predict and suggested in presence of metastases or aggressive disease. Surgery remains the main therapeutic option as tumour are generally not chemo- or radiotherapy sensitive. Few data about efficacy of adjuvant MIBG I131 radiotherapy exists. Adverse effects include neutropenia and thrombopenia. To date, this treatment was only administered in patients with metastatis.
partitioned into a training set (including 90% of the patients) and a validation set (including the remaining 10%). The random forest classi ﬁer was trained on the 90% and used to predict the outcome of the held out 10%. This was repeated ten times, allowing every patient to act as a test case once. The model’s accuracy was determined by its ability on average to predict the outcome of the 10% of patients that were held out. We used the relative abundance in each sample of genera or families as features. The measure of the method’s suc- cess is its ability to classify new samples as coming from one of the two groups (i.e. faecal sample collected before or after chemotherapy). Random Forests assign an importance score to each genus or family by estimat- ing the increase in error caused by removing that genus from the set of predictors. Here, we considered a genus or a family to be highly predictive if its average impor- tance score was at least 0.001. 14, 15
Résumé en français: L’objectif de cette étude est d’évaluer l’impact du bevacizumab
adjuvant sur la lymphocèle symptomatique chez des patientes atteintes d’un cancer de l’ovaire de stade avancé ayant eu une chirurgie complète. L’impact du bevacizumab sur la survie sera ensuite étudié chez ces mêmes patientes. Cette étude rétrospective incluait des patientes atteintes d’un cancer de l’ovaire de stades FIGO (Fédération Internationale de Gynécologie Obstétrique) 1988 IIIB, IIIC et IV ayant été opérées d’une cytoréduction complète avec curages pelviens et lombo-aortique à l’Institut Gustave Roussy entre 2005 et 2014. 255 patientes ont été incluses dans l’étude. Le taux de lymphocèle symptomatique était de 33,6% (85/253). 61 patientes ont été traitées par bevacizumab adjuvant, soit 24,5% des patientes. En analyse multivariée, le traitement par bevacizumab n’était pas significativement associé à la présence d’une lymphocèle symptomatique avec un hazard ratio (HR) à 1,62 (IC95%= 0,87- 3,01) p=0,12). Le bevacizumab adjuvant avait un impact significatif sur la survie sans récidive avec un HR à 0,6 (IC95%=0,41-0,91 et p= 0,01) et la survie médiane sans récidive passait de 23 à 31,7 mois. En conclusion, le bevacizumab n’a pas d’impact sur la survenue de la lymphocèle postopératoire mais a un impact sur la survie sans récidive avec un gain de 8,7 mois dans cette cohorte de patientes de stade avancé et opérées d’une chirurgie complète, ce qui nécessite une confirmation par des essais thérapeutiques.
CARDIOTOXICITY OF CHEMOTHERAPEUTIC AGENTS
Chemotherapy-induced cardiotoxicity is a serious clinical prob- lem faced by both cardiologists and oncologists (Table 1). Con- tractile heart cells, known as cardiomyocytes, are prone to short-term or permanent injury upon exposure to toxic agents such as recreational drugs and therapeutic agents. Unlike most other cells, postnatal cardiomyocytes have limited regenerative capacity. Thus, their loss can cause cardiac dysfunction, which in turn can lead to heart failure, a disease with worse prognosis than some cancers . The realization that chemotherapy might worsen an underlying cardiac problem or create a new one did not become a concern for cardiologists and oncologists until the seventies. The cardiac toxicity of anthracyclines, a class of bacte- rial antibiotics widely used in chemotherapy, was the first to be described [4-6]. This consequently spurred awareness and exten- sive research into basic and clinical aspects of chemotherapy as- sociated cardiotoxicity. Although much of the literature focuses on causes and mechanisms implicated in anthracycline-induced cardiomyopathy, other types of chemotherapy-related cardiac toxicity are also common. For example, Cytarabine, an antimeta- bolic agent, can negatively affect the cardiac vasculature and the pericardium resulting in ischemia and changes in blood pressure, as well as an imbalance in liquid equilibrium and pericardial thick- ening, respectively . Finally, anticancer drugs such as Imatinib and anthracyclines can aggravate or induce cardiac arrhythmias and other cardiac conditions in patients [4,8-10].