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Even though treatment of several types of solid tumors has improved in the past few years with the introduction of molecular targeted agents in the therapeutic armamentarium of the medical oncologist, response rates to these agents are generally modest. Increasing evidence is now revealing that genetic factors are affecting patients' response to these therapeutic agents as well as the frequency and intensity of toxic reactions. Importantly, pharmacogenetic analysis is now required for the administration of several molecular targeted agents in clinical practice. For the vast majority of these agents, however, data remain purely experimental. Herein, we provide an overview of the genetic changes (mutations and polymorphisms) that have been associated with response to treatment with anticancer molecular targeted agents. Special emphasis is given on molecules (monoclonal antibodies and tyrosine kinase inhibitors) that target critical mediators in the epidermal growth factor receptor (EGFR), the human epidermal growth factor receptor 2 (HER2/ERBB2/NEU) and the vascular endothelial growth factor receptor (VEGFR) pathways. The true clinical utility of these applications remains to be proven in future prospective, randomized clinical trials in large patient cohorts of all different ethnic backgrounds.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) represent the standard of care for advanced non-small cell lung cancer (NSCLC) patients whose tumours harbor an activating EGFR mutation. Unfortunately, resistance to first- and second-generation EGFR-TKIs inevitably occurs in all patients with EGFR-mutant disease approximately within a year of treatment. At least half of these cases are attributed to the emergence of a secondary mutation in exon 20 of the EGFR gene, namely the T790M mutation. Third-generation EGFR-TKIs, including osimertinib and rociletinib, target this epigenic mutation, thus re-sensitizing cancer cells to EGFR-TKI inhibition. Osimertinib to date represents the standard of care in EGFR-mutant tumors after failure of first-line EGFR-TKIs by over-performing platinum-based chemotherapy in the recently reported AURA-3 randomized phase III clinical trial. The aim of this review is to describe the different treatment strategies that have been developed to reverse resistance to first- and second-line EGFR-TKIs, the corresponding mechanisms of resistance and the development of novel-generation EGFR-TKIs. We also discuss the challenge posed by the implementation of third-generation EGFR-TKIs earlier in the course of the disease in first-line treatment of EGFR-mutant NSCLC.

Lung cancer remains the leading cause of cancer-related death in men and women, despite its constantly declining rates in incidence and mortality in the developed world. The past decade has witnessed an unprecedented rise in the development of molecular targeted therapies in various types of tumors. In non-small cell lung cancer (NSCLC), the greatest paradigm shift is the implementation of EGFR and ALK tyrosine kinase inhibitors in the first line and subsequent lines of therapy, with impressive results. Though less frequent than the molecular alterations in the aforementioned genes, a number of aberrations in potential oncogenic drivers has been discovered, namely mutations in the genes KRAS, BRAF, HER2, PI3KCA and DDR2, ROS1 and RET rearrangements and MET, HER2 and FGFR1 gene amplifications. A great number of clinical trials are currently underway, evaluating agents specifically designed to target these alterations, with mixed results so far. The greatest cumulative benefit offered by these trials is that, despite their success or failure in their objective goals, they have provided us with a better understanding of the complexity of the molecular intracellular processes, necessitating thus the accurate interpretation of the preclinical data in order to appropriately select the patients that may derive benefit from targeted treatment strategies.

Tumors metastatic to the heart (cardiac metastases) are infrequent and few systematic studies on this topic have been published. Urothelial carcinomas are among the rarest associated with heart metastases and all cases reported to date concern autopsy examinations. We present the first report of urothelial carcinoma metastatic to the endocardium diagnosed antemortem. Notably, the endocardiac infiltration was the only site of recurrence and occurred 6 years after original diagnosis of bladder carcinoma. Although rare enough, the possibility of heart metastases without any other signs of recurrence should be included in the differential diagnosis in cases of urothelial cancer with increasing fatigue and dyspnea.

Objective The rarity of uterine sarcomas along with their pathological and molecular heterogeneities render their study particularly challenging. We evaluated a panel of somatic mutations principally centering on the tyrosine kinase gene family and their downstream signaling cascades in an attempt to identify potential candidate markers that may assist in diagnostic or therapeutic decisions in these tumors. Methods We performed mutational analysis of 20 exons from 9 genes (EGFR, CDKN2A, MET, KIT, RAS, BRAF, PI3KCA, HER-2 and PDGFR-α) on biopsy material from 25 patients who underwent primary surgery for uterine sarcoma between October 1995 and October 2003. Due to the limited number of studies conducted we have also undertaken a literature review of somatic mutations in uterine sarcomas. Results A total of 3 different somatic mutations were identified: one KRAS (codon G12D) in a carcinosarcoma and two exon 20 PI3KCA mutations (H1047R and H1047Y) both in carcinosarcomas. Mutational status of all mutations was confirmed using germline DNA extracted from peripheral blood. Consistent with the literature data, no other mutations regarding the rest of the genes of the panel were identified. Due to the low number of somatic mutations in our series, we did not perform further clinicopathological correlations. Conclusion The absence of somatic mutations in the majority of genes that are considered critical in neoplastic transformation hampers the identification of potential therapeutic targets in patients with uterine sarcoma.

Purpose: There are major differences affecting genes in adenocarcinomas in ever and never smokers. However, data on whether mitogen-activated protein kinase (MAPK) activation state differs according to smoking status are limited.Experimental Design: Expression of activated extracellular signal–regulated kinases, c-Jun NH2-terminal kinases, and P38 enzymes (pP38) were evaluated by means of immunohistochemistry in 188 chemonaïve patients with surgically resected lung adenocarcinoma. Cell viability of the lung adenocarcinoma cell line HCC827 was studied after treatment with cisplatin or the P38 MAPK inhibitor SB 203580.Results: Thirty-seven of 44 never smokers [84%; 95% confidence intervals (95% CI), 70-92%] expressed high pP38 levels compared with 45 of 104 ever smokers (43%; 95% CI, 34-53%; P < 0.0001). The proportion of never smokers expressing high c-Jun NH2-terminal kinase levels (72%; 95% CI, 57-83%) was greater than that of ever smokers (53%; 95% CI, 44-62%; P = 0.03). The proportion of ever smokers expressing high extracellular signal–regulated kinase levels (51%; 95% CI, 42-59%) was similar to that of never smokers (57%; 95% CI, 42-71%; P = 0.47). Never smokers were 10.5 times (95% CI, 3.5-31.5) more likely to express high pP38 levels after adjustment for variables linked to smoking status, including age, sex, and histologic subtype. None of the activated MAPKs predicted for overall survival. Cell viability of HCC827 was significantly reduced after exposure to SB203580 alone or when combined with cisplatin.Conclusions: Life-long nonsmoking is associated with high activated P38 levels in patients with lung adenocarcinoma. Activated P38 can contribute to the viability of adenocarcinoma cells in never smokers, but is not predictive for overall survival.

Aurora kinases represent a family of serine/threonine kinases highly conserved during evolution, whose main function is to promote mitotic spindle assembly by regulating centrosome duplication and separation. Inhibition of Aurora kinase activity may lead to defects in centrosome function, misaligned sister chromatides, mitotic spindle malformation, problematic cytokinesis and eventually mitotic arrest. Aurora kinases are overexpressed in a variety of tumor cell lines, suggesting their potential role in tumorigenesis and indicating that they could represent an appealing target for molecular therapies. Extensive pre-clinical information supports the development of Aurora kinase inhibitors in specific tumor types and a number of these novel agents are currently being extensively studied in phase I and II clinical trials exhibiting an acceptable toxicity profile and promising clinical efficacy. The current study aims to provide a comprehensive overview of the development of Aurora kinases as molecular targets for anticancer therapy by focusing on their physiological role in mitosis, their implication in oncogenesis and the potential ways of inhibiting their activity. The main pre-clinical and clinical studies concerning Aurora kinase inhibitors currently under investigation are reported and important considerations for their future development are discussed.

All patients with epidermal growth factor receptor (EGFR) mutant advanced non-small cell lung cancer (NSCLC) treated with an EGFR-tyrosine kinase inhibitor (EGFR-TKI) such as gefitinib, erlotinib or afatinib will progress after a median of 9-12 months. So far, development of a secondary T790M mutation represents the most common (approximately 60%) mechanism of resistance to these drugs. The relative rarity of mesenchymal-epithelial transition (MET) amplification in NSCLC suggests that this event plays a limited role in primary resistance to EGFR-TKI. In contrast, MET gene amplification has been detected as a secondary event representing one of the most relevant mechanisms involved in the acquired resistance to EGFR-TKIs both in preclinical and clinical studies. The aim of this review is to discuss the role of MET amplification as a mechanism of resistance to anti-EGFR therapies and to review strategies which aim at overcoming this mechanism of resistance, including studies assessing drug combinations targeting both EGFR and MET pathways.

Prophylactic erythropoiesis-stimulating agent (ESA) administration for chemotherapy-induced anemia (CIA) is not supported by current guidelines. Long-term follow-up of patients WHO had been treated with ESA for CIA in the past may provide useful information. In 2002, we undertook a prospective, randomized phase III trial of prophylactic vs. hemoglobin (Hb)-based (threshold: 11 mg/dl) ESA administration in patients with solid tumors and CIA. ESA administration FOR CIA was permanently suspended in 2007 in view of published data at that time, while patient surveillance continued. Among 630 evaluable patients, 38.6% were male, 50.9% had advanced cancer at diagnosis, 40.6% had Hb levels

Cancer originating from germ cells is a special disease, characterized by increased incidence in young men (18–40 years) and extremely good prognosis, even if it is diagnosed in advanced stages. The vast majority of these cancers are originated in the gonads (testicles), while a small percentage of germ cell tumors may appear in midline extragonadal locations that are embryologically developed from the central crest (epiphysis, mediastinum, retro peritoneum).

Non-small-cell lung cancer (NSCLC) is a highly prevalent and aggressive disease. In the metastatic setting, major advances include the incorporation of immunotherapy and targeted therapies into the clinician's therapeutic armamentarium. Standard chemotherapeutic regimens have long been reported to interfere with the immune response to the tumor; conversely, antitumor immunity may add to the effects of those therapies. The aim of immunotherapy is to specifically enhance the immune response directed to the tumor. Recently, many trials addressed the role of such therapies for metastatic NSCLC treatment: ipilimumab, tremelimumab, nivolumab and lambrolizumab are immunotherapeutic agents of main interest in this field. In addition, anti-tumor vaccines, such as MAGE-A3, Tecetomide, TG4010, CIMAvax, ganglioside vaccines, tumor cell vaccines and dendritic cell vaccines, emerged as potent inducers of immune response against the tumor. The current work aims to address the most recent developments regarding these innovative immunotherapies and their implementation in the treatment of metastatic NSCLC.

time, multiple nodular lesions were observed in the left thoracic wall, in front of the major pectoralis muscle, with the largest one corresponding to the fixed breast mass that was reported as the presenting sign of the patient (Fig. 3C, white arrows). A subse- quent computed tomography-guided biopsy of the thoracic mass confirmed the diagnosis of a poorly differentiated adenocarci- noma of the lung with a high mitotic index and a positive stain for TTF1. Morphological and immunohistochemical features of the breast lesions were consistent with metastases from the primary lung adenocarcinoma. Mutation analysis of the tumor specimen revealed no activating mutation of the EGFR gene and fluores- cence in situ hybridization analysis with break-apart probes for the ALK gene was negative for the presence of an ALK rearrange- ment. On the basis of these findings, the patient received first-line chemotherapy encompassing paclitaxel carboplatin and bevaci- zumab. After three cycles of chemotherapy, reevaluation showed progressive disease in both the primary tumor and the metastatic lesions to the breast. The patient is currently receiving second- line chemotherapy with pemetrexed. DISCUSSION

Introduction Adolescents and young adults (AYA) with cancer require dedicated clinical management and care. Little is known about the training and practice of European healthcare providers in regard to AYA and the availability of specialised services.\ud \ud \ud \ud Methods A link to an online survey was sent to members of the European Society for Medical Oncology (ESMO) and the European Society for Paediatric Oncology (SIOPE). The link was also sent to ESMO National Representatives and circulated to other European oncology groups. Questions covered the demographics and clinical training of respondents, their definition of AYA, education about AYA cancer, access to specialised clinical and supportive care, research and further education. Data from Europe were analysed by region.\ud \ud \ud \ud Results Three hundred tweenty two questionnaires were submitted and we focused on data from the 266 European healthcare professionals. Responses revealed considerable variation both within and between countries in the definition of AYA. Over two-thirds of respondents did not have access to specialised centres for AYA (67%), were not aware of research initiatives focusing on AYA with cancer (69%) and had no access to specialist services for managing the late effects of treatment (67%). The majority of the respondents were able to refer AYA patients to professional psychological support and specialised social workers. However, more than half had no access to an age-specialised nurse or specialised AYA education. Overall, 38% of respondents reported that their AYA patients did not have access to fertility specialists. This figure was 76% in Eastern Europe. Lack of specialised AYA care was particularly evident in Eastern and South-Eastern Europe.\ud \ud \ud \ud Conclusion There is important underprovision and inequity of AYA cancer care across Europe. Improving education and research focused on AYA cancer care should be a priority.

Elderly patients with advanced non-small cell lung cancer (NSCLC) are thought to receive suboptimal treatment mainly due to concerns for poor compliance and/or excessive toxicity.Using the age of 70 years as the pre-defined cut-off, we compared elderly patients with advanced NSCLC suitable for first line chemotherapy with their younger counterparts in terms of: i) diagnosis and disease characteristics ii) adherence to treatment schedule, including dose intensity (DI), and relative dose intensity (RDI), iii) toxicity, tolerance, and efficacy outcomes.Among 292 eligible patients, data were available for 245, of whom 107 (43.7%) belonged to the elderly group. This group was more likely to present with co-morbidities, non-smoking current status and diagnosis based on cytology alone. As compared to the non-elderly, elderly patients were more likely to receive single-agent therapy (8.0% vs. 29.2% respectively, p0.001) and less likely to receive platinum-based chemotherapy (80.3% vs. 57.9%, p0.001). Elderly patients also received docetaxel (24.3% vs. 40.4%), and bevacizumab (7.5% vs. 21.3%) significantly less often and received oral vinorelbine (24.3% vs. 11.8%) more frequently. Non-elderly patients were more likely to receive any of the cytotoxic drugs with RDI0.8 (49.6% vs. 33.0%, p = 0.012) and RDI0.9 (29.6% vs. 16%, p = 0.015). Substantial toxicity, as well as median overall survival did not differ significantly between the two groups.Only one third of the elderly patients received at least 80% of the scheduled treatment intensity. Nearly half received diagnosis based on cytology alone, which may deprive them from new, histology-driven, therapeutic approaches.

Human papilloma virus (HPV)-associated squamous cell carcinoma of the head and neck (SCCHN) represents a unique disease entity, with distinct epidemiological and molecular characteristics from those of tobacco- and alcohol-related SCCHN, resulting in different biological and clinical tumor behavior. The implication of HPV in the pathogenesis of a subset of SCCHN patients has generated the hypothesis that vaccine-induced immune response against HPV may provide substantial clinical benefit; however, the impact of prophylactic HPV vaccines on the incidence of HPV-associated SCCHN remains to be clarified. Preliminary evidence also shows that therapeutic HPV vaccines are able to induce potent, HPV-specific, immune responses that correlate with tumor regression, and therapeutic HPV vaccines are currently undergoing intense investigation in early clinical trials, especially in the subset of patients with oropharyngeal cancer. The question of de-escalation of treatment in the favorable prognosis subset of patients with HPV-associated disease is also currently being explored in clinical trials in an effort to minimize unnecessary toxicity without compromising therapeutic efficacy.

Head and neck cancer (HNC) represents the sixth most common malignancy and accounts for approximately 6% of new cancer cases annually worldwide. As life expectancy constantly increases, the onset of HNC in patients older than 65 years of age at diagnosis is not rare and up to one fourth of cases occurs in patients older that 70 years at age. Because elderly cancer patients are severely under-represented in clinical trials, there is a clear need to address the particular aspects of this specific patient group, especially in the context of novel multidisciplinary therapeutic approaches. The frailty of elderly patients with HNC is attributed to the high incidence of smoking and alcohol abuse in this malignancy and the presence of substantial cardiovascular, respiratory or metabolic comorbidities. In the current work, I provide an overview of current and emerging treatment approaches, in elderly patients with HNC. In particular, I discuss modern surgical approaches that improve radical excision rates while preserving functionality, the incorporation of modern radiotherapeutic techniques and the introduction of novel chemotherapeutic combinations and molecular targeted agents in an effort to reduce toxicity without compromising efficacy. Finally, there is an urgent need to increase accrual and active participation of elderly patients with HNC in clinical trials, including biomarker evaluation in biopsy specimens towards an individualized therapeutic approach.

Despite the available prevention and early detection strategies, squamous-cell carcinoma of the uterine cervix is still diagnosed as locally advanced disease in a considerable proportion of patients. As a potent sensitizer of cancer cells, cisplatin has been the “traditional partner” of external beam irradiation in this setting for more than two decades. Induction chemotherapy strategies followed by concurrent chemoradiation or surgery and preoperative concurrent chemoradiation have been recently implemented in clinical trials in an effort to optimize local control and to minimize the risk of distant metastases. In this context, cisplatin has been combined with a number of other potential radiosensitizers, including 5-fluorouracil, capecitabine, and gemcitabine. In patients resistant or intolerant to platinum compounds, numerous non-platinum-containing regimens have been developed, implementing various antimetabolites, taxanes, antineoplastic antibiotics, and topoisomerase II inhibitors. More recently, molecular agents targeting critical pathways in cervical malignant transformation are being assessed in early clinical trials in combination with external-beam irradiation. In the current work, we review the evolving role of cisplatin and other platinum compounds, either alone or in combination regimens, in the context of other potent radiosensitizers. The emerging role of molecular targeted agents, as candidate partners of external beam irradiation, is also discussed.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide. In recent years, through a better understanding of the interactions between the immune system and tumor cells (TC), immunotherapy has emerged as a promising therapeutic strategy. Chemotherapy has long been reported to interfere with the immune response to the tumor and conversely, anti-tumor immunity may add to those effects. Anti-tumor vaccines, such as MAGE-A3, Tecetomide, TG4010, CIMAvax, tumor cell vaccines and dendritic cell (DC) vaccines emerged as potent inducers of the immune response against the tumor. More recently the approval of the anti-programmed cell death 1 (anti-PD-1) monoclonal antibodies nivolumab and pembrolizumab for previously treated advanced squamous and non-squamous NSCLC, as well as other immune checkpoint inhibitors delivering promising results, has radically transformed the therapeutic landscape of NSCLC. Combination strategies now appear as the next step. Notwithstanding these successes, immunotherapy still holds significant drawbacks and currently several improvements are needed before routine use in clinical practice, including identification of robust biomarkers for optimal patient selection, as well as defining the best way to evaluate response.

e18202Background: The importance of continuous medical education in oncology is obvious. The aim of this study was to shed light on the current status in Europe and to identify any obstacles in car...

The advent of microarrays over the past decade has transformed the way genome-wide studies are designed and conducted, leading to an unprecedented speed of acquisition and amount of new knowledge. Microarray data have led to the identification of molecular subclasses of solid tumors characterized by distinct oncogenic pathways, as well as the development of multigene prognostic or predictive models equivalent or superior to those of established clinical parameters. In the field of molecular-targeted therapy for cancer, in particular, the application of array-based methodologies has enabled the identification of molecular targets with 'key' roles in neoplastic transformation or tumor progression and the subsequent development of targeted agents, which are most likely to be active in the specific molecular setting. Herein, we present a summary of the main applications of whole-genome expression microarrays in the field of molecular-targeted therapies for solid tumors and we discuss their potential in the clinical setting. An emphasis is given on deciphering the molecular mechanisms of drug action, identifying novel therapeutic targets and suitable agents to target them with, and discovering molecular markers/signatures that predict response to therapy or optimal drug dose for each patient.

Non-small-cell lung cancer (NSCLC) and pancreatic cancer represent two major causes of cancer-related morbidity and mortality worldwide. Conventional cytotoxic agents seem to have reached a therapeutic plateau in the last decade but prognosis remains dismal for both tumour types. Recent advances in molecular biology have allowed the development of novel molecular agents that target specific pathways implicated in the process of neoplastic transformation. Epidermal growth factor receptor (EGFR) represents an appealing therapeutic target in both malignancies and a number of EGFR-targeting agents have recently been approved for the first- or second-line treatment of locally advanced, recurrent or metastatic disease. Erlotinib, an orally administered EGFR tyrosine kinase inhibitor has recently received approval by both the US FDA and the European Medicines Agency (EMA) for the treatment of advanced NSCLC after chemotherapy failure and in combination with gemcitabine for the treatment of advanced pancreatic cancer, on the basis of large, randomized, phase III trials that demonstrated survival benefit over standard therapy or best supportive care. Erlotinib toxicity, as reported in these trials, seems to be modest, with the most prevalent adverse events being fatigue, acneiform rash and diarrhoea. However, recent pharmacovigilance reports, as well as sporadic case reports from the literature, raise concern of some serious adverse events, including pulmonary toxicity, sepsis and some rare cases of treatment-related deaths. In the current review, we present an evidence-based summary of the benefits and risks associated with erlotinib treatment in both advanced NSCLC and pancreatic cancer. Evidence for survival benefit in each of the drug’s indications is provided, and treatment-related risks and costs are discussed. Finally, synthetic evaluation of the benefit-risk equilibrium is attempted, in order to help clinicians put this drug into perspective.

In cancer biology angiogenesis plays a vital role in tumour growth and its subsequent metastatic potential. By targeting the angiogenic process, a new treatment strategy was added in the clinician's therapeutic armamentarium. On the other hand, numerous classic cytotoxic agents are currently considered as potential angiogenesis inhibitors, although they were not originally developed as such, representing the so-called "accidental" anti-angiogenic drugs. The discovery of these new properties of classic cytotoxic agents led to the re-evaluation of their effect on vascular cells, rendering thus the endothelium an appealing target for therapeutic intervention, either with chemotherapy alone or with combination of cytotoxics with molecular angiogenesis inhibitors. Moreover, current evidence supports that chemotherapy-induced endothelial dysfunction constitutes an integrating predictive marker of future cardiovascular events and correlates well with traditional cardiovascular risk factors. It has therefore been suggested that evaluation of endothelial function may be useful in identifying asymptomatic subjects at high risk for cardiovascular events as well as for risk stratification of patients with established cardiovascular disease. Integration of the assessment of endothelial function in the clinical setting will thus enable effective intervention strategies to prevent or minimize the impact of these late adverse effects and design accurate follow-up protocols focused on cardiovascular complications. In the current review we provide a comprehensive overview of the effects of cytotoxic chemotherapeutic agents on endothelial function and the clinical implications of chemotherapy-associated endothelial toxicity in patients with cancer.

The presence of bone metastases significantly affects clinical outcome and quality of life parameters in patients with lung cancer. In this review, we aimed to evaluate the predictive value of markers of bone turnover in skeletal morbidity and clinical parameters, including disease-free survival (DFS) and overall survival (OS), in patients with lung cancer metastatic to the skeleton who were receiving bisphosphonate treatment. A comprehensive overview of all articles published from 1995 to date in 3 medical databases (PubMed, Scopus, and Cochrane) was performed using the keywords bone markers and lung cancer. Most bone formation markers (including bone alkaline phosphatase [bALP], osteocalcin [OC], and osteoprotegerin [OPG]), most bone absorption markers (including urinary calcium, osteopontin [OPN], receptor activator of nuclear factor κ-B ligand [RANKL], tartrate-resistant acid phosphatase isoform-5b [TRACP 5b]), and the metabolites of type I collagen had elevated concentrations in patients with lung cancer and bone metastases compared with patients without skeletal involvement. Two large studies showed that urinary N-terminal telopeptide (NTX) levels are a valid diagnostic method for early detection of bone metastases and a more consistent prognosticator than bALP. Treatment with zoledronic acid reduces NTX, TRACP-5b, RANKL, and OPG levels. Furthermore posttherapeutic reduction of urinary NTX levels seems to correlate with lower risk of skeletal-related events (SREs). Levels of markers of bone remodeling reflect the presence of bone metastases and may contribute to early detection of occult skeletal disease or monitor the effect of bisphosphonate treatment. However their ability to predict SREs, as well as DFS and OS, remains debatable.

The KRAS oncogene has been extensively studied for more than three decades, however, it is only recently that it attained a central role in the clinical decision-making process for the practicing oncologist. Recently, based on retrospective analyses of large randomized clinical trials, the use of anti-epidermal growth factor (EGFR) monoclonal antibodies, cetuximab and panitumumab, was restricted to patients with metastatic colorectal cancer that carry the "wild-type"KRAS genotype. Challenges remain in the laboratory implementation of KRAS mutational testing and the clinical application of the test for treatment planning. This review attempts to offer a global view of KRAS biology, its functional role in cell signaling, mechanisms of resistance to anti-EGFR agents and its predictive potential in metastatic colorectal cancer. We also survey the growing list of candidate biomarkers that may shortly supplement KRAS in routine clinical patient stratification. Finally, we discuss practical aspects of KRAS testing that may be useful for those involved in mutational screening in their centers. This general overview of KRAS for clinical oncology practice aims to assist in data interpretation and offer insight into potential pitfalls of mutational testing. KRAS is a prime example of how translational research can fulfill the promises of personalized medicine for tailoring treatment to match the underlying tumor biology. Cancer Treat Rev

Background Antitumor activity of paclitaxel is based on promotion of abnormal microtubule (MT) assembly but it is also considered to have significant pro-inflammatory and anti-angiogenic effects in vivo and thus may cause vascular dysfunction. Methods We studied 27 women treated with paclitaxel-containing combinations for breast or ovarian cancer. The control group was represented by 10 women with carcinoma of the uterine cervix who received low doses of weekly cisplatin as radiation sensitizer. We measured endothelial-dependent flow-mediated dilatation (FMD) and nitrate-mediated dilatation (NMD) of the right brachial artery by ultrasonography, as well as levels of the inflammatory cytokines TNF-α and IL-6 before and after chemotherapy. Results Patients who received paclitaxel and an anthracycline had the most marked reduction in both FMD ( p = 0.005) and NMD ( p = 0.027). A significant reduction in FMD was also observed in patients treated with weekly paclitaxel ( p = 0.045), whereas NMD was not affected ( p = 0.421). Although TNF-α and IL-6 levels were different among chemotherapy groups after treatment, no significant differences were observed between levels of both markers before and after chemotherapy. Conclusion Treatment with paclitaxel-containing combinations impairs endothelial function in vivo but endothelial function deterioration is not related to the serum levels of inflammation markers.

The molecular triad, which includes the receptor activator of nuclear factor kappa-B ligand (RANKL), its receptor RANK, and the endogenous soluble RANKL decoy receptor osteoprotegerin (OPG), has emerged as an important determinant of bone metabolism. We aimed to evaluate the effect of treatment with the biphosphonate zoledronic acid (ZA) on biochemical markers of bone remodeling and to detect possible correlations of markerlevel changes with skeletal morbidity and clinical outcomes in patients with solid tumors and osseous metastases. The following serum markers were measured at the onset of skeletal metastases and after 6 months of treatment with ZA (4 mg intravenously monthly) in 70 patients with breast (n = 30), lung (n = 18), or prostate (n = 22) cancer: RANKL, OPG, C-terminal cross-linking telopeptide of type I collagen (CTX), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), bone-specific alkaline phosphatase (bALP), and osteopontin (OPN). Logistic regression models were applied to assess the correlation between marker-level changes and skeletal related events (SRE, primary endpoint), recurrence or progression, and death. Within a median follow-up of 32 months, 34 patients (48.6%) presented with at least 1 SRE and 48 patients (68.6%) relapsed. The RANKL/OPG ratio was upregulated in patients with breast and lung cancer, and it tended to decline after treatment with ZA, whereas prostate cancer patients presented with profound elevation of OPG only that persisted after treatment. CTX levels were significantly reduced after treatment in the whole study population (P = 0.003). None of the markers was able to predict skeletal morbidity or clinical outcomes independently of well-established prognostic clinical parameters. Transl Res

Background We undertook a randomized phase II trial to test whether the addition of paclitaxel (Taxol) to the cisplatin and ifosfamide (IP) combination could improve objective response (OR) rate, progression-free survival (PFS) and overall survival (OS) in patients with recurrent or metastatic cancer of the uterine cervix. Patients and methods One hundred and fifty-three patients were randomly allocated to receive either the IP regimen (ifosfamide 1.5 g/m2, daily, on days 1–3 and cisplatin 70 mg/m2 on day 2) or the same combination with the addition of paclitaxel 175 mg/m2 on day 1 [ifosfamide, paclitaxel and cisplatinum (ITP) regimen]. Cycles were administered every 4 weeks on an outpatient basis. Results A modest increase in neurotoxicity was observed with the triplet combination. OR rate was significantly higher in the ITP group (59% versus 33%, P = 0.002). Median PFS was 7.9 and 6.3 months for patients in the ITP and IP arms, respectively (P = 0.023). Median OS was 15.4 months and 13.2 months in the ITP and IP arms, respectively (P = 0.048). In multivariate analysis, the triplet yielded a hazard ratio of 0.70 for relapse or progression (P = 0.046) and 0.75 for death (P = 0.124) compared with the doublet. Conclusion The ITP combination merits further investigation in randomized phase III studies.

Our understanding of the pathogenesis of tobacco-related lung carcinogenesis is improving but the molecular mechanisms of neoplastic transformation in never-smokers have not yet been elucidated. Mountzios et al. describe the best characterized signaling pathways that are implicated in the transduction of proliferative signals, and discuss the differences in the molecular characteristics of smokers and never-smokers. Although smoking has been established as the most important cause of lung cancer, approximately 10% of patients with this malignancy have no history of smoking. The pathogenesis of tobacco-related lung carcinogenesis is becoming well characterized, but the molecular mechanisms of neoplastic transformation in never-smokers have not yet been adequately elucidated. Nevertheless, numerous recent studies have revealed a distinct biological process of malignant transformation with unique epidemiological and clinicopathological characteristics in never-smokers. The molecular pathways involved in the differential pattern of lung oncogenesis according to smoking status, however, remain fairly obscure. Researchers have studied several molecular pathways implicated in lung carcinogenesis in smokers and never-smokers, examining these processes at the genomic, epigenetic and proteomic level. The differential protein expression according to smoking status in critical signal transduction pathways has attracted scientific interest because of the possibilities of therapeutic intervention. In this Review we describe the best-characterized signaling pathways implicated in the transduction of proliferative signals and discuss the activity of these pathways in smokers and never-smokers.

Purpose: To assess the correlation of excision repair cross complementation group 1 (ERCC1) immunohistochemical expression with objective tumor response and cancer-specific survival in patients with locally advanced head and neck squamous cell carcinoma treated with cisplatin-based induction chemotherapy. Experimental Design: The initial cohort was composed of 107 patients who were treated from 1992 to 1996 by an induction chemotherapy regimen for locally advanced head and neck squamous cell carcinoma. p53 mutations had previously been studied. Pretherapeutic biopsy samples from 96 patients with a known tumor response were available. Two independent observers blinded to clinical annotations evaluated ERCC1 immunohistochemical expression. Results: Of 96 patients, 68 (71%; 95% confidence interval, 61-79%) had tumors that expressed ERCC1 intensively and diffusely. Using the logistic regression method, the 28 (29%) patients with tumors expressing ERCC1 at lower levels had a 4-fold greater odds of benefiting from an objective response to chemotherapy (odds ratio, 4.3; 95% confidence interval, 1.4-13.4; P = 0.01) compared with the group of 68 patients with high ERCC1 expression. ERCC1 and p53 status, but not their interaction, were independent predictors of tumor response. In a Cox proportional hazard model adjusted on age, TNM stage, tumor differentiation, and tumor localization, ERCC1 low expression was associated with a lower risk of cancer death (risk ratio, 0.42; 95% confidence interval, 0.20-0.90; P = 0.04) whereas p53 status had no prognostic value. Conclusion: Our results suggest that those patients characterized by low ERCC1 expression are more likely to benefit from cisplatin induction chemotherapy compared with patients with high ERCC1 expression.

Cisplatin-based chemotherapy remains the treatment of choice in advanced nonsmall-cell lung cancer. The development of predictive biomarkers able to identify lung-cancer patients who are most likely to benefit from cisplatin-based chemotherapy would be a powerful tool. Many reports have explored the role of ERCC1 expression in the repair mechanism of cisplatin-induced DNA adducts in cancer cells.Using immunohistochemistry in resected tumors, the International Adjuvant Lung Cancer Trial showed that high ERCC1 protein expression was associated with improved survival in patients who did not receive chemotherapy. In contrast, the benefit of adjuvant cisplatin-based chemotherapy was more profound in patients with low ERCC1 expression. Other investigators studying mRNA expression in tumor biopsies from patients treated with cisplatin and gemcitabine showed that patients with low ERCC1 mRNA expression have a longer median survival compared to those with high expression.High ERCC1 expression is predictive of resistance to platinum-based therapy. Thus, there is solid evidence to support ERCC1 as a useful marker of clinical resistance to platinum-based chemotherapy in the adjuvant setting of nonsmall-cell lung cancer. Meanwhile, optimization of methodology and standardization of technical procedures seem necessary before larger prospective studies can address the same question.

The role of receptor activator of nuclear factor-kB ligand (RANKL)/osteoprotegerin (OPG) system, and osteopontin (OPN) was studied in patients with solid tumors metastatic to the bone in relation to the type of malignancy and the neoplastic burden to the skeleton. Levels of soluble RANKL (sRANKL), OPG and OPN were assessed in 61 patients with breast, lung and prostate cancer with newly-diagnosed metastasis to the bone, in parallel with bone resorption [C-telopeptide of type-I collagen (CTX), tartrate-resistant acid phosphatase-5b (TRACP-5b)] and bone formation markers [bone-alkaline phosphatase (bALP), osteocalcin (OC), and C-terminal propeptide of collagen type-I (CICP)]. Patients had elevated serum levels of sRANKL, OPG, OPN, TRACP-5b, and bALP, and reduced OC levels compared to controls. OPG correlated with the extent of metastatic bone burden. Patients with breast and lung cancer shared increased levels of sRANKL, OPG, and OPN whereas prostate cancer patients had elevated values of OPG and bALP only. These results suggest that patients with solid tumors metastatic to the bone have severe disruption of the sRANKL/OPG axis. Breast and lung cancer seem to exert their osteolytic action through upregulation of the sRANKL/OPG system and OPN, whereas prostate cancer seems to provoke profound elevation of OPG levels only, thus leading to increased osteoblastic activity. The skeleton represents the most common site of tumor metastases, with at least 25% of cancer patients having bone metastases at autopsy examination [1]. Most frequently, they occur with prostate, breast, lung and renal cell carcinomas (88, 73, 32 and 25% respectively) whereas patients with multiple myeloma present almost universally with bone lesions [2]. Skeletal complications from bone metastases cause significant morbidity and present a major challenge in disease management [3,4]. In the normal skeleton there is a tightly coordinated process of balanced osteoclast-mediated bone resorption and osteoblast-mediated bone formation that counteract and contribute to the constant

Background: The increasing use of biomarkers as molecular determinants of responsiveness to conventional chemotherapy or molecular targeted therapy has raised the question of the reliability and reproducibility of their evaluation in bronchial biopsies as compared with corresponding resected surgical specimens. Patients and methods: Immunohistochemical expression of five markers related to signal transduction [epidermal growth factor receptor (EGFR), phospho-Akt], cell proliferation (Ki-67), DNA repair [excision repair cross-complementing (ERCC)1] and cellular 'immortality' [human telomerase catalytic component (hTERT)], was assessed in 41 patients with operable non-small-cell lung cancer in both bronchial biopsies and whole surgical specimens. Results: High correlation coefficients were observed between the expression of ERCC1, hTERT and Ki-67 in the biopsies and the surgical specimens [0.83 (P < 0.0001); 0.55 (P < 0.001) and 0.64 (P < 0.0001), respectively]. On the other hand, biomarker expression in biopsy was less correlated with the expression in the whole tissue sample for the markers of signal response and transduction [0.24 (P = 0.17) and 0.29 (P = 0.09) for EGFR and phospho-Akt, respectively]. Conclusions: Our results indicate a lack of association in the expression of important biomarkers between lung biopsies and corresponding resected tumors, with discordance rates ranging between 9% and 41 %. Although these results need to be further validated in larger cohorts, they indicate that the evaluation of the expression of biomarkers in bronchial biopsies can be misleading.

Background Synchronous presentation of more than one germ cell tumours of different histology in the same patient is considered to be very rare. In these cases of multiple germ cell tumours, strong theoretical and clinical data suggest an underlying common pathogenetic mechanism concerning genetic instability or abnormalities during the pluripotent embryonic differentiation and maturation of the germ cell. Case presentation A 25 year-old young man presented with an enlarging, slightly painful left cervical mass. Despite the initial disorientation of the diagnosis to a possible thyroid disorder, the patient underwent complete surgical resection of the mass revealing mediastinal choriocarcinoma. Subsequent ultrasound of the scrotum indicated the presence of a small lobular node in the upper pole of the left testicle and the patient underwent radical left inguinal orchiectomy disclosing a typical seminoma. Based on these results, the patient received 4 cycles of Bleomycin, Etoposide and Platinum chemotherapy experiencing only mild toxicity and resulting in complete ongoing clinical and biochemical remission. Conclusion The pathogenesis of concurrent germ cell tumours in the same patient remains an area of controversy. Although the genetic instability of the pluripotent germ cell offers an adequate explanation, the possibility of metastasis from the primary, less differentiated tumour to a distant location as a more mature subtype cannot be excluded. Possible development of a metastatic site of different histology and thus biological behaviour (e.g choriocarcinoma) should be anticipated. Furthermore, urologists, pathologists and medical oncologists should be meticulous in the original pathological diagnosis in these patients, since there is a significant frequency of germ cell tumours with mixed or overlapping histological elements with diverse potential of evolution and differentiation.

Aim: Burnout could potentially have serious negative impact on quality of cancer care, professional satisfaction and personal life. Our aim was to investigate the burnout prevalence, work and lifestyle factors amongst European oncologists ≤40 (YOs). Methods: A survey was conducted using the validated Maslach Burnout Inventory (MBI) and additional questions exploring work/ lifestyle factors. Parametric and non-parametric analyses were performed to identify factors associated with burnout and multivariate analyses to derive a predictive burnout model. Results: 737 surveys (all ages) were collected from 41 European countries. Countries were divided into 6 regions. Results from 595 (81%) YOs were included (81% medical oncologists; 52% trainees, 62% women). 71% of YOs showed burnout (burnout indices: depersonalisation 50%; emotional exhaustion 35%; low accomplishment 35%). 22% requested support for burnout during training and 74% reported no hospital access to support services. Burnout rates were significantly different across Europe (p Conclusions: This is the largest burnout survey of European YOs. Burnout is common amongst YOs and rates vary across Europe. Achieving a good work/life balance and adequate vacation time may reduce burnout levels. Raising burnout awareness, support for oncologists and interventional research are needed. Disclosure: All authors have declared no conflicts of interest.

Aim: Prophylactic erythropoiesis-stimulating agent (ESA) administration for chemotherapy-induced anemia (CIA) is not supported by current guidelines. Long-term follow-up of patients that had been treated with EPO for CIA in the past may provide useful information. Methods: In 2002 we undertook a prospective, randomized phase III trial of prophylactic versus hemoglobin (Hgb)-based (threshold: 12 mg/dl) ESA administration in patients with solid tumors and CIA, which was permanently suspended in 2005 in the view of published data at that time, while patient surveillance continued. Herein we present safety and efficacy outcomes after more than a decade of follow-up. Results: Among 630 evaluable patients, 40.1% were male, 50.9% had advanced cancer at diagnosis, 39.2% had Hgb levels Conclusions: Prophylactic administration of ESA for CIA in patients with solid tumors was associated with increased incidence of a composite of thrombosis-related adverse events, especially in patients receiving adjuvant treatment, but did not have a detrimental impact on relapse/progression and survival rates. Disclosure: All authors have declared no conflicts of interest.

Introduction Prognosis of patients with operable laryngeal cancer is highly variable and therefore potent prognostic biomarkers are warranted. The insulin-like growth factor receptor (IGFR) signaling pathway plays a critical role in laryngeal carcinogenesis and progression. Patients and Methods We identified all patients with localized TNM stage I–III laryngeal cancer managed with potentially curative surgery between 1985 and 2008. Immunohistochemical (IHC) expression of IGF1R-alpha, IGF1R-beta and IGF2R was evaluated using the immunoreactive score (IRS) and mRNA levels of important effectors of the IGFR pathway were assessed, including IGF1R, IGF-binding protein 3 (IGFBP3), suppressor of cytokine signaling 2 (SOCS2) and members of the MAP-kinase (MAP2K1, MAPK9) and phosphatidyl-inositol-3 kinase (PIK3CA, PIK3R1) families. Cox-regression models were applied to assess the predictive value of biomarkers on disease-free survival (DFS) and overall survival (OS). Results Among 289 eligible patients, 95.2% were current or ex smokers, 75.4% were alcohol abusers, 15.6% had node-positive disease and 32.2% had received post-operative irradiation. After a median follow-up of 74.5 months, median DFS was 94.5 months and median OS was 106.3 months. Using the median IRS as the pre-defined cut-off, patients whose tumors had increased IGF1R-alpha cytoplasm or membrane expression experienced marginally shorter DFS and significantly shorter OS compared to those whose tumors had low IGF1R-alpha expression (91.1 vs 106.2 months, p = 0.0538 and 100.3 vs 118.6 months, p = 0.0157, respectively). Increased mRNA levels of MAPK9 were associated with prolonged DFS (p = 0.0655) and OS (p = 0.0344). In multivariate analysis, IGF1R-alpha overexpression was associated with a 46.6% increase in the probability for relapse (p = 0.0374). Independent predictors for poor OS included node-positive disease (HR = 2.569, p

Introduction Prognosis of patients with operable squamous-cell laryngeal cancer is highly variable and therefore potent prognostic biomarkers are warranted. The Insulin-Growth Factor Receptor (IGFR)-mediated signaling pathway plays a critical role in laryngeal carcinogenesis. Patients and methods We identified all patients with localised TNM stage I-III laryngeal cancer managed with potentially curative laryngectomy between May 1985 and June 2008. Immunohistochemical (ICH) expression of IGFR1-alpha, IGFR1-beta and IGFR2 was evaluated using the Histo-score (H-score) climax and mRNA levels of important effectors of the IGFR-mediated pathway were assessed, including IGFR1, IGF-binding protein 3 (IGFBP3), suppressor of cytokine signaling 2 (SOCS2) and members of the MAP-kinase (MA2K1, MAPK9) and phosphatidyl-inositol-3 kinase (PI3KCA, PI3KR1) families. Cox-regression models were applied to assess the predictive value of the components of the IGFR-mediated pathway on disease-free survival (DFS) and overall survival (OS). Results Among 289 eligible patients, 95.8% were male, 95.2% were current or ex smokers, 75.4% were alcohol abusers, 15.6% had node-positive diease and 32.2% had received post-operative irradiation. After a median follow-up of 74.5 months, median DFS was 94.5 months and median OS was 106.3 months. Using the median H-score as the pre-defined cut-off value, IGFR1-alpha overexpression was associated with decreased DFS (p = 0.0538) and OS (p = 0.0157). Increased mRNA levels of MAPK9 were associated with prolonged DFS (p = 0.0209) and OS (p = 0.0108), as were increased mRNA levels of PI3KCA, albeit not significantly (p = 0.0723 and 0.0726 for DFS and OS respectively). In multivariate analysis, IGFR1-alpha overexpression was associated with a 46.6% increase in the probability for relapse (p = 0.0374). Independent predictors for poor OS included node-positive disease (HR = 2.569, 95%CI: 1.610-4.100, p Conclusion IGFR1-alpha IHC overexpression may serve as an independent predictor of relapse and survival in operable laryngeal cancer. Prospective evaluation of IGFR1-alpha prognostic utility is warranted. Disclosure All authors have declared no conflicts of interest.

6011 Background: The excision repair cross-complementation group 1 (ERCC1) enzyme is a key element of the nucleotide excision repair (NER) pathway which removes cisplatin-induced DNA adducts and has been associated with resistance to platinum-based chemotherapy. We assessed the correlation of ERCC1 immunohistochemical expression with objective tumor response and cancer-specific survival in patients with locally advanced head and neck squamous-cell carcinoma (HNSCC) treated with cisplatin-based induction chemotherapy (CBIC). Methods: The initial cohort comprised 107 patients who had received CBIC (modified Al Saraf protocol) from 1992 to 1996 for locally advanced HNSCC. P53 mutations had been previously studied. Pre-therapeutic biopsy samples from 96 patients with a known tumor response were available. Two independent observers blinded to clinical annotations evaluated ERCC1 expression using the H-score protocol. The median H-score value was a priori selected as the cutpoint in order to dichotomize ERCC1 expression for statistical analysis. Results: In 68 cases [71%, 95% CI: 61% - 79%] tumors expressed ERCC1 intensively and diffusely. Using the logistic regression method, the 28 patients [29 %, 95% CI:21%-39%] with tumors expressing ERCC1 at lower levels had a four time greater odds of benefiting from an objective response to chemotherapy [OR 4.3, 95% CI: 1.4 - 13.4; p = 0.01]. ERCC1 and p53 status, but not their association, were independent predictors of tumor response. In a Cox proportional hazard model adjusted on well-established prognosticators including age, T, N, M, tumor differentiation and localization, ERCC1 low expression was associated with a lower risk of cancer death [RR 2.13, 95% CI: 1.03 - 4.43; p=0.04], while p53 status had no prognostic value. Conclusions: Patients with ERCC1 negative tumors are more likely to derive a substantial benefit from CBIC, translated to a lower risk for cancer-related death compared to patients with ERCC1 positive tumors. Large prospective trials should evaluate ERCC1 and other critical biomarkers involved in DNA damage repair process as molecular predictors of responsiveness to chemotherapy in patients with HNSCC. No significant financial relationships to disclose.

Although platinum-based chemotherapy remains the “standard” in advanced non small-cell lung cancer, not all patients derive clinical benefit from such a treatment. Hence, the development of predictive biomarkers able to identify lung cancer patients who are most likely to benefit from cisplatin-based chemotherapy has become a scientific priority. Among the molecular pathways involved in DNA damage control after chemotherapy, the nucleotide excision repair (NER) is a critical process for the repair of DNA damage caused by cisplatin-induced DNA adducts. Many reports have explored the role of the excision repair cross-complementation group 1 enzyme (ERCC1) expression in the repair mechanism of cisplatin-induced DNA adducts in cancer cells. Using immunohistochemistry in resected tumors from patients included in the International Adjuvant Lung Cancer Trial, the study of important biomarkers showed that high ERCC1 protein expression was associated with improved survival in chemo-naïve patients. On the contrary, the benefit of adjuvant cisplatin-based chemotherapy was more profound in patients with low ERCC1 expression. In a prospective cohort studying mRNA expression in tumor biopsies from patients receiving customized therapy with cisplatin and gemcitabine depending on the molecular profile of the tumour, results showed that patients with low ERCC1 mRNA expression had a longer median survival compared to those with high expression. These data suggest the potent use of ERCC1 as a molecular predictor of clinical resistance to platinum-based chemotherapy in the adjuvant setting of NSCLC. Nevertheless, optimization of methodology, including standardization of technical procedures, as well as validation of ERCC1 protein expression in large prospective cohorts, seem necessary before any routine immunohistochemical validation of ERCC1 can be implemented in daily practice.