Maria Bonomi

Profiling mTOR pathway in neuroendocrine tumors.

The serine/threonine kinase mammalian target of rapamycin (mTOR) plays a central role in regulating critical cellular processes such as growth, proliferation, and protein synthesis. The study of cancer predisposing syndromes within which neuroendocrine tumors (NETs) may arise has furnished clues on the involvement of mTOR pathway in sporadic diseases so far. Recent comprehensive analyses have definitely shown activation of mTOR pathway in both experimental and human sporadic NETs. Upstream regulators of mTOR (PTEN and TSC2) have been found mutated in sporadic pNETs. Activation of mTOR pathways in NETs is already demonstrated by expression profiles analysis that revealed downregulation of TSC2 gene and alterations of TSC2 and PTEN protein expression in the vast majority of well-differentiated tumors. Moreover, a global microRNA expression analysis revealed the overexpression, in highly aggressive tumors, of a microRNA (miR-21) that targets PTEN reducing its expression and therefore leading to mTOR activation as well. Overall, these clues have furnished the rationale for the use of mTOR inhibitors the treatment of pNETs. With the recent approval of Everolimus (mTOR-targeted drug) for the treatment of advanced pNETs, this paradigm has been effectively translated into the clinical setting. In this review, we discuss mTOR pathway involvement in NETs, the clinical evidence supporting the use of mTOR inhibitors in cancer treatment, and the current clinical issues that remain to be elucidated to improve patient management.

Impact of neoadjuvant single or dual HER2 inhibition and chemotherapy backbone upon pathological complete response in operable and locally advanced breast cancer: Sensitivity analysis of randomized trials

The role of the dual HER2 inhibition, and the best chemotherapy backbone for neoadjuvant chemotherapy still represent an issue for clinical practice. A literature-based meta-analysis exploring single versus dual HER2 inhibition in terms of pathological complete response (pCR, breast plus axilla) rate and testing the interaction according to the chemotherapy (anthracyclines-taxanes or taxanes) was conducted. In addition, an event-based pooled analysis by extracting activity and safety events and deriving 95% confidence intervals (CI) was accomplished. Fourteen trials (4149 patients) were identified, with 6 trials (1820 patients) included in the meta-analysis and 31 arms (14 trials, 3580 patients) in the event-based pooled analysis. The dual HER2 inhibition significantly improves pCR rate, in the range of 16-19%, regardless of the chemotherapy backbone (relative risk 1.37, 95% CI 1.23-1.53, p<0.0001); pCR was significantly higher in the hormonal receptor negative population, regardless of the HER2 inhibition and type of chemotherapy. pCR and the rate of breast conserving surgery was higher when anthracyclines were added to taxanes, regardless of the HER2 inhibition. Severe neutropenia was higher with the addition of anthracyclines to taxanes, with an absolute difference of 19.7%, despite no differences in febrile neutropenia. While no significant differences according to the HER2 inhibition were found in terms of cardiotoxicity, a slightly difference for grade 3-4 (1.2%) against the addition of anthracyclines was calculated. The dual HER2 inhibition for the neoadjuvant treatment of HER2-positive breast cancer significantly increases pCR; the combination of anthracyclines, taxanes and anti-Her2 agents should be currently considered the standard of care.

Anti-Angiogenic Drugs and Biomarkers in Non-Small-Cell Lung Cancer: 'A Hard Days Night'

The discovery of specific molecular alterations (i.e. EGFR activating mutations, EML4/ALK translocation, ROS1 rearrangements) in a selected population of patients affected by non small cell lung cancer (NSCLC) translated into effective treatments for this small but well defined fraction of patients, driven by the use of predictive biomarkers of efficacy for targeted agents. Unfortunately, the same reliable predictive biomarkers are lacking for anti-angiogenic drugs. Angiogenesis plays a major role in the progression of NSCLC, however, anti-angiogenic agents provided a minimal, although significant, clinical benefit in unselected populations, burdened by a not negligible toxicities. In this context, no validated angiogenic factor or other molecular biomarker of angiogenesis can reliably predict clinical outcome, sensitivity, early response or resistance to any of the investigated anti-angiogenic therapies currently used. Moreover, the available clinical data are prevalently retrospective, underpowered, and, in many cases, contradictory, thus underscoring that the understanding of the complex architecture of angiogenic signaling is still incomplete. We here review the currently available studies on the effect of anti-angiogenic drugs in NSCLC, with a particular focus on bio-molecular factors that are regarded as potential predictors of treatment efficacy.

Clinical meta-analyses of targeted therapies in adenocarcinoma

Although the interpretation of the data reported in meta-analyses may hide several issues, it is undoubtable that this methodological approach may significantly contribute to implement the results of clinical trials, and represent a useful and practical tool for the evidence-based medicine process. Indeed, level-one recommendations should consider well-conducted meta-analyses as well as large and adequately powered randomized trials as the main contributors for the definition of guidelines for clinical practice. In addition, the role of meta-analyses for issues whereas conflicting data (and/or unpowered results) are provided, is well established. In the field of lung cancer, meta-analyses already participated to change the current standard, and are now facing the challenging issues of predictive biomarkers of prognosis and/or efficacy of targeted agents. With this aim, the meta-analytic approach helped in the recent years to implement the quantification of the magnitude of the benefit of targeted agents, and added new insights by interpreting the data coming from clinical trials by integrating them with biomarkers. The treatment-interaction analyses according to putative predictive factors of efficacy may clarify unknown issues and generate new hypotheses for future perspectives. The current review attempts to put in the context of the clinical data of targeted agents for lung cancer all the pros and cons of the meta-analytic process published to date, and critically analyze all the potential perspectives which this methodology may add for both current practice and forthcoming research.

Novel Approaches of Treatment with Radium-223 Targeted Therapy

The role of radium-223 (Ra-223) in metastatic castration-resistant prostate cancer (mCRPC) with bone metastases and no visceral disease is well established in clinical practice. Treatment with Ra-223 is well tolerated and significantly improves overall survival and time to first symptomatic skeletal event. Several questions, however, remain open. Patient selection is critical, and treatment assessment is challenging. There is no standard imaging, and PSA has limited usefulness in this setting.

Bone Metastases in Prostate Cancer

Bone metastases occur in more than 80% of men with metastatic prostate cancer. Affecting the structural integrity of the bone, they can lead to skeletal complications and pain, with a negative impact on patient quality of life and survival. The last decade has witnessed tremendous advances in the treatment of metastatic PCa. New therapeutic options that prolong overall survival are now available. The optimization of bone metastasis management (and prevention of skeletal morbidities) is therefore of paramount importance to improve clinical outcome. Some issues are still debated, such as the most effective radiologic or nuclear medicine technique to diagnose and monitor bone disease, the ideal surrogate circulating marker to assess response or progression to treatment, patient selection, as well as the optimal sequencing or combination of available therapeutic options. Several healthcare professionals play a role in the treatment of metastatic PCa. The presence of a multidisciplinary team for the discussion of treatment strategies for each patient should be the standard of care.

Approaches for Assessment of Response of Bone Metastases to Therapies

The recent introduction of new therapeutic agents has proven alternative options in the management of patients with metastatic castration-resistant prostate cancer (mCRPC). Moreover, other novel agents are being studied and developed. Bone represents the most common site of recurrence in mCRPC, occurring in more than 80 % of cases. The evaluation of treatment efficacy in bone metastatic prostate cancer (PC) is mainly focused on the assessment of patient outcomes, but the behavior of bone metastases and their changes due to the therapy are also of great interest. The impressive development of technologies offers today various options for describing the skeletal changes caused by metastases before, during, and after treatments. At present, in clinical practice, the only laboratory test currently used to measure metastatic bone progression remains prostate-specific antigen (PSA). Great importance has been progressively assumed by new modalities of metabolic imaging, such as 18F fluoride, 18F/11C choline, and 18F FDG positron emission tomography (PET)/computed tomography (CT) that are flanking the traditional bone scan (BS) with 99mTc phosphonates, both with planar acquisition and single-photon emission computed tomography (SPECT). In addition, radiology, besides CT, is proposing the high performance of multimodality magnetic resonance imaging (MRI) that seems to guarantee a very high accuracy in evaluating skeletal involvement.

Combinations of Hormonal Therapy and Chemotherapy

Prostate cancer (PC) is a heterogeneous disease, with a complex natural history, whose growth is driven by androgens and androgen receptors. In most cases, patients have localized disease at presentation, which may be successfully treated with radical prostatectomy and external beam radiation. However, many patients subsequently develop metastatic disease. De novo metastases can also occur in a minority of cases.Androgen deprivation therapy (ADT) is the standard treatment of metastatic hormone-naive (or castration-sensitive) prostatic cancer (CSPC). ADT usually determines a profound PSA decline and a radiological and clinical benefit in most patients. However, essentially all patients experience progression to castration-resistant prostate cancer (CRPC) despite persisting low testosterone levels in around 1–2 years, and overall prognosis remains disappointing, although subsequent active treatments are available. Early targeting of cells that survive hormonal therapy may potentially prevent the development of CRPC. The aim of these therapeutic strategies is the elimination of resistant cells at the time the tumor is apparently “androgen sensitive”. The large randomized studies analyzed in this chapter, addressing the early use of docetaxel in combination with ADT in men with metastatic CSPC, have shown evidence that at least a subset of patients with metastatic CSPC may benefit from the combination of ADT with docetaxel as initial therapy.

Clinical staging of malignant pleural mesothelioma: current perspectives

Malignant pleural mesothelioma (MPM) is a disease with limited therapeutic options, the management of which is still controversial. Diagnosis is usually made by thoracoscopy, which allows multiple biopsies with histological subtyping and is indicated for staging purposes in surgical candidates. The recommended and recently updated classification for clinical use is the TNM staging system established by the International Mesothelioma Interest Group and the International Association for the Study of Lung Cancer, which is based mainly on surgical and pathological variables, as well as on cross-sectional imaging. Contrast-enhanced computed tomography is the primary imaging procedure. Currently, the most used measurement system for MPM is the modified Response Evaluation Criteria in Solid Tumors (RECIST) method, which is based on unidimensional measurements of tumor thickness perpendicular to the chest wall or mediastinum. Magnetic resonance imaging and functional imaging with 18F-fluoro-2-deoxy-D-glucose positron-emission tomography can provide additional staging information in selected cases, although the usefulness of this method is limited in patients undergoing pleurodesis. Molecular reclassification of MPM and gene expression or miRNA prognostic models have the potential to improve prognostication and patient selection for a proper treatment algorithm; however, they await prospective validation to be introduced in clinical practice.

Prognostic and predictive role of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with unresectable malignant pleural mesothelioma (MPM) treated with up-front pemetrexed-based chemotherapy

The aim of this study was to evaluate the role of metabolic parameters analyzed at baseline and at interim FDG‐PET in predicting disease outcome in unresectable MPM patients receiving pemetrexed‐based chemotherapy. A consecutive series of MPM patients treated between February 2004 and July 2013 with first‐line pemetrexed‐based chemotherapy, and evaluated by FDG‐PET and CT scan at baseline and after two cycles of chemotherapy, was reviewed. Best CT scan response was assessed according to modified RECIST criteria. Progression‐free survival (PFS) and overall survival (OS) were correlated with FDG‐PET parameters, such as maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), and percentage changes in SUVmax (∆SUV) and TLG (∆TLG). Overall, 142 patients were enrolled; 77 (54%) received talc pleurodesis before chemotherapy. Baseline SUVmax and TLG showed a statistically significant correlation with PFS and OS (P < 0.05) in both group of patients (treated and untreated with pleurodesis). In 65 patients not receiving pleurodesis, SUVmax reduction ≥25% (∆SUV ≥ 25%) and TLG reduction ≥30% (∆TLG ≥ 30%) were significantly associated with longer PFS (P < 0.05). Patients showing both ∆SUV ≥ 25% and ∆TLG ≥ 30% responses had a significant reduction in the risk of disease progression (HR:0.31, P < 0.001) and death (HR:0.52, P = 0.044). Neither ∆SUV nor ∆TLG showed similar association with survival outcomes in patients treated with pleurodesis. Our study confirmed the prognostic role of baseline FDG‐PET in a large series of MPM patients treated with first‐line pemetrexed‐based chemotherapy. Moreover, use of ∆SUV ≥ 25% and ∆TLG ≥ 30% as cut‐off values to define early metabolic response supported the role of FDG‐PET in predicting disease outcome and treatment response in patients not receiving pleurodesis.