Publications by authors named "Paolo Marchetti"

377 Publications

Clinical Outcomes and Toxic Effects of Single-Agent Immune Checkpoint Inhibitors Among Patients Aged 80 Years or Older With Cancer: A Multicenter International Cohort Study.

JAMA Oncol 2021 Nov 4. Epub 2021 Nov 4.

Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, Ohio.

Importance: Geriatric (aged ≥80 years) patients are historically underrepresented in cancer clinical trials. Little is known about the efficacy of immune checkpoint inhibitors (ICIs) in geriatric patients. These agents are associated with immune-related adverse events (irAEs), which may be particularly associated with morbidity in this population.

Objective: To provide insight into the clinical outcomes and safety of ICIs among geriatric patients (aged ≥80 years) with cancer.

Design, Setting, And Participants: A Multicenter, international retrospective study of 928 geriatric patients with different tumors treated with single-agent ICIs between 2010 to 2019 from 18 academic centers in the US and Europe. Analyses were conducted from January 2021 to April 2021.

Main Outcomes And Measures: Clinical outcomes and irAE patterns in geriatric patients treated with single-agent ICIs.

Results: Median (range) age of the 928 patients at ICI initiation was 83.0 (75.8-97.0) years. Most patients (806 [86.9%]) were treated with anti-programmed cell death 1 therapy. Among the full cohort, the 3 most common tumors were non-small cell lung cancer (NSCLC, 345 [37.2%]), melanoma (329 [35.5%]), and genitourinary (GU) tumors (153 [16.5%]). Objective response rates for patients with NSCLC, melanoma, and GU tumors were 32.2%, 39.3%, and 26.2%, respectively. Median PFS and OS, respectively, were 6.7 and 10.9 months (NSCLC), 11.1 and 30.0 months (melanoma), and 6.0 and 15.0 months (GU). Within histologically specific subgroups (NSCLC, melanoma, and GU), clinical outcomes were similar across age subgroups (aged <85 vs ≥85 years). Among all 928 patients, 383 (41.3%) experienced ≥1 irAE(s), including 113 (12.2%) that were reported to be grade (G) 3 to 4 based on Common Terminology Criteria for Adverse Events (version 5.0). The median time to irAE onset was 9.8 weeks; 219 (57%) occurred within the first 3 months after ICI initiation. Discontinuation of treatment with ICIs owing to irAEs occurred in 137 (16.1%) patients. There was no significant difference in the rate of irAEs among patients aged younger than 85, 85 to 89, and 90 years or older. Despite the similar rate of G3 or higher irAEs, ICIs were discontinued owing to irAEs more than twice as often among patients aged 90 years or older compared with patients younger than 90 years (30.9% vs 15.1%, P = .008).

Conclusions And Relevance: The findings of this international cohort study suggest that treatment with ICIs may be effective and generally well tolerated among older patients with cancer, though ICI discontinuation owing to irAEs was more frequent with increasing age.
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http://dx.doi.org/10.1001/jamaoncol.2021.4960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8569601PMC
November 2021

Multi-omic approach identifies a transcriptional network coupling innate immune response to proliferation in the blood of COVID-19 cancer patients.

Cell Death Dis 2021 10 29;12(11):1019. Epub 2021 Oct 29.

Scientific Direction, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

Clinical outcomes of COVID-19 patients are worsened by the presence of co-morbidities, especially cancer leading to elevated mortality rates. SARS-CoV-2 infection is known to alter immune system homeostasis. Whether cancer patients developing COVID-19 present alterations of immune functions which might contribute to worse outcomes have so far been poorly investigated. We conducted a multi-omic analysis of immunological parameters in peripheral blood mononuclear cells (PBMCs) of COVID-19 patients with and without cancer. Healthy donors and SARS-CoV-2-negative cancer patients were also included as controls. At the infection peak, cytokine multiplex analysis of blood samples, cytometry by time of flight (CyTOF) cell population analyses, and Nanostring gene expression using Pancancer array on PBMCs were performed. We found that eight pro-inflammatory factors (IL-6, IL-8, IL-13, IL-1ra, MIP-1a, IP-10) out of 27 analyzed serum cytokines were modulated in COVID-19 patients irrespective of cancer status. Diverse subpopulations of T lymphocytes such as CD8T, CD4T central memory, Mucosal-associated invariant T (MAIT), natural killer (NK), and γδ T cells were reduced, while B plasmablasts were expanded in COVID-19 cancer patients. Our findings illustrate a repertoire of aberrant alterations of gene expression in circulating immune cells of COVID-19 cancer patients. A 19-gene expression signature of PBMCs is able to discriminate COVID-19 patients with and without solid cancers. Gene set enrichment analysis highlights an increased gene expression linked to Interferon α, γ, α/β response and signaling which paired with aberrant cell cycle regulation in cancer patients. Ten out of the 19 genes, validated in a real-world consecutive cohort, were specific of COVID-19 cancer patients independently from different cancer types and stages of the diseases, and useful to stratify patients in a COVID-19 disease severity-manner. We also unveil a transcriptional network involving gene regulators of both inflammation response and proliferation in PBMCs of COVID-19 cancer patients.
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http://dx.doi.org/10.1038/s41419-021-04299-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553595PMC
October 2021

Prediction of Recurrence by Machine Learning in Salivary Gland Cancer Patients After Adjuvant (Chemo)Radiotherapy.

In Vivo 2021 Nov-Dec;35(6):3355-3360

Department of Radiotherapy, Policlinico Umberto I "Sapienza" University of Rome, Rome, Italy.

Background/aim: To investigate survival outcomes and recurrence patterns using machine learning in patients with salivary gland malignant tumor (SGMT) undergoing adjuvant chemoradiotherapy (CRT).

Patients And Methods: Consecutive SGMT patients were identified, and a data set included nine predictor variables and a dependent variable [disease-free survival (DFS) event] was standardized. The open-source R software was used. Survival outcomes were estimated by the Kaplan-Meier method. The random forest approach was used to select the important explanatory variables. A classification tree that optimally partitioned SGMT patients with different DFS rates was built.

Results: In total, 54 SGMT patients were included in the final analysis. Five-year DFS was 62.1%. The top two important variables identified were pathologic node (pN) and pathologic tumor (pT). Based on these explanatory variables, patients were partitioned in three groups, including pN0, pT1-2 pN+ and pT3-4 pN+ with 26%, 38% and 75% probability of recurrence, respectively. Accordingly, 5-year DFS rates were 73.7%, 57.1% and 34.3%, respectively.

Conclusion: The proposed decision tree algorithm is an appropriate tool to partition SGMT patients. It can guide decision-making and future research in the SGMT field.
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http://dx.doi.org/10.21873/invivo.12633DOI Listing
October 2021

Androgen Receptor Targeted Therapy + Radiotherapy in Metastatic Castration Resistant Prostate Cancer.

Front Oncol 2021 23;11:695136. Epub 2021 Sep 23.

Department of Radiation Oncology, "Sapienza" University, Sant'Andrea Hospital, Rome, Italy.

Objectives: To investigate whether radiotherapy as metastasis-directed therapy (MDT) on oligo-progressive sites in metastatic castration-resistant prostate cancer (mCRPC) patients during treatment with androgen receptor-targeted therapy (ARTT) may lead to control resistant lesions, prolonging ARTT. We analysed progression free survival, overall survival and prognostic parameters that can identify patients that best suit to this approach.

Patients And Methods: Retrospective analysis of a total of 67 lesions in 42 mCRPC patients treated with ablative or palliative RT to oligoprogressive lesions during ARTT. Twenty-eight patients (67%) underwent ARTT with Abiraterone acetate and 14 patients (33%) underwent ARTT with Enzalutamide. Median time between the start of ADT and ARTT beginning was 50.14 months (range 3.37-219 months). We treated 58 lesions (87%) with 3D conformal radiotherapy (3DCRT) and nine lesions (13%) with stereotactic body radiotherapy (SBRT). The Kaplan Meier method was used to assess the median overall survival (OS) and the progression-free survival (PFS).

Results: Median follow-up was 28 months (range 3-82 months). Median OS was 32.5 months (95% CI 25.77-39.16), 1 and 2-year OS were 71.6% and 64.1%, respectively. Median PFS was 19,8 months (95% CI 11.34-28.31), 1 and 2-year PFS were 67.2% and 47.4%, respectively. Median OS for patients that underwent radiotherapy before 6 months from the start of ARTT was 23.4 months (95% CI 2.04-44.89) and 45.5 months (95% CI 31.19-59.8) for patients that underwent radiotherapy after 6 months ().

Conclusion: Local ablative radiation therapy directed to progressive metastasis is a non-invasive, well tolerated treatment with efficacy on prolonging clinical benefit of systemic therapies with ARTT. Patients who underwent RT >6 months from the start of ARTT presented a statistically better OS and PFS compared with patients who underwent radiotherapy <6 months from the start of ARTT.
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http://dx.doi.org/10.3389/fonc.2021.695136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495216PMC
September 2021

Vitiligo-like leukoderma as an indicator of clinical response to immune checkpoint inhibitors in late-stage melanoma patients.

J Cancer Res Clin Oncol 2021 Sep 30. Epub 2021 Sep 30.

Epidemiology Unit, IDI-IRCCS, Rome, Italy.

Purpose: Although development of immune checkpoint inhibitors has revolutionized the treatment of metastatic melanoma, more than a half of treated patients experience disease progression during therapy. Cases of spontaneous vitiligo-like leukoderma have been described in melanoma patients and have been associated with a favorable outcome. This vitiligo-like leukoderma can also appear in melanoma patients undergoing immune therapies such as immune checkpoint inhibitors. However, no consensus exists about the relationship between vitiligo-like leukoderma onset and improved overall survival. Our study investigates the possible association between the onset of vitiligo-like leukoderma during immune checkpoint inhibitor treatment and a better prognosis.

Methods: A non-concurrent cohort study was conducted by identifying retrospectively 280 patients who had inoperable or metastatic melanoma and had undergone immune therapy with checkpoint inhibitors in any line of treatment. Toxicities developed during therapy were evaluated.

Results: Among the 280 study participants, 50% developed at least one type of toxicity, and vitiligo-like leukoderma was observed in 43 patients (15.4%). In the multivariate Cox model, a protective effect for mortality was observed for patients with vitiligo-like leukoderma development (HR : 0.23; 95% CI 0.11-0.44, p < 0.0001). In a sub-group analysis comprising only cutaneous melanoma in first line of treatment (N = 153), occurrence of vitiligo-like leukoderma was also an independent predictor factor for duration of clinical benefits measured by time to the next treatment (HR: 0.17; 95% CI 0.06-0.44).

Conclusion: Our findings indicate that onset of vitiligo-like leukoderma during melanoma treatment could be a marker of favorable outcome in patients treated with immune checkpoint inhibitors.
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http://dx.doi.org/10.1007/s00432-021-03811-3DOI Listing
September 2021

Integrated care pathways and the hub-and-spoke model for the management of non-melanoma skin cancer: A proposal of the Italian Association of Hospital Dermatologists (ADOI).

Dermatol Reports 2021 Aug 5;13(2):9278. Epub 2021 Aug 5.

Centro Studi GISED, Bergamo and San Bortolo Hospital, Vicenza, Italy.

The term (NMSC) refers to skin cancer different from melanoma, and it is usually restricted to basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and their pre-cancerous lesions, , actinic keratosis. These conditions represent the most frequent tumors in Caucasians and are characterized by an increasing incidence worldwide and a high socio-economic impact. The term (ICP) refers to "a complex intervention for the mutual decision making and organization of care processes for a well-defined group of patients during a well-defined period". The purpose of this paper is to present a proposal from the Italian Association of Hospital Dermatologists (ADOI) for an ICP organization of care of NMSC, considering the hub-and-spoke model in the different geographical areas. This proposal is based on the most recent literature and on documents from the Italian Association of Medical Oncology (AIOM), the European consensus-based interdisciplinary guidelines from the European Association of Dermato- Oncology (EADO), and the National Comprehensive Cancer Network (NCCN). We initially discuss the NMSC outpatient clinic, the role of the multidisciplinary working groups, and the hub-and-spoke model regarding this topic. Then, we define the ICP processes specific for BCC and SCC. The ICP for NMSC is an innovative strategy to guarantee the highest possible quality of health care while the hub-andspoke model is crucial for the organization of different health care structures. Considering the importance on this topic, it is essential to create a valid ICP together with an efficient organization within the different geographical areas.
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http://dx.doi.org/10.4081/dr.2021.9278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404423PMC
August 2021

The Challenge of ICIs Resistance in Solid Tumours: Could Microbiota and Its Diversity Be Our Secret Weapon?

Front Immunol 2021 20;12:704942. Epub 2021 Aug 20.

Department of Clinical and Molecular Medicine, Sant' Andrea University Hospital, Sapienza University of Rome, Rome, Italy.

The human microbiota and its functional interaction with the human body were recently returned to the spotlight of the scientific community. In light of the extensive implementation of newer and increasingly precise genome sequencing technologies, bioinformatics, and culturomic, we now have an extraordinary ability to study the microorganisms that live within the human body. Most of the recent studies only focused on the interaction between the intestinal microbiota and one other factor. Considering the complexity of gut microbiota and its role in the pathogenesis of numerous cancers, our aim was to investigate how microbiota is affected by intestinal microenvironment and how microenvironment alterations may influence the response to immune checkpoint inhibitors (ICIs). In this context, we show how diet is emerging as a fundamental determinant of microbiota's community structure and function. Particularly, we describe the role of certain dietary factors, as well as the use of probiotics, prebiotics, postbiotics, and antibiotics in modifying the human microbiota. The modulation of gut microbiota may be a secret weapon to potentiate the efficacy of immunotherapies. In addition, this review sheds new light on the possibility of administering fecal microbiota transplantation to modulate the gut microbiota in cancer treatment. These concepts and how these findings can be translated into the therapeutic response to cancer immunotherapies will be presented.
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http://dx.doi.org/10.3389/fimmu.2021.704942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417795PMC
August 2021

KEAP1 and TP53 Frame Genomic, Evolutionary, and Immunologic Subtypes of Lung Adenocarcinoma With Different Sensitivity to Immunotherapy.

J Thorac Oncol 2021 12 25;16(12):2065-2077. Epub 2021 Aug 25.

Division of Medical Oncology 2, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Regina Elena National Cancer Institute, Rome, Italy. Electronic address:

Introduction: The connection between driver mutations and the efficacy of immune checkpoint inhibitors is the focus of intense investigations. In lung adenocarcinoma (LUAD), KEAP1/STK11 alterations have been tied to immunoresistance. Nevertheless, the heterogeneity characterizing immunotherapy efficacy suggests the contribution of still unappreciated events.

Methods: Somatic interaction analysis of top-ranking mutant genes in LUAD was carried out in the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) (N = 6208). Mutational processes, intratumor heterogeneity, evolutionary trajectories, immunologic features, and cancer-associated signatures were investigated, exploiting multiple data sets (AACR GENIE, The Cancer Genome Atlas [TCGA], TRAcking Cancer Evolution through therapy [Rx]). The impact of the proposed subtyping on survival outcomes was assessed in two independent cohorts of immune checkpoint inhibitor-treated patients: the tissue-based sequencing cohort (Rome/Memorial Sloan Kettering Cancer Center/Dana-Farber Cancer Institute, tissue-based next-generation sequencing [NGS] cohort, N = 343) and the blood-based sequencing cohort (OAK/POPLAR trials, blood-based NGS cohort, N = 304).

Results: Observing the neutral interaction between KEAP1 and TP53, KEAP1/TP53-based subtypes were dissected at the molecular and clinical levels. KEAP1 single-mutant (KEAP1 SM) and KEAP1/TP53 double-mutant (KEAP1/TP53 DM) LUAD share a transcriptomic profile characterized by the overexpression of AKR genes, which are under the control of a productive superenhancer with NEF2L2-binding signals. Nevertheless, KEAP1 SM and KEAP1/TP53 DM tumors differ by mutational repertoire, degree of intratumor heterogeneity, evolutionary trajectories, pathway-level signatures, and immune microenvironment composition. In both cohorts (blood-based NGS and tissue-based NGS), KEAP1 SM tumors had the shortest survival; the KEAP1/TP53 DM subgroup had an intermediate prognosis matching that of pure TP53 LUAD, whereas the longest survival was noticed in the double wild-type group.

Conclusions: Our data provide a framework for genomically-informed immunotherapy, highlighting the importance of multimodal data integration to achieve a clinically exploitable taxonomy.
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http://dx.doi.org/10.1016/j.jtho.2021.08.010DOI Listing
December 2021

Role of Chemotherapy in Vulvar Cancers: Time to Rethink Standard of Care?

Cancers (Basel) 2021 Aug 12;13(16). Epub 2021 Aug 12.

Sperimentazioni di Fase IV, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy.

The actual role of chemotherapy in vulvar cancer is undeniably a niche topic. The low incidence of the disease limits the feasibility of randomized trials. Decision making is thus oriented by clinical and pathological features, whose relevance is generally weighted against evidence from observational studies and clinical practice. The therapeutic management of vulvar cancer is increasingly codified and refined at an individual patient level. It is of note that the attitude towards evidence sharing and discussion within a multidisciplinary frame is progressively consolidating. Viable options included in the therapeutic armamentarium available for vulvar cancer patients are frequently an adaption from standards used for cervical or anal carcinoma. Chemotherapy is more frequently combined with radiotherapy as neo-/adjuvant or definitive treatment. Drugs commonly used are platinum derivative, 5-fluorouracil and mitomicin C, mostly in combination with radiotherapy for radiosensitization. Exclusive chemotherapy in the neo-/adjuvant setting comprises platinum-derivative, combined with bleomicin and methotrexate, 5-fluorouracil, ifosfamide or taxanes. In advanced disease, current regimens include cisplatin-based chemoradiation, with or without 5-fluorouracil, or doublets with platinum in combination with a taxane. Our work is also enriched by a concise excursus on the biologic pathways underlying vulvar cancer. Introductory hints are also provided on targeted agents, a rapidly evolving research field.
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http://dx.doi.org/10.3390/cancers13164061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391130PMC
August 2021

Multidimensional Statistical Technique for Interpreting the Spontaneous Breakthrough Cancer Pain Phenomenon. A Secondary Analysis from the IOPS-MS Study.

Cancers (Basel) 2021 Aug 10;13(16). Epub 2021 Aug 10.

Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80100 Naples, Italy.

Breakthrough cancer pain (BTcP) is a temporary exacerbation of pain that "breaks through" a phase of adequate pain control by an opioid-based therapy. The non-predictable BTcP (NP-BTcP) is a subtype of BTcP that occurs in the absence of any specific activity. Since NP-BTcP has an important clinical impact, this analysis is aimed at characterizing the NP-BTcP phenomenon through a multidimensional statistical technique. This is a secondary analysis based on the Italian Oncologic Pain multiSetting-Multicentric Survey (IOPS-MS). A correlation analysis was performed to characterize the NP-BTcP profile about its intensity, number of episodes per day, and type. The multiple correspondence analysis (MCA) determined the identification of four groups (phenotypes). A univariate analysis was performed to assess differences between the four phenotypes and selected covariates. The four phenotypes represent the hierarchical classification according to the status of NP-BTcP: from the best (phenotype 1) to the worst (phenotype 4). The univariate analysis found a significant association between the onset time >10 min in the phenotype 1 (37.3%)' vs. the onset > 10 min in phenotype 4 (25.8%) ( < 0.001). Phenotype 1 was characterized by the gastrointestinal type of cancer (26.4%) with respect to phenotype 4, where the most frequent cancer affected the lung (28.8%) ( < 0.001). Phenotype 4 was mainly managed with rapid-onset opioids, while in phenotype 1, many patients were treated with oral, subcutaneous, or intravenous morphine (56.4% and 44.4%, respectively; = 0.008). The ability to characterize NP-BTcP can offer enormous benefits for the management of this serious aspect of cancer pain. Although requiring validation, this strategy can provide many indications for identifying the diagnostic and therapeutic gaps in NP-BTcP management.
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http://dx.doi.org/10.3390/cancers13164018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391336PMC
August 2021

Anti-PD-1 and Anti-PD-L1 in Head and Neck Cancer: A Network Meta-Analysis.

Front Immunol 2021 9;12:705096. Epub 2021 Aug 9.

Department of Clinical and Molecular Oncology, "Sapienza" University of Rome, Rome, Italy.

Objective: The monoclonal antibodies anti-programmed death protein-1 (anti-PD-1) nivolumab and pembrolizumab are the first immune checkpoint inhibitors (ICIs) approved for treatment of recurrent/metastatic head and neck carcinoma R/M HNSCC in first line and in platinum refractory disease. This network meta-analysis aims to investigate the efficacy of anti-PD-1- anti-PD-L1-based therapy in R/M HNSCC cancer patients through a systematic review of the literature to provide support for evidence-based treatment decisions. In particular, the effectiveness of ICIs for R/M HNSCC is analyzed according to the different mechanisms of action of the check-points inhibitory drugs in different subgroups of patients.

Methods: We did a systematic literature review and network meta-analysis (NMA) of randomized controlled trials (RCTs) in PubMed, ClinicalTrials.gov, Embase, Medline, the Cochrane Central Register of Controlled Trials, Web of Science. Our search identified a total of five randomized controlled trials: Keynote 040, Keynote 048, Eagle, Condor, Checkmate 141. These trials included 3001 patients. Treatment was sub-categorized into PD-L1-based, PD-1-based, and standard chemotherapy. Treatments were indirectly compared with anti-PD-L1-based therapy.

Results: The network meta-analysis demonstrated no significant differences in OS between different subgroups except for the metastatic patients in which anti-PD-1-based therapy was associated with significantly less risk of death. Furthermore, anti-PD-1-based therapy appeared to be effective in smoker patients and in human papilloma-negative (HPV) patients. Conversely, anti-PD-L1-based therapy seems to be better efficient in female patients, in locally recurrent setting and in HPV positive patients.

Conclusion: This is the first NMA study that aimed to indirectly compare anti-PD-1- and anti-PD-L1-based therapy in HNSCC patients. The results of our NMA could help define a profile of patient responder or resistant to specific classes of immune drugs and can be used to guide/design future studies in the novel scenario of precision immune-oncology.
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http://dx.doi.org/10.3389/fimmu.2021.705096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380817PMC
August 2021

Individualized Drugs' Selection by Evaluation of Drug Properties, Pharmacogenomics and Clinical Parameters: Performance of a Bioinformatic Tool Compared to a Clinically Established Counselling Process.

Pharmgenomics Pers Med 2021 5;14:955-962. Epub 2021 Aug 5.

Department of Neurosciences, Mental Health and Sensory Organs, Faculty of Medicine and Psychology, Sapienza University and Laboratory of Clinical Biochemistry, Sant'Andrea Hospital, Rome, Italy.

Purpose: Inefficacy and safety concerns are main medications' problems, especially in the case of poly-therapies, when drug-drug interactions may alter the expected drug disposition. Ongoing efforts are aimed to establish drug selection processes aimed to preemptive evaluation of a plethora of factors affecting patient's specific drug response, including pharmacogenomic markers, in order to minimize prescription of improper medications. In previous years, we established at the University Hospital Sant'Andrea of Rome, Italy, a Precision Medicine Service based on a multi-disciplinary experts' team. The team is in charge to produce a drug therapy counselling report, including pharmacogenomic, pharmacokinetic and pharmacodynamic considerations. In this study, we aimed to evaluate the performance of this established "manual" process of therapy selection with a novel bioinformatic tool, the Drug-PIN system.

Patients And Methods: A total of 200 patients diagnosed with Major Depressive Disorders or a depressive episode in Bipolar Disorder, with at least three previous failed treatments, who underwent pharmacogenomic profiling and therapy counselling in the Sant'Andrea Hospital from 2017 to 2020. The baseline poly-therapy of these patients was re-evaluated and optimized by Drug-PIN. Results of the Drug-PIN poly-therapy evaluation/optimization were compared with the results of the original poly-therapy evaluation/optimization by therapy counselling. To compare the results between the two processes, the risk associated with each poly-therapy was classified as low, moderate, or high.

Results: The number of baseline poly-therapies classified in low-, moderate- or high-risk did not change significantly between manual system or Drug-PIN system. As the counselling process, also the Drug-PIN system produces a significant decrease in the predicted treatment-associated risk.

Conclusion: Drug-PIN substantially replicates the output of the counselling process, allowing a substantial reduction in the time needed for therapy evaluation. Availability of an effective bioinformatic tool for proper drug selection is expected to exponentially increase the actuation of targeted therapy strategies.
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http://dx.doi.org/10.2147/PGPM.S316556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352633PMC
August 2021

The Role of Soluble LAG3 and Soluble Immune Checkpoints Profile in Advanced Head and Neck Cancer: A Pilot Study.

J Pers Med 2021 Jul 10;11(7). Epub 2021 Jul 10.

Department of Clinical and Molecular Oncology, University of Rome "Sapienza", 00185 Rome, Italy.

Unresectable recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) has a very poor prognosis. Soluble immune checkpoints (sICs) are circulating proteins that result from the alternative splicing of membrane proteins and can modulate the immune response to cancer cells. The aim of our pilot study was to determine the possible role of a comprehensive evaluation of sICs in the classification of prognosis and response to treatment in patients with advanced disease. We evaluated several sICs (CD137, CTLA-4, PD-1, PD-L1, PD-L2, TIM3, LAG3, GITR, HVEM, BTLA, IDO, CD80, CD27, and CD28) from peripheral blood at baseline and investigated the association with clinical characteristics and outcomes. A high baseline soluble LAG3 (sLAG3 > 377 pg/mL) resulted in an association with poor PFS and OS ( = 0.047 and = 0.003, respectively). Moreover, sLAG3 emerged as an independent prognostic factor using an MVA ( = 0.005). The evaluation of sICs, in particular sLAG3, may be relevant for identifying patients with worse prognoses, or resistance to treatments, and may lead to the development of novel targeted strategies.
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http://dx.doi.org/10.3390/jpm11070651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304359PMC
July 2021

Molecular tests and target therapies in oncology: recommendations from the Italian workshop.

Future Oncol 2021 Sep 13;17(26):3529-3539. Epub 2021 Jul 13.

Cell Biology & Biotherapy Unit, INT-Fondazione 'Pascale', Naples, Italy.

Next-generation sequencing (NGS) and liquid biopsy are new technologies that can allow overall tumor profiling in a single analysis and play an important role in the implementation of precision oncology. However, the lack of guidelines in this setting has limited the development of precision oncology in Italy. This article summarizes recommendations for the appropriate use of NGS in tumor gene profiling, as well as access to tests and target drugs, that were prepared by a group of key opinion leaders and relevant stakeholders. In particular, the need to create laboratory networks capable of carrying out NGS tests in Italy is highlighted. It also appears necessary to establish an adequate reimbursement system for NGS tests. However, the expert panel recommends that the use of NGS tests in clinical practice should be limited to specific tumor types, based on the number and complexity of biomarkers and the availability of treatments.
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http://dx.doi.org/10.2217/fon-2021-0286DOI Listing
September 2021

Weekly chemotherapy as first line treatment in frail head and neck cancer patients in the immunotherapy era.

J Transl Med 2021 07 12;19(1):303. Epub 2021 Jul 12.

Department of Clinical and Molecular Oncology, "Sapienza" University of Rome, 00185, Rome, Italy.

Objective: First-line therapy for metastatic squamous cell carcinoma of the head and neck (R/M HNSCC) has been revolutionized by the introduction of anti-checkpoint monoclonal antibodies, which have shown a significant improvement in overall survival (OS) gaining approval in a first line setting. Efficacy and safety of first-line weekly chemotherapy, compared to 3-weeks treatment, was retrospectively evaluated in a frail patient population with R/M HNSCC with the aim to evaluate its role as part of a personalized first-line approach.

Methods: A total of 124 patients with locally incurable R/M HNSCC receiving weekly (21) or three-weekly (103) chemotherapy plus cetuximab in a first line setting from December 2010 to September 2020 were retrospectively reviewed. Treatment outcomes in terms of objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicities were analysed.

Results: Patients in the three-week subgroup were ECOG PS 0 (39) and 1 (64) while patients in weekly group (21) were all PS 2. No significant differences were reported in terms of age, sex, smoking and previous alcohol abuse considering the two distinct subgroups. Moreover, no statistically significant difference was found in PFS and OS between the two treatment subgroups. The response rate was 35% (36 patients) and 34% (7 patients) in three-week and weekly treatment group, respectively. Seventy patients (68%) in the three-week group experienced chemotherapy-related toxicities, predominantly G3. In the weekly group a predominantly low-grade toxicity was found in a lower number of patients (52%).

Conclusion: The weekly schedule appears to be an active and safe strategy in frail patients with R/M HNSCC. Based on these data, a weekly schedule could be considered as a first line treatment in all frail patients excluded from pembrolizumab treatment and a study on the combination of weekly chemotherapy and immunotherapy should be performed.
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http://dx.doi.org/10.1186/s12967-021-02975-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274020PMC
July 2021

Global mapping of cancers: The Cancer Genome Atlas and beyond.

Mol Oncol 2021 Nov 20;15(11):2823-2840. Epub 2021 Jul 20.

Department of Experimental Medicine, Torvergata Oncoscience Research Centre of Excellence, TOR, University of Rome Tor Vergata, Italy.

Cancer genomes have been explored from the early 2000s through massive exome sequencing efforts, leading to the publication of The Cancer Genome Atlas in 2013. Sequencing techniques have been developed alongside this project and have allowed scientists to bypass the limitation of costs for whole-genome sequencing (WGS) of single specimens by developing more accurate and extensive cancer sequencing projects, such as deep sequencing of whole genomes and transcriptomic analysis. The Pan-Cancer Analysis of Whole Genomes recently published WGS data from more than 2600 human cancers together with almost 1200 related transcriptomes. The application of WGS on a large database allowed, for the first time in history, a global analysis of features such as molecular signatures, large structural variations and noncoding regions of the genome, as well as the evaluation of RNA alterations in the absence of underlying DNA mutations. The vast amount of data generated still needs to be thoroughly deciphered, and the advent of machine-learning approaches will be the next step towards the generation of personalized approaches for cancer medicine. The present manuscript wants to give a broad perspective on some of the biological evidence derived from the largest sequencing attempts on human cancers so far, discussing advantages and limitations of this approach and its power in the era of machine learning.
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http://dx.doi.org/10.1002/1878-0261.13056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564642PMC
November 2021

H-Ras gene takes part to the host immune response to COVID-19.

Cell Death Discov 2021 Jun 25;7(1):158. Epub 2021 Jun 25.

Medical Oncology Sant'Andrea Hospital, University La Sapienza, via di Grottarossa 1035-1039, 00189, Rome, Italy.

Ras gene family members play a relevant role in cancer, especially when they are mutated. However, they may play additional roles in other conditions beside cancer. We performed gene expression analysis using the NanoString PanCancer IO 360 panel in the peripheral blood mononuclear cell (PBMC) of six COVID-19 patients and we found that H-Ras gene was significantly upregulated, while both K-Ras and N-Ras genes were downregulated. In particular, H-Ras gene upregulation was more evident in COVID-19 patients with a more severe disease. We compared our results with those obtained by analyzing two different and independent datasets, including a total of 53 COVID-19 patients, in which the gene expression analysis was performed using the Immunology_V2 panel. Comparative analysis of the H-Ras gene expression in these patients confirmed our preliminary results. In both of them, in fact, we were able to confirm the upregulation of the expression of the H-Ras gene. The exact role of this specific upregulation of the H-Ras gene in response to SARS-CoV-2 infection and its possible role in cancer still remains to be elucidated. In conclusion, H-Ras gene participates to the host immune response to SARS-CoV-2 virus infection, especially in patients affected by the most severe form of the COVID-19.
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http://dx.doi.org/10.1038/s41420-021-00541-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256395PMC
June 2021

The prognostic relevance of HER2-positivity gain in metastatic breast cancer in the ChangeHER trial.

Sci Rep 2021 07 2;11(1):13770. Epub 2021 Jul 2.

Department of Ematology and Oncology, Pugliese-Ciaccio Hospital, Catanzaro, Italy.

In metastatic breast cancer (mBC), the change of human epidermal growth factor receptor 2 (HER2) status between primary and metastatic lesions is widely recognized, however clinical implications are unknown. Our study address the question if relevant differences exist between subjects who preserve the HER2 status and those who gain the HER2 positivity when relapsed. Data of patients affected by HER2-positive mBC, treated with pertuzumab and/or trastuzumab-emtansine (T-DM1) in a real-world setting at 45 Italian cancer centers were retrospectively collected and analyzed. From 2003 to 2017, 491 HER2-positive mBC patients were included. Of these, 102 (20.7%) had been initially diagnosed as HER2-negative early BC. Estrogen and/or progesterone receptor were more expressed in patients with HER2-discordance compared to patients with HER2-concordant status (p < 0.0001 and p = 0.006, respectively). HER2-discordant tumors were characterized also by a lower rate of brain metastases (p = 0.01) and a longer disease free interval (p < 0.0001). Median overall survival was longer, although not statistically significant, in the subgroup of patients with HER2-discordant cancer with respect to patients with HER2-concordant status (140 vs 78 months, p = 0.07). Our findings suggest that patients with HER2-positive mBC with discordant HER2 status in early BC may have different clinical, biological and prognostic behavior compared to HER2-concordant patients.
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http://dx.doi.org/10.1038/s41598-021-92774-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253801PMC
July 2021

Knowledge and attitudes of Italian medical oncologists and palliative care physicians toward medical use of cannabis in cancer care: a national survey.

Support Care Cancer 2021 Dec 26;29(12):7845-7854. Epub 2021 Jun 26.

Medical Oncology Unit, Azienda Ospedaliero Universitaria Sant'Andrea, Via di Grottarossa, 1035-39 00189, Rome, Italy.

Purpose: Despite advances in supportive care, cancer-related symptoms tend to be persistent regardless of cancer type, stage of disease, or treatment received. There is an increasing prescription for complementary and alternative medicines, such as medical cannabis (MC). Knowledge and attitudes of Italian medical oncologists and palliative care physicians toward medical cannabis in cancer care remain unknown.

Methods: We conducted a cross-sectional study to investigate the knowledge and attitude toward MC prescription among cancer care professionals in Italy. All invited participants received an email with the electronic questionnaire accessible through a direct link.

Results: Among the 2616 members who received the invitation, 475 replied to the questionnaire and were considered for the survey analysis. The most prescribed formulations among those available in Italy were cannabis FM2. The most frequent clinical indications for the use of MC were pain, gastrointestinal, and mood disorders. Only 9 responders reported MC-related side effects like anxiety insomnia and muscle spasms. The question regarding the normative references for MC prescription and use in Italy had conflicting results: only 14% indicated the exact legislative reference.

Conclusion: Our study highlights a significant discrepancy between personal attitudes, prescription levels, and actual knowledge on MC. This represent a critical issue that should be systemically faced, building educational programs and national guidelines that sublimate personal physicians' beliefs and predispositions, resulting in a robust science-based MC practice. Only through coordinated interventions on science and health policy of MC, there will be success of safety and efficacy, ensuring the best knowledge for the best outcomes.
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http://dx.doi.org/10.1007/s00520-021-06383-7DOI Listing
December 2021

PD-1/PD-L1 checkpoint inhibitors during late stages of life: an ad-hoc analysis from a large multicenter cohort.

J Transl Med 2021 06 24;19(1):270. Epub 2021 Jun 24.

Division of Medical Oncology, University of Insubria, Varese, Italy.

Background: The favourable safety profile and the increasing confidence with immune checkpoint inhibitors (ICIs) might have boosted their prescription in frail patients with short life expectancies, who usually are not treated with standard chemotherapy.

Methods: The present analysis aims to describe clinicians' attitudes towards ICIs administration during late stages of life within a multicenter cohort of advanced cancer patients treated with single agent PD-1/PD-L1 checkpoint inhibitors in Italy.

Results: Overall, 1149 patients with advanced cancer who received single agent PD-1/PD-L1 checkpoint inhibitors were screened. The final study population consisted of 567 deceased patients. 166 patients (29.3%) had received ICIs within 30 days of death; among them there was a significantly higher proportion of patients with ECOG-PS ≥ 2 (28.3% vs 11.5%, p < 0.0001) and with a higher burden of disease (69.3% vs 59.4%, p = 0.0266). In total, 35 patients (6.2%) started ICIs within 30 days of death; among them there was a higher proportion of patients with ECOG-PS ≥ 2 (45.7% vs 14.5%, p < 0.0001) and with a higher burden of disease (82.9% vs 60.9%, p = 0.0266). Primary tumors were significantly different across subgroups (p = 0.0172), with a higher prevalence of NSCLC patients (80% vs 60.9%) among those who started ICIs within 30 days of death. Lastly, 123 patients (21.7%) started ICIs within 3 months of death. Similarly, within this subgroup there was a higher proportion of patients with ECOG-PS ≥ 2 (29.3% vs 12.8%, p < 0.0001), with a higher burden of disease (74.0% vs 59.0%, p = 0.0025) and with NSCLC (74.0% vs 58.8%, p = 0.0236).

Conclusion: Our results confirmed a trend toward an increasing ICIs prescription in frail patients, during the late stages of life. Caution should be exercised when evaluating an ICI treatment for patients with a poor PS and a high burden of disease.
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http://dx.doi.org/10.1186/s12967-021-02937-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223272PMC
June 2021

Primary Analysis and 4-Year Follow-Up of the Phase III NIBIT-M2 Trial in Melanoma Patients With Brain Metastases.

Clin Cancer Res 2021 Sep 10;27(17):4737-4745. Epub 2021 Jun 10.

Department of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy.

Purpose: Phase II trials have shown encouraging activity with ipilimumab plus fotemustine and ipilimumab plus nivolumab in melanoma brain metastases. We report the primary analysis and 4-year follow-up of the NIBIT-M2 study, the first phase III trial comparing these regimens with fotemustine in patients with melanoma with brain metastases.

Patients And Methods: This phase III study recruited patients 18 years of age and older with wild-type or mutant melanoma, and active, untreated, asymptomatic brain metastases from nine centers, randomized (1:1:1) to fotemustine, ipilimumab plus fotemustine, or ipilimumab plus nivolumab. The primary endpoint was overall survival (OS).

Results: From January, 2013 to September, 2018, 27, 26, and 27 patients received fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab. Median OS was 8.5 months [95% confidence interval (CI), 4.8-12.2] in the fotemustine arm, 8.2 months (95% CI, 2.2-14.3) in the ipilimumab plus fotemustine arm (HR vs. fotemustine, 1.09; 95% CI, 0.59-1.99; = 0.78), and 29.2 months (95% CI, 0-65.1) in the ipilimumab plus nivolumab arm (HR vs. fotemustine, 0.44; 95% CI, 0.22-0.87; = 0.017). Four-year survival rate was significantly higher for ipilimumab plus nivolumab than fotemustine [(41.0%; 95% CI, 20.6-61.4) vs. 10.9% (95% CI, 0-24.4; = 0.015)], and was 10.3% (95% CI, 0-22.6) for ipilimumab plus fotemustine. In the fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab arms, respectively, 11 (48%), 18 (69%), and eight (30%) patients had treatment-related grade 3 or 4 adverse events, without treatment-related deaths.

Conclusions: Compared with fotemustine, ipilimumab plus nivolumab significantly improved overall and long-term survival of patients with melanoma with asymptomatic brain metastases.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1046DOI Listing
September 2021

A Longitudinal Study of Breakthrough Cancer Pain: An Extension of IOPS-MS Study.

J Clin Med 2021 May 24;10(11). Epub 2021 May 24.

Medical Oncology Department, Campus Bio-Medico University of Rome, 00128 Rome, Italy.

The aim of this study was to longitudinally assess the characteristics of background pain and breakthrough pain (BTcP), analgesic treatment, and satisfaction with treatment four weeks after the first assessment.

Methods: Adult cancer patients with a diagnosis of BTcP were included. At T0, age, gender, visit setting, cancer diagnosis, the extent of the disease, ongoing anticancer treatments, and Karnofsky level were recorded. The background pain intensity in the last 24 h (on a numerical scale 0-10), opioids used for background pain, and their doses, expressed as oral morphine equivalents (OME), as well as other analgesic drugs, were recorded. The number of BTcP episodes, their intensity, predictability and precipitating factors, onset duration of untreated episodes, and interference with daily activities were collected. Analgesics and doses used for BTcP, and the mean time to meaningful pain relief after taking medication, were assessed. The level of satisfaction with BTcP medication was also assessed. Adverse effects to be attributed to these medications were also recorded. At T4, the same data were evaluated.

Results: After one-month follow-up, patients had a lower number of BTcP episodes and peak intensity, possibly due to the optimization of background analgesia. The principal characteristics of BTcP did not change significantly.

Conclusion: A careful and continuous assessment should be guaranteed to all patients to limit the burden induced by BTcP, other than treating BTcP episodes with short-onset opioids.
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http://dx.doi.org/10.3390/jcm10112273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197313PMC
May 2021

A Case of Pathological Complete Response and Resolution of Dermatomyositis Following Neoadjuvant Chemotherapy in HER2-Positive Early Breast Cancer.

Curr Oncol 2021 05 24;28(3):1957-1961. Epub 2021 May 24.

Oncology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, University "La Sapienza", 00189 Rome, Italy.

Introduction: Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) mainly characterized by subacute muscle weakness and skin rash sometimes associated with malignancy.

Case Presentation: A 61-year-old female was admitted to our hospital because of progressive proximal muscular weakness, heliotropic rash and left breast rash. Muscle biopsy findings were consistent with dermatomyositis (DM). A full panel of myositis associated (MAA) and specific antibodies (MSA) revealed the presence of anti-nuclear antibodies (1:160, speckled), Anti-Ro52 and anti TIF1-γ antibodies. A whole body Computed Tomography Scan showed three left mammary nodules and homolateral axillary lymphadenopathy. The breast biopsy confirmed the diagnosis of ductal carcinoma. Patient was initiated to neoadjuvant chemotherapy followed by surgery for cancer, and corticosteroid and intravenous immunoglobulins for DM with a complete resolution of muscle weakness and pathological complete response of breast cancer. Similar cases in literature are commonly referred to a first-line surgery and the role of neoadjuvant chemotherapy is debatable.
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http://dx.doi.org/10.3390/curroncol28030182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161769PMC
May 2021

An Example of Personalized Treatment in HR+ HER2+ Long Survivor Breast Cancer Patient (Case Report).

Curr Oncol 2021 05 25;28(3):1980-1987. Epub 2021 May 25.

Department of Clinical and Molecular Medicine, Oncology Unit, Sant' Andrea Hospital, University "La Sapienza", 00167 Rome, Italy.

Background: Personalized therapy is becoming increasingly popular in oncological scenarios, not only based on molecular pharmacological targets, but also preventing any drug-drug-gene interaction (DDGI), which could lead to severe toxicities. Single nucleotide polymorphisms (SNPs), the individual germline sequence variations in genes involved in drug metabolism, are correlated to interindividual response to drugs and explain both efficacy and toxicity profiles reported by patients.

Case Presentation: We present the case of a woman suffering from triple-positive breast cancer; she had early-stage disease at the onset and after four years developed metastatic disease. During her history, she presented different toxicities due to antineoplastic treatments. Particularly, hypertransaminasemia was found during every line of treatment. Nevertheless, we were able to guarantee the patient an excellent therapeutic adhesion thanks to the supportive treatments and the reduction of drug dosage. Moreover, we conducted a simultaneous analysis of the patient's biochemical and genomic data thanks to Drug-PIN software, and we found several significant SNPs of the main enzymes and transporters involved in drug metabolism.

Conclusion: Our case report demonstrated the relevance of DDGI in clinical practice management of a patient treated for advanced breast cancer, suggesting the role of Drug-PIN software as an easy-to-use tool to prevent adverse events during cancer treatment and to help physicians in therapeutic algorithms. However, further studies are needed to confirm these results.
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http://dx.doi.org/10.3390/curroncol28030184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161821PMC
May 2021

Evaluation of Drug-Drug Interactions in EGFR-Mutated Non-Small-Cell Lung Cancer Patients during Treatment with Tyrosine-Kinase Inhibitors.

J Pers Med 2021 May 18;11(5). Epub 2021 May 18.

Medical Oncology Unit B, Policlinico Umberto I, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Roma, Italy.

(1) Background. The onset of a drug-drug interaction (DDI) may affect treatment efficacy and toxicity of advanced non-small-cell lung cancer (aNSCLC) patients during epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) use. Here we present the use of Drug-PIN (Personalized Interactions Network) software to detect DDIs in aNSCLC patients undergoing EGFR-TKIs. (2) Methods. We enrolled patients with Stage IV aNSCLC already treated with or candidates to receive EGFR-TKIs, in any line; ECOG PS 0-2; taking at least one concomitant drug. Cancer treatments, concomitant drugs, and clinical and laboratory data were collected and inserted in Drug-PIN. (3) Results. Ninety-two patients, median age of 68.5 years (range 43-89), were included. In total, 20 clinically relevant DDIs needing medical intervention in a total of 14 patients were identified; the 14 major DDIs were related to a high-grade interaction between TKIs and SSRIs, antipsychotics, antiepileptics, H2-receptor antagonist and calcium antagonists. A negative association between statin intake and PFS was identified ( = 0.02; HR 0.281, 95% CI 0.096-0.825). (4) Conclusions. This is the first retrospective study assessing the prevalence of DDIs, the clinical need for medical intervention and the impact of concomitant drugs on EGFR-TKIs survival in aNSCLC.
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http://dx.doi.org/10.3390/jpm11050424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157378PMC
May 2021

Precision medicine in breast cancer: From clinical trials to clinical practice.

Cancer Treat Rev 2021 Jul 12;98:102223. Epub 2021 May 12.

European Institute of Oncology, IRCCS, 20141 Milan, Italy; Department of Oncology and Hematology (DIPO), University of Milan, 20122 Milan, Italy. Electronic address:

Introduction: Breast cancer (BC) is the most common cancer in women and, despite the undeniable improvements in the outcome of these patients obtained in the last decade, the discovery and the validation of new actionable molecular targets represent a priority. ESCAT permits to rank molecular alterations in different classes according to their evidence of actionability in a specific cancer type, assisting clinicians in their therapeutical decisions. MAIN: ERBB2, PIK3CA and germline BRCA1/2 alterations are biomarkers prospectively validated in BC, driving the selection of targeted therapies, and are therefore classified in the highest level of evidence (Ia). Agnostic biomarkers, namely microsatellite instability, NTRK fusions and high tumor mutational burden, demonstrated similar activity across different tumor types and are consequently ranked in tier Ic. In tier II are classified alterations that still need confirmatory prospective studies but for which evidence of efficacy is available. Somatic BRCA1/2 mutations, germline PALB2 mutations, HER2-low expression, ERBB2 mutations, PTEN deletions, AKT1 mutations, ESR1 resistance mutations satisfy the requirements to be classified in this tier. In tier III are ranked various molecular alterations for which there is evidence of actionability in other tumors (IIIa) or that have similar functional impact in the same gene or pathway of a tier I alteration, without clinical data (IIIb). In tier IV are listed the molecular alterations for which only preclinical studies are available.

Conclusion: In this review we report the most relevant molecular targets in BC, ordered pursuant to their pathway and classified in concordance with ESCAT.
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http://dx.doi.org/10.1016/j.ctrv.2021.102223DOI Listing
July 2021

Metastatic Renal Cell Carcinoma Management: From Molecular Mechanism to Clinical Practice.

Front Oncol 2021 22;11:657639. Epub 2021 Apr 22.

Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy.

The therapeutic sc"enario of metastatic renal cell cancer (mRCC) has noticeably increased, ranging from the most studied molecular target therapies to those most recently introduced, up to immune checkpoint inhibitors (ICIs). The most recent clinical trials with an ICI-based combination of molecular targeted agents and ICI show how, by restoring an efficient immune response against cancer cells and by establishing an immunological memory, it is possible to obtain not only a better radiological response but also a longer progression-free and overall survival. However, the role of tyrosine kinase inhibitors (TKIs) remains of fundamental importance, especially in patients who, for clinical characteristics, tumor burden and comorbidity, could have greater benefit from the use of TKIs in monotherapy rather than in combination with other therapies. However, to use these novel options in the best possible way, knowledge is required not only of the data from the large clinical trials but also of the biological mechanisms, molecular pathways, immunological mechanisms, and methodological issues related to both new response criteria and endpoints. In this complex scenario, we review the latest results of the latest clinical trials and provide guidance for overcoming the barriers to decision-making to offer a practical approach to the management of mRCC in daily clinical practice. Moreover, based on recent literature, we discuss the most innovative combination strategies that would allow us to achieve the best clinical therapeutic results.
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http://dx.doi.org/10.3389/fonc.2021.657639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100507PMC
April 2021

Circulating HPV DNA in the Management of Oropharyngeal and Cervical Cancers: Current Knowledge and Future Perspectives.

J Clin Med 2021 Apr 6;10(7). Epub 2021 Apr 6.

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy.

Human papillomaviruses (HPVs) are associated with invasive malignancies, including almost 100% of cervical cancers (CECs), and 35-70% of oropharyngeal cancers (OPCs). HPV infection leads to clinical implications in related tumors by determining better prognosis and predicting treatment response, especially in OPC. Currently, specific and minimally invasive tests allow for detecting HPV-related cancer at an early phase, informing more appropriately therapeutical decisions, and allowing for timely disease monitoring. A blood-based biomarker detectable in liquid biopsy represents an ideal candidate, and the use of circulating HPV DNA (ct-DNA) itself could offer the highest specificity for such a scope. Circulating HPV DNA is detectable in the greatest part of patients affected by HPV-related cancers, and studies have demonstrated its potential usefulness for CEC and OPC clinical management. Unfortunately, when using conventional polymerase chain reaction (PCR), the detection rate of serum HPV DNA is low. Innovative techniques such as droplet-based digital PCR and next generation sequencing are becoming increasingly available for the purpose of boosting HPV ct-DNA detection rate. We herein review and critically discuss the most recent and representative literature, concerning the role of HPV ctDNA in OPC and CEC in the light of new technologies that could improve the potential of this biomarker in fulfilling many of the unmet needs in the clinical management of OPC and CEC patients.
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http://dx.doi.org/10.3390/jcm10071525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038737PMC
April 2021

Second-line Eribulin in Triple Negative Metastatic Breast Cancer patients. Multicentre Retrospective Study: The TETRIS Trial.

Int J Med Sci 2021 27;18(10):2245-2250. Epub 2021 Mar 27.

Bio-Statistics Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Large and consistent evidence supports the use of eribulin mesylate in clinical practice in third or later line treatment of metastatic triple negative breast cancer (mTNBC). Conversely, there is paucity of data on eribulin efficacy in second line treatment. We investigated outcomes of 44 mTNBC patients treated from 2013 through 2019 with second line eribulin mesylate in a multicentre retrospective study involving 14 Italian oncologic centres. Median age was 51 years, with 11.4% of these patients being metastatic at diagnosis. Median overall survival (OS) and progression free survival (PFS) from eribulin starting were 11.9 (95%CI: 8.4-15.5) and 3.5 months (95%CI: 1.7-5.3), respectively. We observed 8 (18.2%) partial responses and 10 (22.7%) patients had stable disease as best response. A longer PFS on previous first line treatment predicted a better OS (HR=0.87, 95%CI: 0.77-0.99, p= 0.038) and a longer PFS on eribulin treatment (HR=0.92, 95%CI: 0.85-0.98, p=0.018). Progression free survival to eribulin was also favorably influenced by prior adjuvant chemotherapy (HR=0.44, 95%CI: 0.22-0.88, p=0.02). Eribulin was generally well tolerated, with grade 3-4 adverse events being recorded in 15.9% of patients. The outcomes described for our cohort are consistent with those reported in the pivotal Study301 and subsequent observational studies. Further data from adequately-sized, ad hoc trials on eribulin use in second line for mTNBC are warranted to confirm our findings.
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http://dx.doi.org/10.7150/ijms.54996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040412PMC
November 2021

Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy.

J Immunother Cancer 2021 04;9(4)

Pneumo-Oncology Unit, Ospedali dei Colli Monaldi Cotugno CTO, Napoli, Italy.

Background: Some concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate.

Methods: We present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses.

Results: 950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, β-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); p<0.0001), and OS (HR=1.93 (95% CI 1.59 to 2.35); p<0.0001) following pembrolizumab, and shorter PFS (HR=1.30 (95% CI 1.08 to 1.56), p=0.0046) and OS (HR=1.58 (95% CI 1.29 to 1.94), p<0.0001), following chemotherapy. PPIs were associated with worse OS (HR=1.49 (95% CI 1.26 to 1.77); p<0.0001) with pembrolizumab and shorter OS (HR=1.12 (95% CI 1.02 to 1.24), p=0.0139), with chemotherapy. At the pooled analysis, there was a statistically significant interaction with treatment (pembrolizumab vs chemotherapy) for corticosteroids (p=0.0020) and PPIs (p=0.0460) with respect to OS, for corticosteroids (p<0.0001), ATB (p=0.0290), and PPIs (p=0.0487) with respect to PFS, and only corticosteroids (p=0.0033) with respect to objective response rate.

Conclusion: In this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features.
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http://dx.doi.org/10.1136/jitc-2021-002421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031700PMC
April 2021
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