Lapatinib in II linea dopo il doppio blocco pertuzumab-trastuzumab: un caso clinico

We report the case of a young, 36-year-old patient diagnosed with multifocal breast carcinoma, undergoing neoadjuvant chemotherapy, surgery and adjuvant treatment. The patient presented an early recovery of liver disease after only 7 months of free interval. Histological reevaluation after liver biopsy revealed a HER2-positive disease, for which it was treated with first line chemotherapy including double anti-HER2 block. After 3 cycles the disease progressed at liver and encephalic level. It was therefore decided to treat brain localizations with whole-brain radiotherapy and to start a second line with capecitabine associated with lapatinib. This chemo-radiotherapy approach allowed to control the disease for 8 months. Following further progression (lymph node and bone), a third line was chosen with trastuzumab emtansine (TDM1). The encephalic disease remained stable for another 8 months, when due to visceral progression and worsening of clinical picture, TDM1 was interrupted and supportive therapies were started (Oncology).

A network approach to define the predictive role of immune profile on tumor response and toxicity of anti PD-1 single agent immunotherapy in patients with solid tumors

Background: The immune profile of each patient could be considered as a portrait of the fitness of his/her own immune system. The predictive role of the immune profile in immune-related toxicities (irAEs) development and tumour response to treatment was investigated. Methods: A prospective, multicenter study evaluating, through a multiplex assay, the soluble immune profile at the baseline of 53 patients with advanced cancer, treated with immunotherapy as single agent was performed. Four connectivity heat maps and networks were obtained by calculating the Spearman correlation coefficients for each group: responder patients who developed cumulative toxicity (R-T), responders who did not develop cumulative toxicity (R-NT), non-responders who developed cumulative toxicity (NR-T), non-responders who did not develop cumulative toxicity (NR-NT). Results: A statistically significant up-regulation of IL-17A, sCTLA4, sCD80, I-CAM-1, sP-Selectin and sEselectin in NR-T was detected. A clear loss of connectivity of most of the soluble immune checkpoints and cytokines characterized the immune profile of patients with toxicity, while an inversion of the correlation for ICAM-1 and sP-selectin was observed in NR-T. Four connectivity networks were built for each group. The highest number of connections characterized the NR-T. Conclusions: A connectivity network of immune dysregulation was defined for each subgroup of patients, regardless of tumor type. In patients with the worst prognosis (NR-T) the peculiar connectivity model could facilitate their early and timely identification, as well as the design of a personalized treatment approach to improve outcomes or prevent irAEs

Molecular profiling of male breast cancer by multigene panel testing: Implications for precision oncology

Introduction: Compared with breast cancer (BC) in women, BC in men is a rare disease with genetic and molecular peculiarities. Therapeutic approaches for male BC (MBC) are currently extrapolated from the clinical management of female BC, although the disease does not exactly overlap in males and females. Data on specific molecular biomarkers in MBC are lacking, cutting out male patients from more appropriate therapeutic strategies. Growing evidence indicates that Next Generation Sequencing (NGS) multigene panel testing can be used for the detection of predictive molecular biomarkers, including Tumor Mutational Burden (TMB) and Microsatellite Instability (MSI). Methods: In this study, NGS multigene gene panel sequencing, targeting 1.94 Mb of the genome at 523 cancer-relevant genes (TruSight Oncology 500, Illumina), was used to identify and characterize somatic variants, Copy Number Variations (CNVs), TMB and MSI, in 15 Formalin-Fixed Paraffin-Embedded (FFPE) male breast cancer samples. Results and discussion: A total of 40 pathogenic variants were detected in 24 genes. All MBC cases harbored at least one pathogenic variant. PIK3CA was the most frequently mutated gene, with six (40.0%) MBCs harboring targetable PIK3CA alterations. CNVs analysis showed copy number gains in 22 genes. No copy number losses were found. Specifically, 13 (86.7%) MBCs showed gene copy number gains. MYC was the most frequently amplified gene with eight (53.3%) MBCs showing a median fold-changes value of 1.9 (range 1.8-3.8). A median TMB value of 4.3 (range 0.8-12.3) mut/Mb was observed, with two (13%) MBCs showing high-TMB. The median percentage of MSI was 2.4% (range 0-17.6%), with two (13%) MBCs showing high-MSI. Overall, these results indicate that NGS multigene panel sequencing can provide a comprehensive molecular tumor profiling in MBC. The identification of targetable molecular alterations in more than 70% of MBCs suggests that the NGS approach may allow for the selection of MBC patients eligible for precision/targeted therapy

The role of opioids in cancer response to immunotherapy

BACKGROUND: The response to immunotherapy can be impaired by several factors including external intervention such as drug interactions with immune system. We aimed to examine the immunomodulatory action of opioids, since immune cells express opioid receptors able to negatively influence their activities.METHODS: This observational, multicenter, retrospective study, recruited patients with different metastatic solid tumors, who have received immunotherapy between September 2014 and September 2019. Immunotherapy was administered according to the standard schedule approved for each primary tumor and line of treatment. The concomitant intake of antibiotics, antifungals, corticosteroids and opioids were evaluated in all included patients. The relationship between tumor response to immunotherapy and the oncological outcomes were evaluated. A multivariate Cox-proportional hazard model was used to identify independent prognostic factors for survival.RESULTS: One hundred ninety-three patients were recruited. Overall, progression-free survival (PFS) and overall survival (OS) were significantly shorter in those patients taking opioids than in those who didn't (median PFS, 3months vs. 19months, HR 1.70, 95% CI 1.37-2.09, p<0.0001; median OS, 4months vs. 35months, HR 1.60, 95% CI 1.26-2.02, p<0.0001). In addition, PFS and OS were significantly impaired in those patients taking corticosteroids, antibiotics or antifungals, in those patients with an ECOG PS≥1 and in patients with a high tumor burden. Using the multivariate analyses, opioids and ECOG PS were independent prognostic factors for PFS, whereas only ECOG PS resulted to be an independent prognostic factor for OS, with trend toward significance for opioids as well as tumor burden.DISCUSSION: Our study suggests that the concomitant administration of drugs as well as some clinical features could negatively predict the outcomes of cancer patients receiving immunotherapy. In particular, opioids use during immunotherapy is associated with early progression, potentially representing a predictive factor for PFS and negatively influencing OS as well.CONCLUSIONS: A possible negative drug interaction able to impair the immune response to anti-PD-1/PD-L1 agents has been highlighted. Our findings suggest the need to further explore the impact of opioids on immune system modulation and their role in restoring the response to immunotherapy treatment, thereby improving patients' outcomes

Free and cued selective reminding test predicts progression to Alzheimer's disease in people with mild cognitive impairment

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The Impact of Locoregional Treatment on Response to Nivolumab in Advanced Platinum Refractory Head and Neck Cancer: The Need Trial

Background: Previous locoregional treatment could affect the response to nivolumab in platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). The aim of this study is to evaluate the impact of the clinicopathological characteristics and previous treatment in predicting early progression to nivolumab in a real-world population. Methods: This is an observational, multicenter retrospective/prospective study including patients (pts) with platinum refractory R/M HNSCC who received nivolumab 240 mg every 2 weeks from October 2018 to October 2019. We analyzed the association between previous treatment, clinicopathological characteristics, and early progression (within 3 months). Results: Data from 61 pts were reviewed. Median age was 67 years (30–82). Forty-two pts (69%) received previous locoregional treatment. Early progression to nivolumab occurred in 36 pts (59%), while clinical benefit (stable disease and partial response) was achieved in 25 pts (41%). Early progression to nivolumab was significantly associated to previous locoregional treatment both at univariate and multivariate analysis (p = 0.005 and p = 0.048, respectively). Conclusion: nivolumab in R/M HNSCC is burdened with a high early progression rate. Previous wide neck dissection and high dose radiotherapy may compromise the efficacy of nivolumab, distorting the anatomy of the local lymphatic system and hindering the priming of immune response

Exploratory pilot study of circulating biomarkers in metastatic renal cell carcinoma

With the introduction of immune checkpoint inhibitors (ICIs) and next-generation vascular endothelial growth factor receptor–tyrosine kinase inhibitors (VEGFR–TKIs), the survival of patients with advanced renal cell carcinoma (RCC) has improved remarkably. However, not all patients have benefited from treatments, and to date, there are still no validated biomarkers that can be included in the therapeutic algorithm. Thus, the identification of predictive biomarkers is necessary to increase the number of responsive patients and to understand the underlying immunity. The clinical outcome of RCC patients is, in fact, associated with immune response. In this exploratory pilot study, we assessed the immune effect of TKI therapy in order to evaluate the immune status of metastatic renal cell carcinoma (mRCC) patients so that we could define a combination of immunological biomarkers relevant to improving patient outcomes. We profiled the circulating levels in 20 mRCC patients of exhausted/activated/regulatory T cell subsets through flow cytometry and of 14 immune checkpoint-related proteins and 20 inflammation cytokines/chemokines using multiplex Luminex assay, both at baseline and during TKI therapy. We identified the CD3+CD8+CD137+ and CD3+CD137+PD1+ T cell populations, as well as seven soluble immune molecules (i.e., IFNγ, sPDL2, sHVEM, sPD1, sGITR, sPDL1, and sCTLA4) associated with the clinical responses of mRCC patients, either modulated by TKI therapy or not. These results suggest an immunological profile of mRCC patients, which will help to improve clinical decision-making for RCC patients in terms of the best combination of strategies, as well as the optimal timing and therapeutic sequence

Immune-related toxicity and soluble profile in patients affected by solid tumors: a network approach

Background: Immune checkpoint inhibitors (ICIs) have particular, immune-related adverse events (irAEs), as a consequence of interfering with self-tolerance mechanisms. The incidence of irAEs varies depending on ICI class, administered dose and treatment schedule. The aim of this study was to define a baseline (T0) immune profile (IP) predictive of irAE development. Methods: A prospective, multicenter study evaluating the immune profile (IP) of 79 patients with advanced cancer and treated with anti-programmed cell death protein 1 (anti-PD-1) drugs as a first- or second-line setting was performed. The results were then correlated with irAEs onset. The IP was studied by means of multiplex assay, evaluating circulating concentration of 12 cytokines, 5 chemokines, 13 soluble immune checkpoints and 3 adhesion molecules. Indoleamine 2, 3-dioxygenase (IDO) activity was measured through a modified liquid chromatography-tandem mass spectrometry using the high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method. A connectivity heatmap was obtained by calculating Spearman correlation coefficients. Two different networks of connectivity were constructed, based on the toxicity profile. Results: Toxicity was predominantly of low/moderate grade. High-grade irAEs were relatively rare, while cumulative toxicity was high (35%). Positive and statistically significant correlations between the cumulative toxicity and IP10 and IL8, sLAG3, sPD-L2, sHVEM, sCD137, sCD27 and sICAM-1 serum concentration were found. Moreover, patients who experienced irAEs had a markedly different connectivity pattern, characterized by disruption of most of the paired connections between cytokines, chemokines and connections of sCD137, sCD27 and sCD28, while sPDL-2 pair-wise connectivity values seemed to be intensified. Network connectivity analysis identified a total of 187 statistically significant interactions in patients without toxicity and a total of 126 statistically significant interactions in patients with toxicity. Ninety-eight interactions were common to both networks, while 29 were specifically observed in patients who experienced toxicity. Conclusions: A particular, common pattern of immune dysregulation was defined in patients developing irAEs. This immune serological profile, if confirmed in a larger patient population, could lead to the design of a personalized therapeutic strategy in order to prevent, monitor and treat irAEs at an early stage

The predictive role of immune profile in patients with solid tumours in treatment with immunotherapy: a network analysis of efficacy and toxicity

Background: Despite immunotherapy has deeply changed the treatment landscape and prognosis of several cancers, only a small percentage of patients achieve long-term benefit in terms of overall survival (OS). In addition, ICIs have particular immune-related adverse events (irAEs). Soluble immune profiles, resulting from the combined evaluation of circulating checkpoints, adhesion and inflammatory molecules, rather than the evaluation of individual marker, could be considered as a portrait of the immune system fitness of each patient at the baseline, which affects the response to treatment and the development of toxicities. The aim of this study was to define an immune profile predicting outocomes to ICIs and irAE development. Methods: A prospective, multicenter study evaluating the immune profile of patients with advanced cancer, treated with ICIs was performed. The immune profile was studied evaluating circulating concentration of 12 cytokines, 5 chemokines, 13 soluble immune checkpoints (sIC), 3 adhesion molecules and indoleamine 2,3-dioxygenase (IDO) at the baseline (T0) through a multiplex assay. Four connectivity heat maps and networks were obtained by calculating the Spearman correlation coefficients, according to the response to immunotherapy and onset of cumulative toxicity: responder patients without toxicity, non-responder with toxicity, responder with toxicity, non-responder without toxicity. Then, connectivity heat maps were defined for OS and progression-free survival (PFS) using the median values as cut-off. Results: Immune profile of 53 patients with advanced solid tumours treated with ICIs was evaluated at T0. Cumulative toxicity occurred in 18 patients (34%). A subgroup of non-small cell lung cancer (NSCLC) patients with high cytokine/chemokine concentrations was identified in non-responder patients without toxicity. A statistically significant up-regulation of IL17A and all the adhesion molecules in non-responder patients with toxicity with respect to the other ones was detected. CTLA4 was significantly higher in non-responders with toxicity compared to both responders and non-responders without toxicity, as well as sCD80 compared to both non-responders without toxicity and responders with toxicity. Four connectivity maps in responder and non-responder patients with and without toxicity were defined. In patients with toxicity, we observed a clearly different connectivity patterns with a loss of connectivity of mostly of sICs and cytokines correlations. In non-responder patients with toxicity, an inversion of the correlation for some adhesion molecules was observed 7 (from positive or null correlation became negative). Four corresponding connectivity networks were built. Only 14 connections among the four networks were common, while connections specifically observed for each group of patients were: 26 in responder with toxicity, 38 in responder without toxicity, 80 in non-responder with toxicity, 31 in non-responder without toxicity. IL10, IL8, IL4, IL6, INFgamma, INFalpha, TNFalpha, GM-CSF, MIP-1alpha, IL13, sLAG3, sTIM3, sCD27, sCD28, sCD 137 and sPDL-2 showed a statistically significant down-regulation in patients with a longer OS. IL10, IL12p70, GM-CFS and sCD27 were statistically significant down-regulated in patients with longer PFS. No connectivity differences were instead observed when we compared the correlations maps between patients with OS and PFS above and below the respective median values. Conclusions: The combined evaluation of soluble molecules, rather than a single circulating factor, may be more suitable to represent the fitness of the immune system status in each patient and could allow to identify different prognostic and predictive outcome profiles. A specific connectivity model for each of the 4 clinical situation patterns, based on response to immunotherapy and irAE onset, was defined by a network analysis. Moreover, an organ-dependent immunity has also been highlighted. In patients who develop irAEs and in patients with the worst prognosis (non-responders who will develop toxicity), peculiar connectivity network of immune dysregulation was defined, which could facilitate their early and timely identification. The detection of these specific immune profiles before treatment, if confirmed in a larger patient population, could lead to the design of a personalized treatment approach fit to the peculiar characteristic of patient immune status, to improve outcomes and preventing avoidable irAEs

Standard of Care and Promising New Agents for the Treatment of Mesenchymal Triple-Negative Breast Cancer

The pathologic definition of triple negative breast cancer (TNBC) relies on the absence of expression of estrogen, progesterone and HER2 receptors. However, this BC subgroup is distinguished by a wide biological, molecular and clinical heterogeneity. Among the intrinsic TNBC subtypes, the mesenchymal type is defined by the expression of genes involved in the epithelial to mesenchymal transition, stromal interaction and cell motility. Moreover, it shows a high expression of genes involved in proliferation and an immune-suppressive microenvironment. Several molecular alterations along different pathways activated during carcinogenesis and tumor progression have been outlined and could be involved in immune evasion mechanisms. Furthermore, reverting epithelial to mesenchymal transition process could lead to the overcoming of immune-resistance. This paper reviews the current knowledge regarding the mesenchymal TNBC subtype and its response to conventional therapeutic strategies, as well as to some promising molecular target agents and immunotherapy. The final goal is a tailored combination of cytotoxic drugs, target agents and immunotherapy in order to restore immunocompetence in mesenchymal breast cancer patients