Circulating Osteopontin Predicts Clinical and Radiological Response in First-Line Treatment of Advanced Non-Small Cell Lung Cancer.

PURPOSE: Pembrolizumab-based regimens are conditioned by the expression of PD-L1, but durable response rate is limited by innate and acquired resistance mechanisms. Here, we focus on osteopontin (OPN), an upfront biomarker of senescence, which closely associated with natural history of non-small cell lung cancer (NSCLC). METHODS: Seventy-nine patients eligible to pembrolizumab regimens-alone or in combination with chemotherapy-as first-line treatment of advanced NSCLC were enrolled. Predictive value of OPN toward iRECIST progression disease (PD) was set as first outcome. Secondary ones included performance status (ECOG) at baseline, early (first and best) responses, and overall survival (OS). RESULTS: High Serum OPN characterized patients with worse ECOG-PS (p = 0.015) at baseline and subjects experienced PD/death at first (OR 1.17 [1.02 to 1.35]; p = 0.030) and best responses (0.04 [0.00 to 0.81]; p = 0.035). OPN was associated with time-to-progression (B -2.74 [-4.46 to -1.01]) and time-to death (-0.13 [-0.20 to -0.05]). Cox regression models unveil a predictive value for iRECIST-PD (HR 1.01 [1.00 to 1.02]; p = -0.005), RECIST-PD (HR 1.01 [1.00 to 1.02]; p = 0.017), and OS (HR 1.02 [1.01 to 1.03]; p = 0.001). These models were internally validated through bootstrap resampling and characterized by relevant discrimination ability at ROC curve analyses. CONCLUSION: Baseline levels of serum OPN is closely associated with performance status and short/long term outcomes in patients with advanced NSCLC, which are candidate to pembrolizumab-based regimens. As upfront biomarker of senescence, OPN may pave the way for future studies focusing on senescence patterns in NSCLC.

Diagnosis of lung cancer following emergency admission: Examining care pathways, clinical outcomes, and advanced NSCLC treatment in an Italian cancer Center.

Background: Lung cancer patients diagnosed following emergency admission often present with advanced disease and poor performance status, leading to suboptimal treatment options and outcomes. This study aimed to investigate the clinical and molecular characteristics, treatment initiation, and survival outcomes of these patients. Methods: We retrospectively analyzed data from 124 patients diagnosed with lung cancer following emergency admission at a single institution. Clinical characteristics, results of molecular analyses for therapeutic purpose, systemic treatment initiation, and survival outcomes were assessed. Correlations between patients' characteristics and treatment initiation were analyzed. Results: Median age at admission was 73 years, and 79.0 % had at least one comorbidity. Most patients (87.1 %) were admitted due to cancer-related symptoms. Molecular analyses were performed in 89.5 % of advanced non-small cell lung cancer (NSCLC) cases. In this subgroup, two-thirds (66.2 %) received first-line therapy. Median overall survival (OS) was 3.9 months for the entire cohort, and 2.9 months for patients with metastatic lung cancer. Among patients with advanced NSCLC, OS was significantly longer for those with actionable oncogenic drivers and those who received first-line therapy. Improvement of performance status during hospitalization resulted in increased probability of receiving first-line systemic therapy. Discussion: Patients diagnosed with lung cancer following emergency admission demonstrated poor survival outcomes. Treatment initiation, particularly for patients with actionable oncogenic drivers, was associated with longer OS. These findings highlight the need for proactive medical approaches, including improving access to molecular diagnostics and targeted treatments, to optimize outcomes in this patient population.

Immune Checkpoint Blockade: A Strategy to Unleash the Potential of Natural Killer Cells in the Anti-Cancer Therapy.

Immune checkpoint inhibitors (ICIs) immunotherapy has represented a breakthrough in cancer treatment. Clinical use of ICIs has shown an acceptable safety profile and promising antitumor activity. Nevertheless, some patients do not obtain clinical benefits after ICIs therapy. In order to improve and cure an increasing number of patients, the field has moved toward the discovery of new ICIs expressed by cells of innate immunity with an elevated inherent antitumor activity, such as natural killer cells. This review will focus on the recent findings concerning the role of classical and non-classical immune checkpoint molecules and receptors that regulate natural killer cell function, as potential targets, and their future clinical application.

Immunotherapy-chemotherapy combinations for non-small cell lung cancer: current trends and future perspectives.

INTRODUCTION: In recent years, immunotherapy has become a pillar in the treatment of advanced, non-oncogene-addicted non-small cell lung cancer (NSCLC). Programmed death ligand 1 (PD-L1) expression is currently the only factor used to predict response to immunotherapy in clinical practice. Specifically, single-agent pembrolizumab as first-line therapy is approved for tumors with high expression of PD-L1 (≥50%) while immunotherapy and chemotherapy are approved for any PD-L1. However, combinations of immune-checkpoint inhibitors (ICIs) and other agents may confer higher benefit than immunotherapy alone in some circumstances. AREAS COVERED: We reviewed the available data regarding the combined use of ICIs and chemotherapy in patients with advanced, treatment-naïve NSCLC. In light of the benefit demonstrated in advanced disease, these combinations have been subsequently tested in other settings. We collected the most relevant findings regarding efficacy and safety of chemo-immunotherapy combinations in early and locally advanced NSCLC. EXPERT OPINION: Immune-chemotherapy combinations demonstrated benefit in the advanced setting, and this strategy in now being applied in the early and local advanced settings. A description of clinical and biological predictors of response is required in order to identify patients who may benefit the most from combination therapy.

Epidemiological Characteristics and Survival in Patients with De Novo Metastatic Prostate Cancer.

The real-world outcomes of patients with metastatic prostate cancer (mPCa) are largely unexplored. We investigated the trends in overall survival (OS) and cancer-specific survival (CSS) in patients with de novo mPCa according to distinct time periods. The U.S. Surveillance, Epidemiology, and End Results (SEER) Research Data (2000-2017) were analyzed using the SEER*Stat software. The Kaplan-Meier method and Cox regression were used. Patients with de novo mPCa were allocated to three cohorts based on the year of diagnosis: A (2000-2003), B (2004-2010), and C (2011-2014). The maximum follow-up was fixed to 5 years. Overall, 26,434 patients were included. Age, race, and metastatic stage (M1) significantly affected OS and CSS. After adjustment for age and race, patients in Cohort C showed a 9% reduced risk of death (hazard ratio (HR): 0.91 (95% confidence interval [CI] 0.87-0.95), p < 0.001) and an 8% reduced risk of cancer-specific death (HR: 0.92 (95% CI 0.88-0.96), p < 0.001) compared with those in Cohort A. After adjustment for age, race, and metastatic stage, patients in Cohort C showed an improvement in OS and CSS compared with Cohort B (HR: 0.94 (95% CI 0.91-0.97), p = 0.001; HR: 0.89 (95% CI 0.85-0.92), p < 0.001). Patients with M1c disease had a more pronounced improvement in OS and CSS compared with the other stages. No differences were found between Cohorts B and C. In conclusion, the real-world survival of de novo mPCa remains poor, with a median OS and CSS improvement of only 4 months in the latest years.

Insights from a Long-Term Follow-Up Evaluation of Early Breast Cancer Outcomes by Tumor Subtype.

INTRODUCTION: Our understanding of the granularity of breast cancer (BC) clinical outcomes by biologic subtype may be impaired by limited study follow-up times. OBJECTIVE: We evaluated the impact of modern immunohistochemistry (IHC)-based BC subtypes on long-term mortality. METHOD: We used a cohort of 200 women diagnosed with stage I-III BC in the period 1985-1990. Surgical samples underwent centralized pathology review. Multivariate models assessed associations of subtype with overall survival (OS) and BC-related survival (BCRS). RESULT: 42.0% women had luminal A-like, 32.5% luminal B-like/human epidermal growth factor receptor (HER)2-negative, 8.5% had HER2-positive, and 17.0% had triple-negative BC. 53.0% had tumor size (T) >2 cm and 47.5% had a positive nodal status (N). Over 18.7 years of median follow-up (range 0.3-32.0 years),140 deaths were recorded (75 BC-related). Median OS was longest for patients with luminal A-like tumors (21.2 years; 95% confidence interval [CI] 17.4-24.9]). The luminal B-like/HER2-negative subtype was significantly associated with worse BCRS (adjusted hazard ratio [HR] = 1.86; 95% CI 1.09-3.16). After multivariable analysis, T >2 cm (HR [vs. ≤2 cm] = 1.71 [95% CI 1.03-2.84]) and positive N (HR [vs. negative] = 2.19 [95% CI 1.03-4.65]) impacted BCRS. CONCLUSION: IHC-defined subtype will continue informing treatment algorithms for BC, until more precise tools like molecular profiling become widely available. Although confirmation in larger and adequately powered studies is warranted, modern surrogate subtype definitions produced a valid long-term prognostic stratification in this mature cohort.

Integrative Analysis of Periostin in Primary and Advanced Prostate Cancer.

Periostin (POSTN) is an extracellular matrix protein associated with tumor progression and shorter survival in prostate cancer (PCa). Here, we performed an integrative analysis of POSTN's role in patients with PCa. Clinical and POSTN data from large-scale datasets were analyzed. POSTN cutoffs were identified with X-Tile, and STRING was used for protein-protein interaction analysis. In a cohort of 48 patients with metastatic castration-resistant prostate cancer (mCRPC), we used the AdnaTest platform to isolate circulating tumor cells and extract POSTN mRNA. Plasma samples were also tested for POSTN protein expression by dot blot assay. Data from large-scale datasets did not reveal any association between POSTN genetic alterations and outcome. In primary tumors, we found a significant correlation between POSTN mRNA overexpression, worse baseline prognostic features, and shorter disease-free survival. POSTN was overexpressed in mCRPC and correlated with aggressive features. In our cohort of mCRPC patients, we found a positive correlation between POSTN plasma levels and androgen-receptor variant 7 positivity and an association with shorter overall survival. Our integrative analysis shows that POSTN is associated with poor clinical features and worse outcome in patients with PCa. Further studies are warranted to uncover the function of POSTN in PCa progression and to validate the prognostic significance of POSTN in mCRPC.

Role of Circulating Tumor Cells (CTC), Androgen Receptor Full Length (AR-FL) and Androgen Receptor Splice Variant 7 (AR-V7) in a Prospective Cohort of Castration-Resistant Metastatic Prostate Cancer Patients.

BACKGROUND: Circulating tumor cells (CTC), androgen receptor full-length (AR-FL), and androgen receptor splice variant 7 (AR-V7) are prognostic in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). AR-V7 seems to predict resistance to androgen-receptor signaling inhibitors (ARSi). METHODS: We assessed the association of CTC, AR-FL, and AR-V7 with prostate-specific antigen (PSA) response and overall survival (OS). We used a modified AdnaTest CTC-based AR-FL and AR-V7 mRNA assay. Chi-square test, Fisher Exact test, Kaplan-Meier method, log-rank test, Cox proportional hazards models were used as appropriate. RESULTS: We enrolled 39 mCRPC pts, of those 24 started a first-line treatment for mCRPC (1L subgroup) and 15 had received at least two lines for mCRPC (>2L subgroup). CTC, AR-FL, and AR-V7 were enriched in >2L compared to 1L subgroup. Detection of these biomarkers was associated with a lower percentage of biochemical responses. Only 1/7 AR-V7+ pts had a PSA response and received cabazitaxel. Median OS was 4.7 months (95% CI 0.6-8.9) in AR-V7+ pts and not reached in AR-V7- pts. AR-V7 was the only variable with prognostic significance in the Cox model. CONCLUSION: AR-V7, CTC, and AR-FL are associated with advanced mCRPC and AR-V7+ predicts for shorter OS.

Prognostic Variables in Patients With Non-metastatic Small-cell Neuroendocrine Carcinoma of the Bladder: A Population-Based Study.

BACKGROUND: Small-cell carcinoma of the bladder (SCCB) is a rare, highly aggressive, neoplasm. We retrospectively analyzed the Surveillance, Epidemiology, and End Results (SEER) database to investigate the impact of chemotherapy, surgery, and radiotherapy on overall survival (OS) of patients with non-metastatic SCCB. MATERIALS AND METHODS: The SEER Research Data (2000-2014) were reviewed using the SEER*Stat software. Patients with pure or mixed SCCB, T2-T4, any N, M0, and who received either surgery or radiotherapy with or without chemotherapy (neo-adjuvant, adjuvant, or perioperative treatment) were included. We used the Kaplan-Meier method and log-rank test for estimating survival. Cox proportional hazard regression was used to evaluate the prognostic variables. RESULTS: A total of 384 cases of SCCB were included in the study (T2, n = 204; T3/4, n = 180), of whom 233 (60.7%) were treated with surgery, whereas 151 (39.3%) received radiotherapy. The median OS was 21.0 months (95% confidence interval [CI], 16.7-25.3 months). Age, race, chemotherapy, type of local treatment, and T and N staging were identified as independent prognostic variables (P < .05). In multivariate analysis, chemotherapy (n = 264) was associated with significant better OS (adjusted hazard ratio [HR], 0.56; 95% CI, 0.42-0.74; P < .000). Patients who underwent surgery showed longer outcome compared with those treated with radiotherapy (adjusted HR, 0.62; 95% CI, 0.47-0.82; P = .001). However, only in the T2 subgroup did surgery (n = 92) retain a significant survival difference compared with radiotherapy (n = 112) (adjusted HR, 0.37; 95% CI, 0.24-0.57; P < .000). CONCLUSIONS: Surgery was associated with better outcome compared with radiotherapy in patients with T2 disease. Chemotherapy was associated with a longer survival in patients with non-metastatic SCCB.

Overexpression of Periostin in Tumor Biopsy Samples Is Associated With Prostate Cancer Phenotype and Clinical Outcome.

BACKGROUND: Overexpression of periostin (POSTN) is associated with prostate cancer (PCa) aggressiveness. We investigated the prognostic significance of POSTN expression in tumor biopsy samples of patients with PCa. METHODS: We scored POSTN expression by immunohistochemistry analysis on 215 PCa biopsy samples using an anti-POSTN-specific antibody. A total immunoreactive score (T-IRS) was calculated by adding the POSTN staining scores of stromal and epithelial tumor cells. Prostate-specific antigen (PSA) progression/recurrence-free survival (PFS), radiographic progression/recurrence-free survival (rPFS), and overall survival (OS) were the study end points. RESULTS: A total of 143 patients received therapy with radical attempt, whereas 72 had locally advanced or metastatic disease and received hormone therapy alone. Median T-IRS was 9 and 12 (range, 0-20), respectively (P = .001). Overall, we found a weak positive correlation of T-IRS with prebiopsy PSA levels (r = 0.166, P = .016) and Gleason score (r = 0.266, P < .000). T-IRS ≥ 8 independently predicted for shorter PSA-PFS and OS (hazard ratio [HR] [95% confidence interval (CI)] ≥ 8 versus < 8: 1.50 [1.06-2.14], P = .024 and 1.92 [1.20-3.07], P = .007, respectively). In the subgroup analysis, the association between T-IRS and patient outcome was retained in patients who received therapy with radical attempt (HR [95% CI] ≥ 8 vs. < 8: rPFS: 2.06 [1.18-3.58], P = .01; OS: 2.36 [1.24-4.50], P = .009) and in those with low to intermediate Gleason scores (HR [95% CI] ≥ 8 vs. < 8: PSA-PFS: 1.65 [1.06-2.59], P = .028; rPFS: 2.09 [1.14-3.87], P = .018; OS: 2.57 [1.31-5.04], P = .006). CONCLUSION: POSTN T-IRS on PCa biopsy samples independently predicted the risk of recurrence, progression, and death in patients with localized disease and in those with low to intermediate Gleason scores.

Abiraterone acetate and prednisone in the pre- and post-docetaxel setting for metastatic castration-resistant prostate cancer: a mono-institutional experience focused on cardiovascular events and their impact on clinical outcomes.

BACKGROUND: The aim of this work was to to evaluate the incidence and risk factors of adverse events (AEs), focusing on cardiovascular events (CVEs) and hypokalemia, in patients treated with abiraterone acetate (AA) and prednisone (PDN) outside clinical trials, and their association with survival outcomes. METHODS: This was a retrospective cohort study of 105 patients treated from 2011 to 2016. Incidence of AEs was descriptively summarized in the whole cohort and by subgroup (pre- versus post-docetaxel). Multivariable Cox proportional hazards models assessed factors associated with progression-free survival (PFS) and overall survival (OS). RESULTS: Overall, median PFS and OS were 14.9 and 24.6 months, respectively. Prostate-specific antigen (PSA) ⩾ 10 ng/ml (p = 0.007), Gleason Score >7 (p = 0.008), Eastern Cooperative Oncology Group (ECOG) performance status (PS)1-2 (p = 0.002), duration of androgen deprivation therapy (ADT) ⩽ 43.2 months (p = 0.01), and body mass index (BMI) > 25 (p = 0.03) were associated with worse PFS; presence of pain (p = 0.01), ECOG PS1-2 (p = 0.004), duration of ADT ⩽ 43.2 (p = 0.05), and BMI > 25 (p = 0.042) were associated with worse OS. Incidence of CVEs was as follows: hypertension 17.1%, fluid retention 4.8%, cardiac disorders 8.6%. 16.2% of patients developed hypokalemia. Age ⩾ 75 years was associated with higher probability of cardiac disorders (p = 0.001) and fluid retention (p = 0.03). CVEs did not impact on PFS or OS. Hypokalemia was associated with better median OS (p = 0.036). Similar associations were observed after stratification by subgroup. CONCLUSIONS: Median PFS and OS estimates and incidence of CVEs and hypokalemia in our series are consistent with those of pivotal trials of AA plus PDN, confirming the efficacy and safety of this regimen also in the real-world setting. Elderly patients have higher odds of developing/worsening CVEs. However, regardless of age, CVEs were not associated with worse outcomes. Treatment-related hypokalemia seemed to be associated with longer OS, albeit this finding needs confirmation within larger, prospective series.

Prognostic Value of Preoperative Serum Levels of Periostin (PN) in Early Breast Cancer (BCa).

PN is a secreted cell adhesion protein critical for carcinogenesis. Elevated serum levels of PN have been implicated as playing an important role in different types of cancer, and a few reports suggest a potential role as a prognostic marker. We evaluated the prognostic significance of preoperative serum PN concentration in patients with BCa receiving curative surgery. Enzyme-Linked Immunosorbent Assay (ELISA) was performed to determine the preoperative serum PN level in 182 patients. The correlations between serum PN concentration with clinical pathological features and PN expression in primary tumor samples were analyzed. The prognostic impact of serum PN levels with all-cause and BCa-specific mortality was also investigated. Appropriate statistics were used. Elevated serum PN levels were significantly associated with patient age (p = 0.005), adjuvant systemic therapy (p = 0.04) and progesterone receptor (PgR) status (p = 0.02). No correlation between PN preoperative serum levels and other clinical-pathological parameters, including either the epithelial or the stromal PN expression of primary tumor or the combination of the two, was found. Similarly, no association between serum PN levels and either all-cause or BCa-specific mortality was found. However, subgroup analysis revealed a correlation between higher PN serum levels and all-cause mortality in patients with node-negative disease (p = 0.05) and in those with a low PgR expression (p = 0.03). Higher levels of serum PN were also found to correlate with BCa-specific mortality in the subgroup of patients who did not receive any adjuvant systemic therapy (p = 0.04). Our findings suggest that PN was detectable in the serum of early BCa patients before surgery and increased base-line serum levels predicted worse long-term survival outcomes in specific subgroups of patients.

Periostin: a novel prognostic and therapeutic target for genitourinary cancer?

Many of the cellular abnormalities present in solid tumors are structural in nature and involve the proteins of the extracellular matrix (ECM). Periostin is a protein produced and secreted by the fibroblasts as a component of the ECM where it is involved in regulating intercellular adhesion. The expression of periostin has an important physiological role during embryogenesis and growth, namely at the level of bone, dental, and cardiac tissues. Many studies indicate that periostin plays an important role for tumor progression in various types of cancer, such as colon, lung, head and neck, breast, ovarian, and prostate. To the best of our knowledge, a limited number of studies have investigated periostin expression in urogenital cancer, such as prostate, bladder, penile, and renal cancer, and no studies were performed in testis cancer. In this review article, we summarize the most recent knowledge of periostin, its genetic and protein structure, and the role of the different isoforms identified and sequenced so far. In particular, we focus our attention on the role of this protein in genitourinary tumors, trying to emphasize the role not only as a possible prognostic marker, but also as a possible target for the development of future anticancer therapies.

Prognostic value of nuclear matrix protein expression in localized prostate cancer.

PURPOSE: The aim of the study was to correlate nuclear matrix (NM) protein expression profiles with the risk of PSA progression or death in early prostate cancer (PCa). METHODS: High-resolution two-dimensional gel electrophoresis (2D-PAGE) was used to identify tumor-associated NM proteins in the PCa specimens obtained from 94 patients. The association between the expression of each protein and the probability of PSA progression or death was studied through univariate analysis. Unsupervised hierarchical clustering analysis was then used to generate patient clusters showing comparable outcomes by including the proteins that were predictive at univariate analysis. PSA-free and overall survival curves relative to each cluster were constructed by means of the Kaplan-Meier method and curves compared by the log-rank test. Multi-parametric models were constructed according to Cox proportional hazard technique. RESULTS: After a median follow-up of 11.7 years (range, 6.5-16.2), 50 patients progressed and 22 died. Of the eight NM proteins identified through 2D-PAGE, proteins NM-6, NM-7 and NM-8 were confirmed to be individually associated with a higher risk of PSA progression at univariate analysis. Proteins NM-6 and NM-8 were also predictive of survival probability. Hierarchical clustering analysis of these proteins allowed to identify one cluster of tumors co-expressing the three proteins or proteins NM-6 and NM-8, characterized by a very poor outcome, suggesting a specific role for these proteins in PCa progression. The predictive value of this mini-signature in respect to PSA-free survival was confirmed by multivariate analysis. CONCLUSIONS: Changes in NM scaffolding are strongly associated with the clinical outcome of patients following radical prostatectomy.

Prognostic value of stromal and epithelial periostin expression in human prostate cancer: correlation with clinical pathological features and the risk of biochemical relapse or death.

BACKGROUND: The purpose of the present study was to evaluate the prognostic value of POSTN expression following prostatectomy. METHODS: Periostin (POSTN) expression in prostate cancer (PCa) and in normal specimens was evaluated in 90 patients by an immuno-reactive score(IRS) based on the intensity of immunostaining and on the quantity of stained cells. The t-test was applied to compare IRS values in cancer specimens to values in normal specimens. Pearson's test was used to correlate POSTN expression to clinical pathologic features. PSA progression-free and survival curves were constructed by the Kaplan-Meier method and compared using the log-rank test. Multi-parametric models were constructed according to the Cox technique adding all the covariates predicting for either PSA progression or death into the models after univariate analysis. RESULTS: Both stromal and epithelial POSTN expression were significantly increased in tumor tissues. In particular, we found stromal expression to be significantly higher than epithelial expression as compared to normal tissues (p<0.000 and p=0.001).A significant correlation between POSTN epithelial expression and extra-prostatic extension was found (p=0.03). While high stromal expression was significantly associated with shorter survival (p=0.008), a low epithelial score significantly correlated with shorter PSA-free survival (p=0.04), suggesting that POSTN plays an apparently opposing biological role depending on its compartmentalization.Regardless of the mechanism that is involved, patients showing both high stromal and low epithelial expression made up a subgroup with a very bleak prognosis. CONCLUSIONS: Although requiring further validation through larger studies, our findings show that POSTN might represent a novel prognostic marker for PCa.