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, 3 months vs. 19 months, HR 1.70, 95% CI 1.37–2.09, p < 0.0001; median OS, 4 months vs. 35 months, 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.

The recurrent genetic anomalies used to classify prostate cancer (PC) into distinct molecular subtypes have limited relevance for clinical practice. In consideration of WHO 2016 histological classification, which includes the introduction of Gleason Score 4 for patients with cribriform component and the definition of intraductal carcinoma as a new entity, a retrospective pilot study was conducted to investigate, by histological review, if there were any variations of Gleason Score and the incidence of intraductal carcinoma and cribriform pattern, intended as “phenotypic” markers of potentially lethal PC, among metastatic castration-sensitive PC (mCSPC) and metastatic castration-resistant PC (mCRPC) samples. Potentially predictive factors were also assessed. Among 125 cases, a variation in the Gleason Score was reported in 26% of cases. A cribriform (36%) or intraductal (2%) pattern was reported in a higher percentage. Of them, a primary Gleason pattern 4 was reported in 80% of cases. All patients with intraductal carcinoma present a BRCA2 mutation, also found in 80% of cases with a cribriform pattern. This pilot study documented some hypothesis-generating data, as the evaluation of de novo mCSPC and mCRPC as phenotypic/biologic model to be translated in clinical practice. A cribriform pattern/intraductal carcinoma might be a marker of potentially lethal PC. The high incidence of TP53 and BRCA2 mutations in de novo mCSPC may also have a therapeutic implication.

BackgroundTo quantify the effect of traditional prognostic factors [nodal status, estrogen-receptor (ER), progesterone-receptor (PR), human epidermal growth factor receptor 2 (HER2)] on long-term outcome of patients with early breast cancer (EBC), treated in clinical practice over a period of about twenty years.Results1198 consecutive patients were identified. Median DFS (disease-free survival): ER+/PR±/HER2−, 165 months (mo) if node-negative (N0) and 114mo if node-positive (N+) (p < 0.001); triple-negative (TN), 109mo if N0 and 65mo if N+ (p 0.144); ER+/PR±/HER2+ in patients not-treated with adjuvant trastuzumab (T−), not reached if N0 and 114mo if N+ (p 0.297); ER+/PR±/HER2+ in patients treated with trastuzumab (T+), 95mo if N0 and 85mo if N+ (p 0.615); ER−/PR−/HER2+ T−, not reached if N0 and 26mo if N+ (p 0.279); ER−/PR−/HER2+ T+, not reached if N0 and 66mo if N+ (p 0.014). Median OS (overall survival): ER+/ PR±/HER2−, 166mo if N0 and 144mo if N+ (p 0.028); TN, 158mo if N0 and 96mo if N+ (p 0.384); ER+/PR±/HER2+ T−, not reached if N0 and 157mo if N+ (p 0.475), ER+/PR±/HER2+ T+, not reached if N0 and 106mo if N+ (p 0.436); ER−/PR−/HER2+ T−, not reached if N0 and 34mo if N+ (p 0.273); ER−/PR−/HER2+ T+, not reached neither if N0 nor if N+ (p 0.094).Materials and MethodsDisease-free survival (DFS) and overall survival (OS) were evaluated according to tumor characteristics, based on information retrospectively retrieved from patients’ medical records.ConclusionsPathological tumor characteristics and nodal status still represent useful tools in treatment selection and follow-up decision making of EBC patients in clinical practice.

Purpose: BRAF mutations represents the main negative prognostic factor for metastatic colorectal cancer. Right-sided colon cancer (RCC) reported a higher prevalence of BRAF mutations than leftsided, hence the different response to anti-EGFR targeted therapy in first line setting. Methods: A retrospective study of RCC patients, with BRAF known mutation status, treated with chemotherapy (CT) from October 2008 to June 2019 in 5 Italian centers, was conducted. Results: We identified 207 advanced RCC patients: 20.3% BRAF-mutant and 79.7% BRAF wild-type (wt). BRAF-mutant cancers were more likely to be pT4 (50.0% v 25.7%, p=0.016), undifferentiated (71.4% v 44.0%, p=0.004), KRAS wt (90.5% v 38.2%, p<0.001) and MSI-H (41.7% v 16.2%, p= 0.019) tumors, with synchronous (52.4% v 31.5%, p=0.018) and peritoneal metastases ( 38.1% v 22.4%, p=0.003).Median overall survival (OS) was 16 vs 27 months in BRAF-mutant and BRAF wt (P = 0.020). In first line setting, BRAF-mutant showed a 2y OS of 80% in clinical trials, 32% in anti-VEGF, 14% in anti-EGFR and 0% in chemotherapy alone regimens (P = 0.009). BRAF-mutant patients demonstrated worse survival, regardless of targeted-therapy administered. However, survival difference was statistically significant in the anti-EGFR treated subgroup (16 v 28 months, P = 0.005 in BRAF mutant v BRAF wt, respectively). Conclusions: Our study demonstrated that BRAF status makes the difference in treatment's outcome. Therefore, the anti-EGFR should not to be excluded in all advanced RCC but considered on a case-by-case basis.