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The drugs activity at the target tissue could help to define the minimal effective dose to promote cancer preventive therapy. Here we present exemestane and sex hormone concentrations within breast tissue from a presurgical study of alternative exemestane schedules. Postmenopausal women candidates for breast surgery for estrogen receptor-positive breast cancer were randomly assigned to exemestane 25 mg once daily (QD), 25 mg 3 times/week (TIW), or 25 mg per week (QW) for 4-6 weeks before surgery. Drug and sex hormones were analyzed from homogenized frozen tissue using a QTRAP 6500+ LC-MS/MS System. Tissue drug concentrations were detectable only in the QD arm with higher concentrations in nonmalignant tissue. Estradiol was nearly suppressed in all groups in the nonmalignant tissue (QD vs TIW P = .364 and QD vs QW P = .693). In contrast, a dose-response trend was observed in cancer tissue. Based on estradiol suppression in nonmalignant tissue, lower exemestane schedules should be explored for breast cancer preventive therapy. Trial Registration: Clinical Trials.gov NCT02598557 and EudraCT 2015-005063-1.

PURPOSE: We investigated the effect of metformin and lifestyle intervention on metabolic, inflammatory, and steroid biomarkers of breast cancer (BC) recurrence risk in two intervention trials among BC survivors with overweight or obesity. METHODS: Baseline and follow-up serum samples collected during the two trials were analyzed and data pooled. The USA trial (Reach for Health) included postmenopausal BC survivors (n = 333) randomly assigned to 6-month metformin vs placebo and lifestyle intervention (LSI) vs control (2 × 2 factorial design). The Italian trial (MetBreCS) included BC survivors (n = 40) randomized to 12-month metformin vs placebo. Insulin resistance (HOMA-IR), adipokines, cytokines, and steroids were measured. RESULTS: Metformin compared to placebo showed a favorable decrease in leptin (- 8.8 vs - 3.5 ng/mL; p

Background: Up to now, endometrial cancer (EC) treatments are mainly represented by surgery followed by adjuvant chemotherapy or radiotherapy. The updated guidelines give a 2A recommendation for the use of hormone therapy only in advanced low-grade ECs, underlying the need for more data on the role of hormone therapy in the adjuvant setting. Methods: The clinicopathological data of 158 early-stage EC patients was retrospectively collected. A Ki-67 cut-off value of 40% was established based on literature data. Disease-free survival (DFS) and Overall survival (OS) were evaluated. Results: Results: Multivariate analysis of DFS and OS showed a significantly increased risk of progression in patients with >40% Ki-67 [HR = 3.13 (95% CI; 1.35–7.14); p = 0.007] and a significantly higher relative risk of death [HR = 3.70 (95% CI; 1.69–8.33); p = 0.001]. The predictive role of the Ki-67 index was highlighted by the clinical benefit of adjuvant hormone in patients with high Ki-67. Conclusions: Our results suggest a positive role of the Ki-67 index as a prognostic and potentially predictive marker in EC, although further studies are warranted to reach a definitive conclusion.

Background: Serum biomarkers have been investigated as predictive risk factors for cancer-related cardiovascular (CV) risk, but their analysis is limited to their baseline level rather than their overtime change. Besides historically validated causal factors, inflammatory and oxidative stress (OS) related markers seem to be correlated to CV events but this association needs to be further explored. We conducted an observational study to determine the predictive role of the longitudinal changes of commonly used and OS-related biomarkers during the cancer treatment period. Methods: Patients undergoing anticancer therapies, either aged 75+ years old or younger with an increased CV risk according to European Society of Cardiology guidelines, were enrolled. We assessed the predictive value of biomarkers for the onset of CV events at baseline and during therapy using Cox model, Subpopulation Treatment-Effect Pattern Plot (STEPP) method and repeated measures analysis of longitudinal data. Results: From April 2018 to August 2021, 182 subjects were enrolled, of whom 168 were evaluable. Twenty-eight CV events were recorded after a median follow up of 9.2 months (Interquartile range, IQR: 5.1–14.7). Fibrinogen and troponin levels were independent risk factors for CV events. Specifically, patients with higher than the median levels of fibrinogen and troponin at baseline had higher risk compared with patients with values below the medians, hazard ratio (HR) = 3.95, 95% CI, 1.25–12.45 and HR = 2.48, 0.67–9.25, respectively. STEPP analysis applied to Cox model showed that cumulative event-free survival at 18 and 24 months worsened almost linearly as median values of fibrinogen increased. Repeated measure analysis showed an increase over time of D-Dimer (p-interaction event*time = 0.08), systolic (p = 0.07) and diastolic (p = 0.05) blood pressure and a decrease of left ventricular ejection fraction (p = 0.15) for subjects who experienced a CV event. Conclusions: Higher levels of fibrinogen and troponin at baseline and an increase over time of D-Dimer and blood pressure are associated to a higher risk of CV events in patients undergoing anticancer therapies. The role of OS in fibrinogen increase and the longitudinal monitoring of D-dimer and blood pressure levels should be further assessed.

Simple Summary: This study aimed to address an urgent issue: about 20% of cancer patients undergoing treatment do not respond adequately to the standard two-dose COVID-19 vaccination. This highlights the need to identify factors influencing vaccine efficacy in this vulnerable group, including psychological conditions such as distress, anxiety, and depression. The primary objectives were to determine whether these psychological factors, along with clinical variables such as metastatic stage and smoking, influenced antibody response and vaccine activation six months post-vaccination. This study also examined changes in psychological distress over time in relation to gender and education. The results showed that 14.2% of patients did not achieve an antibody response at six months, with high distress and metastatic cancer as significant predictors of non-response (OR = 2.46, p = 0.04). These findings suggest that integrating distress management strategies into oncology care could enhance vaccine response, supporting improved health outcomes for cancer patients. Background/Objectives: Our previous study of 291 cancer patients, we showed that 20% did not respond to two doses of COVID-19 vaccine administered six weeks apart. Methods: Here, we investigated if psychological factors (distress, anxiety, and depressive symptoms) affected antibody response and markers of vaccine activation (D-dimer) after 6 months from initial vaccination. Results: Overall, 31 subjects (14.2%) had no antibody response at 6 months. Our analysis revealed significant predictors of vaccine failure, including the stage of metastatic disease and high-stress levels (OR = 2.46, 95% CI, 1.05–5.77, p = 0.04). Notably, nonresponders showed twice the prevalence of distress than responders (21% vs. 10%, p = 0.04). Longitudinal measurements of IgG levels indicated that participants with high depressive symptoms at baseline maintained lower antibody levels over six months (p = 0.003). In addition, women with high anxiety showed reduced levels of D-dimer at 6 months (p = 0.03). These data also showed that smokers and former smokers had significantly lower antibody levels than their nonsmoking counterparts (p = 0.0004). At baseline, the high discomfort rate (≥5) was 34.4% in women and 23.8% in men; only men experienced an increase in median discomfort during the observation period. Moreover, a higher educational level was related to increased distress among women (p = 0.046). Conclusions: These findings underscore a critical association between elevated psychological distress and reduced immune responses to the COVID-19 vaccine, emphasizing the urgent need for targeted psychological and behavioral support within this vulnerable population. [ABSTRACT FROM AUTHOR]

Despite recent advances in ovarian cancer (OC) treatment, including the introduction of bevacizumab and PARP-inhibitors, OC remains a lethal disease. Other therapeutic options are being explored, such as immunotherapy (IT), which has been proved effective in many solid tumors. Findings about tumor-infiltrating cytotoxic and regulatory T cells, together with the expression of PD-1 on immune cells and of PD-L1 on tumor cells, gave the rationale for an attempt to the use of IT also in OC. We treated two patients with avelumab, an anti-PD-L1 monoclonal antibody, after the first line of chemotherapy: Patient A underwent 19 cycles of maintenance therapy with avelumab with a disease-free interval of 12 months, whereas patient B showed a slight progression of disease after only eight cycles. A higher PD-L1 expression in tumor cells of patient A was detected. She also underwent a genomic assessment that described the presence of a high Tumor Mutational Burden (TMB) and a status of Loss of Heterozygosity (LoH). This different response to the same treatment puts in evidence that some genomic and immune features might be investigated.

Until recently endometrial cancer has classically been divided into two categories, type 1 estrogen-dependent and predominantly endometrioid and type 2 estrogen-independent and predominantly serous, according to etiological and morphological factors. The advent of molecular oncology has led to a new classification based on cancer mutational features centered on the analysis of p53, POLE and the microsatellite status. These new findings have provided the rationale for endometrial cancer to benefit from immunotherapy as well. Here, we describe the case of a patient with advanced recurrent endometrial cancer and microsatellite instability who obtained a durable complete remission with Pembrolizumab even if she developed immune-related interstitial pneumonitis. Therefore, due to its remarkable efficacy, immunotherapy is a reasonable therapeutic option for pretreated endometrial cancer patients; nonetheless,careful surveillance during therapy is necessary for the risk of developing severe immune-related adverse events.

Background: Breast Cancer (BC) prevention strategies range from lifestyle changes such as increasing physical activity and reducing body weight to preventive drugs like tamoxifen, known to reduce BC incidence in high-risk women. Sex Hormone Binding Globulin (SHBG) is related to BC risk due to its ability to bind circulating estradiol at high affinity and to regulate estradiol action. A study protocol is presented based on the assessment of the effect of different interventions such as tamoxifen at 10 mg every other day (LDT), intermittent caloric restriction (ICR) two days per week, lifestyle intervention (LI, step counter use) and their combination on the modulation of SHBG and several other biomarkers associated to BC. Methods: A randomized phase II biomarker study will be conducted in 4 Italian centers. Unaffected women aged between 18 and 70 years, carriers of a germline pathogenetic variant (BRCA1, BRCA2, PALB2, or other moderate penetrance genes), or with a >5% BC risk at 10 years (according to the Tyrer-Cuzick or the Breast Cancer Surveillance Consortium Risk models) or with a previous diagnosis of intraepithelial neoplasia will be eligible. A total of 200 participants will be randomized to one of the four arms: LDT; LDT + ICR; LI; LI + ICR. Interventions will span six months, with baseline and follow-up clinic visits and interim phone calls. Discussion: The aim of the study is to verify whether LDT increases circulating SHBG more than LI with or without ICR after 6 months. Secondary objectives include assessing HOMA-index, inflammatory markers, adiponectin/leptin ratio, quality of life (QoL), safety, toxicity, mammographic density, and changes in microbiome composition across groups. The study's innovation lies in its inclusion of diverse BC risk categories and combination of pharmaceutical and behavioral interventions, potentially enhancing intervention efficacy while balancing tamoxifen's side effects on QoL, especially menopausal symptoms. Trial registration: EuCT number:2023-503994-39-00; Clinical trials.gov NCT06033092. [ABSTRACT FROM AUTHOR]

Abstract Low-dose tamoxifen halves recurrence in non-invasive breast cancer without significant adverse events. Some adjuvant trials with tamoxifen 20 mg/day had shown an association between low endoxifen levels (9–16 nM) and recurrence, but no association with CYP2D6 was shown in the NSABP P1 and P2 prevention trials. We studied the association of CYP2D6 genotype and tamoxifen metabolites with tumor biomarkers and recurrence in a randomized phase III trial of low-dose tamoxifen. Median (IQR) endoxifen levels at year 1 were 8.4 (5.3–11.4) in patients who recurred vs 7.5 (5.1–10.2) in those who did not recur (p = 0.60). Tamoxifen and metabolites significantly decreased C-reactive protein (CRP, p

BackgroundA previously carried out randomized phase IIb, placebo-controlled trial of 1 year of inhaled budesonide, which was nested in a lung cancer screening study, showed that non-solid and partially solid lung nodules detected by low-dose computed tomography (LDCT), and not immediately suspicious for lung cancer, tended to regress. Because some of these nodules may be slow-growing adenocarcinoma precursors, we evaluated long-term outcomes (after stopping the 1-year intervention) by annual LDCT.Patients and methodsWe analyzed the evolution of target and non-target trial nodules detected by LDCT in the budesonide and placebo arms up to 5 years after randomization. The numbers and characteristics of lung cancers diagnosed during follow-up were also analyzed.ResultsThe mean maximum diameter of non-solid nodules reduced significantly (from 5.03 mm at baseline to 2.61 mm after 5 years) in the budesonide arm; there was no significant size change in the placebo arm. The mean diameter of partially solid lesions also decreased significantly, but only by 0.69 mm. The size of solid nodules did not change. Neither the number of new lesions nor the number of lung cancers differed in the two arms.ConclusionsInhaled budesonide given for 1 year significantly decreased the size of non-solid nodules detected by screening LDCT after 5 years. This is of potential importance since some of these nodules may progress slowly to adenocarcinoma. However, further studies are required to assess clinical implications.Clinical trial numberNCT01540552.

Obesity is a risk factor for postmenopausal breast cancer (BC), and evidence suggests a role for adiponectin in the relationship between obesity and BC. We investigated whether adiponectin or other biomarkers mediate the effect of body mass index (BMI) on postmenopausal BC risk in a cohort study nested in the IBIS-II Prevention Trial. We measured adiponectin, leptin, IGF-I, IGFBP-1, high-sensitivity C-reactive protein, glycemia, insulin, HOMA-IR index, and SHBG in baseline and 12-month serum samples from 123 cases and 302 matched controls in the placebo arm of the IBIS-II Prevention trial. We conducted the main mediation analysis considering baseline BMI as an exposure and the 12-month adiponectin increase as a mediator after adjustment for the Tyrer–Cuzick score and the lipid-lowering medications/supplements use. In the multivariable Cox model, both the 12-month adiponectin increase (HR, 0.60; 95%CI, 0.36–1.00) and BMI were associated with BC risk (HR, 1.05; 95%CI, 1.00–1.09), with a 40% reduction in women with a 12-month increase in adiponectin. A significantly higher cumulative hazard of BC events was observed in obese women (BMI > 30) with decreased adiponectin (p = 0.0087). No mediating effect of the adiponectin increase on the total effect of BMI on BC risk was observed (natural indirect effect: HR, 1.00; 95%CI, 0.98–1.02). Raising adiponectin levels might be an attractive target for postmenopausal BC prevention. [ABSTRACT FROM AUTHOR]

Human Natural Killer (NK) cells are all round players in immunity thanks to their powerful and immediate response against transformed cells and the ability to modulate the subsequent adaptive immune response. The potential of immunotherapies based on NK cell involvement has been initially revealed in the hematological setting but has inspired the design of different immune tools to also be applied against solid tumors, including colorectal cancer (CRC). Indeed, despite cancer prevention screening plans, surgery, and chemotherapy strategies, CRC is one of the most widespread cancers and with the highest mortality rate. Therefore, further efficient and complementary immune-based therapies are in urgent need. In this review, we gathered the most recent advances in NK cell-based immunotherapies aimed at fighting CRC, in particular, the use of monoclonal antibodies targeting tumor-associated antigens (TAAs), immune checkpoint blockade, and adoptive NK cell therapy, including NK cells modified with chimeric antigen receptor (CAR-NK).

BackgroundTamoxifen and raloxifene reduce the risk of breast cancer in women at elevated risk of disease, but the duration of the effect is unknown. We assessed the effectiveness of selective oestrogen receptor modulators (SERMs) on breast cancer incidence.MethodsWe did a meta-analysis with individual participant data from nine prevention trials comparing four selective oestrogen receptor modulators (SERMs; tamoxifen, raloxifene, arzoxifene, and lasofoxifene) with placebo, or in one study with tamoxifen. Our primary endpoint was incidence of all breast cancer (including ductal carcinoma in situ) during a 10 year follow-up period. Analysis was by intention to treat.ResultsWe analysed data for 83,399 women with 306,617 women-years of follow-up. Median follow-up was 65 months (IQR 54-93). Overall, we noted a 38% reduction (hazard ratio [HR] 0·62, 95% CI 0·56-0·69) in breast cancer incidence, and 42 women would need to be treated to prevent one breast cancer event in the first 10 years of follow-up. The reduction was larger in the first 5 years of follow-up than in years 5-10 (42%, HR 0·58, 0·51-0·66; p

Abstract Background Epidemiological studies and cardiovascular prevention trials have shown that low-dose aspirin can reduce colorectal cancer (CRC) incidence and mortality, including inhibition of distant metastases. Metformin has also been associated with decreased colon adenoma recurrence in clinical trials and lower CRC incidence and mortality in epidemiological studies in diabetics. While both drugs have been tested as single agents, their combination has not been tested in cancer prevention trials. Methods/design This is a randomized, placebo-controlled, double-blind, 2 × 2 biomarker trial of aspirin and metformin to test the activity of either agent alone and the potential synergism of their combination on a set of surrogate biomarkers of colorectal carcinogenesis. After surgery, 160 patients with stage I-III CRC are randomly assigned in a four-arm trial to either aspirin (100 mg day), metformin (850 mg bis in die), their combination, or placebo for one year. The primary endpoint biomarker is the change of IHC expression of nuclear factor kappa-B (NFκB) in the unaffected mucosa of proximal and distal colon obtained by multiple biopsies in two paired colonoscopies one year apart. Additional biomarkers will include: 1) the measurement of circulating IL-6, CRP and VEGF; 2) the IHC expression of tissue pS6K, p53, beta-catenin, PI3K; 3) the associations of genetic markers with treatment response as assessed by next generation sequencing of primary tumors; 4) the genomic profile of candidate genes, pathways, and overall genomic patterns in tissue biopsies by genome wide gene expression arrays; and 5) the evaluation of adenoma occurrence at 1 year. Discussion A favorable biomarker modulation by aspirin and metformin may provide important clues for a subsequent phase III adjuvant trial aimed at preventing second primary cancer, delaying recurrence and improving prognosis in patients with CRC. Trial registration EudraCT Number: 2015–004824-77; ClinicalTrial.gov Identifier: NCT03047837. Registered on February 1, 2017.

Background and Objectives: 18F-fluorodeoxyglucose (FDG) positron emission tomography/X-ray computed tomography (PET/CT) represents the mainstay diagnostic procedure for suspected ovarian cancer (OC) recurrence. PET/CT can be integrated with contrast medium and in various diagnostic settings; however, the effective benefit of this procedure is still debated. We aimed to compare the diagnostic capabilities of low-dose and contrast-enhanced PET/CT (PET/ldCT and PET/ceCT) in patients with suspected ovarian cancer relapse. Materials and Methods: 122 OC patients underwent both PET/ldCT and PET/ceCT. Two groups of nuclear medicine physicians and radiologists scored the findings as positive or negative. Clinical/radiological follow-up was used as ground truth. Sensitivity, specificity, negative/positive predictive value, and accuracy were calculated at the patient and the lesion level. Results: A total of 455 and 474 lesions were identified at PET/ldCT and PET/ceCT, respectively. At the lesion level, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were not significantly different between PET/ldCT and PET/ceCT (98%, 93.3%, 97.4%, 94.9%, and 96.9% for PET/ldCT; 99%, 95.5%, 98.3%, 97%, and 98% for PET/ceCT, p = ns). At the patient level, no significant differences in these parameters were identified (e.g., p = 0.22 and p = 0.35 for accuracy, in the peritoneum and lymph nodes, respectively). Smaller peritoneal/lymph node lesions close to physiological FDG uptake sources were found in the cases of misidentification by PET/ldCT. PET/ceCT prompted a change in clinical management in four cases (3.2%) compared to PET/ldCT. Conclusions: PET/ceCT does not perform better than PET/ldCT but can occasionally clarify doubtful peritoneal findings on PET/ldCT. To avoid unnecessary dose to the patient, PET/ceCT should be excluded in selected cases.

Background: Up to now, endometrial cancer (EC) treatments are mainly represented by surgery followed by adjuvant chemotherapy or radiotherapy. The updated guidelines give a 2A recommendation for the use of hormone therapy only in advanced low-grade ECs, underlying the need for more data on the role of hormone therapy in the adjuvant setting. Methods: The clinicopathological data of 158 early-stage EC patients was retrospectively collected. A Ki-67 cut-off value of 40% was established based on literature data. Disease-free survival (DFS) and Overall survival (OS) were evaluated. Results: Results: Multivariate analysis of DFS and OS showed a significantly increased risk of progression in patients with >40% Ki-67 [HR = 3.13 (95% CI; 1.35–7.14); p = 0.007] and a significantly higher relative risk of death [HR = 3.70 (95% CI; 1.69–8.33); p = 0.001]. The predictive role of the Ki-67 index was highlighted by the clinical benefit of adjuvant hormone in patients with high Ki-67. Conclusions: Our results suggest a positive role of the Ki-67 index as a prognostic and potentially predictive marker in EC, although further studies are warranted to reach a definitive conclusion. [ABSTRACT FROM AUTHOR]