A Mediation Analysis of Obesity and Adiponectin Association with Postmenopausal Breast Cancer Risk: A Nested Cohort Study in the International Breast Cancer Intervention Study II (IBIS-II) Prevention Trial.

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.

Circulating tumor DNA-based assessment of molecular residual disease in non-metastatic melanoma.

In patients with resected non-metastatic melanoma, the liquid biopsy for the assessment of molecular residual disease (MRD) by circulating tumour DNA (ctDNA) represents a promising tool to stratify the risk and to monitor tumour evolution. However, its validation requires the demonstration of analytical validity, clinical validity and utility. Indeed, the development of sensitive and specific assays can optimize prognostication and eventually help clinicians to modulate adjuvant treatments, in order to improve clinical outcomes. Data about ctDNA-guided prognosis stratification is emerging, but clinical trials assessing ctDNA-guided therapeutic decisions are still ongoing. This review aims to depict the role of ctDNA-based MRD assessment in patients with non-metastatic melanoma and to provide a roadmap to face challenges for its introduction into clinical practice.

Effect of age on safety and efficacy of novel cancer drugs investigated in early-phase clinical trials.

BACKGROUND: Elderly patients are underrepresented in clinical trials, particularly in early-phase studies. Our study assessed the safety and efficacy of novel anti-cancer treatments investigated in early-phase clinical trials, comparing outcomes between younger and elderly patients. METHODS: This retrospective study analyzed data from patients enrolled in phase I/II trials at our center between January 2014 and April 2021. We evaluated clinicopathologic characteristics, toxicity, and clinical efficacy, categorizing patients into younger (≤ 65 years) and elderly (> 65 years) groups. RESULTS: 419 patients were included with a median age of 56 years. Among these, 107 (26 %) were older than 65 years. Predominant cancers included breast (48 %), lung (10 %), and melanoma (5 %). Patients were treated in 64 trials, predominantly receiving immunotherapy-based (47 %) or targeted therapy-based (45 %) treatment. Elderly presented with poorer ECOG performance status (P = 0.001) and had fewer prior therapy lines (P = 0.01) than younger patients. Grade ≥ 3 adverse events (AEs) were similar across age groups (31 % younger vs 33 % elderly; P = 0.7), including in combination therapy scenarios. However, elderly patients experienced more AEs with antibody-drug conjugates compared to younger counterparts (56 % vs 14 %, P = 0.036) and were more likely to discontinue treatment due to toxicity (15 % vs 7 %; P = 0.011). No significant age-related differences in response rates and survival outcomes were observed across treatment modalities, except for immunotherapy-based regimens for which elderly patients exhibited higher response rates, disease control rates, and prolonged progression-free survival. CONCLUSIONS: Our findings suggest that elderly exhibit comparable safety and efficacy outcomes to younger patients in early-phase clinical trials for new cancer drugs. This underscores the importance of including elderly patients in phase I/II trials to ensure the generalizability of study results and mitigate age-related disparities in cancer treatment access.

Post-operative intensity-modulated vs 3D conformal radiotherapy after conservative surgery for laryngeal tumours of the supraglottic region: a dosimetric analysis on 20 patients.

Objective: To perform a dosimetric comparison between intensity modulated radiotherapy (IMRT) and 3D conformal radiotherapy in patients with locally advanced (stage III and IV) tumours of the supraglottic region treated with conservative surgery and post-operative radiotherapy. Methods: An in-silico plan using a 3D conformal shrinking field technique was retrospectively produced for 20 patients and compared with actually delivered IMRT plans. Eighteen structures (arytenoids, constrictor muscles, base of tongue, floor of mouth, pharyngeal axis, oral cavity, submandibular glands and muscles of the swallowing functional units [SFU]) were considered. Results: IMRT allowed a reduction of maximum and mean doses to 9 and 14 structures, respectively (p < .05). Conclusions: IMRT achieved a reduction of unnecessary dose to the remnant larynx and the majority of surrounding SFUs. Further prospective analyses and correlations with functional clinical outcomes are required to confirm these dosimetric findings.

Delphi consensus on stereotactic ablative radiotherapy for oligometastatic and oligoprogressive renal cell carcinoma-a European Society for Radiotherapy and Oncology study endorsed by the European Association of Urology.

The purpose of this European Society for Radiotherapy and Oncology (ESTRO) project, endorsed by the European Association of Urology, is to explore expert opinion on the management of patients with oligometastatic and oligoprogressive renal cell carcinoma by means of stereotactic ablative radiotherapy (SABR) on extracranial metastases, with the aim of developing consensus recommendations for patient selection, treatment doses, and concurrent systemic therapy. A questionnaire on SABR in oligometastatic renal cell carcinoma was prepared by a core group and reviewed by a panel of ten prominent experts in the field. The Delphi consensus methodology was applied, sending three rounds of questionnaires to clinicians identified as key opinion leaders in the field. At the end of the third round, participants were able to find consensus on eight of the 37 questions. Specifically, panellists agreed to apply no restrictions regarding age (25 [100%) of 25) and primary renal cell carcinoma histology (23 [92%] of 25) for SABR candidates, on the upper threshold of three lesions to offer ablative treatment in patients with oligoprogression, and on the concomitant administration of immune checkpoint inhibitor. SABR was indicated as the treatment modality of choice for renal cell carcinoma bone oligometatasis (20 [80%] of 25) and for adrenal oligometastases 22 (88%). No consensus or major agreement was reached regarding the appropriate schedule, but the majority of the poll (54%-58%) retained the every-other-day schedule as the optimal choice for all the investigated sites. The current ESTRO Delphi consensus might provide useful direction for the application of SABR in oligometastatic renal cell carcinoma and highlight the key areas of ongoing debate, perhaps directing future research efforts to close knowledge gaps.

Prognostic Value of PCSK9 Levels in Premenopausal Women at Risk of Breast Cancer-Evidence from a 17-Year Follow-Up Study.

BACKGROUND AND AIM: The involvement of cholesterol in cancer development remains a topic of debate, and its association with breast cancer has yet to be consistently demonstrated. Considering that circulating cholesterol levels depend on several concomitant processes, we tested the liability of plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of cholesterol levels, as a prognostic biomarker in the context of breast neoplastic events. METHODS: Within a prospective randomized breast cancer prevention trial we measured baseline plasma levels of PCSK9. A total of 235 at-risk premenopausal women were randomized and followed up for 17 years. Participants enrolled in this placebo-controlled, phase II, double-blind trial were randomly assigned to receive either tamoxifen 5 mg/d or fenretinide 200 mg/d, both agents, or placebo for 2 years. The associations with breast cancer events were evaluated through competing risk and Cox regression survival models, adjusted for randomization strata (5-year Gail risk ≥ 1.3% vs. intraepithelial neoplasia or small invasive breast cancer of favorable prognosis), age, and treatment allocation. PCSK9 associations with biomarkers linked to breast cancer risk were assessed on blood samples collected at baseline. RESULTS: The plasmatic PCSK9 median and interquartile range were 207 ng/mL and 170-252 ng/mL, respectively. Over a median follow-up period of 17 years and 89 breast neoplastic events, disease-free survival curves showed a hazard ratio of 1.002 (95% CI: 0.999-1.005, p = 0.22) for women with PCSK9 plasma levels ≥ 207 ng/mL compared to women with levels below 207 ng/mL. No differences between randomization strata were observed. We found a negative correlation between PCSK9 and estradiol (r = -0.305), maintained even after partial adjustment for BMI and age (r = -0.287). Cholesterol (r = 0.266), LDL-C (r = 0.207), non-HDL-C (r = 0.246), remnant cholesterol (r = 0.233), and triglycerides (r = 0.233) also correlated with PCSK9. CONCLUSIONS: In premenopausal women at risk of early-stage breast cancer, PCSK9 did not appear to have a role as a prognostic biomarker of breast neoplastic events. Larger studies are warranted investigating patients in different settings.

CDH1 Genotype Exploration in Women With Hereditary Lobular Breast Cancer Phenotype.

Importance: Pathogenic or likely pathogenic (P/LP) germline CDH1 variants are associated with risk for diffuse gastric cancer and lobular breast cancer (LBC) in the so-called hereditary diffuse gastric cancer (HDGC) syndrome. However, in some circumstances, LBC can be the first manifestation of this syndrome in the absence of diffuse gastric cancer manifestation. Objectives: To evaluate the frequency of germline CDH1 variants in women with the hereditary LBC (HLBC) phenotype, somatic CDH1 gene inactivation in germline CDH1 variant carriers' tumor samples, and the association of genetic profiles with clinical-pathological data and survival. Design, Setting, and Participants: This single-center, longitudinal, prospective cohort study was conducted from January 1, 1997, to December 31, 2021, with follow-up until January 31, 2023. Women with LBC seen at the European Institute of Oncology were included. Testing for germline CDH1, BRCA1, and BRCA2 genes was performed. Somatic profiling was assessed for germline CDH1 carriers. Main Outcomes and Measures: Accurate estimates of prevalence of germline CDH1 variants among patients with HLBC and the association of somatic sequence alteration with HLBC syndrome. The Kaplan-Meier method and a multivariable Cox proportional hazards regression model were applied for overall and disease-free survival analysis. Results: Of 5429 cases of primary LBC, familial LBC phenotype accounted for 1867 (34.4%). A total of 394 women with LBC were tested, among whom 15 germline CDH1 variants in 15 unrelated families were identified. Among these variants, 6 (40.0%) were P/LP, with an overall frequency of 1.5% (6 of 394). Of the 6 probands with P/LP CDH1 LBC, 5 (83.3%) had a positive family history of BC and only 1 (16.7%) had sporadic juvenile early-onset LBC. No germline BRCA1 and BRCA2 variants were identified in CDH1 carriers. An inactivating CDH1 mechanism (second hit) was identified in 4 of 6 explored matched tumor samples (66.7%) in P/LP germline carriers. The P/LP CDH1 LBC variant carriers had a significantly lower age at diagnosis compared with the group carrying CDH1 variants of unknown significance or likely benign (42.5 [IQR, 38.3-43.0] vs 51.0 [IQR, 45.0-53.0] years; P = .03). Conclusions and Relevance: In this cohort study, P/LP germline CDH1 variants were identified in individuals not fulfilling the classic clinical criteria for HDGC screening, suggesting that identification of these variants may provide a novel method to test women with LBC with early age at diagnosis and/or positive family history of BC.

Expression of immune-related genes and breast cancer recurrence in women with ductal carcinoma in situ.

BACKGROUND AND AIM: Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer with highly variable clinical behavior, but risk stratification is still challenging. We sought to identify immune-related gene expression signatures of pure DCIS associated with different risks of breast cancer recurrence. METHODS: A retrospective nested case-control study of 143 pure DCIS was performed including 70 women with subsequent ipsilateral breast event (IBE, in situ or invasive; cases) and 73 DCIS women with no IBE and matched for age, tumor size, treatment, hormone receptors/HER2 status, and follow-up time (controls). RNA was extracted from DCIS samples and subjected to next-generation sequencing gene expression analysis of 395 immune-related genes. Correlations between DCIS immune-related gene expression and IBE were analyzed using weighted Cox regression for nested case-control data. RESULTS: Eight immune-related genes were differentially expressed between cases and controls. MAGEA10 expression (present vs. absent) and high expression levels of IFNA17 and CBLB (Q4 vs. Q1) were observed more frequently in DCIS of women with subsequent IBE, mainly invasive (p-valueFDR < 0.05). Conversely, expression of IL3RA1, TAGAP, TNFAIP8, and high expression levels of CCL2 and LRP1 were associated with a lower risk of IBE (p-valueFDR < 0.05). CONCLUSION: This exploratory analysis of pure DCIS showed significant differences in immune-related gene expression profiles between women with and with no subsequent IBE, particularly as invasive IBE. These results, after additional validation, could improve risk stratification and management of DCIS patients.

A multicenter high-quality data registry for advanced proton therapy approaches: the POWER registry.

BACKGROUND: Paucity and low evidence-level data on proton therapy (PT) represent one of the main issues for the establishment of solid indications in the PT setting. Aim of the present registry, the POWER registry, is to provide a tool for systematic, prospective, harmonized, and multidimensional high-quality data collection to promote knowledge in the field of PT with a particular focus on the use of hypofractionation. METHODS: All patients with any type of oncologic disease (benign and malignant disease) eligible for PT at the European Institute of Oncology (IEO), Milan, Italy, will be included in the present registry. Three levels of data collection will be implemented: Level (1) clinical research (patients outcome and toxicity, quality of life, and cost/effectiveness analysis); Level (2) radiological and radiobiological research (radiomic and dosiomic analysis, as well as biological modeling); Level (3) biological and translational research (biological biomarkers and genomic data analysis). Endpoints and outcome measures of hypofractionation schedules will be evaluated in terms of either Treatment Efficacy (tumor response rate, time to progression/percentages of survivors/median survival, clinical, biological, and radiological biomarkers changes, identified as surrogate endpoints of cancer survival/response to treatment) and Toxicity. The study protocol has been approved by the IEO Ethical Committee (IEO 1885). Other than patients treated at IEO, additional PT facilities (equipped with Proteus®ONE or Proteus®PLUS technologies by IBA, Ion Beam Applications, Louvain-la-Neuve, Belgium) are planned to join the registry data collection. Moreover, the registry will be also fully integrated into international PT data collection networks.

Can we predict pathology without surgery? Weighing the added value of multiparametric MRI and whole prostate radiomics in integrative machine learning models.

OBJECTIVE: To test the ability of high-performance machine learning (ML) models employing clinical, radiological, and radiomic variables to improve non-invasive prediction of the pathological status of prostate cancer (PCa) in a large, single-institution cohort. METHODS: Patients who underwent multiparametric MRI and prostatectomy in our institution in 2015-2018 were considered; a total of 949 patients were included. Gradient-boosted decision tree models were separately trained using clinical features alone and in combination with radiological reporting and/or prostate radiomic features to predict pathological T, pathological N, ISUP score, and their change from preclinical assessment. Model behavior was analyzed in terms of performance, feature importance, Shapley additive explanation (SHAP) values, and mean absolute error (MAE). The best model was compared against a naïve model mimicking clinical workflow. RESULTS: The model including all variables was the best performing (AUC values ranging from 0.73 to 0.96 for the six endpoints). Radiomic features brought a small yet measurable boost in performance, with the SHAP values indicating that their contribution can be critical to successful prediction of endpoints for individual patients. MAEs were lower for low-risk patients, suggesting that the models find them easier to classify. The best model outperformed (p ≤ 0.0001) clinical baseline, resulting in significantly fewer false negative predictions and overall was less prone to under-staging. CONCLUSIONS: Our results highlight the potential benefit of integrative ML models for pathological status prediction in PCa. Additional studies regarding clinical integration of such models can provide valuable information for personalizing therapy offering a tool to improve non-invasive prediction of pathological status. CLINICAL RELEVANCE STATEMENT: The best machine learning model was less prone to under-staging of the disease. The improved accuracy of our pathological prediction models could constitute an asset to the clinical workflow by providing clinicians with accurate pathological predictions prior to treatment. KEY POINTS: • Currently, the most common strategies for pre-surgical stratification of prostate cancer (PCa) patients have shown to have suboptimal performances. • The addition of radiological features to the clinical features gave a considerable boost in model performance. Our best model outperforms the naïve model, avoiding under-staging and resulting in a critical advantage in the clinic. •Machine learning models incorporating clinical, radiological, and radiomics features significantly improved accuracy of pathological prediction in prostate cancer, possibly constituting an asset to the clinical workflow.

Extreme-hypofractionated RT with concomitant boost to the DIL in PCa: a 5-year update on oncological and patient-reported outcomes for the phase II trial "GIVE ME FIVE".

AIM: The present work reports updated oncological results and patients-reported outcomes at 5 years of phase II trial "Short-term high precision RT for early prostate cancer with SIB to the dominant intraprostatic lesion (DIL) for patients with early-stage PCa". METHODS: Data from patients enrolled within AIRC IG-13218 (NCT01913717) trial were analyzed. Clinical and GU/GI toxicity assessment and PSA measurements were performed every 3 months for at least 2 years after RT end. QoL of enrolled patients was assessed by IPSS, EORTC QLQ-C30, EORTC QLQ-PR25, and IIEF-5. Patients' score changes were calculated at the end of RT and at 1, 12, and 60 months after RT. RESULTS: A total of 65 patients were included. At a median follow-up of 5 years, OS resulted 86%. Biochemical and clinical progression-free survival at 5 years were 95%. The median PSA at baseline was 6.07 ng/ml, while at last follow-up resulted 0.25 ng/ml. IPSS showed a statistically significant variation in urinary function from baseline (p = 0.002), with the most relevant deterioration 1 month after RT, with a recovery toward baseline at 12 months (p ≤ 0.0001). A numerical improvement in QoL according to the EORTC QLQ-C30 has been reported although not statistically significant. No change in sexual activity was recorded after RT. CONCLUSIONS: The study confirms that extreme hypofractionation with a DIL boost is safe and effective, with no severe effects on the QoL. The increasing dose to the DIL does not worsen the RT toxicity, thus opening the possibility of an even more escalated treatment.

Prognostic and predictive value of non-steroidal anti-inflammatory drugs in the EORTC 1325/KEYNOTE-054 phase III trial of pembrolizumab versus placebo in resected high-risk stage III melanoma.

BACKGROUND: Pain is common in patients with cancer. The World Health Organisation recommends paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) for mild pain and combined with other agents for moderate/severe pain. This study estimated associations of NSAIDs with recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and the incidence of immune-related adverse events (irAEs) in high-risk patients with resected melanoma in the EORTC 1325/KEYNOTE-054 phase III clinical trial. PATIENTS AND METHODS: Patients with AJCC7 stage IIIA, IIIB or IIIC resected melanoma were randomized to receive 200 mg of adjuvant pembrolizumab (N = 514) or placebo (N = 505) 3-weekly for one year or until recurrence. As previously reported, pembrolizumab prolonged RFS and DMFS. NSAID use was defined as administration between 7 days pre-randomization and starting treatment. Multivariable Cox and Fine and Gray models were used to estimate hazard ratios (HRs) for associations of NSAIDs with RFS, DMFS and irAEs. RESULTS: Of 1019 patients randomized, 59 and 44 patients in the pembrolizumab and placebo arms, respectively, used NSAIDs. NSAIDs were not associated with RFS (HR 0.91, 95% CI 0.58-1.43) or DMFS in the pembrolizumab (HR 1.03, 95% CI 0.65-1.66) or placebo arms (for RFS, HR 0.76, 95% CI 0.48-1.20; for DMFS, HR 0.80, 95% CI 0.49-1.31). NSAIDs were associated with the incidence of irAEs in the placebo arm (HR 3.06, 95% CI 1.45-6.45) but not in the pembrolizumab arm (HR 0.94, 95% CI 0.58-1.53). CONCLUSION: NSAIDs were not associated with efficacy outcomes nor the risk of irAEs in patients with resected high-risk stage III melanoma receiving adjuvant pembrolizumab.

Evolving paradigms in breast cancer screening: Balancing efficacy, personalization, and equity.

Breast cancer remains a significant global health challenge, with projections indicating a troubling increase in incidence. Breast cancer screening programs have long been hailed as life-saving initiatives, yet their true impact on mortality rates is a subject of ongoing debate. Screening poses the risk of false positives and the detection of indolent tumors, potentially leading to overtreatment. Bias factors, including lead time, length time, and selection biases, further complicate the assessment of screening efficacy. Recent studies suggest that AI-driven image analysis may revolutionize breast cancer screening, maintaining diagnostic accuracy while reducing radiologists' workload. However, the generalizability of these findings to diverse populations is a critical consideration. Personalized screening approaches and equitable access to advanced technologies are essential to mitigate disparities. In conclusion, the breast cancer screening landscape is evolving, emphasizing the need for risk stratification, appropriate imaging modalities, and a personalized approach to reduce overdiagnosis and focus on cancers with the potential to impact lives while prioritizing patient-centered care.

Alternative dosing regimen of exemestane in a randomized presurgical trial: the role of obesity in biomarker modulation.

In a 3-arm presurgical trial, four-six weeks exemestane 25 mg three times/week (TIW) was non-inferior to 25 mg/day (QD) in suppressing circulating estradiol in postmenopausal women with ER-positive breast cancer. Since obesity may decrease exemestane efficacy, we analyzed changes in sex steroids, adipokines, Ki-67, and drug levels in relation to obesity. Postmenopausal women with early-stage ER-positive breast cancer were randomized to either exemestane 25 mg QD (n = 57), 25 mg TIW (n = 57), or 25 mg/week (QW, n = 62) for 4-6 weeks before breast surgery. Serum and tissue pre- and post-treatment biomarkers were stratified by body mass index (BMI)< or ≥30 kg/m2. Post-treatment median exemestane and 17-OH exemestane levels were 5-6 times higher in the QD arm compared to the TIW arm. For obese women, TIW maintained comparable reductions to QD in systemic estradiol levels, although the reduction in estrone was less with the TIW regimen. There was less suppression of SHBG with the TIW versus the QD dose schedule in obese women which should result in less systemic bioavailable estrogens. Metabolically, the effect of the TIW regimen was similar to the QD regimen for obese women in terms of leptin suppression and increase in the adiponectin-leptin ratio. Reduction in tissue Ki-67 was less for obese women on the TIW regimen than QD, although changes were similar for non-obese women. Our findings suggest that TIW exemestane should be explored further for primary cancer prevention in both normal weight and obese cohorts.

Hippocampal region avoidance in whole brain radiotherapy in brain metastases: For all or for some? A real-world feasibility report.

PURPOSE: Hippocampal sparing whole-brain radiotherapy (HS-WBRT) showed significantly lower long-term side effects compared to standard WBRT. Aim of this study is to describe a HS-WBRT real-world monoinstitutional experience within a retrospective cohort. METHODS: Patients who completed HS-WBRT course, with Karnofsky Performance Status ⩾ 60 and radiological diagnosis of brain metastases (BMs) were enrolled. Treatment was performed using helical Tomotherapy scheduled in 30 Gy in 10 or 12 fractions or 25 Gy in 10 fractions. Oncological outcomes were clinically and radiologically assessed every three months. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events 4.3. RESULTS: One hundred and nineteen patients from 2016 to 2020 met inclusion criteria; after a median follow-up of 18 months, 29 patients were alive; 6- and 12-months overall survival rates were 66% and 41%, respectively. HS-WBRT response was assessed for 72 patients. Median time to any progression and intracranial failure (IF) was 4.5 and 13.7 months, respectively. The 6- and 12-month IF rates were 85% and 57%. Among 40 patients (34%) who experienced IF, 17 (42%) were oligometastatic, 23 (58%) polymetastatic and 15/40 developed IF within the hippocampi avoidance zone. No grade (G) ⩾ 2 acute toxicities were reported and one G2 (dizziness) late toxicity was described. CONCLUSIONS: HS-WBRT is well tolerated, and despite the hippocampal sparing region, the oncological control is satisfying. Further investigation is warranted to find patients who could most benefit from a HS-WBRT approach.

Effect of metformin and lifestyle intervention on adipokines and hormones in breast cancer survivors: a pooled analysis from two randomized controlled trials.

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 < 0.01) and HOMA-IR (- 0.48 vs - 0.25; p = 0.03), and an increase in SHBG (2.80 vs 1.45 nmol/L; p < 0.01). Excluding women taking aromatase inhibitors, metformin (n = 84) compared to placebo (n = 99) decreased estradiol (- 4 vs 0 pmol/L; p < 0.01), estrone (- 8 vs 2 pmol/L; p < 0.01) and testosterone (- 0.1 vs 0 nmol/L-; p = 0.02). LSI favorably affected adiponectin (0.45 vs - 0.06 ug/mL; p < 0.01), leptin (- 10.5 vs - 4.4 ng/mL; p < 0.01), HOMA-IR (- 0.6 vs 0.2; p = 0.03), and SHBG (2.7 vs 1.1 nMol/L; p = 0.04) compared to controls. The strongest impact was observed combining metformin with LSI on adipokines, CRP, SHBG, and estrogens. CONCLUSIONS: Supportive healthy lifestyle programs combined with metformin to achieve maximal risk reduction among BC cancer survivors are recommended, especially for those with obesity in menopause.

Baseline Tumor Size as Prognostic Index in Patients With Advanced Solid Tumors Receiving Experimental Targeted Agents.

BACKGROUND: Baseline tumor size (BTS) has been associated with outcomes in patients with cancer treated with immunotherapy. However, the prognostic impact of BTS on patients receiving targeted therapies (TTs) remains undetermined. METHODS: We reviewed data of patients with advanced solid tumors consecutively treated within early-phase clinical trials at our institution from 01/2014 to 04/2021. Treatments were categorized as immunotherapy-based or TT-based (biomarker-matched or not). BTS was calculated as the sum of RECIST1.1 baseline target lesions. RESULTS: A total of 444 patients were eligible; the median BTS was 69 mm (IQR 40-100). OS was significantly longer for patients with BTS lower versus higher than the median (16.6 vs. 8.2 months, P < .001), including among those receiving immunotherapy (12 vs. 7.5 months, P = .005). Among patients receiving TT, lower BTS was associated with longer PFS (4.7 vs. 3.1 months, P = .002) and OS (20.5 vs. 9.9 months, P < .001) as compared to high BTS. However, such association was only significant among patients receiving biomarker-matched TT, with longer PFS (6.2 vs. 3.3 months, P < .001) and OS (21.2 vs. 6.7 months, P < .001) in the low-BTS subgroup, despite a similar ORR (28% vs. 22%, P = .57). BTS was not prognostic among patients receiving unmatched TT, with similar PFS (3.7 vs. 4.4 months, P = .30), OS (19.3 vs. 11.8 months, P = .20), and ORR (33% vs. 28%, P = .78) in the 2 BTS groups. Multivariate analysis confirmed that BTS was independently associated with PFS (P = .03) and OS (P < .001) but not with ORR (P = .11). CONCLUSIONS: Higher BTS is associated with worse survival outcomes among patients receiving biomarker-matched, but not biomarker-unmatched TT.

Efficacy and safety of systemic chemotherapy for radically resectable esophago-gastric adenocarcinoma in older patients: A systematic review and meta-analysis.

INTRODUCTION: A significant proportion of locally-advanced esophago-gastric adenocarcinoma (EGA) is diagnosed in patients ≥70 years old (y.o.) who are commonly underrepresented in clinical trials. MATERIALS AND METHODS: The PubMed database was searched for phase 2/3 clinical trials enrolling patients ≥70 y.o and reporting efficacy/safety information of chemotherapy for resectable EGA. The main outcomes were overall survival (OS) and recurrence-free survival (RFS). RESULTS: Among 6,128 records, only seven studies reported these outcomes (three peri-operative, three adjuvant, and one neoadjuvant), including 1004 older patients, <20% of the overall population. No significant benefit in terms of OS and RFS was observed for perioperative or adjuvant chemotherapy vs surgery alone. No trial reported safety endpoints in this subgroup. DISCUSSION: This work did not show any significant benefit in OS or RFS for chemotherapy vs surgery alone or conventional vs de-escalated chemotherapy in the curative setting of EGA in ≥70 y.o patients. Specific ad hoc trials should be performed to derive reliable data.

SARS-CoV-2 trends in Italy, Germany and Portugal and school opening during the period of Omicron variant dominance: A quasi experimental study in the EuCARE project.

OBJECTIVES: We investigated the impact of school reopening on SARS-CoV-2 transmission in Italy, Germany, and Portugal in autumn 2022 when the Omicron variant was prevalent. METHODS: A prospective international study was conducted using the case reproduction number (Rc) calculated with the time parametrization of Omicron. For Germany and Italy, staggered difference-in-differences analysis was employed to explore the causal relationship between school reopening and Rc changes, accounting for varying reopening dates. In Portugal, interrupted time series analysis was used due to simultaneous school reopenings. Multivariable models were adopted to adjust for confounders. RESULTS: In Italy and Germany, post-reopening Rc estimates were significantly lower compared to those from regions/states that had not yet reopened at the same time points, both in the student population (overall average treatment effect for the treated subpopulation [O-ATT]: -0.80 [95% CI: -0.94;-0.66] for Italy; O-ATT-0.30 [95% CI: -0.36;-0.23] for Germany) and the adult population (O-ATT: -0.04 [95% CI: -0.07;-0.01] for Italy; O-ATT: -0.07 [95% CI: -0.11;-0.03] for Germany). In Portugal, there was a significant decreasing trend in Rc following school reopenings compared to the pre-reopening period (sustained effect: -0.03 [95% CI: -0.04; -0.03] in students; -0.02 [95% CI: -0.03; -0.02] in adults). CONCLUSIONS: We found no evidence of a causal relationship between school reopenings in autumn 2022 and Omicron SARS-CoV-2 transmission.