Bone health and body composition in prostate cancer: Meet-URO and AIOM consensus about prevention and management strategies.

BACKGROUND: Prostate cancer (PCa) treatments are associated with a detrimental impact on bone health (BH) and body composition. However, the evidence on these issues is limited and contradictory. This consensus, based on the Delphi method, provides further guidance on BH management in PCa. MATERIALS AND METHODS: In May 2023, a survey made up of 37 questions and 74 statements was developed by a group of oncologists and endocrinologists with expertise in PCa and BH. In June 2023, 67 selected Italian experts, belonging to the Italian scientific societies Italian Association of Medical Oncology and Italian Network for Research in Urologic-Oncology (Meet-URO), were invited by e-mail to complete it, rating their strength of agreement with each statement on a 5-point scale. An agreement ≥75% defined the statement as accepted. RESULTS: In non-metastatic hormone-sensitive PCa, the panel agreed that androgen deprivation therapy (ADT) alone implies sufficient fracture risk to warrant antifracture therapy with bone-targeting agents (BTAs) for cancer treatment-induced bone loss (CTIBL) prevention (79%). Therefore, no consensus was reached (48%) for the treatment with BTAs of patients receiving short-term ADT (<6 months). All patients receiving active treatment for metastatic hormone-sensitive PCa (75%), non-metastatic castration-resistant PCa (89%) and metastatic castration-resistant PCa (mCRPC) without bone metastases (84%) should be treated with BTAs at the doses and schedule for CTIBL prevention. All mCRPC patients with bone metastasis should be treated with BTAs to reduce skeletal-related events (94%). In all settings, the panel analyzed the type and timing of treatments and examinations to carry out for BH monitoring. The panel agreed on the higher risk of sarcopenic obesity of these patients and its correlation with bone fragility. CONCLUSIONS: This consensus highlights areas lacking major agreement, like non-metastatic hormone-sensitive prostate cancer patients undergoing short-term ADT. Evaluation of these issues in prospective clinical trials and identification of early biomarkers of bone loss are particularly urgent.

Efficacy and safety of high-dose chemotherapy as the first or subsequent salvage treatment line in patients with relapsed or refractory germ cell cancer: an international multicentric analysis.

BACKGROUND: In relapsed or refractory (RR) metastatic germ cell cancer (GCC), high-dose (HD) chemotherapy (CTX) plus autologous stem cell transplantation is considered the standard of care. Limited data exist regarding the efficacy of HD-CTX following conventionally dosed salvage regimens (CDRs). This analysis explores and contrasts the efficacy of HD-CTX as the first or subsequent salvage regimen. PATIENTS AND METHODS: Data were retrospectively collected to explore the efficacy of HD-CTX administered as the first (group A) or subsequent salvage CTX (group B) after a CDR. The primary endpoint was OS from the time of HD-CTX. Associations of survival, overall response rate (ORR), and toxicity with clinical characteristics were explored using stratified Kaplan-Meier and Cox regression models. RESULTS: Overall, 283 patients with GCC were included from 11 international centers, with 159 patients (56%) in group A and 124 patients (44%) in group B. The first salvage treatment was administered between 1998 and 2022, with a median follow-up of 27.0 [standard deviation (SD) 46.2] months for group A and 17.0 (SD 48.5) months for group B. The median OS from HD-CTX treatment initiation was not reached in group A, compared with 25 months in group B (P = 0.00027), associated with 2- and 5-year OS rates of 74% and 63% (group A) versus 53% and 37% (group B), respectively. When administered as the first salvage treatment, HD-CTX was associated with a higher ORR (79% versus 60%; P = 0.013) and lower nonhematologic grade ≥3 toxicity rate (78% versus 97%; P < 0.001). Concerning risk factor analysis for the total cohort, the International Prognostic Factors Study Group score was the only independent predictor of OS in multivariable analysis (P = 0.006). CONCLUSIONS: When administered as the initial salvage treatment or after CDR, HD-CTX exhibits curative potential for patients with RR GCC. The efficacy and safety outcomes were more favorable when HD-CTX was conducted as the first salvage treatment line.

MITO END-3: efficacy of avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy.

BACKGROUND: Immunotherapy combined with chemotherapy significantly improves progression-free survival (PFS) compared to first-line chemotherapy alone in advanced endometrial cancer (EC), with a much larger effect size in microsatellite instability-high (MSI-H) cases. New biomarkers might help to select patients who may have benefit among those with a microsatellite-stable (MSS) tumor. PATIENTS AND METHODS: In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab. RESULTS: Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases with MSI-H, 26 with MSS TP53 wild type (wt), 47 with MSS TP53 mutated (mut), and 1 case with POLE mutation. Four mutated genes were present in >30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High tumor mutational burden (≥10 muts/Mb) was observed in all MSI-H patients, in 4 out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on PFS significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction = 0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction = 0.01; PTEN P interaction = 0.002). CONCLUSION: The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced EC.

Navigating the complexity of PI3K/AKT pathway in HER-2 negative breast cancer: biomarkers and beyond.

The results of the SOLAR-1 and CAPItello-291, highlight the benefit of the ɑ-selective phosphoinositide 3-Kinase Pathway inhibitor (PI3Ki) alpelisib and the AKT inhibitor (AKTi) capivasertib in patients with hormone receptor-positive (HR+)/Human Epidermal Growth Factor Receptor 2 (HER2)- negative metastatic breast cancer (mBC) that have PIK3CA/AKT1/PTEN tumour alterations. Although effective, these drugs are associated with significant toxicities, which often limit their use, particularly in frail patients. Following the recent incorporation of these agents into clinical practice, and with many others currently in development, significant challenges have emerged, particularly those regarding biomarkers for patient selection. This review will discuss biomarkers of response and their resistance to PI3K/AKT inhibitors (PI3K/AKTis) in HR+/HER- BC in early and advanced settings to ascertain which populations will most benefit from these drugs. Of the biomarkers that were analysed, such as PIK3CA, AKT, PTEN mutations, insulin levels, 18 F-FDG-PET/TC, only the PIK3CA-mutations (PIK3CA-mut) and the AKT pathway alterations seem to have a predictive value for treatments with alpelisib and capivasertib. However, due to the retrospective and exploratory nature of the study, the data did not provide conclusive results. In addition, the different methods used to detect PIK3CA/AKT1/PTEN alterations underline the fact that the optimal diagnostic companion has yet to be established. We have summarised the clinical data on the approved and discontinued agents targeting this pathway and have assessed the drugs development, successes, and failures. Finally, because of tumour heterogeneity, we emphasise the importance of reassessing the mutational status of PI3KCA in both metastatic tissue and blood at the time of disease progression to better tailor treatment for patients.

Longitudinal assessment of plasma androgen receptor copy number predicts overall survival in subsequent treatment lines in castration-resistant prostate cancer: analysis from a prospective trial.

BACKGROUND: Baseline plasma androgen-receptor copy number (AR-CN) is a promising biomarker for metastatic castration-resistant prostate cancer (mCRPC) outcome and treatment response; however, the role of its longitudinal testing is unproven. We aimed to evaluate the prognostic role of AR-CN assessed before subsequent treatment lines in mCRPC patients. METHODS: A subgroup analysis of a prospective multicenter biomarker trial (IRSTB030) was carried out. Plasma AR-CN status (classified as normal or gain, cut-off value = 2) was assessed with digital PCR before each treatment line. RESULTS: Forty mCRPC patients receiving sequentially docetaxel, cabazitaxel and an AR signaling inhibitor (abiraterone or enzalutamide) were analyzed. At multivariate analysis, at each assessment overall survival (OS) was independently correlated with AR-CN status [first line: hazard ratio (HR) 4.1 [95% confidence interval (CI) 1.6-10.5]; second line: HR 2.4 (95% CI 1.1-5.3); third line: HR 2.1 (95% CI 1.0-4.3)] and median prostate-specific antigen [first line: HR 4.4 (95% CI 1.8-10.9); second line: HR 3.4 (95% CI 1.6-7.2); third line: HR 2.5 (95% CI 1.2-5.6)]. In the three subsequent assessments, AR-CN status changed from normal to gain in 15 (38%) patients. These patients had longer OS (47 months) compared with patients presenting AR-CN gain from first assessment (36 months), but shorter than those maintaining normal AR-CN (69 months) (P = 0.003). CONCLUSIONS: Plasma AR-CN correlates with survival not only at baseline (before first treatment), but also in the assessments before the following lines. Interestingly, AR-CN status may change from normal to gain across subsequent treatments in a significant number of cases, identifying a group of patients with intermediate outcomes. Longitudinal assessment of AR-CN status could represent a promising method to capture mCRPC intrinsic heterogeneity and to improve clinical management.

A phase II study of pembrolizumab plus carboplatin in BRCA-related metastatic breast cancer (PEMBRACA).

BACKGROUND: BRCA1/2-related metastatic breast cancers (mBC) are sensitive to DNA-damage agents and show high tumor-infiltrated lymphocytes. We hypothesized that the association between pembrolizumab and carboplatin could be active in BRCA-related mBC. PATIENTS AND METHODS: In this phase II Simon's design multicenter single-arm study, BRCA1/2-related mBC patients received carboplatin at area under the curve 6 every 3 weeks for six courses associated with 200 mg pembrolizumab every 3 weeks until disease progression or unacceptable toxicity. The primary aim at first stage was overall response rate (ORR) ≥70%. Disease control rate (DCR), time to progression (TTP), duration of response (DOR), and overall survival (OS) were the secondary aims. RESULTS: Among 22 patients enrolled at the first stage, 5 BRCA1 and 17 BRCA2, 16 (76%) were luminal tumors and 6 (24%) triple-negative BC (TNBC). In 21 patients, ORR and DCR were 43% and 76% (47% and 87% in luminal, 33% and 50% in TNBC), respectively. TTP was 7.1 months, DOR was 6.3 months, and median OS was not reached. Grade ≥3 adverse events (AEs) or serious AEs occurred in 5/22 patients (22.7%). Since the primary aim was not met, the study was terminated at the first stage. CONCLUSIONS: Although the primary aim was not reached, data on efficacy and safety of pembrolizumab plus carboplatin in first-line visceral disease BRCA-related luminal mBC were provided and they need to be further investigated.

INOVATYON/ ENGOT-ov5 study: Randomized phase III international study comparing trabectedin/pegylated liposomal doxorubicin (PLD) followed by platinum at progression vs carboplatin/PLD in patients with recurrent ovarian cancer progressing within 6-12 months after last platinum line.

BACKGROUND: This trial investigated the hypothesis that the treatment with trabectedin/PLD (TP) to extend the platinum-free interval (TFIp) can improve overall survival (OS) in patients with recurrent ovarian cancer (OC). METHODS: Patients with OC (up to two previous platinum-based lines), with a TFIp of 6-12 months, were randomised to receive carboplatin/PLD (CP) or TP followed by platinum therapy at relapse. The primary endpoint was OS (HR: 0.75). RESULTS: The study enrolled 617 patients. The median TFIp was 8.3 months and 30.3% of patients had received two previous platinum lines. 74% and 73.9% of patients, respectively, received a subsequent therapy (ST) in the CP and TP arm; in the latter TP arm 87.2% of ST was platinum-based, as per protocol. The median OS was 21.4 for CP and 21.9 months for TP (HR 1.13; 95% CI: 0.94-1.35; p = 0.197). Grade 3-5 adverse reactions occurred in 37.1% of patients in the CP arm and 69.7% of patients in the TP arm, and the most frequent were neutropenia (22.8% CP, 39.5% TP), gastrointestinal (7.1% CP, 17.4% TP), hepatic (0.7% CP, 19.1% TP). CONCLUSIONS: This study did not meet the primary endpoint. CP combination remains the standard for patients with recurrent OC and a 6-12 months TFIp; TP is an effective treatment in patients suffering from persistent platinum toxicities. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT01379989.

Validation of the Meet-URO score in patients with metastatic renal cell carcinoma receiving first-line nivolumab and ipilimumab in the Italian Expanded Access Program.

BACKGROUND: The Meet-URO score allowed a more accurate prognostication than the International Metastatic RCC Database Consortium (IMDC) for patients with pre-treated metastatic renal cell carcinoma (mRCC) by adding the pre-treatment neutrophil-to-lymphocyte ratio and presence of bone metastases. MATERIALS AND METHODS: A post hoc analysis was carried out to validate the Meet-URO score on the overall survival (OS) of patients with IMDC intermediate-poor-risk mRCC treated with first-line nivolumab plus ipilimumab within the prospective Italian Expanded Access Programme (EAP). We additionally considered progression-free survival (PFS) and disease response rates. Harrell's c-index was calculated to compare the accuracy of survival prediction. RESULTS: Overall the EAP included 306 patients, with a median follow-up of 12.2 months, median OS was not reached, 1-year OS was 66.8% and median PFS was 7.9 months. By univariable analysis, both the IMDC score and the two additional variables of the Meet-URO score were associated with either OS or PFS (P < 0.001 for all comparisons). The four Meet-URO risk groups (G) had 1-year OS of 92%, 72%, 50% and 21% for G2 (29.1% of patients), G3 (28.8%), G4 (33.0%) and G5 (9.1%), respectively. OS was significantly shorter in each consecutive G (P = 0.001 for G3, P < 0.001 for both G4 and G5 compared to G2). Similarly, Meet-URO Gs 2-5 showed decreasing median PFS and response rates. The Meet-URO score showed the highest c-index for both OS (0.73) and PFS (0.67). Limitations include the post hoc nature of this analysis and the lack of a comparative arm to assess predictive value. CONCLUSION: The Meet-URO score appeared to show better prognostic classification than the IMDC alone in patients with mRCC at IMDC intermediate-poor risk treated with first-line nivolumab and ipilimumab.

Addition of androgen receptor-targeted agents to androgen-deprivation therapy and docetaxel in metastatic hormone-sensitive prostate cancer: a systematic review and meta-analysis.

BACKGROUND: Androgen-deprivation therapy (ADT) historically represented the milestone for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC). Recently, combining androgen receptor-targeted agents (ARTA) or docetaxel with ADT significantly improved clinical outcomes in this setting. The efficacy of the combined use of an ARTA with docetaxel and ADT (triplet), however, was unknown, and often conflicting data derived from subgroup analysis of randomized phase III trials. In order to better define the benefits and risks of the triplet in mHSPC, we carried out a systematic review and meta-analysis of available clinical trials. METHODS: A literature search with no data restriction using Medline/PubMed, the Cochrane Library, and American Society of Clinical Oncology/European Society for Medical Oncology (ASCO/ESMO) Meeting abstracts was carried out up to April 2022. The meta-analysis was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statements. Overall survival (OS) was the primary endpoint; progression-free survival (PFS) and safety were secondary endpoints. For OS and PFS, summary hazard ratios (HRs) were calculated; for safety, risk ratio (RR) was assessed. Random- or fixed-effects models were used, depending on studies heterogeneity. RESULTS: Five randomized clinical trials fulfilled the prespecified inclusion criteria. The triplet significantly improved OS (fixed-effect, HR = 0.74; P < 0.00001) and PFS (fixed-effect; HR = 0.50 for clinical PFS, HR = 0.49 for radiological PFS; P < 0.0001) compared with docetaxel plus ADT. We did not show heterogeneity between treatment efficacy and the disease burden, metachronous versus synchronous presentation, concomitant versus sequential strategy. Compared with docetaxel + ADT, the triplet did not increase the risk of adverse events (AEs) (RR = 1.00, P = 0.27 for any-grade AEs; RR = 1.13, P = 0.14 for severe AEs), except for severe hypertension (RR = 1.73, P = 0.001). CONCLUSIONS: Emerging evidence supports the combination of an ARTA plus docetaxel and ADT in mHSPC patients. Given the availability of several strategies in this setting, clinical characteristics and drug safety profile may help clinicians select the appropriate treatment for mHSPC patients who are more likely to benefit from treatment intensification.

Implementation of preventive and predictive BRCA testing in patients with breast, ovarian, pancreatic, and prostate cancer: a position paper of Italian Scientific Societies.

Constitutional BRCA1/BRCA2 pathogenic or likely pathogenic variants (PVs) are associated with an increased risk for developing breast and ovarian cancers. Current evidence indicates that BRCA1/2 PVs are also associated with pancreatic cancer, and that BRCA2 PVs are associated with prostate cancer risk. The identification of carriers of constitutional PVs in the BRCA1/2 genes allows the implementation of individual and family prevention pathways, through validated screening programs and risk-reducing strategies. According to the relevant and increasing therapeutic predictive implications, the inclusion of BRCA testing in the routine management of patients with breast, ovarian, pancreatic and prostate cancers represent a key requirement to optimize medical or surgical therapeutic and prevention decision-making, and access to specific anticancer therapies. Therefore, accurate patient selection, the use of standardized and harmonized procedures, and adherence to homogeneous testing criteria, are essential elements to implement BRCA testing in clinical practice. This consensus position paper has been developed and approved by a multidisciplinary Expert Panel of 64 professionals on behalf of the AIOM-AIRO-AISP-ANISC-AURO-Fondazione AIOM-SIAPEC/IAP-SIBioC-SICO-SIF-SIGE-SIGU-SIU-SIURO-UROP Italian Scientific Societies, and a patient association (aBRCAdaBRA Onlus). The working group included medical, surgical and radiation oncologists, medical and molecular geneticists, clinical molecular biologists, surgical and molecular pathologists, organ specialists such as gynecologists, gastroenterologists and urologists, and pharmacologists. The manuscript is based on the expert consensus and reports the best available evidence, according to the current eligibility criteria for BRCA testing and counseling, it also harmonizes with current Italian National Guidelines and Clinical Recommendations.

Grade group system and plasma androgen receptor status in the first line treatment for metastatic castration resistant prostate cancer.

In localized prostate cancer (PCa), Grade Group (GG) and Gleason Score (GS) have a well-established prognostic role. In metastatic castration resistant prostate cancer (mCRPC), the prognostic role of GS and GG is less defined. In first-line treatment of mCRPC, androgen receptor (AR)-directed drugs (abiraterone acetate, enzalutamide) and docetaxel represent the referring options. There is no evidence that the GS/GG systems can add information to guide the choice between AR-directed drugs and docetaxel in the first-line setting of mCRPC. Nowadays there are no validated biomarkers, which define patients who may benefit or not from hormonal treatments or chemotherapy. Androgen receptor (AR) copy number variations (CNV) are predictive factors of poor response to abiraterone and enzalutamide. There are no available data about the association between AR CNV and GG. In this retrospective study, we analysed the association of the highest GG score with AR CNV and their impact on the clinical outcome of AR-directed drugs and docetaxel as first-line therapy for mCRPC patients. Patients benefit from docetaxel, abiraterone or enzalutamide regardless the GG. However, the presence of GG5 and AR CNV gain identifies a subgroup of patients with poor prognosis, which could benefit from front-line docetaxel instead of AR-directed drugs.

Maintenance therapy of patients with recurrent epithelial ovarian carcinoma with the anti-tumor-associated-mucin-1 antibody gatipotuzumab: results from a double-blind, placebo-controlled, randomized, phase II study.

BACKGROUND: Gatipotuzumab is a humanized monoclonal antibody recognizing the carbohydrate-induced epitope of the tumor-associated mucin-1 (TA-MUC1). This study aimed to evaluate the efficacy and safety of switch maintenance therapy with gatipotuzumab in patients with TA-MUC1-positive recurrent ovarian, fallopian tube, or primary high-grade serous peritoneal cancer. PATIENTS AND METHODS: In this double-blind, randomized, placebo-controlled, phase II trial, patients with at least stable disease (SD) following chemotherapy were randomized 2:1 to receive intravenous gatipotuzumab (500 mg followed by 1700 mg 1 week later) or placebo every 3 weeks until tumor progression or unacceptable toxicity occurred. Stratification factors were the number of prior chemotherapy lines (2 versus 3-5), response versus SD after the most recent chemotherapy, and progression-free survival (PFS) <6 versus 6-12 months following the prior therapy. Primary endpoint was PFS according to modified immune-related RECIST 1.1 response criteria. Secondary endpoints were PFS at 6 months, safety, overall response rate, CA-125 progression, overall survival, quality of life, and pharmacokinetics. RESULTS: Overall, 216 patients were randomized to gatipotuzumab (n  = 151) or placebo (n  = 65). Median PFS with gatipotuzumab was 3.5 months as compared with 3.5 months with placebo (hazard ratio 0.96, 95% confidence interval 0.69-1.33, P  = 0.80). No advantage for gatipotuzumab over placebo was seen in the secondary efficacy endpoints or in any stratified subgroups. Gatipotuzumab was well tolerated, with mild to moderate infusion-related reactions being the most common adverse events. CONCLUSIONS: Gatipotuzumab switch maintenance therapy does not improve outcome in TA-MUC1-positive ovarian cancer patients. TRIAL REGISTRATION: ClinicalTrials.govNCT01899599; https://clinicaltrials.gov/ct2/show/NCT01899599.

Anogenital lichen sclerosus et atrophicus lesions in a case series of cancer patients on immunotherapy.

Lichenoid reactions are one of the most frequently observed toxicities with anticancer agents and, recently, a rapid emergence of immunotherapies in oncology has hastened the need to better characterize their unique toxicity profiles, particularly for less common skin toxicities, including anogenital lichen sclerosus et atrophicus (LSA). This case series describes four patients with advanced cancer (one melanoma, two lung cancers, and one kidney tumor) developing LSA lesions while receiving an immunotherapy. Medical records from 2017 to 2020 were retrospectively reviewed. Two patients received pembrolizumab, anti-programmed cell death-1 (PD-1), one nivolumab, anti-programmed cell death-1 (PD-1), and one ipilimumab, an immune checkpoint inhibitor. LSA emerged after a median of 3 months (range, 2-4 months) from starting immunotherapy. All LSA cases were grade 2. Three cases occurred on the penis and one case on the anus. All patients improved after a specific treatment for LSA, and no LSA-related antineoplastic treatment interruption/life-threatening condition were reported. To date, this is the first case series of LSA lesions associated with immunotherapy. Early LSA recognition and management is helpful in cancer patients on immunotherapy allowing a long survival and treatment response.

Drug-drug interactions between palbociclib and proton pump inhibitors may significantly affect clinical outcome of metastatic breast cancer patients.

BACKGROUND: Proton-pump-inhibitors (PPIs) are frequently prescribed for the management of anticancer drug-related gastrointestinal symptoms. Palbociclib is a weak base with pH-dependent solubility and potential drug-drug interaction at the absorption level may affect clinical pharmacokinetics. The current study was aimed at investigating the effect of co-administration of PPIs and palbociclib on progression-free survival (PFS) in metastatic breast cancer (mBC) patients. PATIENTS AND METHODS: Patients affected by estrogen receptor-positive, human epidermal growth factor receptor 2-negative mBC, who were candidates for first-line treatment with palbociclib, were enrolled in this retrospective observational study. Patients were defined as 'no concomitant PPIs' if no PPIs were administered during palbociclib treatment, and as 'concomitant PPIs' if the administration of PPIs covered the entire or not less than two-thirds of treatment with palbociclib. All clinical interventions were made according to clinical practice. RESULTS: A total of 112 patients were enrolled in the study; 56 belonged to the 'no concomitant PPIs' group and 56 to the 'concomitant PPIs' group. Seventy-one patients were endocrine-sensitive and received palbociclib and letrozole, and 43 were endocrine-resistant and were treated with palbociclib and fulvestrant. The most prescribed PPI was lansoprazole. Patients taking PPIs had a shorter PFS than those taking palbociclib and endocrine therapy alone (14.0 versus 37.9 months, P < 0.0001). Multivariate analysis confirmed concomitant PPIs as the only independent predictive factor for shorter PFS (P = 0.0002). PFS was significantly longer in estrogen-sensitive mBC with no concomitant PPIs compared with patients taking PPIs or estrogen-resistant patients, with and without PPIs (P < 0.0001). No correlation with adverse events was found when considering grade >2 hematological toxicities [Common Terminology Criteria for Adverse Events (CTCAE) scale]. CONCLUSIONS: The present study demonstrates that concomitant use of PPIs in mBC patients treated with palbociclib has a detrimental effect on PFS. Therefore, it is recommended to prescribe PPIs with caution in these patients, strictly adhering to the indications in the summary of product characteristics (RCP).

Immune-inflammatory biomarkers as prognostic factors for immunotherapy in pretreated advanced urinary tract cancer patients: an analysis of the Italian SAUL cohort.

BACKGROUND: Reliable and affordable prognostic and predictive biomarkers for urothelial carcinoma treated with immunotherapy may allow patients' outcome stratification and drive therapeutic options. The SAUL trial investigated the safety and efficacy of atezolizumab in a real-world setting on 1004 patients with locally advanced or metastatic urothelial carcinoma who progressed to one to three prior systemic therapies. PATIENTS AND METHODS: Using the SAUL Italian cohort of 267 patients, we investigated the prognostic role of neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) and the best performing one of these in combination with programmed death-ligand 1 (PD-L1) with or without lactate dehydrogenase (LDH). Previously reported cut-offs (NLR >3 and NLR >5; SII >1375) in addition to study-defined ones derived from receiver operating characteristic (ROC) analysis were used. RESULTS: The cut-off values for NLR and SII by the ROC analysis were 3.65 (sensitivity 60.4; specificity 63.0) and 884 (sensitivity 64.4; specificity 67.5), respectively. The median overall survival (OS) was 14.7 months for NLR <3.65 [95% confidence interval (CI) 9.9-not reached (NR)] versus 6.0 months for NLR ≥3.65 (95% CI 3.9-9.4); 14.7 months for SII <884 (95% CI 10.6-NR) versus 6.0 months for SII ≥884 (95% CI 3.7-8.6). The combination of SII, PD-L1, and LDH stratified OS better than SII plus PD-L1 through better identification of patients with intermediate prognosis (77% versus 48%, respectively). Multivariate analyses confirmed significant correlations with OS and progression-free survival for both the SII + PD-L1 + LDH and SII + PD-L1 combinations. CONCLUSION: The combination of immune-inflammatory biomarkers based on SII, PD-L1, with or without LDH is a potentially useful and easy-to-assess prognostic tool deserving validation to identify patients who may benefit from immunotherapy alone or alternative therapies.

Hypersensitivity to platinum salts according to BRCA status in ovarian cancer: A retrospective analysis of clinical outcomes and systematic review of literature.

BACKGROUND: Hypersensitivity reactions (HSRs) to platinum are an important issue in the treatment of patients (pts) with ovarian cancer (OC). Germline BRCA mutations have been proposed as a risk factor. We aimed at evaluating the incidence and severity of HSRs to platinum in OC pts. with known BRCA status. PATIENTS AND METHODS: We retrospectively analyzed 432 pts. from 5 Italian Centers. In addition, we performed a systematic review and meta-analysis of published series. RESULTS: Four hundred nine pts. received at least one prior platinum-based treatment line: 314 were BRCA wild type (77%) and 95 were BRCA mutated (23%). There was no statistical difference in exposure to platinum. Incidence of any grade HSRs was higher among BRCA mutated pts. [9% vs 18%, p = 0.019] and the time-to-HSRs curves show that the risk increases with the duration of platinum exposure, in BRCA mutated pts. more than in BRCA wild type. A multivariable analysis showed that harboring a germline BRCA mutation was related to a higher incidence of HSRs (HR: 1.84, 95% CI 1.00-3.99, p = 0.05) while having received pegylated liposomal doxorubicin (PLD) was related to a lower incidence of HSRs (HR: 0.03 95% CI 0.004-0.22, p = 0.001). The systematic review confirmed the higher incidence of HSRs in BRCA mutated pts., though heterogeneity among series was significant. CONCLUSIONS: In OC pts. with BRCA mutations, there is a significantly higher incidence of HSRs to carboplatin, not justified by longer drug exposure. On the other hand, PLD exerted a protective role in our series.

COVID-19 infection in cancer patients: what has been the contribution of Associazione Italiana Oncologia Medica (AIOM) to oncological care since the beginning of the first pandemic wave?

High mortality rates in elderly patients or in those with underlying chronic illnesses and/or a compromised immune system is a peculiar feature of COVID-19 infection. The possible coexistence of a cancer and COVID-19 infection in the same individual prompted concerns regarding their synergistic effect on prognosis. In order to balance patients' needs with the risks related to the infection, the question oncologists have asked from the beginning of the first wave of the pandemic has been: 'how can we deal with COVID-19 infection in cancer patients?' In pursuing its mission, the Associazione Italiana Oncologia Medica (AIOM) has made every possible effort to support cancer patients, health care professionals and institutions in the decision-making processes the pandemic has engendered within this scenario. The relevant documents as well as the educational and institutional initiatives the AIOM has taken are reported in this article.