Single-Agent Trabectedin Versus Physician's Choice Chemotherapy in Patients With Recurrent Ovarian Cancer With BRCA-Mutated and/or BRCAness Phenotype: A Randomized Phase III Trial.

PURPOSE: Literature evidence suggests that trabectedin monotherapy is effective in patients with recurrent ovarian cancer (OC) presenting BRCA mutation and/or BRCAness phenotype. METHODS: A prospective, open-label, randomized phase III MITO-23 trial evaluated the activity and safety of trabectedin 1.3 mg/m2 given once every 3 weeks (arm A) in BRCA 1/2 mutation carriers or patients with BRCAness phenotype (ie, patients who responded to ≥two previous platinum-based treatments) with recurrent OC, primary peritoneal carcinoma, or fallopian tube cancer in comparison with physician's choice chemotherapy in the control arm (arm B; pegylated liposomal doxorubicin, topotecan, gemcitabine, once-weekly paclitaxel, or carboplatin). The primary end point was overall survival (OS) evaluated in the intention-to-treat population. RESULTS: Overall, 244 patients from 21 MITO centers were randomly assigned (arm A = 122/arm B = 122). More than 70% of patients received ≥three previous chemotherapy lines and 35.7% had received a poly (ADP-ribose) polymerase inhibitor (PARPi) before enrollment. Median OS was not significantly different between the arms: arm A: 15.8 versus arm B: 17.9 months (P = .304). Median progression-free survival was 4.9 months in arm A versus 4.4 months in arm B (P = .897). Among 208 patients evaluable for efficacy, the objective response rate was 17.1% in arm A and 21.4% in arm B, with comparable median duration of response (5.62 v 5.66 months, respectively). No superior effect was observed for trabectedin in the prespecified subgroup analyses according to BRCA mutational status, chemotherapy type, and pretreatment with a PARPi and/or platinum-free interval. Trabectedin showed a higher frequency of grade ≥3 adverse events (AEs), serious AEs, and serious adverse drug reactions compared with control chemotherapy. CONCLUSION: Trabectedin did not improve median OS and showed a worse safety profile in comparison with physician's choice control chemotherapy.

Metastatic site patterns by intrinsic subtype and HER2DX in early HER2-positive breast cancer.

BACKGROUND: Even with contemporary treatment strategies, more than 10% of HER2-positive early stage breast cancer patients may experience distant metastasis as first event during follow-up. Tools for predicting unique patterns of metastatic spread are needed to plan personalized surveillance. We evaluated how molecular heterogeneity affects the pattern of distant relapse in HER2-positive breast cancer. METHODS: A total of 677 HER2-positive stage I-III breast cancer patients from ShortHER trial, Cher-LOB trial, and 2 institutional cohorts were included. PAM50 molecular subtypes and research-based HER2DX scores were evaluated. The cumulative incidence of distant relapse as the first event (any site and site specific) was evaluated using competing risk analysis. Median follow-up was 8.4 years. Tests of statistical significance are 2-sided. RESULTS: Stage III and high HER2DX risk score identified patients at the highest risk of distant relapse as first event (10-year incidence 24.5% and 19.7%, respectively). Intrinsic molecular subtypes were associated with specific patterns of metastatic spread: compared with other subtypes, HER2-enriched tumors were more prone to develop brain metastases (10-year incidence 3.8% vs 0.6%, P = .005), basal-like tumors were associated with an increased risk of lung metastases (10-year incidence 11.1% vs 2.6%, P = .001), and luminal tumors developed more frequently bone-only metastases (10-year incidence 5.1% vs 2.0%, P = .042). When added to stage or HER2DX risk score in competing risk regression models, intrinsic subtype maintained an independent association with site-specific metastases. CONCLUSIONS: The integration of intrinsic molecular subtypes with stage or HER2DX risk score predicts site-specific metastatic risk in HER2-positive breast cancer, with potential implications for personalized surveillance and clinical trials aimed at preventing site-specific recurrence.

Randomized, open-label, phase II, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with locally advanced, inflammatory, or early HER2-positive breast cancer-Immun-HER trial (GOIRC-01-2016).

BACKGROUND: It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab. METHODS: In this multicenter randomized phase II trial, all enrolled patients (pts) with T2-T4d HER2-positive BC received 3 cycles of neoadjuvant treatment (NAT) with fluorouracil, epirubicin and cyclophosphamide every 3 weeks (q21), followed by docetaxel/pertuzumab plus intravenous trastuzumab (arm A) or, docetaxel/pertuzumab plus subcutaneous (SC) trastuzumab (arm B) q21x4 cycles. After surgical operation, each pt was treated with trastuzumab q21x14 cycles using the same SC or intravenous formulation of NAT. Primary endpoint was the proportion of subjects with high stromal tumor-infiltrating lymphocytes (sTILs) in postneoadjuvant residual disease (RD). RESULTS: Sixty-three pts (31 (arm A) and 32 (arm B)) were enrolled. Pathological complete response was obtained by 20/31 pts (64.5%; 95% CI 45.4% to 80.1%) in arm A and 19/32 pts (59.4%; 95% CI 40.1% to 76.3%) in arm B. High sTILs were observed in 27% and 46% of postneoadjuvant residual tumors in arms A and B, respectively. CD8+ T cells increased significantly in RDs of both arms (p=0.014 and 0.002 for arm A and B, respectively), whereas a significant decline in the level of CD4+ FoxP3+ regulatory T cells was observed only in arm B (p=0.016). A significant upregulation of PD-1 on sTILs was found in RD of pts enrolled in arm B (p=0.012), while programmed death-ligand 1 (PD-L1) was significantly overexpressed in residual tumors of arm A (p=0.02). A strong negative correlation was reported in arm B between expression of PD-L1 on pretreatment sTILs and CD3 expression on sTILs in RD (τ: -0.73). Grade≥3 AE incidence rates were similar between the two arms. CONCLUSIONS: SC trastuzumab induced relevant sTILs enrichment, with favorable variations of immune parameters in HER2-positive BC pts with RD after NAT. Novel immunotherapy strategies should be tested to achieve SC-specific, antitumor immune response. TRIAL REGISTRATION NUMBER: NCT03144947, and EudraCT number: 2016-000435-41.

Neoadjuvant Systemic Therapy in Early Breast Cancer: Results of a Prospective Observational Multicenter BRIDE Study.

To evaluate the rate of early breast cancer (EBC) patients treated with neoadjuvant systemic therapy (NAT) in Italy, criteria of patient selection and types of therapies delivered, an analysis of 1276 patients with stage I-II-III was conducted out of 1633 patients enrolled in the multicenter prospective observational BRIDE study. A total of 177 patients (13.9%) were treated with NAT and 1099 (85.9%) with surgery; in multivariate analysis, menopausal status, cT, cN, grade, HER2-positive and Triple negative (TN) subgroups were significantly associated with the decision to administer NAT. The type of NAT delivered was influenced by EBC subtype. NAT was administered to 53.2% of HER2+/HR-negative, 27.9% of HER2+/HR+, 7.1% of HER2-negative/HR+ and 30.3% of TN EBC patients. The pCR rates were similar to the ones reported in the literature: 74.2% in HER2+/HR-negative, 52.3% in HER2+/HR+, 17.2% in HER2-negative/HR+ and 37.9% in TN. In clinical practice, patient and tumor characteristics influenced oncologists in the decision to administer NAT in EBC and in the choice of the type of systemic therapy, according to ESMO and AIOM Guidelines. Currently, it is recommended always to evaluate the use of NAT in EBC, mainly in HER2+ and TN patients, considering that pCR is associated with significantly better survival of the patient and that effective therapies are now available for residual disease.

SNP of Aromatase Predict Long-term Survival and Aromatase Inhibitor Toxicity in Patients with Early Breast Cancer: A Biomarker Analysis of the GIM4 and GIM5 Trials.

PURPOSE: In estrogen receptor-positive (ER+) breast cancer, single-nucleotide polymorphisms (SNP) in the aromatase gene might affect aromatase inhibitors (AI) metabolism and efficacy. Here, we assessed the impact of SNP on prognosis and toxicity of patients receiving adjuvant letrozole. EXPERIMENTAL DESIGN: We enrolled 886 postmenopausal patients in the study. They were treated with letrozole for 2 to 5 years after taking tamoxifen for 2 to 6 years, continuing until they completed 5 to 10 years of therapy. Germline DNA was genotyped for SNP rs4646, rs10046, rs749292, and rs727479. Log-rank test and Cox model were used for disease-free survival (DFS) and overall survival (OS). Cumulative incidence (CI) of breast cancer metastasis was assessed through competing risk analysis, with contralateral breast cancer, second malignancies and non-breast cancer death as competing events. CI of skeletal and cardiovascular events were assessed using DFS events as competing events. Subdistribution HR (sHR) with 95% confidence intervals were calculated through Fine-Gray method. RESULTS: No SNP was associated with DFS. Variants rs10046 [sHR 2.03, (1.04-2.94)], rs749292 [sHR 2.11, (1.12-3.94)], and rs727479 [sHR 2.62, (1.17-5.83)] were associated with breast cancer metastasis. Three groups were identified on the basis of the number of these variants (0, 1, >1). Variant-based groups were associated with breast cancer metastasis (10-year CI 2.5%, 7.6%, 10.7%, P = 0.035) and OS (10-year estimates 96.5%, 93.0%, 89.6%, P = 0.030). Co-occurrence of rs10046 and rs749292 was negatively associated with 10-year CI of skeletal events (3.2% vs. 10%, P = 0.033). A similar association emerged between rs727479 and cardiovascular events (0.3% vs. 2.1%, P = 0.026). CONCLUSIONS: SNP of aromatase gene predict risk of metastasis and AI-related toxicity in ER+ early breast cancer, opening an opportunity for better treatment individualization.

Immune Checkpoint Inhibitors in "Special" NSCLC Populations: A Viable Approach?

Over the last decade, the therapeutic scenario for advanced non-small-cell lung cancer (NSCLC) has undergone a major paradigm shift. Immune checkpoint inhibitors (ICIs) have shown a meaningful clinical and survival improvement in different settings of the disease. However, the real benefit of this therapeutic approach remains controversial in selected NSCLC subsets, such as those of the elderly with active brain metastases or oncogene-addicted mutations. This is mainly due to the exclusion or underrepresentation of these patient subpopulations in most pivotal phase III studies; this precludes the generalization of ICI efficacy in this context. Moreover, no predictive biomarkers of ICI response exist that can help with patient selection for this therapeutic approach. Here, we critically summarize the current state of ICI efficacy in the most common "special" NSCLC subpopulations.

The Impact of NUTRItional Status at First Medical Oncology Visit on Clinical Outcomes: The NUTRIONCO Study.

Malnutrition affects up to 75% of cancer patients and results from a combination of anorexia and metabolic dysregulation. Metabolic and nutritional abnormalities in cancer patients can lead to cachexia, a multifactorial syndrome characterized by involuntary loss of skeletal muscle mass, systemic inflammation and increased protein catabolism. Cancer cachexia negatively affects patients' outcomes, response to anticancer treatments, quality of life, and survival. However, risk of malnutrition, and cachexia are still under-recognized in cancer patients. The Prevalence of Malnutrition in Oncology (PreMiO) study revealed that 51% of patients already had nutritional deficiencies at their first medical oncology visit. Here, we report the results of the subsequent retrospective, observational NUTRItional status at first medical oncology visit ON Clinical Outcomes (NUTRIONCO) study, aimed at assessing the impact of baseline nutritional and non-nutritional variables collected in the PreMiO study on the clinical outcomes of the same patients followed up from August 2019 to October 2021. We have highlighted a statistically significant association between baseline variables and patient death, rehospitalization, treatment toxicity, and disease progression at follow-up. We found a higher overall survival probability in the well-nourished general study population vs. malnourished patients (p < 0.001). Of major interest is the fact that patient stratification revealed that malnutrition decreased survival probability in non-metastatic patients but not in metastatic patients (p < 0.001). Multivariate analysis confirmed that baseline malnutrition (p = 0.004) and VAS score for appetite loss (p = 0.0104), in addition to albumin < 35 g/L (p < 0.0001) and neutrophil/lymphocyte ratio > 3 (p = 0.0007), were independently associated with the death of non-metastatic patients at follow-up. These findings highlight the importance of proactive, early management of malnutrition and cachexia in cancer patients, and in particular, in non-metastatic patients, from the perspective of a substantial improvement of their clinical outcomes.

Prognostic and clinical impact of the endocrine resistance/sensitivity classification according to international consensus guidelines for advanced breast cancer: an individual patient-level analysis from the Mammella InterGruppo (MIG) and Gruppo Italiano Mammella (GIM) studies.

Background: Prior exposure to adjuvant endocrine therapy (ET) and timing to recurrence are crucial factors for first-line treatment choices in patients with hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC) and in clinical trial eligibility, classifying metastatic HR+/HER2- BC as endocrine sensitive (ES) or primary (1ER)/secondary (2ER) resistant. However, this classification is largely based on expert opinion and no proper evidence exists to date to support its possible prognostic and clinical impact. Methods: This analysis included individual patient-level data from 4 adjuvant phase III randomized trials by the Mammella InterGruppo (MIG) and Gruppo Italiano Mammella (GIM) study groups. The impact of endocrine resistance/sensitivity classification on overall survival (mOS, defined as time between date of distant relapse and death) was assessed in both univariate and multivariate Cox proportional hazards models. Findings: Between November 1992 and July 2012, 9058 patients were randomized in 4 trials, of whom 6612 had HR+/HER2- BC. Median follow-up was 9.1 years (interquartile range [IQR] 5.6-15.0). In the whole cohort, disease-free survival and OS were 90.4% and 96.6% at 5 years, and 79.1% and 89.4% at 10 years, respectively. The estimated hazard of recurrence raised constantly during the first 15 years from diagnosis, being more pronounced during the first 2 years and less pronounced after year 7. Among the 493 patients with a distant relapse as first disease-free survival event and available date on ET completion, 72 (14.6%), 207 (42.0%) and 214 (43.4%) were classified as having 1ER, 2ER and ES, respectively. Median follow-up from diagnosis of a distant relapse was 3.8 years (IQR 1.6-7.5). Patients with 1ER were significantly more likely to be younger, to have N2/N3 nodal status, grade 3 tumours and to develop visceral metastases. Site of first distant relapse was significantly different between the 3 groups (p = 0.005). In patients with 1ER, 2ER and ES breast cancer, median mOS was 27.2, 38.4 and 43.2 months, respectively (p = 0.03). As compared to patients with ES disease, a higher risk of death was observed in those with 1 ER (adjusted Hazard Ratio [aHR] 1.54; 95% CI 1.03-2.30) and 2ER (aHR 1.17; 95% CI 0.87-1.56) (p = 0.11). Interpretation: This large analysis with long-term follow-up provides evidence on the prognostic and clinical impact of the currently adopted endocrine resistance/sensitivity classification in patients with HR+/HER2- advanced BC. This classification may be considered a valid tool to guide clinical decision-making and to design future ET trials in the metastatic setting. Funding: AIRC.

Circular RNAs Could Encode Unique Proteins and Affect Cancer Pathways.

circRNAs constitute a novel class of RNA, generally considered as non-coding RNAs; nonetheless, their coding potential has been under scrutiny. In this work, we systematically explored the predicted proteins of more than 160,000 circRNAs detected by exome capture RNA-sequencing and collected in the MiOncoCirc pan-cancer compendium, including normal and cancer samples from different types of tissues. For the functional evaluation, we compared their primary structure and domain composition with those derived from the same linear mRNAs. Among the 4362 circRNAs potentially encoding proteins with a unique primary structure and 1179 encoding proteins with a novel domain composition, 183 were differentially expressed in cancer. In particular, eight were associated with prognosis in acute myeloid leukemia. The functional classification of the dysregulated circRNA-encoded polypeptides showed an enrichment in the heme and cancer signaling, DNA-binding, and phosphorylation processes, and disclosed the roles of some circRNA-based effectors in cancer.

Type of adjuvant endocrine therapy and disease-free survival in patients with early HR-positive/HER2-positive BC: analysis from the phase III randomized ShortHER trial.

The optimal adjuvant endocrine therapy for HR-positive/HER2-positive breast cancer patients is unknown. We included in this analysis 784 patients with HR-positive/HER2-positive BC from the randomized ShortHER trial of adjuvant trastuzumab (1 year vs 9 weeks) + chemotherapy. At a median follow-up of 8.7 years, patients who received AI had a significantly better DFS vs patients who received TAM or TAM-AI: 8-yr DFS 86.4 vs 79.7%, log-rank P = 0.013 (HR 1.52, 95% CI 1.09-2.11). In multivariate analysis, the type of endocrine therapy maintained a significant association with DFS (HR 1.64, 95% CI 1.07-2.52, p = 0.025 for TAM/TAM-AI vs AI). Among premenopausal patients aged ≤45 years, the use of GnRHa was associated with longer DFS: 8-yr DFS rate 85.2 vs 62.6% (log-rank p = 0.019, HR 0.41, 95% CI 0.19-0.88). In this post-hoc analysis of the ShortHER trial adjuvant treatment with AI was independently associated with improved DFS. Subgroup analysis in premenopausal patients suggests benefits with ovarian suppression.Trial registration: NCI ClinicalTrials.gov number: NCT00629278.

Erratum: miR-199a-3p increases the anti-tumor activity of palbociclib in liver cancer models.

[This corrects the article DOI: 10.1016/j.omtn.2022.07.015.].

Safety and Efficacy of Ribociclib in Combination with Letrozole in Patients with HR+, HER2- Advanced Breast Cancer: Results from the Italian Subpopulation of Phase 3b CompLEEment-1 Study.

BACKGROUND: Ribociclib plus letrozole demonstrated manageable safety and efficacy profiles in hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) in the Phase 3b CompLEEment-1 trial. OBJECTIVE: To evaluate the safety and efficacy of ribociclib plus letrozole in the Italian subpopulation with HR+, HER2- ABC from the CompLEEment-1 trial. PATIENTS AND METHODS: Patients with HR+, HER2- ABC received ribociclib (600 mg/day, 3 weeks on/1 week off) plus letrozole (2.5 mg/day) while men and premenopausal women additionally received goserelin. Patients were allowed with ≤ 1 line of prior chemotherapy and an Eastern Cooperative Oncology Group performance status of ≤ 2. The primary outcome included safety and tolerability. RESULTS: Of the 554 Italian patients, 246 (44.4 %) patients completed treatment. The reasons for treatment discontinuation included progressive disease (PD; 36.6 %), adverse events (AEs; 11.9 %), and death (1.6 %). All-grade AEs and grade ≥ 3 AEs occurred in 98.9 % and 77.8 % patients, respectively. The most common treatment-related AEs were neutropenia (73.6 %), followed by leukopenia (32.1 %), and nausea (25.3 %). The overall response rate was 28.2 % (95 % confidence interval [CI], 24.4-32.1); clinical benefit rate was 71.7 % (95 % CI, 67.7-75.4); and median time to progression was 26.7 months (95 % CI, 24.8-non-estimable). Health-related quality of life scores were maintained during treatment. CONCLUSION: The safety and efficacy profiles of ribociclib plus letrozole in the Italian subpopulation was found to be consistent with the CompLEEment-1 global population result, MONALEESA-2, and MONALEESA-7 outcomes, which reaffirm ribociclib plus letrozole as the frontline treatment option in patients with HR+, HER2- ABC. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: NCT02941926 (30 November 2016).

Monitoring Somatic Genetic Alterations in Circulating Cell-Free DNA/RNA of Patients with "Oncogene-Addicted" Advanced Lung Adenocarcinoma: A Real-World Clinical Study.

Liquid biopsy has advantages over tissue biopsy, but also some technical limitations that hinder its wide use in clinical applications. In this study, we aimed to evaluate the usefulness of liquid biopsy for the clinical management of patients with advanced-stage oncogene-addicted non-small-cell lung adenocarcinomas. The investigation was conducted on a series of cases-641 plasma samples from 57 patients-collected in a prospective consecutive manner, which allowed us to assess the benefits and limitations of the approach in a real-world clinical context. Thirteen samples were collected at diagnosis, and the additional samples during the periodic follow-up visits. At diagnosis, we detected mutations in ctDNA in 10 of the 13 cases (77%). During follow-up, 36 patients progressed. In this subset of patients, molecular analyses of plasma DNA/RNA at progression revealed the appearance of mutations in 29 patients (80.6%). Mutations in ctDNA/RNA were typically detected an average of 80 days earlier than disease progression assessed by RECIST or clinical evaluations. Among the cases positive for mutations, we observed 13 de novo mutations, responsible for the development of resistance to therapy. This study allowed us to highlight the advantages and disadvantages of liquid biopsy, which led to suggesting algorithms for the use of liquid biopsy analyses at diagnosis and during monitoring of therapy response.

18F-Choline PET/CT or PET/MR and the evaluation of response to systemic therapy in prostate cancer: are we ready?

Purpose: During the last decade, [18F]F-choline positron emission tomography (PET) had a rising role in prostate cancer (PCa) imaging. However, despite auspicious premises, [18F]F-choline PET is not currently recommended for the evaluation of response to therapy assessment in PCa, mainly due to the lack of large-scale prospective trials. Methods: We report the cases of seven patients affected by PCa, in which [18F]F-choline PET (either with computed tomography-CT or magnetic resonance imaging-MR) contributed significantly in the systemic therapy response evaluation. Results and conclusion: [18F]F-choline PET/CT or PET/MR demonstrated to be a useful imaging modality in the assessment of response to systemic therapy in metastatic PCa patients, irrespective of the stage of disease (either in hormone sensitive and in castrate resistant condition) and the kind of systemic treatment. In most cases, PSA serum values and [18F]F-choline PET showed a synchronous disease evolution after systemic therapy. ADT can alter [18F]F-choline uptake, therefore the time of scan should be correctly planned. Finally, PET/CT with [18F]F-choline is a useful tool for reinforcing the identification of metastatic disease in case of a switch from metastatic castration sensitive to castration resistant PCa.

miR-199a-3p increases the anti-tumor activity of palbociclib in liver cancer models.

Palbociclib is in early-stage clinical testing in advanced hepatocellular carcinoma (HCC). Here, we investigated whether the anti-tumor activity of palbociclib, which prevents the CDK4/6-mediated phosphorylation of RB1 but simultaneously activates AKT signaling, could be improved by its combination with a PI3K/AKT/mTOR inhibitor in liver cancer models. The selective pan-AKT inhibitor, MK-2206, or the microRNA-199a-3p were tested in combination with palbociclib in HCC cell lines and in the TG221 HCC transgenic mouse model. The combination palbociclib/MK-2206 was highly effective, but too toxic to be tolerated by mice. Conversely, the combination miR-199a-3p mimics/palbociclib not only induced a complete or partial regression of tumor lesions, but was also well tolerated. After 3 weeks of treatment, the combination produced a significant reduction in number and size of tumor nodules in comparison with palbociclib or miR-199a-3p mimics used as single agents. Moreover, we also reported the efficacy of this combination against sorafenib-resistant cells in vitro and in vivo. At the molecular level, the combination caused the simultaneous decrease of the phosphorylation of both RB1 and of AKT. Our findings provide pre-clinical evidence for the efficacy of the combination miR-199a-3p/palbociclib as anti-HCC treatment or as a new approach to overcome sorafenib resistance.

Definition of High-Risk Early Hormone-Positive HER2-Negative Breast Cancer: A Consensus Review.

Breast cancer is one of the major causes of cancer-related morbidity and mortality in women worldwide. During the past three decades, several improvements in the adjuvant treatment of hormone receptor-positive/HER2-negative breast cancer have been achieved with the introduction of optimized adjuvant chemotherapy and endocrine treatment. However, estimating the risk of relapse of breast cancer on an individual basis is still challenging. The IRIDE (hIGh Risk DEfinition in breast cancer) working group was established with the aim of reviewing evidence from the literature to synthesize the current relevant features that predict hormone-positive/HER2-negative early breast cancer relapse. A panel of experts in breast cancer was involved in identifying clinical, pathological, morphological, and genetic factors. A RAND consensus method was used to define the relevance of each risk factor. Among the 21 features included, 12 were considered relevant risk factors for relapse. For each of these, we provided a consensus statement and relevant comments on the supporting scientific evidence. This work may guide clinicians in the practical management of hormone-positive/HER2-negative early breast cancers.

Role of PSMA-ligands imaging in Renal Cell Carcinoma management: current status and future perspectives.

BACKGROUND: Renal masses detection is continually increasing worldwide, with Renal Cell Carcinoma (RCC) accounting for approximately 90% of all renal cancers and remaining one of the most aggressive urological malignancies. Despite improvements in cancer management, accurate diagnosis and treatment strategy of RCC by computed tomography (CT) and magnetic resonance imaging (MRI) are still challenging. Prostate-Specific Membrane Antigen (PSMA) is known to be highly expressed on the endothelial cells of the neovasculature of several solid tumors other than prostate cancer, including RCC. In this context, recent preliminary studies reported a promising role for positron emission tomography (PET)/CT with radiolabeled molecules targeting PSMA, in alternative to fluorodeoxyglucose (FDG) in RCC patients. PURPOSE: The aim of our review is to provide an updated overview of current evidences and major limitations regarding the use of PSMA PET/CT in RCC. METHODS: A literature search, up to 31 December 2021, was performed using the following electronic databases: PubMed, SCOPUS, Web of Science, and Google Scholar. RESULTS: The findings of this review suggest that PSMA PET/CT could represent a valid imaging option for diagnosis, staging, and therapy response evaluation in RCC, particularly in clear cell RCC. CONCLUSIONS: Further studies are needed for this "relatively" new imaging modality to consolidate its indications, timing, and practical procedures.

Impact on the long-term prognosis of FDG PET/CT in luminal-A and luminal-B breast cancer.

PURPOSE: The aim of the present study was to explore the prognostic role of 2- deoxy-2-[18F]fluoro-D-glucose PET (FDG PET)/CT in recurrent luminal A and luminal B breast cancer. MATERIALS AND METHODS: From two institutional databases, we retrospectively retrieved data about breast cancer patients undergoing FDG PET/CT between 2011 and 2018 for the assessment of recurrency. Molecular subtypes of breast cancer were defined based on the expression of estrogen, progesterone, human epidermal growth factor receptor 2 (HER2)-b receptors and proliferation index. Overall survival (OS, intended as the time from PET/CT and the time of death) was registered for each patient, by checking the medical charts. Parametric and survival analyses were computed. RESULTS: Data of 179 patients were retrieved. Sixty-three patients had luminal A, 88 luminal B and 28 luminal B/He breast cancer. At the time of PET/CT scan, cancer antigen (CA) 15.3 levels was within the normal range in 119 patients, whereas it was increased in 60 patients. FDG PET/CT results were suggestive for disease recurrence in 114 (63.7%) patients. The median time lapse from the FDG PET/CT scan to the last clinical follow-up visit was 51 months (1-192 months). Patients with evidence of a PET/CT scan suggestive for disease recurrence showed a significantly shorter OS (P < 0.001) compared to patients with no PET/CT evidence of recurrence, in each subset of luminal breast cancer. Moreover, PET/CT was able to stratify the prognosis of patients independently from the level of tumor marker. CONCLUSION: These data suggest that FDG PET/CT may be an attractive prognostic tool in recurrent breast cancer. Our study supports its prognostic role both in luminal A and B-type molecular subtypes, regardless of the CA 15.3 levels.

A phase II, open-label, single-arm trial of carboplatin plus etoposide with bevacizumab and atezolizumab in patients with extended-stage small-cell lung cancer (CeLEBrATE study): background, design and rationale.

Based on improved survival from the addition of PD-L1 inhibitors in phase III trials, the combination of immunotherapy and platinum-doublet chemotherapy has become the new standard treatment for extended-stage small-cell lung cancer (ES-SCLC). Furthermore, the antiangiogenetic agent bevacizumab showed a longer progression-free survival by targeting VEGF that has pleiotropic effects, including immunosuppressive ones. We, therefore, hypothesized that targeting angiogenesis would improve the efficacy of chemoimmunotherapy. The CeLEBrATE trial is an open-label, multicenter, phase II study designed to assess the efficacy and safety of the combination of carboplatin and etoposide plus bevacizumab and atezolizumab in treatment-naive patients with ES-SCLC. The primary end point is overall survival rate at 1 year, while secondary end points include overall response rate, progression-free survival and toxicity.

Lay abstract Extended-stage small-cell lung cancer (ES-SCLC) is a highly aggressive lung cancer subtype, accounting for 13­15% of all lung cancers. For several years, the standard treatment for this disease was based on polychemotherapy, with a rapid disease response but with an equally rapid disease progression. The new standard treatment has recently been changed, based on the results of two large clinical trials, which showed the efficacy and safety of the combination of chemotherapy with immunotherapy compared to chemotherapy alone. Nevertheless, prognosis of ES-SCLC remains poor, and new treatment strategies are urgently needed. Therefore, we designed the CeLEBrATE trial to investigate whether the combination of chemotherapy with antiangiogenetic therapy and immunotherapy is safe and could improve survival in patients with ES-SCLC.