Background/Objectives: In metastatic colorectal cancer (mCRC), liquid biopsy has enabled the identification of "neo-RAS-Wild-Type (WT)", a transient phase characterized by the disappearance of RAS mutations, with significant clinical implications for re-sensitization to EGFR blockade. This study aimed to prospectively track the kinetics of neo-RAS-WT in circulating tumor DNA (ctDNA) among RAS-mutant mCRC patients receiving first-line and subsequent systemic therapies. Methods: A total of 380 serial blood samples from 35 patients were analyzed. Each patient provided a median of 10 ctDNA samples at three-month intervals during first-line and subsequent therapies. The patients were categorized into three groups: neo-RAS-WT, non-shedding, and persistent mutant. Results: During first-line treatment, 68% of patients transitioned to RAS-WT. Of these, 17% were neo-RAS-WT, while the majority were classified as non-shedding. In the second-line setting, the percentage of neo-RAS-WT increased to 34%, which dropped to 8.5% during the third-line setting. The duration of the neo-RAS-WT window was significantly longer in neo-RAS-WT patients compared to non-shedding patients (p = 0.037). Patients who achieved RAS-WT status had improved progression-free survival (PFS) compared to those with persistent mutant, with significant differences observed across all treatment lines: first-line (p = 0.004), second-line (p < 0.0001), and third-line (p = 0.001). Multivariate analysis revealed that the duration of the RAS-WT window correlated with extended first-line PFS (HR: 0.78; 95% CI: 0.69-0.89; p < 0.0001), second-line PFS (HR: 0.66; 95% CI: 0.52-0.84; p = 0.001), and overall survival (OS) (HR: 0.82; 95% CI: 0.72-0.95; p = 0.006). Conclusions: While the neo-RAS-WT window is transient in non-shedding, it is durable in neo-RAS-WT patients, persisting until disease progression. These findings highlight the potential utility of ctDNA testing in refining treatment strategies for RAS-mutant mCR.

Abstract Background: The exploration of heterogeneity in mBC has gained significant interest in optimizing therapeutic strategies. While the impact of differential HER2 IHC staining has been extensively studied in HER2-low neoplasms, limited data is available regarding IHC 2+ and IHC 3+ categories in HER2-pos mBC. The aim of our study is to compare, the clinical variables, metastatic patterns, and prognosis between patients classified as IHC 2+ and IHC 3+ in HER2-pos mBC. Methods: Pts with HER2 pos mBC, determined by HER2 IHC staining of 3+ or 2+ with amplification at the in situ hybridization assay, were selected from the GIM14 study database for analysis. Associations among variables were assessed by conducting logistic regression analyses. Additionally, prognostic factors for overall survival (OS) and time to treatment failure (TTF) were evaluated using both uni- and multi-variable Cox regression models. Results: A total of 766 HER2-pos mBC pts were included in the analysis. Among them, 302 (39%) had IHC score of 2+ and 464 (61%) had a IHC score of 3+. Central nervous system (CSN) metastases (mts) were observed in 68 (9%) pts (32% IHC 2+; 68% IHC 3+), lymph node (LN) mts in 330 (43%) pts (46% IHC 2+; 54% IHC 3+), lung (LU) mts in 182 (24%) pts (46% IHC 2+; 54% IHC 3+), liver (LI) mts in 227 (30%) pts (45% IHC 2+, 55% IHC 3+), skin (SK) mts in 68 (9%) pts (28% IHC 2+; 72% IHC 3+) and pleural (PL) mts in 40 (5%) pts (47% IHC 2+, 53% IHC 3+). In univariable (uni) analysis, IHC 3+ compared to IHC 2+ was significantly associated with SK mts (OR 1.76, P=0.043) and less likely to be associated with LI (OR 0.71, P=0.031), LU (OR 0.70, P =0.036), and LN (OR 0.63, P=0.002) mts. In multivariable (multi) analysis, LN mts maintained statistical significance (OR 0.62, P=0.004). In subgroup analysis, among IHC 3+ patients, factors associated with worse OS pts were neo Tx (HR 1.55, P=0.032), adjuvant radiotherapy (HR 1.34, P=0.042), neo ChT (HR 1.63, P=0.002), CNS mts (HR 1.98, P=0.002), and LI mts (HR 1.68, P< 0.0001). In multi analysis, CNS mts (HR 1.73, P=0.028) and LI mts (HR 1.47, P=0.017) remained prognostic for IHC 3+ subgroup. The only factor associated with worse OS in IHC 2+ pts was LI mts (HR 1.67, P=0.005). Multi analysis in the overall HER2-pos population identified neo chemotherapy (ChT) (HR 1.49, P=0.009), CNS mts (HR 1.53, P=0.003) and PL mts (HR 1.50, P=0.036) as negative prognostic factors for OS, while PL mts (HR 1.74, P=0.048) were associated with a shorter time to treatment failure (TTF). Conclusions: Our exploratory data revealed that HER2-pos mBC with a IHC score of 3+ is less likely to be associated with LN mts and with visceral mts. The site of mts has prognostic significance, as CNS mts are associated with worse OS in pts with an IHC score of 3+ pts, while LI mts are associated with worse OS in both IHC 2+ and 3+ subgroups. However, the IHC score itself (2+ or 3+) does not have independent prognostic value. The relationship between HER2 IHC staining and treatment outcomes requires further investigation to better understand its potential impact on clinical practice. Citation Format: Arianna Dri, Eva Blondeaux, Claudia Bighin, Simona Gasparro, Stefania Russo, Lorenzo Foffano, Palma Pugliese, Andrea Fontana, Enrico Cortesi, Antonella Ferzi, Ferdinando Riccardi, Valentina Sini, Luca Boni, Alessandra Fabi, Filippo Montemurro, Michelino De Laurentiis, Grazia Arpino, Lucia Del Mastro, Lorenzo Gerratana, Fabio Puglisi. HER2 immunohistochemistry (IHC) expression in HER2-positive (HER2-pos) metastatic breast cancer (mBC): clinical and prognostic differences between IHC 2+ and IHC 3+ populations [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-05.

Abemaciclib demonstrated clinical benefit in women affected by HR+/HER2− advanced breast cancer (aBC). Drug-drug interactions (DDIs) can lead to reduced treatment efficacy or increased toxicity. This retro-prospective study aimed to evaluate outcomes, DDIs’ impact, and toxicities of abemaciclib combined with endocrine therapy in a real-world setting. Patients from 12 referral Italian hospitals with HR+/HER2− aBC who received abemaciclib were included. Clinical data about comorbidities, concurrent medications, outcomes, and adverse events (AE) were collected. Drug-PIN® (Personalized Interactions Network) is a tool recognizing the role of multiple interactions between active and/or pro-drug forms combined with biochemical and demographic patient data. The software was used to define the Drug-PIN score and Drug-PIN tier (green, yellow, dark yellow, and red) for each patient. Univariate and multivariate analyses were performed to identify predictors of patients’ PFS or toxicity. One hundred seventy-three patients were included. 13% of patients had >75years. The overall response rate (ORR) was 63%. The general population’s median PFS (mPFS) was 22 months (mo), while mOS were not reached. Patients treated with abemaciclib in combination with AI and fulvestrant had a mPFS of 36 and 19 mo, respectively. The most common toxicities were diarrhea, asthenia, and neutropenia detected in 63%,49%, and 49% of patients. The number of concomitant medications and comorbidities were not associated with survival outcomes (22 vs 17 mo, p = 0.068, p = 0.99). Drug-PIN tier from dark yellow to red and Drug-PIN score >12 were associated with shorter PFS compared to no/low-risk DDIs and score <12 (15 vs 23, p = 0.005, p = 0.0017). Drug interaction was confirmed as an independent biomarker in a multivariate model (p = 0.02). No difference in any grade AE, severe toxicities, and diarrhea were detected among different age subgroups. No association was found between Drug-PIN score or Drug-PIN tier and overall toxicity (p = 0.44), severe AEs (p = 0.11), or drug reduction (p = 0.27). The efficacy and safety of abemaciclib plus ET were confirmed in a real-world setting, even in the elderly population and patients with comorbidities. Evaluation of DDIs with Drug-PIN appears to be an independent predictor of PFS.

Patients with nonresectable breast cancer liver metastasis (BCLM) face a dismal prognosis. Despite liver transplantation (LT) for metastatic liver tumors having recently shown good results, BCLM represents an absolute contraindication. This study aimed to investigate the potential for long-term survival after LT for BCLMs in a patient experiencing end-stage liver disease, following multiple oncologic treatments. In July 2019, we performed a deceased donor LT on a 41-year-old female with BCLM controlled with human epidermal growth factor receptor 2 targeted therapy, who developed liver failure following multiple locoregional liver-directed treatments. The primary tumor was treated with surgical resection and adjuvant chemoradiation in 2000. The procedure was performed under a protocol approved by the local ethical committee, and by the Italian National Transplant Center. A 12-month treatment with trastuzumab was performed immediately after LT. Immunosuppression following transplantation was undertaken without steroids, and with everolimus. The patient completed 12 months of follow-up without recurrence. Trastuzumab was then withdrawn. Fifteen months after LT, a liver recurrence occurred that was treated with chemotherapy. In October 2021, she developed 2 brain lesions that were treated with stereotactic radiation. The patient is still alive, with a positron emission tomography/computed tomography performed in January 2024 showing no disease. LT for this patient with BCLM of extreme selectivity showed a good clinical outcome. Perioperative systemic treatment and tumor control are necessary. A specific protocol should be discussed within a multidisciplinary team, and with local and national authorities. Even if tumor recurrence occurs, multimodal therapy can control the disease.

Cancer patients (CPs), being immunosuppressed due to the treatment received or to the disease itself, are more susceptible to infections and their potential complications, showing therefore an increased risk of developing severe COVID-19 compared to the general population.We evaluated the immune responses to anti-SARS-CoV-2 vaccination in patients with solid tumors one year after the administration of the third dose and the effect of cancer treatment on vaccine immunogenicity was assessed. Healthy donors (HDs) were enrolled. Binding and neutralizing antibody (Ab) titers were evaluated using chemiluminescence immunoassay (CLIA) and Plaque Reduction Neutralization Test (PRNT) respectively. T-cell response was analyzed using multiparametric flow cytometry.CPs who were administered three vaccine doses showed lower Ab titers than CPs with four doses and HDs. Overall, a lower cell-mediated response was found in CPs, with a predominance of monofunctional T-cells producing TNFα. Lower Ab titers and a weaker T-cell response were observed in CPs without prior SARS-CoV-2 infection when compared to those with a previous infection. While no differences in the humoral response were found comparing immunotherapy and non-immunotherapy patients, a stronger T-cell response in CPs treated with immunotherapy was observed.Our results emphasize the need of booster doses in cancer patients to achieve a level of protection similar to that observed in healthy donors and underlines the importance of considering the treatment received to reach a proper immune response.

AIMS:To analyze the long-term results of a prospective phase II trial testing intensified total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer (LARC). MATERIALS AND METHODS:Patients with histologically confirmed LARC adenocarcinoma were enrolled. Intensified TNT consisted of targeted agent (bevacizumab or panitumumab/cetuximab) plus FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) induction chemotherapy followed by intensified (oxaliplatin and 5-fluorouracil) chemoradiotherapy (CRT) and surgical resection. Follow-up data were collected for all patients included in the trial. Survival outcomes were calculated using the Kaplan-Meier method and curves were compared by the log-rank test. RESULTS:Between October 2015 and September 2019, 28 LARC patients were enrolled. Follow-up data were available for all included patients. In total, 11 (39.3%) patients had a complete response (CR). At 6.3 years (median follow-up), 5-year overall survival (OS) and DFS were 74.6% and 57.1%, respectively. Five-year OS was 80.8% for CR patients and 70.1% for no-CR patients (p-value 0.07). Those patients with CR after TNT treatment had a 5-year DFS of 81.8% versus 41.2% for those with no CR (p-value 0.015). CONCLUSION:The addition of a targeted agent to induction FOLFOXIRI and oxaliplatin to 5-fluorouracil-based CRT, with the doses and intensities used in this study, resulted in high CR rates. Patients who achieve a CR demonstrate superior DFS compared to patients without CR. Intensified TNT may have the potential to increase survival outcomes. Further research on TNT strategies in LARC is encouraged.

This study aimed to identify the clinico-pathological variables predictive of radiologic complete response (rCR) to first-line anti-HER2 therapy in patients with HER2-positive metastatic breast cancer. Patients were selected from the database of the GIM14 study and classified according to the best radiologic response obtained to first-line anti-HER2 therapy and upon time-to-treatment-discontinuation (TTD). A total of 545 patients were included in the analysis. Eighty patients experienced a rCR to first-line anti-HER2 therapy with a TTD > 3 months and HER2 Immunohistochemistry score 3+, presence of non-visceral metastases and 1 metastatic site were significantly associated with higher odds of obtaining a CR. Of the 80 patients achieving a rCR, 56 experienced a CR with a TTD > 18 months, with anti-HER2 therapy being the only variable significantly associated with a higher probability of achieving such sustained CR.

BACKGROUND:Bilateral testicular germ cell tumours (B-GCT) are rare, with an incidence of 2-5%, and can be classified as synchronous (sB-GCT) or metachronous (mB-GCT). Our study aimed to identify clinical, biochemical, and radiological risk factors for mB-GCT in a cohort of patients with GCT at a single tertiary referral centre. METHODS:This retrospective case-control study included patients with GCT referred to Policlinico Umberto I-Sapienza University of Rome, from 2005 to 2023. We evaluated clinical history, testicular ultrasound features, hormone levels, semen analysis, histological characteristics, staging, and treatments. mB-GCTs were compared with unilateral GCT patients with a follow-up longer than the median time-to-onset of the second tumour. RESULTS:Of 319 patients, 52 experienced B-GCT, with a median time-to-onset of the second tumour of 62 months (range: 8-229). The mB-GCT group showed higher gonadotropin levels (FSH 13.6mUI/mL vs. 7.4mUI/mL, p < 0.001; LH 6.6mUI/mL vs. 3.9mUI/mL, p = 0.004), lower sperm concentration (27 × 106/ejaculate vs. 78 × 106/ejaculate, p = 0.009), smaller residual testis volume (10.4 mL vs. 16.3 mL, p < 0.001), more inhomogeneous echotexture [57.5% vs. 14%, p < 0.001], and presence of microlithiasis (75% vs. 19.5%, p < 0.001). Kaplan-Meier curves confirmed that ultrasound features of the residual testis increased the cumulative risk of developing a second tumour. Microlithiasis was a strong independent predictor (OR 30.712, 95% CI 3.357-280.942, p = 0.002). CONCLUSIONS:Histological features of the first tumour or its treatment do not influence the onset of a second tumour. However, low residual testis volume, inhomogeneous echotexture, and microlithiasis significantly increase this risk. A comprehensive evaluation of the residual testis at baseline is essential for developing a personalised surveillance programme in GCT survivors, with regular ultrasound follow-up recommended beyond the conventional 5-year limit.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of tumors. Natural killer (NK) cells can play an important role in cancer immune surveillance. The aim of this prospective observational study was to analyze peripheral blood mononuclear cells (PBMCs) in patients with advanced non-small-cell lung cancer (NSCLC) receiving ICIs in order to identify predictive factors for better survival outcomes. Methods: Forty-seven stage IV NSCLC patients were enrolled. Patients underwent baseline (T0) and longitudinal (T1) evaluations after ICIs. Peripheral immune blood cell counts were analyzed using flow cytometry. Results: Basal levels of CD3−CD56+ NK cells were higher in patients with controlled disease (DC) compared to progression disease (PD) patients (127 cells/µL vs. 27.8 cells/µL, p < 0.001). Lower NK cell values were independent prognostic factors for shorter overall survival (OS) (HR 0.992; 95% CI 0.987–0.997, p < 0.001) and progression-free survival (PFS) (HR 0.988; 95% CI 0.981–0.994, p < 0.001). During the longitudinal evaluation, CD3−CD56+ NK cells (138.1 cells/µL vs. 127 cells/µL, p = 0.025) and CD56bright NK cells (27.4 cells/µL vs. 18.1 cells/µL, p = 0.034) significantly increased in the DC group. Finally, lower values of CD3−CD56+ NK cells (28.3 cells/µL vs. 114.6 cells/µL, p = 0.004) and CD56dim NK cells (13.2 cells/µL vs. 89.4 cells/µL, p < 0.001) were found in sarcopenic patients compared to patients without sarcopenia. Conclusions: Peripheral NK cells could represent a non-invasive and useful tool to predict ICI therapy response in NSCLC patients, and the association of low NK cell levels with sarcopenia deserves even more attention in clinical evaluation.

No evidence exists as to whether body mass index (BMI) impairs clinical outcomes from ALK inhibitors (ALKi) in patients with ALK-rearranged non-small cell lung cancer (NSCLC). Retrospective data of patients affected by metastatic ALK-rearranged NSCLC treated with ALKi were collected. We divided patients into "low- BMI" (≤25 kg/m2) and "high- BMI" (>25 kg/m2) categories and correlated them with overall survival (OS) and progression-free survival (PFS). We included 40 patients treated with ALKi. We observed a 3-year OS of 81.5% in high-BMI vs. 49.6% in low-BMI categories (p = 0.049); the 3-year first-line PFS was superior in high-BMI vs. low-BMI patients (47% vs. 19%, p = 0.019). As expected, patients treated with Alectinib had a 55.6% 3-year PFS vs. 7.1% for others treated with ALKi (p = 0.025). High-BMI was associated with a 100% 3-year PFS rate vs. 25.4% in low-BMI Alectinib patients (p = 0.03). BMI was independently correlated with first-line PFS and OS at multivariate analysis with PS (HR 0.39, CI 95% 0.16-0.96, p = 0.042; HR 0.18, CI 95% 0.05-0.61, p = 0.006). High-BMI was associated with higher efficacy in ALK-rearranged patients. These results are particularly exciting for Alectinib and could be correlated to mechanisms that should be investigated in subsequent prospective studies.

The use of neoadjuvant or perioperative anti-PD(L)1 was recently tested in multiple clinical trials. We performed a systematic review and meta-analysis of randomised trials comparing neoadjuvant or perioperative chemoimmunotherapy to neoadjuvant chemotherapy in resectable NSCLC. Nine reports from 6 studies were included. Receipt of surgery was more frequent in the experimental arm (odds ratio, OR 1.39) as was pCR (OR 7.60). EFS was improved in the experimental arm (hazard ratio, HR 0.55) regardless of stage, histology, PD-L1 expression (PD-L1 negative, HR 0.74) and smoking exposure (never smokers, HR 0.67), as was OS (HR 0.67). Grade > = 3 treatment-related adverse events were more frequent in the experimental arm (OR 1.22). The experimental treatment improved surgical outcomes, pCR rates, EFS and OS in stage II-IIIB, EGFR/ALK negative resectable NSCLC; confirmatory evidence is warranted for stage IIIB tumours and with higher maturity of the OS endpoint.

Oligometastatic disease has been described as an intermediate clinical state between localized cancer and systemically metastasized disease. Recent clinical studies have shown prolonged survival when aggressive locoregional approaches are added to systemic therapies in patients with oligometastases. The aim of this review is to outline the newest options to treat oligometastatic colorectal cancer (CRC), also considering its molecular patterns. We present an overview of the available local treatment strategies, including surgical procedures, stereotactic body radiation therapy (SBRT), thermal ablation, as well as trans-arterial chemoembolization (TACE) and selective internal radiotherapy (SIRT). Moreover, since imaging methods provide crucial information for the early diagnosis and management of oligometastatic CRC, we discuss the role of modern radiologic techniques in selecting patients that are amenable to potentially curative locoregional treatments.

The new landscape of treatments for metastatic clear cell renal carcinoma (mRCC) is constantly expanding, but it is associated with the emergence of novel toxicities, adding to up to those observed in the tyrosine-kinase inhibitor (TKI) era. Indeed, the introduction of immune checkpoint inhibitors (ICIs) alone or in combination has been associated with the development of immune-related adverse events (irAEs) involving multiple-organ systems which, even if rarely, had led to fatal outcomes. Moreover, due to the relatively recent addition of ICIs to the previously available treatments, the potential additive adverse effects of these combinations are still unknown. A prompt recognition and management of these toxicities currently represents a fundamental issue in oncology, since it correlates with the outcome of cancer patients. Even if clinical guidelines provide indications for the management of irAEs, no specific protocol to evaluate the individual risk of developing an adverse event during therapy is currently available. A multidisciplinary approach addressing appropriate interventions aimed at reducing the risk of any insidious, severe, and/or dose-limiting toxicity might represent the most efficacious strategy to timely prevent and manage severe irAEs, allowing indirectly to improve both patients' cancer-specific survival and quality of life. In this review, we reported a five-case series of toxicity events that occurred at our center during treatment for mRCC followed by the remarks of physicians from different specialties, pinpointing the relevant role of an integrated and extended multidisciplinary team in a modern model of mRCC patient management.

Abstract BACKGROUND Abemaciclib demonstrated clinical benefit in women affected by HR+/HER2- advanced breast cancer (aBC). Drug-drug interactions (DDIs) can lead to a reduced treatment efficacy or increased toxicity. This retro-prospective study aimed to evaluate outcomes, DDIs’ impact and toxicities of abemaciclib combined with endocrine therapy in a real-world setting. METHODS Patients from 12 referral Italian hospitals with HR+/HER2- aBC who received abemaciclib were included. Clinical data about comorbidities, concurrent medications, outcomes and adverse events (AE) were collected. Drug-PIN® (Personalized Interactions Network) is a tool recognizing the role of multiple interactions between active and/or pro-drug forms combined with biochemical and demographic patient data. The software was used to define the Drug-PIN score and Drug-PIN tier (green, yellow, dark yellow and red) for each patient. Univariate and multivariate analysis were performed to identify predictors of patients PFS or toxicity. RESULTS One hundred seventy-three patients were included. 13% of patients had > 75years. Overall response rate (ORR) was 63%. The median PFS (mPFS) of the overall population was 22 months (mo), while mOS was not reached. Patients treated with abemaciclib in combination with AI and fulvestrant had a mPFS of 36 and 19 mo, respectively. The most common toxicities were diarrhoea, asthenia and neutropenia detected in 63%,49%,49% of patients, respectively. The number of concomitant medications and comorbidities were not associated with survival outcomes (22 vs 17 mo, p = 0.068, p = 0.99). Drug-PIN tier from dark yellow to red and Drug-PIN score > 12 were associated with shorter PFS compared to no/low risk DDIs and score < 12 (15 vs 23, p = 0.005, p = 0.0017). Drug interaction was confirmed as an independent biomarker in a multivariate model (p = 0.02). No difference in any-grade AE, severe toxicities and diarrhoea was detected among different age subgroups. No association was found between Drug-PIN score or Drug-PIN tier and overall toxicity (p = 0.44), severe AEs (p = 0.11) or drug reduction (p = 0.27) CONCLUSIONS Efficacy and safety of abemaciclib plus ET were confirmed in a real-world setting, even in elderly population and patients with comorbidities. Evaluation of DDIs with Drug-PIN appear to be an independent predictor of PFS.

Background: Abscopal effect (AE) describes the ability of radiotherapy (RT) to induce immune-mediated responses in nonirradiated distant metastasis. Bone represents the third most frequent site of metastasis and an immunologically favorable environment for the proliferation of cancer cells. We revised the literature, searching documented cases of AE involving bone metastases (BMs) and evaluated the incidence of AE involving BMs in patients requiring palliative RT on BMs or non-BMs treated at our department. Methods: Articles published in the PubMed/MEDLINE database were selected using the following search criteria: ((abscopal effect)) AND ((metastases)). Patients with BMs, who underwent performed bone scintigraphy before and at least 2–3 months after RT, were selected and screened between January 2015 and July 2022. AE was defined as an objective response according to the scan bone index for at least one nonirradiated metastasis at a distance > 10 cm from the irradiated lesion. The primary endpoint was the rate of AE on BMs. Results: Ten cases experiencing AE of BMs were identified from the literature and eight among our patients. Conclusions: The analysis performed here suggests the use of hypofractionated radiotherapy as the only triggering factor for AE of BMs through the activation of the immune response.

Non-metastatic castration resistant prostate cancer (nmCRPC) is a clinical setting defined as confirmed rising levels of PSA in patients treated with ADT but without detectable metastases on conventional imaging with computerized tomography (CT) and technetium-99 m scintigraphy. Men with nmCRPC and a PSA doubling time (PSADT) <= 10 months are considered at high risk of rapidly developing metastases with a consequent possible impact on survival. Three recent phase III trials have demonstrated, in this setting, the efficacy of adding a next -generation androgen receptor targeted agent (ARTA) to ADT in respect to ADT only, in delaying the development of metastases (metastasis-free survival, MFS) and prolong overall survival. The magnitude of clinical benefit of these agents was even more meaningful if considering the low incidence of drug related adverse events. Our review described the latest advances in the management of nmCRPC, deriving from the pivotal clinical trials, SPARTAN, PROSPER and ARAMIS, in order to support clinicians to optimally manage these patients. Of note, the emergence of novel, more accurate, next-generation imaging techniques (including Ga PSMA-PET/CT), as well as eventual future tumor biomarkers, is modifying the entity and definition of the nmCRPC setting, with a consequent impact on patient's diagnosis and management.

Nutritional issues, including malnutrition, low muscle mass, sarcopenia (i.e., low muscle mass and strength), and cachexia (i.e., weight loss characterized by a continuous decline in skeletal muscle mass, with or without fat loss), are commonly experienced by patients with cancer at all stages of disease. Cancer cachexia may be associated with poor nutritional status and can compromise a patient's ability to tolerate antineoplastic therapy, increase the likelihood of post-surgical complications, and impact long-term outcomes including survival, quality of life, and function. One of the primary nutritional problems these patients experience is malnutrition, of which muscle depletion represents a clinically relevant feature. There have been recent calls for nutritional screening, assessment, treatment, and monitoring as a consistent component of care for all patients diagnosed with cancer. To achieve this, there is a need for a standardized approach to enable oncologists to identify patients commencing and undergoing antineoplastic therapy who are or who may be at risk of malnutrition and/or muscle depletion. This approach should not replace existing tools used in the dietitian's role, but rather give the oncologist a simple nutritional protocol for optimization of the patient care pathway where this is needed. Given the considerable time constraints in day-to-day oncology practice, any such approach must be simple and quick to implement so that oncologists can flag individual patients for further evaluation and follow-up with appropriate members of the multidisciplinary care team. To enable the rapid and routine identification of patients with or at risk of malnutrition and/or muscle depletion, an expert panel of nutrition specialists and practicing oncologists developed the PROtocol for NuTritional risk in Oncology (PRONTO). The protocol enables the rapid identification of patients with or at risk of malnutrition and/or muscle depletion and provides guidance on next steps. The protocol is adaptable to multiple settings and countries, which makes implementation feasible by oncologists and may optimize patient outcomes. We advise the use of this protocol in countries/clinical scenarios where a specialized approach to nutrition assessment and care is not available.

Background The term “neo-RAS wild-type” refers to the switch to RAS wild-type disease in plasma circulating tumor DNA (ctDNA) from originally RAS mutant colorectal cancers. Consistently, the hypothesis to re-determine RAS mutational status in ctDNA at disease progression in RAS mutant mCRC opened to a new perspective for clinically-based selection of patients to be treated with EGFR inhibitors. Currently, the genomic landscape of “neo-RAS wild-type” is unknown. This is a prospective study aimed to investigate clinical and genomic features associated with RAS mutation clearance in a large cohort of RAS mutant mCRC patients who converted to RAS wild- type in liquid biopsy at failure of first-line treatments. Secondary aim was to investigate the long term prognostic significance of “true neo-RAS wild- type”. Patients and methods 70 patients with stage IV RAS mutant colorectal cancer were prospectively enrolled. Plasma samples were collected at progression from first-line treatment. RAS/BRAF mutations in plasma were assessed by RT-PCR. In RAS/BRAF wild-type samples, ctDNA was used to generate libraries using a 17 genes panel whose alteration has clinical relevance. To investigate the prognostic significance of RAS mutation clearance, test curves for PFS and OS were represented by Kaplan-Meier estimator plot and Log-rank test. Results The most commonly detected actionable mutations in “neo-RAS wild-type” were: PIK3CA (35.7%); RET (11.9%); IDH1 (9.5%); KIT (7%); EGFR (7%); MET (4.7%); ERBB2 (4.7%); FGFR3 (4.7%). Both OS and post-progression survival were longer in patients with “neo-RAS wild-type” compared to those who remained RAS mutant (p<0.001 for both). Conclusions De-novo-targetable mutations occured in a large percentage of “neo-RAS wild-type”, being PIK3CA the most commonly detected. RAS mutation clearance in ctDNA is associated with long- term improvement of overall survival.

BACKGROUND/AIM:We conducted a retrospective analysis in our center (Umberto I Polyclinic) in collaboration with Campus Biomedico Polyclinic to assess the results of the REFLECT study, which was the first study that demonstrated the non-inferiority of Lenvatinib to Sorafenib.PATIENTS AND METHODS:We identified 21 patients affected by advanced hepatocellular carcinoma during the last 3 years who were treated in our centers. They were subdivided according to the treatment administered (Lenvatinib or Sorafenib). Progression-free survival (PFS) and overall survival (OS) were calculated, and subgroups were compared using the log-rank test. Specific predictive and prognostic factors were identified. The safety profile of the two drugs and the collateral effects were evaluated.RESULTS:The OS in patients in the Lenvatinib arm was 19 (months and 12.5 months in the Sorafenib arm. PFS in patients in the Lenvatinib arm was 6 months and 2.5 months in the Sorafenib arm. OS and PFS in patients treated with Lenvatinib were higher in any subcategory analyzed whereas no positive predictors of response to Sorafenib were found. Based on data from literature, the albumin bilirubin index (ALBI) grade was found to be a key prognostic factor. Patients treated with Sorafenib had more adverse events than those treated with Lenvatinib (100% versus 81.8%, respectively). Patients treated with Sorafenib had more frequently hand-foot syndromes, diarrhea, and nausea whereas patients treated with Lenvatinib commonly had hypertension, proteinuria, and weight loss.CONCLUSION:Lenvatinib was found to be better than Sorafenib in terms of both survival and toxicity, in advanced hepatic cell carcinoma patients.