International multicenter real-world REGistry for patients with metastatic renAL cell carcinoma - Meet-URO 33 study (REGAL study).

BACKGROUND: Nowadays, different therapeutic options are available for the first-line treatment of metastatic renal cell carcinoma (mRCC). Immuno-combinations are the standard first-line therapy in all mRCC patients regardless of the International Metastatic RCC Database Consortium (IMDC) risk category, even though TKI monotherapy is still a therapeutic option in selected patients. However, comparisons between the different first-line treatment strategies are lacking and few real-world data are available in this setting. For this reason, the regimen choice represents an important issue in clinical practice and the optimal treatment sequence remains unclear. METHODS: The REGAL study is a multicentric prospective observational study enrolling mRCC patients treated with first-line systemic therapy according to clinical practice in a real-world setting. A retrospective cohort of mRCC patients who received first-line systemic therapy from the 1st of January 2021 will also be included. The primary objective is to identify potential prognostic and predictive factors that could help guide the treatment choice; secondary objectives included the assessment of the prognostic performance of the novel prognostic Meet-URO score (IMDC score + neutrophil-to-lymphocyte ratio + bone metastases) compared with the IMDC score and the comparison between treatment strategies according to response and survival outcomes and toxicity profile. DISCUSSION: Considering the high number of therapeutic first-line strategies available for mRCC, the identification of clinical prognostic and predictive factors to candidate patients to a preferable systemic therapy is still an unmet clinical need. The Meet-URO 33 study aims to provide a large-scale real-world database on mRCC patients, to identify the clinical predictive and prognostic factors and the different performances between the ICI-based combinations according to response, survival and toxicity. TRIAL REGISTRATION: CESC IOV 2023-78.

Stage 3 N2 Lung Cancer: A Multidisciplinary Therapeutic Conundrum.

PURPOSE OF REVIEW: The treatment of stage III N2 non-small cell lung cancer (NSCLC) remains debated. There is an absence of a universally agreed definition of resectability for this heterogeneous group and a lack of trial data. RECENT FINDINGS: We reviewed and compared current international guidelines and evidence surrounding management of stage III N2 NSCLC. The Irish and Australian guidelines advise subcategorising N2 disease into N2a (may be resectable) and N2b (never resectable). On the contrary, American and British guidelines avoid subcategorising N2 disease, emphasising importance of local MDT decisions. It is suggested that evidence for resection of stage III tumours is relatively weak, but that stage IIIA should generally be considered for resection, and stage IIIB is not recommended for resection. For resectable disease, surgery may be combined with neoadjuvant chemoimmunotherapy, or adjuvant chemotherapy followed by immunotherapy and radiotherapy in selected patients. There is some evidence that technically resectable disease can be treated solely with radiotherapy with similar outcomes to resection. In the event of unresectable disease, chemoradiotherapy has been the traditional management option. However, recent studies with chemoradiotherapy alongside immunotherapy appear promising. There are many factors that influence the treatment pathway offered to patients with stage III N2 NSCLC, including patient factors, team expertise, and local resources. Therefore, the role of MDTs in defining resectability and formulating an individualised treatment plan is crucial.

Antibody Drug Conjugates in Urological Cancers: A Review of the Current Landscape.

PURPOSE OF REVIEW: Our review delves into the progress across urological malignancies and discusses ongoing challenges and future directions in antibody-drug conjugate (ADC) development, emphasising their transformative potential in cancer care. RECENT FINDINGS: ADCs have advanced from hematologic to solid tumours, notably in breast cancer, and are now pivotal in metastatic urological cancers as both monotherapies and in combination regimens, underscored by the FDA's approval of enfortumab vedotin and sacituzumab govitecan for metastatic urothelial cancer. Progress in metastatic prostate cancer, particularly with ADCs targeting PSMA and STEAP1, is noteworthy, although renal cell cancer presents ongoing challenges. There is a continual search for agents in the metastatic, relapsed testicular cancer landscape. ADCs have emerged as a pivotal innovation in oncology, blending targeted antibody therapy with potent cytotoxic drugs, significantly advancing treatment options for urological malignancies.

Analyses of tumor microenvironment in patients with advanced renal cell carcinoma receiving immunotherapy (Meet-URO 18 study).

Introduction: The Meet-URO 18 study is a multicentric study of patients with metastatic renal cell carcinoma receiving nivolumab in the second-line and beyond, categorized as responders (progression-free survival ≥ 12 months) and non-responders (progression-free survival < 3 months). Areas covered: The current study includes extensive immunohistochemical analysis of T-lineage markers (CD3, CD4, CD8, CD8/CD4 ratio), macrophages (CD68), ph-mTOR, CD15 and CD56 expression on tumor cells, and PD-L1 expression, on an increased sample size including 161 tumor samples (113 patients) compared with preliminary presented data. Responders' tumor tissue (n = 90; 55.9%) was associated with lower CD4 expression (p = 0.014), higher CD56 expression (p = 0.046) and higher CD8/CD4 ratio (p = 0.030). Expert opinion/commentary: The present work suggests the regulatory role of a subpopulation of T cells on antitumor response and identifies CD56 as a putative biomarker of immunotherapy efficacy.

[Box: see text].

Analyses of tumor microenvironment in patients with advanced renal cell carcinoma receiving immunotherapy (Meet-URO 18 study).

Introduction: The Meet-URO 18 study is a multicentric study of patients with metastatic renal cell carcinoma receiving nivolumab in the second-line and beyond, categorized as responders (progression-free survival ≥ 12 months) and non-responders (progression-free survival < 3 months). Areas covered: The current study includes extensive immunohistochemical analysis of T-lineage markers (CD3, CD4, CD8, CD8/CD4 ratio), macrophages (CD68), ph-mTOR, CD15 and CD56 expression on tumor cells, and PD-L1 expression, on an increased sample size including 161 tumor samples (113 patients) compared with preliminary presented data. Responders' tumor tissue (n = 90; 55.9%) was associated with lower CD4 expression (p = 0.014), higher CD56 expression (p = 0.046) and higher CD8/CD4 ratio (p = 0.030). Expert opinion/commentary: The present work suggests the regulatory role of a subpopulation of T cells on antitumor response and identifies CD56 as a putative biomarker of immunotherapy efficacy.

Healthcare Professional Communication on Sexual Health: A Report from the Italian Working Group on Adolescents and Young Adults with Cancer.

BACKGROUND: Sexual function is an important concern for adolescent and young adult (AYA) with cancer. The aim of this study was to explore the attitude of Italian health care professionals who deal with AYA patients with cancer toward sexual health communication. MATERIALS AND METHODS: A 11-question survey was developed by the AIOM (Associazione Italiana di Oncologia Medica) and AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) AYA workgroup and sent to AIOM and AIEOP members. RESULTS: The sample comprised 360 respondents, 54.2% AIEOP and 45.8% AIOM members. Eighty percent were physicians, 14.5% nurses, 4.7% psychologists, and 0.8% other professionals. Medical oncologists are more used to investigate about AYA sexual health than pediatric oncologists (58.2% vs. 46.2%), even if pediatrics more frequently refer patients to specific and shared protocol (40% vs. 26.1%). Both AIOM and AIEOP participants mostly talk about sexual health only on request or occasionally (78.8% and 79%, respectively). Clinician-reported barriers to communication identified in this study are lack of preparation and embarrassment for both the categories, plus the presence/interference of parents for pediatrics and lack of time for medical oncologists. Overall, less than 5% of clinicians in our survey received specific training on potential sexual health issues in AYA patients with cancer and only 2% felt adequately prepared to speak about it. CONCLUSION: Sexual health is a key component of comprehensive care for AYA with cancer during treatments. This study highlighted the need of Italian providers for specific training and guidelines on sex-related health issues encountered by AYA patients.

Navigating the Rapidly Evolving Advanced Urothelial Carcinoma Treatment Landscape: Insights from Italian Experts.

PURPOSE OF REVIEW: To discuss recent advances in the treatment of advanced urothelial carcinoma (UC) and how best to incorporate new therapies into clinical practice. RECENT FINDINGS: There have been several recent practice-changing phase 2 and 3 trials of immune checkpoint inhibitors (ICIs), antibody-drug conjugates (ADCs), and targeted agents in advanced UC. Based on data from these trials, ICIs can be used as first-line maintenance therapy in patients who do not progress on platinum-based chemotherapy, second-line therapy for those with progression, and first-line therapy in cisplatin-ineligible patients with PD-L1 expression; ADCs and targeted agents provide later-line treatment options. Despite substantial progress in the treatment of advanced UC, there are still many uncertainties, including the optimal treatment sequence for novel agents, and reliable predictive biomarkers to aid in treatment selection. There is also an unmet need for effective treatment options in patients unfit for any platinum-based chemotherapy.

The role of the caregiver in older patients with advanced prostate cancer: results from the ADHERE Prospective Study of the Meet-URO network.

PURPOSE: To assess caregivers' characteristics and influence of the presence or absence of the caregiver on clinical outcomes of older (≥70 years) metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone (ABI) or enzalutamide (ENZ). METHODS: Patients from the Meet-URO 5 ADHERE study were assessed with a 5-item caregiver evaluation questionnaire focusing on the presence, age, degree of kinship, working status and qualification of the caregiver. We investigated the association between the presence of a caregiver and the clinical characteristics and outcomes of enrolled patients. RESULTS: No differences were found in the main clinical characteristics between patients with or without a caregiver, except for a lower median G8 score (p = 0.0453) in the caregiver group. A longer radiographic PFS (rPFS) was observed in the group without a caregiver, with a trend towards more prolonged overall survival (OS) in the same group. CONCLUSION: Our work suggests a detrimental effect of caregivers in managing older mCRPC patients treated with ABI or ENZ, especially those identified as frail by the geriatric G8 screening score. Further work is needed to identify and address patients' vulnerability areas, which could have a detrimental effect on prognosis.

Apalutamide-induced lichenoid reaction in a patient with non-metastatic castrate-resistant prostate cancer.

INTRODUCTION: Apalutamide is an oral selective androgen receptor inhibitor, approved by the FDA for the treatment of patients with non-metastatic, castration-resistant prostate cancer (M0 CRPC) at high risk of developing metastases and for patients with metastatic castration-sensitive prostate (mHSPC) in association with androgen deprivation therapy (ADT). In the registration studies, skin reactions were reported among the most common side effects and as an adverse event of special interest. CASE REPORT: Apalutamide-induced rash includes a wide spectrum of different types of skin reactions, but few cases reports and case series have described this adverse event. Here, we report an M0 CRPC patient who experienced a rare skin adverse event, a lichenoid reaction. MANAGEMENT & OUTCOME: After 4 months of therapy with apalutamide, the patient reported dorsal pricking and dry skin. Lichenoid reaction was confirmed histologically and its correlation to the drug was demonstrated after pursuing a multidisciplinary approach. DISCUSSION: To our knowledge, this is one of the first cases of Apalutamide-related lichenoid reaction and this clinical case showed the relevance of a multidisciplinary management when assessing drug-related adverse events. A broader knowledge of the spectrum of drug-related reactions would allow for a better diagnosis and therapy management by both physicians and patients.

The Effects of GCSF Primary Prophylaxis on Survival Outcomes and Toxicity in Patients with Advanced Non-Small Cell Lung Cancer on First-Line Chemoimmunotherapy: A Sub-Analysis of the Spinnaker Study.

GCSF prophylaxis is recommended in patients on chemotherapy with a >20% risk of febrile neutropenia and is to be considered if there is an intermediate risk of 10−20%. GCSF has been suggested as a possible adjunct to immunotherapy due to increased peripheral neutrophil recruitment and PD-L1 expression on neutrophils with GCSF use and greater tumour volume decrease with higher tumour GCSF expression. However, its potential to increase neutrophil counts and, thus, NLR values, could subsequently confer poorer prognoses on patients with advanced NSCLC. This analysis follows on from the retrospective multicentre observational cohort Spinnaker study on advanced NSCLC patients. The primary endpoints were OS and PFS. The secondary endpoints were the frequency and severity of AEs and irAEs. Patient information, including GCSF use and NLR values, was collected. A secondary comparison with matched follow-up duration was also undertaken. Three hundred and eight patients were included. Median OS was 13.4 months in patients given GCSF and 12.6 months in those not (p = 0.948). Median PFS was 7.3 months in patients given GCSF and 8.4 months in those not (p = 0.369). A total of 56% of patients receiving GCSF had Grade 1−2 AEs compared to 35% who did not receive GCSF (p = 0.004). Following an assessment with matched follow-up, 41% of patients given GCSF experienced Grade 1−2 irAEs compared to 23% of those not given GCSF (p = 0.023). GCSF prophylaxis use did not significantly affect overall or progression-free survival. Patients given GCSF prophylaxis were more likely to experience Grade 1−2 adverse effects and Grade 1−2 immunotherapy-related adverse effects.

Differential prognostic effect of systemic inflammation in patients with non-small cell lung cancer treated with immunotherapy or chemotherapy: A post hoc analysis of the phase 3 OAK trial.

BACKGROUND: A proinflammatory diathesis, as measured by the neutrophil to lymphocyte ratio (NLR), heralds an adverse disease course for non-small cell lung cancer (NSCLC). METHODS: This post hoc analysis used data from the phase 3 OAK trial (NCT02008227), which randomized previously treated patients with NSCLC to atezolizumab or docetaxel. The main objective was assessing the differential impact of the pretreatment NLR on overall survival according to the treatment modality. In addition, patients' genomic characteristics were assessed according to their inflammatory status with a circulating free DNA (cfDNA) next-generation sequencing (NGS) analysis. RESULTS: In all, 600 and 575 patients with NLR data were included in the atezolizumab and docetaxel cohorts, respectively, with a median NLR of 4 (interquartile range, 2.6-6.7) for the pooled population. An NLR ≥4 was associated with a positive smoking status (88.6% vs. 78.1%; p < .01), male sex (66.4% vs. 57.6%; p = .01), a worse performance status (71.3% vs. 55.2%; p < .01), a higher number of metastatic sites (63.2% vs. 51.6%; p = .01), squamous histology (32.1% vs. 21.4%; p < .01), and tissue KRAS mutations (30% vs. 18.7%; p = .02) but not with programmed death ligand 1 (PD-L1) expression or the tissue epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) status. A pretreatment NLR ≥4 was more strongly associated with mortality after atezolizumab (adjusted hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.35-2.01) versus docetaxel (HR, 1.32; 95% CI, 1.08-1.60; multivariable [MVA] interaction p = .08). The HR for an increased risk of death for PD-L1-negative/NLR ≥4 patients (compared with PD-L1-positive/NLR <4 patients) was significantly higher in the atezolizumab cohort (MVA interaction p = .01). The exclusion of EGFR/ALK-positive patients further increased the prognostic ability of the baseline NLR in favor of atezolizumab (MVA interaction p = .02). Pretreatment cfDNA data from NGS showed that patients with a high blood tumor mutation burden (cutoff, 16 mut/Mb) had a higher median NLR (4.6 vs. 3.7; p = .01). After adjustments for multiple comparisons, none of the selected variants of interest (EGFR, KRAS, TP53, KEAP1, STK11, SMARCA4, ARID1A, and targeted DNA damage response and repair genes) were significantly associated with the NLR. CONCLUSIONS: A low baseline NLR identified patients with NSCLC who derived a greater survival benefit from atezolizumab in comparison with those identified in the docetaxel cohort. The NLR could complement PD-L1 expression in tailoring treatment in this setting.

International Survey on Frailty Assessment in Patients with Cancer.

BACKGROUND: Frailty negatively affects the outcomes of patients with cancer, and its assessment might vary widely in the real world. The objective of this study was to explore awareness and use of frailty screening tools among the ONCOassist healthcare professionals (HCPs) users. MATERIALS AND METHODS: We sent 2 emails with a cross-sectional 15-item survey in a 3-week interval between April and May 2021. Differences in the awareness and use of tools according to respondents' continents, country income, and job types were investigated. RESULTS: Seven hundred thirty-seven HCPs from 91 countries (81% physicians, 13% nurses, and 5% other HCPs) completed the survey. Three hundred and eighty-five (52%) reported assessing all or the majority of their patients; 518 (70%) at baseline and before starting a new treatment. Three hundred and four (43%) HCPs were aware of performance status (PS) scores only, 309 (42%) age/frailty/comorbidity (AFC) screening, and 102 (14%) chemotoxicity predictive tools. Five hundred and thirty-seven (73%) reported using tools; 423 (57%) just PS, 237 (32%) AFC, and 60 (8%) chemotoxicity ones. Reasons for tools non-use (485 responders) were awareness (70%), time constraints (28%), and uselessness (2%). There were significant differences in awareness and use of screening tools among different continents, country income, job types, and medical specialties (P < .001 for all comparisons). CONCLUSION: Among selected oncology HCPs, there is still a worldwide lack of knowledge and usage of frailty screening tools, which may differ according to their geography, country income, and education. Targeted initiatives to raise awareness and education are needed to implement frailty assessment in managing patients with cancer.

Adherence to Oral Treatments in Older Patients with Advanced Prostate Cancer, the ADHERE Study: A Prospective Trial of the Meet-URO Network.

BACKGROUND: Novel androgen receptor signaling inhibitors for prostate cancer (PC) impose the burden of self-administration on older patients overwhelmed by the requirement of many other concomitant medications. PATIENTS AND METHODS: This study evaluated the proportion of non-adherence in a 12-month follow-up period and the first 3 months to abiraterone (ABI) or enzalutamide (ENZ). In a prospective multicenter observational cohort study, patients with metastatic castration-resistant PC (mCRPC) aged ≥70 years receiving ABI or ENZ pre- or post-docetaxel were enrolled. Treatment monitoring included pill counting, a self-assessment questionnaire, and clinical diaries at each clinical visit. Non-adherence rates were based on proportions of missed/prescribed pills ratios by pill counting. RESULTS: Overall, 234 patients were recruited with median age of 78 years (range, 73-82); 86 (37%) were treated with ABI, and 148 (63%) with ENZ. The median follow-up for adherence was seven monthly cycles (IQR: 4-12). The two cohorts were well balanced for baseline characteristics. The percentage of non-adherence by pill counting was slightly higher for ABI than ENZ (5.2% vs. 4.2%, P < .001). By self-reporting, patients on ENZ tended to report more frequently than those with ABI forgetfulness as the reason for missing events (42% vs. 17%, P < .001). A lower Geriatric G8 score correlated with non-adherence (P = .004). Overall survival (OS) was 48.8 months. Patients on ABI had radiographic progression-free survival (rPFS) of 28.4 [24.2-32.5], while for ENZ patients, we reported a median rPFS of 23.1 [18.2-28.1] months. CONCLUSION: Physicians tend to treat older mCRPC patients with ENZ. Non-adherence rate is relatively low overall but can be higher with ABI than with ENZ and correlates with the Geriatric G8 score. Forgetfulness is a potential barrier for ENZ.

Circulating tumor cell gene expression and plasma AR gene copy number as biomarkers for castration-resistant prostate cancer patients treated with cabazitaxel.

BACKGROUND: Cabazitaxel improves overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients progressing after docetaxel. In this prospective study, we evaluated the prognostic role of CTC gene expression on cabazitaxel-treated patients and its association with plasma androgen receptor (AR) copy number (CN). METHODS: Patients receiving cabazitaxel 20 or 25 mg/sqm for mCRPC were enrolled. Digital PCR was performed to assess plasma AR CN status. CTC enrichment was assessed using the AdnaTest EMT-2/StemCell kit. CTC expression analyses were performed for 17 genes. Data are expressed as hazard ratio (HR) or odds ratio (OR) and 95% CI. RESULTS: Seventy-four patients were fully evaluable. CTC expression of AR-V7 (HR=2.52, 1.24-5.12, p=0.011), AKR1C3 (HR=2.01, 1.06-3.81, p=0.031), AR (HR=2.70, 1.46-5.01, p=0.002), EPCAM (HR=3.75, 2.10-6.71, p< 0.0001), PSMA (HR=2.09, 1.19-3.66, p=0.01), MDK (HR=3.35, 1.83-6.13, p< 0.0001), and HPRT1 (HR=2.46, 1.44-4.18, p=0.0009) was significantly associated with OS. ALDH1 (OR=5.50, 0.97-31.22, p=0.05), AR (OR=8.71, 2.32-32.25, p=0.001), EPCAM (OR=7.26, 1.47-35.73, p=0.015), PSMA (OR=3.86, 1.10-13.50, p=0.035), MDK (OR=6.84, 1.87-24.98, p=0.004), and HPRT1 (OR=7.41, 1.82-30.19, p=0.005) expression was associated with early PD. AR CN status was significantly correlated with AR-V7 (p=0.05), EPCAM (p=0.02), and MDK (p=0.002) expression. In multivariable model, EPCAM and HPRT1 CTC expression, plasma AR CN gain, ECOG PS=2, and liver metastases and PSA were independently associated with poorer OS. In patients treated with cabazitaxel 20 mg/sqm, median OS was shorter in AR-V7 positive than negative patients (6.6 versus 14 months, HR=3.46, 1.47-8.17], p=0.004). CONCLUSIONS: Baseline CTC biomarkers may be prognosticators for cabazitaxel-treated mCRPC patients. Cabazitaxel at lower (20 mg/sqm) dose was associated with poorer outcomes in AR-V7 positive patients compared to AR-V7 negative patients in a post hoc subgroup analysis. TRIAL REGISTRATION: Clinicaltrials.gov NCT03381326 . Retrospectively registered on 18 December 2017.

The prognostic value of the previous nephrectomy in pretreated metastatic renal cell carcinoma receiving immunotherapy: a sub-analysis of the Meet-URO 15 study.

BACKGROUND: Nephrectomy is considered the backbone of managing patients with localized and selected metastatic renal cell carcinoma (mRCC). The prognostic role of nephrectomy has been widely investigated with cytokines and targeted therapy, but it is still unclear in the immunotherapy era. METHODS: We investigated the Meet-URO-15 study dataset of 571 pretreated mRCC patients receiving nivolumab as second or further lines about the prognostic role of the previous nephrectomy (received in either the localized or metastatic setting) in the overall population and according to the Meet-URO score groups. RESULTS: Patients who underwent nephrectomy showed a significantly reduced risk of death (HR 0.44, 95% CI 0.32-0.60, p < 0.001) with a longer median overall survival (OS) (35.9 months vs 12.1 months), 1-year OS of 71.6% vs 50.5% and 2-years OS of 56.5% vs 22.0% compared to those who did not. No significant interaction between nephrectomy and the overall five Meet-URO score risk groups was observed (p = 0.17). It was statistically significant when merging group 1 with 2 and 3 and group 4 with 5 (p = 0.038) and associated with a longer OS for the first three prognostic groups (p < 0.001), but not for groups 4 and 5 (p = 0.54). CONCLUSIONS: Our study suggests an overall positive impact of the previous nephrectomy on the outcome of pretreated mRCC patients receiving immunotherapy. The clinical relevance of cytoreductive nephrectomy, optimal timing and patient selection deserves further investigation, especially for patients with Meet-URO scores of 1 to 3, who are the once deriving benefit in our analyses. However, that benefit is not evident for IMDC poor-risk patients (including the Meet-URO score groups 4 and 5) and a subgroup of IMDC intermediate-risk patients defined as group 4 by the Meet-URO score.

Risk of SARS-CoV2-Related Mortality in Non-Small Cell Lung Cancer Patients Treated with First-Line Immunotherapy Alone or in Combination with Chemotherapy.

BACKGROUND: The impact of systemic anticancer treatments on SARS-CoV-2-related mortality is still debatable. METHODS: By a retrospective analysis of patients with non-small-cell lung cancer (NSCLC) treated with first-line Pembrolizumab or in combination with chemotherapy (ChT) during the first surge of the pandemic. RESULTS: The adjusted risk of death was higher in patients treated with ChT + Pembrolizumab (HR 4.6, 1.2-17.4, p = 0.02). The SARS-CoV-2-related mortality rate was higher in patients treated with ChT + Pembrolizumab (p = 0.03), ≥70 years (p = 0.03) and current smokers (p = 0.17). CONCLUSIONS: The addition of ChT to immunotherapy could be associated with increased risk of mortality and higher SARS-CoV-2-related mortality rate.

Cancer Predisposition Genes in Adolescents and Young Adults (AYAs): a Review Paper from the Italian AYA Working Group.

PURPOSE OF REVIEW: The present narrative systematic review summarizes current knowledge on germline gene mutations predisposing to solid tumors in adolescents and young adults (AYAs). RECENT FINDINGS: AYAs with cancer represent a particular group of patients with specific challenging characteristics and yet unmet needs. A significant percentage of AYA patients carry pathogenic or likely pathogenic variants (PV/LPVs) in cancer predisposition genes. Nevertheless, knowledge on spectrum, frequency, and clinical implications of germline variants in AYAs with solid tumors is limited. The identification of PV/LPV in AYA is especially critical given the need for appropriate communicative strategies, risk of second primary cancers, need for personalized long-term surveillance, potential reproductive implications, and cascade testing of at-risk family members. Moreover, these gene alterations may potentially provide novel biomarkers and therapeutic targets that are lacking in AYA patients. Among young adults with early-onset phenotypes of malignancies typically presenting at later ages, the increased prevalence of germline PV/LPVs supports a role for genetic counseling and testing irrespective of tumor type.

Biological Rationale for Peripheral Blood Cell-Derived Inflammatory Indices and Related Prognostic Scores in Patients with Advanced Non-Small-Cell Lung Cancer.

PURPOSE OF REVIEW: To describe the biological rationale of peripheral blood cells (PBC)-derived inflammatory indexes and assess the related prognostic scores for patients with advanced non-small cell lung cancer (aNSCLC) treated with immune-checkpoint inhibitors (ICI). RECENT FINDINGS: Inflammatory indexes based on PBC may indicate a pro-inflammatory condition affecting the immune response to cancer. The lung immune prognostic index (LIPI), consisting of derived neutrophils-to-lymphocyte ratio (NLR) and lactate dehydrogenase, is a validated prognostic tool, especially for pretreated aNSCLC patients, where the combination of NLR and PD-L1 tumour expression might also be predictive of immunotherapy benefit. In untreated high-PD-L1 aNSCLC patients, the Lung-Immune-Prognostic score (LIPS), including NLR, ECOG PS and concomitant steroids, is prognostic, and its modified version might indicate patients with favourable outcomes despite an ECOG PS of 2. NLR times platelets (i.e., SII), included in the NHS-Lung score, might improve the prognostication for combined chemoimmunotherapy. PBC-derived inflammatory indexes and related scores represent accurate, reproducible and non-expensive prognostic tools with clinical and research utility.

COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study.

BACKGROUND: Early reports on patients with cancer and COVID-19 have suggested a high mortality rate compared with the general population. Patients with thoracic malignancies are thought to be particularly susceptible to COVID-19 given their older age, smoking habits, and pre-existing cardiopulmonary comorbidities, in addition to cancer treatments. We aimed to study the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with thoracic malignancies. METHODS: The Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry is a multicentre observational study composed of a cross-sectional component and a longitudinal cohort component. Eligibility criteria were the presence of any thoracic cancer (non-small-cell lung cancer [NSCLC], small-cell lung cancer, mesothelioma, thymic epithelial tumours, and other pulmonary neuroendocrine neoplasms) and a COVID-19 diagnosis, either laboratory confirmed with RT-PCR, suspected with symptoms and contacts, or radiologically suspected cases with lung imaging features consistent with COVID-19 pneumonia and symptoms. Patients of any age, sex, histology, or stage were considered eligible, including those in active treatment and clinical follow-up. Clinical data were extracted from medical records of consecutive patients from Jan 1, 2020, and will be collected until the end of pandemic declared by WHO. Data on demographics, oncological history and comorbidities, COVID-19 diagnosis, and course of illness and clinical outcomes were collected. Associations between demographic or clinical characteristics and outcomes were measured with odds ratios (ORs) with 95% CIs using univariable and multivariable logistic regression, with sex, age, smoking status, hypertension, and chronic obstructive pulmonary disease included in multivariable analysis. This is a preliminary analysis of the first 200 patients. The registry continues to accept new sites and patient data. FINDINGS: Between March 26 and April 12, 2020, 200 patients with COVID-19 and thoracic cancers from eight countries were identified and included in the TERAVOLT registry; median age was 68·0 years (61·8-75·0) and the majority had an Eastern Cooperative Oncology Group performance status of 0-1 (142 [72%] of 196 patients), were current or former smokers (159 [81%] of 196), had non-small-cell lung cancer (151 [76%] of 200), and were on therapy at the time of COVID-19 diagnosis (147 [74%] of 199), with 112 (57%) of 197 on first-line treatment. 152 (76%) patients were hospitalised and 66 (33%) died. 13 (10%) of 134 patients who met criteria for ICU admission were admitted to ICU; the remaining 121 were hospitalised, but were not admitted to ICU. Univariable analyses revealed that being older than 65 years (OR 1·88, 95% 1·00-3·62), being a current or former smoker (4·24, 1·70-12·95), receiving treatment with chemotherapy alone (2·54, 1·09-6·11), and the presence of any comorbidities (2·65, 1·09-7·46) were associated with increased risk of death. However, in multivariable analysis, only smoking history (OR 3·18, 95% CI 1·11-9·06) was associated with increased risk of death. INTERPRETATION: With an ongoing global pandemic of COVID-19, our data suggest high mortality and low admission to intensive care in patients with thoracic cancer. Whether mortality could be reduced with treatment in intensive care remains to be determined. With improved cancer therapeutic options, access to intensive care should be discussed in a multidisciplinary setting based on cancer specific mortality and patients' preference. FUNDING: None.

The METeoric rise of MET in lung cancer.

Over the years, there has been a continuous increase in clinically relevant driver mutations in patients with non-small cell lung cancer (NSCLC). Among these, dysregulated activation of the MET tyrosine kinase receptor has gained importance due to the recent development of quite effective treatments. MET dysregulation encompasses a heterogeneous array of alterations leading to the prolonged activation of the cellular MET (c-MET or MET) receptor and downstream proliferation pathways. It can arise through several mechanisms, including gene amplification, overexpression of the receptor and/or its ligand hepatocyte growth factor, and the acquisition of activating mutations. MET mutations are found in approximately 3% to 5% of patients with NSCLC, mainly adenocarcinoma, and are overrepresented in the sarcomatoid subtype. De novo MET amplifications are found in 1% to 5% of NSCLC cases, also predominantly in adenocarcinoma. In the current review, the authors discussed the biology of MET, how to diagnose clinically relevant alterations, and the rising clinical importance of these alterations in light of the emergence of multiple targeted therapies, both within the context of MET as a driver of resistance and in its own right.