Symptomatic androgen deficiency and sexual dysfunctions in male patients receiving alectinib for ALK-positive advanced nonsmall cell lung cancer.

BACKGROUND: It is reported that treatment with anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) induces hypogonadism both in male patients with ALK-positive cancer and in murine models. METHODS: In this study, three groups, including an experimental group of male patients with ALK-positive, advanced nonsmall cell lung cancer (ANSCLC) who were receiving alectinib (cohort A), a control group of female patients with ALK-positive ANSCLC who were receiving alectinib (cohort B), and a control group of male patients with ALK-negative ANSCLC (cohort C), prospectively underwent a full hormone assessment for androgen deficiency at 8 weeks after the start of treatment and in case of reported suspected symptoms. Patients with major sexual dysfunctions were referred to an endocrinologist. RESULTS: Ninety-five patients were consecutively enrolled onto the study. Among sixty-eight male patients, both median total testosterone levels (2.93 vs. 4.92 ng/ml; p = .0001) and free testosterone levels (0.11 vs. 0.17 pg/ml; p = .0002) were significantly lower in ALK-positive ANSCLC patients in cohort A compared with ALK-negative patients in cohort C; conversely, median FSH (10.32 vs. 17.52 mUI/ml; p = .0059) and LH levels (4.72 vs. 7.49 mUI/ml; p = .0131) were significantly higher in cohort C compared to cohort A. Median inhibin B levels were higher in ALK-positive male patients (74.3 vs. 44.24 pg/ml; p = .0038), but all patients had inhibin B values within the normal range. The percentage of male patients who had positive scores on the Androgen Deficiency in Aging Males (ADAM) questionnaire was 62% in cohort A and 26.8% in cohort C, including eight patients who reported at least one major symptom and were referred to Andrology Unit. No significant differences in the endocrine assessment were reported between cohorts A and B. CONCLUSIONS: Symptoms of androgen deficiency should be tracked in male patients with ALK-positive ANSCLC who are receiving alectinib, and testosterone replacement should be considered, as appropriate.

Atezolizumab Plus Carboplatin and Etoposide in Patients with Untreated Extensive-Stage Small-Cell Lung Cancer: Interim Results of the MAURIS Phase IIIb Trial.

BACKGROUND: MAURIS is an Italian multicenter, open-label, phase IIIb ongoing trial, aiming at evaluating the safety and effectiveness of atezolizumab + carboplatin/etoposide in patients with newly diagnosed, extensive-stage small-cell lung cancer (ES-SCLC). The primary objective is the safety evaluation. MATERIALS AND METHODS: Patients received atezolizumab + carboplatin/etoposide Q3W for 4-6 cycles in the induction phase, followed by atezolizumab maintenance Q3W. We presented the interim analysis on safety (referring to the induction phase) and clinical effectiveness, in all patients (N = 154) and in subgroups that received ≤3 (N = 23), 4 (N = 43), and 5-6 cycles (N = 89) of induction. RESULTS: At a median follow-up of 10.5 months, 139 patients (90.3%) discontinued treatment. Serious adverse events occurred in 29.9% of patients overall, and the rate was lower in patients with 5-6 cycles (19.1%) than in those with 4 (34.9%) or ≤3 (63.6%) cycles. Immune-mediated adverse events were reported in 14.9%, 15.7%, 11.6%, and 18.2% of patients, overall and by subgroup, respectively. The median overall survival and progression-free survival were 10.7 and 5.5 months, respectively. Overall, 111 patients (71.6%) had a tumor response. CONCLUSIONS: Interim results provide further evidences about safety and efficacy profile of atezolizumab + carboplatin/etoposide treatment in a ES-SCLC patient population closer to that observed in clinical practice. CLINICAL TRIAL REGISTRATION: Eudract No. 2019-001146-17, NCT04028050.

Response to first-line pembrolizumab in metastatic KRAS-mutated non-small-cell lung cancer.

Aims: This retrospective study aims to identify a possible predictive role of KRAS mutations in non-small-cell lung cancer in response to first-line pembrolizumab, either as monotherapy or combined with chemotherapy. Methods: Patients received pembrolizumab alone (n = 213) or associated with chemotherapy (n = 81). Results: A mutation in the KRAS gene was detected in 27% of patients. In patients on pembrolizumab alone, median progression-free survival in KRAS-mutated cases was longer than in wild-type cases (11.3 vs 4.4 months; p = 0.019), whereas median overall survival did not reach statistical significance (22.1 vs 12.5 months; p = 0.119). Patients receiving chemo-immunotherapy with KRAS-positive tumors had a similar progression-free survival (9.7 vs 7.3 months; p = 0.435); overall survival data were immature. Conclusion: This study suggests a correlation between KRAS status and response to pembrolizumab.

Incorporating weekly carboplatin in anthracycline and paclitaxel-containing neoadjuvant chemotherapy for triple-negative breast cancer: propensity-score matching analysis and TIL evaluation.

BACKGROUND: The generation of data capturing the risk-benefit ratio of incorporating carboplatin (Cb) to neoadjuvant chemotherapy (NACT) for triple-negative breast cancer (TNBC) in a clinical practice setting is urgently needed. Tumour-infiltrating lymphocytes (TILs) have an established role in TNBC receiving NACT, however, the role of TIL dynamics under NACT exposure in patients receiving the current standard of care is largely uncharted. METHODS: Consecutive TNBC patients receiving anthracycline-taxane [A-T] +/- Cb NACT at three Institutions were enrolled. Stromal-TILs were evaluated on pre-NACT and residual disease (RD) specimens. In the clinical cohort, propensity-score-matching was used to control selection bias. RESULTS: In total, 247 patients were included (A-T = 40.5%, A-TCb = 59.5%). After propensity-score-matching, pCR was significantly higher for A-TCb vs A-T (51.9% vs 34.2%, multivariate: OR = 2.40, P = 0.01). No differences in grade ≥3 haematological toxicities were observed. TILs increased from baseline to RD in the overall population and across A-T/A-TCb subgroups. TIL increase from baseline to RD was positively and independently associated with distant disease-free survival (multivariate: HR = 0.43, P = 0.05). CONCLUSIONS: We confirmed in a clinical practice setting of TNBC patients receiving A-T NACT that the incorporation of weekly Cb significantly improved pCR. In addition, A-T +/- Cb enhanced immune infiltration from baseline to RD. Finally, we reported a positive independent prognostic role of TIL increase after NACT exposure.

Leptin-mediated meta-inflammation may provide survival benefit in patients receiving maintenance immunotherapy for extensive-stage small cell lung cancer (ES-SCLC).

BACKGROUND: Only few ES-SCLC patients experience long-term survival benefit by maintenance IT. Adipokines-induced metabolic meta-inflammation has been related to enhanced responsiveness to IT in obese patients; however, their prognostic role in SCLC is currently controversial. METHODS: Pre-treatment CT scan was used for determining distribution of abdominal adiposity, and blood samples were collected at fasting for measuring glycemia, insulin, ghrelin, leptin and adipokines (TNF-α, IFN-γ, IL-6 and MCP-1). Patients with known history of DM type II or metabolic syndrome with HOMA index > 2.5 were considered insulin resistant (IR). RESULTS: In ES-SCLC pts receiving maintenance IT, increased leptin concentration and higher leptin/visceral adipose tissue (VAT) ratio were significantly associated with prolonged PFS. By applying a hierarchical clustering algorithm, we identified a cluster of patients characterized by higher leptin values and lower pro-inflammatory cytokines (TNF-α, IFN-γ and IL-6) who experienced longer PFS (13.2 vs 8.05 months; HR: 0.42 [0.18-0.93] p = 0.02) and OS (18.04 vs 12.09 mo; HR: 0.53 [0.25-1.29] p = 0.07). CONCLUSIONS: Adipokines can play a crucial role to determining effectiveness of anti-cancer immunotherapy. The role of metabolic immune dysfunctions needs further pre-clinical validation and is currently investigated in the larger prospective cohort.

Talniflumate abrogates mucin immune suppressive barrier improving efficacy of gemcitabine and nab-paclitaxel treatment in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. This is due to its aggressive course, late diagnosis and its intrinsic drugs resistance. The complexity of the tumor, in terms of cell components and heterogeneity, has led to the approval of few therapies with limited efficacy. The study of the early stages of carcinogenesis provides the opportunity for the identification of actionable pathways that underpin therapeutic resistance. METHODS: We analyzed 43 Intraductal papillary mucinous neoplasms (IPMN) (12 Low-grade and 31 High-grade) by Spatial Transcriptomics. Mouse and human pancreatic cancer organoids and T cells interaction platforms were established to test the role of mucins expression on T cells activity. Syngeneic mouse model of PDAC was used to explore the impact of mucins downregulation on standard therapy efficacy. RESULTS: Spatial transcriptomics showed that mucin O-glycosylation pathway is increased in the progression from low-grade to high-grade IPMN. We identified GCNT3, a master regulator of mucins expression, as an actionable target of this pathway by talniflumate. We showed that talniflumate impaired mucins expression increasing T cell activation and recognition using both mouse and human organoid interaction platforms. In vivo experiments showed that talniflumate was able to increase the efficacy of the chemotherapy by boosting immune infiltration. CONCLUSIONS: Finally, we demonstrated that combination of talniflumate, an anti-inflammatory drug, with chemotherapy effectively improves anti-tumor effect in PDAC.

Lung cancer multi-omics digital human avatars for integrating precision medicine into clinical practice: the LANTERN study.

BACKGROUND: The current management of lung cancer patients has reached a high level of complexity. Indeed, besides the traditional clinical variables (e.g., age, sex, TNM stage), new omics data have recently been introduced in clinical practice, thereby making more complex the decision-making process. With the advent of Artificial intelligence (AI) techniques, various omics datasets may be used to create more accurate predictive models paving the way for a better care in lung cancer patients. METHODS: The LANTERN study is a multi-center observational clinical trial involving a multidisciplinary consortium of five institutions from different European countries. The aim of this trial is to develop accurate several predictive models for lung cancer patients, through the creation of Digital Human Avatars (DHA), defined as digital representations of patients using various omics-based variables and integrating well-established clinical factors with genomic data, quantitative imaging data etc. A total of 600 lung cancer patients will be prospectively enrolled by the recruiting centers and multi-omics data will be collected. Data will then be modelled and parameterized in an experimental context of cutting-edge big data analysis. All data variables will be recorded according to a shared common ontology based on variable-specific domains in order to enhance their direct actionability. An exploratory analysis will then initiate the biomarker identification process. The second phase of the project will focus on creating multiple multivariate models trained though advanced machine learning (ML) and AI techniques for the specific areas of interest. Finally, the developed models will be validated in order to test their robustness, transferability and generalizability, leading to the development of the DHA. All the potential clinical and scientific stakeholders will be involved in the DHA development process. The main goals aim of LANTERN project are: i) To develop predictive models for lung cancer diagnosis and histological characterization; (ii) to set up personalized predictive models for individual-specific treatments; iii) to enable feedback data loops for preventive healthcare strategies and quality of life management. DISCUSSION: The LANTERN project will develop a predictive platform based on integration of multi-omics data. This will enhance the generation of important and valuable information assets, in order to identify new biomarkers that can be used for early detection, improved tumor diagnosis and personalization of treatment protocols. ETHICS COMMITTEE APPROVAL NUMBER: 5420 - 0002485/23 from Fondazione Policlinico Universitario Agostino Gemelli IRCCS - Università Cattolica del Sacro Cuore Ethics Committee. TRIAL REGISTRATION: clinicaltrial.gov - NCT05802771.

Bronchoscopically-visible massive central airway cancer cavitation is associated with metastatic disease, lack of actionable mutations and poor prognosis: a case series.

Cavitating lung tumors occur in approximately 10-15% of the patients, are more commonly associated with squamous histology, and are typically located in the lung parenchyma. Herein we describe an exceedingly rare series of 5 patients, 4 of whom treatment-naïve, whose tumor caused the disruption of the normal airway anatomy at the level of lobar or segmental bronchi, leading to the formation of an endoscopically-visible cavity which ended up in the lung parenchyma or even into the pleural space. Sex (3 males, 2 females), smoking habit (2 never smokers, 2 former smokers, 1 current smoker), and histology (3 adenocarcinoma, 2 squamous cell carcinoma) were heterogeneous, but the 4 patients treatment-naïve presented with metastatic disease, poor ECOG performance status, similar clinical complaints of long duration, and lack of actionable mutations. The only patient who exhibited a meaningful response to treatment had the lowest symptoms' duration, the smallest size of the cavitated mass, and the best performance status at the time of diagnosis. This series provides the first comprehensive description of a rare presentation of lung cancer characterized by similar clinical complaints, delayed diagnosis and poor prognosis.

Predictive value of NLR, TILs (CD4+/CD8+) and PD-L1 expression for prognosis and response to preoperative chemotherapy in gastric cancer.

The combination of perioperative chemotherapy plus complete surgical resection is currently accounted as the first-choice strategy in patients with locally advanced Gastric Cancer (LAGC). Nevertheless, the partial response rate makes it necessary to search biological parameters useful to select patients who would benefit most from neoadjuvant chemotherapy (NAD-CT). We performed a retrospective analysis on a cohort of 65 LAGC cases, EBV negative and without MMR defect, submitted to perioperative chemotherapy plus surgical resection. We evaluated the neutrophil-lymphocytes ratio (NLR) in peripheral blood, the TILs density (reported as CD4/CD8 tissue ratio) and PD-L1 expression by immunohistochemistry on bioptic tissues before the treatment. Results were correlated with the biological features, histological response (TRG) and clinical outcome (PFS and OS). We found that NLR, TILs and PD-L1 expression showed a significant correlation with TNM stage, lymphovascular invasion and response to NAD-CT (TRG). Correlating the NLR, TILs and PD-L1 expression with PFS and OS, we found that patients with lower NLR levels (< 2.5 ratio), lower TILs (< 0.2 ratio) and higher PD-L1 level (CPS ≥ 1) had a significantly better PFS and OS than those with higher NLR, higher TILs and lower PD-L1 expression (p < 0.0001). Multivariate and multiple regression analyses confirmed the predictive and prognostic role of all three parameters, especially when all three parameters are combined. Our study demonstrated that pre-treatment NLR, TILs and PD-L1 expression are predictive and prognostic parameters in NAD-CT-treated LAGC suggesting a pivotal role of the systemic and tumor microenvironment immunological profile in the response to chemotherapy.

Evaluating the impact of chemotherapy-induced nausea and vomiting on daily functioning in patients receiving dexamethasone-sparing antiemetic regimens with NEPA (netupitant/palonosetron) in the cisplatin setting: results from a randomized phase 3 study.

BACKGROUND: The non-inferiority of dexamethasone (DEX) on day 1, with or without low-dose DEX on days 2 and 3, combined with oral NEPA (netupitant/palonosetron), compared with the guideline-consistent use of DEX was demonstrated in cisplatin. Here, we complete the analysis by assessing the impact of emesis on daily lives of patients receiving DEX-sparing regimens using the Functional Living Index-Emesis (FLIE). METHODS: Chemotherapy-naïve patients undergoing cisplatin (≥70 mg/m2), were given NEPA and DEX (12 mg) on day 1 and randomized to receive either 1) no further DEX (DEX1), 2) oral DEX (4 mg daily) on days 2-3 (DEX3), or 3) DEX (4 mg twice daily) on days 2-4 (DEX4; control). Patients completed the FLIE questionnaire on day 6 of cycle 1. Endpoints included the FLIE nausea domain, vomiting domain, and overall combined domain scores, as well as the proportion of patients with no impact on daily life (NIDL; overall score > 108). This was a protocol-planned analysis. RESULTS: In the DEX1 group, no significant differences were observed in the FLIE nausea score (48.9 [±1.8; SE] vs. 53.7 [±1.5]), vomiting score (56.6 [±1.4] vs. 58.7 [±0.8]) and overall score (105.6 [±2.8] vs.112.4 [±1.9]) versus DEX4 control; similar results were observed in the DEX3 group for nausea score (49.6 [±1.7]), vomiting score (58.2 [±1]) and overall score (107.8 [±2.4]) versus control. There were no significant between-group differences in the proportion of patients reporting NIDL. CONCLUSION: Reducing DEX, when administered with NEPA, does not seem to adversely impact the daily functioning in patients undergoing cisplatin. TRIAL REGISTRATION: ClinicalTrials.gov NCT04201769 . Registration date: 17/12/2019 - Retrospectively registered.

Role of Peripheral Blood Markers for Detecting Response and Predicting Prognosis in Patients with Non-small-cell Lung Cancer Undergoing Neoadjuvant Therapy and Surgery.

INTRODUCTION: To date, no validated predictors of response before neoadjuvant therapy (NAD) are currently available in locally advanced non-small-cell lung cancer (NSCLC). In this study, different peripheral blood markers were investigated before NAD (pre-NAD) and after NAD/before surgery (post-NAD) to evaluate their influence on the treatment outcomes. METHODS: Patients affected by locally advanced NSCLC (cT1-T4/N0-2/M0) who underwent NAD followed by surgery from January 1996 to December 2019 were considered for this retrospective analysis. The impact of peripheral blood markers on downstaging post-NAD and on overall survival (OS) was evaluated using multivariate logistic and Cox regression models. Time to event analysis was performed by means of Kaplan-Meier survival curves and Log Rank tests at 5 years from surgery. RESULTS: Two hundred and seventy-two consecutive patients were included. Most of the patients had Stage III NSCLC (83.5%). N2 disease was reported in 188 (69.1%) patients. Surgical resection was performed in patients with stable disease or downstaging post-NAD. Nodal downstaging was observed in 80% of clinical N2 (cN2) patients. The median follow-up of the total series was 74 months (range 6-302). Five-year OS in the overall population and in N2 population was 74.6% and 73.5%, respectively. The pre-surgery platelets level (PLT) (p = 0.019) and the variation (pre-NAD/post-NAD) of the neutrophil/lymphocyte ratio (p = 0.024) were identified as independent prognostic factors of OS. The preoperative PLT value (p value = 0.031) was confirmed as the only predictor of NAD response. CONCLUSIONS: The clinical role of peripheral blood markers in locally advanced NSCLC needs to be further investigated. Based on these preliminary results, these factors may be used as auxiliary markers for the prediction of response to neoadjuvant treatment and as prognostic factors for stratification in multimodal approaches.

Dexamethasone-Sparing Regimens with Oral Netupitant and Palonosetron for the Prevention of Emesis Caused by High-Dose Cisplatin: A Randomized Noninferiority Study.

BACKGROUND: To reduce the overall exposure to dexamethasone (DEX) in patients receiving cisplatin-based chemotherapy, we evaluated the noninferiority of DEX on day 1, with or without low-dose DEX on days 2 and 3, combined with an oral fixed-dose combination of netupitant and palonosetron (NEPA), compared with the guideline-consistent use of 4-day DEX. PATIENTS AND METHODS: In this open-label, multicenter study, chemotherapy-naïve patients undergoing high-dose cisplatin (≥70 mg/m2 ), were given NEPA and DEX (12 mg) on day 1 and randomized (1:1:1 ratio) to receive either (a) no further DEX (DEX1), (b) oral DEX (4 mg daily) on days 2-3 (DEX3), or (c) DEX (4 mg twice daily) on days 2-4 (DEX4). The primary efficacy endpoint was complete response (CR: no emesis and no rescue medication) during the 5-day overall phase. The noninferiority margin was set at -15% difference (DEX1 or DEX3 minus DEX4). Secondary efficacy endpoints included complete protection (CP: CR and none or mild nausea). RESULTS: Two-hundred twenty-eight patients, 76 in each arm, were assessable. Noninferiority was met for both DEX-sparing regimens and the reference arm, with overall phase CR rates of 76.3% in each of the DEX1 and DEX3 arms and 75.0% in the DEX4 arm (95% confidence interval, -12.3% to 15% for each comparison). During the overall phase, CP rates were similar between groups. CONCLUSION: A simplified regimen of NEPA plus single-dose DEX offers comparable chemotherapy-induced nausea and vomiting prevention throughout 5 days post-chemotherapy with the advantage of sparing patients additional doses of DEX in the high-emetic-risk setting of cisplatin-based chemotherapy. IMPLICATIONS FOR PRACTICE: Dexamethasone (DEX) has traditionally played an integral role in the management of chemotherapy-induced emesis. Although generally considered safe, even short-term DEX use is associated with various side effects, and some evidence suggests that concurrent steroids may reduce the efficacy of immunotherapies. This study demonstrates comparable antiemetic control during the 5 days post-chemotherapy with a simplified regimen of netupitant/palonosetron plus single-dose DEX versus the standard 4-day DEX reference treatment in high-dose cisplatin. This represents a clinically relevant achievement as it not only simplifies antiemetic prophylaxis but also offers an opportunity to appropriately use in patients where caution with corticosteroid use is advised.

Blood serum amyloid A as potential biomarker of pembrolizumab efficacy for patients affected by advanced non-small cell lung cancer overexpressing PD-L1: results of the exploratory "FoRECATT" study.

BACKGROUND: Identifying the patients who may benefit the most from immune checkpoints inhibitors remains a great challenge for clinicians. Here we investigate on blood serum amyloid A (SAA) as biomarker of response to upfront pembrolizumab in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Patients with PD-L1 ≥ 50% receiving upfront pembrolizumab (P cohort) and with PD-L1 0-49% treated with chemotherapy (CT cohort) were evaluated for blood SAA and radiological response at baseline and every 9 weeks. Endpoints were response rate (RR) according to RECIST1.1, progression-free (PFS) and overall survival (OS). The most accurate SAA cut-off to predict response was established with ROC analysis in the P cohort. RESULTS: In the P Cohort (n = 42), the overall RR was 38%. After a median follow-up of 18.5 months (mo), baseline SAA ≤ the ROC-derived cut-off (29.9 mg/L; n = 28/42.67%) was significantly associated with higher RR (53.6 versus 7.1%; OR15, 95% CI 1.72-130.7, p = 0.009), longer PFS (17.4 versus 2.1 mo; p < 0.0001) and OS (not reached versus 7.2mo; p < 0.0001) compared with SAA > 29.9 mg/L. In multivariate analysis, low SAA positively affects PFS (p = 0.001) and OS (p = 0.048) irrespective of ECOG PS, number of metastatic sites and pleural effusion. SAA monitoring (n = 40) was also significantly associated with survival endpoints: median PFS 17.4 versus 2.1 mo and median OS not reached versus 7.2 mo when SAA remained low (n = 14) and high (n = 12), respectively. In the CT Cohort (n = 30), RR was not affected by SAA level (p > 0.05) while low SAA at baseline (n = 17) was associated with better PFS (HR 0.38, 95% CI 0.16-0.90, p = 0.006) and OS (HR 0.25, 95% CI 0.09-0.67, p < 0.001). CONCLUSION: Low SAA predicts good survival outcomes irrespective of treatment for advanced NSCLC patients and higher likelihood of response to upfront pembrolizumab only. The strong prognostic value might be exploited to easily identify patients most likely to benefit from immunotherapy. A further study (FoRECATT-2) is ongoing to confirm results in a larger sample size and to investigate the effect of SAA on immune response in vitro assays.

Sequential chemo-hypofractionated RT versus concurrent standard CRT for locally advanced NSCLC: GRADE recommendation by the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

INTRODUCTION: Almost 30% of non-small cell lung cancer (NSCLC) patients have locally advanced-stage disease. In this setting, definitive radiotherapy concurrent to chemotherapy plus adjuvant immunotherapy (cCRT + IO) is the standard of care, although only 40% of these patients are eligible for this approach. AIMS: A comparison between cCRT and hypofractionated radiotherapy regimens (hypo-fx RT) with the addition of sequential chemotherapy (sCHT) could be useful for future combinations with immunotherapy. We developed a recommendation about the clinical question of whether CHT and moderately hypo-fx RT are comparable to cCRT for locally advanced NSCLC MATERIALS AND METHODS: The panel used GRADE methodology and the Evidence to Decision (EtD) framework. After a systematic literature search, five studies were eligible. We identified the following outcomes: progression-free survival (PFS), overall survival (OS), freedom from locoregional recurrence (FFLR), deterioration of quality of life (QoL), treatment-related deaths, severe G3-G4 toxicity, late pulmonary toxicity G3-G4, and acute esophageal toxicity G3-G4. RESULTS: The probability of OS and G3-G4 late lung toxicity seems to be worse in patients submitted to sCHT and hypo-fx RT. The panel judged unfavorable the balance benefits/harms. CONCLUSIONS: The final recommendation was that sCHT followed by moderately hypo-fx RT should not be considered as an alternative to cCRT in unresectable stage III NSCLC patients.

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.

Impact of BMI on HER2+ metastatic breast cancer patients treated with pertuzumab and/or trastuzumab emtansine. Real-world evidence.

Body mass index (BMI) is a main indicator of obesity and its association with breast cancer is well established. However, little is known in the metastatic setting, especially in HER2-positive patients. We assessed the influence of BMI on clinical outcomes of patients treated with pertuzumab and/or trastuzumab emtansine (T-DM1) for HER2+ metastatic breast cancer (mBC). BMI was addressed as a categorical variable, being classified on the basis of the following ranges, that is, 18.5-24.9, 25-29.9, and 30.0-34.9, namely, normal weight, overweight, and Class I obesity. The outcomes chosen were progression-free survival to first-line chemotherapy (PFS1) and overall survival (OS). Overall (N = 709), no impact of BMI was observed on PFS1 (p = .15), while BMI ≥ 30 was associated with worse OS (p = .003). In subjects who progressed to first line (N = 575), analyzing data across PFS1 quartiles and strata of disease burden, BMI predicted lower PFS1 in patients within the I PFS1 quartile and with the lowest disease burden (p = .001). Univariate analysis showed a detrimental effect of BMI ≥ 30 on OS for women within the I PFS1 quartile (p = .03). Results were confirmed in multivariate analysis. According to PFS1 quartiles a higher percentage of patients with high BMI and low disease burden progressed within 6 months of therapy. The effect of BMI on prognosis was also confirmed in multivariate analysis of OS for overall population. In our cohort, a BMI ≥ 30 correlated with worse OS in patients with HER2+ mBC who received pertuzumab and/or T-DM1 but had no impact on PFS to first line. BMI predicted worse I PFS1 quartile.

Distinct HR expression patterns significantly affect the clinical behavior of metastatic HER2+ breast cancer and degree of benefit from novel anti-HER2 agents in the real world setting.

We analyzed data from 738 HER2-positive metastatic breast cancer (mbc) patients treated with pertuzumab-based regimens and/or T-DM1 at 45 Italian centers. Outcomes were explored in relation to tumor subtype assessed by immunohistochemistry (IHC). The median progression-free survival at first-line (mPFS1) was 12 months. Pertuzumab as first-line conferred longer mPFS1 compared to other first-line treatments (16 vs. 9 months, p = 0.0001), regardless of IHC subtype. Median PFS in second-line (mPFS2) was 7 months, with no difference by IHC subtype, but it was more favorable with T-DM1 compared to other agents (7 vs. 6 months, p = 0.03). There was no PFS2 gain in patients with tumors expressing both hormonal receptors (HRs; p = 0.17), while a trend emerged for tumors with one HR (p = 0.05). Conversely, PFS2 gain was significant in HRs-negative tumors (p = 0.04). Median overall survival (mOS) was 74 months, with no significant differences by IHC subtypes. Survival rates at 2 and 3 years in patients treated with T-DM1 in second-line after pertuzumab were significantly lower compared to pertuzumab-naïve patients (p = 0.01). When analyzed by IHC subtype, the outcome was confirmed if both HRs or no HRs were expressed (p = 0.02 and p = 0.006, respectively). Our results confirm that HRs expression impacts the clinical behavior and novel treatment-related outcomes of HER2-positive tumors when treatment sequences are considered. Moreover, multivariate analysis showed that HRs expression had no effect on PFS and OS. Further studies are warranted to confirm our findings and clarify the interplay between HER2 and estrogen receptor pathways in HER2-positive (mbc) patients.

Physical Activity and Exercise in Lung Cancer Care: Will Promises Be Fulfilled?

Lung cancer remains the leading cause of cancer-related death worldwide. Affected patients frequently experience debilitating disease-related symptoms, including dyspnea, cough, fatigue, anxiety, depression, insomnia, and pain, despite the progresses achieved in term of treatment efficacy. Physical activity and exercise are nonpharmacological interventions that have been shown to improve fatigue, quality of life, cardiorespiratory fitness, pulmonary function, muscle mass and strength, and psychological status in patients with lung cancer. Moreover, physical fitness levels, especially cardiorespiratory endurance and muscular strength, are demonstrated to be independent predictors of survival. Nevertheless, patients with lung cancer frequently present insufficient levels of physical activity and exercise, and these may contribute to quality of life impairment, reduction in functional capacity with skeletal muscle atrophy or weakness, and worsening of symptoms, particularly dyspnea. The molecular bases underlying the potential impact of exercise on the fitness and treatment outcome of patients with lung cancer are still elusive. Counteracting specific cancer cells' acquired capabilities (hallmarks of cancer), together with preventing treatment-induced adverse events, represent main candidate mechanisms. To date, the potential impact of physical activity and exercise in lung cancer remains to be fully appreciated, and no specific exercise guidelines for patients with lung cancer are available. In this article, we perform an in-depth review of the evidence supporting physical activity and exercise in lung cancer and suggest that integrating this kind of intervention within the framework of a global, multidimensional approach, taking into account also nutritional and psychological aspects, might be the most effective strategy. IMPLICATIONS FOR PRACTICE: Although growing evidence supports the safety and efficacy of exercise in lung cancer, both after surgery and during and after medical treatments, most patients are insufficiently active or sedentary. Engaging in exercise programs is particularly arduous for patients with lung cancer, mainly because of a series of physical and psychosocial disease-related barriers (including the smoking stigma). A continuous collaboration among oncologists and cancer exercise specialists is urgently needed in order to develop tailored programs based on patients' needs, preferences, and physical and psychological status. In this regard, benefit of exercise appears to be potentially enhanced when administered as a multidimensional, comprehensive approach to patients' well-being.

Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ≥ 50.

BACKGROUND: Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of ≥ 50%. METHODS: We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-naïve NSCLC and a PD-L1 expression of ≥ 50%. RESULTS: One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. ECOG-PS ≥ 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of ≥ 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis. CONCLUSION: Pembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. Questions regarding the effectiveness in clinical subgroups, such as patients with poorer PS and with liver/bone metastases, still remain to be addressed. We confirmed that the absence of tobacco exposure, and the presence of bone and liver metastasis are associated with worse clinical outcomes to pembrolizumab. Increasing levels of PD-L1 expression may help identifying a subset of patients who derive a greater benefit from pembrolizumab monotherapy.

AXL Receptor in Breast Cancer: Molecular Involvement and Therapeutic Limitations.

Breast cancer was one of the first malignancies to benefit from targeted therapy, i.e., treatments directed against specific markers. Inhibitors against HER2 are a significant example and they improved the life expectancy of a large cohort of patients. Research on new biomarkers, therefore, is always current and important. AXL, a member of the TYRO-3, AXL and MER (TAM) subfamily, is, today, considered a predictive and prognostic biomarker in many tumor contexts, primarily breast cancer. Its oncogenic implications make it an ideal target for the development of new pharmacological agents; moreover, its recent role as immune-modulator makes AXL particularly attractive to researchers involved in the study of interactions between cancer and the tumor microenvironment (TME). All these peculiarities characterize AXL as compared to other members of the TAM family. In this review, we will illustrate the biological role played by AXL in breast tumor cells, highlighting its molecular and biological features, its involvement in tumor progression and its implication as a target in ongoing clinical trials.