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Background: The impact of the order of treatment with checkpoint inhibitors or BRAF/MEK inhibitors on the development of brain metastases in patients with metastatic unresectable BRAF V600-mutant melanoma is unknown. The SECOMBIT trial examined the impact of the order of receipt of these treatments in such patients., Methods: In this three-arm trial, we reviewed patients without brain metastases who received the BRAF/MEK inhibitors encorafenib and binimetinib until they had progressive disease followed by the immune checkpoint inhibitors ipilimumab and nivolumab (arm A); or treatment with ipilimumab and nivolumab until they had progressive disease followed by encorafenib and binimetinib (arm B); or treatment with encorafenib and binimetinib for 8 weeks followed by ipilimumab and nivolumab until they had progressive disease followed by retreatment with encorafenib arm binimetinib (arm C)., Results: Brain metastases were discovered during the trial in 23/69 patients in arm A, 11/69 in arm B, and 9/68 in arm C. At a median follow-up of 56 months, the 60-month brain metastases-free survival rates were 56% for arm A, 80% for arm B (hazard ratio [HR] vs. A: 0.40, 95% confidence interval [CI] 0.23 to 0.58), and 85% for arm C (HR vs. A: 0.35, 95% CI 0.16 to 0.76)., Conclusions: In patients with unresectable metastatic melanoma, the treatment sequence of immune checkpoint inhibition followed by BRAF/MEK inhibitors was associated with longer periods of new brain metastases-free survival than the reverse sequence. A regimen in which immune checkpoint inhibition was sandwiched between BRAF/MEK inhibition also appeared to be protective against brain metastases. (ClinicalTrials.gov number NCT02631447.).

Purpose: To identify prognostic circulating biomarkers to cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), we performed a mutational analysis on circulating tumor DNA (ctDNA) samples from patients included in the TREnd trial, which randomly assigned patients to receive the CDK4/6i palbociclib alone or with the endocrine treatment (ET) to which they had progressed., Methods: Forty-six patients were enrolled in this substudy. Plasma was collected before treatment (T0), after the first cycle of therapy (T1), and at the time of progression (T2). ctDNA hybridization and capture were performed using the Illumina TruSight Tumor 170 Kit. Acquired mutations were confirmed by digital polymerase chain reaction. Progression-free survival analysis was estimated using the Kaplan-Meier method and compared with the log-rank test., Results: The most frequently mutated genes at T0 were ESR1 (23%), PIK3CA (17%), AR , FGFR2, and TP53 (10%). Mutations in ESR1 at T0 conferred higher risk of progression in the entire population ( P = .02) and in patients treated with palbociclib + ET ( P = .04). ESR1 mutation effect remained significant after correction for clinical variables ( P = .03). PIK3CA mutations at T0 were not prognostic, but higher risk of progression was observed when a broader analysis of PI3K pathway was performed ( P = .04). At T2, we observed the emergence of nine new mutations in seven genes., Conclusion: Mutations in ESR1 and in PI3K pathway genes at T0 were associated with worse prognosis in palbociclib-treated patients. We describe the emergence of newly acquired mutations in palbociclib-treated patients, which might potentially affect subsequent treatment.

No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV600-mutant melanoma. SECOMBIT (NCT02631447) was a randomized, three-arm, noncomparative phase II trial in which patients were randomized to one of two sequences with immunotherapy or targeted therapy first, with a third arm in which an 8-week induction course of targeted therapy followed by a planned switch to immunotherapy was the first treatment. BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. Primary outcome of overall survival was previously reported, demonstrating improved survival with immunotherapy administered until progression and followed by BRAF/MEK inhibition. Here we report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAFV600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy., (© 2024. The Author(s).)

Patients with melanoma brain metastases (MBM) have poor prognosis, albeit advances in locoregional and systemic treatments. The melanoma-specific Graded Prognostic Assessment (GPA) effectively stratifies survival for patients with MBM. Nevertheless, lactate dehydrogenase (LDH), a well known prognostic factor for patients with melanoma, is not represented in the GPA scores and might add prognostic information for patients with MBM. In this study, 150 consecutive patients with MBM were retrospectively analyzed with the aim of evaluating independent prognostic factors for MBM patients, including LDH. Furthermore, we implemented a disease-specific prognostic score and estimated survival according to treatment modalities. On the basis of multivariable Cox regression analyses, six prognostic factors (age, BRAF status, number of MBM, number of extracranial metastatic sites, performance status, and LDH level) resulted statistically significant in terms of survival and were combined in a prognostic score to stratify patients in distinct prognostic groups ( P  < 0.0001). Among treatment modalities, a multimodal approach with stereotactic radiosurgery or neurosurgery associated with systemic therapy showed the best outcome (median overall survival: 12.32 months, 95% confidence interval, 7.92-25.30). This is the first study to demonstrate that LDH has independent prognostic value for patients with MBM and might be used to improve prognostic stratification, albeit external validation is mandatory. Survival of patients with MBM is affected by both disease-specific risk factors and treatment modalities, with locoregional treatments associated with better outcomes., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Limited prospective data are available on sequential immunotherapy and BRAF/MEK inhibition for BRAFV600 -mutant metastatic melanoma., Methods: SECOMBIT is a randomized, three-arm, noncomparative phase II trial (ClinicalTrials.gov identifier: NCT02631447). Patients with untreated, metastatic BRAFV600 -mutant melanoma from 37 sites in nine countries were randomly assigned to arm A (encorafenib [450 mg orally once daily] plus binimetinib [45 mg orally twice daily] until progressive disease [PD] -> ipilimumab plus nivolumab [ipilimumab 3 mg/kg once every 3 weeks and nivolumab 1 mg/kg once every 3 weeks × four cycles -> nivolumab 3 mg/kg every 2 weeks]), arm B [ipilimumab plus nivolumab until PD -> encorafenib plus binimetinib], or arm C (encorafenib plus binimetinib for 8 weeks -> ipilimumab plus nivolumab until PD -> encorafenib plus binimetinib). The primary end point was overall survival (OS) at 2 years. Secondary end points included total progression-free survival, 3-year OS, best overall response rate, duration of response, and biomarkers in the intent-to-treat population. Safety was analyzed throughout sequential treatment in all participants who received at least one dose of study medication., Results: A total of 209 patients were randomly assigned (69 in arm A, 71 in arm B, and 69 in arm C). At a median follow-up of 32.2 (interquartile range, 27.9-41.6) months, median OS was not reached in any arm and more than 30 patients were alive in all arms. Assuming a null hypothesis of median OS of ≤ 15 months, the OS end point was met for all arms. The 2-year and 3-year OS rates were 65% (95% CI, 54 to 76) and 54% (95% CI, 41 to 67) in arm A, 73% (95% CI, 62 to 84) and 62% (95% CI, 48 to 76) in arm B, and 69% (95% CI, 59 to 80) and 60% (95% CI, 58 to 72) in arm C. No new safety signals emerged., Conclusion: Sequential immunotherapy and targeted therapy provide clinically meaningful survival benefits for patients with BRAFV600 -mutant melanoma.

Purpose: To assess the efficacy and exploratory biomarkers of continuing palbociclib plus endocrine therapy (ET) beyond progression on prior palbociclib-based regimen in patients with hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer (ABC)., Patients and Methods: The multicenter, open-label, phase II BioPER trial included women who had experienced a progressive disease (PD) after having achieved clinical benefit on the immediately prior palbociclib plus ET regimen. Palbociclib (125 mg, 100 mg, or 75 mg daily orally for 3 weeks and 1 week off as per prior palbociclib-based regimen) plus ET of physician's choice were administered in 4-week cycles until PD or unacceptable toxicity. Coprimary endpoints were clinical benefit rate (CBR) and percentage of tumors with baseline loss of retinoblastoma (Rb) protein expression. Additional endpoints included safety and biomarker analysis., Results: Among 33 patients enrolled, CBR was 34.4% [95% confidence interval (CI), 18.6-53.2; P < 0.001] and 13.0% of tumors (95% CI, 5.2-27.5) showed loss of Rb protein expression, meeting both coprimary endpoints. Median progression-free survival was 2.6 months (95% CI, 1.8-6.7). No new safety signals were reported. A signature that included baseline mediators of therapeutic resistance to palbociclib and ET (low Rb score, high cyclin E1 score, ESR1 mutation) was independently associated with shorter median progression-free survival (HR, 22.0; 95% CI, 1.71-282.9; P = 0.018)., Conclusions: Maintaining palbociclib after progression on prior palbociclib-based regimen seems to be a reasonable, investigational approach for selected patients. A composite biomarker signature predicts a subset of patients who may not derive a greater benefit from palbociclib rechallenge, warranting further validation in larger randomized controlled trials., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: A multidisciplinary team meeting (MDM) approach in breast cancer (BC) management is a standard of care. One of the roles of MDMs is to identify the best diagnostic and therapeutic strategies for patients (pts) with new diagnosis of early BC. The purpose of this study was to define whether there was an agreement between the planned program (i.e., MDMs-based decision) and that actually applied. In addition, the study explored factors associated with discordance., Methods: We conducted a retrospective study of a consecutive series of 291 patients with new diagnosis of early BC, discussed at MDMs at the University Hospital of Udine (Italy), from January 2017 to June 2018. The association between clinico-biological factors and discordance between what was decided during the MDMs and what was consequently applied by the oncologist was explored through uni- and multivariate logistic regression analyses., Results: The median age was 62 years (range 27-88 years). Among invasive early BC patients, the most frequent phenotype was luminal A (38%), followed by luminal B (33%), HER2-positive (12%), and triple-negative (5%). In situ carcinoma (DCIS) represented 12% of cases. The median time from MDM discussion to first oncologic examination was 2 weeks. The rate of discordance between MDM-based decision and final choice, during a face-to-face consultation with the oncologist, was 15.8% (46/291). The most frequent reason for changing the MDM-based program was clinical decision (87%). Follow-up was preferred to the chemotherapy (CT) proposed within the MDMs in 15% of cases, and to the endocrine therapy (ET) in 39% of cases (among these, 44.5% had a diagnosis of DCIS). Therapeutic change from sequential CT-ET to ET alone was chosen in 16/46 pts (35%): among these patients, seven had a luminal B disease and six had an HER2-positive disease. On univariate analysis, factors associated with discordance were values of Ki-67 14%-30% (OR 3.91; 95% CI 1.19-12.9), age >70 years (OR 2.44, 95% CI 1.28-4.63), housewife/retired status (OR 2.35, 95% CI 1.14-4.85), polypharmacy (OR 1.95; 95% CI 1.02-3.72), postmenopausal status (OR 4.15; 95% CI 1.58-10.9), and high Charlson Comorbidity Index (OR 1.31; 95% CI 1.09-1.57). The association with marital status, educational level, alcohol and smoke habits, presence of a caregiver, parity, grading, histotype and phenotype, and stage was not statistically significant. On multivariate analysis, only Ki-67 value maintained its statistical significance., Conclusion: The results of our study could be useful for enhancing the role of MDMs in the clinical decision-making process in early BC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bortot, Targato, Noto, Giavarra, Palmero, Zara, Bertoli, Dri, Andreetta, Pascoletti, Poletto, Russo, Seriau, Mansutti, Cedolini, Basile, Fasola, Bonotto and Minisini.)

Background: To evaluate the capability of basal and one-month differed white blood cells (WBC), neutrophil, lymphocyte and platelet values and their ratios (neutrophils-to-lymphocytes ratio, NLR, and platelets-to-lymphocytes ratio, PLR) in predicting the response to immune checkpoint inhibitors (ICI) in metastatic melanoma (MM)., Methods: We performed a retrospective study of 272 BRAF wild-type MM patients treated with first line ICI. Bivariable analysis was used to correlate patient/tumor characteristics with clinical outcomes. Variations between time 1 and time 0 (Δ) of blood parameters were also calculated and dichotomized using cut-off values assessed by ROC curve., Results: At baseline, higher neutrophils and NLR negatively correlated with PFS, OS and disease control rate (DCR). Higher PLR was also associated with worse OS. In multivariable analysis, neutrophils (p = 0.003), WBC (p = 0.069) and LDH (p = 0.07) maintained their impact on PFS, while OS was affected by LDH (p < 0.001), neutrophils (p < 0.001) and PLR (p = 0.022), while DCR by LDH (p = 0.03) and neutrophils (p = 0.004). In the longitudinal analysis, PFS negatively correlated with higher Δplatelets (p = 0.039), ΔWBC (p < 0.001), and Δneutrophils (p = 0.020), and with lower Δlymphocytes (p < 0.001). Moreover, higher ΔNLR and ΔPLR identified patients with worse PFS, OS and DCR. In the multivariable model, only ΔNLR influenced PFS (p = 0.004), while OS resulted affected by higher ΔWBC (p < 0.001) and lower Δlymphocytes (p = 0.038). Higher ΔWBC also affected the DCR (p = 0.003). When clustering patients in 4 categories using basal LDH and ΔNLR, normal LDH/lower ΔNLR showed a higher PFS than high LDH/higher ΔNLR (20 vs 5 months). Moreover, normal LDH/higher Δlymphocytes had a higher OS than high LDH/lower Δlymphocytes (50 vs. 10 months)., Conclusions: Baseline and early variations of blood cells, together with basal LDH, strongly predict the efficacy of ICI in MM. Our findings propose simple, inexpensive biomarkers for a better selection of patient treatments. Prospective multicenter studies are warranted to confirm these data., (© 2022. The Author(s).)

Patients with newly resected stage II melanoma ( n = 104) were randomized to receive adjuvant vitamin D3 (100,000 IU every 50 days) or placebo for 3 years to investigate vitamin D3 protective effects on developing a recurrent disease. Median age at diagnosis was 50 years, and 43% of the patients were female. Median serum 25-hydroxy vitamin D (25OHD) level at baseline was 18 ng/mL, interquartile range (IQ) was 13-24 ng/mL, and 80% of the patients had insufficient vitamin D levels. We observed pronounced increases in 25OHD levels after 4 months in the active arm (median 32.9 ng/mL; IQ range 25.9-38.4) against placebo (median 19.05 ng/mL; IQ range 13.0-25.9), constantly rising during treatment. Remarkably, patients with low Breslow score (<3 mm) had a double increase in 25OHD levels from baseline, whereas patients with Breslow score ≥3 mm had a significantly lower increase over time. After 12 months, subjects with low 25OHD levels and Breslow score ≥3 mm had shorter disease-free survival ( p = 0.02) compared to those with Breslow score <3 mm and/or high levels of 25OHD. Adjusting for age and treatment arm, the hazard ratio for relapse was 4.81 (95% CI: 1.44-16.09, p = 0.011). Despite the evidence of a role of 25OHD in melanoma prognosis, larger trials with vitamin D supplementation involving subjects with melanoma are needed.

Background: Endocrine therapy (ET) plus cyclin-dependent-kinases 4/6 inhibitors (CDK4/6i) represents the standard treatment for luminal-metastatic breast cancer (MBC). However, prospective head-to-head comparisons are still lacking for 1st line (L) options, and it is still crucial to define the best strategy between 1st and 2nd L., Materials and Methods: 717 consecutive luminal-MBC pts treated between 2008 and 2020 were analyzed at the Oncology Department of Aviano and Udine, Italy. Differences about survival outcomes (OS, PFS and PPS) were tested by log-rank test. The attrition rate (AR) between 1st and 2ndL was calculated., Results: At 1 st L, pts were treated with ET (49%), chemotherapy (CT) (31%) and ET-CDKi (20%) while, at 2 nd L, 33% received ET, 33% CT and 8% ET-CDKi. Overall AR was 10%, 7% for CT, 8% for ET and 17% for ET-CDKi. By multivariate analysis, 1 st L ET-CDK4/6i showed a better mPFS1 and OS. Moreover, 2 nd L ET-CDK4/6i demonstrated better mPFS2 compared to ET and CT. Notably, 1 st L ET-CDKi resulted in higher mPFS than 2ndL ET-CDKi. Intriguingly, 1 st L ET-CDK4/6i was associated with worse mPPS compared to CT and ET. Secondarily, 1 st L ET-CDK4/6i followed by CT had worse OS compared to 1 st L ET-CDK4/6i followed by ET. Notably, none of baseline characteristics at 2 nd L influenced 2 nd L treatment choice (ET vs. CT) after ET-CDKi., Conclusion: Our real-world data demonstrated that ET-CDKi represents the best option for 1 st L luminal-MBC compared to ET and CT. Also, the present study pointed out that 2 nd L ET, potentially combined with other molecules, could be a feasible option after CDK4/6i failure, postponing CT on later lines., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Historically, metastatic melanoma was considered a highly lethal disease. However, recent advances in drug development have allowed a significative improvement in prognosis. In particular, BRAF/MEK inhibitors and anti-PD1 antibodies have completely revolutionized the management of this disease. Nonetheless, not all patients derive a benefit or a durable benefit from these therapies. To overtake this challenges, new clinically active compounds are being tested in the context of clinical trials. CDK4/6 inhibitors are drugs already available in clinical practice and preliminary evidence showed a promising activity also in melanoma. Herein we review the available literature to depict a comprehensive landscape about CDK4/6 inhibitors in melanoma. We present the molecular and genetic background that might justify the usage of these drugs, the preclinical evidence, the clinical available data, and the most promising ongoing clinical trials.

Approximately 40% of malignant melanomas are diagnosed in patients older than 65 years. Elderly patients with melanoma present clinicopathological features related to a more aggressive biology, and they are often diagnosed with advanced stage of disease. Interestingly, in older patients the immune system can be altered with changes both in the innate system and in the adaptive immune system with the acquisition of a pro-inflammatory and immune suppressive phenotype. Immunotherapy with immune checkpoint inhibitors has reshaped the treatment strategies and prognosis of patients with melanoma, and particularly, older age should not be considered a contraindication for immunotherapy. However, data regarding efficacy and safety of immunotherapy in elderly population are still limited because frail older patients are generally excluded from clinical trials. Recently, real-world data have shed light on similar efficacy and safety of immunotherapy in older population compared with younger counterpart. The aim of the present review was to summarize the available knowledge on the underlying immune system in older patients with a diagnosis of melanoma and the immunotherapeutic approaches in this population., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Triage procedures have been implemented to limit hospital access and minimize infection risk among patients with cancer during the coronavirus disease (COVID-19) outbreak. In the absence of prospective evidence, we aimed to evaluate the predictive performance of a triage system in the oncological setting., Materials and Methods: This retrospective cohort study analyzes hospital admissions to the oncology and hematology department of Udine, Italy, during the COVID-19 pandemic (March 30 to April 30, 2020). A total of 3,923 triage procedures were performed, and data of 1,363 individual patients were reviewed., Results: A self-report triage questionnaire identified 6% of triage-positive procedures, with a sensitivity of 66.7% (95% confidence interval [CI], 43.0%-85.4%), a specificity of 94.3% (95% CI, 93.5%-95.0%), and a positive predictive value of 5.9% (95% CI, 4.3%-8.0%) for the identification of patients who were not admitted to the hospital after medical review. Patients with thoracic cancer (odds ratio [OR], 1.69; 95% CI, 1.13-2.53, p = .01), younger age (OR, 1.52; 95% CI, 1.15-2.01, p < .01), and body temperature at admission ≥37°C (OR, 9.52; 95% CI, 5.44-16.6, p < .0001) had increased risk of positive triage. Direct hospital access was warranted to 93.5% of cases, a further 6% was accepted after medical evaluation, whereas 0.5% was refused at admission., Conclusion: A self-report questionnaire has a low positive predictive value to triage patients with cancer and suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) symptoms. Differential diagnosis with tumor- or treatment-related symptoms is always required to avoid unnecessary treatment delays. Body temperature measurement improves the triage process's overall sensitivity, and widespread SARS-CoV-2 testing should be implemented to identify asymptomatic carriers., Implications for Practice: This is the first study to provide data on the predictive performance of a triage system in the oncological setting during the coronavirus disease outbreak. A questionnaire-based triage has a low positive predictive value to triage patients with cancer and suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) symptoms, and a differential diagnosis with tumor- or treatment-related symptoms is mandatory to avoid unnecessary treatment delays. Consequently, adequate recourses should be reallocated for a triage implementation in the oncological setting. Of note, body temperature measurement improves the overall sensitivity of the triage process, and widespread testing for SARS-CoV-2 infection should be implemented to identify asymptomatic carriers., (© 2021 AlphaMed Press.)

Background: Circulating tumor cells (CTCs) are prognostic in patients with advanced breast cancer (ABC). However, no data exist about their use in patients treated with palbociclib. We analyzed the prognostic role of CTC counts in patients enrolled in the cTREnd study, a pre-planned translational sub-study of TREnd (NCT02549430), that randomized patients with ABC to palbociclib alone or palbociclib plus the endocrine therapy received in the prior line of treatment. Moreover, we evaluated RB1 gene expression on CTCs and explored its prognostic role within the cTREnd subpopulation., Methods: Forty-six patients with ER-positive, HER2-negative ABC were analyzed. Blood samples were collected before starting palbociclib treatment (timepoint T0), after the first cycle of treatment (timepoint T1), and at disease progression (timepoint T2). CTCs were isolated and counted by CellSearch® System using the CellSearch™Epithelial Cell kit. Progression-free survival (PFS), clinical benefit (CB) during study treatment, and time to treatment failure (TTF) after study treatment were correlated with CTC counts. Samples with ≥ 5 CTCs were sorted by DEPArray system® (DA). RB1 and GAPDH gene expression levels were measured by ddPCR., Results: All 46 patients were suitable for CTCs analysis. CTC count at T0 did not show significant prognostic value in terms of PFS and CB. Patients with at least one detectable CTC at T1 (n = 26) had a worse PFS than those with 0 CTCs (n = 16) (p = 0.02). At T1, patients with an increase of at least three CTCs showed reduced PFS compared to those with no increase (mPFS = 3 versus 9 months, (p = 0.004). Finally, patients with ≥ 5 CTCs at T2 (n = 6/23) who received chemotherapy as post-study treatment had a shorter TTF (p = 0.02). Gene expression data for RB1 were obtained from 19 patients. CTCs showed heterogeneous RB1 expression. Patients with detectable expression of RB1 at any timepoint showed better, but not statistically significant, outcomes than those with undetectable levels., Conclusions: CTC count seems to be a promising modality in monitoring palbociclib response. Moreover, CTC count at the time of progression could predict clinical outcome post-palbociclib. RB1 expression analysis on CTCs is feasible and may provide additional prognostic information. Results should be interpreted with caution given the small studied sample size.

Aims: It is debated whether the NRAS-mutant melanoma is more aggressive than NRAS wildtype. It is equally controversial whether NRAS-mutant metastatic melanoma (MM) is more responsive to checkpoint inhibitor immunotherapy (CII). 331 patients treated with CII as first-line were retrospectively recruited: 162 NRAS-mutant/BRAF wild-type (mut/wt) and 169 wt/wt. We compared the two cohorts regarding the characteristics of primary and metastatic disease, disease-free interval (DFI) and outcome to CII. No substantial differences were observed between the two groups at melanoma onset, except for a more frequent ulceration in the wt/wt group ( p = 0.03). Also, the DFI was very similar in the two cohorts. In advanced disease, we only found lung and brain progression more frequent in the wt/wt group. Regarding the outcomes to CII, no significant differences were reported in overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) or overall survival (OS) (42% versus 37%, 60% versus 59%, 12 (95% CI, 7-18) versus 9 months (95% CI, 6-16) and 32 (95% CI, 23-49) versus 27 months (95% CI, 16-35), respectively). Irrespectively of mutational status, a longer OS was significantly associated with normal LDH, <3 metastatic sites, lower white blood cell and platelet count, lower neutrophil-to-lymphocyte (N/L) ratio. Our data do not show increased aggressiveness and higher responsiveness to CII in NRAS-mutant MM.

Background: The coronavirus disease 2019 (COVID-19) pandemic has overwhelmed the health systems worldwide. Data regarding the impact of COVID-19 on cancer patients (CPs) undergoing or candidate for immune checkpoint inhibitors (ICIs) are lacking. We depicted the practice and adaptations in the management of patients with solid tumors eligible or receiving ICIs during the COVID-19 pandemic, with a special focus on Campania region., Methods: This survey (25 questions), promoted by the young section of SCITO (Società Campana di ImmunoTerapia Oncologica) Group, was circulated among Italian young oncologists practicing in regions variously affected by the pandemic: high (group 1), medium (group 2) and low (group 3) prevalence of SARS-CoV-2-positive patients. For Campania region, the physician responders were split into those working in cancer centers (CC), university hospitals (UH) and general hospitals (GH). Percentages of agreement, among High (H) versus Medium (M) and versus Low (L) group for Italy and among CC, UH and GH for Campania region, were compared by using Fisher's exact tests for dichotomous answers and χ 2 test for trends relative to the questions with 3 or more options., Results: This is the first Italian study to investigate the COVID-19 impact on cancer immunotherapy, unique in its type and very clear in the results. The COVID-19 pandemic seemed not to affect the standard practice in the prescription and delivery of ICIs in Italy. Telemedicine was widely used. There was high consensus to interrupt immunotherapy in SARS-CoV-2-positive patients and to adopt ICIs with longer schedule interval. The majority of the responders tended not to delay the start of ICIs; there were no changes in supportive treatments, but some of the physicians opted for delaying surgeries (if part of patients' planned treatment approach). The results from responders in Campania did not differ significantly from the national ones., Conclusion: Our study highlights the efforts of Italian oncologists to maintain high standards of care for CPs treated with ICIs, regardless the regional prevalence of COVID-19, suggesting the adoption of similar solutions. Research on patients treated with ICIs and experiencing COVID-19 will clarify the safety profile to continue the treatments, thus informing on the most appropriate clinical conducts., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We performed a multicenter retrospective observational study to investigate the impact of clinical-pathological features and therapeutic strategies on both the complications and survival of patients with bone metastases (BMs) from malignant melanoma., Patients and Methods: A total of 305 patients with melanoma and radiological evidence of BMs were retrospectively enrolled from 19 Italian centers. All patients received conventional treatments in accordance with each own treating physician's practice. Both univariate and multivariate models were used to explore the impact of melanoma features, including skeletal-related events (SREs), and different treatments on both overall survival (OS) and time-to-SREs. The chi-squared test evaluated the suitability of several parameters to predict the occurrence of SREs., Results: Eighty-three percent of patients had metachronous BMs. The prevalent (90%) bone metastatic site was the spine, while 45% had involvement of the appendicular skeleton. Forty-seven percent experienced at least one SRE, including palliative radiotherapy (RT) in 37% of cases. No melanoma-associated factor was predictive of the development of SREs, although patients receiving early treatment with bone-targeted agents showed 62% lower risk and delayed time of SRE occurrence. Median OS from the diagnosis of bone metastasis was 10.7 months. The multivariate analysis revealed as independent prognostic factors the number of BMs, number of metastatic organs, baseline lactate dehydrogenase levels, and treatment with targeted therapy or immunotherapy. Subgroup analyses showed the best OS (median = 16.5 months) in the subset of patients receiving both immunotherapy and palliative RT., Conclusion: Based on our results, patients undergoing immunotherapy and palliative RT showed an OS benefit suggestive of a possible additive effect. The apparent protective role of bone targeting agent use on SREs observed in our analysis should deserve prospective evaluation., (Copyright © 2020 Mannavola, Mandala, Todisco, Sileni, Palla, Minisini, Pala, Morgese, Di Guardo, Stucci, Guida, Indini, Quaglino, Ferraresi, Marconcini, Tronconi, Rossi, Nigro, Occelli, Cortellini, Quadrini, Palmieri, Pigozzo, Ascierto, Vitale, Strippoli, Ferrucci, Berardi, Randon, Cardone, Schinzari, Silvestris and Tucci.)

Aim: A monitoring strategy for metastatic breast cancer patients (M-MBC) has been little studied. Materials & methods: This retrospective study analyzed a consecutive cohort of 382 MBC patients to analyze different M-MBC strategies to identify factors influencing intensive M-MBC. Results: Elevated baseline serum tumor markers (STM) was the strongest factor associated with increased use of STM tests. Having more frequent oncology office visits was associated with more intensive chemotherapy/magnetic resonance imaging (MRI) using. Increased use of imaging tests was associated with participation to clinical trial. Single and elderly patients were less likely to have frequent testing. Having clinically measurable disease was less likely to have more intensive M-MBC. Conclusion: STM testing and scans were frequently ordered in M-MBC. In the present study, strategies are little influenced by clinico-pathological characteristics.

Background: Limited data are available regarding the use of nab-paclitaxel in older patients with breast cancer. A weekly schedule is recommended, but there is a paucity of evidence regarding the optimal dose. We evaluated the efficacy of two different doses of weekly nab-paclitaxel, with a specific focus on their corresponding impact on patient function, in order to address the lack of data specifically relating to the older population., Methods: EFFECT is an open-label, phase II trial wherein 160 women with advanced breast cancer aged ≥ 65 years were enrolled from 15 institutions within Italy. Patients were randomly assigned 1:1 to receive nab-paclitaxel 100 mg/m 2 (arm A) or 125 mg/m 2 (arm B) on days 1, 8, and 15 on a 28-day cycle, as first-line treatment for advanced disease. The primary endpoint was event-free survival (EFS), wherein an event was defined as disease progression (PD), functional decline (FD), or death. In each arm, the null hypothesis that the median EFS would be ≤ 7 months was tested against a one-sided alternative according to the Brookmeyer Crowley test. Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety., Results: After a median follow-up of 32.6 months, 140 events were observed in 158 evaluable patients. Median EFS was 8.2 months (90% CI, 5.9-8.9; p = 0.188) in arm A vs 8.3 months (90% CI, 6.2-9.7, p = 0.078) in arm B. Progression-free survival, overall survival, and response rates were similar in both groups. A higher percentage of dose reductions and discontinuations due to adverse events (AEs) was noted in arm B. The most frequently reported non-haematological AEs were fatigue (grade [G] 2-3 toxicity occurrence in arm A vs B, 43% and 51%, respectively) and peripheral neuropathy (G2-3 arm A vs B, 19% and 38%, respectively)., Conclusion: Pre-specified outcomes were similar in both treatment arms. However, 100 mg/m 2 was significantly better tolerated with fewer neurotoxicity-related events, representing a more feasible dose to be recommended for older patients with advanced disease., Trial Registration: EudraCT, 2012-002707-18 . Registered on June 4, 2012. NIH ClinicalTrials.gov, NCT02783222 . Retrospectively registered on May 26, 2016.

Despite surgical resection and adjuvant therapies, stage III melanomas still have a substantial risk of relapse. Neoadjuvant therapy is an emerging strategy that might offer superior efficacy compared to adjuvant therapy. Moreover, neoadjuvant therapy has some virtual advantages: it might allow for less demolitive surgery, permit the in vivo evaluation of drug efficacy, help tailor adjuvant treatments, and play a crucial role in innovative translational research. Herein, we review the available literature to explore the scientific background behind the neoadjuvant approach. We also discuss published clinical trials with a focus on predictive biomarkers and ongoing studies. Finally, we outline a possible framework for future neoadjuvant clinical trial development based on the International Neoadjuvant Melanoma Consortium guidelines.

Purpose: Thymidine kinase 1 (TK1) is downstream to the CDK4/6 pathway, and TK activity (TKa) measured in blood is a dynamic marker of outcome in patients with advanced breast cancer (ABC). This study explores TK1 as a biomarker of palbociclib response, both in vitro and in patients with ABC., Experimental Design: Modulation of TK1 levels and activity by palbociclib were studied in seven estrogen receptor-positive breast cancer cell lines: sensitive (PDS) and with palbociclib acquired resistance (PDR). TKa was assayed in plasma obtained at baseline (T0), after one cycle (T1), and at disease progression on palbociclib (T2) in patients enrolled in the "To Reverse ENDocrine Resistance" (TREnd) trial ( n = 46)., Results: Among E2F-dependent genes, TK1 was significantly downregulated after short-term palbociclib. Early TKa reduction by palbociclib occurred in PDS but not in PDR cells. In patients, median TKa (mTKa) at T0 was 75 DiviTum units per liter (Du/L), with baseline TKa not proving prognostic. At T1, mTKa decreased to 35 Du/L, with a minority of patients ( n = 8) showing an increase-correlating with a worse outcome than those with decreased/stable TKa ( n = 33; mPFS 3.0 vs 9.0 months; P = 0.002). At T2, mTKa was 251 Du/L; patients with TKa above the median had worse outcomes on post-study treatment compared with those with lower TKa (2.9 vs 8.7 months; P = 0.05)., Conclusions: TK is a dynamic marker of resistance to palbociclib which may lead to early identification of patients in whom treatment escalation may be feasible. In addition, TKa may stratify prognosis in patients with acquired resistance to palbociclib., (©2020 American Association for Cancer Research.)

High neutrophil to lymphocyte ratio (NLR) and monocyte to lymphocyte ratio (MLR) are respectively associated with systemic inflammation and immune suppression and have been associated with a poor outcome. Plasmatic exosomes are extracellular vesicles involved in the intercellular communication system that can exert an immunosuppressive function. Aim of this study was to investigate the interplay between the immune system and circulating exosomes in metastatic breast cancer (MBC). A threshold capable to classify patients according to MLR, NLR and PLR, was computed through a receiving operator curve analysis after propensity score matching with a series of female blood donors. Exosomes were isolated from plasma by ExoQuick solution and characterized by flow-cytometry. NLR, MLR, PLR and exosomal subpopulations potentially involved in the pre-metastatic niche were significantly different in MBC patients with respect to controls. MLR was significantly associated with number of sites at the onset of metastatic disease, while high levels of MLR and NLR were found to be associated with poor prognosis. Furthermore, exosomal subpopulations varied according to NLR, MLR, PLR and both were associated with different breast cancer subtypes and sites of distant involvement. This study highlights the nuanced role of immunity in MBC spread, progression and outcome. Moreover, they suggest potential interaction mechanisms between immunity, MBC and the metastatic niche.

Neuroblastoma rat sarcoma (NRAS) mutation, occurring in about 20%-30% of cutaneous melanomas, leads to activation of RAS-RAF-MAPK cascade and represents a clear distinct clinicopathological entity in melanoma. In contrast with BRAF mutant melanoma, no specific target therapies are available outside the setting of clinical trials. In the field of immunoncology, the predictive role of NRAS mutation with respect to checkpoint inhibitors treatment has not clearly established and deserves further investigation. At present, the standard treatment is the same as for BRAF wild type melanoma. Ongoing trials are exploring novel combination strategies among patients with advanced NRAS mutant melanoma., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Advanced melanoma (AM) represents the leading cause of death from skin cancer. To date, the crucial role of the immune system in AM pathogenesis and progression is well known, but the prognostic value of clinicopathological characteristics remains unclear. Lactate dehydrogenase (LDH) is an ascertained prognostic indicator and previous data showed that AM patients treated with BRAF and MEK inhibitors with normal LDH values and fewer than three metastatic sites achieved a better outcome. Moreover, the neutrophil-to-lymphocytes ratio and the lymphocyte-to-monocyte ratio (LMR) have been suggested as other potential prognostic factors. The aim of this study was to evaluate the prognostic value of LMR together with other clinical biomarkers in patients with AM. We retrospectively analyzed 162 consecutive patients with AM treated between January 2010 and March 2016. Outcome was measured in terms of overall survival (OS). In our cohort, the BRAF mutation was present in 74 (46%) patients. Overall, 42 and 26% of the patients received targeted therapy and immunotherapy, respectively. After 48 months of follow-up, 129 (78%) patients died; the median OS was 12.8 months. High LMR was associated with the following clinicopathological characteristics: absence of central nervous system localization (P = 0.011), fewer than three metastatic sites (P = 0.014), and normal LDH (P = 0.006). In multivariate analysis, Eastern Cooperative Oncology Group Performance Status >1 [hazard ratio (HR) 7.87, P = 0.001], high LDH (HR 2.76, P = 0.006), and high LMR (HR 0.76, P = 0.033) were associated significantly with OS. In conclusion, LMR seems to be associated with OS. Further prospective investigations are needed to confirm these data and introduce peripheral blood cell count in daily clinical use.

Background: Elevated plasmatic lactate dehydrogenase (LDH) levels are associated with worse prognosis in various malignancies, including metastatic breast cancer (MBC). Nevertheless, no data are available on the prognostic role of LDH as a dynamic biomarker during first-line treatment in unselected MBC. Methods: We reviewed data of 392 women with MBC to evaluate the association between LDH variation after 12 weeks of first-line treatment and survival. The prognostic impact was tested by multivariate Cox regression analysis. Results: Plasmatic LDH was confirmed as an independent prognostic factor in MBC. Patients who maintained elevated LDH levels after 12 weeks of first-line treatment experienced worse progression-free survival (PFS, HR 2.88, 95% CI: 1.40-5.89, p = 0.0038) and overall survival (OS, HR 2.61, 95% CI 1.16-5.86, p = 0.02) compared to patients with stable normal LDH levels, even after adjustment for other prognostic factors. Notably, LDH low-to-high variation emerged as an unfavorable prognostic factor for PFS (HR 3.96, 95% CI 2.00-7.82, p = 0.0001). Conclusions: Plasmatic LDH and its variation during first-line treatment predict PFS and OS in MBC, providing independent prognostic information. It would be worthwhile to prospectively evaluate the association between LDH variation and therapeutic benefit in MBC, and explore how it may affect treatment strategies.

Currently, there is limited data regarding the effectiveness of standard subsequent line therapies such as endocrine therapy, chemotherapy, or targeted agents after progression on CDK4/6 inhibitor-based regimens. This paper describes time-to-treatment failure beyond progression on palbociclib or palbociclib+endocrine therapy in patients enrolled in the phase II, multicenter TREnd trial. Our results indicate that there is limited benefit from post-palbociclib treatment, regardless of the type of therapy received. A small population of long responders were identified who demonstrated ongoing benefit from a subsequent line of endocrine therapy after progression to palbociclib-based regimens. A translational research program is ongoing on this population of outliers.

Age is an important prognostic factor in melanoma; notably, elderly patients tend to present with advanced stage skin melanoma (SM) and worse outcome. Moreover, SM is an immunogenic cancer, and its interaction with the aging immune system could have an effect on biologic behaviour of this disease. Tumour-infiltrating lymphocytes (TILs) could represent the host response in SM; it has been shown that higher grade of TILs is associated with better survival. Moreover, programmed death ligand 1 (PD-L1) and cyclooxygenase-2 (COX-2) are potential markers of host immune response and inflammation. We retrospectively reviewed 113 consecutive cases of early-stage SM that occurred in patients aged greater than or equal to 65 years at the time of diagnosis, followed between January 2010 and March 2014 at the University and General Hospital of Udine, Italy. The aim of this study was to evaluate TILs grade, PD-L1 expression on TILs and tumour expression of PD-L1 and COX-2 and their prognostic value in elderly patients with early SM. A better disease-free survival as well as melanoma-specific survival (MSS) was significantly associated with TILs [hazard ratios (HR): 0.41, 95% confidence interval (CI): 0.20-0.84, P=0.02 and HR: 0.37, 95% CI: 0.17-0.82, P=0.01, respectively]. PD-L1 positivity on TILs was associated with a better MSS (HR: 0.41, 95% CI: 0.17-0.97, P=0.04). Moreover, among patients with TILs, those showing COX-2 positivity on tumour cells and no PD-L1 expression on TILs had a worse disease-free survival and MSS (HR: 5.18, 95% CI: 1.33-20.23, P=0.018; HR: 6.21, 95% CI: 1.20-32.24, P=0.03; respectively). Immune and inflammatory markers deserve further investigation in aging patients with melanoma.

Background: The optimal strategy for monitoring metastatic breast cancer (M-MBC) is unclear. Nevertheless, M-MBC influences patient's quality of life and it affects the use of resources in terms of both drugs and diagnostic exam prescription. We aim to disclose oncologists' approach on M-MBC, identifying controversial areas., Methods: An anonymous online survey was conducted among GIM members who, based on their on-field experience, shared their own method for M-MBC planning. Chi-square tests and Fisher exact tests were used as appropriate., Results: The survey was completed by 256 recipients (51%). The majority of them were medical oncologists. Approximately 50% of respondents reported that M-MBC was primarily based on the monitoring strategies used in clinical trials, and for 70% of them M-MBC should be evidence-based. Areas of controversies included the primary goal of M-MBC, the use of tumour markers, the optimal timing for baseline assessment and frequency of repeating testing. Respondents agreed on planning M-MBC before treatment's start and on discussing with the patient about the M-MBC strategy and on choosing CT-scan as the preferred reassessment imaging method. The most relevant factors influencing the M-MBC strategy were performance status, triple negative histology, exam's contraindication, the presence of clinically measurable disease, and treatment safety profile; on the contrary, patients' socio-economic status, exam's cost, and hospital's logistic limits were less relevant. Experienced oncologists seemed less prone to intensive follow-up., Conclusion: M-MBC strategy still has controversial issues and its potential clinical effects for breast cancer patients need ad hoc studies., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The activity of palbociclib as a single agent in advanced breast cancer has not been extensively studied, with the only available clinical data limited to heavily pretreated patients. Preclinical data suggests palbociclib may partially reverse endocrine resistance, though this hypothesis has not been evaluated in previous clinical studies. This phase II, open-label, multicenter study examined the activity of palbociclib monotherapy, as well as palbociclib given in combination with the same endocrine therapy (ET) that was received prior to disease progression, in postmenopausal women with moderately pretreated, estrogen receptor-positive, HER2 negative advanced breast cancer., Patients and Methods: Eligible women with advanced disease which had progressed on one or two prior ETs were randomized 1 : 1 to receive either palbociclib alone, or palbociclib in combination with the ET as previously received. Primary end point was clinical benefit rate (CBR); secondary end points included progression-free survival (PFS)., Results: Between October 2012 and July 2016, a total of 115 patients were randomized. The CBR was 54% [95% confidence interval (CI): 41.5-63.7] for combination therapy, and 60% (95% CI: 47.8-72.9) for monotherapy. Median PFS was 10.8 months (95% CI: 5.6-12.7) for combination therapy, and 6.5 months (95% CI: 5.4-8.5) for monotherapy [hazard ratio (HR) 0.69; 95% CI: 0.4-1.1, exploratory P-value = 0.12]. Exploratory analyses revealed the PFS advantage for combination therapy was seen in the subgroup of patients who received prior ET for >6 months (HR 0.53; 95% CI: 0.3-0.9, exploratory P-value = 0.02), but not in those who received prior ET for ≤6 months., Conclusion: Palbociclib has clinical activity as a single agent in women with moderately pretreated, oestrogen receptor-positive, HER2-negative advanced breast cancer. Palbociclib may have potential to reverse endocrine resistance in patients with a history of previous durable response to ET., Clinical Trial Information: NCT02549430.

Aim: Discordance between primary tumor and paired metastases biology has been widely detected in metastatic breast cancer. The aim of this study was to evaluate the prognostic impact of Ki67, estrogen receptor (ER), progesterone receptor (PR) and HER2 discordance., Methods: We retrospectively analyzed a cohort of 544 patients affected by metastatic breast cancer. Variation in ER, PR, Ki67 and HER2 expression between primary site and recurrence was tested through the McNemar test., Results: A significant variation was observed in respect to ER, PR and Ki67 status (12.65%, p = 0.0072; 49.71%, p < 0.0001; 35%, p < 0.0001, respectively). Among patients with ER or PR discordance, the driver of therapeutic decisions was the ER status. Moreover, we observed a therapy-related reduction of ER in taxanes or aromatase inhibitors-exposed patients (odds ratio: 3.59; 95% CI: 1.66-7.77; p = 0.001 and odds ratio: 2.07; 95% CI: 0.96-4.44; p = 0.06, respectively)., Conclusion: Biopsy of metastatic lesions may influence the decision-making process translating into better outcome.

Background: Overweight and obesity are associated with an increased risk of developing many types of cancer, including breast cancer. Moreover, increased body mass index (BMI) seems to be associated with a worse prognosis in patients with HER2-positive early breast cancer. However, little is known about the impact of BMI on the clinical outcomes of HER2-positive metastatic breast cancer (MBC)., Methods: This was a multicenter retrospective cohort study including 329 consecutive patients with HER2-positive MBC treated with first-line trastuzumab-based regimens. BMI at the time of MBC diagnosis was collected. World Health Organization BMI categories were used: underweight <18.5, normal 18.5-24.9 Kg/m 2 , overweight 25-29.9 Kg/m 2 , and obese ≥30 Kg/m 2 . The analyses were conducted using two categories: BMI < 25.0 (normal/underweight) and BMI ≥ 25 (overweight/obese). Progression-free survival (PFS) and overall survival (OS) rates were estimated using Kaplan-Meier method. Univariate and multivariate survival analyses were performed using the Cox's proportional hazards model. Disease response to therapy was analyzed using univariate and multivariate logistic regression., Results: Overall, 176 (53.5%) patients were normal/underweight and 153 (46.5%) overweight/obese. Median PFS was 14.8 months in BMI < 25 group and 15.7 months in BMI ≥ 25 group (adjusted-HR 0.88; 95% CI 0.66-1.17; p = 0.387). Median OS was 58.6 months in BMI < 25 group and 52.6 in BMI ≥ 25 group (adjusted-HR 0.88; 95% CI 0.59-1.31; p = 0.525). Overall response rate was 71.7% and 65.9% (p = 0.296) and clinical benefit rate was 82.1% and 83.3% (p = 0.781) in BMI < 25 and BMI ≥ 25 groups, respectively., Conclusions: BMI does not seem to be associated with clinical outcomes in HER2-positive MBC patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The BALLET study was an open-label, multicenter, expanded access study designed to allow treatment with everolimus plus exemestane in postmenopausal women with hormone receptor-positive metastatic breast cancer progressed following prior endocrine therapy. A post hoc analysis to evaluate if previous chemotherapy in the metastatic setting affects the safety profile of the combination regimen of everolimus and exemestane was conducted on the Italian subset, as it represented the major part of the patients enrolled (54%)., Patients and Methods: One thousand one hundred and fifty-one Italian patients were included in the present post hoc analysis, which focused on two sets of patients: patients who never received chemotherapy in the metastatic setting (36.1%) and patients who received at least one chemotherapy treatment in the metastatic setting (63.9%)., Results: One thousand one hundred and sixteen patients (97.0%) prematurely discontinued the study drug, and the main reasons reported were disease progression (39.1%), local reimbursement of everolimus (31.1%), and adverse events (AEs) (16.1%). The median duration of study treatment exposure was 139.5 days for exemestane and 135.0 days for everolimus. At least one AE was experienced by 92.5% of patients. The incidence of everolimus-related AEs was higher (83.9%) when compared with those that occurred with exemestane (29.1%), and the most commonly reported everolimus-related AE was stomatitis (51.3%). However, no significant difference in terms of safety related to the combination occurred between patients without and with chemotherapy in the metastatic setting., Conclusion: Real-life data of the Italian patients BALLET-related cohort were an adequate setting to state that previous chemotherapy did not affect the safety profile of the combination regimen of everolimus and exemestane., Implications for Practice: With the advent of new targeted agents for advanced or metastatic breast cancer, multiple lines of therapy may be possible, and components of the combined regimens can overlap from one line to another. Thus, it is important to assess even the potential of cumulative and additive toxic effects among the drugs. Previous chemotherapy did not affect the safety profile of the combination regimen of everolimus and exemestane. The continuous monitoring of the safety signals of this drug combination from general clinical practice is important, in particular for stomatitis., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2017.)

Background: According to current guidelines, endocrine therapy (ET) is recommended as first-line treatment of luminal-like metastatic breast cancer (MBC), whereas chemotherapy (CT) should be considered in presence of life-threatening disease. In daily practice, CT is often used outside of this clinical circumstance. Factors influencing first-line choice and the relative impact on outcome are unknown., Methods: A consecutive series of luminal-like HER2-negative MBC patients treated from 2004 to 2014 was analyzed to test the association of disease- and patient-related factors with the choice of first-line treatment (ET vs. CT). A propensity score method was used to estimate impact of first-line strategy on outcome., Results: Of 604 consecutive luminal-like MBC patients identified, 158 cases were excluded due to unknown or positive HER2-status. Among 446 HER2-negative cases, 171 (38%) received first-line CT. On multivariate analysis, the only factors significantly associated with lower CT use were old age (OR 0.25, 95%C.I. 0.13-0.49) or presence of bone metastases only (OR 0.26, 95%C.I. 0.13-0.53). In propensity score matched population, no differences were observed between CT and ET as first-line treatment either in terms of overall survival (37.5 months and 33.4 months respectively, log-rank test, P = 0.62) or progression-free survival (13.3 months and 9.9 months respectively, log-rank test, P = 0.92)., Conclusions: High percentage of patients with luminal-like MBC received CT as first-line therapy in real-life. The choice was mainly driven by age and site of metastases. With the limitations of a non-randomized comparison, no differences on patients' outcome were observed depending on the first-line strategy., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Despite the availability of several therapeutic options for metastatic breast cancer (MBC), no robust predictive factors are available to help clinical decision making. Nevertheless, a decreasing benefit from first line to subsequent lines of treatment is commonly observed. The aim of this study was to assess the impact of benefit from first-line therapy on outcome with subsequent lines., Methods: We analyzed a consecutive series of 472 MBC patients treated with chemotherapy (CT) and/or endocrine therapy (ET) between 2004 and 2012. We evaluated progression-free survival (PFS) at first (PFS1), second, third, and fourth therapeutic lines, according to treatment (ET and/or CT) and tumor subtypes., Results: In the whole cohort, median overall survival was 34 months, and median PFS1 was 9 months. A 6-month benefit was shown by 289 patients (63.5%) at first line, 128 (40.5%) at second line, 76 (33.8%) at third line, and 34 (23.3%) at fourth line. Not having a 6-month benefit at PFS1 was associated with less chance of benefit at second line (odds ratio [OR]: 0.48; 95% confidence interval [CI]: 0.29-0.77, p = .0026) and at any line beyond first (OR: 0.39; 95% CI: 0.24-0.62, p < .0001). In the total series, after stratification for tumor subtypes, a strong predictive effect was observed among HER2-positive tumors (OR: 0.2; 95% CI: 0.05-0.73, p = .0152)., Conclusion: Our results suggest that the absence of at least a 6-month benefit in terms of PFS with first-line therapy predicts a reduced probability of benefit from subsequent therapeutic lines, especially in HER2-positive disease., Implications for Practice: This study supports evidence showing that the absence of a 6-month benefit in terms of progression-free survival with first-line therapy predicts a lack of benefit from subsequent therapeutic lines in metastatic breast cancer. The random distribution of benefit experienced by a subset of the cohort further spurs an interest in identifying predictive factors capable of identifying the most appropriate therapeutic strategy., (©AlphaMed Press.)

There is growing evidence about differences in metastatic spread among breast cancer (BC) biologic subtypes (BS). Aim of this study was to analyze the pattern of metastasization according to BS and to explore the corresponding prognosis. A series of 544 consecutive patients receiving anticancer therapy for metastatic BC from 2004 to 2013, was analyzed. BS were defined by immunohistochemistry according to St Gallen 2013 criteria. Association between BS and the different distant localizations was analyzed. Prognosis was described in terms of overall survival (OS), progression free survival (PFS) and post progression survival (PPS). Results were reported taking luminal A BC as reference. Triple negative BC showed a higher tropism for lung (OR 4.30 95% CI 1.41-13.1), while non luminal HER2 subtype was associated with a higher rate of liver metastases (OR 3.61 95% CI 1.36-9.58). All subtypes were associated with a lower risk of bone-only localization. Central nervous system (CNS) involvement was more common in HER2 positive BC (OR 6.3, 95% CI 1.08-36.66). Liver, lung and CNS involvement influenced negatively OS (HR 1.64, 95% CI 1.29-2.07; HR 1.49, 95% CI 1.18-1.90; HR 2.891, 95% CI 1.85-4.51, respectively) and PFS (HR 1.39, 95% CI 1.13-1.71; HR 1.26, 95% CI 1.02-1.55; HR 1.75, 95% CI 1.12-2.71, respectively). Multivariate analysis confirmed liver involvement as independent predictor of worse OS (HR 1.64, 95% CI 1.15-2.34). Stratification by metastatic pattern showed significant differences in terms of PPS but not in terms of PFS. The study suggests that BS may be characterized by typical patterns of metastatic spread and have different impact on clinical outcome.

No gold standard treatment exists for metastatic breast cancer (MBC). Clinical decision making is based on knowledge of prognostic and predictive factors that are extrapolated from clinical trials and, sometimes, are not reliably transferable to a real-world scenario. Moreover, misalignment between endpoints used in drug development and measures of outcome in clinical practice has been noted. The roles of overall survival (OS) and progression-free survival (PFS) as primary endpoints in the context of clinical trials are the subjects of lively debate. Information about these parameters in routine clinical practice is potentially useful to design new studies and/or to interpret the results of clinical research. This study analyzed the impact of patient and tumor characteristics on the major measures of outcome across different lines of treatment in a cohort of 472 patients treated for MBC. OS, PFS, and postprogression survival (PPS) were analyzed. The study showed how biological and clinical characteristics may have different prognostic value across different lines of therapy for MBC. After first-line treatment, the median PPS of luminal A, luminal B, and human epidermal growth factor receptor 2 (HER2)-positive groups was longer than 12 months. The choice of OS as a primary endpoint for clinical trials could not be appropriate with these subtypes. In contrast, OS could be an appropriate endpoint when PPS is expected to be low (e.g., triple-negative subtype after the first line; other subtypes after the third line). The potential implications of these findings are clinical and methodological., (©AlphaMed Press.)

Development of central nervous system (CNS) metastases in breast cancer (BC) is associated with poor prognosis. The incidence of CNS metastases in metastatic BC is reported to be about 10-16 %, but different subtypes of BC are associated with different risk of developing CNS metastases. We retrospectively analysed the risk of CNS metastases and the outcome in a cohort of 473 patients with metastatic BC. CNS metastases were diagnosed in 15.6 % of patients and median survival from diagnosis of CNS metastases was 7.53 (25th-75th 2.8-18.9) months. The risk of developing CNS metastases was higher in patients with grade 3, hormone receptor negative, HER2-positive, high Ki-67 BC. When compared to luminal A subtype, only HER2-positive BC was associated with increased risk of CNS metastases. Survival from diagnosis of CNS metastases was longer in patients with HER2-positive BC, while it was shorter in patients that did not receive any locoregional treatment, or with extra-CNS disease, or with more than 3 CNS lesions.