Sarcopenia is a complex syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength. Malignancy is a major determinant of sarcopenia, and gastric cancer (GC) is ...among the most common causes of this phenomenon. As sarcopenia is a well-recognized poor prognostic feature in GC and has been associated with worse tolerance of surgical and medical treatments, members of the multidisciplinary team should be aware of the clinical relevance, pathogenic mechanisms, and potential treatments for this syndrome. The importance of sarcopenia is often underestimated in everyday practice and clinical trials, particularly among elderly or fragile patients. As treatment options are improving in all disease stages, deeper knowledge and greater attention to the metabolic balance in GC patients could further increase the benefit of novel therapeutic strategies and dramatically impact on quality of life. In this review, we describe the role of sarcopenia in different phases of GC progression. Our aim is to provide oncologists and surgeons dealing with GC patients with a useful tool for comprehensive assessment and timely management of this potentially life-threatening condition.
Background:
Programmed cell death 1 (PD-1) and PD-ligand 1 (PD-L1) inhibitors represent novel therapeutic options for advanced non-small cell lung cancer (NSCLC). However, approximately 50% of ...patients do not benefit from therapy and experience rapid disease progression. PD-L1 expression is the only approved biomarker of benefit to anti-PD-1/PD-L1 therapy. However, its weakness has been evidenced in many studies. More recently, tumor mutational burden (TMB) has proved to be a suitable biomarker, but its calculation is difficult to obtain for all patients.
Methods:
We tested specific NSCLC genetic alterations as potential immunotherapy biomarkers. Tumor DNA was obtained from advanced NSCLC patients treated with anti-PD-1 monoclonal antibody nivolumab (n = 44) or pembrolizumab (n = 3). The mutational status of 22 genes was assessed by targeted next-generation sequencing and the association with survival was tested in uni- and multivariate models. The association between gene mutations and clinical benefit was also investigated.
Results:
The most frequently mutated genes were TP53 (49%), KRAS (43%), ERBB2 (13%), SMAD4 (13%), DDR2 (13%), STK11 (9%), ERBB4 (6%), EGFR (6%), BRAF (6%), and MET (6%). We confirmed that KRASmut patients have a better response to PD-1 inhibitors, showing a longer progression-free survival (PFS) and overall survival (OS) than KRASwt patients. In addition, we observed that patients with ERBB-family mutations, including EGFR, ERBB2, and ERBB4 all failed to respond to PD-1 antibodies, independently of KRAS status.
Conclusions:
This study suggests that the analysis of KRAS and ERBB-family gene mutational status is valuable when assessing the clinical practice for the selection of NSCLC patients to treat with PD-1 inhibitors.
Purpose
Epigenetic variations in the O6-methylguanine-methyltransferase gene had been widely associated with a favorable impact on survival in patients affected by glioblastoma multiforme (GBM). Aim ...of this study is to explore a scoring system based on the gene promoter methylation in order to predict patients’ prognosis.
Methods
A series of 128 patients with GBM was retrospectively analyzed. A training set and a validations set were then generated. The methylation level of CpGi from 74 to 83 was determined by pyrosequencing. In accordance to previous literature, each island was assigned with 1 point if the corresponding methylation level was higher than 9%. The sum consisted in a score that went from 0 (all CpGi < 9%) to 10 (all CpGi ≥ 9%). A threshold capable to detect a favorable outcome (overall survival, OS > 24 months) was identified by ROC analysis.
Results
Median OS and follow-up were 14 and 32.6 months respectively. Among the total population, 35% of the pts had a score of 0, while 29% had a score of 10. A score ≥ 6 was associated with a favorable prognosis also when corrected for age (> 70 vs. ≤ 70 years) and ECOG performance status (0–1 vs. 2–3). Similar results were observed also in terms of PFS. Results were consistent in the training and in the validation set.
Conclusions
The present manuscript explored a novel scoring system capable to take into consideration the methylation status of each single CpGi, capable to better predict prognosis in GBM patients.
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e20612
Background: Acquired T790M EGFR mutation (mut) is not predictable by any clinical-pathological feature. The best time point for T790M mut detection by liquid or tissue biopsy is ...currently undefined. Methods: This is an observational study at 6 Italian Centers enrolling EGFR mutant NSCLC patients (pts) progressing after first/second generation EGFR TKI, between 2014 and 2018. The primary endpoint of the study was to compare clinical features in acquired T790M+ compared with T790M- cases. The secondary endpoint was to assess different progression (PD) patterns between the two groups. We also explored the PD pattern at the time of cfDNA negativity and subsequent positivity, in a subgroup of pts receiving serial liquid biopsies. Statistical analysis was performed by the Chi-square test to correlate clinical features with T790M status, and by the Kaplan-Meier estimator to evaluate median progression free (mPFS) and overall survival (mOS). Multiple logistic regression and log-rank tests were applied. Results: 219 pts were included. Median follow-up since diagnosis was 25 months. First line treatment was gefitinib (N = 119, 54%), erlotinib (N = 48, 22%) or afatinib (N = 52, 24%). In 108 (49%) cases a T790M acquired mut was detected in liquid (70), tissue (31) biopsy or both (7). Age younger than 65 years ( p= 0.05) and presence of sensitizing exon 19 deletion ( p= 0.04) were correlated with T790M mut; this association was confirmed at multivariate analysis ( p= 0.010 and p= 0.006, respectively). At the time of PD, new PD sites ( p= 0.005) and liver PD ( p< 0.001) were more commonly observed in T790M+ group; at multivariate analysis statistical significance was confirmed ( p= 0.01 and p= 0.008, respectively). Longer mOS was observed in T790M+ cases at univariate (53 versus 22 months, p < 0.0001) and multivariate analysis. In 13 pts undergoing serial liquid biopsies, an oligoprogressive disease was correlated with a negative test outcome, while PS/symptoms worsening, higher number of new lesions and PD sites were observed at the time of T790M positivity, although without statistical significance. Conclusions: This is the first caucasian series showing different clinical features and progression patterns of T790M+ versus T790M- EGFR mutant NSCLC.
Clinical-pathologic predictors of acquired T790M epidermal growth factor receptor (EGFR) mutation in Caucasian patients with non–small-cell lung cancer (NSCLC) progressing after ...first-/second-generation tyrosine kinase inhibitors (TKIs) is an open field for research. Similarly, the best time point for T790M detection by liquid or tissue biopsy after disease progression is currently matter of debate.
This is an observational study at 7 Italian centers enrolling patients with EGFR-mutant NSCLC progressing after first-/second-generation EGFR TKIs, between 2014 and 2018, aiming at comparing baseline clinical-pathologic features and progression patterns in acquired T790M-positive compared with T790M-negative cases.
A total of 235 patients received first-line treatment with gefitinib (N = 126; 53%), erlotinib (N = 51; 22%), or afatinib (N = 58; 25%). In 120 (51%) cases, T790M was detected in liquid biopsy, tissue biopsy, or both. Age younger than 65 years (P = .037), the presence of common mutations (P = .004), and better response to first-line TKI (P = .023) were correlated with T790M positivity. T790M detection was associated with higher number of new progressing sites (P = .04), liver progression (P = .002), and a lower frequency of lung metastases (P = .027). When serial liquid biopsies were performed (N = 15), an oligoprogressive disease was correlated with a negative test outcome, whereas systemic progression was observed at the time of T790M positivity.
This study on a Caucasian population showed that age, type of EGFR mutation at diagnosis, response to first-line treatment, and peculiar progression pattern are associated with T790M status. Serial liquid biopsy might be useful for treatment selection, especially when tissue rebiopsy is not feasible.
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Clinical features and disease course of patients with epidermal growth factor receptor (EGFR)-mutant non–small-cell lung cancer progressing to first-line EGFR-tyrosine kinase inhibitors might be heterogeneous. Age younger than 65, common EGFR mutations, overall response, and typical progression pattern might predict the T790M-positive status. Serial liquid biopsies during treatment could be useful in this population, especially when tissue rebiopsy is not feasible.
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e21502
Background: Limited data are available on how the setting and timing of palliative care (PC) referral can affect end-of-life (EoL) care and survival in cancer patients (pts). The ...aim of our study was to evaluate the impact of PC referral (hospice and/or home-care services) versus family physician care (FP-C), in terms of both EoL quality of care and survival in cancer pts. Methods: The study included 337 cancer pts who died between January 2015 and February 2016. We retrieved data on type of EoL care and on poor quality of care indicators in the last 30 days of life. Palliative Care Survival (PCS) was defined as the interval between timing of PC referral and death. The survival after treatment (Treatment-Free Survival, TFS) was defined as the interval between the last administration of anticancer therapy and death. Results: FP-C court included 89 pts and PC services court 248 pts. The 248 PC pts were divided in three groups: 99 assisted by both PC services, 58 only by home-care and 91 only by hospice care. The median PCS was 24 days. TFS was significantly longer for the three groups assisted by PC (105, 95, and 82 days respectively) than for that assisted only by FP-C (49 days, p < 0.0001). Compared to PC services, FP-C was associated with higher frequency of poor quality of care indicators, such as emergency room visits (p < 0.0001), hospitalizations (p < 0.0001), hospital death (p < 0.0001) and chemotherapy administration (p < 0.0001). In addition, earlier PC referral (30-60 and > 60 days before death) versus late referral ( < 30 days before death) was associated with a lower frequency of poor quality indicators. Variables such as age, sex and primary tumor were not associated with a different quality of care. Conclusions: Pts referred to PC services, compared to pts referred only to FP-C, had improved EoL survival and quality of care. A better definition of PC referral timing can affect the quality of EoL care in cancer pts.
We retrospectively analyzed a series of metastatic breast cancer patients to identify factors that could potentially improve the prognostic valuation and clinical decision-making at the end of life. ...Worse Eastern Cooperative Oncology Group performance status and liver function impairment were associated with a greater risk of death within 1 month. Age < 70 years, luminal B-like disease, and number of previous treatment lines were associated with receiving chemotherapy in a subset of patients.
In metastatic breast cancer (MBC) patients, the identification of factors helping clinicians in the choice between active therapy versus best supportive care is needed clinically. The aim of the present study was to identify the clinicopathologic factors that could improve the prognostic valuation of MBC patients and clinical decision-making at the end of life.
The present study analyzed data from a retrospective series of 522 MBC patients treated at the oncology department (University Hospital of Udine) from January 2004 to June 2014. The association between clinicopathologic features and death within 30 or 90 days since last-line treatment prescription was explored. Differences between lightly (≤ 3 lines) and heavily (> 3 lines) pretreated patients and the factors affecting treatment choice were investigated.
The event “death” occurred in 410 patients. The median last-line survival was 100 days. The median number of therapeutic lines was 3. On multivariate analysis, worse Eastern Cooperative Oncology Group performance status was significantly associated with death within 90 and 30 days since last-line treatment prescription. Among the heavily pretreated patients, liver function impairment and evaluation by a breast cancer specialist were significantly associated with a greater and lower risk of death within 30 days, respectively. Among the lightly pretreated patients with luminal disease, age < 70 years, luminal B-like disease, and number of previous lines were associated with a greater chance of receiving chemotherapy.
In the present study, the Eastern Cooperative Oncology Group performance status was the most robust independent factor driving the last-line therapeutic choice for MBC patients. In addition, the molecular subtype and oncologist subspecialization also influenced the decision-making process.
Since angiogenesis plays an important role in cancer growth, infiltration and metastasis, many agents targeting this pathway have been developed over the last decade. Antiangiogenic drugs interfere ...with this process and may inhibit neoplastic growth or induce tumor dormancy by blocking the expanding network of newly formed capillaries. Despite the initial promise, targeting angiogenesis in breast cancer has not reached major breakthroughs. Nevertheless, the immunologic role of VEGF deserves to be further explored. We aim to describe the biological mechanisms which underlie the role of angiogenesis in breast cancer carcinogenesis, to depict its contribution to the metastatic process and to review the most important clinical trials testing angiogenic inhibitors in breast cancer, including monoclonal antibodies and novel small molecules.
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2048
Background: The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter has been associated with improved outcome in glioblastoma (GBM) patients (pts). ...Pyrosequencing (PSQ) has been reported to be an accurate method for quantitative detection of CpG islands (CpGs) methylation, but the role of methylation heterogeneity among different CpGs sites is still unclear. Aim of this study was to evaluate on a large multicentric cohort a novel prognostic score based on the evaluation of the MGMT promoter methylation at 10 different CpGs sites. Methods: We retrospectively analyzed a series of 185 pts with GBM treated at the University Hospital of Udine and Istituto Oncologico Veneto in Padua between 2006 and 2015. The methylation level of 10 CpGs (74 – 83) was determined by PSQ. The cut-off point of 9% was used to define a CpG as methylated. One point was assigned to each methylated CpG, with a total score from 0 (all CpGs < 9%) to 10 (all CpGs ≥ 9%). A threshold capable to detect a favorable outcome (Overall Survival, OS > 24 months) has been identified through ROC analysis as 6 by a previous study conducted at our center. The prognostic impact was explored through Cox regression. Results: After a median follow-up of 59 months, the median OS and Progression Free Survival (PFS) in the whole population were 16.41 and 9.67 months, respectively. A score ≥ 6 identified pts with a considerably better median OS (24.85 vs 12.99 months, p < .0001) and PFS (11.44 vs 8.22 months, p < .0001). On multivariate analysis, it remained independently associated with a favorable prognosis (HR 0.38, 95% CI 0.27-0.55, p < 0.0001) after adjustment for IDH1 mutational status (HR 0.42, 95% CI 0.20-0.87, p = .02), age ( > 70 vs ≤ 70 years HR 2.20, 95% CI 1.48-3.28, p = .0001) and ECOG performance status (2-3 vs 0-1 HR 2.35, 95% CI 1.59-3.49, p < .0001). The score’s prognostic value was maintained in all the explored subgroups. Conclusions: Combining methylation data from multiple CpGs increases the prognostic value of the MGMT promoter methylation assessment. The study confirmed the independent prognostic value of a novel score system based on the evaluation of the MGMT promoter methylation at 10 different CpGi sites.
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