Endocrine adverse events related to immune-oncology agents: retrospective experience of a single institution.

BACKGROUND: Immune-oncology agents (IOA) represent a turning point in the treatment of several solid tumors (ST). Although their toxicity compares favorably with other treatments, IOA associate immune-related adverse events (IR-AE), among which endocrine-related AE stand out. We retrospectively evaluated the occurrence of endocrine (E) IR-AE in a cohort of patients with several ST treated with IOA. In addition, we assessed the correlation between likelihood of survival and the occurrence of IR-AE. METHODS: We collected data on clinical and molecular characteristics, efficacy and AE of 260 patients with ST treated with IOA from 2013 to 2017. We excluded patients with prior conditions or treatments potentially affecting thyroid test results. RESULTS: Lung cancer was the most prevalent diagnosis (70.2%). EIR-AE appeared in 18.1% of patients (total of 38 EIR-AE) and consisted of hypothyroidism, hyperthyroidism, pituitary disorders and type 1 diabetes mellitus in 60.5%, 21.1%, 15.8% and 2.6% of patients, respectively. EIR-AE were associated mainly to nivolumab, nivolumab plus ipilimumab (41.2% and 26.5%) and appeared after a median of 4.2 cycles of treatment. Specific therapy was required in 65.8% patients. There were significant differences in both progression-free survival (PFS) and overall survival (OS) for patients who experienced EIR-AE compared to those who did not [PFS: 56.7 (NC-NC) vs. 27.7 (14.3-41.3) months, P=0.008; OS: NC (NC-NC) vs. 31.4 (20.7-42.1) months, P=0.001]. CONCLUSIONS: The incidence of EIR-AE in our study is similar to other series. Patients who develop EIR-AE might have a better prognosis compared to those who do not experience them.

Prognostic value of stem cell markers in glioblastoma.

Background/Context: Glioblastoma (GB) is the most common primary brain tumour in adults and it is associated with a high mortality rate. According to the stem cell theory, the growth, relapse and treatment response of GB is determined by the stem cell subpopulation present in the tumour. Objective: Our aim is to study the prognostic value of stem cell markers (CD44, Nestin, Olig2 and SOX2) in a series of homogeneously treated GBs. Material and methods: We study 280 GBs treated with STUPP acheme with a histologican review of the cases and TMA with a máximum of 4 spots for each case. Each slide was immunohistochemically stained and Reading. We compared the immunohistochemical results with survival tme. Results: Only SOX2 immunoexpression (IE) excedding 10% of the tumour cells was found to be related to good survival (p= 0.037) in univariate analysis. However, amultivariate analysis indicate the age, surgery and MGMT promotes methylation but no SOX2 IE are prognostic factors. Conclusions: We conclude the immunohistochemical studies of stem cell markers in GB are not useful for predicting prognosis in daily practice.

Real-world data on T-DM1 efficacy - results of a single-center retrospective study of HER2-positive breast cancer patients.

T-DM1 is an antibody drug conjugate that combines trastuzumab with emtansine via a stable thioether linker. In two phase III clinical trials, EMILIA and TH3RESA, T-DM1 was shown to be effective in HER2-positive metastatic breast cancer patients who had progressed to taxanes and trastuzumab. We have performed a real-world study to complement the findings of the clinical trials. From 2012 to 2016, 15 patients with HER2-positive breast cancer who had progressed to prior treatment received T-DM1 at our center. We have retrospectively analyzed outcomes in these patients and compared our findings with those of the two clinical trials. Progression-free survival (PFS) was 10 months compared with the 9.6 months of the EMILIA trial and the 6.2 months of the TH3RESA trial, overall survival was 34 months compared with the 29.9 months of the EMILIA trial and the 22.7 months of the TH3RESA trial. PFS was ≥12 months in five patients, three of whom attained a PFS of ≥23 months. Among five patients with metastases of the central nervous system, PFS was six months, OS was not reached, and the objective response rate was 80%. Our findings are in line with those of the EMILIA study and slightly superior to those of the TH3RESA study. In our series of patients, T-DM1 has demonstrated efficacy in the treatment of HER2-positive metastatic breast cancer. Our real-world data thus confirm and support the findings of the two major phase III trials and indicate the usefulness of T-DM1 in routine clinical practice.

Pyrosequencing versus methylation-specific PCR for assessment of MGMT methylation in tumor and blood samples of glioblastoma patients.

Circulating biomarkers in blood may provide an interesting alternative to risky tissue biopsies in the diagnosis and follow-up of glioblastoma patients. We have assessed MGMT methylation status in blood and tissue samples from unresected glioblastoma patients who had been included in the randomized GENOM-009 trial. Paired blood and tissue samples were assessed by methylation-specific PCR (MSP) and pyrosequencing (PYR). After establishing the minimum PYR cut-off that could yield a significant difference in overall survival, we assessed the sensitivity, specificity, positive predictive value and negative predictive value (NPV) of the analyses. Methylation could be detected in cfDNA by both MSP and PYR but with low concordance with results in tissue. Sensitivity was low for both methods (31% and 38%, respectively), while specificity was higher for MSP in blood than for PYR in plasma (96% vs 76%) and NPV was similar (56 vs 57%). Concordance of results in tissue by MSP and PYR was 84.3% (P < 0.001) and correlated with outcome. We conclude that detection of cfDNA in the blood of glioblastoma patients can be an alternative when tumor tissue is not available but methods for the detection of cfDNA in blood must improve before it can replace analysis in tumor tissue.

Correction: Monitoring EGFR-T790M mutation in serum/plasma for prediction of response to third-generation EGFR inhibitors in patients with lung cancer.

[This corrects the article DOI: 10.18632/oncotarget.25478.].

A Single-Center Retrospective Study of Patients with Double Primary Cancers: Breast Cancer and EGFR-Mutant Non-Small Cell Lung Cancer.

BACKGROUND: Second primary malignancies (SPM) in the lung are not common in breast cancer (BC) patients. EGFR-mutant lung cancer (LC) is a separate molecular subset, and the co-existence of EGFR-mutant LC and BC has not been explored. We hypothesized that EGFR-mutant LC patients could have higher rates of primary BC than those with EGFR-wild type (WT). METHODS: We collected data on clinical and molecular characteristics and outcomes of female patients with LC and a previous or simultaneous history of primary BC treated in our hospital from 2008 to 2014. RESULTS: Data on treatment, follow-up, and EGFR mutation status were available for 356 patients. 17.7% (11/62) of patients with EGFR mutations had BC, compared to 1.02% (3/294) of EGFR-WT patients (p < 0.001). Both tumors were metachronous in 81.8%, with LC diagnosed 9 years after the diagnosis of BC. 5 of the 6 (83.3%) BC patients treated with radiotherapy developed LC in an area within the radiation field. No EGFR mutations were detected in BC tissue and no HER2 expression was detected in LC samples. CONCLUSION: SPM in the lung and breast occur more frequently among EGFR-mutant compared to EGFR-WT LC patients. Radiotherapy for BC may increase the risk of developing primary LC.

Monitoring EGFR-T790M mutation in serum/plasma for prediction of response to third-generation EGFR inhibitors in patients with lung cancer.

BACKGROUND: Osimertinib is efficacious in lung cancer patients with epidermal growth factor receptor (EGFR) mutations and acquired resistance (AR) to EGFR tyrosine kinase inhibitors due to EGFR-T790M mutation (T790M). We sought to describe T790M changes in serum/plasma during osimertinib therapy and correlate these changes with treatment outcomes. MATERIAL AND METHODS: Serum/plasma from EGFR-mutant lung cancer patients with T790M-AR was collected before and during osimertinib treatment. Changes in T790M were evaluated using a peptide-nucleic acid-PCR assay, and correlated with clinical and radiographic response. RESULTS: Thirteen patients were included. Median time on osimertinib treatment was 10.6 months with a median progression-free survival of 13.6 months. Best response to osimertinib was partial response (PR), stable disease (SD) or progression (PD) in 46.1%, 30.8% and 23.1% of patients, respectively.Most of the patients were paucisymptomatic at baseline. Symptom improvement was reported in 66.6% of responder patients; while symptoms remained stable in 75% of patients with SD, and 66% of patients with PD had clinical deterioration.Three patterns of T790M changes during osimertinib treatment were identified. T790 remained detectable with PD or a short-lasting SD in 15.4% of the patients. T790M disappeared in 69.2% of patients with PR or SD. T790M disappeared, despite clinical and/or radiographic progression in 15.4% of the patients. CONCLUSION: Changes of T790M in serum/plasma in EGFR-mutant lung cancer patients with T790M-AR might be a useful marker of symptomatic and radiographic outcome to osimertinib. Longer follow-up is needed to establish if subsequent emergence of T790M could be a marker of resistance.

Is a pretreatment radiological staging system feasible for suggesting the optimal extent of resection and predicting prognosis in glioblastoma? An observational study.

To assess the value of resection in glioblastoma based on pre-surgical tumor characteristics and a subsequent staging system. The lack of a staging system for glioblastoma hinders the analysis of treatment outcome. We classified 292 uniformly treated glioblastoma patients as stage I, II, or III based on tumor size, location, and eloquence and then analyzed the impact of the extent of resection. We classified 62% of patients as stage I, 25.3% as stage II, and 12.7% as stage III. Gross total resection (GTR) was performed mainly in stage I rather than stage II or III patients (79.2% vs. 14.6% vs. 6.3%; P < 0.001). Overall survival (OS) was 17.7, 14.6, and 10.8 months for stage I, II, and III patients, respectively (P = 0.005). Longer OS was significantly associated with greater extent of resection, younger age, KPS ≥ 70%, MGMT methylation, lower stage, and tumor ≤ 5 cm. In the subgroups of stage I (P = 0.04) and stage II (P < 0.001)-but not stage III-patients, GTR and partial resection (PR) were associated with longer OS. We constructed several multivariable models including different variables, and greater extent of resection, smaller tumor size, and MGMT methylation consistently emerged as independent markers of longer OS. This staging system provides a feasible tool for comparison of results. We confirmed the value of partial resection in stage I and II patients, in contrast to some reports suggesting that biopsy only is sufficient when gross total resection cannot be safely achieved.