Search

Aim: To evaluate treatment results in advanced/metastatic melanoma patients treated with anti-PD-1 immunotherapy in routine practice in oncology centers in Poland. Methods: Multicenter retrospective analysis included 499 patients with unresectable/metastatic (stage IIIC–IV) melanoma treated with anti-PD-1 in first-line therapy. Results: Estimated median overall survival (OS) and progression-free survival (PFS) were 19.9 and 7.9 months, respectively. Multivariate analysis confirmed that ECOG 0, no brain metastases, normal lactate dehydrogenase level and occurrence of immune-related adverse events (irAEs) were statistically significantly associated with improved OS and PFS. Any irAE occurred in 24% of patients. Grade 3 or Grade 4 irAEs occurred in 6% of patients. Conclusion: Analysis revealed a slightly worse OS in real-world treatment in comparison to clinical trials (KEYNOTE-006 and CheckMate 066). Polish population treatment results are similar to other studies of real-world data. PFS and ORR are similar in our research and clinical trials.

Introduction The treatment outcomes of patients with advanced/metastatic melanoma were poor before the use of new therapeutic options. Material and methods A retrospective analysis was conducted among 287 patients with unresectable stage III and stage IV melanoma treated at the Maria Sklodowska-Curie National Research Institute of Oncology Cracow Branch, from 2013 to 2019. All enrolled patients were treated with immunotherapy (IT; consisting of pembrolizumab/nivolumab, or ipilimumab) or target therapy (TT; consisting of vemurafenib ±cobimetinib or dabrafenib ±trametinib) in at least one treatment line. Results mutation was detected in 152 (55%) patients. In general, the majority of patients (92%) were in very good or good condition (Eastern Cooperative Oncology Group [ECOG] 0 or 1). Brain metastasis was detected in 64 (22%) patients. Median OS and PFS in the experimental group from the beginning of the first-line treatment were 14.9 and 6.7 months, respectively. Across the study population, as a first-line treatment patients received IT, TT as well as CHT, and the median OS was 19.2, 12.6 and 15.9 months, respectively. Multivariate analysis confirmed that normal LDH levels, no brain metastases, ECOG 0, and objective response to the treatment were strong predictors of longer OS. For PFS, absence of brain metastases, ECOG 0, and treatment response were found to be predictive factors on multivariate analysis. Conclusions The administration of new therapies for the treatment of patients with advanced/disseminated melanoma significantly prolonged survival in this group of patients. Nevertheless, further studies should be conducted to assess the effectiveness of various sequences of treatment.

e21514 Background: Anti-programmed cell death-1 antibodies (anti-PD-1) have become a standard treatment option for melanoma patients. Currently, two anti-PD-1 antibodies are registered in the treatment of melanoma patients: nivolumab and pembrolizumab. Nivolumab is a human monoclonal antibody, while pembrolizumab is a humanized antibody. Unfortunately, there are very few clinical data comparing the efficacy and toxicity of nivolumab and pembrolizumab in routine practice. Methods: Consecutive patients treated in the first line with anti-PD-1 (nivolumab or pembrolizumab) for unresectable or metastatic melanoma in comprehensive cancer centers between 03/2016 and 09/2020 were enrolled in the analysis. Baseline factors (age, gender, primary location of melanoma, BRAF mutation status, ECOG performance status, baseline LDH level, and location of metastases) were evaluated to identify predictors of overall survival (OS). Data on response to treatment and the occurrence of irAEs were collected prospectively during anti-PD-1 treatment. OS were assessed using Kaplan–Meier and Cox models. The Chi-Square statistic was used for testing relationships between categorical variables. Median follow up for nivolumab and pembrolizumab group was 12.6 (range 0.2-52.1) and 10.7 (range 0.03-53.5) months, respectively. Results: Overall, 736 patients were included in the present analysis (443 nivolumab, 293 pembrolizumab). There were no statistically significant differences in baseline factors (age, gender, primary location of melanoma, BRAF mutation status, ECOG performance status, baseline LDH level (normal vs elevated), brain metastasis and TNM stage) between the groups. Median OS for patients treated with nivolumab and pembrolizumab was 22 and was 17.3 months, respectively. There was no statistically significant difference in OS between the nivolumab and pembrolizumab groups (p = 0.12, HR = 1.2, Cl 95% 0.9-1.4). At multivariate analysis normal LDH levels, no brain metastases, and ECOG 0 or 1 were positive prognostic factors for OS both in nivolumab and pembrolizumab groups. In the nivolumab and pembrolizumab groups, 6% and 5% CR (complete response), 33% and 31% PR (partial response), 25% and 24% SD (stable disease), respectively, were observed. There was no statistical difference between the groups in the response to treatment (p = 0.65). There was no statistical difference between the groups in occurrence of the irAEs (p = 0.97) as well as in the type of irAEs. Conclusions: Our analysis in melanoma patients treated in routine practice with nivolumab or pembrolizumab confirmed no statistical differences in OS and treatment responses between these two anti-PD-1 antibodies. There were also no differences in toxicity between the two drugs. The choice of treatment should be based on the preferences of the patient and the physician.

Certain common inherited variations in genes involved in tumor angiogenesis, progression and metastasis may contribute to cancer therapy outcome and prognosis by altering the gene expression and protein activity. In this report, we examined the effect of functional polymorphisms in MMP-1, MMP-2, MMP-3, VEGF, VEGFR2, FGFR4 and COX-2 genes on overall (OS) and progression-free survival (PFS) of 350 Caucasian patients with inoperable non-small cell lung cancer (NSCLC). The results of multivariate analysis indicated that VEGFR2 -906C and COX-2 -1195G alleles were strongly associated with poor OS and PFS (p = 0.002 and 0.015, respectively, for OS; p = 0.009 and 0.015, respectively, for PFS), while MMP-2 -1306 T allele carriers had significantly reduced PFS (p = 0.010). Moreover, an increased risk of death and progression was significantly associated with the number of adverse alleles for VEGFR2/COX-2 (p = 0.0005 for OS and 0.0006 for PFS in >1 adverse allele carriers) and VEGFR2/COX-2/MMP-2 combinations (p = 0.0003 for OS and 0.0001 for PFS in patients with >2 adverse alleles). Finally, VEGFR2 TC/CC, COX-2 AG/GG and MMP-2 CT/TT genotypes as well as "at risk" allele combinations were identified as independent predictors of unfavorable OS and PFS in the group. In conclusion, the data suggest that selected VEGFR2, COX-2 and MMP-2 polymorphisms may be potential prognostic markers in unresectable NSCLC treated with radiotherapy with or without chemotherapy, although further validation studies are warranted to confirm our observations.

Background: PPM1D (WIP1) negatively regulates by dephosphorylation many proteins including p53 tumour suppressor. The truncating mutations (nonsense and frameshift) in exon 6 of PPM1D were found recently in blood cells of patients with breast, ovarian or colorectal cancer. These mutants code for gain-of-function PPM1D with retained phosphatase activity. Their significance in carcinogenesis is unknown. Methods: The exon 6 of PPM1D was sequenced in blood DNA of 543 non-small-cell lung cancer patients (NSCLC). The functional significance of selected PPM1D alterations (Arg458X, Lys469Glu) was compared with the wild-type gene and examined by recombinant DNA techniques, immunoblotting and luciferase reporter assays. Results: The frameshift mutations were found in five NSCLC patients (5/543; 0.92%), all of them had squamous cell carcinomas (5/328; 1.5%). All patients with the mutations were exposed, before the blood collection, to the DNA damaging agents as a part of chemotherapeutic regimen. Functional tests demonstrated that truncating mutation Arg458X causes enhancement of dephosphorylation activity of PPM1D toward serine 15 of p53, whereas Lys469Glu version is equivalent to the wild-type. Neither version of PPM1D (wild-type, Arg458X, Lys469Glu) significantly modulated the ability of p53 to transactivate promoters of the examined p53-target genes (BAX and MDM2). Conclusions: The truncating mutations of PPM1D are present in blood DNA of NSCLC patients at frequency similar to percentage determined for ovarian cancer patients. Our findings raise a question if the detected lesions are a result of chemotherapy.

Aim of the study: Metaplastic breast carcinomas (MBC) are a rare group of cancers, accounting for about 1% of all breast cancers. The study presents a case series of MBC patients diagnosed, treated and followed up in one healthcare center. Material and methods: The study group comprised 18 women at the median age of 63 years. The most common carcinoma type in the study group was MBC with squamous epithelial differentiation (56%). Estrogen receptor expression was identified in one patient. No steroid or HER2 receptor expression was found in the remaining patients. We analyzed recurrence and survival rates in relation to clinical and therapeutic factors by using the Kaplan-Meier method. Results: A significantly longer overall survival time was noted among patients treated with adjuvant radiation therapy, p = 0.018. No other factors had a significant influence on survival. Because of the small size of the study group, results obtained in the study should be treated with caution.

Gastric cancer is one of the most frequent neoplasms. Although the incidence of gastric cancer worldwide has declined, there is still high mortality. Treatment of inoperable disease is under evaluation in clinical trials. In palliative treatment chemotherapy containing cisplatin and 5-fluorouracil is the most widely used. In the past years progress in tumour biology has advanced greatly and has led to development of new molecules aimed at targets important for cancer expansion. There are several randomized trials under targeted therapies for gastric cancer patients. One of them led to approval of trastuzumab. In the current paper the authors illustrate new possibilities in systemic treatment with particular attention to targeted therapy and personalization in medicine.

Polymorphism in signal-induced proliferation-associated 1 (SIPA1) gene may contribute to the development of metastasis in human cancers. In this preliminary study, we examined the association of the SIPA1 -313A>G (rs931127) polymorphism with overall survival (OS) and progression-free survival (PFS) in 351 inoperable patients with non-small cell lung cancer (NSCLC) treated with radiotherapy or radiochemotherapy (curative or palliative). The GG homozygotes had significantly shorter PFS under codominant and recessive models in all patients (hazard ratio (HR) 1.47, p = 0.035, and HR 1.47, p = 0.022, respectively) and in advanced stage subgroup (HR 1.49, p = 0.037, and HR 1.48, p = 0.023, respectively). The GG genotype was also associated with reduced OS and PFS (codominant model: HR 2.41, p = 0.020, and HR 2.34, p = 0.020, respectively; recessive model: HR 2.16, p = 0.026, and HR 2.18, p = 0.022, respectively) in radiotherapy alone subgroup. Moreover, the SIPA1 -313GG was identified as an independent adverse prognostic factor for PFS in the cohort. Our results indicate, for the first time, that the SIPA1 -313A>G may have a prognostic role in unresected NSCLC making it a potential predictor of poor survival due to earlier progression.

Polymorphisms in DNA repair genes may modulate not only an individual DNA repair capacity, DNA damage levels and cancer risk but also clinical outcome after DNA damage-inducing anticancer therapy. In this study, we analyzed the association between the XPA -4G>A, XPD Asp312Asn, hOGG1 Ser326Cys, XRCC1 Arg399Gln, XRCC2 -4234G>C, XRCC3 -4541A>G and Thr241Met polymorphisms and prognosis in 250 inoperable non-small cell lung cancer (NSCLC) patients treated with radiotherapy and platinum-based chemotherapy. In univariate model, the XPA-4A and XRCC1 399Gln alleles alone and in combination influenced survival only in stage III group. In multivariate analysis, the XPA-4 GA/AA was associated with poor survival (HR 1.55, p = 0.011 overall and HR 1.72, p = 0.008 in stage III). In chemoradiotherapy group, the XPA-4A carriers were at increased risk of death and progression (HR 1.73, p = 0.013 and HR 1.65, p = 0.016, respectively), especially in stage III (p = 0.008). Moreover, individuals with ≥ 2 XPA/XRCC1 adverse alleles showed a higher risk of death (HR 1.46, p = 0.036 overall; HR 1.85, p = 0.004 in stage III and HR 1.71, p = 0.022 in chemoradiotherapy group) and progression (HR 1.75, p = 0.011 overall and HR 1.93, p = 0.005 in stage III). The XPA-4 GA/AA genotype individually and together with the XRCC1 399Gln was an independent unfavorable prognostic factor in our study. Thus, our findings indicate a prognostic potential of the XPA-4G>A in unresected NSCLC treated with radiotherapy and chemoradiotherapy. The results require validation in an independent population.