The Impact of Sidedness on the Efficacy of Anti-EGFR-Based First-Line Chemotherapy in Advanced Colorectal Cancer Patients in Real-Life Setting-A Nation-Wide Retrospective Analysis (RACER).

Anti-EGFR antibodies combined with chemotherapy doublets are a cornerstone of the upfront treatment of colorectal cancer. RAS and BRAF mutations are established negative predictive factors for such therapy. The primary tumour located in the proximal colon has recently emerged as another negative predictive factor. We have conducted a retrospective multicentre study to collect data on real-world population characteristics, practice patterns, and outcomes in patients with metastatic colorectal cancer treated in a first-line setting with either cetuximab or panitumumab in combination with either FOLFOX or FOLFIRI chemotherapy. The presented analysis focuses on the impact of the primary tumour location. 126 of 842 patients analysed (15.0%) had proximal primary. It was associated with a lower BMI at diagnosis, mucinous histology, and peritoneal metastases. It was also associated with inferior treatment outcomes in terms of response ratio: 59.4% vs. 74.22% (odds ratio [OR] 0.51, 95% CI 0.33-0.78, p = 0.010), and median depth of response: -36.7% vs. -50.0% (p = 0.038). There was only a borderline non-significant trend for inferior PFS in patients with proximal tumours. OS data was incomplete. The presented analysis confirms the negative impact of tumour sidedness on the efficacy of an upfront anti-EGFR-chemotherapy combination and provides valuable data on real-world population characteristics.

Clinical Characterization of Targetable Mutations (BRAF V600E and KRAS G12C) in Advanced Colorectal Cancer-A Nation-Wide Study.

BRAF V600E and KRAS mutations that occur in colorectal cancer (CRC) define a subpopulation of patients with an inferior prognosis. Recently, the first BRAF V600E-targeting therapy has been approved and novel agents targeting KRAS G12C are being evaluated in CRC. A better understanding of the clinical characteristics of the populations defined by those mutations is needed. We created a retrospective database that collects clinical characteristics of patients with metastatic CRC evaluated for RAS and BRAF mutations in a single laboratory. A total of 7604 patients tested between October 2017 and December 2019 were included in the analysis. The prevalence of BRAF V600E was 6.77%. Female sex, primary in the right colon, high-grade, mucinous, signet cell, partially neuroendocrine histology, perineural and vascular invasion, and surgical tissue sample were factors associated with increased mutation rates. The prevalence of KRAS G12C was 3.11%. Cancer of primary origin in the left colon and in samples from brain metastases were associated with increased mutation rates. The high prevalence of the BRAF V600E mutation in cancers with a neuroendocrine component identifies a potential candidate population for BRAF inhibition. The association of KRAS G12C with the left part of the intestine and brain metastases of CRC are new findings and require further investigation.

Metronomic Chemotherapy Based on Topotecan or Topotecan and Cyclophosphamide Combination (CyTo) in Advanced, Pretreated Ovarian Cancer.

Patients with advanced ovarian cancer (OC) have a detrimental prognosis. The options for systemic treatment of advanced OC in later lines of treatment are limited by the availability of active therapies and their applicability to often fragile, exhausted patients with poor performance status. Metronomic chemotherapy (MC) is a concept of a continuous administration of cytotoxic drugs, which is characterized by multidirectional activity (anti-proliferative, anti-angiogenic, and anti-immunosuppressive) and low toxicity. We have performed a retrospective analysis of consecutive, advanced, chemo-refractory OC patients treated with MC based on single-agent topotecan (1 mg p.o. q2d) or on a topotecan (1 mg q2d) and cyclophosphamide (50 mg p.o. qd) combination (CyTo). Metronomic chemotherapy demonstrated promising activity, with 72% and 86% of patients achieving biochemical or objective disease control and 18% and 27% of patients achieving a biochemical or objective response, respectively. The median PFS in the whole population was 3.65 months, but the median PFS in patients with a biochemical response to MC (18.2% of patients) reached 10.7 months. The study also suggested that overweight or obese patients had significantly better outcomes on MC than patients with BMI <25 kg/m2. This article is the first report in the literature on metronomic chemotherapy based on a topotecan + cyclophosphamide combination (CyTo). The CyTo regimen demonstrated safety, clinical activity, and potential broad clinical applicability in advanced OC patients and will be evaluated in a forthcoming clinical trial.

Metronomic Chemo-Endocrine Therapy (FulVEC) as a Salvage Treatment for Patients with Advanced, Treatment-Refractory ER+/HER2-Breast Cancer-A Retrospective Analysis of Consecutive Patients Data.

BACKGROUND: Breast cancer, with 2.3 million new cases and 0.7 million deaths every year, represents a great medical challenge worldwide. These numbers confirm that approx. 30% of BC patients will develop an incurable disease requiring life-long, palliative systemic treatment. Endocrine treatment and chemotherapy administered in a sequential fashion are the basic treatment options in advanced ER+/HER2- BC, which is the most common BC type. The palliative, long-term treatment of advanced BC should not only be highly active but also minimally toxic to allow long-term survival with the optimal quality of life. A combination of metronomic chemotherapy (MC) with endocrine treatment (ET) in patients who failed earlier lines of ET represents an interesting and promising option. METHODS: The methodology includes retrospective data analyses of pretreated, metastatic ER+/HER2- BC (mBC) patients who were treated with the FulVEC regimen combining fulvestrant and MC (cyclophosphamide, vinorelbine, and capecitabine). RESULTS: Thirty-nine previously treated (median 2 lines 1-9) mBC patients received FulVEC. The median PFS and OS were 8.4 and 21.5 months, respectively. Biochemical responses (CA-15.3 serum marker decline ≥50%) were observed in 48.7%, and any increase in CA-15.3 was observed in 23.1% of patients. The activity of FulVEC was independent of previous treatments with fulvestrant of cytotoxic components of the FulVEC regimen. The treatment was safe and well tolerated. CONCLUSIONS: Metronomic chemo-endocrine therapy with FulVEC regimen represents an interesting option and compares favorably with other approaches in patients' refractory to endocrine treatments. A phase II randomized trial is warranted.

Reduction of Cancer-Induced Thrombocytosis as a Biomarker of Improved Outcomes in Advanced Gastric Cancer.

BACKGROUND: Interplay between non-specific inflammatory reaction and tumor microenvironment in gastric cancer (GC) can be measured indirectly by assessing fluctuations in concentration of platelets. Cytotoxic chemotherapy affects these morphotic elements directly by inducing myelosuppression. It was hypothesized that chemotherapy not only directly affects malignant cells, but also through immunomodulation related to myelosuppression. METHODS: Metastatic GC patients (N: 155) treated with chemotherapy +/- trastuzumab were enrolled in this retrospective study. Platelet pretreatment concentration (PLT-count) and the deepest level of platelet reduction, as well as other inflammatory and general confounders were collected in the first 12 weeks of treatment (PLT-red). Martingale residuals were used to visualize the relationship between PLT-count, PLT-red, and overall survival (OS). Multiple multivariate Cox regression models were built to assess the impact of platelet reduction on OS and progression-free survival (PFS). RESULTS: Reduction of PLT (PLT-red) to 60% of baseline concentration was associated with improved survival rates (HR = 0.60, p = 0.026 for OS and HR 0.56, p = 0.015 for PFS). Cross-classification into four groups based on PLT-count (high vs low) and PLT-red (high vs low) showed significantly worse survival rates in both high PLT-count (HR = 3.60, p = 0.007 for OS and HR = 2.97, p = 0.024 for PFS) and low PLT-count (HR = 1.75, p = 0.035 for OS and HR = 1.80, p = 0.028 for PFS) patients with insufficient platelets reduction. CONCLUSION: Thrombocytosis reduction represents a novel, clinically important, prognostic factor for OS and PFS in patients with stage IV GC.

Combined Neutrophil-to-Lymphocyte and Platelet-Volume-to-Platelet Ratio (NLR and PVPR Score) Represents a Novel Prognostic Factor in Advanced Gastric Cancer Patients.

BACKGROUND: Chemotherapy is a cornerstone of treatment in advanced gastric cancer (GC) with a proven impact on overall survival, however, reliable predictive markers are missing. The role of various inflammatory markers has been tested in gastric cancer patients, but there is still no general consensus on their true clinical applicability. High neutrophil-to-lymphocyte (NLR) and low (medium)-platelets-volume-to-platelet ratio (PVPR) are known markers of unspecific immune system activation, correlating significantly with outcomes in advanced GC patients. METHODS: Metastatic GC patients (N:155) treated with chemotherapy +/- trastuzumab were enrolled in this retrospective study. Pre-treatment NLR and PVPR, as well as other inflammatory markers were measured in peripheral blood. Univariate Cox regression was conducted to find markers with a significant impact on overall survival (OS) and progression-free survival (PFS). Spearman correlation and Cohen's kappa was used to analyze multicollinearity. Multiple multivariable Cox regression models were built to study the combined impact of NLR and PVPR, as well as other known prognostic factors on OS. RESULTS: Elevated NLR was significantly associated with increased risk of death (HR = 1.95; 95% CI: 1.17-3.24), and lower PVPR was significantly associated with improved outcomes (HR = 0.53; 95% CI: 0.32-0.90). A novel inflammatory marker, based on a combination of NLR and PVPR, allows for the classification of GC patients into three prognostic groups, characterized by median OS of 8.4 months (95% CI 5.8-11.1), 10.5 months (95% CI 8.8-12.1), and 15.9 months (95% CI 13.5-18.3). CONCLUSION: The NLR and PVPR score (elevated NLR and decreased PVPR) is a marker of detrimental outcome of advanced GC patients treated with chemotherapy.

Whole cell melanoma vaccine genetically modified to stem cells like phenotype generates specific immune responses to ALDH1A1 and long-term survival in advanced melanoma patients.

Allogeneic whole cell gene modified therapeutic melanoma vaccine (AGI-101H) comprising of two melanoma cell lines transduced with cDNA encoding fusion protein composed of IL-6 linked with the soluble IL-6 receptor (sIL-6R), referred to as H6 was developed. H6 served as a molecular adjuvant, however, it has altered vaccine cells phenotype towards melanoma stem cells (MSC)-like with high activity of aldehyde dehydrogenase isoenzyme (ALDH1A1). AGI-101H was applied in advanced melanoma patients with non-resected and resected disease. In the adjuvant setting, it was combined with surgery in case of recurring metastases, which were surgically removed and vaccination continued. A significant fraction of AGI-101H treated melanoma patients is still alive (11-19 years). Out of 106 living patients, 39 were HLA-A2 positive and were the subject of the study. Immunization of melanoma patients resulted in the generation of cytotoxic CD8+ T cells specific for ALDH1A1, which were detected in circulation by HLA-A0201 MHC dextramers loaded with ALDH1A188-96(LLYKLADLI) peptide. Phenotypically they were central memory CD8+ T cells. Re-stimulation with ALDH1A188-96ex vivo resulted in IFN-γ secretion and cells degranulation. Following each vaccine dose administration, the number of ALDH1A1-CD8+ T cells increased in circulation and returned to the previous level until next dose injection (one month). ALDH1A1-CD8+ T cells were also found, however in the lower number than in vaccinated patients, in the circulation of untreated melanoma with stage IV but were not found in stage II or III and healthy donors. Specific anti-ALDH1 antibodies were present in treated patients. Long-term survival suggests immuno-targeting of MSC in treated patients.

The outcomes of Polish patients with advanced BRAF-positive melanoma treated with vemurafenib in a safety clinical trial.

AIM OF THE STUDY: The BRAF inhibitor vemurafenib has improved progression-free survival and overall survival in patients with BRAFV600-mutation-positive metastatic melanoma. Here we present the results of an open-label safety study with vemurafenib in patients with metastatic melanoma enrolled in Polish oncological centres. MATERIAL AND METHODS: Patients with untreated or previously treated Stage IIIC/IV BRAFV600 mutation-positive melanoma were treated with oral vemurafenib in an initial dose of 960 mg twice daily. Assessments for safety and efficacy were made every 28 days. For the survival analysis the Kaplan-Meier estimator was used with the log-rank tests for bivariate comparisons. RESULTS: In total, 75 Polish patients were enrolled in the safety study across four centres. At data cut-off, 28 patients died (37%), mainly (26) due to disease progression; 33 (44%) patients continued vemurafenib after disease progression. The objective response rate was 46%, including two patients with a complete response and 29 with a partial response. Median progression-free survival was 7.4 months. The one-year overall survival rate was 61.9% (median overall survival was not reached). Seventy-three (97.3%) patients reported adverse events (AEs), and grade 3-5 toxicity was reported in 49.4% (37) patients. The most common AEs were: skin lesions (including rash and photosensitivity), arthralgia, and fatigue. CONCLUSIONS: The overall safety profile and response rate of vemurafenib were comparable to those reported in previous studies of this drug. Our study confirmed the value of well-established prognostic features for overall survival, such as initial LDH (lactate dehydrogenase) level and AJCC staging.

Febrile neutropenia in a metastatic melanoma patient treated with ipilimumab - case report.

BACKGROUND: Ipilimumab is a fully human monoclonal antibody (mAb) targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab is currently approved in the U.S. and Europe for the treatment of metastatic melanoma in the first- and second-line treatment. Treatment with ipilimumab is linked to immune-related adverse events (irAEs) occurring in the majority of patients. These specific AEs include dermatitis, gastrointestinal disorders (diarrhea, colitis), hepatitis, hypophysitis, hypothyroidism, neuropathy, and iritis/inflammation of the ciliary body. CASE REPORT: We report a case of febrile neutropenia with agranulocytosis in the blood smear of a 35-year-old metastatic melanoma patient treated with ipilimumab 3 mg/kg. CONCLUSION: This AE was probably caused by antineutrophil antibodies associated with ipilimumab treatment. To our knowledge this is the first case report of febrile neutropenia in a metastatic melanoma patient treated with ipilimumab 3 mg/kg.