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Background:To investigate whether copy number gain of MET or hepatocyte growth factor (HGF) affect trastuzumab sensitivity in HER2-positive metastatic breast cancer (MBC).Methods:We analysed 130 HER2-positive MBC treated with trastuzumab-based therapy. MET and HGF gene copy numbers (GCN) were assessed by fluorescence in situ hybridisation (FISH) in primary breast cancer samples. Receiver operating characteristic analysis was applied to find the best cutoff point for both MET and HGF GCN.Results:MET FISH-positive cases (N=36, mean 3.72) had a significantly higher trastuzumab failure rate (44.4% vs 16.0%; P=0.001) and a significantly shorter time to progression (5.7 vs 9.9 months; HR 1.74; P=0.006) than MET FISH-negative cases (N=94, mean <3.72). Hepatocyte growth factor GCN was evaluated in 84 cases (64.6%). Receiver operating characteristic analysis identified 33 HGF FISH-positive patients (mean HGF GCN 3.01). HGF FISH-positive status was significantly associated with higher risk of failure (30.3% vs 7.8%; P=0.007) as compared with HGF FISH-negative cases (N=51, mean <3.01). MET and HGF FISH-positive status was highly correlated (P<0.001) and combination of both biomarkers did not increase predictive value of either considered separately.Conclusion:High GCNs of MET and HGF associate with an increased risk of trastuzumab-based therapy failure in HER2-positive MBC. [ABSTRACT FROM AUTHOR]

Background: Expression of p95HER2 (p95), a truncated form of HER2 also known as p110 or M611-CTF, is a possible trastuzumab resistance mechanism and has been associated with poor prognosis in trastuzumab-treated HER2-positive metastatic breast cancer (MBC). Previously we reported on optimal clinical cutoffs for quantitative p95 (Clin Cancer Res, 16:4226, 2010) and quantitative HER2 protein expression (H2T) by HERmark® (Cancer, 116:5168, 2010) that defined patient subsets with different progression-free survival (PFS). These cutoffs were confirmed in an independent trastuzumab-treated MBC cohort (ASCO 2011, #586). Here, using individual patient data, we performed an analysis on the combined data set of 243 cases from the discovery and validation cohorts to derive optimal cutoffs for quantitative p95 and H2T. Methods: Both quantitative H2T (HERmark, Monogram Biosciences) and p95 assays employed the VeraTag® method to quantify protein expression in formalin-fixed, paraffin-embedded tumor samples from two cohorts of 101 and 142 cases of trastuzumab-treated MBC with 7.4 and 9.2 months median PFS, respectively. All analyses were stratified by hormone receptor status, tumor grade (3 vs. 1+2) and cohort. H2T measurements were compared to pre -specified cutoffs for HERmark negative (H2T<10.5 Relative Fluorescence/mm² tumor [RF/mm²]) and HERmark positive (H2T>17.8 RF/mm²), derived from the <5th percentile of centrally determined HER2-positives and the >95th percentile of centrally determined HER2-negatives, respectively, within a reference database of 1,090 breast cancer patient samples. Results: Patients classified as HERmark-positive had longer PFS than those classified as HERmark-negative (HR = 0.52; p = 0.0006; medians 10.0 and 5.9 months). The previously determined optimal H2T cutoff of 13.8 RF/mm² in the center of the HERmark-equivocal zone, gave a similar result (HR = 0.54; p = 0.0005). This was close to the optimal cutoff of 12.75 RF/mm² (HR = 0.48; p < 0.0001, unadjusted) for the combined data set. The PFS for the small group of patients in the HERmark-equivocal zone (n = 20) was more similar to the HERmark-negatives (equivocal vs. negative: HR=0.98; p = 0.9) than the HERmark-positives (positive vs. equivocal: HR=0.57; p = 0.057). The pre-specified p95 cutoff at 2.8 RF/mm² separated the 174 HERmark-positive cases into two groups of longer (p95<2.8 RF/mm²) vs. shorter PFS (HR = 1.9; p = 0.0014; medians 13.1 and 7.4 months). Increasing continuous p95 also correlated with shorter PFS (HR = 1.9/log; p = 0.022) in the HERmark-positive subset. An optimal p95 cutoff was identified at 2.7 RF/mm² (HR = 2.0; p = 0.0009, unadjusted), although a slightly higher local HR maximum was found at 1.55 RF/mm² (HR = 2.3; p = 0.0004, unadjusted). Conclusions: HERmark positive and negative categories, defined by analytical comparison with centrally determined HER2 status, were confirmed to have significantly different PFS in trastuzumab-treated MBC patients. The optimal H2T clinical cutoff for this combined analysis was centered in the HERmark analytical equivocal zone. An optimal p95 clinical cutoff of 2.7 RF/mm² derived from this combined analysis was nearly identical to the previously established cutoff of 2.8 RF/mm². [ABSTRACT FROM AUTHOR]

(1) Background: It was suspected that the COVID-19 pandemic would negatively affect health care, including cancer treatment. The aim of the study was to assess the impact of the COVID-19 pandemic on the number of radiotherapy procedures and patients treated with radical and palliative radiotherapy in Poland. (2) Methods: The study was carried out in Warmia and Masuria voivodeship. The number of procedures and treated patients one year before and in the first year of the COVID-19 pandemic were compared. (3) Results: In the first year of the COVID-19 pandemic, the number of radiotherapy procedures and cancer patients treated with radiotherapy in Warmia and Masuria voivodeship in Poland was stable compared to the period before the pandemic. The COVID-19 pandemic has not affected the ratio of palliative to radical procedures. The percentage of ambulatory and hostel procedures significantly increased with the reduction of inpatient care in the first year of the COVID-19 pandemic. (4) Conclusion: No significant decrease in patients treated with radiotherapy during the first year of the pandemic in Warmia and Masuria voivodeship in Poland could indicate the rapid adaptation of radiotherapy centers to the pandemic situation. Future studies should be carried out to monitor the situation because the adverse effects of the pandemic may be delayed.

Background: Patients with human epidermal growth factor receptor (HER)-2+ breast cancer are at particularly high risk for brain metastases; however, the biological basis is not fully understood. Using a novel HER-2 assay, we investigated the correlation between quantitative HER-2 expression in primary breast cancers and the time to brain metastasis (TTBM) in HER-2+ advanced breast cancer patients treated with trastuzumab., Methods: The study group included 142 consecutive patients who were administered trastuzumab-based therapy for HER-2+ metastatic breast cancer. HER-2/neu gene copy number was quantified as the HER-2/centromeric probe for chromosome 17 (CEP17) ratio by central laboratory fluorescence in situ hybridization (FISH). HER-2 protein was quantified as total HER-2 protein expression (H2T) by the HERmark® assay (Monogram Biosciences, Inc., South San Francisco, CA) in formalin-fixed, paraffin-embedded tumor samples. HER-2 variables were correlated with clinical features and TTBM was measured from the initiation of trastuzumab-containing therapy., Results: A higher H2T level (continuous variable) was correlated with shorter TTBM, whereas HER-2 amplification by FISH and a continuous HER-2/CEP17 ratio were not predictive (p = .013, .28, and .25, respectively). In the subset of patients that was centrally determined by FISH to be HER-2+, an above-the-median H2T level was significantly associated with a shorter TTBM (hazard ratio, [HR], 2.4; p = .005), whereas this was not true for the median HER-2/CEP17 ratio by FISH (p = .4). Correlation between a continuous H2T level and TTBM was confirmed on multivariate analysis (HR, 3.3; p = .024)., Conclusions: These data reveal a strong relationship between the quantitative HER-2 protein expression level and the risk for brain relapse in HER-2+ advanced breast cancer patients. Consequently, quantitative assessment of HER-2 protein expression may inform and facilitate refinements in therapeutic treatment strategies for selected subpopulations of patients in this group.

Purpose: The purpose of this study was to characterize insulin-like growth factor-1 receptor (IGF1R) protein expression, mRNA expression, and gene copy number in surgically resected non-small-cell lung cancers (NSCLC) in relation to epidermal growth factor receptor (EGFR) protein expression, patient characteristics, and prognosis., Patients and Methods: One hundred eighty-nine patients with NSCLC who underwent curative pulmonary resection were studied (median follow-up, 5.3 years). IGF1R protein expression was evaluated by immunohistochemistry (IHC) with two anti-IGF1R antibodies (n = 179). EGFR protein expression was assessed with PharmDx kit. IGF1R gene expression was evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) from 114 corresponding fresh-frozen samples. IGF1R gene copy number was assessed by fluorescent in situ hybridization using customized probes (n = 181)., Results: IGF1R IHC score was higher in squamous cell carcinomas versus other histologies (P < .001) and associated with stage (P = .03) but not survival (P = .46). IGF1R and EGFR protein expression showed significant correlation (r = 0.30; P < .001). IGF1R gene expression by qRT-PCR was higher in squamous cell versus other histologies (P = .006) and did not associate with other clinical features nor survival (P = .73). Employing criteria previously established for EGFR copy number, patients with IGF1R amplification/high polysomy (n = 48; 27%) had 3-year survival of 58%, patients with low polysomy (n = 87; 48%) had 3-year survival of 47% and patients with trisomy/disomy (n = 46; 25%) had 3-year survival of 35%, respectively (P = .024). Prognostic value of high IGF1R gene copy number was confirmed in multivariate analysis., Conclusion: IGF1R protein expression is higher in squamous cell versus other histologies and correlates with EGFR expression. IGF1R protein and gene expression does not associate with survival, whereas high IGF1R gene copy number harbors positive prognostic value.

Brain relapse is a common occurrence in HER2-positive breast cancer patients. However, the factors determining the risk of brain metastasis in these patients remain to be established. The aim of this study was to assess the impact of particular clinical and pathological factors on the risk of brain relapse in HER2-positive advanced breast cancer patients. The study group included 264 consecutive HER-2 positive metastatic breast cancer patients, most of whom (210; 80%) were administered trastuzumab, usually in combination with chemotherapy. Time from the diagnosis to distant relapse ranged from 0 to 142 months (median 16 months). The most common dominant site of metastatic disease was viscera (80%), followed by soft tissue (11%) and bones (10%). After a median follow-up of 3.1 years, the symptomatic brain relapse occurred in 103 patients (39%). Median time from treatment dissemination to brain relapse was 15 months (range, 0-81 months), and the cumulative 1-year, 3-year and 5-year risk of brain relapse was 17, 42 and 55%, respectively. The average annual risk of brain relapse for surviving patients during consecutive 7 years of follow-up was 10.0% (95% CI, 6.6-13.5%). In the univariate analysis the only variable significantly related to the increased risk of brain relapse was time from initial diagnosis to distant relapse shorter than 2 years (HR = 1.55, 95% CI, 1.03-2.33, P = 0.034). Patients with dominant site of disease in soft tissue or bones tended to have lower risk of relapse (HR = 0.54 and 0.62; P = 0.098 and 0.203, respectively) compared to patients with visceral metastases. Treatment with trastuzumab was not associated with reduced risk of brain relapse (HR = 0.91, 95% CI, 0.47-1.77, P = 0.78). In the multivariate analysis, time from initial diagnosis to distant relapse shorter than 2 years remained the only significant variable related to increased risk of brain relapse (adjusted HR = 1.62, 95% CI, 1.07-2.44; P = 0.022). HER2-positive breast cancer patients remain at high and continuous risk of brain relapse for a prolonged period of time after diagnosis of disease dissemination. Short time from initial diagnosis to distant relapse is related to increased risk of brain relapse. Molecular predictors are sorely needed to better characterize patients with high probability of early brain relapse.

To assess the effect of 3 calcium channel antagonists (amlodipine, diltiazem, and verapamil) on the anticonvulsant action of topiramate (a new generation antiepileptic drug) in the mouse maximal electroshock seizure (MES) model. Amlodipine (20 mg/kg) significantly enhanced the anticonvulsant activity of topiramate in the MES test in mice, reducing its ED50 value from 54.83 to 33.10 mg/kg (p < 0.05). Similarly, diltiazem (5 and 10 mg/kg) markedly potentiated the antiseizure action of topiramate against MES, lowering its ED50 value from 54.83 to 32.48 mg/kg (p < 0.05) and 28.68 mg/kg (p < 0.01), respectively. In contrast, lower doses of amlodipine (5 and 10 mg/kg) and diltiazem (2.5 mg/kg) and all doses of verapamil (5, 10, and 20 mg/kg) had no significant impact on the antiseizure action of topiramate. Pharmacokinetic verification of the interaction of topiramate with amlodipine and diltiazem revealed that neither amlodipine nor diltiazem affected total brain topiramate concentration in experimental animals, and thus, the observed interactions were concluded to be pharmacodynamic in nature. The favorable combinations of topiramate with amlodipine or diltiazem deserve more attention from a clinical viewpoint because the enhanced antiseizure action of topiramate was not associated with any pharmacokinetic changes in total brain topiramate concentration.

The aim of this study was to assess the effect of three calcium channel antagonists (amlodipine, diltiazem and verapamil) on the anticonvulsant action of lamotrigine (a second generation antiepileptic drug) against maximal electroshock-induced seizures in mice. Results indicated that all three calcium channel antagonists when administered alone [amlodipine (up to 20 mg/kg, ip), diltiazem (up to 10 mg/kg, ip) and verapamil (up to 20 mg/kg, ip)], did not significantly affect the threshold for maximal electroconvulsions in mice. However, amlodipine at a non-protective dose of 20 mg/kg, ip significantly enhanced the anticonvulsant activity of lamotrigine in the maximal electroshock-induced seizure test in mice by reducing its ED(50) value from 6.33 to 2.87 mg/kg (p < 0.05). In contrast, amlodipine at lower doses of 5 and 10 mg/kg, ip, diltiazem (at doses up to 10 mg/kg, ip) and verapamil (at doses up to 20 mg/kg, ip) had no significant impact on the antiseizure action of lamotrigine in the maximal electroshock-induced seizure test in mice. In conclusion, one can ascertain that the favorable combination of lamotrigine with amlodipine deserves more attention from a clinical viewpoint because of the enhanced antiseizure action of lamotrigine.