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Podstawą nowoczesnego leczenia chorych na raka piersi jest kojarzenie metod miejscowych (chirurgia i napromienianie) i systemowych (chemioterapia, hormonoterapia, leki molekularnie ukierunkowane) w sposób sekwencyjny lub jednoczasowy. Wybór właściwego postępowania powinien mieć miejsce tuż po uzyskaniu rozpoznania histopatologicznego. Na decyzje terapeutyczne wpływa szereg czynników zależnych od choroby (m.in. stopień klinicznego zaawansowania, podtyp biologiczny raka), ale także od pacjentki (m.in. wiek biologiczny, stan menopauzalny, współistniejące schorzenia, preferencje) i systemu (dostęp do nowoczesnych terapii, dostęp do specjalistycznej opieki lekarskiej). W tym kontekście istotne jest, aby pacjentka trafiła od początku do ośrodka o dużym doświadczeniu i dysponującym wielodyscyplinarnym zespołem specjalistów. Ma to szczególne znaczenie w odniesieniu do chorych na wczesnego raka piersi. W ciągu ostatnich dekad operacyjne leczenie wczesnego raka piersi istotnie ewoluowało w kierunku zmniejszenia agresywności (amputację piersi zastąpił zabieg oszczędzający, a w miejsce rutynowej limfadenektomii wykonuje się biopsję węzła wartowniczego). Upowszechnienie technik chirurgii onkoplastycznej pozwala na zachowanie lub odtworzeni piersi, co ma ogromne znaczenie dla jakości życia pacjentek. Jednak w większości przypadków inwazyjnego raka piersi sam zabieg operacyjny nie jest postępowaniem wystarczającym. W celu poprawy wyników leczenia stosuje się systemowe leczenie, a w niektórych przypadkach dodatkowo radioterapię. Systemowe leczenie może być prowadzone przed leczeniem lub po leczeniu operacyjnym. Jego celem jest zniszczenie mikroprzerzutów, które potencjalnie mogą być obecne już w chwili rozpoznania nowotworu. Dobór tego leczenia zależy od podtypu biolo gicznego definiowanego na podstawie ekspresji receptorów steroidowych, receptora HER2 oraz wskaźnika Ki76. Zgodnie z wytycznymi polskich i międzynarodowych towarzystw naukowych kompleksowa opieka nad chorymi powinna odbywać się w ramach profilowanych ośrodków, które dysponują zespołem doświadczonych specjalistów z różnych dziedzin. [ABSTRACT FROM AUTHOR]

Background. Bones constitute the most frequent localization of distant failure in breast cancer patients. Treatment of bone metastases is virtually palliative, but in a proportion of patients can effectively prolong survival and improve quality of life. Currently, there are no effective strategies to prevent bone dissemination with systemic adjuvant therapies. Thus, better molecular selection and identification of patients who have particularly high risk of skeletal metastases may facilitate designing future clinical trials. In this study we analyzed expression of selected tumor proteins potentially associated with skeletal metastases in breast cancer patients. Patients and methods. The study group included 184 metastatic breast cancer patients; 113 with clinically diagnosed bone metastases and 71 with exclusively other sites of metastases, respectively. In all patients, using tissue microarrays technology, IHC expression of the following proteins was evaluated in the primary tumor: estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), Ki67, cyclooxygenase 2 (COX2), chemokine receptor CXCR4, osteopontin (OPN), calcium sensing receptor (CaSR), cytokeratins 5/6 (CK5/6) and parathyroid hormone-related protein receptor 1 (PTHrPR1). Additionally based on ER/PR, HER2 and Ki67 expression, following molecular breast cancer subtypes were selected: luminal A, luminal B HER2-negative, luminal B HER2-positive, nonluminal HER2-positive and triple negative. Results. Median survival in patients with bone vs. other site of metastases was 56 vs. 37 months respectively (p = 0.0098). ER expression was more common in patients who did, compared with those who did not develop bone metastases (74.% vs. 45% respectively; p = 0.0001), whereas cytoplasmic overexpression of OPN (1.9% vs. 14% respectively; p = 0.002) and PTHrPR1 (16% vs. 34% respectively; p = 0.007) was more common in patients with other sites of metastases. The impact of ER and cytoplasmic OPN expression on the risk of bone dissemination was confirmed in the multivariate analysis (Table 1). Luminal A breast cancer subtype (43% vs. 23% respectively; p = 0.009) and luminal B HER2-positive (16% vs. 4.9%, respectively; p = 0.032) were more common among patients with bone dissemination, whereas triple negative tumors prevailed in patients with other sites of metastases (16% vs. 38%; p = 0.002). Median survival of patients with luminal A subtype was significantly longer than that with remaining subtypes (67 vs. 38 months respectively; p = 0.0004). Conclusions. These results suggest that ER expression and lack of OPN expression are independent factors predicting increased risk of bone dissemination in breast cancer patients. Bone metastases are specifically associated with luminal A and luminal B HER2-positive subtypes. [ABSTRACT FROM AUTHOR]

Background: About 10-30% of breast cancer patients will develop brain metastases. In untreated patients with brain metastases the median survival is 1-2 months, and in those undergoing palliative radiotherapy -- 3-6 months. The mechanism of brain metastases remains largely unknown. The identification of molecular markers might help in selecting high risk patients, and enable active surveillance, prevention and early treatment. The aim of this study was to analyze predictive value of expression of selected tumor proteins for the risk of brain metastases in breast cancer patients. Material and methods: This study included 198 advanced breast cancer patients treated between 2001 and 2007 in 11 oncology centers in Poland, including 96 woman with and 102 without overt brain metastases, respectively. The median age at diagnosis in these two groups was 52 and 60 years, respectively, with 52% and 32% of patients being premenopausal. Stage at diagnosis was similar in both groups and ductal carcinoma was a dominant histological type (76% and 86% of cases, respectively). Immunohistochemistry was performed on formalin-fixed paraffin embedded microarray cores derived from the primary tumor. Expression analysis included ER, PR, HER2, Ki67, CK5/6, EGFR, HER3, CXCR4, RAD51, E-cadherin, and claudin 3 and 4. Cox regression model was used to estimate the relative risk of brain metastases. Results: Expression of HER2, CK5/6, EGFR, RAD51 (both cytoplasmatic and nuclear staining), CXCR4 (cytoplasmatic staining) and Ki67 ≥14%, as well as ER or PR negativity was associated with increased risk of brain metastases in the univariate analysis (Table 1). Of those, Ki67 ≥ 14% (HR 2.76 [95%CI 1.70-4.48]; p < 0.001), cytoplasmatic expression of double strand DNA repair gene RAD51 (HR 1.87 [95%CI 1.14-3.08]; p = 0.014) and ER negativity (HR 1.72 [95%CI 0.36-0.94]; p = 0.029) were found to be significantly related to the risk of brain relapse in the multivariate analysis. Four molecular profiles composed of the latter three markers were created, of which a profile including ER, Ki67 and RAD51 was associated with the highest risk of brain metastases (HR 4.43 [95%CI 2.69-7.27]; p < 0.001). Molecular subtype analysis showed the highest risk of BM in the ER/PR/ HER2-negative (triple negative) subset (HR 1.21 [95%CI 1.11-1.32]; p < 0.001). Conclusion: Expression of proteins related to high tumor proliferation, DNA repair and ER negativity is associated with increased risk of brain metastases in breast cancer patients. [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]

In advanced-stage colorectal cancer (CRC), a strategy based on a sequence of systemic therapies brings survival benefits in most patients. Trifluridine and tipiracil hydrochloride (TT) is a chemotherapy drug effective in patients in the third- or later line setting. No highly specific biomarkers have been established for TT therapy so far. However, a systemic immune-inflammation index (SII), which is based on platelet, neutrophil and lymphocyte counts is applied to predict prognosis. In this retrospective, multicenter study, clinical data on 179 metastatic CRC patients treated with TT were collected. To evaluate factors predicting TT therapy response and overall survival, univariate logistic regression analysis was conducted. Subsequently, factors with p < 0.05 in univariate analysis were included in multivariate analysis. In the multivariate analysis of progression-free survival (PFS), three favorable parameters were significant: good to moderate histological differentiation ( p = 0.0038), carcinoembryonic antigen (CEA) < 5 ng/L ( p = 0.0316) and SII ≤ 550 ( p = 0.007). Favorable prognostic factors revealed in the multivariate analysis of overall survival (OS) were: <3 prior lines of treatment ( p = 0.02), good to moderate histological differentiation ( p = 0.0003), CEA < 5 ng/L ( p = 0.0227) and SII ≤ 550 ( p = 0.0001). Our study indicated that pre-treatment SII may be clinically useful for selecting likely responder patients and assessing the prognosis for mCRC patients treated with TT.

Introduction: This study aimed to evaluate the impact of tumour-infiltrating lymphocytes (TILs) on the expression of immune-related genes and prognosis in single hormone receptor-positive breast cancer. Material and methods: Tumour-infiltrating lymphocytes were analysed according to the guidelines of the International TILs Working Group in a cohort of 206 patients with single hormone receptor-positive breast cancer. Of these, 44.7% were classified as ER+/PgR-/HER2-, 18.4% as ER+/PgR-/HER2+, 26.2% as ER-/PgR+/HER2-, and 10.7% as ER-/PgR+/HER2+. Moreover, in 52 samples the analysis of gene expression profiling was performed using nCounter technology., Results: Most cases (74.3%) showed at least 1% of stromal TILs, with a median of 4%, mean of 16.3%, and interquartile range of 0-20%. ER-/PgR+ tumours displayed significantly higher TILs density than ER+/PgR- cases (p < 0.001, Wilcoxon test), regardless of HER2 status. The abundance of TILs was positively associated with ER-/PgR+ phenotype, higher Ki-67, and higher grade, but not with age, tumour size, or regional and distant metastases at diagnosis. Additionally, in ER+/PgR- subgroup higher TILs were associated with HER2-positive status. Stromal TILs > 5% were associated with better survival in the whole group, but this effect was less prominent in ER-/PgR+ patients. We identified 50 differentially expressed genes (DEGs) between single hormone receptor-positive breast tumours with high and low TILs, including 39 up-regulated and 11 down-regulated genes in the high TILs group., Conclusions: The up-regulated expression of immune-related genes was consistent also among separately analysed single hormone receptor-positive groups (ER+/PgR- and ER-/PgR+)., Competing Interests: None., (Copyright © 2024 Termedia.)

Introduction: Radical resection is the only potentially curative treatment for pancreatic adenocarcinoma; however, only a minor fraction of patients are eligible for resection. Induction therapy may be offered to patients, but the response rate in cases with significant vascular involvement is limited. This study aimed to evaluate the efficacy and safety of modified of FOLFIRINOX chemotherapy (mFFX) + stereotactic body radiotherapy (SBRT) in combination as induction therapy for locally advanced pancreatic carcinoma. The primary endpoints were the resection rate and one-year overall survival (OS). The secondary endpoints were progression-free survival (PFS), toxicity, and quality of live (QoL)., Material and Methods: Thirty patients with locally advanced pancreatic adenocarcinoma were treated with 6 cycles of mFFX, followed by SBRT and additional 3 cycles of mFFX. The response was measured prior to SBRT and after regimen completion. In the absence of disease progression, the patients were referred for surgery. The patients were requested to complete quality of life questionnaires (QLQ)-C30 and QLQ-PAN26 questionnaires biweekly., Results: On the first evaluation, disease control was noted in 26 (86.7%) patients. Stereotactic body radiotherapy was performed in 20 patients. Twelve patients underwent laparotomy, with radical resection possible in 3 cases. The one-year OS rate was 63.3%. Overall, 11 grade ≥ 3 adverse events were noted. No deterioration in the overall QoL was observed. The median PFS was 7.53 months., Conclusions: The expected resection rate of ≥ 30% was not achieved. However, the combination was associated with good local control, low adverse event rate, and good QoL, which advocate its further investigation in this clinical situation., Competing Interests: None., (Copyright © 2024 Termedia.)

Aims: In recent years, survival in patients with breast cancer has increased. Despite the improvement in outcomes of those patients, the risk of treatment-related cardiotoxicity remains high, and its presence has been associated with a higher risk of treatment termination and thus lower therapeutic efficacy. Prior trials demonstrated that a preventive initiation of heart failure drugs, including the renin-angiotensin-aldosterone inhibitors, might reduce the risk of treatment-related cardiotoxicity. However, to date, no study investigated the efficacy of sacubitril/valsartan, a novel antineurohormonal drug shown to be superior to the previous therapies, in the prevention of cardiotoxicity in patients with early-stage breast cancer, which is the aim of the trial., Methods and Results: MAINSTREAM is a randomized, placebo-controlled, double-blind, multicentre, clinical trial. After the run-in period, a total of 480 patients with early breast cancer undergoing treatment with anthracyclines and/or anti-human epidermal growth factor receptor 2 drugs will be randomized to the highest tolerated dose of sacubitril/valsartan, being preferably 97/103 mg twice daily or placebo in 1:1 ratio. The patients will be monitored, including routine transthoracic echocardiography (TTE) and laboratory biomarker monitoring, for 24 months. The primary endpoint of the trial will be the occurrence of a decrease in left ventricular ejection fraction by ≥5% in TTE within 24 months. The key secondary endpoints will be the composite endpoint of death from any cause or hospitalization for heart failure, as well as other imaging, laboratory, and clinical outcomes, including the occurrence of the cancer therapy-related cardiac dysfunction resulting in the necessity to initiate treatment. The first patients are expected to be recruited in the coming months, and the estimated completion of the study and publication of the results are expected in December 2027, pending recruitment., Conclusions: The MAINSTREAM trial will determine the efficacy and safety of treatment with sacubitril/valsartan as a prevention of cardiotoxicity in patients with early breast cancer (ClinicalTrials.gov number: NCT05465031)., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Pancreatic adenocarcinoma is one of the leading causes of cancer-related death in developed countries. Only 15% of patients are candidates for radical surgery, and adequate prognostication may guide proper postsurgical management. We aimed to retrospectively assess the prognostic significance of the immunohistochemical expression of immune checkpoint receptors (PD-L1 and VISTA), markers of systemic inflammation, thrombosis in the tumor area, and the tumor budding in the group of 107 patients diagnosed with pancreatic adenocarcinoma in a single center. The high expression of PD-L1 on tumor cells (TCs) was associated with worse overall survival (OS, p = 0.041, log-rank). On the contrary, high PD-L1 or VISTA on tumor-associated immune cells (TAICs) was correlated with better OS (p = 0.006 and p = 0.008, respectively, log-rank). The joint status of PD-L1 on TCs and TAICs stratified patients into three prognostic groups. The cases with high-grade budding were characterized by higher PD-L1 expression on TCs (p = 0.008) and elevated systemic inflammatory markers. Moreover, budding was identified as the independent prognostic factor in multivariate Cox regression analysis (HR = 2.87; 95% CI = 1.75−4.68; p < 0.001). To conclude, the pattern of PD-L1 and VISTA expression was associated with survival in univariate analysis. Tumor budding accurately predicts outcomes in pancreatic cancer and should be incorporated into routine histopathological practice.

Oestrogen receptor (ER)-negative (-) progesterone receptor (PgR)-positive (+) is the least common combination of steroid receptor expression observed in breast cancer. There are many controversies regarding the actual existence of ER-/PgR+ phenotype. In the current study, we aimed to perform comprehensive immunohistochemical re-evaluation of ER-/PgR+ breast cancers from multiple institutions. A total of 135 cases of ER-/PgR+ breast cancer were collected from 11 institutions from the period 2006-2020 and subsequently stained with three clinically validated anti-ER antibody clones: SP1 (Roche), 1D5 (Dako), and EP1 (Dako), and two anti-PgR antibody clones: 636 (Dako), and 1E2 (Roche). Clinicopathological characteristics of confirmed and re-categorised cases were analysed. Seventy-six cases retained the original ER-/PgR+ phenotype, including 21 HER2+ and 55 HER2- tumours. Forty-seven cases were ER+ with at least one anti-ER antibody, and 12 cases were re-categorised as double-negatives across all anti-ER and anti-PgR antibodies. No significant differences in survival were observed between groups in the HER2+ category. In the HER2- cohort, confirmed ER-/PgR+, ER+ tumours with discrepant ER staining, and triple negatives had inferior overall survival compared to concordant ER+ cases. Progesterone receptor expression in >20% of cells was identified as an adverse prognostic factor in ER-/PgR+/HER2- breast cancer in a multivariable model adjusted by stage (HR 5.0, 95% CI 1.3-19.2, p=0.019). We performed one of the largest validation studies so far on ER-/PgR+ breast cancer and confirmed the existence of this subgroup. Moreover, we identified high PgR expression as an adverse prognostic factor., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Sarcopenia is common in metastatic colorectal cancer (mCRC), increases the risk of treatment-related toxicity and reduces survival. Trifluridine/tipiracil (TT) chemotherapy significantly improved survival in refractory mCRC patients, but the prognostic and predictive role of pretherapeutic sarcopenia and variation in the skeletal muscle index (SMI) during this treatment has not been investigated so far. In this retrospective, observational study, clinical data on mCRC patients treated with TT at six cancer centres in Poland were collected. Computed tomography (CT) scans acquired at the time of initiation of TT (CT1) and on the first restaging (CT2), were evaluated. SMI was assessed based on the skeletal muscle area (SMA) at the level of the third lumbar vertebra. Progression-free survival (PFS) and overall survival (OS) were calculated from the treatment start. Neither initial sarcopenia nor ≥5% skeletal mass loss (SML) between CT1 and CT2 had a significant effect on PFS in treated patients ( p = 0.5526 and p = 0.1092, respectively). In the multivariate analysis, reduced OS was found in patients with ≥5% SML (HR: 2.03 (1.11-3.72), p = 0.0039). We describe the prognostic role of sarcopenia beyond second line treatment and analyze other factors, such as performance status, tumor histological differentiation or carcinoembryonic antigen level that could predict TT treatment response.

Background: Oxaliplatin-based therapy with FOLFOX-4 or CAPOX administered over 6 months remains the standard adjuvant treatment for stage III colon cancer (CC) patients. However, many patients experience dose reduction or early termination of chemotherapy due to oxaliplatin toxicity, which may increase the risk of early recurrence. The objective of this study was to analyze the relationship between the relative dose intensity of oxaliplatin (RDI-O) and early recurrence among stage III CC patients., Methods: The study included 365 patients treated at five oncology centers in Poland between 2000 and 2014. Survival analysis was performed using the Kaplan-Meier method. Univariate analysis was performed using the Cox proportional hazard model; multivariate analysis was performed with the stepwise forward approach. For all analyses the α level of 0.05 was employed., Results: The median follow-up was 51.8 months (range 8.2-115.1). Early recurrence < 36 months after surgery occurred in 130 patients (37.8%). In this group 51 (39.2%) and 87 (66.9%) of patients were low and high-risk, respectively. Receipt < 60% of RDI-O was associated with early recurrence within 18 months after surgery (OR = 2.05; 95%CI: 1.18-3.51; p = 0.010), especially in low-risk group (HR = 1.56 (95%CI: 0.96-2.53), p = 0.07). In the multivariate analysis early recurrence was correlated with grade (OR = 2.47; 95% CI: 1.25-4.8; p = 0.008), pN (OR = 2.63; 95% CI: 1.55-4.54; p < 0.001), the number of lymph nodes harvested (OR = 0.51; 95% CI: 0.29-0.86; p = 0.013) and RDI-O (OR = 1.91; 95%CI: 1.06-3.39; p = 0.028). The early vs. late recurrence negatively correlated with OS regardless of the RDI-O (HR = 22.9 (95%CI: 13.9-37.6; p < 0.001)., Conclusions: RDI-O < 60% in adjuvant therapy among stage III CC (especially in low-risk group) increases the risk of early recurrence within 18 months of surgery. Patients with early recurrence showed worse overall survival regardless of the RDI-O.

Heat shock proteins (HSPs) are chaperones with highly conservative primary structure, necessary in the processes of protein folding to the most energetically advantageous conformation and maintaining their stability. HSPs perform a number of important functions in various cellular processes and are capable of modulating pathophysiological conditions at the cellular and systemic levels. An example is the high level of HSP expression in neoplastic tissues, which disrupts the apoptosis of transformed cells and promotes the processes of proliferation, invasion, and metastasis. In addition, an increasing amount of information is appearing about the participation of HSPs in the formation of multidrug resistance.This paper provides a review of the current state of research on the fundamental importance as well as the diagnostic and prognostic role of various classes of HSP in cancer treatment. It presents the prospects for using HSPs as biological markers of disease progression and targets in various cancer treatment strategies. However, the need for additional research is quite high. Only numerous joint efforts of research groups will allow the effective use of HSPs as a tool to combat cancer., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Termedia.)

The most common cause of mortality due to malignant neoplasms in the general population around the world is lung cancer. In the last 10 years, there has been an enormous improvement in the treatment of this disease, mainly due to the immunotherapy that activates the immune system to fight cancer. Patients with metastatic non-small cell lung cancer are a special group of patients requiring not only cancer treatment but also considerable support in the treatment of cancer-related problems, as well as comorbidities. Early palliative care is important in this area. In addition, there is certain evidence that medicines most commonly administered in palliative care may lower the efficacy of immunotherapy. The present review article compares information on the prolonging of life after early hospice care, which has become the foundation of current standards of management in patients with metastatic lung cancer, and reports of decreased efficacy of the immunotherapy due to the administration of major palliative care medications., (Copyright: © Pieniążek et al.)

Gallbladder cancer (GBC) is a highly malignant tumor with poorly understood etiology. An insight into phenotypic features of this malignancy may add to the knowledge of its carcinogenesis and pave the way to new therapeutic approaches. We assessed the expression of female sex hormone receptors (ERα, ERβ, PR), connective tissue growth factor (CTGF) and HER2 in GBC, and adjacent normal tissue (NT), and determined their prognostic impact. Immunohistochemical (IHC) expression of all biomarkers was performed in formalin-fixed, paraffin-embedded specimens in 60 Caucasian GBC patients (51 women and 9 men). ERβ, cytoPR and CTGF expression were found in 89%, 27%, 91% of GBC, and in 63%, 87%, 100% of NT, respectively. No ERα expression was found in GBC and NT. Strong (3+) HER2 expression by IHC or HER2 amplification was seen in five GBC (10.4%). A positive correlation was found between HER2 and CTGF and ERβ expression in GBC and matched NT. In the multivariate analysis, patient age >70 years, tumor size and ERβ expression in GBC was highly predictive for OS (p = 0.003). The correlation between HER2, CTGF and ERβ expression in GBC and NT may indicate the interaction of these pathways in physiological processes and gallbladder pathology.

Purpose: The methods (IHC/FISH) typically used to assess ER, PR, HER2, and Ki67 in FFPE specimens from breast cancer patients are difficult to set up, perform, and standardize for use in low and middle-income countries. Use of an automated diagnostic platform (GeneXpert®) and assay (Xpert® Breast Cancer STRAT4) that employs RT-qPCR to quantitate ESR1, PGR, ERBB2, and MKi67 mRNAs from formalin-fixed, paraffin-embedded (FFPE) tissues facilitates analyses in less than 3 h. This study compares breast cancer biomarker analyses using an RT-qPCR-based platform with analyses using standard IHC and FISH for assessment of the same biomarkers., Methods: FFPE tissue sections from 523 patients were sent to a College of American Pathologists-certified central reference laboratory to evaluate concordance between IHC/FISH and STRAT4 using the laboratory's standard of care methods. A subset of 155 FFPE specimens was tested for concordance with STRAT4 using different IHC antibodies and scoring methods., Results: Concordance between STRAT4 and IHC was 97.8% for ESR1, 90.4% for PGR, 93.3% for ERBB2 (IHC/FISH for HER2), and 78.6% for MKi67. Receiver operating characteristic curve (ROC) area under the curve (AUC) values of 0.99, 0.95, 0.99, and 0.85 were generated for ESR1, PGR, ERBB2, and MKi67, respectively. Minor variabilities were observed depending on the IHC antibody comparator used., Conclusion: Evaluation of breast cancer biomarker status by STRAT4 was highly concordant with central IHC/FISH in this blinded, retrospectively analyzed collection of samples. STRAT4 may provide a means to cost-effectively generate standardized diagnostic results for breast cancer patients in low- and middle-income countries.

Lapatinib is a HER1 and HER2 tyrosine kinase inhibitor (TKI) approved in second line treatment of advanced or metastatic breast cancer following progression on trastuzumab-containing therapy. Biomarkers for activity of lapatinib and other TKIs are lacking. Formalin-fixed, paraffin-embedded primary tumor samples were obtained from 189 HER2-positive patients treated with lapatinib plus capecitabine following progression on trastuzumab. The HERmark ® Breast Cancer Assay was used to quantify HER2 protein expression. HER3 and p95HER2 protein expression was quantified using the VeraTag ® technology. Overall survival (OS) was inversely correlated with HER2 (HR = 1.9/log; P = 0.009) for patients with tumors above the cut-off positivity level by the HERmark assay. OS was significantly shorter for those with above median HER2 levels (HR = 1.7; P = 0.015) and trended shorter for those below the cut-off level of positivity by the HERmark assay (HR = 1.7; P = 0.057) compared to cases with moderate HER2 overexpression. The relationship between HER2 protein expression and OS was best captured with a U-shaped parabolic function (P = 0.004), with the best prognosis at moderate levels of HER2 protein overexpression. In a multivariate model including HER2, increasing p95HER2 expression was associated with longer OS (HR = 0.35/log; P = 0.027). Continuous HER3 did not significantly correlate with OS. Patients with moderately overexpressed HER2 levels and high p95HER2 expression may have best outcomes while receiving lapatinib following progression on trastuzumab. Further study is warranted to explore the predictive utility of quantitative HER2 and p95HER2 in guiding HER2-directed therapies., Competing Interests: CONFLICTS OF INTEREST Jeff Sperinde, John Winslow, Christos Petropoulos and Weidong Huang are employees of Monogram Biosciences, Integrated Oncology, Laboratory Corporation of America® Holdings. All other authors have not declared a conflicts of interest.

Background: Triple-negative breast cancer (TNBC) lacks expression of steroid hormone receptors (estrogen receptor α and progesterone) and epidermal growth factor receptor type 2. This phenotype shows high metastatic potential, with particular predilection to lungs and brain. Determination of TNBC transcriptomic profiles associated with high risk of brain metastasis (BM) might identify patients requiring alternative, more aggressive, or specific preventive and therapeutic approaches., Patients and Methods: Using a cDNA-mediated annealing, selection, extension, and ligation assay, we investigated expression of 29,369 gene transcripts in primary TNBC tumor samples from 119 patients-71 in discovery cohort A and 48 in independent cohort B-that included best discriminating genes. Expression of mRNA was correlated with the occurrence of symptomatic BM., Results: In cohort A, the difference at the noncorrected P < .005 was found for 64 transcripts (P = .23 for global test), but none showed significant difference at a preset level of false-discovery rate of < 10%. Of the 30 transcripts with the largest differences between patients with and without BM in cohort A, none was significantly associated with BM in cohort B., Conclusion: Analysis based on the primary tumor gene transcripts alone is unlikely to predict BM development in advanced TNBC. Despite its negative findings, the study adds to the knowledge on the biology of TNBC and paves the way for future projects using more advanced molecular assays., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Prostate cancer treatment is currently based on surgical removal, radiotherapy, and hormone therapy. In recent years, another therapeutic method has emerged-immunological treatment. Immunotherapy modulates and strengthens one's immune responses against cancer. Neoplastic cells naturally escape from the control of the immune system, and the main goal of immune therapy is to bring the control back. Satisfying outcomes after treatment of advanced melanoma and lung cancer suggest a great potential of immunotherapy as an approach for other tumors' treatment, especially in patients primarily introduced to palliative care. After initial clinical trials, immunotherapy seems to have different side effects than chemotherapy. Prostate cancer was the first neoplasm in which a specific vaccine significantly improved survival. There is a tremendous potential for synergistic combinations of immunotherapy with conventional cancer treatments. A combination of several drugs or methods can be a key in radical treatment of metastatic prostate cancer as demonstrated by preliminary studies.

Background: A better understanding of immune response in breast cancer brain metastases (BCBM) may prompt new preventive and therapeutic strategies., Methods: Immunohistochemical expression of stromal tumor-infiltrating lymphocytes (TILs: CD4, CD8, CTLA4), macrophage/microglial cells (CD68), programmed cell death protein 1 receptor (PD-1), programmed cell death protein 1 receptor ligand (PD-L)1, PD-L2 and glial fibrillary acid protein was assessed in 84 BCBM and their microenvironment., Results: Median survival after BCBM excision was 18.3 months (range 0-99). Median number of CD4+, CD8+ TILs and CD68+ was 49, 69 and 76 per 1 mm(2), respectively. PD-L1 and PD-L2 expression in BCBM was present in 53 % and 36 % of cases, and was not related to BCBM phenotype. PD-1 expression on TILs correlated positively with CD4+ and CD8+ TILs (r = 0.26 and 0.33), and so did CD68+ (r = 0.23 and 0.27, respectively). In the multivariate analysis, survival after BCBM excision positively correlated with PD-1 expression on TILs (hazard ratio (HR) = 0.3, P = 0.003), CD68+ infiltration (HR = 0.2, P < 0.001), brain radiotherapy (HR = 0.1, P < 0.001), endocrine therapy (HR = 0.1, P < 0.001), and negatively with hormone-receptor-negative/human epidermal growth factor receptor 2 (HER2)-positive phenotype of primary tumor (HR = 2.6, P = 0.01), HER2 expression in BCBM (HR = 4.9, P = 0.01)., Conclusions: PD-L1 and PD-L2 expression is a common occurrence in BCBM, irrespective of primary tumor and BCBM phenotype. Favorable prognostic impact of PD-1 expression on TILs suggests a beneficial effect of preexisting immunity and implies a potential therapeutic role of immune checkpoint inhibitors in BCBM.

Unlabelled: Molecular mechanisms of lapatinib resistance in breast cancer are not well understood. The aim of this study was to correlate expression of selected proteins involved in ErbB family signaling pathways with clinical efficacy of lapatinib. Study group included 270 HER2-positive advanced breast cancer patients treated with lapatinib and capecitabine. Immunohistochemical expression of phosphorylated adenosine monophosphate-activated protein (p-AMPK), mitogen-activated protein kinase (p-MAPK), phospho (p)-p70S6K, cyclin E, phosphatase and tensin homolog were analyzed in primary breast cancer samples. The best discriminative value for progression-free survival (PFS) was established for each biomarker and subjected to multivariate analysis. At least one biomarker was determined in 199 patients. Expression of p-p70S6K was independently associated with longer (HR 0.45; 95% CI: 0.25-0.81; p = 0.009), and cyclin E with shorter PFS (HR 1.83; 95% CI: 1.06-3.14; p = 0.029). Expression of p-MAPK (HR 1.61; 95% CI 1.13-2.29; p = 0.009) and cyclin E (HR 2.99; 95% CI: 1.29-6.94; p = 0.011) was correlated with shorter, and expression of estrogen receptor (HR 0.65; 95% CI 0.43-0.98; p = 0.041) with longer overall survival. Expression of p-AMPK negatively impacted response to treatment (HR 3.31; 95% CI 1.48-7.44; p = 0.004) and disease control (HR 3.07; 95% CI 1.25-7.58; p = 0.015)., In Conclusion: the efficacy of lapatinib seems to be associated with the activity of downstream signaling pathways - AMPK/mTOR and Ras/Raf/MAPK. Further research is warranted to assess the clinical utility of these data and to determine a potential role of combining lapatinib with MAPK pathway inhibitors.

Breast cancer (BC) in young women is rare, affecting only 4-6% of women under the age of 40. Regardless, BC remains the most common malignancy among younger patients. Recently, a significant increase in BC rates has been observed among pre-menopausal subjects. Breast cancer in young women requires special attention due to its specific morphologic and prognostic characteristics and unique aspects, including fertility preservation and psychosocial issues (e.g. its impact on family life and career). Young women are more likely to have tumors with higher incidence of negative clinicopathologic features (higher histological grade, more lymph node positivity, lower estrogen receptor (ER) positivity, higher rates of Her2/neu overexpression). Also, they tend to be diagnosed at more advanced stages of the disease. That, in turn, contributes to less favorable prognosis as compared to older women. Young women are generally treated similarly to older patients. Surgical management includes mastectomy or breast-conserving surgery, followed by radiation therapy (younger women have higher local recurrence rates than older women, especially after breast-conserving therapy). Although the basics of chemotherapy are the same for patients of all ages, younger women have some special considerations. It is important to consider options for fertility preservation before starting systemic treatment. Patients should have access to genetic testing as their results may affect the choice of therapy. Younger women and their families should receive adequate psychological support and counselling.