Aspirin and cancer: has aspirin been overlooked as an adjuvant therapy?

Aspirin inhibits the enzyme cyclooxygenase (Cox), and there is a significant body of epidemiological evidence demonstrating that regular aspirin use is associated with a decreased incidence of developing cancer. Interest focussed on selective Cox-2 inhibitors both as cancer prevention agents and as therapeutic agents in patients with proven malignancy until concerns were raised about their toxicity profile. Aspirin has several additional mechanisms of action that may contribute to its anti-cancer effect. It also influences cellular processes such as apoptosis and angiogenesis that are crucial for the development and growth of malignancies. Evidence suggests that these effects can occur through Cox-independent pathways questioning the rationale of focussing on Cox-2 inhibition alone as an anti-cancer strategy. Randomised studies with aspirin primarily designed to prevent cardiovascular disease have demonstrated a reduction in cancer deaths with long-term follow-up. Concerns about toxicity, particularly serious haemorrhage, have limited the use of aspirin as a cancer prevention agent, but recent epidemiological evidence demonstrating regular aspirin use after a diagnosis of cancer improves outcomes suggests that it may have a role in the adjuvant setting where the risk:benefit ratio will be different.     

Eukaryotic cell encystation and cancer cell dormancy: is a greater devil veiled in the details of a lesser evil?

Cancer cell dormancy is the main cause of cancer recurrence and failure of therapy as dormant cells evade not only the anticancer drugs but also the host immune system. These dormant cells veil themselves from detection by imaging and/or using biomarkers, which imposes an additional problem in targeting such cells. A similar form of hibernation process known as encystation is studied in detail for pathogenic unicellular eukaryotic microorganisms. By examination using microarray gene expression profiles, immunocytochemistry tools, and siRNAs during the process of encystation, understanding the covert features of cancer cell dormancy as proposed could be possible. This knowledge can be extended to dormant cancer cells to uncover the mechanisms that underlie this ghost, yet dangerous state of human cancers. We propose a strategy to induce dormancy and exit this state by application of knowledge gained from the encystation induction and retrieval processes in pathogenic eukaryotic microorganisms. Given that early detection and characterization of dormant malignant tumor cells is important as a general strategy to monitor and prevent the development of overt metastatic disease, this homology may enable the design of therapies that could either awake the dormant cell from dormancy to make it available for therapies or prolong such a phase to make cancer appear as a chronic disease.KEYWORDS : Cancer cell dormancy, cancer recurrence, encystation, metastasis     

Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target?

Regulatory T (Treg) cells suppress abnormal/excessive immune responses to self‐ and nonself‐antigens to maintain immune homeostasis. In tumor immunity, Treg cells are involved in tumor development and progression by inhibiting antitumor immunity. There are several Treg cell immune suppressive mechanisms: inhibition of costimulatory signals by CD80 and CD86 expressed by dendritic cells through cytotoxic T‐lymphocyte antigen‐4, interleukin (IL)‐2 consumption by high‐affinity IL‐2 receptors with high CD25 (IL‐2 receptor α‐chain) expression, secretion of inhibitory cytokines, metabolic modulation of tryptophan and adenosine, and direct killing of effector T cells. Infiltration of Treg cells into the tumor microenvironment (TME) occurs in multiple murine and human tumors. Regulatory T cells are chemoattracted to the TME by chemokine gradients such as CCR4‐CCL17/22, CCR8‐CCL1, CCR10‐CCL28, and CXCR3‐CCL9/10/11. Regulatory T cells are then activated and inhibit antitumor immune responses. A high infiltration by Treg cells is associated with poor survival in various types of cancer. Therefore, strategies to deplete Treg cells and control of Treg cell functions to increase antitumor immune responses are urgently required in the cancer immunotherapy field. Various molecules that are highly expressed by Treg cells, such as immune checkpoint molecules, chemokine receptors, and metabolites, have been targeted by Abs or small molecules, but additional strategies are needed to fine‐tune and optimize for augmenting antitumor effects restricted in the TME while avoiding systemic autoimmunity. Here, we provide a brief synopsis of these cells in cancer and how they can be controlled to achieve therapeutic outcomes.     

Male breast cancer: a special therapeutic problem. Anything new? (Review)

Carcinoma of the male breast (MBC) is an uncommon phenomenon, accounting for <1% of all malignancies in man. It represents a biologically heterogeneous disorder, and its clinical course may vary from indolent and slowly progressive to rapidly metastatic disease. Most of our current knowledge regarding its biology, natural history, and treatment strategies has been extrapolated from its female counterpart. Information regarding prognostic relevance of new molecular markers is limited. At the European Institute of Oncology we performed a study showing data in which p21Waf1 and p27Kip1 proteins were evaluated in a series of male breast cancer patients. Our data suggest that the immunohistochemical evaluation of p21Waf1 and p27Kip1 expression in male breast carcinomas may be a further useful marker for selecting patients who express functional proteins that can be predictive for the most efficient endocrine response. Moreover, searching for more conservative treatment, we introduced in our clinical practice sentinel node biopsy, and if present, sentinel node biopsy of the internal mammary chain. The potential clinical implications of complete nodal staging are far-reaching, and give us a major new opportunity to stratify male patients with breast cancer for appropriate surgery as well as giving valuable prognostic information. Male breast cancer has biological differences compared with female breast cancer. It responds to hormonal manipulation and chemotherapy, but optimal treatment regimens in males are unknown. By analogy to the female breast cancer, post-mastectomy radiotherapy should be proposed in case of advanced T stage and/or lymph node positivity (considering the small volume of the male mammary gland, we suggest post-mastectomy irradiation in case of T >1 cm and/or presence of >1 metastatic axillary lymph node). Breast conserving surgery, performed in selected cases of male breast cancer, should be always followed by radiotherapy. Despite a wealth of small retrospective studies on MBC, its rarity means there is a lack of prospective randomized controlled treatment trials, which needs to be addressed if significant advances are to be made in the treatment of this unusual challenging disease.     

T cell adhesion and cytolysis of pancreatic cancer cells: a role for E-cadherin in immunotherapy?

Pancreatic cancer is an aggressive and potent disease, which is largely resistant to conventional forms of treatment. However, the discovery of antigens associated with pancreatic cancer cells has recently suggested the possibility that immunotherapy might become a specific and effective therapeutic option. T cells within many epithelia, including those of the pancreas, are known to express the alphaEbeta7-integrin adhesion molecule, CD103. The only characterised ligand for CD103 is E-cadherin, an epithelial adhesion molecule which exhibits reduced expression in pancreatic cancer. In our study, CD103 was found to be expressed only by activated T cells following exposure to tumour necrosis factor beta 1, a factor produced by many cancer cells. Significantly, the expression of this integrin was restricted mainly to class I major histocompatibility complex-restricted CD8+ T cells. The human pancreatic cancer cell line Panc-1 was transfected with human E-cadherin in order to generate E-cadherin negative (wild type) and positive (transfected) sub-lines. Using a sensitive flow cytometric adhesion assay it was found that the expression of both CD103 (on T cells) and E-cadherin (on cancer cells) was essential for efficient adhesion of activated T cells to pancreatic cancer cells. This adhesion process was inhibited by the addition of antibodies specific for CD103, thereby demonstrating the importance of the CD103-->E-cadherin interaction for T-cell adhesion. Using a 51Cr-release cytotoxicity assay it was found that CD103 expressing T cells lysed E-cadherin expressing Panc-1 target cells following T cell receptor stimulation; addition of antibodies specific for CD103 significantly reduced this lysis. Furthermore, absence of either CD103 from the T cells or E-cadherin expression from the cancer cells resulted in a significant reduction in cancer cell lysis. Therefore, potentially antigenic pancreatic cancer cells could evade a local anti-cancer immune response in vivo as a consequence of their loss of E-cadherin expression; this phenotypic change may also favour metastasis by reducing homotypic adhesion between adjacent cancer cells. We conclude that effective immunotherapy is likely to require upregulation of E-cadherin expression by pancreatic cancer cells or the development of cytotoxic immune cells that are less dependent on this adhesion molecule for efficient effecter function.     

Breast conservation therapy versus mastectomy in the community-based setting: can this rate be used as a benchmark for cancer care?

Despite strong evidence supporting the use of breast conservation therapy (BCT) in the treatment of breast carcinoma, the actual rates of use remain low. This article is a retrospective review of a sample of patients from the cancer registry of the Carolinas Medical Center (CMC), comparing breast conservation and mastectomy rates during an 11-year period. BCT rates have increased in CMC during this time frame and have reached national levels. Further research is needed to determine whether BCT rates can be used as a benchmark for the care of patients with cancer.     

Targeted therapy in advanced non-small cell lung cancer (NSCLC): Where do we stand?

Cytotoxic chemotherapy has helped improve the outcomes in patients with advanced non-small cell lung cancer (NSCLC), but we seem to have reached a plateau with respect to the benefit obtained. Also, a large subset of elderly patients and those with a poor performance status cannot tolerate these drugs at recommended doses. There is a growing need to incorporate newer drugs with different mechanisms of action and better safety profile. The epidermal growth factor receptor family (EGFR) and vascular endothelial growth factor (VEGF) have been identified as potential targets and agents acting specifically against these targets have been developed with the hope of improving outcomes. Although recent data with the small molecule EGFR tyrosine kinase inhibitors have been disappointing, there have been instances of dramatic responses thereby raising questions about the ideal patient to whom these drugs should be administered. Cetuximab, the anti-EGFR antibody has shown promising results. Bevacizumab, the anti-VEGF antibody was the first drug to demonstrate a survival benefit in first line treatment when added to chemotherapy. This review will briefly discuss the important trials using these targeted agents in advanced NSCLC.     

Efficacy of oral tegafur-uracil (UFT) as adjuvant therapy as compared with classical cyclophosphamide,methotrexate, and 5-fluorouracil (CMF) in early breast cancer: a pooled analysis of two randomized controlled trials (N·SAS-BC 01 trial and CUBC trial)

Two randomized clinical studies comparing the efficacy of oral UFT (2 years) with that of classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (six courses) have been conducted in patients with resected early breast cancer. We have performed a pooled analysis of these two randomized studies. A pooled analysis was performed using individual patient data from the two trials. Hazard ratios (HRs) were determined with a Cox model stratified by study and adjusted for clinical characteristics. We preplanned to verify the following two hypotheses: UFT is non-inferior to CMF in all patients (hypothesis 1) or in ER-positive patients (hypothesis 2) with respect to relapse-free survival (RFS). Non-inferiority of UFT versus CMF was established if the upper limit of the two-sided confidence interval (CI) of the HR for RFS did not exceed 1.30. Hochberg multiplicity adjustment for the significance level was performed. A total of 1,057 patients were analyzed (CMF, n = 528; UFT, n = 529). Median follow-up time was 5.6 years. The HR for RFS was 1.04 (95% CI, 0.78–1.40) in all patients and 0.79 (97.5% CI, 0.49–1.27) in ER-positive patients. UFT was shown to be non-inferior to CMF in ER-positive patients. An exploratory subgroup analysis showed that RFS was better with UFT than with CMF in ER-positive patients who were 50 years or older (HR, 0.58; 95% CI, 0.34–1.01). UFT is non-inferior to CMF in terms of inhibiting recurrence of ER-positive, early breast cancer.     

Do programmed death 1 (PD-1) and its ligand (PD-L1) play a role in patients with non-clear cell renal cell carcinoma?

Clinical trials targeting programmed death 1 (PD-1) and its ligand PD-L1 (PD-L1) for metastatic renal cell cancer (RCC) are ongoing. The aim of this study is to validate their roles as prognostic markers in non-clear cell (non-cc) RCC. Sixty-four non-cc RCC tissue specimens were collected from patients undergoing renal tumor surgery. Expressions of biomarkers were assessed using immunohistochemistry and compared with clinical characteristics. Survival analyses were performed with a median follow-up of 77.5 (range: 0–176) months. No significant correlations were found for PD-1⁺ tumor-infiltrating mononuclear cells (TIMC) or PD-L1⁺ expression and clinical attributes in patients with non-cc RCC. Kaplan–Meier analysis revealed no differences in 5- and 10-year cancer-specific survival (CSS) for PD-1^? TIMC compared to PD-1⁺ TIMC (71.4 and 63 % versus 72.2 and 61.9 %; p = 0.88). Intratumoral expression of PD-L1 did not appear to influence the 5- and 10-year CSS significantly, even though a trend was identified (68 and 53.6 % versus 80.1 and 75.7 %; p = 0.08). In multivariate analysis, neither PD-1⁺ TIMC nor intratumoral PD-L1⁺ expression proved to be independent predictors of CSS (p = 0.99 and p = 0.68, respectively). Our study demonstrates that PD-1⁺ TIMC and intratumoral PD-L1⁺ expression did not significantly impact tumor aggressiveness or clinical outcome in non-ccRCC specimens. Due to rare incidence of non-cc RCC in particular according to PD-L1 expression, further analyzes are warranted.     

Does axitinib (AG-01376) have a future role in metastatic renal cell carcinoma and other malignancies?

Axitinib (Pfizer Inc., UK) is an oral small-molecule receptor tyrosine kinase inhibitor that targets angiogenesis. Axitinib has greater affinity and is a more selective inhibitor of VEGF receptor 1, -2 and -3, PDGFR and c-KIT than both sunitinib and sorafenib. It has encouraging efficacy and safety data in Phase II trials for metastatic renal cell carcinoma and advanced thyroid cancer patients. It is now being investigated in two Phase III trials in metastatic renal cell carcinoma and in Phase II trials in a range of tumor types. These trials will determine whether axitinib is an effective and safe antiangiogenic therapy.     

Estrogen-receptor-directed neoadjuvant therapy for breast cancer: Results?of?a randomised trial using formestane and methotrexate, mitozantrone and mitomycin C (MMM) chemotherapy

Background:We wanted to determine whether neoadjuvant systemic chemoendocrine therapy guided by the estrogen receptor (ER) status of the primary breast cancer, followed by conventional surgery and/or radiotherapy, reduces local and distant recurrence and improves survival compared with adjuvant treatment given conventionally postoperatively. Patients and methods:Two hundred ten patients with primary breast cancer (T₁–T₄, N₀, N_1–2) were randomised to receive treatment with neoadjuvant chemoendocrine therapy or conventional post-operative chemoendocrine therapy. Systemic therapy was based on the estrogen receptor (ER) status of the primary tumour obtained by trucut core biopsy. ER-negative patients received MMM chemotherapy (methotrexate (30 mg/m²), mitozantrone (7 mg/m²) and mitomycin (7 mg/m²) three-weekly for three months and ER-positive patients who were premenopausal received goserelin (3.75 mg monthly), and post menopausal women formestane (250 mg every two weeks) over three months. Results:With a minimum of five years follow-up, there is no evidence of any survival benefit from the pretreatment neoadjuvant therapy regimen, with five year overall survival being 79% ± 4.7% (neoadjuvant) and 87% ± 3.4% (adjuvant). Similarly, there was no apparent benefit in terms of disease-free survival. There was, however, a significant reduction in the incidence of distant metastases in responders (4 of 51; 8%) compared with non-responders (17 of 49; 35%) (P < 0.01). There was a reduction in the need for surgery in responding patients with T₁ and T₂ tumours, since 10 of 74 (14%) had no detectable residual tumour, without any apparent increase in the risk of local or distant recurrence. Conclusion:In this study neoadjuvant treatment with endocrine or chemotherapy provided no obvious survival benefit to women with breast cancer. However, it does allow avoidance of surgery in some cases. Also, the patients whose tumours respond to neoadjuvant systemic therapy have a lower incidence of distant metastases after five year follow-up compared to those whose tumours fail to respond.     

Targeting receptor tyrosine kinase signalling in small cell lung cancer (SCLC): What have we learned so far?

Small cell lung cancer (SCLC) is an aggressive form of lung cancer, which represents 13% of all cases and is strongly associated with cigarette smoking. The survival of SCLC patients is dismal and has not greatly improved in the last 20 years, despite advances in chemotherapy regimens and a better understanding of SCLC biology. The development of resistance to chemotherapy and metastasis are commonly recognized as important causes of poor clinical outcome in SCLC. Targeting receptor tyrosine kinase (RTK) signalling represents an attractive approach to develop new drugs for SCLC, in view of the accumulating data demonstrating that polypeptide growth factors play a key role in driving SCLC cell proliferation, chemoresistance and metastasis. The insulin-like growth factor-I receptor (IGF-IR), c-Kit, vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) have been identified as potential drug targets in SCLC. Moreover, downstream signalling mediators of RTKs, such as phosphoinositide 3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) may also represent attractive candidate molecules for anti-cancer therapies in SCLC. Here we will review the available data concerning results with RTK inhibitors in SCLC and the clinical trials undertaken to investigate the potential of these compounds as anti-tumour agents in SCLC.     

Gemcitabine–cisplatin (GC) as adjuvant chemotherapy in resected stage II and stage III gallbladder cancers (GBC): a potential way forward

Data on adjuvant chemotherapy with gemcitabine–cisplatin (GC) in resected gallbladder cancers (GBC) are scarce. Patients who underwent upfront curative resection for GBC from 2010 to 2016 were analyzed. Patients with stage II–III GBC treated with adjuvant GC were analyzed. A total of 242 patients were evaluated, of whom 125 patients received GC regimen as adjuvant chemotherapy. The median age was 50 years (range 31–74), majority were female (77.6%), and 37 patients (29.6%) had raised CA 19.9 levels at baseline. One hundred and thirteen patients (90.4%) underwent radical cholecystectomy with R0 resections. Median number of GC administered was 6, with completion rates of 84%. Toxicity data were comprehensively available for 110 patients, with common grade 3 and grade 4 being neutropenia (9.9%), fatigue (7.3%) and febrile neutropenia (3.6%), respectively. With a median follow-up of 36.88 months, 3-year RFS was 60.3%. Patients with stage II (28%; n?=?35), stage IIIA (28%; n?=?35) and stage IIIB GBC (44%; n?=?55) had a 3-year OS of 91.9, 67 and 58.1% (p?=?0.001), respectively. Patients with stage II–III GBC undergoing R0 resections receiving adjuvant GC have good tolerance, high completion rates and encouraging outcomes in a non-trial high GBC prevalence scenario.