Immune cell profiles of metastatic HER2-positive breast cancer patients according to the sites of metastasis

Purpose Recent works have characterized that metastatic site can affect the tumour immune profiles and efficiency of cancer immunotherapies. The prognosis of HER2-positive breast cancer is associated with the characteristics of the tumour immune microenvironment, with immunological cells playing a central role in efficiency of HER2-targeted antibodies. Here we investigated the prognostic significance of different metastatic sites and their correlation to tumour immune profiles in HER2-positive breast cancer treated with trastuzumab. Methods We collected all (n = 54) HER2-positive metastatic breast cancer patients treated with trastuzumab containing regimens at Oulu University Hospital 2009-2014. Pathological and clinical data were collected from electronic patient records. The tumour immune profiles were analysed from pre-treatment primary tumours using well-characterized immunological markers with computer-assisted immune cell counting. Results Of the metastatic sites, only liver metastases were associated with poor prognosis (hazard ratio 1.809, 95% confidence interval 1.004-3.262), especially when presented as the primary site of metastases. Of the other sites, pulmonary metastases characterized a patient profile with trend to improved survival. Of the studied tumour immunological markers, patients with liver metastases had low densities of CD3(+) T cells (p = 0.030) and M1-like macrophages in their primary tumours (p = 0.025). Of the other studied markers and sites, patients with pulmonary metastases had low STAB1(+)-immunosuppressive macrophage density in their primary tumours. Conclusion Our results suggest that the site of metastasis is associated with prognosis in HER2-positive breast cancer, highlighted by the poor prognosis of liver metastases. Furthermore, liver metastases were associated with adverse tumour immune cell profiles.Peer reviewe

Immune cell profiles of metastatic HER2-positive breast cancer patients according to the sites of metastasis

Purpose Recent works have characterized that metastatic site can affect the tumour immune profiles and efficiency of cancer immunotherapies. The prognosis of HER2-positive breast cancer is associated with the characteristics of the tumour immune microenvironment, with immunological cells playing a central role in efficiency of HER2-targeted antibodies. Here we investigated the prognostic significance of different metastatic sites and their correlation to tumour immune profiles in HER2-positive breast cancer treated with trastuzumab. Methods We collected all (n = 54) HER2-positive metastatic breast cancer patients treated with trastuzumab containing regimens at Oulu University Hospital 2009-2014. Pathological and clinical data were collected from electronic patient records. The tumour immune profiles were analysed from pre-treatment primary tumours using well-characterized immunological markers with computer-assisted immune cell counting. Results Of the metastatic sites, only liver metastases were associated with poor prognosis (hazard ratio 1.809, 95% confidence interval 1.004-3.262), especially when presented as the primary site of metastases. Of the other sites, pulmonary metastases characterized a patient profile with trend to improved survival. Of the studied tumour immunological markers, patients with liver metastases had low densities of CD3(+) T cells (p = 0.030) and M1-like macrophages in their primary tumours (p = 0.025). Of the other studied markers and sites, patients with pulmonary metastases had low STAB1(+)-immunosuppressive macrophage density in their primary tumours. Conclusion Our results suggest that the site of metastasis is associated with prognosis in HER2-positive breast cancer, highlighted by the poor prognosis of liver metastases. Furthermore, liver metastases were associated with adverse tumour immune cell profiles.Peer reviewe

Oxidative damage and counteracting mechanisms in breast carcinoma

Abstract Breast cancer is the leading cause of death from cancer among Finnish women, but the ultimate causation of carcinogenesis still remains unclear. Reactive oxygen species (ROS) is a collective term for several types of reactive oxygen metabolites that are continuously generated in human cells mainly as by-products of aerobic respiration. ROS, including nitric oxide and its derivatives, play highly important roles in cell physiology. If ROS production exceeds the capacity of detoxification systems, principally antioxidant enzymes, oxidative stress is said to occur. This state is known to contribute to all stages of carcinogenesis. To explore the widely unstudied role of ROS and cell redox state modulating enzymes in breast carcinomas, the extent of ROS-derived macromolecule damage and the expression of the vast majority of known antioxidant enzymes were assessed in a large series of breast carcinomas, and the results were compared to the patients' clinicopathological parameters. The results were also compared to angiogenesis, DNA repair enzymes, cell proliferation, NF-κB, p53 expression, and survival. Immunohistochemistry was the main method applied, but western blotting and immunoelectron microscopy were also used. There is extensive oxidative damage in breast carcinomas, which seems to associate with tumor development. Oxidative macromolecule damage is notable even in stage I tumors. Cell redox state regulating enzymes, such as peroxiredoxin V, thioredoxin, thioredoxin reductase, and glutamate-cysteine ligase, associate with more aggressive phenotypes of tumors, including larger primary tumors, growth of metastases, increased cell proliferation, and poor differentiation. This indirectly suggests that cell redox state modulating enzymes may be inductive of tumor promotion in an oxidated environment. The results of this thesis support the importance of ROS in all stages of carcinogenesis. These observations are largely in line with the previous studies on different carcinomas, but there seem to be certain carcinoma type specific differences in the expression of these enzymes. Since the expression of given cell redox state modulating enzymes distinctly associates with clinicopathological parameters, these enzymes may be useful as prognostic indicators and facilitate the choice of appropriate treatment in the future

Mutational signatures and their association with survival and gene expression in urological carcinomas

Abstract Different sources of mutagenesis cause consistently identifiable patterns of mutations and mutational signatures that mirror the various carcinogenetic processes. We used publicly available data from the Cancer Genome Atlas to evaluate the associations between the activity of the mutational signatures and various survival endpoints in six types of urological cancers after adjusting for established prognostic factors. The predictive power of the signatures was evaluated with dynamic area under curve models. In addition, links between mutational signature activities and differences in gene expression patterns were analysed. APOBEC-related signature SBS2 was associated with improved overall survival (OS) and disease-specific survival (DSS) in bladder carcinomas in the multivariate analysis, while clock-like signature SBS1 predicted shortened DSS and progression-free interval (PFI) in clear cell renal cell carcinomas (ccRCC). In papillary renal cell carcinomas (pRCC), SBS45 was a predictor of improved outcomes, and APOBEC-related SBS13 was a predictor of worse outcomes. Gene expression analyses revealed various enriched pathways between the low- and high-signature groups. Interestingly, in both the ccRCC and pRCC cohorts, the genes of several members of the melanoma antigen (MAGE) family were highly upregulated in the signatures, which predicted poor outcomes, and downregulated in signatures, which were associated with improved survival. To summarize, SBS signatures provide substantial prognostic value compared with just the traditional prognostic factors in certain cancer types. APOBEC-related SBS2 and SBS13 seem to provide robust prognostic information for particular urological cancers, maybe driven by the expression of specific groups of genes, including the MAGE gene family

Kohdennetut syövän hoidot:häviääkö syöpäkirurgia?

Tiivistelmä Kirurgia on keskeistä kiinteiden kasvainten kuratiivisessa hoidossa mutta tarpeen joskus myös oireiden hoidossa tai diagnostiikassa. Syövän täsmähoitojen nopea kehitys on mahdollistanut entistä tehokkaamman ja siedettävämmän hoidon, ja kokonaan uusia hoitomuotoja on tullut laajamittaiseen käyttöön. Voivatko täsmähoidot vähentää kirurgian merkitystä syövän hoidossa? Nykyisin on käytettävissä vähän laadukkaita tutkimuksia, jotka osoittaisivat täsmähoitojen yhdenvertaisuuden tai paremmuuden syöpäkirurgiaan verrattuna. Olemme kaukana tilanteesta, jossa syövän täsmähoidot syrjäyttäisivät kirurgian aseman parantavana hoitomuotona.Abstract Targeted cancer therapies : is cancer surgery vanishing? Surgery plays a central role in the diagnosis of solid tumors and in curative and sometimes even symptomatic treatment. The rapid progress in targeted treatments for cancer has enabled a more effective and better tolerated treatment, and entirely new therapies have been widely adopted. Can targeted therapies reduce the importance of surgery in the treatment of cancer? There are currently few high-quality studies available that would demonstrate the equality or superiority of targeted therapies over cancer surgery. We are far from a situation where targeted treatments for cancer would displace the role of surgery as a curative treatment

Reactive oxygen species-mediated mechanisms of action of targeted cancer therapy

Abstract Targeted cancer therapies, involving tyrosine kinase inhibitors and monoclonal antibodies, for example, have recently led to substantial prolongation of survival in many metastatic cancers. Compared with traditional chemotherapy and radiotherapy, where reactive oxygen species (ROS) have been directly linked to the mediation of cytotoxic effects and adverse events, the field of oxidative stress regulation is still emerging in targeted cancer therapies. Here, we provide a comprehensive review regarding the current evidence of ROS-mediated effects of antibodies and tyrosine kinase inhibitors, use of which has been indicated in the treatment of solid malignancies and lymphomas. It can be concluded that there is rapidly emerging evidence of ROS-mediated effects of some of these compounds, which is also relevant in the context of drug resistance and how to overcome it

The role of redox-regulating enzymes in inoperable breast cancers treated with neoadjuvant chemotherapy

Abstract Although validated predictive factors for breast cancer chemoresistance are scarce, there is emerging evidence that the induction of certain redox-regulating enzymes may contribute to a poor chemotherapy effect. We investigated the possible association between chemoresistance and cellular redox state regulation in patients undergoing neoadjuvant chemotherapy (NACT) for breast cancer. In total, 53 women with primarily inoperable or inflammatory breast cancer who were treated with NACT were included in the study. Pre-NACT core needle biopsies and postoperative tumor samples were immunohistochemically stained for nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), thioredoxin (Trx), and peroxiredoxin I (Prx I). The expression of all studied markers increased during NACT. Higher pre-NACT nuclear Prx I expression predicted smaller size of a resected tumor (p = 0 00052; r = −0 550), and higher pre-NACT cytoplasmic Prx I expression predicted a lower amount of evacuated nodal metastasis (p = 0 0024; r = −0 472). Pre-NACT nuclear Trx expression and pre-NACT nuclear Keap1 expression had only a minor prognostic significance as separate factors, but when they were combined, low expression for both antibodies before NACT predicted dismal disease-free survival (log-rank p = 0 0030). Our results suggest that redox-regulating enzymes may serve as potential prognostic factors in primarily inoperable breast cancer patients

Metformin diminishes the unfavourable impact of Nrf2 in breast cancer patients with type 2 diabetes

Abstract Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a major regulator of the oxidative stress response and it is negatively regulated by Kelch-like ECH-associated protein 1 (Keap1). The Keap1–Nrf2 axis has a fundamental role in carcinogenesis. In previous studies, the widely used diabetes drug metformin has appeared to have a critical role in the regulation of Nrf2 function. In this study, we assessed the expression of Nrf2 and Keap1 immunohistochemically in 157 patients with type 2 diabetes who underwent breast cancer surgery with curative intent. In total, 78 (49.7%) of these patients were taking metformin alone or combined with other oral anti-diabetic medication at the time of breast cancer diagnosis. We found that high-level cytoplasmic Nrf2 expression predicted dismal overall survival and breast cancer–specific survival, but only in the patients who were not taking metformin at the time of diagnosis. Similarly, low-level nuclear Keap1 expression had an adverse prognostic value in terms of overall survival and breast cancer–specific survival in patients without metformin. On the other hand, high-level nuclear Keap1 expression was associated with prolonged overall survival and breast cancer–specific survival. The results may be explained in terms of non-functioning or displaced Keap1, although more mechanistic pre-clinical and prospective clinical studies are warranted