Real-World Clinical Outcomes in Biological Subgroups of Breast Cancer in the Hospital District of Southwest Finland.

BACKGROUND: Comparing breast cancer survival trends globally, Finland is among the top three countries in Europe. However, outcome data on breast cancer subgroups in the Finnish population are limited. This retrospective, registry-based study aimed to assess patient characteristics and clinical outcomes of different breast cancer subgroups in early (EBC) and metastatic breast cancer (MBC) in a real-life clinical setting. MATERIALS AND METHODS: The study consisted of 6,977 adult, female patients with breast cancer diagnosed in Southwest Finland during 2005-2018. Patients were divided into four mutually exclusive groups: human epidermal growth factor receptor 2 positive (HER2+), triple negative, HER2-/hormone receptor positive (HR+), and HER2 and/or HR status unknown, and further into patients with EBC and MBC. Overall survival (OS) was assessed as a clinical outcome, as well as the following real-world (rw) clinical outcomes: disease-free survival (rwDFS), progression-free survival (rwPFS), and distant recurrence-free interval (rwDRFI). RESULTS: Within EBC, 5-year survival was the highest (88%) in HER2-/HR+, followed by 85% in HER2+, and 75% in triple negative. The rwDFS varied significantly in EBC (5-year rwDFS HER2 -/HR+, HER2+, triple negative: 87%, 80%, 71% respectively). In MBC, median survival was 2 years for both HER2-/HR+ and HER2+ and markedly shorter for triple negative (0.8 years). Independent predictors of mortality were age (hazard ratio [HR], 1.1), other subgroups than HER2-/HR+ (HR, 1.2-1.9), metastatic disease (HR, 9.8), and other malignancies (HR, 2.7). CONCLUSION: This registry-based study demonstrates significant differences in breast cancer outcomes on the subgroup level, as well as poorer outcomes compared with clinical trials, giving complementary insight on clinical characteristics in an unselected patient population. IMPLICATIONS FOR PRACTICE: This retrospective, registry-based study assessed the clinical outcomes of different breast cancer subgroups in 6,977 adult, female patients with breast cancer diagnosed in Southwest Finland during 2005-2018. Results demonstrated significant variation in the survival between subgroups in both early breast cancer and metastatic breast cancer, as well as differences between unselected patients representing the standard of care and randomized clinical trials. Although, according to the global comparison of survival trends, the net survival of patients with breast cancer in Finland is generally high, there is great variation between subgroups. These real-life breast cancer data provide tools to further evaluate medical need in different breast cancer subgroups.

Engineering chimeric thermostable GH7 cellobiohydrolases in Saccharomyces cerevisiae.

We report here the effect of adding different types of carbohydrate-binding modules (CBM) to a single-module GH7 family cellobiohydrolase Cel7A from a thermophilic fungus Talaromyces emersonii (TeCel7A). Both bacterial and fungal CBMs derived from families 1, 2 and 3, all reported to bind to crystalline cellulose, were used. Chimeric cellobiohydrolases with an additional S-S bridge in the catalytic module of TeCel7A were also made. All the fusion proteins were secreted in active form and in good yields by Saccharomyces cerevisiae. The purified chimeric enzymes bound to cellulose clearly better than the catalytic module alone and demonstrated high thermal stability, having unfolding temperatures (T m) ranging from 72 °C to 77 °C. The highest activity enhancement on microcrystalline cellulose could be gained by a fusion with a bacterial CBM3 derived from Clostridium thermocellum cellulosomal-scaffolding protein CipA. The two CBM3 fusion enzymes tested were more active than the reference enzyme Trichoderma reesei Cel7A both at moderate (45 °C and 55 °C) and at high temperatures (60 °C and 65 °C), the hydrolysis yields being two- to three-fold better at 60 °C, and six- to seven-fold better at 65 °C. The best enzyme variant was also tested on a lignocellulosic feedstock hydrolysis, which demonstrated its potency in biomass hydrolysis even at 70 °C.

Effect of temperature on lignin-derived inhibition studied with three structurally different cellobiohydrolases.

Non-productive enzyme adsorption onto lignin inhibits enzymatic hydrolysis of lignocellulosic biomass. Three cellobiohydrolases, Trichoderma reesei Cel7A (TrCel7A) and two engineered fusion enzymes, with distinctive modular structures and temperature stabilities were employed to study the effect of temperature on inhibition arising from non-productive cellulase adsorption. The fusion enzymes, TeCel7A-CBM1 and TeCel7A-CBM3, were composed of a thermostable Talaromyces emersonii Cel7A (TeCel7A) catalytic domain fused to a carbohydrate-binding module (CBM) either from family 1 or from family 3. With all studied enzymes, increase in temperature was found to increase the inhibitory effect of supplemented lignin in the enzymatic hydrolysis of microcrystalline cellulose. However, for the different enzymes, lignin-derived inhibition emerged at different temperatures. Low binding onto lignin and thermostable structure were characteristic for the most lignin-tolerant enzyme, TeCel7A-CBM1, whereas TrCel7A was most susceptible to lignin especially at elevated temperature (55 °C).