Long-term effects of aromatase inhibitor withdrawal on bone mineral density in early breast cancer patients: 10-year follow-up results of the BREX study.

PURPOSE: We aimed to provide long-term bone mineral density (BMD) data on early breast cancer patients of the BREX (Breast Cancer and Exercise) study. The effects of exercise and adjuvant endocrine treatment 10 years after randomization were analyzed, with special emphasis on aromatase inhibitor (AI) therapy discontinuation at 5 years. METHODS: The BREX study randomized 573 pre- and postmenopausal breast cancer patients into a 1-year supervised exercise program or a control group. 372 patients were included into the current follow-up analysis. BMD (g/cm2) was measured by dual-energy X-ray absorptiometry at lumbar spine (LS), left femoral neck (FN), and the total hip. Separate groups were displayed according to baseline menopausal status, and whether the patient had discontinued AI therapy at 5 years or not. RESULTS: The BMD change from 5 to 10 years did not significantly differ between the two randomized arms. AI discontinuation at 5 years had statistically significant BMD effects. The FN BMD continued to decrease in patients who discontinued AI therapy during the first 5-year off-treatment, but the decrease was three-fold less than in patients without AI withdrawal (- 1.4% v. - 3.8%). The LS BMD increased (+ 2.6%) in patients with AI withdrawal during the first 5 years following treatment discontinuation, while a BMD decrease (-1.3%) was seen in patients without AI withdrawal. CONCLUSION: This study is to our knowledge the first to quantify the long-term impact of AI withdrawal on BMD. Bone loss associated with AI therapy seems partially reversible after stopping treatment. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov/ (Identifier Number NCT00639210).

Neuropilin-1 and placental growth factor as prognostic factors in metastatic breast cancer.

BACKGROUND: Angiogenesis is crucial for tumor development, progression, and metastasizing. The most important regulator of angiogenesis is the vascular endothelial growth factor (VEGF) family, which is involved in multiple pathways in tumor microenvironment. The objective of this study was to investigate the prognostic value of the VEGF family in patients treated for metastatic breast cancer. The emphasis was on neuropilin-1 (NRP-1) and placental growth factor (PlGF). MATERIALS AND METHODS: An analysis of eight members of the VEGF family was performed using baseline plasma samples of 65 patients treated for metastatic HER2 negative breast cancer in a phase II first-line bevacizumab plus chemotherapy trial. The patients were divided into two groups, high or low, according to the median for each VEGF family member. Progression-free survival (PFS) and overall survival (OS) were determined for each VEGF family member. RESULTS: The patients with low plasma levels of NRP-1 and PlGF had a longer OS than those with high plasma levels [multivariable adjusted hazard ratios (HRs) 2.54 (95% confidence interval (CI) 1.11-5.82, p = 0.02) and 3.11 (95% CI 1.30-7.47, p = 0.01), respectively]. The patients with low levels of both NRP-1 and PlGF had a remarkably long OS with HR of 6.24, (95% CI 1.97-19.76, p = 0.002). In addition, high baseline NRP-1 level was associated with a significantly shorter PFS [multivariable adjusted HR 2.90 (95% CI 1.02-8.28, p = 0.04)] than that in the low-level group, and a high baseline vascular endothelial growth factor receptor-2 level was associated with a longer PFS [multivariable adjusted HR 0.43 (95% CI 0.19-0.98, p = 0.04)]. CONCLUSION: Especially NRP-1 and PlGF have prognostic potential in metastatic breast cancer patients treated with a bevacizumab-taxane combination. Patients with low plasma levels of NRP-1 or PlGF have longer OS than patients with high levels. Patients with both low NRP-1 and PlGF levels appear to have excellent long-term survival. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00979641, registration date 18/09/2009. The regional Ethics Committee: R08142M, registration date 18/11/2008.

Long-term patient-reported outcomes from monarchE: Abemaciclib plus endocrine therapy as adjuvant therapy for HR+, HER2-, node-positive, high-risk, early breast cancer.

BACKGROUND: In monarchE, abemaciclib demonstrated a sustained benefit in invasive disease-free survival and a tolerable safety profile at 42-months median follow-up. With no expected disease-related symptoms, therapies in the adjuvant setting should preserve quality of life (QoL). With all patients off abemaciclib, we report updated patient-reported outcomes (PROs) for the full 2-year treatment period and follow-up. METHODS: Patients completed PROs including FACT-B, FACT-ES, and FACIT-Fatigue at baseline, 3, 6, 12, 18, and 24 months during treatment, and 1, 6, and 12 months after treatment discontinuation. Mixed effects repeated measures model estimated changes from baseline within and between arms for QoL scales and individual items. Meaningful changes were prespecified and no statistical testing was performed. Frequencies of responses to items associated with relevant adverse events and treatment bother were summarized. RESULTS: At baseline, completion rates for PRO instruments were >96 %. Mean changes from baseline for all QoL scales were numerically similar within and between arms (ie, less than prespecified thresholds). The same was observed for all individual items, except diarrhea. Within abemaciclib arm, meaningful differences for diarrhea were observed at 3 and 6 months (mean increases of 1.19 and 1.03 points on 5-point scale, respectively). During treatment, most patients in both arms (69-78 %) reported being bothered "a little bit" or "not at all" by side effects. Overall, patterns for fatigue were similar between arms. During post-treatment follow-up, PROs in both arms were similar to baseline. CONCLUSION: PRO findings confirm a tolerable and reversible toxicity profile for abemaciclib. QoL was preserved with the addition of adjuvant abemaciclib to endocrine therapy, supporting its use in patients with HR+, HER2-, high-risk early breast cancer.

Safer and More Convenient Modern Curative Radiotherapy for Patients With Early Prostate Cancer.

BACKGROUND/AIM: New fractionation schedules with modern tools are a very rapidly developing area in curative radiotherapy (RT) for early prostate cancer (PC). To apply these techniques in everyday clinical practice, we planned this phase II trial with different fractionation schedules and followed up patients using careful health-related quality of life (QoL) questionnaires for three years. PATIENTS AND METHODS: Seventy-three PC patients with one or two intermediate PC risk factors according to the National Comprehensive Cancer Network criteria were recruited. Forty-two patients were treated with 78/2 Gy (conventional fractionation, CF) or 60/3 Gy (moderately hypofractionation RT, MHF), and 31 patients were treated with 36.25/7.25 Gy (stereotactic body RT, SBRT). Their PSA levels were measured, and QoL data were assessed for genitourinary (GU), gastrointestinal (GI), and sexual well-being between the baseline and three years after treatment. A Rectafix™ (RF) fixation device was used in 30 patients in the CF/MHF group. RESULTS: Three years after radiotherapy (RT), there were no differences between the groups regarding GU, GI, sexual well-being, PSA response, or clinical outcomes. On QoL questionnaires, men in the SBRT group were more satisfied with their QoL at the end of RT. Urinary symptoms (p=0.004) and urinary incontinence were more common in the CF/MHF group (p=0.016) three months after RT. The use of RF reduced GI toxicity, especially urgency (p=0.002), at three years after RT. CONCLUSION: Modern, short, five-fraction stereotactic radiotherapy as a local curative treatment for PC is well tolerated and safe. Our novel results showing a decrease in GI toxicity using Rectafix™ fixation should be confirmed in future randomized trials.

The past and present of prostate cancer and its treatment and diagnostics: A historical review.

The prognosis of local prostate cancer has improved drastically during the past 60 years. Similarly, the prognosis in metastatic stage is constantly improving due to a number of new pharmaceuticals introduced over the past 10 years. Previously, only palliative treatments were available for prostate cancer, but today, there are multiple options for treatment with curative intent: robotic-assisted radical prostatectomy, stereotactic radiotherapy and brachytherapy. Additionally, life-prolonging chemotherapeutic and androgen-suppressive treatments, as well as diagnostic imaging and staging, have improved considerably. This review summarizes the history of the treatment and diagnostics of prostate cancer, with a focus on the past 60 years. The aim was to provide a concise and easy-to-read introduction on the matter for all people that work with prostate cancer, as well as for patients. The literature was thoroughly examined covering the period from the earliest traceable records to the latest state-of-the-art studies.

Radiotherapy-induced diffuse myocardial fibrosis in early-stage breast cancer patients - multimodality imaging study with six-year follow-up.

BACKGROUND: Breast radiotherapy (RT) induces diffuse myocardial changes, which may increase the incidence of heart failure with preserved ejection fraction. This study aimed to evaluate the early signs of diffuse fibrosis after RT and their evolution during a six-year follow-up. METHODS: Thirty patients with early-stage left-sided breast cancer were studied with echocardiography and electrocardiography (ECG) at baseline, after RT, and at three-year and six-year follow-up visits. Echocardiography analysis included an off-line analysis of integrated backscatter (IBS). ECG was analysed for fragmented QRS (fQRS). In addition, cardiac magnetic resonance (CMR) imaging was performed at the six-year control. The left ventricle 16-segment model was used in cardiac imaging, and respective local radiation doses were analysed. RESULTS: Regional myocardial reflectivity in inferoseptal segments increased by 2.02 (4.53) dB (p = 0.026) and the percentage of leads with fQRS increased from 9.2 to 16.4% (p = 0.002) during the follow-up. In CMR imaging, abnormal extracellular volume (ECV) and T1 mapping values were found with anteroseptal and apical localization in a median of 3.5 (1.00-5.75) and 3 (1.25-4.00) segments, respectively. A higher left ventricle radiation dose was associated with an increased likelihood of having changes simultaneously in CMR and echocardiography (OR 1.26, 95% Cl. 1.00-1.59, p = 0.047). CONCLUSIONS: After radiotherapy, progressive changes in markers of diffuse myocardial fibrosis were observed in a multimodal manner in ECG and echocardiography. Changes in echocardiography and abnormal values in CMR were localized in the septal and apical regions, and multiple changes were associated with higher radiation doses.

End-of-life Decision-making Differs Between a Cancer and a Dementia Patient: Influences of the Physician's Background Factors.

BACKGROUND/AIM: Appropriate decision-making is essential for end-of-life (EOL) care without futile therapies. However, these decisions might vary in cases of cancer and other advanced diseases according to physicians' experience, education, and values. This study aimed to compare the decisions in EOL care of advanced cancer and dementia and the factors that influence them in medical students, general practitioners (GPs), and physicians with special competence in palliative medicine (cPM). PATIENTS AND METHODS: A questionnaire presenting patient scenarios concerning different decisions and ethical aspects of EOL care with additional questions on attitudes and background factors was delivered to 500 Finnish GPs, all Finnish physicians with cPM (n=82), and all graduating medical students (n=639) in 2015-2016. Altogether 601 responses were obtained (53%). RESULTS: Palliative care was chosen more often for a patient with advanced prostate cancer (83%) than for a patient with advanced dementia (41%) (both patients males, same age). A suspicion of iatrogenic bleeding in the prostate cancer patient decreased the willingness to choose palliative care, especially among the students. Patient benefit was regarded as an important background factor in decision making by all respondent groups, but physicians' legal protection was not considered as important among the physicians with cPM as it was among the other respondent groups. CONCLUSION: Finnish doctors and students were more likely to choose palliative care options for an advanced prostate cancer patient than for an advanced dementia patient. Decision-making was influenced by respondents' background factors and attitudes. Education on EOL care for different types of advanced and incurable diseases is highly needed.

Transient Changes in Serum CEA, CA19-9, CRP, YKL-40, and IL-6 during Adjuvant Chemotherapy and Survival of Patients with Colorectal Cancer.

Serum carcinoembryonic antigen (CEA) is frequently monitored to detect colorectal cancer (CRC) recurrence after surgery. The clinical significance of transiently increased CEA during adjuvant chemotherapy is poorly understood. Serum CEA, CA19-9, CRP, YKL-40, and IL-6 were measured before, during, and after adjuvant 5-fluorouracil-based chemotherapy in the randomised LIPSYT study population. The biomarker kinetic patterns were classified into three groups: no increase, a transient increase (≥10% increase followed by a decrease), and a persistent increase during the adjuvant treatment, and the associations of these patterns with disease free-survival (DFS) and overall survival (OS) were investigated by using Cox regression analyses. The findings were validated in two single-centre cohorts that received modern adjuvant chemotherapy. A transient increase in CEA occurred in about a half of the patients during chemotherapy, in all the cohorts. The patients with a transient increase had a roughly similar DFS and OS to the patients with no increase, and a more favourable survival compared to the patients with a persistent increase. In the LIPSYT cohort, the hazard ratio was 0.21 for DFS (CI95% 0.07-0.66) and 0.24 for OS (CI95% 0.08-0.76). Transient increases in CA19-9 and YKL-40 tended to be associated with a favourable survival. A transient increase in CEA during adjuvant chemotherapy is associated with a favourable survival when compared with a persistent increase.

Transcripts of the Prostate Cancer-Associated Gene ANO7 Are Retained in the Nuclei of Prostatic Epithelial Cells.

Prostate cancer affects millions of men globally. The prostate cancer-associated gene ANO7 is downregulated in advanced prostate cancer, whereas benign tissue and low-grade cancer display varying expression levels. In this study, we assess the spatial correlation between ANO7 mRNA and protein using fluorescent in situ hybridization and immunohistochemistry for the detection of mRNA and protein in parallel sections of tissue microarrays prepared from radical prostatectomy samples. We show that ANO7 mRNA and protein expression correlate in prostate tissue. Furthermore, we show that ANO7 mRNA is enriched in the nuclei of the luminal cells at 89% in benign ducts and low-grade cancer, and at 78% in high-grade cancer. The nuclear enrichment of ANO7 mRNA was validated in prostate cancer cell lines 22Rv1 and MDA PCa 2b using droplet digital polymerase chain reaction (ddPCR) on RNA isolated from nuclear and cytoplasmic fractions of the cells. The nuclear enrichment of ANO7 mRNA was compared to the nuclearly-enriched lncRNA MALAT1, confirming the surprisingly high nuclear retention of ANO7 mRNA. ANO7 has been suggested to be used as a diagnostic marker and a target for immunotherapy, but a full comprehension of its role in prostate cancer progression is currently lacking. Our results contribute to a better understanding of the dynamics of ANO7 expression in prostatic tissue.

Health-related Quality of Life of Patients Treated With Different Fractionation Schedules for Early Prostate Cancer Compared to the Age-standardized General Male Population.

BACKGROUND: The effects of radiotherapy (RT) patients' health-related quality of life (HRQoL) are usually compared to those of other treatment modalities instead of HRQoL of the general population in oncological studies. We examined HRQoL of patients with an early prostate cancer (PC) not receiving hormonal treatment up to 3 years after RT using the 15D instrument and the FACT-P questionnaire. METHODS: The 15D results were compared to those in the age-standardized general male population (N = 952) using an independent-sample t test. The study population (N = 73) received RT either with 78/2 Gy, 60/3 Gy or 36.25/7.25 Gy fractionation. RESULTS: No significant differences in the mean total HRQoL scores were found between the RT groups and the general male population at any time point. Patients with PC had more depression (P = .015) and distress (P = .029) than the general male population before the treatment and depression up to 3 months after treatment (P = .019), which did not persist at 3 years. The sexual activity dimension had declined by the end of treatment, and this decline persisted 3 years later (P = .033). Excretion functions were worse compared to those in peers at the end of treatment (P < .001) but no longer at 3 months and later after RT. Regarding the FACT-P, HRQoL remained good at 3 years after RT in all the treatment groups and there were no significant differences between the different RT groups at this time point. CONCLUSION: This study demonstrated that patients treated with RT for early PC had similar HRQoL compared to the age-standardized general male population at 3 years after treatment.

2-weekly versus 3-weekly docetaxel for metastatic castration-resistant prostate cancer: complete quality of life results from the randomised, phase-III PROSTY trial.

INTRODUCTION: Treatment with 2-weekly docetaxel 50 mg/m2 was shown to improve overall survival and was better tolerated than the standard 75 mg/m2 3-weekly regimen in men with metastatic castration-resistant prostate cancer (mCRPC) in the original randomised PROSTY trial. The aim of this study was to investigate, whether quality of life (QoL) effects would differ between the 2-weekly docetaxel 50 mg/m2 regimen from the standard 3-weekly 75 mg/m2 treatment. MATERIALS AND METHODS: QoL data were collected with the Functional Assessment of Cancer Therapy - Prostate (FACT-P) and Functional Assessment of Cancer Therapy Advanced Prostate Symptom Index - 8 Item version (FAPSI-8). Pain was measured using the Visual Analogue Scale (VAS). A total of 743 forms from 163 patients were analysed in Arm A (2-weekly docetaxel), and 704 forms from 173 patients were analysed in Arm B (3-weekly docetaxel). The data were analysed using both the Wilcoxon signed rank test (with Holm-Bonferroni adjustment) and Mann-Whitney U models. RESULTS: No major differences were found in total QoL. Total QoL was higher at month 8 in Arm B (p = .020), but this was reversed in the following month (p = .043), and no statistically significant differences were found during other months. Compared to Arm A, participants in Arm B had longer-lasting deterioration in FAPSI-8 scores and emotional well-being subdomain at the beginning of treatment (p < .05). Various one-month differences were found in FACT-P subdomains (except for functional well-being), and these favoured participants in Arm A, except for the prostate-cancer subdomain. There were no differences in pain. CONCLUSION: Based on our results, 2-weekly docetaxel was not inferior to 3-weekly docetaxel in terms of total health-related QoL and seemed to be superior at least in terms of the FAPSI-8 and emotional well-being subdomain in the first three to four months of treatment. More research on the topic is suggested to confirm the results.

Factors predicting long-term physical activity of breast cancer survivors. 5-year-follow-up of the BREX exercise intervention study.

BACKGROUND: The benefits of exercise training are well documented among breast cancer (BC) survivors. Patients decrease their physical activity during treatment, and many fail to regain their previous exercise levels. There is therefore a need to define factors supporting long-term physical activity behavior in this patient group, to target supporting interventions aimed at preventing the decline in physical activity (PA). AIM: The aim of this study was to determine physical and psychosocial factors explaining long-term physical activity after the adjuvant treatments in BC survivors. METHODS: Four-hundred forty-six BC survivors followed for 5-years within a randomized exercise trial participated. Factors explaining (1) physical activity after the adjuvant treatments and (2) changes in physical activity in long-term were analyzed using linear regression models and general estimating equation models. Pretreatment leisure-time physical activity (LTPA), demographic, and treatment factors, physical fitness, and quality of life (Qol) at baseline were independent factors. RESULTS: Exercise levels increased during the first year, and thereafter remained mostly stable. Higher LTPA, higher fitness level, better Qol and older age at baseline were associated with higher physical activity level after adjuvant treatments (p < .001) in multivariate analysis. Higher levels of fatigue (p < .008) and better emotional functioning (p = .017) at baseline were the main factors associated with increased physical activity during the follow-up. CONCLUSION: Previous exercise habits and Qol after adjuvant chemo-, and radiotherapy were the strongest determinants of long-term physical activity levels in breast cancer survivors. Patients with better emotional functioning increased their exercise activity most as did those patients with higher fatigue levels at baseline. Patients suffering from fatigue after adjuvant treatment managed to increase their exercise levels, in contrast to patients with low emotional functioning, and may benefit from physical exercise interventions. Emotionally deprived patients may benefit from psychosocial support to regain their previous exercise levels.

Acute Side-effects of Different Radiotherapy Treatment Schedules in Early Prostate Cancer.

BACKGROUND: Optimal radiation therapy (RT) fractionation in early prostate cancer in elderly patients is controversial. We compared acute toxicities of fractionation schedules: 78/2 Gy, 60/3 Gy and 36.25/7.25 Gy, in this single-centre study. We also evaluated the effect of the rectal immobilization system Rectafix on quality of life (QoL). PATIENTS AND METHODS: Seventy-three patients with one or two intermediate prostate cancer risk factors according to National Comprehensive Cancer Network criteria were recruited. Twenty-one patients were treated with 78/2 Gy and 60/3 Gy, and 31 patients with 36.25/7.25 Gy. Their QoL data were assessed with regard to genitourinary, gastrointestinal and sexual wellbeing at the beginning and end of RT and at 3 months after treatment. Rectafix was used in the 78/2 Gy and 60/3 Gy groups. RESULTS: There were no statistically significant QoL differences in between the treatment groups 3 months after RT. The 78/2 Gy group had significantly increased bowel movements between baseline and 3 months after RT (p=0.036). At 3 months after RT, this group also had significantly more erectile dysfunction than the 60/3 Gy group (p=0.025). At the end of RT, the 78/2 Gy group had more symptoms than the 36.25/7.25 Gy group. Rectafix did not reduce acute toxicities in the 78/2 Gy or 60/3 Gy groups. CONCLUSION: Treatment with the 78/2 Gy schedule is no longer to be recommended due to its increased acute toxicity compared to treatments of 60/3 Gy and 36.25/7.25 Gy. The shortest schedule of 36.25 Gy in five fractions seems to be a convenient treatment option with tolerable acute toxicity.

Dynamic Integrated Backscatter Detects Radiotherapy-induced Cardiac Changes Better than Strain Analysis - A Prospective Three-year Study.

BACKGROUND/AIM: Radiotherapy (RT) related myocardial changes were analyzed by deformation imaging echocardiography in this study. PATIENTS AND METHODS: Ninety-nine breast cancer patients were studied at baseline, after chemotherapy, after RT, and three years after RT (3Y). Eighty patients received RT only, and twenty patients had right-sided breast cancer. Echocardiography included cyclic variation of the integrated backscatter in the septum (sCV) and posterior wall (pCV), global longitudinal strain (GLS), and left ventricular ejection fraction (LVEF). RESULTS: In patients with left-sided breast cancer, sCV declined from 11.3±3.3 dB at baseline to 10.3±2.9 dB after RT (p=0.001). No changes were observed after chemotherapy (p=0.211) or in patients with right-sided breast cancer after RT (p=0.977). No other parameters declined after RT. The decline in sCV was independently associated with the left anterior descending coronary artery radiation dose (ß=-0.290, p=0.020). CONCLUSION: In contrast to other parameters, sCV correlated with heart radiation dose.

A Higher Mean Heart Radiation Dose Induces Higher Frequency of Multiple Cardiac Changes.

BACKGROUND/AIM: Radiotherapy (RT) induces late changes in all cardiac structures. Most studies of early changes focus on individual parameters. PATIENTS AND METHODS: Data from eighty early-stage breast cancer patients at baseline, post-RT and three-year follow-up visit were assessed prospectively. Changes in ten cardiac parameters were collected including electrocardiogram (ECG), echocardiography, and biomarkers. A percentage of abnormal changes was calculated. RESULTS: The mean heart radiation dose (Dmean) was independently associated with the increased incidence of changes post-RT (ß=0.403, p<0.001) and at the three-year follow-up (ß=0.353, p=0.001). Each 1-Gray increase in Dmean increased the cardiac changes by 3.7% (95%CI=1.9-5.6%) after RT and 3.1% (95%CI=1.3, 4.9%) at the three-year follow-up. CONCLUSION: A higher cardiac radiation dose was independently associated with a higher incidence of changes in cardiac parameters. Multiparameter changes imply that the early phase after RT is already characterized by several overlapping cardiac changes.

Health-Related Quality of Life in Metastatic Colorectal Cancer Patients Treated with Curative Resection and/or Local Ablative Therapy or Systemic Therapy in the Finnish RAXO-Study.

Metastasectomy and/or local ablative therapy in metastatic colorectal cancer (mCRC) patients often provide long-term survival. Health-related quality of life (HRQoL) data in curatively treated mCRC are limited. In the RAXO-study that evaluated repeated resectability, a multi-cross-sectional HRQoL substudy with 15D, EQ-5D-3L, QLQ-C30, and QLQ-CR29 questionnaires was conducted. Mean values of patients in different treatment groups were compared with age- and gender-standardized general Finnish populations. The questionnaire completion rate was 444/477 patients (93%, 1751 questionnaires). Mean HRQoL was 0.89−0.91 with the 15D, 0.85−0.87 with the EQ-5D, 68−80 with the EQ-5D-VAS, and 68−79 for global health status during curative treatment phases, with improvements in the remission phase (disease-free >18 months). In the remission phase, mean EQ-5D and 15D scores were similar to the general population. HRQoL remained stable during first- to later-line treatments, when the aim was no longer cure, and declined notably when tumour-controlling therapy was no longer meaningful. The symptom burden affecting mCRC survivors' well-being included insomnia, impotence, urinary frequency, and fatigue. Symptom burden was lower after treatment and slightly higher, though stable, through all phases of systemic therapy. HRQoL was high in curative treatment phases, further emphasizing the strategy of metastasectomy in mCRC when clinically meaningful.

A graphical LASSO analysis of global quality of life, sub scales of the EORTC QLQ-C30 instrument and depression in early breast cancer.

We aimed to (a) investigate the interplay between depression, symptoms and level of functioning, and (b) understand the paths through which they influence health related quality of life (QOL) during the first year of rehabilitation period of early breast cancer. A network analysis method was used. The population consisted of 487 women aged 35-68 years, who had recently completed adjuvant chemotherapy or started endocrine therapy for early breast cancer. At baseline and at the first year from randomization QOL, symptomatology and functioning by the EORTC QLQ-C30 and BR-23 questionnaires, and depression by the Finnish version of Beck's 13-item depression scale, were collected. The multivariate interplay between the related scales was analysed via regularized partial correlation networks (graphical LASSO). The median global quality of life (gQoL) at baseline was 69.9 ± 19.0 (16.7-100) and improved to 74.9 ± 19.0 (0-100) after 1 year. Scales related to mental health (emotional functioning, cognitive functioning, depression, insomnia, body image, future perspective) were clustered together at both time points. Fatigue was mediated through a different route, having the strongest connection with physical functioning and no direct connection with depression. Multiple paths existed connecting symptoms and functioning types with gQoL. Factors with the strongest connections to gQoL included: social functioning, depression and fatigue at baseline; emotional functioning and fatigue at month 12. Overall, the most important nodes were depression, gQoL and fatigue. The graphical LASSO network analysis revealed that scales related to fatigue and emotional health had the strongest associations to the EORTC QLQ-C30 gQoL score. When we plan interventions for patients with impaired QOL it is important to consider both psychological support and interventions that improve fatigue and physical function like exercise.Trial registration: http://www.clinicaltrials.gov/ (identifier number NCT00639210).

Outcome and Biomarker Supervised Deep Learning for Survival Prediction in Two Multicenter Breast Cancer Series.

BACKGROUND: Prediction of clinical outcomes for individual cancer patients is an important step in the disease diagnosis and subsequently guides the treatment and patient counseling. In this work, we develop and evaluate a joint outcome and biomarker supervised (estrogen receptor expression and ERBB2 expression and gene amplification) multitask deep learning model for prediction of outcome in breast cancer patients in two nation-wide multicenter studies in Finland (the FinProg and FinHer studies). Our approach combines deep learning with expert knowledge to provide more accurate, robust, and integrated prediction of breast cancer outcomes. MATERIALS AND METHODS: Using deep learning, we trained convolutional neural networks (CNNs) with digitized tissue microarray (TMA) samples of primary hematoxylin-eosin-stained breast cancer specimens from 693 patients in the FinProg series as input and breast cancer-specific survival as the endpoint. The trained algorithms were tested on 354 TMA patient samples in the same series. An independent set of whole-slide (WS) tumor samples from 674 patients in another multicenter study (FinHer) was used to validate and verify the generalization of the outcome prediction based on CNN models by Cox survival regression and concordance index (c-index). Visual cancer tissue characterization, i.e., number of mitoses, tubules, nuclear pleomorphism, tumor-infiltrating lymphocytes, and necrosis was performed on TMA samples in the FinProg test set by a pathologist and combined with deep learning-based outcome prediction in a multitask algorithm. RESULTS: The multitask algorithm achieved a hazard ratio (HR) of 2.0 (95% confidence interval [CI] 1.30-3.00), P < 0.001, c-index of 0.59 on the 354 test set of FinProg patients, and an HR of 1.7 (95% CI 1.2-2.6), P = 0.003, c-index 0.57 on the WS tumor samples from 674 patients in the independent FinHer series. The multitask CNN remained a statistically independent predictor of survival in both test sets when adjusted for histological grade, tumor size, and axillary lymph node status in a multivariate Cox analyses. An improved accuracy (c-index 0.66) was achieved when deep learning was combined with the tissue characteristics assessed visually by a pathologist. CONCLUSIONS: A multitask deep learning algorithm supervised by both patient outcome and biomarker status learned features in basic tissue morphology predictive of survival in a nationwide, multicenter series of patients with breast cancer. The algorithms generalized to another independent multicenter patient series and whole-slide breast cancer samples and provide prognostic information complementary to that of a comprehensive series of established prognostic factors.

Tumor infiltrating lymphocyte stratification of prognostic staging of early-stage triple negative breast cancer.

The importance of integrating biomarkers into the TNM staging has been emphasized in the 8th Edition of the American Joint Committee on Cancer (AJCC) Staging system. In a pooled analysis of 2148 TNBC-patients in the adjuvant setting, TILs are found to strongly up and downstage traditional pathological-staging in the Pathological and Clinical Prognostic Stage Groups from the AJJC 8th edition Cancer Staging System. This suggest that clinical and research studies on TNBC should take TILs into account in addition to stage, as for example patients with stage II TNBC and high TILs have a better outcome than patients with stage I and low TILs.

Adjuvant Capecitabine for Early Breast Cancer: 15-Year Overall Survival Results From a Randomized Trial.

PURPOSE: Few data are available regarding the influence of adjuvant capecitabine on long-term survival of patients with early breast cancer. METHODS: The Finland Capecitabine Trial (FinXX) is a randomized, open-label, multicenter trial that evaluates integration of capecitabine to an adjuvant chemotherapy regimen containing a taxane and an anthracycline for the treatment of early breast cancer. Between January 27, 2004, and May 29, 2007, 1,500 patients with axillary node-positive or high-risk node-negative early breast cancer were accrued. The patients were randomly allocated to either TX-CEX, consisting of three cycles of docetaxel (T) plus capecitabine (X) followed by three cycles of cyclophosphamide, epirubicin, and capecitabine (CEX, 753 patients), or to T-CEF, consisting of three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil (CEF, 747 patients). We performed a protocol-scheduled analysis of overall survival on the basis of approximately 15-year follow-up of the patients. RESULTS: The data collection was locked on December 31, 2020. By this date, the median follow-up time of the patients alive was 15.3 years (interquartile range, 14.5-16.1 years) in the TX-CEX group and 15.4 years (interquartile range, 14.8-16.0 years) in the T-CEF group. Patients assigned to TX-CEX survived longer than those assigned to T-CEF (hazard ratio 0.81; 95% CI, 0.66 to 0.99; P = .037). The 15-year survival rate was 77.6% in the TX-CEX group and 73.3% in the T-CEF group. In exploratory subgroup analyses, patients with estrogen receptor-negative cancer and those with triple-negative cancer treated with TX-CEX tended to live longer than those treated with T-CEF. CONCLUSION: Addition of capecitabine to a chemotherapy regimen that contained docetaxel, epirubicin, and cyclophosphamide prolonged the survival of patients with early breast cancer.