The treatment of patients with ERBB2 (HER2)-positive breast cancer with anti-ERBB2 therapy is based on the detection of ERBB2 gene amplification or protein overexpression. Machine learning (ML) ...algorithms can predict the amplification of ERBB2 based on tumor morphological features, but it is not known whether ML-derived features can predict survival and efficacy of anti-ERBB2 treatment. In this study, we trained a deep learning model with digital images of hematoxylin-eosin (H&E)-stained formalin-fixed primary breast tumor tissue sections, weakly supervised by ERBB2 gene amplification status. The gene amplification was determined by chromogenic in situ hybridization (CISH). The training data comprised digitized tissue microarray (TMA) samples from 1,047 patients. The correlation between the deep learning-predicted ERBB2 status, which we call H&E-ERBB2 score, and distant disease-free survival (DDFS) was investigated on a fully independent test set, which included whole-slide tumor images from 712 patients with trastuzumab treatment status available. The area under the receiver operating characteristic curve (AUC) in predicting gene amplification in the test sets was 0.70 (95% CI, 0.63-0.77) on 354 TMA samples and 0.67 (95% CI, 0.62-0.71) on 712 whole-slide images. Among patients with ERBB2-positive cancer treated with trastuzumab, those with a higher than the median morphology-based H&E-ERBB2 score derived from machine learning had more favorable DDFS than those with a lower score (hazard ratio HR 0.37; 95% CI, 0.15-0.93; P = 0.034). A high H&E-ERBB2 score was associated with unfavorable survival in patients with ERBB2-negative cancer as determined by CISH. ERBB2-associated morphology correlated with the efficacy of adjuvant anti-ERBB2 treatment and can contribute to treatment-predictive information in 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).
We investigated the value of reactive stroma as a predictor for trastuzumab resistance in patients with early HER2‐positive breast cancer receiving adjuvant therapy. The pathological reactive stroma ...and the mRNA gene signatures that reflect reactive stroma in 209 HER2‐positive breast cancer samples from the FinHer adjuvant trial were evaluated. Levels of stromal gene signatures were determined as a continuous parameter, and pathological reactive stromal findings were defined as stromal predominant breast cancer (SPBC; ≥50% stromal) and correlated with distant disease‐free survival. Gene signatures associated with reactive stroma in HER2‐positive early breast cancer (N = 209) were significantly associated with trastuzumab resistance in estrogen receptor (ER)‐negative tumors (hazard ratio HR = 1.27 p interaction = 0.014 DCN, HR = 1.58, p interaction = 0.027 PLAU, HR = 1.71, p interaction = 0.019 HER2STROMA, novel HER2 stromal signature), but not in ER‐positive tumors (HR = 0.73 p interaction = 0.47 DCN, HR = 0.71, p interaction = 0.73 PLAU, HR = 0.84; p interaction = 0.36 HER2STROMA). Pathological evaluation of HER2‐positive/ER‐negative tumors suggested an association between SPBC and trastuzumab resistance. Reactive stroma did not correlate with tumor‐infiltrating lymphocytes (TILs), and the expected benefit from trastuzumab in patients with high levels of TILs was pronounced only in tumors with low stromal reactivity (SPBC <50%). In conclusion, reactive stroma in HER2‐positive/ER‐negative early breast cancer tumors may predict resistance to adjuvant trastuzumab therapy.
What's new
Tumor cells can interact with the surrounding microenvironment, to alter gene expression, suppress immune function, and enhance their own growth. While trastuzumab has dramatically improved clinical outcomes for patients with HER2‐positive breast cancer, not all tumors respond to treatment. In this study, the authors found that one mechanism of trastuzumab resistance may be due to altered gene expression representing “reactive” stromal cells surrounding the tumor, even when high levels of tumor‐infiltrating lymphocytes (TILs) are present. These “reactive” genetic signatures may provide valuable biomarkers for predicting treatment response.
Prostate cancer is one of the most common and heritable human cancers. Our aim was to find germline biomarkers that can predict disease outcome. We previously detected predisposing signals at 2q37, ...the location of the prostate specific ANO7 gene. To investigate, in detail, the associations between the ANO7 gene and PrCa risk and disease aggressiveness, ANO7 was sequenced in castration resistant tumors together with samples from unselected PrCa patients and unaffected males. Two pathogenic variants were discovered and genotyped in 1769 patients and 1711 unaffected males. Expression of ANO7 vs. PrCa aggressiveness was investigated. Different databases along with Swedish and Norwegian cohorts were used for validation. Case–control and aggressive vs. nonaggressive association analyses were performed against risk and/or cancer aggressiveness. The ANO7 mRNA level and patient survival were analyzed using expression data from databases. Variant rs77559646 showed both risk (OR 1.40; p = 0.009, 95% CI 1.09–1.78) and association with aggressive PrCa (Genotype test p = 0.04). It was found to be an eQTL for ANO7 (Linear model p‐values for Finnish patients p = 0.009; Camcap prostate tumor p = 2.53E‐06; Stockholm prostate tumor cohort p = 1.53E‐13). rs148609049 was not associated with risk, but was related to shorter survival (HR 1.56; 95% CI 1.03–2.36). High ANO7 expression was independently linked to poor survival (HR 18.4; 95% CI 1.43–237). ANO7 genotypes correlate with expression and biochemical relapse, suggesting that ANO7 is a potential PrCa susceptibility gene and that its elevated expression correlates with disease severity and outcome.
What's new?
The discovery of germline biomarkers to predict outcome in prostate cancer could greatly aid disease management. One such marker of particular interest in this regard is the prostate‐specific gene ANO7, which previous studies have associated with high‐grade prostate cancer. Here, specific germline ANO7 genotypes were associated with increased prostate cancer risk. In patients, ANO7 expression correlated with disease severity, with elevated expression associated with decreased overall survival. The data suggest that ANO7 is a susceptibility marker in prostate cancer and, with further characterization, could be used to inform patient selection strategies and therapeutic approaches.
The aim of the current study was to conduct a pooled analysis of studies that have investigated the prognostic value of tumor-infiltrating lymphocytes (TILs) in early-stage triple negative breast ...cancer (TNBC).
Participating studies had evaluated the percentage infiltration of stromally located TILs (sTILs) that were quantified in the same manner in patient diagnostic samples of early-stage TNBC treated with anthracycline-based chemotherapy with or without taxanes. Cox proportional hazards regression models stratified by trial were used for invasive disease-free survival (iDFS; primary end point), distant disease-free survival (D-DFS), and overall survival (OS), fitting sTILs as a continuous variable adjusted for clinicopathologic factors.
We collected individual data from 2,148 patients from nine studies. Average age was 50 years (range, 22 to 85 years), and 33% of patients were node negative. The average value of sTILs was 23% (standard deviation, 20%), and 77% of patients had 1% or more sTILs. sTILs were significantly lower with older age ( P = .001), larger tumor size ( P = .01), more nodal involvement ( P = .02), and lower histologic grade ( P = .001). A total of 736 iDFS and 548 D-DFS events and 533 deaths were observed. In the multivariable model, sTILs added significant independent prognostic information for all end points (likelihood ratio χ
, 48.9 iDFS; P < .001; χ
, 55.8 D-DFS; P < .001; χ
, 48.5 OS; P < .001). Each 10% increment in sTILs corresponded to an iDFS hazard ratio of 0.87 (95% CI, 0.83 to 0.91) for iDFS, 0.83 (95% CI, 0.79 to 0.88) for D-DFS, and 0.84 (95% CI, 0.79 to 0.89) for OS. In node-negative patients with sTILs ≥ 30%, 3-year iDFS was 92% (95% CI, 89% to 98%), D-DFS was 97% (95% CI, 95% to 99%), and OS was 99% (95% CI, 97% to 100%).
This pooled data analysis confirms the strong prognostic role of sTILs in early-stage TNBC and excellent survival of patients with high sTILs after adjuvant chemotherapy and supports the integration of sTILs in a clinicopathologic prognostic model for patients with TNBC. This model can be found at www.tilsinbreastcancer.org .
Objectives
Testicular diffuse large B‐cell lymphoma (T‐DLBCL) is a rare and aggressive extranodal lymphoma. We have previously shown that high content of tumor‐infiltrating lymphocytes (TILs) and ...PD‐1 expressing TILs associate with better survival in T‐DLBCL. In this study, we have further characterized distinct TIL subtypes and their proportions in association with patient demographics and survival.
Methods
We used multiplex immunohistochemistry to characterize TIL phenotypes, including cytotoxic T‐cells (CTLs; CD8+, OX40+, Granzyme B+, Ki‐67+, LAG‐3+, TIM‐3+, PD‐1+), CD4+ T‐cells (CD3+, CD4+, TIM‐3+, LAG‐3+), regulatory T‐cells (Tregs; CD3+, CD4+, FoxP3+), and T helper 1 cells (Th1; CD3+, CD4+, T‐bet+) in 79 T‐DLBCLs, and correlated the findings with patient demographics and outcome.
Results
We observed a substantial variation in TIL phenotypes between the patients. The most prominent CD8+ TILs were Ki‐67+ and TIM‐3+ CTLs, whereas the most prominent CD4+ TILs were FoxP3+ Tregs. Despite the overall favorable prognostic impact of high TIL content, we found a subpopulation of T‐bet+FoxP3+ Tregs that had a significant adverse impact on survival. Lower content of CTLs with activated or exhausted phenotypes correlated with aggressive clinical features.
Conclusions
Our results demonstrate significant variation in TIL phenotypes and emphasize the adverse prognostic impact of Tregs in T‐DLBCL.
Abstract
Background
Physicians’ decision-making for seriously ill patients with advanced dementia is of high importance, especially as the prevalence of dementia is rising rapidly, and includes many ...challenging ethical, medical and juridical aspects. We assessed the change in this decision-making over 16 years (from 1999 to 2015) and several background factors influencing physicians’ decision.
Methods
A postal survey including a hypothetical patient-scenario representing a patient with an advanced dementia and a life-threatening gastrointestinal bleeding was sent to 1182 and 1258 Finnish physicians in 1999 and 2015, respectively. The target groups were general practitioners (GPs), surgeons, internists and oncologists. The respondents were asked to choose between several life-prolonging and palliative care approaches. The influence of physicians’ background factors and attitudes on their decision were assessed.
Results
The response rate was 56%. A palliative care approach was chosen by 57 and 50% of the physicians in 1999 and 2015, respectively (
p
= 0.01). This change was statistically significant among GPs (50 vs 40%,
p
= 0.018) and oncologists (77 vs 56%,
p
= 0.011). GPs chose a palliative care approach less often than other responders in both years (50 vs. 63% in 1999 and 40 vs. 56% in 2015,
p
< 0.001). In logistic regression analysis, responding in 2015 and being a GP remained explanatory factors for a lower tendency to choose palliative care. The impact of family’s benefit on the decision-making decreased, whereas the influence of the patient’s benefit and ethical values as well as the patient’s or physician’s legal protection increased from 1999 to 2015.
Conclusions
Physicians chose a palliative care approach for a patient with advanced dementia and life-threatening bleeding less often in 2015 than in 1999. Specialty, attitudes and other background factors influenced significantly physician decision-making. Education on the identification and palliative care of the patients with late-stage dementia are needed to make these decisions more consistent.
Expression of the ectonucleotidase CD73 by tumor cells, stromal cells, and immune cells is associated in cancer with immune suppression. In this study, we investigated the role of CD73 on the ...activity of the anti-HER2/ErbB2 monoclonal antibody (mAb) trastuzumab. In a prospective, randomized phase III clinical trial evaluating the activity of trastuzumab, high levels of CD73 gene expression were associated significantly with poor clinical outcome. In contrast, high levels of PD-1 and PD-L1 were associated with improved clinical outcome. In immunocompetent mouse models of HER2/ErbB2-driven breast cancer, CD73 expression by tumor cells and host cells significantly suppressed immune-mediated responses mediated by anti-ErbB2 mAb. Furthermore, anti-CD73 mAb therapy enhanced the activity of anti-ErbB2 mAb to treat engrafted or spontaneous tumors as well as lung metastases. Gene ontology enrichment analysis from gene-expression data revealed a positive association of CD73 expression with extracellular matrix organization, TGFβ genes, epithelial-to-mesenchymal transition (EMT) transcription factors and hypoxia-inducible-factor (HIF)-1 gene signature. Human mammary cells treated with TGFβ or undergoing EMT upregulated CD73 cell-surface expression, confirming roles for these pathways. In conclusion, our findings establish CD73 in mediating resistance to trastuzumab and provide new insights into how CD73 is regulated in breast cancer.
.
Appropriate decision-making in end-of-life (EOL) care is essential for both junior and senior physicians. The aim of this study was to compare the decision-making and attitudes of medical students ...with those of experienced general practitioners (GP) regarding EOL-care.
A questionnaire presenting three cancer patient scenarios concerning decisions and ethical aspects of EOL-care was offered to 500 Finnish GPs and 639 graduating medical students in 2015-2016.
Responses were received from 222 (47%) GPs and 402 (63%) students. The GPs withdrew antibiotics (p<0.001) and nasogastric tubes (p=0.007) and withheld resuscitation (p<0.001), blood transfusions (p=0.002) and pleural drainage (p<0.001) more often than did the students. The students considered euthanasia and assisted suicide less reprehensible (p<0.001 in both) than did the GPs.
Medical students were more unwilling to withhold and withdraw therapies in EOL-care than were the GPs, but the students considered euthanasia less reprehensible. Medical education should include aspects of decision-making in EOL-care.
The ethics of hastened death are complex. Studies on physicians' opinions about assisted dying (euthanasia or assisted suicide) exist, but changes in physicians' attitudes towards hastened death in ...clinical decision-making and the background factors explaining this remain unclear. The aim of this study was to explore the changes in these attitudes among Finnish physicians.
A questionnaire including hypothetical patient scenarios was sent to 1182 and 1258 Finnish physicians in 1999 and 2015, respectively. Two scenarios of patients with advanced cancer were presented: one requesting an increase in his morphine dose to a potentially lethal level and another suffering a cardiac arrest. Physicians' attitudes towards assisted death, life values and other background factors were queried as well. The response rate was 56%.
The morphine dose was increased by 25% and 34% of the physicians in 1999 and 2015, respectively (p < 0.001). Oncologists approved the increase most infrequently without a significant change between the study years (15% vs. 17%, p = 0.689). Oncological specialty, faith in God, female gender and younger age were independent factors associated with the reluctance to increase the morphine dose. Euthanasia, but not assisted suicide, was considered less reprehensible in 2015 (p = 0.008). In both years, most physicians (84%) withheld cardiopulmonary resuscitation.
Finnish physicians accepted the risk of hastening death more often in 2015 than in 1999. The physicians' specialty and many other background factors influenced this acceptance. They also regarded euthanasia as less reprehensible now than they did 16 years ago.
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