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 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.

Deep learning identifies morphological features in breast cancer predictive of cancer ERBB2 status and trastuzumab treatment efficacy.

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.

Breast cancer outcome prediction with tumour tissue images and machine learning.

Purpose: Recent advances in machine learning have enabled better understanding of large and complex visual data. Here, we aim to investigate patient outcome prediction with a machine learning method using only an image of tumour sample as an input.

Methods: Utilising tissue microarray (TMA) samples obtained from the primary tumour of patients (N = 1299) within a nationwide breast cancer series with long-term-follow-up, we train and validate a machine learning method for patient outcome prediction.

The presence of sinusoidal CD163(+) macrophages in lymph nodes is associated with favorable nodal status in patients with breast cancer.

As macrophages are some of the first cells to encounter metastatic tumor cells in sentinel lymph nodes (SLN) and natural killer (NK) cells are critical to the cytotoxicity of abnormal cells, we sought to determine if these cell populations were altered in the presence of nodal metastasis. We used immunohistochemistry to assess the SLN of 47 patients with breast cancer (36 with nodal metastasis and 11 without nodal metastasis) and 10 control lymph nodes. We assessed metastatic areas and nonmetastatic areas separately for CD163, a marker of macrophages, and ANK-1, a marker for precursors of activated NK cells.

Metastasis to sentinel lymph nodes in breast cancer is associated with maturation arrest of dendritic cells and poor co-localization of dendritic cells and CD8+ T cells.

The regional immune systems of patients with breast cancer are immunosuppressed. Dendritic cells are professional antigen-presenting cells and present cancer-associated antigens to the adaptive immune system in sentinel lymph nodes. Dendritic cells may promote, or inhibit, an adaptive immune response to specific antigens.

Comparison of in vitro breast cancer visibility in analyser-based computed tomography with histopathology, mammography, computed tomography and magnetic resonance imaging.

High-resolution analyser-based X-ray imaging computed tomography (HR ABI-CT) findings on in vitro human breast cancer are compared with histopathology, mammography, computed tomography (CT) and magnetic resonance imaging. The HR ABI-CT images provided significantly better low-contrast visibility compared with the standard radiological images. Fine cancer structures indistinguishable and superimposed in mammograms were seen, and could be matched with the histopathological results.

Germ-line variation at a functional p53 binding site increases susceptibility to breast cancer development.

Unlabelled: Multiple lines of evidence suggest regulatory variation to play an important role in phenotypic evolution and disease development, but few regulatory polymorphisms have been characterized genetically and molecularly. Recent technological advances have made it possible to identify bona fide regulatory sequences experimentally on a genome-wide scale and opened the window for the biological interrogation of germ-line polymorphisms within these sequences. In this study, through a forward genetic analysis of bona fide p53 binding sites identified by a genome-wide chromatin immunoprecipitation and sequence analysis, we discovered a SNP (rs1860746) within the motif sequence of a p53 binding site where p53 can function as a regulator of transcription.

Metastatic outgrowth encompasses COL-I, FN1, and POSTN up-regulation and assembly to fibrillar networks regulating cell adhesion, migration, and growth.

Although the outgrowth of micrometastases into macrometastases is the rate-limiting step in metastatic progression and the main determinant of cancer fatality, the molecular mechanisms involved have been little studied. Here, we compared the gene expression profiles of melanoma lymph node micro- and macrometastases and unexpectedly found no common up-regulation of any single growth factor/cytokine, except for the cytokine-like SPP1. Importantly, metastatic outgrowth was found to be consistently associated with activation of the transforming growth factor-beta signaling pathway (confirmed by phospho-SMAD2 staining) and concerted up-regulation of POSTN, FN1, COL-I, and VCAN genes-all inducible by transforming growth factor-beta.

Concordance between HER-2 and steroid hormone receptor expression between primary breast cancer, sentinel node metastases, and isolated tumor cells.

Our aim was to compare the HER-2 and hormone receptor status between primary tumor (PT) and sentinel node (SN) metastases in breast cancer. We analyzed 65 PTs with 42 macrometastases, 18 micrometastases, and 5 ITCs for the HER-2 amplification status and for the hormone receptor status. In HER-2-positive PTs, 26 of 29 metastases were HER-2-positive, including all six analyzed micrometastases and ITCs.

Simultaneous Foxp3 and IDO expression is associated with sentinel lymph node metastases in breast cancer.

Background: There is evidence that the immune systems of patients with breast cancer are dysfunctional. Regulatory T cells (Tregs), and IDO, an immunosuppressive enzyme, are associated with more advanced disease in some cancers and may promote immunologic tolerance to tumors. Our aim was to assess whether expression of Foxp3, a marker of Tregs, and IDO were linked with nodal metastasis in breast cancer patients.

The outcome of sentinel node biopsy in breast cancer patients with preoperative surgical biopsy.

Background: The aim of the study was to evaluate the outcome of sentinel node biopsy (SNB), especially the medium term axillary recurrence rate after negative SNB in patients with preoperative surgical biopsy (SB).

Patients And Methods: The study included 1,641 patients with a histological stage T1 tumours and SNB. In 77 patients, the diagnosis was obtained with SB, while 1,564 patients had underwent needle biopsy (NB) only.

Margin status after breast-conserving treatment of breast cancer: how much free margin is enough?

In breast conserving surgery the margins of the specimen have to be tumor free. There is no universal agreement on the width of the tumor free margin. The width has some impact on recurrence rate, and at least 5 mm seems to be preferred and this is especially important in extensive intraductal component.

Toward high-contrast breast CT at low radiation dose.

This study was approved by the local research ethics committee, and patient informed consent was obtained. The purpose of this study was to demonstrate that high-spatial-resolution low-dose analyzer-based x-ray computed tomography (CT) can substantially improve the radiographic contrast of breast tissue in vitro when compared with that attained by using diagnostic mammography and CT. An excised human breast tumor was examined by using analyzer-based x-ray imaging with synchrotron radiation.

Unsuccessful preoperative biopsies, fine needle aspiration cytology or core needle biopsy, lead to increased costs in the diagnostic workup in breast cancer.

Correct preoperative diagnosis of a breast lesion is essential for optimal treatment planning. Our aim was to compare feasibility of fine needle aspiration cytology (FNAC) and core needle biopsy (CNB) in diagnosis of breast lesions. The special aim was to evaluate the extra costs and delay in surgical treatment due to unsuccessful preoperative biopsies.

NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer.

NQO1 guards against oxidative stress and carcinogenesis and stabilizes p53. We find that a homozygous common missense variant (NQO1(*)2, rs1800566(T), NM_000903.2:c.

Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics.

A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies.

Complications of skin-sparing mastectomy followed by immediate breast reconstruction: a prospective randomized study comparing high-frequency radiosurgery with conventional diathermy.

Skin-sparing mastectomy (SSM) followed by immediate breast reconstruction delivers superior cosmetic and functional outcome. However, SSM is vulnerable to complications of the native skin envelope. This study aims to compare the effects of radiofrequency coagulation and conventional diathermy on complications of SSM.

VEGF-D in association with VEGFR-3 promotes nodal metastasis in human invasive lobular breast cancer.

We assessed the expression of vascular endothelial growth factors (VEGF-C and VEGF-D) in breast cancer cells and the density of lymph vessels and VEGF receptor-3 (VEGFR-3)-positive vessels in and around the tumor in invasive lobular breast cancer. We found significant correlation between peritumoral lymph vessel density and presence of lymph node metastases (P=.001) and the number of metastatic lymph nodes (P<.

Predicting invasion in patients with DCIS in the preoperative percutaneous biopsy.

When ductal carcinoma in situ (DCIS) is suspected in mammography, core needle biopsy or vacuum assisted biopsy is recommended. However, invasion remains undetected with percutaneous biopsy techniques in 10-20% of the patients. Our aim was to evaluate the prevalence of and predictive factors for invasion in the surgical specimen in patients with DCIS in the preoperative biopsy.

High-resolution CT by diffraction-enhanced x-ray imaging: mapping of breast tissue samples and comparison with their histo-pathology.

The aim of this study was to introduce high-resolution computed tomography (CT) of breast tumours using the diffraction-enhanced x-ray imaging (DEI) technique and to compare results with radiological and histo-pathological examinations. X-ray CT images of tumour-bearing breast tissue samples were acquired by monochromatic synchrotron radiation (SR). Due to the narrow beam and a large sample-to-detector distance scattering is rejected in the absorption contrast images (SR-CT).

Systemic efficacy of oncolytic adenoviruses in imagable orthotopic models of hormone refractory metastatic breast cancer.

Conditionally replicating oncolytic adenoviruses represent a promising developmental strategy for the treatment of cancer refractory to current treatments, such as hormone refractory metastatic breast cancer. In clinical cancer trials, adenoviral agents have been well tolerated, but gene transfer has been insufficient for clinical benefit. One of the main reasons may be the deficiency of the primary adenovirus receptor, and therefore viral capsid modifications have been employed.

Ki-67, p53, ER receptors, ploidy and S phase as long-term prognostic factors in T1 node-negative breast cancer.

Background: The aim of the present study was to evaluate a series of biomarkers with regard to long-term prognostic value in patients with T1 (< or =2 cm) node-negative breast cancer.

Method: The prognostic value of Ki-67, p53, oestrogen receptor (ER) immunohistochemical labelling, flow-cytometric S phase fraction and ploidy was evaluated in 212 patients with pT1N0M0 breast cancer. The median follow-up time was 15.

Ultrasonography of the axilla in the follow-up of breast cancer patients who have a negative sentinel node biopsy and who avoid axillary clearance.

The clinical value of ultrasonography of the axilla in detection of breast cancer recurrence is not known among patients who have a negative sentinel node biopsy and avoid axillary clearance. We studied a cohort of 205 such patients using ultrasonography one and three years after breast surgery. A recurrent tumour was found in the axilla in only two (0.

The clinical value of parasternal sentinel node biopsy in breast cancer.

Background: Lymphoscintigraphy (LS) with sentinel node (SN) biopsy is proposed to provide a feasible method to complete lymphatic staging in breast cancer. The aim of this study was to evaluate the clinical value of parasternal SN biopsy.

Methods: A total of 984 consecutive patients with clinical stage T1/2N0 invasive breast cancer who underwent LS and SN biopsy were included in the study.

BARD1 variants Cys557Ser and Val507Met in breast cancer predisposition.

BARD1 (BRCA1-associated RING-domain 1) is a tumor suppressor whose protein product interacts with BRCA1, and in which rare somatic and germline mutations have been reported in breast, uterine, and endometrial cancers. We aimed to evaluate whether there are BARD1 genetic variants that contribute to breast cancer risk by screening the gene for germline alterations in 45 Finnish familial breast cancer patients and in seven patients with both breast and ovarian cancer. Two of the missense alterations identified (Cys557Ser and Val507Met) were recently suggested to associate with an increased breast cancer risk.