
Ingrid HedenfalkLund University | LU · Division of Oncology, Department of Clinical Sciences
Ingrid Hedenfalk
Professor
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169
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Introduction
Publications
Publications (169)
Breast cancer is the most common cancer form in women and it has been extensively studied on the molecular level. Male breast cancer (MBC), on the other hand, is rare and has not been thoroughly investigated in terms of transcriptional profiles or genomic aberrations. Most of our understanding of MBC has therefore been extrapolated from knowledge o...
Predicting any future metastatic site of early-stage breast cancer is important as it significantly influences the prognosis of advanced disease. This study aimed at investigating the potential of claudin-2, over-expressed in breast cancer liver metastases, as a biomarker for predicting liver metastatic propensity in primary breast cancer.
Claudin-...
The rapidly growing collection of diverse genome-scale data from multiple tumor types sheds light on various aspects of the underlying tumor biology. With the objective to identify genes of importance for breast tumorigenesis in men and to enable comparisons with genes important for breast cancer development in women, we applied the computational f...
Tertiary lymphoid structures (TLS) in the tumor microenvironment are prognostically beneficial in many solid cancer types. Reports on TLS in high-grade serous tubo-ovarian carcinoma (HGSC) are few, and the prognostic impact is unclear. We investigated mature TLS (mTLS), immature TLS (iTLS) and lymphoid aggregates (LA) in primary adnexal tumors (PTs...
Although metabolic reprogramming within tumor cells and tumor microenvironment (TME) is well described in breast cancer, little is known about how the interplay of immune state and cancer metabolism evolves during treatment. Here, we characterize the immunometabolic profiles of tumor tissue samples longitudinally collected from individuals with bre...
Treatment with the anti‐angiogenic drug bevacizumab in addition to chemotherapy has shown efficacy for breast cancer in some clinical trials, but better biomarkers are needed to optimally select patients for treatment. Here, we present an omics approach where DNA methylation profiles are integrated with gene expression and results from proteomic da...
Immune checkpoint blockade (ICB) has improved outcome for patients with metastatic melanoma but not all benefit from treatment. Several immune- and tumor intrinsic features are associated with clinical response at baseline. However, we need to further understand the molecular changes occurring during development of ICB resistance. Here, we collect...
Immune checkpoint blockade (ICB) has improved outcome for metastatic melanoma patients but not all benefit from treatment. Several immune- and tumor intrinsic features are associated with clinical response at baseline. However, we need to further understand the molecular changes occurring during development of ICB resistance. Here, we collected bio...
CD169⁺ resident macrophages in lymph nodes of breast cancer patients are for unknown reasons associated with a beneficial prognosis. This contrasts CD169⁺ macrophages present in primary breast tumors (CD169⁺ TAMs), that correlate with a worse prognosis. We recently showed that these CD169⁺ TAMs were associated with tertiary lymphoid structures (TLS...
Simple Summary
We here show that CD169⁺ TAMs in primary breast tumors are associated with tertiary lymphoid-like structures (TLLSs), Treg and Breg signatures, and a worse prognosis for the patient. In contrast, CD169⁺ TAMs and TLLSs present in lymph node metastases were associated with better prognosis. We propose that the negative prognostic value...
Cisplatin, a platinum-based chemotherapeutic agent, is widely used as a front-line treatment for several malignancies. However, treatment outcomes vary widely due to intrinsic and acquired resistance. In this study, cisplatin-perturbated gene expression and pathway enrichment were used to define a gene signature, which was further utilized to devel...
In early breast cancer, a preoperative core-needle biopsy (CNB) is vital to confirm the malignancy of suspected lesions and for assessing the expression of treatment predictive and prognostic biomarkers in the tumor to choose the optimal treatments, emphasizing the importance of obtaining reliable results when biomarker status is assessed on a CNB...
Multigene assays for molecular subtypes and biomarkers can aid management of early invasive breast cancer. Using RNA-sequencing we aimed to develop single-sample predictor (SSP) models for clinical markers, subtypes, and risk of recurrence (ROR). A cohort of 7743 patients was divided into training and test set. We trained SSPs for subtypes and ROR...
Here we present an integrated omics approach for DNA methylation profiling using copy number alteration, gene expression and proteomic data to predict response to therapy and to pinpoint response-related epigenetic events. Fresh frozen tumor biopsies taken before, during and after treatment from patients receiving neoadjuvant chemotherapy with or w...
Background: The conventional biomarkers estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), Ki67, and Nottingham histologic grade (NHG) are used to classify breast cancer into its molecular subtypes, determine prognosis, and guide treatment. A preoperative core needle biopsy (CNB) is used to confirm...
Background: Multigene expression assays for molecular subtypes and biomarkers can aid clinical management of early breast cancer. Based on RNA-sequencing we aimed to develop robust single-sample predictor (SSP) models for conventional clinical markers as well as molecular intrinsic subtype and risk of recurrence (ROR) that provide clinically releva...
Male breast cancer (BCa) is a rare disease accounting for less than 1% of all breast cancers and 1% of all cancers in males. The clinical management is largely extrapolated from female BCa. Several multigene assays are increasingly used to guide clinical treatment decisions in female BCa, however, there are limited data on the utility of these test...
Overexpression of the receptor tyrosine kinase MET has been linked to poor survival in several cancer types, and MET has been suggested to interact with stem cell networks. In vitro studies have further suggested a possible benefit of a combined treatment using PARP and MET inhibitors. We used a tissue microarray (TMA) with 130 samples of advanced-...
Background
Emerging data support the use of thymidine kinase 1 (TK1) activity as a prognostic marker and for monitoring of response in breast cancer (BC). The long-term prognostic value of TK1 kinetics during neoadjuvant chemotherapy is unclear, which this study aimed to elucidate.
Methods
Material from patients enrolled to the single-arm prospect...
Splicing is a central RNA-based process commonly altered in human cancers; however, how spliceosomal components are co-opted during tumorigenesis remains poorly defined. Here we unravel the core splice factor SF3A3 at the nexus of a translation-based program that rewires splicing during malignant transformation. Upon MYC hyperactivation, SF3A3 leve...
Background
Resistance to endocrine treatment in metastatic breast cancer is a major clinical challenge. Clinical tools to predict both drug resistance and possible treatment combination approaches to overcome it are lacking. This unmet need is mainly due to the heterogeneity underlying both the mechanisms involved in resistance development and brea...
Background
Patients diagnosed with metastatic breast cancer have poor outcome with a median survival of approximately 2 years. While novel therapeutic options are urgently needed, the great majority of breast cancer research has focused on the primary tumor and less is known about metastatic breast cancer and the prognostic impact of the metastatic...
PURPOSE
Antiangiogenic therapy using bevacizumab has proven effective for a number of cancers; however, in breast cancer (BC), there is an unmet need to identify patients who benefit from such treatment.
PATIENTS AND METHODS
In the NeoAva phase II clinical trial, patients (N = 132) with large (≥ 25 mm) human epidermal growth factor receptor 2 (HER...
Serous endometrial cancer (SEC) resembles high-grade serous ovarian cancer (HGSOC) genetically and clinically, with recurrent copy number alterations, TP53 mutations and a poor prognosis. Thus, SEC patients may benefit from targeted treatments used in HGSOC, e.g., PARP inhibitors. However, the preclinical and clinical knowledge about SEC is scarce,...
Objective
Survival in epithelial ovarian cancer (EOC) remains poor. Most patients are diagnosed in late stages. Early diagnosis increases the chance of survival. We used the proximity extension assay from Olink Proteomics to search for new protein biomarkers with the potential to improve the diagnostic performance of CA125 and HE4 in patients with...
Ovarian clear cell carcinomas (OCCC) constitute a rare subtype of epithelial ovarian cancer, lacking efficient treatment options. Based on previous studies, we assessed the anti-proliferative effect of simvastatin, a Rho GTPase interfering drug, in three OCCC cell lines: JHOC-5, OVMANA and TOV-21G, and one high-grade serous ovarian cancer (HGSOC) c...
Objective:
Pre-clinical studies have identified marker- and tumor compartment-defined functionally distinct macrophage subsets. Our study analyzes marker-defined macrophage subsets in different tumor compartments of high-grade serous ovarian cancer (HGSC).
Methods:
A discovery cohort (N = 113) was subjected to immunohistochemistry (IHC) analyses...
The transcription factor SOX2 is a well-established and important stem cell marker. Its role in cancer biology remains unclear, but it has been proposed to also be a marker of cancer stem cells. We investigated the role of SOX2 protein expression in women with high-grade serous ovarian cancer (HGSOC) to determine its potential prognostic and treatm...
Background:
The aetiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study (GWAS) of MBC identified two predisposition loci for the disease, both of which were also associated with risk of FBC....
Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) has been proposed as a surrogate endpoint for the prediction of long-term survival in breast cancer (BC); however, an increased pCR rate has not clearly correlated with improved survival. We hypothesized that some transcriptomic and functional pathway features correlate with...
The response rate to checkpoint inhibitors for women with high-grade serous carcinoma of the ovary, fallopian tube, and peritoneum (HGSC) is modest, and development of predictive biomarkers is needed. The main focus has been on tumor cell PD-L1 expression, but its assessment alone is insufficient for patient selection in most malignancies. We mappe...
p>Introduction: Male breast cancer (BCa) is a rare disease accounting for less than 1% of all breast cancers (BC) and 1% of all cancers in males. The clinical management is largely extrapolated from female BCa. Few studies have examined the genomic landscape of male BCas, with six male BCas included in The Cancer Genome Atlas (TCGA). Familial studi...
High-grade serous ovarian cancer (HGSOC) is the predominant and most lethal histological type of epithelial ovarian cancer. During the last few years, several new treatment options with PARP inhibitors have emerged. The FDA has approved the PARP inhibitor olaparib (Lynparza™) as maintenance treatment after first-line platinum-containing chemotherap...
High-grade serous ovarian cancer (HGSOC) is the most common subtype of epithelial ovarian cancer and early detection is challenging. TP53 mutations are a hallmark of HGSOC and detection of these mutations in liquid-based Pap samples could provide a method for early diagnosis. Here we evaluate the use of IBSAFE, an ultra-sensitive droplet digital PC...
Background:
Primary brain tumors, in particular glioblastoma (GBM), remain among the most challenging cancers. Like most malignant tumors, GBM is characterized by hypoxic stress that triggers paracrine, adaptive responses, such as angiogenesis and macrophage recruitment, rescuing cancer cells from metabolic catastrophe and conventional oncological...
Introduction: Male breast cancer (MBC) is a rare disease accounting for less than 1% of all breast cancers (BC) and 1% of all cancers in males. The clinical management is largely extrapolated from female BC. Several multigene assays are increasingly used to guide clinical treatment decisions in female BC, however there is little data on the utility...
Claudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that the PDZ-binding motif of Claudin-2 is necessary for anchorage-independent growth of cancer cells and is required for liver metastasis. Several PDZ domain-containing proteins were identified that interact with the PDZ-binding...
Ghrelin and obestatin are two gastrointestinal peptides, derived from a common precursor. Expression of both peptides have been found in breast cancer tissue and ghrelin has been associated with breast cancer development. Ghrelin expression is associated with longer survival in women diagnosed with invasive and node negative breast cancer. The clin...
Gene expression (GE) signatures and Tumor Infiltrating Lymphocytes (TIL) enumeration are predictive for response to neoadjuvant chemotherapy in HR- and in HER2+ breast cancer, but data are conflicting in HR+/HER2- disease. This study aimed to explore their predictive value in this subset, measured both at baseline and after short exposure to chemot...
Introduction: Epithelial ovarian cancer is the seventh most common malignancy diagnosed in women, but the fifth most common cause of cancer-related deaths with a relative five-year survival less than 50%. High-grade serous ovarian cancer (HGSOC) is the predominant histological subtype. PARP inhibitors such Olaparib and Niraparib have been approved...
Background: Ovarian clear cell carcinomas (OCCC) constitute a rare subtype of epithelial ovarian cancer with distinct clinical features. Resistance to first-line platinum-based treatment is common. We recently reported deregulated Rho GTPase signaling in OCCC. Rho GTPases are small signaling G proteins, and a subfamily of the RAS superfamily. Rho G...
Introduction. Male breast cancer (male BC) is a rare disease for which disease management is extrapolated from females. IMBC, an international consortium, which previously reported on clinico-pathological aspects, now reports on molecular subgroups revealed by RNA sequencing and their relation to patient outcome.
Methods. Tumor samples from the ret...
Introduction: Preoperative chemotherapy in early breast cancer increases the rate of breast preservation and provides prognostic information. Treatment decisions in these cases rely on biomarker assessments and subtyping from tissue acquired through core needle biopsies. Tumor heterogeneity and representativity are pit-falls when limited tissue is...
Male breast cancer (MBC) is rare and poorly characterized. Like the female counterpart, most MBCs are hormonally driven, but relapse after hormonal treatment is also noted. The pan-hormonal action of steroid hormonal receptors, including estrogen receptor alpha (ERα), androgen receptor (AR), progesterone receptor (PR), and glucocorticoid receptor (...
Cytotoxic T cells infiltrating tumors are thought to utilize HIF transcription factors during adaptation to the hypoxic tumor microenvironment. Deletion analyses of the two key HIF isoforms found that HIF-1α, but not HIF-2α, was essential for the effector state in CD8⁺ T cells. Furthermore, loss of HIF-1α in CD8⁺ T cells reduced tumor infiltration...
Cytotoxic T cells infiltrating tumors are thought to utilize HIF transcription factors during adaptation to the hypoxic tumor microenvironment. Deletion analyses of the two key HIF isoforms found that HIF-1α, but not HIF-2α, was essential for the effector state in CD8+ T cells. Further, loss of HIF-1α in CD8+ T cells reduced tumor infiltration and...
Background:
Male breast cancer (BC) is rare, managed by extrapolation from female BC. The International Male BC Program aims to better characterize and manage this disease. We report the results of part 1, a retrospective-joint-analysis of cases diagnosed during a 20-year-period.
Methods:
Patients with follow-up and tumor samples, treated betwee...
Background
Metastases from primary breast cancers can involve single or multiple organs at metastatic disease diagnosis. Molecular risk factors for particular patterns of metastastic spread in a clinical population are limited.
Methods
A case-control design including 1357 primary breast cancers was used to study three distinct clinical patterns of...
Pathologic complete response (pCR) is a predictor for favorable outcome after neoadjuvant treatment in early breast cancer. Modulation of gene expression may also provide early readouts of biological activity and prognosis, offering the possibility for timely response-guided treatment adjustment. The role of early transcriptional changes in predict...
Objective
Ovarian clear cell carcinomas (OCCCs) constitute a rare ovarian cancer subtype with distinct clinical features, but may nonetheless be difficult to distinguish morphologically from other subtypes. There is limited knowledge of genetic events driving OCCC tumorigenesis beyond ARID1A, which is reportedly mutated in 30–50% of OCCCs. We aimed...
The tight junction protein claudin-4 has been reported to be overexpressed in advanced ovarian cancer. We investigated the prognostic significance of claudin-4 overexpression and whether claudin-4 expression could predict platinum response in primary ovarian carcinoma (OC). Claudin-4 expression was evaluated by immunohistochemistry in a tissue micr...