| 1. |
- Larsson, Peter, et al.
(författare)
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Optimization of cell viability assays to improve replicability and reproducibility of cancer drug sensitivity screens.
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Cancer drug development has been riddled with high attrition rates, in part, due to poor reproducibility of preclinical models for drug discovery. Poor experimental design and lack of scientific transparency may cause experimental biases that in turn affect data quality, robustness and reproducibility. Here, we pinpoint sources of experimental variability in conventional 2D cell-based cancer drug screens to determine the effect of confounders on cell viability for MCF7 and HCC38 breast cancer cell lines treated with platinum agents (cisplatin and carboplatin) and a proteasome inhibitor (bortezomib). Variance component analysis demonstrated that variations in cell viability were primarily associated with the choice of pharmaceutical drug and cell line, and less likely to be due to the type of growth medium or assay incubation time. Furthermore, careful consideration should be given to different methods of storing diluted pharmaceutical drugs and use of DMSO controls due to the potential risk of evaporation and the subsequent effect on dose-response curves. Optimization of experimental parameters not only improved data quality substantially but also resulted in reproducible results for bortezomib- and cisplatin-treated HCC38, MCF7, MCF-10A, and MDA-MB-436 cells. Taken together, these findings indicate that replicability (the same analyst re-performs the same experiment multiple times) and reproducibility (different analysts perform the same experiment using different experimental conditions) for cell-based drug screens can be improved by identifying potential confounders and subsequent optimization of experimental parameters for each cell line.
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| 2. |
- Larsson, Peter, et al.
(författare)
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Pan-cancer analysis of genomic and transcriptomic data reveals the prognostic relevance of human proteasome genes in different cancer types.
- 2022
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Ingår i: BMC cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 22
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Tidskriftsartikel (refereegranskat)abstract
- The human proteasome gene family (PSM) consists of 49 genes that play a crucial role in cancer proteostasis. However, little is known about the effect of PSM gene expression and genetic alterations on clinical outcome in different cancer forms.Here, we performed a comprehensive pan-cancer analysis of genetic alterations in PSM genes and the subsequent prognostic value of PSM expression using data from The Cancer Genome Atlas (TCGA) containing over 10,000 samples representing up to 33 different cancer types. External validation was performed using a breast cancer cohort and KM plotter with four cancer types.The PSM genetic alteration frequency was high in certain cancer types (e.g. 67%; esophageal adenocarcinoma), with DNA amplification being most common. Compared with normal tissue, most PSM genes were predominantly overexpressed in cancer. Survival analysis also established a relationship with PSM gene expression and adverse clinical outcome, where PSMA1 and PSMD11 expression were linked to more unfavorable prognosis in≥30% of cancer types for both overall survival (OS) and relapse-free interval (PFI). Interestingly, PSMB5 gene expression was associated with OS (36%) and PFI (27%), and OS for PSMD2 (42%), especially when overexpressed.These findings indicate that several PSM genes may potentially be prognostic biomarkers and novel therapeutic targets for different cancer forms.
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| 3. |
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| 4. |
- Biermann, Jana, et al.
(författare)
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A 17-marker panel for global genomic instability in breast cancer.
- 2020
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Ingår i: Genomics. - : Elsevier BV. - 0888-7543 .- 1089-8646. ; 112:2, s. 1151-1161
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Tidskriftsartikel (refereegranskat)abstract
- Genomic instability is a hallmark of cancer that plays a pivotal role in breast cancer development and evolution. A number of existing prognostic gene expression signatures for breast cancer are based on proliferation-related genes. Here, we identified a 17-marker panel associated with genome stability. A total of 136 primary breast carcinomas were stratified by genome stability. Matched gene expression profiles showed an innate segregation based on genome stability. We identified a 17-marker panel stratifying the training and validation cohorts into high- and low-risk patients. The 17 genes associated with genomic instability strongly impacted clinical outcome in breast cancer. Pathway analyses determined chromosome organisation, cell cycle regulation, and RNA processing as the underlying biological processes, thereby offering options for drug development and treatment tailoring. Our work supports the applicability of the 17-marker panel to improve clinical outcome prediction for breast cancer patients based on a signature accounting for genomic instability.
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| 5. |
- Chin, Kian, et al.
(författare)
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Tumor-infiltrating lymphocytes as a predictor of axillary and primary tumor pathological response after neoadjuvant chemotherapy in patients with breast cancer: a retrospective cohort study
- 2024
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Ingår i: Breast Cancer Research and Treatment. - : SPRINGER. - 0167-6806 .- 1573-7217.
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Tumor-infiltrating lymphocytes (TILs) can predict complete pathological response (pCR) of tumor in the breast but not so well-defined in the axilla after neoadjuvant chemotherapy. Since axillary surgery is being increasingly de-escalated after NACT, we aimed to investigate the relationship between TILs and pCR in the axilla and breast, as well as survival amongst NACT patients.Methods Clinicopathological data on patients who underwent NACT between 2013 and 2020 were retrospectively examined. Specifically, pre-TILs (before NACT), post-TILs (after NACT) and Delta TIL (changes in TILs) were assessed. Primary endpoint was pCR and secondary endpoints were breast cancer-free interval (BCFI) and overall survival (OS).Results Two hundred and twenty patients with nodal metastases were included. Overall axillary and breast pCR rates were 42.7% (94/220) and 39.1% (86/220), respectively, whereas the combined pCR rate was 32.7% (72/220). High pre-TILs (OR 2.03, 95% CI 1.02-4.05; p = 0.04) predicted axillary pCR whereas, high post-TILs (OR 0.33, 95% CI 0.14-0.76; p = 0.009) and increased Delta TILs (OR 0.25, 95% CI 0.08-0.79; p = 0.02) predicted non-axillary pCR. TILs were not a significant predictor for BCFI and OS.Conclusions This study supports the potential use of pre-TILs to select initially node-positive patients for axillary surgical de-escalation after NACT.
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| 6. |
- Janeva, Slavica, et al.
(författare)
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Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) - Case Report
- 2020
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Ingår i: Annals of Clinical and Medical Case Reports. - 2639-8109. ; 3:3, s. 1-6
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Forskningsöversikt (refereegranskat)abstract
- Demand for aesthetic breast surgery is increasing worldwide, both for cosmetic reasons and postop- erative breast reconstruction for breast cancer patients. Although the number of women with breast prostheses is steadily increasing, incidence rates for breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) are low, with an estimated incidence of 0.1-0.3 per 100,000 women with prostheses annually. Common clinical presentation of BIA-ALCL may include breast asymmetry, palpable mass, late seroma, local pain, and firmness. However, cytological examination of seroma fluid may reveal the condition, which should be followed by implant removal and total capsulectomy. In the majority of cases, capsulectomy is curative. Preoperative information about the risk of developing BIA-ALCL is recommended for patients with breast implants. Here, we report two BIA-ALCL cases, where one case was diagnosed after breast cosmetic surgery and the other patient had undergone breast reconstructive surgery with implants after breast cancer treatment.
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| 7. |
- Janeva, Slavica, et al.
(författare)
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Clinical evaluation of molecular surrogate subtypes in patients with ipsilateral multifocal primary breast cancer
- 2023
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Ingår i: Breast Cancer Research. - 1465-5411. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundWhen ipsilateral multifocal primary breast cancer (IMBC) is detected, standard routine is to evaluate the largest tumor with immunohistochemistry (IHC). As all foci are not routinely characterized, many patients may not receive optimal adjuvant treatment. Here, we assess the clinical relevance of examining at least two foci present in patients with IMBC.MethodsPatients diagnosed and treated for IMBC at Sahlgrenska University Hospital (Gothenburg, Sweden) between 2012 and 2017 were screened. In total, 180 patients with >= 2 invasive foci (183 specimens) were assessed with IHC and included in this study. Expression of the estrogen (ER) and progesterone (PR) receptors, Ki67, HER2, and tumor grade were used to determine the molecular surrogate subtypes and discordance among the foci was recorded. An additional multidisciplinary team board was then held to re-assess whether treatment recommendations changed due to discordances in molecular surrogate subtype between the different foci.ResultsDiscordance in ER, PR, HER2, and Ki67 was found in 2.7%, 19.1%, 7.7%, and 16.9% of invasive foci, respectively. Discordance in the molecular surrogate subtypes was found in 48 of 180 (26.7%) patients, which resulted in therapy changes for 11 patients (6.1%). These patients received additional endocrine therapy (n = 2), chemotherapy (n = 3), and combined chemotherapy and trastuzumab (n = 6).ConclusionTaken together, when assessing at least two tumor foci with IHC, regardless of shared morphology or tumor grade between the different foci, 6.1% of patients with IMBC were recommended additional adjuvant treatment. A pathologic assessment using IHC of all foci is therefore recommended to assist in individualized treatment decision making.
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| 8. |
- Nyqvist, Jenny, et al.
(författare)
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Genetic alterations associated with multiple primary malignancies.
- 2021
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Ingår i: Cancer medicine. - : Wiley. - 2045-7634. ; 10:13, s. 4465-4477
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer (BC) patients are frequently at risk of developing other malignancies following treatment. Although studies have been conducted to elucidate the etiology of multiple primary malignancies (MPM) after a BC diagnosis, few studies have investigated other previously diagnosed primary malignancies (OPPM) before BC. Here, genome-wide profiling was used to identify potential driver DNA copy number alterations and somatic mutations that promote the development of MPMs. To compare the genomic profiles for two primary tumors (BC and OPPM) from the same patient, tumor pairs from 26 young women (≤50years) diagnosed with one or more primary malignancies before breast cancer were analyzed. Malignant melanoma was the most frequent OPPM, followed by gynecologic- and hematologic malignancies. However, significantly more genetic alterations were detected in BC compared to the OPPM. BC also showed more genetic similarity as a group than the tumor pairs. Clonality testing showed that genetic alterations on chromosomes 1, 3, 16, and 19 were concordant in both tumors in 13 patients. TP53 mutations were also found to be prevalent in BC, MM, and HM. Although all samples were classified as genetically unstable, chromothripsis-like patterns were primarily observed in BC. Taken together, few recurrent genetic alterations were identified in both tumor pairs that can explain the development of MPMs in the same patient. However, larger studies are warranted to further investigate key driver mutations associated with MPMs.
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| 9. |
- Nyqvist, Jenny, et al.
(författare)
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Previously diagnosed multiple primary malignancies in patients with breast carcinoma in Western Sweden between 2007 and 2018.
- 2020
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Ingår i: Breast cancer research and treatment. - : Springer Science and Business Media LLC. - 1573-7217 .- 0167-6806. ; 184, s. 221-228
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Tidskriftsartikel (refereegranskat)abstract
- Multiple primary malignancies (MPMs) caused by breast cancer treatment are well described, but only few studies to date describe which other previous primary malignancies (OPPMs) occur before breast cancer. The purpose of the present study was to evaluate the prevalence of OPPMs in patients with breast cancer between 2007 and 2018 in Western Sweden.Patient selection was performed using both pathology reports at Sahlgrenska University Hospital (Sweden) and the Swedish Cancer Registry. All newly diagnosed breast cancer patients were screened for presence of OPPM.In total, 8031 breast cancer patients were diagnosed at Sahlgrenska University Hospital between 2007 and 2018. The prevalence of breast cancer patients with OPPMs (n=414) increased from on average 2.6% to 8.2% during this 12-year period and ranged from 17 to 59 patients annually.The most striking increase in prevalence was found among the gynecological tumors (endometrium and ovarian adenocarcinomas), malignant melanomas and gastrointestinal malignancies.These findings were validated using data of the Swedish Cancer Registry.The overall survival rates for cancer patients have improved tremendously during the past 40years, in part due to individually tailored therapies and screening programs. Our study revealed an increasing trend of OPPMs in breast cancer patients.
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| 10. |
- Pistioli, Lida, et al.
(författare)
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The Effect of Melatonin Intake on Survival of Patients with Breast Cancer-A Population-Based Registry Study.
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:23
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Tidskriftsartikel (refereegranskat)abstract
- Previous research has demonstrated the antitumoral effects of melatonin on breast cancer in both in vitro and in vivo studies. The aim of the present study was to investigate whether melatonin has a favorable effect on the survival of patients diagnosed with early breast cancer. This retrospective registry-based study included all patients diagnosed with breast cancer in Sweden between 2005 and 2015. Data were linked to the Swedish Prescribed Drug Registry and the Swedish Cause of Death Registry. A multivariate Cox regression model, including patient age, tumor size, tumor grade, ER status, HER2 status, nodal status and defined daily doses (DDDs) of melatonin, was used to analyze breast-cancer-specific survival as well as overall survival. Of the 37,075 included patients, 926 (2.5%) were prescribed melatonin, with a median DDD of 30. Melatonin was found to have a protective effect on breast-cancer-specific survival (BCSS) in the univariate analysis (HR: 0.736, 95% CI: 0.548-0.989, p = 0.042), but when adjusting for known prognostic factors in the multivariate analysis, this beneficial effect disappeared (HR: 1.037, 95% CI: 0.648-1.659, p = 0.879). Melatonin was not proven to have a favorable effect on the survival of patients diagnosed with early breast cancer in this retrospective registry study.
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