| 41. |
- Jönsson, Jenny-Maria, et al.
(författare)
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Molecular subtyping of serous ovarian tumors reveals multiple connections to intrinsic breast cancer subtypes.
- 2014
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:9
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Tidskriftsartikel (refereegranskat)abstract
- Transcriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities with the well-established intrinsic molecular subtypes of breast cancer.
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| 42. |
- Jönsson, Jenny-Maria, et al.
(författare)
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Sex Steroid Hormone Receptor Expression Affects Ovarian Cancer Survival.
- 2015
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Ingår i: Translational Oncology. - : Elsevier BV. - 1936-5233. ; 8:5, s. 424-433
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Tidskriftsartikel (refereegranskat)abstract
- Although most ovarian cancers express estrogen (ER), progesterone (PR), and androgen (AR) receptors, they are currently not applied in clinical decision making. We explored the prognostic impact of sex steroid hormone receptor protein and mRNA expression on survival in epithelial ovarian cancer.
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| 43. |
- Kaminska, Kamila, et al.
(författare)
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Distinct mechanisms of resistance to fulvestrant treatment dictate level of ER independence and selective response to CDK inhibitors in metastatic breast cancer
- 2021
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Ingår i: Breast cancer research : BCR. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 23:1, s. 26-26
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Tidskriftsartikel (refereegranskat)abstract
- 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 breast cancer itself.METHODS: To study the complexity of the mechanisms involved in the resistance to the selective estrogen receptor degrader (SERD) fulvestrant, we performed comprehensive biomarker analyses using several in vitro models that recapitulate the heterogeneity of developed resistance. We further corroborated our findings in tissue samples from patients treated with fulvestrant.RESULTS: We found that different in vitro models of fulvestrant resistance show variable stability in their phenotypes, which corresponded with distinct genomic alterations. Notably, the studied models presented adaptation at different cell cycle nodes to facilitate progression through the cell cycle and responded differently to CDK inhibitors. Cyclin E2 overexpression was identified as a biomarker of a persistent fulvestrant-resistant phenotype. Comparison of pre- and post-treatment paired tumor biopsies from patients treated with fulvestrant revealed an upregulation of cyclin E2 upon development of resistance. Moreover, overexpression of this cyclin was found to be a prognostic factor determining resistance to fulvestrant and shorter progression-free survival.CONCLUSIONS: These data highlight the complexity of estrogen receptor positive breast cancer and suggest that the development of diverse resistance mechanisms dictate levels of ER independence and potentially cross-resistance to CDK inhibitors.
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| 44. |
- Kauraniemi, P, et al.
(författare)
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MYB oncogene amplification in hereditary BRCA1 breast cancer
- 2000
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Ingår i: Cancer Research. - 1538-7445. ; 60:19, s. 5323-5328
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Tidskriftsartikel (refereegranskat)abstract
- Comparative genomic hybridization analysis has demonstrated that breast tumors from BRCA1 and BRCA2 germ-line mutation carriers contain a large number of chromosomal copy number gains and losses. A high regional copy number gain at 6q22-q24 was observed in one BRCA1 tumor, and fluorescence in situ hybridization analysis indicated a strong amplification of the MYB oncogene (15 copies of MYB compared with 1 copy of chromosome 6 centromere). Fluorescence in situ hybridization analysis revealed amplification of MYB in 5 (29%) of 17 BRCA1 breast tumors, whereas none of 8 BRCA2 tumors and 13 breast cancer cell lines, and only 2 of 100 sporadic breast tumors exhibited altered MYB copy numbers. Gene amplification resulted in mRNA overexpression as determined by Northern blot and cDNA microarray analysis, and protein overexpression by immunohistochemical staining. We conclude that MYB amplification is infrequent in sporadic breast cancer but common in breast tumors from BRCA1 mutation carriers, suggesting a role of this cell cycle regulator and transcription factor in the progression of some BRCA1 tumors. However, we cannot rule out the significance of other genes in the 6q22-q24 amplicon.
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| 45. |
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| 46. |
- Kimbung, Siker, et al.
(författare)
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Assessment of early response biomarkers in relation to long-term survival in patients with HER2-negative breast cancer receiving neoadjuvant chemotherapy plus bevacizumab : Results from the Phase II PROMIX trial
- 2018
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 142:3, s. 618-628
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Tidskriftsartikel (refereegranskat)abstract
- 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 predicting response to neoadjuvant chemotherapy plus bevacizumab was investigated. One-hundred-and-fifty patients with large, operable and locally advanced HER2-negative breast cancer received epirubicin and docetaxel, with the addition of bevacizumab. Patients underwent tumor biopsies at baseline, after Cycle 2 and at the time of surgery. The primary end point, pCR, and its relation with the secondary endpoints event-free survival (EFS), overall survival (OS) and gene expression profiles, are reported. The pCR rate was 13% (95% CI 8.6-20.2), with significantly more pCRs among triple-negative [28% (95% CI 14.8-45.4)] than among hormone receptor positive (HR+) tumors [9% (95% CI 4.6-16.3); (OR=3.9 [CI=1.5-10.3])]. pCR rates were not associated with EFS or OS. PAM50 subtypes significantly changed after Cycle 2 (p=0.03) and an index of absolute changes in PAM50 correlations between these time-points was associated with EFS [HR=0.62 (CI=0.3-1.1)]. In univariable analyses, signatures for angiogenesis, proliferation, estrogen receptor signaling, invasion and metastasis, and immune response, measured after Cycle 2, were associated with pCR in HR+ tumors. Evaluation of changes in molecular subtypes and other signatures early in the course of neoadjuvant treatment may be predictive of pCR and EFS. These factors may help guide further treatment and should be considered when designing neoadjuvant trials.
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| 47. |
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| 48. |
- Kimbung, Siker, et al.
(författare)
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Clinical and molecular complexity of breast cancer metastases.
- 2015
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Ingår i: Seminars in Cancer Biology. - : Elsevier BV. - 1096-3650 .- 1044-579X. ; 35, s. 85-95
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Forskningsöversikt (refereegranskat)abstract
- Clinical oncology is advancing toward a more personalized treatment orientation, making the need to understand the biology of metastasis increasingly acute. Dissecting the complex molecular, genetic and clinical phenotypes underlying the processes involved in the development of metastatic disease, which remains the principal cause of cancer-related deaths, could lead to the identification of more effective prognostication and targeted approaches to prevent and treat metastases. The past decade has witnessed significant progress in the field of cancer metastasis research. Clinical and technological milestones have been reached which have tremendously enriched our understanding of the complex pathways undertaken by primary tumors to progress into lethal metastases and how some of these processes might be amenable to therapy. The aim of this review article is to highlight the recent advances toward unraveling the clinical and molecular complexity of breast cancer metastases. We focus on genes mediating breast cancer metastases and organ-specific tropism, and discuss gene signatures for prediction of metastatic disease. The challenges of translating this information into clinically applicable tools for improving the prognostication of the metastatic potential of a primary breast tumor, as well as for therapeutic interventions against latent and active metastatic disease are addressed.
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| 49. |
- Kimbung, Siker, et al.
(författare)
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Co-targeting of the PI3K pathway improves the response of BRCA1 deficient breast cancer cells to PARP1 inhibition.
- 2012
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Ingår i: Cancer Letters. - : Elsevier BV. - 1872-7980 .- 0304-3835. ; 319:2, s. 232-241
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Tidskriftsartikel (refereegranskat)abstract
- Although pre-clinical and clinical studies on PARP1 inhibitors, alone and in combination with DNA-damaging agents, show promising results, further ways to improve and broaden the scope of application of this therapeutic approach are warranted. To this end, we have investigated the possibility of improving the response of BRCA1 mutant breast cancer cells to PARP1 inhibition by co-targeting the PI3K pathway. Human breast cancer cell lines with or without the expression of BRCA1 and/or PTEN were treated with PARP1 and PI3K inhibitors as single agents and in combination. PARP1 inhibition induced DNA damage conferring a G2/M arrest and decrease in viability, paralleled by the induction of apoptosis. PI3K inhibition alone caused a G1 arrest and decreased cell growth. Most importantly, sequential combination of PARP and PI3K inhibitors interacted synergistically to significantly decrease growth compared to PARP inhibition alone. Global transcriptional profiling revealed that this decrease in growth was associated with down-regulation of macromolecule biosynthesis and the induction of apoptosis. Taken together, these results suggest an improved treatment strategy for BRCA1-mutant and possibly also triple-negative breast cancers with similar molecular defects.
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| 50. |
- Kimbung, Siker, et al.
(författare)
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Contrasting breast cancer molecular subtypes across serial tumor progression stages: biological and prognostic implications.
- 2015
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:32, s. 33306-18
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Tidskriftsartikel (refereegranskat)abstract
- The relevance of the intrinsic subtypes for clinical management of metastatic breast cancer is not comprehensively established. We aimed to evaluate the prevalence and prognostic significance of drifts in tumor molecular subtypes during breast cancer progression. A well-annotated cohort of 304 women with advanced breast cancer was studied. Tissue microarrays of primary tumors and synchronous lymph node metastases were constructed. Conventional biomarkers were centrally assessed and molecular subtypes were assigned following the 2013 St Gallen guidelines. Fine-needle aspirates of asynchronous metastases were transcriptionally profiled and subtyped using PAM50. Discordant expression of individual biomarkers and molecular subtypes was observed during tumor progression. Primary luminal-like tumors were relatively unstable, frequently adopting a more aggressive subtype in the metastases. Notably, loss of ER expression and a luminal to non-luminal subtype conversion was associated with an inferior post-recurrence survival. In addition, ER and molecular subtype assessed at all tumor progression stages were independent prognostic factors for post-recurrence breast cancer mortality in multivariable analyses. Our results demonstrate that drifts in tumor molecular subtypes may occur during tumor progression, conferring adverse consequences on outcome following breast cancer relapse.
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