| 1. |
- Koliadi, Anthoula, 1978-
(författare)
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Cyclin A is an excellent proliferation marker for identifying luminal breast cancer subgroups using immunohistochemistry
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background. Gene arrays have demonstrated different outcomes for breast cancer subtypes highlighting the heterogeneity of breast cancer. The limited availability of gene expression analysis and financial issues have contributed to the development of surrogate markers to identify corresponding subgroups using IHC. 2011 ESMO and St Gallen guidelines suggest the use of an IHC panel consisting of ER, PgR, HER2 and Ki67 cut-off value ≥14 % (Ki6714%) for discriminating luminal A from B.The cut-off value suggested from 2013 St Gallens guidelines was ≥20% (Ki6720%). We wanted to evaluate if the different cut-off values for Ki67 or cyclins A/B1 could reliably separate luminal A from B. Patients. In a case-control study, we defined 190 women who died from breast cancer as cases and 190 women alive at the time for the corresponding case's death as controls. Inclusion criteria were tumor size ≤50 mm, no lymph node metastases and no adjuvant chemotherapy. Immunohistochemical evaluation of ER, PgR, HER2, Ki 67, cyclin A and cyclin B1 were utilized for subgrouping. Results. Conditional logistic regression analysis was used to estimate odds ratios (OR) for breast cancer death. Ki6714% did not detect differences in outcome between luminal A and B breast cancer (OR 1.4, 95% CI 0.8-2.26 p-value 0.24). Corresponding values for cyclin A was OR 3.6 (95% CI 1.8-7.0 p-value 0.00), cyclin B1 2.2 (95% CI 1.1-4.5 p-value 0.04) and Ki6720% 2.0 (95% CI 1.1-3.9 p-value 0.04) using luminal A as reference.Conclusion. In our study, Ki6714% failed to detect any difference in outcome between luminal A and B. In contrast, using cyclin A as a proliferation marker luminal B was found to have an almost 3.5 -fold higher risk of dying from breast cancer. Cyclin B1 and Ki6720%, could also separate luminal A from B but cyclin A separated more effectively these subtypes . We conclude that cyclin A distinctly separates luminal A from B in node negative breast cancer.
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| 2. |
- Koliadi, Anthoula, et al.
(författare)
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Cyclin B is an immunohistochemical proliferation marker which can predict for breast cancer death in low-risk node negative breast cancer
- 2010
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 49:6, s. 816-820
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Tidskriftsartikel (refereegranskat)abstract
- Patients with low-risk node negative breast cancer have an excellent prognosis with 5% breast cancer mortality at 10 years. However, prognostic factors are needed to identify poor prognostic patients who might benefit from adjuvant systemic therapy. Proliferation has been identified as the most important component of gene expression profiles. Cyclin B is a proliferative marker easily assessed by immunohistochemistry. We wanted to examine cyclin B as a prognostic factor in low-risk breast cancer patients. Patients and methods. Using an experimental study design, we compared women dying early from their breast cancer (n=17) with women free from relapse more than eight years after initial diagnosis (n=24). All women had stage I, node negative and hormone receptor positive disease. None had received adjuvant chemotherapy. Tumor samples were immunostained for cyclin B using commercial antibodies. Results. The mean percentage of cyclin B (12%) was significantly higher (p=0.001) in women dying from their breast cancer compared with women free from relapse ( 5%). High cyclin B (>= 9%) identified 11/17 patients dying from breast cancer and low cyclin B identified 22/24 patients free from relapse. The sensitivity and specificity of cyclin B was 65% and 92%, respectively. Discussion. We found that low-risk node negative patients with high expression of cylin B had a significantly worse outcome than patients with low expression of cyclin B. Cyclin B could separate patients with poor survival from those with good survival with 80% accuracy. We suggest that cyclin B might be a potent prognostic factor in this low-risk patient group.
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| 3. |
- Koliadi, Anthoula, 1978-
(författare)
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PPH3 is an independent prognostic factor in node negative breast cancer, however outperformed by cyclin A in the ER positive patients.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background. Proliferation conveys prognostic information and directs treatment choices in early and especially in estrogen receptor (ER) positive breast cancer. Ki67 is the proliferation marker, which is recommended by the 2013 St Gallen International Breast Cancer Conference to distinguish Luminal A-like from Luminal B-like breast cancer. However, the lack of standardization and absence of a clearly established cut-off value are limitations for the clinical use of Ki67. Recent studies in node negative breast cancer suggest that phosphorylated histone 3 (PPH3) may predict breast cancer death. Our aim was to examine the prognostic role of PPH3 compared to the proliferation markers Ki67, cyclin A and cyclin B1 in node negative breast cancer with a special focus on ER positive disease.Patients and methods. In a case-control study, we defined 190 women who died from node negative breast cancer as cases and 190 women who were alive at the time for the corresponding case's death as controls. Inclusion criteria were tumor size ≤50 mm, no lymph node metastases and no adjuvant chemotherapy. Of these 380 subjects, 249 had ER positive disease. Tumor tissues were immunostained for PPH3 using commercially available antibodies. The actual number of immunostained cells in 10 fields of view (PPH3 index) and the percentage of immunostained cells counting 200 and 500 tumor cells were calculated.Results. In node negative patients, PPH3 indexrevealed an odds ratio (OR) for breast cancer death of 2.6 (95% confidence interval (CI) 1.6-4.5 p-value <0.001). PPH3 was strongly correlated to Ki67, histological grade, mitotic count and cyclin A and B1. In ER positive patients the OR for PPH3 index was 2.9 (95% CI 1.6-5.2 p-value <0.001) while the OR for Cyclin A was 3.8 (95% CI 2.2-6.6 p-value <0.001), for cyclin B1 2.9 (95%CI 1.7-4.9 p-value <0.001) and for Ki67 1.6 (95% CI 0.9-4.9 p-value 0,09). However, multivariate analyses showed that cyclin A was the only independent prognostic marker for breast cancer death in ER positive patients, OR 3.6 (95% CI 1.6-8.1 p-value 0.002).Conclusion. In this study of node negative breast cancer patients, PPH3 showed to be a prognostic factor for breast cancer death. In ER positive patients PPH3 and cyclin A/B1 but not Ki67 could predict breast cancer death. However in the multivariate analysis of proliferation markers, only cyclin A remains as a prognostic factor.
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| 4. |
- Koliadi, Anthoula
(författare)
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The Prognostic Impact of Proliferation Markers in Breast Cancer with Emphasis on Cyclin B1 and PPH3
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to investigate the prognostic role of the proliferation markers cyclin B1 and Phosphorylated Histone 3 (PPH3) in breast cancer (BC).In paper I we used an experimental study design, we compared women dying early from their BC with women free from relapse more than eight years after initial diagnosis. All women had stage I, node-negative and hormone receptor positive disease. None had received adjuvant chemotherapy. We found that low-risk node negative patients with high expression of cyclin B1 had a significantly worse outcome than patients with low expression of cyclin B1.In paper II a population-based case control study was performed to further investigate the prognostic value of cyclin B1. One hundred and ninety women who died from BC were defined as cases and 190 women alive at the time for the corresponding case’s death were defined as controls. Inclusion criteria were tumor size 50 mm, no lymph node metastases, and no adjuvant chemotherapy. Two investigators evaluated the stainings independently. Cyclin B1 was found to be a prognostic factor for BC death that could identify high-risk patients with a good to very good reproducibility.Paper III aimed to investigate the role of proliferation in male breast cancer (MBC). One hundred and ninety-seven MBC tumors were stained for cyclin A, B1, D1 and Ki67. Overexpression of cyclin A and B1 and elevated mitotic count were predictive of breast cancer death. Ki67 was re-evaluated and different cut-offs were used, but no prognostic value could be demonstrated. On the other hand high levels of cyclin D1 were associated with better outcome in MBC.In paper IV we applied the immunohistochemichal panel suggested from international guidelines to the same patient material as in paper II, to discriminate luminal A from luminal B BC. We wanted to evaluate if different cut-off values of Ki67, cyclin A or B1 could more clearly separate luminal A from B. Cyclin A, B1 and Ki67 (cut-off 20%) could detect difference in outcome between these subtypes with cyclin A showing greater prognostic value.The aim of paper V was to examine the prognostic role of PPH3 compared to the proliferation markers Ki67, cyclin A and cyclin B1 with focus on ER positive disease. PPH3 was found to be a prognostic factor for breast cancer death but in the multivariate analysis including all proliferation markers, only cyclin A remained a prognostic factor.Finally, we conclude that both cyclin B1 and PPH3 are prognostic factors for breast cancer death, but are outperformed by cyclin A in ER positive patients. In male breast cancer prognostic factors need to be further studied.
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| 5. |
- Ladjevardi, Cecilia Olsson, et al.
(författare)
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Multiple immune-related adverse events secondary to checkpoint inhibitor therapy in patients with advanced cancer : association with treatment effectiveness
- 2024
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Ingår i: Frontiers in Oncology. - : Frontiers Media S.A.. - 2234-943X. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Checkpoint inhibitors (CPI) are widely used in cancer treatment with a potential of causing immune-related adverse events (IRAEs). Several studies have reported a positive correlation between development of IRAEs and improved survival outcome. However, few studies have focused on the potential role of multiple IRAEs on treatment effectiveness. This study aimed at investigating the association between multiple IRAEs and treatment effectiveness in terms of progression-free survival (PFS) and overall survival (OS) in advanced cancer patients.METHODS: We performed a retrospective cohort study at three Swedish centers. All patients (n=600) treated with PD-L1 or PD-1 inhibitor, in monotherapy or in combination for advanced cancer between January 2017 and December 2021 were included. Multiple IRAEs were defined as IRAEs involving more than one organ system either simultaneously or sequentially. Time-depending Cox-regression model to mitigate the risk for immortal time bias (ITB) was applied.RESULTS: The major tumor types were non-small cell lung cancer (205 patients; 34.2%) and malignant melanoma (196 patients; 32.7%). Of all patients,32.8% developed single IRAE and 16.2% multiple IRAEs. Patients with multiple IRAEs showed significantly improved PFS (Hazard Ratio, HR=0.78 95% Confidence Interval, CI: 0.57-0.98) and OS (HR=0.65 95% CI: 0.44-0.95) compared to patients with single IRAE or no IRAE (HR=0.46 95% CI:0.34-0.62 for PFS vs HR=0.41 95% CI: 0.28-0.60 for OS).CONCLUSION: In conclusion, our data supports a stronger association between development of multiple as opposed to single IRAEs and clinical effectiveness in advanced cancer patients treated with CPIs.
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| 6. |
- Ladjevardi, Cecilia Olsson, et al.
(författare)
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Predicting immune-related adverse events using a simplified frailty score in cancer patients treated with checkpoint inhibitors : A retrospective cohort study
- 2023
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Ingår i: Cancer Medicine. - : John Wiley & Sons. - 2045-7634. ; 12:12, s. 13217-13224
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Checkpoint inhibitors (CPIs) are in widespread clinical use. Little is known about which patients are at risk for developing toxicity. It is essential being able to identify patients with higher risk of experiencing immune-related adverse events (IRAEs) before initiation of CPI treatment to optimize treatment decisions and follow-up strategy. The aim of this study was to investigate whether a simplified frailty score based on performance status (PS), age, and comorbidity expressed as Charlson comorbidity index (CCI) could predict development of IRAEs.METHODS: We performed a retrospective cohort study at three Swedish centers. All patients (n = 596) treated with PD-L1 or PD-1 inhibitor for advanced cancer between January 2017 and December 2021 were included.RESULTS: In total, 361 patients (60.6%) were classified as nonfrail and 235 (39.4%) as frail. The most common cancer type was non-small cell lung cancer (n = 203; 34.1%) followed by malignant melanoma (n = 195; 32.7%). Any grade of IRAE occurred in 138 (58.7%) frail and in 155 (42.9%) non-frail patients (OR: 1.58; 95% CI: 1.09-2.28). Age, CCI, and PS did not independently predict the occurrence of IRAEs. Multiple IRAEs occurred in 53 (22.6%) frail and in 45 (12.5%) nonfrail patients (OR: 1.62; 95% CI: 1.00-2.64).DISCUSSION: In conclusion, the simplified frailty score predicted all grade IRAEs and multiple IRAEs in multivariate analyses whereas age, CCI, or PS did not separately predict development of IRAEs suggesting that this easy-to-use score may be of value in clinical decision making but a large prospective study is needed to assess its true value.
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| 7. |
- Nilsson, Cecilia, et al.
(författare)
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High proliferation is associated with inferior Outcome in male breast cancer patients
- 2013
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Ingår i: Modern Pathology. - : Nature Publishing Group. - 0893-3952 .- 1530-0285. ; 26:1, s. 87-94
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Tidskriftsartikel (refereegranskat)abstract
- Assessment of proliferation is important in female breast cancer and individual treatment decisions are based upon its results, especially in the lumina! subgroups. Gene expression analyses fail to group male breast cancer into the intrinsic subgroups previously established in female breast cancer. Even though proliferation has been shown to divide male breast cancer into molecular subgroups with different prognoses, the clinical importance of proliferation markers has not yet been elucidated. Previous studies in male breast cancer have demonstrated contradictory results regarding the prognostic impact of histological grade and Ki-67, parameters strongly associated with proliferation. The aim of the present project was to study proliferation in male breast cancer by assessing other proliferation-related markers viz. cyclins A, B, D1 and mitotic count. A total of 197 male breast cancer cases with accessible paraffin-embedded material and outcome data were investigated. Immunohistochemical stainings were performed on tissue microarrays. Kaplan-Meier estimates and the Cox proportional regression models were used for survival analyses with breast cancer death as the event. The subset of patients with high expression of cyclin A (hazard ratio (HR) 3.7; P=0.001) and B (HR 2.7; P=0.02) demonstrated a poorer survival. Furthermore, high mitotic count was associated with an increased risk of breast cancer death (HR 2.5; P=0.01). In contrast, cyclin D1 overexpression was predictive of better breast cancer survival (HR 0.3; P=0.001). In conclusion, high levels of cyclin A and B expression and an elevated mitotic count result in a two to threefold higher risk for breast cancer death, whereas cyclin D1 overexpression halves the risk. The clinical utility of these proliferation markers needs further elucidation. Modern Pathology (2013) 26, 87-94; doi:10.1038/modpathol.2012.145; published online 24 August 2012
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| 8. |
- Niméus, Emma, et al.
(författare)
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Cyclin B1 is a prognostic proliferation marker with a high reproducibility in a population-based lymph node negative breast cancer cohort
- 2010
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 127:4, s. 961-967
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Tidskriftsartikel (refereegranskat)abstract
- A large proportion of women with lymph node negative breast cancer treated with chemotherapy do not benefit from such treatment. Proliferation markers have been shown to recognize patients at high risk for recurrence. Ki67 has recently been included in the St Gallen guidelines. We investigated the prognostic importance of cyclin B1 in node negative breast cancer and included a study of reproducibility. In a population-based case-control study 190 women who died from breast cancer were defined as cases and 190 women alive at the time for the corresponding case's death as controls. Inclusion criteria were tumor size < 50 mm, no lymph node metastases, and no adjuvant chemotherapy. Tumor tissue was immunostained for cyclin B1. Two investigators evaluated the staining independently by counting approximately 100, 200, 500, and 1000 cells. Cyclin B1 was statistically significantly associated to breast cancer death, in both uni- and multivariate analyses (adjusted for tumor size, age, and endocrine therapy), with odds ratios 2-3 for both investigators. The agreement between the two investigators was good to very good, regardless of the number of counted cells (kappa values between 0.74 and 0.82).Cyclin B1 is a prognostic factor for breast cancer death in a population-based node negative patient cohort which can identify high-risk patients with a good to very good reproducibility. (c) 2009 UICC.
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| 9. |
- Rydén, Viktoria, et al.
(författare)
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The role of dacarbazine and temozolomide therapy after treatment with immune checkpoint inhibitors in malignant melanoma patients : A case series and meta-analysis
- 2024
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Ingår i: Pigment Cell & Melanoma Research. - : John Wiley & Sons. - 1755-148X. ; 37:3, s. 352-362
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Tidskriftsartikel (refereegranskat)abstract
- Dacarbazine (DTIC) and its oral counterpart temozolomide (TMZ) have been the most used agents in advanced malignant melanoma (MM) patients and they are still used routinely. The preferred first line treatment, immune checkpoint inhibitors (CPIs) might shape the tumor and the tumor microenvironment, possibly affecting the response to subsequent therapies. The aim of this study was to investigate the treatment effect of DTIC/TMZ in MM patients after CPI therapy in a consecutive patient cohort and through systematic literature review and meta-analysis. Thirty-five patients with advanced MM treated with DTIC/TMZ after previous CPI therapy in three Swedish regions between 2017 and 2021 were recognized and seven case series studies were identified through systematic database review. Pooled data from all 345 patients showed a median real-world progression-free survival (rwPFS) of 1.9 months and overall survival (OS) of 6.0 months. Three of these studies were included in a meta-analysis comparing DTIC/TMZ after CPI treatment, versus no previous immunotherapy, showing no statistically significant differences in rwPFS or OS but higher real-world response rate to chemotherapy for the prior-CPI treated group (Odds Ratio: 2.24; 95% Confidence Interval: 1.04-4.86). The current study supports consideration of DTIC/TMZ in later line of treatment in the immunotherapy era.
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| 10. |
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