| 1. |
- Klintman, Marie, et al.
(författare)
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The Prognostic Value of Mitotic Activity Index (MAI), Phosphohistone H3 (PPH3), Cyclin B1, Cyclin A, and Ki67, Alone and in Combinations, in Node-Negative Premenopausal Breast Cancer
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:12
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Tidskriftsartikel (refereegranskat)abstract
- Proliferation, either as the main common denominator in genetic profiles, or in the form of single factors such as Ki67, is recommended for clinical use especially in estrogen receptor-positive (ER) patients. However, due to high costs of genetic profiles and lack of reproducibility for Ki67, studies on other proliferation factors are warranted. The aim of the present study was to evaluate the prognostic value of the proliferation factors mitotic activity index (MAI), phosphohistone H3 (PPH3), cyclin B1, cyclin A and Ki67, alone and in combinations. In 222 consecutive premenopausal node-negative breast cancer patients (87% without adjuvant medical treatment), MAI was assessed on whole tissue sections (predefined cut-off >= 10 mitoses), and PPH3, cyclin B1, cyclin A, and Ki67 on tissue microarray (predefined cut-offs 7th decile). In univariable analysis (high versus low) the strongest prognostic proliferation factor for 10-year distant disease-free survival was MAI (Hazard Ratio (HR)=3.3, 95% Confidence Interval (CI): 1.8-6.1), followed by PPH3, cyclin A, Ki67, and cyclin B1. A combination variable, with patients with MAI and/or cyclin A high defined as high-risk, had even stronger prognostic value (HR=4.2, 95% CI: 2.2-7). When stratifying for ER-status, MAI was a significant prognostic factor in ER-positive patients only (HR=7.0, 95% CI: 3.1-16). Stratified for histological grade, MAI added prognostic value in grade 2 (HR=7.2, 95% CI: 3.1-38) and grade 1 patients. In multivariable analysis including HER2, age, adjuvant medical treatment, ER, and one proliferation factor at a time, only MAI (HR=2.7, 95% CI: 1.1-6.7), and cyclin A (HR=2.7, 95% CI: 1.2-6.0) remained independently prognostic. In conclusion this study confirms the strong prognostic value of all proliferation factors, especially MAI and cyclin A, in all patients, and more specifically in ER-positive patients, and patients with histological grade 2 and 1. Additionally, by combining two proliferation factors, an even stronger prognostic value may be found.
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| 2. |
- Strand, Carina, et al.
(författare)
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The combination of Ki67, histological grade and estrogen receptor status identifies a low-risk group among 1,854 chemo-naive women with N0/N1 primary breast cancer
- 2013
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Ingår i: SpringerPlus. - : Springer Science and Business Media LLC. - 2193-1801. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim was to confirm a previously defined prognostic index, combining a proliferation marker, histological grade, and estrogen receptor (ER) in different subsets of primary N0/N1 chemo-naive breast cancer patients. Methods/design: In the present study, including 1,854 patients, Ki67 was used in the index (KiGE), since it is the generally accepted proliferation marker in clinical routine. The low KiGE-group was defined as histological grade 1 patients and grade 2 patients which were ER-positive and had low Ki67 expression. All other patients made up the high KiGE-group. The KiGE-index separated patients into two groups with different prognosis. In multivariate analysis, KiGE was significantly associated with disease-free survival, when adjusted for age at diagnosis, tumor size and adjuvant endocrine treatment (hazard ratio: 3.5, 95% confidence interval: 2.6-4.7, P<0.0001). Discussion: We have confirmed a prognostic index based on a proliferation marker (Ki67), histological grade, and ER for identification of a low-risk group of patients with N0/N1 primary breast cancer. For this low-risk group constituting 57% of the patients, with a five-year distant disease-free survival of 92%, adjuvant chemotherapy will have limited effect and may be avoided.
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| 3. |
- Boraka, Öykü, et al.
(författare)
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FGF/FGFR1 system in paired breast tumor-adjacent and tumor tissues, associations with mammographic breast density and tumor characteristics
- 2023
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Ingår i: Frontiers in Oncology. - 2234-943X. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Mammographic breast density (MBD) is an established breast cancer risk factor, yet the underlying molecular mechanisms remain to be deciphered. Fibroblast growth factor receptor 1 (FGFR1) amplification is associated with breast cancer development and aberrant FGF signaling found in the biological processes related to both high mammographic density and breast cancer microenvironment. The aim of this study was to investigate the FGF/FGFR1 expression in-between paired tumor-adjacent and tumor tissues from the same patient, and its associations with MBD and tumor characteristics.METHODS: FGFR1 expression in paired tissues from 426 breast cancer patients participating in the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) cohort study was analyzed by immunohistochemistry. FGF ligand expression was obtained from RNA-sequencing data for 327 of the included patients.RESULTS: FGFR1 levels were differently expressed in tumor-adjacent and tumor tissues, with increased FGFR1 levels detected in 58% of the tumors. High FGFR1 expression in tumor tissues was associated with less favorable tumor characteristics; high histological grade (OR=1.86, 95% CI 1.00-3.44), high Ki67 proliferative index (OR=2.18, 95% CI 1.18-4.02) as well as tumors of Luminal B-like subtype (OR=2.56, 95%CI 1.29-5.06). While no clear association between FGFR1 expression and MBD was found, FGF ligand (FGF1, FGF11, FGF18) expression was positively correlated with MBD.DISCUSSION: Taken together, these findings support a role of the FGF/FGFR1 system in early breast cancer which warrants further investigation in the MBD-breast cancer context.
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| 4. |
- Boraka, Öykü, et al.
(författare)
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Physical Activity and Long-Term Risk of Breast Cancer, Associations with Time in Life and Body Composition in the Prospective Malmö Diet and Cancer Study
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:8
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Tidskriftsartikel (refereegranskat)abstract
- Being physically active as part of everyday life reduces breast cancer risk. Less is known whether the benefits of an active lifestyle differ depending on the timing of physical activity in life or anthropometric characteristics. The aim of this study was to bring further insights to the association of physical activity in relation to menopausal status and body composition with breast cancer risk by making use of a prospective Swedish cohort (Malmö Diet and Cancer Study) with long-term follow-up. Physical activity information of 15,983 participants for the past 12 months prior to study entry was assessed according to metabolic equivalent task (MET)-hours/week to integrate duration and intensity of reported activities. During 23.2 years median follow-up, 1302 invasive breast cancers occurred. Women reporting a high physical activity at study baseline, corresponding to >1 h daily walking/week (≥28.5 MET-h/week), had a 23% lower long-term breast cancer risk (HRadj = 0.77, 95% CI 0.66–0.90) than those reporting low physical activity, being most pronounced among perimenopausal and postmenopausal women, and women with waist circumference, body fat percentage, or BMI in the upper-normal and overweight range. For premenopausal women or women having obesity or the largest body composition, high physical activity alone did not modify the breast cancer risk, suggesting additional preventive measures indicated in these groups to reduce the long-term risk of breast cancer.
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| 5. |
- Buus, Richard, et al.
(författare)
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Novel 18-gene signature for predicting relapse in ER-positive, HER2-negative breast cancer
- 2018
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several prognostic signatures for early oestrogen receptor-positive (ER+) breast cancer have been established with a 10-year follow-up. We tested the hypothesis that signatures optimised for 0-5-year and 5-10-year follow-up separately are more prognostic than a single signature optimised for 10 years. Methods: Genes previously identified as prognostic or associated with endocrine resistance were tested in publicly available microarray data set using Cox regression of 747 ER+/HER2- samples from post-menopausal patients treated with 5 years of endocrine therapy. RNA expression of the selected genes was assayed in primary ER+/HER2- tumours from 948 post-menopausal patients treated with 5 years of anastrozole or tamoxifen in the TransATAC cohort. Prognostic signatures for 0-10, 0-5 and 5-10 years were derived using a penalised Cox regression (elastic net). Signature comparison was performed with likelihood ratio statistics. Validation was done by a case-control (POLAR) study in 422 samples derived from a cohort of 1449. Results: Ninety-three genes were selected by the modelling of microarray data; 63 of these were significantly prognostic in TransATAC, most similarly across each time period. Contrary to our hypothesis, the derived early and late signatures were not significantly more prognostic than the 18-gene 10-year signature. The 18-gene 10-year signature was internally validated in the TransATAC validation set, showing prognostic information similar to that of Oncotype DX Recurrence Score, PAM50 risk of recurrence score, Breast Cancer Index and IHC4 (score based on four IHC markers), as well as in the external POLAR case-control set. Conclusions: The derived 10-year signature predicts risk of metastasis in patients with ER+/HER2- breast cancer similar to commercial signatures. The hypothesis that early and late prognostic signatures are significantly more informative than a single signature was rejected.
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| 6. |
- Harborg, Sixten, et al.
(författare)
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Obesity and breast cancer prognosis : pre-diagnostic anthropometric measures in relation to patient, tumor, and treatment characteristics
- 2023
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Ingår i: Cancer & Metabolism. - 2049-3002. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Examine the association between obesity and clinical outcomes in early breast cancer and assess if patient, tumor, and treatment characteristics modify such associations in Malmö Diet and Cancer Study patients (MDCS).METHODS: The MDCS enrolled 17,035 Swedish women from 1991 to 1996. At enrollment, participants' body mass index (BMI), waist circumference and body fat percentage measures were collected. We identified all female MDCS participants with invasive breast cancer from 1991 to 2014. Follow-up began at breast cancer diagnosis and ended at breast cancer recurrence (BCR), death, emigration, or June 8, 2020. The World Health Organization guidelines were used to classify BMI, waist circumference, and body fat percentage into three categories of healthy weight, overweight, and obesity. We fit Cox regression models to compute adjusted hazard ratios (HRs) with 95% confidence intervals (CI) of BCR according to body composition. To evaluate effect measure modification, we stratified Cox models by patient, tumor, and treatment characteristics.RESULTS: In total, 263 BCRs were diagnosed over 12,816 person-years among 1099 breast cancer patients with a median follow-up of 11.1 years. Obesity according to BMI (HR = 1.44 [95%CI 1.00-2.07]), waist circumference (HR = 1.31 [95%CI 0.98-1.77]), and body fat percentage (HR = 1.41 [95%CI 1.02-1.98]) was associated with increased risk of BCR compared with healthy weight. Obesity was stronger associated with BCR in patients with low socioeconomic position (HR = 2.55 [95%CI 1.08-6.02]), larger tumors > 20 mm (HR = 2.68 [95%CI 1.42-5.06]), estrogen-receptor-negative breast cancer (HR = 3.13 [95%CI 1.09-8.97]), and with adjuvant chemotherapy treatment (HR = 2.06 [95%CI 1.08-4.31]).CONCLUSION: Higher pre-diagnostic BMI, waist circumference, and body fat percentage was associated with increased risk of BCR. The association between obesity and BCR appears dependent on patient, tumor, and treatment characteristics.
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| 7. |
- Klintman, Marie, et al.
(författare)
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A prospective, multicenter validation study of a prognostic index composed of S-phase fraction, progesterone receptor status, and tumour size predicts survival in node-negative breast cancer patients : NNBC, the node-negative breast cancer trial
- 2013
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 24:9, s. 2284-2291
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Tidskriftsartikel (refereegranskat)abstract
- In a retrospective study on node-negative breast cancer, a prognostic index consisting of a proliferation factor, S-phase fraction (SPF), progesterone receptor status (PR), and tumour size identified one-third of patients as high risk, with a sixfold increased risk of breast cancer death. This prospective multicenter cohort study was set up to validate the index. In 576 T1-2N0 patients < 60 years, prospective analyses of PR and SPF were carried out. High risk was defined as >= 2 of the following: size > 20 mm, PR-negativity, and high SPF (in the absence of SPF, Bloom-Richardson grade 3). Median follow-up was 17.8 years. Thirty-one percent were high risk. In univariate analysis, the index was prognostic for breast cancer-specific survival after 5 years [hazard ratio (HR) = 4.7, 95% confidence interval (95% CI) 2.5-8.9], 10 years (HR = 2.2, 95% CI 1.5-3.3), and 15 years (HR = 1.7, 95% CI 1.2-2.5), and remained significant after adjustment for adjuvant medical treatment and age. In the 37% of patients with no risk factors, only one patient died of breast cancer the first 5 years. This prospective study validates a prognostic index consisting of a proliferation factor, PR-status, and tumour size. The index may be helpful for prognostic considerations and for selection of patients in need of adjuvant therapy.
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| 8. |
- Klintman, Marie, et al.
(författare)
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Association between tumor tissue TIMP-1 levels and objective response to first-line chemotherapy in metastatic breast cancer.
- 2010
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 1573-7217 .- 0167-6806. ; 121, s. 365-371
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Tidskriftsartikel (refereegranskat)abstract
- In a previous study from our laboratory, high tumor levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) have been associated with an adverse response to chemotherapy in metastatic breast cancer suggesting that TIMP-1, which is known to inhibit apoptosis, may be a new predictive marker in this disease. The purpose of this study was to investigate the association between TIMP-1 and objective response to chemotherapy in an independent patient population consisting of patients with metastatic breast cancer from Sweden and Denmark. TIMP-1 was measured using ELISA in 162 primary tumor extracts from patients who later developed metastatic breast cancer and these levels were related to the objective response to first-line chemotherapy. Increasing levels of TIMP-1 were associated with a decreasing probability of response to treatment, reaching borderline significance (OR = 1.59, 95% CI: 0.97-2.62, P = 0.07). This OR is very similar to the result from our previous study. Increasing levels of TIMP-1 were also associated with a shorter disease-free survival and overall survival, however, not statistically significant. The results from the present study support previous data that TIMP-1 is associated with objective response to chemotherapy for metastatic breast cancer.
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| 9. |
- Klintman, Marie, et al.
(författare)
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Changes in expression of genes representing key biologic processes after neoadjuvant chemotherapy in breast cancer, and prognostic implications in residual disease
- 2016
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 22:10, s. 2405-2416
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The primary aim was to derive evidence for or against the clinical importance of several biologic processes in patients treated with neoadjuvant chemotherapy (NAC) by assessing expression of selected genes with prior implications in prognosis or treatment resistance. The secondary aim was to determine the prognostic impact in residual disease of the genes' expression. Experimental Design: Expression levels of 24 genes were quantified by NanoString nCounter on formalin-fixed paraffinembedded residual tumors from 126 patients treated with NAC and 56 paired presurgical biopsies. The paired t test was used for testing changes in gene expression, and Cox regression and penalized elastic-net Cox Regression for estimating HRs. Results: After NAC, 12 genes were significantly up- and 8 downregulated. Fourteen genes were significantly associated with time to recurrence in univariable analysis in residual disease. In a multivariable model, ACACB, CD3D, MKI67, and TOP2A added prognostic value independent of clinical ER-, PgR-, and HER2- status. In ER+/HER2- patients, ACACB, PAWR, and ERBB2 predicted outcome, whereas CD3D and PAWR were prognostic in ER-/HER2- patients. By use of elastic-net analysis, a 6-gene signature (ACACB, CD3D, DECORIN, ESR1, MKI67, PLAU) was identified adding prognostic value independent of ER, PgR, and HER2. Conclusions: Most of the tested genes were significantly enriched or depleted in response to NAC. Expression levels of genes representing proliferation, stromal activation, metabolism, apoptosis, stemcellness, immunologic response, and Ras-ERK activation predicted outcome in residual disease. Themultivariable gene models identified could, if validated, be used to identify patients needing additional post-neoadjuvant treatment to improve prognosis.
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| 10. |
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