| 1. |
- Carlsson, Anders, et al.
(författare)
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Molecular serum portraits in patients with primary breast cancer predict the development of distant metastases.
- 2011
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 108:34, s. 14252-14257
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Tidskriftsartikel (refereegranskat)abstract
- The risk of distant recurrence in breast cancer patients is difficult to assess with current clinical and histopathological parameters, and no validated serum biomarkers currently exist. Using a recently developed recombinant antibody microarray platform containing 135 antibodies against 65 mainly immunoregulatory proteins, we screened 240 sera from 64 patients with primary breast cancer. This unique longitudinal sample material was collected from each patient between 0 and 36 mo after the primary operation. The velocity for each serum protein was determined by comparing the samples collected at the primary operation and then 3-6 mo later. A 21-protein signature was identified, using leave-one-out cross-validation together with a backward elimination strategy in a training cohort. This signature was tested and evaluated subsequently in an independent test cohort (prevalidation). The risk of developing distant recurrence after primary operation could be assessed for each patient, using her molecular portraits. The results from this prevalidation study showed that patients could be classified into high- versus low-risk groups for developing metastatic breast cancer with a receiver operating characteristic area under the curve of 0.85. This risk assessment was not dependent on the type of adjuvant therapy received by the patients. Even more importantly, we demonstrated that this protein signature provided an added value compared with conventional clinical parameters. Consequently, we present here a candidate serum biomarker signature able to classify patients with primary breast cancer according to their risk of developing distant recurrence, with an accuracy outperforming current procedures.
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| 2. |
- Falck, Anna-Karin, et al.
(författare)
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Analysis of and prognostic information from disseminated tumour cells in bone marrow in primary breast cancer: a prospective observational study
- 2012
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Disseminated tumour cells (DTCs) in the bone marrow of patients with breast cancer have been identified as an independent predictor of poor prognosis in patients with non-metastatic disease. This prospective study aimed to evaluate the presence and prognostic value of DTCs in the bone marrow of female patients with primary breast cancer. Methods: Between 1999 and 2003, bone marrow aspirates were obtained from patients at the time of surgery for primary invasive breast cancer. DTCs in bone marrow were identified using monoclonal antibodies against cytokeratins for detection of epithelial cells. The detection of DTCs was related to clinical follow-up with distant disease-free survival (DDFS) and breast cancer-specific survival as endpoints. Bone marrow aspirates from adult healthy bone marrow donors were analysed separately. Results: DTCs were analysed in 401 patients, and cytokeratin-positive cells were found in 152 of these (38%). An immunofluorescence (IF) staining procedure was used in 327 patients, and immunocytochemistry (IC) was performed in 74 patients. The IF-based method resulted in 40% DTC-positive cases, whereas 30% were positive using IC (p = 0.11). The presence of DTCs in bone marrow was not significantly related to patient or tumour characteristics. The presence of DTCs was not a prognostic factor for DDFS (IF: hazards ratio [HR], 2.2; 95% confidence interval [CI], 0.63-2.2; p = 0.60; IC: HR, 0.84; 95% CI, 0.09-8.1; p = 0.88). Significant prognostic factors were lymph node metastases, oestrogen receptor positivity, Nottingham histological grade, and tumour size using Cox univariate analysis. The analyses were positive for epithelial cells in bone marrow from adult healthy donors in 19 (25%) samples. Conclusions: The detection of DTCs in bone marrow in primary breast cancer was previously shown to be a predictor of poor prognosis. We were not able to confirm these results in a prospective cohort including unselected patients before the standard procedure was established. Future studies with a standardised patient protocol and improved technique for isolating and detecting DTCs may reveal the clinical applications of DTC detection in patients with micrometastases in the bone marrow.
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| 3. |
- Grabau, Dorthe, et al.
(författare)
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Analysis of sentinel node biopsy - a single-institution experience supporting the use of serial sectioning and immunohistochemistry for detection of micrometastases by comparing four different histopathological laboratory protocols.
- 2011
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Ingår i: Histopathology. - : Wiley. - 0309-0167. ; 59, s. 129-138
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Tidskriftsartikel (refereegranskat)abstract
- Histopathology Analysis of sentinel node biopsy - a single-institution experience supporting the use of serial sectioning and immunohistochemistry for detection of micrometastases by comparing four different histopathological laboratory protocols Aims: Detecting micrometastases (>0.2 and ≤2 mm/>200 cells) and isolated tumour cells (ITCs; ≤0.2 mm/<200 cells) is important for staging of breast cancer patients. The aim of this study was to systematically compare several laboratory protocols used to detect metastases after initial intraoperative frozen section examination. Methods and results: Four different protocols for the work-up of sentinel lymph nodes (SLNs) after frozen sectioning were applied in the routine diagnostic process from 2001 to 2009. In addition, team-work with a limited number of laboratory technicians and pathologists handling SLNs was introduced in 2008. The present study shows that there were, overall, significantly more node-positive patients in the period when team-work and intensive step sections including immunohistochemistry (IHC) were used (P = 0.01). This resulted in 13% more patients being found to have ITCs and micrometastases than in a time period when only step sections were performed. No increase in the number of false-negative frozen sections was seen. Conclusions: Future guidelines for pathological work-up of sentinel nodes in women with breast cancer might include team-work and IHC if frozen sections are used intraoperatively.
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| 4. |
- Grabau, Dorthe, et al.
(författare)
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Completion axillary dissection can safely be omitted in screen detected breast cancer patients with micrometastases. A decade's experience from a single institution.
- 2013
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Ingår i: European Journal of Surgical Oncology. - : Elsevier BV. - 1532-2157 .- 0748-7983. ; 39:6, s. 601-607
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The need for completion axillary lymph node dissection (ALND) in breast cancer patients with micrometastases in the sentinel nodes (SNs) is controversial. The aim of this retrospective observational study is to determine if the method of detection of early breast cancer is predictive for additional positive nodes in patients with micrometastases in the SNs. METHODS: Between 2001 and 2011 a total of 1993 women with primary unilateral breast cancer had surgery at Skåne University Hospital, Lund. Of 1993 patients, 1458 had an SN biopsy and nearly all patients with micro- and macrometastases had ALND. RESULTS: Micrometastases defined as >0.2 mm/>200 cells and ≤2.0 mm were found in 62 of 757 screen-detected patients and in 81 of 701 patients with symptomatic breast cancer. Only 3 of the screen-detected patients with micrometastases, all with tumour size >15 mm (range 18-39 mm), had metastases in the completion ALND whereas this was found in 18 of the symptomatic patients with micrometastases (p = 0.01), (tumour size, range 10-30 mm). Logistic regression analysis adjusted for method of detection, tumour size and histological grade showed 5 times higher odds for further metastases in ALND in patients with symptomatic presentation vs. screen-detected breast cancer. CONCLUSION: Despite the small number of patients with micrometastases in this large cohort of breast cancer patients, these results support the contention that completion ALND can safely be omitted in screen-detected breast cancer patients with micrometastases in the SNs.
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| 5. |
- Idvall, Ingrid, et al.
(författare)
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Histopathological and cell biological factors of ductal carcinoma in situ before and after the introduction of mammographic screening
- 2001
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 1651-226X .- 0284-186X. ; 40:5, s. 653-659
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Tidskriftsartikel (refereegranskat)abstract
- With the introduction of mammographic screening the incidence of ductal carcinoma in situ (DCIS) has increased to 10-15% of all breast cancers. The aim of this study was to investigate whether there were any morphological and cell biological differences between DCIS detected during the pre-screening (n = 39) as opposed to the screening period (n = 120). We could not demonstrate any statistically significant differences between the pre-screening and the screening period with regard to nuclear grade, presence of necrosis, the Van Nuys classification system, growth pattern, or cell biological factors (estrogen and progesterone receptors, c-erbB-2, p53, DNA ploidy status, Ki67, and Auer classes). These findings suggest that DCIS tumors detected during the two time periods have a similar malignant potential. DCIS detected during the screening period was further divided into the prevalence period versus the period thereafter, and symptomatic versus screening-detected asymptomatic cases. More cases with diffuse growth patterns were seen during the prevalence period than after the prevalence period, and screening-detected asymptomatic DCISs were more often 15 mm or smaller in diameter than DCISs detected symptomatically.
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| 6. |
- Narbe, Ulrik, et al.
(författare)
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AIB1 is a new putative prognostic biomarker in the luminal A and B-like (HER2-negative) classification of invasive lobular carcinoma
- 2017
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Ingår i: ; , s. 1-07
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Konferensbidrag (refereegranskat)abstract
- Body: Background: Estrogen receptor (ER) positive HER2-negative breast cancer comprises 75–80% of all breast cancer. Thisfraction is even higher (>90%) in invasive lobular carcinoma (ILC). According to the St Gallen surrogate definitions of the intrinsicsubtypes, Ki67 and progesterone receptor (PgR) are used to classify these tumors as luminal A- and luminal B-like(HER2-negative). These guidelines are based on information derived from patient materials with mixed histological types, wherethe vast majority of the patients have invasive ductal carcinoma. The `luminal-like classification´ together with histological grade,tumor size and lymph node status is widely used in the clinic for prognostication. The aim of the present study was to investigateif the same markers are applicable for ILC, and furthermore, if additional biomarkers involved in the endocrine signaling system,e.g. Amplified in breast cancer 1 (AIB1) and the putative G protein-coupled estrogen receptor (GPER), might providecomplementary prognostic information.Patients: Two hundred and thirty-three (N = 233) well-characterized patients with primary ILC, diagnosed between 1980 and1991 were included. Forty-two percent of the patients received adjuvant endocrine treatment and 2 % received adjuvantchemotherapy. All biomarkers were analyzed immunohistochemically on tissue microarray, whereas histological grade wasevaluated on whole sections according to Elston and Ellis (NHG). The primary endpoint was breast cancer mortality (BCM).Results: In univariable analyses with 10-year follow-up, Ki67 (high vs. low), NHG (3 vs. 1+2) and AIB1 (high vs. low) weresignificantly associated to BCM (Hazard Ratio: 4.7, 95% CI: 2.1–10.4, p 95% CI: 1.4–7.2, p = 0.005 respectively), whereas PgR (respectively). Essentially the same effect was seen after multivariable adjustment for lymph node status (+ vs. -), tumor size (>20mm vs. according to St Gallen surrogate definitions did not show significant prognostic differences between the two groups (p = 0.12).Patients with AIB1) had a 10-year BCM of 4.2% (95% CI: 1.4–12%). This group constituted 34% of the patients included in the present study.Conclusions: In contrast to other previous studies, where breast cancers of mixed histological types were included, PgR was notsignificantly associated to prognosis in the ER-positive HER2-negative subgroup in the present study, consisting only of ILC. Theprognostic role of PgR and the clinical usefulness of the luminal A and B-like (HER2-negative) classification (using only Ki67 andPgR) in ILC is still to be further investigated. The prognostic importance of Ki67 and NHG in this subgroup was, however,confirmed also in ILC, and AIB1 might be a new putative prognostic factor. By combining Ki67, NHG, and AIB1, together withlymph node status and tumor size, a group of patients with an excellent prognosis could be identified.
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| 7. |
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| 8. |
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| 9. |
- Narbe, Ulrik, et al.
(författare)
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The estrogen receptor coactivator AIB1 is a new putative prognostic biomarker in ER-positive/HER2-negative invasive lobular carcinoma of the breast
- 2019
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 175:2, s. 305-316
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: According to the 2017 St Gallen surrogate definitions of the intrinsic subtypes, Ki67, progesterone receptor (PR) and Nottingham histological grade (NHG) are used for prognostic classification of estrogen receptor (ER) positive/HER2-negative breast cancer into luminal A- or luminal B-like. The aim of the present study was to investigate if additional biomarkers, related to endocrine signaling pathways, e.g., amplified in breast cancer 1 (AIB1), androgen receptor (AR), and G protein-coupled estrogen receptor (GPER), can provide complementary prognostic information in a subset of ER-positive/HER-negative invasive lobular carcinoma (ILC). Methods: Biomarkers from 224 patients were analyzed immunohistochemically on tissue microarray. The primary endpoint was breast cancer mortality (BCM), analyzed with 10- and 25-year follow-up (FU). In addition, the prognostic value of gene expression data for these biomarkers was analyzed in three publicly available ILC datasets. Results: AIB1 (high vs. low) was associated to BCM in multivariable analysis (adjusted for age, tumor size, nodal status, NHG, Ki67, luminal-like classification, and adjuvant systemic therapy) with 10-year FU (HR 6.8, 95% CI 2.3–20, P = 0.001) and 25-year FU (HR 3.0, 95% CI 1.1–7.8, P = 0.03). The evidence of a prognostic effect of AIB1 could be confirmed by linking gene expression data to outcome in independent publicly available ILC datasets. AR and GPER were neither associated to BCM with 10-year nor with 25-year FU (P > 0.33). Furthermore, Ki67 and NHG were prognostic for BCM at both 10-year and 25-year FU, whereas PR was not. Conclusions: AIB1 is a new putative prognostic biomarker in ER-positive/HER2-negative ILC.
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| 10. |
- Olsson, Eleonor, et al.
(författare)
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Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease.
- 2015
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 7:8, s. 1034-1047
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Tidskriftsartikel (refereegranskat)abstract
- Metastatic breast cancer is usually diagnosed after becoming symptomatic, at which point it is rarely curable. Cell-free circulating tumor DNA (ctDNA) contains tumor-specific chromosomal rearrangements that may be interrogated in blood plasma. We evaluated serial monitoring of ctDNA for earlier detection of metastasis in a retrospective study of 20 patients diagnosed with primary breast cancer and long follow-up. Using an approach combining low-coverage whole-genome sequencing of primary tumors and quantification of tumor-specific rearrangements in plasma by droplet digital PCR, we identify for the first time that ctDNA monitoring is highly accurate for postsurgical discrimination between patients with (93%) and without (100%) eventual clinically detected recurrence. ctDNA-based detection preceded clinical detection of metastasis in 86% of patients with an average lead time of 11 months (range 0-37 months), whereas patients with long-term disease-free survival had undetectable ctDNA postoperatively. ctDNA quantity was predictive of poor survival. These findings establish the rationale for larger validation studies in early breast cancer to evaluate ctDNA as a monitoring tool for early metastasis detection, therapy modification, and to aid in avoidance of overtreatment.
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