Sequencing of breast cancer stem cell populations indicates a dynamic conversion between differentiation states in vivo

Peer reviewe

Sequencing-based breast cancer diagnostics as an alternative to routine biomarkers

Sequencing-based breast cancer diagnostics have the potential to replace routine biomarkers and provide molecular characterization that enable personalized precision medicine. Here we investigate the concordance between sequencing-based and routine diagnostic biomarkers and to what extent tumor sequencing contributes clinically actionable information. We applied DNA- and RNA-sequencing to characterize tumors from 307 breast cancer patients with replication in up to 739 patients. We developed models to predict status of routine biomarkers (ER, HER2,Ki-67, histological grade) from sequencing data. Non-routine biomarkers, including mutations in BRCA1, BRCA2 and ERBB2(HER2), and additional clinically actionable somatic alterations were also investigated. Concordance with routine diagnostic biomarkers was high for ER status (AUC = 0.95;AUC(replication) = 0.97) and HER2 status (AUC = 0.97;AUC(replication) = 0.92). The transcriptomic grade model enabled classification of histological grade 1 and histological grade 3 tumors with high accuracy (AUC = 0.98;AUC(replication) = 0.94). Clinically actionable mutations in BRCA1, BRCA2 and ERBB2(HER2) were detected in 5.5% of patients, while 53% had genomic alterations matching ongoing or concluded breast cancer studies. Sequencing-based molecular profiling can be applied as an alternative to histopathology to determine ER and HER2 status, in addition to providing improved tumor grading and clinically actionable mutations and molecular subtypes. Our results suggest that sequencing-based breast cancer diagnostics in a near future can replace routine biomarkersNonePublishe

Impact of Primary Breast Surgery on Overall Survival of Patients With De Novo Metastatic Breast Cancer: A Systematic Review and Meta-Analysis

Breast surgery; Metastatic; Overall survivalCirurgia de mama; Metastàtic; Supervivència generalCirugía de mama; Metastásico; Supervivencia generalBackground Breast surgery in cases of de novo metastatic breast cancer (MBC) is associated with improved outcomes in retrospective studies, although the results of randomized controlled trials (RCTs) are conflicting. We aimed to investigate whether surgery in this context prolongs patient survival. Methods We performed a systematic review of the literature to identify RCTs comparing surgery of primary breast cancer to no surgery in patients with de novo MBC. Cochrane Library, Embase, Medline (OVID), and Web of Science were searched with latest update in July 2023, while conference proceedings were manually searched. Data concerning patient and tumor characteristics, as well as outcomes, were extracted. A meta-analysis with random effects models was performed considering heterogeneity between trials. Results Overall, 3255 entries were identified and 5 RCTs fulfilled all inclusion criteria, which had enrolled 1381 patients. The overall estimation in the intention-to-treat population showed no benefit for patients who had surgical excision of the primary breast tumor (HR = 0.93; 95% CI, 0.76-1.14). No subgroups in terms of receptor status or patterns of metastasis seemed to benefit from surgery, except for younger/premenopausal patients (HR = 0.74, 95% CI, 0.58-0.94). Breast surgery was associated with improved local progression-free survival (HR = 0.37, 95% CI, 0.19-0.74). Conclusion Surgery of the primary tumor in patients with de novo MBC does not prolong survival, except possibly in younger/premenopausal patients. Breast surgery should be offered within the context of well-designed clinical trials examining the issue

Obstetric and perinatal outcomes in women with previous breast cancer: A nationwide study of singleton births 1973-2017

publishedVersio

Risk of ischemic heart disease after radiotherapy for ductal carcinoma in situ

The use of adjuvant radiotherapy (RT) in the management of ductal carcinoma in situ (DCIS) is increasing. Left-sided breast irradiation may involve exposure of the heart to ionising radiation, increasing the risk of ischemic heart disease (IHD). We examined the incidence of IHD in a population-based cohort of women with DCIS. The Breast Cancer DataBase Sweden (BCBase) cohort includes women registered with invasive and in situ breast cancers 1992-2012 and age-matched women without a history of breast cancer. In this analysis, 6270 women with DCIS and a comparison cohort of 31,257 women were included. Through linkage with population-based registers, data on comorbidity, socioeconomic status and incidence of IHD was obtained. Hazard ratios (HR) for IHD with 95% confidence intervals (CI) were analysed. Median follow-up time was 8.8 years. The risk of IHD was not increased for women with DCIS versus women in the comparison cohort (HR 0.93; 95% CI 0.82-1.06), after treatment with radiotherapy versus surgery alone (HR 0.77; 95% CI 0.60-0.98) or when analysing RT by laterality (HR 0.85; 95% CI 0.53-1.37 for left-sided versus right-sided RT). The risk of IHD was lower for women with DCIS allocated to RT compared to non-irradiated women and to the comparison cohort, probably due to patient selection. Comparison of RT by laterality did not show any over-risk for irradiation of the left breast.Peer reviewe

Proteogenomics decodes the evolution of human ipsilateral breast cancer

Ipsilateral breast tumor recurrence (IBTR) is a clinically important event, where an isolated in-breast recurrence is a potentially curable event but associated with an increased risk of distant metastasis and breast cancer death. It remains unclear if IBTRs are associated with molecular changes that can be explored as a resource for precision medicine strategies. Here, we employed proteogenomics to analyze a cohort of 27 primary breast cancers and their matched IBTRs to define proteogenomic determinants of molecular tumor evolution. Our analyses revealed a relationship between hormonal receptors status and proliferation levels resulting in the gain of somatic mutations and copy number. This in turn re-programmed the transcriptome and proteome towards a highly replicating and genomically unstable IBTRs, possibly enhanced by APOBEC3B. In order to investigate the origins of IBTRs, a second analysis that included primaries with no recurrence pinpointed proliferation and immune infiltration as predictive of IBTR. In conclusion, our study shows that breast tumors evolve into different IBTRs depending on hormonal status and proliferation and that immune cell infiltration and Ki-67 are significantly elevated in primary tumors that develop IBTR. These results can serve as a starting point to explore markers to predict IBTR formation and stratify patients for adjuvant therapy

Gene expression profiling in primary breast cancer distinguishes patients developing local recurrence after breast-conservation surgery, with or without postoperative radiotherapy

Introduction Some patients with breast cancer develop local recurrence after breast-conservation surgery despite postoperative radiotherapy, whereas others remain free of local recurrence even in the absence of radiotherapy. As clinical parameters are insufficient for identifying these two groups of patients, we investigated whether gene expression profiling would add further information. Methods We performed gene expression analysis (oligonucleotide arrays, 26,824 reporters) on 143 patients with lymph node-negative disease and tumor-free margins. A support vector machine was employed to build classifiers using leave-one-out cross-validation. Results Within the estrogen receptor-positive (ER+) subgroup, the gene expression profile clearly distinguished patients with local recurrence after radiotherapy (n = 20) from those without local recurrence (n = 80 with or without radiotherapy). The receiver operating characteristic (ROC) area was 0.91, and 5,237 of 26,824 reporters had a P value of less than 0.001 (false discovery rate = 0.005). This gene expression profile provides substantially added value to conventional clinical markers (for example, age, histological grade, and tumor size) in predicting local recurrence despite radiotherapy. Within the ER- subgroup, a weaker, but still significant, signal was found (ROC area = 0.74). The ROC area for distinguishing patients who develop local recurrence from those who remain local recurrence-free in the absence of radiotherapy was 0.66 (combined ER+/ER-). Conclusion A highly distinct gene expression profile for patients developing local recurrence after breast-conservation surgery despite radiotherapy has been identified. If verified in further studies, this profile might be a most important tool in the decision making for surgery and adjuvant therapy

Local recurrence after breast conserving surgery in breast cancer

The general aim of this thesis was to gain increased insight into the problem of local recurrences after breast conserving surgery for breast cancer. In a population-based cohort of 4,694 women with invasive breast cancer, operated in 1981 to 1990 and followed through 1997, we studied how breast conserving surgery had been adopted into clinical practice. As adoption became more widespread, the indications for this type of surgery broadened. A simultaneous moderate impairment of the results was noted. Generally, the risk of local recurrence was higher than expected, but the estimated survival rates were gratifying. The overall risk of local recurrence was 9.2% at five years and 2 1. 1% at ten years, and the breast cancer-specific survival was 93.3% and 85.2% at five and ten years, respectively. A large proportion of the women had non- protocol treatment; nearly 30% were not given radiotherapy. Prognosis and prognostic factors after a local recurrence in the breast were studied in 391 women from a population-based cohort of 6,613 women. The prognosis differed notably between the different subgroups of breast recurrences, the subgroups being defined by time to and location of recurrence. Radiotherapy prevented or delayed the appearance of a local recurrence, but had little influence on the breast cancer-specific survival in women who experienced a local recurrence. The strongest independent prognostic factors for breast cancer-specific survival were time to local recurrence and Nottingham Prognostic Index. In the cohort of 6,613 women, 92 women experienced a local recurrence in the axilla. The overall risk of axillary recurrence in the cohort was 1.0% at five years and 1.7% at ten years. The major risk factors for axillary recurrence were low age, large tumour size and minor or no axillary surgery, while radiotherapy to the breast reduced the risk of axillary recurrence. The breast cancer-specific survival after axillary recurrence was poor, 59.2% and 43.5% at five and ten years, respectively. In an analysis of risk factors for local recurrence including 491 cases and 1,098 controls from a cohort of 7,502 women with invasive or non-invasive breast cancer, multivariate analysis showed low age, multicentricity and unclear/unknown surgical margins to be associated with an increased risk of local recurrence, while radiotherapy to the breast and adjuvant hormonal therapy were protective. Cancer in situ was not associated with a higher risk of local recurrence than invasive cancer. Nottingham Histologic Grade and Nottingham Prognostic Index were not helpful in determining the risk of local recurrence. The time relation between local recurrences and distant metastases was studied in a cohort of 5,496 women with invasive breast cancers. Women who had experienced a local recurrence had a higher hazard rate of distant metastases than women with no local recurrence, and the hazard rate curve showed two peaks, at three and seven years after the primary operation. In women with early breast cancer who had experienced a local recurrence, the second peak represented approximately half of the documented distant metastases, and may be explained by dissemination from the local recurrences

Short-term mortality in older (=70 years) patients with early breast cancer treated with neo-/adjuvant chemotherapy: A Swedish nationwide retrospective population-based study

Introduction: There are substantial differences in the utilization of chemotherapy between younger and older patients, mainly due to the higher risk for adverse events among older patients. Short-term mortality after chemotherapy could reveal fatal side effects of treatment. The aim of this study was to explore the impact of treatment setting (neoadjuvant vs. adjuvant) and different chemotherapeutic agents on short-term mortality among older patients with early breast cancer. Material and Methods: The population-based, national, research database BCBaSe 3.0 was used as a data source to identify older (&amp;gt;= 70 years old) patients with stage I-III breast cancer, diagnosed between 2008 and 2019, who received neoadjuvant or adjuvant chemotherapy. Primary outcome was short-term mortality defined as death due to any cause within one year after breast cancer diagnosis. Multivariable logistic regression analysis was applied to investigate the impact of treatment setting and different chemotherapeutic agents (anthracyclinebased vs. taxane-based vs. sequential anthracyclines and taxanes) on outcome, adjusted for potential confounders. Results: In total, 4072 older patients were treated with neoadjuvant or adjuvant chemotherapy and median age was 73 years (quartile [Q]1-Q3; 71-75). The one-year mortality rate was 1.5 % (95 % confidence interval [CI]: 1.2-1.9 % [63 of 4072 patients]). Risk factors independently associated with one-year mortality were older age, larger tumor size, positive nodal status, presence of triple negative breast cancer, and use of neoadjuvant as compared to adjuvant chemotherapy (odds ratio [OR]: 2.00, 95 % CI: 1.04-3.84). No association was found between type of chemotherapeutic regimen and one-year mortality. Median time to death was 7 months (interquartile range: 5-9). The reason for death was mainly classified as breast cancer-related (neoadjuvant: 78 %, n = 14; adjuvant: 49 %, n = 22), followed by potential treatment-related deaths (neoadjuvant: 11 %, n = 2; adjuvant: 27 %, n = 12). Discussion: The short-term mortality rate at first year after diagnosis among older (&amp;gt;= 70 years) patients with breast cancer was relatively low. The higher risk among patients treated with neoadjuvant chemotherapy could be attributed to residual confounding and deserves further evaluation. The low risk of potential treatmentassociated death suggests that chemotherapy in this respect is safe, and older patients should not be disqualified for this treatment.Funding Agencies|Foundation for Clinical Cancer Research in Jonkoping; Region Jonkoping County; Swedish Breast Cancer Association; Futurum - the Academy for Health and Care, Region Jonkoping County</p