Effects of systemic inflammation on relapse in early breast cancer.
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ABSTRACT:
SUBMITTER: McAndrew NP
PROVIDER: S-EPMC7822844 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
Publications
Effects of systemic inflammation on relapse in early breast cancer.
McAndrew Nicholas P NP Bottalico Lisa L Mesaros Clementina C Blair Ian A IA Tsao Patricia Y PY Rosado Jennifer M JM Ganguly Tapan T Song Sarah J SJ Gimotty Phyllis A PA Mao Jun J JJ DeMichele Angela A
NPJ breast cancer 20210122 1
Chronic inflammation has been a proposed mechanism of resistance to aromatase inhibitors in breast cancer. Stratifying by HER2 status, a matched case-control study from the Wellness After Breast Cancer-II cohort was performed to assess whether or not elevated serum inflammatory biomarkers (C-Reactive protein [CRP], interleukin-6 [IL-6], and serum amyloid A [SAA]) and/or the presence of a high-risk IL-6 promoter genotype were associated with recurrence of hormone receptor positive (HR+) early bre ...[more]
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Project description:PurposeObesity, insulin resistance, and elevated levels of circulating proinflammatory mediators are associated with poorer prognosis in early-stage breast cancer. To investigate whether white adipose tissue (WAT) inflammation represents a potential unifying mechanism, we examined the relationship between breast WAT inflammation and the metabolic syndrome and its prognostic importance.Experimental designWAT inflammation was defined by the presence of dead/dying adipocytes surrounded by macrophages forming crown-like structures (CLS) of the breast. Two independent groups were examined in cross-sectional (cohort 1) and retrospective (cohort 2) studies. Cohort 1 included 100 women undergoing mastectomy for breast cancer risk reduction (n = 10) or treatment (n = 90). Metabolic syndrome-associated circulating factors were compared by CLS-B status. The association between CLS of the breast and the metabolic syndrome was validated in cohort 2, which included 127 women who developed metastatic breast cancer. Distant recurrence-free survival (dRFS) was compared by CLS-B status.ResultsIn cohorts 1 and 2, breast WAT inflammation was detected in 52 of 100 (52%) and 52 of 127 (41%) patients, respectively. Patients with breast WAT inflammation had elevated insulin, glucose, leptin, triglycerides, C-reactive protein, and IL6 and lower high-density lipoprotein cholesterol and adiponectin (P < 0.05) in cohort 1. In cohort 2, breast WAT inflammation was associated with hyperlipidemia, hypertension, and diabetes (P < 0.05). Compared with patients without breast WAT inflammation, the adjusted HR for dRFS was 1.83 (95% CI, 1.07-3.13) for patients with inflammation.ConclusionsWAT inflammation, a clinically occult process, helps to explain the relationship between metabolic syndrome and worse breast cancer prognosis. Clin Cancer Res; 22(9); 2283-9. ©2015 AACR.
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Project description:ImportanceCurrent treatment cures most cases of early-stage, primary breast cancer. However, better techniques are required to identify which patients are at risk of relapse.ObjectiveTo assess the clinical validity of molecular relapse detection with circulating tumor DNA (ctDNA) analysis in early-stage breast cancer.Design, setting, and participantsThis prospective, multicenter, sample collection, validation study conducted at 5 United Kingdom medical centers from November 24, 2011, to October 18, 2016, assessed patients with early-stage breast cancer irrespective of hormone receptor and ERBB2 (formerly HER2 or HER2/neu) status who were receiving neoadjuvant chemotherapy followed by surgery or surgery before adjuvant chemotherapy. The study recruited 170 women, with mutations identified in 101 patients forming the main cohort. Secondary analyses were conducted on a combined cohort of 144 patients, including 43 patients previously analyzed in a proof of principle study.InterventionsPrimary tumor was sequenced to identify somatic mutations, and personalized tumor-specific digital polymerase chain reaction assays were used to monitor these mutations in serial plasma samples taken every 3 months for the first year of follow-up and subsequently every 6 months.Main outcomes and measuresThe primary end point was relapse-free survival analyzed with Cox proportional hazards regression models.ResultsIn the main cohort of 101 female patients (mean [SD] age, 54 [11] years) with a median follow-up of 35.5 months (interquartile range, 27.9-43.0 months), detection of ctDNA during follow-up was associated with relapse (hazard ratio, 25.2; 95% CI, 6.7-95.6; P < .001). Detection of ctDNA at diagnosis, before any treatment, was also associated with relapse-free survival (hazard ratio, 5.8; 95% CI, 1.2-27.1; P = .01). In the combined cohort, ctDNA detection had a median lead time of 10.7 months (95% CI, 8.1-19.1 months) compared with clinical relapse and was associated with relapse in all breast cancer subtypes. Distant extracranial metastatic relapse was detected by ctDNA in 22 of 23 patients (96%). Brain-only metastasis was less commonly detected by ctDNA (1 of 6 patients [17%]), suggesting relapse sites less readily detectable by ctDNA analysis.Conclusions and relevanceThe findings suggest that detection of ctDNA during follow-up is associated with a high risk of future relapse of early-stage breast cancer. Prospective studies are needed to assess the potential of molecular relapse detection to guide adjuvant therapy.
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Project description:Molecular subtypes and gene expression signatures are widely used in early breast cancer but their role in metastatic disease is less explored. Two hundred-twenty patients diagnosed with primary breast cancer and subsequent relapse in Stockholm, Sweden between 1997 and 2006 were identified and their primary tumor was assessed for immunohistochemistry (IHC)- and PAM50-based subtypes, risk of recurrence (ROR-S) score, 21-gene and 70-gene signatures using research-based microarray expression profiles. Clinical and pathological data were retrospectively collected. Post-relapse survival within intrinsic subtypes and genomic signatures was investigated by Kaplan-Meier and Cox regression methods. ROR weighted for proliferation index (ROR-P) was explored and the prognostic contribution provided when combined to a clinical model estimated as change in LR- χ(2). IHC classified 27%, 24%, 36% and 13% of the tumors as luminal A, luminal B, HER2+ and triple negative, respectively. PAM50 categorized 22%, 24%, 26%, 22%, 6% of the tumors as luminal A, luminal B, HER2-enriched, basal-like and normal-like. Triple negative and basal tumors had a significantly shorter median post-relapse survival in comparison with luminal. Overall, neither IHC nor PAM50 subtypes, 21- and 70- gene profiles were prognostic in multivariable models. Low and medium ROR-S had a longer survival compared with the high-risk group (23 vs 10 months; p = 0.04). ROR-P independently correlated with post-relapse survival (p = 0.002) and provided the most significant prognostic information when added to a clinical model. ROR score from primary tumor represents an independent prognostic factor of post-relapse survival beyond classical clinical and pathological variables.
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Project description:CYP2C19*2 and CYP2C19*17 might influence tamoxifen metabolism and clinical outcome. Our aim was to investigate the effect of CYP2C19 genotypes on tamoxifen concentrations and metabolic ratios (MRs) and breast cancer recurrence in a large cohort of Caucasian women. Genetic variants (CYP2D6 and CYP2C19 genotypes), tamoxifen and metabolites concentrations, baseline characteristics, and breast cancer recurrence from the CYPTAM study (NTR1509) were used. CYP2C19*2 and CYP2C19*17 genotypes were evaluated as alleles and as groups based on CYP2D6 genotypes (high, intermediate and low activity). Log-rank test and Kaplan-Meier analysis were used to evaluate differences in recurrence defined as relapse-free survival (RFS). Classification tree analyses (CTAs) were conducted to assess the levels of interactions per polymorphism (CYP2D6 and CYP2C19 genotypes) on endoxifen concentrations. No differences in mean concentrations and MRs were observed when comparing CYP2C19 genotypes (CYP2C19*1/*1; CYP2C19*1/*2; CYP2C19*2/*2; CYP2C19*1/*17; CYP2C19*17/*17; CYP2C19*2/*17). Only significant differences (p value < 0.05) in mean concentrations and MRs were observed when comparing tamoxifen activity groups (high, intermediate and low activity). A log-rank test did not find an association across CYP2C19 genotypes (p value 0.898). CTAs showed a significant relationship between CYP2D6 and endoxifen (p value < 0.0001), but no association with CYP2C19 genotypes was found. CYP2C19 polymorphisms do not have a significant impact on tamoxifen metabolism or breast cancer relapse.
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Project description:BackgroundApproximately 10-15% of all breast tumors are triple-negative breast cancer (TNBC). TNBC have a higher risk of relapse and distant metastases compared to other subtypes. The optimal systemic management of TNBC according to national and international guidelines is discussed herein.SummaryAnthracycline/taxane-based chemotherapy for patients with TNBC either in the neoadjuvant (NACT) or the adjuvant setting is considered standard of care. Exceptions are small tumors and a low-risk histology, in which chemotherapy can be spared. Dose-dense therapy is more effective in preventing recurrence and increasing survival. The use of nab-paclitaxel instead of a solvent-based taxane can lead to higher pathological complete response (pCR) rates and better outcomes. Platinum agents are effective in increasing pCR when added to anthracycline/taxane-based chemotherapy at the cost of increased toxicity. Long-term outcome data are lacking. In patients without a pCR, capecitabine leads to improved outcomes.Key messagesThe standard treatment approach of TNBC is anthracycline/taxane-based chemotherapy, preferably within the NACT setting. Dose-dense schedules as well as platinum should be considered in the NACT setting. For patients without a pCR, capecitabine is an option to improve the outcome. The role of nab-paclitaxel is under debate. In case of immunogenic tumors, checkpoint inhibitors are promising new agents that merit further investigation.
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Project description:BackgroundDespite the known association between healthy lifestyles and reduced risk of breast cancer, it remains unclear whether systemic inflammation, as a consequence of unhealthy lifestyles, may mediate the association.MethodsA cohort study of 259,435 female participants in the UK Biobank was conducted to estimate hazard ratio (HR) for breast cancer according to 9 inflammation markers using Cox regression models. We further estimated the percentage of total association between healthy lifestyle index (HLI) and breast cancer that is mediated by these inflammation markers.ResultsDuring 2,738,705 person-years of follow-up, 8,889 cases of breast cancer were diagnosed among 259,435 women in the UK Biobank cohort. Higher level of C-reactive protein (CRP), systemic immune-inflammation index (SII), CRP-to-albumin Ratio (CAR), CRP-to-lymphocyte Ratio (CLR), monocyte-to-HDL-c ratio (MHR), and neutrophil-to-HDL-c ratio (NHR) were associated with increased breast cancer risk, while a higher lymphocyte-to-monocyte ratio (LMR) was associated with a lower risk. The inverse association between HLI and breast cancer was weakly mediated by CRP (8.5%), SII (1.71%), CAR (8.66%), CLR (6.91%), MHR (6.27%), and NHR (7.33%). When considering individual lifestyle factors, CRP and CAR each mediated 16.58% and 17.20%, respectively, of the associations between diet score and breast cancer risk, while the proportion mediated for physical activity and breast cancer were 12.13% and 11.48%, respectively. Furthermore, MHR was found to mediate 13.84% and 12.01% of the associations between BMI, waist circumference, and breast cancer.ConclusionThe association of HLI and breast cancer is weakly mediated by the level of inflammation, particularly by CRP and CAR. Systemic inflammatory status may be an intermediate in the biological pathway of breast cancer development.
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Project description:The benefits of breast cancer adjuvant systemic treatments are generally assumed to be proportional (or constant) over time, but limited data suggest that some treatment effects may vary with time. We therefore systematically assessed the proportional hazards assumption across all 19 breast cancer adjuvant systemic therapy trials in the National Surgical Adjuvant Breast and Bowel Project (NSABP) database. The NSABP breast cancer trials were tested for the proportionality of hazard rates between randomized treatment groups for five endpoints: overall survival, disease-free survival and recurrence, local-regional recurrence, or distant recurrence as first events. When the proportional hazards assumption did not hold, a "change point for the relative risk" technique was used to identify the temporal breakdown of the treatment effect. Time-varying treatment effects were observed in nearly half of the trials (nine of 19). In six (B-05, B-11, B-12, B-14, B-16, and B-20), novel treatment benefits diminished statistically significantly at specific time points following surgery. In B-09 and B-31, novel treatment benefits were delayed and emerged more than one year after surgery (1.57 and 1.32 years correspondingly), but the benefit in B-09 reversed after the third year of follow-up. In one trial (B-23), the initial advantage and subsequent disadvantage of one of the regimens was evident. Breast cancer adjuvant systemic therapy can have statistically significant time-varying effects, which should be considered in the design, analysis, reporting, and translation of clinical trials. These time-dependent effects will have greater relevance as the number of long-term breast cancer survivors increases.
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