ICAM1 expression is induced by proinflammatory cytokines and associated with TLS formation in aggressive breast cancer subtypes.
ABSTRACT: Intratumoral formation of tertiary lymphoid structures (TLS) within the tumor microenvironment is considered to be a consequence of antigen challenge during anti-tumor responses. Intracellular adhesion molecule 1 (ICAM1) has been implicated in a variety of immune and inflammatory responses, in addition to associate with triple negative breast cancer (TNBC). In this study, we detected TLS in the aggressive tumor phenotypes TNBC, HER2+ and luminal B, whereas the TLS negative group contained solely tumors of the luminal A subtype. We show that ICAM1 is exclusively expressed in TNBC and HER2 enriched subtypes known to be associated with inflammation and the formation of TLS. Furthermore, cell from normal mammary epithelium and breast cancer cell lines expressed ICAM1 upon stimulation with the proinflammatory cytokines TNF?, IL1? and IFN?. ICAM1 overexpression was induced in MCF7, MDA-MB-468 and SK-BR-3 cells regardless of hormone receptor status. Taken together, our findings show that ICAM1 is expressed in aggressive subtypes of breast cancer and its expression is inducible by well-known proinflammatory cytokines. ICAM1 may be an attractive molecular target for TNBC, but further investigations elucidating the role of ICAM1 in targeted therapies have to take into consideration selective subtypes of breast cancer.
Project description:Purpose:Neoadjuvant chemotherapy (NAC) is less effective for luminal breast cancer because luminal breast cancer has a lower rate of pathological complete response (pCR) after NAC than human epidermal growth factor receptor 2 (HER2)-type and triple-negative breast cancer (TNBC). We investigated the efficacy of NAC and the predictive factors of a better response in luminal breast cancer. Methods:Between 2010 and 2016, we retrieved data of 244 patients with clinically node-positive breast cancer who were treated with NAC followed by surgery from a prospectively collected database. We classified breast cancer into luminal HER2- and non-luminal HER2- breast cancer (luminal HER2+, HER2+, and TNBC types). We analyzed each subtype with respect to surgical outcomes, response to NAC, and determined variables associated with surgical outcomes and response in patients with luminal HER2- breast cancer. Results:The total, breast, and axillary pCR rates were significantly lower in 114 patients with luminal HER2- breast cancer than in those with other subtypes (7.9%, 12.3%, and 22.8%, respectively). However, breast-conserving surgery (BCS) conversion and tumor response rates did not significantly differ between patients with luminal HER2- and those with non-luminal HER2- breast cancer (p = 0.836 and p = 0.180, respectively). In the multivariate analysis, high tumor response rate (≥ 46.4%) was significantly associated with an increased BCS conversion rate. In the subgroup analysis of luminal HER2- breast cancer, the multivariate analysis showed that higher Ki67 expression and axilla pCR and BCS conversion rates were significantly associated with tumor response to NAC. Conclusion:Despite the low pCR rate, the tumor response and BCS conversion rates after NAC of luminal HER2- breast cancer were similar to those of other subtypes. NAC has the potential benefit of reducing the size of breast cancer, thereby increasing the BCS conversion rate in luminal HER2- breast cancer.
Project description:<b>Background: </b>The cost of breast cancer care rises with higher stage at diagnosis; however, there are no real-world data regarding the cost of care according to breast cancer subtypes. This study aimed to estimate direct medical costs for early breast cancer care in the first 3?years after diagnosis according to subtype and stage, using patient-level data.<br><br><b>Methods: </b>Women with newly diagnosed stage I-III breast cancer, admitted in 2012 to a Portuguese cancer centre were prospectively followed within the NEON-BC cohort. The use of health resources was obtained from each patient's clinical and administrative records and costs were computed. Tumours were classified into the classic subtypes (hormone receptor-positive (HR+)/HER2-; HER2-positive (HER2+); triple-negative breast cancer (TNBC)) and surrogate intrinsic subtypes (luminal A-like; luminal B-like; HER2 enriched; basal like).<br><br><b>Results: </b>A total of 703 patients were included: 48.9% had stage I, 35.8% stage II and 15.2% stage III breast cancer; 76.4% had HR+/HER2-, 15.9% HER2+ and 7.7% TNBC. Median cost of care was €9215/patient in stage I, €13 019/patient in stage II and €15 011/patient in stage III and €10 540/patient in HR+/HER2-, €11 224/patient in TNBC and €41 513/patient in HER2+ breast cancer. Systemic therapy accounted for 69.2% of the cost of care among patients with HER2+, 12.0% among HR+/HER2- and 7.5% among TNBC patients. Similar differences were observed across surrogate intrinsic subtypes.<br><br><b>Conclusions: </b>The cost of early breast cancer care was mainly driven by the tumour subtype and, to a lesser extent, by stage. The median cost of care was fourfold higher among patients with HER2+ tumours compared with those with HR+/HER2- and TNBC. These data provide information for the economic evaluation of innovative treatments for early breast cancer and highlight the weight that targeted systemic therapy might have in the overall cost of care among patients with early breast cancer.
Project description:Aim: The risk of recurrence in breast cancer depends on factors such as treatment but also on the intrinsic subtype. We analyzed the risk factors for local, loco-regional and systemic recurrence, evaluated the differences and analyzed the risk of recurrence for different molecular subtypes. Material and Methods: A total of 3054 breast cancer patients who underwent surgery followed by adjuvant treatment at HSK hospital or Essen Mitte Hospital between 1998 and 2011 were analyzed. Based on immunohistochemical parameters, cancers were divided into the following subgroups: luminal A, luminal B (HER2-), luminal B (HER2+), HER2+ and TNBC (triple negative breast cancer). Results: 67?% of tumors were classified as luminal A, 13?% as luminal B (HER2-), 6?% as luminal B (HER2+), 3?% as HER2+ and 11?% as TNBC. After a median follow-up time of 6.6 years there were 100 local (3.3?%), 32 loco-regional (1?%) and 248 distant recurrences (8?%). Five-year recurrence-free survival for the overall patient collective was 92?%. On multivariate analysis, positive nodal status, TNBC subtype and absence of radiation therapy were found to be independent risk factors for all forms of recurrence. Age <?50 years, tumor size, luminal B (HER2-) subtype and breast-conserving therapy were additional risk factors for local recurrence. Compared to the luminal A subtype, the risk of systemic recurrence was higher for all other subtypes; additional risk factors for systemic recurrence were lymphatic invasion, absence of systemic therapy and mastectomy. Conclusion: Overall, the risk of local and loco-regional recurrence was low. In addition to nodal status, subgroup classification was found to be an important factor affecting the risk of recurrence.
Project description:Purpose:Accumulated evidence suggests that reproductive factors are related to different breast cancer subtypes, but most studies on these relationships are mainly focused on middle-aged and older patients, and it remains unclear how reproductive factors impact different subtypes of breast cancer in young women. Methods:We assessed the relationships between fertility factors and luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, and triple-negative breast cancer (TNBC) subtypes in 3792 patients and 4182 controls aged 20-70 years. Data on the reproductive history of the study participants were acquired through face-to-face interviews and questionnaires. We conducted case-control comparisons among tumor subtypes based on estrogen receptor (ER), progesterone receptor (PR), and HER2 statuses using unconditional polychotomous multivariate logistic regression models to compute odds ratios (ORs) and 95% confidence intervals (CIs). Results:Parity was inversely related to both luminal A and luminal B subtypes in young women and older women (all P trend < 0.05). Later age at first full-term birth was inversely related to the luminal A subtype (P trend < 0.05) in young women but correlated with an increased risk of the luminal A subtype (P trend < 0.05) in older women. Parous Chinese women 40 years old or younger who breastfed for 12 months or longer had a lower risk of luminal B and TNBC subtypes than women who never breastfed (OR = 0.55, 95% CI 0.36-0.84 and OR = 0.52, 95% CI 0.28-0.99, respectively). Conclusions:Our results implied that parity exerted a strong protective effect against luminal A and luminal B subtype breast cancer in young Chinese women, and long-term breastfeeding obviously decreased the risk of luminal B and TNBC subtypes in this population.
Project description:<h4>Background</h4>Differences in the incidence and outcome of breast cancer among Hispanic women compared with white women are well documented and are likely explained by ethnic differences in genetic composition, lifestyle, or environmental exposures. METHODOLGY/PRINCIPAL FINDINGS: A population-based study was conducted in Galicia, Spain. A total of 510 women diagnosed with operable invasive breast cancer between 1997 and 2010 participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics were collected. The different breast cancer tumor subtypes were compared on their clinico-pathological characteristics and risk factor profiles, particularly reproductive variables and breastfeeding. Among the 501 breast cancer patients (with known ER and PR receptors), 85% were ER+/PR+ and 15% were ER-&PR-. Among the 405 breast cancer with known ER, PR and HER2 status, 71% were ER+/PR+/HER2- (luminal A), 14% were ER+/PR+/HER2+ (luminal B), 10% were ER-/PR-/HER2- (triple negative breast cancer, TNBC), and 5% were ER-/PR-/HER2+ (non-luminal). A lifetime breastfeeding period equal to or longer than 7 months was less frequent in case patients with TNBC (OR?=?0.25, 95% CI?=?0.08-0.68) compared to luminal A breast cancers. Both a low (2 or fewer pregnancies) and a high (3-4 pregnancies) number of pregnancies combined with a long breastfeeding period were associated with reduced odds of TNBC compared with luminal A breast cancer, although the association seemed to be slightly more pronounced among women with a low number of pregnancies (OR?=?0.09, 95% CI?=?0.005-0.54).<h4>Conclusions/significance</h4>In case-case analyses with the luminal A cases as the reference group, we observed a lower proportion of TNBC among women who breastfed 7 or more months. The combination of longer breastfeeding duration and lower parity seemed to further reduce the odds of having a TNBC compared to a luminal A breast cancer.
Project description:AIM:To investigate the impact of biological subtypes in locoregional recurrence in Chinese breast cancer patients receiving postmastectomy radiotherapy (PMRT). METHODS AND MATERIALS:About 583 patients who received postmastectomy radiation between 2010 and 2012 were retrospectively analyzed. According to immunohistochemical staining profile, patients were classified into: Luminal A-like, Luminal B-like, HER2-positive, and triple-negative breast cancer (TNBC). Local and regional recurrence (LRR) cumulative incidences were calculated by competing risks methodology and the power of prognostic factors was examined by Gray's test and the test of Fine and Gray. RESULTS:The median follow-up was 70.9 months. About 34 LRR events occurred. For Luminal A, Luminal B, HER2-positive, and TNBC patients, the 5-year LRR cumulative incidence rates were 1.57%, 4.09%, 10.74%, and 10.28%. Compared with Luminal A, HER2-positive subtype and TNBC had a significant increased risk of LRR (HR was 5.034 and 5.188, respectively). In univariate analysis, predictive factors for higher LRR were HER2-positive subtype (HR = 4.43, P < .05), TNBC (HR = 4.70, P < .05), and pN3 (HR = 5.83, P < .05). In the multivariate model, HER2-positive subtype (HR = 5.034, P < .05), TNBC (HR = 5.188, P < .05), and pN3 (HR = 9.607, P < .01) were independent predictors of LRR. LRR without trastuzumab was similar to that of TNBC (without vs TNBC, 17.88% vs 10.28%, P > .05) in HER2-positive subtype patients, while LRR with trastuzumab was approximate to Luminal A (with vs Luminal A, P > .05). Additionally, endocrine therapy also significantly reduced LRR incidence in the luminal subtype cohort (without vs with therapy, 6.25% vs 2.89%, HR = 0.365, P < .1). CONCLUSIONS:Biological subtype was a prognostic factor of LRR in the PMRT setting among Chinese breast cancer patients.
Project description:Copy number alterations (CNAs) are a frequent feature in human breast cancer, and one of the hallmarks of genomic instability. The FOSL1, GSTP1 and CCND1 genes are located at 11q13, a cytoband commonly affected by CNA in breast cancer, with relevant function in progression and invasion. Our main goal was to analyze CNAs of these genes and determine their association with breast cancer subtypes. Seventy-three cases of invasive breast tumors [52 Luminal, 7 HER2+ and 14 triple negative (TNBC) subtypes] were analyzed by TaqMan assays. CNAs were observed for all genes, with gains more frequently observed. Gains of the FOSL1 gene were observed in 71% of the cases. This gene was the only one with a statistically significant difference (p<0.001) among tumor subtypes, with increased copy number in TNBC compared to luminal and HER2+. No significant association of CNA and clinical and histopathological parameters from the patients was observed. Additional studies in larger breast cancer patient cohorts based on more refined molecular subtypes are necessary to confirm the observed association of FOSL1 gain with aggressive breast tumors phenotypes.
Project description:High triglycerides and low levels of high density lipoprotein (HDL)-cholesterol are observed to promote tumor growth. However, whether breast cancer heterogeneity may explain the contradictory influence of triglycerides and cholesterol observed on breast cancer prognosis remains unclear.A population-based survival study among 464 breast cancer cases identified within the Tromsø study was conducted. Pre-diagnostic triglycerides, total-cholesterol and HDL-cholesterol were measured, and detailed clinical and histopathological data were obtained. Using tissue microarray, all breast cancer cases were reclassified into the following subtypes: Luminal A, Luminal B, HER2-enriched, and triple negative breast cancer (TNBC). Multivariable Cox proportional hazards regression models were used to study the associations between pre-diagnostic lipids and breast cancer recurrence, mortality, and survival.A total of 464 breast cancer patients, with mean age at diagnosis of 57.9 years, were followed for a mean 8.4 years. TNBC patients in the highest tertile of triglycerides (? 1.23 mmol/l) had 3 times higher overall mortality compared to TNBC patients in the lowest tertile (? 0.82 mmol/l) (HR 2.99, 95% CI 1.17-7.63), and the 5-year overall survival was 19% lower for TNBC patients in the highest vs. lowest tertile of triglycerides (65% vs. 84%). TNBC patients in the highest tertile of the HDL-cholesterol/total-cholesterol ratio (?0.35), compared to those in the lowest tertile (?0.27), had a 67% reduced overall mortality risk (HR 0.33, 95% CI 0.12-0.89). No associations were observed between lipids and prognostic outcome among breast cancer patients overall, or among patients with luminal A and luminal B subtypes. Among HER2-enriched patients, pre-diagnostic triglyceride level was inversely associated with overall mortality.Our study suggests that pre-diagnostic triglycerides and the HDL-cholesterol/total-cholesterol ratio may independently provide unique information regarding prognostic outcome among triple negative breast cancer patients. However, a small sample size underlines the need for additional studies.
Project description:Acute-phase proteins (APPs) are associated with a variety of disorders such as infection, inflammatory diseases, and cancers. The signature profile of APPs in breast cancer (BC) is poorly understood. Here, we identified serum amyloid A (SAA) for proinflammatory predisposition in BC through the signature profiles of APPs, interleukin (IL) and tumor necrosis factor (TNF) superfamily using publicly available datasets of tumor samples and cell lines. Triple-negative breast cancer (TNBC) subtype highly expressed SAA1/2 compared to HER2, luminal A (LA) and luminal B (LB) subtypes. IL1A, IL1B, IL8/CXCL8, IL32 and IL27RA in IL superfamily and CD70, TNFSF9 and TNFRSF21 in TNF superfamily were highly expressed in TNBC compared to other subtypes. SAA is restrictedly regulated by nuclear factor (NF)-?B and IL-1?, an NF-?B activator highly expressed in TNBC, increased the promoter activity of SAA1 in human TNBC MDA-MB231 cells. Interestingly, two ?B-sites contained in SAA1 promoter were involved, and the proximal region (-96/-87) was more critical than the distal site (-288/-279) in regulating IL-1?-induced SAA1. Among the SAA receptors, TLR1 and TLR2 were highly expressed in TNBC. Cu-CPT22, TLR1/2 antagonist, abrogated IL-1?-induced SAA1 promoter activity. In addition, SAA1 induced IL8/CXCL8 promoter activity, which was partially reduced by Cu-CPT22. Notably, SAA1/2, TLR2 and IL8/CXCL8 were associated with a poor overall survival in mesenchymal-like TNBC. Taken together, IL-1-induced SAA via NF-?B-mediated signaling could potentiate an inflammatory burden, leading to cancer progression and high mortality in TNBC patients.
Project description:Breast cancer (BC) is a molecularly heterogeneous disease that encompasses five major molecular subtypes (luminal A (LA), luminal B HER2 negative (LB-), luminal B HER2 positive (LB+), HER2 positive (HER2+) and triple negative breast cancer (TNBC)). BC treatment mainly depends on the identification of the specific subtype. Despite the correct identification, therapies could fail in some patients. Thus, further insights into the genetic and molecular status of the different BC subtypes could be very useful to improve the response of BC patients to the range of available therapies. In this way, we used gold nanoparticles (AuNPs, 12.96 ± 0.72 nm) as a scavenging tool in combination with Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) to quantitatively analyze the serum proteome alterations in the different breast cancer intrinsic subtypes. The differentially regulated proteins specific of each subtype were further analyzed with the bioinformatic tools STRING and PANTHER to identify the major molecular function, biological processes, cellular origin, protein class and biological pathways altered due to the heterogeneity in proteome of the different BC subtypes. Importantly, a profile of blood coagulation proteins was identified in the serum of HER2-overexpressing BC patients.