The elusive Luminal B breast cancer and the mysterious chemokines.

PURPOSE: Invasive ductal breast cancer (IDC) is heterogeneous. Staging and immunohistochemistry (IH) allow for effective therapy but are not yet ideal. Women with Luminal B tumors show an erratic response to treatment. This prospective study with 81 women with breast cancer aims to improve the prognostic stratification of Luminal B patients. METHODS: This is a prospective translational study with 81 women with infiltrating ductal carcinoma, grouped by TNM staging and immunohistochemistry, for survival analysis, and their correlations with the chemokines. Serum measurements of 13 chemokines were performed, including 7 CC chemokines [CCL2(MCP1), CCL3(MIP1α), CCL4(MIP1ß), CCL5(Rantes), CCL11(Eotaxin), CCL17(TARC), CCL20(MIP3α)], 6 CXC chemokines [CXCL1(GroAlpha), CXCL5(ENA78), CCXCL8(IL-8), CXCL9(MIG), CXCL10(IP10), CXCL11(ITAC)]. RESULTS: Overall survival was significantly dependent on tumor staging and subtypes by immunohistochemistry, with a median follow-up time the 32.87 months (3.67-65.63 months). There were age correlations with IP10/CXCL10 chemokines (r = 0.4360; p = 0.0079) and TARC/CCL17 (Spearman + 0.2648; p = 0.0360). An inverse correlation was found between body weight and the chemokines Rantes/CCL5 (r = - 0.3098; p = 0.0169) and Eotaxin/CCL11 (r = - 0.2575; p = 0.0470). Smokers had a higher concentration of MIP3α/CCL20 (Spearman + 0.3344; p = 0.0267). Luminal B subtype patients who expressed lower concentrations of ENA78/CXCL5 (≤ 254.83 pg/ml) (Log-Rank p = 0.016) and higher expression of MIP1ß/CCL4 (> 34.84 pg/ml) (Log-Rank p = 0.014) had a higher risk of metastases. CONCLUSION: Patients with Luminal B breast tumors can be better stratified by serum chemokine expression, suggesting that prognosis is dependent on biomarkers other than TNM and IH.

Epidermal growth factor receptor (EGFR) expression in the serum of patients with triple-negative breast carcinoma: prognostic value of this biomarker.

Background: Epidermal growth factor receptor (EGFR) overexpression has been considered a poor prognostic factor in breast cancer. Methodology: A prospective study of 206 women with breast cancer analysed by stages (I, II, III and IV) and by immunohistochemical subtype (Luminal A, Luminal B, HER2+ and triple-negative (TN)); 89 healthy controls with normal recent mammography were included. The EGFR measured in the serum (sEGFR) was detected by the Enzyme-Linked Immunosorbent Assay (ELISA) method (R&D Systems kit DY231) collected by blood before any treatment in patients. Kaplan-Meier method and Cox regression were carried out to obtain the prognostic value, considering significance if p < 0.05. Results: With a median follow-up of 36.6 months, 47 deaths occurred. Multivariable Cox regression showed difference of overall survival (OS) associated with sEGFR levels (sEGFR ≤ or > 47.8 ng/mL) in patients with TN cancers, but not of Luminal A, Luminal B or HER2+ subtypes; adjusted by stage, the death risk increased by approximately 415% [hazard ratio (HR): 5.149 (1.900-13.955), p = 0.001] for patients with sEGFR > 47.8 ng/mL compared to patients with a lower sEGFR value. There was no significant correlation of sEGFR with staging, histological tumour grade (G1/G2/G3), Ki67 (< or ≥14%) or body mass index. Conclusions: Increased sEGFR expression in patients with TN tumours is a significant predictor of lower OS and its quantification is inexpensive and straightforward.

The effect of delayed treatment in breast cancer patients: How much is too late? An experience of a single-center study effect of surgery delay in survival.

BACKGROUND AND OBJECTIVES: Proper treatment is critical for control and curative intent in breast cancer. Delays in receiving treatment can influence patients' prognoses. METHODS: Retrospective, observational, single-center study based on data from medical records of 747 patients with non-metastatic invasive ductal breast carcinoma (I-III) in the initial analysis, comprising 554 patients undergoing adjuvant and 193 neoadjuvant treatment. Kaplan-Meier, Cox regression and time-dependent Cox regression were performed to obtain the predictive value of time to surgery and time to first treatment. Immortal time bias was managed and only 721 patients were included in the multivariable analysis. RESULTS: During a median observation of 64.4 months, there were 140 death events and 177 disease progression events. Time to surgery (TTS) and time from completion of neoadjuvant chemotherapy to surgery (TNS) showed a significant impact on overall survival, associated with a 6% increased chance of death [HR: 1.06 (1.03-1.09), p < 0.001] and 4% [HR: 1.04 (1.00-1.09), p = 0.048] with a one-month increment, respectively. By multivariable analysis, continuous TTS had a different weight as a prognostic factor in stage IIIA/IIIB [adjusted HR: 1.249 (1.072-1.454), p = 0.004] compared to stage I/II [adjusted HR: 1.093 (1.048-1.141), p < 0.0005]. Likewise, TNS was significant after adjusting for other factors [adjusted HR: 1.092 (1.038-1.148), p = 0.001]. CONCLUSION: Delay in receiving surgery with curative intent impairs the survival of patients with breast cancer.

A hierarchical approach to combine histological grade and immunohistochemical factors to identify high-risk luminal breast cancers.

Background: The luminal subtype accounts for ~70% of newly diagnosed breast cancer patients. Although it has a better prognosis, approximately 30% of them develop a late relapse. Identifying those patients is of interest to improve treatment decisions. Methods: A retrospective observational, single-centre study based on data from medical records of 572 non-metastatic (I-III) invasive ductal breast carcinoma patients, 448 with luminal tumours and 124 with triple-negative tumours. Kaplan-Meier, Cox regression and time-dependent Cox regression were carried out to obtain the prognosis value of risk factors. Results: During a median observation of 5.5 years, 105 distant metastasis events and 105 all-cause deaths were observed. In addition to known clinicopathological factors (i.e., age, tumour size and lymph node metastasis), the high semi-quantitative expression of both hormone receptors was associated with distant metastasis-free survival (DMFS) (adjusted hazard ratio (HaR): 0.524 (0.316-0.867), p = 0.012) and overall survival (OS) (adjusted HaR: 0.486 (0.286-0.827), p = 0.008). The stratified analysis made it possible to identify risk modification factors. Subsequent stratification by histological grade, Ki-67 and semi-quantitative PR expression or, mainly, the composite semi-quantitative expression of hormone receptors (cHR) enabled the identification of luminal breast cancer patients of adjuvant schema at higher risk for metastasis and death. However, initial analyses including patients of neoadjuvant therapy pointed to a path of subsequent stratification by cHR and histological grade, also enabling grouping of luminal breast cancer patients with similar prognosis for DMFS (cHR ≤ 4+ G2 or G3 versus triple-negative, adjusted HaR: 0.703 (0.415-1.189), p = 0.189) and OS (cHR ≤4+ G2 or G3 versus triple-negative, adjusted HaR: 0.662 (0.403-1.088), p = 0.104). Conclusion: The semi-quantitative expression of both cHR, Ki-67 proliferation index and histological grade can identify luminal breast cancer patients at greater risk of developing metastasis and death when combined in a hierarchical fashion, and could be useful for a better prognosis stratification in services from low- and middle-income countries.

Prognosis value of lymphovascular invasion in patients with invasive ductal breast carcinoma according to lymph node metastasis status.

Background: Tumour lymphovascular invasion is not routinely assessed in all pathology services, and whether reporting it quantitatively or qualitatively is the main factor associated with the loss of this prognostic event. This study aimed to analyse the prognostic value of qualitatively reported lymphovascular invasion in patients with invasive breast ductal carcinoma. Methods: This was a retrospective, single-center study, enrolling a total of 426 patients with invasive ductal carcinoma of the breast with a report of lymphovascular invasion, with a median follow-up of approximately 4.5 years. Kaplan-Meier and Cox regression was performed to obtain the predictive value of lymphovascular invasion. Propensity score matching was performed to reduce bias by standardising factors with significant differential distribution of lymphovascular invasion status. Results: Lymphovascular invasion was present in 197 (49.2%) patients. Multivariate Cox regression showed that lymphovascular invasion independently increases the risk of death by almost two times (adjusted hazard ratio (HR): 2.045 (1.226-3.406), p = 0.006) and the risk of distant metastasis by more than two times (adjusted HR: 2.373 (1.404-4.010), p = 0.001). Subgroup analysis after matching by propensity score in adjuvant-only patients showed that the lymphovascular invasion is a factor of increased death in N- patients (adjusted HR: 12.597 (1.624-97.728), p = 0.015) and of distant metastasis-free survival in N+ patients (adjusted HR: 4.862 (1.649-14.335), p = 0.004) and almost for N- patients (adjusted HR 7.905 (0.969-64.509), p = 0.004). Conclusion: The presence of lymphovascular invasion is a predictor of worse prognosis in patients with invasive ductal carcinoma of the breast, even with metastatic lymph node disease (N1-N3).

The benefits of trastuzumab in the treatment of HER2+ breast cancer as a function of exposure time.

BACKGROUND: Breast cancer is a heterogeneous disease with overexpression of several receptors, such as human epidermal receptor 2 (HER2), which is a prognostic and predictive biomarker for treatment with the anti-HER2 monoclonal antibody trastuzumab. This study aimed to test the contribution of this regimen in patients with overexpression/amplification of HER2 for periods shorter than the 1-year treatment recommendation. METHODS: A retrospective single-centre study involving 155 patients with non-metastatic (stages I-III) invasive ductal HER2+ breast carcinoma, with a median follow-up of 48.9 months after completion of adjuvant therapy, except endocrine therapy. RESULTS: About 60% of patients received trastuzumab therapy for a median time of 365 days. Although the use of trastuzumab for a short period has provided some benefit, analyses of survival with a continuous dependent variable have revealed a minimum time for improved survival. In the multivariate analysis by Cox regression, trastuzumab use duration exceeding 9 weeks resulted in protection against distant metastasis (adjusted HR: 0.307 (0.139-0.678), p = 0.004), disease progression (adjusted hazard ratio (HR) 0.353 (0.175-0.714), p = 0.004) and death (adjusted HR: 0.267 (0.105-0.678), p = 0.005), being superior to multimodal systemic therapy with chemotherapy and to endocrine therapy without trastuzumab, but inferior to almost 1 year of administration of this monoclonal antibody, especially regarding overall survival (adjusted HR: 0.203 (0.069-0.596), p = 0.004). CONCLUSION: Despite showing some benefits, the protective effect derived from a suboptimal time of trastuzumab exposure is inferior to the standard course of 1 year.

The effectiveness of radiotherapy in preventing disease recurrence after breast cancer surgery.

BACKGROUND AND OBJECTIVES: The locoregional management of breast cancer has a critical impact on prognosis. This study aimed to analyze the effectiveness of radiotherapy against the deleterious effect of positive surgical margins on disease outcomes. METHODS: Retrospective, single-center study enrolled 721 breast cancer patients with a median follow-up of approximately 64.50 months (3.67-247.40). Analyses were performed considering the end of adjuvant therapy, except endocrine therapy. Kaplan-Meier and Cox regression were performed to obtain the predictive value of treatments. RESULTS: The minimally adequate radiotherapy (≥45 cGy) was associated with improved outcomes in breast cancer patients compared to inadequate radiotherapy (<45 cGy/no) by controlling locoregional relapses and distant metastasis. In patients with positive surgical margins (n = 53), radiotherapy was associated with an approximate decrease of 90% in locoregional relapse risk [adjusted HR: 0.108 (0.012-0.932), p = 0.043]. Radiotherapy did not alter the adverse effect of positive surgical margins, especially in patients with a higher risk of poorly differentiated tumors (n = 146), presence of lymphovascular invasion (n = 163), and triple-negative subtype (n = 113). Notwithstanding, radiotherapy was associated with respective decreases of distant metastasis risk of 75.2% [adjusted HR: 0.248 (0.081-0.762), p = 0.015] and 67.8% [adjusted HR: 0.322 (0.101-1.029), p = 0.056] in patients with triple-negative tumors or with lymphovascular invasion. CONCLUSION: Adequate radiotherapy is associated with better outcomes in breast cancer. Despite improving locoregional relapse-free survival, radiotherapy does not ablate positive surgical margins, a factor of poorer prognosis that prevails mainly in patients with factors of higher relapse risk.