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EGFR inhibitors, even with therapeutics superiorities in anticancer, can cause idiosyncratic pulmonary and hepatic toxicities that are associated with the reactive electrophile bioactivated by Cytochrome P450s (P450s). Until now, neither has the electrophilic intermediate been caught experimentally, nor has the subtle mechanism been declared. Herein, the underlying mechanism of bioactivation mediated by P450s was explored by DFT calculations for a case of EGFR inhibitor, Erlotinib. Based on the calculation and analysis, we suggest that with other metabolites, reactive electrophiles of Erlotinib: epoxide and quinine-imine, can be generated by several steps along the oxidative reaction pathway. The generation of epoxide needs two steps: (1) the addition of Erlotinib to Compound I (Cpd I) and (2) the rearrangement of protons. Whereas, quinine-imine needs a further oxidation step (3) via which quinone is generated and ultimately turns into quinine-imine. Although both reactive electrophiles can be produced for either face-on or side-on pose of Erlotinib, the analysis of energy barriers indicates that the side-on path is preferred in solvent environment. In the rate-determining step, e.g. the addition of Erlotinib to the porphyrin, the reaction barrier for side-on conformation is decreased in aqueous and protein environment compared with gas phase, whereas, the barrier for face-on pose is increased in solvent environment. The simulated mechanism is in good agreement with the speculation in previous experiment. The understanding of the subtle mechanism of bioactivation of Erlotinib will provide theoretical support for toxicological mechanism of EGFR inhibitors. [ABSTRACT FROM AUTHOR]

Background: Toll-like receptors (TLRs) regulate the balance between the innate and adaptive immune responses. Missense single nucleotide polymorphisms (SNPs) in TLRs might be functional and thus influence the risks of chronic infection and cancer development. Here, we investigated the association of two missense SNPs, rs3775291 (c.1234G>A) in the TLR3 gene and rs4833095 (c.743T>C) in the TLR1 gene, with relapse-free survival (RFS) in a cohort of prospectively observed breast cancer patients. Methods: In this prospective observational study, rs3775291 in TLR3 and rs4833095 in TLR1 were genotyped in 715 patients with primary breast cancer in a Chinese population. Results: Univariate analysis revealed that the patients with the AA genotype of rs3775291 had a shorter RFS compared with those carrying the G allele in the recessive model (P<0.01), but this finding was not observed with the dominant model (P = 0.31). The results remained significant after adjusting for the clinical parameters in the recessive model (HR = 3.53, 95% confidence interval [CI]: 1.98–6.31, P<0.01). Further survival analysis indicated that this SNP was significant in the luminal-B, triple-negative breast cancer (TNBC), and human epidermal growth factor receptor 2-positive (HER2+) patients using the recessive model but that it was not significant in the luminal-A patients. The SNP rs4833095 showed a non-significant tendency toward an increased RFS rate in the patients with the TT genotype. Conclusion: Our results suggest that the SNP rs3775291 in TLR3 may influence patient outcome. Further studies with larger sample sizes should be conducted to validate our findings. [ABSTRACT FROM AUTHOR]

Purpose: Neoadjuvant chemotherapy (NCT) is a standard treatment option for locally advanced breast cancer. However, the lack of an efficient method to predict treatment response and patient prognosis hampers the clinical evaluation of patient eligibility for NCT. An elevated lymphocyte-to-monocyte ratio (LMR) has been reported to be associated with a favorable prognosis for certain hematologic malignancies and for nasopharyngeal carcinoma; however, this association has not been investigated in breast cancer. The purpose of this study was to evaluate whether pre-NCT LMR analysis could predict the prognosis of patients with locally advanced breast cancer. Methods: A retrospective cohort of 542 locally advanced breast cancer patients (T3/T4 and/or N2/N3 disease) receiving NCT followed by radical surgery was recruited between May 2002 and August 2011 at the Fudan University Shanghai Cancer Center. Counts for pre-NCT peripheral absolute lymphocytes and monocytes were obtained and used to calculate the LMR. Results: Univariate and multivariate analysis revealed that higher LMR levels (≥4.25) were significantly associated with favorable DFS (P = 0.009 and P = 0.011, respectively). Additionally, univariate analysis revealed that a higher lymphocyte count (≥1.5×109/L) showed borderline significance for improved DFS (P = 0.054), while a lower monocyte count (<0.4×109/L) was associated with a significantly better DFS (P = 0.010). Conclusions: An elevated pre-NCT peripheral LMR level was a significantly favorable factor for locally advanced breast cancer patient prognosis. This easily obtained variable may serve as a valuable marker to predict the outcomes of locally advanced breast cancer. [ABSTRACT FROM AUTHOR]

Background: Reduced overall survival has been observed in patients with left-sided versus right-sided breast cancer due to cardiac toxicity after radiotherapy. However, the effect of laterality and primary tumor site on breast cancer-specific mortality (BCSM) remains unclear. Patients and Methods: We analyzed data from 305,443 women ages 20- to 79-years-old diagnosed with breast cancer between 1990 and 2009. The data were obtained from the population-based Surveillance, Epidemiology, and End Results (SEER) program of the U.S. National Cancer Institute. The survival outcomes with regard to laterality and primary tumor site were compared using univariate and multivariate (Cox proportional hazards regression model) methods. Results: In the multivariate analysis, BCSM was affected by the primary tumor site (P<0.0001) but not laterality (P = 0.331). The combined effect was piecewise: using the left upper-outer quadrant as the reference, the BCSM hazard ratio (HR) was not significant in the right upper quadrant (P = 0.755) and the right central portion (P = 0.329). The BCSM HR was slightly increased in the left central portion as well as the left and right lower-outer quadrants (HRs from 1.136 to 1.145; P<0.0001). The BCSM HR was significantly increased in the upper-inner and lower-inner quadrants (HRs from 1.242 to 1.372; P<0.0001) on both sides. Laterality only impacted BCSM in patients with breast cancer located in the central portion (HR, 1.100; P = 0.013, using the right side as the reference). Conclusion: Patients with tumors in the upper-outer quadrant of both sides and the right central portion have a better prognosis than patients with tumors at other locations. Laterality is not regarded as a prognostic factor in breast cancer. [ABSTRACT FROM AUTHOR]

Background: Tumor size is one of the most important factors in making clinical and pathological assessment of breast cancer. In the present study, we aimed to determine whether the preoperative measurement of tumor size, by imaging modalities, deviate from the postoperative pathological measurement in breast cancer. Patients and Methods: 1296 patients diagnosed with invasive ductal breast carcinoma (IDC) during 2007 and 2009 were involved. Pre- and postoperative measurements of tumor size were compared using paired t-test and Chi-square test. Results: The mean maximum diameters of tumors by imaging modalities and pathology were 27.9 mm and 22.4 mm, respectively. There was a statistically significant difference of 5.5 mm (95% CI: 4.7–6.2, p<0.001) between them. The discordance between pre- and post-surgical measurements of tumor size had significant effect on choosing surgery type, causing less application of breast conserving therapy (p<0.0001). Conclusion: Compared to pathological size, preoperative measurement by imaging modalities tends to overestimate tumor size. These differences could have implications in the treatment of patients with breast cancer. [ABSTRACT FROM AUTHOR]

Background: Postmastectomy breast reconstruction is widely used in breast cancer patients for its aesthetic effect. Although several studies have casted suspicion upon the oncological safety of immediate breast reconstruction after mastectomy, the potential impact of different reconstruction methods on patient survival remains unclear. Patients and Methods: We identified 35,126 female patients diagnosed with breast cancer from January 1, 1998 to December 31, 2002 in the Surveillance, Epidemiology, and End Results database. Breast cancer-specific survival (BCSS) and overall survival (OS) were compared among patients who underwent mastectomy with or without immediate breast reconstruction (autologous reconstruction or implant reconstruction) using Cox proportional hazard regression models. Results: In multivariate analysis unadjusted for family income, patients undergoing immediate postmastectomy reconstruction exhibited improved BCSS [pooled reconstruction (any types of reconstruction): hazard ratio (HR)  =  0.87, 95% confidence interval (CI) 0.80–0.95, P = 0.001] and OS (pooled reconstruction: HR = 0.70, 95% CI 0.65–0.75, P<0.001) compared to patients who underwent mastectomy alone. However, after stratifying by family income, patients receiving reconstruction showed limited advantage in BCSS and OS compared with those undergoing mastectomy alone. When comparing between the two reconstruction methods, no significant differences were observed in either BCSS (implant versus autologous reconstruction: HR = 1.11, 95%CI 0.90–1.35, P = 0.330) or OS (implant versus autologous reconstruction: HR = 1.07, 95% 0.90–1.28, P = 0.424). Conclusions: Compared to mastectomy alone, immediate postmastectomy reconstruction had limited advantage in survival after adjusting for confounding factor of family income. Our findings, if validated in other large databases, may help to illustrate the actual effect of immediate postmastectomy reconstruction on patient survival. [ABSTRACT FROM AUTHOR]