Yi Zhou Jiang

An elevated peripheral blood lymphocyte-to-monocyte ratio predicts favorable response and prognosis in locally advanced breast cancer following neoadjuvant chemotherapy.

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.

The residual tumor autophagy marker LC3B serves as a prognostic marker in local advanced breast cancer after neoadjuvant chemotherapy

Purpose: This study sought to investigate the prognostic value of the autophagy marker microtubule–associated protein chain 3B (LC3B) in patients with residual tumors after neoadjuvant chemotherapy (NCT) for locally advanced breast cancer (LABC). Patients and Methods: The expression of LC3B in residual breast cancer cells was assessed by immunohistochemistry in surgical specimens from 229 patients diagnosed with histologically proven invasive breast cancer. All patients underwent NCT followed by mastectomy and were considered nonpathologic complete responders (non-pCR) after a pathologic evaluation. The prognostic value of various clinicopathologic factors was evaluated. Results: The LC3B density was similar between the peripheral and central area of the tumors (P = 0.328) but was significantly lower in the extratumoral area (P < 0.001 and P < 0.001, respectively). Furthermore, LC3B density, which correlated with Beclin-1 expression, Ki-67 index, and breast cancer subtype, served as an independent prognostic factor for both relapse-free survival (RFS; P = 0.012) and overall survival (OS; P = 0.008); the prognostic value of LC3B was most significant in triple-negative patients. Using a combination of LC3B expression and the status of residual involved lymph nodes, the patients were classified into four groups with different risks of relapse and death (P < 0.001 for RFS and P = 0.003 for OS). Conclusion: LC3B can be used as a prognostic marker in patients with non-pCR after NCT for breast cancer, which highlights the importance of autophagy in the biologic behavior of chemoresistant cancer cells. Furthermore, evaluating and targeting autophagy in the neoadjuvant setting may help prevent disease relapse in patients with non-pCR. Clin Cancer Res; 19(24); 6853–62. ©2013 AACR.

GATA3 mutations define a unique subtype of luminal‐like breast cancer with improved survival

The GATA3 gene (GATA‐binding protein 3) is one of the most frequently mutated genes in breast cancer. The objective of the current study was to determine the clinicopathologic characteristics of patients with breast cancer harboring GATA3 mutations.

Favorable Prognostic Impact in Loss of TP53 and PIK3CA Mutations after Neoadjuvant Chemotherapy in Breast Cancer

We investigated the loss of somatic mutations in TP53 and PIK3CA in breast cancer tissue after neoadjuvant chemotherapy (NCT) and the clinical relevance of the observed mutation profiles. Samples were derived from three cohorts: Cohort 1 consisting of 206 patients undergoing NCT with matched pre- and postchemotherapy tumor tissues; Cohort 2 consisting of 158 additional patients undergoing NCT; and Cohort 3, consisting of 81 patients undergoing chemotherapy with prechemotherapy tumor tissues. In the first cohort, somatic mutations in TP53 or PIK3CA were identified in 24.8% of the pre-NCT tumor samples but in only 12.1% of the post-NCT tumor samples (P < 0.001). Patients with initial TP53 and PIK3CA mutations who became negative for the mutations after NCT had a higher Miller-Payne score (P = 0.008), improved disease-free survival, and improved overall survival than those with no change or the opposite change. The association of loss of mutations in TP53 and PIK3CA and improved survival was successfully validated in the second cohort. In addition, 28.4% of the tumors showed intratumoral heterogeneity of somatic mutations in TP53 or PIK3CA, whereas 71.6% were homogeneous, either with or without the mutations. Our data reveal the novel concept that chemotherapy may reduce mutation frequency in patients with breast cancer. Furthermore, the loss of somatic mutations in TP53 and PIK3CA may be translated to biomarkers for prognosis via further verification, which may optimize the choice of sequential therapy and improve patient survival.

The effect of laterality and primary tumor site on cancer-specific mortality in breast cancer: a SEER population-based study.

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.

The demographic features, clinicopathologic characteristics, treatment outcome and disease-specific prognostic factors of solitary fibrous tumor: a population-based analysis.

Background Solitary fibrous tumors (SFT) demographic features, clinicopathologic characteristics, treatment outcome and disease-specific prognostic factors were unexplored comprehensively. Methods SEER program was used to identify patients diagnosed with SFT from 1973 to 2012. Overall collected data were analyzed by using the SPSS 18.0. Results In total, 804 cases were found including 613 cases with SFT-specific mortality and 801 patients were analyzed for overall survival (OS). The 3-year disease specific survival (DSS), 5-year DSS and 10-year DSS were 73.3%, 65.7% and 53.3%. The 3-year OS, 5-year OS and 10-year OS were 71.9%, 63.3% and 47.3%. In the multivariate survival analysis, the age > 51 years (hazard ratio [HR] = 1.851 for DSS, P = 0.024 and HR = 1.652 for OS, P = 0.033; Reference [Ref] ≤ 51 years for DSS and ≤ 53 years for OS), SEER stage metastasized tumor (HR = 4.269 for DSS, P = 0.000 and HR = 2.905 for OS, P = 0.028, Ref - localized + regional tumor), pathologic grade III + IV (HR = 2.734 for DSS, P = 0.001 and HR = 2.585 for OS, P = 0.000, Ref - grade I + II) were adversely associated with DSS and OS. In addition, surgery was favorably associated with DSS (HR = 0.217, P = 0.045, Ref - surgery + radiotherapy). Conclusions The surgery was an independent prognostic factor for DSS. The patients age, SEER stage and pathologic grade were SFT-specific independent prognostic indicators for DSS and OS.

Enriched variations in TEKT4 and breast cancer resistance to paclitaxel

Among chemotherapeutic agents, paclitaxel has shown great efficacy against breast cancer. Prediction of paclitaxel response may improve patient outcomes. Here we show, using exome sequencing, that in comparison with pre-treatment biopsies, two TEKT4 germline variations are enriched in post-treatment tumours. We find TEKT4 variations in ~ 10% of an independent cohort of 84 pairs of samples. Tektin4 (encoded by TEKT4) associates closely with tubulin in doublet microtubules and helps stabilize these structures. These two TEKT4 germline variations in a high cis linkage are biologically relevant, as the ectopic expression of variant TEKT4 deregulates the microtubule stability, antagonizes the paclitaxel-induced stabilizing effect of microtubules and increases paclitaxel resistance. Furthermore, TEKT4 germline variations are associated with reduced disease-free survival and overall survival compared with wild-type TEKT4 in patients undergoing paclitaxel-based chemotherapy. Taken together, we reveal a potential mechanism of resistance to paclitaxel through the acquisition of germline variations in breast cancer.

Dual characteristics of novel HER2 kinase domain mutations in response to HER2-targeted therapies in human breast cancer

Purpose: Somatic mutations in the tyrosine kinase domain of human epidermal growth factor receptor 2 (HER2) may be an alternative mechanism to HER2 activation and can affect the sensitivity toward HER2-targeted therapies. We aimed to investigate the prevalence, clinicopathologic characteristics, and functional relevance of novel HER2 mutations in breast cancer. Experimental Design: We performed Sanger sequencing of all exons of the HER2 gene in 1,248 primary tumors and 18 paired metastatic samples. Novel HER2 mutations were functionally characterized. Results: The total HER2 somatic mutation rate was 2.24% (28/1,248). Of the seven novel HER2 mutations, L768S and V773L were only detected in HER2-negative tumors, whereas K753E was found in HER2-positive disease. L768S and V773L mutations exhibited a significant increase in tyrosine kinase–specific activity and strongly increased the phosphorylation of signaling proteins in various cell lines. Xenograft experiments showed that NIH3T3 cells bearing the L768S and V773L mutations displayed more rapid growth. MCF10A, BT474, and MDA-MB-231 cells bearing the K753E mutation were resistant to lapatinib, but could be inhibited by neratinib. Finally, comparison of HER2 mutations in 18 pairs of primary and metastatic lesions revealed that the drug-resistant HER2 mutations (K753E and L755S) were enriched in metastatic lesions. Conclusions: HER2-negative breast cancer with activating mutations can benefit from HER2-targeted therapies. Meanwhile, mutations in the HER2 kinase domain might be a key mechanism of resistance to HER2-targeted therapy, and irreversible tyrosine kinase inhibitors such as neratinib may offer alternative treatment options. Clin Cancer Res; 22(19); 4859–69. ©2016 AACR.

A prospective evaluation of the association between a single nucleotide polymorphism rs3775291 in toll-like receptor 3 and breast cancer relapse

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.

PIK3CA mutations define favorable prognostic biomarkers in operable breast cancer: A systematic review and meta-analysis

Background Mutations of the p110α catalytic subunit of phosphatidylinositol 3-kinase (PIK3CA) are among the most common genetic aberrations in human breast cancer. At present, controversy exists concerning the prognostic value of the mutations. Methods We performed a systematic review and meta-analysis to clarify the association between PIK3CA mutations and survival outcomes. A comprehensive, computerized literature search of PubMed, Web of Science databases, the Chinese Biomedical Literature Database, and Wangfang Data until August 27, 2013 was carried out. Eligible studies were included according to specific inclusion criteria. Pooled hazard ratio was estimated by using the fixed effects model or random effects model according to heterogeneity between studies. Results Eight eligible studies were included in the analysis, all of which were retrospective cohort studies. The overall meta-analysis demonstrated that the PIK3CA mutations were associated with better clinical outcomes (hazard ratio 0.72; 95% confidence interval: 0.57–0.91; P=0.006). None of the single studies materially altered the original results and no evidence of publication bias was found. Further subgroup analysis of mutations in exons 9 and 20 did not show statistical significance. Conclusion PIK3CA mutations in operable primary breast cancer indicate a good prognosis. Further studies should be conducted to investigate the effect of PIK3CA mutations on clinical outcomes in different histologic types, different molecular subtypes of breast cancer, and different exons of PIK3CA.