JAK2 regulates paclitaxel resistance in triple negative breast cancers.

We investigated the molecular mechanisms of paclitaxel resistance in TNBC using seven patient-derived xenograft (PDX) models and TNBC cell lines. Among the seven PDX models, four models showed resistance to paclitaxel. Dysregulation of JAK/STAT pathways and JAK2 copy number gains were observed in the four paclitaxel-resistant PDX tumors. In TNBC cell lines, silencing the JAK2 gene showed a significant but mild synergistic effect when combined with paclitaxel in vitro. However, JAK1/2 inhibitor treatment resulted in restoration of paclitaxel sensitivity in two out of four paclitaxel-resistant PDX models and JAK1/2 inhibitor alone significantly suppressed the tumor growth in one out of the two remaining PDX models. Transcriptome data derived from the murine microenvironmental cells revealed an enrichment of genes involved in the cell cycle processes among the four paclitaxel-resistant PDX tumors. Histologic examination of those PDX tumor tissues showed increased Ki67-positive fibroblasts in the tumor microenvironment. Among the four different cancer-associated fibroblast (CAF) subtypes, cycling CAF exhibiting features of active cell cycle was enriched in the paclitaxel-resistant PDX tumors. Additionally, fibroblasts treated with the conditioned media from the JAK2-silenced breast cancer cells showed downregulation of cell cycle-related genes. Our data suggest that the JAK2 gene may play a critical role in determining responses of TNBC to paclitaxel by modulating the intrinsic susceptibility of cancer cells against paclitaxel and also by eliciting functional transitions of CAF subtypes in the tumor microenvironment. KEY MESSAGES : We investigated the molecular mechanisms of paclitaxel resistance in TNBC. JAK2 signaling was associated with paclitaxel resistance in TNBC PDX models. Paclitaxel-resistant PDX tumors were enriched with microenvironment cCAF subpopulation. JAK2 regulated paclitaxel-resistant CAF phenotype transition.

Intensity of metastasis screening and survival outcomes in patients with breast cancer.

Previous randomized trials, performed decades ago, showed no survival benefit of intensive screening for distant metastasis in breast cancer. However, recent improvements in targeted therapies and diagnostic accuracy of imaging have again raised the question of the clinical benefit of screening for distant metastasis. Therefore, we investigated the association between the use of modern imaging and survival of patients with breast cancer who eventually developed distant metastasis. We retrospectively reviewed data of 398 patients who developed distant metastasis after their initial curative treatment between January 2000 and December 2015. Patients in the less-intensive surveillance group (LSG) had significantly longer relapse-free survival than did patients in the intensive surveillance group (ISG) (8.7 vs. 22.8 months; p = 0.002). While the ISG showed worse overall survival than the LSG did (50.2 vs. 59.9 months; p = 0.015), the difference was insignificant after adjusting for other prognostic factors. Among the 225 asymptomatic patients whose metastases were detected on imaging, the intensity of screening did not affect overall survival. A small subgroup of patients showed poor survival outcomes when they underwent intensive screening. Patients with HR-/HER2 + tumors and patients who developed lung metastasis in the LSG had better overall survival than those in the ISG did. Highly intensive screening for distant metastasis in disease-free patients with breast cancer was not associated with significant survival benefits, despite the recent improvements in therapeutic options and diagnostic techniques.

Association between Number of Retrieved Sentinel Lymph Nodes and Breast Cancer-related Lymphedema.

PURPOSE: Sentinel lymph node biopsy (SLNB) has become a standard axillary staging surgery for early breast cancer, and the proportion of patients requiring axillary lymph node dissection (ALND) is decreasing. We aimed to evaluate the association between the number of sentinel lymph nodes (SLNs) retrieved and the risk of lymphedema of the ipsilateral arm. METHODS: Prospectively collected medical records of 910 patients were reviewed. Lymphedema was defined as a difference in circumference > 2 cm compared to the contralateral arm and/or having clinical records of lymphedema treatment in the rehabilitation clinic. RESULTS: Together with an objective and subjective assessment of lymphedema, 36 patients (6.1%) had lymphedema in the SLNB group and 85 patients (27.0%) had lymphedema in the ALND group (p < 0.001). In a multivariate analysis of the whole cohort, risk factors significantly associated risk with the development of lymphedema were body mass index, mastectomy (vs. breast-conserving surgery), ALND, and radiation therapy. In logistic regression models in the SLNB group only, there was no correlation between the number of retrieved SLNs and the incidence of lymphedema. In addition, in the Pearson correlation analysis, no correlation was observed between the number of retrieved SLNs and the difference in circumference between the ipsilateral and contralateral upper extremities (correlation coefficients = 0.067, p =0.111). CONCLUSION: The risk of lymphedema in breast cancer surgery and adjuvant treatments is multifactorial. The number of retrieved lymph nodes during sentinel biopsy was not associated with the incidence of lymphedema.

Effects of tamoxifen and aromatase inhibitors on the risk of acute coronary syndrome in elderly breast cancer patients: An analysis of nationwide data.

BACKGROUND: Aromatase inhibitors (AIs) are the preferred endocrine treatment for postmenopausal hormonal receptor-positive breast cancer. However, there is controversy on the long-term cardiovascular and cerebrovascular safety of AIs over that of tamoxifen. METHODS: We analyzed the National Health Information Database (NHID) of 281,255 women over a 20-year-old diagnosed with breast cancer between 2009 and 2016. Cardiovascular events (CVEs) were defined as the development of the following, acute coronary syndrome (ACS), ischemic and hemorrhagic stroke, defined by using insurance claim records. The model was constructed by Cox proportional hazard regression and this model was used to analyze the effects of AI and tamoxifen on CVE. RESULTS: We included 47,569 women for the final analysis. Patients were classified into 'No hormonal treatment (n = 18,807), 'Switch (n = 2097)', 'Tamoxifen (n = 7081)' and 'AI (n = 19,584)'. There were 2147 CVEs in 2032 patients (4.1%). Univariate analysis showed that women with tamoxifen had significantly lower risk for CVEs compared to no-treatment (hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.74-0.97) while AI showed no such effect (HR 0.93, 95% CI 0.84-1.02). After adjusting for other risk factors (hypertension, dyslipidemia, family history), the use of tamoxifen was associated with significant protective effect against ACS (HR 0.63, 95% CI 0.47-0.84). CONCLUSIONS: Our results, based on the NHID, supports the protective effect of tamoxifen against CVE in Korean breast cancer patients aged 55 and older that is not seen with AIs. Our results can guide the selection of adjuvant hormonal treatment agents for Korean breast cancer patients based on their risk of developing CVE.