bluuebunny/crossref_metadata_2025_split huggingface dataset:
Significance of systemic and local immune responses to the pathological therapeutic effect of neoadjuvant chemotherapy in breast cancer.
Authors: Kim Ryungsa , Kawai Ami , Wakisaka Megumi , Funaoka Yuri , Sawada Sayaka , Shimoyama Mika , Yasuda Naomi , Hidaka Masayuki , Morita Yukitaka , Ohtani Shoichiro , Arihiro Koji 
Published: May 2019

e12084 Background: Activation of the immune response including T lymphocytes, natural killer (NK) cells, and tumor microenvironment factors (TMEFs) is important in inducing a therapeutic response after neoadjuvant chemotherapy (NAC) in breast cancer. We examined the significance of systemic and local immune responses to the pathological therapeutic effect of NAC in breast cancer. Methods: From 2012 to 2018, 38 patients with stage II–III breast cancer received NAC with anthracyclines and taxanes followed by surgery. Therapeutic effects were evaluated according to the histopathology criteria for the assessment of therapeutic effects in breast cancer indicated by the Japanese Breast Cancer Society. Peripheral NK (pNK) cell activity was measured by chromium release assay. Levels of TMEFs were assessed by next-generation sequencing for CD4, CD8, NK, FOXP3, CTLA-4, PD-1, PD-L1, IL-2, IL-6, IL-12, IFN-γ, IL-10, TGF-β, and VEGF in FFPE sections collected from preoperative VAB samples and surgical specimens. Results: The stages, tumor subtypes, and therapeutic outcomes were as follows: II (N = 21), III (N = 17); luminal (N = 22), HER-2 positive (N = 12), TN (N = 4); G1a (N = 8), G1b (N = 13), G2a (N = 7), G2b (N = 4), G3 (i.e. complete) (N = 6). A G2 or better therapeutic effect were significantly associated with high post-NAC levels of NK, and potentially associated with higher CD4, CD8, and lower CTLA-4 after NAC. Multivariate logistic regression analysis showed that a G2 or better therapeutic effect was significantly associated with higher NK after NAC (OR = 1.07; 95% CI, 1.00–1.14; P = .0255). Disappearance of axillary lymph node metastasis was significantly associated with increased NK and pNK cell activity, as well as decreased VEGF level, and potentially associated with lower CTLA-4 after NAC. Conclusions: Increased NK cells after NAC are critical in producing a better therapeutic effect in collaboration with increased CD4 and CD8, and decreased CTLA-4 and VEGF. Systemic activation of pNK cells may improve the elimination of metastatic tumor cells in axillary lymph nodes by coordinating with release of immunosuppression derived from VEGF and activation of immune cells in the tumor microenvironment in breast cancer patients after NAC. An immune checkpoint inhibitor targeting CTLA-4 may improve NAC efficacy for breast cancer.
Impact of serum vitamin D on the response and the prognosis in breast cancer patients treated with neoadjuvant chemotherapy.
Authors: Tokunaga Eriko , Masuda Takanobu , Ijichi Hideki , Koga Chinami , Tajiri Wakako , Tanaka Junko , Nakamura Yoshiaki , Taguchi Kenichi , Okamoto Masahiro 
Published: May 2019

e12088 Background: Neoadjuvant chemotherapy (NAC) is one of the standard therapeutic strategies for operable early breast cancer (BC). A relationship between chemotherapy response and the prognosis has been suggested, especially in HER2+ or triple negative breast cancer (TNBC). Recently, the impact of vitamin D (VD) on pathological complete response (pCR) after NAC has been reported, however, there are no data regarding the relationship between VD level and the efficacy of NAC in Japanese BC patients. Methods: This study included 236 patients with BC at clinical stage I-III, who were treated with anthracycline and taxane-based NAC. HER2-directed therapies were used for HER2+ tumors. Serum 25, hydroxyl VD levels were evaluated using by ELISAusing blood samples obtained before NAC. VD deficiency was defined as <20 ng/ml. Results: Pathological complete response (pCR) was obtained in 52 patients (22.0%). The pCR rate was significantly higher in the patients with HER2+ or TNBC compared with hormone receptor (HR)+/HER2-tumors (p<0.0001). Median VD level was 10.7 ng/ml, and only 7 patients (3.0%) had a VD level ≥20 ng/ml. These results show that most Japanese women are deficient for VD. VD levels increase with age, and the VD levels are significantly higher in postmenopausal patients than in the premenopausal patients (p=0.0029). Patients were dichotomized into VD-low and -high groups at the median value (10.7 ng/ml). Serum VD was not associated with pCR in the all cohort, however, pCR rate was higher in VD-high group in premenopausal patients, especially in the patients withHER2+ or TNBC (p=0.0328). High VD was significantly associated with better prognosis in terms of relapse-free survival (p=0.0327) and distant metastasis-free survival (p=0.0051). This association was observed both in pre- and post-menopausal patients, especially in the patients with HER2+ or TNBC. Conclusions: High VD levels were associated with high pCR rate in premenopausal patients with HER2+ or TNBC. High VD levels were also associated with better prognosis operable BC patients treated with NAC, although VD levels of most Japanese BC patients were lower than the cut-off value.
Serial circulating tumor DNA analysis indicating the efficacy and prognosis of neoadjuvant chemotherapy for locally advanced breast cancer.
Authors: Zhou Yidong , Xu Yaping , Gong Yuhua , Zhou Jiaolin , Lu Yaping , Wang Changjun , Yao Ru , Peng Li , Guan Yan-Fang , Wang Jiayin , Xia Xuefeng , Yang Ling , Yi Xin , Sun Qiang 
Published: May 2019

e12089 Background: The efficacy evaluation of neoadjuvant chemotherapy (NCT) for locally advanced breast cancer (LABC) is still a questionable issue. The clinical imaging is always discrepant from pathological assessment postoperatively, and conventional tumor markers, such as CEA and CA15-3, did not show significantly correlation with the response to NCT in breast cancer patients. Analysis of circulating tumor DNA (ctDNA) from blood may provide a promising alternative. Methods: Collectively, 63 tissue and 204 blood samples from 32 patients with LABC were collected. There were four sampling nodes for blood collection: at baseline, during chemotherapy, after chemotherapy and after operation. Hybrid capture-based genomic profiling with a 1021-gene panel was carried out for both tissue and blood samples. Results: Totally, 151 somatic mutations were detected in tissue samples from 32 patients. TP53 (n = 14, 43.75%) and PIK3CA (n = 13, 40.63%) were the most recurrent mutant genes. Among 11 patients with HER2 overexpression, 10 (90.91%) carried ERBB2 amplification. All of 21 patients with normal HER2 present diploid ERBB2. The overall concordance between HER2 overexpression and ERBB2 amplification was 96.88%. At least one tissue mutation could be detected in blood collected at baseline for 21 patients, during chemotherapy for three patients, after chemotherapy for nine patients, and after operation for four patients. There was no tissue mutation in blood collected during and after chemotherapy for four patients reached pathologic complete response (pCR). The median of pathological tumor decrease in situ was 54.63% (17.07% to 98.04%) for patients with tissue mutations in blood collected either during or after chemotherapy, and 86.53% (7.69% to 98.04%) for patients without tissue mutation in both blood samples. Furthermore, the median number of pathologically involved lymph nodes was 3.5 (0 to 16) and 1 (0 to 9) for two patients cohort, respectively. All of four patients with tissue mutations in postoperative blood experienced distant metastasis during follow-up, while only 7.14% (2/28) of those without tissue mutation relapsed. The median DFS was 9.8 and 22.7 months, respectively (HR 26.14, 95% CI 1.161 to 588.5, p < 0.0001). Conclusions: Sequential genomic profiling of blood ctDNA can be used to evaluate the therapeutic efficacy of NCT, as well as the postoperative survival. This study highlights the feasibility of integrating ctDNA profiling into the clinical management for LABC undergoing NCT. Clinical trial information: NCT02797652.
Investigating the utility of breast cancer (BC) molecular signatures and immune signature profiling (ISP) as predictors of pathological complete response (pCR) to neoadjuvant chemotherapy + trastuzumab (NAC+T) in HER2+ BC.
Authors: Stemmer Salomon M. , Shvartser Yulia , Shemesh Itay Israel , Peretz Idit , Yerushalmi Rinat , Hendler Daniel , Haviv Izhak , Brauer Heather Ann , Castro Michael 
Published: May 2019

e12109 Background: Trastuzumab targets HER2 directly as well as contributes to activation of the immune system against the tumor. We investigated the utility of BC molecular signatures and ISP as predictors of pCR to NAC+T in HER2+ BC pts. Methods: The analysis included 73 consecutive HER2+ BC pts with pathological samples at diagnosis, who received NAC+T. RNA was extracted from 73/22 biopsy/surgical specimens (FFPE). RNA was analyzed using NanoString PanCancer Immunoncology 360 (IO360) panel with PAM50 spike-in. Raw gene counts were log2-transformed and normalized (using housekeeping genes). The analysis assessed 47 gene signatures including immune related and PAM50 signatures. Signatures were computed after removing samples with low expression of the housekeeping genes and normalization. Signature scores range from ~0 to 10 and have an average value of 5 in tumor samples from The Cancer Genome Atlas. Results: Overall, 46% of the pts achieved pCR; of 13 pts who were IHC 2+ and FISH positive, one achieved pCR. Significant associations were found between response to NAC+T (pCR, no response) and molecular signatures/ISP from the initial biopsy (Table). For pts who did not experience pCR and who underwent surgery, paired sample analysis was performed assessing molecular signatures/ISP in the initial biopsy sample vs the surgical sample. This analysis demonstrated a significant increase post-treatment (compared to the initial biopsy sample) in Risk of Recurrence (ROR) score (p=.036), interferon (IFN) downstream signature (p=.038), and antigen‐processing machinery (APM) loss (p=.002). Conclusions: Combining molecular BC signatures and ISP on biopsy samples may have a predictive value in HER2+BC pts for whom NAC+T is considered. Luminal A pts and IHC 2+ (FISH positive) are unlikely to achieve pCR with NAC+T. [Table: see text]
Long-term toxicity profile of trastuzumab emtansine (T-DM1): A multicenter real-life study.
Authors: Buono Giuseppe , Fabi Alessandra , Del Mastro Lucia , Cannita Katia , La Verde Nicla Maria , Ardito Raffaele , Riccardi Ferdinando , Montemurro Filippo , Cazzaniga Marina Elena , Garrone Ornella , Zambelli Alberto , Conte Benedetta , Caputo Roberta , Cianniello Daniela , Bonotto Marta , Bartoletti Michele , Parola Sara , De Placido Sabino , Di Maio Massimo , Arpino Grazia 
Published: May 2019

e12507 Background: T-DM1 is widely used in HER2 positive metastatic breast cancer (MBC) patients (pts), often for many cycles until progression. However, little is known about its long term toxicity. The aim of this study was to evaluate the safety profile of T-DM1 when delivered for ≥12 cycles. Methods: HER2 positive MBC pts who had received ≥12 cycles of T-DM1 across 18 Italian cancer centers were enrolled from January 2017 to September 2018. The 12 cycles cut-off was chosen based on the EMILIA trial median PFS (9.6 months), to identify a patient population treated with T-DM1 for longer time. Tumor and clinical characteristics were collected. Standard haematological tests, blood chemistries and side effects (nausea, vomiting, diarrhea, stomatitis, asthenia) were recorded cycle by cycle, according CTCAE criteria version 4. Haematological and laboratory toxicities were available for 86 patients, while other toxicities for all 115 patients. Results: Overall, 115 pts were enrolled. Median age was 54.5 (range 29.6–81.9); median time from diagnosis of metastatic disease to first T-DM1 cycle was 32.5 months. T-DM1 was administered as 2nd line and 3rd line of treatment in 45.2% and 27.8% of pts, respectively. Median number of cycles was 18 (range 12-59). Complete response, partial response and stable disease rates were 11.4%, 43% and 45.6%, respectively. Treatment related side effects are shown in table 1. Interestingly, no increased liver toxicity was observed in pts with liver metastases. Analysis of mean CTCAE grade by cycle showed that no relevant incremental toxicity was observed during long term T-DM1 therapy. Conclusions: T-DM1 is safe and well tolerated in these long responding pts. We found no relevant cumulative toxicity. Patients should be treated with T-DM1 as long as their tumor responds, as no safety issues are related to its long term use. [Table: see text]
Outcomes with CDK4/6 inhibitors based on endocrine sensitivity in hormone receptor-positive metastatic breast cancer (HR+ MBC).
Authors: Jain Amit L , Mullins Janice Nhan , Poorman Kelsey Anne , Chaudhry Amina , Ranganath Harsha Avinash , Miller Emily McCollum , Valasareddy Poojitha , Smith Justin R , Ryder Julie , Winerip Michelle , Schwartzberg Lee S. , Vidal Gregory A. 
Published: May 2019

e12526 Background: PALOMA-3 results demonstrated that patients (pts) with sensitivity to previous endocrine therapy had a substantial benefit with Palbociclib compared to those with intrinsic endocrine resistance (Turner NC et al. NEJM 2018). ESR1 mutation has been associated with decreased response to endocrine therapy (Fribbens C et al. JCO 2016) and NSD3 amplification in breast cancer cells have been correlated with the overexpression of ESR1 (Irish JC et al. Mol Oncol 2016). Here we demonstrate a real-world response to CDK4/6i based on high-risk features and correlation to biomarkers of response. Methods: We retrospectively analyzed 115 HR+MBC pts at a single large community cancer center who received CDK4/6i + endocrine therapy and 40 matched controls treated with endocrine therapy and underwent NextGen Sequencing (NGS) profiling of 592 genes (Caris Life Sciences, Phoenix, AZ). The primary outcome was progression-free survival (PFS). Hazard ratios were calculated from Cox proportional hazards models built using the survival package[1] in R. Results: Among 115 pts in the CDK4/6i cohort, the median PFS for pts treated in the first-line (N=77) versus (vs.) second-line (N=38) was 9.7 and 4.6 months (mo) respectively (HR 2.04, p=0.001). Further, the median PFS in first-line cases who had a Disease-Free Survival (DFS) of >2 years (endocrine sensitive) (N=27) was 11.9 mo, and in pts with DFS < 2years (endocrine resistant) (N=24), it was 7.7 mo (HR 0.71, p= 0.397). Six pts with ESR1 mutations had worse PFS compared to ESR1 wild-type (N=40) when treated with CDK4/6i in 1st line, 6.4 vs. 18 mo (HR: 2.25, p=0.052) and 2nd line 2.5 (N=9) vs. 5.6 mo (N=17) HR: 2.09, p=0.1). NSD3 amplification was the only other genomic alteration showing significance as a negative predictor of PFS (first-line: 6.1 vs. 14.7 mo, HR: 2.40, p=0.04; second-line: 2.8 vs. 6.5 mo, HR: 3.61, p=0.06). NSD3 amplification appeared to have no significant effect in the control cohort 6.5 vs. 4.4 mo, (HR 1.29, p=0.63). Conclusions: In this real-world cohort, CDK 4/6 combination therapy benefits HR+ MBC patients in the first and second-line setting. ESR1 mutation is a predictor of worse outcome. NSD3 gene amplification is a potential biomarker of resistance to CDK4/6i combination therapy. (Therneau T (2015). A Package for Survival Analysis in S version 2.38, https://CRAN.R-project.org/package=survival).
Immunohistochemical evaluation of Cyclin D1 and β-Catenin expression in subtypes of triple-negative breast cancer.
Authors: Gudtskova Tatiana N. , Vashchenko Larisa N. , Karnaukhov Nikolay S. , Kvarchiya Mramza V. , Bosenko Ekaterina S. , Saforyan Natalya S. , Luganskaya Roza G. 
Published: May 2019

e12553 Background: The purpose of the study was to reveal characteristics of Cyclin D1 and β-Catenin expression in subtypes of triple negative breast cancer (TNBC). Methods: The study included 60 patients diagnosed with verified TNBC (T1N1M0/T2N0M0, ER-/PR-/Her2-). Immunohistochemical staining with CK5/6, EGFR, Cyclin D1, β-Catenin antibodies was performed. Basal-like (BL) subtype was identified when > 25% cells were CK5/6+ and/or EGFR+ (any staining). The expression of β-Catenin was assessed by its location: the membrane, cytoplasm, nucleus. Cells with negative staining on the membrane and cytoplasmic staining were counted and calculated as a percentage of the total number of tumor cells. Nuclear expression of β-Catenin was considered positive with at least 1 positively stained cell in the field of view at x200 magnification. Parametric statistical methods were used. Significance of the difference between the two means was assessed by the Student's t-test. Results: A number of TNBC samples showed Cyclin D1 overexpression. The loss of β-Catenin on the cell membrane and its abnormal accumulation in the cytoplasm was significantly more frequent in TNBC with Cyclin D1 overexpression. These processes were more pronounced in BL cancers. Loss of membrane expression in BL cancers: 29.6±6.1 and 58±7.4%; accumulation in the cytoplasm: 33.4±5.4 and 63.3±7.2%, with low and high Cyclin D1 respectively. Loss of membrane expression in non-BL cancers: 17.6±3.8 and 33.3±4.3%; accumulation in the cytoplasm: 27.3±6.3 and 49.5±8.2%, with low and high Cyclin D1 respectively. Only BL TNBC demonstrated β-catenin translocation to the nucleus (up to 20 stained cells in the field of view): in 33.3% tumors with Cyclin D1 overexpression and in 12% of tumors with its low expression. Conclusions: Levels of expression of β-catenin and Cyclin D1 in TNBC may have predictive value, and the choice of these biomarkers as targets will improve the treatment with new-generation medications.
The relationship of lncRNA NR2F1 and breast cancer angiogenesis via IL-8/lncRNA NR2F1/miR-200s/IL-8 loop.
Authors: Zhang Qi , Zhang Jin , Lu Sihong , Shao Nan , Lin Ying 
Published: May 2019

e12573 Background: Angiogenesis is key for metastasis and predicts a poor prognosis in breast cancer. Among the pro-angiogenic factors, interleukin-8 (IL-8) could be secreted by tumor cells mediated by microRNA-200 family (miR-200s). Long non-coding RNA (LncRNA), was reported to absorb microRNA to play multiple roles in various diseases including breast cancer. Our preliminary results recognized lncRNA NR2F1 through Agilent Human LncRNA array from breast cancer cells overexpressing IL-8. However, the relationship between LncRNA NR2F1 and breast cancer angiogenesis remains unknown. Methods: Breast cancer cell migration, invasion, proliferation and angiogenesis were assessed by Transwell, CCK8, tube formation, and wound healing assays. The expression of LncRNA NR2F1, miR-200s and IL-8 were detected by qPCR, Western blotting and ELISA. Breast cancer metastasis and angiogenesis in vivo were measured in a zebrafish model. Results: We found that the basal expression of lncRNA NR2F1 is higher in breast cancer cell lines than it in normal cells. In vitro, lncRNA NR2F1 induced breast cancer migration, invasion, and proliferation. Meanwhile, lncRNA NR2F1 promoted human umbilical vascular endothelial cell (HUVEC) proliferation, tube formation, and migration both via breast cancer conditioned medium and via direct HUVEC transfection. In the zebrafish model, lncRNA NR2F1 promoted breast cancer cell metastasis and neo-angiogenesis. Further study disclosed that lncRNA NR2F1 downregulated the expression of miR-200s, which in turn upregulated the expression of IL-8 in breast cancer cells. Conclusions: Our findings suggest that LncRNA NR2F1, as a potential promoter of breast cancer, may induce breast cancer angiogenesis through IL-8/lncRNA NR2F1/miR-200s/IL-8 loop.
Retrospective study of neuroendocrine breast cancer cases from a single institution in Québec.
Authors: Plante Marie-Michèle , Houle Paul-Michel , Prady Catherine C. M. , Martel Samuel , Geha Sameh , Pavic Michel 
Published: May 2019

e12588 Background: Within numerous breast cancer types, the neuroendocrine subtype distinguishes itself from the others by its rarity. Most of the actual data comes from European and Asian retrospective studies, whom were mostly published before the 2012 WHO classification. Methods: The aim of our study was to describe a North American cohort of neuroendocrine breast cancer tumors homogenized for the latest WHO classification of 2012. We describe the clinical presentation, diagnostic, therapeutic management and prognosis of our population recensed between 2006 and 2016 at the CHUS in Sherbrooke, Québec. A pathological review of the cases was done to unify the cohort by the latest WHO classification. Results: 59 cases were identified from the 5238 cases of breast cancer evaluated between 2006 and 2016. After review from the pathologist, 9 cases were discarded since they did not meet the diagnostic criterias. 47 patients had invasive breast carcinoma with neuroendocrine differentiation, 4 patients had poorly differentiated/small cell carcinoma and none had well differentiated neuroendocrine tumor. 44 patients were not metastatic whereas 7 patients were metastatic at disease onset with a mean age at diagnosis of 70 and 67 years respectively. 10% (4/44) developed a metastatic disease with a median time of 30 months. The mean size of the tumor was 26,1 mm and had a mean Ki67% of 28,3%. All of our patients were ER+, 98% PR+ and 4% Her2+. None had a triple negative disease. 6 patients were SBR grade 1, 31 were grade 2 and 12 were grade 3. The median follow-up for the non-metastatic patients was 42 months and 23 months for the metastatic patients. The median overall survival of our metastatic cohort was 30 months. The histologic subtype did not statistically influence the overall survival and the progression-free survival. Conclusions: Our study is the largest North American cohort of neuroendocrine breast cancer tumors classified with the latest WHO classification of 2012. More details about each subgroup analysis will be presented at the meeting. Even with this classification, the histologic diagnosis remains challenging. Further studies are needed to better characterize these patients and define their optimal management.