bluuebunny/crossref_metadata_2025_split huggingface dataset:
The clinical impact of the expression of the cancer stem cell marker CD44v9 in early triple negative breast cancer (TNBC).
Authors: Tokunaga Eriko , Tajiri Wakako , Takizawa Katsumi , Ijichi Hideki , Ueo Hiroki , Koga Chinami , Nakamura Yoshiaki , Taguchi Kenichi , Okamoto Masahiro 
Published: May 2020

e12566 Background: The adhesion molecule CD44 is expressed in cancer stem-like cells (CSCs). CD44 variant 9 (CD44v9), a splicing variant of CD44, has emerged as a novel marker of cancer stemness. CD44v9 was reported to be associated with the resistance to chemotherapy in several malignancies. We recently reported that the high expression of CD44v9 is associated with the poor prognosis of the patients with triple negative breast cancer (TNBC), who received neoadjuvant chemotherapy (NAC). In this study, we investigated the clinical impact of the expression of CD44v9 in early TNBC who underwent surgery without NAC. Methods: Among 2257 primary breast cancer patients at clinical stage I-III who underwent surgery without NAC form 2002 to 2015, 201 patients with TNBC were included in this study. The expression of CD44v9 was analyzed immunohistochemistry (IHC). The associations between the CD44v9 expression and the clinicopathological characteristics and the prognosis were investigated. The tumors with the positive staining in more than two third of the cancer cells were regarded to be high expression of CD44v9. Results: CD44v9 high expression was observed in 62 cases (30.8%) and the low expression was in 139 cases (69.2%). Many of the CD44v9 high tumors were low grade than the tumors with low CD44v9. There were no significant associations between the expression levels of CD44v9 and the tumor size, lymph node metastasis and the pathological stage (pStage). There were no differences in the prognosis between the high and low CD44v9 expression in pStage I. However, in the patients with the tumors with pT1c or more (pT2, pT3) and the patients with pStage 2 and more, the high CD44v9 expression was significantly associated with the poor prognosis in terms of distant recurrence-free survival (DRFS) and overall survival (OS). In addition, high CD44v9 was associated with significantly shorter survival after recurrence. Many of these patients received various chemotherapy in the adjuvant setting and after recurrence. Therefore, CD44v9 high expression is considered to be associated with the poor prognosis due to the resistance to various chemotherapeutic agents. Conclusions: The prognosis of the TNBC patients with the high expression of CD44v9 is poor, which might be induced by the resistance to various chemotherapeutic agents. These results suggest that CD44v9 might be a novel therapeutic target for TNBC.
Real-world clinical analysis and overall survival-related biomarker of breast cancer (BC) patients under 35 years old.
Authors: Yu Jinpu , Li Yang , Li Xuesong , Yang Beibei , Wang Shuaibing , Lu Su , Shi Yehui , Hao Chunfang , Zhang Geng , Wang Xiaohong , Ma Jie , Liu Hong , Shi Xiaoliang , Qiao Huidong , Liu Zhenzhen 
Published: May 2020

e12569 Background: Breast cancer (BC) is one of the most common malignant tumors among women in the world. Although under 7% of all BC cases, young BC is more difficult to diagnose and can be aggressive and less likely to respond to treatment. Exploring and identifying potential biomarkers for the diagnosis and prognosis of younger BC patients is necessary. Methods: A total of 1,202 BC patients under 35 years old (YD) were enrolled. Deep sequencing targeting 450 cancer genes was performed in a laboratory accredited by College of American Pathologists (CAP) and certified by Clinical Laboratory Improvement Amendments (CLIA) for genomic alteration identification. Statistical analysis was performed by Fisher’s exact test. Results: Of 1,202 young BC patients, 3 were under 20 YD, 85 were 20-25 YD, 371 were 26-30 YD, and 747 were 31-35 YD. Based on pathological, there were 899 infiltrative duct carcinomas, 10 infiltrative lobular carcinomas, and 292 BCs with unclear pathological type. According to molecular features, 587 HR+/HER2- (group I), 118 HR+/HER2+ (group II), 75 HR-/HER2+ (group III) and 193 HR-/HER2- (group IV) were included. Chemotherapy, radiotherapy, endocrine therapy and targeted therapy were received and 1074 patients were followed up. The median overall survival (OS) was 76 (5-156) months. There was no significant difference in OS between different treatments. The median OS was 81 (range 5-156) months, 67 (range 10-153) months, 76 (range 14-146) months, and 78 (range 13-151) months for group I, II, III, and IV, respectively. The significantly lower OS was observed in group II ( P=0.044). Although group II and group III had similar proportion of targeted treatment (43.22% vs 43.24%, respectively), the OS rate was different (67 vs 76 months, P=0.064). Samples from 46 young BC patients were performed on deep sequencing targeting 450 cancer genes. The most common mutations were TP53 (56%), GATA3 (29%), ERBB2 (27%), CDK12 (20%), and FGFR1 (20%). Different from previous studies, only 4.35% (2/46) of BRCA1/2 mutations were detected in this cohort. The mutation frequency of GATA3 in group II was significantly lower than that in group III (0% vs 71.43%, P=0.017). Conclusions: The most common pathological type of young BC was infiltrative duct carcinoma. The OS of HR+/HER2+ patients were significantly lower than that of others. Our results showed that GATA3 could be a potential biomarker for OS prediction for BC with HER2+, which help to further guide targeted therapy in young BC patients.
Biological and clinical features of early triple-negative invasive lobular carcinomas of the breast.
Authors: Conforti Fabio , Pala Laura , Guerini Rocco Elena , Pagan Eleonora , Bagnardi Vincenzo , Montagna Emilia , Peruzzotti Giulia , De Pas Tommaso Martino , Fumagalli Caterina , Pileggi Silvana , Pesenti Chiara , Marchini Sergio , Marchiò Caterina , Sapino Anna , Gelber Richard D. , Viale Giuseppe , Colleoni Marco , Goldhirsch Aron 
Published: May 2020

e12570 Background: Hormone receptors and HER2 negative (triple negative, TN) invasive lobular carcinomas (ILCs) are very rare, accounting for 1-2% of all TN breast cancers (BCs). Methods: We extracted data from our prospectively collected institutional database on all consecutive patients (pts) with early stage TN ILC operated at the European Institute of Oncology (IEO) between June 1994 and December 2012. Invasive disease-free survival (iDFS) and cumulative incidence of distant metastases (CI-DM) were calculated. Biological features of these tumors, including molecular intrinsic subtypes based on PAM50 assay, expression of androgen receptor (AR) and mutational status of c-erbB2 gene were also evaluated. Additionally, NGS data of 45 TN ILCs were obtained from 3 large public databases, to confirm mutations in c-erbB2 gene and to identify other recurrently mutated genes. Results: Among 2952 ILCs treated at IEO, 44 (1.5%) were TN and were included in the analysis. All pts received adjuvant chemotherapy. The iDFS rates at 5 and 10 years of follow-up were 47.4% (95% CI, 31.1-62.0) and 29.5% (95% CI, 14.8-45.8), respectively. The corresponding CI-DM percentages were 17.6% (95% CI, 7.6-31.2) and 20.8% (95% CI, 9.5-35.1). The molecular intrinsic subtype was defined through PAM50 for 31 out of 44 TN ILCs: 48% were classified as luminal A, 3% luminal B, 32% HER2-enriched, and only 16% basal-like. The group of pts with luminal A or B tumors had a significantly better CI-DM as compared with pts with non-luminal tumors (i.e. HER2-enriched and basal-like; p=0.003). Luminal tumors expressed AR more frequently than non-luminal tumors (AR≥1% in 96% of luminal tumors versus 53% in non-luminal tumors; p=0.001), and at significantly higher levels (median percentage of AR-positive cells was 80% in luminal tumors versus 15% in non-luminal tumors; p=0.01). Higher AR expression was associated with significantly better iDFS in the whole cohort of TN ILCs (p=0.01), as well as in the group of luminal tumors (p=0.05). 27 TN ILCs of the IEO cohort were analyzed for mutations in c-erbB2 gene, and 9 (33%) harbored mutations. Analysis of the 3 public databases, confirmed c-erbB2 mutations in 9 out of 45 (20%) TN ILCs. All the c-erbB2 mutations found were previously reported to be pathogenetic in BCs and to predict response to neratinib. ErbB signaling and DNA damage response were among the top 10 pathways significantly enriched for mutated genes in TN ILCs. Conclusions: TN ILCs are rare tumors with dire prognosis. Their specific biological features require newly defined targeted therapeutic strategies.
Clinical relevance of miR-143 expression in ER-positive breast cancer patients.
Authors: Tokumaru Yoshihisa , Oshi Masanori , Katsuta Eriko , Matsuhashi Nobuhisa , Futamura Manabu , Yoshida Kazuhiro , Takabe Kazuaki 
Published: May 2020

e12574 Background: MicroRNA-143(miR-143) is a well-known tumor suppressive microRNA in various malignancies, including breast cancer. Recently, the tumor immune microenvironment has been reported to associate with progression of breast cancers. However, the association with the tumor immune microenvironment and miR-143 in breast cancers remains ambiguous. Given these backgrounds, we hypothesized that high expression of miR-143 is associated with favorable effect to the tumor immune microenvironment which leads to better survival of ER positive breast cancer patients. Methods: Two major publicly available breast cancer cohorts were used for this study. A total of 753 patients from The Cancer Genome Atlas (TCGA) and total of 1283 patients from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used. Results: We defined the higher quartile of miR-143 expression levels as high and the remainder as low expression groups. There was no significant difference in patient clinicopathlogical features between two groups. Gene set enrichment analysis (GSEA) revealed that miR-143 high expression tumors enriched Helper T cell type 1 (Th1) related gene sets indicating the upregulation of anti-cancer immune cells. Also, the cell composition of anti-cancer immune cells, such as Th1 and Macrophage M1 were higher with miR-143 high tumors (p < 0.001 and p < 0.01 respectively) in whole group. On the contrary, pro-cancer immune cells such as Th2 and M1 were lower with miR-143 high tumors (p < 0.01 and p < 0.001 respectively) in whole group. Interestingly, among the subtypes, we found that ER positive subgroup followed this trend of high infiltration rate of anti-cancer immune cells and low infiltration rate of pro-cancer immune cells. Furthermore, only ER positive subgroup demonstrated the survival benefit with miR-143 high expression tumors. Conclusions: We demonstrated that high expression of miR-143 in ER breast cancer associate with favorable tumor immune microenvironment, upregulation of the anti-cancer immune cells and suppression of the pro-cancer immune cells, and associate with better survival of the breast cancer patients.
Functional hotness score based on three genes predicts long-term survival of triple-negative breast cancer independent from tumor mutational burden.
Authors: Katsuta Eriko , Yan Li , Opyrchal Mateusz , Kalinski Pawel , Takabe Kazuaki 
Published: May 2020

e12583 Background: Cytotoxic T-lymphocytes (CTLs) infiltration into tumor is a positive prognostic factor in breast cancer. Infiltration of CTLs are believed to be driven by mutation-induced neoantigens, thus, higher tumor mutation burden (TMB) is considered an important predictor of tumor immunogenicity and response to immunotherapy, but the association between intratumoral CTL counts and TMB in the overall cancer prognosis remains unclear. Methods: Utilizing publicly available breast cancer cohorts, we established Functional Hotness Score (FHS), based on CD8A, GZMB and CXCL10 gene expression levels of bulk tumors. The associations of FHS and breast cancer patient prognosis as well as distinct immunity markers were analyzed. Results: Breast cancer patients with high-FHS tumors demonstrated significantly better survival. FHS was lower in metastatic breast cancer. Among breast cancer subtypes, triple-negative breast cancer (TNBC) showed the highest FHS. FHS predicted patient survival not in hormone receptor (HR)-positive but in HR-negative, especially TNBCs. The high-FHS TNBCs enhanced not only CD8+ T cell infiltration, but also a broader type-1 anti-cancer immunity. The patients with the high-FHS patients showed better prognosis not only in high-TMB tumors but also in low-TMB TNBCs. The combination of high-TMB with high-FHS identified the unique subset of patients who did not recur over time. Conclusions: In conclusion, TNBCs with high-FHS based on the expression levels of CD8A, GZMB and CXCL10 showed improved prognosis with higher anti-cancer immunity regardless of TMB, and constituting an independent prognostic marker of survival, particularly robust when combined with TMB.
4-gene score to predict response to neoadjuvant chemotherapy, metastasis, and survival.
Authors: Oshi Masanori , Katsuta Eriko , Yan Li , Endo Itaru , Takabe Kazuaki 
Published: May 2020

e12592 Background: At this point, there is no treatment to cure metastatic breast cancer. On the other hand, improvement of treatment of metastatic breast cancer is the key to further improve breast cancer survival. One possible opportunity is to detect metastatic breast cancer in it’s “early” phase when it many respond to treat such as immune therapy. We hypothesized that a scoring system generated from metastatic clone predict metastasis and survival. Methods: A gene signature score was generated using differentially expressed genes between MDA-MB-231 human breast cancer cell-line and its highly metastatic variant, LM2-4, and TCGA breast cancer dataset. METABRIC cohort as well as six neoadjuvant therapeutic cohorts and four metastatic cohorts were used as validation cohort. The totals of 4,199 samples from a large number of cohorts were analyzed in the study. Results: Among the 297 genes that were up-regulated in LM2-4, tumor expression of four genes had the strongest association with disease-free survival in TCGA breast cancer dataset (hazard ratio [HR] > 1.2 with p < 0.02). A 4-gene score calculated from the combined expression of these genes correlated with overall survival in TCGA data, with HR of 1.44 (95% confidence interval [CI] = 1.52-2.98; p < 0.001). The association of higher scores with worse survival was also observed for disease-specific survival in the METABRIC breast cancer cohort (HR = 1.57, 95% CI = 1.23-1.72, p < 0.001). Tumors with high score enriched gene sets related with cancer aggressiveness such as E2F, G2F, MYC v1 and v2 (FDR = 0.23, 0.19, 0.20, 0.21, respectively), whereas those with lower score enriched estrogen response pathway related set (FDR = 0.13) in TCGA and it was validated with METABRIC cohorts. We also found that the score associated with distant metastasis to brain or lung (p < 0.001). Kaplan-Meier analyses of site-specific metastasis-free interval demonstrated that for all three cohorts, patients with high scores had significantly increased risk for development of metastasis to the lung (p≤0.02). This association of the score with metastasis risk was also seen for brain for two cohorts, and it was seen for bone in one cohort. Importantly, we found that the high score group had a higher pCR rate than the low score group for especially ER+/HER2- breast cancer in two cohorts (p = 0.003 and p = 0.004). And the score significantly decreases with good response to neoadjuvant chemotherapy (p = 0.022) or hormonal therapy (p = 0.013). Conclusions: This novel gene score may be clinically useful with both prognostic and predictive values for breast cancer.
Five day accelerated partial breast irradiation (APBI) using stereotactic body radiation therapy (SBRT) in stage 0-II breast cancer: A report of 135 cases with up to two-year follow-up.
Authors: Mark Rufus J. , Gorman Valerie , McCullough Steven 
Published: May 2020

e12596 Background: Randomized trials in stage 0-II breast cancer have proven that APBI given via HDR implant in 5 days is equivalent to whole breast External Radiation Therapy (XRT) given in 5-6 weeks in regard to breast tumor local recurrence (LR). However, complications have been significant. Recently APBI using non-invasive IMRT given in 5 fractions has been shown in another randomized trial to be equivalent to XRT in 6 weeks, with respect to LR. IMRT was superior in regard to acute effects, late effects, and cosmesis. In the randomized clinical trial of APBI IMRT, the Clinical Target Volume (CTV) was defined by the injection of individual fiducial markers bordering the surgical cavity. At our institution, we have used the Biozorb fiducial system to localize the CTV for IMRT. We sought to confirm the APBI IMRT results with this simpler less labor intensive fiducial placement system. Methods: Between 2017 and 2020, 135 patients have undergone SBRT targeted to a Biozorb defined CTV with the walls of the surgical cavity sewn to the Biozorb device. Eligible patients were older than age 40, had tumor sizes < 3 cm, negative surgical margins, and negative sentinel node dissections. SBRT dose was 30 Gy given in 5 fractions. Dose Constraints were as follows: V-30 Gy < 105%, Ipsilateral Breast V-15 Gy < 50%, Ipsilateral Lung V-10 Gy < 20%, Contralateral Lung V-5 Gy < 10%, Heart V-3 Gy < 20%, Contralateral Breast Dmax < 2 Gy and Skin Dmax < 27 Gy. The Planning Target Volume (PTV) ranged from 27 to 355 cc with a median of 80 cc. PTV = CTV + 1-2 cm. Results: Follow-up ranged from 1-26 months with a median of 12 months. LR has been 0% (0/135). There have been no skin reactions or seromas. Infection has occurred in one patient (0.7%). Three (2.2%) patients developed pain around the Biozorb site. This resolved within 2 days on a short course of steroids in all cases. Cosmetic results as rated by the Surgeon, Radiation Oncologist, and Nurse, were rated excellent in 98.5% (133/135) of cases. Conclusions: Non-invasive APBI with SBRT given qd over 5 days targeted to Biozorb has resulted in LR, complications, and cosmetic results which compare favorably to invasive APBI given bid with HDR implant. At last follow-up, there have been no LR, skin reactions, or significant complications. Cosmesis has been excellent in 98.5% of patients.
Long-term outcomes of preoperative radiotherapy in locally advanced breast cancer: Analysis of Surveillance, Epidemiology, and End Results (SEER) database.
Authors: Pan Zhe , Yao Zhiyuan , Huang Mingkai , Huang Junfeng , Ao Xiang 
Published: May 2020

e12600 Background: Currently the treatment paradigm for locally advanced breast cancer (LABC) is multimodality therapy with neoadjuvant systematic treatment, surgery and postoperative radiation therapy (RT). However, with improving outcomes from systematic therapy, the survival rates remain unpromising, which leads to the investigation of the concept of preoperative RT in LABC due to the potential advantages including a possible tumor downstaging and better cosmetic outcomes. We evaluated the overall survival (OS) and breast cancer specific survival (BCSS) of preoperative versus postoperative RT in LABC patients. Methods: Patients diagnosed with non-inflammatory LABC (defined as T3 N1, T4 N0, any N2 or N3, and M0) who received RT before or after surgery between 2010 and 2015 were identified using the SEER database. OS and BCSS were analyzed using Kaplan-Meier method and multivariate Cox proportional hazards model. Results: Among 19249 patients with LABC, 140 (0.7%) received preoperative RT and 19109 (99.3%) received postoperative RT. Overall, 5-year survival and BCSS are 59% and 63% in the preoperative RT group while 77% and 80% in the postoperative RT group. In all patients, treatment with preoperative RT was significantly associated with poor OS (HR 1.82, 95%CI 1.25 to 2.45, P < 0.001) and BCSS (HR 2.00, 95%CI 1.46 to 2.73, P < 0.001) after adjustment for other clinically relevant factors. However, there were no significant difference in terms of both OS and BCSS in ER+ (OS: HR 1.44, 95%CI 0.91 to 2.27, P = 0.12; BCSS: HR 1.55, 95%CI 0.94 to 2.54, P = 0.08) and HER2+ patients (OS: HR 1.33, 95%CI 0.55 to 3.22, P = 0.53; BCSS: HR 1.64, 95%CI 0.67 to 3.97, P = 0.28). Conclusions: Overall, preoperative RT in LABC may reduce overall survival and breast cancer specific survival. However, OS and BCSS were independent of radiation sequence for ER+ and HER2+ patients. This finding warrants further exploration of potential mechanisms of the disparity and the definitive role of preoperative RT in the multimodality therapy of LABC patients.
The impact of endogenous estrogen exposure on the characteristics of estrogen receptor (ER) positive, early-stage breast cancer (EBC).
Authors: Yariv Orly , Yerushalmi Rinat , Moore Assaf , Shohat Tzippy , Tsoref Dalia , Goldvaser Hadar 
Published: May 2020

e12605 Background: Menstrual and parity history might impact the risk for ER positive breast cancer. Data on the impact of these factors on other tumor characteristics are limited. Methods: A single center retrospective cohort study comprising all women with ER positive, human epidermal growth factor receptor 2 (HER2) negative, EBC whose tumors were sent to OncotypeDX analysis and were treated in our institute between 2005 to 2012. Data on endogenous estrogen exposure were collected including: age of menarche and menopause, number of deliveries and age of first delivery. Subsequently, data on pre-specified clinical and histopathological features were collected including: tumor size, nodal status, ER and progesterone receptor (PR) staining, grade, Oncotype recurrence score (RS), ki67, lymphovascular and perineural invasion. The impact of endogenous estrogen exposure was evaluated by multiple comparisons including: early age of (<12 years) compared to older age of menarche, nulliparity compared to women who had at least one delivery, multiparty (≥5 deliveries) compared to other, late age of first delivery (≥30 years) compared to other and postmenopausal compared to premenopausal. In postmenopausal women the age of menopause was also assessed using early age of menopause (<45 years) and late age of menopause (>55 years). Results: A total of 620 women were included. 79% were postmenopausal, median age of menarche was 13 (range 9-17) and median number of deliveries was three (range 0-14). Post-menopausal women were more likely to have stronger ER intensity (79% vs. 65%, p=0.002) and less likely to have high (≥31) RS (8% vs. 16%, p=0.021), but PR negativity was significantly more frequent (16% vs. 7%, p=0.007. Additionally, early age of menarche was associated with PR positivity (94% vs. 85%, p=0.039).). No other associations were found between endogenous estrogen exposures and tumor characteristics. Conclusions: These findings suggest that premenopausal women with luminal EBC might have more aggressive disease. Large scale studies are needed to elucidate the impact of endogenous estrogen on luminal breast cancer.