bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bone safety profile of steroidal aromatase inhibitor in comparison to non-steroidal aromatase inhibitors in postmenopausal women with breast cancer: A network meta-analysis.
Authors: Chen Shanshan , Lan Bo , Lv Dan , Ma Fei 
Published: June 2021

527 Background: Steroidal and non-steroidal aromatase inhibitors (AIs) provide better therapeutic response in comparison to other endocrine therapies in the adjuvant treatment of breast cancer (BC). They interfere with bone turnover which may lead to increased incidence of bone related safety events. There are no head-on studies comparing the incidence of bone safety events and hence we performed this network meta-analysis (NMA) to compare the incidence of bone safety events among patients treated with steroidal and non-steroidal AIs. Methods: Literature searches were performed in PubMed and Embase with key words to identify randomized controlled trials in BC patients treated with AIs in adjuvant settings compared against tamoxifen or other AIs, reporting any bone-related safety events. The study was designed as per PRISMA guidelines; publication bias was evaluated by comparison-adjusted funnel plots. Bayesian NMA was done by R software (ver 3.2), GemtC package. Odds ratio (OR) and the surface under the cumulative ranking curve (SUCRA) values were used to interpret the results. Results: 15 studies reporting 6 different bone-related endpoints were included. Treatment with steroidal AI, exemestane led to lower incidence of bone pain (OR Vs anastrozole and letrozole: 0.59, p=0.63; 0.54, p=0.75), fracture episodes (OR Vs anastrozole and letrozole: 0.84, p=0.41; 0.85, p=0.73), joint stiffness (OR Vs anastrozole: 0.55, p=0.73) and osteoporosis (OR Vs anastrozole and letrozole: 0.86, p=0.41; 0.74, p=0.29) (Table) in comparison to letrozole and anastrozole. Reduction in bone mineral density was also lesser in exemestane than anastrozole (mean reduction in hip: 1.08; lumbar spine: 1.34). SUCRA values suggested exemestane to be the drug with maximum likelihood for reducing the incidence of bone-related adverse events. Conclusions: This NMA suggested that bone-related safety events might be lower in early BC patients treated with exemestane in comparison to non-steroidal AIs, anastrozole and letrozole. Although there was no statistical significance, further head-on studies are required to substantiate our results.[Table: see text]
Lurbinectedin (LUR) in combination with Irinotecan (IRI) in patients (pts) with advanced endometrial carcinoma.
Authors: Falcon Gonzalez Alejandro , Paz-Ares Luis G. , Cote Gregory Michael , Ponce Aix Santiago , Martinez Julia , Jimenez Aguilar Elizabeth , Brehcist Elena , Nuñez Rafael , Fernandez Jesus R , Extremera Sonia , Kahatt Carmen Maria , Zeaiter Ali Hassan , Sanchez-Simon Inmaculada 
Published: June 2021

5586 Background: LUR is a new agent that exerts antitumor activity through inhibition of trans-activated transcription and modulation of tumor microenvironment. Preclinical synergism/additivity in combination with IRI has been reported, thus prompting the conduct of this trial. This synergism had been evaluated and recently reported in patients with Small Cell Lung Cancer, with encouraging results (Ponce et al. WCLC, 2020). Methods: Phase I trial to evaluate escalating doses of LUR on Day (D) 1 plus a fixed dose of IRI 75 mg/m2 on D1 and D8 every 3 weeks (q3w) in pts with advanced solid tumors, enrolled following a standard 3+3 dose escalation design. Phase II to expand in selected indications at the Recommended Dose (RD). In this abstract, the cohort of patients with endometrial carcinoma treated at the RD is presented. Results: 21 pts (all female) with endometrial carcinoma were treated at the RD (LUR 2 mg/m2 + IRI 75 mg/m2 + G-CSF); 57% had ECOG PS=1; median age was 64 years (range 34-74); subtype of tumour was split: 67% (14 pts) endometroid, 33% non-endometroid (3 pts serous-papilar, 3 pts clear-cell and 1 pt undifferentiated); median of 2 prior lines (range, 1−7) per pt. Common G1/2 toxicities were nausea, vomiting, fatigue, diarrhea and anorexia; G3/4 hematological toxicities comprised neutropenia (33%), thrombocytopenia (5%) and anemia (38%). Two episodes of febrile neutropenia occurred (9.5%). G3/4 non hematological toxicities consisted of diarrhea (24%), asthenia (19%), nausea (14%) and vomiting (5%), all were transient and manageable. 1 patient (5%) discontinued treatment due to toxicity drug-related (generalized muscular weakness), but no treatment-related deaths were reported. Objective RECIST responses were documented in 4/21 evaluable pts (19%). With 6 pts censored for progression, median PFS was 4.4 months (95% CI 2.1-9.6 months), and PFS at 6 months was 40.4%. The clinical benefit rate (% of pts with Complete Response (CR), Partial Response (PR) or Stable Disease > 4 months) was 43%, and the Disease Control Rate (% of pts with CR, PR or SD) 81%. 3/21 pts (14%) have been more than 12 months on treatment so far. Conclusions: The combination of Lurbinectedin and Irinotecan is active in heavily pretreated patients with endometrial carcinoma. The combination was well-tolerated and consistent with the known safety profile for this combination. Myelosuppression, diarrhea, nausea and asthenia were predictable and manageable. Updated results of this cohort will be presented at the meeting. Clinical trial information: NCT02611024.
Prospective longitudinal evaluation of microbiome diversity in patients with hematological malignancy undergoing allogeneic hematopoietic stem cell transplantation (HSCT).
Authors: Walsh Emily , Tsakmaklis Anastasia , Diao Liyang , Bryant Jessica , Lombardo Mary-Jane , McGovern Barbara , von Moltke Lisa , Henn Matthew R. , Ford Christopher B. , Vehreschild Maria J.G.T. 
Published: June 2021

7005 Background: Studies suggest that decreased microbial diversity due to chemotherapeutic and antibiotic exposure may be associated with acute graft vs host disease (aGvHD) and mortality in patients undergoing allogeneic HSCT. In addition, disruption of the microbiome by antibiotics may lead to intestinal domination by pro-inflammatory bacteria, resulting in increased risk of aGvHD. This relationship has been described in settings with prophylactic antibiotic use, a standard of care in most transplant centers. Here we assessed how the microbiome and GvHD outcomes differ when prophylactic use of antibiotics is avoided. Methods: We collaborated on an observational study (COLLECT) to evaluate changes in microbial diversity over time in subjects undergoing allogeneic HSCT. According to protocol at the University Hospital of Cologne, antibiotics were administered only as empiric treatment for febrile neutropenia or as targeted treatment. Stool was collected weekly from 65 subjects at baseline (pre-HSCT) to day 28 with additional time points taken at day 56, day 90, day 365, and upon diagnosis of intestinal GvHD (GvHD-day 0 and GvHD-day 7). Patients were monitored for incidence of GvHD, including acute GvHD of the liver, intestine, and skin. Microbiome 16SV4 profiles were generated from 381 stool samples. Linear effects models were developed to evaluate the association between Shannon diversity, intestinal domination, and the incidence of intestinal GvHD and mortality. Results: Of the 65 subjects, 28 subjects (42%) went on to develop intestinal GvHD, and 16 subjects (25%) did not survive to day 365. A decline in Shannon diversity was observed during the neutropenic period following HSCT. Subjects who went on to develop intestinal GvHD had significantly lower Shannon diversity at the time of stem cell engraftment (p < 0.0468). Furthermore, lower diversity was observed throughout the study period in subjects experiencing intestinal GvHD. We developed a linear model evaluating the association between mortality and Shannon diversity and found a significant relationship at days 28 and 90 post HSCT (p < 0.0001 and 0.0121, resp). Intestinal domination by Enterobacteriaceae or Enterococcus was significantly associated with the incidence of intestinal GvHD (p < 0.0082) or mortality (p < 0.001), respectively. Conclusions: Data from this observational study (COLLECT) suggests decreases in microbial diversity over time occur in subjects undergoing allogeneic HSCT despite the lack of prophylactic antibiotics. Investigation of whether administration of microbiome therapeutic drugs prior to transplant and/or at the time of engraftment can reduce morbidity and mortality in this high-risk patient population is warranted. Clinical trial information: NCT03148197.
IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC).
Authors: Wakelee Heather A. , Altorki Nasser K. , Zhou Caicun , Csőszi Tibor , Vynnychenko Ihor O. , Goloborodko Oleksandr , Luft Alexander , Akopov Andrey , Martinez-Marti Alex , Kenmotsu Hirotsugu , Chen Yuh-Min , Chella Antonio , Sugawara Shunichi , Gitlitz Barbara J. , Bennett Elizabeth , Wu Fan , Yi Jing , Deng Yu , McCleland Mark , Felip Enriqueta 
Published: June 2021

8500 Background: Adjuvant platinum-based chemotherapy (chemo) provides only a modest 5-year survival benefit in fully resected, high-risk early-stage NSCLC. We report the primary disease-free survival (DFS) results from the pre-planned interim analysis of IMpower010, a randomized phase 3 open-label trial of adjuvant atezolizumab (atezo; anti–PD-L1) vs best supportive care (BSC) after adjuvant chemo in patients (pts) with early-stage resected NSCLC. Methods: Eligible pts had completely resected (4-12 weeks prior to enrollment) Stage IB (≥4 cm)-IIIA NSCLC (AJCC/UICC v7) and ECOG PS 0-1. A total of 1280 pts were enrolled, and 1269 pts received up to four 21-day cycles of cisplatin-based chemo (plus pemetrexed, docetaxel, gemcitabine or vinorelbine). Of these pts (n=1269), 1005 were subsequently randomized 1:1 to 16 cycles of atezo 1200 mg Q3W or BSC. The primary endpoint of investigator-assessed DFS and secondary endpoint of overall survival (OS) were tested hierarchically: first DFS in the PD-L1 TC ≥1% (SP263) subgroup with Stage II-IIIA disease, then DFS in all randomized pts with Stage II-IIIA disease, then DFS in the ITT population (Stage IB-IIIA) and finally OS in the ITT population. Efficacy assessments were based on randomized pts. Safety was assessed in the safety-evaluable population, defined as pts who received ≥1 dose of atezo or who had ≥1 post-baseline safety assessment if randomized to the BSC arm. Results: At data cutoff (January 21, 2021), median follow-up was 32.2 months in the ITT population. Baseline characteristics were generally balanced between arms. Atezo showed statistically significant DFS benefit vs BSC in the PD-L1 TC ≥1% Stage II-IIIA and all randomized Stage II-IIIA populations; the significance boundary was not crossed for DFS in the ITT population (Table). OS data were immature and not formally tested. Pts in the atezo arm received a median of 16 (range, 1-16) atezo doses. Any-grade AEs occurred in 92.7% (atezo) and 70.7% (BSC); events were Grade 3/4 in 21.8% and 11.5%, respectively. Grade 5 treatment-related AEs occurred in 0.8% of pts in the atezo arm. AEs leading to atezo discontinuation occurred in 18.2% of atezo-treated pts. Conclusions: IMpower010 met its primary endpoint, showing DFS benefit with adjuvant atezo vs BSC after adjuvant chemo in pts with resected Stage II-IIIA NSCLC, with pronounced benefit in the PD-L1 TC ≥1% subgroup. The safety profile of atezo was consistent with prior experience of atezo monotherapy across indications and lines of therapy. Funding: F. Hoffmann-La Roche Ltd. Clinical trial information: NCT02486718. [Table: see text]
Racial disparities in lung adenocarcinoma: The contribution of African ancestry.
Authors: Lee Michelle Jeung-Eun , Chang Eric , Shah Manan , Jain Sanjay R. 
Published: June 2021

8516 Background: Racial disparities in lung cancer are well-known with African Americans disproportionally affected by lung cancer in terms of incidence and survival. Previous comparative analyses of molecular features of lung cancer revealed racial differences in genomic profiles, which supports somatic differences arising from genetic ancestry. Using The Cancer Genome Atlas (TCGA), we investigated the genetic alterations in lung adenocarcinomas (LUAD) on individuals of African (AFR) ancestry. Methods: The genomic and clinical data of TCGA PanCancer Atlas LUAD were downloaded through the GDC Data Portal. Given that substantial proportion of the US population consist of genetically admixed populations, we utilized The Cancer Genome Ancestry Atlas (TCGAA) and LAMP for estimates of genetic ancestry and quantitative ancestral compositions. This dataset contains 518 samples, including 393 self-reported whites and 52 African Americans. For each case the proportion of European, AFR, East Asian, native American ancestry was estimated. The dominant ancestry was defined as ≥50% of admixture from one reference population. Differences in gene mutation frequency were analyzed based on AFR ancestry proportion. The Kaplan-Meier curves were generated, and Cox regression analyses were performed. Results: Global ancestry analysis identified 50 AFR ancestry cases with mean ancestry of 78.3%. The dominant AFR ancestry group matched the self-reported race with 96% accuracy. We identified 9 subjects with ≥90% AFR ancestry, 22 subjects with 80-90% AFR ancestry, 12 subjects with 70-80% AFR ancestry, and 7 subjects with 50-70% AFR ancestry. TP53 was the most frequently mutated gene, and ≥90% AFR ancestry had the highest rate of mutations (77.8%) compared with 80-90% AFR ancestry (68.2%), and 70-80% AFR ancestry (66.8%). We evaluated classic driver gene mutations (EGFR, KRAS, NRAS, PIK3CA, ALK) and found only 33% of ≥90% AFR ancestry subjects carry a known driver mutation, compared to 58-77% in lower proportion of AFR ancestry subjects. Higher AFR ancestry was associated with worse overall survival (OS) and progression free survival (PFS). Median OS was 14.5 months for ≥90% AFR ancestry compared to 71.47 months in 70-80% AFR ancestry (P = 0.048). ≥90% AFR ancestry had median PFS of 12.8 months compared to 33.5 months in 80-90% AFR ancestry, and 47.1 months in 70-80% AFR ancestry (P = 0.002). Conclusions: This study demonstrates the power of genomic study to investigate the etiology of health disparities by analyzing the effect of ancestry on genetic alterations in LUAD. Our results reveal different mutation loads even among AFR ancestry patients. We observed that AFR ancestry is associated with worse OS, suggesting possible influence of germline ancestry in subsequent somatic alterations. Further work is needed to explore how genetic ancestry impacts tumorigenesis and cancer progression to eliminate lung cancer disparities.
Updated overall efficacy and safety of selpercatinib in patients (pts) with RET fusion+ non-small cell lung cancer (NSCLC).
Authors: Besse Benjamin , Drilon Alexander E. , Solomon Benjamin J. , Subbiah Vivek , Tan Daniel Shao-Weng , Park Keunchil , De Braud Filippo G. , Alonso Guzman , Wolf Juergen , Soldatenkova Victoria , Lin Aimee K. , French Pearl Plernjit , Goto Koichi , Gautschi Oliver 
Published: June 2021

9065 Background: Selpercatinib, a first-in-class highly selective and potent, CNS-active RET kinase inhibitor, is approved in multiple countries for treatment of RET fusion+ lung or thyroid cancers. Here we report an update of efficacy and safety results which provide a longer follow up and increased number of patients (safety population: N = 345 vs N = 329). Methods: Pts with RET fusion+ NSCLC enrolled in the global, multicenter, ongoing LIBRETTO-001 trial (NCT03157128; 16 countries, 89 sites) were included in this analysis. Pts with the opportunity to be followed ≥6 months from their first dose were included in the efficacy-evaluable population for these analyses. Integrated analysis set (IAS) included 218 NSCLC pts with prior platinum-chemotherapy. Primary analysis set (PAS) was a subset of the IAS and included the first 105 consecutively enrolled pts. The treatment-naïve population included 48 efficacy-evaluable pts. Primary endpoint was objective response rate (ORR, RECIST v1.1) by independent review committee (IRC). Secondary endpoints included ORR by investigator, duration of response (DoR), progression-free survival (PFS), clinical benefit rate (CBR; CR+PR+SD ≥16 weeks), and safety. Safety population (N = 345) included all pts with NSCLC who received ≥1 selpercatinib dose by data cutoff (30 Mar 2020). Results: In pts with prior treatment (N = 218) and treatment-naïve (N = 48) pts, 56% and 60% were female, with a median pt age of 61 and 64 years, respectively. The ORR with selpercatinib was 57% in the IAS, 64% in the PAS, and 85% in the treatment-naïve population (Table). In both the IAS and PAS, the median DoR was 17.5 months, median PFS was 19.3 months at median follow-up of 12.0 and 15.7 months, respectively (Table). The most common treatment-emergent adverse events (TEAEs) reported in ≥25% of pts were dry mouth, diarrhea, hypertension, increased ALT/AST, edema peripheral, and fatigue. Twenty-five pts (7%) permanently discontinued due to TEAEs, with 10 pts (3%) discontinuing selpercatinib due to treatment-related AEs as per investigator. Conclusions: In this updated data set, selpercatinib continued to demonstrate durable antitumor activity in pts with RET-fusion+ NSCLC. Selpercatinib was well-tolerated with a safety profile consistent with previous reports. A global, randomized, phase 3 trial (LIBRETTO-431) evaluating selpercatinib compared with standard frontline therapy is ongoing. Clinical trial information: NCT03157128. [Table: see text]
Association between mammographic breast density and achievement of a pathologic complete remission (pCR) after neoadjuvant chemotherapy (NACT) for early breast cancer (EBC).
Authors: Kolberg-Liedtke Cornelia , Shaheen Mohamed , Hoffmann Oliver , Bittner Ann-Kathrin , Wetzig Sarah , Stephanou Miltiades , Kolberg Hans-Christian 
Published: June 2021

e12611 Background: Neoadjuvant chemotherapy (NACT) is indicated in early breast cancer (EBC) with an unfavorable tumor biology. Achievement of pathologic complete remission (pCR) after NACT is indicating an improved prognosis. An association between pCR and mammographic breast density as defined by BIRADS (Breast Imaging Reporting and Data System) could be demonstrated. However, the definition of mammographic breast density by the American College of Radiology (ACR) is widely used worldwide and data regarding an association of breast density by this definition and pCR after NACT are missing. Methods: We conducted a retrospective analysis among patients who had received neoadjuvant chemotherapy (NACT) for EBC and had available data regarding mammographic breast density as defined by ACR before therapy, pCR, age, estrogen and progesterone receptor (ER, PR) status, HER2neu status and grading were included. An association between mammographic breast density (ACR) and pCR was analyzed. Results: 185 patients were included in this analysis, 35.7% of whom achieved a pCR. Mammographic breast density was ACR 1 in 15.1%, ACR 2 in 41.6%, ACR3 in 38.4% and ACR 4 in 4.9% of the patients. A negative correlation (Spearman-Rho) between mammographic breast density and pCR (correlation coefficient (CC) -0.240) was highly statistically significant (p = 0.001). The association of decreasing pCR rates with increasing mammographic breast density (pCR rates by ACR 1: 53.6%, ACR 2: 41.6, ACR 3: 25.4% and 11.1 %) was statistically significant (Chi-Square, p = 0.013). These results were independent of age, ER status, PR status, HER2neu status and grading. Conclusions: In our analysis higher mammographic breast density as defined by ACR was significantly correlated with a lower chance of achieving a pCR after NACT. Although this result has to be interpreted with caution due to the small sample size and the retrospective character of our investigation, it is completely in line with other investigations using other definitions of mammographic breast density. The pathophysiological cause of this association should be further elucidated to reveal potential mechanisms of treatment resistance.
BRMS1L inhibits bone metastasis of breast cancer cells through epigenetic silence of CXCR4.
Authors: Cen Yinghuan , Gong Chang , Li Jun , Liang Gehao , Liu Zihao , Luo Qing , Lin Qun , Shi Yu , Li Juanmei , Fang Xiaolin 
Published: June 2021

e13002 Background: We previously demonstrated that BRMS1L (breast cancer metastasis suppressor 1 like) suppresses breast cancer metastasis through HDAC1 recruitment and histone H3K9 deacetylation at the promoter of FZD10, a receptor for Wnt signaling. It is still unclear whether BRMS1L regulates organ-specific metastases, such as bone metastasis, the most prevalent metastatic site of breast cancer. Methods: Examination of the expression of BRMS1L in primary tumors, bone metastatic and other metastatic tissues from breast cancer patients was implemented using qRT-PCR and immunohistochemistry staining. To investigate the mechanism by which BRMS1L drives breast cancer bone metastasis, we tested the mRNA expression by qRT-PCR of a set of potential bone related genes (BRGs) based on PubMed database in MDA-MB-231 cells over expressing BRMS1L and MCF-7 cells knocking-down BRMS1L, and detected the expression of CXCR4 in these established cells by western blot. Transwell assays were performed to assess the migration abilities of breast cancer cells towards osteoblasts. ChIP (Chromatin Immuno-Precipitation) were employed to test the interaction between BRMS1L and CXCR4. Results: At both mRNA and protein levels, the expression of BRMS1L was significantly lower in bone metastatic sites than that in primary cancer tissues and other metastatic sites of breast cancer patients. CXCR4 was screened out in a set of BRGs and negatively correlated with the expression of BRMS1L in breast cancer cell lines. BRMS1L inhibited the migration of breast cancer cells towards osteoblasts through CXCL12/CXCR4 axis. In the presence of TSA treatment, breast cancer cell lines showed an increased expression of CXCR4 in a TSA concentration-dependent manner. In addition, ChIP assays verified that BRMS1L directly bound to the promoter region of CXCR4 and inhibited its transcription through promoter histone deacetylation. Conclusions: BRMS1L mediates the migration abilities of breast cancer cells to bone microenvironment via targeting CXCR4 and contributes to bone metastasis of breast cancer cells. Thus, BRMS1L may be a potential biomarker for predicting bone metastasis in breast cancer.