bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of STK11 mutation on first-line immune checkpoint inhibitor (ICI) outcomes in a real-world KRAS G12C mutant lung adenocarcinoma cohort.
Authors: Heist Rebecca Suk , Yu Junhua , Donderici Elifnur Yay , Zhang Nicole , Espenschied Carin R. , Lang Kathryn , Korytowsky Beata , Chi Andrew S. , Christensen James G 
Published: June 2021

9106 Background: The introduction of KRAS G12C inhibitors into clinical trials has demonstrated promise and may provide a new therapeutic option for patients (pts) harboring KRAS G12C mutations. Recent data has also indicated that immune checkpoint inhibitors (ICI) have shown benefit in KRAS G12C mutant lung adenocarcinoma (LUAD); however, data on the impact of co-occurring STK11 mutations on outcomes are conflicting. We utilized the Guardant INFORM real-world clinical-genomic database to assess the impact of co-occurring STK11 mutations on outcomes in pts with KRAS G12C mutant LUAD treated with a first-line ICI containing regimen. Methods: This retrospective matched cohort observational study was conducted in a nationally representative clinical-genomic database covering over 137,000 pts with comprehensive ctDNA results and associated clinical information. Adult pts with metastatic LUAD who received ≥ 1 dose of first-line anti-PD1/PD-L1 ± chemotherapy and had at least 90 days follow-up after first KRAS G12C detection were included. A cohort of pts without KRAS G12C, including KRAS wildtype pts and pts with other KRAS mutations, were matched 3:1 for age, gender, year of index and baseline comorbidity. Time to next treatment (TTNT), time to discontinuation (TTD), real-world overall survival (rwOS) were compared with vs. without STK11 mutations for both cohorts using cox proportional-hazards model. Results: Among 330 pts in the KRAS G12C cohort, 21% (n = 70) had an STK11 mutation. Among the matched cohort (n = 938), 754 pts were KRAS wildtype, of whom 6% (n = 49) had STK11 mutations. Within the KRAS G12C cohort, pts with STK11 mutations had statistically significant shorter TTNT (hazard ratio [HR] 2.7, 95% confidence internal [CI] 1.8-4.0, p < 0.0001), TTD (HR 1.4, 95% CI 1.0-2.0, p < 0.04) and rwOS (HR 3.2, 95% CI 2.0-5.1, p < 0.0001) than pts without STK11 mutations. Within the matched KRAS wildtype cohort, the differences in TTD (HR 1.4, 95% CI = 1.0-2.0, p = 0.08) and rwOS (HR 1.4, 95% CI = 0.8-2.4, p = 0.3) in patients with vs. without STK11 mutation did not reach statistical significance (Table). Conclusions: This study provides real-world evidence that STK11 co-mutations are associated with worse outcomes among pts with KRAS G12C mutant LUAD treated with first-line ICI. These inferior outcomes indicate a high unmet medical need among LUAD pts harboring co-occurring KRAS G12C and STK11 mutations and demonstrate the need for effective targeted and/or combination therapies in this patient population.[Table: see text]
Long-term efficacy and safety of larotrectinib in patients with TRK fusion-positive lung cancer.
Authors: Lin Jessica Jiyeong , Kummar Shivaani , Tan Daniel Shao-Weng , Lassen Ulrik Niels , Leyvraz Serge , Liu Yongmei , Moreno Victor , Patel Jyoti D. , Rosen Lee S. , Solomon Benjamin Maurice , Norenberg Ricarda , Dima Laura , Brega Nicoletta , Shen Lin , Drilon Alexander E. 
Published: June 2021

9109 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions have been identified as oncogenic drivers in a diverse array of tumor types including lung cancer. Larotrectinib is a first-in-class, highly selective, central nervous system (CNS)-active tropomyosin receptor kinase (TRK) inhibitor approved for the treatment of adult and pediatric patients (pts) with TRK fusion cancer, with an objective response rate (ORR) of 78% across multiple non-CNS cancers (McDermott et al, ESMO 2020). Here, we report the updated data on pts with lung cancer treated with larotrectinib. Methods: Pts with lung cancer harboring a NTRK gene fusion enrolled in two clinical trials (NCT02576431 and NCT02122913) were identified for this analysis. Larotrectinib 100 mg PO BID was administered on a continuous 28-day schedule until disease progression, withdrawal, or unacceptable toxicity. Response was assessed by the investigator per RECIST v1.1. Results: As of July 20, 2020, a total of 20 pts with TRK fusion-positive lung cancer (19 with non-small cell lung cancer and 1 with small cell lung cancer) were enrolled. Median age was 48.5 years (range 25.0–76.0). The gene fusions involved NTRK1 (n = 16; 80%) or NTRK3 (n = 4; 20%). Pts were heavily pre-treated with a median of 3 systemic therapies (range 0–6). Among 15 evaluable pts, the confirmed ORR was 73% (95% CI 45–92): 1 complete response, 10 partial responses (PR), 3 stable disease (SD) and 1 progressive disease (PD). The median time to response was 1.8 months. Among 8 evaluable pts with baseline measurable and non-measurable CNS metastases, the ORR was 63% (95% CI 25–91): 5 PR, 2 SD, and 1 PD. In all evaluable pts, the 12-month rates for duration of response and progression-free survival were 81% and 65%, respectively. Median overall survival was 40.7 months (95% CI 17.2 to not estimable) at a median follow-up of 16.2 months. Duration of treatment ranged from 0.03+ to 51.55+ months. Adverse events (AEs) were predominantly Grade 1–2. Treatment-related AEs were reported in 16 pts, of which 2 experienced Grade 3 events (myalgia, hypersensitivity, weight increase). There were no treatment discontinuations due to AEs. Conclusions: These data confirm that larotrectinib is highly active with rapid and durable responses, extended survival benefit, and a favorable long-term safety profile in pts with advanced lung cancer harboring NTRK gene fusions, including in pts with CNS metastases. These results underscore the importance of screening for NTRK gene fusions in pts with lung cancer. Clinical trial information: NCT02576431 and NCT02122913.
Effect of continuing osimertinib with chemotherapy in the post-progression setting on progression-free survival among patients with metastatic epidermal growth factor receptor (EGFR) positive non-small cell lung cancer.
Authors: Patil Tejas , Tsui David Chun Cheong , Nicklawsky Andrew , Schenk Erin Lynn , Purcell William T. , Bunn Paul A. , Pacheco Jose Maria , Camidge D. Ross 
Published: June 2021

9124 Background: Continuing a 1st generation EGFR TKI with chemotherapy upon TKI progression was not shown to be beneficial in the IMPRESS trial. However, the validity of this approach with osimertinib remains under explored. We attempted to characterize the efficacy of continuing osimertinib with chemotherapy in the post-progression setting. Methods: A single-center retrospective review of patients with metastatic EGFR mutant NSCLC who had progressed on osimertinib was performed. Clinical characteristics and treatment outcomes were noted. Progression free survival (PFS), duration of treatment (DOT), overall survival (OS) and rates of intracranial progression were captured. ANOVA or a Fisher exact test were used to identify associations between cohort characteristics and treatment outcomes. Differences in PFS, DOT and OS were assessed using a log-rank test. A Cox proportional hazard model was used to adjust for potential confounders. Results: 73 patients with EGFR mutant NSCLC with post-osimertinib treatment outcomes were identified. Cohort characteristics are summarized in Table. Median duration of follow up was 41 months. Upon progression, osimertinib was discontinued in 34 patients (Cohort A) and continued with next line of therapy in 39 patients (Cohort B). Survival analyses were adjusted for prior lines of therapy, use of platinum doublet chemotherapy, and use of immune checkpoint inhibitors in the post-progression setting. After adjusting for covariates, continuing osimertinib post-progression was associated with an improved PFS (7 vs 4 months; HR 0.58; 95% CI 0.34 – 1.00; p = 0.003) and DOT (7 vs 4 months; HR 0.52; 95% CI 0.31 – 0.87; p = 0.006). There was no difference in OS between Group A and B (52 vs 41 months; HR 0.73; 95% CI 0.43 – 1.24; p = 0.234). Rates of intracranial progression were similar between Group A and B (28% vs 23%; p = 0.649). Conclusions: After adjusting for covariates, continuing osimertinib with chemotherapy in the post-progression setting was associated with a significant difference in PFS and DOT, but with no differences in OS. Continuing osimertinib does not appear to influence the rate of subsequent intracranial progression. Prospective studies are needed to identify the optimal practice pattern.[Table: see text]
Atezolizumab in combination with bevacizumab in patients with unresectable locally advanced or metastatic mucosal melanoma: Interim analysis of an open-label phase II trial.
Authors: Si Lu , Fang Meiyu , Chen Yu , Mao Lili , Zhang Peng , Lin Jing , Bai Xue , Cao Xiao , Chen Yi , Guo Jun 
Published: June 2021

9511 Background: Mucosal melanoma is a rare malignant melanoma in Caucasians but ranks the second most common subtype in the Asian population. It is more often diagnosed at an advanced stage and responds poorly to current PD-1/PD-L1 inhibitors. Here we report the interim analysis results of ML41186, an open-label, multicenter, single-arm phase II study, aiming to evaluate the efficacy and safety of atezolizumab in combination with bevacizumab in patients (pts) with advanced mucosal melanoma. Methods: Eligible pts aged 18 to 75 years with histologically confirmed unresectable locally advanced or metastatic mucosal melanoma had at least one measurable lesion per RECIST version 1.1 at baseline, with an ECOG PS 0 or 1 and adequate hematologic and organ function. ML41186 is a Simon two-stage design study, if 22 pts completed ORR evaluation and more than 3 pts respond in stage I, the study then continue to Stage II. Atezolizumab and bevacizumab were administered at a fixed dose of 1200 mg and 7.5 mg/kg Q3W respectively (on day 1 of each 21-day cycle) until unacceptable toxicity or loss of clinical benefit. The primary endpoint is the objective response rate (ORR). The secondary endpoints include progression-free survival (PFS), duration of objective response (DoR), disease control rate (DCR), and safety. Results: By the cut-off date of 9th September 2020, 35 pts has been enrolled, among whom 22 pts in the stage I analysis set has completed two efficacy evaluation, while 28 pts (full analysis set) has completed at least one efficacy evaluation. In ITT populations (n=35), mean age was 58.9 years with 10 (28%) pts had ECOG PS of 1. LDH level elevated in 9 (25.7%) pts. More than half pts (19, 54.3%) had metastatic mucosal melanoma, of whom 3 (15.8%) pts had more than 3 metastasis sites and 4 (21.1%) pts had liver metastasis. In stage I analysis set (n=22), the best confirmed ORR was 36.4% (95% CI, 17.0%-59.3%). Median progression-free survival was 5.32 months (95% CI, 1.58-not reached), and the best confirmed DCR was 59.1% (95%CI, 36.4%-79.3%). The median confirmed DoR was not reached (95% CI, 2.76-NR). In the full analysis set (n=28), the unconfirmed ORR was 42.9% (95%CI, 24.5%-62.8%). In ITT populations (n=35), 28 pts (80%) experienced at least one adverse event (AE) and 5 pts (14.3%) experienced at least one grade 3-4 AEs. Only one patient experienced AE leading to treatment discontinuation. One patient died of autoimmune lung disease. Conclusions: The combination of atezolizumab plus bevacizumab showed promising benefit and was tolerable in pts with advanced mucosal melanoma. At the time of this interim analysis, the primary endpoint did not cross the futility boundary, thus the study will run into Stage II. Clinical trial information: NCT04091217.
Adverse effects of adjuvant tamoxifen treatment on bone mineral density in premenopausal breast cancer patients: A systematic review and meta-analysis.
Authors: Cha Chihwan , Lee Soo Jin , Hong Hanpyo , Choi Yun Young , Chung Min Sung 
Published: June 2021

e12500 Background: It is well known that adjuvant tamoxifen treatment for breast cancer in postmenopausal women decreases bone loss. However, the adverse effect of adjuvant tamoxifen therapy for bone mineral density (BMD) in premenopausal breast cancer patients remains uncertain. This meta-analysis aimed to assess the effects of adjuvant tamoxifen therapy on BMD changes in premenopausal women with primary breast cancer. Methods: Through April 2020, studies reporting BMD changes of lumbar spine or hip in premenopausal women with primary breast cancer treated with adjuvant tamoxifen were collected from EMBASE and PubMed. The pooled analysis was performed using random effects model of the standardized mean difference (SMD) of BMD in patients. Results: A total of 1,432 premenopausal patients from eight studies were included in the pooled analysis. After 3 years of median follow up, adjuvant tamoxifen therapy decreased BMD by as much as SMD of -0.79 [95% confidence interval (CI); -1.25 to -0.33, P < 0.01] at lumbar spines and -0.38 at hip (95%CI; -0.88 to 0.12, P > 0.05). Compared with patients received tamoxifen alone, patients who received combination therapy with chemotherapy or ovarian function suppression (OFS) showed decreased bone loss at lumbar spine (SMD -1.17 with 95%CI -1.59 to -0.75, -0.43 with 95%CI -2.26 to 1.40, and -0.75 with 95%CI -1.38 to -0.13, respectively). Conclusions: Our meta-analysis revealed that premenopausal women who received adjuvant tamoxifen treatment showed significant bone loss over a period of time, especially at lumbar spine. However, tamoxifen attenuated bone loss in those who received tamoxifen after chemotherapy or along with OFS.[Table: see text]
Abemaciclib, a CDK4 and 6 inhibitor with unique pharmacological properties for breast cancer therapy.
Authors: Torres-Guzmán Raquel , Ganado Maria Patricia , Mur Pérez Cecila , Marugán Carlos , Baquero Carmen , Yang Yanzhu , Du Jian , de Dios Alfonso , Puig Oscar , Lallena Maria Jose 
Published: June 2021

e12506 Background: Breast cancer is the second most common cancer worldwide. Pharmacologically targeting cyclin-dependent kinases 4 and 6 (CDK4 & 6) has proven to be a successful therapeutic approach in patients with estrogen receptor positive (ER+) breast cancer. Differences in both efficacy and toxicity among the available CDK4 & 6 inhibitors has generated interest in a biological explanation. Abemaciclib is an adenosine triphosphate-competitive, reversible, selective inhibitor of CDK4 & 6 that has shown antitumor activity as a single agent and in combination with standard endocrine therapy (ET), in hormone receptor positive (HR+) metastatic breast cancer patients including those with ET resistance, and in combination with ET in high-risk early breast cancer patients. This study examines attributes of abemaciclib and other CDK4 & 6 inhibitors. Methods: The potency of abemaciclib for CDK4 was evaluated using biochemicals and breast cancer cell-based assays. Additionally, different combinations with an anti-estrogen therapy (e.g., tamoxifen, fulvestrant) were analyzed in an in vitro palbociclib (CDK4 & 6 inhibitor)-resistant breast cancer cell model, as well as in a set of CDK4 & 6 sensitive breast cancer cell models. Using cell-free assays, high content imaging and flow cytometry approaches, a subset of markers were monitored to characterize the phenotype of sensitive cell lines in a continuous dose schedule. Results: In in vitro, cell-free assays, abemaciclib shows selectivity for CDK4 over CDK6, and in cell-based assays, abemaciclib preferentially inhibits the proliferation of cells dependent on the presence of CDK4, not CDK6. Abemaciclib inhibits cell proliferation in a wide range of breast cancer cell lines, showing activity regardless of human epidermal growth factor receptor 2 (HER2) and PI3KCA gene mutation status. Furthermore, in a cell line resistant to palbociclib, abemaciclib in combination with fulvestrant (ET) restores CDK4 & 6 sensitivity, leading to cell senescence and cell death. Finally, in human bone marrow progenitor cells, abemaciclib shows a lesser impact on myeloid maturation than other CDK4 & 6 inhibitors, palbociclib and ribociclib, allowing for continuous dosing. Conclusions: In pre-clinical experiments, abemaciclib is a potent cell growth inhibitor, inhibiting preferentially the CDK4/CyclinD1 complex, leading to cell senescence and cell death. These pre-clinical results support the differentiated safety and efficacy profile of abemaciclib observed in clinical trials.
Metaplastic breast cancer: Disease characteristics and outcome in Arab women.
Authors: Alsayed Adher , Alshamsan Bader I , Alshibany Aisha , Elshenawy Mahmoud Abdelsatar , Badran Ahmed ali , Al-Tweigeri Taher , Ajarim Dahish Saed , Suleman Kausar 
Published: June 2021

e12534 Background: Metaplastic breast cancer (MPBC) accounts for less than 1% of all breast cancer subtypes. Methods: Patients diagnosed with MPBC between 2001 are 2018 were reviewed. Disease characteristics, progression-free survival (PFS), and overall survival (OS) were estimated by the Kaplan-Meier method and compared by log-rank test. Results: Fifty-five MPBC patients were analyzed. The median was 46 years (IQR 40–55). 14.5% had a positive family history of cancer. The majority (98.2%) presented with a lump, and two patients presented with bilateral disease. The median BMI was 31 (IQR 24.5–37.5). The majority had stage III (56.4%), and stage IV was (7.3%). Most patients (90.9%) had triple-negative disease. The tumor grade (G) was available for 63.6% of patients (G2 11.4% and G3 88.6%). Nineteen patients (34.5%) received neoadjuvant chemotherapy (NAC) [anthracycline-based (15,78.9%), and platinum-taxane (11, 57.8%)]. The majority (92.7%) underwent surgery, 56.4% MRM, 12.7% BCT, 12.7% simple mastectomy, 7.3% palliative mastectomy. 54.5% underwent ALND and 20% SLNB. One patient had pCR. Adjuvant radiation was given for (33, 60%) and (37, 67.3%) received adjuvant radiation therapy. The median follow-up duration is 44 months (IQR 21–69). For nonmetastatic disease, 3-years DFS was 67.5%. There was no difference in DFS with using NAC (p-0.96) or being obese (p = 0.50). The 3-years OS was 72.9%, and the Log-rank test revealed prolonged survival with radiation therapy 87.1% vs. 56.6% ( p = 0.02) and earlier stage at diagnosis. 3-years OS for stage II was 92.9%, stage III was 71%, and no survival in stage IV (p < 0.001). There was a clinical difference in 3 years OS between obese vs. nonobese 61.3% vs. 85.9%, with no statistical significance (p = 0.15). Conclusions: The majority of patients diagnosed with MPBC had large tumor size, nodal disease, and more triple-negative disease, locally advanced and nonmetastatic. The DFS and OS were comparable to reported survival. There is a significant correlation between survival and stage and adjuvant radiation therapy.
The intra-tumor heterogeneity of ER and HER2 expression in patients with ER-positive and HER2-positive breast cancer.
Authors: Ju Jie , Du Feng , Gao Songlin , Si Yiran , Hu Nanlin , Liu Dongxu , Wang Xue , Yue Jian , Zheng Fangchao , Kang Yikun , Yang Zixuan , Ma Fei , Xu Binghe , Yuan Peng 
Published: June 2021

e12550 Background: ER- positive and HER2-positive (double-positive) breast cancers are known to display significant heterogeneity; however, traditional immunohistochemistry (IHC) only reflects inter-tumor heterogeneity. Studies are needed to demonstrate the intra-tumor heterogeneity of ER and HER2 expression and to further explore its impact. Methods: The retrospective study included three double-positive breast cancer cohorts. Data from a total of 141 patients from The Cancer Genome Atlas (TCGA) and 104 patients from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used to investigate the molecular characteristics of double-positive breast cancers at the tissue level via somatic mutation and RNA-seq analyses, while 43 patients treated at our hospital were selected to analyze ER and HER2 expression and localization at a single-cell level using multiple IF. The rH/R was proposed to reflect ER and HER2 expression profiles based on multiple IF or RNA-seq results, as follows: rH/E = HER2+ cell percentage / (ER+ cell percentage + 1) or rH/E = ERBB2 expression quantity / (ESR1 expression quantity + 1). Results: In the first two cohorts, we found that the HER2-enriched subtype displayed unique molecular characteristics, including increased TP53, ERBB3, and PI3KCA mutation rates and the abnormal expression of important signaling pathways (e.g., G2/M cell cycle checkpoint and epithelial mesenchymal transition); The rH/E was a significant index for diagnosing HER2-enriched patients (area under the receiver operating characteristic curve [AUC] = 0.92 and 0.75, both P < 0.0001). In the third cohort, we found that 86 % of the patients contained all four tumor cell types (ER+HER2+, ER+HER2-, ER-HER2+, and ER-HER2- cells); The rH/E was an independent risk factor for recurrence (hazard ratio [HR] = 2.63, P = 0.02) and patients with a rH/E ≥ 1.5 had a significantly shorter 5-year disease-free survival (DFS = 67 % vs. 92 %, P = 0.046). Conclusions: The significant intra- and inter-tumor heterogeneity of double-positive breast cancers is closely related to the prognosis of patients, which is of great significance for precision treatment.
Correlation of Trop-2 expression with clinicopathological characteristics, sTILs, AR expression and outcome in primary TNBC.
Authors: Izci Hava , Punie Kevin , Waumans Lise , Laenen Annouschka , Wildiers Hans , Verdoodt Freija , Desmedt Christine , Ardui Jan , Smeets Ann , Han Sileny N. , Nevelsteen Ines , Neven Patrick , Floris Giuseppe 
Published: June 2021

e12558 Background: Trophoblast cell-surface antigen-2 (Trop-2) is a transmembrane calcium signal transducer highly expressed in multiple tumor types including breast cancer. Trop-2 overexpression is associated with poor survival. Given the approval of sacituzumab govitecan in advanced triple-negative breast cancer (TNBC), Trop-2 emerges as an important target for antibody-drug conjugates. Limited data exist about correlations of Trop-2 expression with clinicopathological characteristics and outcome in early TNBC. Methods: We included 127 patients with early TNBC, treated with primary surgery at UZLeuven from 2005-2017. Trop-2 expression was determined with IHC (ab227689, Abcam) on whole slide tumor sections from resection specimens and assessed as continuous (H-score 0-300) and categorical (high 201-300, medium 100-200 and low < 100) variables. Stromal tumor infiltrating lymphocytes (sTIL; low, intermediate and high), mitotic score and androgen receptor (AR) expression (1% or 10%-cutoff) were scored. We assessed associations between Trop-2 expression and age, BMI, BRCA status, tumor grade and size, lymphovascular invasion (LVI), DCIS, nodal status, sTILs, AR, mitotic index and outcome (Invasive disease free survival and breast cancer specific survival). Results: The median age at diagnosis was 51y (range 26-80y) and the median follow-up 8.5y. Low, medium and high Trop-2 expression was seen in 50%, 37% and 13% of cases. AR was positive in 32% of cases (10%-cutoff). Higher Trop-2 expression was correlated with age (ρ = 0.192, p = 0.03) and inversely correlated with mitosis/mm² (ρ = -0.2, p = 0.02). Patients with high Trop-2-expression were older compared to patients with low Trop-2-expression (median 58 vs 47 years, p = 0.02). LVI was more frequent in Trop-2-high (65%) compared to TROP-2-medium (15%) or -low (16%) (p < 0.001). Median mitosis/mm² was higher in Trop-2-low (14) compared to Trop-2-medium (10) and -high (8) (p = 0.004). Patients in Trop-2-high subgroup had more nodal involvement (53%) compared to Trop-2-medium (23%) and -low (21%) (p = 0.03). There was no correlation between Trop-2 expression and sTILs, AR or outcome. Conclusions: In this patient cohort with TNBC treated with upfront surgery, higher Trop-2 expression was correlated with older age, with more LVI and nodal involvement, while mitosis/mm² were higher in tumors with low Trop-2 expression. Trop-2 expression was not correlated with sTILs, AR or outcome. Limited numbers of events warrant caution in interpretation.