bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular characteristics and clinical outcomes of breast cancer with HRAS mutations.
Authors: Kareff Samuel , Rodriguez Estelamari , Dawar Richa , Trabolsi Asaad , Ocejo Gallegos Jesus Antonio , Yin Jun , Walker Phillip , Kang Irene , Bustos Matias A. , Neman Josh , Hoon Dave S. , Graff Stephanie L. , Spetzler David , Lopes Gilberto 
Published: June 2022

561 Background: The RAS pathway regulates tumorigenesis and cell proliferation. HRAS is a RAS family member that activates via farnesylation. Indirectly targeting mutant HRAS with tipifarnib, a farnesyltransferase inhibitor (FTI), recently demonstrated efficacy in head and neck tumors. We aimed to investigate the molecular characteristics and clinical outcomes of HRAS mutations (HRASmut) for any potential role as a prognostic and therapeutic biomarker in breast cancer (BC). Methods: A total of 14,013 BC tissue samples had molecular profiling, including next generation DNA (592 Gene Panel, NextSeq, or WES, NovaSeq) or RNA sequencing (NovaSeq, WTS), and immunohistochemistry analyses, at Caris Life Sciences. MAP kinase (MAPK) activation and likelihood of a tumor’s response to anti-PD1 therapy were evaluated via MAPK Pathway Activity Score (MAPS) and interferon (IFN) score, respectively. Wilcoxon, Fisher’s exact, or Dunnett’s tests were used to determine statistical significance. Overall survival (OS) was calculated from date of tissue collection to insurance claims last contact using the Kaplan-Meier method. HRAS mutations (HRASmut) were compared to the general BC cohort (GC). Results: HRASmut were significantly enriched in older patients (median 69 vs 60 yrs; q<.0001), and in primary compared to metastatic BC tumor samples (55.9% vs 41.9%, p<.05). There were 70 total HRASmut (0.5%): Q61 was the most frequent (41.4%), followed by G12 (28.6%) and G13 (24.3%). Patients with Q61 HRASmut had significantly worse OS compared to GC (HR 1.86, 95% CI [1.10-3.13]; p<0.05). HRASmut had significantly higher MPAS compared to GC (1.26, all; 1.31, Q61; 1.7, G12; -.39, GC, q<.01). HRASmut were found in HR+/HER2- (22.6%) and TNBC (77.4%) tumors, but no HR-/HER2+ BC. TNBC samples with HRASmut displayed more PIK3CA (62.5% VS. 18.9%, q<.05) but less TP53 mutations (50% vs 84.9%, q<.05), higher expression of PD-L1 (41.2% vs 10.8%, p<.05) and androgen receptor (AR, 45.8% vs 24.4%, p<.05), and more frequent ARv7 fusions (20.7% vs 4.3%, p<.05) compared to HR+/HER2- (Table 1). Q61 HRASmut had the highest MPAS (2.39 vs -0.28, p<.01) in TNBC, whereas G12 HRASmut displayed the highest MPAS (2.01 VS -0.47, p<.05) in HR+/HER2- BC. Conversely, Q61 had the lowest IFN score (-0.45 vs -0.3) in HR+/HER2- but the highest (-0.18 vs -0.3) in TNBC. Conclusions: HRASmut were mutually exclusive with HER2+ BC. The association of Q61 HRASmut with worse survival highlights the oncogenic role of these mutations and supports therapeutic investigation using FTI. PIK3CA was significantly co-mutated in HRASmut, highlighting a potential benefit of combining PIK3CA inhibitors with tipifarnib. Overall, HRASmut displayed a subtype-specific distinct genomic landscape and may represent a key therapeutic target in BC. [Table: see text]
Associations of a breast cancer polygenic risk score with tumor characteristics and survival.
Authors: Lopes Cardozo Josephine , Andrulis Irene L. , Peter Devilee , Dörk Thilo , Drukker Caroline , Fasching Peter A. , Hooning Maartje J. , Keeman Renske , Nevanlinna Heli , Rutgers Emiel J. , van 't Veer Laura , Hall Per , Bojesen Stig Egil , Douglas Easton , Eccles Diana , Pharoah Paul , Schmidt Marjanka 
Published: June 2022

563 Background: A polygenic risk score (PRS) consisting of 313 single nucleotide polymorphisms (PRS313) is associated with risk of breast cancer and contralateral breast cancer. One of the most promising clinical applications for the use of PRS is to provide a personalized risk assessment to individualize breast cancer screening programs. This study aimed to evaluate the association of the PRS313 with clinical-pathological characteristics and survival of breast cancer. Methods: Women of European ancestry with invasive breast cancer were included, 98,397 women from the Breast Cancer Association Consortium (BCAC) and 683 women from the MINDACT trial. Associations between PRS313 (continuous, per SD) and clinical-pathological characteristics, including the 70-gene signature for patients included in MINDACT, were evaluated with logistic regression analyses. Associations of PRS313 with overall survival (OS), breast cancer-specific survival (BCSS) and distant metastasis-free interval (DMFI) were evaluated with Cox regression analyses, adjusted for clinical-pathological characteristics and treatment. Results: The PRS313 was associated with favorable tumor characteristics. In BCAC, increasing PRS313 was mostly associated with lower grade, hormone receptor-positive tumors, and with smaller tumor size. In MINDACT, PRS313 was associated with a low risk 70-gene signature, but the association was attenuated after adjustment for clinical-pathological characteristics. In BCAC, univariable analyses showed an association of PRS313 with better survival, hazard ratio (HR) per unit SD increase of PRS313 for OS: 0.96 (95% confidence interval (CI): 0.94-0.97), for BCSS HR: 0.96 (95% CI: 0.94-0.98) and for DMFI HR: 0.98 (95% CI: 0.96-1.00). The association in the unadjusted analysis was explained by differences in clinical-pathological characteristics (and treatment) and disappeared after adjustment: OS HR: 1.01 (95% CI: 0.98-1.05), BCSS HR: 1.02 (95% CI: 0.98-1.07) and DMFI HR: 1.03 (95% CI: 0.99-1.07). Conclusions: An increased PRS313 is associated with favorable tumor characteristics but was not independently associated with prognosis. This information is crucial input for modelling effective stratified screening programs, especially in the current era of optimized (systemic) treatments. Given the significant increase in breast cancer risk associated with increasing PRS313, absolute breast cancer mortality will still be higher for women with higher PRS313.
Low TMB as predictor for additional benefit from neoadjuvant immune checkpoint inhibition in triple-negative breast cancer.
Authors: Karn Thomas , Denkert Carsten , Rey Julia , Weber Karsten Ernst , Holtrich Uwe , Hanusch Claus , Sinn Bruno Valentin , Jank Paul , Huober Jens Bodo , Blohmer Jens U. , Schmitt Wolfgang D. , van Mackelenbergh Marion , Schem Christian , Stickeler Elmar , Jackisch Christian , Untch Michael , Schneeweiss Andreas , Loibl Sibylle 
Published: June 2022

581 Background: It is commonly anticipated that a high tumor mutational burden (TMB) is a predictor of response to immune checkpoint blockade (ICB). We previously showed that triple-negative breast cancer (TNBC) from the GeparNuevo study with high TMB displayed increased response both to neoadjuvant chemo-ICB with durvalumab but also to chemotherapy alone, with no significant interaction with treatment arm (Karn et al. Ann Oncol 2020). In contrast, we also observed that cases with very low TMB more often displayed a pCR after treatment with chemo-ICB than with chemotherapy alone. This may in fact suggest a benefit of ICB to those TNBC with rather low TMB. Methods: We have analyzed the distant disease-free survival (DDFS) of GeparNuevo patients according to TMB and treatment arm (neoadjuvant chemotherapy plus durvalumab or chemotherapy plus placebo). For TMB (mut/Mb) we applied the identical cutoff of the upper tertile as in our previous analysis. Results: The median follow-up of the time-to-event data was 43.7 months. Data of TMB was available in 149 of 174 patients. We found that within the high-TMB tumors (durvalumab: n=27; placebo: n=23), DDFS was similar between both arms of the trial (durvalumab vs. placebo: HR (hazard ratio) 0.95 [95%CI 0.19-4.69], p=0.95). Strikingly however, within the low-TMB group (durvalumab: n=47; placebo: n=52) we observed a significantly better DDFS in the durvalumab-chemotherapy combination arm, in contrast to the arm treated only with chemotherapy (durvalumab vs. placebo: HR 0.23 [95%CI 0.06-0.79], p=0.02; interaction test for TMB and treatment arm p=0.17). The observation was also robust to alternative TMB cutoffs. Similar results were obtained for invasive disease-free survival. Conclusions: Our results show, in contrast to other published data, that patients with early TNBC and low TMB/neoantigen counts may benefit from short-term neoadjuvant durvalumab treatment, while for those with high TMB, durvalumab plus chemotherapy does not improve efficacy over chemotherapy alone.
Peripheral lipidomics analyses with ensemble machine learning predict response to neoadjuvant therapy in breast cancer.
Authors: Wang Jiani , Ma Fei , Sun Xiaoying , Wang Jinsong , Guo Fengzhu , Liu Binliang , Wang Wenna , Li Qing , Xu Binghe 
Published: June 2022

582 Background: Neoadjuvant therapy (NAT) is critical in the therapeutic strategy for locally advanced breast cancer (BC) patients. Biomarkers to predict the pathologic complete response (pCR) and to screen beneficial responders need to be urgently explored. Lipidomics is a high-throughput analysis technique, which has potential applications for peripheral biomarkers’ detection to overcome the difficulty in serial pathological biopsies and tumor heterogeneity. Machine learning is a method for mining high-dimensional information with high group and low intermolecular correlation. Here we construct multidimensional models with machine learning approach combining clinical clinicopathological and lipidomics data to predict NAT response. Methods: Plasma samples were collected from 119 BC patients before after two cycles of NAT. Peripheral lipidomic profiles at multiple levels of lipid composition, concentration, chain length, and saturation were dynamically monitored by using absolute quantitative lipidomics. Responders (pCR) and non-responders (non-pCR) groups were randomly sampled in a 1:1.5 ratio for subsequent analysis. Screening of candidate lipidomic biomarkers were performed according to the criteria “VIP>1, FC>2 or FC<0.5 and p<0.05”. Above feature screening were validated by using ensemble machine learning algorithms (Logistic regression, Random forest and Support vector machine). Pearson correlation coefficients were calculated for the expressions of candidate biomarkers. Multidimensional prediction models with the logistic regression algorithm were constructed by correlating candidate lipidomics features with clinicopathologic phenotypes prospectively collected with baseline and dynamic changes. The performance of the models constructed above were assessed by ROC analysis. Results: A total of 8 major classes, 39 subclasses, and 2292 molecules of lipid metabolites were identified in the 235 plasma samples. Most of the candidate biomarkers had lower correlations, indicating lower overlapping and more optimal combination of panels. The prediction models constructed by baseline correlating candidate lipidomics features with ensemble machine learning achieved an Area under the Curve (AUC) of 0.84 for the training set and 0.72 for the validation set with the accuracy 0.84, the specificity 0.92, and the sensitivity 0.71 when the cutoff value is 0.57.The prediction models constructed with lipidomics dynamic changes also achieved good performance. Conclusions: The study suggested a possibility that peripheral lipidomics provided a potential tool to develop multidimensional models with ensemble machine learning for predicting response to NAT for BC patients with good discrimination power, which might guide individual optimal NAT strategies and avoid unnecessary treatment.
Real-world outcomes of patients with human epidermal growth factor 2 (HER2)–positive breast cancer receiving neoadjuvant therapy without adjuvant ado-trastuzumab emtansine (T-DM1).
Authors: Di Iorio Massimo , Elliott Mitchell J. , Scott Jordan L , Mittal Abhenil , Molto Consolacion , Tamimi Faris , Cescon David W. , Amir Eitan , Meti Nicholas 
Published: June 2022

584 Background: HER2-positive early-stage breast cancer (EBC) treated with neoadjuvant chemotherapy and HER2-targeted therapy has favourable outcomes, especially for those attaining pathologic complete response (pCR). Among those with residual invasive disease (RD), outcomes are variable. Replacing adjuvant trastuzumab with ado-trastuzumab emtansine (T-DM1) reduces the risk of recurrence, but increases toxicity and cost. The magnitude of benefit of T-DM1 may be small among patients with RD and favourable prognostic features. Here we report on real-world outcomes of patients with HER2-positive EBC treated with neoadjuvant therapy without adjuvant T-DM1. Methods: We performed a single institution, retrospective review of HER2-positive EBC treated with neoadjuvant chemotherapy and trastuzumab between January 1st, 2012 and February 1, 2021. We excluded patients who received adjuvant T-DM1. We collected clinical and pathologic characteristics, treatment data, and outcomes events. We estimated 3-year disease-free survival (DFS), a validated endpoint in HER2-positive EBC, using Kaplan-Meier with recurrence and/or death as events. Outcomes were reported in subgroups based on known prognostic factors. The study was approved by the University Health Network Research Ethics Board. Results: The study comprised 193 patients with a median follow-up of 30 months. The majority (n=160, 83%) received neoadjuvant anthracycline and taxane-based chemotherapy; 42 (22%) received neoadjuvant pertuzumab. All received adjuvant trastuzumab. Median age was 53 years (range 25-87), 113 (59%) patients had estrogen receptor (ER) positive disease, and 82 (42%) had pCR. In total, 16 events were observed, of which 13 (81%) were distant recurrences (including 5 (31%) in the brain) and 3 (19%) were locoregional. Of these, 14 (88%) occurred in the first 3 years of follow-up. Estimated 3-year DFS was 98.6% in patients with pCR, and 85.4% in patients with RD. Patients with ER positive disease had excellent outcomes, regardless of pathologic nodal (ypN) status. The highest risk of recurrence was in ER negative and ypN positive disease (Table). Conclusions: Real-world outcomes of patients with HER2-positive EBC treated with neoadjuvant therapy without adjuvant T-DM1 are favorable, including those with RD if ER positive. The expected benefit of adjuvant T-DM1 in this group is therefore likely to be small. Patients with ER- disease had poorer outcomes irrespective of nodal status. Further research to identify patients with RD for whom the benefit of T-DM1 is unlikely to merit its added toxicity and cost is warranted. [Table: see text]
Association of facility volume with pathologic complete response and overall survival in patients with non-metastatic breast cancer.
Authors: Ma Sung Jun , Hashmi Mahnoor , Yu Brian , Yao Song , Oladeru Oluwadamilola Temilade , Singh Anurag K. 
Published: June 2022

586 Background: High facility volume has been previously shown to be associated with a higher likelihood of pCR among patients with breast cancer following neoadjuvant chemotherapy. However, factors underlying the association of high facility volume with pCR and the impact of facility volume on survival remain unclear. We performed an observational cohort study to investigate the association of overall survival (OS) with facility volume and identify variables associated with high facility volume. Methods: The National Cancer Database (NCDB) was queried for women diagnosed between 2010 and 2017 with non-metastatic breast cancer treated with neoadjuvant chemotherapy followed by surgery. Facility volume was stratified by tertiles of low, intermediate, and high. Logistic and Cox multivariable analyses (MVA) were performed to evaluate factors associated with facility volume and OS, respectively. Propensity score matching was used to reduce selection bias. Results: A total of 105,804 women met our inclusion criteria (low facility volume: n=6,172; intermediate facility volume: n=20,199; high facility volume: n=79,433). The median follow up was 49.2 months (IQR 32.7-71.3). On logistic MVA, both intermediate (adjusted odds ratio [aOR] 1.24, 95% confidence interval [CI] 1.14-1.35, p<0.001) and high (aOR 1.53, 95% CI 1.42-1.65, p<0.001) facility volumes were associated with pCR. On Cox MVA, high (adjusted hazards ratio [aHR] 0.89, 95% CI 0.83-0.96, p=0.001), but not intermediate (aHR 0.97, 95% CI 0.90-1.04, p=0.40), facility volume was associated with improved OS. Similar findings were noted in 18,671 matched pairs between high versus low or intermediate facility volumes (HR 0.90, 95% CI 0.85-0.94, p<0.001). On logistic MVA, patients were more likely to receive treatments at high volume facilities if they were academic (adjusted odds ratio [aOR] 5.47, 95% CI 5.24-5.71, p<0.001), African American (aOR 1.25, 95% CI 1.20-1.30, p<0.001) with private insurance (aOR 1.13, 95% CI 1.04-1.22, p=0.005), and higher tumor grades (grade 2: aOR 1.10, 95% CI 1.03-1.18, p=0.008; grade 3: aOR 1.12, 95% CI 1.05-1.20, p=0.001). Patients were less likely to undergo treatments at high volume facilities if they reside in urban (aOR 0.63, 95% CI 0.60-0.66, p<0.001) or rural (aOR 0.75, 95% CI 0.67-0.85, p<0.001) areas with limited education (aOR 0.90, 95% CI 0.87-0.93, p<0.001), had government-led insurance (aOR 0.87, 95% CI 0.80-0.94, p=0.001), and had time interval of <180 or >240 days between diagnosis and surgery (aOR 0.92, 95% CI 0.90-0.95, p<0.001). Conclusions: To our knowledge, this is the largest study using a nationwide oncology database to report the association of high facility volume with pCR and improved OS, with various patient demographics associated with high facility volume. Our findings suggest an integral role of facility volume on pCR and survival for breast cancer.
Combined assessment of metabolic response and tumor infiltrating lymphocytes as a predictor of outcomes following neoadjuvant therapy for HER2-positive breast cancer: Results from the randomized PREDIX HER2 trial.
Authors: Matikas Alexios , Johansson Hemming , Grybäck Per , Bjöhle Judith , Lekberg Tobias , Fredholm Hanna , Acs Balazs , Elinder Ellinor , Isaksson-Friman Erika , Agartz Susanne , Hellstrom Mats , Zerdes Ioannis , Hartman Johan , Bergh Jonas C. S. , Hatschek Thomas , Foukakis Theodoros 
Published: June 2022

593 Background: Abundance of tumor infiltrating lymphocytes (TIL) is prognostic in early HER2-positive breast cancer (BC). Response to neoadjuvant therapy (NAT) according to positron emission tomography combined with computed tomography (PET-CT) has been shown to predict pathologic complete response (pCR). There is paucity of data regarding long-term prognostication using PET-CT and the potential value of the combined assessment of both these biomarkers. Methods: PREDIX HER2 (NCT02568839) is a prospective randomized phase 2 trial that compared standard NAT (docetaxel, trastuzumab, pertuzumab) with trastuzumab emtansine, in patients with HER2-positive BC. Overall, 202 patients were included (197 evaluable) and the primary efficacy analysis showed no difference in pCR or event-free survival (EFS) between the two groups (Hatschek, JAMA Oncology 2021). Assessment with fluorine 18–labeled fluorodeoxyglucose PET-CT was performed at baseline and after 2 and 6 treatment cycles, and SUVmax was evaluated as a continuous variable. TILs were assessed at baseline biopsies according to guidelines from the International TIL Working Group (J.H.). The aim of this secondary analysis was to investigate the combined assessment of TIL and PET-CT as an early predictor of response to NAT. Results: Overall, 112 patients underwent baseline PET-CT and 109 after C2, whereas 173 had baseline TIL. In multivariable analysis, baseline SUVmax did not predict pCR (ORadj= 1.04, 95% CI 0.97-1.12, p = 0.259) or EFS (HRadj= 1.07, 95% CI 0.98-1.17, p = 0.117). In contrast, higher SUVmax at C2 predicted lower pCR (ORadj= 0.65, 95% CI 0.48-0.87, p = 0.005) and worse EFS (HRadj= 1.18, 95% CI 1.04-1.34, p = 0.01). Baseline TIL > 10% (median cut-off) provided additional prognostic information to clinical parameters (stage and hormone receptor expression) and C2 SUVmax (LR-Δχ2 = 7.19, p = 0.007; ORadj= 3.52, 95% CI 1.37 – 9.06, p = 0.009). 75% of patients with high TIL and C2 SUVmax < 2.49 achieved pCR, compared with 13.8% of those with low TIL and high C2 SUVmax and 39.1%-41.3% for the intermediate groups (p = 0.001). Conclusions: SUVmax after two cycles of NAT for HER2-positive BC is an independent predictor of both short- and long-term outcomes. A combined assessment with TIL may facilitate early selection of good responders for de-escalation and poor responders for alternative treatment strategies. Clinical trial information: NCT02568839.
Prediction of pathologic complete response to neoadjuvant chemotherapy in breast cancer (SWOG S0800) using image analysis-based tumor infiltrating lymphocyte measurements.
Authors: Blenman Kim , Fanucci Kristina , Bai Yalai , Pelekanou Vasiliki , Nahleh Zeina A. , Shafi Saba , Burela Sneha , Barlow William E. , Sharma Priyanka , Thompson Alastair Mark , Godwin Andrew K. , Rimm David L. , Hortobagyi Gabriel N. , Pusztai Lajos 
Published: June 2022

594 Background: Image analysis-based tumor infiltrating lymphocyte (TIL) quantitation methods are being developed to eliminate reader-to-reader variation in TIL assessment that hinders its clinical adoption as prognostic and chemotherapy response predictive marker. We evaluated the ability of an image analysis-based TIL score to predict pathologic complete response (pCR) and event free survival (EFS) in breast cancer. Methods: 113 pretreatment samples were analyzed from the SWOG S0800 trial that randomized stage IIB-IIIC HER-2-negative breast cancers to neoadjuvant chemotherapy with or without bevacizumab. TIL quantitation was performed on H&E sections using QuPath open-source software and a convolutional neural network cell classifier (CNN11). The digital easTILs% score was calculated as [sum of TIL Area (mm2) / Stromal Area (mm2)] x 100. Pathologist-read stromal TIL score (sTILs%) was defined using international guidelines. A previously validated threshold of easTILs% > 19.9% defined high easTILs% status. Results: Pretreatment easTILs% was significantly higher in cases with pCR compared to residual disease (RD) (means, 31% vs. 17%, p < 0.001). easTILs% high and low cases had pCR rates of 41% and 21% (p = 0.019), respectively. In logistic regression adjusting for other factors, easTILs% was prognostic for pCR as continuous score (p < 0.001) and as high vs low categories (p = 0.035). There was strong positive correlation between easTILs% and sTILs% (r = 0.606, p < 0.0001), and sTILs% was also predictive of pCR. The areas under the prediction curve (AUC) were 0.709 and 0.627 for easTILs% and sTILs%, respectively. There was no statistically significant interaction between easTILs% and bevacizumab benefit (p = 0.26), and higher easTILs% or sTILs were not associated with better EFS. Conclusions: Image analysis-based TIL quantification is predictive of pCR in breast cancer and had better pCR outcome discrimination than pathologist-read sTIL count. [Table: see text]