bluuebunny/crossref_metadata_2025_split huggingface dataset:
The association between mediators of the receptor for advanced glycation end product (RAGE) axis and immune checkpoint inhibitor (ICI)–induced colitis in patients with melanoma.
Authors: Simons Morgan , Manigrasso Michaele , Li Xiaochun , Goldberg Judith , Osman Iman , Schmidt Ann Marie 
Published: June 2022

9587 Background: Colitis and other gastrointestinal (GI) toxicity are a frequent and occasionally severe form of immune-related adverse events (irAEs) in patients treated with ICIs. To date, no definitive mechanism has been identified, and this area remains an active field of investigation. We hypothesized that activation of the RAGE axis, known to be implicated in inflammatory bowel disease through stimulation of signal transduction targeted by pro-inflammatory RAGE ligands, members of the S100 family and High Mobility Group Box 1 (HMGB1), might be associated with irAE- colitis. Methods: We examined sera from 111 advanced melanoma patients prospectively accrued and followed up at NYULH (treated with anti-PD-L1, n = 44; antiCTL4, n = 23; and combination, n = 44). 24 (22%) developed GI toxicity grade >2. Serum biomarkers of the ligand-RAGE pathways, soluble (s)RAGE, endogenous secretory (es)RAGE, S100B, and HMGB1, were measured in the patients’ sera during ICI treatment. Multivariable ordinal logistic regression analyses with all grades of GI toxicity as the primary outcome for all the recorded covariates (including serum biomarkers, clinical covariates) were performed. We then used ordinal multivariable logistic regression with stepwise variable selection. Similar analyses with GI toxicity as a binary outcome ((≥grade 1 vs no toxicity) were also conducted. Only those variables that jointly contributed to the odds of developing toxicity were included in the final stepwise model. No adjustments for multiplicity were included. As sRAGE and esRAGE are highly correlated (r = 0.86), esRAGE concentrations were not used in the joint models. Results: A significant association between GI toxicity and concentrations of sRAGE and S100B was identified. The final stepwise multivariable logistic model includes only sRAGE and S100B. The odds of having a one level increase in GI toxicity grade increase 1.100 times (95% CI: 1.008, 1.199; p = 0.029) for each unit decrease of sRAGE ( = sRAGE/100). The odds of a one level increase in GI toxicity increase 1.059 times (95% CI: 1.004, 1.116; p = 0.035) for each unit increase of S100B ( = s100B/100). All other analyses yielded comparable results. In contrast, concentrations of HMGB1 and other clinical covariates, including response and treatment category, were not associated with GI toxicity. Conclusions: Mediators of the RAGE axis, specifically sRAGE and S100B, might have a role in GI toxicity in patients receiving ICIs. The ligand-RAGE axis may be a novel target for irAE therapies for patients receiving ICIs to mitigate the severity of GI toxicity.
Breast cancer: Online education’s effect on clinician ability to assess risk of recurrence and understanding the latest data.
Authors: Patel Urvi , Dorkhom Nabil , Abair Tristin , Cameron Davecia Ragoonath , Cohen Jacob 
Published: June 2022

e12509 Background: Hormone receptor positive breast cancer (HR+ BC) is often diagnosed in the early, curable, stage. Emerging treatment options make it important to educate clinicians on how to identify patients eligible for these options and increase their understanding of the clinical data associated with therapies in HR+/HER2- early breast cancer (EBC). The study objective was to assess the impact of 2 educational activities on HR+/HER2- EBC on oncologists’ knowledge, competence, and confidence related to risk of recurrence and clinical data. Methods: Two online continuing medical education activities were launched in 2021 covering a range of topics focused on identification of patients at high risk of recurrence and the latest clinical trial data for CDK4/6 inhibitors (CDK4/6i) in HR+/HER2- EBC. Educational impact was assessed using a repeated pair design, with knowledge/competence and confidence questions pre- and post-education. Confidence was assessed on a Likert-type scale ranging from not confident to very confident. Questions were designed to assess if certain learning objectives (LOs), covering identified educational gaps, were met. Data was collected from 06/14/2021 to 01/31/2022. Statistical significance was assessed using McNemar’s test ( P < .05 level). Results: 5,544 learners participated in these 2 activities, including 727 oncologists. The LOs were grouped in 3 themes that assessed oncologists’ knowledge/competence and confidence related to identifying patients with HR+/HER2- EBC at high risk of recurrence and understanding the clinical trial data investigating CDK4/6i in this setting. Two themes showed a significant improvement. The number of oncologist learners assessed per theme differed from 228 to 260. Conclusions: Participation in text- and video-based activities resulted in a significant improvement of oncologists’ knowledge, competence, and confidence related to CDK4/6i clinical data and treatment eligibility for patients with HR+/HER2- EBC. Baseline knowledge regarding the identification of high risk of recurrence in HR+/HER2-EBC was high (89% correct responses pre-education) in comparison that of clinical trial data and confidence in identification of patients eligible for adjuvant therapy (54% and 21% respectively). This finding could be reflective of clinicians having a high-level knowledge and competence related to risk stratification prior to the developments that occurred secondary to the approval of CDK4/6i in the adjuvant setting. With these new developments additional education around this topic will be required.[Table: see text]
Assessing association of heavy metal levels in urine and sera with neurotoxicity in breast cancer(BC) patients undergoing adjuvant/neoadjuvant chemotherapy.
Authors: Whitaker Kristen Danielle , Ross Eric A. , Klaunig James E. , Singh Tanu , Veggeberg Rosanna , Alpaugh Katherine , Goldstein Lori J. 
Published: June 2022

e12510 Background: Standard adjuvant chemotherapy for early stage BC includes taxane therapy with paclitaxel or docetaxel. Taxanes are associated with peripheral neuropathy in some patients, which can impact appropriate dosing and quality of life. In this study, we investigated whether there is an association between the levels of heavy metals in serum or urine and the development of high-grade peripheral neuropathy, defined as grade ≥2 (utilizing CTCAE v.4.0) in a cohort of BC patients undergoing neo/adjuvant taxane chemotherapy. Methods: BC patients undergoing treatment with taxanes were identified in the clinic. Patient eligibility included: histologically confirmed invasive mammary carcinoma, Stage I-III BC, undergoing neo/adjuvant treatment with taxane chemotherapy. Patients previously treated with chemotherapy or who had pre-existing neuropathy were not eligible. Patients were consented and prior to study enrollment, study participants provided blood and urine samples to assess for heavy metals. Neurotoxicity was measured using the NCI CTCAE v.4 criteria throughout patient’s taxane treatment. Serum and urine samples collected at baseline were analyzed for heavy metals by inductively coupled plasma mass spectrometry (ICP-MS). Results: 115 female patients were enrolled. 111 patients were included in the analysis; 4 patients were excluded due to withdrawal from study prior to receiving any taxane treatment. Participants were 78% White (6% of Hispanic origin), 19% Black and 3% Asian with an average age of 51 years (range 26-72). ICP-MS was used for the analysis of Aluminum (Al), Manganese (Mn), Cobalt (Cu), Zinc (Zn), Arsenic (As), Cadmium (Cd), Mercury (Hg), Thallium (Tl), and Lead (Pb) levels in patients’ serum and urine. Patients with neurotoxicity grade >=2 had significantly lower serum Arsenic levels (mean=0.37 [SD=1.08], n=89] than subjects with toxicity grades 0-1 [mean=1.21 (SD=2.33), n=22] (p=0.037; Wilcoxon test). Other than Arsenic no relationship of the other heavy metals and neurotoxicity was found in the serum. We did not observe significant associations between heavy metal levels in urine and neurotoxicity grade. Conclusions: Taxane treatment is an effective BC therapy but its utility is limited by its associated toxicity of peripheral neuropathy. The source of the higher arsenic levels is unclear. We conclude that there is no evidence that high levels of heavy metals were associated with taxane induced neurotoxicity in our study.
Physicians’ acceptance of extended or intermittent adjuvant endocrine therapy (AET): A survey on breast cancer (BC) physicians.
Authors: Chow Louis Wing-Cheong ,   Asian Institute of Clinical Oncology (AICO) Expert Panel
Published: June 2022

e12515 Background: The results from the GIM4, SALSA, and SOLE trials are potentially practice-changing, but it was unknown whether physicians would accept these trial results and adjust their AET prescriptions for postmenopausal women with BC. Methods: A cross-sectional survey involving 77 BC physicians in China was conducted. The survey questions were developed based on the GIM4, SALSA, and SOLE trial results, as well as referred to the latest NCCN guidelines. Statistical analyses were performed using SPSS version 28.0. Results: Almost half (48%) of the respondents were breast surgeons, 19% were breast specialists, 8% were medical oncologists, and 2% were general surgeons. Forty-five percent of the respondents had a clinical experience of ≥15 years, and the mean ± SD number of BC patients managed annually was 762.10 ± 1,254.50. For pN0, tumor size ≤0.5cm, postmenopausal patients, respondents with ≥15 years of clinical experience were more likely to prescribe a longer duration of AET as compared to those with <15 of clinical experience (p=0.025 and p=0.038 for patients receiving prior 4-5 years of tamoxifen [TAM] and prior 5 years of aromatase inhibitor [AI], respectively). More than half (57.1%) did not agree with the hypothesis that AI resistance can be reversed by intermittent letrozole treatment (the SOLE trial hypothesis), but 50.6% considered intermittent letrozole as an acceptable option, especially for patients with ≤3 positive nodes (79.5%), tumor grade 1 (84.6%), tumor size ≤2cm (82.1%), HER2 negative disease (74.4%). Conclusions: A high proportion of the BC physician respondents would prescribe extended AET with AI beyond 5 years for postmenopausal women with BC, especially for those with higher risk. Intermittent letrozole was considered as an acceptable option for low-risk patients.[Table: see text]
Automated H&E image-based detection and prognostic evaluation of HER2 heterogeneity in ER+ breast cancers.
Authors: Mukhopadhyay Satabhisa , Dasgupta Tathagata , Berwick Angelene , Walsh Elizabeth , Cummings Michele , Orsi Nicolas M. 
Published: June 2022

e12517 Background: HER2 amplification or overexpression is negative prognostic factor that occurs in circa 15% of primary invasive breast cancers, with positive results opening up eligibility for HER2 targeted (e.g. trastuzumab) combination therapy. However, HER2 intratumoral heterogeneity has been proposed as an explanation for the development of resistance to anti-HER2 targeted therapy. The aim of this retrospective study was to test the prognostic value of a HER2 heterogeneity index on ER+ breast cancer H&E whole slide images (WSIs). Methods: ER+ breast cancers slides ( n=60 cases) of known HER2 status (immunohistochemically assessed over the 0 to 3+ range, with HER2 2+ borderline cases validated by fluorescence in situ hybridization) were digitized on an Aperio AT3 scanner. A subset of these patients ( n=29) was accounted for by HER2 amplified/borderline cases. A HER2 heterogeneity index was tested and compared to standard clinical HER2 status in these cases and related to progression free survival (PFS). Survival analyses were performed using Kaplan-Meier (KM; with median cut-off) and Cox Proportional Hazards (as a continuous variable) models. Results: The HER2 heterogeneity index performed better in terms of prognostication than clinical HER2 status alone in relation to PFS (KM P=0.019; HR 8.06, P=0.01 vs. KM P=0.02; HR 6.75, P=0.048). These differences were more pronounced in the HER2 amplified/borderline tumor subset, where the HER2 heterogeneity index outperformed clinical HER2 status (KM P=0.04; HR 6.38, P=0.001 vs. KM P=0.10; HR 0.64, P=0.20). Conclusions: These findings highlight the merit of identifying HER2 heterogeneity from H&E slides alone and establish this index as a robust prognostic factor in determining PFS in ER+ breast tumors. Future work will extend this investigation into ER- tumors and evaluate patient-specific tumor responses to anti-HER2 targeted therapy.
Analysis of prognostic factors and survival outcomes for patients with T1N0 HER2-positive infiltrating ductal carcinoma of the breast: A real-world study with long-term follow-up.
Authors: Gao Song-lin , Wang Ding-yuan , Wang Xi , Xu Binghe , Yuan Peng , Zhang Bo 
Published: June 2022

e12530 Background: The optimal adjuvant systemic treatment and prognostic factors for patients with T1N0 HER2-positive infiltrating ductal carcinoma (IDC) of the breast are still unclear. We conducted a real-world study in China to identify potential prognostic factors in this low-risk population, and to characterize survival outcomes of patients treated with different adjuvant strategies. Methods: We included patients with T1N0 HER2-positive IDC of the breast who were treated at the Cancer Hospital, Chinese Academy of Medical Sciences from April 2010 to April 2017. We performed Cox multivariate analysis to identify potential prognostic factors for invasive disease-free survival (IDFS). We also compared survival outcomes of 1) patients treated with adjuvant chemotherapy alone, or chemotherapy plus trastuzumab (Chemo+T), or observation only; 2) patients receiving adjuvant anthracycline (AC)-based and non-AC regimens, both combined with trastuzumab. Inverse probability of treatment weighting (IPTW) propensity score was used to reduce the selection bias. Results: Overall, 692 consecutive patients with pT1N0 HER2-positive IDC of the breast were included. The median follow-up was 78.0 months. Cox multivariate analysis demonstrated that age≤40 (HR = 2.62, 95%CI 1.39-4.92, P = 0.003) and T1c (HR = 2.35, 95%CI 1.17-4.74, P = 0.017) were associated with inferior IDFS, whereas ER+PR+ (HR = 0.44, 95%CI 0.26-0.77, P = 0.004) and adjuvant trastuzumab (HR = 0.21, 95%CI 0.12-0.35, P< 0.001) were associated with favorable IDFS. For adjuvant treatment, 104, 195, and 373 patients were identified for observation, chemotherapy alone, and Chemo+T, respectively. The IPTW-adjusted Kaplan-Meier analysis demonstrated that compared with observation and chemotherapy alone, the IDFS was significantly longer in the Chemo+T group ( P = 0.034 and < 0.001, respectively). Meanwhile, compared with observation, chemotherapy alone did not significantly prolong IDFS ( P = 0.424). For the comparison of AC-based vs. non-AC regimens, 141 patients were identified in the AC-based group and 227 in the non-AC group. The Kaplan-Meier analysis indicated that patients in both groups had similar IDFS ( P = 0.242). Conclusions: For patients with T1N0 HER2-positive IDC of breast, age≤40, T1c, ER+PR+, adjuvant trastuzumab are independent prognostic factors. We recommend adjuvant chemotherapy plus trastuzumab, especially for patients with T1c tumors. When used in combination with trastuzumab, non-AC regimens may have similar efficacy with AC-based regimens.
Low-dose tamoxifen for breast cancer prevention in patients with ductal carcinoma in situ (DCIS) and atypical lesions: A real-world experience.
Authors: Patel Rima , Jin Cao , Tiersten Amy 
Published: June 2022

e12537 Background: Patients diagnosed with non-invasive breast lesions such as DCIS and lobular carcinoma in situ (LCIS) and atypical breast lesions such as atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH) are at increased risk of developing invasive breast cancer (BC). Tamoxifen 20mg daily for 5 years has shown to be effective for BC prevention in these at-risk patients but its use can be limited by its adverse effects. The recent Tam01 study found that low dose tamoxifen (5mg daily for 3 years) in patients with DCIS, ALH, and ADH resulted in an approximate 50% risk reduction in BC events compared to placebo with a slight increase in hot flashes but no increases in uterine cancer or venous thromboembolism within the tamoxifen group (PMID: 30973790). The objective of this study was to evaluate the use of low dose tamoxifen at our institution and determine how many patients preferred this option. Methods: We performed a retrospective chart review of women who were diagnosed with DCIS, LCIS, ADH, and/or ALH at our institution from January 2019 to December 2021 and subsequently started adjuvant tamoxifen. Patients with history of invasive BC were excluded. Patients were categorized as being on standard dose (20mg daily) or low dose (5mg daily or 10mg every other day) tamoxifen. Fisher’s exact test was used to compare rates of standard and low dose tamoxifen use in the entire cohort as well as in pathology-based subgroups. Results: We included 130 women diagnosed with DCIS, LCIS, ADH and/or ALH and who started adjuvant tamoxifen. The median age at diagnosis was 50 years and 68% were premenopausal. Overall, 62% (n = 80) of women started standard dose tamoxifen and 38% (n = 50) low dose tamoxifen. Among 63 patients who were offered both standard and low dose options, 76% (n = 48) initiated low dose tamoxifen (p < 0.0001). Twenty women were noted to be hesitant to start standard dose tamoxifen due to concern for side effects or preexisting menopausal symptoms but were agreeable to the low dose option. Of the 86 patients with DCIS, a preference for standard dose tamoxifen was observed (74% vs 26%, p = 0.0016). Among 44 patients with LCIS, ADH, and/or ALH, more patients were on low dose tamoxifen (64% vs 36%, p = 0.282). Nine percent (n = 7) of patients on standard dose tamoxifen switched to low dose due to adverse effects including hot flashes, mood changes, and insomnia. Conclusions: At our institution, in patients offered both low dose and standard dose tamoxifen, more than 75% started low dose tamoxifen. The low dose option was more frequently used for atypical lesions such as ADH, ALH and LCIS. In women at higher risk of invasive BC who may be reluctant to start standard dose tamoxifen or intolerant of it, low dose tamoxifen should be considered and offered.
The case for simul-omics: Identifying IO biomarkers of ganitumab-metformin pathological complete response (pCR).
Authors: Pfeiffer John R. , Zhang Yuhan , Antony Anu K. , Team The SimBioSys , Cole John A. 
Published: June 2022

e12551 Background: During the I-SPY2 clinical trial, ganitumab (G) immunotherapy (IO) was co-administered with metformin (GM) to counteract G-induced hyperglycemia. The GM + standard of care (SOC) combination showed promising results but did not meet the statistical threshold for phase III. Predicting individual patient response to IO is a key limitation for clinical use and a reason why IO phase II to III oncology trial transitions fail. Thus, we used SimBioSys TumorScope (TS), a 4D spatiotemporal multiscale biophysical model, to identify predictive IO biomarkers of pCR in response to GM+SOC. Methods: Patients that received GM+SOC therapy (n=41) and SOC (n=41) matched controls from the I-SPY2 trial were included in analyses. Using SOC clinical data and DCE MRIs, we generated biophysical simulations of each individual patient’s response to SOC therapy. Derived from the TS simulation object of each patient, our “simul-omics” data represent tumor morphology, breast tissue proportions, drug response and delivery, and microvasculature-related feature sets. We also had access to the pre-treatment tumor biopsy-derived transcriptome microarray data. Predictive modeling was performed in a modular 3-step fashion: 1. clinical-only data to predict pCR, 2. clinical data plus candidate simul-omics data to predict pCR, and 3. available feature space for features that interact with treatment to provide the strongest predictive model of pCR. Results: The SOC data model (HR status, grade, treatment, age, race) predicted pCR with an accuracy (acc) of 0.67, sensitivity (sens)=0.71, specificity (spec)=0.66, and Cohen’s kappa=0.27. Simul-omic features median tumoral Kt at sim week 1 (acc=0.73), and tumoral pre-contrast small area emphasis (acc=0.77) improved model performance over SOC. When included in the same model, they increased predictive acc of the model to 0.79 (sens=0.64, spec=0.82, kappa=0.41). Simulation-derived features improved predictive power beyond SOC data. Exploratory search of the feature-space identified simul-omic features that would generate the most predictive models with a significant treatment interaction effect. Two simul-omics features added predictive strength to the model, with near-nominal interaction effects: phi_quant_90_regimen_wk22 (late timepoint mv density) (acc=0.84, kappa=0.58), and slopemap_tumor_glcm_clustershade (acc=0.86, kappa=0.60). We tested transcript expression as interaction terms in the model. The best performing model with an interaction effect was SHISA4 (acc=0.88, sens=0.86, spec=0.88, kappa=0.67). Conclusions: Our results show value in: 1. predicting pCR, the additive value of TS simulation data over just clinical/SOC data, 2. identification of potentially mechanistic drug targets facilitating GM response, and 3. potential to stratify patient populations into responder vs. non-responder categories prior to treatment.
The use of sentinel lymph node biopsy in patients undergoing mastectomy for DCIS.
Authors: Johnson Morgan K. , Cortina Chandler Scott , Aldakkak Mohammed , Kong Amanda L. 
Published: June 2022

e12572 Background: Current NCCN guidelines do not recommend sentinel node biopsy (SLNB) for the treatment of DCIS, except in the setting of a mastectomy. The extent of utilization of SLNB in patients undergoing mastectomy for DCIS and which factors are associated with a higher likelihood of SLNB use is unknown. The objective of this study is to evaluate the use of SLNB in patients undergoing mastectomy for DCIS and determine predictors of SLNB utilization. Methods: A retrospective cohort analysis was performed using the NCDB. Women diagnosed with DCIS who underwent a unilateral or bilateral mastectomy from 2012-2017 were included. Patient, tumor, and treatment variables were compared between patients who received a SLNB and those who did not. A multivariate logistic regression model was then used to identify factors predictive of SLNB utilization. Results: A total of 29,962 patients met inclusion criteria. Of these, 25,734 (85.9%) underwent SLNB and 4,228 (14.1%) had no surgical axillary staging. Most patients were age 50-69 (52.0%), non-Hispanic white (71.7%), and had private insurance (65.9%). In those who underwent SLNB, only 10 (<0.01%) were found to have nodal involvement. On multivariate analysis, older patients were less likely to receive SLNB ( p<0.05), while those with grade 2 and 3 DCIS were more likely to undergo SLNB (OR 1.4 and 2.2, respectively, p<0.001) (Table). Patients who were treated from 2014-2017 were also more likely to undergo SLNB (OR 1.2, p<0.01) as were patients treated in the Atlantic and West Central United States ( p<0.05). Treatment at a comprehensive community program, academic/research program, or integrated network program were also more likely to undergo SLNB (OR 1.5, 2.1, 2.3 respectively, p<0.001) compared to community programs. Conclusions: Patterns of SLNB utilization in DCIS varied in clinical practice. Given the low rate of nodal involvement in DCIS patients (<0.01%), and with a 5-10% rate of upper extremity lymphedema after SLNB alone, it may be reasonable to omit SLNB in the setting of a mastectomy for DCIS.[Table: see text]