bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of systemic therapy sequencing on overall survival for patients with advanced BRAF-mutated melanoma.
Authors: Kartolo B. Adi , Deluce Jasna , Hopman Wilma M. , Liu Linda , Baetz Tara D. , Ernst D. Scott , Lenehan John Gordon 
Published: June 2021

9552 Background: Both immune checkpoint inhibitors (ICI) and BRAF targeted therapy (TT) are effective treatments for patients with advanced BRAF-mutated melanoma. However, the choice of first-line (1L) therapy is at the discretion of treating oncologists without clear guidance from current available data or established guidelines. Utilizing prospectively collected data from the Canadian Melanoma Research Network (CMRN) database, we provide real-world evidence to highlight the impact of sequencing these therapies. Methods: Prospective data from 9 cancer centres in Canada was retrieved from the CMRN database for patients with unresectable/metastatic melanoma, with BRAF targetable subtypes, who received at least one-cycle of 1L palliative-intent ICI or TT, and at least 1-year of follow-up. We categorized patients into 2 groups: 1L BRAF±MEK inhibitors with/without subsequent PD-1±CTLA-4 inhibitors (1L-TT), or vice versa (1L-ICI). The primary study outcome was overall survival (OS). Survival outcomes were analyzed through Kaplan-Meier methods, and multivariable Cox analysis was utilized to account for potential confounders. Results: Our study (N=235) included 152 and 83 patients in 1L-TT and 1L-ICI groups, respectively. Combined BRAF-MEK inhibitors accounted for 59% of the 1L-TT group, whereas single-agent IO accounted for 66% of the 1L-ICI group. There were 93 patients who received second-line (2L) therapy, with a non-significant trend of 1L-TT group receiving more 2L therapy compared to 1L-ICI group (65% vs. 43%, P=0.404). Neither treatment group showed significant differences in median time on 1L therapy (P=0.645) or 2L therapy (P=0.686). The 1L-ICI group was associated with a favourable median overall survival (OS) compared to 1L-TT group (19.3 vs. 10.0 months, P=0.031). Specifically, the ICI only group had the highest median OS, followed by TT-ICI sequence, ICI-TT sequence, and TT only groups respectively (not reached vs. 38.3 vs. 16.9 vs. 6.1 months, P<0.001). However, this OS benefit (HR 0.89, 95% 0.51-1.53, P=0.644) was non-significant upon controlling for confounders such as baseline metastatic sites >2 (HR 2.07, 95%CI 1.24-3.46, P=0.006) and ECOG ≥2 (HR 3.47, 95%CI 2.02-5.97, P<0.001) in multivariable Cox analysis. Conclusions: There was no significant difference in OS between 1L-TT and 1L-IO groups. Rather, OS is driven mostly by the patient’s clinical status and tumour-associated features. Our study provides real-world evidence in an understudied area. Further studies are needed to validate our findings to inform guideline development.[Table: see text]
Pathology of durable stable disease in melanoma patients treated with ipilimumab, nivolumab, or ipilimumab, and nivolumab combination therapy.
Authors: Buchbinder Elizabeth Iannotti , Pfaff Kathleen L. , Manos Michael P. , Ouyang Olivia , Ott Patrick Alexander , Rodig Scott J. , Hodi F. Stephen 
Published: June 2021

9567 Background: As immunotherapy with checkpoint blockade becomes the backbone of melanoma treatment there is a need to better understand the biology associated with long term benefit. One particularly interesting set of patients are those with prolonged stable disease or response with residual findings on imaging. It is unknown if immunotherapy has led to scarring at the site of prior disease or if there are residual tumor cells being controlled by an ongoing immune response. Evaluating tissue from patients with prolonged responses provides a unique opportunity to determine the composition of residual lesions. Correlation with PET/CT helps determine if this is an accurate modality to reflect presence of residual viable tumor tissue. Methods: Metastatic melanoma patients that have attained long term stable disease after treatment with ipilimumab, nivolumab, or ipilimumab plus nivolumab were identified. Patients must have received ipilimumab, nivolumab or combination therapy 2+ years prior to enrollment and must have had stable disease for ≥ 6 months. Patients were consented and underwent PET/CT scans and biopsies of residual areas of stable disease. Pre- and post-treatment tissue samples underwent pathologic assessment to look at tumor cell content, fibrotic content, and inflammation. Results: Ten patients were consented for evaluation but only 7 met the screening criteria and underwent PET/CT and tissue biopsy. Six patients had FDG avid lesions on PET/CT which ranged in intensity from SUV 2.4-22. One patient had no FDG avidity in the areas of residual disease observed on CT. Biopsies from the residual stable lesions demonstrated predominantly necrosis and fibrosis with prominent pigment containing macrophages. One patient with an axillary nodal lesion with an SUV of 22 had active melanoma on pathology which was resected, and the patient has subsequently remained without progression of disease. Conclusions: Patients with durable stable disease after treatment with ipilimumab, nivolumab or ipilimumab and nivolumab combination therapy represent a unique population of melanoma patients treated with immune checkpoint inhibition. An examination of the residual lesions observed in these patients demonstrated predominantly necrosis and fibrosis consistent with resolving lesions. The presence of melanophages in these samples may suggest some ongoing immune surveillance. One patient did demonstrate residual melanoma suggesting the need for ongoing monitoring of this patient population.
Analysis of patients (pts) with in-transit metastases treated with nivolumab (NIVO) or ipilimumab (IPI) in CheckMate 238.
Authors: Larkin James , Gogas Helen , Del Vecchio Michele , Maio Michele , Arenberger Petr , Arance Ana Maria , Grob Jean-Jacques , Chiarion-Sileni Vanna , Lewis Karl D. , Mortier Laurent , Ott Patrick Alexander , Long Georgina V. , Van Den Eertwegh Alfonsus , Cowey C. Lance , Schenker Michael , Butler Marcus O. , Lobo Maurice , Askelson Margarita , Ascierto Paolo Antonio , Weber Jeffrey S. 
Published: June 2021

9569 Background: In the phase 3 CheckMate 238 study, NIVO has demonstrated improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) vs IPI in pts with resected stage IIIB–C or IV melanoma, which was sustained at the 4-y analysis. Having in-transit metastases/satellites (ITM) is a poor prognostic factor, and pts with ITM are generally omitted from clinical trials. This study was the first and only adjuvant checkpoint inhibitor trial to include pts with ITM. Here, we present post hoc outcomes in this subgroup. Methods: Pts aged ≥15 y with completely resected stage IIIB–C or IV melanoma stratified by stage and tumor PD-L1 status were randomized 1:1 to NIVO (3 mg/kg Q2W; n = 453) or IPI (10 mg/kg Q3W for 4 doses, Q12W thereafter; n = 453) for a maximum of 1 y or until disease recurrence/unacceptable toxicity. Pts with ITM, with or without synchronous nodal involvement, were included. The primary study endpoint was RFS; overall survival (OS) was a secondary endpoint; and DMFS was exploratory. Results: Each of the 2 treatment groups had 164 pts with ITM. Baseline characteristics were generally similar between treatment groups in pts with or without ITM; in pts with ITM vs without ITM, tumor ulceration was less frequent in NIVO-treated pts, and fewer IPI-treated pts had PD-L1 expression ≥5%. RFS and DMFS favored NIVO vs IPI in all ITM subgroups (table). OS was similar to the intention-to-treat (ITT) population with no differences noted between treatment groups or between ITM subgroups. Among pts with or without ITM, dominant metastatic sites were lung and lymph nodes, followed by brain, liver, and soft tissue (in varying order). Similar metastasis patterns were observed in pts with ITM regardless of nodal involvement. Treatment-related adverse events (any grade and grade 3/4) in pts with ITM were similar to those of the ITT population. Conclusions: Results of this post hoc 4-y analysis of CheckMate 238 showed that safety and efficacy were similar in pts with or without ITM, supporting the use of adjuvant NIVO in pts with ITM, regardless of nodal involvement. Clinical trial information: NCT02388906. [Table: see text]
Impact of a randomized weight loss trial on breast tissue markers in breast cancer survivors.
Authors: Dieli-Conwright Christina Marie , Harrigan Maura , Cartmel Brenda , Chagpar Anees B. , Bai Yalai , Rimm David L. , Pusztai Lajos , Lu Lingeng , Sanft Tara B. , Irwin Melinda L. 
Published: June 2021

e12501 Background: Weight loss interventions are effective approaches to reduce body weight and alter serum biomarkers in breast cancer survivors, however the impact on breast tissue biomarkers is unknown. The Lifestyle, Exercise and Nutrition (LEAN) study was a randomized trial designed to test the effect of a weight loss intervention on body composition and breast tissue and serum biomarkers. Methods: Fifity-one women with a BMI ³ 25.0 kg/m2 diagnosed with breast cancer, who had completed chemotherapy and/or radiation therapy were randomized to weight loss intervention or usual care. Breast tissue biopsies from the unaffected breast, fasting serum samples, and body composition were measured at baseline and 6-months. Ki67, insulin receptor (IR), CD68 and CD163 were measured by Automated Quantitative Analysis (AQUA) method. Mean baseline to 6-month changes were compared using ANCOVA adjusting for baseline values. Results: Pre- and post-intervention biopsies were conducted in 49 and 42 women respectively, with both pre- and post- epithelial tissue available from 25 women; epithelial tissue was unavailable in the remaining 66 women. Women were 56.8 ± 8.9 years old, diagnosed 3.3 + 3.8 years prior, primarily Stage I breast cancer (54%), with a BMI of 32.8 ± 6.0 kg/m2. At baseline, breast tissue levels of IR were inversely associated with both percent body fat (r = -0.47, p = .03) and serum insulin levels (r = -0.45, p = .04); serum insulin levels were inversely associated with CD68 (r = -0.47, p = .03). Significant between-group biomarker changes are presented in Table 1. At month 6, loss in percent body fat was associated with increased IR (r = -0.42, p = .05). Increased CD68 breast tissue expression was associated with reductions in serum levels of CRP (r = -0.49, p=0.02). There was no significant effect of the intervention on IR expression or Ki67 (p>0.10). Conclusions: Breast tissue biopsies are feasible to collect in a clinical research setting among breast cancer survivors. A 6-month weight loss intervention led to decreased levels of CD163 in breast tissue and serum levels of leptin, and increased serum levels of adiponectin among breast cancer survivors. At baseline and month 6, changes in breast tissue biomarkers were favorably associated with serum biomarkers and body composition. Future confirmation is required to confirm the added benefit of tissue biomarkers beyond serum as an endpoint for lifestyle interventions among breast cancer survivors. Clinical trial information: NCT02110641. [Table: see text]
Impact of oncotype Dx score on treatment and long-term outcomes.
Authors: Warrior Surbhi , Thomas Joshua , Behrens Elizabeth , Rao Ruta D. 
Published: June 2021

e12518 Background: Oncotype dx is a 21 gene breast cancer assay that helps predict benefit of chemotherapy in early-stage hormone receptor positive (HR+), HER2 negative, 0 to 3 node positive breast cancer as reported by TAILORx and RxPonder trials. Both trials found no benefit of adjuvant therapy in mid-range scores of 11-25 with the exception of some benefit in age under 50 or premenopausal status, no benefit if score was 0-10, and benefit of chemotherapy if >25. Methods: All breast cancer patients between 2019-2020 were chart checked to evaluate oncotype dx scores. Patient characteristics were analyzed between oncotype dx scores of 0-10, 11-25, and >25 using X square tests. 2000-2020 institutional cancer registry data was analyzed to understand recurrence and mortality in patients with oncotype dx testing. Results: 173 patients had oncotype dx testing between 2019-2020, and most were HR+, HER2-, and had 0-3 lymph nodes. There was no difference in race or ethnicity between the groups of oncotype dx scores (Table), and average age at diagnosis for all three groups was 58 years. More patients with lower oncotype dx score had hormone therapy, but this was not significant (0-10 at 93.6%, 11-25 at 90.8%, and >25 at 82.1%, p=0.26). Patients with a higher oncotype score were significantly more likely to have chemotherapy (0-10 at 0%, 11-25 at 17.3%, and >25 at 82.1%, p<0.01). When looking at long term outcomes, the mortality rate was highest in the 11-25 score group at 9.5%, but was not significantly higher than 0-10 at 4.7% and >25 at 2.1% (p=0.15). The recurrence was highest in the 0-10 group at 5.4%, but not significant compared to the 11-25 group at 4.1% and >25 group at 4.2% (p=0.09). Conclusions: Race, ethnicity, and age does not impact predisposition to high oncotype dx score, which is interesting since literature shows minority women have higher mortality rates. This could be because oncotype dx looks at early-stage breast cancers and many minority women have later stages at diagnosis. There was no difference in which group received hormone therapy and there was significantly higher rate of chemotherapy administration in patients with scores >25, which is consistent with prospective trial recommendations. When evaluating long term outcomes between oncotype dx groups over 20 years, there was no significant difference in recurrence of disease or mortality indicating that oncotype dx scoring accurately predicted overall benefit of chemotherapy.[Table: see text]
Latent atherosclerosis as a risk factor in chemotherapy-induced cardiomyopathy.
Authors: Paulenka Yuliya , Cotto Maritza , Rickette Christine , Hunter Krystal 
Published: June 2021

e12525 Background: Anthracyclines and monoclonal antibodies targeting HER2/neu receptors are widely used antineoplastic agents in breast cancer treatment. Both therapies have been known to cause cardiovascular adverse effects, notably chemotherapy-induced congestive heart failure, especially if used in combination. Multiple factors have been postulated to increase the risk of doxorubicin and trastuzumab-associated cardiotoxicity, including a pre-existing coronary artery disease, but the role of latent atherosclerosis has not been widely studied. Methods: We retrospectively reviewed health records of female breast cancer patients at our institution treated with doxorubicin or trastuzumab between 2012 and 2017. Using echocardiography, we identified patients with underlying atherosclerotic lesions at the start of the treatment and those who subsequently developed cardiotoxicity. Chemotherapy-induced cardiomyopathy was defined as a drop in the ejection fraction (EF) to < 50% from the normal EF of > 53% pre-therapy. We used a χ2 test to search for the relationship between atherosclerosis and subsequent cardiotoxicity. Results: A total of 518 patient records were reviewed. Of 518 patients with breast cancer, 93 (18%) received doxorubicin or trastuzumab-based chemotherapy. The median age for breast cancer diagnosis was 58. Sixty-one patients (66%) were identified to have atherosclerosis on echocardiography at the time of the first chemotherapy cycle. The most common location for atherosclerotic lesions was in the aortic arch and proximal upper abdominal aorta. Of 61 patients with atherosclerosis, ten (16.4%) subsequently developed chemotherapy-induced cardiomyopathy (p = 0.77). A post hoc analysis was performed to compare the two cohorts aged 40 to 50 (p = 0.49) and 51 to 75 (p = 1.00) as they represented the majority of breast cancer cases. Conclusions: The role of atherosclerosis in doxorubicin and trastuzumab-induced toxicity remains unclear. We did not observe any statistical correlation between atherosclerosis at the start of chemotherapy and increased rates of cardiac injury. A younger population may be more susceptible to cardiotoxicity, but further research is needed as the study has limitations. Although we identified patients with latent atherosclerosis, additional evaluation via carotid artery intima-media thickness measurements would yield more precision. Other methods such as the use of computed tomography and coronary artery calcium scores would also allow for assessing atherosclerotic plaque burden. Still, not all patients were subjected to these techniques. Furthermore, the study was challenged by the small sample size and its retrospective nature. Larger prospective studies are essential to explore this area further. Identifying the means of reducing cardiovascular complications remains a priority as heart disease is currently the leading cause of death among breast cancer survivors.
Integrated immune-related gene signature to predict clinical outcome for patients with luminal B breast cancer.
Authors: Kuang Xiaying , Cai Du , Lin Ying , Gao Feng 
Published: June 2021

e12526 Background: Luminal B breast cancer is always routinely treated with chemotherapy and endocrine therapy but heterogeneous with respect to sensitivity to treatment, identification of patients who may most benefit remains a matter of controversy. Immune-related genes (IRGs) was found to be associated with the prognosis of breast cancer. The aim of this study is to evaluate the impact of IRGs in predicting the outcome of luminal B breast cancer patients. Methods: According to the Metabric microarray dataset also as a training cohort, 488 luminal B breast cancer patients were selected for generation of immune-related gene signature (IRGS). Another independent dataset (n=250) of patients with complete prognostic information was analyzed as a validation cohort. Prognostic analysis was assessed to test the predictive value of IRGS. Results: A model of prognostic IRGS containing 12 immune-related genes was developed. In both training and validation cohorts, IRGS significantly stratified luminal B breast cancer patients into immune low- and high-risk groups in terms of disease free survival (DFS, HR=4.95, 95% CI=3.22-7.62, P<0.001 in training cohort, HR=2.47, 95% CI=1.29-4.75, P<0.001 in validation cohort). Multivariate analysis revealed IRGS as an independent prognostic factor (HR=4.96, 95% CI=3.00-8.18, P<0.001 in training cohort, HR=2.56, 95% CI=1.28-5.09, P=0.007 in validation cohort). Furthermore, those 12 genes mostly related with response to chemical, and the expression levels of them were completely opposite in patients of immune low- and high-risk groups. Conclusions: The proposed IRGS is a satisfactory prognostic model for estimating DFS of luminal B breast cancer patients. Further studies are needed to assess the clinical effectiveness of this system in predicting prognosis and treatment options for luminal B breast cancer patients. This work was supported by National Natural Science Foundation of China (No. 81602520), Natural Science Foundation of Guangdong Province (No. 2017A030313596).
Automated immunostaining-free prediction of breast carcinoma ER and PR status, Ki67 count, patient therapy stratification index and quantification of prognostic quiescence burden in TNBC from pretreatment H&E stained histopathology images in breast cancer.
Authors: Dasgupta Tathagata , Mukhopadhyay Satabhisa , Orsi Nicolas M , Cummings Michele , Berwick Angelene 
Published: June 2021

e12535 Background: Categorical combinations of ER, PR, HER2, and Ki67 levels are traditionally used to classify patients into luminal A and B-like subtypes in order to inform treatment choice. Accounting for nearly 70% of all breast malignancies, luminal cancer is heterogeneous, harboring subtypes with distinct molecular profiles and clinical outcomes. Although most patients with luminal-type disease respond well to endocrine therapy alone, some develop recurrences benefiting from additional cytotoxic therapy. Identifying such cases a priori remains a challenge but would enable patients to be spared the debilitating side-effects of ineffective chemotherapy. In this regard, the efficacy of chemotherapy and disease recurrence relate to (i) ER driven G1/S perturbations and/or (ii) quiescent cell populations arrested in the G0/G1 phase of cell cycle. This study aimed to develop a histopathology whole slide image (WSI)-based, low cost, rapid and automated approach to: (i) predict ER/PR/Ki67 status, (ii) quantify quiescence burden, (iii) develop a G1/S-based patient stratification system for luminal A/B patients, and (iv) achieve a quiescence burden-based stratification of TNBC patients. Methods: This investigation centered on the initial clinical validation of a novel, immunostaining-free technology which uses information extracted from pre-treatment hematoxylin and eosin (H&E) stained slide WSIs alone to achieve these aims. Unlike conventional artificial intelligence-based approaches, the underlying proprietary algorithm and its prediction criteria are based on deterministic, hard-coded observational relationships of continuous scales drawn from WSI morphological features. In this instance, these represent tumor-related biological pathway disruptions and mitotic checkpoint perturbations, where G1/S perturbations enable luminal subtype stratification, and G0/G1 perturbations reflect quiescence burden. Back projecting the algorithm’s quiescence burden output on to the original WSIs enables morphological patterns to be mapped to quiescence burden.