Triple Negative Research Articles

Site‐specific venous thrombosis in essential thrombocythemia: Impact on subsequent vascular events and survival

Site‐specific venous thrombosis in essential thrombocythemia: Impact on subsequent vascular events and survival

The role of tumor phenotype in the surgical treatment of early-stage breast cancer

BackgroundWe investigated whether tumor phenotype influences surgical decision-making, and how that may impact overall survival (OS) for early-stage breast cancer. MethodsWomen aged 18–69 with cT0-2/cN0/cM0 breast cancer in the National Cancer Database (2010–2017) were included. A generalized logistic model was used to identify factors associated with surgery type. A Kaplan-Meier curve was used to visualize unadjusted OS, and the log-rank test was used to test for differences in OS between surgery types. ResultsOf 597,149 patients, 58% underwent lumpectomy with radiation (BCT), 25% unilateral mastectomy (UM), and 17% bilateral mastectomy (BM). After adjustment, HER2+ and triple-negative (TN) tumors were less likely to undergo UM than BCT, versus hormone receptor-positive tumors (OR = 0.881, 95% CI = 0.860–0.903; OR = 0.485, 95% CI = 0.470–0.501). UM and BM had worse 5-year OS versus BCT (UM: 0.926, vs BM: 0.952, vs BCT: 0.960). ConclusionsBCT is increasingly used to treat HER2+ and TN tumors. More extensive surgery is not associated with better survival outcomes, regardless of tumor phenotype.

Relationship between Aldehyde Dehydrogenase, PD-L1 and Tumor-Infiltrating Lymphocytes with Pathologic Response and Survival in Breast Cancer.

Simple SummaryAldehyde dehydrogenase 1A1 (ALDH1A1) can be used to identify breast cancer stem cells (CSC). Interaction between CSC and the tumor microenvironment might be related to the treatment response, relapse and death. The aim of this retrospective, historical cohort study was to analyze the relationship between ALDH1A1, programmed death ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs), assessed through immunohistochemistry, in triple negative (TN) and human epidermal growth factor receptor 2-positive (HER2+) breast cancer tumors, and its association with clinicopathological characteristics and survival. In this study, tumors with positive ALDH1A1 expression also presented positive PD-L1 expression, higher infiltration of lymphocytes and achieved higher response to treatment. It is crucial to understand the possible implication of these biomarkers on neoadjuvant treatment response in certain subtypes of breast cancer as well as its prognostic role in early and locally advanced breast tumors, as they might be possible targets for promising treatments as immunotherapy.Aldehyde dehydrogenase 1A1 (ALDH1A1) is a cancer stem cell (CSC) marker related to clinical outcomes in breast cancer (BC). The aim of this study was to analyze the relationship between ALDH1A1, programmed death ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs) in triple negative (TN) and human epidermal growth factor receptor 2-positive (HER2+) BC tumors, and its association with clinicopathological characteristics and outcomes. A retrospective, historical cohort study of patients diagnosed with early or locally advanced BC treated with neoadjuvant chemotherapy was conducted. ALDH1A1, PD-L1 expression and TILs were assessed using immunohistochemistry. A total of 75 patients were analyzed (42.7% TN, 57.3% HER2+ tumors). ALDH1A1+ was related to HTILs (p = 0.005) and PD-L1+ tumors (p = 0.004). ALDH1A1+ tumors presented higher CD3+ (p = 0.008), CD4+ (p = 0.005), CD8+ (p = 0.003) and CD20+ (p = 0.006) TILs. ALDH1A1+ (p = 0.018), PD-L1+ (p = 0.004) and HTILs (p < 0.001) were related to smaller tumors. ALDH1A1+ was related to pathologic complete response (pCR) (p = 0.048). At the end of the follow-up (54.4 [38.3–87.6] months), 47 patients (62.7%) remained disease-free, and 20 (26.7%) had died. HTILs were related to improved disease-free survival (p = 0.027). ALDH1A1+ was related to PD-L1+ and HITLs, that might be related to higher pCR rates with neoadjuvant therapy.

Clinicopathological Features and Prognosis of Invasive Micropapillary Carcinoma Compared to Invasive Ductal Carcinoma-NOS: Worse or Better?

To evaluate whether there are differences in invasive micropapillary carcinoma (IMPC) and invasive ductal carcinoma-NOS (IDC-NOS) according to the clinicopathological features and prognosis including molecular subtypes. Descriptive study. Department of Pathology, University of Health Sciences, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey, from 2003 to 2016. Operated breast cancer cases (58 IMPC + 326 IDC-NOS), with long-term follow-up findings (cases followed up until 2020), were reviewed. The cases, whose other component was only IDC-NOS, were included in the mixed IMPC group. The clinical features, including clinical presentation, treatments, and follow-up information were obtained from the patient clinical database. The IMPC cases included in the study were re-examined, and micropapillary tumour components were confirmed based on the criteria set by the World Health Organisation (WHO). The clinicopathological findings, recurrence, and survival data of both groups were compared. In addition, IDC-NOS was divided into the molecular subgroups and compared with IMPC cases in terms of 5-year overall survival (OS). There was no significant difference between the two groups for the distribution of molecular subtypes. There was a statistically significant difference among the nuclear grade, tumour size, nodal status, lymphovascular, and perineural invasion. In the first 5-year period, the OS rate for IDC-NOS and IMPC was 90.8% and 86.2% (p<0.05). The 5-year OS rate of luminal A, luminal B, HER2, triple negative (TN), and IMPC patients was 97.6%, 91.3%, 90%, 70%, and 86.2%, respectively (p<0.05). The OS rate in patients with TN and IMPC was similar which was found significantly lower than the other groups (luminal A, luminal B, and HER2). The median OS was 51.3 months and 53.9 months for the patients with TN and IMPC, respectively (p<0.001). This difference disappeared in the 10th and 15th years of follow-up. The majority of the deaths in IMPC occurred within the first 5 years. The 5-year OS rates were similar in the TN and IMPC patients. The survival pattern of IMPC is parallel with TN, Therefore, clinical, therapeutic, and prognostic evaluation in IMPC can be done like TN. Invasive ductal carcinoma, Invasive micropapillary carcinoma, Survival.

243P Tumor-infiltrating lymphocytes (TILs) in paired samples from patients with phenotypic switch from early luminal-like to metastatic triple-negative breast cancer

Loss of Hormone Receptors (HR) at metastatic (met) relapse has been widely described in breast cancer (BC). Higher TILs have been associated with better prognosis in patients (pts) with early triple-negative (TN) BC, but to worse outcome in HR-positive (HR+)/HER2- BC. TILs significance in pts with HR-loss has never been investigated.

Epithelial-mesenchymal plasticity determines estrogen receptor positive breast cancer dormancy and epithelial reconversion drives recurrence

More than 70% of human breast cancers (BCs) are estrogen receptor α-positive (ER+). A clinical challenge of ER+ BC is that they can recur decades after initial treatments. Mechanisms governing latent disease remain elusive due to lack of adequate in vivo models. We compare intraductal xenografts of ER+ and triple-negative (TN) BC cells and demonstrate that disseminated TNBC cells proliferate similarly as TNBC cells at the primary site whereas disseminated ER+ BC cells proliferate slower, they decrease CDH1 and increase ZEB1,2 expressions, and exhibit characteristics of epithelial-mesenchymal plasticity (EMP) and dormancy. Forced E-cadherin expression overcomes ER+ BC dormancy. Cytokine signalings are enriched in more active versus inactive disseminated tumour cells, suggesting microenvironmental triggers for awakening. We conclude that intraductal xenografts model ER + BC dormancy and reveal that EMP is essential for the generation of a dormant cell state and that targeting exit from EMP has therapeutic potential.

Predicting the molecular subtypes of breast cancer using nomograms based on three-dimensional ultrasonography characteristics.

BackgroundMolecular subtyping of breast cancer is commonly doneforindividualzed cancer management because it may determines prognosis and treatment. Therefore, preoperativelyidentifying different molecular subtypes of breast cancery can be significant in clinical practice.Thisretrospective study aimed to investigate characteristic three-dimensional ultrasonographic imaging parameters of breast cancer that are associated with the molecular subtypes and establish nomograms to predict the molecular subtypes of breast cancers.MethodsA total of 309 patients diagnosed with breast cancer between January 2017and December 2019 were enrolled. Sonographic features were compared between the different molecular subtypes. A multinomial logistic regression model was developed, and nomograms were constructed based on this model.ResultsThe performance of the nomograms was evaluated in terms of discrimination and calibration.Variables such as maximum diameter, irregular shape, non-parallel growth, heterogeneous internal echo, enhanced posterior echo, lymph node metastasis, retraction phenomenon, calcification, and elasticity score were entered into the multinomial model.Three nomograms were constructed to visualize the final model. The probabilities of the different molecular subtypes could be calculated based on these nomograms. Based on the receiver operating characteristic curves of the model, the macro-and micro-areaunder the curve (AUC) were0.744, and 0.787. The AUC was 0.759, 0.683, 0.747 and 0.785 for luminal A(LA), luminal B(LB), human epidermal growth factor receptor 2-positive(HER2), and triple-negative(TN), respectively.The nomograms for the LA, HER2, and TN subtypes provided good calibration.ConclusionsSonographic features such as calcification and posterior acoustic features were significantly associated with the molecular subtype of breast cancer. The presence of the retraction phenomenon was the most important predictor for the LA subtype. Nomograms to predict the molecular subtype were established, and the calibration curves and receiver operating characteristic curves proved that the models had good performance.

A Simultaneous Multiparametric 18F-FDG PET/MRI Radiomics Model for the Diagnosis of Triple Negative Breast Cancer.

Simple SummaryIn this study, we aimed to build a machine-learning predictive model for the identification of triple negative breast cancer, the most aggressive subtype, using quantitative parameters and radiomics features extracted from tumor lesions on hybrid PET/MRI. The good performance of the model supports the hypothesis that hybrid PET/MRI can provide quantitative data able to non-invasively detect tumor biological characteristics using artificial intelligence software and further encourages the conduction of additional studies for this purpose.Purpose: To investigate whether a machine learning (ML)-based radiomics model applied to 18F-FDG PET/MRI is effective in molecular subtyping of breast cancer (BC) and specifically in discriminating triple negative (TN) from other molecular subtypes of BC. Methods: Eighty-six patients with 98 BC lesions (Luminal A = 10, Luminal B = 51, HER2+ = 12, TN = 25) were included and underwent simultaneous 18F-FDG PET/MRI of the breast. A 3D segmentation of BC lesion was performed on T2w, DCE, DWI and PET images. Quantitative diffusion and metabolic parameters were calculated and radiomics features extracted. Data were selected using the LASSO regression and used by a fine gaussian support vector machine (SVM) classifier with a 5-fold cross validation for identification of TNBC lesions. Results: Eight radiomics models were built based on different combinations of quantitative parameters and/or radiomic features. The best performance (AUROC 0.887, accuracy 82.8%, sensitivity 79.7%, specificity 86%, PPV 85.3%, NPV 80.8%) was found for the model combining first order, neighborhood gray level dependence matrix and size zone matrix-based radiomics features extracted from ADC and PET images. Conclusion: A ML-based radiomics model applied to 18F-FDG PET/MRI is able to non-invasively discriminate TNBC lesions from other BC molecular subtypes with high accuracy. In a future perspective, a “virtual biopsy” might be performed with radiomics signatures.

Treatment Strategies for Residual Disease following Neoadjuvant Chemotherapy in Patients with Early-Stage Breast Cancer.

Breast cancer continues to be the most diagnosed cancer among women worldwide. Neoadjuvant chemotherapy is the standard of care for breast cancer patients with locally advanced disease and patients with poor pathological features, such as triple-negative (TN) or human epidermal growth factor receptor-2 (HER2)-positive subtypes. Neoadjuvant therapy offers several advantages, including better surgical outcomes, early systemic treatment for micro-metastases, and accurate tumor biology and chemosensitivity assessment. Multiple studies have shown that achieving pathological complete response (pCR) following neoadjuvant chemotherapy is associated with better prognosis and better treatment outcomes; almost half of such patients may fail to achieve pCR. Tumor proliferative index, hormone receptor (HR) status, and HER2 expression are the major predictors of pCR. Strategies to improve pCR have been dependent on augmenting neoadjuvant chemotherapy with the addition of taxanes and dual anti-HER2 targeted therapy in patients with HER2-positive tumor, and more recently, immunotherapy for patients with TN disease. The clinical management of patients with residual disease following neoadjuvant chemotherapy varies and depends mostly on the level of HR expression and HER2 status. Recent data have suggested that switching trastuzumab to trastuzumab-emtansine (T-DM1) in patients with HER2-positive disease and the addition of capecitabine for patients with HER2-negative and HR-negative subtype is associated with a better outcome; both strategies are incorporated into current clinical practice guidelines. This paper reviews available and ongoing studies addressing strategies to better manage patients who continue to have residual disease following neoadjuvant chemotherapy.

Different Prognostic Values of Tumour and Nodal Response to Neoadjuvant Chemotherapy Depending on Subtypes of Inflammatory Breast Cancer, a 317 Patient-Study.

Simple SummaryInflammatory breast cancer is a rare entity associated with a poor prognosis, especially for the triple-negative subtype. This study investigates the independent prognostic value of tumour and nodal responses after neoadjuvant chemotherapy. It shows that tumour and lymph node responses did not have the same prognostic value regarding HR and HER2 statuses. We identified a subgroup of patients with triple-negative inflammatory breast cancer with residual lymph node disease for whom adjuvant treatment intensification may be worth investigating.Inflammatory breast cancer (IBC) is a rare entity with a poor prognosis. We analysed the survival outcomes of patients with nonmetastatic IBC and the prognostic value of tumour or nodal responses to assess their individual prognostic impact across IBC subtypes. This retrospective multicentre study included patients diagnosed with IBC between 2010 and 2017 to account for advances in neoadjuvant systemic therapies and modern radiotherapy at seven oncology centres in France. Three hundred and seventeen patients were included and analysed. After a median follow-up of 52 months, the 5-year DFS was lower for triple-negative (TN) (50.1% vs. 63.6%; p < 0.0001). After multivariate analyses, incomplete nodal response was the only significant prognostic factor in the triple-negative group (HR:6.06). The poor prognosis of TN-IBC was reversed in the case of nodal response after neoadjuvant chemotherapy. Breast response does not appear to be a decisive prognostic factor in patients with TN-IBC compared to lymph node response. Despite improvements in neoadjuvant treatments, IBC remains associated with a poor prognosis. In TN-IBC patients, lack of pathological complete node response was associated with poorer survival than any other group. Treatment intensification strategies are worth investigating.

A comparative clinicopathological and survival analysis of synchronous bilateral breast cancers.

The present study aimed to explore the clinicopathological characteristics, potential heterogeneity and prognostic factors in synchronous bilateral breast cancer (SBBC). We performed a retrospective review and paired comparison of the clinicopathological characteristics of 114 patients with SBBC in the Peking Union Medical College Hospital from January 2008 to September 2019. The prognostic significance of triple negativity status and coexistence ductal carcinoma in situ (DCIS) with bilateral invasive ductal carcinomas of no special type (IDC-NST) was analyzed in SBBC. Most bilateral lesions on both sides were of IDC-NST, grade 2, luminal subtype, and stage I. Although most lesions were concordant between the left and right side, discordances were observed in histological type (25 cases, 21.9%), histological grade (31 cases, 27.2%), pTNM (61 cases, 53.5%), molecular subtypes (20 cases, 17.5%), and immunohistochemical staining of ER (18 cases, 15.8%), PR (26 cases, 22.8%), and HER2 (12 cases, 10.5%). Moreover, there was no significant difference in disease-free survival (DFS) and overall survival (OS) between IDC-NST with coexisting DCIS on both sides and IDC-NST with coexisting DCIS on one side or pure IDC-NST. SBBC with triple negativity on both sides exhibited a significantly shorter DFS and OS when compared with triple negativity on one side or non-triple negativity on both sides (p<0.001), and remained an independent prognostic factor by multivariate analysis. A considerable proportion of discordance in clinicopathological characteristics is observed in SBBC, supporting the necessity of comprehensive pathological examination including immunohistochemical testing on both sides in clinical practice. Moreover, SBBC with triple negativity on both sides is a prognostic for poor survival.

Stromal Tumor Infiltrating Lymphocytes (sTIL) as an Independent Predictor of Pathologic Response to Neadjuvant Chemotherapy in Breast Cancer in Indonesia: A Hospital-based Study.

We aim to describe the sTIL profiles of Indonesian breast cancer patient and its role in predicting neoadjuvant chemotherapy response. This retrospective cohort study used secondary data from the archive of Anatomic Pathology Department FMUI/CMH. We did total sampling of 62 cases of locally advanced breast cancer cases that were biopsied, had neoadjuvant chemotherapy, and operated on from 2015 to 2020. We collected the clinicopathological data of each sample, measured the sTIL intensity in the biopsy specimen and evaluated the chemotherapy response from the mastectomy specimen using residual cancer burden (RCB) scoring method. Multivariate linear regression determined the independent predictors of RCB score. There were 62 female patients, 45.2% were Luminal-HER2-, 43.5% were HER2+, and 11.3% were triple negative (TN). Most sTIL intensity (59.7%) were low (median 10%; 1%-60%). Moderate-high sTIL intensity was associated with HER2+ type, while low sTIL was with luminal-HER2- (p=0.038). Only 8.1% patients achieved pCR. Statistically different median sTIL intensity in minimal, moderate, and extensive burden group were 28%, 20%, and 8%, respectively (p=0.002). sTIL was an independent predictor for better response (lower RCB score), which were 0.07 (95% CI 0.04-0.09) lower for every 1% increase in sTIL intensity. sTIL intensity was mostly low in Indonesian breast cancer patient. However, it can predict neoadjuvant chemotherapy response, with 0.07 lower RCB score for every 1% increase of sTIL intensity.

De-escalating Surgery Among Patients with HER2 + and Triple Negative Breast Cancer.

Purpose of ReviewDe-escalation of surgery has been central in the evolution of multidisciplinary management of breast cancer. Advances in oncology and increasing use of neoadjuvant chemotherapy (NACT) have opened opportunities for further surgical de-escalation especially for HER2 + and triple negative (TN) disease. The aim of this review is to discuss the recent data on de-escalation of surgery as well as the future directions.Recent FindingsPatients with TN and HER2 + breast cancer with excellent response to NACT would be the ideal candidates for surgical de-escalation. Post-NACT image-guided biopsy, potentially combined with machine learning algorithms, may accurately identify patients achieving pathologic complete response that would be eligible for clinical trials assessing safety of omission of breast and axillary surgery.SummaryMultidisciplinary research is required to further support results of preliminary studies. Current data point towards a future when even less or no surgery may be required for exceptional responders.

Breast Carcinoma in Young Females: A Prospective Study in Terms of Clinicopathological Presentation at a Tertiary Care Center in India.

Introduction: The incidence of breast carcinoma in young women is on the rise, particularly in developing Asian countries like India. Owing to a unique presentation in terms of genetic background, clinical features, and histological characteristics, the prognosis becomes challenging, which therefore entails a detailed study for better understanding and management of the disease. This study aimed to establish the role of clinical and pathological parameters in breast cancer disease in young women.Methods: This was a prospective comparative study conducted at the Department of Surgery, Hamidia Hospital, Bhopal, India, which spanned a total duration of one year between November 2018 and October 2019, and included a total of 98 consecutive in-house breast carcinoma patients. The patients were categorized into two groups based on age, i.e., the young age group (age < 40 years) and the old age group (age ≥ 40 years).Results: Of the patients, 37 fell in the young age group and 61 in the old age group. There was a significant association between positive family history of breast carcinoma and young age (p = 0.01). Estrogen and progesterone receptor positivity was found to be associated more commonly with old age group patients. The proportion of patients with human epidermal growth factor receptor 2 (HER2)/neu over-expression was higher among the young age group. Triple negativity was more frequently observed amongst young age group patients.Conclusion: Hormone receptor analysis should be an absolute part of the initial work-up of breast carcinoma. Raising awareness among women in society should be of paramount importance. Family history is crucial, particularly in young women, and should not be dismissed. With timely presentation and effective diagnosis, a safer state with a relatively better prognosis can be achieved.

Epidermal growth factor receptor (EGFR) expression in the serum of patients with triple-negative breast carcinoma: prognostic value of this biomarker.

BackgroundEpidermal growth factor receptor (EGFR) overexpression has been considered a poor prognostic factor in breast cancer.MethodologyA prospective study of 206 women with breast cancer analysed by stages (I, II, III and IV) and by immunohistochemical subtype (Luminal A, Luminal B, HER2+ and triple-negative (TN)); 89 healthy controls with normal recent mammography were included. The EGFR measured in the serum (sEGFR) was detected by the Enzyme-Linked Immunosorbent Assay (ELISA) method (R&D Systems kit DY231) collected by blood before any treatment in patients. Kaplan–Meier method and Cox regression were carried out to obtain the prognostic value, considering significance if p < 0.05.ResultsWith a median follow-up of 36.6 months, 47 deaths occurred. Multivariable Cox regression showed difference of overall survival (OS) associated with sEGFR levels (sEGFR ≤ or > 47.8 ng/mL) in patients with TN cancers, but not of Luminal A, Luminal B or HER2+ subtypes; adjusted by stage, the death risk increased by approximately 415% [hazard ratio (HR): 5.149 (1.900–13.955), p = 0.001] for patients with sEGFR > 47.8 ng/mL compared to patients with a lower sEGFR value. There was no significant correlation of sEGFR with staging, histological tumour grade (G1/G2/G3), Ki67 (< or ≥14%) or body mass index.ConclusionsIncreased sEGFR expression in patients with TN tumours is a significant predictor of lower OS and its quantification is inexpensive and straightforward.

Statins inhibit proliferation and induce apoptosis in triple-negative breast cancer cells

TP53 (p53) is mutated in 80–90% of cases of triple-negative breast cancer (TNBC). Statins, which are widely used to treat elevated cholesterol, have recently been shown to degrade mutant p53 protein and exhibit anti-cancer activity. The aim of this work was to evaluate the potential of statins in the treatment of TNBC. The anti-proliferative effects of 2 widely used statins were investigated on a panel of 15 cell lines representing the different molecular subtypes of breast cancer. Significantly lower IC50 values were found in triple-negative (TN) than in non-TN cell lines (atorvastatin, p < 0.01; simvastatin p < 0.05) indicating greater sensitivity. Furthermore, cell lines containing mutant p53 were more responsive to both statins than cell lines expressing wild-type p53, suggesting that the mutational status of p53 is a potential predictive biomarker for statin response. In addition to inhibiting proliferation, simvastatin was also found to promote cell cycle arrest and induce apoptosis. Using an apoptosis array capable of detecting 43 apoptosis-associated proteins, a novel protein shown to be upregulated by simvastatin was the IGF-signalling modulator, IGBP4, a finding we confirmed by Western blotting. Finally, we found synergistic growth inhibition between simvastatin and the IGF-1R inhibitor, OSI-906 as well as between simvastatin and doxorubicin or docetaxel. Our work suggests repurposing of statins for clinical trials in patients with TNBC. Based on our findings, we suggest that these trials investigate statins in combination with either doxorubicin or docetaxel and include p53 mutational status as a potential predictive biomarker.

Dyslipidemia is insufficiently treated in antiphospholipid syndrome patients.

Although dyslipidemia is a strong risk factor for thrombosis in antiphospholipid syndrome (APS), it has been poorly studied. This study aimed to assess lipids profile and risk factors for unachieved cholesterol levels in a real-life APS population. Inclusion criteria were: APS diagnosis according to international classification criteria, referring to the out-patients clinic of our tertiary care center for their follow-up, and having a blood sample collection for lipids levels determination. Cholesterol level targets for each patient were defined according to 2019 ESC/EAS guidelines for the management of dyslipidemia. Between January 2020 and April 2021, 114 APS patients were included (male 37 (32.5%); mean age 49 ± 14years). Among them, 40 (35.1%) had a history of dyslipidemia, 48 (42.1%) were under lipid-lowering therapies, and 59 (51.8%) had a history of cardiovascular disease (CVD). Mean levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride were, respectively, 110 ± 40mg/dL, 60±20mg/dL, and 120 (80-190)mg/dL. Unachieved LDL-C levels were found in 77 (67.5%) patients of whom 53 had history of CVD. Overall, 90 (78.9%) had protective HDL-C and 31 (27.2%) had hypertriglyceridemia. In the multivariate analysis, independent risk factors for unachieved LDL-C levels were older age and history of CVD; triple aPL negativity, defined as complete disappearance of aPL over time in APS patients who were previously positive in accordance to international criteria, was an independent protective factor for unachieved LDL-C. Our finding suggested that dyslipidemia is frequent in APS patients and mainly insufficiently treated, especially in patients with history of CVD, who are at highest risk of future CV events.

TP53 Mutation Estimation Based on MRI Radiomics Analysis for Breast Cancer.

Noninvasive detection of TP53 mutations is useful for the molecular stratification of breast cancer. To explore MRI radiomics features reflecting TP53 mutations in breast cancer and propose a classifier for detecting such mutations. Retrospective. A total of 139 breast cancer patients with TP53 expression profiling (98 with TP53 mutations and 41 without TP53 mutations). 1.5 T, T1-weighted (T1W) DCE-MRI. Lesions were manually segmented using subtracted T1WI. A total of 944 radiomics features (including 744 wavelet-related features) and 7 clinicopathological features were extracted from each lesion. Principal component analysis and Pearson's correlation analysis were used to preprocess the features. Linear discriminant analysis, logistic regression (LR), support vector machine (SVM), and random forest (RF) were used as the classifiers. Analysis of variance, Kruskal-Wallis and recursive features elimination were used to select features. Receiver operating characteristic (ROC) analysis was performed to compare the diagnostic accuracy. For the radiomics model, the validation cohorts AUCs of the four classifiers ranged from 0.69 (RF) to 0.74 (LR), and LR (0.74) attained the highest AUCs. For the clinicopathological-radiomics combined model, the validation AUCs of the four classifiers ranged from 0.68 (RF) to 0.86 (SVM), and SVM (0.86) attained highest AUCs. In the subgroup analysis of triple-negative (TN) and luminal type breast cancer, RF achieved the highest AUCs (0.83 and 0.94). Clinicopathological-radiomics combined model with SVM could be used as noninvasive biomarkers for predicting TP53 mutations. RF was recommended for the detection of TP53 mutations in TN and luminal type breast cancer. 3 TECHNICAL EFFICACY: Stage 2.

P985: THE ALLELIC RATIO OF DRIVER AND ASXL1 MUTATIONS IS PROGNOSTICALLY RELEVANT IN PMF

Background: Primary myelofibrosis (PMF) is a clonal disorder driven by mutations in JAK2, CALR, and MPL. Somatic mutations in myeloid-associated genes were shown to impact prognosis of PMF patients (pts). Among these, ASXL1 mutations (ASXL1mt) are by far the most frequent and prognostically relevant, in fact they are included in the category of “high molecular risk” (HMR), along with EZH2, IDH1/2, SRSF2, and U2AF1Q157 mutations. Aims: To investigate the phenotypic and prognostic implications of ASXL1mt and variant allele frequency (VAF) in PMF. Methods: After IRB approval, consecutive pts with WHO-defined PMF were included in the study. Mutational analysis by targeted NGS was performed by previously described methods (Guglielmelli P et al., JCO 2017). Results: The study enrolled a total of 384 pts, including 190 (49%) prefibrotic and 194 (51%) overt PMF. Median age was 60 (18-90) years, 236 (61%) were male. JAK2, CALR and MPL mutations were found in 255 (66%), 83 (22%), and 17 (4%) pts, respectively; 36 (9%) were triple negative (TN). Among HMR mutations, ASXL1 was mutated in 88 (23%) pts, SRSF2 in 35 (9%), EZH2 in 32 (8%), U2AF1 in 15 (5%), and IDH1/2 in 11 (3%). VAF distribution of driver and HMR mutations was as reported in Fig.1A. We did not find any significant correlation of ASXL1mt VAF with other clinical and molecular characteristics, including PMF subtype, gender, age, hemoglobin, leukocyte, platelet and blast counts, splenomegaly, BM fibrosis grade, cytogenetics, mutational status for driver and other HMR genes and their VAFs. The only exception was the association of CALR-mutated PMF with lower ASXL1 VAF (median 28% vs 40%, p=.0332). Median overall survival (OS) was 120 (102-151) months. In univariate Cox analysis, ASXL1mt VAF did not correlate with OS, nor did other single driver and HMR mutations. When considered as a whole (for the purpose of this study, TN pts were considered has having driver VAF equal to 0), the VAF of driver mutations inversely correlated with survival (HR 0.4 [0.2-0.9], p=.0219). We next investigated the allelic ratio between driver and ASXL1 mutations (d/Aratio) and its prognostic correlates. Median (range) of d/Aratio was 1.24 (0-13), and ROC analysis with death as an endpoint identified 1.31 as the optimal cut-off value. In univariate analysis, pts with a d/Aratio <1.31 had a significantly worse OS compared to those with a ratio ≥1.31 (median 45 vs 104 months, p=.0014; HR 2.4 [1.4-4.1]) (Fig.1B). When TN pts with ASXL1mt were considered apart, having a d/Aratio <1.31 retained its inferior prognostic impact compared to the d/Aratio ≥1.31 group (median OS 57 vs 104 months, p<0.0453; HR 1.8 [1-3.2]), with TN/ASXL1mt pts being associated with the worst outcome (median OS 24 months) (Fig.1C). In a multivariate Cox model including VAF-adjusted ASXL1 mutant status (ASXL1wtvs ASXL1mt with d/Aratio ≥1.3 vs ASXL1mt with d/Aratio <1.3) and other HMR mutations, the former and mutated SRSF2 were confirmed to be independent predictors of inferior OS. Both d/Aratio <1.31 and ≥1.31 remained significant compared to ASXL1wt with respective HRs of 3.4 (2.3-5.1; p<.0001) and 1.6 (1-2.6; p=.0342). Notably, d/Aratio <1.31 still retained its inferior prognostic impact compared to d/Aratio ≥1.31 (HR 2 [1.2-3.5]; p=.0095). Image:Summary/Conclusion: This study explores the implications of ASXL1mt VAF and its interplay with driver mutant burden. The adverse prognosis of pts with a d/Aratio <1.31 suggests that this disease entity is predominantly driven by ASXL1mt-clones characterized by a more aggressive biology. Further research is needed.

PB2042: CLINICAL AND MOLECULAR CORRELATION OF PATIENTS WITH ESSENTIAL THROMBOCYTHEMIA: A RETROSPECTIVE ANALYSIS FROM A TERTIARY CARE CENTER IN INDIA.

Background: Approximately 50–70% of patients of ET harbor JAK2 mutation while about 20–30% patients carry CALR mutations. Data from developed countries has shown that CALR mutated patients have higher platelet count and lower thrombotic risk compared to JAK2 mutated patients. In India, testing for CALR and MPL mutation and next generation sequencing has become available only in last 5 years. There is lack of data regarding mutation status and its clinical correlation. We studied clinical features of ET patients presented to our hospital according to their mutation status. Aims: To study the molecular mutations and correlate them with the clinical features in ET patients Methods: We did the retrospective analysis of the patients diagnosed as ET from January 2016 to December 2021. Allele Specific PCR and fragment analysis was done to detect JAK2 (V617F), MPL (W515L/K) and CALR exon-9 mutations. Risk stratification done as per revised IPSET (International Prognostic Scoring for thrombosis in Essential Thrombocythemia) score. Therapy was started in all the patients according to their risk score with hydroxyurea or aspirin as the standard of care. Results: A total of 39 diagnosed cases of ET were identified. Median age was 55 years (30-83), 20/39 males (51.3%) and 19/39 females (48.7%). JAK2 mutation was found in 25.6% (10/39), CALR in 38.5% (15/39) and MPL in 5.1% (2/39) cases. Triple negativity was found in 30.8% (12/39) cases. Very low, low, intermediate and high-risk patients as per IPSET score were 53.9% (21/39), 10.2% (4/39), 20.5% (8/39) and 15.4% (6/39) respectively. The median age was statistically significantly lower in CALR positive cases compared to the JAK2 positive cases (45.9 vs 60.9years, p=0.011). The median Hemoglobin and platelet counts were slightly higher in CALR positive group (12.3 g/dL and 10.15x109/l) compared to JAK2 mutated and triple negative groups but the difference was not statistically significant. Three patients (7.7%) presented with thrombosis; two with cerebral venous thrombosis both CALR positive, one with arterial stroke and MPL gene mutation. Ten (25.6%) patients were lost to follow up. One (2.6%) died to pulmonary infection. Median follow up period was 24 months. None of the patient transformed to acute myeloid leukemia or myelofibrosis. None of the patient developed thrombotic event after diagnosis and appropriate treatment. Summary/Conclusion: We observed that CALR was the most common mutation in our study. The CALR mutated patients were younger in age but the median platelet counts, WBC count and Hemoglobin were not statistically different among different mutation groups. In contrast to western studies, thrombosis was observed to be higher in CALR mutated group than others in our patient population. We recommend larger multicenter study for further elucidation of these observations.