bluuebunny/crossref_metadata_2025 huggingface dataset:
Glycoproteomics as a powerful liquid biopsy-based predictor of checkpoint inhibitor treatment benefit in metastatic malignant melanoma.
Authors: Lindpaintner Klaus , Mitchell Alan , Pickering Chad , Xu Gege , Vigal Kimberly , Axenfeld Bianca , Rice Rachel , Cong Xin , Frederick Dennie T. , Michaud William , Boland Genevieve Marie , Serie Danie
Published: June 2022

9545

Background: Protein glycosylation is the most abundant and complex form of post-translational protein modification. Glycosylation profoundly affects protein structure, conformation, and function. The elucidation of the potential role of differential protein glycosylation as biomarkers has so far been limited by the technical complexity of generating and interpreting this information. We have recently established a novel, powerful platform that combines liquid chromatography/mass spectrometry with a proprietary artificial-intelligence-based data processing engine that allows, for the first time highly scalable interrogation of the glycoproteome. Methods: Using this platform, we interrogated 526 glycopeptide (GP) signatures derived from 75 serum proteins in pretreatment blood samples from a cohort of 205 individuals (66 females, 139 males, age range 24 to 97 years) with metastatic malignant melanoma treated either with nivolumab plus ipilimumab (95 patients) or pembrolizumab (110 patients) immune-checkpoint inhibitor (ICI) therapy. Results: In an optimized assay containing 27 glycopeptides and 20 non-glycosylated peptides, we identified 14 GPs with abundance differences at FDR q≤0.05 with regard to PFS. Using 40% of the cohort as a training set and selecting 12 glycopeptide and non-glycosylated peptide biomarker features of the 47 total by LASSO shrinkage, we created a multivariable-model-based classifier for PFS that yielded a hazard ratio (HR) for prediction of likely ICI benefit of 7.5 at p < 0.0001. This classifier was validated in the test set comprised of the held-out 60% of patients, yielding a HR of 4.7 at a similar p-value for separating patients likely benefiting from ICI therapy and those likely not benefiting from ICI therapy (50% PFS of 18 months vs. 3 months based on classifier score above/below cutoff). This classifier has a sensitivity of > 99% to predict likely ICI benefit, while still performing at a specificity of 26%, thus helping to safely reduce ultimately unnecessary and non-beneficial exposure to these agents of one in four who otherwise would unnecessarily be exposed to them. Conclusions: Our results indicate that glycoproteomics holds a strong promise as a predictor for checkpoint inhibitor treatment benefit that appears to significantly outperform other currently pursued biomarker approaches in this context.
Clinical predictors of longer survival in patients with BRAFV600-mutated metastatic melanoma receiving immunotherapy prior to BRAF/MEK inhibition in the metastatic setting.
Authors: Kahn Adriana Matutino , Perry Curtis , Etts Katrina , Kluger Harriet M. , Sznol Mario
Published: June 2022

9555

Background: Patients with advanced BRAFV600-mutated melanoma are typically treated with immunotherapy in the first-line setting, followed by BRAF/MEKi upon disease progression based on an absolute 20% improvement in 2-year overall survival over initial treatment with BRAF/MEKi in the DREAMseq trial. Our goal was to identify clinical predictors of longer survival for patients treated in our institution with this approach. Methods: We identified 40 patients with BRAFV600-mutated metastatic melanoma treated at our institution from 2011 to 2020 with immunotherapy followed by BRAF/MEKi upon progression. Clinical data were collected and analyzed by Cox regression and Kaplan-Meier methods. Favorable outcome was defined as survival > 2 years (y) after starting BRAF/MEKis. Results: Median follow up was 33 months (m, 3 – 172 m). Median age was 54 y (20 - 83). Most patients were female (n = 24, %). Most patients were initially treated with ipilimumab plus nivolumab (n = 34, 85%), with 13 of these patients (38%) tolerating all 4 cycles of initial ipilimumab. Adverse events of any grade were seen in 28 (70%) patients after first-line immunotherapy, with the most common being hepatitis, colitis, hypothyroidism, rash, and fatigue. Median duration of first-line immunotherapy was 3.5 m (.75 - 42.5 m). Most common sites of progression on immunotherapy were lymph nodes (n = 14, 35%), liver (n = 12, 30%), bone (n = 10, 25%) and brain (n = 10, 25%). Prior to BRAF/MEKis, median ECOG-PS was 1 (0-4) and median LDH was 268 mg/dL (151 - 11,300). Most common BRAF/MEKi regimen was dabrafenib plus trametinib (n = 34, 85%). Adverse events of any grade were seen in 30 (75%) patients, with the most common being fever, fatigue, nausea, and vomiting. Best response to BRAF/MEKi was CR (n = 4, 10%), PR (n = 26, 65%), SD (n = 4, 10%) and PD (n = 6, 15%), and at the data cutoff, 35 (87.5%) patients progressed on BRAF/MEKi. Median duration of BRAF/MEK inhibition was 7 m (0.5 – 106 m). Median survival since starting BRAF/MEKi was 19.2 m (1.7 – 106 m). On multivariable analyses assessing predictors of survival, presence of bone metastases after disease progression on first-line immunotherapy was associated with worse 2-year survival after initiation of BRAF/MEKi (OR 2.5, 95% CI, 0.51-5.6, p = 0.0121). Other factors, such as ECOG-PS 0-2, normal LDH prior to BRAF/MEKi, and age at metastatic diagnosis < 60 years were not significantly associated with longer survival after initiation of BRAF/MEKi. Conclusions: We showed that the presence of bone metastases upon progression on first-line immunotherapy was associated with worse 2-y survival on salvage BRAF/MEKi for patients with BRAFV600-mutated metastatic melanoma. Predictive and prognostic biomarkers for long-term response to both immunotherapy and BRAF/MEKi are needed to optimize treatment strategies and patient outcomes.
Adjuvant dabrafenib plus trametinib (D + T) versus placebo in patients with resected stage III BRAFV600-mutant melanoma: Updated 5-year distant metastases-free survival (DMFS) analysis of COMBI-AD.
Authors: Schadendorf Dirk , Hauschild Axel , Mandalà Mario , Kirkwood John M. , Robert Caroline , Grob Jean-Jacques , Nathan Paul D. , Davies Michael A. , Banerjee Hiya , Shah Rohan , Lau Mike R. , Dummer Reinhard , Long Georgina V.
Published: June 2022

9563

Background: DMFS is an important endpoint for patients with stage III cutaneous melanoma, as delaying or preventing systemic disease is associated with improved clinical and patient-reported outcomes. Prior results from the phase 3 COMBI-AD trial (NCT01682083) showed 5-year DMFS rates of 65% with adjuvant D + T vs 54% with placebo (PBO; hazard ratio [HR] = 0.55; 95% CI: 0.44-0.70). An analysis of DMFS by AJCC-7 stages IIIA-C suggested a similar benefit of D + T vs PBO regardless of stage (Dummer R et al. N Engl J Med. 2020). Here, we report 5-year DMFS rates by AJCC-8 stages IIIA-D, other prognostic subgroups, and results of a regression tree analysis with DMFS. Methods: Patients with resected AJCC-7 stage III BRAFV600E/K-mutant melanoma were randomized to either D (150 mg twice daily) + T (2 mg once daily) or 2 matched PBOs for 12 months. Primary endpoint was relapse-free survival (RFS); DMFS was a secondary endpoint. Kaplan-Meier survival analyses were performed to assess the long-term benefits for DMFS rates with D + T vs PBO. The regression tree analysis (data cutoff: 5 years) for all patients (N = 870) evaluated potential prognostic/predictive factors of long-term DMFS including baseline age, sex, region, BRAF mutation type, body mass index, lactate dehydrogenase levels, ECOG, T and N categories, histology, primary tumor ulceration, treatment type, number of lymph nodes with metastases, tumor mutational burden, and interferon-gamma gene expression signature (IFN-γ GES). Results: At 5 years, DMFS rates were higher for patients with AJCC-8 stages IIIB-D disease receiving adjuvant D + T vs PBO (table). Five-year DMFS rates also favored D + T vs PBO in subgroups of patients with microscopic or macroscopic lymph node involvement (table) and those with or without primary tumor ulceration and/or in-transit metastases. A regression tree revealed T and N stage, treatment type, and IFN-γ GES as important variables defining 5-year DMFS subgroups. Conclusions: In this retrospective analysis, adjuvant D + T provided long-term DMFS benefit vs PBO in stage IIIB-D patients with resected BRAFV600E/K-mutant melanoma. Key clinical and patient factors impacting DMFS were similar to prior RFS findings (ESMO 2021; Robert C et al. Ann Oncol. 2021) and included T and N stage, treatment type, and IFN-γ GES. These results further validate the robust long-term clinical benefit of adjuvant D + T for patients with melanoma. Clinical trial information: NCT01682083. [Table: see text]
Body composition changes in a 12-week exercise intervention for breast cancer patients.
Authors: Asato Chloe , Vance Alanna , Cheng Shirley , Lim Shannon , Yamada Paulette , Teranishi-Hashimoto Cheri , Shepherd John , Fukui Jami Aya
Published: June 2022

e12500

Background: Evidence has linked weight gain and obesity to increased breast cancer risk, poorer outcomes, decreased survivorship, and increased risk of recurrence. Adjuvant therapies can increase weight gain, making tailored exercise interventions beneficial in maintaining a healthy weight. In this study, body composition changes were examined after a 12-week exercise program in a cohort of breast cancer survivors. Methods: The Breast Cancer Exercise Rehabilitation Research Study recruited breast cancer survivors to undergo a 12-week exercise program (NCT04013568) and examine body composition changes. Measurements taken included anthropometry (waist circumference, waist-to-hip ratio, BMI), DXA body composition measurements (fat mass-visceral and subcutaneous, trunk to limb, muscle mass-appendicular, and whole body), and BIA (Bio-electrical Impedance Analysis-muscle, fat, and water). 34 participants completed the exercise program and baseline and post-12-week measurements were obtained. Descriptive statistics and a paired t-test analysis was done to analyze changes in body composition using SAS onDemand. A correlation analysis between measurements simple to do in clinic and DXA measurements were run to determine proxy use for DXA. Results: After a 12-week exercise program, reductions in body fat via DXA scan, BIA, and InBody (whole body fat, whole body fat %, trunk fat, leg fat, body fat %, hip width at maximum girth, body fat mass, and percent body fat) were observed. Additionally, increases in lean mass (Appendicular Lean Mass (ALM)/height2, Appendicular Lean/height2, ALM index, and lean body mass), whole body mass measured by DXA, basal metabolic rate, water retention (extracellular water and total body water), and skeletal muscle mass were observed. Correlation analysis revealed BMI can be used as a surrogate measure for whole body mass measured by DXA (r=0.91, p<0.001) and can be utilized to measure change over time. Skinfold sum showed moderate correlation for measuring subcutaneous fat mass by DXA (r=0.45, p=0.0096). Conclusions: In our population of breast cancer survivors, a 12-week exercise program did show various changes in body composition according to InBody, DXA, and BIA measurements. DXA and InBody measurements were feasible, making it readily available for patients. Additionally, simple measures such as BMI and skinfold sum showed moderate to strong correlation with DXA measurements, validating use of these measurements in routine practice. Clinical trial information: NCT04013568. [Table: see text]
Adherence to different adjuvant endocrine therapies in HR+ HER2-breast cancer and its relation to real-world progression rates.
Authors: Durutovic Ivana , Gendy Shady , Kumar Deepa , Amioka Elise
Published: June 2022

e12507

Background: Adjuvant hormonal therapy (Adj.) has significantly improved long-term survival of breast cancer (BC) patients with hormone receptor-positive (HR+) disease1. Despite proven efficacy, many breast cancer patients fail to adhere to treatment2. This study aims to assess patient adherence to different Adj. regimens by observing Proportion Days Covered (PDC) in relation to Real-World Data Overall Response Rate (RWD-ORR), Event Free Survival (EFS) & Adverse Events Rates (AEs). Methods: ICON US Medical & Prescription data was used. Analysis was limited to female BC patients who started Adj. [July’13 - June’14] & further refined to HR+ & HER2 negative patients by drug proxy. Patients were followed for 72 months. RWD-ORR was defined as percent of patients with no evidence of progression during follow-up. EFS was defined as time from Adj. start to first observed progression. PDC was calculated as (days on drug/duration on Adj.). AEs evaluated were endometrial & bone density changes. Chi square, t-tests & Fisher exact tests were used to examine Adj. regimen associations with age & adherence. General linear models (GLMs) were used to examine the effect of adherence on RWD-ORRs and AEs by treatment group, adjusting for patient age at diagnosis. Results: 1,498 patients met study criteria & data integrity procedures. Mean age was 60 years. Adherent patients were significantly older (57.8 vs 60.4 p < 0.001). RWD-ORR was 70.4%, median EFS was not reached, median Duration on Therapy was 52 months and overall AEs was 9%; highest in leuprolide group but no statistical difference across groups. RWD-ORR was observed to be highest among the AI group. High treatment adherence (PDC 80%+) was the strongest indicator of ORR (p < 0.001). RWD-ORR among those treated with AI or Tamoxifen were found to be more sensitive to adherence compared to AI/Tamoxifen. Conclusions: This study offers evidence to support provider´s messaging to patients that adherence improves outcomes when prescribing treatments. While adherence is important for positive outcomes for all regimens, some regimens appear to be more sensitive to adherence changes with respect to RWD-ORR. Further analysis including disease risk factors is needed to explain ORR - PDC relationship.[Table: see text]
The population characteristic analysis in RecurIndex for clinical decision-making on adjuvant therapy for early breast cancer: Results of a real-world study.
Authors: Wang Xiaojia , Lei Lei , Fu Peifen , Wang Ouchen , Xie Xiaohong , Xu Haibin , Feng Weiliang , Yang Hongjian , Hu Guinv , Li Shuguang , Dai Zhijun , Guo Guilong , Lv Xiaoai , Zheng Ya-bing , Chen Zhan-hong , Shao Xi-Ying
Published: June 2022

e12514

Background: 28-gene signature (RecurIndex) is the first multi-gene panel for recurrence risk prediction after surgery developed from the Asian breast cancer population. In this study, we aimed to report the clinical and genomic characteristics of Chinese early-stage breast cancer patients whose primary lesions have been evaluated by 28-gene signature testing. Methods: In this study, 363 patients were assessed by 28-gene signatures between November 2019 and August 2021. Of these, 330 (90.9%) had stage I-II, hormone receptor-positive, HER2-negative breast cancer, 16 (4.4%) had triple-negative breast cancer (TNBC), and 17 (4.7%) had HER2-enriched breast cancer. The genomic risks of local and distant recurrence were determined by 28-gene signature respectively; the clinical risk was evaluated by the modified Adjuvant! Online. The molecular subtyping of the 28-gene signature was also compared with immunohistochemistry (IHC) status. In the future analysis, we will report the clinical decisions and outcomes of these patients. Results: The 28-gene signature classified 86.8% (n = 315/363) of patients as genomic Low Risk (LR) and 13.2% (n = 48/363) as genomic High Risk (HR) for local recurrence; 83.7% (n = 304/363) and 16.3% (n = 59/363) for distant recurrence. Among clinical HR patient, a total of 72 patients (64.9%) were deemed to be genomic LR of distant recurrence, and a total of 88 patients (79.3%) were deemed to be genomic LR of local recurrence. The concordance of luminal type identified by IHC or 28-gene based molecular subtyping was 99.1% (n = 327/330); TNBC type was 25% (n = 4/16), and HER2 enriched was 70.6% (n = 12/17). Conclusions: This study showed that in clinical HR patients, 64.9% 28-gene LR patients who could waive their adjuvant chemotherapy and 79.3% who could have the adjuvant radiotherapy adjusted. Additionally, the results of IHC and 28-gene signature-based molecular subtyping were highly consistent in luminal type, while the potential value of TNBC and HER2 enriched subtyping identified by the 28-gene signature needs to be further explored in the future.[Table: see text]
The use of clinical impact of the breast cancer intrinsic subtype-Prosigna assay for adjuvant treatment decision in early breast cancer with hormone receptor positive and HER-2 negative Middle East women.
Authors: Zidan Jamal , Leviov Michelle , Kuchuk Iryna , Bar-Sela Gil , Shai Ayelet , Kazarin Olga , Suheil Nasralla
Published: June 2022

e12527

Background: Clinico-pathological evaluations of intrinsic subtypes by immunohistochemistry (IHC) are routinely used for treatment decision in patients with early-stage breast cancer (EBC). The Prosigna (PAM50) gene signature, is validated test measures the expression levels of 50 genes from formalin-fixed paraffin-embedded (FFPE) tumor samples. It permits intrinsic subtype classification of tumor and prognostic test of risk of recurrence (ROR) score. The objectives of this study were to evaluate the impact of Prosigna results on type of adjuvant treatment in EBC, to overcome disparities by comparing the results on different ethnicity groups in Israel and to asses physicians treatment decision before and after Prosigna results. Methods: This prospective, observational study was carried out in 7 Medical Centers at Northern Israel. Postmenopausal women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative invasive EBC were enrolled. Physicians completed treatment confidence questionnaires prior to and after receiving Prosigna test results. Only EBC : T 1-2, N0 and N1 were included. Results: Between May 2018 and April 2021, 238 women were enrolled, 204 patients are eligible for this analysis. Ashkenazi Jews were 38%, Sephardi Jews 32% and 30% were Palestinian Arab women. Mean age was 65.28 years. T1 was diagnosed in 82.3%, T2 in 17.3% and N1 in 22.4% of pts. At time of diagnosis tumor subtypes were categorized based on IHC as Luminal A in 50%, 54.4%, 59.5% and Luminal B in 50%, 44.6% and 40.5% of Sephardi, Ashkenazi and Arab patients retrospectively. Intrinsic tumor subtypes detected by the Prosigna test were Luminal A in 63.8%, 71%, 74.3% and Luminal B in 34.5% (+1.7% basal like), 29% and 25.7% respectively. No significant different between these groups. Overall 50.5% of pts were low risk, 26% intermediate risk and 23.5% high risk due to Prosigna results. Following Prosigna results 23.4% of the physicians changed their treatment recommendation. Conclusions: To our knowledge this is the first study using Prosigna test in Middle East women with early breast cancer. The use of Prosigna results led to a 23.4% change in adjuvant treatment decision. The results of this prospective study is similar to the data published in other studies in the literature. The intrinsic tumor subtypes and risk of recurrence detected by Prosigna adds to the physicians' confidence in the choice of treatment type. Prosigna test was additive for understanding the biology and for adjuvant treatment choice in both Jewish and Palestinian women in Israel.
Assessing adherence to adjuvant hormone therapy in breast cancer patients in routine clinical practice.
Authors: Camejo Natalia , Castillo Cecilia , Tambasco Clara , Strazzarino Noelia , Requena Nicolás , Peraza Silvina , Boronat Anna , Herrera Guadalupe , Esperon Patricia , Cuello Toledo Mauricio , Krygier Gabriel David
Published: June 2022

e12532

Background: Adjuvant hormone therapy (HT) in patients with hormone receptor-positive breast cancer (BC) increases overall survival (OS). Adherence to HT in routine clinical practice is still poorly reported. Many BC patients are treated for other diseases and experience polypharmacy. Methods: Objective To assess adherence to HT in routine clinical practice.Materials and Methods: Adjuvant hormone therapy (HT) in patients with hormone receptor-positive breast cancer (BC) increases overall survival (OS). Adherence to HT in routine clinical practice is still poorly reported. Many BC patients are treated for other diseases and experience polypharmacy. Results: A total of 118 patients were included; 65.2% were treated with aromatase inhibitors (AI) and the rest with tamoxifen, with 36% presenting polypharmacy. Treatment adherence was observed in 81% of the patients, and it was associated with age (p=0.03, OR=0.96 for non-adherence), with adherent and non-adherent patients having a median age of 66 and 61.5 years, respectively; however, adherence was not associated with polypharmacy, territory of origin, marital status, living alone, level of education, occupation, or stage. The adherence profile was similar for both drugs, but homemakers and retired women showed greater adherence to AI. Conclusions: Adherence to HT was assessed in real life, with 19% of the patients not adhering to the treatment, despite the known benefit for OS, being a well-tolerated treatment, and being provided free of charge. The most adherent patients were the oldest. The results show the need to investigate the reasons for discontinuing HT, with Pharmacy and Medical Oncology fields combining efforts to develop coordinated strategies and interventions to increase adherence, given the impact that this may have on patients' OS.
Use of breast MRI to distinguish treatment failure versus new primary tumor following single fraction breast intraoperative radiotherapy for breast cancer (SF-IORT).
Authors: Payne Shelby , Payne Sydney , Horst Kathleen C. , Ikeda Debra M. , Dirbas Frederick M.
Published: June 2022

e12534

Background: Single-fraction, intraoperative radiation therapy (SF-IORT) can replace whole breast radiotherapy (WBT) in select patients after lumpectomy for breast cancer. By combining histology review with co-registration of breast MRI at diagnosis and following an in-breast tumor recurrence, we sought to characterize IBTR as: missed on initial MRI, treatment failure, or new primary tumor. This has important implications for both breast MRI and understanding the effectiveness of SF-IORT. Methods: We reviewed our IORT database for patients with IBTR. Three radiologists recorded findings on DCE-MRI, mammograms and ultrasound, pathology at initial diagnosis and IBTR, and time to IBTR. Results: 90 women received SF-IORT between 12/6/2002 - 4/10/2019. There were 6 IBTRs (average age at recurrence 63, range 49-71 years). For these 6 patients, initial diagnostic mammograms showed fatty (1), scattered (4) or extremely dense (1) breasts with suspicious masses (4), calcifications (1), or asymmetry (1), average size 1.4 cm: range 0.3 - 2.0 cm. On MRI, background parenchymal enhancement was minimal (2), mild (2), moderate (1), or marked (1), showing a mass (4), mass/distortion (1), or post-biopsy marker/no abnormal enhancement (1). Initial pathology showed 2 IDC, 3 IDC/DCIS, and 1 DCIS, (average size 1.7 cm, range 1.1 - 2.4 cm) with 6/6 ER +, 5/6 PR + and 6 HER2 negative. IDC Ki-67 ranged from 5-25%. 5/6 patients had sentinel lymph node biopsy (SLNB) with 1/5 having a positive SLN. 4/6 received endocrine therapy. One patient declined follow-up mammography. After IORT, IBTR (average size 1.4 cm, range 0.7 - 3.6 cm) was diagnosed by mammography (3), palpable breast lump (2), or palpable axillary lymph node (LN) (1) shown as mass (4), mass/calcifications (1), or abnormal LN (1). IBTR occurred post-SF-IORT an average of 141.7 months, range 88.3 to 195.8 months. 2/6 IBTR occurred near the biopsy cavity. Subsequent surgery included mastectomy (3), re-excision lumpectomy/RT (2), or axillary LN dissection/RT (1) showing 4 IDC, 1 IDC/DCIS, and 1 IDC /ILC (6/6 ER +; 3/6 PR positive; 2 PR weakly positive; and 5 HER2 negative, 1 HER2 equivocal). Ki-67 ranged from 1-70%. Conclusions: 6/90 (6.6%) patients had an IBTR an average of 141.7 months post SF-IORT with 2/6 near the biopsy cavity. Breast MRI reliably screens patients for SF-IORT. Co-registration of imaging can help distinguish true recurrences from new primary tumors.
Is BMD (Bone Mineral Density) a prognostic factor for luminal A breast cancer in postmenopausal women?
Authors: Lee Seungju , Kim Hyun Yul
Published: June 2022

e12542

Background: There are some studies concerned about the relationship of BMD (Bone Mineral Density) and breast cancer risks in menopausal women. However, most studies have limitations in that they did not distinguish the subtypes of breast cancer. Therefore, we assessed the BMD as a risk factor of recurrences, metastases, or occurrences of contralateral breast cancer in the luminal A breast cancer patients with menopause. Methods: In this retrospective study, the data of 348 luminal A type breast cancer patients, who underwent treatment at the Pusan National University Yangsan Hospital from 2012 to 2016, were analyzed. BMD of the lumbar spine, total femur, and femoral neck was measured by Dual Energy X-ray Absorptiometry (DXA). According to the measured BMD and WHO criteria, the group with T scores ≥ -1.0 was defined as normal, the group with T scores < -1.0 and > -2.5 was defined as osteopenia, and the group with T scores < -2.5 was defined as osteoporosis. The patients were divided into two groups: those with normal BMD and those with low BMD including osteopenia or osteoporosis in preoperative examination. We also divided patients as three groups: one group with no change of BMD, the other group with improvement of BMD and the other with deterioration of BMD during treatment. We used Chi-squared tests, Kaplan-Meier method and Cox-regression model to analyze the relationship between BMD and breast cancer risk. Results: Among the 348 patients, normal BMD was confirmed by preoperative examination in 129 patients and low BMD was identified in 219 patients. There was no change in BMD during the treatment in 243 patients. The improvement in BMD was identified in 37 patients, and the deterioration of BMD was confirmed in 68 patients. Younger patients were distributed in normal BMD compared to low BMD (55.7±6.9 vs 61.8±8.0, p<0.05). There were only 14 patients (4.0%) with recurrences, distant metastases or occurrences of contralateral breast cancer during a median follow-up period of 78 months. Among the 219 patients with low BMD, disease-free survival at 5 years was 98.2% compared to 95.0% for 129 patients with normal BMD ( p=0.326). In addition, disease-free survival at 5-years was 97.0% in no change of BMD during treatment, 94.6% in improvement of BMD, and 98.4% in deterioration of BMD ( p=0.785). Conclusions: In this study, BMD did not have statistically significance in the recurrences, metastases, or occurrences of contralateral breast cancer in luminal A breast cancer patients with menopause. In addition, there was no statistically importance in relationship between BMD change during treatment and recurrences, metastases, or occurrences of contralateral breast cancer. Therefore, we should perform treatments to breast cancer patients preventing decreased BMD.
Correlation of the oncotype DX breast recurrence score and the ki-67 IHC MIB-1 pharmDX score in HR+, HER2-, node-positive early breast cancer.
Authors: Crager Michael , Wijayawardana Sameera R. , Gruver Aaron M. , Blacklock Andrea , Baehner Frederick L , Russell Christy , Sapunar Francisco J.
Published: June 2022

e12556

Background: In monarchE, abemaciclib, an oral CDK4/6 inhibitor, when combined with endocrine therapy (ET, tamoxifen or aromatase inhibitor) significantly improved invasive disease-free survival in patients with HR+, HER2-, node positive early breast cancer (EBC) at high risk of early recurrence and Ki-67 score ≥20%. The US FDA subsequently approved the Ki-67 IHC MIB-1 pharmDx assay (Dako Omnis) as a companion diagnostic. The Oncotype DX Breast Recurrence Score assay has similarly been validated in HR+, HER2- invasive breast cancers (IBC) to predict chemotherapy benefit and risk of distant recurrence at 10 years regardless of node status. While several studies have previously shown a relationship between Ki-67 IHC assays and RS, this relationship has not yet been evaluated using the standardized Ki-67 assay established for monarchE. The primary objective was to estimate the correlation between the Recurrence Score (RS) result and the monarchE Ki-67 IHC score using prospectively collected node positive, HR+, HER2- IBC specimens. A secondary objective assessed the proportion of node positive, HR+ patients with RS 26-100 that have Ki-67 IHC score >20%. Methods: IBC samples were acquired from Exact Sciences following an IRB-approved protocol. Samples from US patients with HR+, HER2- IBC, 1-3 positive lymph nodes (N1) with available RS result and sufficient tumor content were eligible. After collection of 275 samples with all RS results eligible (“All- RS pool”), 36 more samples with RS 26-100 were collected with high RS (HI RS only”). Unstained tissue sections were subsequently sent to Agilent Technologies for Ki-67 IHC using the monarchE assay. The consensus diagnostic category (positive/negative) and an average of the two closest % positivity scores were used for the final dataset. Spearman rank correlation and cross tabulations of RS result with % Ki-67 were performed according to the predetermined statistical analysis plan. Results: 311 samples were collected, 1 with a null Ki-67 result. Twelve samples had a pathology report with node negative assessment, leaving 298 samples and 262 in the All-RS pool. The rank correlation between % Ki-67 and RS result in the all-RS pool in the node positive population was 0.396 (95% CI 0.288 – 0.493). Cross-tabulations of the Ki-67 diagnostic category (< 20% vs ≥ 20%) against the RS were made using all available data (All-RS pool+HI RS only). Among 218 samples with RS 0-25, 164 (75%) had Ki-67 <20% and 54 (25%) had Ki-67 ≥20%. Among 80 samples with RS 26-100, 57 (71%) had Ki-67 ≥20% and 23 (29%) had Ki-67 <20%. Conclusions: A moderately positive correlation between the Oncotype DX Breast Recurrence Score result and the Ki-67 IHC MIB-1 pharmDx Score in HR+, HER2- node positive EBC was observed in the All-RS pool. These findings are consistent with prior studies.
Assessing the interrelation between oestrogen receptor status, heart rate variability and serum nitric oxide in breast cancer patients: Understanding their prognostic relevance.
Authors: Taranikanti Madhuri , Mudunuru Aswin Kumar , Dronamraju Akhila , Guntuka Rohith Kumar , Yerra Aruna Kumari , Maddur Srinivas , Manchikanti Lasya , Taranikanti Sai Shriya
Published: June 2022

e12564

Background: Heart Rate Variability (HRV) is a non-invasive procedure to assess cardiac functions and provides an index of autonomic function that intricately controls vascular tone. Studying the alteration in HRV with agents producing oxidative stress will provide useful information about disease progression. Lower HRV indicates low level of Parasympathetic Nervous System activation and dysregulation of cardiac functions. Elements of tumour microenvironment like prostaglandin E2, oestrogen and hypoxia stimulate nitric oxide (NO) production which reacts with free radicals released by tumour tissue forming oxidising agents. NO enhances oxidative stress causing vascular dysfunction. Very few studies have reported an interrelationship between NO and HRV parameters in breast cancer. The aim of the study is to verify the relation between HRV and serum NO levels in ER+ and ER- breast cancer groups. Methods: Study design: Analytical, Cross sectional. Sample Size: 135 women above 20 years of age with and without breast cancer. 69 women with histologically proven breast cancer in different stages and 66 women who were healthy age matched controls were included. Oestrogen Receptor (ER) status was obtained from clinical records. Out of 69 women with breast cancer, 31 were ER- with 15 in stage 1 and 16 in stage 2. 38 women were ER+ with 5 in stage 2 and 33 in stage 3. Serum NO was measured using colorimetry. Heart Rate Variability was measured from lead II ECG using Power Lab 15T and lab chart software. Serum NO levels and HRV parameters were compared between ER groups. Results: ER+ women had higher HRV with parasympathetic predominance compared to ER- with p<0.001. ER+ women also had higher serum NO levels compared to ER- group with p<0.001. Though no direct correlation was noticed between NO and HRV, multiple analysis of variance showed significant (p<0.001) difference of all values across the groups. irrespective of menopausal status. Conclusions: A significant difference was observed in HRV of ER+ and ER- women with breast cancer. Most ER+ women were in stage 3 with significantly higher NO levels. Serum NO is expected to be the factor most responsible for HRV changes particularly in stage 3/ER+. Parasympathetic predominance seen in ER+ women possibly is due to high NO levels.[Table: see text]
Single cell profile of tumor and immune cells in primary triple-negative breast cancer and different sites in the axillary lymph nodes.
Authors: Liao Ning , Li Cheukfai , Cao Li , Chen Yanhua , Ren Chongyang , Chen Xiaoqing , Mok Hsiaopei , Wen Ling-Zhu , Li Kai , Wang Yulei , Zhang Yuchen , Li Yingzi , Lv Jiaoyi , Cao Fangrong , Luo Yuting , Li Hongrui , Wu Wendy , Balch Charles M. , Giuliano Armando E.
Published: June 2022

e12570

Background: Little is known about the host-tumor interaction in the lymph node basin at a single cell level. This study examines single cell sequences in breast cancer nodal metastasis of a patient with triple negative breast cancer. Methods: The primary breast tumor, sentinel lymph node, an adjacent lymph node with metastatic involvement and a clinically normal-appearing lymph node were collected during operation. Single-cell sequencing was performed on all specimens. Results: 14,016 cells were clustered as 6 cell populations. Cancer cells demonstrated the molecular characteristics of TNBC basal B subtype and highly expressed genes in the MAPK signaling cascade. Tumor associated macrophages regulated antigen processing and presentation and other immune-related pathways to promote tumor invasion. CD8+ and CD4+ T lymphocytes concentrated more in sentinel lymph node and mainly stratified as two transcriptional states. Conclusions: The first single cell report investigates the host-tumor interaction in the lymph node basin of triple-negative breast cancer. Single-cell sequencing analysis suggested that the sentinel lymph node was the initial meeting site of tumor infiltration and immune response, where partial T lymphocytes perform anti-tumor activity while other T cells exhibit an exhaustion state. We proposed a molecular explanation to the well-established clinical principle that the 5-year and 10-year survival outcomes were noninferior between sentinel lymph node dissection (SLND) and axillary lymph node dissection (ALND).
Nanosomal docetaxel lipid suspension (NDLS) based (neo) adjuvant chemotherapy improves pathological complete response (pCR) in patients with breast cancer.
Authors: Revathi Badiginchala , Dattatreya Palanki Satya , Suresh Attili Venkata Satya , Nirni Sharanabasappa Somanath , Andra Vindhya Vasini
Published: June 2022

e12591

Background: Nanosomal docetaxel lipid suspension (NDLS) was developed to overcome toxicity issues associated with conventional docetaxel. We evaluated the safety and efficacy of NDLS versus conventional docetaxel-based neo/adjuvant chemotherapy in patients with breast cancer. Methods: Patients with stage IIb-III breast cancer were randomized (1:1) to receive neoadjuvant doxorubicin and cyclophosphamide (AC) followed by conventional docetaxel (arm A) or NDLS (Doceaqualip; arm B) at a dose 75 mg/m2 IV every 3-weekly for 4 cycles as neo/adjuvant therapy. Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer received treatment as per clinical practice. The study outcomes included pathologic and clinical response rates (pCR, CR), and overall survival (OS). Results: 60 patients were randomized to arm A (n=30) or arm B (n=30). The baseline characteristics were similar in both groups. The pathological and clinical response rates were comparable between the NDLS and conventional docetaxel arms (P>0.05) (Table). The efficacy outcomes were not affected by the receptor (estrogen, progesterone, and HER2) status. The pCR and CR rates were higher in patients who received neoadjuvant AC followed by neoadjuvant NDLS/T versus neoadjuvant AC followed by adjuvant NDLS/T. At a follow-up of 6 months, median OS was not evaluable in both arms as all patients were alive at follow-up post study completion. Grade 3/4 infusion-related reactions, hyperglycemia and neuropathy were noted in 5, 8 and 3 patients, respectively, in the conventional docetaxel arm while it was not reported in any patient in the NDLS arm. Conclusions: NDLS based neo/adjuvant chemotherapy was efficacious in the treatment of breast cancer and showed comparable pCR, CR and OS rates versus conventional docetaxel. NDLS was better tolerated than conventional docetaxel.[Table: see text]
Multimodal approach to capture spatially resolved single-cell tumor heterogeneity in breast cancer.
Authors: Cook Daniel , Lopez Dorys , Antony Anu K. , Team The SimBioSys , Cole John A.
Published: June 2022

e12597

Background: Tumor heterogeneity is known to play a key role in drug response and resistance. However, knowledge of tumor heterogeneity is largely limited to genetics and biopsy samples representing one region of the tumor. The study of spatial tumor heterogeneity is gaining more interest as researchers and clinicians realize that biopsies might miss biomarker information. Although several approaches like single-cell RNA seq and multiplex IHC/IF are used to study spatial heterogeneity, these methods tend to be costly and time consuming. Additionally, there is no consensus on how to interpret these results for optimizing therapy, making it harder to implement these approaches in the clinic. Methods: Here we present a state-of-the-art technique to characterize tumor heterogeneity within individual patient tumors by integrating single cell RNA-seq data with biophysical modeling, using SimBioSys’ TumorScope (TS) – a biophysical modeling platform. As a proof of concept, we compared intra-tumoral heterogeneity from experimental single cell RNA-seq studies from TNBC patients (n=8) to to simulated intra-tumoral heterogeneity within TNBC patients from the ISPY-1 trial (n = 10). We also compared simulated vs. experimentally measured bulk transcriptional profiles within individual patients. Results: We found that the correlation between individual single-cell transcriptomes to biopsy transcriptomes was low (median Spearman correlation ̃ 0.5). However, using TS to predict single-cell scale transcriptomics within a tumor based on biophysical characteristics of the tumor resulted in correlations of ̃ 0.86, between simulated and experimentally measured transcriptomes (range = 0.85 - 0.87). TS allowed the simulated single-cell RNA-seq data to create spatially resolved single-cell maps that quantify the spatial expression of key tumor biomarkers across the whole tumor including Ki67, HER2 and PDL1. The spatial distribution of these biomarkers can have important implications for therapy and patient prognosis. A more comprehensive understanding of the distribution of these molecular markers across the tumor could inform if some tumors deserved a different Ki67 score, if some patients are not receiving HER2-targeted therapy because of HER2 uneven expression across the tumor, and if PD-L1 could improve as a biomarker by considering its spatial expression. Conclusions: In summary, we present a novel approach to characterize spatial tumor heterogeneity directly from patient MRIs using the TS biophysical modeling platform. This technology is less time consuming and less costly than other approaches, making it accessible for use in hospitals at a larger scale.
Serum thymidine kinase 1 and its kinetics in HER2-positive breast cancer: Results from the Swedish phase II PREDIX HER2 trial.
Authors: Zhu Yajing , Wang Kang , Zerdes Ioannis , Matikas Alexios , Bergqvist Mattias , Elinder Ellinor , Bosch Ana , Lindman Henrik , Einbeigi Zakaria , Andersson Anne , Carlsson Lena , Dreifaldt Ann Charlotte , Isaksson-Friman Erika , Hellstrom Mats , Johansson Hemming , Bergh Jonas C. S. , Hatschek Thomas , Foukakis Theodoros
Published: June 2022

e12598

Background: Thymidine kinase 1 (TK1) plays a pivotal role in DNA synthesis and cellular proliferation. TK1 has been studied as a prognostic marker and as an early indicator of treatment response in HER2-negative early and metastatic breast cancer (BC). Here we present the first report of TK1 in HER2-postitive BC. Methods: In the PREDIX HER2 trial, 202 patients with HER2-positive BC were randomized to 6 cycles of neoadjuvant trastuzumab, pertuzumab and docetaxel or trastuzumab emtansine every three weeks followed by surgery and adjuvant epirubicin and cyclophosphamide. Serum was prospectively collected from all participants at multiple timepoints: At baseline, after cycles 2, 4 and 6, at end of adjuvant therapy and then annually for 5 years and in case of recurrence. TK1 activity was measured by DiviTum assay (Biovica, Sweden), blinded to treatment allocation, patient characteristics and outcome. TK1 activity was correlated with baseline characteristics, pathologic complete response (pCR) and event-free survival (EFS). Results: Baseline TK1 activity as categorical variable was not associated with tumor size or hormone receptor expression. An increase of TK1 activity was seen in the majority of cases after treatment (mean TK1 at baseline = 111.7, after cycle 2 = 1257.0, after cycle 4 = 1157.0, after cycle 6 = 1178.0). Neither baseline TK1, on-treatment TK1 nor its change from baseline to cycle 2 were significantly associated with pCR in multivariable logistic regression analysis (Table). Baseline TK1 activity was not predictive for differential benefit to the study treatments ( pinteraction = 0.19). After a median follow-up of 52.5 months, 21 patients had EFS events. There was no significant correlation between baseline TK1 activity and EFS in multivariable Cox regression analysis. Conclusions: Serum TK1 activity in HER2-positive BC increased following treatment with neoadjuvant therapy but was not correlated to pCR rates or EFS. [Table: see text]
Construction of a model for evaluating the efficacy of neoadjuvant chemotherapy for breast cancer and dynamic monitoring of ctDNA response to neoadjuvant chemotherapy.
Authors: Liu Zhaoyun , Yu Bo , Su Mu , Yuan Chenxi , Liu Cuicui , Yu Zhiyong , Yu Jinming
Published: June 2022

e12600

Background: Neoadjuvant chemotherapy (NAC) is a routine treatment of choice for patients with locally advanced breast cancer. The pathological complete response (pCR) to NAC in breast cancer is closely related to a better prognosis. In addition, there have been few studies of the role of ctDNA in the dynamic monitoring of NAC, so we explored the prediction model of NAC to predict pCR and evaluated the role of ctDNA in the dynamic monitoring of NAC. Methods: A total of 269 breast cancer patients receiving NAC were enrolled, and a total of 266 tissue samples were collected. The tissue samples were sequenced using a panel covering 457 cancer-related genes to construct a pCR prediction model after NAC. A total of 267 blood samples were collected from 56 patients. Blood samples were collected at the indicated time points: before NAC (T0), after the first NAC and before cycle two (T1), during intermediate evaluation (T2), and after the end of NAC but before surgery (T3). We constructed a model to predict pCR after NAC by mutated genes and clinical factors, analyzed ctDNA of blood samples according to the mutated genes of the prediction model, and detected the dynamic monitoring role of ctDNA in NAC to predict prognosis. The median follow-up time for survival analysis was 898 days. Results: A total of 192 patients were enrolled to construct the prediction model. There were 51 patients in the additional validation set. We analysed the somatic mutations of 192 samples and constructed a predictive NAC response model including 5 SNV mutations (TP53, SETBP1, PIK3CA, NOTCH4 and MSH2), 4 CNV mutations (FOXP1-gain, EGFR-gain, IL7R-gain, and NFKB1A-gain), and 3 clinical factors (luminal A, Her2+ and Ki67). Analysing the ctDNA of 267 blood samples through a unique panel composed of 9 mutant genes in the prediction model, it was found that ctDNA positivity decreased with the passage of time during NAC, the ctDNA positive rates of ctDNA from T0, T1, T2 to T3 were 46%, 14%, 13% and 10%, respectively. According to survival data, pCR patients did not have disease progression after NAC. Among the non-pCR patients who had disease progression, the probability of non-pCR in patients with ctDNA cleared at T1, T2, and T3 was significantly lower than that in patients with uncleared ctDNA. Interestingly, patients who failed to achieve pCR but were ctDNA negative had a similar risk of metastasis and recurrence as those who achieved pCR. Finally, we found that the prediction model combined with ctDNA could predict pCR after NAC. It had high sensitivity and specificity and the AUC value reached 0.961. Conclusions: This study established a predictive model for predicting pCR after NAC. At the same time, ctDNA dynamic monitoring found that ctDNA status could predict NAC response and metastasis recurrence. Combining the prediction model and ctDNA status could better predict the NAC results.
Utility of interval imaging during neoadjuvant treatment of locoregional breast cancer.
Authors: Chacko Rebecca , Li Pin , Abdel-Razeq Nayef Hikmat , Godbole Manasi , Dabak Vrushali S.
Published: June 2022

e12611

Background: National guidelines for breast cancer management do not recommend routine imaging during preoperative chemotherapy. Despite this, some clinicians use radiographic results as a surrogate marker of treatment response during the preoperative phase. In this retrospective investigation, we studied the correlation between neoadjuvant clinical decision making, midway imaging results and final pathologic responses. Methods: 394 patients with locoregional breast cancer who received neoadjuvant chemotherapy and definitive surgery within the Henry Ford Health System between 2015-2021 were included. Final pathologic response of patients who completed midway imaging were compared with patients who did not. The primary outcome was overall pathologic response rate. Results: Tumor histology and final pathologic response (PR) was compared in patients who received midway imaging (MI) to those who did not (Table). In the MI group, no statistically significant association between midway radiographic response and final PR was found (p = 0.078). Systemic treatment was changed in 14.7% of patients after MI, there was no association with treatment change and complete PR (p = 0.488), however none of patients who received a treatment change after MI had progressive disease on final PR, compared to 9.7% of patients who did not have a treatment change and had progressive disease on final PR (p = 0.035). Multivariate analyses showed no association between MI and complete PR, irrespective of the histological subtypes. 78.4% of patients had imaging at the end of systemic treatment, prior to surgery. Radiographic response on post-treatment imaging correlated with final PR (p < 0.001). Conclusions: This study did not detect an association between midway imaging during neoadjuvant therapy and a complete pathologic response in locoregional breast cancer, however a correlation was detected between post-treatment imaging response and final pathologic response. Changes to systemic treatment based on midway radiographic findings were not shown to improve the likelihood of complete pathologic response but may reduce risk of progressive disease. Based on this study, midway imaging should not be broadly ordered during preoperative treatment, unless there is concern for progressive disease, in which midway imaging may provide diagnostic benefit.[Table: see text]