bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor PD-L1 expression and gene panel mutational profile as outcome predictors of PD-1-based checkpoint inhibition therapy in metastatic melanoma: A prospective multicenter DeCOG study.
Authors: Ugurel Selma , Griewank Klaus , Horn Susanne , Herbst Rudolf , Terheyden Patrick , Utikal Jochen , Pföhler Claudia , Ulrich Jens , Kreuter Alexander , Mohr Peter , Gutzmer Ralf , Meier Friedegund Elke , Dippel Edgar , Sucker Antje , Placke Jan-Malte , Hadaschik Eva , Becker Jürgen C. , Weichenthal Michael , Schadendorf Dirk ,   Dermatologic Oncology Group (DeCOG)
Published: June 2021

9568

Background: PD-1 checkpoint inhibition (CPI) has recently advanced to one of the most effective treatment strategies in melanoma. However, since a considerable proportion of patients shows upfront therapy resistance, baseline predictive biomarkers of therapy outcome are needed. Methods: This prospective multicenter study included metastatic melanoma patients whose formalin-fixed paraffin-embedded tumor tissue samples taken prior to the start of a systemic non-adjuvant therapy of any line were analyzed for PD-L1 expression on tumor cells by immunohistochemistry (clone 28-8, DAKO) and for COSMIC-annotated oncogenic mutations by 29-gene panel sequencing (MiSeq, Illumina). Clinical baseline and follow-up data were collected within the DeCOG multicenter skin cancer registry ADOREG. Results: From 09/2015 until 10/2020, 706 enrolled patients from 15 centers were evaluable for the endpoints best overall response (BOR), progression-free (PFS) and overall survival (OS). Thereof, 540 patients received PD-1-based CPI as first systemic treatment after tumor tissue analysis. 197/540 patients tested positive for PD-L1 (cut-off = 5%) in pre-treatment tumors, and revealed a favourable BOR (objective response 34.4% versus 19.1%; p < 0.0001), PFS (median 10.4 versus 4.2 months; p < 0.0001) and OS (median 45.1 versus 18.8 months; p = 0.001) compared to patients with PD-L1 negative tumors. 47/540 patients presented oncogenic mutations of three or more genes in pre-treatment tumors, and revealed a favourable BOR (objective response 46.8% versus 32.1%; p = 0.041), PFS (median 15.1 versus 6.1 months; p = 0.008) and OS (median not reached versus 25.2 months; p = 0.027) compared to patients whose tumors showed mutations in two or less genes. Multivariable Cox regression including sex, primary site, non-adjuvant systemic pre-treatment, serum LDH, and ECOG performance state demonstrated tumor PD-L1 expression and gene panel mutational profile as independent predictors of survival upon treatment with PD-1-based CPI. In contrast, in 106/706 patients treated with BRAF/MEK inhibitors as first systemic treatment after tumor tissue analysis, no association was found between tumor PD-L1 expression or gene panel mutational profile and therapy outcome. Conclusions: PD-L1 expression quantification and gene panel mutational profiling provide useful outcome predictors of PD-1-based CPI therapy in metastatic melanoma patients.
Granulomatous and sarcoid-like immune related adverse events (irAEs) in melanoma patients following CTLA4 blockade adjuvant therapy: An analysis of 1670 high-risk patients.
Authors: Noor Arish , Yassine Ibrahim , Lee Sandra J. , Othus Megan , Moon James , Kirkwood John M. , Sondak Vernon K. , Ribas Antoni , Grossmann Kenneth F. , Tarhini Ahmad A.
Published: June 2021

9582

Background: Granulomatous and sarcoid-like lesions (GSL) affecting the skin, lungs, thoracic lymph nodes, eyes and other organs following treatment with immune checkpoint inhibitors (ICIs) have been described in sporadic reports in the literature but the true incidence is unknown. Methods: We sought to estimate the incidence of GSL in the context of prospectively conducted ECOG-ACRIN E1609 phase III adjuvant trial in high-risk resected melanoma (N=1670 patients) testing ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus high-dose interferon-α (HDI). Descriptive statistics were used to calculate the incidence. Results: Among 1670 total patients treated with ICIs or with HDI in E1609, 1034 were treated with ipilimumab and 636 with HDI. Six GSL cases were reported among 1670 total patients treated with ipilimumab or with HDI as summarized in the table along with the corresponding CTCAE grades. More cases were observed with ipi10, followed by ipi3 and HDI, respectively. Organs involved included skin and subcutaneous tissue (granuloma annulare, granulomatous dermatitis), eye (ocular sarcoidosis), lymph nodes (noncaseating granulomatous lymphadenitis), lung and mediastinal lymph nodes (sarcoidosis, granulomatous inflammation). Conclusions: The incidence of granulomatous and sarcoid-like lesions (GSL) with adjuvant ipilimumab therapy in high-risk melanoma is rare. Reported cases ranged in grade from 1-3 and appeared manageable. Since most cases are asymptomatic, it is possible that GSLs are under-recognized and therefore, under-reported. A larger analysis including patients treated with anti-PD1 antibodies is currently underway. Clinical trial information: NCT01274338. [Table: see text]
Retrospective analysis of HER2-low in young breast cancer patients.
Authors: Omar Abeid Mohamed Athman , Darwish Azza Mohamad Amin
Published: June 2021

e12515

Background: Traditionally, breast cancer (BC) is considered human epidermal growth factor receptor-2 (HER2) positive based on HER2 overexpression or amplification (HER2 3+ or ISH positive HER2 2+). However, an emerging subgroup of HER2 negative (HER2 1+ or 2+ and ISH negative) known as HER2-Low is associated with poor prognosis than HER2-normal (HER2 0). Currently, there is an increased interest in developing new drugs targeting HER2-Low BC to improve survival. The fact that BC in young constitutes a significant minority outside the western world but is underrepresented in clinical trials, it is worth conducting a dedicated study of HER2-low in this population to determine whether it affects their outcome. Methods: Confirmed HER2 negative BC patients aged ≤40 diagnosed in 2012-2017 were retrospectively reviewed in two centers in Alexandria, Egypt. Patients were classified as HER2-low (1+, 2+) and HER2-normal. The clinicopathological characteristics and survival outcome were determined and compared. Results: There were five hundred HER2 negative BC patients; 82% were hormone receptor-positive (HR+) vs.18% triple-negative (TNBC). Among the HER2 negative, only 31% were HER2-Low (n = 155), of which 20% was HER2-Low 1+ while 11% was HER2-Low 2+. In comparison, HER2-Low was significantly more HR+ than HER2-normal (89% vs. 79% respectively, p = 0.009). Other tumor characteristics (T-size, nodal status, Ki-67, lymphovascular invasion - LVI, extracapsular extension - ECE) were similar in HER2-Low and HER2-normal. So were the disease-free survival (DFS) and overall survival (OS). Nevertheless, sub-grouping HER2-Low into 1+ and 2+ showed significant differences in tumor characteristics between HER2-normal, HER2-Low 1+, and HER2-Low 2+, in nodal status, tumor stage, ECE, and HR status. Moreover, DFS was significantly lower in HER2-Low 2+ (63.5%) compared to HER2-normal (70%) and HER2-Low 1+ (75%); p = 0.039. Also, the OS was also significantly lower in HER2-Low 2+ compared to HER2-normal, 90% vs 96% respectively, p = 0.023. Conclusions: Our results suggest no significant difference in DFS and OS between HER2-Low and HER2-normal in young BC patients. However, subdividing HER-low into HER2-low 1+ and HER2-Low 2+ better discriminates this group; HER2-Low 2+ had significantly poor DFS and OS and this should be considered in the clinical trials.
Concordance between 21-gene score (Oncotype DX) and clinical-pathologic prognostic models in early-breast cancer in Medellín, Colombia.
Authors: Lujan Mauricio , Lema Mauricio , Moran Diego , Preciado Beatriz , Egurrola Jorge , Lema Camila
Published: June 2021

e12521

Background: The genomic-based 21-gene recurrence-score assay (Oncotype DX, Genomic Health)(ODx) is used to decide on the use of adjuvant chemotherapy (ACT) in luminal-type Early-Breast Cancer (LT-EBC). Patients with low RS can safely avoid ACT. Other predictive models based on standard clinical and histopathological (C&H) variables also have been developed. These include, Magee equations (ME), Predict model (PM), and Tennessee nomogram score (TNS). This study aims to establish the concordance between ODx and ME, PM and TNS models in a set of patients with EBC in Medellín, Colombia. Methods: Patients with unifocal, stage I and IIA, LT-EBC (HR+/Her2-) with results for ODx were included. For inclusion, key standard C&H variables needed to be available as to allow accurate assessment of ME, PM and TNS predictive models. ODx was used as the reference test and the predictive models as index tests. Low-risk (LR) was defined < 18 in all three ME; < 3% in the PM; and a probability calculated for LR > 90% in the TNS. A second analysis was performed in the > 50 years-old cohort (+50C), using standard and a modified criteria. In the last one, intermediate-risk (IR) patients were either excluded or grouped with high-risk scores for analysis. Concordance between the models and the ODx was evaluated using Cohen's kappa index (K). The degree of concordance was classified according to the categories established by Landis and Koch. AUROC (area under receiver operating characteristics) was estimated. Statistical analyses were performed with Stata v16. Results: 122 patients were included. Median age: 58 (IQR 49-66). Main histology was ductal carcinoma (85.2%), and median size was 15 mm (IQR 10-20). LR was adjudicated in 80.3%, 57.4%, 89.3% and 69.7% with ODx, ME, PM and TNS, respectively. Concordance between the ODx and ME and PM in the all patient population was fair, with K of 0.35 (95% CI: 0.18-0.50; p < 0.001), and 0.24 (95% CI: 0, 04 - 0.45; p < 0.001), respectively. Concordance of ODx and TNS was inferior with a K of 0.16 (95% CI: 0.03-0.34, p = 0.04). AUC for ME, PM, and TNS was 0.61 (95% CI: 0.49-0.73), 0.61 (95% CI: 0.52-0.70) and 0.59 (95% CI: 0.48-0.70), respectively. 85 patients were included in the +50C (69.7%). For one analysis, 41 patients with IR with either ME or PM were excluded. Concordance between the ME and the ODx was fair. LR in both ME and ODx was found 41/43 patients (95.5%, 95% CI 87.9-100). As for PM and TNS, the degree of concordance with ODx were low, and non-significant, respectively. Concordance between ODx LR was found in 36/37 patients with LR in all three ME, PM and TNS (97.3%, 95% CI: 90.7-100). Discrimination capacity: 79%. Conclusions: The high cost of ODx can be safely avoided in stage I/IIA luminal-type EBC and > 50 year-old with low-risk scores in all three ME, PM, and TNS.
Predominance of the luminal B molecular subtype in a group of women with infiltrating breast ductal carcinoma in the Colombian coffee region: Analysis by immunohistochemistry.
Authors: Toro Paula , Pava-De Los Rios Juliana , Pava-Ripoll Alex Enrique , Chica Sebastian , Perez Edgar , Villegas Manuel , Preciado Juan Paulo , Celis Camilo , Mejía Andrés Felipe
Published: June 2021

e12571

Background: Breast cancer is the most common cancer in women and constitutes a public health problem due to its high rates of morbidity and mortality. Diagnosis is made through routine histopathology studies that are complemented by phenotypic expression studies of hormone receptors (estrogen and progesterone receptors), human epidermal growth factor 2 (HER2) and cell proliferation index (Ki67) for their subtyping into molecular groups (luminal A, luminal B, Her2, and triple negative), which have different prognostic and therapeutic implications. Globally, a high prevalence of the Luminal A subtype has been reported, predominantly in North America, Europe, and some Latin American countries; however, the reports in the Colombian population are heterogeneous. The objective of this research is to establish an incidence profile of these molecular subtypes in a population of the coffee region in Colombia. Methods: Samples of 377 patients with a diagnosis of infiltrating breast cancer were collected retrospectively between 2015 and 2018. Inclusion criteria included: 1) Availability of personal data (year of diagnosis and age) 2) Infiltrating breast carcinoma. 3) Diagnosis between 2015 and 2018. 4) Study of complete immunohistochemistry and/or in situ hybridization (ISH) markers. Results: The histological subtypes included: NOS infiltrating ductal carcinomas (339 cases; 89.9 %), infiltrating lobular (23 cases; 6.1 %), infiltrating mucinous (6 cases; 1.5 %), infiltrating papillary (1 case; 0.2 %) and mixed patterns: ductal - lobular (3 cases; 0.7 %) and mucinous - ductal (5 cases; 1.3 %), of whom 56.2% (212 cases) correspond to luminal B, 22.2% (84 cases) to Luminal A, 14.8% (56 cases) to triple negative and 6.6% (25 cases) to HER2. Conclusions: These findings contrast with the prevalence reported worldwide. Therefore, in the population of the Colombian coffee region, this predominance of the molecular subtype luminal B should be considered when establishing prognosis and treatment plan by the medical staff.
MELK is a downstream target of Del-1 and promotes breast cancer progression.
Authors: Lee Soo Jung , Chae Yee Soo , Lee Jeeyeon , Kang Jieun , Kim Eun Ae , Jung Jin Hyang , Park Ho Yong , Lee In Hee
Published: June 2021

e12578

Background: Del-1 is a promising prognostic marker for breast cancer in our previous study. However, the downstream targets and biological effectors of Del-1 remain unclear and still untargetable in breast cancer. We performed transcriptome analysis using RNA-seq and explored the mechanism of Del-1 in regulating the progression of breast cancer to find druggable target. Methods: Total RNA was isolated using RNAiso Plus (TaKaRa, Otsu, Shiga, Japan), Libraries were prepared from total RNA using the NEBNext Ultra II Directional RNA-Seq Kit. High-throughput sequencing was performed as paired-end 100 sequencing using NovaSeq 6000 (Illumina, Inc., USA). OTSSP167(OTS167) were treated for inhibition of MELK. The effects of MELK on cell proliferation, invasion were determined using MTT, Matrigel Transwell assays. The tumoral expression of Del-1 and MELK were determined based on tissue microarrays and immunohistochemistry results from 440 early breast cancer patients. Results: To investigate Del-1 downregulation effect on breast cancer, we performed RNA-seq of Del-1 knock downed MDA-MB-231 and MCF 7-Tamoxifen resistant (TamR) cell line. Compared with si-control, MELK gene were downregulated in both knock downed cell lines. While a high Del-1 and MELK mRNA expressions were found in all the breast cancer cell lines, both expressions were significantly higher in MDA MB-231. MELK inhibitor (OTS167) treatment to breast cancer cell line MDA-MB-231 and MCF 7-TamR showed similar results as Del-1 down regulation by si-RNA. Inhibition of MELK suppressed proliferation and invasion of breast cancer cell line. Tumoral MELK expression correlate with increased aggressiveness and poor clinical outcomes in 440 breast cancer patients. Conclusions: Our results indicate that Del-1 may regulate MELK expression which has a role in breast cancer progression. In conclusion, modulation of Del-1 status by targeting MELK may be a new therapeutic strategy for breast cancer patients.
Long-term outcomes and predictors of recurrence in patients with early-stage node negative breast cancer.
Authors: Dogan Izzet , Aydin Esra , Paksoy Nail , Ferhatoglu Ferhat , Ak Naziye , Ibis Kamuran , Onder Semen , Tukenmez Mustafa , Cabioglu Neslihan , Muslumanoglu Mahmut , Saip Pinar , Aydiner Adnan
Published: June 2021

e12597

Background: In this study, we aimed to assess the outcomes, and predictors of recurrence in patients with early-stage node-negative breast cancer. Methods: We evaluated data of the patients who were treated between 1988 and 2018 years retrospectively. Demographical, clinical, pathological, and treatment features of the patients were recorded. SPSS 25 version was used for statistical analysis. We used Kaplan-Meier and Cox regression analysis to assess survival analysis. Also, we performed logistic regression and ROC analysis for recurrence predictors. Results: In total, 347 patients were included in the study.The median age was 50 (range, 18-81) at diagnosis. The percent of the patients who had stage 1 and 2 were 86.6% and 13.4%, respectively. The most common histopathological type was invasive ductal carcinoma (71.6%). Estrogen receptor and progesterone receptor positivity were 80.3% and 62.1%, respectively. Her2 receptor positivity was 15.9%. The number of patients who had undergone lumpectomy and mastectomy was 85.5% and 14.5%, respectively. Sentinel lymph node biopsy was performed on 78.7% of the patients, and axillary lymph node dissection 21.3%. Also, the patients received adjuvant radiotherapy (88.7%), adjuvant chemotherapy (48.5%), and adjuvant hormonotherapy (82.1%). Tumor recurrence was occurred in 31 (8.7%) patients (local recurrence-45.2% and metastasis-54.8%). Five-, ten- and twenty-years recurrence ratios were 4.3%, 8%, and 23%. Also, contralateral breast cancer has occurred in 19 (5.3%) patients. During the study period, 30 (8.4%) patients died. Ten-years and twenty-years survival ratios were 91.6% and 76.6%, respectively. In univariate analysis, aged over 65 years (p = 0.004), nuclear pleomorphism (p = 0.049), mitosis (p = 0.003), and necrosis (p = 0.002) were statistically significant for recurrence. In ROC analysis, the tumor's longest size was not statistically significant for recurrence (for over 1.45 cm, p = 0.07). Conclusions: In this study, we determined thirty-years outcomes in patients with early-stage node-negative breast cancer. In the follow-up, we detected the recurrences ratios, between ten and twenty years, were more common than the first ten-years. Despite a small number of patients who had a recurrence, we showed that being age over 65 years and pathological features (nuclear pleomorphism, mitosis, and necrosis) were statistically significant for disease recurrence in univariate analysis.
Chemotherapy-elicited exosomal miR-378a-3p and miR-378d to promote breast cancer stemness and chemoresistance via the activation of EZH2/STAT3 signaling.
Authors: Zhang Jin
Published: June 2021

e12615

Background: Not all breast cancer (BC) patients who receive neoadjuvant chemotherapy achieve a pathologic complete response (pCR), but the reasons for this are unknown. Previous studies have shown that exosomes produced in the tumor microenvironment in response to chemotherapy promote a chemotherapy-resistant phenotype in tumors. However, the role of BC chemo-elicited exosomes in regulating chemoresistance is poorly understood. Methods: Using commercial kits, serum exosomes were extracted from patients before neoadjuvant chemotherapy, after one cycle of chemotherapy and after four cycles of chemotherapy consisting of doxorubicin (DOX) and paclitaxel (PTX). Their miRNAs were sequenced, and the correlation between the sequencing results and chemotherapy effects was further verified by RT-qPCR using patient serum exosomes. Cell Counting Kit-8 (CCK-8) was used to detect chemosensitivity. Stemness was assessed by CD44+/CD24- population analysis and mammosphere formation assays. Chromatin immunoprecipitation (ChIP) experiments were performed to verify the binding of signal transducer and activator of transcription 3 (STAT3) to the promoter of miRNAs. Results: Here, we provide clinical evidence that chemotherapy-elicited exosomal miR-378a-3p and miR-378d are closely related to the chemotherapy response and that exosomes produced by BC cells after stimulation with DOX or PTX deliver miR-378a-3p and miR-378d to neighboring cells to activate WNT and NOTCH stemness pathways and induce drug resistance by targeting Dickkopf 3 (DKK3) and NUMB. In addition, STAT3, which is enhanced by zeste homolog 2 (EZH2), bound to the promoter regions of miR-378a-3p and miR-378d, thereby increasing their expression in exosomes. More importantly, chemotherapeutic agents combined with the EZH2 inhibitor tazemetostat reversed chemotherapy-elicited exosome induced drug resistance in a nude mouse tumor xenograft model. Conclusions: This study revealed a novel mechanism of acquired chemoresistance whereby chemotherapy activates the EZH2/STAT3 axis in BC cells, which then secrete chemotherapy-elicited exosomes enriched in miR-378a-3p and miR-378d. These exosomes are absorbed by chemotherapy-surviving BC cells, leading to activation of WNT and NOTCH stem cell pathways via the targeting of DKK3 and NUMB and subsequently resulting in drug resistance. Therefore, blocking this adaptive mechanism during chemotherapy may reduce the development of chemotherapy resistance and maximize the therapeutic effect.
Impact of pre-treatment lymphocyte monocyte ratio and neutrophil lymphocyte ratio on pathologic response in breast cancer patients receiving neoadjuvant chemotherapy.
Authors: Mosalem Osama , Alsubait Saud , Kherallah Shouq , Gogineni Venumadhavi , Wang Ling , Rana Jatin , Isaac Daniel
Published: June 2021

e12623

Background: Hematologic markers have been looked at as potential prognostic biomarkers in a variety of cancers. Ni and colleagues (2014) have shown that an elevated pre-treatment lymphocyte-to-monocyte ratio (LMR) was significantly associated with improved disease-free survival (DFS) in patients with locally advanced breast cancer receiving neoadjuvant chemotherapy (NACT). Given the prognostic implications of hematologic inflammatory parameters, we sought to understand if such biomarkers will predict response to neoadjuvant chemotherapy (NACT) in patients with breast cancer. Methods: We conducted a retrospective review of breast cancer patients treated with NACT at our institution (2008-2018). Data on patient characteristics, stage, pathologic characteristics, and blood counts were collected. Blood parameters prior to NACT were used to calculate LMR and neutrophil-to-lymphocyte ratio (NLR). To test the impact of LMR and NLR on pathologic response, a two sample mean test was used first as univariate analysis. Next, logistic regression was employed for multivariate analysis controlling for patient characteristics with interaction of LMR and NLR with ER, PR and HER2 status. Results: A total of 50 patients were included. 38% of patients achieved a pathologic complete response (pCR). The mean LMR was 3.69 (1.4-12.5), and the mean NLR was 2.55 (0.66 – 9.31). On univariate analysis, a high NLR was associated with a higher likelihood of achieving a pCR (OR = 1.64, 95% CI = 1.01-2.63). A high LMR was associated with a higher likelihood of pCR; however, this was not statistically significant (OR = 1.08, 95% CI = 0.78-1.47). On multivariate analysis, patients with HER-2 positive disease with a high LMR had a significantly higher chance of having a pCR (OR = 1.72, 95% CI = 1.06-2.78). Conclusions: Our study showed that NLR was a predictor of pCR in breast cancer patients receiving neoadjuvant chemotherapy. A high NLR was associated with achieving a pCR on univariate analysis. Multivariate analysis suggested that HER-2 positive disease with a high LMR had a significantly higher chance of achieving a pCR. The results of this cohort correlate with previous reports by others showing that pre-NACT LMR and NLR provide prognostic information in patients with breast cancer. Although limited by sample size, this adds to the growing body of literature supporting peripheral blood counts as a biomarker for outcomes in breast cancer.
Modeling shows the NK3R antagonist, ACER-801, reduces treatment-induced vasomotor symptoms.
Authors: Baillie Rebecca , Schelling Chris , Ridgewell Rick , Kudrycki Katherine , Chung Douglas , Friedrich Christina , Reed Mike
Published: June 2021

e13013

Background: Hot flashes or vasomotor symptoms (VMS) are a common side effect of hormone deprivation (HD) therapy. Up to 80 % of cancer patients treated with tamoxifen (antiestrogen treatment) or leuprolide (androgen deprivation) have VMS. In some cases, patients discontinue HD therapy due to VMS severity and lower quality of life; therefore, reducing VMS is critical for patient compliance. NK3 receptor (NK3R) antagonists have previously been shown to reduce VMS in postmenopausal women. ACER-801 is a candidate NK3R antagonist drug intended to alleviate VMS severity when used with HD therapy. We used Quantitative Systems Pharmacology (QSP) modeling to predict the likely efficacy of ACER-801 in patients on HD therapy and evaluate the potential of hepatic drug-drug interactions between ACER-801 and tamoxifen or leuprolide. Methods: The model is composed of KNDy neurons in the arcuate nucleus with NKB, dynorphin, and estradiol effects on KNDy neurons, HPG axis, sex hormones, and neuroendocrine feedback. ACER-801, tamoxifen, and leuprolide PK, PD, and hepatic metabolism are included in the model. The model was developed, qualified, and tested using literature data. A tamoxifen-treated postmenopausal female virtual patient (VP) and leuprolide-treated male VP were created based on typical patients included in clinical trials. VMS severity and frequency were estimated based on the level of NKB binding to NK3R. Results: In the male VP, simulated leuprolide administration induced hypertrophy of KNDy neurons and VMS over six months. Coadministration of ACER-801 with leuprolide reduced VMS frequency and severity to near 0 in short-term (5-week) simulations. Simulations predict ACER-801 will not alter leuprolide metabolism nor increase plasma testosterone concentrations. Tamoxifen treatment increased VMS by 15% in simulations with the postmenopausal VP. Coadministration of ACER-801 with tamoxifen in this VP reduced VMS by 75% compared to tamoxifen monotherapy. ACER-801 had minimal effects on plasma estradiol concentrations in the postmenopausal VP. Drug-drug interactions between ACER-801 and tamoxifen were dependent on the simulated bioavailability of ACER-801. Using current estimates of ACER-801 bioavailability in the model, the hepatic concentration of ACER-801 had limited effects on tamoxifen metabolism, which are not expected to necessitate dose adjustments. Conclusions: Using a QSP neurobiology model as a research tool enabled us to evaluate the efficacy of the NK3R antagonist, ACER-801, to treat HD therapy-induced VMS. Simulations show ACER-801 may be highly efficacious for the treatment of induced-VMS. The research provided estimates of DDI with ACER-801 and tamoxifen and what clinical experiments would be needed to confirm those estimates.
Single center observational study of the efficacy of chemotherapy in breast cancer patients treated before and after the widespread use age of CD4/6 inhibitors: Is there evidence that chemotherapy response is impacted by prior use of CD4/6 inhibitors?
Authors: Hogg Martin S. , Mugisa Tweisge , Gaur Smriti
Published: June 2021

e13019

Background: Recently CD4/6 inhibitors have radically changed treatment pathways, leading to a deferment of chemotherapy for advanced disease. Patients still relapse following this treatment; we wish to share our experience of chemotherapy both before and after this change and explore whether there is a change in efficacy. In England CD4/6 inhibitors are prescribed according to the guidelines set out by NHS England (NICE), and are generally utilised in the first line setting unless there is visceral crisis. Methods: This is a retrospective double cohort observational single centre study comparing the efficacy of a chemotherapy regimen (vinorelbine and capecitabine vin cap) before and after the incorporation of CD4/6 inhibitors into breast cancer treatment (Jan 2017- Nov 20). The doublet chemotherapy is widely used at our centre providing a well tolerated and effective alternative to intravenous treatments such as taxanes or single agent capecitabine. Data was collected contemporaneously using e prescribing software and audited retrospectively Results: In the audit period n=19 treated with cap, n= 97 with vin cap, n= 24 treated with CD4/6, (of whom 5 relapsed). 5 patients received abemaciclib first line, as initial therapy, all G3, stage 11A or above, median number of cycles 4.2, I received ribociclib, G2, stage 111A, 7 cycles and 17 received palbociclib, 10 first line, 4 following 1 course chemo, 2 after 2 courses and 1 and after 3 courses, 30% G3 and 70% G2, mean number of cycles 11.06. Patients who received first line cap progressed after a median of 3.5 cycles, with a range of 0-22 months (RR= 47%), for cape vin a median of 8.6, a range of 0-60 months (RR=77%), post CD4/6 mean of 8, median of 9, a range of 0-17 (RR=80%). Conclusions: Those post CD4/6 requiring chemo relapsed far short of the median TTP of around 26months and may have specific characteristics predicting poor response to CD4/6. Despite small numbers salvage chemotherapy remains effective with similar responses. First line vin cap is more efficacious and better tolerated than Cap.[Table: see text]
Ki67 and PR to predict sensitivity of palbociclib: A real-world study.
Authors: Shao Xi-Ying , Shen Xia-Bo , Li Guang-Liang , Zheng Ya-Bing , Cao Wen-Ming , Chen Zhan-Hong , Wang Xiao-Jia
Published: June 2021

e13032

Background: Palbociclib combined with endocrine therapy are approved as a front-line treatment for hormone receptor (HR)-positive, HER2-negative advanced breast cancer (ABC). A key challenge remains to uncover biomarkers to identify those patients who may benefit from palbociclib treatment. Methods: We retrospectively analyzed the values of Ki67 and progesterone receptor (PR), detected by immunohistochemistry, in 81 ABC patients with palbociclib and hormone therapy treatment, and evaluated the impact on progression-free survival (PFS). Results: In total population, women with Ki67≥14% had marginal significant shorter PFS than those with Ki67<14%. Patients with Ki67≥30% had significant shorter PFS than those with Ki67<30% ( P=0.048). While PR≥ 20% was associated with longer PFS. And what’s more, the change trend of Ki67 or PR from primary tissue to metastatic lesions was related to PFS. In regard with hormone therapy subgroup, there were significant association between Ki67 and PR levels and PFS in aromatase inhibitors (AIs) subgroup. Patients with Ki67≥14% or Ki67≥ 30% had shorter PFS than those with Ki67<14% or Ki67<30%, respectively ( P=0.024, P <0.001). Additionally, the change trend of Ki67 or PR from primary tissue to metastatic lesions was related to PFS. When both Ki67 and PR are considered, there were significant differences between different cohort. Compared with those with Ki67≥14% and PR <20%, patients with Ki67<14% and PR≥20% had significant longer PFS. In addition, patients with Ki67<30% and PR≥20% had significant longer PFS than those with Ki67≥30% and PR<20%. Besides, in AIs cohort, patients with Ki67<14% and PR≥20% had significant longer PFS than those with Ki67≥14% and PR <20%. Women with Ki67<30% and PR≥20% had significant longer PFS than those with Ki67≥30% and PR<20%. Conclusions: The present study indicates that both Ki67 and PR have a greater impact on palbociclib and hormone therapy and may help selecting a more effective partner of palbociclib.
Relative risk of hepatotoxicity associated with cyclin-dependent kinase inhibitors (CDK4/6i): A systematic review and meta-analysis of phase 3 randomized controlled trials.
Authors: Jahan Nusrat , Wongsaengsak Sariya , Rehman Shabnam , Adhikari Nimesh , Tijani Lukman Aderoju , Raghunath Arrvind
Published: June 2021

e13037

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) such as palbociclib, abemaciclib, and ribociclib have changed the landscape of management of estrogen receptor-positive and HER2-negative breast cancer in recent years. We conducted a systematic review and meta-analysis of phase 3 randomized controlled trials (RCTs) to determine the relative risk of hepatic dysfunction associated with the use of CDK4/6i. Methods: We conducted a systematic search using PRISMA guidelines in PubMed, EMBASE, American Society of Clinical Oncology (ASCO) and San Antonio Breast Cancer Symposium meeting abstracts from inception through Jan 30, 2021. Phase 3 RCTs using CDK4/6i in the intervention arm and reporting the number of events for elevation of liver enzymes were included in the analysis. The Cochran-Mantel-Haenszel method and random effects model were used to calculate the pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested by Cochran’s Q test and I2 value. Results: Nine phase 3 RCTs — MONALEESA-2, MONALEESA-3, MONALEESA-7, MONARCH 2, MONARCH 3, MONARCH plus, monarchE, PALOMA-2, and PALOMA-3 — randomizing 5,809 patients in the CDK4/6i arms and 4,638 patients in the control arms were included in the analysis. The CDK4/6i arms used CDK4/6i such as palbociclib, abemaciclib, or ribociclib in combination with one of the standard-of-care endocrine therapies such as letrozole, anastrozole, tamoxifen, or fulvestrant. The control arms received placebo along with respective endocrine therapies. The incidence of any grade alanine aminotransferase (ALT) elevation was 13.1% in the CDK4/6i arm and 5.4% in the control arm, pooled RR: 2.18, 95% CI: 1.74-2.72, P < 0.00001, I2 = 45%. The incidence of any grade aspartate aminotransferase (AST) elevation was 12.5% in the CDK4/6i arm and 5.3% in the control arm, pooled RR: 2.00, 95% CI: 1.57-2.54, P < 0.00001, I2 = 57%. The incidence of grade 3/4 ALT elevation was 4.1% in the CDK4/6i arm and 0.8% in the control arm, pooled RR: 4.43, 95% CI: 3.08-6.37, P < 0.00001, I2 = 0%. The incidence of grade 3/4 AST elevation was 2.9% in the CDK4/6i arm and 0.9% in the control arm, pooled RR: 2.70, 95% CI: 1.75-4.19, P < 0.00001, I2 = 29%. No fatal case of hepatotoxicity has been reported. Conclusions: Cyclin-dependent kinase 4/6 inhibitors are associated with significant risk of any grade and grade 3/4 hepatic enzymes elevation. Regular monitoring of liver function is a key to early detection and initiation of appropriate management.
Telemedicine use and satisfaction amongst radiation oncologists during the COVID-19 pandemic: Evaluation of current trends and future opportunities.
Authors: Deshane Alok , Damico Nicholas , Kharouta Michael , Wu Anna , WANG GI-Ming , Machtay Mitchell , Kumar Aryavarta M. S. , Choi Serah , Bhatt Aashish D.
Published: June 2021

e13503

Background: During the COVID-19 pandemic telemedicine became an attractive alternative to in person appointments. The role of telemedicine in patients who undergo frequent on site treatment, such as radiation therapy, is unclear. The purpose of this study was to examine telemedicine use, physician satisfaction and barriers to continued use in radiation oncology. Methods: An anonymous, electronic survey was distributed to radiation oncologists internationally. Participants described demographic and practice characteristics and a 5 point Likert scale assessed provider satisfaction, ease of use and overall utility of telemedicine. Analyses include descriptive statistics and subgroup comparisons using Chi-square and Fisher’s exact test. Results: 232/5343 (4.3%) completed the survey, 63.8% of whom were male, 52.6% age 50 or younger and 78.0% from the United States (U.S.). Only 14.2% used Telemedicine previously, which increased to 93.1% during COVID-19. Amongst all telemedicine users, usage rates were 77.9% for initial consultations, 97.2% for follow-up visits, and 35.9% for on-treatment visits. 69.8% report that <25% of patients requiring treatment experienced delays due to COVID-19. Most conducted appointments from the workplace, with 40.1% also doing so from home. Satisfaction was high at 73.8%, perceived usefulness was 76.9% and 81.5% hope to continue using telemedicine after the pandemic. However, 82.4% had concerns with the inability to examine patients. Although 82.1 % believed that telemedicine would improve patient access to health care services overall, 63.0% were concerned with patient ability to access required technology. 49.5% had concerns regarding continued billing/reimbursement; less commonly at government centers (18.8%) compared to academic/satellite facilities (52.7%) and free-standing centers/community hospitals (50.7%), p=0.039 for both comparisons. These concerns were also significantly higher amongst US physicians (53.2% vs 34.9%, p=0.048). Conclusions: Widespread adoption of telemedicine by radiation oncologists occurred during COVID-19 with high rates of satisfaction and interest in continued use. Sustained reimbursement for telemedicine services is a significant concern, particularly in the US and outside of government facilities. [Table: see text]
Evaluation of patient navigation and delivery of head and neck cancer therapy during COVID-19 pandemic: A single institution experience.
Authors: Cervantez Sherri Rauenzahn , Mesa Ruben A. , Viles Jeremy , Salazar Mary , Villarreal Leslie , Bonnen Mark , Asper Joshua
Published: June 2021

e13510

Background: The COVID-19 (COVID) pandemic presents many challenges to cancer patient treatment. Care coordination pathways are more complex to ensure safe screening and monitoring for COVID while reducing person-to-person interaction. The oncologic management of head and neck cancer (HNC) involves an interdisciplinary workflow. Time from diagnosis/specialized oncologic referral to initiation of treatment is critical for optimal outcomes. The insertion of any additional rate limiting factor could drastically increase the timeliness to care. Our study evaluates the effectiveness of patient navigation and the impact of institutional COVID process on timeliness to treatment. Methods: Operational workflow changes were set in place with goal of obtaining COVID testing prior to initiation of therapy. Patients with COVID symptoms after initial clearance were subjected to additional COVID testing. COVID screening was obtained in a single location when feasible. COVID positive or patients with pending results were triaged to determine risk/benefits of delaying treatment initiation and CDC guidelines for safe administration of therapy were considered. Patients with pending or positive results, but acute situation, were treated after hours in full PPE gear in order to reduce exposure risks. Results: Navigation information for 88 HNC patients were collected from 1/1/20 to 1/1/21. All patients were treated with curative intent. COVID testing data were collected contemporaneously with the pandemic from 4/1/20 to 1/31/21. Thirty patients with HNC required coordination of CMT and completed COVID screening test an average of 19 days prior to the start of therapy (29 negative; 1 positive). Two (6%) patients received their screening results after therapy initiation. Four patients did not complete therapy (13%); 26 completed (86%). Patients treated with radiation averaged 31 treatments (range 30-35) each treatment indicative of an aerosolized risk exposure. Each infusion representing and aerosolized and IV risk exposure. During the course of care we experienced zero patient-to-staff contracted COVID positives. Five staff members tested positive for COVID however contact tracing indicated outside source. Prior to the pandemic, average time from referral to appointment (TRA) with oncology specialist was 14.62 days, time from first appointment with oncology specialist to first treatment modality (TAT) was 46.29 days, and time from referral to our center and initiation of first treatment (TRT) was 60.91 days. During the pandemic, from March 2020 to May 2020, average TRA was 10.51 days, TAT was 24.09 days, and TRT was 34.6 days. Conclusions: Appropriate navigation, protocols and team vigilance resulted in improved timeliness to treatment. Continued delivery of oncologic care to HNC patients can be achieved without increased patient or staff risk for contraction of COVID.
Can acute care utilization be reduced by a risk score-based intervention alone?
Authors: Csik Valerie Pracilio , Binder Adam F , Handley Nathan , Li Michael , Croyle Megan , Waldman Lauren , Worster Brooke
Published: June 2021

e13523

Background: Acute care utilization (ACU), encompassing both emergency department visits and hospitalizations, is common in patients with cancer, with nearly three quarters of patients with advanced disease hospitalized at least once in the year after their diagnosis. From a population health perspective, focusing on the highest risk patients is likely to identify the top 5% while the next 30% can be considered rising risk and are likely to need care management support. Many risk scoring systems have been developed, but few have demonstrated effective integration in clinical practice. We sought to evaluate if a risk assessment tool alone was adequate to determine an appropriate patient outreach strategy that results in reduced ACU. Methods: We utilized the REDUCE score (Reducing ED Utilization in the Cancer Experience - see 2020 ASCO Quality Abstract 208) to develop an intervention conducted in two phases. Phase I included a chart review and targeted outreach to high risk patients identified by REDUCE by a nurse navigator. Outreach resulted in communication of patient needs to the care team. Phase II involved initial identification by REDUCE followed by further screening assessment with a distress screen. Those who were high risk and had high distress (score ≥4) were discussed by an interdisciplinary team (supportive medicine physicians, social work, nurses, nurse practitioners) to determine an intervention. Results: Of the patients in phase I (N = 138), 26.1% had ACU afterward, while in phase II (N = 169) 7.1% had ACU. The average distress score among all patients in the phase II group was 6.0 and the REDUCE score was 2.87, while the subset of patients who experienced ACU had an average distress score of 6.4 and a REDUCE score of 3.22. These findings indicate that there is a directional correlation between REDUCE score and distress screening results. Conclusions: The REDUCE score may be a valuable tool to assist in identifying patients at risk for ACU, but the significantly less ACU in phase II compared to phase I suggests that the risk score combined with a biopsychosocial screening, such as distress as required by the Commission on Cancer, may prove more valuable than the risk score alone. To identify the most impactful intervention, and to fully understand the implications of a patient’s specific REDUCE score within the high risk category, additional assessment would be beneficial. These preliminary results highlight that directionally correlated measures obtained from a biopsychosocial screening in combination with a risk score gives a more complete picture of patient’s overall risk of ACU.
Geolocation of uterine cervical neoplasms (UCN) in the context of a prevention program in Tucumán, Argentina.
Authors: Holgado Silvia Victoria , Vinuales Ana , Goroso Daniel Gustavo , Watanabe William Tsutomu , Zarba Juan Jose , Gonzalez Adriana , Bliss Natalia , Vega Italia
Published: June 2021

e13535

Background: : UCN is one of the major public health problems in Tucumán, that must be related to the type of population to which it belongs (Rural or Urban). Geolocation allows the processing and analysis of geographic information whose results support decision-making in solving complex planning and management problems on the territory. The objective of this study is to carry out management quality controls of the PPCCUT (Programa de Prevención de Cáncer Cervical Uterino-Tucumán) to achieve adequate prevention and detection of uterine cervical lesions in the province. Methods: An observational cross-sectional study of 1343 women, (16-90 years), with a biopsy diagnosis UCN, under PPCCUT (years 2013-2020). Preanalytical work: allowed the review quality the registries and the diagnoses follow-up. Data recollection from SITAM (Online Information System for Screening), population registry database. Variables: Address: registered in SITAM, joined by information from the provincial female electoral roll 2019. Histological Diagnosis: High grade squamous intraepithelial lesion (HSIL), Invasive Squamous Carcinoma (ISC), Adenocarcinoma In situ (AIS), Invasive Adenocarcinoma (IDA). Analytical work: The conversion from address to latitude and longitude was performed by programming Google Sheet. This data was segmented by hospital center and opened in layers inside QGIS, as well as the map of Argentina. Results: Preanalytical. Register showed from 1343 patients received 1748 biopsies, were excluded 160 without address (incomplete data loading by the effectors). Lack of coordination in diagnosis area: 33 patients received first “in situ diagnosis” and in a short time later were consider “invasive lesions”. Some Patients had 2 bis 6 biopsies with same diagnosis. Analytical (geolocation): showed the influence of PPCCUT outside the province, including living abroad. It was found correlation between patients’ distribution with the population density. Conclusions: The importance of the work lays in the lack of antecedents in the application of the geolocation tool in programs of UCN in Tucumán and in other regions of Argentina. This allowed monitoring in different aspects of the programmatic management.
Cancer patients diagnosed with COVID-19 infection: A multicenter retrospective cohort of nine Brazilian cancer centers.
Authors: Padua Tiago Costa de , Monteiro Mariana Ribeiro , Almeida Kaique , Souza Camila Brambilla , Pezzutti Daniela , Borges De Andrade Maria Clara , Maiolino Angelo , do Carmo Rafael Luis Moura Lima , Freitas Tuane Borges do Livramento , Longo Cecilia , Perdigao Maria Carolina Lopes , Ferreira Cynthia Lemos , Sousa Tercia Tarciane Soares de , Cruz Sueli Monterroso da , Kinupe Abrahao Ana Beatriz , Piotto Gustavo Henrique Munhoz , Vieira Fernando Meton de Alencar Camara , Araujo Luiz H.
Published: June 2021

e13600

Background: The COVID-19 infection was declared pandemic in March 2020. Since then, multiple studies have attempted to correlate clinical factors with risk of complications from COVID-19, including cancer. However, cancer patients are underrepresented in clinical trials and the results vary between different cohorts. Methods: We conducted a multicentre retrospective study, based on systematic review of medical records, including nine cancer centers, located in five different Brazilian cities. Patients were diagnosed with COVID-19 through RT-PCR between March 15, 2020 and August 13 , 2020. Poisson regression models were then used to test for an association between clinical characteristics and severity of COVID-19 infections. Results: 102 patients had data collected for analysis, 85 (83.3%) of whom were hospitalized due to complications from COVID-19 infection. The median age was 65.8 years, most were female patients (61.8%) and white (73,5%). 78.4% had a performance status of 0-1, and the most common cancer subtypes were gastrointestinal (30.4%), breast (22.6%) and hematological (13.7%). Almost 40% of population had stage IV disease. Mortality rate for all hospitalized patients was 36.5%, while for those admitted to the ICU it was 68.4%. Key univariable risk factors for mortality included age (RR 1.03), ECOG ≥ 2 (RR 1.83), hypertension (RR 1.72), lung metastasis (RR 1.67), and lymphocytes ≤ 1000 admission (RR 2.40). At the multivariable analysis, the risk factors were also age (RR 1.02), primary lung cancer (RR 2.61), lung metastasis (RR 2.86), and coronary disease (RR 3.76). Conclusions: Despite the high mortality of patients hospitalized with COVID-19, our data are compatible with other cohorts. Cancer patients must be carefully monitored in pandemic periods of infectious diseases.