bluuebunny/crossref_metadata_2025 huggingface dataset:
Abemaciclib, a CDK4 and 6 inhibitor with unique pharmacological properties for breast cancer therapy.
Authors: Torres-Guzmán Raquel , Ganado Maria Patricia , Mur Pérez Cecila , Marugán Carlos , Baquero Carmen , Yang Yanzhu , Du Jian , de Dios Alfonso , Puig Oscar , Lallena Maria Jose
Published: June 2021

e12506

Background: Breast cancer is the second most common cancer worldwide. Pharmacologically targeting cyclin-dependent kinases 4 and 6 (CDK4 & 6) has proven to be a successful therapeutic approach in patients with estrogen receptor positive (ER+) breast cancer. Differences in both efficacy and toxicity among the available CDK4 & 6 inhibitors has generated interest in a biological explanation. Abemaciclib is an adenosine triphosphate-competitive, reversible, selective inhibitor of CDK4 & 6 that has shown antitumor activity as a single agent and in combination with standard endocrine therapy (ET), in hormone receptor positive (HR+) metastatic breast cancer patients including those with ET resistance, and in combination with ET in high-risk early breast cancer patients. This study examines attributes of abemaciclib and other CDK4 & 6 inhibitors. Methods: The potency of abemaciclib for CDK4 was evaluated using biochemicals and breast cancer cell-based assays. Additionally, different combinations with an anti-estrogen therapy (e.g., tamoxifen, fulvestrant) were analyzed in an in vitro palbociclib (CDK4 & 6 inhibitor)-resistant breast cancer cell model, as well as in a set of CDK4 & 6 sensitive breast cancer cell models. Using cell-free assays, high content imaging and flow cytometry approaches, a subset of markers were monitored to characterize the phenotype of sensitive cell lines in a continuous dose schedule. Results: In in vitro, cell-free assays, abemaciclib shows selectivity for CDK4 over CDK6, and in cell-based assays, abemaciclib preferentially inhibits the proliferation of cells dependent on the presence of CDK4, not CDK6. Abemaciclib inhibits cell proliferation in a wide range of breast cancer cell lines, showing activity regardless of human epidermal growth factor receptor 2 (HER2) and PI3KCA gene mutation status. Furthermore, in a cell line resistant to palbociclib, abemaciclib in combination with fulvestrant (ET) restores CDK4 & 6 sensitivity, leading to cell senescence and cell death. Finally, in human bone marrow progenitor cells, abemaciclib shows a lesser impact on myeloid maturation than other CDK4 & 6 inhibitors, palbociclib and ribociclib, allowing for continuous dosing. Conclusions: In pre-clinical experiments, abemaciclib is a potent cell growth inhibitor, inhibiting preferentially the CDK4/CyclinD1 complex, leading to cell senescence and cell death. These pre-clinical results support the differentiated safety and efficacy profile of abemaciclib observed in clinical trials.
Metaplastic breast cancer: Disease characteristics and outcome in Arab women.
Authors: Alsayed Adher , Alshamsan Bader I , Alshibany Aisha , Elshenawy Mahmoud Abdelsatar , Badran Ahmed ali , Al-Tweigeri Taher , Ajarim Dahish Saed , Suleman Kausar
Published: June 2021

e12534

Background: Metaplastic breast cancer (MPBC) accounts for less than 1% of all breast cancer subtypes. Methods: Patients diagnosed with MPBC between 2001 are 2018 were reviewed. Disease characteristics, progression-free survival (PFS), and overall survival (OS) were estimated by the Kaplan-Meier method and compared by log-rank test. Results: Fifty-five MPBC patients were analyzed. The median was 46 years (IQR 40–55). 14.5% had a positive family history of cancer. The majority (98.2%) presented with a lump, and two patients presented with bilateral disease. The median BMI was 31 (IQR 24.5–37.5). The majority had stage III (56.4%), and stage IV was (7.3%). Most patients (90.9%) had triple-negative disease. The tumor grade (G) was available for 63.6% of patients (G2 11.4% and G3 88.6%). Nineteen patients (34.5%) received neoadjuvant chemotherapy (NAC) [anthracycline-based (15,78.9%), and platinum-taxane (11, 57.8%)]. The majority (92.7%) underwent surgery, 56.4% MRM, 12.7% BCT, 12.7% simple mastectomy, 7.3% palliative mastectomy. 54.5% underwent ALND and 20% SLNB. One patient had pCR. Adjuvant radiation was given for (33, 60%) and (37, 67.3%) received adjuvant radiation therapy. The median follow-up duration is 44 months (IQR 21–69). For nonmetastatic disease, 3-years DFS was 67.5%. There was no difference in DFS with using NAC (p-0.96) or being obese (p = 0.50). The 3-years OS was 72.9%, and the Log-rank test revealed prolonged survival with radiation therapy 87.1% vs. 56.6% ( p = 0.02) and earlier stage at diagnosis. 3-years OS for stage II was 92.9%, stage III was 71%, and no survival in stage IV (p < 0.001). There was a clinical difference in 3 years OS between obese vs. nonobese 61.3% vs. 85.9%, with no statistical significance (p = 0.15). Conclusions: The majority of patients diagnosed with MPBC had large tumor size, nodal disease, and more triple-negative disease, locally advanced and nonmetastatic. The DFS and OS were comparable to reported survival. There is a significant correlation between survival and stage and adjuvant radiation therapy.
The intra-tumor heterogeneity of ER and HER2 expression in patients with ER-positive and HER2-positive breast cancer.
Authors: Ju Jie , Du Feng , Gao Songlin , Si Yiran , Hu Nanlin , Liu Dongxu , Wang Xue , Yue Jian , Zheng Fangchao , Kang Yikun , Yang Zixuan , Ma Fei , Xu Binghe , Yuan Peng
Published: June 2021

e12550

Background: ER- positive and HER2-positive (double-positive) breast cancers are known to display significant heterogeneity; however, traditional immunohistochemistry (IHC) only reflects inter-tumor heterogeneity. Studies are needed to demonstrate the intra-tumor heterogeneity of ER and HER2 expression and to further explore its impact. Methods: The retrospective study included three double-positive breast cancer cohorts. Data from a total of 141 patients from The Cancer Genome Atlas (TCGA) and 104 patients from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used to investigate the molecular characteristics of double-positive breast cancers at the tissue level via somatic mutation and RNA-seq analyses, while 43 patients treated at our hospital were selected to analyze ER and HER2 expression and localization at a single-cell level using multiple IF. The rH/R was proposed to reflect ER and HER2 expression profiles based on multiple IF or RNA-seq results, as follows: rH/E = HER2+ cell percentage / (ER+ cell percentage + 1) or rH/E = ERBB2 expression quantity / (ESR1 expression quantity + 1). Results: In the first two cohorts, we found that the HER2-enriched subtype displayed unique molecular characteristics, including increased TP53, ERBB3, and PI3KCA mutation rates and the abnormal expression of important signaling pathways (e.g., G2/M cell cycle checkpoint and epithelial mesenchymal transition); The rH/E was a significant index for diagnosing HER2-enriched patients (area under the receiver operating characteristic curve [AUC] = 0.92 and 0.75, both P < 0.0001). In the third cohort, we found that 86 % of the patients contained all four tumor cell types (ER+HER2+, ER+HER2-, ER-HER2+, and ER-HER2- cells); The rH/E was an independent risk factor for recurrence (hazard ratio [HR] = 2.63, P = 0.02) and patients with a rH/E ≥ 1.5 had a significantly shorter 5-year disease-free survival (DFS = 67 % vs. 92 %, P = 0.046). Conclusions: The significant intra- and inter-tumor heterogeneity of double-positive breast cancers is closely related to the prognosis of patients, which is of great significance for precision treatment.
Correlation of Trop-2 expression with clinicopathological characteristics, sTILs, AR expression and outcome in primary TNBC.
Authors: Izci Hava , Punie Kevin , Waumans Lise , Laenen Annouschka , Wildiers Hans , Verdoodt Freija , Desmedt Christine , Ardui Jan , Smeets Ann , Han Sileny N. , Nevelsteen Ines , Neven Patrick , Floris Giuseppe
Published: June 2021

e12558

Background: Trophoblast cell-surface antigen-2 (Trop-2) is a transmembrane calcium signal transducer highly expressed in multiple tumor types including breast cancer. Trop-2 overexpression is associated with poor survival. Given the approval of sacituzumab govitecan in advanced triple-negative breast cancer (TNBC), Trop-2 emerges as an important target for antibody-drug conjugates. Limited data exist about correlations of Trop-2 expression with clinicopathological characteristics and outcome in early TNBC. Methods: We included 127 patients with early TNBC, treated with primary surgery at UZLeuven from 2005-2017. Trop-2 expression was determined with IHC (ab227689, Abcam) on whole slide tumor sections from resection specimens and assessed as continuous (H-score 0-300) and categorical (high 201-300, medium 100-200 and low < 100) variables. Stromal tumor infiltrating lymphocytes (sTIL; low, intermediate and high), mitotic score and androgen receptor (AR) expression (1% or 10%-cutoff) were scored. We assessed associations between Trop-2 expression and age, BMI, BRCA status, tumor grade and size, lymphovascular invasion (LVI), DCIS, nodal status, sTILs, AR, mitotic index and outcome (Invasive disease free survival and breast cancer specific survival). Results: The median age at diagnosis was 51y (range 26-80y) and the median follow-up 8.5y. Low, medium and high Trop-2 expression was seen in 50%, 37% and 13% of cases. AR was positive in 32% of cases (10%-cutoff). Higher Trop-2 expression was correlated with age (ρ = 0.192, p = 0.03) and inversely correlated with mitosis/mm² (ρ = -0.2, p = 0.02). Patients with high Trop-2-expression were older compared to patients with low Trop-2-expression (median 58 vs 47 years, p = 0.02). LVI was more frequent in Trop-2-high (65%) compared to TROP-2-medium (15%) or -low (16%) (p < 0.001). Median mitosis/mm² was higher in Trop-2-low (14) compared to Trop-2-medium (10) and -high (8) (p = 0.004). Patients in Trop-2-high subgroup had more nodal involvement (53%) compared to Trop-2-medium (23%) and -low (21%) (p = 0.03). There was no correlation between Trop-2 expression and sTILs, AR or outcome. Conclusions: In this patient cohort with TNBC treated with upfront surgery, higher Trop-2 expression was correlated with older age, with more LVI and nodal involvement, while mitosis/mm² were higher in tumors with low Trop-2 expression. Trop-2 expression was not correlated with sTILs, AR or outcome. Limited numbers of events warrant caution in interpretation.
Can high Ki67 predict distant recurrence in early-stage breast cancer with low Oncotype Dx score?
Authors: Fallah Parvaneh , Mulla Nasser Khleel , Aloyz Raquel , Aleynikova Olga , Florea Anca , Pelmus Manuela , Panasci Lawrence C.
Published: June 2021

e12561

Background: Ki-67 is a marker of proliferating cells. The recurrence score based on the 21-gene breast cancer assay also called Oncotype Dx provides prognostic and predictive information for recurrence in early stage breast cancer patients. We previously showed that there is a moderate correlation between Ki67 and oncotype Dx recurrence score. In this retrospective study, we aimed to examine whether high Ki67 could predict the distant recurrence in early stage breast cancer with low oncotype Dx scores ( < 25). Methods: This retrospective study included 278 consecutive cases of hormone receptor-positive, HER2 negative (T1-2 N0 M0) breast cancer who were diagnosed between 2008 and 2015 with low oncotype Dx ( < 25). Patients’ clinical outcome in terms of distant recurrence after breast surgery was determined up to December 2020 (median follow-up of 7 years). Patients were divided in to low risk (Ki67 < 15%) and high risk (Ki67 > = 15%) groups. Results: Of 278 cases with average and median age of 59 and 60 respectively, 148 (53%) were in Ki67 low risk and 130 (47%) were in Ki67 high risk group. Average and median oncotype Dx were 13.86 and 15 respectively in Ki67 low risk versus 15.23 and 16 respectively in Ki67 high risk group. 13 patients (4%) experienced distant metastasis in lung, liver, bone and skin. Of these 13 cases with average and median oncotype Dx 15.84 and 19 respectively, 12 (92%) were in the Ki67 high risk group and only 1 (8%) belonged to the low risk category. High Ki67 patients were overrepresented in group with recurrent distant metastasis compare to group without recurrent disease (Pearson Chi-Square = 51.18 with 1 degree of freedom and P = < 0.001). Conclusions: Ki67 high patients in the low risk oncotype Dx group are relapsing at a significantly higher rate suggesting that Ki67 combined with low oncotype Dx further refines the risk of distant relapse.
Creation of a primary breast cancer culture repository from patients with a BMI >30 kg/m2: A Mexican endeavor.
Authors: Shveid Gerson Daniela , Zentella - Dehesa Alejandro , Gerson Cwilich Raquel , Rodriguez Benigno , Serrano Villamayor Omar , Villegas Osorno Diana Alejandra , Enciso López Ervin Saúl , Camarin Sanchez Efrain Isaias , Noguez-Ramos Alejandro , López Zepeda Lorena , Villalobos Alberto , Olivares Guillermo , Martínez-Herrera José Fabián
Published: June 2021

e12574

Background: Currently there are no primary cultures or cell lines derived from patients with breast cancer and obesity. It has been postulated that breast cancer in obese women behaves differently as it does in non-obese women, as is composed of distinct biological features, as was generated in a different metabolic environment, as well as pertains to a different prognosis and different response to chemotherapy, lower rates of overall survival and a greater probability of recurrence. By creating a primary breast cancer culture bank of breast cancer tumors from women with obesity (BMI > 30kg/m2), we will establish a cell line exclusive to obese women in Mexico, where targeted therapy may be tested and treatment may be individualized depending on the characteristics of the patient. Methods: This study recruited 32 women with breast cancer and a BMI > 30 kg/m2, matched by 6 controls with are non-obese women with breast cancer. Elegibility criteria was determined by women with breast cancer confirmed by pathology, who had not been subjected to prior treatment regarding the neoplasm. The breast cancer removing surgeries and the patients were selected from the ABC Medical Center in Mexico City and all procedures were approved by the research and ethics committee of the hospital in question. Results: Through extensive communication a cooperative protocol was established between the departments of surgery, oncology, pathology and nursing to coordinate efforts and be able to take a 2 – 5 mm sample of the breast tumor removed from the patient. To be able to distinguish cancer cells from non-cancer cells (epithelial cells, fibroblasts, adipocytes) the Hayflick limit was be utilized. Once a primary breast cancer culture was established, 12 million cells will be injected into the subscapular area of athymic, nu-nu mice to be able to monitor tumoral growth in vivo and conduct a subsequent cellular analysis, determining it still pertains to the same characteristics of the tumor from which it was obtained. Conclusions: A primary breast cancer culture repository from patients with a BMI > 30 kg/m2 was established. This is the first primary breast cancer culture for both Mexican and obese women with breast cancer, the first in vitro method of analysis of specific characteristics typical of the Mexican population. Translational research may now be conducted on these new tumoral cultures to create individualized therapy for women with the distinct, aforementioned characteristics.
Aesthetic outcome and patient’s quality of life in breast cancer patients undergoing mastectomy with or without immediate reconstruction.
Authors: Afzal Sidra , Parvaiz Asad , Javed Nida
Published: June 2021

e12587

Background: : Although post mastectomy Immediate breast reconstruction has shown to improve physical and psychosocial well-being of breast cancer patients, this is not a usual procedure in Pakistan due to limited resources and lack of awareness. The aim of our study is to evaluate patient’s satisfaction/ aesthetic outcomes between the patients undergoing mastectomy alone (Group A) and the ones undergoing mastectomy followed by immediate reconstruction (Group B). Methods: This is a prospective study conducted at Shaukat Khanum Hospital Pakistan comparing aesthetic outcome, patient’s satisfaction and Quality of life between two groups using Breast Q module. All patients undergoing mastectomy with and without reconstruction between April 2017 to July 2019 are included. Sample size of 84 was calculated (42 in each group). Results: The mean Q score of satisfaction with the breast in group B is 82.64 and in group A is 35.82 (P = 0.001). The mean Q score of Psychosocial well-being in group B is 89 vs 44.95 in group A (P = 0.001). The mean Q score of Physical well-being in group B is 98.23 vs 90.41 in group A (P = 0.002). The mean Q score of sexual well-being in group B is 81.93 vs 43 in Group A (P = 0.001). [Mean difference in score of 5-10 - little change, 10-20 - moderate change, > 20 - significant change].The mean difference between two groups in satisfaction with breast , psychosocial well-being and sexual well-being is more than 20 with a statistically significant p-value, while in physical well-being the mean difference is 7.8 which falls in little change group. Conclusions: Our study shows that reconstruction helps breast cancer patients in providing comprehensive care in a manner that they achieve a higher satisfaction with their appearance, psychological and sexual well-being without compromising oncological safety and this should be practiced more in our country. Also patients education about these procedures should be raised to help them fighting against this disease
Micro-organospheres: An automated patient-derived model platform for rapid drug screening of breast cancer.
Authors: Wang Zhaohui , Cortes-Sanchez Emilio , Yang Chieh-Hsiang , Nelson Daniel , Delubac Daniel , Hsu Shiaowen David , Welm Alana , Shen Xiling
Published: June 2021

e12628

Background: Patient-derived breast cancer (BC) organoids are valuable preclinical models to study patient drug responses, demonstrating good correlations with patients’ clinical outcomes. However, establishment and expansion of such organoids from patient tumors for drug screening is currently a time-consuming and labor-intensive process. A more rapid and high-throughput method will enable broader utility in diagnostics and drug development. Methods: An automated, rapid and scalable microfluidic platform was used to process and develop BC micro-organospheres. Drug sensitivities studies on BC micro-organospheres were performed on day 3 and day 6 using 10-FDA approved drugs, including palbociclib, adriamycin, 5-FU, gemcitabine, methotrexate, everolimus, paclitaxel, docetaxel, ixabepilone, and vinblastine. The responses of micro-organospheres and organoids to the drugs were assessed by CellTiter 3D Glo assay on day 6 after the drug treatment. The growth and establishment of the micro-organospheres by imaging. The drug sensitivity and resistance of the micro-organospheres were analyzed by calculating the percentage cell viability and normalized growth rate inhibition (GRI) and compared to organoids. Results: We successfully established micro-organospheres from eight patient-derived BC organoids with a 100% success rate. The micro-organospheres preserved similar cell morphologies to the bulk organoids. 7/8 micro-organosphere models had similar drug response patterns to organoids between day 3 and day 6 as evident by the GRI heatmap. Specifically, we treated matching micro-organospheres and conventional organoids from two patients with 10 frontline BC chemotherapy drugs, and both showed similar response patterns with GRI heatmap. For the other 6 patient-derived models, the responses of micro-organospheres to docetaxel and everolimus also matched the historical drug responses of in bulk organoid culture with similar GRI heatmap. Conclusions: We have now shown the feasibility of establishing micro-organospheres as a rapid, scalable, and cost-effective platform to study patient-derived BC drug response. This technology has the potential to be used for both diagnostics to guide patient treatment and as a screening platform for new BC drug discovery.
Real-world Indian scenario of CDK4/6 inhibitors (palbociclib and ribociclib) with endocrine therapy in upfront hormone positive metastatic breast cancer.
Authors: Gogia Ajay , Arora Shalabh , Choudhary Priyanshu , Kumar Rakesh , Thulkar Sanjay , Deo S. V. S. , Sharma Dayanand , Bhatnagar Sushma
Published: June 2021

e13028

Background: CDK4/6 inhibitors (CDKi), in combination with endocrine therapy (ET), has become the standard of care in the treatment of hormone positive (HR+)/ HER2 neu negative metastatic breast cancer (MBC) patients. We evaluated clinical outcomes and toxicity in MBC patients, who have received ET with two CDKi, namely palbociclib and ribociclib. Methods: This is an ambispective, single institutional analysis of de-novo HR+ MBC patients treated with CDKi (palbociclib 125 mg and ribociclib 600 mg once a day for 21 days /28 days cycle) from November 2016- October 2020 at AIIMS, New Delhi, India. The primary endpoint was progression-free survival (PFS) and the secondary endpoint was response rate and toxicity. A total of 157 female patients were recruited in this study however the response and toxicity data were available in 120 cases. All premenopausal women received ovarian suppression or ovarian ablation. Results: A total of 120 patients were included in this study with a median age of 57 years (35-75) and 93 (77.5%) cases were postmenopausal. Twenty-three (19.1%) patients had a bone-only disease, 49 (40.9%) had bone and visceral disease and 48 (40%) had only visceral disease. In this study 91 (75.9%) patients received palbociclib and 29 (24.2%) received ribociclib. The median PFS was 18 months (4-36). Twenty four (20%) patients achieved a complete response, 69 (57.5%) patients attained partial response, 18(15%) patients had stable disease and 9 (7.5%) had disease progression. Grade 3–4 neutropenia, thrombocytopenia, and anaemia were observed in 18(15%), 8 (6.7%), and 4 (3.3%) cases respectively. None of the patients developed febrile neutropenia. Cutaneous, renal, hepatic, and gastrointestinal toxicity was observed in 1,1,3,4 cases respectively. Prolonged QTc was observed in one case. Grade 3 fatigue was observed in 7 cases. Dose interruption/delay (mean dose delay of 7 days), dose modification, and drug discontinuation were observed in 24 (20%), 12 (10%), and 10 (8.3%) of cases respectively. Conclusions: This is one of the largest real-world Indian data on CDK4/6 inhibitors on upfront HR+ MBC. Side effects are less than published literature with similar efficacy. Neutropenia was the most common side effect which was managed by brief dose interruption.
Neuroendocrine differentiation in metastatic breast cancer following CDK 4/6 inhibitors.
Authors: Sekkate Sakina , Ladrat Laure , Pouliquen Christelle , Callens Celine , Geay Jean Francois , Beuzeboc Philippe
Published: June 2021

e13029

Background: First-line treatment with a CDK4/6 inhibitor in combination with an aromatase inhibitor for HR+/HER2- postmenopausal metastatic breast cancer (mBC) is considered as a standard of care based on the compelling data across all landmark trials. Methods: We report our experience about two cases with metastatic breast cancer treated by CDK4/6 inhibitor in combination with an aromatase inhibitor, which develop neuroendocrine differentiation. After observing an unusual massive progression, a biopsy of the metastasis was performed in both patients. Both histological analysis confirmed a lobular breast cancer with small cell neuroendocrine features and a high proliferation index (KI 67 90%). An NGS (Next generation sequencing) profile was realized on primary and metastatic tumors to detect new acquired genomic alterations. Results: The comparative analysis of the NGS results of primary and metastatic tumors revealed the occurrence of several events in both patients under treatment. For one patient, we identified new mutations in the genes CDH1, FANCG, PIK3CA, PTEN and TP53, which did not exist initially. For the second patient, we found an amplification of the segment containing FGFR1, CCND1, FGF4, FGF3, FADD genes and the deletion of the segment containing RB1 andTP53 genes. Such events were not observed on the primary tumor. Conclusions: Prostate adenocarcinoma may develop neuroendocrine features in later stages of castration-resistant prostate cancer but neuroendocrine differentiation is atypical in breast carcinoma. In case of unusual rapidly progressive disease after CDK4/6 inhibitor, biopsy of new metastases should be recommanded to search neuroendocrine differentiation, or druggable mutations to guide the treatment.
Real-world analysis of disease progression after CDK 4/6 inhibitor (CDKi) therapy in patients with hormone receptor positive (HR+)/HER2- metastatic breast cancer (MBC).
Authors: West Malinda , Kaempf Andy , Goodyear Shaun , Kartika Thomas , Ribkoff Jessica , Mitri Zahi Ibrahim
Published: June 2021

e13030

Background: CDKi with endocrine therapy (ET) is approved treatment of metastatic HR+/HER2- breast cancer based on PFS benefit vs ET alone. Outcomes data following CDKi discontinuation (dc) is limited, with trials ongoing in this setting. The reported phenomenon of rapid progression within 4 months of CDKi dc raises concern over CDKi impact on HR+/HER2- MBC biology. This study aims to define outcomes after CDKi dc and identify predictors of progression. Methods: This is a retrospective review of women ≥18 years with HR+/HER2- MBC who received CDKi between 4/1/14 and 12/1/19. Patient and tumor characteristics, pre and post CDKi tx, and reason for CDKi dc were collected. Time to event outcomes from date of CDKi dc (primary = PFS, secondary = Overall Survival, OS) were analyzed with Kaplan Meier estimators and Cox regression. Results: Analysis included 140 patients (median age 65 years), with most MBC (84%) arising from earlier stage disease. 51% of MBCs had visceral disease, and 66% received tx prior to CDKi. The most common CDKi was palbociclib (93%); and most common ET were letrozole (52%) and fulvestrant (40%). Median CDKi tx duration was 9 months (3.5 – 17.4) with 80% dc due to progression. Post CDKi txs included chemotherapy (44%), ET (24%), targeted tx (21%), no further tx (7%) and CDKi tx (4%). Median follow up was 12 months. mPFS post CDKi dc were 6.5 months (95% CI: 5.0 – 7.9) and 11.3 months (95% CI: 4.6 – 23.7) in patients who dc CDKi due to progression or other reasons, respectively (HR 1.77, 95%CI: 1.10-2.85). Among 112 patients who progressed on CDKi, estimated 4-month incidence of post CDKi progression or death was 31% (Table ). mOS post CDKi dc was 15.4 months (95%CI: 13.3-19.0) and mOS post CDKi initiation was 26.5 months (95% CI: 23.3 – 34.3). Visceral disease (HR 1.45, 95%CI: 1.01-2.08) and progression as reason for CDKi dc (HR 1.77, 95%CI: 1.1-2.85) were predictors of PFS (p < 0.05). Receiving fulvestrant with CDKi (HR 1.42, 95%CI: 0.96-1.0), prior chemotherapy in the metastatic setting (HR = 1.39, 95% CI: 0.90 – 2.14), and shorter CDKi duration were associated with non-significant increased risk of PFS. Conclusions: Rapid progression or death at 4 months occurred in 31% of MBCs following CDKi dc due to progression. Ongoing studies to define clinical and molecular characteristics of rapidly progressing tumors are underway to develop targeted tx approaches and improve outcomes.[Table: see text]
Real-world outcomes from the systemic use of CDK 4/6 inhibitors (CDKIs) in the management of ER positive (+) HER2 negative (-) metastatic breast cancer (mBC).
Authors: DeSouza Karen , Yeo Daniel , Diossy Maria , Umar Sumbal , Gore Emma , Trivedi Sachin , Anand Anjana , Madhusudan Srinivasan , Khan Sarah
Published: June 2021

e13031

Background: The use of CDKIs have transformed the management of ER+HER2- mBC. As the real-world data matures, this project describes patterns in response to systemic therapy that may inform treatment planning and prognostication. Methods: We analysed the ER+HER2- mBC dataset at Nottingham University Hospitals NHS Trust (NUH) generated by reviewing clinical notes, radiology and e-prescribing records to collect clinical data on patients treated with CDKIs between 01/10/2016 - 01/10/2020. Results: 272 patients with a median age of 65 years (30-90 years) were treated with CDKIs (palbociclib 54.0% (n=147); ribociclib 19.5% (n=53); abemaciclib 26.5% (n=72)) in combination with endocrine therapies (letrozole, anastrozole, exemestane and, fulvestrant). Median overall survival was 49.5 months. Treatment with first-line CDKIs (69.8%; n=190) resulted in superior PFS when compared to CDKIs in a ≥ second-line setting (30.2%; n=82) i.e., mPFS 21.3 vs 12.2 months (HR 0.67; 95% CI, 0.47-0.96; P=0.02). Univariate analysis shown in the table below indicates the benefit to PFS from presentations with de novo mBC and the absence of visceral metastases. In patients treated curatively for early breast cancer (EBC), better outcomes were demonstrated in patients presenting with mBC, >12 months versus ≤12 months of completion of adjuvant endocrine therapy i.e., mPFS 28.4 vs 12.1 months (HR 0.50; 95% CI, 0.30-0.84; P=0.004) when treated with first-line CDKIs. A multivariate analysis identified benefit to PFS from first-line therapy with CDKIs (HR 0.70; 95% CI, 0.49-1.01; P=0.05) and presentation with de novo mBC (HR 0.56; 95% CI, 0.37-0.85; P=0.006). The presence of visceral metastases was associated with poorer outcomes (HR 1.52; 95% CI, 1.08-2.15; P=0.01). Conclusions: This analysis confirms the PFS benefit from CDKIs demonstrated in clinical trials is mirrored in the real-world setting. The analysis was not powered to delineate survival benefit between the individual CDKIs. Presentations with mBC following a prior history of EBC, within ≤12 months of completion of adjuvant endocrine therapy, and with visceral metastases may help predict poorer clinical outcomes and may need to be considered when prognosticating and in treatment planning. This analysis is hypotheses-generating and we will confirm our findings in a prospective manner as the dataset is expanded.[Table: see text]
Plasma kallikrein-kinin system as markers of locally advanced breast cancer prognosis.
Authors: Samaneva Natalia Yu. , Vladimirova Liubov Yu , Frantsiyants Elena M. , Storozhakova Anna E. , Kalabanova Elena A. , Kabanov Sergey N. , Tishina Anna V. , Svetitskaya Yana V. , Shatova Iuliana S. , Vashchenko Larisa N.
Published: June 2021

e13040

Background: The kallikrein-kinin system is a complex multifunctional signaling cascade. Studies confirm its role in the development of cancer, as well as a role of some of its proteins with pro-inflammatory properties. Criteria for assessing the risk of breast cancer (BC) progression are required. The purpose of the study was to reveal the effect of blood levels of plasminogen, plasmin, precallikrein, and kallikrein in patients with triple-negative BC on the disease course. Methods: The study included 162 patients with triple-negative BC divided into 2 groups: group 1 – 58 patients with an early progression within 6 to 12 months after combination treatment; group 2 – 104 patients without progression during 2 years after combination treatment. Blood levels of plasminogen, plasmin, prekallikrein, and kallikrein were measured by ELISA before anticancer therapy and after 8 chemotherapy cycles. The levels in the blood plasma of healthy donors were reference values. Results were statistically processed using the Statistika 6.0 program with the Student’s T-test. Results: In patients with an early progression, plasminogen levels before the treatment were decreased by 1.7 times (p≤0.05), while plasmin was elevated by 1.9 times (p≤0.05). Kallikrein was increased by 1.9 times (p≤0.05), and prekallikrein was similar to the values in healthy donors. In patients with prolonged remission, plasminogen levels before the treatment were decreased on average by 2 times (p≤0.05). Plasmin was elevated by 2.3 times (p≤0.05), and kallikrein – by 1.8 times (p≤0.05). During this period of the study, prekallikrein levels decreased by 2 times (p≤0.05), compared with healthy donors. After chemotherapy, prekallikrein levels in the group with an early progression decreased by 1.4 times (p≤0.05), compared to the values before treatment, and kallikrein increased on the average by 1.3 times (p≤0.05). In patients with prolonged remission, no changes in the studied indices were registered. Conclusions: Patients with an early progression of BC demonstrated decreased levels of prekallikrein and increased kallikrein after the treatment, which allowed predicting resistance to chemotherapy and further tumor progression.
Efficacy of platinum-based chemotherapy in advanced triple-negative breast cancer in association with homologous recombination deficiency.
Authors: Chen Yimeng , Cui Lina , Zhang Bei , Zhao Xiaochen , Xu Binghe
Published: June 2021

e13051

Background: Previous studies have identified that at least 50% of triple negative breast cancer (TNBC) harbor mutation characteristics of homologous recombination deficiency (HRD). Thus, more sophisticated research into comprehensive genomic profiling of HRD is urgently needed. Whereas BRCA1/2-deficient advanced TNBC patients are sensitive to treatment with platinum, it is not yet clear whether HRD status could predict platinum response. Methods: 3DMed-HRD algorithm was developed based on loss of heterozygosity score (LOH), telomeric allelic imbalance score (TAI) and large-scale state transition score (LST) as previously described. HRD status was defined as HRD positive (deleterious mutation in BRCA1/2 or HRD score ≥30) or HRD negative (no deleterious mutation in BRCA1/2 and HRD score < 30). Tumor samples from 207 TNBC patients were analyzed by next-generation sequencing. Deleterious or suspected deleterious mutations were included for analysis. Among the overall cohort, 34 patients with advanced TNBC treated with chemotherapy were analyzed. Cox regression model was applied to evaluate the relationship between HRD status and clinical outcomes. Results: Deleterious BRCA1/2 mutations were detected in 22.2% (46/207) of TNBC patients as well as 54.6% (113/207) were defined as HRD positive. The most frequent mutations in HRD-positive patients were TP53 (93.5%), MYC (29.0%), PIK3R1 (22.6%), PTEN (22.6%) and MCL1 (19.4%), while TP53 (77.8%), MYC (29.6%), PIK3CA (18.5%), KMT2C (14.8%) and RIT1 (14.8%) enriched in HRD-negative patients. Mutations in DNA Damage Response (DDR), P53, Checkpoint and Receptor Tyrosine Kinase (RTK) pathways were most involved in HRD positive patients. In advanced TNBC cohort, 19 patients received platinum-based and 15 received platinum-free chemotherapy in the first-line treatment. The progression-free survival (PFS) of the platinum-based group was longer than that of the platinum-free group (media PFS 9.1 vs 2.2 months, HR 0.44, 95%CI, 0.20-0.94, P = 0.009). In HRD-positive patients, median PFS was significantly longer in platinum-based group (N = 6) than platinum-free group (N = 8) (media PFS 13.6 vs 1.9 months, HR 0.30, 95%CI, 0.09-0.95, P = 0.008). No significant difference in PFS between platinum-based and platinum-free group (p = 0.332) in patients with HRD-negative tumors. Patients with mutations in homologous recombination (HR) pathway had a worse PFS compared to wild-type in platinum-free group (1.4 vs 3.0 months, p = 0.050). Conclusions: Our findings illustrate the potential of HRD status as a marker to guide chemotherapy in advanced TNBC. In HRD positive patients, platinum-based chemotherapy might be a preferable regimen. Patients with mutations in HR pathway had a shorter PFS in platinum-free group. Prospective study with a larger sample-size is needed for further validation of our findings.
Preliminary data on antitumor activity of extracorporeal subtraction of soluble TNFRs to unleash the activity of endogenous TNFα combined with chemotherapy in treatment-refractory, advanced, triple-negative breast cancer patients.
Authors: Wysocki Piotr Jan , Ostrowski Adam , Segal Robert , Potocki Pawel , Konopka Kamil Wladyslaw , Kwinta Lukasz , Florin Lawrence , Prince Stephen
Published: June 2021

e13052

Background: Tumor necrosis factor-alpha (TNFα) is a pleiotropic cytokine, with known antitumor activity, produced mainly by activated immune cells. Cancer cells neutralize TNFα by shedding soluble TNF receptors 1&2 (sTNFRs), which act as TNFα-binding decoys. In addition, sTNFRs can directly promote proliferation, survival, and chemoresistance of cancer cells by binding to membrane-bound TNFα and initiating retrograde signaling. Therefore, the reduction of systemic and intratumoral concentrations of sTNFRs represents a novel and unique strategy to reinvent the anticancer use of TNFα. Methods: In this clinical trial (CP7-005; NCT04004910) we evaluated extracorporeal Immunopheresis (subtractive apheresis) with the novel LW-02 immunoadsorption column in advanced chemo-refractory metastatic triple-negative breast cancer (mTNBC). The LW-02 column, which utilizes a proprietary, recombinant single-chain TNFα as the sTNFR-scavenger ligand has received FDA breakthrough designation for cancer treatment. Here we present data on the second cohort of mTNBC patients treated with LW-02 combined with weekly chemotherapy; Cohort 1 (n=10) evaluated Immunopheresis as monotherapy only. In Cohort 2, patients are treated with LW-02 immunopheresis only in week 1 (3 treatments involving processing of 2 plasma volumes (2PV)). From week 2, paclitaxel [60 mg/m2]+carboplatin[AUC2] combination is administered once weekly along with LW-02 immunopheresis (2PV 3x/week). Results: To date, 7 mTNBC patients who failed ≥2 lines of chemotherapy (median=3; 2-5) in the advanced setting have been enrolled. The combination of LW-02 column immunopheresis and chemotherapy resulted in a 29% ORR (1CR, 1PR). In 5 patients who completed at least 4 weeks of treatment, the ORR was 40%. Median OS in the whole population as of this report is 13.3 weeks, and 18.4 weeks in the patients treated for >4 weeks. Treatment-related AEs occurred in most patients; however, most being attributed to chemotherapy - CTCAE G3-4 in 71% (anemia – 71%, neutropenia 29%, thrombocytopenia 29%). Immunopheresis-related G3-4 AEs were CVC complications (29%), hypophosphatemia (14%) and hypercalcemia (14%). Conclusions: The combination of LW-02-column immunopheresis and weekly chemotherapy procedure was shown to be generally safe and provided early, promising signs of antitumor activity in heavily pretreated mTNBC patients with short life expectancy. Further clinical evaluation of the antitumor activity of LW02-based immunopheresis combined chemotherapy is ongoing; however, due to myelotoxicity, the chemotherapy regimen will be adapted accordingly. Clinical trial information: NCT04004910.
Binimetinib activity in PIK3R1-mutant patient-derived xenografts (PDX) implanted into immunodeficient mice.
Authors: Cobleigh Melody A. , Abukhdeir Abde M.
Published: June 2021

e13062

Background: The PIK3R1 gene is genetically altered in ̃3% of breast cancers in the Western and ̃17% in the Eastern worlds. We recently reported that breast cancer cells lacking protein expression of PIK3R1 had elevated levels of activated MEK, sensitizing them to the MEK inhibitor trametinib. To better understand whether MEK inhibition is a therapeutic option for breast cancer patients with mutated PIK3R1, we tested the newer generation MEK inhibitor, binimetinib, in a PDX mouse model. Methods: Two PDx models (table) were tested in athymic nude-foxn1nu (immune-compromised) mice. Both patients had had metastatic, grade 3 breast cancer and expressed moderate RNA levels of PIK3R1. Results: Body weights of treatment arms were unchanged throughout the experiment. The TNBC PDx study was halted early at 13 days because tumors reached the predefined maximum size of 1500 mm2. The binimetinib treated mice experienced slowed tumor growth (522.8 +/- 172.8%) compared to the vehicle control (720.7 +/- 229.1%), (p=0.0693). In the HR+ PDx model, the combination of binimetinib plus tamoxifen resulted in a statistically significant decrease (371.5 +/- 108.1%) in tumor volume compared to tamoxifen alone (525.0 +/- 154.1%; p = 0.0302). Conclusions: Our previous and current results suggest that mutation in PIK3R1 sensitizes cells to MEK inhibitors. Binimetinib inhibited growth in both models. This inhibition was of borderline significance in the TNBC model and was statistically significant in the ER+, HER2- model. To the best of our knowledge, these results provide the first evidence of binimetinib efficacy in PIK3R1-mutant, HR+, HER2- PDX immunodeficient mice. Plans for a phase II trial in patients with PIK3R1-mutant, HR+, HER2- breast cancer are underway.[Table: see text]
Oral etoposide in heavily pre-treated metastatic breast cancer: A retrospective study.
Authors: Jagiello-Gruszfeld Agnieszka I. , Meluch Malgorzata , Kunkiel Michal , Gorniak Anna , Majstrak-Hulewska Anna , Gorska Katarzyna , Konieczna Aleksandra , Nowecki Zbigniew
Published: June 2021

e13070

Background: Patients with metastatic breast cancer can derive clinical benefit from several subsequent lines of chemotherapy. However, in heavily pre-treated patients, agents with clinical activity, a favourable side effects profile and a convenient administration modality are preferred. Oral etoposide may be an interesting treatment option in this group of patients. Methods: This was a retrospective observational study performed in single institution in 22 patients with MBC refractory to prior anthracycline, taxane, and capecitabine therapy. All patients were treated with oral etoposide at 50 mg/day on days 1-20. Treatment cycles were repeated every 28 days. Results: The median age were 53 years (42-68). The median number of previous chemotherapy lines was 5 (range 2-7). There were no complete or partial responses. Median PFS was 7 months. In 5 patients, the disease stabilized for over 12 months. Interestingly, etoposide activity was unrelated to the number of previous lines and type of metastatic involvement. Oral etoposide was well tolerated with only one patients discontinuing therapy due to toxicity. Conclusions: In real practice oral etoposide is a valuable and safe option for pre-treated metastatic breast cancer patients and might be considered in patients failing other approaches, but still suitable for chemotherapy.
Novel treatment options in advanced adenoid cystic carcinoma of the breast.
Authors: Wenig Evan , Birhiray Reumu E.
Published: June 2021

e13071

Background: Adenoid cystic carcinoma (ACC) accounts for less than 0.1% of all breast cancer cases. The disease typically remains localized and indolent, and frequently occurs with triple negative status. Methods: In patients with locally advanced or metastatic disease, chemotherapy for triple negative breast carcinoma is seldom effective. Thus new treatment paradigms are desired. Drug targeted analysis derived from next generation sequencing and identification of driver mutations may offer a bright future in treatment options in chemo-resistant malignancy. Results: A 53 year old woman presented with breast mass and mastectomy with stage pT3N0M0 triple negative ACC of the breast resulting in observation. She later relapsed with chest wall disease, resulting in resection and radiation therapy. Shortly thereafter, she relapsed with pulmonary metastatic disease. She was treated with carboplatin and doxorubicin which were discontinued due to disease progression. Liquid assay revealed an IDH2 mutation, prompting treatment with enasidenib with ongoing evidence of disease control at 4 months. Patient tolerated treatment well without grade 3 or 4 adverse reactions. A 48 year old woman presented with an increasing 9.5 cm unresectable breast mass without distant metastasis. Pathology showed triple negative ACC of the breast, resulting in chemotherapy with doxorubicin, cyclophosphamide, and paclitaxel with clinically progressive disease. She represented with necrotic and ulcerating changes of the breast. Foundational genomic testing showed an FGFR2 mutation. After four months of treatment with erdafitinib, she had resolution of pain and cessation of pain medication. Her therapy led to a grade 2 adverse event related to hyperphosphatemia. She underwent surgical resection with negative margins. Conclusions: These examples illustrate a potential treatment paradigm for a rare malignancy for which there is no standard of care. Here we present two desperate cases, one of which had a driver mutation of IDH2, and the other FGFR2 for which there are targeted therapies approved in other disease states. The use of these two agents resulted in clinical benefit. A patient with metastatic disease treated with enasidenib has ongoing disease control for over 4 months with minimal adverse reaction. A patient with advanced local disease requiring narcotics and gabapentin for pain control treated with erdafitinib had significant symptomatic control with successful cessation of pain medications and ability to undergo potentially curable mastectomy with negative margins despite progression on prior chemotherapy. In summary, ongoing research of ACC of the breast will be required. Alternative therapeutic options related to targeted treatment may offer promise to clinical outcomes in the future. For cases of locally advanced or metastatic disease, the use of targeted therapy may offer new therapeutic options.
Utility and acceptability of the EXCEEDS algorithm for oncology stakeholders: Results of a Delphi study.
Authors: Covington Kelley Renee , Marshall Timothy F , Sharp Julia L , Kendig Tiffany , Williams Grant Richard , Pergolotti Mackenzi
Published: June 2021

e13538

Background: The Exercise in Cancer Decision Support (EXCEEDS) algorithm is an evidence-based, risk stratified framework. This framework allows for enhanced decision making for exercise pre-participation medical clearance and triage to cancer rehabilitation or exercise services across the cancer continuum. We conducted a Delphi study to examine utility and acceptability of the EXCEEDS algorithm for oncology stakeholders. Methods: Delphi study participants were randomized to two case studies, then made pre-participation medical clearance (yes/no) and intervention triage recommendations (cancer rehabilitation, clinically-supervised exercise, cancer-specific community-based exercise, and unsupervised exercise) in two conditions: independent (IND) and using EXCEEDS. Immediately following, participants rated algorithm acceptability in four domains using 4-point Likert scales (1- strongly disagree, to 4- strongly agree). We dichotomously coded accuracy (correct/incorrect) for each medical clearance and triage recommendation, then calculated the proportion of correct answers for each case to determine accuracy. We compared triage decision time (seconds) between conditions (IND vs. EXCEEDS) using paired-samples t-tests. We calculated the proportion of participants who ‘agreed’ (i.e., score ≥3) with each acceptability domain. Results: Oncology stakeholders (N=33) were mostly female (69.7%), 35-44 years old (42.4%), located in the United States (60.6%), and had at least 10 years of experience (60.6%). When using EXCEEDS, accuracy for medical clearance decisions improved in 3 of 4 cases (75%), triage decision accuracy improved in 4 of 4 (100%) cases, and triage time (seconds) improved significantly in 3 of 4 cases (75%, p<.05). Table shows average improvement in decision accuracy and triage time for each case study. Most participants agreed that the algorithm was acceptable in each domain: “meets my approval” (n=21, 63.6%), “is appealing” (n=29, 87.9%), “enjoyable to use” (n=19, 57.6%), and “welcomed in my discipline or practice” (n=24, 72.7%). Conclusions: Accuracy and efficiency of decision-making for medical clearance and triage to cancer rehabilitation or exercise services was enhanced when using the EXEECDS algorithm. Most participants agreed the algorithm was acceptable. Future research is needed to validate the tool and explore avenues for dissemination and clinical implementation. % difference between EXCEEDS and Individual condition (EXCEEDS – IND) for medical clearance decision, triage decision and mean (M) and standard deviation (SD) of triage decision time.[Table: see text]