bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptomic mapping on Notch signaling in A luminal phenotype breast cancer.
Authors: Rojas Katerin Ingrid , Martín M Rocio , Rojo Federico , Gámez-Pozo Angelo , De Castro Francisco J. , Filipovich Elena , Ceballos Jaime , Hernández M. Rosario , Ales-Martinez Jose
Published: June 2021

e12539

Background: The Notch signaling pathway plays an important role in cell-differentiation, survival, proliferation, stem-cell renewal, and in determining cell fate during development and morphogenesis. The dysregulation of the Notch pathways contributes to carcinogenesis, cancer stem cell renewal, angiogenesis, and chemo-resistance. Elevated levels of Notch receptors and ligands have been associated with cancer-progression and poor survival. A less explored function of Notch pathways in cancer is their role in leukocyte homing and activation. Understanding their role and relationship with immune infiltrates is an area of interest in cancer research. Methods: The expression of four different Notch genes (Notch1, Notch2, Notch3 and Notch4) was explored in relation with A luminal breast cancer patient outcome using transcriptomic data (Affymetrix dataset, exploratory cohort) and the METABRIC study (validation cohort). The TIMER online tool was used to explore the association of the identified notch and immune infiltration, and the TCGA and METABRIC studies to analyze the correlation between notch1 - 4 expression and genomic signatures of immune activation. Results: We identified 2 individual genes called Notch1 and Notch2, which predict favorable prognosis in luminal A breast cancer. Their expression positively correlated with the presence of immune infiltrates within the tumor (dendritic cells, CD4+ T cells, neutrophils, CD8+ T cells and B cells), with markers of T cell activation and antigen presentation, and with gene signatures of immune surveillance (cytotoxic T lymphocyte activation and IFN gamma signature). By contrast Notch3 and Notch4 which predicted for detrimental outcome were not associated with any of these parameters. Conclusions: Our analysis identifies a Notch signature composed of 2 genes with potential to recognize immune infiltrated and activated A luminal phenotype breast cancers with favorable prognosis.
Final report of Breast Cancer Care Registry at the Kenyatta National Hospital, Nairobi.
Authors: Othieno-Abinya Nicholas Anthony , Musibi Alice , Nyongesa Catherine , Njihia Benjamin , Gachii Andrew , Kiarie Gladwell Wanjiru Kamere , Nyawira Beatrice , Onyango Ochieng' Noel
Published: June 2021

Retraction

The abstract by Othieno-Abinya et al entitled, “Final report of Breast Cancer Care Registry at the Kenyatta National Hospital, Nairobi,” published in the Journal of Clinical Oncology 39, no. 15 suppl (May 20, 2021) e12552-e12552, was retracted by the authors as it did not meet the study sponsor's prior scientific verification and approval.

This abstract was retracted on June 29, 2021.

e12552

Background: Breast cancer is the commonest cancer among women in Kenya. We wanted to examine breast cancer seen at the Kenyatta National Hospital in relation to local factors that influence prognosis and quality of life, local variations in treatment and outcomes; describe the clinical care patterns, monitor the safety of the therapies provided to patients in a routine clinic setting. Methods: A prospective study of patients with breast cancer between 11.08.2011 and 11.09.2014 inclusive. Data included demographic details, diagnostic and staging procedures, stage, treatment and outcome. Estimates of relative survival used period approach. hi-square tests and analysis of variance (ANOVA) were utilised to make comparisons. Cross sectional data are presented in proportions, means and medians. Results: Four hundred patients were included, age range 20 to 83, median 49 years. Out 312, 65 (20.8%) were obese. Eight of 397 (2%) were smokers and 22(5.5%) took alcohol. Early disease was diagnosed in 269 out of 354 (76%) and metastatic disease in 85(24%). Breast lump presented in 388 out of 400 (97%), breast pain in 104 out of 388 (26.8%). Fifteen of 394 (3.8%) had second breast cancer, 4 (1%) had had ovarian cancer and 9 (2.3%) had had had other malignancy. History of breast cancer in first and second-degree relative was elicited in 41 out of 394 (10.4%). Ductal carcinoma NOS was commonest in 343 (88.2%), lobular carcinoma in 9(2.5%). Cases by T stage were T1 - 25(7.2%), T2 -130(37.4%), T3 - 96(27.6%), T4 - 87(25%). Of 322 cases, 187(58.1%) were ER positive and 175 (54.4%) PR positive. Her2 positive cases were 78 out of 322 (24.2%). Neo adjuvant and adjuvant chemotherapy mainly consisted of combinations of cyclophosphamide and doxorubicin [AC] +/- a taxane[AC→T] ( mainly by medical oncologists) or AC+ 5-FU [CAF] (mainly by clinical oncologists). Of 305 cases 272 (89.2%) completed adjuvant therapy, 8(2.6%) died during treatment. Median overall survival was 57.1 months (95% CI; 55.6 to 59.5 months). For metastatic disease, median PFS was worse for patients < 40 years. Conclusions: Pathology and biology mirrored global situation, over 75% of patients had non metastatic disease. A significant proportion of early disease patients did not complete treatment.
The role of Ki67 in involved lymph nodes as a predictive biomarker for response to neoadjuvant chemotherapy in patients with early breast cancer.
Authors: Kolberg-Liedtke Cornelia , Hussein Shady , Bankfalvi Agnes , Steinborn Julia , Ting Saskia , Bittner Ann-Kathrin , Hoffmann Oliver , Pott Birgit , Hannig Carla Verena , Wetzig Sarah , Kolberg Hans-Christian
Published: June 2021

e12553

Background: Neoadjuvant chemotherapy (NACT) is a standard in early breast cancer (EBC) with an unfavorable tumor biology and pathologic complete remission (pCR) after NACT is indicating an improved prognosis. Ki67 is well established as a prognostic and predictive biomarker in early breast cancer and the association of high Ki67-results in breast tumors at the time of initial diagnosis and pCR after NACT is used for decision making for versus against NACT in daily routine in many countries. Data about associations of Ki67 in involved lymph nodes and response to NACT are missing. Methods: We conducted a retrospective analysis among patients in our database who had received NACT for EBC, had lymph node involvement verified by core cut biopsy and available data for pCR, age, estrogen and progesterone receptor (ER, PR) status, HER2neu status, Ki67 in the breast tumor and grading. Patients treated in clinical studies were excluded. Ki67 was measured in the archived material of biopsies from involved lymph nodes and the association between Ki67 in involved lymph nodes and response to neoadjuvant chemotherapy was analyzed. Results: 52 patients were included with regard to the criteria mentioned above, 21 had to be excluded because there was not enough lymph node biopsy material for Ki67 analysis. 7 (22.6) of the remaining 31 patients achieved a pCR and 11 (35.5%) achieved a nodal conversion to ypN0. Median Ki67 was 35% [3%, 85%] in involved lymph nodes and 40% [10%, 90%] in the breast. There was no significant correlation (Spearman Rho) between Ki67 in involved lymph nodes and pCR whereas there was for Ki67 in the breast (p = 0.046). The ROC-analysis resulted in a cut-off of 47% with the highest sensitivity for Ki67 in lymph nodes regarding prediction of nodal conversion. An analysis with a cut-off of Ki67 in involved lymph nodes of 47% predicted a nodal conversion in 60% of the cases (Chi-Square and Fisher’s Exact test; p = 0.0049). Conclusions: Our analysis supports Ki67 as a strong predictive biomarker regarding pCR after neoadjuvant chemotherapy. Although high Ki67 expression in involved lymph nodes is significantly associated with nodal conversion, it does not add clinically meaningful information to Ki67 in the breast.
Trastuzumab-dkst versus trastuzumab: Real-world pCR rates in patients with HER2+ breast cancer treated with neoadjuvant chemotherapy plus trastuzumab from Alberta, Canada.
Authors: Yang Charlie , Khwaja Raida , King Karen , Tang Patricia A. , Nixon Nancy Alice , Lupichuk Sasha M.
Published: June 2021

e12569

Background: Biosimilars are defined as medical products that contains a version of the active substance with similar biological characteristics, efficacy, and safety as the original product. Differences however, exist between biosimilars and their original comparator. Unlike small-molecule drugs, identical generic versions cannot be mass produced since manufacturers often have proprietary rights to living cell lines and processes involved in producing biologics. Due to this inherent alteration in production, the potential for clinically meaningful differences may exists. These risks are reduced from bench to clinic through a minimum of one phase 1 study to demonstrate comparability of PK and PD between the biosimilar and the original product, and one phase 3 study to demonstrate equivalency for at least one indication. To date, studies have mainly looked at trastuzumab-dkst in the metastatic setting. This retrospective study compared the pathological complete response (pCR) rates of trastuzumab-dkst to trastuzumab in the neoadjuvant setting for HER2+ early breast cancer (EBC) in Alberta. Methods: Neoadjuvant patients with HER2+ EBC treated with trastuzumab from November 2018 -October 2019 and trastuzumab-dkst from December 2019 - September 2020 were identified. There was no crossover between products. Logistic regression was used to control for variables potentially associated with pCR: trastuzumab product (trastuzumab vs trastuzumab-dkst), age ( < 40 vs 40+), pre-operative T (T1/2 vs T3/4) and N stage (negative vs positive), grade (I/II vs III), HR status (ER and/or PR positive vs ER/PR negative), HER2 (3+ vs SISH+), chemotherapy (anthracycline containing vs not), and chemotherapy completion (yes vs no). Results: 136 patients were identified (56% trastuzumab; 43% trastuzumab-dkst) and there were no significant differences in baseline characteristics except more patients in the trastuzumab-dkst group were clinically N negative; 39% vs 14.3% trastuzumab (p = 0.001). pCR was 35.6% for patients treated with trastuzumab-dkst versus 40.3% with trastuzumab (p = 0.598). In the logistic regression model, there was no significant difference in the odds of a pCR for patients treated with trastuzumab-dkst versus trastuzumab after controlling for the variables selected a priori (OR 1.1, 95% CI 0.5-2.4, p = 0.850). There was a trend for decreased odds of pCR for anthracycline use (OR 0.72 95% CI 0.3-1.6, p = 0.417). Conclusions: pCR rates were similar for patients treated with trastuzumab-dkst compared to trastuzumab in our real world study of HER2+ neoadjuvant EBC and comparable to pivotal phase 3 trials. For a 65 kg patient, the estimated cost savings of trastuzumab-dkst therapy is $22,000, and approximately $240-300 for a non-anthracycline chemotherapy backbone.
Low expression of microRNA-195 is a poor prognostic marker for ER-positive breast cancer patients.
Authors: Tokumaru Yoshihisa , Oshi Masanori , Katsuta Eriko , Murthy Vijayashree , Matsuhashi Nobuhisa , Futamura Manabu , Yoshida Kazuhiro , Takabe Kazuaki
Published: June 2021

e12576

Background: MicroRNA-195 (miR-195) is a tumor suppressive microRNA in breast cancer; however, its clinical relevance remains debatable because most data is either in vitro or from small cohort studies. In this study, we hypothesized that miR-195 low expressing tumors associate with high proliferative characteristics and poor survival. Methods: We obtained the clinical data and survival information of breast cancer patients from two large publicly available databases and one small cohort; The Cancer Genome Atlas (TCGA),The Molecular Taxonomy of Breast Cancer International Consortium (METARBRIC), and GSE45666. Total of 755, 1287, and 116 patients’ data were obtained from TCGA, METABRIC, and GSE45666 respectively. Survival analysis, Overall survival (OS) and Disease-free survival (DFS) was performed by comparing the high and low expression groups. CYT score, xCell, and other immunological factors were used to evaluate intratumoral immune cell composition. Also, gene set enrichment analysis (GSEA) was performed between miR-195 high and low expression groups. Results: The patients were divided into miR-195 high and low groups by utilizing median cutoff. At first, we confirmed that miR-195 expression was significantly lower in tumors compared to normal breast tissue in TCGA as well as GSE45666. Advanced grades were significantly associated with lower expression of miR-195 in ER positive/HER2 negative (ER+/HER2) subtype with both TCGA and METABRIC cohorts ( p< 0.001 and p< 0.001, respectively). On the contrary this was not consistent with other subtypes, HER2+ and triple negative (TN). Also, Low miR-195 expressing tumors demonstrated higher MKI67 expressions in ER+/HER2- subtype with TCGA ( p< 0.001). This was validated with METABRIC cohort ( p< 0.001). Furthermore, GSEA demonstrated that low miR-195 expressing tumors enriched the gene sets related with cell cycle or cell proliferation, such as MYC signaling, mTOR signaling, E2F signaling, G2M Checkpoint signaling and PI3K_Akt_mTOR signaling, compared with high miR-195 expressing tumors in ER+/HER2-. Conclusions: Low expression of miR-195 was associated with improved OS in ER positive breast cancer patients. Also, low miR-195 expressing tumors were found to associate with advanced grades as well as enriching the genes relating to cell proliferation and cell cycle, which may explain the poor survival of low miR-195 expressing patients in ER positive breast cancer.
A deep learning survival model for triple-negative breast cancer patients.
Authors: Xu Yiyue , Zou Bing , Fan Bingjie , Li Wanlong , Wang Shijiang , Yu Jinming , Wang Linlin
Published: June 2021

e12594

Background: Triple-negative breast cancer (TNBC) is the subtype of breast cancer with the worst prognosis. There is no reliable model for survival prediction of TNBC patients. The traditional Cox regression analysis with poor prediction power cannot satisfy the clinical needs. The purpose was to establish a deep learning model and develop a new prognostic system for TNBC patients. Methods: This study collected data of TNBC patients from the Surveillance, Epidemiology, and End Results (SEER) program between 2010 and 2016. 70% were used to develop the deep learning model, 15% were used as the validation set, and 15% as the independent testing set. Then the concordance-index (c-index) and Brier score (IBS) were calculated and compared with the Cox regression analysis and random forest. Finally, according to the classification of the deep survival model, an individualized prognosis system was established. Results: A total of 37,818 patients were enrolled in this study. In the validation set, the c-index of the deep learning was 0.799, which was better than the traditional Cox regression model (0.774) and random forest (0.763). The independent testing set further proved the robustness of the deep survival model (c-index 0.788). The new prognosis system based on the deep survival model reached an area under the curve (AUC) of 0.805, which was better than the Tumor, Node, Metastases (TNM) staging system (0.771). Conclusions: Deep learning model had better prediction power than the Cox regression analysis and the random forest. The established prognosis system can better predict prognosis and aid individual risk stratification for TNBC patients patients.
ASTRO suitability criteria assessment in early-stage breast cancer patients treated with intraoperative radiation therapy (IORT) plus 21 gene recurrence score (RS) assay result guided adjuvant medical therapy.
Authors: Schwartzberg Barbara Stewart , Howell Kathryn T. , Moore Joyce A , Paul Devchand
Published: June 2021

e12598

Background: A patient subset consented in an institutional review board-approved single institution clinical trial designed to determine the efficacy and outcome of single fraction IORT received adjuvant medical therapy recommendations based on their RS results. Patients were categorized according to American Society for Radiation Oncology (ASTRO) suitability criteria for accelerated partial breast irradiation. Comparison was made between ASTRO suitability criteria, RS and post-IORT outcomes. Methods: Outcome of pts completing single fraction (20Gy) IORT per protocol using disposable balloon electronic brachytherapy and RS assessment were reviewed. Data collection included demographics, pathology, RS, medical therapy, local (LR) and axillary (AR) recurrences, and survival. Results: From Nov 2011 – Jan 2016, 115 pts (aged 43 – 84, mean 63 years) completed both IORT per protocol and RS assessment. Pts with estrogen receptor positive invasive carcinomas (range 0.2 – 2.4 cm, median size 0.9 cm) and RS results were categorized by ASTRO suitability criteria, LR and AR, as shown in Table 1. The recurrence rate at mean follow-up of 6.8 years was 3.5%. There were 3 LR (RS 0, 17, 18) and 1 AR (RS 19). There has been no breast cancer related death. Adjuvant endocrine therapy was recommended to all pts. Twenty-three (20%) patients received chemotherapy, including 12 (71%) pts in the high RS (RS >25) groups. Chemotherapy was not given to any pt with a RS <18. One LR (RS 0, ASTRO Suitable, age 65, 1.5 cm) declined endocrine therapy. Ten (19%) pts with RS of 11 – 25 received chemotherapy. One LR (RS 17, ASTRO suitable, age 64, 1.5 cm) and 1 axillary recurrence (RS 19, ASTRO Suitable, age 66, 1.3 cm), neither receiving chemotherapy, were compliant with endocrine therapy. One LR (RS 18, ASTRO Suitable, age 51, 0.6 cm) was treated with cyclophosphamide and docetaxel. Seven (78%) pts with RS of 26 - 30 and 5 (63%) pts with RS >30 received chemotherapy, with no recurrences in these groups. Conclusions: One hundred fifteen pts treated with single fraction IORT per protocol and RS guided adjuvant medical therapy at a single institution were found to have a 3.5% recurrence rate at mean follow-up of 6.8 years. ASTRO suitability criteria and high RS results (RS > 25) did not correlate with recurrence. The success of IORT observed in this trial as local therapy for early-stage breast cancer patients was independent of genomic factors or patient suitability criteria. Recurrence rates were comparable to those reported in IORT peer-reviewed published data and treatments using breast conserving surgery plus whole breast radiation therapy. [Table: see text]
Sociodemographic and clinicopathologic features of elderly breast cancer patients in Brazil: A sub-analysis of AMAZONA III study (GBCAM 0115).
Authors: Pavei Carla , Rosa Daniela Dornelles , Bines Jose , Werutsky Gustavo , Barrios Carlos H. , Cronemberger Eduardo , Simon Sergio D. , Queiroz Geraldo Silva , Cordeiro De Lima Vladmir Claudio , Freitas-Junior Ruffo , Resende Heloisa Magda , Costa Susanne C. , Reinert Tomas , Van Eyll Brigitte M. , Bertoni Vanessa Dybal , Neron Yeni Verónica , Lazaretti Nicolas , Gomes Rafaela , Rebelatto Taiane Francieli , Liedke Pedro Emanuel Rubini
Published: June 2021

e12603

Background: Breast cancer (BC) is the most common invasive cancer diagnosed in women worldwide. The risk of developing BC increases with age. Studies have shown that approximately up to half of BC cases occur in patients aged 65 years and older. To better understand and characterize elderly patients with BC in Brazil, we performed a sub analysis of AMAZONA III study (ClinicalTrials.gov identifier: NCT02663973). Methods: The AMAZONA III study (GBCAM 0115) is a prospective cohort study that included 2,950 women with newly diagnosed invasive BC from January 2016 to March 2018 in 23 Brazilian sites. For this sub analysis, only BC patients aged 65 years and older were included. To compare sociodemographic and clinicopathologic features we classify patients into two groups: cohort 65 to 75 years of age and cohort 75 years and older. Qualitative variables were described by absolute and relative frequencies and compared with Chi-square test. Results: Of 2,950 BC patients from AMAZONA IIII study, 602 (20.8%) were ≥ 65 years-old and were included in this sub analysis. Most patients (93.1%) had ECOG performance status 0-1, 63.4% were white. In terms of educational level, 68.6% had reported completing primary school or less. At diagnosis, 23.7% of patients had clinical stage (CS) I, 41.9% had CS II, 28.2% had CS III, and 6.2% had CS IV disease. The majority of BC were detected by symptoms and only 34.2% were detected by screening. Regarding pathological characteristics, half of cases were grade 2, 58.7% were hormone receptor positive, 25% were HER-2 positive, and 16.0% were triple negative. When evaluated by subgroup, patients from cohort 75 years and older were more frequently diagnosed at advanced clinical stages and had worse ECOG performance status at diagnosis. There was no statistically significant difference in molecular subtype, tumor grade, and mode of BC detection (Table). Conclusions: Elderly patients commonly had BC detected by symptoms. Patients from cohort 75 years and older are diagnosed more frequently with advanced disease and worse performance status than patients from cohort 65 to 75 years. Strategies to improve BC screening and educational programs among elderly patients are warranted to guarantee accessibility to early BC diagnosis.[Table: see text]
Which therapeutic strategy is less cardiotoxic in the treatment of breast cancer: Using paclitaxel before or after doxorubicin?
Authors: de Melo Marcelo Dantas Tavares , Almeida André L.C. , Neto Aluisio Jose de Oliveira Monteiro , Júnior Edval Gomes dos Santos , Reis Israel Costa , Mota Ludmila , Lopes Nilson Lima , De Afonseca Samuel Oliveira , do Espírito Santo Thyago Monteiro
Published: June 2021

e12617

Background: The combination of doxorubicin (DOX) with paclitaxel (PTX) is effective in the treatment of breast cancer (BC). However, DOX-associated cardiotoxicity (CTX) is aggravated by the use of PTX. There´s no consensus on which sequence is most safe. Methods: Prospective study of women with primary BC. All of participants received four cycles of DOX and 12 infusions of PTX. Participants were divided into two groups, at the discretion of the oncologist: Group 1-PTX before DOX and Group 2-DOX before PTX. CTX was defined as an absolute reduction in left ventricular ejection fraction (LVEF)>10% to a value <53%. Patients underwent clinical evaluation and echocardiography before treatment (phase 1) and one year after treatment (phase 2). Results: Sixty-nine women were evaluated: 19 in G1 and 50 in G2. The groups had similar clinical characteristics. The doses of radiation, DOX and PTX used were similar. Eight (11.6%) patients developed CTX: two (10.5%) in G1 and six (12.0%) in G2 (p=0.62). LVEF was similar between the groups in phase 1 (G1=65.1±3.5; G2=65.2±3.9; p=0.96), with a significant reduction after one year in both groups: G1=61.4±8.1% (p=0.021) and G2=60.8±7.6% (p<0.001). Although lower, LVEF remained similar between groups after phase 2 (p=0.79). Conclusions: In women with BC who underwent chemotherapy, the incidence of CTX at the end of the first year of treatment was similar regardless of whether DOX was used before or after PTX. [Table: see text]
PI3Kγδ inhibitor combined radiation enhances the antitumor immune effect of PD-1 blockade in syngenic triple negative breast cancer models.
Authors: Kim In Ah , Han Min Guk , Jang Bum Sup , Kang Mi Hyun
Published: June 2021

e13041

Background: Breast cancer is generally viewed as immunologically cold, imposing an immune-suppressive tumor microenvironment (TME) and responding poorly to lone immune checkpoint blockade (ICB). As an adjunct to ICB, radiation therapy (RT) holds promise in terms of in situ tumor vaccination effect, although it is known to promote immune suppression, increasing regulatory T cells (Treg), myeloid-derived suppressor cells (MDSCs), and M2 tumor-associated macrophages (TAMs). It was our contention that combined use of RT and a PI3Kγδ inhibitor to combat immune suppression might enhance the efficacy of ICB. Methods: Murine breast cancer cells (4T1) were grown in both immune-competent BALB/c mice, humanized patient-derived xenograft (PDX) were established, and both were irradiated by 3 fractions of 24 Gy. A PD-1 blockade (10 mg/kg) and a PI3Kγδ inhibitor (IPI145; 15 mg/kg) were then administered every other day for 2 weeks. Tumors from humanized PDX was sequenced to identify immune-related pathways and to profile infiltrated immune cells. Transcriptomic and clinical data were acquired from The Cancer Genome Atlas (TCGA) pan-cancer cohort, and the deconvolution algorithm was used to profile immune cellular distributions at certain levels (high vs. low) of PIK3Cand PIK3CD expression. Results: In the immune-competent syngenic 4T1 murine tumor model, PD-1 blockade alone led to tumor hyperprogression, whereas a three-pronged strategy of PI3Kγδ inhibitor, RT, and PD-1 blockade significantly delayed primary tumor growth, boosted abscopal effect, and improved animal survival. According to FACS analysis, RT significantly increased not only CD8+cytotoxic T-cell fractions but also immune-suppressive Tregcells, MDSCs, and M2 TAMs. However, PI3Kγδ inhibitor significantly lowered proportions of Treg, MDSCs, and M2 TAMs, achieving dramatic gains in splenic, nodal, and tumor CD8+ T-cell populations after triple combination therapy. There were significantly decreased tumor expressions of p-AKT, PD-L1, and HIF1α by PI3Kγδ inhibition. Triple combination therapy significantly delayed primary tumor growth in humanized PDX model as well and analyses of RNA sequencing data of humanized PDX samples showed decreased immune suppressive pathways with decreased and M2 macrophage and increased CD8+ T-cell by triple combination therapy. In the TCGA pan-cancer cohort, high Treg/CD8+T-cell and M2/M1 TAM ratios and poor overall patient survival was associated with high PIK3CG (PI3Kγ) or PIK3CD (PI3Kδ) gene expression. Conclusions: These findings collectively indicate that PI3Kγ and PI3Kδ are clinically relevant targets in an immunosuppressive TME. Combining PI3Kγδ inhibitor, RT, and PD-1 blockade may thus be a viable approach, helping to overcome the therapeutic resistance of immunologically cold tumors such as breast cancer.
Pathology molecular reflex testing improves turn-around-time and overall molecular testing rates in NSCLC.
Authors: Braxton David R. , Huang Yancui , Darabi Sourat , Chavez Frank , Das Partha Manas , Bowen TJ
Published: June 2021

e13507

Background: Dozens of genetic aberrations have become druggable targets or act as biomarkers of diseases for which pts may qualify for precision medicine treatment options. Biomarker informed treatments can lead to vast improvements in patient outcomes over traditional approaches like chemo. However, comprehensive molecular profiling (CMP) to identify eligible pts is not always accomplished, particularly in the community setting where molecular testing is often outsourced to third party laboratories. Here we report our experience with reflex testing protocols, where a pathology department has responsibility for initiating biomarker testing without the need for direct oncologist involvement. In this study we investigate and report how pathologist initiated reflex protocols influences access to molecular biomarker testing and assessed changes in testing rates, result tracking, and timeliness of results. Methods: We reviewed a reflex testing protocol at Hoag Hospital (Newport Beach, California), for NSCLC pts. A process map was generated to identify pts who qualified for reflex testing. After developing the process map, we used VIPER software that gathers data from electronic medical records and pathology systems to perform our analysis. We evaluated protocol adherence, failures, QNS rates, and TAT from test ordering to sample receipt and processing and ultimately all the way to results being received and compared patients that followed the reflex protocol as compared to those that did not to determine any differences. Data analysis was performed to understand how effective the reflex system was in ensuring the appropriate patients received CMP and any benefits in efficiency that resulted. Results: We evaluated 300 NSCLC pts over a 12-month timeframe for their reflex testing statuses. 78.5% of those pts tested received Next Generation Sequencing (NGS) tests, vs. 21.5% receiving non-NGS based tests. We also found over 75% of the pts that were qualified for reflex testing had complete tests, while 25% were not able to be completed. Of those who did not meet reflex criteria, only 28% went on to receive CMP. The primary reason for a patient who qualified for reflex testing but did not have testing initiated was due to insurance or reimbursement concerns (42%). The average time from a reflex test being ordered to results available was 25.9 days. Without reflex the TAT averaged 40.5 days (15.4 days difference). For reflexed cases, 78% of CMP results were available prior to treatment initiation. Conclusions: We demonstrate that implementation of a CMP reflex testing program is feasible and can ensure that a higher percentage of NSCLC pts receive molecular testing and that these results can be provided nearly two times sooner than without such programs. Our next steps are to automate this process to allow practices that do not have the personnel to manage such programs can still benefit via technology assistance.
Right-censoring bias in trials shared at the Project Data Sphere platform.
Authors: Barrajon Enrique , López Jiménez Antonio , Barrajon Laura
Published: June 2021

e13543

Background: Independent of the bias inherent to the design and execution of clinical trials, bias may be the result of patient censoring. A bias index (BI) was developed to detect right-censoring bias and tested in datasets availabe at Project Data Sphere, a data sharing research platform maintained by the CEO Roundtable on Cancer, Inc.,* a nonprofit corporation to improve outcomes for cancer patients by openly sharing deidentified data. Methods: Project Data Sphere platform was searched for clinical comparative trials with available experimental and comparator survival datasets: overall survival (OS) and event-free survival (EFS: disease-free survival, DFS, or progresssion-free survival, PFS). The R language and the integrated development environment Rstudio were used to import and manage the datasets. BI was defined in the events time domain as the adjusted proportion of censor times below the mean event time. Comparison of BI in different datasets were made with the two-sided Wilcoson unpaired test. A weighted regression model was applied to estimate the influence of bias on survival results as measured by the hazard ratio (HR). Results: Out of 184 trials, 19 trials offered both comparator and experimental arms, 3 of them not based on survival analysis and 4 of them with 2 substudies, providing 72 datasets based on OS and/or EFS, for a total of 16532 patients (90.8% of the 18198 patients in published trials). BI over the theshold was found in 24% of EFS datasets (versus 0% in OS datasets, Wilcoxon p = 0.0007), especially in PFS (35% vs 0% in DFS datasets, p = 0.00004). Nearly two thirds of the variance in the HR of EFS datasets was explained by the HR of OS datasets (adj.R2 = 0.638, p = 1.5e-5), approaching to what was found in the corresponding publications (adj.R2 = 0.751, p = 7.81e-5). Though the trials sample is small, introducing the BI of control and experimental datasets in the model decreases the residual standard error (3.831 vs 3.958) and increases the correlation (adj.R2 = 0.99, p < 2.2e-16), resulting in the model: HR(EFR) = 0.985 HR(OS) + 0.36 BI(exper) – 0.42 BI(control). Conclusions: This study is a proof of concept that right-censoring bias may be detected and estimated in clinical trials, especially in PFS datasets, and opens the possibility for correcting biased estimations in survival and increasing the precision in the prediction of OS from preliminary EFS. (*) This abstract is based on research using information obtained from ProjectDataSphere.org, which is maintained by Project Data Sphere LLC. Neither Project Data Sphere nor the owners of any information from the web site have contributed to, approved or are in any way responsible for the contents of this abstract.
Assessment of objective response rate (ORR) by investigator versus blinded independent central review in pivotal trials of drugs approved for solid tumor indications.
Authors: Zettler Marjorie E. , Lee Choo H. , Gajra Ajeet , Feinberg Bruce A.
Published: June 2021

e13570

Background: Objective response rate (ORR), defined as the proportion of patients with a complete response or partial response to treatment according to Response Evaluation Criteria in Solid Tumors (RECIST), is the most common endpoint used in pivotal trials supporting FDA approval of cancer drugs for solid tumor indications. Blinded independent central review (BICR) is frequently employed in clinical trials to minimize bias in evaluation of response rate, as historically, assessment of response by investigators (INV) has been shown to overestimate treatment effect. In this study, we analyzed the variability in assessment of ORR between INV and BICR in trials supporting recent Food and Drug Administration (FDA) approvals of drugs for solid tumor indications. Methods: The FDA’s novel drug approvals (2015-2019) were reviewed to identify drugs receiving primary approval for solid tumor indications. Drug approval packages accessed via the Drugs@FDA database and primary publications for the pivotal trials accessed via PubMed were reviewed for investigator-assessed and BICR-assessed ORR. For trials reporting both assessments, the difference between INV and BICR ORR was determined across all study arms. Data are presented using descriptive statistics. Results: A total of 36 drugs received primary approval for the treatment of solid tumors between 2015 and 2019. Of the 40 supporting trials, ORR was the primary endpoint for 21 (52.5%), progression-free survival for 13 (32.5%), and overall survival for 2 (5.0%). ORR was evaluated in 35 of the 40 trials (87.5%). Eight (22.9%) of the 35 trials evaluated INV ORR only, 5 (14.3%) evaluated BICR ORR only, and 22 (62.9%) evaluated both INV and BICR ORR. Among the 22 trials (29 arms in total), the mean difference between BICR- and INV-assessed ORR was -4.3% (95% CI: -6.4, -2.3); the range was -13.1 to 5. INV-assessed ORR was greater than BICR-assessed ORR in 22 of 29 arms (75.9%). The mean difference between BICR- and INV-assessed ORR among the 6 arms representing placebo or active control was -6.0 (95% CI: -11.0, -0.9), compared with -3.9 (95% CI: -6.3, -1.5) among the 23 experimental arms. Conclusions: Compared with BICR, INV overestimated ORR in three-quarters of the trial arms, including those representing control and experimental treatments. Despite this variability, for one fifth of the trials supporting approval of drugs to treat solid tumors, INV was the only method used to assess ORR. For consistency, and the ability to make relative cross-trial comparisons of ORR between agents, BICR should be considered for evaluation of tumor response in all registrational trials.
The role of digital clinical measures in improving cancer care and research.
Authors: Goldsack Jennifer , Aguilo Ariel , Coravos Andrea , Economos Chris , Lyden Kate
Published: June 2021

e13584

Background: From objectively assessing performance status to recording simple vital signs, the adoption of high quality digital clinical measures offers enormous possibilities for transforming cancer care & research. However, the development & deployment of high quality digital measures in oncology lags behind adoption in other therapeutic areas. At the time of submission, the DiMe library of digital endpoints reports 166 unique digital endpoints being used in industry sponsored trials of new medical products, but none are being used in an oncology trial. There are seven digital clinical measures working their way through the FDA qualification program, but none in oncology. During the pandemic, care for patients with cardiac and other chronic conditions transitioned out of the clinic & into the home powered not only by virtual visits, but high quality information from remote monitoring. A study of oncology care facilities worldwide reported 89% finding difficulty in delivering usual care due to the challenges of safely bringing patients into the clinic during COVID. Methods: From March to Sep 2020, cross-industry stakeholders at the Digital Medicine Society (DiMe), Elektra Labs, Genentech, Koneksa, Myokardia, Sage Bionetworks, Scripps Research, and the US Food & Drug Administration came together to synthesize best practices from the digital health field, breaking down silos to create ‘ The Playbook’, the comprehensive and accessible “how-to” guide to support all stakeholders working to advance the safe, effective, ethical, and equitable use of digital clinical measures to improve lives. In October 2020, DiMe -- a 501c3 non-profit dedicated to advancing digital medicine to improve lives -- convenened a pre-competitive collaboration of 44 participants from 29 organizations to drive the adoption of the best practices articulated in The Playbook. Results: The Playbook describes trans-industry consensus for best practices for developing and deploying digital clinical measures across patient care, clinical research, and public health, including for oncology. Conclusions: The clinical, technical, and operational best practices necessary to develop and deploy high quality digital clinical measures into cancer care & research have been established. There is no reason for their successful adoption in oncology to lag behind other therapeutic areas. The Playbook and additional resources to support implementation due for launch on April 30 are critical tools for the field of oncology.
Flow redesign to improve prostate cancer access and care at the public healthcare system in Sao Jose dos Campos, Brazil.
Authors: Pinto Carlos Frederico , Stanzani Danilo , Pontes Elitania , Coelho Stela Maris , Correa Margarete , Benjamin Joana , Silva Messias Borges
Published: June 2021

e13595

Background: Prostate cancer is the second most common cancer diagnosis in São José dos Campos (SJC) and the sixth cause of cancer mortality. Access to early diagnosis and treatment is one big challenge in the local public healthcare system (Sistema Único de Saude) due limited resources. Between 2018 and 2020 the healthcare public system of SJC redesigned the access flow for diagnosis and prostate cancer care in SJC is a mid-sized city (720,000 hab.) in Sao Paulo state, Brazil. Methods: The local SUS was designed to provide access to all patients with elevated PSA (>4.00µg) to a urologist for further evaluation and subsequent reevaluation if needed. This process created long queues and median time to access the few overburdened specialists available to over a year (410 days median), risking significant disease progression and stage upgrade. The flow redesign was done using lean and queue theory techniques and involved basically a new Fast Track to patients with PSA > 10.0µg with age between 50 and 79, considering the probability of 67% chance of prostate cancer (Catalona, et al. NEJM 1991; 324: 1156-61). Patients were referred from the primary care doctor straight forward to a biopsy and then to a medical oncologist, that would recommend further treatment, including a urologist evaluation. Patients with PSA between 4 and 10 would keep regular access to urology. The aim was to guarantee access to specialist up to 60 days from the first PSA > 4.0µg. Results: From April 2019 to September 2020, 277 patients (PSA > 10.0µg) were submitted to a biopsy through the Fast Track; 150 were positive (54,2%) for prostate cancer; and 72% with Gleason score 7 or higher. The diagnosis of prostate cancer from 2017 to 2020 increased over 300% (from 93 to 283), and access to treatment in less than 60 days increased from 15 to 140 patients in 2020. Patient with PSA > 4.0µg access to urology in less than 60 days also increased dramatically by eliminating several medical appointments and unneeded process steps (Table). Conclusions: The process redesign for patients with elevated PSA was able to provide access to care < 60 days for more than 80% of patients with elevated PSA or positive for prostate cancer by splitting high risk and low risk patients and using alternative flows to reduce urology overloaded agenda. Access to Urology for patients with PSA >4.00 < 10.00µg (not in Fast Track).[Table: see text]
Decrease of oncological patients’ hospital visits during Covid-19 pandemic: The experience of a tertiary Romanian center.
Authors: Crisan Cristina , Cainap Calin Ioan , Deac Andrada Larisa , Havasi Andrei Dan , Balacescu Ovidiu , Balacescu Loredana , Bochis Ovidiu Vasile , Vlad Ioan-Cătălin , Cainap Simona Sorana
Published: June 2021

e13607

Background: The outbreak of COVID-19 pandemic has changed the provision of medical services worldwide. Oncological patients continued receiving specialty treatments. We assess the impact of the pandemic on the oncological patients' visits to a tertiary cancer center. Methods: We analyzed registrations from the administrative data system of in and outpatients in all departments of the Cluj-Napoca Oncology Institute, during March-October 2020, compared to the same 7-month period of the previous year. Results: The decrease during March-October 2020 was of 40.2% for new referrals overall (with the most significant drop in April, of 80%), of 52.5% for medical oncology inpatients, 39% for pediatric oncology department inpatients, 69% for radiotherapy inpatients, 34.9% for surgical interventions and 31% decrease of issued pathology reports. The decrease was less important for outpatients: only 10% for medical oncology outpatient department, 33% for radiotherapy, and 27% for breast cancer unit outpatients. Imaging investigations were only slightly influenced by the pandemic (reduction of 5% for MRI scans, 19% for mammograms, whereas performed CT scans were even more after the outbreak of COVID-19). Conclusions: Our results show a decrease in the number of patients during the period after the outbreak of the COVID-19 pandemic, more for inpatients and less significant for outpatient departments, probably because of the internal circuits reorganization but also because of healthcare measures taken nationally and locally to limit the spread of the pandemic. Keywords: COVID-19, pandemic, oncology referrals, disruption.
Regorafenib in recurrent glioblastoma patients: A large real-life experience.
Authors: Caccese Mario , Cerretti Giulia , Padovan Marta , Zagonel Vittorina , Lombardi Giuseppe
Published: June 2021

e14024

Background: Regorafenib (REG), an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases showed encouraging benefit in recurrent GBM patients enrolled in the randomized, phase 2 REGOMA trial. We investigated the clinical outcome and safety of REG in a real-life population of recurrent glioblastoma patients treated at Veneto Institute of Oncology as off-label use. Methods: The clinical data of patients receiving REG at Veneto Institute of Oncology (Padua, Italy) were entered prospectively into clinical records and were retrospectively analyzed. The primary endpoints of the study were overall survival (OS) and safety. The major inclusion criteria were: histologically confirmed diagnosis of GBM, disease progression as defined by RANO criteria after surgery followed by radiochemotherapy with temozolomide, ECOG PS ≤ 2; PTS with ≥ 2 prior lines of therapy were excluded. According to original schedule, patients received REG 160 mg once daily for the first 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity, or consent withdrawal. Kaplan-Meier method was used to estimate the survival curves, RANO criteria for radiological assessment, CTCAE v5.0 for drug related adverse events. Results: From February 2018 to September 2020, 54 consecutive patients were treated with REG and enrolled in this study: median age was 56, ECOG PS 0-1 in 91% of patients, MGMTmet in 53%, second surgery at the time of relapse were performed in 30% of enrolled patient, 41% of patients underwent steroids at baseline. At the time of analysis, median follow-up was 11.1 ms, 30 PTS (56%) had died and 50 PTS (93%) had progressed. Median OS was 10.2 ms (95%CI, 6.4-13.9), 12m-OS was 43%; median PFS was 2.3ms (95%CI, 1.3-3.3) and 6m-PFS was 18%. All patients were evaluable for response: disease control rate (DCR) was 46.3%; stable disease was reported in 38.8% and partial response in 7.4%. Age, MGMT status and corticosteroid use at baseline were not statistically significant on multivariate analysis for OS. Grade 3 drug-related adverse events (AEs) occurred in 10 patients (18%) and the most frequent were hand-foot skin reaction, asthenia and increased lipase and transaminases; 1 PT (2%) reported a grade 4 AE (rash maculo-papular). AEs led to REG dose reductions in 37% of patients and, it was permanently discontinued in 5%. No death was considered to be drug-related. Conclusions: We reported a large, mono-institutional “real world” experience of REG in recurrent glioblastoma patients. Overall, results are close to those reported in REGOMA trial although, we showed a longer OS. Toxicity was moderate and manageable. Encouraging clinical benefits of REG in recurrent GBM population were confirmed.