tbuckley/cabot-search huggingface dataset:
Proper dosage of primary pegylated G-CSF prophylactic use for breast cancer patients receiving adjuvant or neo-adjuvant chemotherapy.
Authors: Liang Yu, Xin Lei, Ying Lin
Journal: Journal of Clinical Oncology (2019)

e18354 Background: Myelosuppression during chemotherapy can lead to life-threatening infections, dose reductions, treatment delays, as well as prolonged hospitalizations, early morbidity, and early mortality. According to NCCN guideline, Pegfilgrastim 6mg per cycle is recommended for breast cancer patients receiving chemotherapy, and dosage modification based on body weight is not required. However, primary PEGylated G-CSF prophylaxis comes with significant extra cost, which has a great impact on health care resources, especially for patients without insurance coverage. Methods: We analyzed clinical data of patients, weighing between 45 and 65 kilogram, received a single subcutaneous PEGylated recombinant human G-CSF injection at fixed doses of either 3 mg or 6 mg per chemotherapy cycle approximately 24 hours after completion of each cycle of chemotherapy. Data for this retrospective study were obtained from Thyroid and Breast Surgical Department of the First Affiliated Hospital of Sun Yat-sen University between July 1, 2017, and October 31, 2017. Results: 41 cycles in 33 patients were included in 3mg PEGylated G-CSF group, and 46 cycles in 39 patients were included in 6mg PEGylated G-CSF group. Among chemotherapy cycles, the incidence of neutropenic event was19.5%and 2.2% in 3mg PEGylated G-CSF group and 6mg PEGylated G-CSF group, respectively. No patients experienced dose reductions or treatment delays in both groups. Using single-factor Logistic Regression Analysis, we found that dose of PEGylated G-CSF(3mg vs 6mg) was significantly associated with occurrence of neutropenic event(p = 0.028). Multi-factor Logistic Regression Analysis also showed that dose of PEGylated G-CSFwas significantly associated with occurrence of neutropenic event (p = 0.031). Conclusions: Our study showed that dose of prophylactic PEGylated G-CSF was significantly associated with occurrence of neutropenic events. So adequate dose of PEGylated G-CSF is important to reduce chemotherapy induced neutropenic events and to guarantee the quality of chemotherapy in patients with breast cancer.
Unique perspectives from the transgender community: A retrospective chart review of cancer care needs for transgender patients.
Authors: Carolyn Moloney, Margaret Allen, Deirdre O'Mahony, Derek Power, Richard Bambury, Seamus O'Reilly, Dearbhaile Catherine Collins
Journal: Journal of Clinical Oncology (2019)

6566 Background: It is estimated that 1% of a population experience some degree of gender non-conformity. There is scant information worldwide on cancer incidence and mortality for this population however due to a lack of investigating large-scale prospective studies. National cancer registries do not hold demographics on this population. Current literature indicates transgender people may face an increased cancer risk. Transgender patients may avoid screening programmes for cancers which are themselves gendered. Transgender patients can feel excluded from gender specific cancer support groups. We set out to identify how cancer services in Ireland can better meet transgender people’s unique needs. Methods: Medical oncology consultants in the South/South-West of Ireland were contacted to identify patients who identified as transgender or gender non-conforming. We carried out a retrospective chart review of the four transgender patients identified. We analysed staging at diagnosis, family supports, smoking history, alcohol use and whether cancer treatment affected gender transitioning treatment and if this had documented effects on mental well-being. We also noted if medical records reflected a new name or change of gender and if not, whether original name and gender used for chemotherapy and blood product administration. Results: All four patients were diagnosed with relatively advanced disease at diagnosis- Stage IIIc high grade ovarian cancer, stage IV gastrointestinal tumour, stage IVb diffuse large B Cell and locally advanced extra-abdominal desmoid tumour. Of the four patients, three had a smoking and alcohol history on diagnosis. All four patient’s recent medical correspondence reflected a name and gender change but the medical records did not reflect this. Three patients had documented depression for which they were attending psychiatry services. It was noted that two patients had gender transitioning treatment postponed due to cancer care. Minimal family support was noted for two patients. Conclusions: The transgender community is a growing population that will continue to integrate into mainstream society. Our retrospective chart review adds to a growing body of evidence which suggests gender minorities may suffer from cancer-related disparities and have an increased need for psychosocial support. As in other studies, it is difficult to identify these individuals. We should identify gender minority individuals and report this data in medical records in order to build much needed epidemiological information.
Dynamics of the immune status in patients with cervical cancer receiving complex treatment with dendritic cell vaccine.
Authors: Anna P. Menshenina, Oleg I. Kit, Elena Yu. Zlatnik, Elena S. Bondarenko, Inna A. Novikova, Tatiana I. Moiseenko, Elena M. Frantsiyants, Ekaterina V. Verenikina, Olga G. Selezneva, Meri L. Adamyan, Anna A. Cherkasova
Journal: Journal of Clinical Oncology (2019)

e17005 Background: The purpose of the study was to determine the influence of complex treatment with dendritic cell vaccine on the dynamics of the immune status of patients with cervical cancer. Methods: 17 patients with cervical cancer (CC) T2b-4аN0-1M0-1 received chemotherapy with combined radiotherapy to the pelvic area. Between courses of cytostatic treatment, patients underwent dendritic cell vaccination (DCV) planned individually depending on the treatment effect, which was evaluated by the results of examination, US, CT and MRI. A control group included 19 patients with locally advanced CC receiving standard polychemotherapy (PCT) and radiotherapy. Immune status of patients was evaluated by flow cytometry (FACSCantoII BD) including T, B, NK cells, Tregs (CD4+CD25+CD127dim), memory T cells (Тm) and naïve T lymphocytes (Th0) was determined in the dynamics of the treatment. Results were calculated as a percentage from the total number of lymphocytes, for Tregs – in % from CD3+CD4+ cells, for Тm and Th0 – in % from CD3+CD4+ and CD3+CD8+ cells. Results: 1 to 4 cycles of PCT with DCV caused a transient increase in Tregs after the 1 st cycle, with further regression to the initial levels; other studied lymphocyte subsets remained unchanged. Only after 8 or more DCV cycles, a favorable immunological dynamics developed; however, it was not observed in controls. DCV increased levels of lymphocytes with potential cytotoxicity: CD3+CD8+ (from 19.0±2.0 to 28.8±1.5%), NK cells (from 12.0±2.0 to 21.2±1.9%). During DCV courses helper-inducer Tm amount rose from 51.7±6.3 to 69.7±4.3%, while in remission – CD8+Tm grew from 28.5±2.1 to 40.4±5.3% (p &lt; 0.05 for all cases). Repeated DCV was satisfactorily tolerated by CC patients and, when used in complex treatment, caused a pronounced clinical effect. DCV did not lead to serious adverse events. Patients in remission are still observed. Conclusions: Treatment for CC with DCV causes a positive dynamics of the immune status, with the maximal effect after 8 and more DCV cycles. Remission is apparently maintained due to an increase in the level of TmCD8+ cells.
Blood tumor mutational burden (bTMB) and tumor PD-L1 as predictive biomarkers of survival in MYSTIC: First-line durvalumab (D) ± tremelimumab (T) versus chemotherapy (CT) in metastatic (m) NSCLC.
Authors: Naiyer A. Rizvi, Byoung Chul Cho, Niels Reinmuth, Ki Hyeong Lee, Alexander Luft, Myung-Ju Ahn, Michel van den Heuvel, Manuel Cobo Dols, David Vicente, Alexey Smolin, Vladimir Moiseyenko, Scott Joseph Antonia, Kazuhiko Nakagawa, Sarah B. Goldberg, Edward S. Kim, Jill Walker, Rajiv Raja, Feng Liu, Urban J. Scheuring, Solange Peters
Journal: Journal of Clinical Oncology (2019)

9016 Background: MYSTIC, an open-label, Ph3 trial of first-line D (anti-PD-L1) ± T (anti-CTLA-4) vs platinum-based CT, showed an improvement in OS with D vs CT in pts with tumor cell PD-L1 expression ≥25% (PD-L1 TC ≥25%; HR 0.76 [97.54% CI 0.56–1.02], p = 0.036). Exploratory analyses showed bTMB was a predictive biomarker for OS with D±T vs CT. We report further exploratory analyses of OS according to PD-L1 and bTMB. Methods: Immunotherapy/CT-naïve pts with mNSCLC were randomized (1:1:1) to D, D+T or CT. bTMB levels (mut/Mb) were evaluated with the GuardantOMNI platform (Guardant Health), and PD-L1 TC expression with the VENTANA PD-L1 (SP263) IHC assay. Results: D improved OS vs CT in pts with PD-L1 TC ≥25% across bTMB levels (PD-L1 TC ≥25%/bTMB≥20 HR 0.79 [95% CI 0.45, 1.39]; PD-L1 TC ≥25%/bTMB &lt; 20 HR 0.64 [95% CI 0.45, 0.90]). In contrast, D+T improved OS vs CT in pts with bTMB≥20 across different PD-L1 TC expression levels (Table; PD-L1 TC ≥25%/bTMB≥20 HR 0.44 [95% CI 0.23, 0.84]; PD-L1 TC &lt; 1%/bTMB≥20 HR 0.42 [95% CI 0.17, 0.97]). Additional cutoffs and outcomes in subgroups defined by both biomarkers will be presented. Conclusions: These exploratory analyses from MYSTIC support PD-L1 TC expression as an appropriate predictive biomarker for OS with D vs CT, while suggesting bTMB as a predictive biomarker for OS with D+T in mNSCLC. These biomarkers appear to be independent and both may be important for mNSCLC treatment decisions. Interpretation of these data may be limited by small sample sizes; further investigations are warranted. Clinical trial information: NCT02453282. [Table: see text]
The risk of second primary malignancy in patients with localized thymoma: A U.S. population-based study.
Authors: Dipesh Uprety, Lubina Arjyal, Swapna Narayana, Peter James Polewski, Amir Bista, Yazhini Vallatharasu, Bilal Haider Lashari, Amit Khanal
Journal: Journal of Clinical Oncology (2019)

8568 Background: Thymoma is a rare neoplasm of anterior mediastinum. Patients often have an indolent disease. The prognosis of limited stage disease is excellent with a 10-year survival rate of 70 to 80%. Data regarding the risk of second primary malignancy in thymoma survivors are limited in recent years. In this study, we aimed to determine the risk of second primary malignancies (SPMs) among patients with limited stage thymoma. Methods: We utilized the Surveillance, Epidemiology and End Results (SEER)-13 registry to identify adult patients (≥ 18 years) with limited stage thymoma. We calculated the risk of SPM, developing ≥ 6 months after an index thymoma diagnosis, using Multiple Primary Standardized Incidence Ratio and an Absolute Excess Risk (AER) between 2004 and 2010. Statistical significance was defined as p &lt; 0.05. Results: The database identified a cohort of 1,544 patients with limited stage thymoma with a median follow-up duration of 107 months (11-281 months). A total of 176 (11.39%) patients developed SPMs with a median latency of 62.5 months (range 6-272 months). Median age at diagnosis of SPM was 69 years (range 25- 96 years). Overall, SPM occurred at an observed to expected (O/E) ratio of 1.53 (95% CI 1.32-1.76), p &lt; 0.001 with an AER of 60.52 per 10,000 patient-years at risk. A significantly increased risk was noted for cancer of lung and bronchus (O/E 1.77, 95% CI 1.21-2.52, p = 0.004; AER 12.17/10,000), skin excluding basal and squamous (O/E 2.09, 95% CI 1.04-3.75, p = 0.03; AER 5.17/10,000), urinary bladder (O/E 2.14, 95% CI 1.17-3.6, p = 0.014; AER 6.72/10,000), thyroid (O/E 3.48, 95% CI 1.4-7.17,p = 0.009; AER 4.49/10,000), and leukemia (O/E 3.26, 95% CI 1.63-5.83, p = 0.001; AER 6.86/10,000), including acute lymphocytic leukemia (O/E 16.09, CI: 1.95-58.11; AER 1.69/10,000), acute myeloid leukemia (O/E 3.83, CI: 1.04-9.8; AER 2.66/10,000) and other acute leukemia (O/E 29.45, CI: 3.57-106.39; AER 1.74/10,000). The risk was not significant for lymphoma (Hodgkin and non-Hodgkin), chronic leukemia, oropharyngeal, digestive tract and hepatobiliary cancer as SPM. Conclusions: The risk for SPMs is significantly increased in patient with thymoma compared to general population. Given the long-term risk of SPM, patient should be followed closely with judicious use of age-appropriate cancer screening.
The spatiotemporal evolution of early-stage non-small-cell lung cancer.
Authors: Siwei Wang, Jingyuan Zhang, Weizhang Xu, Hua Bao, Xiaojun Fan, Yunlong Jiang, Xue Wu, Xiaonan Wang, Yang Shao, Lin Xu, Rong Yin
Journal: Journal of Clinical Oncology (2019)

8539 Background: Lung cancer is a genetically heterogeneous disease. The genomic basis of tumorigenesis and cancer cell spread, as well as intratumor heterogeneity (ITH) and subclonal evolutionary patterns might correlate with patients’ clinical outcomes. In this prospective study, we aimed to investigate such associations through comprehensive spatiotemporal genomic profiling in early-stage non-small cell lung cancers (NSCLCs). Methods: We performed deep targeted sequencing (GeneseeqPrime, 425 genes) of 503 primary tumor regions and 141 metastatic lymph node tumors from surgery and 378 longitudinal plasma biopsies (pre- and post-operation) across 128 Stage I-III NSCLC patients. ITH and phylogenetic tree for each patient were analyzed and correlated with clinical outcomes. Longitudinal and phylogenetic ctDNA analyses were further performed. Results: Spatial ITH varied among patients and was associated with clinical phenotypes. Geographical stratification of clonal structure, with localized confinement of subclones, was linked with slower tumor progression. In contrast, early expansion of subclones to multiregions was associated with rapid tumor growth and lymph node metastases. EGFR and TP53 mutations were nearly always clonal, whereas subclonal mutations in PI3K, WNT and TGF-beta pathway that occurred later in evolution were found in more than 50% of the patients. By tracking these phylogenetic events, we identified five evolutionary subtypes with distinct clinical outcomes, including a rare subtype characterized by independent origin of multiple EGFR driver mutations. ctDNA profiling could capture the spatial ITH to a certain extent with additional unique signatures. Further longitudinal and phylogenetic ctDNA analyses indicated early detection of relapse and adjuvant chemotherapy resistance. Conclusions: ITH is a key factor associated with clinical outcomes of early-stage NSCLC patients, which show diverse evolutionary subtypes underpinning the disease progression such as lymph metastasis and relapse. ctDNA sequencing can be used to capture spatial ITH, predict recurrence and track drug resistance.
Oncobox, gene expression-based second opinion system for predicting response to treatment in advanced solid tumors.
Authors: Elena Poddubskaya, Anton Buzdin, Andrew Garazha, Maxim Sorokin, Alex Glusker, Alexey Aleshin, Daria Allina, Alexey Moiseev, Marina Sekacheva, Maria Suntsova, Ella L Kim, Nurshat Gaifullin, Victor Tkachev, Alf Giese, Viktoria Barbara, Pieter Borger, Nikolay Borisov
Journal: Journal of Clinical Oncology (2019)

e13143 Background: Anticancer Targeted Drugs (ATDs) specifically target one or a few types of tumor-related molecules in a cell. More than two hundred of ATDs were approved worldwide. They have different mechanisms of action and are effective for different cohorts of patients. However, many individual cases remain poorly responsive and it is of great importance to identify predictive markers of ATD efficacy. Our aim was to develop a platform enabling smart selection of the most efficient ATD therapies. Methods: We generated a second-opinion platform for clinical oncologists termed Oncobox. It is based on the analysis of gene expression profile of a cancer sample in comparison with the corresponding normal tissue biosamples in order to personalize selection of targeted drugs for individual cancer patients. Based on RNA-seq gene expression data, pathway activation levels are calculated and along with the concentrations of molecular target genes products used as predictors of tumor response to ATDs. Results: The Oncobox method was tested first on the retrospective samples of advanced tumors: gastric, renal cell, ovarian and colorectal cancers, thus showing ROC AUC values &gt; 0.7. In currently ongoing prospective trial for advanced solid tumor patients, the Oncobox tests were completed for 239 patients, primary feedback information received for 144 patients. 25 patients (17%) died before prescription of the therapy, 19% received palliative care treatment, 39% received Oncobox-recommended therapies and 25% received other therapies (February 2019). Tumor responses were estimated for 30 patients (breast, colorectal, ovarian and other cancers) receiving therapies, with disease control rate of 71% for Oncobox-recommended ATDs (Bevacizumab, Crizotinib, Trastuzumab and others) and 44% for other therapies. Our results also suggest that cancer metastases and primary tumors may have different gene expression, molecular pathway activation and drug scoring patterns, thus pointing to the importance of testing multiple tumor sites. Conclusions: Our study suggests that profound analysis of gene expression profiles of tumor tissues may be useful for ATDs treatment of advanced and metastatic cancers. Clinical trial information: NCT03724097.
Lasofoxifene as a potential treatment for ER+ metastatic breast cancer.
Authors: Muriel Laine, Sean William Fanning, Marianne Greene, Ya-fang Chang, Linda Phung, Tina T Tan, Richard Hiipakka, Barry Komm, Geoffrey Greene
Journal: Journal of Clinical Oncology (2019)

1056 Background: Estrogen receptor positive (ER+) metastatic breast cancers (MBC) that express constitutively active somatic ESR1 mutations at Y537S and D538G allow tumors to progress in the presence of approved endocrine therapies. For patients with ER+ MBC, fulvestrant is the first line of treatment. Palbociclib or other CDK4/6 inhibitors are now being included. Preliminary studies show that lasofoxifene, a selective ERα modulator (SERM), was effective in reducing tumor growth in an endocrine resistant xenograph model expressing ERα mutations Y537S or D538G. Additionally, lasofoxifene more effectively inhibited the development of liver and lung metastases than fulvestrant. Lasofoxifene is currently under evaluation in a phase 2 study. Because certain combinations of a hormonal agents like fulvestrant improved efficacy, we investigated the combination of palbociclib and lasofoxifene as a potential therapeutic for mutant ESR1 MBC. We hypothesized that this combination should improve outcome and compared it to a combination with fulvestrant. Methods: We first determined the optimal dose of lasofoxifene in an intraductal (MIND) xenograph model of MCF-7 cells that express active ERα Y537S and D538G. Subsequently, we performed combination studies with lasofoxifene (10mg/kg 5/week SQ) +/- palbociclib (100mg/kg gavage, 5/week) or fulvestrant (5mg/mouse/week, SQ) +/- palbociclib. Results: Lasofoxifene alone was significantly more effective than fulvestrant at inhibiting the metastasis of both MCF7 Y537S and D538G tumors to the lungs and liver. Lasofoxifene + palbociclib was more effective than fulvestrant + palbociclib at reducing primary tumor growth; both combinations demonstrated an increased response. Lasofoxifene + palbociclib was more effective at inhibiting liver metastasis than either drug alone and was more effective than fulvestrant + palbociclib at reducing metastasis to the liver and lung. Structural studies showed that lasofoxifene effectively disrupts the active conformation of the ERα Y537S ligand-binding domain. Conclusions: These results demonstrate that lasofoxifene, in combination with CDK4/6 inhibitors like palbociclib, has promise for treating endocrine therapy resistant ER+ MBC patients whose tumors express activating ESR1 mutations, more effectively than either drug alone.
Predictive biomarkers for response to nivolumab in head and neck squamous cell carcinoma (HNSCC) (NCT#03652142).
Authors: Amanda Psyrri, Niki Gavrielatou, Aris Spathis, Maria Anastasiou, Ekaterina Fortis, Maria Gkotzamanidou, Athina Kladi-Skandali, Evgenia Kousidou, Panagiota Economopoulou, Ioannis Kotsantis, Sylvie Rusakiewicz, Elena Mihal Vagia, Ioannis Panayiotides, George Coukos, Periklis Foukas
Journal: Journal of Clinical Oncology (2019)

6060 Background: Tumor immune cell compositions determine response to immunotherapy. For a better understanding of the mechanisms of resistance to nivolumab in HNSCC, we sought to investigate a prospective cohort of longitudinal HNSCC samples from recurrent/metastatic HNSCC pts treated with nivolumab and identify biomarkers of response and resistance. We will specifically focus on modulation of immune markers following two cycles of nivolumab. Methods: Patients with platinum-refractory HNSCC with no contraindication to nivolumab therapy are included in this study. Tumor biopsies are performed at baseline, 24-72 hours after the second cycle and at progression with appropriate written informed consent. Samples were assessed for the presence of Tertiary Lymphoid Structures (TLS), PD-L1 expression (TPS and CPS) and CD8 T cell infiltrates combined with Ki67 (CD8/Ki67 double IHC stain). The primary outcome measure of the study is change in the percentage of immune cells in post treatment compared to baseline biopsies. Secondary endpoints include safety of performing a second biopsy, best overall response rate, biomarker expression in association with response and survival. Evaluation of other biomarkers including tumor mutational burden, HLA class I and II expression and adaptive immunity cell populations using multiplex IF is ongoing. Results: Of 20 patients evaluable for response, 14 had PD (8 of whom showed hyper-progression) and 6 attained disease control (1 with PR). PD-L1 status (CPS or TPS) was not altered by treatment (p = 0.905) and CPS &gt; 20 pre-treatment showed a favorable trend towards response (p = 0.117). Absence of tertiary lymphoid structures was associated with disease progression (p = 0.0374). Infiltrating plasma cell count remained unchanged pre- and post-treatment and was unrelated to response (p = 0.458). The percentage of proliferating CD8+ T cells (CD8+/Ki67+) increased in post-treatment biopsies in the entire population (p = 0.022) and especially in progressors (p = 0.039). Pre-treatment CD8+ T cell density was higher in patients with hyper-progression compared to progressors (p = 0.029). Conclusions: Increased percentage of proliferating CD8+ T cells in progressors might represent dysfunctional T cells as has been recently shown in melanoma pts (Li H et al Cell 2019) and clinical efforts to reactivate intratumoral T cells may augment the efficacy of PD1 checkpoint inhibitors. Clinical trial information: NCT03652142.