tbuckley/cabot-search huggingface dataset:
Abstract 3417: A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: The small bowel tumor cohort
Authors: Young Kwang Chae, Megan Othus, Sandip Pravin Patel, Mark Zalupski, Anup Kasi, Maged Khalil, Aparna Kalyan, Blase Polite, Sarah Fenton, Sewan Gurung, Christine M. McLeod, Francis Giles, Helen X. Chen, Elad Sharon, Edward Mayerson, Melissa Plets, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock
Journal: Cancer Research (2020)

Abstract Background: The potential therapeutic benefits of checkpoint inhibitors and their application to many different tumor types has been a key factor in the advancement of medical oncology since their first approval for metastatic melanoma in 2011. However, their efficacy in rare tumor types remains to be seen. This paper presents the results of combination therapy with both anti-CTLA and anti-PD-1 in the small bowel cohort of SWOG S1609 Dual Anti-CTLA-4 &amp; Anti-PD-1 blockade in Rare Tumors (DART). Methods: This study is designed as a prospective, open-label, multicenter phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks) in rare tumors. Here we report the outcomes from patients diagnosed with small bowel cancer (SBC). The primary endpoints included overall response rate (ORR) (RECIST v1.1) (complete response (CR) and partial responses (PR)); progression-free survival (PFS), overall survival (OS), stable disease &amp;gt;6 months, and toxicity were the secondary endpoints. Results: Twenty five patients were registered to the cohort and twenty three received therapy. The duodenum was the primary site of origin in 52% (N=11), 14% (N=3) arose in the ileum and 14% (N=3) arose in the jejunum. The primary site of origin was unknown in 19% (N=4). The overall response rate was 8% (CR, 4%, N= 1; PR, 4%, N= 1). The median PFS was 2 months; 6-month OS was 48% and median OS 6 months. The most common toxicities were diarrhea and fatigue (both 17%) followed by dyspnea (13%) with diarrhea, increased bilirubin, colitis and elevated lipase (all 4.3%) as the most common grade 3-5 immune-related adverse events. Conclusions: Combination therapy with ipilimumab plus nivolumab in small bowel tumors resulted in an overall response rate of 8% with one partial and one complete response in twenty three treated patients. Citation Format: Young Kwang Chae, Megan Othus, Sandip Pravin Patel, Mark Zalupski, Anup Kasi, Maged Khalil, Aparna Kalyan, Blase Polite, Sarah Fenton, Sewan Gurung, Christine M. McLeod, Francis Giles, Helen X. Chen, Elad Sharon, Edward Mayerson, Melissa Plets, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: The small bowel tumor cohort [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3417.
Abstract 848: Taming numerous information on variants for better treatment decisions
Authors: Katrin Glocker, Alexander Knurr, Janine Al-Hmad, Dennis-Immanuel Czogalla, Marvin Izzo, Christian Koch, Benjamin Roth, Frank Ückert
Journal: Cancer Research (2020)

Abstract The developments in the field of genetic screening make high throughput sequencing of patient samples not only technically, but also financially feasible. However, this confronts physicians with a vast amount of information for one patient. Additionally, as more research is done on single variants, the knowledge about predictive biomarkers is also extensive and increasing steadily. To make information like the clinical relevance of single variants available to physicians, multiple databases are available. This adds to the enormous load of data physicians in a molecular Tumor Board (MTB) have to review on top of clinical data to find a suitable therapy for a specific patient. To support a MTB in making informed therapy decisions based on genomic data, relevant clinical data like the diagnosis and previous therapies is extracted from the electronic health record used by the physicians to document the patients and their course of disease. After sequencing, the variants get pre-filtered by bioinformaticians and their characteristic features like the specific amino acid exchange for SNVs or total copy number for CNVs are presented. With these data, knowledge bases are queried in the background and relevant information is displayed in the Knowledge Connector. For each variant, information about effect of the mutation on the protein, an assessment of oncogeneity, drugs targeting the specific variation or the gene and pathways the gene is involved in, are summarized in one view to grasp all important facts at a glance. Furthermore, the tool offers the opportunity to manually assess the variants according to evidences and automatically generates a report upon this curation, which can be sent to treating physicians. With this, physicians are supported in managing the huge amount of information referring to one patient in the whole process of a MTB. Additionally, the number of patients benefiting from this comprehensive analysis of specific characteristics can be increased by not only saving time of experienced specialists, but also by enabling physicians with less extensive knowledge about genetics to find therapies based on genetic variants. Citation Format: Katrin Glocker, Alexander Knurr, Janine Al-Hmad, Dennis-Immanuel Czogalla, Marvin Izzo, Christian Koch, Benjamin Roth, Frank Ückert. Taming numerous information on variants for better treatment decisions [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 848.
Abstract 1932: Effect of the C677T <i>MTHFR</i> polymorphism on toxicity in patients with colon adenocarcinoma treated with fluoropyrimidine based chemotherapy
Authors: Allan Ramos-Esquivel, Marta Valle-Cano
Journal: Cancer Research (2020)

Abstract Background: Fluoropyrimidines (5FU and capecitabine) are the backbone of treatment for metastatic colorectal cancer. Their mechanism of action mainly consists on the inhibition of tymidylate synthase in a reaction where the 5,10-methylenetetrahydrofolate (MTHF) acts as a cofactor. This cofactor is highly regulated by the MTHF reductase (MTHFR) activity. It has been previously shown that C677T and A1298C polymorphisms of MTHFR are associated with a low activity of this enzyme, which can result in a higher therapeutical activity and toxicity from these compounds. The aim of this study was to assess the relationship between C677T and A1298 MTHFR polymorphisms and adverse events in first-line patients treated with fluoropyrimidine-based chemotherapy for stage IV colorectal adenocarcinoma. (NCT registration number: 03852290) Methods: Patients with metastatic colorectal cancer were prospectively recruited in the San Juan de Dios Hospital (San José, Costa Rica). First line therapy consisted in any fluoropyrimidine used alone or in combination with oxaliplatin and/or irinotecan +/- bevacizumab, panitumumab or cetuximab. Germline DNA extraction was done from blood samples to determine the C677T (rs1801133) and A1298C (rs18011131) polymorphisms of MTHFR. Patients were followed by their treating physician every 12 weeks in order to assess the response and tolerability of their treatment. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 4.0. Results: A total of fifty patients were enrolled. C677T MTHFR genotypic frequencies were distributed as follows: CC (30%), CT(50%), and TT (20%). The C allele frequency was 55%, following the Hardy-Weinberg equilibrium (HWE) (p=0.91). A1298C MTHFR genotypic frequencies were: AA (70%), AC (26%), and CC (4%). The A allele frequency was 80%, also following the HWE (p=0.58). MTHF 677 TT genotype was associated to high risk of grade III or IV anaemia (p=0.004), neutropenia (p&amp;lt;0.001), thrombocytopenia (p=0.001), neuropathy (p=0.03), diarrhea (p=0.015), and hand-foot syndrome (p=0.045). There was no statistically significant association between the A1298 MTHFR polymorphism and side effects. Conclusion: The MTHF 677 TT genotype can potentially predict toxicity in a subset of Hispanic patients treated with fluoropyrimidine-based therapy for metastatic colorectal cancer. Citation Format: Allan Ramos-Esquivel, Marta Valle-Cano. Effect of the C677T MTHFR polymorphism on toxicity in patients with colon adenocarcinoma treated with fluoropyrimidine based chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1932.
Abstract 115: Hedgehog signaling pathway promotes breast cancer adaptation to hypoxia
Authors: Tshering D. Lama-Sherpa, Sarah C. Kammerud, Lalita A. Shevde
Journal: Cancer Research (2020)

Abstract Breast cancer is the most commonly diagnosed cancer in women in the US. Metastasis accounts for the majority of breast cancer-related deaths. Rapidly proliferating primary tumors experience oxygen levels that are lower in comparison to the normal tissue. The proportions of these hypoxic tumor cells in breast cancer strongly correlate to the incidence of metastasis. Around 70% of breast cancers present with bone metastasis. Tumor cells that metastasize to the bone can lead to an imbalance in bone homeostasis, often leading to osteolysis. Our lab has previously reported that the activation of Hedgehog (Hh) signaling, one of the embryonic developmental pathways found to be abnormally activated in breast cancer, leads to increased osteolysis in vivo. The incidence of osteolytic metastasis at the tibio-femoral junction was significantly reduced in the Hh signaling-deficient mice. Since a hypoxic microenvironment is prevalent in bone, it is imperative to understand how Hh signaling drives tumor cell adaptation to hypoxia. The hypoxic tumor microenvironment in the primary tumor might select for metastatic cells that are better able to metastasize to the bone. We hypothesize that Hh signaling enables the adaptation of breast cancer cells to hypoxia and consequently their metastatic potential. Hh signaling can be canonically activated through smoothened (SMO)-dependent activation of the transcriptional regulator GLI. Cellular response to hypoxia is mediated by the hypoxia-inducible factors (HIFs). To understand the importance of Hh signaling activation in hypoxic condition, we inhibited the Hh signaling pathway using GLI and SMO inhibitors. Additionally, we knocked-down GLI1 in breast cancer cell lines. We have identified a feed-forward mechanism between Hh signaling and HIF signaling in hypoxic conditions leading to sustained hypoxia response by stabilization of HIF-1α. Future investigations will address the significance of Hh signaling inhibition in a murine model of TNBC. This study will help determine the therapeutic benefit of hedgehog inhibitors in controlling hypoxia-mediated metastasis and tumorigenesis. Citation Format: Tshering D. Lama-Sherpa, Sarah C. Kammerud, Lalita A. Shevde. Hedgehog signaling pathway promotes breast cancer adaptation to hypoxia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 115.
Abstract 5749: The association between physical health-related quality of life, physical functioning and risk of contralateral breast cancer
Authors: Nita Mukand, Nadia Nabulsi, Ali Alobaidi, Alemseged Asfaw, Brian C. Chiu, Naomi Y. Ko, Gregory S. Calip
Journal: Cancer Research (2020)

Abstract Background: Physical limitations and disability among older cancer patients can lead to suboptimal treatment and surveillance for secondary cancers. Our objective was to evaluate the effects of poor physical health-related quality of life (PQOL) and physical functioning (PF) on contralateral breast cancer (CBC) risk among older women diagnosed with unilateral breast cancer (UBC). Methods: We performed a nested case-control study within a cohort from the Surveillance, Epidemiology and End Results Medicare Health Outcomes Survey (MHOS) database. Women were required to have first primary UBC without prophylactic contralateral mastectomy. Among 2,938 women ages 65 years and older with stages I-III UBC between 1997 and 2011, we identified 100 subsequent CBC cases and 915 controls using incidence density sampling without replacement matched on age, race, and quarter-year of diagnosis. PQOL and PF were determined from survey responses to the Medical Outcomes Trust Short Form 36 component scores. Conditional logistic regression models were used to estimate relative risks (RR) and 95% confidence intervals (CI) for metachronous CBC. Results: Cases and controls were similar with respect to comorbidities, stage, surgery and radiation treatments but differed by hormone receptor status (ER/PR-negative, cases 23% and controls 11%). Cases had lower mean PQOL (-1.8; 95% CI -4.3, 0.7) and PF (-2.2, 95% CI -4.9, 0.5) component scores, but these differences were not statistically significant. In multivariable models, estimates suggest increased CBC risk for women in the lowest quartile of PQOL compared to those in the upper quartile (RR=1.8; 95% CI 0.8, 4.3). Compared to women in the upper quartile of physical functioning scores, women in the lower three quartiles had a 2.6-fold (95% CI 1.2, 5.9) increased risk of CBC. Conclusions: Our findings indicate that low physical health-related quality of life is common among older women diagnosed with breast cancer, and poor physical functioning is related to risk of CBC. Efforts to understand and minimize declines in physical functioning post-breast cancer diagnosis may help optimize treatment strategies to reduce the risk of this adverse outcome. Citation Format: Nita Mukand, Nadia Nabulsi, Ali Alobaidi, Alemseged Asfaw, Brian C. Chiu, Naomi Y. Ko, Gregory S. Calip. The association between physical health-related quality of life, physical functioning and risk of contralateral breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5749.
Abstract 4327: Progranulin (GP88) is an independent prognostic factor for prostate cancer patients
Authors: Helge W. Taubert, Amer Abdulrahman, Markus Eckstein, Rudolf Jung, Juan Guzman, Katrin Weigelt, Ginette Serrero, Binbin Yue, Carol Geppert, Robert Stöhr, Arndt Hartmann, Bernd Wullich, Sven Wach
Journal: Cancer Research (2020)

Abstract Prostate cancer, is still a major cause of morbidity and mortality among men worldwide. The expression of the survival and proliferation factor progranulin (GP88) has not yet been comprehensively studied in PCa tumors. The aim of this study was to characterize GP88 protein expression in PCa by immunohistochemistry and to correlate the findings to the clinico-pathological data and prognosis. Immunohistochemical staining for GP88 was performed by TMA with samples from 442 PCa patients using an immunoreactive score (IRS). Altogether, 233 cases (52.7%) with negative GP88 staining (IRS&amp;lt;2) and 209 cases (47.3%) with positive GP88 staining (IRS≥2) were analyzed. A significant positive correlation was found for the GP88 IRS with the PSA value at prostatectomy and the cytoplasmic cytokeratin 20 IRS, whereas it was negatively associated with follow-up times. The association of GP88 staining with prognosis was further studied by survival analysis (Kaplan-Meier, univariate and multivariate Cox's regression analysis). Increased GP88 protein expression appeared as independent prognostic factor for overall, disease-specific and relapse-free survival in all PCa patients. Interestingly, in the subgroup of younger PCa patients (≤65 years), GP88 positivity was associated with a 3.8-fold (P=0.004), a 6.0-fold (P=0.008) and a 3.7-fold (P=0.003) increased risk for death, disease-specific death and occurrence of a relapse, respectively. This finding gains impact against the background of increasing numbers of PCa cases among younger men below 65 years of age. Summarizing, GP88 protein positivity appears to be an independent prognostic factor for PCa patients. Citation Format: Helge W. Taubert, Amer Abdulrahman, Markus Eckstein, Rudolf Jung, Juan Guzman, Katrin Weigelt, Ginette Serrero, Binbin Yue, Carol Geppert, Robert Stöhr, Arndt Hartmann, Bernd Wullich, Sven Wach. Progranulin (GP88) is an independent prognostic factor for prostate cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4327.
Measuring bonding or attachment in the parent-infant-relationship: A systematic review of parent-report assessment measures, their psychometric properties and clinical utility
Authors: A. Wittkowski, S. Vatter, A. Muhinyi, C. Garrett, M. Henderson
Journal: Clinical Psychology Review (2020)

Meaningful, valid and reliable self-report measures can facilitate the identification of important parent-infant-relationship factors, relevant intervention development and subsequent evaluation in community and clinical contexts. We aimed at identifying all available parent-report measures of the parent-infant-relationship or bond and to appraise their psychometric and clinimetric properties. A systematic review (PROSPERO: CRD42017078512) was conducted using the, 2018 COSMIN criteria. Eight electronic databases were searched. Papers describing the development of self-report measures of the parent-infant-bond, attachment or relationship from pregnancy until two years postpartum or the assessment of their psychometric properties were included. Sixty-five articles evaluating 17 original measures and 13 modified versions were identified and reviewed. The studies' methodological quality (risk of bias) varied between 'very good' and 'inadequate' depending on the measurement property assessed; however, scale development studies were mostly of 'inadequate' quality. Although most measures had good clinical utility, the psychometric evaluation of their properties was largely poor. The original or modified versions of the Postpartum Bonding Questionnaire collectively received the strongest psychometric evaluation ratings with high quality of evidence. This novel review revealed that only a few antenatal and postnatal measures demonstrated adequate psychometric properties. Further studies are needed to determine the most robust perinatal measures for researchers and clinicians.
Abstract 4264: Liquid biopsy and FFPE tissue based somatic <i>BRCA1/2</i> variant screening in breast and ovarian cancer
Authors: Ibrahim Boga, Ozge Sonmezler, Atil Bisgin
Journal: Cancer Research (2020)

Abstract Next generation sequencing (NGS) has widened its use since it provides highly precise and accurate genetic testing with reasonable costs in tumor genetic profiling from somatic materials such as FFPE (formalin fixed paraffin embedded) tissue and liquid biopsy [circulating cell free DNA (ccfDNA)]. It has a high value in differentiating treatment strategies especially in BRCA1/2 genomic profiling in breast and ovarian cancer. However, somatic BRCA1/2 testing still remains unclear algorithm versus germ-line testing approved in human genetics for many decades. Thus, we sum up our testing results in relation with clinical diagnosis. FFPE samples from 89 and 74 liquid biopsy samples from breast and/or ovarian cancer patients were collected and sequenced via the GeneReader NGS system for BRCA1 and BRCA2 genes. QCI-Analyze and QCI-Interpret bioinformatics tools were used for bioinformatics analyses. We detected 56 actionable variants in 48 patients (29.5%) out of 163 patients. The 46.4% (nvariant=26) of the mutations were detected in BRCA1 gene while 53.6% (nvariant=30) of them were in BRCA2 gene. The allele frequencies vary from 1.43% to 100% with an average of 43% in 89 FFPE tissue samples with the positivity rates of 30% (nsample=27) while the rate is 28.4% (nsample=21) in 74 liquid biopsy samples. Interestingly, 8 patients had more than one actionable variant and 5 of them had mutations both in BRCA1 and BRCA2 genes. To sum up, genetic testing for targeted treatments has become first-line clinical testing in cancer and taken its place in international guidelines. Thus, somatic testing to profile BRCA genes should be considered in breast and ovarian cancer algorithm since 5% percent of the patients additionally carry somatic actionable mutation with regarding 15% positivity in germ-line BRCA1/2 studies. Citation Format: Ibrahim Boga, Ozge Sonmezler, Atil Bisgin. Liquid biopsy and FFPE tissue based somatic BRCA1/2 variant screening in breast and ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4264.
Abstract 625: Selective inhibition of NF1 loss-of-function driven oncogenic signaling in melanomas
Authors: Cara Abecunas, Mohammad Fallahi-Sichani, Judith Leopold, Christopher Whitehead, Elizabeth Ziemke
Journal: Cancer Research (2020)

Abstract Oncogenic activation of the MAPK signaling pathway occurs across &amp;gt;90% of melanomas, motivating the clinical evaluation of MAPK-targeted therapies in these tumors. However, only BRAFV600E/K-mutated melanomas show consistent clinical responses to MAPK-targeted therapies. Inactivation of the tumor suppressor gene neurofibromin 1 (NF1) is among the mechanisms that drive hyperactivated RAS signaling in &amp;gt;10% of melanomas. These tumors, however, have variable dependency on RAS-mediated pathways, such as MAPK and PI3K/mTOR, and thus exhibit inconsistent sensitivity to targeted inhibitors of these pathways. It is of paramount importance, therefore, to identify new therapeutic strategies to block tumor cell growth or improve MAPK- or PI3K-targeted therapy response in NF1 loss-of-function (NF1LoF) melanomas. To identify actionable vulnerabilities in NF1LoF melanoma cells, we apply a systematic approach, combining multiplexed high-throughput immunofluorescence microscopy, single-cell measurements and computational analysis, to study the responses of differentially mutated human melanoma cell lines to a variety of RAS-related pathway inhibitors. Our analysis led to the identification of a multi-kinase inhibitor, MTX-216, which is efficacious in induction of tumor cell death and inhibition of NF1LoF melanoma growth both in vitro and in vivo, but does not exhibit cytotoxicity in BRAFV600E melanomas and wild-type melanocytes. Single-cell analysis of downstream RAS-mediated signaling markers (e.g. phospho-S6) and proliferation markers (e.g. Ki-67) demonstrated cell-to-cell heterogeneity in NF1LoF melanoma cells treated with commercially available kinase inhibitors, resulting in incomplete drug responses. MTX-216 reduces this single-cell variability, providing evidence that co-suppression of signaling and proliferation pathways is correlated with drug-induced cytotoxicity. Our systematic analysis, together with ongoing studies to uncover the mechanism of action of MTX-216 in NF1LoF melanomas, has the potential to identify new and effective treatment strategies for NF1-mutant melanomas. Citation Format: Cara Abecunas, Mohammad Fallahi-Sichani, Judith Leopold, Christopher Whitehead, Elizabeth Ziemke. Selective inhibition of NF1 loss-of-function driven oncogenic signaling in melanomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 625.