tbuckley/cabot-search huggingface dataset:
HGG-07. RADIATION INDUCED SENESCENCE IN DIFFUSE INTRINSIC PONTINE GLIOMA CELLS REVEALS SELECTIVE VULNERABILITY TO BCL-XL INHIBITION
Authors: Ashley Vardon, Romain Guiho, Diana Carvalho, Chris Jones, Darren Hargrave, Juan-Pedro Martinez-Barbera
Journal: Neuro-Oncology (2021)

Abstract Diffuse intrinsic pontine glioma remains a devastating condition with a dismal five year survival rate less than 5%. New approaches for treating this aggressive disease are critical to driving progress. Conventional radiotherapy remains the cornerstone of treatment, with no chemotherapeutic agent found to improve survival. However, radiotherapy is often delivered as a palliative treatment, and disease often recurs 3–6 months after. Radiation causes DNA damage and oxidative stress yielding a senescent state of replicative arrest in susceptible cells. However, increasing evidence demonstrates malignant cells can escape senescence leading to tumour recurrence. Targeted ablation of non-replicating senescent tumour cells following radiation could negate tumour recurrence. It remains unknown whether DIPG undergoes senescence following radiation, and furthermore, whether senolytics can be utilised to target senescent DIPG cells. We employed radiation to induce a senescent state in primary human DIPG cell lines. Senescence was confirmed using SA-β-gal staining, lack of EdU incorporation and qRT-PCR to characterise the SASP in three primary human DIPG cell lines. RNA-sequencing on DIPG cells following radiation revealed senescence and SASP signatures. Viable cells that survive radiation were then utilised to screen candidate senolytic drugs, only Bcl-XL inhibitors demonstrated reproducible senolytic activity in radiation treated DIPG cells. Conversely, Bcl-2 inhibitors failed to show any consistent senolytic activity. These results demonstrate future possibilities of targeting radiation induced senescence in DIPG, using novel senolytic therapies and highlight Bcl-XL dependency as a potential vulnerability of surviving DIPG cells following exposure to radiation.
Three-dimensional folding dynamics of the Xenopus tropicalis genome
Authors: Longjian Niu, Wei Shen, Zhaoying Shi, Yongjun Tan, Na He, Jing Wan, Jialei Sun, Yuedong Zhang, Yingzhang Huang, Wenjing Wang, Chao Fang, Jiashuo Li, Piaopiao Zheng, Edwin Cheung, Yonglong Chen, Li Li, Chunhui Hou
Journal: Nature Genetics (2021)

Abstract Animal interphase chromosomes are organized into topologically associating domains (TADs). How TADs are formed is not fully understood. Here, we combined high-throughput chromosome conformation capture and gene silencing to obtain insights into TAD dynamics in Xenopus tropicalis embryos. First, TAD establishment in X. tropicalis is similar to that in mice and flies and does not depend on zygotic genome transcriptional activation. This process is followed by further refinements in active and repressive chromatin compartments and the appearance of loops and stripes. Second, within TADs, higher self-interaction frequencies at one end of the boundary are associated with higher DNA occupancy of the architectural proteins CTCF and Rad21. Third, the chromatin remodeling factor ISWI is required for de novo TAD formation. Finally, TAD structures are variable in different tissues. Our work shows that X. tropicalis is a powerful model for chromosome architecture analysis and suggests that chromatin remodeling plays an essential role in de novo TAD establishment.
Trends in cancer screening volumes at an urban health center during the COVID-19 pandemic.
Authors: Mahir Khan, Margaret Wright, Karriem Watson, Shikha Jain
Journal: Journal of Clinical Oncology (2021)

10551 Background: The Coronavirus-19 (COVID-19) pandemic has disrupted cancer screening for reasons including healthcare resource preservation, infection control efforts, and patient factors. There is limited literature quantifying this interruption of care, particularly in vulnerable and racial/ethnic minorities. Methods: We compared the volume of cancer screening at the University of Illinois Hospital &amp; Health Sciences System before and during the COVID-19 pandemic using data obtained from the electronic medical record. Modalities included mammogram, ultrasound, and MRI for breast; Pap test for cervical; colonoscopy, CT colonography, and flexible sigmoidoscopy for colorectal; low-dose CT for lung; and prostate-specific antigen test for prostate. Of note, screening and diagnostic tests could not be distinguished for colorectal cancer. We examined percent changes in cancer screening counts for each month from February 2020-August 2020, using January 2020 as a reference. Results were stratified by gender, race, and ethnicity. Results: Screening volume declined rapidly after January 2020, with the nadir for each cancer site occurring in April 2020: breast ( n = 0, -100%), cervical ( n = 169, -84%), colorectal ( n = 35, -89%), lung ( n = 0, -100%), and prostate ( n = 108, -72%). Values recovered by August 2020 for most cancer sites except cervical cancer, which remained decreased (-23%). There were no differences in screening trends by gender. With respect to race, breast screening volume in Black patients decreased earlier and exhibited slower recovery compared to White patients. White patients had poorer cervical screening recovery than Black patients by August 2020 (-60% vs. -23%). Hispanics had poorer recovery of breast screening compared to non-Hispanics by August 2020 (-23% vs. 6%). Conclusions: We observed widely decreased cancer screening attributable to COVID-19. Breast cancer screening data specifically showed persistent disparities affecting Black and Hispanic patients. Despite the reassuring recovery of multiple screening methods by August 2020, an increase above baseline is needed to compensate for initial declines. Further studies will likely reveal long-term consequences of this unprecedented situation.[Table: see text]
Comparison of patient-reported impact of COVID19 on cancer care delivery: A prospective, cross-sectional study.
Authors: Emily Hsu, Jyoti Chhabra, Oscar Serrano, Alvaro G. Menendez
Journal: Journal of Clinical Oncology (2021)

6551 Background: Impact of COVID19 on cancer care delivery and outcomes remains unknown. Few trials have investigated patients’ perceived risks and benefits, and cancer care delivery (CCD) alterations related to COVID19. We sought to identify differences on behaviors and social determinants of health in Hispanics and other underrepresented populations (H/UP) compared to the general population (GP). Methods: An IRB-approved validated 27-item questionnaire was offered in English and Spanish to all pts. receiving cancer care at participating cancer centers over a 4 month period. Examined variables included demographic information, social risk and behavioral factors, preferred sources of health information, and overall satisfaction with CCD during the pandemic. Results: A total of 180 pts were enrolled in the study. Compared to GP, H/UP’s perceived risk of COVID19 was higher with 93% vs 87% more likely to cancel or avoid social gatherings and 54% vs 46% more likely to change daily routine. H/UP appeared more concerned with personal and financial safety; if unable to find work/get paid for 2 weeks, 26% H/UP vs 10% GP would struggle to keep up with expenses. 40% H/UP vs 10% GP have concerns on perceived ability to secure food on short term and consider COVID19 a major threat to their health (70% vs 46%) and financial situation (63% vs 35%). H/UP’s perceived benefits of protective measures is higher with 81% vs 60% routinely practicing social distancing (SD) and 79% vs 66% in agreement with punitive actions for not following SD. Analysis demonstrated no significant difference by age, gender, level of education, marital status, however Hispanic ethnicity and Spanish as primary language was a statistically significant variable (p = 0.025) in perceived risks and satisfaction with CCD. No major differences were noted on sources of health information although more H/UP relied on social media (33% vs 24%). H/UP appeared to be more skeptical about availability and safety of targeted vaccines (40% vs 15%). Satisfaction regarding CCD was comparable (84% vs 86%), although more H/UP perceived CCD alterations (15% vs 10%). Going forward, H/UP would prefer to incorporate virtual visits (VV) when possible (36% vs 25%). Conclusions: COVID19-related societal, financial, health and personal fears are increased in H/UP which likely negatively affects quality of life of these at-risk populations. H/UP’s trust in SD recommendations is heightened although linguistically and culturally appropriate information may be deficient. H/UP’s belief in vaccine availability and safety is comparable to GP, although recent reports suggest deeper fear and emphasize their fear of experimentation. Interventions aimed to decrease these differences could incorporate standard communications with special attention to social media. H/UP would prefer to incorporate VV into their care, although most do not possess appropriate technology to do so.
Association of combined phase I/II study of a novel bicyclic peptide and MMAE conjugate BT8009 in patients with advanced malignancies with Nectin-4 expression.
Authors: Meredith McKean, Gerald Steven Falchook, Johanna C. Bendell, Babar Bashir, Neil Palmisiano, Roshawn Watson, Mary-Anne McKenna, Carly Campbell, Dominic Paul Smethurst, Phil Jeffrey, Julius Kirui, Hendrik-Tobias Arkenau, Elisa Fontana
Journal: Journal of Clinical Oncology (2021)

TPS2668 Background: BT8009 is a Bicycle Toxin Conjugate (BTC), a novel class of chemically synthesized molecules, comprising a bicyclic peptide targeting Nectin-4 tumor antigen, linked to cytotoxin (monomethyl auristatin E [MMAE]) via a valine-citrulline (val-cit) cleavable linker. Nectins (Nectin-1, -2, -3, and -4) and nectin-like molecules (Necl) are Ca2+ independent immunoglobulin-like cell adhesion molecules. Recent studies have shown the importance of Nectin-4 in several human cancers, including lung, ovarian, breast and bladder cancer; however, the precise roles and clinical relevance of Nectin-4 in tumors remain largely unknown. The Nectin-4 targeted enfortumab vedotin, linked to MMAE via a val-cit linker, is highly active in late-stage bladder cancer and demonstrates notable additional clinical activity as a single agent and in combination with pembrolizumab 1 . Skin toxicities, bone marrow suppression, peripheral neuropathy and diabetes have been associated with enfortumab, with some of these toxicities already noted with MMAE-bearing antibody therapies. We anticipate a similar toxicity profile for BT8009 in clinical studies. BT8009 exhibited a favorable preclinical profile and was effective in a range of cell-derived xenograph tumor models. Methods: Study BT8009-100 (NCT04561362) will evaluate safety and tolerability of weekly and every other week BT8009 administration, alone and in combination with q4w nivolumab. Determination of both a realistic phase 2 dose and a sequence will also be key to further exploration of safety and efficacy signals, along with an early examination of the role of baseline immunohistochemistry-ascertained levels of tumor Nectin-4. Patients will be recruited with advanced solid tumors associated with Nectin-4 expression after exhausting SOC options (i.e., bladder, breast, pancreatic, head and neck, gastric, esophageal and ovarian). Patients must have available tumor tissue, acceptable hematologic and other critical organ function and be willing to participate. Appropriate ethical and regulatory approvals and advice will be in place and adhered to. Exclusion criteria include uncontrolled brain metastases, uncontrolled hypertension, concomitant CYP3A4 inhibitors and significant history of autoimmune disease for the nivolumab cohorts. PK serial collections will be taken on D1 through D15. Radiologic tumor assessments for response per RECIST will be taken every two months. 1. Enfortumab Vedotin. FDA_data. 761137Orig1s000MultiDiscliplineR.pdf (fda.gov). Clinical trial information: NCT04561362.
Initial real life experience with ribociclib in breast cancer: Outcome with focus on tolerance and cardiac toxicity.
Authors: Azhar Nawaz, Jamal Zekri, Haleem J. Rasool
Journal: Journal of Clinical Oncology (2021)

e13024 Background: CDK4/6 inhibitors, such as ribociclib, are a new class of medications that are used in combination with hormonal therapy to treat advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The primary objective of this study is to evaluate the tolerance and cardiac toxicity of ribociclib in all patients at our institution. Secondary objectives include progression free survival and response rates. Methods: Patients who received ribociclib between December 2018 and August 2020 were included. Rates of dose reduction and discontinuation of ribociclib were used as surrogate markers for intolerance and were compared to those reported in land-mark trials. QTc changes and cardiac adverse events (AEs) were also collected. Results: Thirty one patients were included. Ribociclib was administered in the first-, second-, third-, and fourth-line palliative hormonal therapy settings in 5 (16%), 14 (45%), 11 (35%) and 1 (3%) patients respectively and 8/31 (26%) received prior 1-4 palliative chemotherapy lines. Ribociclib was combined with letrozole in 21 (68%) and with fulvestrant in 10 (32%) patients. QTc interval was ≤ 470 msec in all patients prior to treatment and 11 (35%) patients had preexisting cardio vascular (non electro-conductive) co-morbidities. AEs related dose reduction was reported in 12 (39%) patients [bone marrow toxicity 6 (19%), QTc prolongation 4 (13%), abnormal liver function tests 1 (3%) and abdominal pain 1 (3%)]. Ribociclib was permanently discontinued due to AEs in 5 (16%) patients (2: prolonged QTc, 2: coronary events and 1: suspected allergic reaction). The median duration of follow up was 14 months. Objective response was evaluable in 28 patients [CR: 1 (3.6%), PR: 1 (3.6%), SD: 20 (71.4%) and PD: 6 (21.4%)]. The median progression free survival was 18 months (95% CI: 12.3-23.7). Conclusions: Although objective response rates were low in this mixed cohort of heavily pretreated patients, ribociclib combined with letrozole or fulvestrant has shown a robust progression free survival in real life practice. Treatment discontinuation rate is higher than that reported in clinical trials with stringent inclusion criteria. Ribociclib associated cardiac toxicity can be appropriately managed with careful monitoring.[Table: see text]
Profiling of immune checkpoint biomarkers by multiplex immunofluorescence in breast cancer brain metastases.
Authors: Gaia Griguolo, Anna Tosi, Valentina Guarneri, Maria Vittoria Dieci, Susan Fineberg, Annavera Ventura, Luc Bauchet, Jack Jacob, Valerie Rigau, William Jacot, Antonio Rosato, Amelie Darlix, Pierfranco Conte
Journal: Journal of Clinical Oncology (2021)

2021 Background: Despite potential clinical implications, the complexity of immune microenvironment in breast cancer (BC) brain metastases (BM) is still poorly understood. Multiplex immunofluorescence (mIF) allows simultaneous visualization of several IF labeled proteins while maintaining spatial information. This novel technique can be used to comprehensively describe BCBM immune microenvironment, potentially providing useful information to guide novel therapeutic approaches. Methods: Clinical data and archival BM samples from 60 BC patients undergoing neurosurgery (2003-2018) at three institutions were collected. BCBMs were characterized using a custom mIF panel, including immune checkpoint and co-inhibitory molecules (CD3, PD1, PD-L1, TIM3, LAG3, CD163) and localization (keratin for tumor recognition) markers. Mean marker density was determined by digital image analysis (positive cells/mm2) and classified in tumor and stroma areas. Associations between immune marker densities, BC subtype and overall survival from BM diagnosis (OS) were studied. Results: Sixty BCBM samples were analyzed; 32% HR+/HER2-, 38% HER2+, 30% HR-/HER2-. At a median follow-up of 43 months, the only clinical variable associated with OS was BC subtype (shortest for HR-/HER2- and longest for HER2+, p=0.02). In the total sample area and tumor area, no significant difference in marker density was observed according to BC subtype. In the stroma area, a significant difference in TIM3+ cell density was observed according to BC subtype (highest density in HR+/HER2- and lowest density in HER2+ tumors, Kruskal-Wallis p=0.017). Higher CD163 density (a marker of M2 macrophage polarization), both in the tumor and in the stroma area, was significantly associated with worse OS, even after correction by BC subtype. In the subgroup of patients with HR+/HER2- BCBM, high TIM3+ cell density in the stroma area was significantly associated with longer OS (median OS 54.1 versus 23 months respectively for TIM3+ density above and below median value; p=0.01). Conclusions: In BCBM, stromal TIM3+ immune infiltrate differs according to BC subtype. M2 macrophage polarization is consistently associated with worse OS across all BC subtypes and might represent a potential therapeutic target for these patients.[Table: see text]
Molecular profiling and survival outcomes of p16+ compared to p16- oropharynx squamous cell cancer patients.
Authors: Brittany Nicole Hughes, Hira Ghazal Shaikh, Julie Elaine McGrath, Joanne Xiu, Ammar Sukari, Wolfgang Michael Korn, Chadi Nabhan, Punita Grover, Sourat Darabi, Rebecca Chernock, Chukwuemeka Ikpeazu, Trisha Michel Wise-Draper
Journal: Journal of Clinical Oncology (2021)

e18026 Background: Previous studies have consistently shown that p16+ oropharynx squamous cell cancer (OPSCC) patients have better outcomes. The significance of molecular and transcriptional signatures and its correlation with p16 expression remains unclear. Methods: We queried the Caris Life Sciences database to assess the molecular and transcriptional signatures related to p16+ and p16- head and neck squamous cell cancer (HNSCC) patients. Comprehensive molecular profiling including whole exome sequencing (WES), targeted Next-Generation Sequencing (NGS), and immunohistochemistry (IHC) 22c3 for PD-L1 was performed (CPS ≥1 considered positive) (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations. A standard cut-off of 2+, &gt; 70% p16 staining was used. HPV16/18 was tested using WES. Patients were considered smokers if they had &gt; 15 pack-years. Real world overall survival (rwOS) was obtained from insurance claims data and Kaplan-Meier estimates were calculated from the date of start of treatment to the date of last contact. Results: 948 cases of OPSCC were identified in the Caris database. 41% (82/199) were smokers. Where p16 and HPV data was available, 41% were p16+ (171/420) while HPV positivity rate was 52% (71/148). We noted a small number of patients with discordant p16 and HPV status (7 p16+/HPV-, 8 p16-/HPV+) in 327 patients who had HPV status available. Most common mutations were TP53 (33%), PIK3CA (17%) and KMT2D (10.6%). 87% were PD-L1 positive (342/394), with high expression in both p16+ and p16- subgroups, 90% and 85% respectively. 10% had TMB≥10/Mb (48/463). TP53 mutations were more common in p16- (49%) tumors in contrast to p16+ (10%) (p &lt; 0.0005), while no statistical difference was detected in TMB≥10/Mb between the groups. CDKN2A, TERT and NOTCH1 mutations were more prevalent in tumors that were p16- or HPV- in contrast to tumors that were p16+ or HPV+ (p &lt; 0.05). FGF3, CCND1, FGF4, FGF19 copy number alterations (CNA) were less common in p16+ OPSCC compared to p16- or HPV16- OPSCC (p &lt; 0.0005). P16+ patients had longer rwOS when compared to p16-, 47 months versus 20 months (HR = 0.55, p = 0.014) respectively. Conclusions: Higher frequency of CDKN2A, TERT and NOTCH1 mutations among p16- (versus p16+) raise the possibility of potential targets for treatment in this group with poor prognosis. However, it remains unclear if these can serve as independent predictors of survival.[Table: see text]
Metaplastic breast cancer: Disease characteristics and outcome in Arab women.
Authors: Adher Alsayed, Bader I Alshamsan, Aisha Alshibany, Mahmoud Abdelsatar Elshenawy, Ahmed ali Badran, Taher Al-Tweigeri, Dahish Saed Ajarim, Kausar Suleman
Journal: Journal of Clinical Oncology (2021)

e12534 Background: Metaplastic breast cancer (MPBC) accounts for less than 1% of all breast cancer subtypes. Methods: Patients diagnosed with MPBC between 2001 are 2018 were reviewed. Disease characteristics, progression-free survival (PFS), and overall survival (OS) were estimated by the Kaplan-Meier method and compared by log-rank test. Results: Fifty-five MPBC patients were analyzed. The median was 46 years (IQR 40–55). 14.5% had a positive family history of cancer. The majority (98.2%) presented with a lump, and two patients presented with bilateral disease. The median BMI was 31 (IQR 24.5–37.5). The majority had stage III (56.4%), and stage IV was (7.3%). Most patients (90.9%) had triple-negative disease. The tumor grade (G) was available for 63.6% of patients (G2 11.4% and G3 88.6%). Nineteen patients (34.5%) received neoadjuvant chemotherapy (NAC) [anthracycline-based (15,78.9%), and platinum-taxane (11, 57.8%)]. The majority (92.7%) underwent surgery, 56.4% MRM, 12.7% BCT, 12.7% simple mastectomy, 7.3% palliative mastectomy. 54.5% underwent ALND and 20% SLNB. One patient had pCR. Adjuvant radiation was given for (33, 60%) and (37, 67.3%) received adjuvant radiation therapy. The median follow-up duration is 44 months (IQR 21–69). For nonmetastatic disease, 3-years DFS was 67.5%. There was no difference in DFS with using NAC (p-0.96) or being obese (p = 0.50). The 3-years OS was 72.9%, and the Log-rank test revealed prolonged survival with radiation therapy 87.1% vs. 56.6% ( p = 0.02) and earlier stage at diagnosis. 3-years OS for stage II was 92.9%, stage III was 71%, and no survival in stage IV (p &lt; 0.001). There was a clinical difference in 3 years OS between obese vs. nonobese 61.3% vs. 85.9%, with no statistical significance (p = 0.15). Conclusions: The majority of patients diagnosed with MPBC had large tumor size, nodal disease, and more triple-negative disease, locally advanced and nonmetastatic. The DFS and OS were comparable to reported survival. There is a significant correlation between survival and stage and adjuvant radiation therapy.