tbuckley/cabot-search huggingface dataset:
Early combination with mycophenolate mofetil for immune-related hepatitis in patients with solid tumors treated with immune checkpoint inhibitors.
Authors: Yukiko Shimoda Igawa, Tatsuya Yoshida, Yuri Yoshinami, Yukiko Hibino, Takamichi Arima, Jun Sato, Yuta Maruki, Hirokazu Shoji, Kenjiro Namikawa, Kazuki Sudo, Yoshitaka Honma, Hironobu Hashimoto, Naoya Yamazaki, Takuji Okusaka, Kan Yonemori, Noboru Yamamoto, Yuichiro Ohe, Ken Kato
Journal: Journal of Clinical Oncology (2024)

12133 Background: Hepatitis, as an immune-related adverse event (irAE), occurs in 2%-10% of patients treated with immune checkpoint inhibitors (ICIs). Although guidelines recommend the use of mycophenolate mofetil (MMF) for steroid-refractory and steroid-resistant ir-hepatitis, there has been no evidence on the efficacy of MMF. Methods: We retrospectively reviewed consecutive patients with solid tumors who developed grade 2 or higher ir-hepatitis requiring systemic steroids after ICIs (nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab and ipilimumab) between January 2015 and August 2023. The changes in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin level, according to the CTCAE version 5.0, were used to assess ir-hepatitis. ALT improvement was calculated as the ratio of the change in ALT values from onset to day 7, normalized by the ALT values at onset. Results: Among 4405 patients treated with ICI during the study period, 130 patients (3%) developed grade 2 or higher ir-hepatitis requiring systemic steroids. The median age was 62 (range: 19-85) years-old, and 122 patients (94%) had an ECOG performance status (PS) 0/1. These patients included 67 (52%) with melanoma, 35 (27%) with lung cancer, 7 (5%) with esophageal cancer, and 21 (16%) with other cancers. Among 123 evaluable patients, 46 patients (46/123, 37%) received MMF including 20 patients experiencing steroid-refractory and 26 steroid-resistant. The median duration from the start of systemic steroids to MMF was 11 days (range: 0-113 days). Improvement of hepatitis to grade 1 with MMF was observed in 40 patients (40/46, 87%) with a median time of 18 (range: 3-176) days. Of the patients evaluated for the impact of the timing of MMF on the improvement of ir-hepatitis (n=38), ALT improvement at day 7 after ir-hepatitis onset in patients who initiated MMF within 3 days of ir-hepatitis onset (early combination group, n=8) was significantly higher compared with the patients who initiated MMF after 3 days of ir-hepatitis onset (late combination group, n=30) (72.3% vs. 41.7%, p=0.02). Additionally, among patients evaluable for systemic steroid dosage (n=45), the total systemic steroid dosage in patients in the early combination group (n=8) was significantly less than in the late combination group (n=37) (median: 2120mg vs 4005 mg, p=0.02). Conclusions: MMF was effective for both steroid-refractory and steroid -resistant ir-hepatitis. Early combination with MMF in addition to systemic steroids can lead to a more rapid improvement of ir-hepatitis compared to late combination with MMF consequently reducing the total systemic steroid dosage. [Table: see text]
Correlation between Palliative Performance Scale results and observed survival among Mexican patients with advanced cancer.
Authors: Mayte Cruz-Zermeño, Alfredo Covarrubias-Gómez, Alex Lagunas-Medina, María Fernanda Esparza-Orozco, Raúl Emiliano Esparza-Orozco, Wendy Alicia Ramos-Lopez, Enrique Soto Pérez de Celis, Yanin Chavarri Guerra
Journal: Journal of Clinical Oncology (2024)

e24040 Background: Cancer is a common cause of death among Hispanics. Estimating patient survival is critical in cancer care since it allows better shared decision-making and avoids use of futile therapy. Palliative Performance Scale (PPS) has been widely used for survival prediction among patients with cancer. However, its performance has not been validated across populations in Latin America, which could have different outcomes. The aim of this study was to analyze the correlation between PPS score and observed survival among patients with advanced cancer to facilitate physician and patient decision-making near the end of life. Methods: We conducted a retrospective observational analysis of patients with advanced cancer included in “ Te Acompañamos” cohort, a multidisciplinary patient navigator-led supportive care program in a single center in Mexico City. We used descriptive statistics to analyze clinico-demographic variables, PPS score, observed survival in days (from recruitment to death). Pearson correlation coefficients were used for correlating observed survival in days and predicted survival using PPS. U de Mann Whitney was used for comparing survival days between PPS groups. Results: We analyzed 246 patients with advanced cancer included in “Te Acompañamos” who died between August 2017-January 2024. Among these patients, 143 (58%) were women. Mean age was 64 years (SD 13). 153 patients (62%) had gastrointestinal (GI), 43 (17%) gynecologic, 19 (7%) genitourinary, 5 (2%) lung, 5 (2%) thyroid, and 21 (8%) other solid malignancies. Pancreatic cancer was the most common cancer (n = 60, 24%). Patients with GI cancer more frequently reported pain (59%) and had an average PPS of 67.7%. Mean survival was 233 days (SD 247) and mean predicted survival in days according to PPS was 68 days (SD 20). Correlation between observed survival days and PPS-predicted survival was low (R = 0.29). Patients with PPS &lt; 50% had mean survival of 74.6 days while patients with PPS &gt; 50% of 243.2 days (p &lt; 0.05). Patients aged &lt; 60 years with GI tumors had a higher PPS score, while older patients had a lower score (74.6% vs 65%; p &lt; 0.05). No other significant differences were found in other subgroups. Conclusions: Our results show weak correlation between observed and predicted survival in days using PPS. However, lower PPS was associated with decreased survival. Among patients with GI cancers we observed that older patients had the lowest PPS scores. This study emphasizes the need to develop and validate more precise tools for survival prediction across patient populations, including minorities such as the Hispanics. Our study suggests that strategies to diagnose and alleviate pain promptly in patients with advanced cancer near the end of life are urgently required.
Evaluation of the immune landscape associated with the efficacy of immunotherapy in patients with triple-negative breast cancer: Starlet study, synergy between research and clinical work.
Authors: Elisa Gasparini, Moira Ragazzi, Gloria Manzotti, Federica Torricelli, Elisa Salviato, Alessandra Bisagni, Eleonora Zanetti, Annamaria Pappalardo, Saverio Coiro, Guglielmo Ferrari, Silvia Soncini, Giancarlo Bisagni, Carmine Pinto, Alessia Ciarrocchi, Francesca Reggiani
Journal: Journal of Clinical Oncology (2024)

e12568 Background: Neoadjuvant chemotherapy (NACT) is the standard treatment for early-stage TNBC and achieving a pathological complete response (pCR) is an essential prognostic factor. Recently, by applying a morphology-guided spatial transcriptomic approach, we showed that intratumoral infiltrating lymphocytes (iTILs) and stromal Natural Killer (NK) cells are major determinants of chemotherapy efficacy in TNBC. These data underline how spatiality and molecular activation of immune cells are essential to enhance the efficacy of the NACT in TNBC. The fact that immune cells are important players in this setting is corroborated by the clinical success showed by the KEYNOTE-522 study (Schmid et al, NEJM 2020). This trial paved the way for the use of immunotherapy in TNBC, obtaining a significant improvement in the patient’s overall response. The implementation of chemotherapy with immunotherapy in the TNBC neoadjuvant treatment implicates several compelling questions, including how to further increase the percentage of pCR overcoming resistance mechanisms and how to improve the personalization of treatment, evaluating which patients can benefit from a therapy de-scalation or another combined therapeutic strategy. Methods: we enrolled 43 patients with early-TNBC treated with the KEYNOTE-522 regimen. To further clarify the immune dynamics that lead to a complete response to pembrolizumab in these patients, we collected peripheral blood before and after neoadjuvant treatment to isolate peripheral blood mononucleated cells (PBMCs). We applied asingle-cell transcriptome analysis to shape any variations in circulating immune cells occurring during neoadjuvant treatment and associated with patient response. In addition, we collected residual tumor at surgery from partial responders and derived three-dimensional organoids that recapitulate the characteristics of patient tumor. Results: Immune profiling of PBMCs indicated that patients showing pCR during NACT and immunotherapy displayed a decrease of B Lymphocytes and a concomitant enhancement of Natural Killers. We successfully established TNBC patient-derived organoids from 8 TNBC patients. Conclusions: our ongoing study is defining the immune-related molecular mechanisms driving pembrolizumab and chemotherapy response in the neoadjuvant treatment of TNBC patients. Our findings can improve our understanding of which immune populations are determinant players in anti-TNBC immune response and can be proposed as novel biomarkers of pembrolizumab efficacy during the neoadjuvant treatment.
Resident physicians’ knowledge, attitudes, and practices on advance care planning for patients with advanced cancer in a national university hospital in the Philippines.
Authors: Frederic Ivan Leong Ting, Sachiko Solis Estreller, John Christopher Agsalud Pilapil, Irisyl Orolfo Real, Edward Christopher Christopher Dee
Journal: Journal of Clinical Oncology (2024)

e24037 Background: Advance Care Planning (ACP) is part of palliative care, an approach that improves the quality of life of patients and their families in the context of life-threatening illness, through the prevention and relief of suffering by means of early identification, assessment, and treatment of common problems associated with end-of-life care. Little is known about ACP and the utilization of advance directives in the Philippines, a country of 110 million people. The study aimed to explore the knowledge, attitudes, and practices of resident physicians in a national university hospital in the Philippines regarding ACP for patients with advanced cancer. Methods: Using a cross-sectional design involving resident physicians, an online survey with a self-administered questionnaire was distributed and answered by a total of 202 respondents. Results: Results show that a significant proportion of doctors: (1) view palliative and hospice medicine to be the same and without differences, (2) are comfortable with discussing ACP and prognosis of medical conditions with patients and their families, but (3) do not regularly initiate or offer ACP to them, (4) identify a lack of time, fear of imparting emotional distress to patients and their families, and personal discomfort as barriers to conducting ACP, and (5) have had no formal training for ACP but are willing to undergo such formation, given the opportunity. Conclusions: This study highlights the continuing need to bridge and unite knowledge, attitude, and practices pertaining to ACP among physicians. Further studies should be undertaken to device a proper training program and better explore the complexities of end-of-life care as it is experienced by Filipino patients with advanced cancer.
Effect of fructose on anthracycline and HER-2 blocking agent mediated cardiotoxicity through NLRP3 and MyD88 mediated pathways: New roles of sweeteners in cardio-oncology.
Authors: Andrea Paccone, Vincenzo Quagliariello, Giuseppe D'Aiuto, Martina Iovine, Ilaria Giacobbe, Raffaele Arianna, Francesca Izzo, Fabrizio Maurea, Matteo Barbato, Alessandro Inno, Vienna Giordano, Nicola Maurea
Journal: Journal of Clinical Oncology (2024)

e24020 Background: Combinatorial therapy based on anthracyclines and HER-2 blocking agents increases the risk of cardiomyopathy in women with breast cancer. Fructose is a monosaccharide associated with high risk of diabetes, non-alcoholic fatty liver disease, atherosclerosis and visceral obesity. A high fructose diet is a potential cardiometabolic risk factor and may increase cardiac risk in women with breast cancer treated with cardiotoxic drugs. In this study, we highlighted the role of sweeteners fructose in the worsening of cardiotoxicity induced by combinatorial therapy anthracycline-HER2-blocking agents. Methods: Human cardiomyocytes were pre-exposed with doxorubicin combined to trastuzumab (at 300 and 1000 nM) for 48 and 72h alone or combined to fructose at 0.25, 1 and 2.5 mM. After the incubation period, we performed the following tests: determination of cell viability, through mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of peroxisome proliferator-activated receptor-α; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6, CXCL-12). Results: High fructose increases significantly cell mortality of cardiomyocytes exposed to doxorubicin and trastuzumab through the activation of NLRP-3 and Myd-88 expression. Intracellular Ca ++ levels were also increased of 4 times compared to non-fructose exposed cardiomyocytes; MDA and 4-HNA levels were increased of 48,3 and 51,2 % compared to non-fructose exposed cells (p&lt;0.001). Fructose increases IL-1, IL-6 and CXCL-12 expression in cardiomyocytes in a concentration dependent manner, compared to doxorubicin-trastuzumab group (p&lt;0.05). Conclusions: Data of the present study indicate that fructose induces a pro-inflammatory phenotype in human cardiac cells exposed to anticancer cardiotoxic drugs, providing even more data on the harmful role of fructose as a key player of cardiotoxic phenomena.
Advancements in breast cancer progression monitoring: Analysis of methylated circulating cell- free DNA.
Authors: Chin-Sheng Hung, Ruo-Kai Lin
Journal: Journal of Clinical Oncology (2024)

e12548 Background: Breast cancer is a leading cause of mortality among women, with a significant number developing metastasis. Existing markers like CA-153 and CEA have limited sensitivity. Circulating cell-free DNA (ccfDNA) in plasma can be used for the noninvasive sampling of cancer cells obtained from patients with breast cancer. Aberrant circulating methylated GCM2 and TMEM240 have been reported in patients with breast cancer. The study aims to evaluate the potential of simultaneous detection of methylated GCM2 and TMEM240 in plasma for enhanced prediction of residual disease and tumor progression. Methods: In a prospective study conducted in Taipei, Taiwan, we enrolled a total of 396 patients between 2016 and 2023. The retrospective study involving plasma samples from Western populations included a total of 134 samples. Utilizing the Monte Carlo replicates module within the R software, is employed to automate the random partitioning of 70% of the entire patient dataset into a training set, while the remaining 30% is assigned to the validation set. The model's performance, including sensitivity, specificity, accuracy, false positives, and false negatives, will be thoroughly assessed to ensure its robustness. Results: The test demonstrated an accuracy of 91.5%, a sensitivity of 95.7%, and a specificity of 90.3% for prediction of residual disease and tumor progression. CA15-3 and CEA markers show limited sensitivity (53.3% and 33.3%, respectively). The tests also assess the tumor burden dynamically through monitoring circulating methylated GCM2 and TMEM240 in plasma of patients with breast cancer following their treatment. Conclusions: The simultaneous detection of circulating methylated GCM2 and TMEM240 in plasma presents a novel and accurate noninvasive tool for predicting tumor progression. Clinical trial information: N201708049, N202105091, N202202061.
Body and mind and self-consciousness awareness workshops: Improving quality of life in patients with cancer.
Authors: Bar Levy, Fraidy Margalit, Eliya Shachar, Lyri Adar, Lee Pantovitz, Shani Rahmian, Omer Shani, Ido Wolf, Tamar Safra
Journal: Journal of Clinical Oncology (2024)

e24081 Background: Cancer patients, commonly experience disease and treatment related stress, anxiety and difficulties coping with life. Data suggests that body and mind are interrelated and can influences patients' quality of life (QOL). Objectives: The study aimed to evaluate the impact of patients body and mind work developing self consciousness awareness and changing behavioral patterns of women’s cancer patients, on quality of life and coping abilities. By evaluation of QOL, sleep disorders and anxiety tests done during and following our workshop. Methods: The study conducted at the Women's Cancer Center of Tel Aviv Sourasky Medical Center in Tel Aviv Israel between 2022-2024. Female cancer patients and survivors, were enrolled in workshops teaching self consciousness awareness development according to the Metaism methodology. Each workshop with groups of 10-15 patients was conducted weekly for three months, The groups were led by dedicated moderators and supervised by a psychiatrist. Patients completed a validated QOL questionnaire, sleep disorder evaluation and anxiety questionnaires, upon enrollment and every month during the workshop and up to a year from completion of the workshop. Results: one-hundred and twofemale patients diagnosed with cancer and treated at multiple cancer centers were included in the study. Patient mean age was 57 (26-75) years. Patient diagnoses included breast, ovarian, uterine, cervical, and other cancers (58%, 22%, 7%, 5%, respectively). Significant improvement was observed in the QOL assessment at the 5 th week of the workshop, overall educational well-being indicator at the 3 rd week of the workshop, emotional well being at the 3 rd week of the workshop, physical well-being at the end of follow up. Conclusions: The study demonstrated that integrating the metaism methodology of self consciousness awareness development workshops significantly improved patient coping ability and QOL. Further investigation of larger cohorts is warranted.
Change in tumor microenvironment and PD-L1 expression with rucaparib treatment in triple-negative breast cancer.
Authors: Ritika Halder, Nitish Bhamidipati, Alexi Kiss, Walaa Aldhahri, Sima Ehsani, Jennifer Margaret Segar, Nova Foster, Pavani Chalasani
Journal: Journal of Clinical Oncology (2024)

e12569 Background: Triple-Negative Breast Cancers (TNBCs) represent a diverse subset of tumors characterized by varied responses to therapies including immunotherapy (IO). While IO is approved in early-stage and advanced TNBC, responses are modest. Modulation of the tumor microenvironment to improve responses to IO is an active area of research. In-vitro and in-vivo studies have shown Poly-ADP Ribose Polymerase inhibitors (PARPi) to increase PD-L1 expression in sporadic, BRCA1 and BRCA2 mutated TNBC cell lines improving response to IO. In addition, TNBCs have diverse mechanisms leading to Homologous Recombination Deficiency and the role of PARPi in sporadic TNBCs is still unclear. Methods: To further investigate the role of PARPi in tumor immuno-modulation we conducted a single-arm, open-label, window of opportunity (WOO) trial in patients with early-stage TNBC (NCT03911453). This study was approved by our institutional review board. Patients with histologically documented stage I-III TNBC were eligible for definitive surgery were enrolled. Patients were treated with 600mg BID rucaparib for 21 days. Pre- and post-treatment tumor biopsies were collected. Post-treatment, patients went to surgery or proceeded with neoadjuvant chemotherapy (NAC) followed by definitive surgery. Our primary endpoint was to assess change in PD-L1 expression. In addition, change in tumor microenvironment was by evaluating change in percentage of B cells, T cells and macrophages was calculated. Results: Twenty patients were enrolled. Nineteen patients completed 21 days and 1 patient went on extended duration PARPi during the COVID19 pandemic. Almost 50% of patients went to surgery while the rest went onto NAC after PARPi therapy. Pre-treatment tumor samples were obtained from the diagnostic core biopsies while post-treatment, fresh frozen and Formalin Fixed Paraffin Embedded were obtained either at time of surgery or a research biopsy prior to NAC initiation. Primary biomarkers data was successfully done in 14 paired samples. Treatment with rucaparib has increased expression of PD-L1 from median of 15% in pre-treatment tumor samples to a median of 26% in post-treatment tumor samples. Table below summarizes our results. Conclusions: Our study revealed that treatment with PARPi, rucaparib, changed the tumor microenvironment as noted by changes in expression of PD-L1, and immune milieu in and around the tumor. This could lead to change in responsiveness to therapies including CKI. This strategy should be further investigated to evaluate improving responses to immunotherapies. Clinical trial information: NCT03911453 . [Table: see text]
Uncovering of NRAGE/JNK and PI3K/AKT pathways through serial WGS of patients with breast cancer.
Authors: In Hee Lee, Soo Jung Lee, Yunji Lee, Byeongju Kang, Jeeyeon Lee, Jieun Kang, Eun Ae Kim, Seolhwa Jeong, Yee Soo Chae
Journal: Journal of Clinical Oncology (2024)

e12577 Background: Cancer genomic sequencing has fundamentally advanced our understanding of the basic biology of this disease, and more recently, has offered method to guide and evaluate treatment in clinic. We performed whole-genome sequencing (WGS) on three consecutive tissue and blood samples from breast cancer patients: diagnosis, post-neoadjuvant chemotherapy, recurrence after curative resection. Methods: We performed WGS to compare the genetic profiles of the primary, surgical and recurrent samples (tissue and blood) to determine: (1) how closely related the genetics are among the primary, post-neoadjuvant chemotherapy, and the recurrent tumors, (2) whether there are variations in mutational processes among the primary, post- neoadjuvant chemotherapy, and recurrent tumor. WGS was performed on three patients for whom both tissue and blood were available at diagnosis, at surgery after neoadjuvant chemotherapy and at a recurrence. Results: As a result of somatic protein coding variant analysis, PIK3CA mutation was confirmed at the time of diagnosis tissue in all cases. Mutations were found at p.E545K in patient 14, p.R916C in patient 18, and p.R916C in patient 3. Among these, patients 14 and 18 had PIK3CA mutations even at the time of recurrence. In patient 14, the same PIK3CA mutation was found in 3 consecutive samples, but in patient 18, it changed from p.R916C at diagnosis to p.G480E at relapse. Furthermore, functional enrichment analysis identified a common NRAGE signaling system in the cfDNA. The NRAG pathway was found in the blood at diagnosis, surgery, and recurrence in all three patients. Conclusions: This study was a proof-of-concept study, in which we hypothesized that NRAGE/JNK and PI3K/AKT signaling pathways are involved in breast cancer recurrence and treatment response through WGS of consecutive samples. Further research is ongoing with larger numbers of patients.