tbuckley/cabot-search huggingface dataset:
Efficacy of clinical breast examination in chest-irradiated female survivors of childhood Hodgkin lymphoma (HL).
Authors: Florence Lennie Wong, Janie M. Lee, Wendy M. Leisenring, Joseph Philip Neglia, Rebecca M. Howell, Susan A. Smith, Kevin C. Oeffinger, Chaya S. Moskowitz, Tara O. Henderson, Ann Mertens, Paul C. Nathan, Yutaka Yasui, Wendy Landier, Gregory T. Armstrong, Leslie L. Robison, Smita Bhatia
Journal: Journal of Clinical Oncology (2021)

10028 Background: Female survivors of childhood HL treated with ≥10 Gy of chest radiation are at high risk for breast cancer (BC). The Children’s Oncology Group (COG) guidelines recommend CBE annually starting at puberty and then semiannually from age 25, plus lifetime annual mammography (MAM) and breast Magnetic Resonance Imaging (MRI) starting 8y after chest radiation or age 25, whichever is later. While imaging-based screening recommendations are largely consistent with US guidelines for women at high BC risk, only the COG guidelines recommend CBE. The benefits of lifetime CBE starting from puberty for life in chest-irradiated HL survivors is unknown. Methods: Life-years (LYs) and lifetime BC mortality risk were estimated from a simulated cohort of 5-million HL survivors using the data from 5y female survivors of HL in the Childhood Cancer Survivor Study (CCSS) treated with ≥10 Gy of chest radiation. The simulated cohort underwent annual MAM+MRI from age 25 for life, with and without annual CBE from age 11 (presumed age of puberty) to age 24 and with and without semiannual CBE from age 25 for life with 100% adherence. BC included in-situ and invasive BC. Treatment-related BC incidence and non-BC mortality risks were estimated from the CCSS data. Risks at age &lt;25 were extrapolated from the CCSS estimates while risks beyond age 50 were extrapolated additionally using the US population rates. CBE sensitivity (17.8%, in-situ and invasive BC) and specificity (98%) and MAM+MRI sensitivity (84.2-86.0%, in-situ; 96.7-97.1%, invasive) and specificity (75.3%) were obtained from the medical literature. Results: The CCSS cohort included 1057 female HL survivors. BC (all invasive) developed in three patients at age &lt;25 (ages: 23, 24, 24). In the simulated cohort receiving no screening, lifetime BC risk was 40.8% and BC mortality was 17.5%. HL survivors around age 50 were at a 7.4-fold higher risk of developing BC and a 5.2-fold higher risk of non-BC mortality when compared with the general population. Compared to no annual CBE for ages 11-24y, undergoing annual CBE did not increase gains in LYs or reduce lifetime BC mortality relative to no screening (Table). Among those who survived to age ≥25, undergoing semiannual CBE from age 25 for life compared to no semiannual CBE also resulted in little gain in LYs or reduction in lifetime BC mortality relative to no screening. Conclusions: Lifetime CBE starting at puberty in conjunction with MAM+MRI appears to add little survival benefits compared with no CBE, suggesting that COG guidelines may be revised without adverse effect on long-term outcomes for chest-irradiated female survivors of childhood HL.[Table: see text]
Survival outcomes, treatment toxicity, and healthcare utilization in older adults with aggressive non-Hodgkin lymphoma (NHL).
Authors: Mitchell W. Lavoie, Alisha Yi, Ryan David Nipp, Nora K. Horick, Hermioni L. Amonoo, Richard Newcomb, Julia Rice, Matthew J. Reynolds, Areej El-Jawahri, Patrick Connor Johnson
Journal: Journal of Clinical Oncology (2021)

7557 Background: Aggressive NHLs frequently affect older adults, and are often treated with intensive systemic therapy that is potentially curative but can cause substantial toxicities. Although balancing treatment efficacy with the risk of complications is critically important for older adults with NHL, few studies have described these patients’ survival outcomes, rates of toxicities, and healthcare utilization. Methods: We conducted a retrospective analysis of adults &gt; 65 years diagnosed with aggressive NHL and treated with systemic therapy at Massachusetts General Hospital from 4/2000-7/2020. We abstracted patient demographic and clinical information, survival outcomes, treatment toxicity (rates and grade), and healthcare utilization outcomes (intensive care unit [ICU] admissions and unplanned hospitalizations within six months of treatment initiation) from the electronic health record. Using multivariable logistic regression, we examined patient and disease factors associated with rates of grade 3+ non-hematologic toxicity and unplanned hospitalization. Results: Of 295 patients (median age = 73 years [age 65-69: 32.5%; age 70-74: 26.1%; age 75-79: 20.0%; age 80+: 21.4%], 39.0% female), most had advanced stage disease (59.5%) and an ECOG performance status of 0 or 1 (83.1%). The most common diagnosis was de novo diffuse large B-cell lymphoma (DLBCL) or grade 3B follicular lymphoma (69.2%). Most common therapies were CHOP (65.8%) and EPOCH (17.0%) with or without Rituximab. With a median follow up of 5.9 years, 5-year overall survival (OS) was 74.2%. Among patients age 65-69, 70-74, 75-79, and 80+ years, 5-year OS by age group were 82.1%, 72.2%, 73.5%, and 66.3%, respectively. Overall, 42.4% had grade 3+ toxicity, while 8.1% had grade 4 or 5 toxicity. The rates of unplanned hospitalization and ICU admission during the first 6 months of therapy were 41.0% and 6.1%, respectively. In multivariable analysis, hypoalbuminemia (OR 4.22, 95%, p &lt; 0.001) and number of comorbidities (OR 1.75, p &lt; 0.001) were associated with a greater likelihood of grade 3+ toxicity. Hypoalbuminemia (OR 2.76, p = 0.003), number of comorbidities (OR 1.61, p = 0.001), and receipt of EPOCH (OR 5.41, p = 0.012) were associated with a greater likelihood of unplanned hospitalization. Conclusions: The majority of older adults receiving upfront therapy for aggressive NHL survive beyond 5 years, yet nearly half experience substantial treatment toxicities and unplanned hospitalizations. Our findings underscore the need to develop supportive care interventions to enhance the care experience for older adults with NHL.
AXL Inhibition in Macrophages Stimulates Host-versus-Leukemia Immunity and Eradicates Naïve and Treatment-Resistant Leukemia
Authors: Irene Tirado-Gonzalez, Arnaud Descot, Devona Soetopo, Aleksandra Nevmerzhitskaya, Alexander Schäffer, Ivan-Maximilano Kur, Ewelina Czlonka, Carolin Wachtel, Ioanna Tsoukala, Luise Müller, Anna-Lena Schäfer, Maresa Weitmann, Petra Dinse, Emily Alberto, Michèle C. Buck, Jonathan JM. Landry, Bianka Baying, Julia Slotta-Huspenina, Jenny Roesler, Patrick N. Harter, Anne-Sophie Kubasch, Jörn Meinel, Eiman Elwakeel, Elisabeth Strack, Christine Tran Quang, Omar Abdel-Wahab, Marc Schmitz, Andreas Weigert, Tobias Schmid, Uwe Platzbecker, Vladimir Benes, Jacques Ghysdael, Halvard Bonig, Katharina S. Götze, Carla V. Rothlin, Sourav Ghosh, Hind Medyouf
Journal: Cancer Discovery (2021)

Acute leukemias are systemic malignancies associated with a dire outcome. Because of low immunogenicity, leukemias display a remarkable ability to evade immune control and are often resistant to checkpoint blockade. Here, we discover that leukemia cells actively establish a suppressive environment to prevent immune attacks by co-opting a signaling axis that skews macrophages toward a tumor-promoting tissue repair phenotype, namely the GAS6/AXL axis. Using aggressive leukemia models, we demonstrate that ablation of the AXL receptor specifically in macrophages, or its ligand GAS6 in the environment, stimulates antileukemic immunity and elicits effective and lasting natural killer cell- and T cell-dependent immune response against naïve and treatment-resistant leukemia. Remarkably, AXL deficiency in macrophages also enables PD-1 checkpoint blockade in PD-1-refractory leukemias. Finally, we provide proof-of-concept that a clinical-grade AXL inhibitor can be used in combination with standard-of-care therapy to cure established leukemia, regardless of AXL expression in malignant cells. SIGNIFICANCE: Alternatively primed myeloid cells predict negative outcome in leukemia. By demonstrating that leukemia cells actively evade immune control by engaging AXL receptor tyrosine kinase in macrophages and promoting their alternative priming, we identified a target which blockade, using a clinical-grade inhibitor, is vital to unleashing the therapeutic potential of myeloid-centered immunotherapy.This article is highlighted in the In This Issue feature, p. 2659.
A panel of DNA methylation markers for the classification of consensus molecular subtypes 2 and 3 in patients with colorectal cancer.
Authors: Inge van Den Berg, Marcel Smid, Robert R.J. Coebergh van den Braak, Mark A van de Wiel, Carolien H. M. Van Deurzen, Vanja de Weerd, John W.M. Martens, Jan N.M. IJzermans, Saskia M Wilting
Journal: Journal of Clinical Oncology (2021)

3545 Background: Consensus molecular subtypes (CMSs) can guide precision treatment of colorectal cancer (CRC). Currently available assays can identify CMS1 and CMS4 cases well, while a dedicated test to distinguish CMS2 and 3 is lacking. This study aimed to identify a panel of methylation markers to distinguish between CMS2 and 3 in patients with CRC. Methods: Fresh-frozen tumor tissue of 239 patients with stage I-III CRC was included. CMS classification was performed on RNA-seq data using the single-sample-prediction parameter from the “CMSclassifier” package. Methylation profiles were obtained using the Infinium HumanMethylation450 BeadChip. We performed adaptive group-regularised logistic ridge-regression with post-hoc group-weighted elastic net marker selection to build prediction models for classification of CMS2 and CMS3 based on 15, 10 or 5 markers. Data from TCGAwas used for validation. Results: Overall methylation profiles differed between CMS2 and CMS3. Group-regularisation of the probes was done based on their location either relative to a CpG island or relative to a gene present in the CMS classifier resulting in two different prediction models and subsequently different marker panels. For both panels, even when using only 5 markers, sensitivity, specificity, and accuracy were &gt; 90%. Validation showed comparable performances. Conclusions: Our highly sensitive and specific methylation marker panel can be used to distinguish CMS2 and 3. This enables development of a qPCR DNA methylation assay in patients with CRC to provide a specific and non-invasive classification tool.
Study evaluating metastatic castrate resistant prostate cancer (mCRPC) treatment using <sup>177</sup>Lu-PNT2002 PSMA therapy after second-line hormonal treatment (SPLASH).
Authors: Kim N. Chi, Ur Metser, Johannes Czernin, Jeremie Calais, Vikas Prasad, Matthias Eiber, Neal D. Shore, Jessica Jensen, Neil Eric Fleshner, Scott T. Tagawa, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2021)

TPS5087 Background: Treatment options with minimal toxicity and novel mechanisms of action are urgently needed to improve clinical outcomes from mCRPC. Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) represents a new treatment for patients with PSMA-avid mCRPC. 177 Lu-PNT2002 (also known as [Lu-177]-PSMA-I&amp;T) is a PSMA-targeting agent and studies have shown demonstrable promising initial data. This trial seeks to prospectively evaluate the efficacy of 177 Lu-PNT2002 for men with progressive mCRPC after androgen receptor axis-targeted (ARAT) therapy. Methods: This is a multi-center, open-label, phase III study. All patients must be at least 18 years of age, have documented progressive mCRPC at time of screening, high PSMA expression by PSMA PET/CT per blinded independent central review (BICR), chemotherapy naïve for CRPC and unfit or unwilling to receive chemotherapy. The study will commence with a 25-patient dosimetry lead-in. In the dosimetry phase, patients will receive up to four cycles of 177 Lu-PNT2002 at 6.8 GBq every 8 weeks. In the randomization phase, approximately 390 patients will be randomized in a 2:1 ratio to receive 177 Lu-PNT2002 (Arm A) versus enzalutamide or abiraterone (with prednisone or dexamethasone) (Arm B). Patients randomized to Arm B have an option to crossover to 177 Lu-PNT2002 treatment after BICR-assessed radiologic progression. The primary endpoint is Radiological progression-free survival (rPFS) assessed by BICR using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (soft tissue) and Prostate Cancer Working Group 3 (PCWG3) (bone) criteria. Key secondary endpoints include objective response rate, duration of response, PSA response, and overall survival. The study is powered at 90% to test the alternative hypothesis of a hazard ratio (HR) ≤ 0.66 at an α of 0.025. ClinicalTrials.gov identifier: NCT04647526. Clinical trial information: NCT04647526.
Discovery and validation of novel methylated DNA markers of cervical cancer.
Authors: Jamie Nadine Bakkum-Gamez, Rondell P. Graham, Brendan T. Broderick, Seth Slettedahl, Douglas W. Mahoney, Maureen Lemens, Xiaoming Cao, Patrick H. Foote, Kelli Burger, Calise K. Berger, Maria O'Connell, Karen A. Doering, J. Kenneth Schoolmeester, Sarah Kerr, William R. Taylor, Mark E. Sherman, John B. Kisiel
Journal: Journal of Clinical Oncology (2021)

5526 Background: HR-HPV DNA testing, with or without cervical cytology, provides excellent sensitivity for detection of cervical cancer (CC) and its precursors; negative test results indicate that risk of disease is extremely low and enable women to undergo reduced screening with safety. However, management of women who screen positive remains challenging as many will prove to have self-limited HR-HPV infections. DNA methylation is an early event in carcinogenesis that could enhance CC screening specificity. Methods: For discovery, DNA from 70 FFPE CC (36 squamous, 34 adenocarcinoma) tissues that were reviewed microscopically, 18 fresh frozen benign cervicovaginal (BCV) tissues collected at the time of benign hysterectomy, and 18 buffy coats from cancer-free women underwent reduced representation bisulfite sequencing (RRBS) to identify MDMs associated with CC. Candidate MDM selection was based on area under the receiver operating characteristic curve (AUC) discrimination, methylation fold change, and low background methylation among benign controls. Candidate MDMs were re-tested using methylation-specific PCR (MSP) to confirm performance. Blinded biological validation was performed using MSP on DNA extracted from independent FFPE CC (38 squamous, 43 adenocarcinoma) and BCV (40) tissues. The performance of CC MDMs was also tested in DNA extracted from cervical dysplasia (36 adenocarcinoma in situ (AIS), 32 cervical intraepithelial neoplasia (CIN) 2/3, 11 CIN 1) FFPE tissues. Results: From RRBS discovery and technical validation via MSP, 30 candidate MDMs showed marked methylation fold changes (10 to &gt;1000) across both CC histologies compared to BCV tissue from cancer-free women. Each of the 30 MDMs highly discriminated CC from BCV tissue with 9 MDMs having an AUC &gt;0.90 (Table). CC MDMs also highly discriminated AIS from BCV but did not perform well in CIN 2/3 and CIN 1 (Table). Conclusions: Whole methylome sequencing, stringent filtering criteria, and biological validation have yielded outstanding candidate MDMs for CC that highly discriminate CC from BCV, notably with high specificity. Performance in cervical dysplasias varied with higher positivity rates in AIS than in CIN 2/3 and CIN 1. Translation to testing these novel MDMs in lower genital tract biospecimens and the addition of HR-HPV to the CC panel are warranted.[Table: see text]
Survivors Overcoming and Achieving Resilience (SOAR): An 8-week breast cancer survivorship and nutrition program.
Authors: Poorvi Kirit Desai, Diane Riccardi, Heewon L. Gray, Sonya Pflanzer, Zachary Thompson, Smitha Pabbathi
Journal: Journal of Clinical Oncology (2021)

e24025 Background: The American Cancer Society (ACS) published Diet and Physical Activity Guidelines in 2020. Emerging evidence suggests that healthy dietary patterns are associated with reduced cancer risk, especially colon and breast. ACS estimates there are 3.5 million breast cancer survivors in the US. The transition from active treatment into survivorship is a critical period where they are uniquely positioned to adapt healthy behaviors, yet there is a lack of empirical research to best guide the transition. Methods: We developed an 8-week breast cancer survivorship program to educate and develop healthy habits. 40 participants were recruited through Moffitt breast and survivorship clinics, social media, and website. Weekly topics were: cancer survivorship, nutrition, emotional health and well-being, exercise, medical management after treatment, grocery store tour, meditation and mindful eating, and moving forward. To assess health-related quality of life (QoL), we used FACT-G Version 4, a validated patient-reported survey with 27 questions and 4 domains of wellbeing (physical, social/family, emotional, and functional) on a 5-point Likert scale (not at all to very much). Similarly, a nutrition questionnaire evaluated the understanding of healthy choices, confidence in making healthy changes, knowing how to purchase healthy foods and read nutrition labels, confidence in preparing healthy foods, and understanding of a plant-based diet. Surveys were administered pre- and post-intervention. Data analysis included those who completed both (n = 30). Pt characteristics and data trends were summarized using descriptive statistics. Paired Wilcoxon rank sum tests were used to assess the significance of the change in scores between surveys. Results: Participant ages ranged from 41 to 77. The majority (34.5%) completed treatment 13-24 months prior. Compared to baseline, greater proportions of participants had positive responses after intervention in all nutrition questions. The nutrition sum was significantly increased by 3.07 (p = 0.0001). There was no significant change in overall QoL (-1.77; p = 0.1178) or sub-domain wellbeing scores. Conclusions: Our 8-week intervention for breast cancer survivors showed significant improvement in nutrition domain. While a small sample size is limiting, it is evident that survivors can improve their confidence in making healthy changes and develop better understanding of a plant-based diet.[Table: see text]
Network meta-analysis (NMA) of pembrolizumab for first-line (1L) treatment of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
Authors: Karthik Ramakrishnan, Ali Mojebi, Dieter Ayers, Diana Romana Chirovsky, Rebekah Borse, Sam Keeping
Journal: Journal of Clinical Oncology (2021)

e18012 Background: In the KEYNOTE-048 trial, pembrolizumab as monotherapy (P) and in combination with platinum+5FU chemotherapy (P+C) versus cetuximab+platinum+5FU (EXTREME regimen) significantly improved overall survival (OS) in the combined positive score (CPS) ≥1 (hazard ratio: 0.74; 95% confidence interval: 0.61-0.90) and total (0.72; 0.60-0.87) R/M HNSCC populations, respectively, and was approved by the FDA in these patient populations. While the EXTREME regimen is considered standard of care in 1L R/M HNSCC, other systemic treatment options including cetuximab+platinum+docetaxel (TPEx regimen), platinum+paclitaxel/taxane (Pt+T), and platinum+5FU (Pt+F) are also commonly used. Due to lack of head-to-head comparisons with pembrolizumab, an NMA was conducted to estimate the comparative efficacy of P and P+C versus these interventions in 1L R/M HNSCC. Methods: A systematic literature review (SLR) was conducted on November 13, 2019 to identify randomized controlled trials for the relavant interventions. Data were extracted for the OS and progression-free survival (PFS) outcomes. NMA analyses were conducted for the total population and for the CPS ≥1 and CPS ≥20 subgroups in a Bayesian framework using proportional hazards (base case) and time-varying (sensitivity analysis) treatment-effect models. The deviance information criterion was used to compare the goodness-of-fit of the alternative survival models. Results: The SLR identified 28 trials, of which six trials matched the trial eligibility criteria of KEYNOTE-048 and were included in the NMA. Results from the fixed-effects NMA for P and P+C are summarized in table below for the FDA indicated population. Improvement in OS was noted for P and P+C versus EXTREME, Pt+T, and Pt+F, and a trend in improved OS versus TPEx was observed. The sensitivity analysis showed improved OS over time across all comparisons. PFS was improved with P and P+C versus Pt+F and comparable versus other interventions. These results were generally consistent for P and P+C in the CPS (CPS ≥1 or CPS ≥20) patient subgroups. Additionally, NMA results versus EXTREME were consistent with the KEYNOTE-048 trial results. Conclusions: Pembrolizumab (P or P+C), showed improved OS and comparable PFS outcomes versus alternative 1L R/M HNSCC interventions, consistent with the efficacy results versus EXTREME observed in the KEYNOTE-048 trial. [Table: see text]
Differential impact of different TP53 gain-of-function mutations on overall survival of patients with metastatic colorectal cancer: Results from a large integrated healthcare system.
Authors: Minggui Pan, Chen Jiang, Pamela Tse, Elaine Chung, Aleyda Solorzano, Wenwei Hu, Thach-Giao Truong, Amit Arora, Tilak Kumar Sundaresan, Jennifer Marie Marie Suga, Laurel A. Habel, Sachdev P. Thomas
Journal: Journal of Clinical Oncology (2021)

3585 Background: TP53 mutation is present in approximately 50% of metastatic colorectal cancer (CRC). The spectrum of the TP53 mutations is extremely broad including approximately 80% missense mutations. Several missense mutations have been found to possess gain-of-function (GOF) properties in cell line and animal studies, however, confirmation of the concept of GOF in human malignancies is still lacking. Methods: We investigated the impact of TP53 GOF mutations in patients with metastatic CRC using the NGS data within Kaiser Permanente Northern California (KPNC), a large integrated healthcare system. Results: From November 2017 to January 2021, genomic profiling by StrataNGS was performed on 8658 patients, with 1056 patients being metastatic CRC, among whom 740 patients harbored a TP53 mutation (TP53mut) and 316 patients had wild-type TP53 (TP53wt). Ras (KRAS and NRAS) and BRAF mutation appropriately discriminated the overall survival (OS) of patient populations with either TP53wt or TP53mut, confirming the validity of our dataset. We identified seven GOF TP53 mutations (R175H, R248W, R248Q, R249S, R273H, R273L, R282W) in these CRC patients. We show that different GOF mutation differentially impacts the OS. Patients whose CRC harbored TP53mut R248W, R249S, and R282W (poor prognostic TP53mut, N = 47) had significantly worse OS versus patients whose CRC harbored TP53mut R248Q, R175H, R273H and R273L (N = 160, median OS 29.4 vs 44.2 months, HR 0.47, p = 0.007). The OS of the poor prognostic TP53mut patients was also significantly inferior compared to patients whose CRC harbored all other TP53 mutations (N = 1099, median OS 50.1 months, HR 0.55, p = 0.01) or TP53wt (N = 316, median OS 47,5 months, HR 0.54, p = 0.01). The demographics and the percent of Ras, BRAF, and PI3KCA mutations were similar except that the patients with the poor prognostic TP53mut had significantly higher percent of Ras mutation compared to the rest of the GOF TP53mut patients (p = 0.035). When compared to R248Q alone, R248W confers worse OS (median OS 36.3 vs 63.2 months, p = 0.05). Conclusions: Our data suggest that different TP53 GOF mutations are associated with very different clinical outcomes. Additional studies identifying specific TP53 GOF mutations that impact outcomes may provide further insight for drug development and clinical trial design.