tbuckley/cabot-search huggingface dataset:
Incidence trends of advanced breast cancer in an era of its routine screening in the United States: A population-based study.
Authors: Nosakhare Paul Ilerhunmwuwa, Ifeanyi Uche, Mustafa Wasifuddin
Journal: Journal of Clinical Oncology (2024)

10523 Background: One of the purposes of routine screening for cancers is to delay the time of diagnosis of the late or advanced stages of the disease. Breast cancer screening is recommended for women aged 40 years and above. Over 70% of women reported receiving mammograms in the last two years between 2001 and 2020. Despite widespread screening, the impact on incidence trends of advanced breast cancer (aBC) in real-world settings in the last two decades is largely unknown. Methods: This population-based study identified adults aged 40–74 with regional/distant stage breast cancer (advanced) diagnosed between 2004 and 2020, using the Surveillance, Epidemiology, and End Results, 17 Research Plus registries. Age-adjusted incidence rates (AAIR) per 100,000 persons were extracted for aBC, with rates age-adjusted to the US standard population. The annual percentage change (APC) of the age-standardized incidence rate was estimated with the Joinpoint regression program. The APC was used to compare incidence trends stratified by age (40-54 vs. 55-74 years), race/ethnicity, and area of residence. Results: A total of 194,946 cases of aBC were diagnosed between 2004 and 2020; 120 257 (61.7%) were Non-Hispanic White (NHW), 28 585 (14.7%) were Hispanics, 25 691 (13.2%) were Non-Hispanic Black (NHB), 18 192 (9.3%) were Non-Hispanic Asian or Pacific Islander (NHAPI), 1326 (0.7%) were Non-Hispanic American Indians/Alaska Natives (NHAIA), and 895 (0.5%) were of unknown race/ethnicity. From 2004 to 2020, the overall AAIR of aBC showed an increase (APC, 0.2%: 0.00 – 0.40), with a notable rise in NHAPI (APC, 1.43%: 1.00 – 1.90) and Hispanics (APC of 0.66% (0.24 – 1.15), while remaining stable in other racial groups. Additionally, the AAIR increased among individuals aged 40-54 years (APC, 0.58%: 0.38 – 0.79) but was stable in those between 55-74 years. Regarding the area of residence, there was a significant increase in non-metropolitan areas (APC, 0.65%: 0.38 – 0.93), contrasting with no significant change in metropolitan areas. Conclusions: Despite widespread breast cancer screening, the occurrence of aBC has persistently increased, especially among individuals aged 40 to 54 years, NHAIA, and in non-metropolitan areas. Further studies are needed to establish the underlying reasons for these observed trends.
Clinical utility of AlphaMissense in predicting pathogenicity of DNA damage repair genes in cancer.
Authors: Shu Yazaki, Xin Pei, Simon N. Powell, Atif J. Khan, Jeremy Setton, Nadeem Riaz
Journal: Journal of Clinical Oncology (2024)

10581 Background: Deficiencies in DNA damage repair (DDR) impact cancer predisposition and various treatment responses.Functional implications of missense variants in DDR genes remain elusive.AlphaMissense, a new AI-based method, accurately predicts the pathogenicity of missense variants, but its clinical utility requires validation. We evaluated the accuracy of AlphaMissense predictions by analyzing known mutational signatures, genomic characteristics, and therapeutic vulnerabilities of DDR-deficient tumors. Methods: We analyzed data from TCGA (n=8,178) and MSK-IMPACT targeted panel sequencing (n=56,695) to evaluate the performance of AlphaMissense in predicting clinically actionable DDR genes, including core homologous recombination (HR) genes ( BRCA1/2, PALB2, RAD51C), POLE, and ATM. Missense mutations were classified as known pathogenic by OncoKB or previous literature, newly pathogenic identified with AlphaMisense, or benign. Mutational signatures were computed using SigMA algorithm, classifying each signature as positive at &gt;20%. The irradiated tumor control was evaluated in patients with ATM missense mutations who received radiotherapy. Results: Among 6,743 unique DDR missense mutations from MSK-IMPACT, 372 (3.5%) were known pathogenic, and 1,182 (17.5%) were new pathogenic mutations. In 205 tumors with bi-allelic core-HR missense mutations in breast, ovarian, pancreatic, and prostate cancers, 20 (9.8%) had new pathogenic mutations. Tumors with new pathogenic mutations more frequently exhibited HR-deficient signatures (65%) than wild-type (31.8%, p &lt; .001), similar to tumors with known pathogenic mutations (62.8%, p = 1.0). In TCGA, HR-deficient signatures tended to be more frequent in tumors with new pathogenic missense mutations than in wild-type tumors (41.7% vs. 21.0%, p = .16). Of 1,010 tumors with POLE missense mutations from MSK-IMPACT, 300 (30%) had new pathogenic mutations. The presence of POLE signatures in tumors with new pathogenic mutations (11.9%) was not significantly different from those with benign mutations (4.3%, p = .19) and less frequent than in tumors with known pathogenic mutations (91.0%, p &lt; .001). In MSK-IMPACT, tumors with new pathogenic ATM missense mutations were less likely to have TP53 mutations than benign missense mutations (32.7% vs. 56.6%, p &lt; .001), consistent with bona-fide pathogenicity. Further, patients with new pathogenic ATM missense mutations showed increased radiosensitivity, characteristic of ATM deficiency, and improved irradiated tumor control compared to those with benign missense mutations (Hazard ratio 0.58, 95% Cl 0.35-0.95, p = .03). Conclusions: AlphaMissense can identify previously unknown pathogenic DDR missense mutations, but its accuracy is gene-dependent. AlphaMissense pathogenicity predictions for DDR genes can utilized to help classify mutations, but may not be sufficient on their own.
Efficacy and safety of entrectinib in children with extracranial solid or primary central nervous system (CNS) tumors harboring <i>NTRK</i> or <i>ROS1</i> fusions.
Authors: Ami V. Desai, Giles W. Robinson, Yeming Wu, Huanmin Wang, Ellen M. Basu, Aditi Bagchi, Michela Casanova, Cornelis Martinus van Tilburg, Quentin Campbell-Hewson, Amy E. Armstrong, Nicolas André, Clare E. Devlin, Jade Wulff, Alison Cardenas, Georgina Meneses-Lorente, Katherine E. Hutchinson, Qinshu Lian, Carolina Ryklansky, Elizabeth Fox, Amar J. Gajjar
Journal: Journal of Clinical Oncology (2024)

10000 Background: Entrectinib previously yielded durable responses in children with NTRK or ROS1 fusion-positive extracranial solid or primary CNS tumors in STARTRK-NG (NCT02650401). We present updated data from STARTRK-NG, TAPISTRY (NCT04589845) and STARTRK-2 (NCT02568267): pediatric patients from these trials were combined to enable an integrated efficacy and safety analysis on a larger cohort than previously. Methods: Eligible patients were TRK or ROS1 inhibitor naïve and aged &lt; 18 years, had locally advanced or metastatic extracranial solid or primary CNS tumors harboring an NTRK or ROS1 fusion, and had measurable or evaluable-only disease. Once enrolled, patients received ≥1 daily dose of oral entrectinib until disease progression, unacceptable toxicity, or consent withdrawal. Tumor responses were confirmed by blinded independent central review (BICR) per RECIST v1.1 or RANO criteria. Patients were included if they had been followed for ≥6 months. The primary endpoint was confirmed objective response rate (ORR) per BICR. Key secondary endpoints included ORR in patients with baseline measurable disease per BICR, duration of confirmed response (DoR), time to confirmed response (TTR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. Results: At clinical cutoff (16 July 2023), out of 91 safety-evaluable patients (regardless of fusion), 44 patients in the NTRK cohort and 20 patients in the ROS1 cohort were efficacy evaluable. Median duration of survival follow-up was 24.2 months ( NTRK: range 1–66) and 27.6 months ( ROS1: range 1–73). The ORR was 72.7% (95% CI 57.2–85.0) in the NTRK cohort and 65.0% (95% CI 40.8–84.6) in the ROS1 cohort. In patients with baseline measurable disease, the ORR was 81.1% ( NTRK: n=30/37; 95% CI 64.8–92.0) and 62.5% ( ROS1: n=10/16; 95% CI 35.4–84.8). Efficacy outcomes are shown in the Table. The most common adverse events were pyrexia (50.5%), vomiting (40.7%) and anemia (40.7%). Conclusions: Entrectinib continued to yield rapid and durable responses in pediatric patients with extracranial solid or primary CNS tumors harboring an NTRK or ROS1 fusion. The safety profile of entrectinib was in line with previous reports. Clinical trial information: NCT02650401 / NCT04589845 / NCT02568267 . [Table: see text]
Associations between violence, distress, and cancer in transgender and non-transgender people.
Authors: Ash Blythe Alpert, Sabrina Jamileh Sayegh, Scott Cunliffe, Jae Sevelius, Don Operario, John Pachankis, Melinda Irwin, Catherine Cerulli, Jennifer J. Griggs, Myla S. Strawderman
Journal: Journal of Clinical Oncology (2024)

10566 Background: Due to transphobia, transgender people experience extreme rates of violence and distress. In other populations, violence and distress have been linked to increased cancer morbidity and mortality likely due to increased inflammation and higher rates of cancer risk factors. Methods: To evaluate associations between gender identity, violence, distress, cancer risk factors, and cancer, we developed an a priori structural equations model (SEM) and conducted a cross-sectional cohort study using electronic medical record data entered between 2006-2021 at a New York academic hospital. Participants were adults identified as transgender (N=894) by diagnosis codes, keyword searches, and structured gender identity information. We used age and follow-up time to match this cohort with participants not identified as transgender (N=1788) (2:1). We noted experiences of violence using keyword searches, diagnosis codes, and a screening question, “Are you safe at home?” We assessed distress as a latent factor based on mental illness diagnosis codes and keyword searches and diagnosis codes related to childhood violence. Cancer risk factors included ever smoking, body mass index ≥ 30, and history of HIV, HPV, or hepatitis B or C. We made unadjusted comparisons of violence, distress, cancer risk factors, and cancer in transgender and non-transgender people using two-sample chi-square tests. Our SEM included a direct path from gender identity to cancer or precancerous lesions as well as indirect paths through intermediaries of adult violence, distress, and cancer risk factors. We assessed direct paths for statistical significance using z-tests and indirect paths using bias-corrected bootstrap confidence intervals. Results: The association between gender identity and probability of cancer transmitted through the intermediate variables of violence, distress, and having multiple cancer risk factors was significant (p=0.05). Conclusions: In our model, transgender people experienced high rates of violence and distress, both of which were associated with cancer risk factors and cancer. Transphobia and violence experienced by transgender people must be addressed and mitigated. More work is needed to better understand associations between violence, distress, and cancer risk. [Table: see text]
Evaluating genetic features and clinical characteristics of young women diagnosed with breast cancer by the age of 35.
Authors: Christine Jane Kurian, Ahmed K. Abou Hussein, Kristin Mattie, Krystal Hunter, Generosa Grana
Journal: Journal of Clinical Oncology (2024)

10580 Background: Breast cancer in young women tends to be more aggressive with a unique distribution of molecular phenotypes compared to the general population. We evaluated the clinical characteristics and germline genetic test results in this cohort. Methods: We performed a single center retrospective review of 167 women diagnosed with breast cancer by 35, treated at our institution between the years 2013 to 2023. We reviewed medical records under Institutional Review Board approval for demographics, family history, tumor characteristics, surgical interventions performed, germline genetic test results, and number of pathogenic mutations identified. We used both descriptive and comparative quantitative statistics (student’s t test, Mann Whitney U Test and Chi Square tests) to compare data between patients with a pathogenic mutation and those without a pathogenic mutation. Results: Germline genetic testing was performed in 92.2% of individuals. The majority (81.4%) had no pathogenic mutation, whereas 15.6% had a pathogenic mutation implicated in hereditary breast cancer, and 3.0% had a pathogenic mutation not implicated in hereditary breast cancer. Our population was diverse - 60.4% white, 25.1% black, 7.8% Hispanic, and 6.5% Asian. Most patients had tumors that were high grade (56.3%), had a bilateral mastectomy performed (57.4%), did not have recurrence (87.4%), had exposure to oral contraceptives prior to diagnosis (59.9%), and had a family history of breast cancer (52.1%). 3.5% of patients were pregnant at the time of diagnosis. 26 patients were found to have pathogenic mutations implicated in hereditary breast cancer including BRCA1 (10), BRCA2 (10), CHEK2 (2), TP53 (2) and 88.5% of these patients underwent bilateral mastectomy. A higher proportion of patients with a pathogenic mutation were found to be progesterone receptor (PR) negative (56.8% vs 34.9; p = 0.029), undergo bilateral mastectomy (80.8% vs 53.2%; p = 0.009), be stage 1 at diagnosis (50.0% vs 19.1%; p &lt; 0.001), have invasive ductal carcinoma (80.8% vs 59.6%; p = 0.040), and have a family history of breast cancer (73.1% vs 48.9%; p = 0.024) compared to those with no pathogenic mutation. While not statistically significant, a higher proportion of patients with pathogenic mutations experienced recurrence (19.2% vs 11.3%; p = 0.330). Conclusions: Our study showed that breast cancer diagnosed in young women has a more aggressive disease biology with 56.3% of the cohort found to have grade 3 disease. A higher proportion of those who had a pathogenic mutation implicated in hereditary breast cancer were found to be PR negative, underwent bilateral mastectomy, and had a family history of breast cancer. As our study was an exploratory observational study, further prospective multi-center studies are needed to help corroborate our findings and to better elucidate the potential clinical significance.
Impact of molecular therapy on radioactive iodine uptake in patients with oncogene-driven metastatic differentiated thyroid cancer.
Authors: Adeline T Yang, Blair Segers, Olivia Caradonio, Supriya Behl, Yimei Li, Hongming Zhuang, Lisa States, Priya Mahajan, Tyler Garrett Ketterl, Steven G. Waguespack, Amber Isaza, Lindsay Sisko, Aime Franco, Andrew J. Bauer, Theodore Willis Laetsch
Journal: Journal of Clinical Oncology (2024)

TPS10078 Background: Targetable kinase fusions and mutations are common in pediatric and young adult patients with papillary thyroid cancer (TC) and are associated with metastatic disease and lack of response to radioactive iodine therapy (RAI). While survival outcomes are excellent, less than 20% of children with metastatic TC achieve a complete response to standard treatment with surgery and radioactive iodine (RAI). Thus, repeated RAI therapy is common, increasing the risk of pulmonary fibrosis and secondary malignancies. Targeted kinase inhibitors are highly effective at shrinking oncogene-driven TC. Preliminary data suggest that these targeted therapies can improve tumor differentiation and RAI sensitivity. However, optimal integration of targeted therapy with standard of care RAI for TC remains uncertain. The objective of this study is to evaluate if targeted inhibitors in patients with metastatic, oncogene-driven differentiated TC will improve or restore tumor RAI uptake and ultimately induce durable clinical responses in patients with metastatic differentiated TC. Methods: Patients with TC lung metastases, both RAI naïve and refractory, with an identified targetable molecular driver (Table) and intent to start oncogene-specific targeted therapy are eligible for this study. Patients who received a prior oncogene-specific targeted therapy are excluded. A RAI-whole body scan (WBS) is performed at baseline and after 4 weeks of targeted therapy. Patients will be followed for up to 5 years to monitor clinical response. Response parameters include structural (CT, WBS, and/or neck US) and biochemical (thyroglobulin, thyroglobulin antibodies) evaluation. The primary endpoint is the change in RAI avidity between baseline and 4 weeks of treatment. This will be calculated as the ratio of RAI uptake in the lungs/disease sites versus the whole body for each subject at each time point. Secondary endpoints include progression free survival and the proportion of patients who achieve a complete response to the combination of targeted therapy and RAI. Five of 32 patients have been enrolled. Clinical trial information: NCT05024929 . [Table: see text]
Are cancer screening recommendations from top US cancer centers concordant with the USPSTF guidelines?
Authors: Kristin Wright, Brian Shkabari, Christopher M. Booth, Kevin B. Knopf, Bishal Gyawali
Journal: Journal of Clinical Oncology (2024)

10535 Background: The USPSTF is an independent volunteer organization of multi-disciplinary national experts in disease prevention that publishes evidence-based non-binding recommendations for screening diseases, including cancer. Herein we assessed the congruence of cancer screening recommendations between the USPSTF and the Top 10 US Cancer Centers (as per the U.S News and World Report). Methods: This cross-sectional study compared the published screening recommendations from the Top 10 US Cancer Centers for colorectal (CRC), lung (LC), cervical (CC), prostate (PC), and breast cancers (BC) in average risk patients, to those of the USPSTF. The variables of interest included: screening tests, recommendation direction (for/against), strength, frequency, age of start, age of end, and discussion about risks and benefits. Data extraction was done by 2 authors and discrepancies resolved by mutual consensus and discussion with a third author. Results: We demonstrate the differences between the screening recommendations from the Top 10 Cancer Centers relative to those from the USPSTF (Table). Conclusions: Our study found significant variability between the screening recommendations from the 2022-2023 USNWR top 10 cancer centers and the evidence-based USPSTF guidelines for BC, PC, CC, and CRC. The recommendations for LC were overall in line with those of the USPSTF. The discordance was almost always in the direction of the cancer centers recommending more screening beyond the USPSTF’s recommendations, and often without discussion of potential risks and harms. This inconsistency could create confusion to the public, and therefore, a consistent messaging across the cancer centers congruent with the USPSTF recommendations and including a nuanced discussion of benefits and risks may be in the best public health interest.[Table: see text]
Correlation of patient HLA class I genotypes with severe immune-related adverse events: A retrospective study in Chinese population.
Authors: Luoyan Ai, Zhenghang Xu, Mengxuan Zhu, Yiyi Yu, Tianshu Liu
Journal: Journal of Clinical Oncology (2024)

10586 Background: Immune checkpoint inhibitors (ICIs) are effective in multiple tumors. However, about 10% of immune-related adverse events (irAEs) are severe and can have serious or even life-threatening consequences for patients. We investigated whether Human leukocyte antigen (HLA) genes predispose to and thus hold a predictive role of developing of severe irAEs in Chinese population. Methods: In a case/control study, we collected data from patients with metastatic cancer treated with ICIs and developed severe irAEs (Grade ≥3 and required hospitalization). Patients treated with ICIs without any irAEs were used as controls. Data was collected from15th Nov, 2019 until 10th Oct, 2023. HLA typing was performed via next generation sequencing. Results: We enrolled 83 patients with severe irAEs and 286 patients treated with ICIs without any irAEs. We found HLA-B*15:27 (OR=9.1, X 2 1,95 = 7.2, P = 0.008) and HLA-C*04:01 (OR=2.5, X 2 1,95 = 7.0, P =0.008) were significantly associated with severe overall irAEs risk. When assessing irAE individually, a significant association between HLA-B*13:02 and serious myocarditis (OR = 3.4, X 2 1,95 = 6.2, P =0.01) as well as striking enrichment for HLA-A*02:03 haplotypes in severe adrenal insufficiency (OR = 10.0, X 2 1,95 = 19.1, P&lt;0.0001) were observed. Conclusions: Specific HLA alleles were associated with severe irAEs. Consideration of pre-prescription HLA typing and vigilance for serious reactions to ICIs are warranted.
Sugar-sweetened beverage intake and risk of oral cavity cancer: Results from 3 prospective US cohort studies.
Authors: Luis Gomez Castillo, Armita Norouzi, Kara Cushing-Haugen, Rocco Ferrandino, Zain Rizvi, Neal D. Futran, Emily Marchiano, Cristina P. Rodriguez, Holly Harris, Brittany Barber
Journal: Journal of Clinical Oncology (2024)

10570 Background: Approximately 65% of adults in the US consume sugar-sweetened beverages (SSBs) daily, and consumption of SSBs substantially increased across successive birth cohorts in the US until 2000. Previous authors have identified an association between early-onset digestive tract cancers and SSBs. Recently, early-onset (&lt;50 years) oral cavity squamous cell carcinoma has been observed in non-smoking, non-drinking individuals. The objective of this study was to investigate the association between SSBs and development of oral cavity cancer (OCC) in smokers, non-smokers, and those &lt;50 years of age. Methods: We prospectively examined the association between SSB intake and OCC risk among 165,212 women in Nurses’ Health Study (NHS, 1986-2014) and Nurses’ Health Study II (NHSII, 1991-2015), and 45,790 men in the Health Professionals Follow-Up Study (HPFS, 1986-2014). All participants completed validated food frequency questionnaires (FFQs) every 4 years. Cox proportional hazards models adjusted for age, caloric intake, tobacco pack-years, alcohol intake, and BMI were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between SSB intake and OCC incidence. Results: We identified 129 incident OCC cases in NHS/NHSII over 36 years of follow-up and 99 cases in HPFS over 30 years of follow-up for HPFS. The mean age at study baseline was 44.4 years for NHS/NHSII and 54.1 years for HPFS. Notably, in the multivariable adjusted model, increasing SSB intake was associated with a higher risk of OCC only among female participants in NHS/NHSII. Specifically, those in the highest quartile of SSB intake had a 229% increased risk of OCC compared to the lowest quartile (95% CI 1.29-4.07, p trend =0.04). In non- or light-drinkers (&lt;5g/day) in NHS/NHSII, SSBs was associated with OCC (HR=2.58, 95% 1.16-5.70, p trend =0.10, N=81 cases). However, in non- or light-smokers (&lt;5 pack-years), SSB intake was not associated with risk of OCC, though power was limited due to low case numbers (HR=1.56, 95% 0.66-3.68, p trend =0.45, N=64). In contrast, no association of SSB intake with OCC risk was observed in the male HPFS cohort, overall (N=99) or among non-smokers (N=44). Early-onset OCC (&lt;50 years) was limited to 9 patients, and thus a subset analysis could not be performed. Conclusions: Higher SSB intake was associated with a higher risk of developing OCC in women, but not men, after controlling for known risk factors. Reduction of SSB consumption may serve as a potential strategy to address the increase in OCC observed in recent years.