bluuebunny/crossref_metadata_2025 huggingface dataset:
Demographic predictors of successful transition to adult survivorship care for survivors of pediatric cancer.
Authors: Gilbert Renee , Bates Carolyn , Alsman Kyla , Fulbright Joy M. , Lowry Becky N. , Nelson Eve-Lynn
Published: June 2023

10050

Background: There is a growing number of childhood cancer survivors in the U.S. (Chow et al., 2020) who are at risk for experiencing negative long-term health outcomes (Oeffinger et al., 2006). Current guidelines state the importance of receiving risk-based follow-up at adult survivorship clinics, yet available estimates suggest that less than 50% of survivors receive yearly survivorship care (Landier et al., 2004; Daly et al., 2018). The transition from pediatric to adult care is a difficult process, with various factors acting as barriers (Devine et al., 2017). The present study sought to evaluate demographic predictors of successful transition to adult survivorship care in a Midwestern clinic serving a large urban and rural catchment area. Methods: The study includes adult survivors of childhood cancer (n = 203) who received pediatric or adult survivorship care in a Midwestern metropolitan area from 2015 to 2022. For this study, successful transition to adult care was defined as attending at least one appointment in the adult survivorship clinic. Dates of clinic attendance, cancer diagnosis, insurance data, and zip code were abstracted from the medical record. 86.2% of survivors had commercial insurance, 13.8% had government -sponsored insurance, self-pay or other insurance. Participant zip codes were 66.7% urban, 19.5% metropolitan (low and high commuting), 9.2% micropolitan, and 4.6% rural. Survivor ages ranged from 20 to 68 years (M = 29.48, SD = 7.74) and 53.2% were female. Participant-reported race/ethnicity was 90.1% White, 5.4% Hispanic, 3.4% Black and 1% Other. Results: 66% of the sample attended at least 1 appointment in the adult survivorship clinic. Chi-square analyses revealed a significant relationship between insurance type and attendance at the clinic, [Χ2(1) = 16.60, p < .001], such that a greater proportion of survivors with commercial insurance transitioned to adult survivorship care (71%), compared to government-assisted (Medicare), self-pay or other insurance (32%). Analyses revealed a significant relationship between rurality and transition, [Χ2(3) = 14.11, p < .01], such that a greater proportion of survivors from urban areas transitioned (74%) compared to rural areas (22%). Race/ethnicity, gender and cancer type were not significantly associated with transition. Conclusions: Results suggest that a lack of commercial insurance and rurality served as risk factors for not successfully transitioning to an adult survivorship clinic, highlighting opportunities for improvement in clinic reach.
Mortality and the burden of subsequent malignant neoplasms in survivors of childhood cancer beyond age 50: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Bhandari Rusha , Chen Yan , Chow Eric Jessen , Howell Rebecca M. , Kenney Lisa Brazzamano , Krull Kevin R. , Leisenring Wendy M. , Nathan Paul C. , Neglia Joseph Philip , Ness Kirsten K. , Oeffinger Kevin C. , Snyder Claire Frances , Turcotte Lucie Marie , Wong Florence Lennie , Yasui Yutaka , Armstrong Gregory T. , Armenian Saro
Published: June 2023

10052

Background: The first generation of survivors of childhood cancer is now older than 50 years (y) of age. There is a paucity of information on the risk for late mortality and the evolving burden of subsequent malignant neoplasms (SMNs) in these aging survivors. Methods: We assessed cause-specific mortality (National Death Index) and self-reported SMNs (excluding nonmelanoma skin cancers) among CCSS participants diagnosed between 1970-1999, conditional on having survived to 50y by 12/31/2017. There were 4,772 survivors alive at 50y eligible for mortality analyses. Of the 3,355 who completed a baseline CCSS questionnaire, 2,273 also completed a follow-up questionnaire at ≥50y and were included in the SMN analyses. Cumulative mortality, standardized mortality ratios (SMRs), and, for SMNs, cumulative burden, standardized incidence ratios (SIRs), and relative rate (RR) with 95% confidence intervals (CIs) were calculated, compared with the general US population and by survivor subgroups. Piecewise-exponential multivariable regression was used to identify risk factors associated with the development of SMNs after 50y. Results: Mean age at diagnosis was 14y (standard deviation 4.2y). Mortality: Among survivors who attained 50y of age, the subsequent 5y, 10y, and 15y incidences of all-cause mortality were 9%, 19%, and 35%, respectively, (overall SMR 3.7 [95% CI 3.4-4.1]). SMRs were highest for SMN (SMR 5.1 [95% CI 4.4-5.9]), pulmonary (SMR 4.7 [95% CI 3.3-6.5]) and cardiovascular (SMR 3.9 [95% CI 3.2-4.8]) causes of death. The highest SMR (SMR 9.2 [95% CI 7.7-10.8]) was seen in female survivors of Hodgkin lymphoma. SMN: By age 50y, 14% of CCSS participants reported >1 SMN. History of SMN <50y was independently associated with the rate of developing another SMN at >50y (RR 1.6 [95% CI 1.1-2.3]). The most frequent SMNs ≥50y were breast (41%) in females and prostate (21%) in males, followed by gastrointestinal cancers in both (14% [females], 19% [males]). The cumulative burden of SMNs in survivors treated with radiation therapy (RT) increased sharply with age and exceeded 50 per 100 survivors by 65y (SIR 3.3 95%CI 2.0-5.2]). Survivors who did not receive RT had a SMN rate comparable to the general population (Table). Conclusions: This sentinel population of survivors of childhood cancer is at high risk for poor outcomes as they enter older adulthood. RT exposure and history of SMN <50y are associated with increased risk for developing SMNs after 50y. The evolving burden of late morbidity attributed to SMNs may be lower for contemporary survivors projected to have less RT exposure. [Table: see text]
Longitudinal associations between peripheral neuropathy and neurocognitive decline in long-term survivors of pediatric cancer treated without central nervous system (CNS) directed therapy.
Authors: Williams AnnaLynn , Phillips Nicholas Steve , Goodenough Chelsea Goodliffe , Brinkman Tara M. , Papini Chiara , Jacola Lisa M , Delaney Angela , Armstrong Gregory T. , Jefferies John L. , Khan Raja B. , Robison Leslie L. , Hudson Melissa M. , Ness Kirsten K. , Krull Kevin R.
Published: June 2023

10054

Background: Survivors of pediatric cancer treated without CNS-directed therapy are at risk of neurocognitive impairment and peripheral neuropathies. Using the St. Jude Lifetime Cohort, we investigated longitudinal associations with neuropathy to inform contributors to long-term cancer-related neurocognitive decline. Methods: Survivors of pediatric cancer (N=899 mean age 32 [SD 12], 24[10] years from diagnosis) treated without CNS-directed therapy completed neurocognitive testing and medical assessments at two timepoints (T1, T2 4.4[2.3] years apart). Peripheral sensory and motor neuropathy subscales combined with functional tasks were severity graded using a modified CTCAE (no neuropathy = none or grade 1 at T1 and T2; new onset = new grade 2 or 3 at T2; persistent = grade 2 or 3 at T1 & T2). Linear regression models estimated change in neurocognitive Z-score associated with neuropathy groups, adjusted for diagnosis age, time between visits, sex, race/ethnicity, high-dose intravenous methotrexate & baseline neurocognitive Z-score. Results: New onset sensory (n=33, 3.6%) and motor (n=35, 3.9%) neuropathy was associated with a 0.33 standard deviation (SD) decline in visual-motor processing speed (Table). New onset motor neuropathy was associated with a 0.50 SD decline in sustained attention as well as significant declines in verbal recall, working memory, and cognitive flexibility (p’s<0.05). Persistent sensory neuropathy (n=25, 2.8%) was associated with large declines in focused attention and cognitive flexibility (p’s<0.05). Persistent motor neuropathy (n=18, 2.0%) was associated with a 0.50 SD decline in sustained attention, verbal recall, and working memory (p’s<0.05). Conclusions: Peripheral neuropathies are associated with future neurocognitive decline in adult survivors of pediatric cancer. Research is needed to understand shared mechanisms (e.g. pain, inflammation) to inform targeted interventions to improve neuropathic symptoms and neurocognitive function. [Table: see text]
Subsequent meningiomas in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Cooney Tab , Chen Yan , Yuan Yan , Galvin Robert Thomas , Leisenring Wendy M. , Smith Susan A. , Howell Rebecca M. , Arnold Michael A. , Conces Miriam , Bowers Daniel C. , Yasui Yutaka , Diller Lisa , Armstrong Gregory T. , Neglia Joseph Philip , Turcotte Lucie Marie
Published: June 2023

10058

Background: Meningiomas are the most common subsequent central nervous system tumor among aging survivors of childhood cancer, yet incidence across the lifespan, occurrence of multiple meningiomas, and risk for mortality are not established. Methods: Meningiomas were identified by self-report and validated with pathology/medical records. Twenty-year cumulative incidence of meningioma (95% confidence interval) was estimated and multivariable models assessed demographic- and treatment-related meningioma risk factors. Results: Among 24,902 5-year survivors of childhood cancer diagnosed 1970-1999, we identified 472 survivors with 710 meningiomas, 145 (20.4%) of which were WHO grade 2/3. Among survivors with meningioma, 137 (28%) had ≥2 meningiomas, and 80 (16%) met criteria for meningiomatosis. The median latency from childhood cancer to first meningioma diagnosis was 26.2 years (range 5.6-48.2), and the median time from first to second meningioma (among those without meningiomatosis) was 1.4 years (range 0-30.2 years). The twenty-year cumulative incidence did not significantly decrease between survivors diagnosed in the 1970s (0.58, 95% CI 0.41-0.79) and the 1990s (0.42, 95% CI 0.32-0.55). In multivariable analysis, female sex (HR 1.52, 95% CI 1.21-1.91) and all cranial radiotherapy dose levels ( > 0-30Gy, HR 57.0, 95% CI 7.93-419.60; 30.1-50 Gy, HR 228.90, 95% CI 30.89-1695.99; > 50 Gy, HR 113.29, 95% CI 15.09-850.34) were associated with increased meningioma risk, while older age at diagnosis (10-14 years, HR 0.60, 95% CI 0.44-0.82; 15-20 years, HR 0.35, 95% CI 0.22-0.55) was associated with reduced meningioma risk. Among 71 deaths in survivors with meningioma, the most prevalent cause of death was meningioma (N = 25, 35.2%). The 5-year all-cause mortality from first meningioma diagnosis was 4.20% (95% CI: 2.44-5.96%). Conclusions: In conclusion, cranial radiation, younger diagnostic age and female sex were identified as independent meningioma risk factors in, to our knowledge, the largest study to date. The risk for meningioma-associated mortality argues for assertive meningioma surveillance and treatment in this population.
Racial disparities in treatment and outcomes of pediatric hepatoblastoma.
Authors: Billion Taylor , Holland Eva , Silberstein Peter T. , Braaten Marco
Published: June 2023

10062

Background: Hepatoblastoma is the most common malignant liver tumor which affects pediatric patients. However, the incidence is rare with 100 cases reported per year.1 Current management consists of surgery and adjuvant cisplatin chemotherapy and radiation depending on tumor histology, resectability, and metastasis.2 However, due to its rarity, optimal treatment protocol remains unclear. The 5-year overall survival rate in the US is approximately 57-69%1. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with hepatoblastoma from 2004 to 2020 using the histology codes 8970 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, Chi-Square, and ANOVA tests were performed. Data was analyzed using SPSS version 27 and statistical significance was set at α = 0.05. Results: This study identified 1215 patients with hepatoblastoma. Black patients had a significantly lower median survival rate compared to White and other race patients (126.2 months vs 165.4 months vs 166.1 months; all p<0.05). Black patients were more likely to be from low-income households than White patients (29.6% vs 17.3%; p<0.05). The mean age of diagnosis was higher for Black patients compared to White patients (2.42 vs 1.99; p<0.05). Black patients were less likely to receive surgery (63.5% vs. 75.4%; p<0.05). Black patients on average had shorter distances to travel from their residence to the hospital (30.61 vs. 59.52 miles; p<0.05). Black patients had longer mean stay times compared to white patients (16.7 days vs 11.2 days; p<0.05). There was no significant difference in survival across incomes. When comparing Black and White patients there was no significant difference in insurance type, surgical margins, grade, stage, size of tumor, regional lymph nodes and time of diagnosis to treatment. No significant difference was shown between adjuvant therapies including chemotherapy and radiation. Conclusions: This study showed Black patients experienced inferior overall survival when diagnosed and treated for hepatoblastoma compared to White patients. This population was less likely to receive surgery, older when diagnosed, and had longer hospital stays. Poorer outcomes suggest a disparity in hepatoblastoma treatment. References: 1. Rangaswami, Arun A. “Pediatric Hepatoblastoma Treatment & Management: Medical Care, Surgical Care, Consultations.” Pediatric Hepatoblastoma Treatment & Management: Medical Care, Surgical Care, Consultations, Medscape, 9 Dec. 2021, https://emedicine.medscape.com/article/986802-treatment . 2. Pritchard J, Brown J, Shafford E, et al.: Cisplatin, doxorubicin, and delayed surgery for childhood hepatoblastoma: a successful approach--results of the first prospective study of the International Society of Pediatric Oncology. J Clin Oncol 18 (22): 3819-28, 2000.
Randomized trial of fixed dose capecitabine compared to standard dose capecitabine in metastatic breast cancer: The X-7/7 trial.
Authors: Khan Qamar J. , Bohnenkamp Colleen , Monson Taylor , Smith Holly E , Phadnis Milind A. , Raja Vinay , Elia Manana , O'Dea Anne , Crane Gregory James , Fesen Mark Robert , Nye Lauren Elizabeth , Sheehan Maureen , Pluenneke Robert E. , Al-Rajabi Raed Moh'd Taiseer , Baranda Joaquina Celebre , Kasi Anup , McKittrick Richard J. , Mitchell Laura , LaFaver Stephanie , Sharma Priyanka
Published: June 2023

1007

Background: In metastatic breast cancer (MBC), oral capecitabine prescribed at the FDA approved dose of 1250 mg/m2 twice daily, 14 days on followed by 7 days off, is associated with poor tolerance and high discontinuation rates. Mathematical models suggest a fixed dose, dose dense (7 days on, 7 days off) schedule may be optimal for capecitabine efficacy. We conducted a randomized trial to compare the efficacy and tolerability of fixed-dose capecitabine, 1500 mg twice daily, 7 days on, 7 days off (FD) to the FDA approved dose and schedule (SD). Methods: Females with MBC and any prior lines of endocrine therapy or chemotherapy were included. HER-2 positive patients were allowed with concurrent trastuzumab. Patients were stratified by line of chemotherapy (first or subsequent), measurable disease, and ER status, and randomized 1:1 to either FD or SD. The primary endpoint was 3-month progression free survival (PFS). Additional endpoints included PFS and overall survival (OS). Capecitabine related toxicities were solicited and graded at each visit. Results: Between October 2015 and April 2021, 153 patients were enrolled (N=80 FD, N=73 SD) . 78% were hormone receptor positive/HER-2 negative, 11% each were HER-2 positive and triple negative. The 3-month PFS was 76% in the FD arm and 76% in the SD arm (HR=1.01; 95% CI, 0.52 to 1.94; p=0.99). Landmark analysis of PFS at 12, 24 and 36 months is reported. Non-proportional hazards were detected, so restricted mean survival time (RMST) was used to report estimates of effect. PFS (restricted mean) at 36 months was 13.9 months in the FD arm versus 14.6 months in the SD arm (hazard ratio for progression or death, 1.31; 95% CI, 0.56 to 1.15; p=0.24). OS (restricted mean) at 36 months was 21.2 months in the FD arm versus 19.6 months in the SD arm (hazard ratio for death, 0.80; 95% CI, 0.55 to 1.81; p=0.27). Toxicity related treatment discontinuation occurred in 21 patients (28.8%) in the SD arm compared to 6 patients (7.5%) in the FD arm (p<0.0006). Grade 2-4 toxicities (Table) occurred more frequently in patients receiving SD capecitabine (49.3%) as compared to FD capecitabine (25.0%) (p=0.0018). Conclusions: Fixed dose capecitabine (1500 mg twice daily) on a 7/7 schedule has less toxicity and similar survival when compared to standard BSA-based dosing on a 14/7 schedule in MBC. Clinical trial information: NCT02595320 . [Table: see text]
RNA expression levels from peripheral immune cells, a minimally invasive liquid biopsy source to predict response to therapy, survival and immune-related adverse events in patients with triple negative breast cancer enrolled in the GeparNuevo trial.
Authors: Huebner Hanna , Rübner Matthias , Schneeweiss Andreas , Denkert Carsten , Sinn Hans Peter , Braun Michael , Karn Thomas , Sinn Bruno Valentin , Zahm Dirk Michael , Thomalla Jörg , Huober Jens Bodo , Hanusch Claus , Untch Michael , Solbach Christine , Link Theresa , Filmann Natalie , Rey Julia , Loibl Sibylle , Fasching Peter A.
Published: June 2023

1011

Background: The impact of immune checkpoint therapy on the tumor microenvironment including tumor-infiltrating immune cells is well described. However, little is known about the circulating immune repertoire and its association with treatment outcome. Hence, we set out to investigate the RNA phenotype of peripheral immune cells before and during treatment of patients enrolled in the GeparNuevo trial (Loibl S et al. Annals Oncol 2022). Methods: The GeparNuevo trial investigated the outcome after neoadjuvant nabP-EC-chemotherapy in combination with the anti-PD-L1 immune checkpoint inhibitor durvalumab versus placebo in patients with non-metastatic triple negative breast cancer. Blood was collected before therapy (baseline), after window, before epirubicin/cyclophosphamide and at end of treatment. RNA from circulating leucocytes of 117 patients was extracted and analyzed using a custom NanoString nCounter CodeSet. Expression of 290 immune-related genes was quantified. The association of RNA expression and signatures with outcome parameters like pathologic complete response (pCR), distant disease-free survival (DDFS), invasive disease-free survival (iDFS), overall survival (OS), and immune-related adverse events (irAEs) were investigated. Results: Immune cell type scores representing macrophages and neutrophils significantly increased during treatment, while B cell, T and Th1 cell scores decreased (p < 0.0001, respectively) regardless of treatment arm. Multivariate logistic respectively multivariate Cox regression analysis revealed a significant association of each baseline DPP4 and MYC gene expression with pCR, DDFS, iDFS, and OS in patients. CDK2, F5 and HLA-DR mRNA expressions were associated with the presence of irAEs. The signature score for TNFR2 non-canonical NF-kB pathway, which is known for its protective capacity, was inversely associated with irAEs in the durvalumab arm (OR = 0.454, 95% CI 0.231-0.892, p = 0.0220). Multiple immune-related signatures at baseline were associated with tumor mutational burden. Conclusions: Our study indicates the importance of the peripheral immune phenotype for treatment response and survival. This association between RNA expression levels of circulating immune cells and outcome seems to be not only relevant for patients receiving immune checkpoint therapy, but also for those under standard chemotherapy alone. Clinical trial information: NCT02685059 .
Clinico-molecular characteristics associated with outcomes in breast cancer patients treated with CDK4/6 inhibitors: Results from the AURORA Molecular Screening Initiative.
Authors: Agostinetto Elisa , Sotiriou Christos , Ignatiadis Michail , Antoniolli Crestani Thayane , Venet David , Tyekucheva Svitlana , Irrthum Alexandre , Seoane Jose A. , Piccart-Gebhart Martine J. , Cameron David A. , Knox Susan , ROTARU CRISTINA EMILIA , Romagnoli Dario , Zoppoli Gabriele , Aftimos Philippe Georges , Oliveira Mafalda , Regan Meredith M. , Malorni Luca , Benelli Matteo , Hilbers Florentine
Published: June 2023

1019

Background: CDK4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) is the recommended first line standard of care for patients with estrogen receptor positive (ER+), HER2-negative (HER2-) advanced breast cancer (ABC). However, not all patients derive the same benefit from this treatment. We aimed to identify factors associated with outcome in patients treated with CDK4/6i in a real-world setting. Methods: AURORA (NCT02102165) is an international program aimed at studying ABC by performing multi-omics profiling on paired primary tumors and metastases. Here we present exploratory results from AURORA patients treated with first line CDK4/6i + ET. DNA from primary and/or metastatic lesions and germline DNA was sequenced for 411 cancer-related genes. Endocrine resistance was defined according to the 5th ABC international consensus guidelines at the start of the first line. Local histology assessment of the primary tumor was used. Progression-free survival (PFS) was calculated from the start of CDK4/6i treatment until disease progression or death (whichever occurred first). Results: We analyzed 339 patients treated with CDK4/6i + ET in the first line. PFS differed significantly among the endocrine resistance subgroups (p<0.001). Both TP53 and acquired ESR1 mutations were associated with shorter PFS (hazard ratio [HR] 1.59 [95% CI 1.43-6.73], p=0.004 and 3.10 [95% CI 1.16-2.18], p=0.004 respectively). In a multivariable analysis, acquired ESR1 mutations were significantly associated with worse PFS independently of endocrine resistance status (HR 2.42 [95% CI 1.01-5.79], p=0.048). Mutations in PIK3CA were not associated with outcome (HR 0.84 [95% CI 0.63-1.13], p=0.25). No PFS difference was observed between lobular and ductal tumors (HR 1.07 [95% CI 0.66-1.75], p=0.61). Conclusions: Endocrine resistance status and TP53 and acquired ESR1 mutations were associated with shorter PFS. Factors associated with poor outcome may be used to select patients to test alternative treatment strategies in clinical trials. Clinical trial information: NCT02102165 . [Table: see text]
Prostate-specific membrane antigen (PSMA) expression in patients with metastatic triple negative breast cancer: Initial results of the PRISMA study.
Authors: Nader Marta Guilherme , Wimana Zena , Taraji Loubna , Critchi Gabriela , Aftimos Philippe Georges , Piccart-Gebhart Martine J. , Flamen Patrick , Gebhart Geraldine
Published: June 2023

1025

Background: Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) prolongs survival of patients (pts) with prostate cancer. Preliminary immunohistochemistry (IHC)-based studies suggest that PSMA is highly expressed in triple negative breast cancer (TNBC). The PRISMA study aims to assess PSMA expression in pts with metastatic TNBC (mTNBC) via positron-emission tomography/computed tomography (PET/CT) to evaluate the feasibility of PSMA-targeted RLT for TNBC. Methods: PRISMA is a prospective, single-center study that enrolled pts with progressive mTNBC and measurable disease on 18F-FDG PET/CT to undergo 68Ga-PSMA-11 PET/CT. TNBC definition (ASCO/CAP) was based on the IHC of the primary breast cancer (BC) or metastasis. Target lesions (TL) were defined as metastatic lesions ≥1.5 cm with significant uptake in 18FDG-PET/CT. The same TL regions were propagated to the 68Ga-PSMA-PET/CT. 68Ga-PSMA-11 maximum standard uptake value (SUVmax) was measured for each TL. PSMA patterns A and B were defined according to presence of a majority (pattern A) or a minority (pattern B) of positive TL on 68Ga-PSMA (ie. uptake greater than that of normal liver parenchyma). Mann-Whitney U test was used to assess differences in median SUVmax (mSUVmax) between subgroups. Results: Ten pts with progressive mTNBC were enrolled. One pt was excluded due to lack of TL on 18FDG-PET/CT. Median age was 48 years (range 36-68), median number of TL per patient was 8 (5-18). Five pts had a TNBC IHC since the initial BC diagnosis, while 4 had a switch to TNBC (4 with initial estrogen receptor [ER]-positive and 1 with HER2-positive BC). All evaluable pts had inter- and intra-organ heterogeneity in PSMA uptake in TL and 2 pts had some mismatch with FDG-positive and PSMA-negative TL. mSUVmax was 2.99 (range 1.7-6.3) in the overall population and was higher in pts with pattern A (5.1 vs 2.6 in patterns A and B, respectively, p = 0.03). mSUVmax was numerically higher in younger pts (5.0 vs 2.6 in pts <50y and ≥50y, p = 0.28), PD-L1-positive (5.0 vs 2.7 in PD-L1-positive and -negative, p = 0.14), de novo metastatic disease (5.0 vs 2.9 in de novo and recurrent BC, p = 0.38) and those with ER-negative primary breast tumor (3.4 vs 3.0 in ER-negative and ER-positive primary BC, p = 0.9). Conclusions: A significant PSMA uptake was observed in a proportion of pts with mTNBC. Inclusion of additional pts and translational analyses will allow the identification of PSMA expression determinants. PSMA-targeted RLT may be considered as an innovative therapeutic strategy to be explored in selected pts with mTNBC. [Table: see text]
Gene expression profiling of paired primary breast cancers and brain metastases to identify brain metastases-specific biological changes.
Authors: Griguolo Gaia , Dieci Maria Vittoria , Fineberg Susan , Pinato Claudia , Bottosso Michele , Bauchet Luc , Miglietta Federica , Jacob Jack , Zarrilli Giovanni , Rigau Valerie , Guarascio Maria Cristina , Zanconato Francesca , Schiavi Francesca , Fassan Matteo , Jacot William , Piccolo Stefano , Darlix Amelie , Guarneri Valentina
Published: June 2023

1032

Background: Despite the clinical impact of breast cancer (BC) brain metastases (BM), their biological complexity still remains poorly understood. We here evaluate the genomic profile of paired primary and metastatic samples to characterize biological changes acquired by BC during metastatization to the brain. Methods: The expression of 758 BC–related genes was evaluated using the BC360 Panel (nCounter platform) in matched primary BC and their associated BM. Intrinsic molecular subtyping was determined using the PAM50 subtype predictor (Parker et al. JCO 2009). Hormone receptor (HR) and HER2 status were evaluated on the BCBM. A False Discovery Rate (FDR) corrected paired two-class SAM was used to identify changes in single genes expression between paired BC and BMs samples. Results: Twenty-one matched primary BC and BMs samples were analyzed. BC subtype evaluated on the BMs was distributed as follows: 24% (N=5) HR-/HER2-, 24% (N=5) HR+/HER2- and 52% (N=11) HER2+. A considerable shift in PAM50 subtype was observed between primary BC and paired BM. While subtype concordance was high for HER2-enriched (HER2-E) tumors (100%), all Luminal A (LumA) primary BCs switched to either HER2-E (75%) or Luminal B (LumB, 25%) on the BM sample, as did 45% of Basal-like BCs (Basal to HER2-E). A clinical switch from HER2- primary BC to HER2+ BM (defined by IHC and ISH) was observed in only one pair (5%). Consistently, HER2-E (p<0.001) and LumB (p=0.001) PAM50 signatures were significantly more expressed, while the LumA (p<0.001) and Normal-like (p=0.001) signatures were significantly less expressed in BMs as compared to paired primary BCs (FDR-corrected Wilcoxon paired signed rank test). No significant change was observed in the expression of the Basal-like signature (p=0.562). Among the 758 evaluated genes, 60 and 318 genes, respectively, were significantly up- and downregulated in BMs as compared to primary BC (FDR<5%). Upregulated genes were enriched, among others, in genes involved in survival and migration (e.g. FGFR4), cell proliferation (e.g. CCNB1, CDK1) and HER2-amplicon (e.g. ERBB2, GRB7). Downregulated genes were enriched in genes involved in immune response (e.g. CD8A, CCL5, PDCD1LG2, TNF), angiogenesis (e.g. PDGFRB) and response to hormonal stimuli (e.g. ESR1, BCL2). Conclusions: Gene-expression profiling of matched primary BCs and BMs shows recurrent gene expression modifications in metastatic samples which might have potential therapeutic implications (e.g. acquisition of HER2-E subtyping and increase in ERBB2 mRNA levels). [Table: see text]
Metastatic breast cancer (MBC) with ultra-high tumor mutational burden (UHTMB): A comprehensive genomic profiling (CGP) study.
Authors: Fanucci Kristina , Lustberg Maryam B. , Fischbach Neal A. , Pelletier Maureen , Sivapiragasam Abirami , Ashok Kumar Prashanth , Kallem Mansi , Danziger Natalie , Sokol Ethan , Sivakumar Smruthy , Pavlick Dean C. , Ross Jeffrey S. , Pusztai Lajos
Published: June 2023

1036

Background: Pts with MBC whose tumors feature high TMB (≥ 10 mutations/Mb) are eligible for on label immune checkpoint inhibitor (ICI) treatment. This study evaluated the genomic landscape of MBC with “Ultra high” TMB, defined at > 20 mutations/Mb. Methods: 2049 MBC underwent hybrid capture-based CGP to evaluate all classes of genomic alterations (GA), TMB, microsatellite instability (MSI) and trinucleotide mutational signatures. HER2 IHC results were available in a subset of pts. PD-L1 expression on immunocytes was determined by IHC (Ventana SP142). Results: 45/2049 (2.2%) of MBC were UHTMB. 45 (100%) pts had metastatic disease. 38 (84%) had documented Stage IV disease and 7 documented axillary LN metastases at the time of sequencing. Local breast tumor was used for CGP in 19 (42.2%) MBC and metastatic site biopsy was used in 26 (57.8%). When compared with 2004 non-UHTMB pts with UHTMB were older (mean 64.6 yrs vs 58.2 yrs p < .0001), more often had lobular histology (40.0% vs 14.5% p < .0001) and ER+ disease (86.6% vs 70.0%). Of the 35 UHTMB cases with HER2 IHC data available, 11 (31.4%%) were HER2 IHC negative (0+), 21 (60.0%) were HER2-low status (9 1+ and 12 2+/ISH negative) and 3 (8.6%) were HER2 IHC positive (3+). 1/3 HER2 IHC2+ cases and 2/45 (4.4%) of all UHTMB cases were positive for HER2 copy number gain on CGP. UHTMB cases had more driver GA/tumor (mean 9.8 vs 5.7 p < .0001) and were less often TNBC (13.3% vs 27.0% p = .041) compared to non-UHTMB high cancers. Mutation signature analysis revealed APOBEC was predominant in UHTMB samples (82.5%); MMR signature was also observed in 10% of cases. MSI high status was significantly more frequent in UHTMB high cases (11.6% vs 0.4% p < .0001). GA more frequently identified in UHTMB cases included CDH1 (45.5% vs 14.3% p < .0001), PIK3CA (81.8% vs 37.9% p < .0001), CDKN2A (11.4% vs 3.2% p = .017), ARID1A (25.0% vs 5.0% p < .0001) and NF1 (20.5% vs 5.9% p = .0014). PD-L1 ( CD274) gene amplification (2.3% vs 1.3%) or protein expression by the Ventana SP142 assay (57.14% vs 51.10%) were not significantly different among groups. Conclusions: UHTMB MBC is a rare, yet clinically important subset of clinically advanced breast cancer driven by APOBEC mutagenesis, with high incidence of ER+ lobular histology and frequent alterations in CDH1 and PIK3CA. In addition to potential benefit from ICI based treatment, UHTMB MBC present with a high frequency of HER2-low status which may impact therapy decisions for this rare disease. [Table: see text]
Artificial intelligence–powered tumor-infiltrating lymphocytes analyzer to reveal distinct immune landscapes in breast cancer by molecular subtype and HER2 score.
Authors: Shin Seunghwan , Cho Soo Youn , Cho Eun Yoon , Kim So-Woon , Jung Minsun , Song Seung-Geun , Lim Yoojoo , Cho Soo Ick , Kim Sukjun , Park Gahee , Song Heon , Ma Minuk , Yoo Donggeun , Ock Chan-Young
Published: June 2023

1049

Background: Tumor-infiltrating lymphocytes (TIL) reflect an ongoing anti-tumor immune response in the tumor microenvironment (TME) and have been studied as a predictive as well as prognostic biomarker in breast cancer (BC). The immune profile differs depending on BC molecular subtypes, with triple-negative BC (TNBC) and HER2-positive BC more frequently infiltrated by higher numbers of TIL than hormone receptor (HR)-positive tumors. In this study, we analyze TIL and immune phenotype by molecular subtype in BC and explore differences based on HER2 scores using an AI-powered TIL analyzer. Methods: A total of 1,973 cases of BC with molecular subtype, HER2 immunohistochemistry (IHC) or in situ hybridization (ISH) results, and TIL analysis from H&E slides from TCGA (n=1021), Samsung Medical Center (SMC, n=663), and KyungHee Medical Center (KHMC, n=289) were included in the analysis. The density of TIL were spatially analyzed from H&E WSI, and the immune phenotype (IP) was analyzed for each 1 mm2-sized patch. Tumor microenvironment (TME) was categorized into three types: inflamed (TIL distributed intratumorally), Immune-excluded (TIL excluded, out of cancer stroma), immune-desert (scant TIL in TME), and the score for each IP was calculated as the percentage of the total patches in WSI. Results: TNBC showed the highest TIL density in both cancer epithelium (214.5 ± 299.7/mm2) and stroma (1133.3 ± 1245.9/mm2), and a high percentage of inflamed IP (35.7%), IS (28.4 ± 28.1) than other subtypes (inflamed IP: 17.5%, IS 16.2±20.2, both p<0.001). HER2-positive BCs showed higher sTIL density (904.0 ± 901.7/mm2) compared to HR- positive BC (616.7 ± 794.1/mm2) but were associated with a higher percentage of immune-excluded IP (71.2%) and IES (57.6 ± 24.6). HR-positive BC had a high percentage of immune-desert IP (30.4%). In both HR-positive and negative BCs, higher IES was observed as the HER2 score increased. HER2-positive BC significantly showed a higher proportion of cancer stroma in the cancer region from WSI (Stromal ratio, 0.682 ± 0.149 vs. 0.578 ± 0.176, p<0.001). Conclusions: Different TIL densities and IP were seen in BC for each molecular subtype, pointing to a distinct immune landscape. HER2 score was associated with immune-excluded IP despite having higher TIL density, which should be considered for immunotherapy in BC.
Ancestry-adjusted genomic analysis to identify known and novel associations with single and multiple cancer phenotypes.
Authors: Joseph Vijai , Ravichandran Vignesh , Ostrovnaya Irina , Liu Ying L , Tkachuk Kaitlyn , Khurram Aliya , Kemel Yelena , Mandelker Diana , Bandlamudi Chaitanya , Walsh Michael Francis , Conry Michael T , Syed Aijazuddin , Schultz Nikolaus , Solit David B. , Berger Michael F. , Robson Mark E. , Stadler Zsofia Kinga , Offit Kenneth
Published: June 2023

10504

Background: Germline cancer risks are impacted by cancer type, stage, specific mutation, and ancestry. This study aims to determine the magnitude of genetic risks for commonly tested genes across patients with single and multiple primary cancers (MPC). Methods: We conducted a partially de-identified, retrospective cohort study of all patients consented to using the MSK-IMPACT, a matched tumor-normal sequencing assay, over a five-year period. Approximately 83% of IMPACT testing is derived from patients with metastatic disease. We collected data on demographics and clinical cancer features through cBioPortal and institutional databases. MPC were classified based on the IARC guidelines. Clinically actionable, pathogenic variants in cases and gnomAD non-cancer controls were identified using PathoMAN. Statistical methods incorporated ancestry adjusted, weighted generalized linear model, and ancestry specific methods to estimate risk. Biallelic losses were analyzed from paired tumors. Results: We analyzed 28,000 individuals across 35 cancer types, where germline variants were discovered within 100 cancer predisposition genes. 16% carried pathogenic, clinically actionable variants in known and novel cancer predisposition genes (15% in those with single primary and 21% in MPC). We discovered statistically significant novel associations of germline variants with several cancer phenotypes, including BRCA2 and biliary cancer (OR = 4.5, CI = 2.2-8); ATM and BRCA2 with mesothelioma (OR = 4.8, CI = 2.1-9.2; OR = 8, CI = 3.1-16.6, respectively); NF1 and breast cancer (OR = 5.8, CI = 2.4-12.1); NBN and lung cancer (OR = 4.2, CI = 2.3-6.9), bladder with ATR and others. We replicated known associations and discovered pleiotropy of BRCA1/2, NF1, ATM, TP53 with several cancer types. We failed to replicate reported associations such as PALB2 and ovarian cancer and CHEK2 and colon cancer. Amongst cancer pairs of multiple primaries, we observed mismatch repair genes MSH2, MSH6 and MLH1 to be associated with increased risks for stomach, bowel, and uterine cancer pairs, and TP53 in breast MPC compared to breast single primaries. Conclusions: An ancestry adjusted, weighted analysis of a large real-world case-cohort enriched with metastatic disease did not confirm some prior genotype-phenotype correlations, while suggesting novel associations with hereditary cancer types.
Integrating polygenic risk scores into clinical breast cancer models: Influence on prediction in diverse cohorts.
Authors: Busby George B.J. , Bolli Alessandro , Kintzle Jen , Kulm Scott , Neary John , Di Domenico Paolo , Morganstern Daniel , Botta Giordano
Published: June 2023

10506

Background: Breast cancer (BC) is the second leading cause of cancer death in women worldwide. Periodic mammography screening has been shown to reduce breast cancer mortality by around 20% in average-risk women and several BC risk models are currently used to identify women at higher risk who can be targeted with increased or earlier screening. However, despite their broad use, these models display only moderate discrimination performance (AUC ranging between 0.51 to 0.68). Here we explore the potential of integrating PRS into a BC risk model using a testing dataset comprising over 175,000 women of diverse ancestry in the UK Biobank and Women Health’s Initiative Cohorts. Methods: We built and validated novel ancestry-specific BC PRSs utilizing novel methodology that leverage multiple Genome Wide Association Studies (GWASs) and linkage disequilibrium maps. We assessed genetic ancestry from 5 continental level ancestry groups across all individuals and applied the PRSs to our testing dataset to assess the clinical implications of integrating genetic information to the Tyrer-Cuzick (TC) breast cancer clinical risk model. Results: The PRSs were well calibrated and displayed high risk stratification (Odds Ratios per Standard Deviation: 1.41 (1.28-1.62) to 1.76 (1.40-2.20; Table) which were comparable or better than benchmarking comparisons with previously published PRS panels. Across genetic ancestries, integrating PRS led to a relative increase of women identified at high lifetime BC risk (20% or higher) from between 1.7 fold (East-Asian ancestry) to around 3 fold (European ancestry). The Net Reclassification Improvement compared to the TC-only model was around 12% for East-Asian (0.001-0.254), European (0.111-0.133), and Admixed American ancestries (0.002-0.228), 17% (0.079-0.266) for South-Asians, and 5% (0.008-0.094) for African ancestry individuals (Table). Conclusions: Our results demonstrate that optimizing PRSs for genetic ancestries and integrating them into BC risk models can lead to a significant improvement in risk stratification. This can enable more targeted use of enhanced screening and prevention strategies improving their cost/benefit ratio.[Table: see text]
Lung cancer metabolomics: A pooled analysis in the cancer prevention studies.
Authors: Tang Ziyin , Liang Donghai , Deubler Emily L , Sarnat Jeremy A , Chow Sabrina S. , Diver Ryan , Wang Ying
Published: June 2023

10508

Background: Lung cancer is a heterogeneous disease, often diagnosed at advanced stages, with low overall survival rate. To better understand the lung cancer etiology and discover screening and early detection biomarkers, we performed a nested case-control study to examine the metabolic perturbation related to lung cancer. Methods: This study included 741 case-control pairs (mean age = 67 years) from the ongoing Cancer Prevention Study (CPS) cohorts. Participants completed a comprehensive exposure and health questionnaire at enrollment. Pre-diagnosis blood samples were collected between 1998-2001 in CPS-II and 2006-2013 in CPS-3. Cases and controls were 1:1 matched on date of birth, blood draw date, gender, and race/ethnicity. All eligible controls were cancer-free at the time of case diagnosis. Odds ratios (ORs) per standard deviation and 95% confidence intervals (CIs) were estimated using conditional logistic regression, controlling for potential confounders including body mass index, fruit and vegetable consumption, smoking status, and hormone use. We further performed stratified analyses by smoking status (never/former/current) and follow-up time (i.e., within 3 years/ beyond 3 years between blood draw and diagnosis). Statistical significance was determined as false discovery rate (FDR) < 0.2. Results: Sphingomyelin (d18:0/22:0), a bioactive sphingolipid of cell membranes, was associated with lung cancer risk (OR:1.32, 95% CI: [1.15, 1.53], FDR = 0.12). When stratified by follow-up time, participants diagnosed within 3 years of blood draw had a 59% higher risk of lung cancer per standard deviation increase in sphingomyelin (d18:0/22:0) (OR:1.58, 95% CI: 1.16, 2.15, p = 0.004) and 25% higher risk for those diagnosed beyond 3 years (OR:1.27, 95% CI: 1.08, 1.50, p = 0.005). Metabolites associated with lung cancer at raw p-value < 0.05 indicated the perturbation mostly in lipid, amino acid, and xenobiotics metabolism. We observed variants in perturbed metabolic pathways between never-smoker lung cancer cases and current-smoker lung cancer cases. Conclusions: This is the largest prospective study examining lung cancer risk and metabolic response using an untargeted metabolomics platform. These findings provide preliminary support for sphingomyelin (d18:0/22:0) as a potential screening and early detection biomarker for lung cancer. Results also highlight that lipid metabolism including sphingolipid and bile acid metabolism may play an important role in lung cancer etiology.
Redefining early-onset cancer and risk of hereditary cancer predisposition.
Authors: Stadler Zsofia Kinga , Maio Anna , Khurram Aliya , Kemel Yelena , Padunan Angelika , Borio Matilde , Sheehan Margaret , Murciano-Goroff Yonina R. , Walsh Michael Francis , Will Marie , Liu Ying L , Carlo Maria Isabel , Latham Alicia , Glade Bender Julia Lynne , Cercek Andrea , Tap William D. , Solit David B. , Mandelker Diana , Offit Kenneth , Diaz Luis A.
Published: June 2023

10510

Background: For most solid tumors, early age of onset, a marker for potential increased inherited risk, has been arbitrarily defined as a diagnosis of cancer at age < 50. However, this disregards the variation in mean age of diagnoses across solid tumors resulting in the potential misclassification of patients at increased risk of germline alterations. Methods: 25,305 prospectively ascertained cancer patients, representing 32 solid tumor types, underwent sequencing analysis of up to 90 cancer predisposition genes using next-generation genetic analysis with reporting of germline likely pathogenic (LP) and pathogenic variants (P). Mean age of diagnosis by cancer type, with standard deviations (STD), were calculated according to Surveillance, Epidemiology, and End Results Program (SEER) data. Early-onset (EO-CA), average-onset (AO-CA), and late-onset (LO-CA) cancers were defined as cancers diagnosed < -1 STD, -1 < STD > 1, and > 1 STD around the mean age at diagnosis for the specific cancer type, respectively. Prevalence of LP/P variants was classified according to age of onset. Statistical analyses were performed using STATA. Results: Among 25,305 patients with 32 solid tumor types classified as per SEER data, 31% (n = 7,854) of patients were categorized as having EO-CA. Overall prevalence of germline alterations varied as a function of age at diagnosis with 19.2%(n = 1509), 15.9% (n = 2588/16,299), and 12.9% (149/1152) of EO-CA, AO-CA, and LO-CA patients harboring a germline LP/P variant (p < 0.0001). The enrichment of variants in EO-CAs was driven by high- and moderate-penetrance genes with 13.2%, 9.2% and 5.1% of EO-CA, AO-CA, and LO-CA patients having an LP/P variant (p < 0.0001); low-penetrance germline alterations were static across the age groups (6%, 6.7%, 7.8%). An age cutoff of 50 for early-onset cancer was > 1 STD below the mean age at diagnosis in 20 cancer types resulting in 2,226 patients who would not have been classified as having EO-CA inclusive of 394 patients who tested positive for a germline LP/P, representing 26.1% of all germline EO-CA positives. Conclusions: Early-onset cancer should be defined taking into consideration the mean age at diagnosis for a specific cancer type as an arbitrary cutoff of age < 50 misses over 25% of patients with an inherited cancer predisposition syndrome. Due to the high prevalence of inherited predisposition syndromes, genetic testing of all patients with EO-CA, irrespective of tumor type, is warranted.
Real-world performance of a multi-cancer early detection test based on integrative analysis of cell-free DNA whole-methylome sequencing.
Authors: LI Yulong , Song Xiaofeng , Shen Ning , Hong Yuanyuan , Yang Ying , Huang Yu S. , Chen Weizhi
Published: June 2023

10521

Background: Early detection and diagnosis is key to reducing cancer-related mortality. We developed a blood-based multi-cancer early detection test, called THEMIS, using multimodal analysis of plasma cell-free DNA (cfDNA) methylation, fragmentation, and copy number alteration features by whole-methylome sequencing (WMS). The real-world performance of THEMIS was investigated with a prospective cohort of high-risk populations and the preliminary results were reported here. Methods: A total of 1,374 adults over 65 y with additional cancer risk factors for five common cancers (colorectal, esophageal, liver, lung, or stomach cancer) were recruited in the city of Wuxi, Jiangsu province, China. Additional risk factors included fecal occult blood, smoking history, H. pylori infection, HBV infection, and serum protein biomarkers. Participants had no known cancer diagnosis at the time of administration. Blood samples were collected and subject to low-pass WMS assay (~2X) and cancer probability was predicted by the THEMIS model, which was developed and locked in previous studies. Participants predicted as cancer positive by THEMIS were followed up until positive cancer diagnosis in a clinic or one year after receiving the test report, whichever was earlier. Results: At a fixed cutoff rendering 99% training specificity, THEMIS predicted 58 (4.15%) positive cases, among whom 19 participants consented to and completed follow-up. Ten participants received confirmed cancer diagnosis within the follow-up period, including five lung cancers, three liver cancers, one esophageal cancer, and one colorectal cancer. These results yielded a positive predictive value (PPV) of 52.6%. Those who declined follow-up upon a positive THEMIS report were predicted with digestive tract cancers, which need gastrointestinal endoscope for diagnostic confirmation. Conclusions: The nonivasive blood-based THEMIS test demonstrated promising performance and patient compliance for clinical utility to detect cancer early and improve patient outcome. Given that clinical follow-ups were only conducted with a subset of participants, future investigations of the precise real-world performance of THEMIS are needed with more complete patient follow-up.