bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune landscape of breast tumors with low and intermediate estrogen receptor (ER) expression.
Authors: Voorwerk Leonie , Horlings Hugo M. , Sanders Joyce , Keusters Milou S. , Cornelissen Sten , Sonke Gabe S. , Linn Sabine C. , Kok Marleen 
Published: June 2022

566 Background: Immune checkpoint blockade (ICB) is currently only approved for patients with triple-negative breast cancer (TNBC). However, the cut-off used for ER expression (<1% and in some countries <10%) has been developed as a biomarker for endocrine treatment response and not for selection for likelihood of response to ICB. While stromal tumor-infiltrating lymphocytes (sTILs) and PD-L1 expression are higher in TNBC compared to ER-positive tumors, the distribution of these and other key immune parameters in tumors with very low (1-9%), low (10-50%), intermediate (51-99%) and high (100%) ER levels is unknown. Methods: We collected a consecutive series of treatment-naïve tumor blocks of ER+/HER2- breast tumors diagnosed between 2010 and 2019. All available tumor blocks were used from the groups with ER expression between 1-9% and 10-50%. For the other groups, we randomly selected tumor blocks aiming for similar group sizes. This resulted in the following subgroups: ER 0% (n=46), 1-9% (n=17), 10-50% (n=22), 51-99% (n=37) and 100% (n=51). sTILs were scored using H&E slides. Immunohistochemistry was performed for CD8 and PD-L1 (22C3, scored on immune cells, cut-off ≥1%). Gene expression analysis was performed using the NanoString nCounter Breast Cancer 360 panel. Results: We found the highest levels of sTILs and stromal CD8+ cells in tumors with ER0% with comparable levels in tumors with ER1-9% and ER10-50% (Table). The proportion of PD-L1 positive tumors was 86% in tumors with ER0%, 81% in tumors with ER1-9%, 76% in tumors with ER 10-50% and 59% and 50% in tumors with ER51-99% and 100% respectively. As expected, a higher differentiation grade correlated with lower levels of ER expression. Differential gene expression demonstrated that expression of immune-related signatures, such as IDO1, antigen presenting machinery, CD8+ T cells and IFNγ, was comparable in tumors with ER1-50% as compared to ER0%, but statistically significantly higher as compared to tumors with ER100%. Conclusions: Our data suggest that breast tumors with low levels of ER expression (1-9%, 10-50%) comprise a separate entity within ER-positive breast cancer regarding their immune landscape. Here we show that not only tumors with very low ER levels (1-9%) mimic TNBC in terms of immune landscape but also that tumors with low ER levels (10-50%) might be more likely to respond to ICB than tumors with high levels of ER expression. [Table: see text]
Incidental pulmonary nodules, lung cancer screening, and lung cancer in the Medicare population.
Authors: Osarogiagbon Raymond U. , Miller Eric A , Faris Nicholas , Pinsky Paul F 
Published: June 2022

6536 Background: Low-dose CT lung cancer screening (LDCT) saves lives, but only 5%-10% of eligible persons in the US have participated. Management of indeterminate pulmonary nodules (IPNs) identified on CT scans may also reduce lung cancer mortality. We assessed the frequency of IPNs, estimated cumulative lung cancer rates following IPNs, and compared characteristics of lung cancers diagnosed following IPNs versus LDCT screens. Methods: We defined 2 cohorts in the SEER-Medicare database: persons with 12+ months of Medicare Part A&B coverage during 2014-2019 comprised the 5% sample cohort; persons in SEER-Medicare diagnosed with lung cancer during 2015-2017 with Part A&B coverage for the prior 18-month period comprised the lung cancer cohort. We defined IPNs as chest CTs with ICD-10 codes of R91.1 (solitary pulmonary nodule) or R91.8 (other nonspecific abnormal finding of lung field) on the same date as the CT; we used corresponding ICD-9 codes through September 2015. We classified lung cancer cohort cases by whether they had an LDCT (LDCT group), an IPN without an LDCT screen (IPN-only), or neither (Referent) within 18 months before diagnosis. We compared cancer stage and survival between these groups. Results: Of 627,547 subjects in the 5% sample cohort, 58.6% were women; 85.6% were non-Hispanic White (NH-Whites) and 7.7% non-Hispanic Black (NH-Blacks). Over median 5.0 years follow-up, 26.3% had chest CTs and 12.0% had IPNs. The IPN rate was similar by sex but significantly higher in NH-Whites (12.7%) than NH-Blacks (9.7%). The cumulative lung cancer rate following initial IPNs was 2.27% at two years. Of the 44,194 lung cancer cohort cases (85.8% NH-White, 8.2% NH-Black), 26.9%, 2.9% and 70.2% were in the IPN-only, LDCT, and Referent groups, respectively. NH-Whites comprised a higher proportion of LDCT than of IPN-only cases (90.1% vs. 88.4%), while for NH-Blacks, the reverse was true (5.4% vs. 6.5%). The ratio of LDCT:IPN lung cancer cases was 1:9. Among IPN-only and LDCT group cases, 52.0% and 50.3%, respectively, were localized stage, compared to 21.5% for the Referent group. Among all localized cases, 45.4% and 4.9% were in the IPN-only and LDCT groups, respectively. Comparing 3-year survival between IPN vs LDCT vs Referent groups, respectively: aggregate overall survival rates were 53.5% v 59.2% v 29.2%; aggregate lung cancer-specific survival, 71.1% v 75.3% v 46.6%; overall survival for localized cases, 73.2% v 80.7% v 62.9%; lung cancer-specific survival rates for localized cases, 88.2%, 91.8% and 81.4%. Conclusions: Subjects with IPNs had similar stage distribution and survival as LDCT-screened subjects. Almost half of localized cases had prior IPNs, compared to a < 5% of LDCT-screened cases. IPN programs, by circumventing implementation barriers to LDCT, may expand access to early lung cancer detection, including to African American patients and in places where LDCT coverage is not available.
Changes in cancer-related mortality during the COVID-19 pandemic in the United States.
Authors: Zhao Jingxuan , Han Xuesong , Miller Kimberly , Zheng Zhiyuan , Nogueira Leticia M. , Islami Farhad , Jemal Ahmedin , Yabroff K. Robin 
Published: June 2022

6581 Background: The coronavirus disease 2019 (COVID-19) pandemic resulted in delayed medical care that may have led to increased death rates in 2020 among people with medical conditions such as cancer. This study examined changes in cancer-related mortality between 2019 and 2020. Methods: We used the US 2019-2020 Multiple Cause of Death database from the CDC WONDER to identify cancer-related deaths, defined as decedents with invasive or noninvasive cancer as a contributing cause of death (ICD-10 codes: C00-C97 and D00-D09). We compared age-standardized cancer-related annual and monthly mortality rates (per 100,000 person-years and person-months, respectively) in January-December 2020 (pandemic) versus January-December 2019 (pre-pandemic) overall and stratified by rurality and place of death. We calculated the 2020 excess death by comparing the numbers of observed death with the projected death based on age-specific cancer-related death rate from 2015 to 2019. Results: The number of cancer-related deaths was 686 054 in 2020, up from 664 888 in 2019, with an annual increase of 3.2%. Compared to the number of projected deaths for 2020 (666 286), the number of cancer-related excess deaths was 19 768 in 2020. Annual age-standardized cancer-related mortality rate (per 100,000 person-years) continuously decreased from 173.7 in 2015 to 162.1 in 2019, while it increased to 164.1 in 2020 (2020 vs 2019 rate ratio (RR): 1.013, 95% confidence interval (CI): 1.009 - 1.016). The cancer-related monthly mortality rate was higher in April 2020 (RR: 1.032, 95% CI: 1.020 – 1.044) when healthcare capacity was most challenged by the pandemic, subsequently declined in May and June 2020, and higher mortality rates were again observed each month from July to December 2020 compared to 2019. In large metropolitan areas, the largest increase in cancer-related mortality was observed in April 2020, while in non-metropolitan areas, the largest increases occurred from July to December 2020, coinciding with the time-spatial pattern of COVID-19 incidence in the country. Compared to 2019, cancer-related mortality rates were lower from March to December 2020 in medical facilities, hospice facilities, and nursing homes or long-term care settings but higher in decedent's homes. Conclusions: The COVID-19 pandemic led to significant increases in cancer-related deaths in 2020 versus 2019. Ongoing evaluation of the spatial-temporal effects of the pandemic on cancer care and outcomes is warranted, especially in relation to patterns in vaccine uptake and COVID-19 hospitalization rates.[Table: see text]
Cost effectiveness of adjuvant olaparib for BRCA-mutated, early-stage breast cancer.
Authors: Zettler Christie , De Silva Dilanka , Blinder Victoria Susana , Robson Mark E. , Elkin Elena B. 
Published: June 2022

6593 Background: An interim analysis of the OlympiA trial found that olaparib given in the adjuvant setting can improve distant disease-free and overall survival for patients with early-stage, BRCA-mutated breast cancer; however, the cost-effectiveness of adjuvant olaparib is unknown. This study aimed to evaluate the cost-effectiveness of adjuvant olaparib in patients with early-stage, BRCA-mutated breast cancer. Methods: We used a decision-analytic model to compare outcomes of treatment with and without one year of oral olaparib after completion of systemic therapy in 42-year-old women with BRCA-mutated, early-stage breast cancer. Olaparib’s effectiveness was based on the OlympiA trial, and other model parameters were identified from the literature. We calibrated the model to reflect the 1-, 2-, and 3-year distant disease-free survival (DDFS) and overall survival (OS) observed in the OlympiA trial, and we assumed that olaparib reduced the risk of distant recurrence only in the first 3 years. Olaparib was estimated to cost $14,523 per month. Average lifetime costs were estimated from a health care system perspective in 2021 $ US, and incremental cost-effectiveness ratios (ICER) were estimated as $ per quality-adjusted life-year (QALY) gained. Costs, life-years, and QALYs were discounted by 3% annually. Results: Simulating the OlympiA trial, DDFS for the olaparib arm was 94.3% at 12 months, 90.0% at 24 months, and 87.5% at 36 months, compared to placebo with DDFS of 90.2%, 83.9%, and 80.4% respectively. Similarly, OS for the olaparib arm was 98.1%, 94.8%, and 92.0% compared to 96.9%, 92.3%, and 88.3% with placebo at 12, 24, and 36 months respectively. In the base case, adjuvant olaparib was associated with a 1.21-year increase in life expectancy and a 1.15-QALY increase at an incremental cost of $131,167 compared to placebo. The resulting ICER was about $114,500/QALY gained. At a willingness-to-pay threshold of USD$150,000/QALY, olaparib was cost effective at its current price. Results were sensitive to assumptions about the effectiveness of olaparib and its impact on quality of life. Conclusions: Adjuvant olaparib is cost-effective for women with early-stage, BRCA-mutated breast cancer at the current price of olaparib in the U.S. and at a willingness-to-pay threshold of $150,000. As such, clinicians and payers should consider adjuvant olaparib as a cost-effective option for this patient population. [Table: see text]
BTX-1188, a first-in-class dual degrader of GSPT1 and IKZF1/3, for treatment of acute myeloid leukemia (AML) and solid tumors.
Authors: Chourasia Aparajita Hoskote , Majeski Hannah , Pasis Angela , Erdman Paul , Oke Ashwini , Hecht David , Lonergan David , Mercurio Frank , Chan Kyle , Thai Dung Luong , Fung Leah 
Published: June 2022

7025 Background: BTX-1188 is a first-in-class oral molecular glue that degrades GSPT1 and IKZF1/3 and is currently in phase 1 clinical trials for treatment of hematologic and solid malignancies. Targeted protein degradation of cereblon neosubstrates is clinically validated in the treatment (tx) of hematologic malignancies (Lu 2014, Zou 2020). Methods: Cell viability in BTX-1188-treated cells and patient samples was measured by CellTiter-Glo 2.0 assay (Promega). Substrate degradation and apoptosis profiles were analyzed by immunoblots of protein lysates from cells treated with DMSO or BTX-1188. Vehicle, or 30 or 40 mg/kg IP BTX-1188, was used in athymic nude mice AML xenograft models. Results: BTX-1188 is a rapid, deep, and potent degrader of GSPT1 and IKZF1/3 and inhibitor of Myc in several cancer cell lines (Table). Proteomics and immunoblot analysis of AML cell line, MV-4-11, shows significant degradation of GSPT1 and IKZF1 after 2 h tx with 100 nM BTX-1188 ( P<1x10-5) and 6 h tx with 3 nM BTX-1188 (>90% of GSPT1), respectively, indicating rapid and potent neosubstrate degradation. BTX-1188 also durably degrades GSPT1 where tx with 30 nM for 6 h followed by washout maintains significantly lower levels of GSPT1 and sustained apoptosis for up to 24 h. Owing to IKZF1/3 degradation, BTX-1188 has immunomodulatory properties as seen by inhibition of proinflammatory cytokines (IL-1β, IL-6, TNFα) and induction of IL-2 by LPS and αCD3-stimulated PBMCs, respectively. This approach is expected to improve clinical outcomes and reduce toxicities associated with pure GSPT1 degradation (CC-90009), thus expanding the therapeutic window of BTX-1188. Functionally, BTX-1188 is cytotoxic in various cancer cell lines such as Myc-driven lines (IC50 range: 0.5-10 nM) and primary human AML patient samples (IC50 range: 0.4-1.5 nM), including relapsed/refractory-, cytarabine- and venetoclax-resistant samples. The durability of GSPT1 degradation and sustained apoptosis in response to BTX-1188 tx is further reflected in in vivo efficacy models where daily or intermittent dosing of BTX-1188 results in potent and sustained antitumor activity. Conclusions: These preclinical data show that BTX-1188 is a promising drug candidate for AML and other tumor types. Its immunomodulatory properties owing to IKZF1/3 degradation may prevent systemic inflammatory dose-limiting toxicities associated with pure GSPT1 degradation (Uy 2019). BTX-1188 has entered phase 1 clinical studies for advanced solid tumors and AML. DC50 (nM) or inhibitory concentration (nM) of BTX-1188 at 6 h of Tx. [Table: see text]
Association of frailty with clinical and financial outcomes of allogeneic hematopoietic stem cell transplant.
Authors: Sakowitz Sara , Ng Ayesha , Ebrahimian Shayan , Benharash Peyman , Schiller Gary J. 
Published: June 2022

7046 Background: Considered the only curative therapy for many hematological conditions, allogeneic hematopoietic stem cell transplantation (alloHSCT) is increasingly used in older patients. Yet, chronological age alone has been found to be an inaccurate predictor of posttransplant sequelae. More recently, the concept of frailty has emerged as a better marker of physiologic reserve. While formal frailty instruments have not been widely adopted due to their resource intensive nature, we applied a previously-validated coding-based approach to examine the association of frailty with in-hospital outcomes of alloHSCT. Methods: All adults (≥ 18 years) undergoing alloHSCT for hematological malignancies were identified in the 2010-2019 Nationwide Readmissions Database. The previously-validated binary Johns Hopkins Adjusted Clinical Groups indicator was used to classify patients as frail. In this algorithm, the presence of diagnoses across various domains, including malnutrition, dementia, and decubitus ulcer, constitute frailty. Regression models were developed to evaluate the independent association of frailty with in-hospital mortality, periprocedural complications, length of stay, hospitalization costs, and 30-day non-elective readmissions. Results: Of an estimated 48,161 patients, 9.8% were considered frail. Frail patients were not significantly older (51.8 ± 15.0 vs 51.6 ± 14.2, p = 0.685), but had higher Elixhauser scores (2.8 ± 1.3 vs 2.0 ± 1.3, p < 0.001). After adjustment, frailty was associated with increased odds of in-hospital mortality (AOR 2.22; 95% CI 1.68-2.94; P < 0.001), as well as infectious (AOR 1.44, 95% CI 1.18-1.76; P < 0.001) and respiratory (AOR 1.69, 95% CI 1.41-2.02; P < 0.001) complications. Frailty was also associated with greater risk of acute graft-vs-host disease (AOR 1.39, 95% CI 1.12-1.72; P = 0.003) and CMV (AOR 1.72, 95% CI 1.27-2.33; P < 0.001) or invasive fungal infection (AOR 1.49, 95% CI 1.07-2.06; P = 0.017). Further, frailty was linked to increased likelihood of non-home discharge (AOR 1.29, 95% CI 1.03-1.61; P = 0.026), 30-day non-elective readmissions (AOR 1.29, 95% CI 1.11-1.50; P = 0.001), and significant increases in length of stay (+6.05 days, 95% CI 4.41-7.69; P < 0.001) and costs (+$36,660, 95% CI 27,413-45,907; P < 0.001). Conclusions: Among patients undergoing alloHSCT, frailty, as measured by an administrative tool, was independently associated with increased in-hospital mortality, complications and overall resource use. Inclusion of frailty in risk models may better aid benchmarking efforts and inform shared-decision making. [Table: see text]
Bosutinib (BOS) in newly diagnosed chronic myeloid leukemia (CML): Gastrointestinal (GI), liver, effusion, and renal safety characterization in the BFORE trial.
Authors: Cortes Jorge E. , Milojkovic Dragana , Gambacorti-Passerini Carlo , García-Gutierrez Valentin , Mauro Michael J. , Leip Eric , Purcell Simon , Viqueira Andrea , Brümmendorf Tim H. 
Published: June 2022

7049 Background: Efficacy and safety of BOS vs imatinib (IMA) in patients (pts) with newly diagnosed chronic phase CML was assessed in the phase 3 BFORE trial. Here we characterize the safety profile of BOS after 5 yrs follow-up, with a focus on GI, liver, effusion and renal treatment-emergent adverse events (TEAEs). Methods: Pts who received ≥1 dose of BOS (n=268) or IMA (n=265) 400 mg/d in BFORE were included. Adverse events (AEs) of special interest were analyzed by selecting prespecified MedDRA terms to generate TEAE clusters. Final database lock: June 12, 2020. Results: Median duration of treatment (Tx) was 55 mo for pts receiving BOS or IMA; respective median (range) dose intensity was 393.6 (39–583) vs 400.0 (189–765) mg/d. Any grade TEAEs occurred in 98.9% and 98.9% of BOS- vs IMA-treated pts. Most common newly occurring TEAEs (any grade) after 12 mos were increased lipase (9.0%) with BOS, and diarrhea (8.3%) with IMA. In BOS- vs IMA-treated pts, 25.4% vs 14.3% had AEs leading to permanent Tx discontinuation; the majority discontinued in yr 1 (14.2% vs 10.6%). Most frequent AEs leading to discontinuation were increased ALT (overall, 4.9%; yr 1, 4.5%) with BOS vs thrombocytopenia (overall, 1.5%; yr 1, 1.5%) with IMA. GI, liver, effusion and renal TEAEs, respectively, occurred in 79.9%, 44.0%, 6.0% and 10.4% (maximum grade 3/4 [G3/4]: 9.0%, 26.9%, 1.1% and 2.2%) of BOS- vs 61.5%, 15.5%, 2.3% and 9.8% (G3/4: 1.1%, 4.2%, 0.4% and 0.8%) IMA-treated pts. One grade 5 renal TEAE occurred in the BOS arm and was not considered related to Tx. Cumulative rates per Tx yr are shown in the Table. Most common GI TEAEs were diarrhea (BOS vs IMA: 75.0% vs 40.4% [G3/4: 9.0% vs 1.1%]) with BOS, and nausea (37.3% vs 42.3% [G3/4: 0% vs 0%]) with IMA. In both arms, the most common liver, effusion and renal TEAEs, respectively, were increased ALT and/or AST (34.0% vs 8.3% [G3/4: 22.0% vs 2.3%]), pleural effusion (5.2% vs 1.9% [G3/4: 0.7% vs 0.4%]) and increased blood creatinine (6.7% vs 8.3% [G3/4: 0.4% vs 0.4%]). GI, liver, effusion and renal TEAEs infrequently led to Tx discontinuation (1.9%, 7.8%, 0.7% and 0.7% vs 1.1%, 0.8%, 0% and 0.4%). Conclusions: The safety profiles of BOS and IMA in BFORE were distinct, with no new safety signals identified after 5 yrs follow-up. Onset of TEAEs occurred primarily during yr 1 (eg, GI and liver), with an increased incidence of some TEAEs (eg, effusion and renal) in later yrs. Discontinuations due to AEs generally occurred early into Tx, with few due to GI, liver, effusion and renal AEs. These safety results support the use of first-line BOS as a standard of care in pts with CP CML. Clinical trial information: NCT02130557. [Table: see text]
A phase 1 study of ADI-001: Anti-CD20 CAR-engineered allogeneic gamma delta (γδ) T cells in adults with B-cell malignancies.
Authors: Neelapu Sattva Swarup , Hamadani Mehdi , Miklos David Bernard , Holmes Houston , Hinkle John , Kennedy-Wilde Jackie , Maller Ori , Weinstein Maggie , Galimi Francesco , Lai Rose , Stevens Don A. 
Published: June 2022

7509 Background: ADI-001 is a first-in-class allogeneic gamma delta (γδ) CAR T-cell therapy targeting the B-cell antigen CD20. ADI-001 also has both adaptive and innate cytotoxic effector functions to complement CAR targeting, potentially enhancing efficacy and reducing the possibility of tumor escape due to antigen loss. ADI-001 expresses MHC independent γδ T cell receptors, thus lowering the risk of graft versus host disease (GvHD) without the need for gene-editing. Methods: This phase 1 trial evaluates ADI-001 in adults with relapsed/refractory advanced B-cell lymphoma. Eligibility criteria included presence of measurable lesions, expression of CD20 and ≥ 2 prior systemic therapies. All patients received conditioning therapy with fludarabine and cyclophosphamide. ADI-001 is administered at 3 flat dose levels (DL; DL1:3E7, DL2:1E8, or DL3:3E8 cells) in a 3 + 3 dose-escalation scheme. Dose-limiting toxicities (DLT) were monitored during the initial 28-days post-treatment. Patients who completed the 28-day DLT period were considered evaluable. Treatment-emergent adverse events were graded by CTCAE v5.0, and immune effector cell toxicity assessment and grading were performed per ASTCT criteria. Objective response rates (ORR) were evaluated by independent radiographic review per Lugano 2014 criteria. Results: As of 14 February 2022, eight patients were enrolled and six were evaluable. Of these six patients, 2/6 were female (33%) and the median age was 62 years (range 45-75). The median number of prior therapies was 3.5 (range 2-5) and median IPI score was 3.5 (range 2-4). One patient received prior anti-CD19 CAR T cells therapy with lisocabtagene maraleucel. There were five patients with large B-cell lymphoma and one with mantle cell lymphoma. Among the six evaluable patients, three were treated on DL1 and three on DL2. Most related AEs (78%) were of grade 1/2. There were three AESI: two CRS (one grade 1 and one grade 2) and one grade 1 ICANS, and the only related SAEs were the grade 2 CRS and grade 1 ICANS. There was no reported GvHD and no protocol defined DLT events. At day 28, the ORR based upon PET/CT was 67% (4/6 patients) and the CR rate was 67% (4/6 patients). Both patients with ≥ 3 months post-treatment follow-up remained in CR. Additional data will be presented at the meeting. Conclusions: ADI-001 γδ CAR T cells were well tolerated, with a favorable safety profile and encouraging preliminary efficacy. Patients who achieved CR at day 28 appeared to be disease free during further follow-up at month-3. Clinical trial information: NCT04735471.