bluuebunny/crossref_metadata_2025 huggingface dataset:
Management impact of preoperative germline genetic testing in patients with breast cancer at the Lifespan Cancer Institute.
Authors: Lew Kaitlyn P. , Dizon Don S. , Phornphutkul Chanika , Benson Cindy , Wiggins Doreen Leyden , Fenton Mary Anne Anne , Taneja Charu , Massingham Lauren J.
Published: June 2021

10523

Background: Breast cancer is a heterogenous disease and management is complex. Advances in next generation sequencing has allowed genetic testing to be more accessible. However, conveying results to patients and care team can be challenging due to various variant classifications. Diagnostic results have the potential to guide management. Nondiagnostic results can be misinterpreted. The extent to which preoperative genetic testing affects management of newly diagnosed breast cancer is unknown. Methods: Newly diagnosed breast cancer patients were identified via review of breast tumor board between May 2019 and March 2019 followed by chart review to collect detailed information. Results: 408 newly diagnosed breast cancer cases were queried. Genetic evaluation was recommended and completed in 68%, not recommended (did not meet NCCN criteria) in 30% and declined in 2.7%. The genetic evaluation recommended cohort was associated with a higher mastectomy rate in comparison with when not recommended (31% vs. 9%, p=0.0001). Of those who completed genetic testing: 12% harbored a pathogenic/likely pathogenic variant (PV/LPV), 26% had a nondiagnostic variant of uncertain significance (VUS) and 61% had negative testing. Comparison between nondiagnostic test results (negative and VUS) and diagnostic test results revealed significantly increased number of women in the diagnostic group who chose mastectomy over breast conservation therapy (BCT, nondiagnostic 20% vs diagnostic 39%, p=0.018). When negative, VUS, and PV/LPV were each independently analyzed, diagnostic test results again revealed a significantly increased number of mastectomies over BCT (p<0.05). Comparison of surgical choices in nondiagnostic VUS vs. negative results was not significantly different (Table). Comparing the surgical timelines, completing a genetic evaluation did not affect surgery timing (mean 2.3 vs. 2.2 months, p>0.5). Conclusions: Germline genetic testing in patients with newly diagnosed breast cancer impacts clinical management. Those harboring a diagnostic result were more likely to choose mastectomy over BCT. Not surprisingly, mastectomy rate was higher among those where genetic evaluation was recommended, possibly due to concerning personal or family history. The mastectomy rate was higher among those with a diagnostic result, indicating an understanding of the genetic testing significance by patients and the care team. More importantly, those who harbored nondiagnostic VUS did not make significantly different surgical choices compared with negative genetic testing, highlighting the critical role of proper genetic counseling and being part of the care team. We conclude consideration of genetic evaluation is clinically useful and feasible without affecting the surgical timeline.[Table: see text]
The impact of radiological assessment schedules on progression-free survival in metastatic breast cancer: A systemic review and meta-analysis.
Authors: Dabush Dor Reuven , Shepshelovich Daniel , Shochat Tzippy , Amir Eitan , Tibau Ariadna , Goldvaser Hadar
Published: June 2021

1086

Background: The impact of the interval of radiological assessment on the magnitude of benefit observed in randomized trials (RCTs) in metastatic breast cancer is undefined. Methods: All RCTs investigating anti-neoplastic drugs for metastatic breast cancer published between 2006 and 2019 were identified. Intervals for restaging were categorized as short ( < 9 weeks) or long (≥9 weeks). Hazard ratios (HRs) and 95% confidence intervals for progression-free survival (PFS) and overall-survival (OS) were pooled in a meta-analysis and compared between trials employing short and long restaging intervals assessed as subgroup analyses. Analyses were repeated for pre-specified subgroups according to disease subtype, drug type, whether experimental therapy was added to or replaced standard treatment and whether HR for PFS was < 1 or ≥1. Results: Eighty-nine studies comprising 95 comparisons and 44,901 patients were included. The magnitude of PFS benefit was non-significantly larger in trials which employed short compared to long restaging intervals (HR 0.79 vs. 0.86, p = 0.15). Short restaging interval was associated with significantly higher magnitude of effect on PFS in pre-specified subgroups including non-first line studies (HR 0.78 vs. 0.92, p = 0.04), studies with drugs replacing standard treatment (HR 0.86 vs. 1.04, p = 0.02) and studies performed exclusively in human epidermal growth factor receptor 2 (HER2) positive disease (HR 0.72 vs. 0.90, p = 0.02). Restaging interval was not associated with OS for all included studies (HR 0.92 vs. 0.93, p = 0.66) or for any of the pre-specified subgroups. Conclusions: Shorter restaging intervals are associated with a higher magnitude of effect of PFS, but not OS. Awareness of the impact of the restaging interval on quantification of intermediate endpoints such as PFS is important for the design and interpretation of RCTs.
Association between baseline geriatric domains and survival in older adults with chronic lymphocytic leukemia (CLL).
Authors: Rice Julia , Nipp Ryan David , Lage Daniel E , Nelson Ashley M. , Newcomb Richard , Lavoie Mitchell W. , Topping Carlisle E. W. , Ritchie Christine , El-Jawahri Areej , Johnson Patrick Connor
Published: June 2021

12041

Background: CLL is a disease that commonly affects older adults. Although the value of geriatric assessment is increasingly being recognized in older adults with cancer, few studies have examined the relationship between baseline geriatric domains and clinical outcomes in older adults with CLL. Methods: We conducted a secondary data analysis of 369 adults diagnosed with CLL and treated in a phase 3 randomized trial of patients age ≥65 with bendamustine plus rituximab versus ibrutinib plus rituximab versus ibrutinib alone. We evaluated geriatric domains of functional status (activities of daily living [ADL], instrumental activities of daily living [IADL], Timed “Up and Go,” and number of falls in last 6 months), psychological status (Mental Health Inventory), social activity (Medical Outcomes Study [MOS] Social Activity Survey), cognition (Blessed Orientation Memory Concentration Test), social support (MOS Social Support Tangible and Emotional/Informational subscales), and nutritional status ( > 5% weight loss in the preceding 6 months). We examined associations among baseline geriatric domains with overall survival (OS) and progression-free survival (PFS) using multivariable Cox regression models. Results: The median age of patients was 71 years (range: 65-89). Most were male (67.1%) and had an ECOG performance status of 0 or 1 (96.9%). In multivariable models, the following geriatric domains were significantly associated with OS: better functional status (ADL score: HR 0.67, p = 0.012; IADL score: HR 0.98, p = 0.007); social activity score (HR 0.97, p = 0.004); and nutritional status (HR 2.58, p = 0.008). Similarly, functional status (ADL score: HR 0.77, p = 0.028; IADL score: HR 0.99, p = 0.007); social activity score (HR 0.97, p < 0.001); and nutritional status (HR 2.87, p < 0.001) were all associated with PFS. Additionally, the number of impaired geriatric domains was also associated with OS (HR 1.50, p = 0.004) and PFS (HR 1.45, p < 0.001). Timed “Up and Go”, number of falls in last 6 months, psychological status, cognition, and social support were not significantly associated with clinical outcomes. Conclusions: Geriatric domains of functional status, social activity, and nutritional status were associated with OS and PFS in this cohort of older adults with CLL. These findings highlight the importance of assessing geriatric domains to identify high-risk patients with CLL who may benefit from additional support during their treatment.
Cannabidiol (CBD) use among cancer survivors.
Authors: Bailey-Dorton Chasse Margot , Gentile Danielle , Boselli Danielle , Yaguda Susan , Greiner Rebecca
Published: June 2021

12096

Background: Cannabidiol (CBD) is a non-psychoactive component of cannabis touted for various therapeutic effects. The Federal Drug Agency has only approved one prescription CBD product for treatment of severe epilepsy. On December 17, 2020 the Federal Trade Commission announced legal consequences for deceptively marketed CBD products in the rapidly expanding market of various CBD products; the products’ unsupported claims included CBD as a cancer treatment. Little is known about survivors use of CBD. This study explores the prevalence and nature of CBD use by cancer survivors. Methods: A link to an anonymous, electronic survey was posted on the Levine Cancer Institute and SherryStrong (Martin Truex Jr. Foundation: philanthropy for ovarian cancer) Twitter and Facebook social media platforms. Data were managed in REDCap, a secure, web-based, electronic data capture tool. Survey responses were summarized and described with frequencies and compared using Fisher’s Exact tests; p < 0.1 was considered statistically significant. Results: N = 295 self-selected respondents were White (95%), female (86%), middle aged (45-64 years) (58%) and in the US (95%). Ninety percent indicated current (85%) or past (15%) use of CBD product; a third of these participants (N = 102) identified as cancer survivors. Gynecologic (31%) and breast (30%) cancers were the most recorded malignancies, and 38% report active treatment. Most survivors indicated using CBD products daily (77%) for a year or less (79%) and spent @$30 a week on products (70%). Common uses for CBD were easing pain (66%), anxiety (50%), and sleep (50%)—14% reported treating or preventing cancer. 41% learned about CBD from family/friends, fewer learned from the Internet (21%) or local store (11%). Only 12% received information from a physician. Liquid drops (58%) and topicals (19%) were popular products and reported side effects were sparse—sedation and/or euphoria were indicated by 10% and 2%, respectively. Over 82% of cancer survivors indicated that CBD product helped their conditions. CBD use to ease anxiety and stress declined with age; 71% of young survivors (aged 18-44) sought anxiety relief versus 45% and 36% of middle age (aged 45-64) and seniors (aged 65+), respectively (p = 0.05), and 58% of young survivors pursued stress relief versus 39% of middle age and 21% of seniors (p = 0.08). More young (25%) and middle age (37%) survivors indicated spending over $30 on products weekly than seniors (7%) (p = 0.08). No differences were seen in CBD use between cancer survivors by gender or treatment status. Conclusions: Cancer survivors commonly use CBD, yet infrequently under the guidance of a physician. Survivors largely rely on word of mouth and internet information about CBD. Despite lack of standardization of production and labeling of CBD products, the majority of patients reported positive improvements in symptoms. Future research should explore strategies to educate cancer patients and providers in safe CBD use.
Transitioning ifosfamide based chemotherapy to the outpatient setting: A model of implementation of transitioning chemotherapy outpatient in a safety net hospital.
Authors: Banh Cindy , Arrendondo Alejandra , Notbohm Kassie , Valsvik Kendall , Ortega Alicia , Sanders Lauren , Recio Alejandro , Kraft Andrew , Babiker Hani M. , Do Brian , Persky Daniel O , Abraham Ivo , McBride Ali
Published: June 2021

1540

Background: Ifosfamide displays clinical activity against germ cell tumors as well as soft-tissue and bone sarcomas. It is used in different oncology regimens and commonly administered inpatient due to patient monitoring and side effect management. Transitioning certain chemotherapy regimens to the outpatient setting provides a novel approach to treating patients while maximizing patient satisfaction and decreasing total patient care costs1. There is limited data and protocol development to transition ifosfamide regimens to the ambulatory setting. This study’s purpose is to characterize a pharmacy managed ambulatory oncology workflow for transitioning ifosfamide based-regimens to the outpatient setting. Methods: A retrospective cohort chart review was conducted at a single center and included patients 18 years and older receiving at least one cycle of ifosfamide therapy between September 1, 2013 and July 31, 2019. The primary outcome was to evaluate the side effect profile and cost of treatment of ifosfamide. The secondary endpoint included number of hospitalizations. The adverse event grading system was defined using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. The highest grade observed for adverse effects was documented for every cycle of each patient. The cost was evaluated by labs ordered, drug used, length of stay in the hospital for chemotherapy or adverse reactions. Results: Ifosfamide therapy of 86 patients (57 OP, 29 IP) was reviewed. The predominant OP regimens were adriamycin-ifosfamide-mesna (AIM) with 43.9% and ifosfamide-etoposide (IE) with 29.8%. Grade 4 anemia, thrombocytopenia, and neutropenia were most frequent in IP vs OP therapies (22.9% IP vs 4.3% OP, 21.6% IP vs 9.2% OP, and 22.8% IP vs 19.6% OP respectively). Neutropenic fever (NF) occurred in 20 OP patients which were predominantly treated with AIM or IE, and led to average hospital stay of 6 days. Neurotoxicity, treated with methylene blue (MB), occurred in 4 OP patients. OP therapy saved a total of 783 hospital days, leading to a cost savings of $2,103,921. Conclusions: Transitioning to outpatient therapy is feasible for academic and community infusion centers. Administration of chemotherapy in the outpatient setting has shown to be safe, well-tolerated, and associated with decreased total cost of care, thereby lowering costs under the oncology care model when compared with inpatient chemotherapy costs.
Comparison of checkpoint inhibitor treatment-related cutaneous adverse events in racial and ethnic minority and Caucasian cohorts at Memorial Sloan Kettering Cancer Center.
Authors: Geisler Amaris , Barrios Dulce M. , Phillips Gregory , Nouvini Rosa , Lacouture Mario E. , Noor Sarah
Published: June 2021

2632

Background: Immune-related cutaneous adverse events (irCAEs) are the most common and often the first toxicity of immune checkpoint inhibitors (CPIs). In the general population, irCAEs occur on average within 3.6 weeks of treatment initiation and most commonly manifest as maculopapular rash, lichenoid rash, and pruritus. Less is known about these irCAEs in racial and ethnic minority patients. The purpose of this study is to compare the irCAEs of cohorts of Caucasian and racial and ethnic minority patients at Memorial Sloan Kettering Cancer Center. Methods: Herein, we conducted a retrospective chart review of racial and ethnic minority patients treated with CPIs between 2012-2019 at Memorial Sloan Kettering Cancer Center. irCAEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. These were compared to a Caucasian cohort matched by demographics and cancer therapy regimen. Results: One hundred ten racial and ethnic minority patients presented to dermatology for irCAEs. Our population consisted of 59 (53.6%) females and 51 (46.4%) males with a mean age of 59 (range 20-85). Of the patients who were seen by dermatology, 63/110 were Asian (57.3%) followed by 34/110 African American (30.9%), and 1 Native American. Twelve patients were of Hispanic ethnicity (10.9%), which included those of both African American and Caucasian race. The 110 patients that were evaluated by dermatology had 221 cutaneous adverse events. Rash (96, 43.4%), pruritus (40, 18.1%), and xerosis (23, 10.4%) were most frequently diagnosed (average time from treatment start to presentation was 125 days). Dermatology identified 87 (39.3%) grade 1, 103 (46.6%) grade 2, 30 (13.5%) grade 3, and 1 (0.4%) grade 4 events. There were 17 (15.5%) treatment interruptions, including 7 patients who required permanent discontinuation. In the Caucasian cohort, mean time to onset was 228 days (range 1-1500). Dermatology identified 48 (43.6%) grade 1, 44 (40.0%) grade 2, 18 (16.4%) grade 3, and 0 (0.0%) grade 4 events, with maculopapular rash (55, 50.0%) and pruritus (25, 22.7%) most frequently diagnosed. Conclusions: Our findings suggest that irCAEs occur frequently in cancer patients from racial and ethnic minority groups, with similar grade and morphology as Caucasian patients. When irCAEs develop in this population, the diagnosis occurred later than what has previously been reported, possibly due to these patients seeing MSK oncologists with an established dermatology consultation system and insight into how to manage these patients on their own. Prospective evaluation of underrepresented minorities receiving CPI therapy is warranted in order to identify risk factors and therapeutic strategies for these untoward events, so that optimal cancer care may be delivered.
Prognostic value of plasma hPG80 (circulating progastrin), alone or in combination with Alpha-fetoprotein (AFP) in patients with hepatocellular carcinoma.
Authors: Prieur Alexandre , Assenat Eric , Dupuy Marie , Iltache Sarah , Vire Berengere , Soulé Julien , Liaud Pierre , Cousin Thierry , Mahi Younes , Joubert Dominique
Published: June 2021

3033

Background: Alpha-fetoprotein (AFP) is the most widely used biomarker for hepatocellular carcinoma (HCC) prognosis since it is expressed in the advanced stages of the disease. Consequently, AFP is not useful in establishing a prognosis for patients with a tumor in the early stages of the disease. hPG80 (circulating progastrin), a new drug target for cancer treatment which plays a pivotal role in tumorigenesis, is present in the blood of multiple types of cancers at early stages including HCC. The purpose of this study was to evaluate the prognostic value of plasma hPG80 in patients with HCC, in combination or not with AFP. Methods: A total of 168 HCC patients (BCLC from 0 to D) managed with local or systemic treatments, (“Liverpool” biobank) were enrolled prospectively and analyzed retrospectively. hPG80 was quantified using DxPG80 Lab kit (ECS-Progastrin) and AFP was quantified using Cobas E411 in the blood of HCC patients. An optimal cutoff value of hPG80 was identified at 4.5 pM by calculating the minimal p-value based on the log-rank method. For AFP, a cutoff of 100 ng/mL was used as for liver transplantation (Notarpaolo, 2016). The prognostic impact of hPG80 and AFP levels on patient survival was assessed using Kaplan-Meier curves and log-rank tests. Results: The median overall survival (OS) of the full cohort is 20.9 months. HCC patients with high hPG80 levels (hPG80+: >4.5 pM, 105/168) had significantly lower median OS compared to patients with low hPG80 levels (hPG80-: <4.5 pM, 63/168) (12.4 months versus undefined respectively, p < 0.0001). Patients with high AFP (AFP+: >100 ng/mL, 69/165) had significantly lower median OS compared to patients with low AFP (AFP: <100 ng/mL 96/165) (7.2 months versus undefined, p < 0.0001). To improve the stratification, the patients were further categorized into four groups: hPG80-/AFP- (n = 42), hPG80+/AFP- (n = 54), hPG80-/AFP+ (n = 21) and hPG80+/AFP+ (n = 48). In the AFP- group, hPG80+ patients exhibited a significantly worse prognosis than those with hPG80- (26.3 months versus undefined, p=0.0087). Similarly, in the AFP+ group, patients with hPG80+ had a significantly worse survival compared to hPG80- patients (5.7 months versus 13.4 months, p = 0.0391). Finally, we evaluated the median OS of AFP+ patients according to BCLC staging. Interestingly, in the group BCLC 0 to B, hPG80+ had a significantly worse prognosis than those with hPG80- (15.8 months versus 40.25 months, p=0.0317). Conclusions: Our findings show that hPG80 could serve as a new prognostic biomarker in HCC. Used in combination with AFP, it improves the stratification of the patients in good and worst prognosis, especially for those patients with negative AFP and early-stage HCC.
Phase Ia study of CBP-1008, a bi-specific ligand drug conjugate targeting FRα and TRPV6, in patients with advanced solid tumors.
Authors: Gong Jifang , Hu Xichun , Zhang Jian , Du Yiqun , Huang Robert , Teng Yan , Tan Wei , Shen Lin
Published: June 2021

3077

Background: CBP-1008 is a first-in-class bi-specific ligand drug conjugate targeting folate receptor α (FRα) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) with a high potency tublin inhibitor payload, monomethyl auristatin E (MMAE). A first-in-human, multicenter, phase I study of CBP-1008 (NCT 04740398) is ongoing, and we herein report the preliminary result of part A which is to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of CBP-1008 in solid tumors. Methods: Dose escalation commenced in single-patient cohorts for the first 2 planned dose levels and then followed by a standard 3 + 3 scheme. CBP-1008 was administered as intravenous infusion at escalating doses (0.015, 0.03, 0.12, 0.15, and 0.18 mg/kg). The primary endpoints were to determine the safety and maximum tolerated dose (MTD). Adverse events (AEs) and dose-limiting toxicities (DLTs) were evaluated. Results: Eighteen patients with advanced solid tumors who had failed multiple systemic treatment regimens were enrolled. The diseases include colorectal cancer (n = 7), breast cancer (n = 5), non-small cell lung cancer (n = 2), ovarian cancer (n = 2), adrenocortical carcinoma (n = 1), and follicular dendritic cell sarcoma (n = 1). The DLTs observed included grade 4 hypophosphatemia (0.15 mg/kg), grade 4 neutropenia (0.12, 0.15, and 0.18 mg/kg), grade 4 febrile neutropenia (FN) (0.18 mg/kg), grade 3 hyperglycemia (0.15 mg/kg), and grade 3 alanine aminotransferase (ALT) elevation (0.18 mg/kg). The most common all grade AEs suspected to be drug-related were fever (83.3%, totally limited to grade 1-2), aspartate aminotransferase (AST) elevation (72.2%, 5.6% evaluated as grade 3-4), leukopenia (66.7%, 27.8% as grade 3-4), neutropenia (66.7%, 38.9% as grade 3-4) and hypohemoglobinemia (55.6%, 5.6% as grade 3-4), with no drug-related deaths. MTD is estimated between 0.15 mg/kg and 0.18 mg/kg Q2W. Best overall response was partial response (PR) in 1 patient at 0.18 mg/kg and 4 patients (22.2%) achieved stable disease (SD). Responses occurred in patients with FRα and/or TRPV6 -positive expression advanced solid tumors. Conclusions: CBP-1008 has demonstrated acceptable safety profile. Tumor response correlating with dosing and FRα/TRPV6 receptor expression levels has been well observed. Clinical trial information: 04740398.
Bone safety profile of steroidal aromatase inhibitor in comparison to non-steroidal aromatase inhibitors in postmenopausal women with breast cancer: A network meta-analysis.
Authors: Chen Shanshan , Lan Bo , Lv Dan , Ma Fei
Published: June 2021

527

Background: Steroidal and non-steroidal aromatase inhibitors (AIs) provide better therapeutic response in comparison to other endocrine therapies in the adjuvant treatment of breast cancer (BC). They interfere with bone turnover which may lead to increased incidence of bone related safety events. There are no head-on studies comparing the incidence of bone safety events and hence we performed this network meta-analysis (NMA) to compare the incidence of bone safety events among patients treated with steroidal and non-steroidal AIs. Methods: Literature searches were performed in PubMed and Embase with key words to identify randomized controlled trials in BC patients treated with AIs in adjuvant settings compared against tamoxifen or other AIs, reporting any bone-related safety events. The study was designed as per PRISMA guidelines; publication bias was evaluated by comparison-adjusted funnel plots. Bayesian NMA was done by R software (ver 3.2), GemtC package. Odds ratio (OR) and the surface under the cumulative ranking curve (SUCRA) values were used to interpret the results. Results: 15 studies reporting 6 different bone-related endpoints were included. Treatment with steroidal AI, exemestane led to lower incidence of bone pain (OR Vs anastrozole and letrozole: 0.59, p=0.63; 0.54, p=0.75), fracture episodes (OR Vs anastrozole and letrozole: 0.84, p=0.41; 0.85, p=0.73), joint stiffness (OR Vs anastrozole: 0.55, p=0.73) and osteoporosis (OR Vs anastrozole and letrozole: 0.86, p=0.41; 0.74, p=0.29) (Table) in comparison to letrozole and anastrozole. Reduction in bone mineral density was also lesser in exemestane than anastrozole (mean reduction in hip: 1.08; lumbar spine: 1.34). SUCRA values suggested exemestane to be the drug with maximum likelihood for reducing the incidence of bone-related adverse events. Conclusions: This NMA suggested that bone-related safety events might be lower in early BC patients treated with exemestane in comparison to non-steroidal AIs, anastrozole and letrozole. Although there was no statistical significance, further head-on studies are required to substantiate our results.[Table: see text]
Lurbinectedin (LUR) in combination with Irinotecan (IRI) in patients (pts) with advanced endometrial carcinoma.
Authors: Falcon Gonzalez Alejandro , Paz-Ares Luis G. , Cote Gregory Michael , Ponce Aix Santiago , Martinez Julia , Jimenez Aguilar Elizabeth , Brehcist Elena , Nuñez Rafael , Fernandez Jesus R , Extremera Sonia , Kahatt Carmen Maria , Zeaiter Ali Hassan , Sanchez-Simon Inmaculada
Published: June 2021

5586

Background: LUR is a new agent that exerts antitumor activity through inhibition of trans-activated transcription and modulation of tumor microenvironment. Preclinical synergism/additivity in combination with IRI has been reported, thus prompting the conduct of this trial. This synergism had been evaluated and recently reported in patients with Small Cell Lung Cancer, with encouraging results (Ponce et al. WCLC, 2020). Methods: Phase I trial to evaluate escalating doses of LUR on Day (D) 1 plus a fixed dose of IRI 75 mg/m2 on D1 and D8 every 3 weeks (q3w) in pts with advanced solid tumors, enrolled following a standard 3+3 dose escalation design. Phase II to expand in selected indications at the Recommended Dose (RD). In this abstract, the cohort of patients with endometrial carcinoma treated at the RD is presented. Results: 21 pts (all female) with endometrial carcinoma were treated at the RD (LUR 2 mg/m2 + IRI 75 mg/m2 + G-CSF); 57% had ECOG PS=1; median age was 64 years (range 34-74); subtype of tumour was split: 67% (14 pts) endometroid, 33% non-endometroid (3 pts serous-papilar, 3 pts clear-cell and 1 pt undifferentiated); median of 2 prior lines (range, 1−7) per pt. Common G1/2 toxicities were nausea, vomiting, fatigue, diarrhea and anorexia; G3/4 hematological toxicities comprised neutropenia (33%), thrombocytopenia (5%) and anemia (38%). Two episodes of febrile neutropenia occurred (9.5%). G3/4 non hematological toxicities consisted of diarrhea (24%), asthenia (19%), nausea (14%) and vomiting (5%), all were transient and manageable. 1 patient (5%) discontinued treatment due to toxicity drug-related (generalized muscular weakness), but no treatment-related deaths were reported. Objective RECIST responses were documented in 4/21 evaluable pts (19%). With 6 pts censored for progression, median PFS was 4.4 months (95% CI 2.1-9.6 months), and PFS at 6 months was 40.4%. The clinical benefit rate (% of pts with Complete Response (CR), Partial Response (PR) or Stable Disease > 4 months) was 43%, and the Disease Control Rate (% of pts with CR, PR or SD) 81%. 3/21 pts (14%) have been more than 12 months on treatment so far. Conclusions: The combination of Lurbinectedin and Irinotecan is active in heavily pretreated patients with endometrial carcinoma. The combination was well-tolerated and consistent with the known safety profile for this combination. Myelosuppression, diarrhea, nausea and asthenia were predictable and manageable. Updated results of this cohort will be presented at the meeting. Clinical trial information: NCT02611024.
Prospective longitudinal evaluation of microbiome diversity in patients with hematological malignancy undergoing allogeneic hematopoietic stem cell transplantation (HSCT).
Authors: Walsh Emily , Tsakmaklis Anastasia , Diao Liyang , Bryant Jessica , Lombardo Mary-Jane , McGovern Barbara , von Moltke Lisa , Henn Matthew R. , Ford Christopher B. , Vehreschild Maria J.G.T.
Published: June 2021

7005

Background: Studies suggest that decreased microbial diversity due to chemotherapeutic and antibiotic exposure may be associated with acute graft vs host disease (aGvHD) and mortality in patients undergoing allogeneic HSCT. In addition, disruption of the microbiome by antibiotics may lead to intestinal domination by pro-inflammatory bacteria, resulting in increased risk of aGvHD. This relationship has been described in settings with prophylactic antibiotic use, a standard of care in most transplant centers. Here we assessed how the microbiome and GvHD outcomes differ when prophylactic use of antibiotics is avoided. Methods: We collaborated on an observational study (COLLECT) to evaluate changes in microbial diversity over time in subjects undergoing allogeneic HSCT. According to protocol at the University Hospital of Cologne, antibiotics were administered only as empiric treatment for febrile neutropenia or as targeted treatment. Stool was collected weekly from 65 subjects at baseline (pre-HSCT) to day 28 with additional time points taken at day 56, day 90, day 365, and upon diagnosis of intestinal GvHD (GvHD-day 0 and GvHD-day 7). Patients were monitored for incidence of GvHD, including acute GvHD of the liver, intestine, and skin. Microbiome 16SV4 profiles were generated from 381 stool samples. Linear effects models were developed to evaluate the association between Shannon diversity, intestinal domination, and the incidence of intestinal GvHD and mortality. Results: Of the 65 subjects, 28 subjects (42%) went on to develop intestinal GvHD, and 16 subjects (25%) did not survive to day 365. A decline in Shannon diversity was observed during the neutropenic period following HSCT. Subjects who went on to develop intestinal GvHD had significantly lower Shannon diversity at the time of stem cell engraftment (p < 0.0468). Furthermore, lower diversity was observed throughout the study period in subjects experiencing intestinal GvHD. We developed a linear model evaluating the association between mortality and Shannon diversity and found a significant relationship at days 28 and 90 post HSCT (p < 0.0001 and 0.0121, resp). Intestinal domination by Enterobacteriaceae or Enterococcus was significantly associated with the incidence of intestinal GvHD (p < 0.0082) or mortality (p < 0.001), respectively. Conclusions: Data from this observational study (COLLECT) suggests decreases in microbial diversity over time occur in subjects undergoing allogeneic HSCT despite the lack of prophylactic antibiotics. Investigation of whether administration of microbiome therapeutic drugs prior to transplant and/or at the time of engraftment can reduce morbidity and mortality in this high-risk patient population is warranted. Clinical trial information: NCT03148197.
Racial disparities in lung adenocarcinoma: The contribution of African ancestry.
Authors: Lee Michelle Jeung-Eun , Chang Eric , Shah Manan , Jain Sanjay R.
Published: June 2021

8516

Background: Racial disparities in lung cancer are well-known with African Americans disproportionally affected by lung cancer in terms of incidence and survival. Previous comparative analyses of molecular features of lung cancer revealed racial differences in genomic profiles, which supports somatic differences arising from genetic ancestry. Using The Cancer Genome Atlas (TCGA), we investigated the genetic alterations in lung adenocarcinomas (LUAD) on individuals of African (AFR) ancestry. Methods: The genomic and clinical data of TCGA PanCancer Atlas LUAD were downloaded through the GDC Data Portal. Given that substantial proportion of the US population consist of genetically admixed populations, we utilized The Cancer Genome Ancestry Atlas (TCGAA) and LAMP for estimates of genetic ancestry and quantitative ancestral compositions. This dataset contains 518 samples, including 393 self-reported whites and 52 African Americans. For each case the proportion of European, AFR, East Asian, native American ancestry was estimated. The dominant ancestry was defined as ≥50% of admixture from one reference population. Differences in gene mutation frequency were analyzed based on AFR ancestry proportion. The Kaplan-Meier curves were generated, and Cox regression analyses were performed. Results: Global ancestry analysis identified 50 AFR ancestry cases with mean ancestry of 78.3%. The dominant AFR ancestry group matched the self-reported race with 96% accuracy. We identified 9 subjects with ≥90% AFR ancestry, 22 subjects with 80-90% AFR ancestry, 12 subjects with 70-80% AFR ancestry, and 7 subjects with 50-70% AFR ancestry. TP53 was the most frequently mutated gene, and ≥90% AFR ancestry had the highest rate of mutations (77.8%) compared with 80-90% AFR ancestry (68.2%), and 70-80% AFR ancestry (66.8%). We evaluated classic driver gene mutations (EGFR, KRAS, NRAS, PIK3CA, ALK) and found only 33% of ≥90% AFR ancestry subjects carry a known driver mutation, compared to 58-77% in lower proportion of AFR ancestry subjects. Higher AFR ancestry was associated with worse overall survival (OS) and progression free survival (PFS). Median OS was 14.5 months for ≥90% AFR ancestry compared to 71.47 months in 70-80% AFR ancestry (P = 0.048). ≥90% AFR ancestry had median PFS of 12.8 months compared to 33.5 months in 80-90% AFR ancestry, and 47.1 months in 70-80% AFR ancestry (P = 0.002). Conclusions: This study demonstrates the power of genomic study to investigate the etiology of health disparities by analyzing the effect of ancestry on genetic alterations in LUAD. Our results reveal different mutation loads even among AFR ancestry patients. We observed that AFR ancestry is associated with worse OS, suggesting possible influence of germline ancestry in subsequent somatic alterations. Further work is needed to explore how genetic ancestry impacts tumorigenesis and cancer progression to eliminate lung cancer disparities.
Updated overall efficacy and safety of selpercatinib in patients (pts) with RET fusion+ non-small cell lung cancer (NSCLC).
Authors: Besse Benjamin , Drilon Alexander E. , Solomon Benjamin J. , Subbiah Vivek , Tan Daniel Shao-Weng , Park Keunchil , De Braud Filippo G. , Alonso Guzman , Wolf Juergen , Soldatenkova Victoria , Lin Aimee K. , French Pearl Plernjit , Goto Koichi , Gautschi Oliver
Published: June 2021

9065

Background: Selpercatinib, a first-in-class highly selective and potent, CNS-active RET kinase inhibitor, is approved in multiple countries for treatment of RET fusion+ lung or thyroid cancers. Here we report an update of efficacy and safety results which provide a longer follow up and increased number of patients (safety population: N = 345 vs N = 329). Methods: Pts with RET fusion+ NSCLC enrolled in the global, multicenter, ongoing LIBRETTO-001 trial (NCT03157128; 16 countries, 89 sites) were included in this analysis. Pts with the opportunity to be followed ≥6 months from their first dose were included in the efficacy-evaluable population for these analyses. Integrated analysis set (IAS) included 218 NSCLC pts with prior platinum-chemotherapy. Primary analysis set (PAS) was a subset of the IAS and included the first 105 consecutively enrolled pts. The treatment-naïve population included 48 efficacy-evaluable pts. Primary endpoint was objective response rate (ORR, RECIST v1.1) by independent review committee (IRC). Secondary endpoints included ORR by investigator, duration of response (DoR), progression-free survival (PFS), clinical benefit rate (CBR; CR+PR+SD ≥16 weeks), and safety. Safety population (N = 345) included all pts with NSCLC who received ≥1 selpercatinib dose by data cutoff (30 Mar 2020). Results: In pts with prior treatment (N = 218) and treatment-naïve (N = 48) pts, 56% and 60% were female, with a median pt age of 61 and 64 years, respectively. The ORR with selpercatinib was 57% in the IAS, 64% in the PAS, and 85% in the treatment-naïve population (Table). In both the IAS and PAS, the median DoR was 17.5 months, median PFS was 19.3 months at median follow-up of 12.0 and 15.7 months, respectively (Table). The most common treatment-emergent adverse events (TEAEs) reported in ≥25% of pts were dry mouth, diarrhea, hypertension, increased ALT/AST, edema peripheral, and fatigue. Twenty-five pts (7%) permanently discontinued due to TEAEs, with 10 pts (3%) discontinuing selpercatinib due to treatment-related AEs as per investigator. Conclusions: In this updated data set, selpercatinib continued to demonstrate durable antitumor activity in pts with RET-fusion+ NSCLC. Selpercatinib was well-tolerated with a safety profile consistent with previous reports. A global, randomized, phase 3 trial (LIBRETTO-431) evaluating selpercatinib compared with standard frontline therapy is ongoing. Clinical trial information: NCT03157128. [Table: see text]
Association between mammographic breast density and achievement of a pathologic complete remission (pCR) after neoadjuvant chemotherapy (NACT) for early breast cancer (EBC).
Authors: Kolberg-Liedtke Cornelia , Shaheen Mohamed , Hoffmann Oliver , Bittner Ann-Kathrin , Wetzig Sarah , Stephanou Miltiades , Kolberg Hans-Christian
Published: June 2021

e12611

Background: Neoadjuvant chemotherapy (NACT) is indicated in early breast cancer (EBC) with an unfavorable tumor biology. Achievement of pathologic complete remission (pCR) after NACT is indicating an improved prognosis. An association between pCR and mammographic breast density as defined by BIRADS (Breast Imaging Reporting and Data System) could be demonstrated. However, the definition of mammographic breast density by the American College of Radiology (ACR) is widely used worldwide and data regarding an association of breast density by this definition and pCR after NACT are missing. Methods: We conducted a retrospective analysis among patients who had received neoadjuvant chemotherapy (NACT) for EBC and had available data regarding mammographic breast density as defined by ACR before therapy, pCR, age, estrogen and progesterone receptor (ER, PR) status, HER2neu status and grading were included. An association between mammographic breast density (ACR) and pCR was analyzed. Results: 185 patients were included in this analysis, 35.7% of whom achieved a pCR. Mammographic breast density was ACR 1 in 15.1%, ACR 2 in 41.6%, ACR3 in 38.4% and ACR 4 in 4.9% of the patients. A negative correlation (Spearman-Rho) between mammographic breast density and pCR (correlation coefficient (CC) -0.240) was highly statistically significant (p = 0.001). The association of decreasing pCR rates with increasing mammographic breast density (pCR rates by ACR 1: 53.6%, ACR 2: 41.6, ACR 3: 25.4% and 11.1 %) was statistically significant (Chi-Square, p = 0.013). These results were independent of age, ER status, PR status, HER2neu status and grading. Conclusions: In our analysis higher mammographic breast density as defined by ACR was significantly correlated with a lower chance of achieving a pCR after NACT. Although this result has to be interpreted with caution due to the small sample size and the retrospective character of our investigation, it is completely in line with other investigations using other definitions of mammographic breast density. The pathophysiological cause of this association should be further elucidated to reveal potential mechanisms of treatment resistance.
BRMS1L inhibits bone metastasis of breast cancer cells through epigenetic silence of CXCR4.
Authors: Cen Yinghuan , Gong Chang , Li Jun , Liang Gehao , Liu Zihao , Luo Qing , Lin Qun , Shi Yu , Li Juanmei , Fang Xiaolin
Published: June 2021

e13002

Background: We previously demonstrated that BRMS1L (breast cancer metastasis suppressor 1 like) suppresses breast cancer metastasis through HDAC1 recruitment and histone H3K9 deacetylation at the promoter of FZD10, a receptor for Wnt signaling. It is still unclear whether BRMS1L regulates organ-specific metastases, such as bone metastasis, the most prevalent metastatic site of breast cancer. Methods: Examination of the expression of BRMS1L in primary tumors, bone metastatic and other metastatic tissues from breast cancer patients was implemented using qRT-PCR and immunohistochemistry staining. To investigate the mechanism by which BRMS1L drives breast cancer bone metastasis, we tested the mRNA expression by qRT-PCR of a set of potential bone related genes (BRGs) based on PubMed database in MDA-MB-231 cells over expressing BRMS1L and MCF-7 cells knocking-down BRMS1L, and detected the expression of CXCR4 in these established cells by western blot. Transwell assays were performed to assess the migration abilities of breast cancer cells towards osteoblasts. ChIP (Chromatin Immuno-Precipitation) were employed to test the interaction between BRMS1L and CXCR4. Results: At both mRNA and protein levels, the expression of BRMS1L was significantly lower in bone metastatic sites than that in primary cancer tissues and other metastatic sites of breast cancer patients. CXCR4 was screened out in a set of BRGs and negatively correlated with the expression of BRMS1L in breast cancer cell lines. BRMS1L inhibited the migration of breast cancer cells towards osteoblasts through CXCL12/CXCR4 axis. In the presence of TSA treatment, breast cancer cell lines showed an increased expression of CXCR4 in a TSA concentration-dependent manner. In addition, ChIP assays verified that BRMS1L directly bound to the promoter region of CXCR4 and inhibited its transcription through promoter histone deacetylation. Conclusions: BRMS1L mediates the migration abilities of breast cancer cells to bone microenvironment via targeting CXCR4 and contributes to bone metastasis of breast cancer cells. Thus, BRMS1L may be a potential biomarker for predicting bone metastasis in breast cancer.
Evaluation of telehealth based nutrition counselling to improve dietary compliance and nutritional status of cancer patients.
Authors: Jotwani Amit Kumar , NG Krishna Priya , AK Arun , Jain Rashie
Published: June 2021

e13619

Background: According to published literature, regardless of the cancer type, the overall prevalence of malnutrition in cancer is about 40% (range 30%-70%). Malnutrition is known to adversely affect the treatment compliance, quality of life and survival outcomes for cancer patients. Onco.com provides telehealth based nutrition care support (NCS) as a part of cancer care management program. We sought to evaluate impact of telehealth based nutrition counselling on diet compliance and overall nutritional status of patients. Methods: NCS includes virtual nutrition screening, nutrition diagnosis and nutrition intervention. Virtual nutrition screening was done using modified patient generated subjective global assessment (PG-SGA) tool developed by Ottery. An initial nutrition screening was initially performed for 165 patients. After nutrition screening, patients were divided as malnourished (category 1- 47%), nutritionally at risk (category 2- 34%) and well nourished (category 3- 19%). Patients in category 1 & 2 were analysed for the purpose of study. Diet counselling and customized diet plans were provided to the patients between the age group of 12 to 83 years for a period of 3 months from October to December 2020. On follow up, 24 hour diet recall method and food frequency method were used to assess the compliance to the diet plan. One day prior 24 hour diet recall and food frequency method for two weeks was used to analyse the adherence to the plan. If the patient consumed ≥75% of the recommended diet for a minimum of 5 days in a week, he/she was considered a ‘compliant’, while those who consumed < 75% of the recommended diet were considered to be ‘non-compliant’. Data on body weight and performance status (PS) was documented during follow up to track changes. Results: Of 134 study participants, 35.1% were in the early (I & II) stage, 38.7 % were in the locally advanced (III) stage, 21.2 % were in the metastatic stage, and 4.8 % were in the recurrent stage of disease. After 3 months of initiation of the nutrition counselling, 40% of the patients had gained weight, whereas 38% could maintain the body weight and 22 % had lost weight. Change in physical activity, appetite, management of side effects after diet plan initiation were also assessed during the reassessment calls. Overall, 67% patients showed improvement in diet compliance across all stages of disease. Majority of dietary non-compliance was noted in patients with head and neck, upper GI cancers or those with poor PS. Conclusions: Telehealth based nutritional counselling is an effective tool to help cancer patients achieve better diet compliance and nutrition outcomes across all stages of disease. Dietary non-compliance in head and neck cancers and upper gastrointestinal cancers or poos PS could correlate with difficulty in oral intake. Getting accurate information could be one of the challenges in virtual mode of counselling.
Clinical and immunological allergy assessment in cancer patients.
Authors: Carneiro Bruno Gustavo Muzzi Carvalho , Petroianu Andy , Machado Jose Augusto Nogueira , Anjos Paula Martins Ferreira dos , Silva Fabiana Rocha da , Alberti Luiz Ronaldo , Resende Vivian , Barrientos Sofia Candia
Published: June 2021

e15021

Background: Cancer is associated with immunodeficiency, while allergies result from immune system hyperactivity mediated by cytokines and immunoglobulins. The purpose of this study was to determine the relationship between immune environment of specific cancers and allergies, emphasizing cytokines related to Th1 and Th2 responses associated with IgE. Methods: 80 adults were distributed into two groups: control (n = 20) and cancer (n = 60), distributed in three subgroups (n = 20), head and neck, stomach, and prostate cancers. This study considered cytokine deviation in Th1 (IL-2) response to Th2 (IL-4), anti-inflammatory, pro-inflammatory, or regulatory profile regarding both IgE levels and reported allergies, by means of clinical manifestations and IgE, IL-1β, IL-2, IL-4, IL-17, and TGF-β serum concentration. Results: Clinically allergies were observed in 50% of the control group and in 20% of the cancer group (p = 0.01). IL-2 cytokine and TGF-β concentrations were higher in the patients with cancer as compared to the control (p < 0.005). However, there were IL-4, IL-17, and IL-1β decreases in the patients with cancer (p < 0.05). No correlation was observed between the cytokines studied and IgE and clinically proven allergies in both investigated groups. Conclusions: There was an inverse association between cancer and clinical allergy manifestations. In head and neck, stomach, and prostate cancers, an immunosuppressive serum tumor environment was predominant. Cytokine deviation in the Th1 response to Th2 in relation to IgE was not identified. No correlation was found between clinically proved allergies and immunity markers related to the same allergens.