bluuebunny/crossref_metadata_2025 huggingface dataset:
Cancer risk and characteristics in older female BRCA1/2 mutation carriers.
Authors: Ghimire Bipin , Karki Ujjwal , Shrotriya Shiva , Rangarajan Tara , Zakalik Dana
Published: June 2023

10610

Background: Cancer risk and characteristics in older females with BRCA1/2 mutations are less well studied, and the role of risk-reducing strategies in this population remains unclear. Methods: From a database of 1070 female carriers of BRCA1/2 pathogenic (PV) or likely pathogenic variants (LPV) seen at Nancy and James Grosfeld Cancer Genetics Center in Beaumont Health from January 2006 to December 2021, we identified 283 females who lived to age 65 or older. We analyzed cancer risk and clinical characteristics, focusing on females with cancer diagnosed at age 65 or older. Results: Of the 283 BRCA1/2 carriers, 229 (81%) had a cancer diagnosis, out of which 84 (37%) were diagnosed at age 65 or older. Of all the breast cancer diagnoses (n = 173), 45 (26%) were diagnosed at age 65 or older. Among these 45 patients, median age at diagnosis was 69 years (65-87); majority were BRCA2 carriers (62%), with invasive ductal carcinoma (80%), ER-positive (58%), PR-negative (55%), HER2-negative (97%), high grade (55%) and had stage I or II disease (78%). Fifteen patients (38%) were triple-negative. A minority (32%) received adjuvant chemotherapy, 43% received adjuvant endocrine therapy, and 54% received adjuvant radiation. During a median follow-up of 205 months for all breast cancers (n = 173), there were 52 recurrences, 28 of these (54%) were diagnosed at age 65 or older, of which 13 were contralateral (median time to recurrence: 140 months); 5 were local/regional (median time: 186 months) and 10 were metastatic (median time: 76 months). Ten of the 13 contralateral recurrences (77%) were in BRCA1 carriers. Of the ovarian cancer diagnoses (n = 69), 27 (39%) were diagnosed at age 65 or older. Among these 27 patients, median age at diagnosis was 71 years (65-87); majority were BRCA2 carriers (74%), had serous carcinoma (84%), with stage III or IV disease (96%). Of all ovarian cancers (n = 69), there were 15 recurrences (22%), 9 of them (60%) were diagnosed at age 65 or older. Of the 8 pancreatic cancers, 6 were diagnosed at age 65 or older. Of the 283 BRCA1/2 carriers, 249 still had at least one breast at the time of genetic testing, and 34% elected for risk-reducing mastectomy (RRM). Of the 177 patients with intact ovaries, 71% opted for risk-reducing salpingo-oophorectomy (RRSO). Compared to BRCA carriers with cancer diagnosed under age 65, a smaller proportion of those diagnosed at age 65 or older opted to undergo RRM (26% vs. 40%) or RRSO (67% vs. 78%). Conclusions: Our study reveals that female BRCA1/2 mutation carriers over age 65 continue to retain a significant risk of cancer, including breast, contralateral breast, ovarian, and pancreatic cancer. This finding supports the importance of continued high-risk surveillance and risk-reducing interventions in this growing demographic. Further studies are needed to better define the cancer risks and optimal management of older females with BRCA1/2 mutations.
Perceived mental and physical health in patients with common cancers: A study using the PROMIS framework in All of Us database.
Authors: Mohamed Salih Rajaa , Eun Yong , Olusoji Rahman Adesoji , Osei Noah , Ahluwalia Meena
Published: June 2023

10619

Background: The self-perception of one's mental and physical health (MH and PH) is of utmost importance for individuals diagnosed with cancer. This study focuses on the assessment of self-perceived mental and physical health (MH and PH) in individuals diagnosed with cancer. The Patient-Reported Outcomes Measurement Information System (PROMIS) framework is used to measure health outcomes, with PROMIS-PH measuring physical well-being and PROMIS-MH measuring mental health status. The study aims to evaluate self-reported mental and physical health of individuals with common cancers in the All of Us database, which includes over 414,000 participants in the US who have completed PROMIS-PH and PROMIS-MH surveys. Methods: We included participants from All of Us dataset version 6, which includes survey data collected between May 6, 2018 and January 1, 2022 who had available electronic health records data (N = 258,188). From the survey data, we calculated PROMIS-PH and PROMIS-MH score in participants with diagnosis code (ICD9/ICD10) of any cancers (N = 36377), breast (N = 5172), prostate (N = 5234), colon (N = 2366), and lung cancer (N = 2338). The study compared scores each cancer groups using Wilcoxon rank sum test, with a significance level of P < 0.05. Analysis was performed in the web-based platform Jupyter Notebook using programming language R. Results: The study calculated PROMIS-MH and PROMIS-PH scores based on two questions, with response options valued from 1 to 5. The higher the score, the higher the level of perceived mental and physical health. Results showed that the mean PROMIS-MH score for all cancers was 7.38, with the highest score of 7.67 in prostate cancer and the lowest score of 7.10 in lung cancer. The mean PROMIS-PH score for all cancers was 7.31, with the highest score of 7.62 in prostate cancer and the lowest score of 6.71 in lung cancer. Prostate cancer group showed the highest PROMIS-PH and PROMIS-MH scores among the four cancer groups (P < 0.05), while participants with lung cancer reported the lowest PROMIS-PH and PROMIS-MH scores (P < 0.05). Additionally, breast cancer had higher PROMIS-MH and PROMIS-PH scores compared to all cancers (P < 0.05), while lung cancer had lower PROMIS-MH and PROMIS-PH scores (P < 0.05). There was no significant difference in PROMIS-MH score between all cancers and colon cancer. Conclusions: These results suggest that individuals with lung cancer may have a lower level of perceived mental and physical health compared to those with other cancers. Further research is needed to understand the underlying causes of these differences and to evaluate the effectiveness of interventions aimed at improving the well-being of individuals with cancer.
Clinical and social importance of follow-up assessment of family members of patients with BRCA mutations.
Authors: Nascimento Ivana Lucia de Oliveira , Freitas Juliana Cortes , Bomfim-Palma Thais Ferreira , Rodrigues Juliana Lima Gomes , Melo Thamara Ferreira , Oliveira Pollyanna Carozo , Landeiro Luciana , Meyer Roberto , Toralles Maria Betania , Lopes Taisa
Published: June 2023

10621

Background: The identification of BRCA1 and BRCA2 genes mutations are of paramount importance in the treatment and follow-up of hereditary cancer patients. When a pathogenic variant (PV) is identified in one of these genes, the surveillance for new primary tumors becomes individualized. When a pathogenic mutation is identified other family members may also be at high risk for developing tumors. Then the investigation should become familiar. Methods: This study reports the experience of a public oncogenetics service with the identification and follow-up of relatives of patients with BRCA mutations. Of the 1505 patients registered, 773 are probands, of which 71 had a mutation in one of the BRCA genes. A total of 503 family members were evaluated, with an average of 13 relatives per proband. Results: Of the 353 relatives with a BRCA1 mutation, 132 had the familial mutation, and only 18 had cancer diagnosis. The mean age of the evaluated family members was 37 years, lower than the mean age at diagnosis of the probands, which was approximately 41 years, two founder mutations in BRCA1 (NM_007300.4:c.3331_3334del and NM_007300.4:c.211A > G) were more recurrent among index cases, which is associated with the ancestral background of the local population. For the BRCA2 gene, 148 family members were evaluated, of which 77 had a mutation and 23 had a previous cancer diagnosis. The mean age of family members evaluated for BRCA2 mutation was 43 years, similar to the mean age at diagnosis of the proband: 41 years. The NM_000059.4:c.1389_1390del and NM_000059.4:c.7124T > G variants was the most frequent in BRCA2. Conclusions: This data reinforces the importance of genetic counseling and testing of family members when a pathogenic variant is identified in a cancer patient. It is clear that early initiation of surveillance protocols, with screening and prophylactic surgeries are very effective tools for those high risk patients, they just have to be early diagnosed with the PV to benefit from this strategies. In addition, this assessment helps in understanding the mutational profile of the population in order to improve the planning of services in oncogenetics.
A scalable approach to democratizing cancer risk stratification: One healthcare system’s approach using a patient-facing digital platform.
Authors: Fecteau Heather , Kurbegov Dax , Patel Reena Manhar , Keller Haley , Horton Carolyn , Hoang Lily , Kieran Shannon M.
Published: June 2023

10622

Background: Access to genetic testing and risk stratification is primarily gated by referrals from non-genetics providers for patients who meet testing criteria. The majority of Americans seek care at community hospitals that are closer to home; community hospitals are faced with the challenge of how to democratize access to precision oncology and cancer prevention. Research has shown that the establishment of such protocols is challenging, requiring organizational buy-in, capital, resources, and the involvement of multiple levels of clinical and nonclinical stakeholders. Here we highlight Sarah Cannon, the Cancer Institute of HCA Healthcare, and their programmatic approach to risk stratification using a digital platform offered universally to all patients undergoing screening mammography. Methods: From February to November in 2022, fourteen sites were assessed to have appropriate provider and facility capabilities to support the implement the CARE program. The web-based risk-stratification tool is sent to individuals before standard ambulatory appointments to assess their lifetime risk for breast cancer based on the Tyrer-Cuzick (version 8.0) risk algorithm and National Comprehensive Cancer Network (NCCN) genetic testing criteria. Testing criteria included hereditary breast, ovarian, pancreatic, and prostate cancers, Lynch syndrome, and familial adenomatous polyposis (FAP). Retrospective data was pulled from patients seen between February 2022 through January 2023. The outcome measures included percentage of individuals who completed the risk-assessment, met genetic testing criteria, pursued germline genetic testing, received a positive germline result, and/or had a breast cancer risk ≥20%. Results: During the 10 months at the 14 community hospitals a total of 25,671 individuals were invited for risk assessment through the CARE program; 19,277 (75.1%) individuals completed assessment. Overall, 5,070 (26.3%) met genetic testing criteria and 1,536 individuals had a ≥20% lifetime risk of breast cancer, for a total of 34% of patients identified as elevated risk. 23.4% (1,187) of those meeting criteria opted to proceed with germline genetic testing. An additional 126 individuals who did not meet criteria pursued genetic testing. Of the 1,313 completed genetic tests, 96 (7%) had positive genetic test results. Fifty-four of 96 (56%) positive results had an impact on medical management and cancer prevention. Conclusions: Sarah Cannon and HCA Healthcare have successfully begun implementing a comprehensive, digital risk stratification program in the community hospital setting to provide standardized access to genomic testing and risk stratification. By identifying patients with an elevated risk for cancer, the potential for increased early cancer detection and precision oncology can be observed in a scalable and sustainable program.
Newly diagnosed lung cancer in hospitalized patients during the COVID-19 pandemic: How well are LDCTs utilized?
Authors: Assis Jonathan , Neerukonda Thanuja , Farooqi Bilal , Haider Mahvish
Published: June 2023

10624

Background: Medicare covers the cost of lung cancer screening in individuals aged 50-77 years with a high-risk smoking history. The COVID-19 pandemic caused a decrease in outpatient visits and cancer screenings. The objective of this study was to provide a comparison between the multitude of lung cancer diagnoses upon presentation to the hospital predating and during the COVID-19 pandemic in patients with varying insurance types. Methods: We retrospectively reviewed fifteen hospitals in West Florida with newly diagnosed lung cancer during the pre-pandemic period from March 2019-August 2020 and the pandemic period from March 2020- August 2021. These patients were split into subcategories based on insurance type: private medical insurance; Medicare; Medicaid; no insurance; and other. The chi-square test was used for statistical analysis. Results: A total of 1409 inpatients, 676 during the pre-pandemic and 733 during the pandemic, were identified with a new diagnosis of lung cancer upon presentation to the hospital. 74% of the pandemic population and 77% of the pre-pandemic population were patients insured with Medicare. Hospitals without LDCT screening programs were found to have 317 lung cancer diagnoses during the pre-pandemic period and 292 during the pandemic period. Hospitals with LDCT screening programs were found to have 359 lung cancer diagnoses during the pre-pandemic period and 441 during the pandemic period. Chi-square tests comparing pre-pandemic to pandemic did not show a p-value of statistical significance. Conclusions: A substantial number of patients with Medicare were newly diagnosed with lung cancer during the pre-pandemic and pandemic periods compared to patients with other insurance types. Although Medicare provides LDCT screening for lung cancer in high-risk populations at no out-of-pocket cost, about 75% of West Florida’s patients were diagnosed with lung-cancer upon presentation to the hospital. Hospitals with LDCT screening programs had an increase in cancer diagnoses during the pandemic, consistent with prior research data. Instead, the pandemic did not seem to affect hospitals without LDCT screening programs. We need to address the barriers in implementation of LDCT hospital-based screening programs to increase early diagnoses and decrease hospitalization diagnoses, leading to improved lung cancer mortality. [Table: see text]
Immunogenicity after COVID-19 vaccination in patients with solid tumor and hospital staff: A prospective single-center observational study.
Authors: Katsuya Yuki , Yoshida Tatsuya , Yazaki Shu , Yagishita Shigehiro , Nakahama Hiroko , Kobayashi Osamu , Yanagida Masatoshi , Irino Yasuhiro , Hamada Akinobu , Yamamoto Noboru
Published: June 2023

10626

Background: Patients with tumor are at high risk of severe COVID-19, and vaccination against SARS-CoV-2 is recommended. Impact of cancer treatment on immunogenicity has not been evaluated well. Methods: This prospective study was conducted to assess the seroconversion rate of SARS-CoV-2 vaccines among patients with cancer and hospital staff. Further, we focused on the difference among cancer treatment regimens. SARS-CoV-2 spike protein-specific IgG (S-IgG) were evaluated before the first vaccination, 1–3 months, 4–6 months, and 7–12 months after the second vaccination, and 1–3 months after the third vaccination. The primary endpoint was seroconversion rate measured 1–3 months after the second vaccination. Results: From April 2021 to November 2021, consent was obtained from 629 cancer patients and 210 hospital staff. Excluding missing data and withdrawal of consent, 590 cancer patients and 183 hospital staff without complications was analyzed. At 1–3 months after the second vaccination, S-IgG antibody concentration higher than the cut-off value (20 BAU/mL) was found in 96.1% (567/590) patients with cancer and 100% (183/183) of the healthy controls (p = 0.0024). At 4–6 months after second vaccination, S-IgG antibody concentration higher than the cut-off value was found in 93.1% (461/495) patients with cancer and 100% (170/170) of the healthy controls (p < 0.0001). The significant difference in seroconversion rate between the two groups persisted even after 7-12 months. Patients undergoing treatment regimens such as platinum combination therapy (median: 423.7, 95% CI: 264.2–767.0, p = 0.003) and alkylating agent (median: 57.5, 95% CI: 5.4–748, p < 0.0001) among cytotoxic drugs, and PARP inhibitor (median: 264, 95% CI: 43–690.4, p = 0.0004), mTOR inhibitor (median: 227.4, 95% CI: 5.7–323.4, p = 0.0036), BCR-ABL inhibitor among drugs (median: 124.4, 95% CI: 0.0–288.9, p = 0.005) among target molecule drugs showed lower antibody titer compared to the no-treatment patients with cancer group. Conclusions: SARS-CoV-2 vaccine immunogenicity was low among patients with cancer compared to healthy control. Also, several treatment regimens were found to negatively impact immune response. Clinical trial information: UMIN000049403 , UMIN000049430 . [Table: see text]
AI to characterize patients with lung or ovarian cancer and those with cachexia for discovery of undiagnosed, misdiagnosed, and miscoded patients at scale in a privacy-preserving manner.
Authors: Guo Yike , Zhang Jingqing , Burda Marcin , Falakaflaki Parastoo , Sharma Atri Vivek , Gupta Vibhor
Published: June 2023

10627

Background: Discovering undiagnosed, misdiagnosed or miscoded patients is critical to ensure suitability for clinical care pathways and for maximizing clinical trial recruitment. Meta-data (e.g. ICD) and generic NLP based approaches fall short due to: lack of scalability, significant miscoding of patient records and searching a pre-empted list of features without understanding their context or relationships between them. This study addresses these limitations through the application of Pangaea’s novel AI product (PIES) to characterize patients, which has discovered 4x more undiagnosed, misdiagnosed and miscoded patients in a scalable and privacy-preserving manner. Methods: PIES was configured on 235 clinically validated lung, ovarian and cachectic cancer patient records from secondary care. First, PIES determines all concepts which are reflected in a patient’s record based on a medical knowledge base. Second, PIES determines key clinical features and actionable relationships between them which help stratify the target patient population. Third, the findings from steps 1 and 2, are validated by clinicians and all feedback is used to refine these steps and evolve the results through a continuous loop. Following these, PIES’s characterization of the target patient population is applied across clinically validated datasets for evaluation and then across multiple healthcare systems behind their firewalls to ensure scalability and privacy compliance. Results: Applied to a dataset of 100 clinically validated patients, ICD codes correctly discovers 48 lung cancer patients and misses 18 patients (i.e. who had a diagnosis of lung cancer but were miscoded). By contrast, PIES discovers 63 lung cancer patients and misses only 3 patients. Similarly, ICD codes correctly discovers 36 ovarian cancer patients and misses 16 patients in a dataset of 100 clinically validated patients. PIES correctly discovers all 52 ovarian cancer patients. Separately, in a dataset of 235 clinically validated patients, ICD codes correctly discovers 39 cachectic cancer patients and misses 122 patients. By contrast, PIES discovers 146 cachectic cancer patients and misses only 15 patients. Conclusions: Pangaea’s AI-driven product for characterizing patients discovered 48% more lung cancer patients, 62% more ovarian cancer patients and 276% more cachectic cancer patients for screening, compared to ICD codes. This includes undiagnosed and misdiagnosed patients. Pangaea’s product platform permits the evolution of knowledge for characterizing different target patient populations through its application across multiple healthcare systems, without the need to move or touch the data, thereby ensuring scalability in a privacy compliant manner.
Overall and non-lung cancer incidence in the national lung screening trial (NLST) as indicators of potential for multi-cancer screening.
Authors: Chang Ellen T. , Janes Sam M. , Hackshaw Allan , Clarke Dur Christina A. , Buist Diana SM , Hubbell Earl A.
Published: June 2023

10633

Background: Single-cancer screening strategies address only one component of the overall population cancer burden. Even high-risk populations in single-cancer screening trials experience a considerable burden of other cancer incidence; therefore, we assessed non-lung cancer incidence in the NLST to evaluate the proportion of unscreened cancers. Methods: The NLST was a randomized controlled trial of screening for lung cancer in adults aged 55–74 years with ≥30 pack-years of smoking history, enrolled in 2002–2004 and actively followed through 2009. Incident cancers were identified via participant questionnaires, death certificates, and direct notifications, and confirmed by medical record abstraction. The present analysis includes first invasive primary cancers diagnosed after study randomization. Non-lung cancer incidence was similar between the two trial arms, which were therefore combined for analysis. Results: Among 53 229 subjects (median follow-up 6.5 years), the incidence of any first primary cancer was 1941 per 100 000 person-years, of which 1327 per 100 000 (68%) was non-lung cancer. Non-lung cancer incidence rates exceeded that for lung cancer in all 5-year age categories (especially at younger ages) and all quintiles of smoking pack-years (especially with fewer pack-years). After lung cancer, the most common cancers were other leading cancer types in the general US population, as well as other smoking-related cancers (Table). No recommended population-based screens exist for 54% of observed cancer cases (3332 of 6142, excluding lung, colon/rectum, female breast, and cervix). Conclusions: In the NLST, only 32% of first primary cancer incidence was lung; non-lung cancer comprised 68%, and most cases were cancer types with no generally recommended screening strategy. Even in a high-risk population, a single-cancer screening test misses most cancers, illustrating the value of multi-cancer screening tests that can detect a broad spectrum of cancers and, therefore, have the potential to address a currently inaccessible portion of cancer morbidity and mortality. [Table: see text]
Clinical activity of camizestrant, a next-generation SERD, versus fulvestrant in patients with a detectable ESR1 mutation: Exploratory analysis of the SERENA-2 phase 2 trial.
Authors: Oliveira Mafalda , Pominchuk Denys , Hamilton Erika P. , Kulyaba Yaroslav , Melkadze Tamar , Neven Patrick , Nemsadze Gia , Andabekov Timur , Semegen Yuriy , Hotko Yevhen , Zamagni Claudio , Vladimirov Vladimir , Bennett Maxine , Ciardullo Carmela , Klinowska Teresa , Lindemann Justin P O , McEwen Robert , Morrow Christopher J. , Arkania Ekaterine
Published: June 2023

1066

Background: Camizestrant, a next-generation oral selective estrogen receptor antagonist and degrader (ngSERD), was compared at two dose levels to fulvestrant 500 mg (F) in post-menopausal women with advanced ER+, HER2˗ breast cancer with disease recurrence or progression after ≤1 endocrine therapy in the advanced setting in the Phase 2 randomized SERENA-2 study (NCT04214288). Camizestrant demonstrated statistically significant and clinically meaningful benefit vs F in progression-free survival (PFS) in the overall study population (Oliveira M et al. SABCS 2022 Annual Meeting. Abstract GS3-02.). Methods: Baseline circulating tumour DNA was collected at screening and/or Cycle 1 Day 1 and analysed by next-generation sequencing. A post hoc exploratory analysis compared investigator assessed PFS with camizestrant (data from 75 and 150 mg combined) vs F in patients with detectable baseline ESR1 (the gene that encodes ERα) hotspot mutations ( ESR1m). Patients were divided into subgroups based on whether 1 or >1 ESR1m variants were detected, the specific ESR1m, and whether mutations were detected in BRCA1/2 or the MAPK pathway. The most prevalent mutations are presented. A Cox proportional hazards model was used to compare PFS. Results: 48/147 (32.7%) patients treated with camizestrant and 35/73 (47.9%) treated with F had a detectable ESR1m in at least 1 baseline sample. ESR1m were detected in 6/9 (67%) patients with a BRCA1/2 mutation and 5/26 (19%) with a MAPK pathway alteration; however, the numbers were too small to analyse efficacy in these subgroups. Conclusions: Camizestrant showed improved outcome vs F in patients with a detectable ESR1m at baseline and in the subgroups tested. The greatest median PFS improvement was seen in patients where a single ESR1m variant was detected, suggesting that early intervention upon detection of an ESR1m may provide the maximum patient benefit for camizestrant, a hypothesis that is being tested in the SERENA-6 clinical trial (NCT04964934). Clinical trial information: NCT04214288 . [Table: see text]
Phase 1/2 dose expansion study evaluating first-in-class eIF4A inhibitor zotatifin in patients with ER+ metastatic breast cancer.
Authors: Rosen Ezra , Sharma Manish , Berz David , Caswell-Jin Jennifer Lee , Spira Alexander I. , Fulgar Georgina A. , Densel Mark , Rana Nawaid , Sperry Samuel , Warner Douglas , Meric-Bernstam Funda ,   ASCO Authors' Group
Published: June 2023

1080

Background: Zotatifin (eFT226) is a first-in-class, potent and sequence selective inhibitor of RNA helicase eIF4A that promotes a stable mRNA:eIF4A:drug ternary complex at specific polypurine motifs within the 5’-UTR, preventing translation of select transcripts. In preclinical models zotatifin treatment simultaneously down-regulated translation of numerous oncogenes including CDK4, ERα, ERBB2, KRAS, and CCND1. Methods: Following a 3+3 dose escalation portion of the protocol (Part 1), Part 2 is a Simon’s two-stage design of cohorts of up to 18 patients (pts) with ER+ metastatic breast cancer enrolled at the recommended phase 2 dose of zotatifin (0.07 mg/kg IV two weeks on/one week off) in combination with fulvestrant (ful) (ECBF: Expansion, Combination, Breast, Ful) or in combination with ful and abemaciclib (abema) (ECBF+A: Expansion, Combination, Breast, Ful + Abema). Key eligibility criteria included at least one line of therapy for advanced/metastatic disease, progression on hormone therapy, and in addition, the ECBF cohort required prior CDK 4/6 inhibitor (CDKI). Primary endpoint was objective response rate (ORR) per RECIST v1.1. Additional endpoints included safety, other efficacy analyses, and for Parts 1 and 2, characterization of pharmacodynamic (PD) markers and pharmacokinetics. Results: As of a data cut-off of Jan 31, 2023, 18 pts were enrolled in each cohort. Median prior metastatic lines of therapy were 3 and 7 in ECBF+A and ECBF, respectively. In 16 evaluable pts in ECBF+A cohort, there were two confirmed partial responses (PR), two additional PRs awaiting confirmatory scans, and 8 pts with best overall response (OR) of stable disease (SD). All pts with PR/unconfirmed PR received prior CDKI and ful, including one pt with disease progression on combination abema and ful as the last therapy prior to enrollment. In 18 evaluable pts in ECBF, there was one confirmed PR and six SD as best OR. There were no dose-limiting toxicities or grade (Gr) 5 adverse events (AEs) in either cohort. In ECBF+A the most common AEs (all Gr 1/2) were diarrhea (44%) and nausea (31%) and 21% of pts had Gr 3/4 AEs. The most common AEs in ECBF (all Gr 1/2) were nausea (39%) and constipation (27%), and 28% of pts had Gr 3/4 AEs. Blood-based PD markers and ctDNA in Part 1 showed dose-dependent evidence of target engagement and anti-tumor activity. Conclusions: In dose expansion cohorts of heavily pre-treated metastatic breast cancer pts, eIF4A inhibitor zotatifin showed evidence of anti-tumor activity in combination with fulvestrant and abemaciclib and had a favorable safety profile consisting of primarily grade 1/2 adverse events. Clinical trial information: NCT04092673 .
Discovery of CDK4/6 bifunctional degraders for ER+/HER2- breast cancer.
Authors: Majeski Hannah , Okano Akinori , Pasis Angela , Carlson Casey , Shakya Arvind , Huang Shenlin , Chourasia Aparajita Hoskote , Fung Leah M. , Liu Qiao
Published: June 2023

1083

Background: CDK4/6 inhibitors (CDK4/6i) such as palbociclib and ribociclib are used to treat ER+/HER2- breast cancer, but patients can develop resistance via many mechanisms, several of which converge on the upregulation of CDK6. This has been shown to limit the effectiveness of CDK4/6i in ER+ breast cancer with up to 20% patients exhibiting innate resistance and up to 70% patients developing acquired resistance after 3 years on therapy (Scheidemann, 2021, doi:10.3390/ijms222212292). Methods: To address this limitation, we utilized our PRODEGY platform of Cereblon (CRBN) binders to synthesize CRBN mediated CDK4/6 bifunctional degraders to potently inhibit tumor growth for treatment of naïve ER+/HER2- breast cancer and CDK4/6i resistant tumors. Results: Target degradation by immunoblot analysis of the triple negative breast cancer (TNBC) cell line, MDA-MB-231, treated with our CDK4/6 bifunctional degraders for 6 hours showed up to 85% degradation of CDK4 and CDK6 with DC50s of 1-100nM. CDK4/6 phosphorylates the protein RB which releases the transcription factor E2F, inducing the expression of genes which promote cell cycle progression. Analysis of RB phosphorylation by in-cell western upon 24 hours of CDK4/6 degrader treatment showed phospho-RB IC50s at <30nM. Cell cycle analysis by staining with propidium iodide after 24 hours of treatment with CDK4/6 degraders induced G0/G1 cell cycle arrest at concentrations as low as 10nM. We used a 2D colony formation assay (CFA) as a readout for inhibition of proliferation by cell cycle arrest. Our CDK4/6 degraders showed potent inhibition of cell proliferation with CFA IC50s of <100nM in TNBC cell lines and <25nM in ER+ cell lines, including MCF7, T47D and ZR751 compared to CDK4/6i which ranged from 200nM to 500nM in MCF7 cells. We demonstrated that our CDK4/6 bifunctional degraders were significantly more potent in vitro than the CDK4/6i ribociclib and palbociclib, and the increased activity was due to CRBN mediated target degradation. Our CDK4/6 bifunctional degraders display excellent pharmacokinetic properties in mice with half-lives between 2-10 hours, oral bioavailability between 50-96%. MCF7 xenograft results with our proof-of-concept CDK4/6 degrader showed dose-dependent tumor growth inhibition and greater potency compared to the clinical CDK4/6i ribociclib. We saw tumor regression with our degrader at higher doses which we did not see at any dose of CDK4/6i. Conclusions: Our CDK4/6 bifunctional degraders display excellent single agent activity in vitro and in vivo particularly in comparison to clinically approved CDK4/6i, indicating that using a degrader approach to targeting this pathway may be more effective than current inhibitor therapies.
Olaparib (O) + ceralasertib (C) in patients (pts) with metastatic triple-negative breast cancer (mTNBC): Translational analysis of the VIOLETTE trial.
Authors: Lukashchuk Natalia , Punie Kevin , Nowecki Zbigniew , Im Seock-Ah , Armstrong Anne C. , Jacot William , Kim Jee Hyun , Webster Marc A. , Balmaña Judith , Delaloge Suzette , Casson Ed , Loembe Bienvenu , Dean Emma , Armenia Joshua , Tutt Andrew NJ
Published: June 2023

1087

Background: O is a PARP inhibitor approved in a number of tumor types and for use in pts with germline (g) mutations in BRCA ( BRCAm) HER2-negative metastatic breast cancer. C is an inhibitor of DDR kinase ATR. Analysis of VIOLETTE (NCT03330847) in pts with mTNBC showed no improvement in PFS with a combination of C and O vs. O, whether in the context of pathogenic BRCAm, non-BRCA HRR pathway mutations (HRRm), or homologous recombination repair (HRR) wildtype (HRRwt) tumors. We report an exploratory translational analysis of predictive genomic biomarkers of response to O ± C beyond g BRCAm. Methods: Pts received O (300 mg twice daily) ± C (160 mg daily; days 1–7; 28-day cycles) as a second- or third-line treatment option. Pts were prospectively stratified into molecular strata based on pathogenic/likely pathogenic alterations in BRCA1/2 ( BRCAm; n=83) or in ≥1 of 13 selected non- BRCA HRR genes (HRRm; n=40) or HRRwt (n=103) using FoundationOneCDx (F1CDx) sequencing assay of archival tumor sample. Advanced genomic analysis included genome-wide loss of heterozygosity (a marker of HRR deficiency [HRD] with a 16% cut-off to define HRD+ [≥16%] vs HRD− [<16%]), zygosity, and predicted g/somatic (s) status of BRCA and HRR alterations based on a validated computational FMI algorithm. Efficacy was evaluated by blinded independent central review of PFS, RECIST response, and best percentage change from baseline in target lesion size. Results: Out of evaluable pts for origin of BRCAm (n=42), 81% (n=34) were of germline, and 19% (n=8) were of somatic origin. Of pts evaluable for zygosity (n=48), most BRCA alterations were biallelic (90%; n=43), and of pts evaluable for HRD status (n=47), most were HRD+ (94%; n=44). Of HRRwt pts evaluable for HRD status (n=79), 57% were HRD+ (n=45). Responses by biomarker are shown. Responses in BRCAm pts were seen in all subgroups (zygosity, HRD, or g/s origin of mutation), including s BRCAm (ORR: n=3/4 on O; n=2/4 on O+C). Responses were also seen in patients with heterozygous BRCA alteration (n=3/5) by genomic result and in BRCAm/HRD− pts (n=3/3) across both arms. Pts with select HRR genes ( BARD1, RAD51C/D, ATM, CDK12) also achieved responses on O or O+C. Conclusions: Responses to O were seen in pts with both g BRCAm and s BRCAm. Beyond BRCAm, the efficacy of O was observed in pts with alterations in select HRR genes, such as BARD1 or RAD51C/D; further clinical investigation is required. Small sample size and HRD analysis performed on archival tumor samples should be considered limitations. Clinical trial information: NCT03330847 . [Table: see text]
Olaparib (O) in advanced triple negative breast cancer (aTNBC) patients (pts) with BRCA1/2 promoter methylation: GEICAM/2015-06 study (COMETA-Breast).
Authors: De La Haba Juan , Anton Antonio , Quiroga Vanesa , Guerrero Angel , Andrés Raquel , Mele Mireia , Gonzalez- Santiago Santiago , Perez-Fidalgo Jose Alejandro , Ramon y Cajal Teresa , Escudero Maria Jose , Bezares Susana , Caballero Rosalia , Rojo Federico
Published: June 2023

1093

Background: Epigenetic silencing by aberrant BRCA1/2 promoters’ methylation ( BRCA-meth) can be responsible for a dysfunctional BRCA protein. BRCA-meth occurs in 15-57% of TNBC pts. BRCA-meth breast cancer (BC) display pathologic features and genetic profiles like germline BRCA1/2-mutated (g BRCA1/2m) carriers. O is a PARP inhibitor approved for treating g BRCAm HER2-negative advanced BC (aBC) pts. These are the results of a phase II study assessing the O efficacy in aTNBC pts with BRCA1/2-meth (NCT03205761). Methods: We included aTNBC pretreated pts (≥1 line) with centrally confirmed somatic BRCA1/2-meth (in most recent lesion(s) available) and no g BRCA1/2m. O 300mg b.i.d. was administered. BRCA1/2 CpG island was considered methylated if value was ≥25%. Overall response rate (ORR) (complete response [CR] + partial response [PR]) according to RECIST 1.1) was the primary objective. Thirty-one evaluable pts were required based on an optimal 2-stage Simon’s design (α error=0.05, 1-β error=80%), estimating an ORR increase of 24%, with a null hypothesis of 30%. Whole exome/transcriptome and 105-genes NGS assays (Tempus xE & xF) were performed on pretreatment tumor and sequential ctDNA of a long-term responder. Results: Eleven pts received ≥1 cycle of O (ITT population). Median age was 51 years (37-64), and 8 pts were postmenopausal. All M0 pts at diagnosis had neo-/adjuvant chemotherapy (CT). Median O exposure duration was 8 (1-88) weeks and relative dose-intensity was 97% (76-100), with any dose modifications in 6 pts. ORR was 9% (1 PR/11; 95% CI, 0.2-41). Clinical benefit rate (CR + PR + stable disease of any duration) was 36% (4/11; 95% CI, 11-69). Most pts (n=9) discontinued O due to BC progression. Median PFS was 2 months (95% CI, 1-4), and median OS was 9 months (95% CI, 1-14). One pt with confirmed PR was on O for >20 months. AEs were reported in 3 pts in line with O safety profile. No AE led to O discontinuation and no SAEs were reported. The statistical assumptions for the 1st Simon’s model stage were not met (≥ 4/12 pts with CR or PR), so the recruitment did not proceed onto the 2nd stage. Preliminary NGS analysis on the long-term responder identified alterations on tumor (TP53, BCL11A, MYC) and on-treatment ctDNA (PMS2). Conclusions: In this proof-of-concept study, O did not show clinically nor statistically significant antitumor activity in pretreated aTNBC pts with BRCA1/2-meth . Clinical trial information: NCT03205761 . [Table: see text]
Efficacy of oral selective estrogen receptor degraders (SERD)s in the treatment of estrogen receptor positive (ER+), HER2-negative metastatic breast cancer (MBC): A stratified analysis of the ESR1 wild type (wt) and mutant (mt) subgroups.
Authors: Zhao Joseph J , Wong Zhun Hong Nicky , Yap Dominic Wei Ting , Ong Rebecca Jia Min , Sundar Raghav , Lim Joline Si Jing , Dawood Shaheenah S.
Published: June 2023

1096

Background: Oral SERDs are a novel drug class developed to counteract endocrine resistance due to ESR1 mutations. Several SERDs have emerged from phase 2 and 3 trials, and the FDA has most recently limited approval for Elacestrant to patients with ESR1mt tumours despite PFS benefit in the overall population. Questions remain on whether patients with ESR1wt tumours stand to benefit from SERDs. We conducted an IPD meta-analysis of the trials EMERALD, SERENA2, ACELERA and AMEERA3 to compare survival outcomes of SERDs in the 2nd or 3rd line setting against endocrine therapy (ET), using KMSubtraction to unveil HRs of unreported ESR1wt subgroups from AMEERA3 and EMERALD. Meta-analysis results were stratified by ESR1 status. Methods: RCTs investigating the efficacy of novel SERDs versus ET for ER+, HER2- MBC, and which reported the Kaplan Meier (KM) plots of progression free survival (PFS) were selected after a systematic search of Embase and PubMed from inception until January 21,2023. A graphical reconstructive algorithm was applied to estimate time-to-event outcomes from reported KM plots in all overall and reported subgroup cohorts, deriving IPD. A bipartite matching algorithm, KMSubtraction was used to subtract patients in the reported subgroup from the overall cohort, to derive survival data for unreported ESR1wt subgroups. An IPD meta-analysis was then performed, pooling data by ESR1 mutation. Results: A total of 1216 patients were included in this analysis. In the pooled analysis of the overall cohort, PFS benefit was observed with SERDs compared to treatment of physician's choice (TPC) (HR 0.787, 95%CI 0.683-0.908, p<0.001). In the ESR1mt subgroup SERDs demonstrated improved PFS (HR 0.557, 95%CI 0.440-0.705, p<0.001) compared with TPC. In the ESR1wt subgroup, SERDs demonstrated no significant PFS benefit (HR 0.948, 95%CI 0.790-1.137, p=0.565) when compared to TPC. KMSubtraction was implemented on AMEERA3 to reveal survival data in ESR1wt subgroup. Amcenestrant revealed no significant PFS difference in the ESR1wt population (HR 1.197, 95% CI 0.857-1.670, p=0.291) when compared to ET. Additionally, a separate analysis of EMERALD was performed using KMSubtraction to derive survival data of the ESR1wt subgroup comparing Elacestrant vs Fulvestrant. No significant PFS difference was observed between the 2 agents in the ESR1wt population (HR 0.832, 95% CI 0.587-1.178, p=0.299). Conclusions: Our results suggest that PFS benefit in the overall population is mainly driven by the ESR1mt subgroup. These findings are in line with the recent FDA approval of Elacestrant for patients with ESR1mt tumours. [Table: see text]
Phase II study of trifluridine/tipiracil (FTD/TPI) in HER2-negative metastatic breast cancers with or without prior exposure to fluoropyrimidines.
Authors: Lim Joline Si Jing , Ow Samuel Guan Wei , Wong Andrea , Lee Matilda , Chan Gloria HJ , Low Jia Li , Sundar Raghav , Choo Joan RE , Tai Bee Choo , Lee Soo-Chin
Published: June 2023

1099

Background: Fluoropyrimidines are commonly used in the treatment of patients (pts) with metastatic breast cancers (MBC). FTD/TPI is an oral drug combination of trifluridine with tipiracil, a thymidine phosphorylase inhibitor preventing rapid degradation of trifluridine, thus allowing for increased exposure to active agent, and has showed activity in pts with colorectal and gastric cancers despite prior exposure to fluoropyrimidines. We investigate the role of FTD/TPI in MBC pts with (Cohort A) or without (Cohort B) prior exposure to fluoropyridines in a single arm phase II study. Methods: Pts were treated with FTD/TPI, and enrolled first into a lead-in dose confirmation phase, followed by two parallel cohorts based on prior exposure to fluoropyrimidines. Primary objectives for each cohort included determination of progression-free survivals (PFS), and secondary objectives included determination of objective response rates (ORR), safety and tolerability. Results: A total of 74 pts were recruited (42 for Cohort A, 32 for Cohort B), of whom 4 belonged to lead-in phase. Dosing was confirmed at FTD/TPI 35mg/m2 days 1-5 and 8-12 of 4-weekly cycles based on lead-in phase with no dose-limiting toxicities observed, and recruitment then proceeded in 2 parallel cohorts. All pts were evaluable for toxicity and survival analyses, and 72 were evaluable for ORR. Median age at enrolment was 62 years (range 32-85), with median of 4 (range 0-14) prior lines therapy in the metastatic setting, and 47% had de novo metastatic disease. Median PFS was 5.7 months (95% CI 3.8 to 8.3) and 9.4 months (95% CI 5.5 to 14.0) respectively in Cohorts A and B. Similar response rates were observed regardless of prior exposure to fluoropyrimidine, with ORR of 19.5% (95% CI 8.8 to 34.9) and 16.1% (95% CI 5.5 to 33.7) in Cohorts A and B, with 6-month clinical benefit rates of 56.1% (95% CI 39.7 to 71.5) and 61.3% (95% CI 42.2 to 78.2) respectively. Safety profile was consistent with known toxicities of FTD/TPI, with most common treatment-related adverse events of neutropenia, fatigue, nausea and anorexia. 64% of pts required dose modifications during study treatment, most commonly due to neutropenia, that could be overcome by dose reduction or prolongation from 4- to 5-weekly cycles. Only 1 pt required discontinuation due to toxicity from therapy. Conclusions: FTD/TPI showed promising anti-tumor activity with meaningful clinical benefit even among pts with prior exposure to fluoropyrimidines, and has a reasonable toxicity profile with appropriate dose modification. An oral chemotherapy option with good disease control provides an attractive treatment alternative to pts with MBC where quality of life is paramount, warranting further investigation in randomised studies. Clinical trial information: NCT04280536 .
Differential burnout by race, sex, and sexual orientation in academic oncology.
Authors: Odei Bismarck , Velazquez Manana Ana I. , Pandya Sankalp , Dandar Valerie M , Suneja Gita , Chino Fumiko
Published: June 2023

11000

Background: Burnout is a concern in medicine with negative effects on physician wellbeing, workforce retention, and patient outcomes. Research has shown that rising burnout can lead to medical errors, lower patient satisfaction, and decreased professional work effort. The presence of burnout in oncology is well documented, however it is unclear if burnout affects all groups equally in academic oncology. Methods: We obtained national faculty data from the Association of American Medical Colleges StandPoint Faculty Engagement Survey, conducted 2017-2020 (overall response rate 64%). Burnout was considered any response endorsing at least “one or more symptoms of burnout”. Self-reported workplace culture was assessed for key factors: collegiality, diversity, faculty wellness, and recruitment/retention of underrepresented in medicine (UiM) faculty. Faculty demographics included age, sex, race/ethnicity, sexual orientation (heterosexual, bisexual, lesbian/gay), rank, degree, and any department or institutional leadership role. Multivariate analysis (MVA) identified factors associated with faculty burnout. Results: A total of 724 academic oncologists were identified. Most were male (58%) and identified as heterosexual (95%). Race/ethnicity were mostly White (65%), with 29% Asian, 2% Black, and 3% Hispanic/Latino; 7% were considered UiM. Most (53%) were senior faculty; 37% had a leadership role. Overall, 22% reported burnout. Self-identified lesbian/gay/bisexual faculty had the highest rate of burnout (43% vs 21%, p = 0.0005) followed by female faculty (31% vs 16% men, p = < 0.0001). Asian faculty had the lowest burnout rates (12%) followed by White and Hispanic (both 26%), Black (33%), and multi-racial physicians (50%, p = 0.003 for comparisons). Pooled UiM had numerically higher burnout but this was not statistically significant (30% vs 22%, p = NS). On MVA, lesbian/gay/bisexual (OR = 3.56, 95%CI 1.55-8.18, p = 0.003) and female (OR = 2.32, 95%CI 1.51-3.56, p < 0.0001) faculty had increased odds of burnout. Most agreed that their institution cultivates collegiality (80%), diversity (73%), and faculty wellness (53%); men were more likely to endorse positive diversity (77% vs 68% women, p = 0.004). Most agreed their institution was successful in recruiting (63%) and retaining (58%) UiM faculty, however non-UiM were more likely to agree with this for recruitment (64% vs 46% UiM, p = 0.01) and retention (50% vs 42% UiM, p = 0.01). Conclusions: Nearly 1 in 4 oncologists report burnout with self-identified female and lesbian/gay/bisexual faculty at the highest risk. Additionally, in general, men and non-UiM faculty were more likely to feel their workplace culture was favorable. Urgent and tailored interventions at the institutional and departmental level will be critical to address both drivers of faculty burnout and the impact of burnout on attrition and career trajectory for marginalized and minoritized groups.