bluuebunny/crossref_metadata_2025 huggingface dataset:
Geographical impact on prostate cancer genetic testing eligibility: A preliminary study from an academic cancer center.
Authors: Beck Samantha , Tward Jonathan David , Gammon Amanda , Greenberg Samantha
Published: June 2023

10618

Background: Germline testing (GT) for prostate cancer (PCa) helps to determine treatment selection and other cancer risk, which guides screening recommendations. Patients with PCa that is high risk group by NCCN and greater stage should receive genetic counseling (GC) referral. There is limited data on differences in genetic services given the rurality of PCa patients. This study aims to determine the geographical distribution of PCa patients meeting GC referral and GT criteria. Methods: A retrospective analysis evaluated data from electronic medical records of PCa patients at an NCI-designated cancer research facility. Data was abstracted from new PCa patients seen in 2019 and 2021, years before and after the COVID-19 pandemic. Data includes demographic information, cancer staging, and pathology results. Regions of urbanicity, urban and non-urban (rural/frontier), were categorized through zip codes and defined by Utah Department of Health and Human Services. Criteria for GT followed NCCN guidelines (v.1.2023). Statistical methods for descriptive and comparative analysis done using Chisquare, Fisher’s exact, and Mann Whitney tests in R*Stats to compare 2019 and 2021 cohorts. Results: Out of 525 PCa patients' initial treatment at HCI in 2019 (n = 346) and 2021, (n = 179) 94% self-reported as White (p = 0.164) with a median age of 66 (p = 0.690) and 51% being employed (p = 0.396) at time of first treatment. Of these, 414 (79%) were from an urban area and 111 (21%) from a non-urban area (p = 0.883). The cohort was primarily from 2019 (66%), with 274 (79%) and 72 (21%) of the PCa patients living in urban and non-urban areas, respectively. In 2021 (34%), 140 (78%) and 39 (35%) patients were from urban and non-urban areas. Criteria for GT were met in 37% (n = 196) of PCa patients (p = 0.595). Regions were independently compared by race, age, employment, and year. No statistical difference across all variables was found (p > 0.05). Geographical regions did not impact GT eligibility. Conclusions: This preliminary study shows that geographical region does not impact GT eligibility in PCa patients seen at HCI during 2019 and 2021. The years analyzed is a proxy for differences in aggressiveness by rurality. The results show 37% of the PCa patients met criteria for GT. No significant differences were identified by geographical region, race, age, employment, or the year of initial treatment. Further research is being conducted to determine if access to PCa GC uptake is impacted by geography and differing service delivery models after criteria for GT has been met.
Endocrine therapy resistance (ETR) in hormone receptor-positive, HER2-negative metastatic breast cancer (HR+, HER2– mBC): Prevalence, biomarker characteristics, and outcomes.
Authors: Jeselsohn Rinath , Chen Lu , Chaudhary Nayan , Martinalbo Jorge , Fasching Peter A. , Hafner Marc , Luhn Patricia , Montero Alberto J. , Pérez-Moreno Pablo Diego , Wander Seth Andrew , Kalinsky Kevin
Published: June 2023

1062

Background: ETR to prior adjuvant ET poses challenges to first-line treatment (1L tx) of HR+, HER2– mBC. Understanding patient (pt)/disease heterogeneity is crucial for developing new txs that target specific ETR mechanisms to improve pt outcomes. We investigate ETR, including prevalence, genomic profiles, and survival outcomes in pts with HR+, HER2– mBC treated in the 1L setting. Methods: This retrospective two-cohort study of pts initiating 1L systemic tx for mBC (diagnosed after Jan 1, 2015) used data from the Flatiron Health (FH) electronic health record-derived de-identified database (FH cohort), and FH-Foundation Medicine, Inc. (FMI) clinico-genomic database (CGDB cohort; solid biopsy FMI test required). The de-identified data originated from ~280 US cancer clinics (~800 sites of care). Pts with ETR to prior adjuvant ET were defined per ESMO guidelines (table footnote); primary ETR (1ETR) was divided into pts relapsing within 1 year (yr) or 1–2 yrs of adjuvant ET. Genomic profiles were assessed in the CGDB cohort. In both cohorts, real-world (rw) progression-free survival (PFS) and overall survival (OS) were estimated in pts who received 1L tx with fulvestrant (F) + CDK4/6 inhibitor (CDK4/6i). Results: In the FH cohort (N = 4052), 16.1% of pts had 1ETR (ET <1 yr: 7.9%) and 33.9% had secondary ETR (2ETR). In the CGDB cohort (N = 696), ESR1 mutations (ESR1m) were present in 10.8% of 158 pts with 1ETR (ET <1 yr: 4.2%; 1–2 yrs: 16.1%) and 19.9% of 317 pts with 2ETR. In pts who received 1L F + CDK4/6i, shorter median (m) rwPFS (statistically significant) and OS (not significant) were seen in pts with 1ETR vs. 2ETR, but outcomes were not affected by the presence of ESR1m in pts with 2ETR. Conclusions: Overall, half of pts with 1L HR+, HER2– mBC have ETR to prior adjuvant ET. Pts with ETR have tumors with heterogeneous genomic profiles and varied survival outcomes. ESR1m are infrequent in pts with 1ETR and <1 yr of adjuvant ET but are more common in 2ETR. In pts treated with 1L F + CDK4/6i, PFS and OS were worse with 1ETR than 2ETR. This study highlights the importance of further understanding the heterogeneity in molecular profiles and outcomes within ETR. [Table: see text]
Risk of death among lung cancer patients before and during the COVID-19 pandemic.
Authors: Lee Teddy Tai Loy , Zheng Danyang , Wang Sichao , Wai Abraham Ka Chung , Kong Feng-Ming Spring
Published: June 2023

10625

Background: The survival of lung cancer patients in Hong Kong before and during the COVID-19 pandemic is poorly understood. Methods: Patients diagnosed with lung cancer from January 1 2010 to October 31 2022 were recruited from all 43 public hospitals in Hong Kong. Patients who died on the day of cancer diagnosis were excluded. Patients between 2020-2022 (pandemic) were matched with patients diagnosed between 2010-2019 (pre-pandemic) using 1:1 propensity score matching, based on demographics and comorbidities such as age, sex, and Charlson Comorbidity Index (CCI), to study survival before and during the pandemic. The outcomes were 1-year and 6-month all-cause mortality. In subgroup analysis, patients were categorized into 12 groups, from 2010 to 2022, based on the year of first diagnosis of lung cancer to investigate yearly changes in mortality. Patients with confirmed diagnosis of COVID-19 infection were also analyzed. Results: A total of 42102 lung cancer patients (66.0% male, age 72±12 years (median±SD), CCI 7.00±2.42) were recruited from 2010 to 2021 with 1-year follow up. Only 36 patients were confirmed COVID-19 positive. The matched cohort consisted of 4958 pandemic patients (68.6% male, age 72±12 years, CCI 8.00±2.43) and 4958 pre-pandemic patients (67.7% male, age 73±12 years, CCI 7.53±2.48). 2782 (56.1%) and 3846 (77.6%) pandemic patients died within 6 months and 1 year respectively, compared to 2338 (47.2%) and 3194 (64.4%) pre-pandemic patients. In subgroup analysis by year of lung cancer diagnosis, patients diagnosed in 2021 had highest risk of 1-year mortality (85.1%). There was no significant difference in mortality between patients with and without confirmed COVID-19 positivity. The cohort of 2022 lung cancer patients, with higher COVID-19 positivity, was still undergoing follow-up and will be included in the analysis at the time of presentation. Conclusions: Lung patients diagnosed during the COVID-19 pandemic are associated with higher risk of death within the first year compared to that of pre-pandemic patients, and is likely not associated with COVID-19 positivity. [Table: see text]
Inverse association of post-transplant malignancy and graft failure on survival outcome following double lung transplantation.
Authors: Lee Jeeyeon , Kim Hye Sung , Lee Yunjoo , Chung Liam Il-Young , Yang Won Jun , Yu Jisang , Bharat Ankit , Chae Young Kwang
Published: June 2023

10629

Background: Graft failure (GF) and post-transplant malignancy (PTM) are common causes of death in lung transplantation. Immunosuppression to prevent graft failure is known to lead to de novo malignancies after solid organ transplantation. Here, we assess the relationship between graft failure and de novo malignancies after double lung transplantation (DLT). Methods: Data extracted from the Organ Procurement Transplantation Network (OPTN) registry were analyzed. DLT cases for non-cancerous diseases were selected. We evaluated the overall survival (OS) of recipients with or without PTM (PTM+ or PTM-), and that of recipients with or without GF (GF+ or GF-) after DLT. The association between GF and PTM was investigated. Results: Among 23,935 DLT recipients, there were 5,629 cases (23.5%) of PTM+ and 18,306 cases (76.5%) of PTM -, and 2,316 cases (9.7%) of GF+ and 21,619 cases (90.3%) of GF- following DLT. Among GF+ cases, the prevalence of acute, hyperacute, and chronic rejection after DLT was 1,962 cases (84.7%). The OS in recipients with GF+ was worse than that in recipients with GF- (p < 0.001). However, inversely, the OS in recipients with PTM+ was better than that of recipients with PTM- (p < 0.001). When patients were categorized into four categories by each factor (GF-, GF+, PTM+, PTM-), the GF rate was lower in recipients with PTM+ than in those with PTM- [GF+/PTM+ (n = 368, 1.5%) versus GF+/PTM- (n = 1,948, 8.1%)] (p < 0.001), and the PTM+ rate was higher in recipients with GF- than in those with GF+ [GF-/PTM+ (n = 5,261, 22.0%) versus GF+/PTM+ (n = 368, 1.5%)] (p < 0.001). And the GF-/PTM+ group showed the best prognosis with 97.3 months of median OS, and the GF+/PTM- group showed the worst prognosis with 36.8 months of median OS (p < 0.001). Conclusions: Recipients who developed PTM following DLT had longer OS compared with those who did not. And the GF rate was significantly lower in recipients with PTM compared to those without PTM. Further research is needed to investigate the underlying mechanism of the inverse association between PTM and GF in DLT recipients.
Outcomes with first-line (1L) ribociclib (RIB) + endocrine therapy (ET) vs physician’s choice combination chemotherapy (combo CT) by age in pre/perimenopausal patients (pts) with aggressive HR+/HER2− advanced breast cancer (ABC): A subgroup analysis of the RIGHT Choice trial.
Authors: El Saghir Nagi S. , Yap Yoon Sim , Eralp Yesim , Im Seock-Ah , Azim Hamdy A. , Rihani Julie , Volkov Nikita , Chen Shin-Cheh , Harputluoglu Hakan , Sunpaweravong Patrapim , Chang Yuan-Ching , Delgar Alfaro Teresa , Wu Jiwen , Hu Huilin , Gao Ming , Lu Yen-Shen
Published: June 2023

1063

Background: The progression-free survival (PFS; primary endpoint) results from the Phase II RIGHT Choice trial demonstrated a statistically significant median PFS (mPFS) benefit of ≈1 y with RIB + ET over combo CT (mPFS, 24.0 vs 12.3 mo; hazard ratio [HR], 0.54; 95% CI, 0.36-0.79; P = .0007) in pts with aggressive HR+/HER2− ABC. Younger pts with aggressive ABC have a worse prognosis, which impacts treatment (tx) decisions. Hence, a subgroup analysis of key efficacy endpoints from RIGHT Choice by age (< 40 vs ≥ 40 y) was undertaken. Methods: Pre/perimenopausal pts (aged 18-59 y) with HR+/HER2− ABC and no prior systemic therapy for ABC were randomized 1:1 to either RIB with letrozole/anastrozole + goserelin or investigator’s choice of combo CT (docetaxel + capecitabine, paclitaxel + gemcitabine, or capecitabine + vinorelbine). Pts in the trial had ABC not amenable to curative therapy and for which combo CT was clinically indicated by physician’s judgment (ie, symptomatic visceral metastases, rapid progression of disease or impending visceral compromise, or markedly symptomatic non-visceral disease). Results: In total, 70 pts were aged < 40 y and 152 were aged ≥ 40 y. In the combo CT arm, pts aged < 40 y fared worse and had a shorter mPFS, shorter median time to tx failure (mTTF), and higher 3-month tx failure rate (TFR) than pts aged ≥ 40 y. Pts aged < 40 y showed a significant PFS benefit with RIB + ET vs combo CT (mPFS, not reached [NR] vs 10.2 mo; HR, 0.38). This PFS benefit with RIB + ET over combo CT was also observed in pts aged ≥ 40 y (21.2 vs 16.0 mo; HR, 0.71). Regardless of age, the mTTF was longer and the 3-month TFR was lower in the RIB + ET arm than the combo CT arm. The median time to response (mTTR), overall response rate (ORR), and clinical benefit rate (CBR) were similar between the two tx arms in both age groups. Conclusions: This analysis demonstrated a clinically meaningful PFS benefit and improved secondary outcomes with 1L RIB + ET over combo CT along with similar treatment responses in both tx arms in pts aged < 40 y as well as in those ≥ 40 y with aggressive HR+/HER2− ABC. This analysis supports RIB + ET as a preferred tx option in this pt population, including younger pts aged < 40 y. Clinical trial information: NCT03839823 . [Table: see text]
Prevalence of pathogenic germline variants in a cohort of patients with early onset non-small cell lung cancer (EOLUNG).
Authors: Jove Maria , Gausachs Mireia , Bosch-Barrera Joaquim , Carcereny Enric , Teulé Alex , Mosteiro Miguel , Pineda Marta , Tornero Eva , Hijazo-Pechero Sara , Ruffinelli Jose Carlos , Brenes Jesús , Hernandez Alejandro I. , Fina Claudia , Sais Elia , Brunet Joan , Doménech Marta , Saigi Maria , Moran Teresa , Lazaro Conxi , Nadal Ernest
Published: June 2023

10630

Background: Patients with early onset lung cancer might be more likely to carry pathogenic (or likely-pathogenic) germline variants (PGV) in genes associated with cancer predisposition. However, germline testing is not recommended in this population. We designed this study to determine the prevalence of PGVs in patients with early onset lung cancer. Methods: This prospective, multicenter cohort study assessed PGV in patients younger than 51 years diagnosed with non-small cell lung cancer (NSCLC) in 3 sites at the Catalan Institute of Oncology between June 2018 to May 2022. Genomic DNA was sequenced using a custom-designed NGS panel covering 164 cancer-predisposing genes and results were discussed in a multidisciplinary tumor board. Results: 138 patients were included. Median age was 45.5 (28-50) years; 49% were females; 79% were ever-smokers with a median packs-year of 24 and median age of tobacco initiation of 16 years old. Most patients had non-squamous histology (88%) and had stage IV (62%) at diagnosis. Somatic oncogenic drivers were found in 74 patients (54%): EGFR 27 (20%); ALK 22 (16%); KRAS 20 (14%); RET 3 (2%); ROS1 1 (1%); BRAF V600E 1 (1%). Only 4% had past personal history of cancer and 50% had family history of cancer in a first-degree relative, being lung and breast cancer the most common tumors. Overall, 20 patients (14%) carried PGVs involving 12 genes associated with cancer predisposition: PARK2 (n=4); SBDS (n=3); NBN (n=2); ATM (n=2); TSC1 (n=2) and BLM, FANCA, MCPH1, PMS2, POLH, SDHA, RECQL4 (n=1, each). Four patients (3%) fulfilled criteria to be referred to genetic counseling clinic. There were no significant differences in clinical and molecular characteristics among patients with PGVs compared to their counterparts (Table). Conclusions: In this prospective cohort, 14% of patients with early onset NSCLC harbored germline PGVs. As clinicopathological and genomic features were not associated with PGVs, germline testing might be considered in addition to comprehensive genomic characterization of tumor tissue in young patients with NSCLC. However, only a minority of PGVs were deemed clinically actionable.[Table: see text]
Correlation of unobserved incidence of cancer in earlier stages with the observed incidence.
Authors: Chhatwal Jagpreet , ElHabr Andrew , Tyson Christopher , Merdan Selin , Cao Xiting , Raoof Sana , Ozbay A. Burak , Fendrick A. Mark , Limburg Paul J. , Beer Tomasz M. , Deshmukh Ashish
Published: June 2023

10634

Background: Population-level cancer registries report observed (screening or clinically detected) incident cancer cases. However, the underlying true cancer incidence may be higher than observed. We estimate the unobserved cancer incidence by stage for eight different cancers. Methods: Using the CDC’s National Program of Cancer Registries (NPCR) and the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) combined incidence databases, we first estimated observed incidence rates by cancer type and stage. Newly observed cancers in later stages must have existed at a previous point in time at an earlier stage (and age). Considering that, we used backward induction approach to estimate the unobserved incidence rate of cancer. We also accounted for mortality from competing factors before cancer was detected. Cancer progression between stages was defined by dwell times, which were synthesized in an ensemble approach from published literature and empirical estimates. We estimated unobserved annual incidence cases in early-stage (stages I and II) for the age 50+ population and compared them with observed incidence cases for each cancer type between 2015-2019. Results: The below table shows the annual unobserved and total (unobserved plus observed) cancer incidence by stage for the eight most prevalent cancers. We estimated that the top three cancers with the highest proportion of unobserved early-stage annual incident cases were lung (157,400 cancers unobserved out of 226,400 total), with 70% unobserved; pancreatic (34,700 annual unobserved out of 52,500 total), with 66% unobserved, and non-Hodgkin’s lymphoma (46,400 unobserved out of 73,600 total), with 78% unobserved. In contrast, the cancers with the lowest proportion of unobserved early-stage incident cases were breast (29,100/203,400 [14%]), urinary bladder (27,000/81,800 [33%]), and prostate (110,600/258,900 [43%]). Cancers with a high screening rate have lower unobserved early stage incidence than cancers with a low screening rate or without a screening test. Conclusions: We estimated a large undiagnosed incidence of cancer in early stages. This represents an opportunity for novel early detection technologies to detect cancer in earlier stages. [Table: see text]
Efficacy analysis of CDK4/6 inhibitors (CDKi) + endocrine therapy (ET) treatment in hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer (aBC): Biomarker analysis including chemoendocrine score (CES) by CDKi type in SOLTI-1801_CDK-PREDICT study.
Authors: Tolosa Ortega Pablo , Pascual Tomás , Hernando Cristina , Servitja Sonia , Fernández-Abad María , Brasó-Maristany Fara , Benitez Fuentes Javier David , Lema Laura , Parrilla Rubio Lucia , Ruano Yolanda , Roncero Ana María , Sanchez-Bayona Rodrigo , Alva Bianchi Manuel , Villacampa Guillermo , Cobos-Fernández María Ángeles , Moreno María del Rocío , Canes Jordi , Salvador Fernando , Prat Aleix , Ciruelos Eva M
Published: June 2023

1065

Background: CDKi + ET improved progression-free survival (PFS) and ribociclib also overall survival (OS) in HR+/HER2- aBC first-line setting. Intrinsic subtypes (IS) are prognostic and predict benefit from CDKi + ET (Finn. SABCS 2017, Prat. JCO 2021, Tolosa. SABCS 2022). We previously reported a PAM50-based CES in HR+/HER2-negative early BC (Prat et al. CCR 2016). Here, we evaluated the association of CES with PFS following CDKi therapy in aBC. Methods: CDK-PREDICT prospectively evaluated 113 HR+/HER2- aBC patients (pts) treated in the first-line setting with CDKi + ET. RNA from FFPE metastatic tumors was analyzed at the nCounter (Nanostring Technologies) using a 72 custom gene panel including the PAM50 genes. CES was evaluated as a continuous variable, and categorically (CES-E[endocrine-sensitive], CES-I[intermediate] and CES-C[chemo-sensitive]) using the previously reported cut-offs. Multivariable analyses were used to test CES association with PFS. Results: The median follow-up for PFS was 18.5 m. PAM50 IS and CES distribution are shown. No statistically significant difference in mPFS by CDKi. CES (as a continuous variable or as group categories) was found significantly associated with mPFS. mPFS for CES-E pts was NR (95% CI: 26.0 - NR), 20.7m for CES-I (95% CI: 14.2 – 31.7m; HR= 1.98, p<0.05) and 11.7m for CES-C (CI 95%: 7.0 - 18.8; HR= 3.72, p<0.05). CES-C was associated with lower PFS compared to CES-I (aHR= 0.55, p=0.10) and CES-E (aHR= 0.29, p<0.05) independent of CDKi, ET, intrinsic subtype (Luminal versus not), endocrine sensitivity, onset metastatic and visceral disease. CES-C was significantly associated with higher expression of, MIA and lower expression of CCND1, CCNE1, FOXA1, MLPH and UBE2T compared with CES-E (p< 0.05). In CES-E pts mPFS for palbociclib was NR (IC95:22.9-NR) compare with 43.8 m for ribociclib (IC95: 12.0-NR); aHR=1.17 p=0.546), in CES-I pts mPFS for palbociclib was 18.9 m (IC95: 5.8-27.3) compare with 31.7 m for ribociclib (IC95: 12.2-NR); aHR=0.50 p=0.294), and in CES-C pts mPFS for palbociclib was 11.6 m (CI95: 2.7-15-7) compare with 10.0 m for ribociclib (CI95: 2.1-NR; aHR=0.48 p=0.102). Abemaciclib not reported due to low numbers (n=16). Conclusions: We confirmed independent prognostic value of CES in first-line setting, suggesting a not statistically significant benefit with ribociclib vs palbociclib in CES-I. [Table: see text]
Capivasertib (C) and fulvestrant (F) for patients (pts) with aromatase inhibitor (AI)-resistant HR+/HER2– advanced breast cancer (ABC): Characterization and management of common adverse events (AEs) from the phase 3 CAPItello-291 trial.
Authors: Rugo Hope S. , Oliveira Mafalda , Howell Sacha Jon , Dalenc Florence , Cortes Javier , Gomez Henry Leonidas , Hu Xichun , Iwata Hiroji , Jhaveri Komal L. , Loibl Sibylle , Morales Murillo Serafin , Okera Meena , Park Yeon Hee , Sohn Joohyuk , Zhukova Lyudmila , Logan Jill , Twomey Ken , Khatun Mahmuda , D'Cruz Celina M. , Turner Nicholas C.
Published: June 2023

1067

Background: In the CAPItello-291 trial in eligible pts with AI-resistant HR+/HER2– ABC, the addition of C (a potent, selective pan-AKT inhibitor) to F significantly improved PFS (primary endpoint) compared with placebo (P) in the overall (HR 0.60; 95% CI 0.51–0.71; p<0.001) and AKT pathway-altered population (HR 0.50; 95% CI 0.38–0.65; p<0.001). We report a detailed analysis of AEs. Methods: Pts were randomized 1:1 to receive F (500 mg IM on days 1 and 15 of cycle 1, and day 1 of each subsequent 28-day cycle) with either P or C (400 mg BID; 4 days on, 3 days off). Pts with HbA1c <8.0% and diabetes not requiring insulin were eligible. Incidence, management, and time to onset were summarized for common AEs (>10% any grade and >2.0% grade ≥3; CTCAE v5.0). Results: Overall, 708 pts were randomized to C+F (n=355) vs P+F (n=353); safety population C+F (n=355) vs P+F (n=350). Baseline risk factors potentially associated with hyperglycemia were a history of diabetes in 34 pts (10%) in the C+F arm vs 20 pts (6%) in the P+F arm (baseline median [range] HbA1c 5.4% [4.0–8.3] vs 5.4% [3.9–7.7]), median weight 65.0 kg (34–150) vs 66.5 kg (37–147) and 54% vs 53% of pts overweight/obese in the C+F vs P+F arms, respectively. Common AEs were diarrhea, rash, and hyperglycemia; maximum AE grade was mostly 1/2 and led to low rates of discontinuation. In the C+F arm, medications for the management of AEs were used in 151/257 pts (59%) with diarrhea (mostly loperamide; n=135), 109/135 pts (81%) with rash (mostly antihistamines; n=75/topical corticosteroids; n=64), and 28/60 pts (47%) with hyperglycemia (mostly metformin; n=18). Conclusions: Diarrhea, rash, and hyperglycemia, the most commonly reported AEs associated with AKT pathway inhibition, occur early in treatment with C+F, are generally low grade and manageable, and are associated with low rates of dose modifications/discontinuations. Clinical trial information: NCT04305496 . [Table: see text]
Relation between circulating biomarkers at diagnosis of early luminal-like breast cancer and subsequent risk of distant metastases.
Authors: Lambrechts Yentl , Garg Abhishek , Floris Giuseppe , Punie Kevin , Neven Patrick , Nevelsteen Ines , Govaerts Jannes , Richard François , Laenen Annouschka , Desmedt Christine , Wildiers Hans , Hatse Sigrid
Published: June 2023

1077

Background: Predicting development of distant metastases after treatment of early luminal breast cancer (BC) remains a major challenge. Besides clinical-pathological features of the primary tumor, baseline circulating factors could also play a role as prognostic biomarkers. Methods: Patients with newly diagnosed early BC (grade 2/3, ER+, HER2-non- amplified) were selected from our institutional BC registry, with associated blood biobank collecting baseline plasma/serum samples at diagnosis. Circulating biomarkers potentially modulating the metastatic process (chemokines, micro-RNAs (miRNAs), Leukemia Inhibitory Factor (LIF), and osteopontin), and serum-induced functional myeloid interferon (IFN)) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling-responses, were measured at early BC diagnosis (before any treatment) in patients who subsequently developed distant metastasis within five years after diagnosis and therapy (META group) and in a 1:1 control group of patients, pairwise matched for age, tumor grade, stage, and histological subtype, who remained disease-free for at least seven years (NON-META group). All blood biomarkers were analyzed pair-wisely using the univariable Wilcoxon signed rank test (two-tailed). Multiple testing correction was done by applying a false discovery rate (FDR) of 0.05. In addition, a multivariable logistic regression analysis (MVA) was performed to find blood biomarkers signatures that can predict the development of metastases at first diagnosis of early BC. Results: 102 matched patient pairs were included. Univariable paired analysis showed significantly increased baseline expression of LIF (p=0.012) and six miRNAs (miR-143-3p: p=0.015; miR-197-3: p:<0.001; miR-223-3p: p=0.006; miR-223-5p: p=0.045; miR-338-3p: p=0.045; miR-365a-3p: p=0.025), and decreased serum-induced myeloid -IFN-responses (p=0.023) and ten miRNAs (let-7b-5p: p=0.006; miR-106a-5p: p=0.045; miR-106b-5p: p=0.015; miR-107: p=0.014; miR-144-3p: p=0.015; miR-15a-5p: p=0.045; miR-15b-3p: p=0.032; miR-185-5p: p=0.045; miR-18a-5p: p=0.015; miR-30b-5p: p=0.045) in the META group compared to the NON-META group. MVA yielded a seven-biomarker signature, which includes miR-197-3p (p=0.008), miR-139-5p (p<0.001), LIF (p=0.007), miR-106b-5p (p=0.003), serum-induced IFN/ISG response (p=0.006), miR-652-3p (p=0.015), and miR-133b (p=0.025) with a C-index of 0.79 (0.70-0.88) to predict distant metastases. After 5-fold internal cross-validation, C-index was 0.63 (0.52-0.74). Conclusions: Baseline circulating miRNAs, LIF, and serum-induced IFN-response levels at early luminal BC diagnosis are associated with subsequent distant metastases. Further external validation is required to confirm the prognostic value of these biomarkers.
Real-world (RW) outcomes of patients (pts) with advanced breast cancer (aBC) with and without resistance alterations (alts) detected in cell-free circulating tumor DNA (ctDNA) prior to CDK4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) treatment.
Authors: Wander Seth Andrew , Weipert Caroline M. , Liao Jiemin , Safonov Anton , Zhang Nicole , Bardia Aditya , Razavi Pedram
Published: June 2023

1081

Background: CDK4/6i plus ET is standard of care first-line (1L) therapy for hormone receptor positive (HR+), HER2- aBC. While molecular analyses from trials and pts have identified several mechanisms of resistance to CDK4/6i plus ET, currently, no biomarkers (outside of hormone status) are used for therapy selection. We utilized RW data to assess impact of putative baseline CDK4/6i+ET resistance alts (CDK4/6i+ET-R) on clinical outcomes among pts with aBC treated with CDK4/6i. Methods: Pts with aBC were identified via the Guardant INFORM database; those with a ctDNA test within 90 days prior to CDK4/6i start were included in this analysis. Based on previous studies, oncogenic or likely oncogenic alterations (as characterized by OncoKB) in the following genes were considered CDK4/6i+ET-R alts: RB1, PTEN, AKT1, CCNE1, ERBB2, FGFR1, FGFR2, and KRAS. Pts with >1 CDK4/6i+ET-R alt were compared to pts without any CDK4/6i-R alts. Kaplan-Meier plots, log-rank tests (LR) and multivariate Cox proportional hazards models (HR) adjusted (adj) for age, sex, year of ctDNA test and line of therapy were used to assess differences in time to next treatment (TTNT) and overall survival (OS). Results: 1075 pts with aBC treated with CDK4/6i (27% receiving 1L treatment) met inclusion criteria, 293 of whom (27%) had >1 alt in a CDK4/6i+ET-R gene. Pts with CDK4/6+ETi-R alts had significantly shorter TTNT (8.7 mos vs 14.2 mos, LR p=0.001; adj HR 1.36, 95%CI 1.11-1.66, adj p=0.003) and OS (28.3 mos vs 60.9 mos, LR p=<0.0001; adj HR 2.19, 95%CI 1.69-2.82, adj p=<0.0001) compared to those without. This divergence was more pronounced for patients receiving 1L CDK4/6i (TTNT: 10.7 mos vs 24.6 mos, LR p=0.006, adj HR 1.84, 95%CI 1.18-2.87, adj p=0.007; OS: 23.8 mos vs 67.3 mos, LR p<0.0001, adj HR 3.27, 95%CI 1.89-5.62, adj p<0.0001). Individual gene contributions towards less favorable TTNT are shown. Conclusions: We demonstrate via RW data that patients with >1 pre-treatment ctDNA alt in a curated list of CDK4/6i+ET-R genes have significantly worse outcomes on CDK4/6i plus ET treatment, a difference more pronounced among patients receiving 1L therapy. This data is among the first successful efforts to validate a clinically useful multi-gene clinical biomarker that has the potential to predict CDK4/6i plus ET resistance. Further exploration of this signature’s prognostic and predictive utility for CDK4/6i plus ET use is ongoing to better refine personalized treatment selection in HR+/HER2- aBC. [Table: see text]
Influence of chromatin remodeling molecule ARID1A on metastatic heterogeneity in triple negative breast cancer: Binding of YAP.
Authors: Wang Ye , Guo Duancheng , Tao Zhonghua , Hu Xichun
Published: June 2023

1085

Background: Heterogeneity is the prominent character of TNBC and one predominant cause of treatment failure. As a key nuclear SWI/SNF protein complex subunit, ARID1A plays a critical role in tumor identity determining by manipulating gene expression. The present study aimed to investigate whether and how ARID1A determined the metastatic heterogeneity of triple-negative breast cancer. Methods: This study retrospectively collected and analysed clinical and pathological data from 258 patients diagnosed with triple-negative breast cancer at Fudan University Cancer Hospital from August 2015 to June 2016 to define the prognostic ability of ARID1A.CRISPR/Cas9 or plasmids-mediated ARID1A were used to determine the ARID1A function in regulating the metastatic character in TNBC. Cell morphology, tumor invasion, and metastasis were analyzed in terms of ARID1A status both in vitro and in vivo experiments. The molecular mechanism of ARID1A determining metastasis potential of TNBC was explored by RNA-Seq and nuclear positioning. Results: ARID1A low expression was found to have independent prognostic value for poor OS (43.9 vs 53.6 months, P=0.0001) and RFS (31.0 vs 45.5 months, P=0.0029) in TNBC patients. Both nuclear and cytoplasmic protein analysis and Immunofluorescent localization assay confirm that ARID1A recruits the Hippo pathway effector YAP into nucleus in human triple negative breast cancer cells. Next we designed the YAP truncator plasmid and confirmed by Co-Immunoprecipitation that ARID1A could competitively bind to the WW domain of YAP to form the ARID1A/YAP complex. Furthermore, down-regulation of ARID1A promoted migration and invasion both in human triple negative breast cancer cells and xenograft model through Hippo/YAP signaling axis. Conclusions: Our study provides new insights into the previously unrecognized role of ARID1A in TNBC metastasis, which might provide new therapeutic options for patients with TNBC.
The overall survival analysis of FUTURE-C-PLUS: Combination of famitinib with camrelizumab plus nab-paclitaxel as first-line treatment for advanced, immunomodulatory triple-negative breast cancer—An open-label, single-arm, phase 2 trial.
Authors: Chen Li , Zhimin Shao , Wang Zhonghua , Yang Wentao , Jiang Yizhou , Wu Songyang , Wu Jiong , Di Genhong , Liu Guangyu , Yu Keda , Fan Lei , Li Junjie , Hou Yifeng , Hu Zhen , Chen Canming , Huang Xiaoyan , Cao Ayong , Hu Xin , Zhu Xiaoyu
Published: June 2023

1086

Background: Camrelizumab and nab-paclitaxel demonstrated promising anti-tumour activity in refractory metastatic immunomodulatory triple-negative breast cancer (TNBC) in FUTURE trial. Anti-angiogenic agents have been reported to facilitate immune infiltration. Famitinib is a tyrosine kinase inhibitor targeting VEGFR-2, PDGFR and c-kit. The FUTURE-C-PLUS trial (NCT04129996) which added famitinib to camrelizumab and nab-paclitaxel is a single-arm, phase 2 trial evaluating this novel triplet combinatorial strategy in patients with advanced immunomodulatory TNBC. Study design and the primary endpoint ORR has been reported previously (Zhi-ming Shao, et al. ASCO 2021, Abstract 1007). The final PFS data had been published in Clinical Cancer Research (Clin Cancer Res 2022;28:2807–17). Here, we reported the final overall survival of this trial. Methods: Briefly, this study enrolled women aged 18-70 years, with previously untreated, histologically confirmed, unresectable, locally advanced, recurrent or metastatic immunomodulatory TNBC. Immunomodulatory TNBC was defined as CD8 expression on at least 10% of cells using immunohistochemistry analysis. Eligible patients received the triple therapy. Results: Forty-eight patients were enrolled and treated between Oct 2019 and Oct 2020. The median follow-up was 33.1 months (range, 31.8–34.4). 39 (81.3%, 95% CI 70.2-92.3) patients had a confirmed objective response which has been reported in ASCO 2021. At this updating data cutoff (Feb 1, 2023), the median progression-free survival was 13.6 months (95% CI, 8.4-18.8). While overall survival was 29.4 months (95% CI, 23.3-35.5). The disease control rate was 95.8% (46/48). The most common treatment-related grade 3 or 4 adverse events were neutropenia (16 [33.3%]), anemia (5 [10.4%]), febrile neutropenia (5 [10.4%]), and thrombocytopenia (4 [8.3%]). No new safety concerns were detected. No treatment-related deaths were reported. Conclusions: These data, combined with those from our previous reports, provide further evidence for the triplet combination of famitinib, camrelizumab and nab-paclitaxel as an active therapy in advanced Immunomodulatory TNBC. To our knowledge, this is the best overall survival reached in first-line treatment of advanced TNBC. A randomized controlled FUTURE-Super trial is ongoing to further validate these findings. Clinical trial information: NCT04129996 .
ARID1A deficiency in triple-negative breast cancer induces adaptive immune resistance and sensitivity to immune checkpoint inhibitors.
Authors: Chen Margaret , Li Bin , Wang Ye , Hu Xichun , Tao Zhonghua
Published: June 2023

1088

Background: Adaptive immune resistance (AIR) is pivotal to triple-negative breast cancer (TNBC) progression. Although immune checkpoint inhibitors (ICIs) shed new light on reversing AIR, the treatment effect and predictive markers of immunotherapy remain controversial. The present study focused on epigenetic regulation for TNBC AIR and explored whether this could be clinically targeted. Methods: Through screening an epigenetic gene set in TNBC patients from The Cancer Genome Atlas (TCGA), ARID1A was pinpointed as most significantly correlated with AIR. Humanized immune system (HIS) mice were adopted for TNBC transplantation, identifying CD8+ T cells as most significantly correlated with TNBC ARID1A. To probe the mechanism underlying TNBC ARID1A deficiency-induced CD8+ T cell malfunction and AIR, RNA-seq of both TNBC patients and TNBC cell lines were analyzed and the candidate mediator gene, PD-L1, was identified and verified through western blot, qPCR, IHC, dual luciferase reporter assay and cell co-culture. Chromatin immunoprecipitation and ATAC-seq further demonstrated direct binding of ARID1A to NPM1 promoter to regulate PD-L1 expression. Finally, HIS mice were treated with ICI and the clinical trial CTR20191353 was retrospectively analyzed. Results: Among a series of epigenetic modulators, we first observed that ARID1A, a core subunit of the chromatin remodeling complex SWI/SNF, demonstrated highest correlation with AIR in TNBC patients. This was verified in HIS TNBC mice and a patient cohort from Fudan University Shanghai Cancer Center by higher malignancy observed in ARID1A-deficient TNBC. Both bulk and single-cell RNA-seq in TNBC patients uncovered an immunosuppressive microenvironment induced by TNBC ARID1A deficiency, and CD8+ T cells was identified as the immune cell type most significantly correlated with TNBC ARID1A. CD8+ T cell malfunction and AIR in ARID1A-deficient TNBC was induced by upregulated PD-L1, but ARID1A did not directly regulate PD-L1 expression. We found that ARID1A bound to the NPM1 promoter and that ARID1A deficiency increased NPM1 chromatin accessibility as well as gene expression, further activating PD-L1 transcription. In HIS mice, ICI demonstrated the potential to reverse TNBC ARID1A deficiency-induced AIR manifested by reducing tumor malignancy and activating antitumor immunity. In CTR20191353, a phase 1b clinical trial of pucotenlimab combined with chemotherapy for TNBC, patients with ARID1A deficiency demonstrated significantly better prognosis and the longest progression-free survival was found in ARID1A-low/PD-L1-high group. Conclusions: In AIR epigenetics, TNBC ARID1A deficiency induced AIR via the ARID1A/NPM1/PD-L1 axis, leading to poor outcome. While ARID1A deficiency provided survival advantage for TNBC cells, it simultaneously left the Achilles' heel which could be targeted with ICI.
Sociodemographic and clinicopathologic factors of triple negative breast cancer at an academic urban safety-net hospital.
Authors: Wang Judy Jiaqi , Beaulieu-Jones Brendin , Acevedo Jose , Oshry Lauren , Merrill Andrea , Cassidy Michael Ryan , Ko Naomi Yu
Published: June 2023

1090

Background: Racial disparities in breast cancer in the United States is a persistent and ongoing problem. Decades of research is derived from large population based data sets and little is published with granular detail of specific, actionable factors to target for interventions. From a large urban safety-net hospital, we evaluate sociodemographic and clinicopathologic factors on survival outcomes of triple negative breast cancer. Methods: We conducted a single-institution retrospective study of patients with invasive breast cancer, diagnosed and treated between January 2010 and December 2021 at an academic safety-net hospital where insurance systems allow for access and treatment for all patients. Demographic, tumor and treatment characteristics were obtained. Chi-square and ANOVA were used to examine associated factors among White, Black, and other races. Survival was analyzed using the Kaplan-Meier estimator and log-rank test. Significant risk factors were identified with Cox regression analysis. Results: 251 women with invasive triple negative breast cancer were diagnosed and treated during the study period. Median age was 58 years, 68.9% were non-white, and 64.9% were publicly insured or uninsured patients. Median time from diagnosis to treatment initiation was 29 days and follow up period was 1392 days. Having a non-English primary language and living in areas with lower socioeconomic indices are observed in non-White patients (P=0.003, 0.033) and predictive of a higher clinical stage at presentation (P=0.011, 0.021). Black patients were diagnosed at higher histologic grade (Black: 82.4%, White: 79.7%; P=0.003) and White patients were more likely to change facility during the treatment course (White: 32.4%, Black: 16.03%; P=0.005). No significant racial disparities were observed in time to treatment, recurrence rate, and overall survival. Among patients indicated for adjuvant therapies, including chemotherapy, immunotherapy, and radiation, rates of recommendation and completion of therapy did not vary by race. Five year survival did not significantly vary by race when adjusted for demographic and clinicopathologic factors. Conclusions: At an academic urban safety-net hospital where access to diagnostic and treatment resources are comparable across patient populations, no racial disparities were seen in treatment, recurrence, and survival outcomes. Further research on racial differences in breast cancer biology and health behaviors may improve understanding of triple negative disease or mitigate later stage diagnosis.
Preliminary results from a first-in-human study of ESG401, a trophoblast cell-surface antigen 2 (TROP2) antibody drug conjugate (ADC), in patients with locally advanced/metastatic solid tumors.
Authors: Ma Fei , Qiu Fuming , Tong Zhongsheng , Wang Jiani , Tan Yinuo , Bai Rui , Zhou Qing , Xing Xiaoyan
Published: June 2023

1100

Background: ESG401 is an innovative ADC composed of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to topoisomerase I inhibitor SN-38 via a proprietary stable-cleavable linker with DAR of 8. Methods: Patients (pts) aged ≥18 years with locally advanced/metastatic solid tumors refractory to/relapsed from standard treatment with measurable disease (RECIST v1.1) were eligible. ESG401 is administered intravenously by designated dose and regimen until unacceptable toxicity or progressive disease. The Bayesian Optimal Interval (BOIN) design was used to establish the MTD. Results: As of Feb 3, 2023, 35 pts with a median age of 53 were treated with ≥1 dose of ESG401 during escalation at doses of 2-20 mg/kg once Q3W (Regimen A), or 12-16 mg/kg D1,8,15 in a 4-week cycle (Regimen B). 80% of pts were ECOG = 1, 63% of pts were 3L+; median 4 (2-10) prior lines, 94% of pts had visceral metas (11% brain, 63% liver, 60% lung) at baseline. Only one patient treated with 20 mg/kg experienced DLT. The MTD has not reached either regimen. The most common TRAEs were leukopenia (80%), neutropenia (69%), anemia (66%), fatigue (54%), nausea (51%), and vomiting (46%). The most common ≥ Grade 3 TRAEs were leukopenia (29%) and neutropenia (31%). There was no ≥ Grade 3 thrombocytopenia, diarrhea, skin rash, or oral mucositis. No Interstitial Lung Disease (ILD) was observed. Of 33 efficacy evaluable (EE) pts, 12 partial responses (PR) were observed and 4 pts had achieved SD ≥24 wks. The first dose level found PR (16 mg/kg Q3W) and afterward were taken as therapeutically relevant doses (TRD). The ORR and DCR were 36% (4/11) and 64% (7/11) in 11 TRD pts with TNBC, while 62% (8/13) and 77% (10/13) in 13 TRD pts with HR+/HER2-BC. Two pts with brain metas both got an obvious intracranial response (one pt whose intracranial lesion was significantly reduced to too small to measure). Until the cut-off date, 11 (31%) pts remained on treatment. Three pts were treated over 12 mons and the longest on-treatment duration was 12.9 mons. One pt had consistent PR up to 10.8 mons. Conclusions: The preliminary data demonstrated that ESG401 is safe and well-tolerated with promising signals of efficacy in heavily pretreated pts. These encouraging findings warrant further clinical evaluation. Clinical trial information: NCT04892342 . [Table: see text]
The ticking “biological clock”: Reproductive assistance, costs, and elective fertility preservation in female oncologists and trainees.
Authors: MacDuffie Emily , Lee Anna , Kuczmarska-Haas Aleksandra , Dalwadi Shraddha , Gillespie Erin F. , Ludwig Michelle Suzanne , Holliday Emma , Chino Fumiko
Published: June 2023

11001

Background: Women in medicine are often in training during their peak fertility years. Many women defer childbearing until after training due to career concerns; in consequence, female physicians experience a higher rate of infertility than the general population. Experiences of infertility among female physicians and attitudes towards fertility preservation have not been well described. Methods: A novel 39 question survey was designed after comprehensive literature review to collect cross-sectional data on attitudes toward family planning and utilization of assisted reproductive technology (ART) among self-identified US female oncologists of all career levels. Descriptive statistics summarized frequencies of responses. Results: A total of 1005 responses were collected from female oncologists, of which 811 (81%) were attending/practicing physicians and 194 (19%) were trainees (192 residents/fellows and 2 medical students). 32% reported experiencing infertility. Of these 318 women, 9% reported no out-of-pocket expenses for ART while 39% spent more than $10,000 and 20% spent ≥$30,000. Side effects from infertility treatment required missing work for 22% and another 25% suffered mental health concerns related to infertility. Elective cryopreservation of eggs or embryos was reported by 6% of attendings and 4% of trainees. Among the 25 attendings who reported plans/desire to undergo fertility preservation in the future, most (76%) were unsure of feasibility. This was similarly reported in 72% of the 32 trainees with plans/desire to pursue fertility preservation. More trainees than practicing physicians (73% vs 65%) felt that fertility preservation should be discussed during medical training. Similarly, more trainees than attendings (58% vs 47%) felt that fertility concerns have a negative influence of their decision on when to start a family. While only 5% of all respondents reported using fertility preservation, an additional 6% were planning/considering using it and 21% felt that it would have benefitted them had it been available and affordable during training. Of the group that felt it would have been beneficial, 52% had experienced infertility. Conclusions: A third of surveyed female oncologists report experiencing infertility. Those that seek reproductive assistance can incur significant out of pocket costs with treatment related effects that can disrupt work or cause mental health concerns. Although fertility preservation was used by very few, one in five felt it could have been helpful to them if it was available and affordable. These results underscore the need to better support women in medicine to reduce the impact of infertility for female oncologists.