Diagnosis Of Advanced Disease Research Articles

Patterns of referral to supportive oncology (SO) practice embedded in a cancer center and impact of timing of referrals on end-of-life outcomes.

e24064 Background: ASCO guidelines recommend early palliative care (PC) for patients with advanced cancer, defined as within eight weeks of diagnosis, to enhance survival and quality of life. It is unclear which subsets of patients are referred “late” to PC and how timing of referral impacts cancer outcomes and end-of-life care. Methods: Patients >18 years with first SO consult between 01/01/2021-06/30/2023 were included. Data on patient demographics, acute healthcare and hospice utilization, cancer treatment and mortality was extracted from the electronic medical record (EMR) and claims database. Early referral to SO was defined as visit < 3 months after diagnosis of advanced disease, delayed referrals > 3 months and late consults as < 30 days from death. We used descriptive statistics to describe patients’ sociodemographics, clinical characteristics and healthcare utilization. Multinomial logistic regression analysis was utilized to evaluate how patient characteristics influenced the timing of referrals. To examine the effects of late referral on inpatient (IP) and intensive care unit (ICU) stay durations, we applied a hurdle model. Results: Total sample included 1229 patients; majority had ECOG < 2 and received one line of treatment at time of consult, 87% had solid tumors, of whom 74% had stage 4 disease. The solid tumors most referred were gastrointestinal cancers (25%), lung cancer (14%) and head and neck cancers (13%). Early referral rates across cancer groups differed significantly 53% Head and Neck, 48% GI, 46% Lung, 43% GYN, 29% GU, 11% Breast, and 31% Other (p < 0.001). The most common reason for referral was physical symptom management (98%). The median ESAS symptom burden was 5 (range 0-10) symptoms. At time of analysis, 431 (35.1%) patients had died of which 256 (59%) were in-hospital deaths. Of the deceased patients, late referral ( < 30 days from death) showed a trend, although not statistically significant, toward higher in-hospital mortality rates, (Odds Ratio: 1.13; 95% CI: 0.57-2.24), and a trend toward reduced likelihood of hospice enrollment(Odds Ratio: 0.73; 95% CI: 0.36-1.49). Notably, late referral significantly increased the duration of IP stays (p < 0.001) and ICU stays (p = 0.004) in last 30 days of life, without change in admission to IP (p = 0.68) or ICU (p = 0.86). Conclusions: The delivery of the guideline-directed "early” consult among patients with advanced cancer is variable. Preliminary analysis showed a trend towards higher in-hospital mortality rates and lower hospice referral for patients referred < 30 days from death among “late” consults. Further subgroup analysis is ongoing. [Table: see text]

Abstract PO1-16-07: Patient Characteristics and Treatment Sequencing Among HER2-low Metastatic Breast Cancer Patients with Rapid vs. Delayed Progression on First-line Endocrine Therapy

Abstract Background Patients with HER2-low (IHC 1+ or 2+ and negative ISH) and hormone-receptor positive (HR+) metastatic breast cancer (mBC) who rapidly progress on first-line (1L) endocrine therapy may experience different treatment pathways than those with delayed progression. The goal of this multisite study is to describe the characteristics, treatment patterns and outcomes of these patients with rapid vs. delayed progression. Methods This was a retrospective cohort study of HER2-low, HR+, mBC patients who received 1L endocrine-based treatment regimen at the Huntsman Cancer Institute, Moffitt Cancer Center, and the Winthrop P. Rockefeller Cancer Institute between 2017 and 2021. With no conventional definition, our study defined rapid progression as disease progression within 12 months of 1L treatment initiation vs >12 months/no progression during study follow-up as delayed progression. Demographic and clinical characteristics, and 1L and second-line (2L) treatment patterns were assessed using descriptive statistics. Using Kaplan-Meier analysis, overall survival (OS) was estimated from treatment initiation to death while progression-free survival (PFS) was estimated from treatment initiation to death or disease progression according to physician notes in patients’ charts. Censoring was performed at the date of last follow-up or 31 Dec 2021, whichever occurred earlier. Results The study included 118 patients who received 1L endocrine therapy (see table), mostly in combination with a CDK4/6 inhibitor (n = 87, 73.7%). Rapid progression was observed for 25 (21.2%) patients with a median 1L PFS and OS of 6.4 months (95% CI: 5.4-8.2) and 20.5 months (95% CI: 14.4-30.5), respectively, compared to delayed progressors (median 1L PFS = 30.5 months, 95% CI: 21.5-54.2 and median OS = 62.1 months, 95% CI: 46.4 -upper bound not reached). Rapid progressors were more likely than delayed progressors to be current smokers (n = 6, 24.0% vs n = 7, 7.5%, p = 0.015) or had liver metastasis at diagnosis of advanced disease (n = 11, 44.4% vs n = 17, 18.3%, p = 0.007) but less likely to have bone as the only metastasis site (n = 6, 24.0% vs n = 46, 49.5%, p = 0.023). A smaller proportion of rapid progressors were on CDK4/6 inhibitors in 1L (n = 17, 68.0%) compared to delayed progressors (n = 70, 75.3%) but the difference was not statistically significant. A substantial proportion of rapid progressors (68%, n = 17) continued to receive endocrine therapy in 2L, including endocrine therapy alone (n = 6, 24.0%), endocrine therapy with targeted therapy (n = 6, 24.0%) and endocrine therapy with CDK4/6 inhibitors (n = 5, 20.0%). Among patients on 1L endocrine therapy who continued to a 2L treatment, 2L PFS and OS of rapid progressors (n = 24) were 5.7 months (95% CI: 3.2-10.6) and 14.1 months (95% CI: 6.8-24.2), respectively, compared to 9.2 months (95% CI: 3.1-13.7) and 29.2 months (95% CI:14.4- upper bound not reached) among delayed progressors (n = 39). Conclusion In this study of patients with HER2-low and HR+ mBC, many patients with rapid disease progression on 1L endocrine-based regimens continued to receive endocrine therapy in their next line of therapy and experienced poor clinical outcomes. This preliminary chart review study highlights the unmet need for more effective treatments for patients with rapid progression on 1L endocrine-based regimens. Further research with a larger sample size is warranted to confirm these findings. Patient characteristics and treatment patterns Demographic characteristics and treatment patterns of stage IV breast cancer patients with HER2-low disease and received 1L endocrine therapy Citation Format: Chia Jie Tan, Connor Willis, Trang Au, Matthew Schabath, Chenghui Li, Kristen Kelley, Xiaoqing Xu, Leah Park, Clara Lam, Sandhya Mehta, Jackie Kwong, Diana Brixner, David Stenehjem. Patient Characteristics and Treatment Sequencing Among HER2-low Metastatic Breast Cancer Patients with Rapid vs. Delayed Progression on First-line Endocrine Therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-16-07.

Abstract PO3-06-01: Factors associated with first- and second- line attrition among metastatic breast cancer patients

Abstract Background: Estimating patient attrition across lines of treatment, i.e., the probability that upon failing one treatment the patient will be able to receive a subsequent treatment, may be a valuable tool for treatment sequencing. We sought to describe first-to-second line (1to2-line) and second-to third line (2to3-line) attrition rate and factors associated with attrition. Methods: The GIM14/BIO-META is an ongoing, ambispective observational multicenter study enrolling breast cancer patients receiving first-line therapy. In progressing patients, attrition was defined as no further anticancer treatment and death within 6 months from the end of the previous line. Attrition from 1to2-line and from 2to3-line was studied by descriptive analyses, factors associated with attrition by univariate ad multivariable logistic models. Results: From January 2000 to December 2021, 3,109 patients with metastatic breast cancer were enrolled in the GIM14/BIO-META study. After the exclusion of 611 patients with ongoing first-line treatment, we included 2,498 patients in the analysis of 1to2-line attrition. Considering tumor subtype, 1,650 (66.0%) patients were diagnosed with metastatic luminal-like, 622 (24.9%) with HER2-positive and 177 (7.1%) with triple negative (TN) tumors. At the time of diagnosis of advanced disease, almost half of the patients (52.0%) had only one involved metastatic site and 45.9% of the patients were diagnosed with visceral involvement. Overall, 1to2-line attrition was 9.0% (224/2,498) with similar attrition for patients with luminal-like (8.5%) and HER2-positive (7.1%) breast cancer. Patients with TN disease experience the highest 1to2-line attrition (13.0%). Age, disease-free interval from primary tumor diagnosis, and type of metastatic spread independently predicted 1to2-line attrition. Univariate analyses of factors associated with 1to2-line attrition among patients with luminal-like breast cancer were similar to those of the entire cohort. Overall, 2to3-line attrition was 14.0% (260/1,861) with higher attrition rates among patients with TN disease (22.7%) compared to patients with luminal-like (13.4%) and HER2-positive (13.0%) breast cancer. Age, tumor subtype, pattern of visceral spread and shorter time-to treatment discontinuation during first-line therapy were independent factors associated with 2to3-line attrition. Conclusions: Pending confirmation in independent series and integration with biomarkers of treatment failure, these results, may provide a valuable support for treatment decisions and clinical research on treatment sequencing. Citation Format: Eva Blondeaux, Luca Boni, Giovanna Chilà, Arianna Dri, Roberta Caputo, Francesca Poggio, Alessandra Fabi, Grazia Arpino, Federico Pravisano, Elena Geuna, Tommaso Ruelle, Irene Giannubilo, Michelino de Laurentiis, Fabio Puglisi, Claudia Bighin, Matteo Lambertini, Filippo Montemurro, Lucia Del Mastro. Factors associated with first- and second- line attrition among metastatic breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-01.

Abstract A012: Genomic landscape of somatic alterations identified in endometrial cancer using liquid biopsy

Abstract Background: With advances in understanding the biology of endometrial cancer, molecular sub-groups have been defined to assess prognosis and guide treatment decisions. This classification is based on surrogate markers in archival paraffin-embedded tissues. The landscape of somatic alterations as detected by liquid biopsy has not been well described in advanced endometrial cancer. Methods: A retrospective analysis was performed using de-identified genomic data collected from patients with advanced endometrial cancer who underwent liquid biopsy testing with a 74-83 gene panel as part of clinical care (Guardant360, Guardant Health, Inc.). Results: 1,988 females with a median age of 68 [range 23-95] years were included in the analysis. 45% of patients were tested at diagnosis of advanced disease; 43% were tested at time of disease progression. 91.6% of patients had ≥1 somatic alteration detected and 12% of patients were MSI-High. The most frequently altered genes included TP53 (65%), PIK3CA (31%), PTEN (27%), ARID1A (24%), like prior reports of genomic alterations detected in tissue samples. CCNE1 amplifications were enriched in 11% of samples with TP53 alterations (p<0.0001; q<0.0001) and EGFR amplifications were enriched in samples without TP53 alterations (p<0.0001; q<0.0001). MSI-H samples were enriched for alterations in ARID1A, PTEN, PIK3CA, ATM, MSH6 and others, while samples without MSI were enriched for alterations in TP53 and CCNE1 (p<0.0001; q<0.0001). Oncogenic fusions were rare in this cohort (0.2%) and included FGFR1 and FGFR3 rearrangements. Activating, druggable alterations were identified in PIK3CA, KRAS, ERBB2, and BRCA1/2. Putative pathogenic germline alterations were detected in 61 (3%) patients and included ATM (18%), BRCA1 (33%), BRCA2 (21%), and lower frequencies of CHEK2, FANCA, MLH1, MSH2, MSH6, and PALB2. Conclusions: While descriptive in nature, this analysis is the largest cohort of advanced endometrial cancer analyzed using a clinically available liquid biopsy assay and demonstrates the feasibility of somatic alteration detection. This report paves the way for using liquid biopsy as a potential tool for guiding targeted chemotherapeutic strategies. Citation Format: Leylah Drusbosky, Ginger Haynes, Brooke Grant, Pamela Sobernis, Stephanie Lheureux. Genomic landscape of somatic alterations identified in endometrial cancer using liquid biopsy [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A012.

Epidemiological characteristics of gastric and pancreatic cancers in Latin America: The LACOG 0222 GASPAR study.

TPS710 Background: Gastric and pancreatic tumors remain among the cancers with the poorest prognoses in both high and low/middle-income countries. Data on the clinicopathological characteristics, standard treatments, and outcomes of these tumors are scarce in Latin America. This study is the first comprehensive effort to report epidemiological and clinical data in this region. Methods: The LACOG 0222 GASPAR trial ( NCT05924789 ) is a retrospective and prospective (bidirectional) observational cohort study. Enrollment of 200 patients across 15 sites in Latin America is planned, 120 patients in cohort A (gastric cancer) and 80 patients in cohort B (pancreatic cancer). No interventions are proposed. Eligibility criteria include age ≥18 years, histological diagnosis of gastric and gastroesophageal junction cancer (cohort A) or pancreatic cancer (cohort B), advanced disease diagnosis since January 2019, and availability of adequate medical data for data collection. The primary objective is to describe the clinical characteristics, treatment patterns, and outcomes of patients with gastric and pancreatic cancer in Latin America. Data on patients’ clinical characteristics, demographics, tumor pathological features, surgical therapy, radiotherapy, chemotherapy, and target therapy will be collected. Patient outcomes, such as recurrence-free survival, progression-free survival, and overall survival will also be collected. Patients will be followed up for up to 3 years after diagnosis. No a priori sample-size calculations were performed. The demographic and underlying disease characteristics will be evaluated using descriptive statistics. Time-to-event outcomes (disease-free survival, progression-free survival, and overall survival) will be estimated using the Kaplan-Meier method. From August 2023 to September 2023, 34 pts were included. The target accrual is expected to be completed by February 2024. The results are expected to be presented in August 2024.

Comparison between liquid biopsy and tissue NGS in two cohorts of advanced NSCLC.

e21043 Background: Molecular testing is mandatory in advanced non-small cell lung cancer (NSCLC) due to prognostic and therapeutic implications. Correlation between blood and tissue next-generation sequencing (NGS) has recently been demonstrated. Methods: A retrospective observational study of two cohorts of NSCLC patients who underwent liquid biopsy at the time of advanced disease diagnosis was conducted. In cohort 1 (N = 129), liquid biopsy was performed using a 74 genes panel (Guardant360 CDx). In cohort 2 (N = 149), NGS was performed in peripheral blood using a 63 genes panel (FoundationOne Liquid CDx). For tissue NGS analysis, Oncomine Precision Assay and Oncomine Focus Assay, with 50 and 52 genes, respectively, were performed. Data were analyzed in both cohorts independently, and compared by statistical descriptive methods. Results: In cohort 1, 74/129 (57.4%) were men and 55/129 (42.6%) were non-smokers or had a ≤ 20-pack-year tobacco history. The most frequent histology was adenocarcinoma (99/129; 76.7%). In 14/129 (10.9%) patients, a second determination of NGS in peripheral blood was necessary and 1/129 (0.8%) had a total of three determinations. Tissue NGS was not performed in 32/129 (24.8%) because of insufficient sample. In cohort 2, 99/149 (66.4%) were men and 48/149 (32.2%) were non-smokers or had a ≤ 20-pack-year tobacco history. The most frequent histology was adenocarcinoma (99/149; 66.4%). Tissue NGS was not performed in 40/149 (26.8%) due to insufficient sample (26/40; 65%) or technical difficulties to perform a biopsy (14/40; 35%). In cohort 1, pathogenic mutations were detected in 119/129 (92.2%) and in 62/97 (63.9%) patients (p < 0.001), with median time to obtain results of 11 (IQR 9-14) and 29 (IQR 22-39) days for blood and tissue NGS, respectively (p < 0.001). Actionable mutations included alterations of levels I-II according to ESCAT and were found in 40/129 (31%) and 33/97 (34%) patients using blood and tissue NGS, respectively (p = 0.63). In cohort 2, circulating tumor DNA was not detected in 5/149 (3.5%) patients. Pathogenic mutations were found in 123/149 (82.6%) and in 71/109 (65.1%) patients (p = 0.001), with median time to obtain results of 15 (IQR 14-15) and 27 (IQR 16-27) days for blood and tissue NGS, respectively (p < 0.001). Actionable mutations were detected in 41/149 (27.5%) and 41/109 (37.6%) using blood and tissue NGS, respectively (p = 0.08). Targeted therapy was given to 31/129 (24%) and 39/149 (26.2%) patients in cohort 1 and 2, respectively. Conclusions: To our knowledge, this is the first retrospective observational study where liquid biopsy and tissue NGS are compared in two different cohorts of patients with advanced NSCLC. Time to obtain results was shorter for blood NGS than tissue sequencing, and liquid biopsy provided molecular information in cases in which tissue NGS is not available. Further studies to identify patients in which liquid biopsy could replace tissue analysis are needed.

Highly Stretchable Graphene Scrolls Transistors for Self-Powered Tribotronic Non-Mechanosensation Application.

Owing to highly desired requirements in advanced disease diagnosis, therapy, and health monitoring, noncontact mechanosensation active matrix has drawn considerable attention. To satisfy the practical demands of high energy efficiency, in this report, combining the advantage of multiparameter monitoring, high sensitivity, and high resolution of active matrix field-effect transistor (FET) with triboelectric nanogenerators (TENG), we successfully developed the tribotronic mechanosensation active matrix based on tribotronic ion gel graphene scrolls field-effect transistors (GSFET). The tribopotential produced by TENG served as a gate voltage to modulate carrier transport along the semiconductor channel and realized self-powered ability with considerable decreased energy consumption. To achieve high spatial utilization and more pronounced responsivity of the dielectric of this transistor, ion gel was used to act as a triboelectric layer to conduct friction and contact electrification with external materials directly to produce triboelectric charges to power GFET. This tribopotential-driving device has excellent tactile sensing properties with high sensitivity (1.125 mm-1), rapid response time (~16 ms), and a durability operation of thousands of cycles. Furthermore, the device was transparent and flexible with the capability of spatially mapping touch stimuli and monitoring real-time temperature. Due to all these unique characteristics, this novel noncontact mechanosensation GSFET active matrix provided a new method for self-powered E-skin with promising potential for self-powered wearable devices and intelligent robots.

Abstract C032: Increased allostatic load is associated with castrate-resistance and de novo metastatic disease in prostate cancer

Abstract Introduction: Allostatic load (AL) is a composite measure of chronic stress including cardiovascular, immune, and metabolic biomarkers. AL has previously been associated with health disparities in cardiovascular disease, metabolic syndrome, and certain malignancies. However, there are no prior publications to the best of our knowledge evaluating the association of AL and clinical outcomes in patients with advanced prostate cancer (PCa). Methods: We identified 139 subjects with metastatic or biochemically recurrent (BCR) PCa treated at the University of Illinois Hospital and Health Sciences System between January 2015 and May 2022. Subjects were assigned AL scores based on retrospective assessment of 9 biomarkers (systolic and diastolic blood pressure, heart rate, alkaline phosphatase, albumin, creatinine, body mass index, glucose, white blood cell count) collected at the time of diagnosis of advanced disease. Subjects were assigned a total AL score whereby each of the individual 9 biomarkers were given a value of 0 or 1 if threshold value was met. Results: Of the 139 subjects, the median age at PCa diagnosis was 63. The majority were African American (65.4%), 14.4% were Hispanic or Latino, 12.2% were white and non-Hispanic or Latino, and race/ethnicity was other or unknown for 7.9%. A majority (62.6%) had localized or regional nodal disease at diagnosis but later developed metastases or BCR, while 37.4% had de novo metastatic disease. Those with de novo metastatic disease had a higher mean AL score compared to those who had localized or regional nodal disease at diagnosis (2.62 vs. 2.08, p=0.03). Nearly all of the subjects (98.6%) received androgen deprivation therapy (ADT) while 1.4% had surgical castration. Most (66.2%) had local therapies such as surgery or radiation prior to or in addition to ADT. A minority (39.6%) developed castrate-resistant disease while 60.4% did not. For subjects who developed castrate-resistant disease, median time to castrate-resistance was 31 months. Those who developed castrate-resistant disease had a higher mean AL score compared to those who did not (2.58 vs. 2.08, p=0.03). In the study population, 25.9% had a low sum Gleason score (≤7) at diagnosis, 46.0% had a high sum Gleason score (≥8) at diagnosis, and 28.1% did not have a Gleason score available at diagnosis. Subjects with a high sum Gleason score had higher mean AL compared to those with low sum Gleason scores, though this finding did not reach statistical significance (2.47 vs. 1.94, p=0.06). In our study, 32 out of 139 subjects had at least one biomarker missing from their records and therefore not included in the subject’s AL score. The most common biomarkers missing were albumin and alkaline phosphatase. Discussion: In our pilot, single-institution study, higher AL may be associated with more aggressive phenotypes of PCa including de novo metastatic disease, earlier progression to castrate-resistance, and higher Gleason scores. Prospective studies are needed to further validate the role AL plays in PCa aggressiveness. Citation Format: Michael Weinfeld, Ryan Nguyen, Frank Weinberg, Vijayakrishna Gadi, Natalie Reizine. Increased allostatic load is associated with castrate-resistance and de novo metastatic disease in prostate cancer [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C032.

Detection of stage I HPV-driven oropharyngeal cancer in asymptomatic individuals in the Hamburg City Health Study using HPV16 E6 serology - A proof-of-concept study.

SummaryBackgroundThe lack of detectable precancerous lesions poses challenges to the early detection of human papillomavirus-driven oropharyngeal cancer (HPV-OPC). Antibodies against HPV16 early proteins, especially E6, are uniquely sensitive and specific biomarkers detectable years prior to HPV-OPC diagnosis. Thus, HPV16 early protein serology warrants clinical investigation for HPV-OPC screening.MethodsUsing multiplex serology, we analyzed HPV16 serum antibodies of the first 5000 participants (n=4,424 sera, recruited 2016-2017) of the Hamburg City Health Study, a population-based prospective cohort (45-74 years). Participants seropositive for HPV16 E6 and at least one additional early protein (E1, E2, E7) were considered at high risk for HPV-OPC development and invited to six-monthly non-invasive head and neck follow-up (FU) examinations (visual inspection, endoscopy, ultrasonography, performed 2019-2020). Participants with suspicious lesions were examined by magnetic resonance imaging and panendoscopy with biopsy. Histologically confirmed OPC cases were treated according to standard of care.FindingsIn total, 35 out of 4,424 study participants (0·8%, 95% confidence interval (CI) 0·6-1·1%) were HPV16 E6 seropositive. Among these, eleven (0·3%, 95%CI 0·1-0·5%) were considered at high risk for HPV-OPC of which nine were successfully re-contacted and invited to regular clinical FU examinations. Two males and one female were diagnosed with stage I HPV-OPC within 1·3 years of clinical FU (3-4 years after initial blood draw), representing one diagnosis of prevalent advanced disease, one incident diagnosis of advanced disease, and one incident diagnosis of early disease. The remaining participants showed no detectable signs of cancer, and undergo regular examinations (median clinical FU: 1·0 years, median total FU from blood draw to last clinical FU visit: 4·7 years).InterpretationHPV16 early antibodies allowed identifying three asymptomatic stage I HPV-OPC patients, out of eleven participants considered at high risk. However, two of the three cases already showed signs of advanced disease at diagnosis. Targeting multiple early proteins may considerably improve the positive predictive value of HPV16 serology and may have clinical utility for HPV-OPC screening.FundingThis work was funded by DKFZ and UKE intramural funding.

Abstract 3098: The first circulating tumor cell-derived explant (CDX) model of a Merkel cell carcinoma

Abstract NeuroEndocrine Carcinomas (NECs) are rare yet lethal diseases; they are frequently metastatic and have limited treatment options. Whilst progress has been made in understanding the biology of Small Cell Lung Cancer (SCLC), the most studied NEC, research on NECs from other anatomical sites lags behind. In SCLC, circulating tumor cells (CTCs) can be used to generate patient-relevant mouse models; termed CTC-Derived eXplants (CDX) which are faithful in biology and chemotherapy response to donor patients1,2. A pilot prospective study is on-going to assess the potential utility of cell-free DNA (cfDNA) and/or CellSearch (CS) CTCs (EpCAM/cytokeratin positive) as liquid biopsies and feasibility of CDX generation from patients with advanced stage extrapulmonary NECs undergoing palliative chemotherapy. CS CTCs are enumerated before and during treatment and marker-independent RosetteSep-enriched CTCs from parallel blood samples are implanted in immunodeficient mice to attempt CDX generation. Twenty-seven patients were recruited from Jun-19 to Nov-21. CS-CTCs were present in 19/27; 70% pre-treatment samples (mean 57, median 2, range 0-685 CTCs per 7.5mL of blood). CDX generation was successful from a pre-treatment CTC sample from a patient originally diagnosed with a NEC of unknown origin who responded to Platinum/Etoposide. Whole-exome sequencing of this CDX and matched pre-treatment cfDNA from the donor revealed largely overlapping copy number changes and common mutations including an activating PIK3CA mutation. In addition, there was no evidence of TP53 or RB1 loss (hallmarks of SCLC) in neither the CDX nor the donor’s cfDNA. Immunohistochemical (IHC) analysis of this CDX showed a small cell NEC morphology, 90% Ki-67 positive cells, expression of EpCAM, pan-cytokeratins and neuroendocrine (NE) diagnostic markers, concordant with the donor’s biopsy. Further IHC and RNA sequencing revealed expression of the NE transcription factor atonal homolog 1 (ATOH1)2, CK20 and abundant Merkel cell polyomavirus (MCPyV) transcripts. These characteristics prompted reclassification of the original patient diagnosis as Merkel cell carcinoma (MCC). There was only 1 CS-CTC in the parallel pre-treatment blood sample implying that EpCAM-negative CTCs may have given rise to the CDX. The CDX showed in vivo sensitivity to Platinum/Etoposide, mirroring treatment response of the donor. Ex vivo cultures from CDX-derived cells grow as suspension clusters similar to ‘classic’ SCLC and MCPyV-positive MCC cell lines. In summary, this first Merkel Cell Carcinoma CDX recapitulates the biology of the donor’s tumor. As the donor remains alive 25 months from diagnosis of advanced disease, their CDX can serve as an avatar to guide future treatment. 1. Hodgkinson et al., Nature Med 2014, 20: p. 897-903. 2. Simpson et al., Nature Cancer 2020, 1: p. 437-451. Citation Format: Melissa Frizziero, Elaine Kilgour, Kathryn L. Simpson, Dominic Rothwell, Kristopher Frese, Melanie Galvin, Yitao Chen, Alastair Kerr, Sam Humphrey, Mukarram Hossain, Juan W. Valle, Mairéad G. McNamara, Caroline Dive. The first circulating tumor cell-derived explant (CDX) model of a Merkel cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3098.

EA2183: A phase III study of consolidative radiotherapy in patients with oligometastatic HER2-negative esophageal and gastric adenocarcinoma.

TPS4162 Background: Advanced esophageal and gastric adenocarcinomas (EGA) have poor prognosis. Doublet chemotherapy with fluoropyrimidine and platinum agents in combination with nivolumab for PD-L1 positive tumors is now the standard first-line approach, but overall survival (OS) remains < 1.5 years. A subset of EGA patients have limited burden of metastatic disease. There is accumulating evidence that patients with oligometastatic states across disease types may benefit from locoregional ablative therapies during the course of their treatment. EA2183 is the first prospective study to evaluate the potential benefits of consolidative radiotherapy (XRT) in oligometastatic EGA. Methods: This is a prospective, randomized phase 3 study evaluating the role of consolidative XRT in oligometastatic EGA. Patients with ≤3 metastases at the time of diagnosis of advanced disease are eligible for enrollment. After completion of 4 months of systemic therapy, patients whose disease has not progressed are randomized to consolidation with XRT to all sites of disease followed by continuation of systemic therapy or continuation of systemic therapy alone. Patients are able to enroll in the study at the time of diagnosis of advanced disease or after completion of induction therapy. Systemic therapy is left to the discretion of the treating physician and can include FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine, oxaliplatin) in combination with nivolumab. Unless there are contraindications to immunotherapy or a history of prior treatment with immune checkpoint inhibitors, nivolumab use is mandatory if tumor has PD-L1 combined positive score (CPS) ≥5. The goal of radiation is to consolidate gains made by chemotherapy by delivering the highest dose that maintains the greatest tumor control probability that is also safe to deliver given the anatomic and normal tissue constraints. Specific radiation dose and fractionation are recommended in the protocol but is left to the discretion of the treating radiation oncologist to choose the course that is most suitable. Radiation must be administered over a maximum of 15 treatment days to minimize systemic therapy treatment breaks. Primary endpoint is OS from the time of randomization. Secondary endpoints include progression free survival from the time of randomization and safety and tolerability of consolidative XRT. We hypothesize that consolidative XRT will prolong OS from 10 to 15.6 months (an increase in median OS of 55.6%). The study is planning to enroll 314 patients with the goal of randomizing 204 patients in a 2:1 fashion. Stratification factors include number of metastatic sites, choice of immunotherapy with relation to PD-L1 CPS, as well as time of registration to the protocol (before or after systemic therapy initiation). Enrollment to the study is ongoing. Clinical trial information: NCT04248452.

The Continuum of Metastatic Prostate Cancer: Interpreting PSMA PET Findings in Recurrent Prostate Cancer.

Simple SummaryMolecular imaging with PSMA PET–CT is more accurate and sensitive than conventional imaging with CT, MRI, and a Technetium-99 bone scan. This new imaging modality will result in more advanced disease being diagnosed earlier which may improve survival, however, it could also lead to overtreatment. Since molecular imaging has the potential to identify disease prior to its detection on conventional imaging, this highlights that advanced prostate cancer exists on a continuum. This review discusses how PSMA PET–CT can be used in managing prostate cancer using clinical scenarios.Conventional imaging has been the standard imaging modality for assessing prostate cancer recurrence and is utilized to determine treatment response to therapy. Molecular imaging with PSMA PET–CT has proven to be more accurate, sensitive, and specific at identifying pelvic or distant metastatic disease, resulting in earlier diagnosis of advanced disease. Since advanced disease may not be seen on conventional imaging, due to its lower sensitivity, but can be identified by molecular imaging, this reveals that metastatic prostate cancer occurs on a continuum from negative PSMA PET–CT and negative conventional imaging to positive PSMA PET–CT and positive conventional imaging. Understanding this continuum, the accuracy of these modalities, and treatment related outcomes based on imaging, will allow the clinician to counsel patients on management. This review will highlight the differences in conventional and molecular imaging in prostate cancer and how PSMA PET–CT can be used for the management of prostate cancer patients in different clinical scenarios, while providing cautionary notes for overtreatment.

Immune Checkpoint Inhibitors and Palliative Care at the End of Life: An Irish Multicentre Retrospective Study.

Background and Objectives: Immune checkpoint inhibitors (ICIs) have less toxicity than standard chemotherapy and are now standard of care for many patients with advanced cancer. A manageable side effect profile and potential for durable responses may lead to aggressive care of the palliative patient. We sought to evaluate palliative care input and ICI use at the end of life at two Irish cancer centres. Methods: We identified deceased patients who received at least one dose of an ICI between first of January 2013 to 31st of December 2018. A retrospective electronic chart review was performed. Results: The electronic records of 102 patients were analysed. Fifty eight percent were male and the median age of diagnosis of advanced disease was 60 years (range 17-78). Median time from last dose of ICI to death was 57 days (range 8-574) and 20% of patients died within 30 days of last dose of ICI. Most patients, 92%, were referred to palliative care. The median time from palliative care referral to death was 64 days (range 1- 1010). In the last 30 days of life, 39% of patients attended the emergency department (ED) and 46% had at least one hospital admission. Late palliative care referrals, ≤3 months before death, were associated with hospitalisations in the last month of life (64% vs. 36%, P = .02). Timing of palliative care referral did not affect ICI prescribing at the end of life (P = 0.38). ICI use in the last 30 days of life was not associated with increased ED presentations or hospitalisations at the end of life. Patients who received ICI in the last month had a higher likelihood of in-hospital death (43% vs. 16%, P = 0.02). Conclusions: ICI within 30 days of death was associated with dying in hospital but did not lead to more hospitalisations and emergency department presentations. Early palliative care did not affect ICI use but reduced hospitalisations at the end of life.

Real-world clinical outcomes and molecular features of lung-specific and liver-specific metastases in pancreatic ductal adenocarcinoma (PDAC).

532 Background: PDAC remains one of the most lethal malignancies following metastatic presentation, typically to the liver or lung. Previous studies have observed that advanced PDAC patients have variable outcomes depending on site of involvement. Here, we aim to understand survival outcomes and molecular features for PDAC based on involvement of lung vs liver. Methods: We retrospectively analyzed longitudinal clinical outcomes across 787 patients with PDAC with next generation sequencing (NGS) from Perthera’s Real-World Evidence database whose tumors first metastasized to either the lung or the liver. Median overall survival (mOS) was measured from either the date of initial diagnosis (resectable cases only, stage I-III) or advanced diagnosis (stage IV) until death. Differences in survival and frequencies of mutations were evaluated between patients with lung-specific and liver-specific metastases using Cox regression and Fisher's exact test, respectively. Results: Among resectable PDAC, mOS from initial diagnosis was significantly shorter in patients that developed liver only metastasis (Table, left) compared to those patients that developed lung only metastasis (p=2.4e-08, HR=3.04 [2.06-4.49]). In the advanced PDAC cohort, mOS from diagnosis of advanced disease was also significantly shorter (Table, right) in liver only versus lung only metastasis (p=0.0013, HR=1.62 [1.21-2.18]). Differences in treatment-specific outcomes were not significant supporting a potential prognostic role for lung only metastases. PDAC tumors presenting to the liver first were modestly enriched (unadjusted p<0.05) for TP53 mutations (81.4% in liver vs 69.2% in lung), MYC amplifications (8.6% vs 3.0%), and inactivating CDK2NA alterations (51.5% vs 39.1%) whereas lung-specific mutation frequencies were higher for STK11 mutations (2.4% in liver vs 7.5% in lung), CCND1 amplifications (0.5% vs 3.0%), GNAS alterations (2.0% vs 8.5%). No differences in KRAS mutations nor specific isoforms were noted between lung vs liver only metastasis. Conclusions: Lung only metastasis in both resectable and advanced PDAC confers a significant survival advantage compared to liver only metastasis. Deeper investigation into the molecular drivers of site-specific metastases is warranted.[Table: see text]

Diagnosis of Advanced Disease in Cases of Colorectal Cancer in a Developing Country

Abstract Objectives Colorectal cancer (CRC) is the second leading cause of cancer death in the world, with survival correlated with the extension of the disease at diagnosis. In many low-/middle-income countries, the incidence of CRC is increasing rapidly, while decreasing rates are observed in high-income countries. We evaluated the anatomopathological profile of 390 patients diagnosed with CRC who underwent surgical resection, over a six-year period, in the state of Paraíba, northeastern Brazil. Results Adenocarcinomas accounted for 98% of the cases of primary colorectal tumors, and 53.8% occurred in female patients. The average age of the sample was 63.5 years, with 81.8% of individuals older than 50 years of age and 6.4% under 40 years of age. The most frequent location was the distal colon; pT3 status was found in 71% of patients, and pT4 status, in 14.4%. Angiolymphatic and lymph-node involvements were found in 48.7% and 46.9% of the cases respectively. Distant metastasis was observed in 9.2% of the patients. Advanced disease was diagnosed in almost half of the patients (48.1%). The women in the sample had poorly-differentiated adenocarcinomas (p = 0.043). Patients under 60 years of age had a higher rate of lymph-node metastasis (p = 0.044). Tumor budding was present in 27.2% of the cases, and it was associated with the female gender, the mucinous histological type, and the depth of invasion (pT3 and pT4). Conclusions We conclude that the diagnosis of advanced disease in CRC is still a reality, with a high occurrence of aggressive prognostic factors, which results in a worse prognosis.

EP.WE.620The utility of Computerized Axial Tomography (CT) investigation in two week waits colorectal referral pathway: should it be done more often during the pandemic?

AimColorectal two week wait pathway investigations have been majorly affected due to Covid 19 especially with regards to endoscopy as well as virtual colonoscopy procedures in comparison to CT scan. We aimed to analyze the CT scan findings of colorectal rapid access patients.MethodA total of 1900 patients was referred via the straight to test pathway in the year 2020.A retrospective analysis of CT scan investigation performed in these patients was analyzed.ResultsA total of 90 (4.74%) patients had a CT Scan as part of the work.20 patients (22%) of the CT scan revealed malignancy. 10 patients (50%) had metastatic disease on the scan. Among them, 6 (60%) were due to colorectal primary and another 2 (20%) was due to thoracic cancers. The remaining were diagnosed with widespread metastatic disease of unknown origin. Among the remaining 10 patients, Curative surgery was offered to 5 patients with colorectal primary and one patient with hepatocellular carcinoma. The remaining patients were diagnosed with High grade B cell lymphoma, Neuroendocrine tumor, pancreatic mass and primary renal cell carcinoma. One patient had high grade small bowel obstruction due to a band adhesion resulting in emergency surgery and 5% of the patient needed a vascular referral for Abdominal aneurysm.ConclusionCT scan in two week colorectal referral patients play a significant role in diagnosis of advanced disease. The ease of the procedure makes it more attractive during the pandemic in contrast to endoscopy and virtual-colonoscopy which has been significantly impacted by COVID 19.

Suboptimal clinician awareness of appropriate NTRK fusion testing and TRK inhibitor use in solid tumors.

229 Background: Since late 2018, 2 TRK inhibitors—larotrectinib and entrectinib—have been approved by the EMA and FDA for treating patients with advanced solid tumors harboring an NTRK fusion and progressive disease or no therapeutic alternatives. It is recommended that testing for NTRK fusions occur as early as possible after a diagnosis of advanced disease in patients with solid tumors to inform potential use of TRK inhibitors. Methods: Between April 2018 and April 2021, we conducted multiple live and online educational activities for oncology healthcare professionals (HCPs) on NTRK fusion testing and/or TRK inhibitor treatment for varied solid tumors. Each activity included polling questions designed to assess HCP knowledge and practice patterns. In this analysis, we assessed HCP responses to these questions to evaluate awareness of expert recommendations on NTRK fusion testing and the selection of TRK inhibitor therapy for appropriate patients. Results: In 6 live and online activities with data from April 2018 to April 2021, 29% of HCPs (n = 844) indicated that they ordered molecular profiling to test for NTRK fusions in all solid tumors in their current practice. Of note, low rates of testing were reported in TRK inhibitor/ NTRK testing-focused activities throughout this time period, with no significant increase over time. In assessing different patient cases across 8 activities where experts recommended TRK inhibitor therapy as optimal, many HCPs did not select a TRK inhibitor, with considerable variance by tumor type (Table). *For all cases, experts selected larotrectinib and/or entrectinib as optimal treatment. †HCP respondents. GBM, glioblastoma; GI, gastrointestinal; MSI-H, microsatellite instability-high; PD, progressive disease; PTC, papillary thyroid cancer.Conclusions: The rate of broad testing for NTRK fusions across patients with solid tumors remains low, and many HCPs lack awareness of when to consider a TRK inhibitor. Educational activities designed to address these deficiencies would be of clear benefit to HCPs treating patients with advanced solid tumors. A detailed analysis of HCP trends will be presented.[Table: see text]

European and US Real-World Treatment Patterns in Patients with Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer: A Retrospective Medical Record Review.

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred first-line (1L) therapy for EGFR mutation-positive (EGFRm) advanced/metastatic non-small cell lung cancer (NSCLC).ObjectiveOur objective was to describe real-world treatment patterns and T790M testing practices in patients with 1L disease progression (Europe/USA) following treatment with first- or second-generation EGFR-TKIs.MethodsThis was a retrospective, non-interventional medical record review of patients with EGFRm locally advanced/metastatic NSCLC from routine clinical practice (EGFR-TKI initiation: 1 January 2015 to 31 December 2017; follow-up: last available medical record). Endpoints were demographic/clinical characteristics, incidence of central nervous system (CNS) metastases/leptomeningeal disease, second-line (2L) treatment, T790M mutation testing, and osimertinib treatment prevalence.ResultsAmong 469 patients, 73% (n = 341/469) progressed on 1L EGFR-TKI treatment. Of those who progressed, 74% (n = 252/341) were tested for T790M, with 50% (n = 126/252) testing positive; 75% (n = 94/126) of T790M-positive patients received osimertinib (mostly 2L). Of the patients with progression, 24% (n = 83/341) did not receive 2L treatment, and 88% (n = 73/83) of these patients died. At diagnosis of advanced disease, 9% of patients (n = 41) had CNS metastases; at EGFR-TKI initiation, 14% of patients (n = 68) had CNS metastases. Over the study period, 11% of patients (n = 42) developed CNS metastases not detected at NSCLC diagnosis.ConclusionsRates of resistance mutation testing and subsequent utilization of recommended 2L therapies could be improved. As more targeted therapies are developed, it will be crucial to improve the molecular testing rates to ensure patients receive appropriate, effective, and timely treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40801-021-00261-8.

SMARCA4 and Other SWItch/Sucrose NonFermentable Family Genomic Alterations in NSCLC: Clinicopathologic Characteristics and Outcomes to Immune Checkpoint Inhibition

IntroductionThe SWItch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling complex acts as a regulatory component of transcription, and inactivating mutations (muts) within the complex are implicated in genomic instability, higher tumor mutational burden, and an aggressive cancer phenotype. Whether SMARCA4 and other SWI/SNF alterations are independent prognostic factors or associated with clinical outcomes to immune checkpoint inhibitors (ICIs) in NSCLC remains unclear. MethodsWe collected clinicopathologic and genomic data from patients with NSCLC who underwent targeted next-generation sequencing at the Dana-Farber Cancer Institute. Tumors were characterized on the basis of the presence or absence of muts across a set of six SWI/SNF genes (ARID1A, ARID1B, ARID2, PBRM1, SMARCA4, and SMARCB1). ResultsOf 2689 patients with NSCLC, 20.6% (N = 555) had SWI/SNF genomic alterations. Compared with SWI/SNF wild-type (wt) NSCLC, patients with SWI/SNF-mutant NSCLCs had a lower prevalence of concurrent targetable driver muts (33.2% versus 22.2%; p < 0.001), a higher tumor mutational burden (median 8.5 versus 12.2 muts/megabase; p < 0.001), and a shorter median overall survival (mOS) from the time of advanced disease diagnosis (25.0 versus 19.3 mo, p = 0.01); the detrimental effect in OS seemed to be largely driven by SMARCA4 muts (mOS: 25.0 for SMARCA4 wt versus 15.6 mo for SMARCA4 mutant; p < 0.001). Among 532 patients who received ICIs, 25.5% (N = 136) harbored SWI/SNF muts. From the start of immunotherapy, there was no difference in objective response rate (ORR = 19.9% versus 25.0%, p = 0.2), median progression-free survival (mPFS = 3.0 versus 3.0 mo, hazard ratio [HR] = 0.96 [95% confidence interval [CI] = 0.77–1.18], p = 0.7), or mOS (13.1 versus 9.5 mo, HR = 0.81 [95% CI: 0.64–1.02], p = 0.07) in SWI/SNF-wt versus SWI/SNF-mutant NSCLC, respectively. Nevertheless, among KRAS-mutant NSCLCs treated with ICIs (N = 176), a concurrent SWI/SNF mut (N = 39) conferred a numerically lower ORR (21.9% versus 12.8%, p = 0.2), a significantly shorter mPFS (4.1 versus 1.8 mo, HR = 0.57 [95% CI: 0.38–0.84], p = 0.005), and a significantly shorter mOS (15.5 versus 8.2 mo, HR = 0.56 [95% CI: 0.36–0.86], p = 0.008). The deleterious effect on immunotherapy outcomes in KRAS-mutant NSCLC was most pronounced in the SMARCA4-mutant subset (N = 17), with a lower ORR (22% versus 0%, p = 0.03), a significantly shorter mPFS (4.1 versus 1.4 mo, HR = 0.25 [95% CI: 0.14–0.42], p < 0.001), and a significantly shorter mOS (15.1 versus 3.0 mo, HR = 0.29 [95% CI: 0.17–0.50], p < 0.001) compared with SMARCA4-wt KRAS-mutant NSCLCs. ConclusionsAlthough there were no associations between SWI/SNF mut status and immunotherapy efficacy in the overall NSCLC cohort, the presence of a SMARCA4 alteration may confer a worse outcome to immunotherapy among KRAS-mutant NSCLCs.

Beyond Conventional: The New Horizon of Targeted Therapy for the Treatment of Advanced Non Small Cell Lung Cancer.

In the last few years the advent of targeted therapies against oncogenic drivers significantly improved the survival of non small cell lung cancer (NSCLC) patients with a favourable toxicity profile. Therefore, genetic testing, including at least EGFR mutations and ALK/ROS1 rearrangements, should be performed in all NSCLC patients (in particular with adenocarcinoma) who received a diagnosis of advanced disease. This review focuses on novel druggable oncogenic drivers, such as MET exon 14 mutations/MET amplification, RET fusions, BRAF V600E mutations, KRAS G12C mutations, NTRK rearrangements, and HER2 alterations.