Multiple Metastatic Sites Research Articles

Variant allele frequency in circulating tumor DNA correlated with tumor disease burden and predicted outcomes in patients with advanced breast cancer

PurposeIn patients with first-line advanced breast cancer (ABC), the correlation between ctDNA variant allele frequency (VAF) and tumor disease burden, and its prognostic value remains poorly investigated.MethodsThis study included patients with ABC diagnosed at Peking University Cancer Hospital who performed ctDNA test before receiving first-line treatment. Baseline plasma samples were collected for assessing ctDNA alterations and VAF with next-generation sequencing. The sum of tumor target lesion diameters (SLD) was measured with imaging methods according to RECIST 1.1 criteria.ResultsThe final cohort included 184 patients. The median age of the cohort was 49.4 (IQR: 42.3–56.8) years. The median VAF was 15.6% (IQR: 5.4%-33.7%). VAF showed positive correlation with SLD in patients with relatively large tumor lesions (r = 0.314, p = 0.003), but not in patients with small tumor lesions (p = 0.226). VAF was associated with multiple metastasis sites (p = 0.001). Multivariate Cox regression analysis showed that high VAF was associated with shorter overall survival (OS) (HR: 3.519, 95% confidence interval (CI): 2.149–5.761), and first-line progression-free survival (PFS) (HR: 2.352, 95%CI: 1.462–3.782). Combined VAF and SLD improved prediction performance, both median OS and PFS of patients in VAF(H)/SLD(H) group were significantly longer than VAF(L)/SLD(L) group (mOS: 49.3 vs. 174.1 months; mPFS: 9.6 vs. 25.3 months).ConclusionctDNA VAF associated with tumor disease burden, and was a prognostic factor for patients with ABC. A combination of ctDNA test and radiographic imaging might enhance tumor burden evaluation, and improve prognosis stratification in patients with ABC.

Intra- and Interpatient Drug Response Heterogeneity Exist in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Nongynecologic Cancers.

Select patients with peritoneal metastases are treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). We assayed for intra- and interpatient drug response heterogeneity through testing of patient-derived tumor organoids (PDTOs). PDTOs were generated from CRS/HIPEC patients from December 2021 to September 2022 and subjected to an in vitro HIPEC drug screen. Drug response was assessed with a cell viability assay and cleaved caspase-3 staining. A total of 31 patients were consented for tissue collection. Viable tissue was harvested from 23, and PDTO generation was successful in 13 (56%). PDTOs were analyzed from six appendiceal, three colorectal, two small bowel, one gastric, and one adrenal tumor. Drug screen results were generated in as few as 7 days (62%), with an average time of 12 days. Most patients received mitomycin-C (MMC) intraoperatively (n = 9); however, in only three cases was this agent considered the optimal choice in vitro. Three sets of PDTOs were resistant (defined as > 50% PDTO viability) to all agents tested and two were pan-sensitive (defined as 3 or more agents with < 50% PDTO viability). In three patients, organoids were generated from multiple metastatic sites and intrapatient drug response heterogeneity was observed. Both intra- and interpatient drug response heterogeneity exist in patients undergoing CRS/HIPEC for nongynecologic abdominal cancers. Caution must be used when interpreting patient response to chemotherapeutic agents based on a single site of testing in those with metastatic disease.

Survival outcomes according to the tumor location and prognostic factor in metastatic rectal cancer: a multicenter retrospective cohort study.

Prognostic factors of metastatic rectal cancer are not well known. We aim to determine prognostic factors affecting survival for metastatic rectal cancer patients and also to investigate the effect of tumor localization on overall survival. Metastatic rectal cancer patients who received treatment in 5 different centers between 2012 and 2022 were included. Prognostic factors for survival were evaluated using univariate and multivariate analysis. The statistical methods included Pearson's chi-square test, Fisher exact test, Log-rank test, and Cox regression model. A total of 283 patients with metastatic rectal cancer were included in the study. The median OS was not significantly different among the three groups (upper rectum 30.1 months, middle rectum 28.3 months, and low rectum cancer 24.8 months; log-rank p = 0.25). In univariate analysis, Grade 3, ECOG performance status 2, the presence of multiple metastatic sites, the presence of KRAS mutation, the presence of liver metastases, the presence of nonregional lymph node metastases, and the presence of bone metastases were significant predictors of poor survival. In multivariate analysis, Grade 3, ECOG performance status 2, and the presence of multiple metastatic sites were determined as indicators of worse prognosis. Our findings, primary tumor location did not affect survival in metastatic rectal cancer. The most important factors affecting survival were multiple metastatic sites, tumor grade, and ECOG performance status.

A Bayesian framework to study tumor subclone-specific expression by combining bulk DNA and single-cell RNA sequencing data.

Genetic and gene expression heterogeneity is an essential hallmark of many tumors, allowing the cancer to evolve and to develop resistance to treatment. Currently, the most commonly used data types for studying such heterogeneity are bulk tumor/normal whole-genome or whole-exome sequencing (WGS, WES); and single-cell RNA sequencing (scRNA-seq), respectively. However, tools are currently lacking to link genomic tumor subclonality with transcriptomic heterogeneity by integrating genomic and single-cell transcriptomic data collected from the same tumor. To address this gap, we developed scBayes, a Bayesian probabilistic framework that uses tumor subclonal structure inferred from bulk DNA sequencing data to determine the subclonal identity of cells from single-cell gene expression (scRNA-seq) measurements. Grouping together cells representing the same genetically defined tumor subclones allows comparison of gene expression across different subclones, or investigation of gene expression changes within the same subclone across time (i.e., progression, treatment response, or relapse) or space (i.e., at multiple metastatic sites and organs). We used simulated data sets, in silico synthetic data sets, as well as biological data sets generated from cancer samples to extensively characterize and validate the performance of our method, as well as to show improvements over existing methods. We show the validity and utility of our approach by applying it to published data sets and recapitulating the findings, as well as arriving at novel insights into cancer subclonal expression behavior in our own data sets. We further show that our method is applicable to a wide range of single-cell sequencing technologies including single-cell DNA sequencing as well as Smart-seq and 10x Genomics scRNA-seq protocols.

Clinical significance of baseline Epstein-Barr virus DNAfor recurrent or metastatic primary pulmonary lymphoepithelioma-like carcinoma.

Background: This study aimed to evaluate the clinical significance of baseline Epstein-Barr virus (EBV) DNA in recurrent or metastatic primary pulmonary lymphoepithelioma-like carcinoma (PLELC). Methods: 75patients with baseline EBV DNA were included. The relationships between baseline EBV DNA and clinical characteristics, survivaland objective response rate were analyzed. Results: The baseline EBV DNA levels were related to the liver, chest wall, distant lymph node(s)or multiple sites of distant metastasis. The high baseline EBV DNA group (≥41,900copies/ml) was related to shorter progression-freeand overall survival in univariate analysis and remained significant for progression-free survival in multivariate analysis. Conclusion: The baseline EBV DNA is a valuable biomarker for predicting prognosis and reflecting tumor burden in recurrent or metastatic PLELC.

Risk Factors for Synchronous Lung Metastasis in Squamous Cell Carcinoma of Hypopharynx.

Background: The objective of this study is to assess the risk factors for synchronous lung metastases (LM) in patients with hypopharynx squamous cell carcinomas (HPSCC). Methods: HPSCC patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2013. We examined the association between risk factors and synchronous LM using chi-squared tests. Predictors of survival rates were assessed using univariate and multivariate analyses. Results: A total of 1683 patients were analyzed, including 70 patients (4.2%) with synchronous LM, and 1613 patients without synchronous LM (95.8%). Multivariate logistic regression analysis showed that Caucasian (P = .038), lower T (P = .026) or N classification (P = .000), and highly differentiated disease (P = .002) were associated with a significantly lower risk of LM. Elderly not married patients with higher T or N classification, multiple sites of metastases, and no surgical therapy to the primary tumors were more likely to reduce life expectancy. Conclusion: By analyzing data from a large cohort, Caucasian, lower T or N classification, and highly differentiated disease were associated with a significantly lower risk of LM. Elderly not married patients with advanced T or N classification, no surgical therapy to the primary tumors, and multiple sites of metastases were more likely to reduce life expectancy. More accurate assessments of LM will be imperative for early diagnosis and treatment in non-Caucasian patients who harbored higher T or N classification and poorly differentiated disease.

Impact of low serum iron on treatment outcome of PD-1 inhibitors in advanced gastric cancer

BackgroundThe aim of this study was to investigate the influence of serum iron levels in advanced gastric cancer (GC) patients treated with programmed cell death protein-1 (PD-1) inhibitors.MethodsWe retrospectively reviewed 149 GC patients who were treated with PD-1 inhibitors at our center. Clinicopathological characteristics, laboratory data, and clinical outcomes were analyzed.ResultsMultivariate analysis showed that Eastern Cooperative Oncology Group performance status (ECOG PS), histological subtype, and baseline serum iron levels were independent prognostic factors for overall survival (OS), while ECOG PS, multiple metastatic sites, and baseline serum iron levels were independent prognostic factors for progression-free survival (PFS). Patients with baseline low serum iron levels (LSI) had a significantly shorter median OS and PFS compared to patients with normal serum iron levels (NSI) (Median OS: 7 vs. 14 months, p = 0.001; median PFS: 3 vs. 5 months, p = 0.005). Patients with baseline LSI had a disease control rate (DCR) of 58.3% at 2 months after PD-1 inhibitor initiation (M2), compared to 81.1% in patients with NSI (p = 0.005). Patients with baseline LSI had a DCR of 43.8% at 4 months, compared to 64.2% in patients with NSI (p = 0.017).ConclusionsLSI was associated with worse OS, PFS, and DCR in GC patients treated with PD-1 inhibitors and might be a quick and efficient biomarker to predict the efficacy of PD-1 inhibitors.

RADT-17. SINGLE INSTITUTION REVIEW OF OUTCOMES FOLLOWING STEREOTACTIC RADIOSURGERY FOR SIX TO EIGHTEEN BRAIN METASTASES: INTRACRANIAL FAILURE RATES AND NEED FOR FURTHER CRANIAL RADIOTHERAPY

Abstract BACKGROUND A single centre retrospective review of outcomes following linear accelerator - based stereotactic radiosurgery (SRS) for patients with 6 to 18 brain metastases was conducted. METHODS Patients receiving SRS to multiple metastatic sites were identified from our institutional database and subsequently stratified into those with 6-9 metastases (group 1) and 10 or more metastases (group 2). RESULTS 45 patients were evaluated in total with a mean number of metastases of 7 for group 1 and 14 for group 2. Mean total GTV volumes for each SRS treatment were 1.92cc (group 1) and 2.70cc (group 2). Median overall survival was 8 months for group 1 (0 -51 months) and 7 months (3-36 months) for group 2 . Following SRS, median time to intracranial progression was 3 months for both groups, occurring in 59% and 64% of group 1 and group 2 patients respectively. Following relapse, more patients in group 2 received whole brain/posterior fossa radiotherapy rather than SRS when compared with those in group 1 (80% vs 40%). The majority of patients surviving more than 1 year following SRS for ≥6 brain metastases had a targetable mutation (defined as any of ALK/EGFR/ROS1/BRAF mutation, ER+, HER 2+, PDL1 expression ≥ 1) in their primary tumour; 75% of group 1 and 100% of group 2. CONCLUSIONS Although this study represents small patient numbers, we show that long term survival can be achieved for some patients following SRS for more than 5 brain metastases. However, many patients with more than 10 brain metastases develop intracranial relapse shortly after SRS and require whole brain/posterior fossa radiotherapy, indicating these patients are less likely to benefit from SRS. The presence of a targetable mutation in the primary tumour may indicate a better outcome following SRS for more than 5 brain metastases and warrants further investigation.

Anti-PD-1 immunotherapy with androgen deprivation therapy induces robust immune infiltration in metastatic castration-sensitive prostate cancer

When compared to other malignancies, the tumor microenvironment (TME) of primary and castration-resistant prostate cancer (CRPC) is relatively devoid of immune infiltrates. While androgen deprivation therapy (ADT) induces a complex immune infiltrate in localized prostate cancer, the composition of the TME in metastatic castration-sensitive prostate cancer (mCSPC), and the effects of ADT and other treatments in this context are poorly understood. Here, we perform a comprehensive single-cell RNA sequencing (scRNA-seq) profiling of metastatic sites from patients participating in a phase 2 clinical trial (NCT03951831) that evaluated standard-of-care chemo-hormonal therapy combined with anti-PD-1 immunotherapy. We perform a longitudinal, protein activity-based analysis of TME subpopulations, revealing immune subpopulations conserved across multiple metastatic sites. We also observe dynamic changes in these immune subpopulations in response to treatment and a correlation with clinical outcomes. Our study uncovers a therapy-resistant, transcriptionally distinct tumor subpopulation that expands in cell number in treatment-refractory patients.

Clinicopathological Profiles Associated with Discordant RAS Mutational Status between Liquid and Tissue Biopsies in a Real-World Cohort of Metastatic Colorectal Cancer.

We aimed to identify common mCRC profiles associated with a discordant mutational status of RAS between the standard of care (SoC) tumour tissue tests and ctDNA tests to understand ctDNA detection and improve treatment responses. This was a multicentre, retrospective and prospective study. A total of 366 Spanish mCRC patients were independently recruited. BEAMing ddPCR technology was employed to detect ctDNA RAS mutations, and logistic regression analyses were performed to investigate clinicopathological factors associated with discordance. The highest concordance ratios were observed in profiles with multiple metastatic sites when the liver was present (89.7%; 95% CI 84.8-93.2), profiles with synchronous disease without primary tumour resection (90.2%; 95% CI 83.6-94.3) and profiles with mCRC originating in the left colon (91.3%; 95% CI 85.0-95.0). Metachronous disease originating in the right colon (OR = 6.1; 95% CI 1.7-26.5; p-value = 0.006) or rectum (OR = 5.0; 95% CI 1.5-17.8; p-value = 0.009) showed the highest probability of discrepancies. Primary tumour resection and a higher frequency of single metastases in the peritoneum or lungs in these patients were associated with reduced plasmatic mutation allele fractions (MAFs) and an increased probability of showing false-negative genotypes. Additional testing of patients with mCRC originating in the right colon or rectum with a single non-mutated ctDNA test is advised before the choice of therapy.

The Impact of Ethnicity and Age on Distribution of Metastases in Patients with Upper Tract Urothelial Carcinoma: Analysis of SEER Data.

Upper tract urothelial carcinoma (UTUC) constitutes a rare and aggressive entity accounting for 5% to 10% of all urothelial tumors. The importance of stratification and disparities according to ethnicity and age has never been tested in a sufficiently large sample of patients with metastatic UTUC (mUTUC). We conducted this study to address this void, and we hypothesized that the distribution of metastases may vary according to age and ethnicity. Within the Surveillance, Epidemiology, and End Results (SEER) database (2004-2016), we identified 1115 patients with mUTUC. The chi-square and t-test tests were used to examine statistical significance in terms of proportions and mean differences. A total of 925 (83.0%) patients were Caucasians, while 190 (17.0%) were African Americans. Among both ethnicities, lungs were the most common metastatic site (39.1% vs. 48.9%). Brain metastases were infrequent among both ethnicities (1.2 vs. 2.6%; p = 0.13). The trends in the lung metastases decreased with age from 42.3% to 36.6% (p = 0.010) among Caucasians, whereas they increased among African Americans from 34.0% to 51.7% (p = 0.04). Overall, 32.8% of Caucasians and 40.5% of African Americans exhibited more than one metastatic site. Among Caucasians, increasing age was associated with lower rates of having multiple metastatic sites (from 34.3% to 30.2%) (p = 0.004). According to our multivariable analyses, younger age was associated with an increased risk of lung (OR: 1.29, 95% CI 1.04-1.71; p = 0.045) and bone metastases (OR: 1.34, 95% CI 1.07-1.79; p = 0.046). Racial differences exist in the distribution of mUTUC metastasis and vary according to age. Our findings may also be considered in the design of randomized trials.

Detection of the high-risk factors for synchronous bone metastasis in tonsillar squamous cell carcinoma.

To analyze the risk factors for synchronous bone metastases (BM) in patients with tonsillar squamous cell carcinomas. Tonsillar carcinomas patients were extracted from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2013. We examined the association between risk factors and synchronous BM using Chi-squared tests. Predictors of survival rates were assessed using univariate and multivariate analyses. A total of 5752 patients were analyzed, which including 35 patients (0.6%) with synchronous BM, and 5717 patients without synchronous BM (99.4%). Multivariate logistic regression analysis showed that Caucasian, lower T or N classification were associated with a significantly lower risk of BM (P < 0.05, respectively). Elderly not married non-Caucasian patients with highly differentiated disease, higher T or N classification, multiple sites of metastases and no surgical therapy to primary tumor were more likely to reduce life expectancy. By analyzing data from a large cohort, Caucasian, lower T or N classification were associated with a significantly lower risk of BM. Elderly not married non-Caucasian patients with highly differentiated disease, higher T or N classification, multiple sites of metastases and no surgical therapy to primary tumor were more likely to reduce life expectancy. More accurate assessments of BM will be imperative for early diagnosis and treatment in non-Caucasian tonsillar carcinoma patients who harbored with higher T or N classification.

Epidemiological and clinical characteristics of synchronous lung metastasis in major salivary gland mucoepidermoid carcinoma.

To analyze the risk factors for synchronous lung metastases (LM) in patients with major salivary gland mucoepidermoid carcinoma (MaSG-MEC). MaSG-MEC patients were extracted from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2014. Descriptive statistics were used to examine the baseline characteristics of the patients. We examined the association between risk factors and synchronous LM using Chi-squared tests. The primary study outcomes were overall survival (OS) and cancer-specific survival (CSS). Kaplan-Meier survival curves were compared using the log-rank test. Hazard analysis was conducted using the Cox proportional hazards model. A total of 701 patients were analyzed, which including 8 patients (1.1%) with synchronous LM, and 693 patients without synchronous LM (98.9%). Lower T or N classification, and highly differentiated disease were associated with a significantly lower risk of LM and multivariate logistic regression analysis showed that lower T classification were associated with a significantly lower risk of LM (P < 0.05, respectively). Elderly Caucasian male patients with poorly differentiated disease, multiple sites of metastases and no surgical therapy to primary tumor were more likely to reduce life expectancy. By analyzing data from a large cohort, lower T or N classification and highly differentiated disease were associated with a significantly lower risk of LM. Elderly Caucasian male patients with poorly differentiated disease, multiple sites of metastases and no surgical therapy to primary tumor were more likely to reduce life expectancy. More accurate assessments of LM will be imperative for early diagnosis and treatment in patients who harbored with higher T or N classification and poorly differentiated disease.

An association of epidermal growth factor receptor mutation subtypes with prognostic prediction and site-specific recurrence in advanced stage lung cancer patients.

Concerning the different clinical behavior of epidermal growth factor receptor (EGFR) subtypes in advanced-stage lung cancer patients, the current study aimed to evaluate the clinical, pathological, and prognostic significance of EGFR mutation subtypes, and treatment response in patients with advanced-stage lung cancer. A retrospective study enrolled a total of 346 patients with advanced-stage lung cancer tested for EGFR mutation. EGFR mutation was analyzed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Statistical analysis was performed using SPSS version 20.0. EGFR mutation was evident in 38% of patients with the highest prevalence of exon 19 deletions. A higher incidence of 19-deletions and 20-insertions were observed in young patients, while a higher incidence of L858R was noted in old age patients. Patients with de-novo T790M failed to improve their OS by any of the treatment modalities. Patients with de-novo T790M mutation have a higher risk of developing lung, liver, and multiple site metastases while patients with L858R mutation have a higher risk of developing brain metastasis. Additionally, patients with 19 deletion mutation did not improve their OS after receiving conventional chemotherapy hence, they demonstrate better survival only after EGFR-TKIs. Multivariate survival analysis predicted chemotherapy as an independent predictor of OS. Besides clinicopathological and prognostic consequences of EGFR mutation and mutation subtypes, patients harboring TKI sensitive, or insensitive mutations reveal different secondary disease development and hence should be treated accordingly for better survival. Current findings may provide the basis for a better treatment strategy.

Reversible epigenetic alterations mediate PSMA expression heterogeneity in advanced metastatic prostate cancer.

Prostate-specific membrane antigen (PSMA) is an important cell surface target in prostate cancer. There are limited data on the heterogeneity of PSMA tissue expression in metastatic castration-resistant prostate cancer (mCRPC). Furthermore, the mechanisms regulating PSMA expression (encoded by the FOLH1 gene) are not well understood. Here, we demonstrate that PSMA expression is heterogeneous across different metastatic sites and molecular subtypes of mCRPC. In a rapid autopsy cohort in which multiple metastatic sites per patient were sampled, we found that 13 of 52 (25%) cases had no detectable PSMA and 23 of 52 (44%) cases showed heterogeneous PSMA expression across individual metastases, with 33 (63%) cases harboring at least 1 PSMA-negative site. PSMA-negative tumors displayed distinct transcriptional profiles with expression of druggable targets such as MUC1. Loss of PSMA was associated with epigenetic changes of the FOLH1 locus, including gain of CpG methylation and loss of histone 3 lysine 27 (H3K27) acetylation. Treatment with histone deacetylase (HDAC) inhibitors reversed this epigenetic repression and restored PSMA expression in vitro and in vivo. Collectively, these data provide insights into the expression patterns and regulation of PSMA in mCRPC and suggest that epigenetic therapies - in particular, HDAC inhibitors - can be used to augment PSMA levels.

Abstract 1133: A B7-H4 targeting antibody-drug conjugate shows anti-tumor activity in PARPi and platinum resistant cancers with B7-H4 expression

Abstract Purpose: Platinum and PARP inhibitors (PARPi) demonstrate activity in breast and ovarian cancers, but drug resistance ultimately emerges. B7-H4 is over expressed in breast and ovarian cancer compared to normal tissues making it a promising target for therapies, however, to date it has not been evaluated if the expression is maintained in drug resistant cancer. Here we examine B7-H4 expression in high grade serous ovarian carcinoma (HGSOC) tumors at diagnosis and post-platinum or PARPi-resistance. We also evaluate the activity of a novel B7-H4-directed antibody-drug conjugate (ADC) bearing the pyrrolobenzodiazepine-dimer payload tesirine, in preclinical models of breast and ovarian cancer, including those resistant to standard of care therapies. Experimental Design: B7-H4 expression was measured by quantitative flow cytometry and immunohistochemistry. ADC efficacy was tested against multiple cell lines in vitro and patient-derived xenografts (PDX) in vivo. The effect of ADC treatment on cell cycle, DNA damage, and apoptosis was measured using flow cytometry. Results: B7-H4 was over-expressed in 92% of HGSOC tumors at diagnosis (n = 12), persisted in recurrent matched samples after platinum treatment, and was expressed at similar levels at multiple metastatic sites after acquired multi-drug resistance (n = 4 donors). Treatment with the ADC resulted in target-specific growth inhibition in a panel of ten B7-H4 expressing ovarian and breast cancer cell lines (IC50 6.18-273.9 pM, median 48.3 pM). Co-cultures of B7-H4 +/- lines support bystander killing effects leading to further tumor cell death in B7-H4- clones. In platinum- or PARPi-resistant ovarian cancer cells, ADC treatment significantly decreased viability and colony formation (P &amp;lt; 0.001) while increasing S or G2/M phase cell cycle arrest (P &amp;lt; 0.001) and DNA damage (P &amp;lt; 0.0001), ultimately leading to apoptosis (P &amp;lt; 0.01). A single 0.3 mg/kg dose of the ADC resulted in tumor regression in 61% of breast and ovarian PDX models tested (n = 23), where lower activity was identified in B7-H4 low or negative expressing models (P = 0.048). In PARPi- and platinum-resistant HGSOC models (n = 3), continuous B7-H4 ADC treatment (dosed once every 28 days) resulted in sustained anti-tumor activity, leading to complete (7 of 16) or partial responses (3 of 16) and increased survival (P &amp;lt; 0.004). Conclusions: These data support B7-H4 as an attractive ADC target for treatment of drug-resistant HGSOC. Citation Format: Sarah B. Gitto, Margaret Whicker, Gareth Davies, Sushil Kumar, Krista Kinneer, Arthur Lewis, Srinivas Mamidi, Sergey Medvedev, Judith Anderton, Jessica Tang, Benjamin Ferman, Steve Coats, Robert W. Wilkinson, Eric J. Brown, Daniel J. Powell, Fiona Simpkins. A B7-H4 targeting antibody-drug conjugate shows anti-tumor activity in PARPi and platinum resistant cancers with B7-H4 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1133.

Abstract 6642: Rapid tissue donation identifies LAG3 as a potential therapeutic target for ALK fusion positive lung cancer

Abstract Introduction: The rapid tissue donation (RTD) program provides post-therapy primary and metastatic tumor tissue samples at the time of death for the study of resistance mechanisms and the tumor microenvironment to inform therapeutic opportunities. NCCN guidelines (NCCN v5.2022) recommend against PD-1/PD-L1 inhibitor monotherapy in the second-line setting for ALK fusion+ non-small cell lung cancer (NSCLC) due to lack of efficacy, irrespective of tumoral PD-L1 expression. We observed high LAG3 protein expression by multiplex immunofluorescence (mIF) in postmortem ALK fusion-positive tumor tissue samples from 3 RTD donors who were treated with ALK inhibitors. Further studies are recommended to investigate the therapeutic potential of LAG3 inhibitors in this patient population. Case Series: Of the 38 patients with lung cancer tissue collected by RTD, 3 patients had ALK fusion and were treated with ALK inhibitors. Despite the initial response, all 3 patients succumbed to the disease. Tissue samples were collected from primary and multiple metastatic sites after death. Immune checkpoint markers, including LAG3, were quantitated via multiplex immunofluorescence staining, and genomic analyses were performed. Results: Analysis of two tissue microarrays comprised of 130 tumor cores from multiple tissue sites of the first 10 NSCLC RTD donors revealed that 66% of tumor cores had &amp;gt;1% LAG3 expression in CD3+ T cells. Among the three patients with ALK fusion-positive NSCLC, 83% (5 of 6 cores), 85% (6 of 7 cores), and 100% (18 of 18 cores) of the tissue cores had &amp;gt;1% LAG3 expression in T cells. The median LAG3 expression in T cells measured by mIF was 1.8% in 99 tumor cores from the ALK fusion-negative study cohort versus 7.3% in the 31 cores from the ALK fusion-positive subset (p=0.004). Postmortem genomic analyses revealed an ALK p.L1196M resistance mutation in the first patient and an AGK-BRAF fusion in the 2nd patient. No known ALK-TKI resistance mutations were detected in the 3rd patient. Discussion: High-quality post-therapy tumor samples collected by the RTD program enable the investigation of genomic and potential immune-related resistance mechanisms. Such studies can inform potential targets for drug development and the study of new therapies to overcome treatment resistance. Our observation of high LAG3 expression in 3 RTD donors with ALK fusion-positive NSCLC suggests the need for further studies to explore the potential for LAG3 inhibitors in patients with NSCLC whose tumors develop resistance to ALK inhibitors. Citation Format: Hilal Ozakinci, Gina Nazario, Karina Colossi Furlan, Dung-Tsa Chen, Trevor Rose, Matthew B. Schabath, Eric B. Haura, Bruna Pellini, Amer Beg, Theresa A. Boyle. Rapid tissue donation identifies LAG3 as a potential therapeutic target for ALK fusion positive lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6642.

Analysis of prognosis and associated factors in multiple recurrent epithelial ovarian cancer with three times or more cytoreductive surgeries

Objective: To explore the prognosis of epithelial ovarian cancer patients with multiple recurrences (≥2 times) who underwent three times or more cytoreductive surgeries, and to analyze the factors associated with prognosis. Methods: The clinicopathological data and follow-up data of 23 patients with ovarian cancer admitted to the Obstetrics and Gynecology Hospital of Fudan University from January 1, 2015 to January 30, 2022 with three times or more cytoreductive surgeries were collected. The degree of surgical resection, site of recurrence and metastasis, postoperative complications, and prognosis were retrospectively analyzed. The univariate Cox proportional hazards model was performed to identify the variables associated with survival. Results: (1) The median age of 23 patients with multiple recurrent ovarian cancer was 48 years old (44-55 years). Among them, 18 cases underwent tertiary cytoreductive surgery (TCS), 2 cases underwent quaternary cytoreductive surgery, 2 cases underwent quinary cytoreductive surgery, and 1 case underwent senary cytoreductive surgery. Among the 23 patients with multiple recurrent ovarian cancer, 21 cases (91%, 21/23) had serous carcinoma, 16 cases (70%, 16/23) had advanced stage (stage Ⅲ-Ⅳ), and 19 cases (83%, 19/23) had high differentiation. (2) Based on the premise that satisfactory cytoreduction was achieved by primary debulking surgery (PDS) and no visible residual disease (R0) was achieved by secondary cytoreductive surgery (SCS), the maximum diameter of the recurrent tumors was up to 10.0 cm and 62% (20/32) of patients with multiple metastatic sites. The R0 rate for three times or more cytoreductive surgeries (32 times in total) reached 88% (28/32), with a postoperative complication rate of 47% (15/32), and only 3% (1/32) for grade Ⅲ or above. During a median follow-up time of 31.1 months (20.6-43.9 months) after TCS, 20 patients (87%, 20/23) recurred after TCS, and 8 patients (35%, 8/23) eventually died of ovarian cancer. Among them, the three-year postoperative survival rate of 22 patients with R0 was 57.6%, and the patient with residual lesions ≥1 cm died at 9.2 months after TCS. (3) In univariate analysis, ages, the time interval between PDS and SCS >32 months, the interval between SCS and TCS >16 months, and no metastatic peritoneal carcinoma were associated with longer progression free survival after TCS (all P<0.05); while treatment-free interval (TFI) >10 months after SCS, the interval between SCS and TCS >16 months, no ascites and platinum-sensitive status were associated with disease-specific survival after TCS (all P<0.05). Conclusions: It is feasible to perform three times or more cytoreductive surgeries in patients with multiple recurrent ovarian cancer who are expected to achieve R0 and have manageable complications. However, the pros and cons of surgery need to be carefully evaluated for the patients whose ascites are massive and whose previous cytoreduction does not achieve R0. A prolonged TFI and previously longer surgical interval might get potential survival benefits.

Real-world time trends in overall survival, treatments and patient characteristics in HR+/HER2- metastatic breast cancer: an observational study of the SONABRE Registry.

This study aims to evaluate whether changes in therapeutic strategies have improved survival of patients diagnosed with hormone receptor positive (HR+), HER2 negative (HER2-) advanced breast cancer (ABC) in real-world. All 1950 patients systemically treated for HR+/HER2- ABC and diagnosed between 2008 and 2019 in eight hospitals were retrieved from the SONABRE Registry (NCT-03577197). Patients were categorized per three-year cohorts based on year of ABC diagnosis. Tests for trend were used to examine differences in baseline characteristics, Kaplan-Meier methods and Cox proportional hazards for survival analyses, and competing-risk methods for 3-year use of systemic therapy. Over time, patients were older (≥70 years, 37%, n=169/456 in 2008-2010, 47%, n=233/493 in 2017-2019, p=0.004) and more often had multiple metastatic sites at ABC diagnosis (48%, n=220/456 in 2008-2010, 56%, n=275/493 in 2017-2019, p=0.002). Among patients with metachronous metastases the prior exposure to (neo-) adjuvant therapies increased over time (chemotherapy, 38%, n=138/362 in 2008-2010, 48%, n=181/376 in 2017-2019, p=<0.001; endocrine therapy, 64%, n=231/362 in 2008-2010, 72%, n=271/376 in 2017-2019, p=<0.001). Overall survival significantly improved from median 31.1 months (95% CI:28.2-34.3) for patients diagnosed in 2008-2010 to 38.4 months (95% CI:34.0-41.1) in 2017-2019 (adjusted hazard ratio=0.76, 95% CI:0.64-0.90; p=0.001). Three-year use of CDK4/6 inhibitors increased from 0% for patients diagnosed in 2008-2010 to 54% for diagnosis in 2017-2019. Conversely, three-year use of chemotherapy was 50% versus 36%, respectively. Over time, patients diagnosed with HR+/HER2- ABC presented with less favourable patient characteristics. Nevertheless, we observed that overall survival of ABC increased between 2008 and 2019, with increased use of endocrine/targeted therapies. The SONABRE Registry is supported by the Netherlands Organization for Health Research and Development (ZonMw: 80-82500-98-8003); Novartis BV; Roche; Pfizer; and Eli Lilly & Co. Funding sources had no role in the writing of the manuscript.

Vertical level of blood cell division cycle 42 predicts response and survival benefits to PD-1 inhibitor-based regimen in metastatic colorectal cancer patients

Cell division cycle 42 (CDC42) regulates the development of colorectal cancer (CRC) by modulating cancer malignant behaviors and facilitating immune escape. Hence, this study aimed to explore the correlation of blood CDC42 with treatment response and survival benefit to programmed cell death-1 (PD-1) inhibitor-based regimens in inoperable metastatic CRC (mCRC) patients. Fifty-seven inoperable mCRC patients who received PD-1 inhibitor-based regimens were recruited. The CDC42 in peripheral blood mononuclear cell (PBMC) was detected using RT-qPCR in inoperable mCRC patients at baseline and after 2-cycle treatment. Besides, PBMC CDC42 in 20 healthy controls (HCs) was also detected. CDC42 was higher in inoperable mCRC patients compared to HCs (p < 0.001). Elevated CDC42 was related to a higher performance status score (p = 0.034), multiple metastatic sites (p = 0.028), and the presence of liver metastasis (p = 0.035) in inoperable mCRC patients. During the 2-cycle treatment, CDC42 was reduced (p < 0.001). Higher CDC42 at baseline (p = 0.016) and after 2-cycle treatment (p = 0.002) were both linked with decreased objective response rate. CDC42 high at baseline was related to shorter progression-free survival (PFS) (p = 0.015) and overall survival (OS) (p = 0.050). Moreover, CDC42 high after 2-cycle treatment was also related to unfavorable PFS (p < 0.001) and OS (p = 0.001). After adjustment using multivariate Cox’s analyses, CDC42 high after 2-cycle treatment independently related to shorter PFS (hazard ratio (HR): 4.129, p < 0.001), and CDC42 reduction ≤230% also independently correlated with shorter OS (HR: 4.038, p < 0.001). The longitudinal change of blood CDC42 during PD-1 inhibitor-based regimen estimates treatment response and survival in inoperable mCRC patients.