Shorter Progression-free Survival Research Articles

Absolute Lymphocyte Count after BCMA CAR-T Therapy is a Predictor of Response and Outcomes in Relapsed Multiple Myeloma.

BCMA-targeting CAR-T cells used in multiple myeloma (MM) are rapidly becoming a mainstay in the treatment of relapsed/refractory (RR) disease, and CAR-T cell expansion post-infusion has been shown to inform depth and duration of response, but measuring this process remains investigational. This multicenter study describes the kinetics and prognostic impact of absolute lymphocyte count (ALC) in the first 15 days after CAR-T infusion in 156 relapsed MM patients treated with the BCMA-targeting agents cilta-cel and ide-cel. Patients with higher maximum ALC (ALCmax) had better depth of response, progression-free survival (PFS), and duration of response (DoR). Patients with ALCmax >1.0 x103/uL had a superior PFS (30.5 versus 6 months, p <0.001) compared to those ≤1.0x103/uL, while patients with ALCmax ≤0.5 x103/uL represent a high-risk group with early disease progression and short PFS (HR 3.4, 95 CI: 2 -5.8, P <0.001). In multivariate analysis, ALCmax >1.0 x103/uL and non-paraskeletal extramedullary disease were the only independent predictors of PFS and DoR after accounting for ISS staging, age, CAR-T product, high-risk cytogenetics and number of previous lines. Moreover, our flow cytometry data suggests that ALC is a surrogate for BCMA CAR-T expansion and can be used as an accessible prognostic marker. We report for the first time the association of ALC after BCMA CAR-T infusion with clinical outcomes and its utility in predicting response in RRMM patients.

Decline in Smartphone-Assessed Physical Activity Level is Associated With Clinical Outcomes in Phase I/II Clinical Cancer Trials.

A decline in physical function may be an early predictor for complications of cancer treatment. This study examined whether repeated objective smartphone measurements of physical activity and exercise capacity in patients with cancer are feasible during early-phase clinical trials (EPCTs) and whether a decline in physical function is associated with clinical outcomes. Physical activity (steps/day) and exercise capacity (6-minute walk test [6MWT]) were measured with a smartphone before EPCT start (T0) and after 4 weeks (T1) and 8 weeks (T2). Univariable logistic regression analyzed associations between a decline in step count (≥20%), 6MWT distance (≥10%), or deterioration of ECOG performance status (PS) and trial discontinuation at 8 weeks and 90 days. Cox proportional hazards models were used to examine associations with progression-free survival (PFS) and overall survival (OS), adjusting for trial phase (I vs II), cancer type (hematologic malignancy vs solid tumor), and PS (0 vs ≥1). Among 117 included patients, valid step count and 6MWT measurements were available for 96.6% and 76.7% of patients at T0, 74.4% and 53.3% at T1, and 89.7% and 54.4% at T2, respectively. Patients experiencing step count decline between T0 and T1 had higher odds of trial discontinuation at 8 weeks (odds ratio, 8.67; 95% CI, 1.94-61.43), and decline between T1 and T2 was associated with discontinuation at 90 days (odds ratio, 5.20; 95% CI, 1.43-21.14). Step count decline was significantly associated with shorter PFS (hazard ratio, 3.54; 95% CI, 2.06-6.08) and OS (hazard ratio, 2.31; 95% CI, 1.26-4.23). Declines in 6MWT distance or deterioration in ECOG PS were not associated with trial discontinuation or survival. Repeated smartphone measurements of physical activity are feasible in patients participating in EPCTs. Additionally, physical activity decline is significantly associated with trial discontinuation, PFS, and OS. Hence, we envision that objective smartphone measurements of physical activity will contribute to optimal treatment development for patients with cancer.

A retrospective analysis of the clinicopathological features and prognostic value of MAPK12 protein expression in diffuse large B-cell lymphoma.

Mitogen-activated protein kinase 12 (MAPK12), also known as p38γ, is a member of the p38 MAPK family and plays a crucial role in tumor occurrence and invasion. However, there is still uncertainty regarding MAPK12 involvement in diffuse large B-cell lymphoma (DLBCL). Our study investigated the expression of MAPK12 mRNA in various types of cancer using bioinformatic analysis. Furthermore, we performed immunohistochemistry (IHC) to detect the expression of MAPK12 in patients with DLBCL and compared clinical indicators and survival rates. We found that the high expression rate of MAPK12 was 43.1% in DLBCL patients. Several clinical indicators, including IPI scores, Hans classifications, LDH levels, and Ki-67 expression were closely associated with MAPK12 expression. Survival analysis revealed that higher expression of MAPK12 was significantly correlated with shorter progression-free survival (PFS) and overall survival (OS) in DLBCL patients. In addition, both univariate and multivariate analyses revealed IPI score, MAPK12 expression, and rituximab use as the independent OS risk factors (P < 0.05). To explore the functional role of MAPK12 in DLBCL, weighted gene co-expression network analysis (WGCNA) and gene ontology (GO) were used to confirm the involvement of MAPK12 in the regulation of type II interferon production, positive regulation of lymphocyte proliferation, and other related biological processes. DLBCL patients have poor prognoses when MAPK12 levels are high, which is expected to be a therapeutic target and prognostic factor.

Histologically Overt Stromal Response and the Risk of Progression after Radical Prostatectomy for Prostate Cancer.

Given the variable clinical course of prostate cancer and the limitations of current prognostic factors, this study was conducted to investigate the impact of a histologically overt stromal response (HOST-response) to prostate cancer on clinical outcomes after radical prostatectomy. This retrospective analysis utilized The Cancer Genome Atlas (TCGA) to evaluate data from individuals with a confirmed diagnosis of prostate cancer who underwent radical prostatectomy and had available pathology slides. These slides were assessed for the presence of a HOST-response, similar to desmoplasia. The primary endpoint was progression-free survival (PFS). A multivariable competing risk regression analysis was used to assess whether a significant association existed between HOST-response and PFS, adjusting for known prostate cancer prognostic factors. Among the 348 patients analyzed, 166 (47.70%) demonstrated a HOST-response. After a median follow-up of 37.87 months (IQR: 21.20, 65.50), the presence of a HOST-response was significantly associated with a shorter PFS (SDHR, 2.10; 95% CI, 1.26 to 3.50; p = 0.004), after adjusting for covariates. HOST-response in prostate cancer patients treated with radical prostatectomy is significantly associated with reduced PFS, suggesting a potential benefit from adjuvant therapy and highlighting the need for further investigation in a prospective randomized clinical trial.

Abstract PO1-14-08: Real-world clinical genomics study of HR+/HER2- metastatic breast cancers treated by CDK4/6i plus endocrine therapies revealed a drug resistant tumor segment characterized by ER independence

Abstract Background CDK4/6 inhibitors (CDK4/6i) plus endocrine therapies (ET) are the standard-of-care for hormone receptor–positive/human epidermal receptor 2–negative metastatic breast cancer (HR+/HER2− mBC). However, drug resistance remains a major unmet need. Investigations of drug resistance mechanisms has been hampered by a dearth of tumor molecular profiling data from the post-treatment setting. To address this challenge, we have conducted a real-world clinical genomics study to better understand the molecular mechanism of CDK4/6i resistance as well as to stratify patients based on integrated multi-omics profiles. Methods We retrospectively analyzed a multi-omics dataset of 400 HR+/HER2- mBC patients who had received CDK4/6i plus ET and developed progressive disease (PD) from the de-identified Tempus database. Pre-treatment and post-progression biopsies were taken  1 year prior to starting the CDK4/6i treatment or following PD respectively. Tempus xT next-generation sequencing (DNA-seq of 648 genes) and RNA sequencing assays were performed on 427 tumor FFPE samples, including 200 pre-treatment, 227 post-progression and 26 longitudinal pairs. Results The median age of the patients was 57 (54.9-57.4) and median progression free survival (PFS) is 379 (341-433) days. Two genes were found to harbor a significant increase in genomic alteration frequencies (GAF) after adjusting for FDR at post-progression vs. pre-treatment – ESR1 (41.9% vs. 15%, p=5.4e-10), RB1 (13.2% vs. 3%, p=8.5e-05). ESR1 and RB1 also harbored high frequencies of acquired genomic alterations among 26 paired samples at 34.6% and 11.5% respectively. TP53 mutation at baseline was significantly associated with shorter PFS at baseline (p=4.23e-05, HR=2.081) and TP53 GAF significantly increased after PD (37% vs. 28.5%, p=0.039). BRCA1/2 pathogenic mutations (p=1.63e-04, HR=3.066), APOBEC mutation signature S13 (p=0.0125, HR=1.55) and CCNE1 gene expression (p=0.024, HR=1.46) were significantly associated with shorter PFS. APOBEC signature (p=0.0035) and CCNE1 expression (p=1.33e-06) also significantly increased post-progression. Among the top molecular features associated with longer PFS were markers of estrogen signaling such as PGR gene expression (p=6.76e-04, HR=0.565) and the Hallmark estrogen response signature (p=0.021, HR=0.679). Applying a multi-omics pattern recognition algorithm, we identified a molecularly distinct cluster (IC1) characterized by down-regulation of estrogen signaling. IC1 is significantly associated with shorter PFS (p=3.72e-05, HR=0.22) and increased from 4% pre-treatment to 23% post-progression (p=7.3e-08). Further, IC1 is strongly enriched in markers previously implicated in CDK4/6i resistance including CCNE1 expression, RB1 mutation and MYC/E2F activation. We then developed machine learning models to predict gene-level dependency trained on cancer cell line expression and CRISPR-KO screen data. These models predicted decreased dependency on ESR1 and CDK4 and increased dependency on CDK2 in IC1, strengthening the association between ER independence and CDK4/6i resistance. Conclusions Our real-world clinical genomics study identified a comprehensive list of biomarkers associated with resistance to CDK4/6i plus ET and estimated patient prevalence for these markers in the post-treatment setting. Integrated and machine-learning analyses identified a subset of aggressive tumors with estrogen independence characteristics that are implicated in CDK4/6i resistance and suggested new therapeutic strategies. Citation Format: Zhengyan Kan, Ji Wen, Jennifer Webster, Vinicius Bonato, Whijae Roh, Xinmeng Jasmine Mu, Paul Rejto, Jadwiga Bienkowska. Real-world clinical genomics study of HR+/HER2- metastatic breast cancers treated by CDK4/6i plus endocrine therapies revealed a drug resistant tumor segment characterized by ER independence [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 PO1-14-08.

Abstract PO2-13-11: High circulating tumor DNA (ctDNA) concentration was associated with shorter progression free survival in patients with metastatic breast cancer

Abstract Background: Metastatic breast cancer can be classified into different subtypes depending on hormone receptor (HR) and HER2 status. The subtype can change during tumor progression, and repeated biopsy is needed to deliver the most appropriate treatment every time a new lesion is found. It is not always possible to get a new biopsy from metastatic sites, and therefore liquid biopsy using circulating tumor DNA (ctDNA) is suggested as an alternative method to replace conventional biopsy. Methods: We performed a prospective serial collection of 65 ctDNA samples from 17 patients with metastatic breast cancer (mBC) at Seoul National University Hospital from October 2020 to March 2022. We used IMBdx AlphaLiquid®100 method to detect the genetic changes and analyzed the correlation with clinical outcomes. Results: Median age was 45 (range 32 – 62). Fifteen patients (88.2%) were relapsed mBC and most of the patients (14/17: 82.4%) were HR-positive and HER2-negative. Most of the patients had their ctDNA examined at baseline and at the time of maximal response and/or at progression. Fifteen patients (88.2%) received systemic therapy including hormone therapy, anti-HER2 therapy, and cytotoxic chemotherapy. Eight patients (47.1%) were on the first-line treatment for mBC, and 7 patients (41.2%) were on the second or later lines for mBC at the time of baseline sampling. The concentration of ctDNA and the sum of mutated allelic frequency was calculated for each sample. The ctDNA concentration ranged from 0.71 to 1386.00 ng/mL, and the median value was 5.37 ng/mL. We dichotomized these samples into two groups, with ctDNA concentration either higher or lower than the median value. Then we analyzed progression free survival (PFS) of each group. Patients with higher ctDNA concentration showed shorter PFS (7 mo. vs. not reached, p&amp;lt; 0.001). The sum of mutated allelic frequency ranged from 0.00% to 223.46% and the median value was 6.36%. Patients with higher mutated allelic frequency showed shorter PFS (6 mo. vs. 22 mo., p&amp;lt; 0.001). In addition, the PFS was significantly worse in patients who had mutated PIK3CA (5 mo vs. 22 mo, p&amp;lt; 0.001). The patients with mutated TP53 also showed shorter PFS (6 mo vs. 17 mo, p&amp;lt; 0.001) in univariate analysis. High estrogen receptor positivity in immunohistochemistry was correlated with lower mutated allelic frequency in ctDNA (p=0.003) but had no impact on the concentration of ctDNA (p=0.165). The concentration of ctDNA differed by metastatic sites. Patients with metastases to bones (p=0.007), liver (p&amp;lt; 0.001), soft tissue or lymph nodes (p=0.002) were more likely to have higher concentrations of ctDNA, while patients with brain metastases had significantly lower ctDNA concentration (p=0.006). When the sum of mutated allelic frequency of ctDNA and metastatic sites was analyzed, bone (p=0.001), liver (p&amp;lt; 0.001), and soft tissue or lymph node (p&amp;lt; 0.001) metastases had a positive correlation, while brain had negative correlation (p=0.017). Lung or pleural metastases had no significant correlation with ctDNA, neither concentration (p=0.271) nor mutated allelic frequency (p=0.965). Conclusion: Patients with mBC with higher concentrations of ctDNA or higher mutated allelic frequency of ctDNA at baseline showed significantly shorter PFS. PIK3CAmt and TP53mt detected by liquid biopsy could be used as a poor prognostic biomarkers for mBC patients. Citation Format: Hanbaek Yi, Tae-Yong Kim, Myung Geun Song, Hwang-Phill Kim, Tae-You Kim, Jinyong Kim, Dae-Won Lee, Kyung-Hun Lee, Seock-Ah Im. High circulating tumor DNA (ctDNA) concentration was associated with shorter progression free survival in patients with metastatic breast cancer [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 PO2-13-11.

Abstract PO5-18-11: Use of DiviTum®TKa as a biomarker assay for CDK4/6 inhibitor medication compliance and drug-drug interaction assessment in ER/PR positive metastatic breast cancer

Abstract Background: CDK4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) is standard first line (1L) treatment for metastatic hormone positive (ER/PR+) HER2- negative breast cancer (mBC). Some patients have progression free survival (PFS) of 2 years or more whereas some patients have very short PFS on these medications. Thymidine kinase is a biomarker that reflects cell proliferation. DiviTum®TKa is an assay that was cleared by the FDA in July 2022 based on data that showed that thymidine kinase activity (TKa) value of &amp;lt; 250 DiviTum units (DuA) is associated with the decreased likelihood of disease progression within 30 days or 60 days post testing. The purpose of this study is to assess the use of TKa as a biomarker for identifying potential medical compliance issues and drug-drug interactions (DDI) in patients on CDK4/6i and to evaluate whether counseling and optimization of concurrent medications will lead to lower TKa levels in subsequent treatment cycles and possibly longer PFS. Trial design: This is a pilot study to assess whether TKa can serve as a biomarker to identify patients with a suboptimal reduction in tumor cell proliferation caused by a potential CDK4/6i compliance or DDI issue. We will also assess whether correction of the issue can improve suppression of TKa levels in ER/PR+ mBC patients on 1L CDK4/6i and ET. For screening, we are utilizing a novel automated real-time data driven cohort identification system designed by Dr. Guannan Gong at Yale. Patients will be treated and monitored as per standard of care. An aliquot of serum obtained during routine blood draws will be sent to a CLIA-certified Biovica lab for TKa testing. TKa results will be returned in real time. Patients with a detectable TKa baseline level (above 145 DuA), followed by a sustained TKa level (&amp;gt;145 DuA) at cycle 1 D15 and D28 will be assessed for medication compliance and DDI. TKa levels will be repeated at subsequent standard of care blood draws to assess if the intervention affected TKa levels. Patients will be followed for 2 years. Eligibility criteria: Participants must have ER+ mBC and starting 1L CDK4/6i + ET and be previously CDK4/6i -naïve. Specific aims: Primary objective: to estimate the rate of improvement in CDK4/6i response (change in TKa levels) after counseling for medication compliance and adjustment of potential deleterious DDIs. Secondary objectives: 1) estimate the rate of sub-optimal CDK 4/6i response in cycle 1 of treatment. 2) Compare clinical benefit rate (CBR) in patients with sub-optimal and optimal CDK4/6i response after both cycles 1 and cycle 3. 3) Compare PFS in patients with sub-optimal and optimal CDK 4/6i response after both cycles 1 and cycle 3. 4) Assess CDK4/6i response via TKa levels upon CDK4/6i dose reductions or changes in CDK4/6i regimens. 5) Compare CDK4/6i response profiles across the three CDK 4/6i among different patients and within the same patients if CDK4/6i is changed throughout treatment course. 6) Correlate TKa levels with tumor marker levels. 7) Assess plasma concentrations of CDK4/6i in patients with suboptimal TKa levels. Statistical methods: For binary endpoints measured at a given time point, we will estimate the two-sided 95% exact CI using Clopper-Pearson method. With a sample size of 120 patients, assuming 20% drop out rate, we predict that about 15% of patients will have suboptimal CDK4/6i response, estimating a 95% CI of 0.086-0.235 in the first cycle. Comparisons between paired outcomes will be completed using the paired t-test or Wilcoxon signed-rank test for continuous parameters of interest, or McNemar’s Chi-square test for categorical parameters of interest. Time to event endpoints will be estimated using Kaplan-Meier method. Present accrual and target accrual: This trial has just been activated. Target accrual is 120 patients. Contact information for people with a specific interest in the trial: Mariya.Rozenblit@yale.edu Citation Format: Mariya Rozenblit, Adriana Kahn, Guannan Gong, Amy Williams, Lajos Pusztai. Use of DiviTum®TKa as a biomarker assay for CDK4/6 inhibitor medication compliance and drug-drug interaction assessment in ER/PR positive metastatic breast cancer [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 PO5-18-11.

Abstract PO5-04-11: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) beyond progression in hormone receptor positive advanced breast cancer: a systematic review and meta-analysis

Abstract Introduction The use of CDK 4/6i (palbociclib/ribociclib/abemaciclib) with endocrine therapy (ET) is a widely adopted first line standard treatment for hormone receptor positive advanced breast cancer (HR+ABC). Data supporting incorporation of CDK 4/6i ± ET beyond progression are less clear. Recent studies have evaluated either the continuation of or switching to a different CDK 4/6i, with a change in ET after progression on 1st line CDK4/6i with varying results. A pooled analysis of this strategy could be useful for clinical decision making. Methods We reviewed reports of both observational and clinical studies that evaluated continuing the same CDK4/6i or switching to a different agent after progression on first line CDK4/6i with ET. The search included the grey literature without exclusions for publication year or language. The mean overall response rate (ORR), clinical benefit rate (CBR) and progression free survival (PFS) weighted by study sample size were calculated. Meta-regression comprising linear regression weighted by sample size (mixed effects) was performed to explore the association between disease and treatment-related factors and benefit from continuing a CDK4/6i. Quantitative significance was assessed using the Burnand criteria. Analyses were performed using SPSS version 28 (IBM Corp, Armonk NY). Results Thirteen studies (N=1006 patients) were included; 7 were prospective trials and 2 cohorts of the same retrospective study included separately). Study patients had a median age of 57.8 years and 66% had visceral metastases. Among patients whose type of first-line CDK 4/6i exposure was reported (84.5%), 81.21% received Palbociclib 3.28% received Ribociclib and 0.89% received Abemaciclib. Six patients received both Palbociclib and Ribociclib. The median duration of first line CDK 4/6i therapy was 13.8 months. In the second line,the mean ORR was 12.8%, CBR 38.8%, and median PFS was 4.6 months. The ORRs for Palbociclib, Ribociclib and Abemaciclib, irrespective of type of prior CDK 4/6i, were 7.3%, 14.7% and 18.6%, respectively. The CBR for Palbociclib, Ribociclib and Abemaciclib were 33.1%, 42.2% and 46.8%, respectively. The median PFS based the CDK 4/6i used in second line was 4.2 (Palbociclib), 5.5 (Ribociclib) and 9.2 (Abemaciclib) months. Meta-regression analysis of PFS is included in the table. Conclusion Continuing a CDK 4/6i± ET beyond progression yields modest benefits. Switching CDK4/6i offers slightly better ORR and PFS. Continuing Palbociclib beyond progression does not seem beneficial. Longer duration of CDK4i exposure in the first line appears to be associated with shorter PFS in the second line. Small number of studies with limited number of patients likely affect results. Meta-regression analysis of PFS of CDK 4/6i with or without ET in subsequent line of therapy. Citation Format: Neha Pathak, Sudhir Kumar, Diego Malon Gimenez, Massimo Di Iorio, Consolacion Molto Valiente, Danielle Cuthbert, Meredith Li, Atul Batra, Michelle Nadler, Eitan Amir, Abhenil Mittal. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) beyond progression in hormone receptor positive advanced breast cancer: a systematic review and meta-analysis [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 PO5-04-11.

Abstract PO2-27-05: Composite biomarkers for the prediction of progression-free survival with CDK4/6 inhibitors in metastatic HR+/HER2- breast cancer

Abstract CDK4/6 inhibitors are widely used in combination with endocrine therapy in the treatment of HR+/HER2- metastatic breast cancer. Generally the CDK4/6 inhibitors lead to a doubling of progression-free survival (PFS) over single agent endocrine therapy. In spite of a known mechanism of action, biomarkers to define the duration of response to CDK4/6 inhibitors with either aromatase inhibitors (AI) or fulvestrant (FUL) remain lacking. A cohort of over 300 patients receiving standard of care CDK4/6 inhibitor combination therapy for metastatic disease were consented for participation (NCT04526587). The duration of PFS in both AI and FUL treated sub-groups were comparable to that observed in randomized clinical trials. In this cohort progesterone receptor-status (HR 0.70, p=0.0123), visceral disease (HR 1.55, p=0.0013), prior endocrine therapy (HR 2.34, p&amp;lt; 0.001), and type of endocrine therapy (HR 2.16, p&amp;lt; 0.001) were associated with duration of PFS. To develop biomarkers, gene expression analyses was performed on 313 tumor samples representing over 200 individual patients. Focusing on the pre-treatment metastatic biopsy, established signatures associated with prognosis in HR+/HER2- breast cancer were employed to determine association with response to combination therapy in the metastatic setting. Proliferation-associated signatures were associated with shorter PFS. For example, an established RB loss signature was associated with PFS in both AI (HR 1.9, p=0.009) and FUL (HR 2.8, p=0.007) treated patients. Clinically employed signatures (e.g. OncotypeDx and Mammaprint) harbored variable associations with outcomes. Random Survival Forest feature selection was applied to individual and combined prognostic signatures. This approach resulted in a potent classifier for progression-free survival (HR 10, p&amp;lt; 1E-20). To enable applicability to different manifestations of disease, significant clinical pathological variables were incorporated into the model so that there was equivalent performance in AI and FUL treated patients for prediction of PFS. This predictive algorithm was also strongly associated with overall survival (HR 4.6, p=2.7E-8). Ongoing studies are evaluating the algorithms prospectively in NCT04526587. Citation Format: Agnieszka Witkiewicz, Jianxin Wang, Erik Knudsen, Ellis Levine, Tracey O'Connor. Composite biomarkers for the prediction of progression-free survival with CDK4/6 inhibitors in metastatic HR+/HER2- breast cancer [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 PO2-27-05.

Abstract PS12-02: Exploration of ctDNA Dynamics in the PACE Trial: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab for HR+/HER2- Metastatic Breast Cancer

Abstract Background The PACE trial for HR+/HER2- metastatic breast cancer (MBC) prospectively evaluated whether continuation of the CKD4/6 inhibitor (CDK4/6i) palbociclib (P) beyond progression on prior CDK4/6i and aromatase inhibitor (AI), with a change in endocrine therapy (ET) to fulvestrant (F), improved outcomes beyond change to F alone, as well as explored the activity of a palbociclib, fulvestrant, and avelumab (P+F+A) triplet. The primary analysis did not show improvement in progression-free survival (PFS) with F+P versus F alone. In this analysis, an evaluation of serial translational PACE samples was performed to gain insights into the mutational landscape of HR+/HER2- MBC after prolonged exposure to CDK4/6i, evaluate early mutational dynamics with ongoing therapy, and identify potential genetic markers predictive of treatment response. Additionally, the identification of acquired mutations at the time of tumor progression could provide valuable information about mechanisms of treatment resistance. Methods PACE is a multicenter randomized open-label investigator-initiated phase II trial. Eligible patients (pts) had HR+/HER2- evaluable MBC with prior progression on AI and any CDK4/6i after &amp;gt; 6 months (mo) of therapy in the MBC setting, or during/within 12 mo in the adjuvant setting, with no more than 1 prior line of chemotherapy for MBC. Pts were randomized 1:2:1 to F alone, F+P, or F+P+A, with tumor assessments every 8 weeks. Correlative samples including circulating tumor DNA (ctDNA) were collected at baseline (BL), times of tumor assessments (C3D1), and end of study/progression (EOT). Targeted NGS (Guardant360) to evaluate mutations (somatic single nucleotide variants and indels) was performed. Kaplan-Meier survival curves were used for assessing PFS and the log-rank test for comparisons. McNemar’s test with continuity correction was used to test the changes in the frequency of mutations. Results Of the 220 randomized pts, 211 contributed ctDNA samples (200 at BL, 129 at C3D1, 146 at EOT). Characteristics of the correlative science population were similar to the intention to treat population. At BL, the most common mutations observed were ESR1 (57%), TP53 (38%), PIK3CA (36%), GATA3 (20%) ATM (12%) and Rb1 (12%). The presence of a PIK3CA mutation vs WT-PIK3CA at BL was associated with shorter PFS in the F alone arm (p=0.001) but not in the F+P or F+P+A arms. ESR1 mutations present at baseline were D538G (34%), Y537S (21%), Y537N (15%), E380Q (10%) and L536H (4%). At C3D1, the most common mutations observed were ESR1 (47%), TP53 (33%), PIK3CA (26.1), GATA3 (18.1), ATM (13%) and PTEN (8.6%). Including only BL and C3D1 matched samples (N=124), the prevalence of ESR1 mutations decreased after 2 cycles of treatment (57% at BL vs 44% at C3D1), predominantly observed in the F+P+A arm. For those in any arm with at least 6 months of disease stability on study (N=53), the presence of an ESR1 D538G mutation decreased during therapy, with 38% having a mutation at BL, 24% at C3D1, and no pts gaining ESR1 D538G at C3D1. The prevalence of PIK3CA mutations also decreased on treatment (32% at BL to 24% at C3D1), with the greatest decrease in the F+P arm. A predictive model correlating early genomic dynamics and associations with outcome will be presented. Conclusions The PACE trial offers one of the largest clinical trial cohorts describing the genomic landscape of HR+/HER2- MBC post-CDK4/6 exposure. Results from this correlative study provide a comprehensive mutational landscape post-CDK4/6i, demonstrate associations between mutations and clinical outcomes, and suggest the potential value of early ctDNA dynamics in this setting. Citation Format: Rinath Jeselsohn, Jingxin Fu, Yue Ren, Reshma Mahtani, Cynthia Ma, Angela DeMichele, Massimo Cristofanilli, Jane Meisel, Kathy Miller, Yara Abdou, Elizabeth Riley, Rubina Qamar, Priyanka Sharma, Sonya Reid, Naomi Ko, Yuan Liu, Harold Burstein, Michelle DeMeo, Sara Tolaney, Erica Mayer. Exploration of ctDNA Dynamics in the PACE Trial: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab for HR+/HER2- Metastatic Breast Cancer [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 PS12-02.

Abstract PO1-16-02: Correlation of Circulating Tumor Cells (CTC) with Clinical Characteristics, Pathological Factors, and Treatment Response in Patients with Metastatic Breast Cancer (MBC)

Abstract Background: Circulating Tumor Cells (CTC) can be isolated in 40-80% of patients with metastatic breast cancer (MBC). High levels of CTC, defined as ≥5/7.5 ml of blood are associated with shorter progression-free survival and overall survival. CTC can be tested for clinically relevant biomarkers, such as ER, and HER2 status, and have the potential to guide therapy as well as help with disease monitoring. We investigated CTC detection rate, its correlation with clinical characteristics, pathological characteristics, and response to treatment in patients with any type of metastatic breast cancer who progressed on at least one line of therapy. Methods: Eligible patients with MBC were enrolled in the IMAGE-II study (Individualized Molecular Analyses Guide Efforts in Breast Cancer) NCT02965755, in which we obtained archival tissue as part of the standard of care, and prospectively collected serial blood samples for CTC analysis. We compared CTC levels and biomarker status with clinical factors, tissue-based pathology, and molecular biomarkers. We assessed whether changes in CTC count correlated with treatment response. Blood samples were collected at baseline (Day 1), after 1-2 weeks of therapy, after 8-12 weeks, and at subsequent restaging (every 8-12 weeks). Medical records were reviewed every 3 months for ongoing treatment response, and death. Samples were processed at the Biocept CLIA-certified Laboratory. CTC were enumerated by the presence of CD45- and DAPI+ cells. Further CTC characterization was performed by antibody staining of specific protein biomarkers (ER, HER2). Fisher’s exact test was used to evaluate the association between baseline CTC &amp;lt; 5 and ≥5/7.5ml with patient characteristics. McNemar’s test was used to assess discordance between tissue-based and CTC-defined markers. Results: Between 1/26/2018 and 12/31/22 baseline samples were collected from 70 women with a median age of 56 (36-82) who were enrolled at four study sites. CTC was detected in 59 (84%) of participants. Baseline CTC counts were &amp;lt; 5/7.5 ml in 37/59 (63%) and ≥5/7.5 ml in 22/59 (37%) of participants. Differences between breast cancer subtype and CTC-receptor status were observed (Table 1). Among the 41 patients who were ER-positive, 31 (76%) were CTC ER-negative(p&amp;lt; 0.001). Among 29 patients who were ER-negative, 4 (14%) were CTC ER-Positive (P&amp;lt; 0.001). Among the 7 patients who were HER2 positive, 2(29%) were HER2 positive on CTC. Among 63 patients who were HER2 negative, 7(11%) had HER2 expression on their CTC. The discordance in the classification of HER2 wasn't statistically significant (p=0.77). Elevated CTC at baseline was more frequently detected in younger participants (&amp;lt; 50 years old) (55% vs 27%; P=0.22), in Black women compared to White (60 % vs 29 %, P=0.27), and in participants with visceral vs non-visceral metastasis (52% vs 28 %, P=0.40). Patients with CTC ≥5 vs &amp;lt; 5/7.5mL at baseline had a shorter duration of anti-HER2-based therapy (61.5 vs 836 days, p=0.04). There were no statistically significant differences among participants who received chemotherapy agents (316.5 vs 365.5 days, P=0.88), endocrine therapy (376 vs 490 days, P=0.89), or overall therapy (272 vs 390 days, P=0.21). Conclusions: We observed significant differences in the expression of ER between tumor tissue and CTC, which can be partly due to tumor evolution over time. Additionally, participants who are young, Black, and those who have visceral metastasis may have higher CTC counts. Higher CTC counts were associated with a shorter duration of anti-HER2 therapy. Although it didn’t meet statistical significance, a similar trend was observed in patients who received chemotherapy and endocrine therapy. Table 1: MBC Tissue-Based Subtype and CTC-receptor status at baseline Citation Format: Asnakech Bayable, Tingchang Wang, Amanda Blackford, Jessica Tao, Jenna Canzoniero, Seoho Lee, Faith Too, Barbara Blouw, Mary Wilkinson, Rima Couzi, Antonio Wolff, Christie Hiton, Ben Park, Vered Stearns, Cesar Santa-Maria. Correlation of Circulating Tumor Cells (CTC) with Clinical Characteristics, Pathological Factors, and Treatment Response in Patients with Metastatic Breast Cancer (MBC) [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 PO1-16-02.

DNA double-strand break repair capacity and its pathway gene variants predict the risk and prognosis of lung cancer

ObjectivesThis study aims to investigate the association between DNA double-strand breaks (DSBs) repair capacity, variations in DSBs-related genes, and the occurrence and prognosis of lung cancer in the Chinese population. MethodsPeripheral blood mononuclear cells (PBMC) were collected from 98 lung cancer patients and 60 healthy individuals. The individual DSBs repair capacity was assessed by measuring changes in γ-H2AX levels after treatment with etoposide. Exonic sequencing of 45 DSBs-related genes was performed on PBMC DNA. Logistic regression analysis was conducted to examine the relationship between lung cancer risk and DSBs repair capacity as well as germlines gene variations. Survival analysis employed the Cox proportional hazards regression model, Kaplan-Meier method, and Log-rank test. ResultsLower DSBs repair capacity predicted an increased risk of developing lung cancer (OR = 0.94, 95 %CI = 0.917–0.964, P＜0.001). Among lung cancer patients, higher DSBs repair capacity was associated with shorter progression-free survival (PFS) during first-line treatment (HR = 1.80, 95 %CI = 1.10–3.00, P = 0.031). Patients with BRCA1 mutations had shorter overall survival (OS) (HR = 1.92, 95 %CI = 1.12–3.28, P = 0.018). Patients with FOXO3 mutations had shorter PFS (HR = 4.23, 95 %CI = 1.44–12.36, P = 0.009). Analysis of patients treated with immune checkpoint inhibitors (ICIs) indicated that LIG4 mutations were associated with shorter PFS (HR = 2.90, 95 %CI = 1.00–8.10, P = 0.041). ConclusionsThis study concludes that assessing DSBs repair capacity holds promise for predicting both lung cancer risk and prognosis in the Chinese population. Further large-scale studies and functional validation of specific gene mutations related to double-strand breaks are necessary for confirmation.

Impact of obstructive sleep apnea risk on prognosis and treatment responses of lung cancer

Aims: Obstructive sleep apnea (OSA) may affect oncogenic processes in a specific way for each tumor type. This study was conducted to reveal the relationship between OSA risk and prognosis and treatment responses in patients with lung cancer. Methods: This prospective study included stage III and IV lung cancer patients aged between 18 and 75 years. Patients with poor performance status, cranial metastasis, congestive heart failure, surgery history, and positive airway pressure device use were excluded. STOP-BANG questionnaire was used to assess the OSA risk. The primary end-point was the differences in the survival and treatment responses of patients at intermediate/high risk of OSA compared with those at low OSA risk. Data from the patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) were analyzed separately. Results: Ninety-eight patients (34 SCLC and 64 NSCLC), mostly male (85.7%), with a mean age of 59.3±8 were included in the analysis. Overall survival was similar in the groups. However, in the SCLC group, those at low OSA risk had a shorter progression-free survival (PFS) than those at intermediate/high risk (105±31.8 days, vs 272±16.2 days, p=0.001). Cox regression analysis showed that low OSA risk was an independent risk factor for PFS in only the SCLC group (HR:4.9 CI:1.6-14.7, p=0.005). Conclusion: IOur results showed that low OSA risk was an independent poor prognostic factor for PFS in SCLC regardless of the tumor stage.

Parathyroid hormone related-protein (PTHrP) in tissues with poor prognosis in prostate cancer patients.

Parathyroid hormone-related peptide (PTHrP) is known to have a pivotal role in the progression of various solid tumors, among which prostate cancer stands out. However, the extent of PTHrP expression and its clinical implications in prostate cancer patients remain shrouded in obscurity. The primary objective of this research endeavor was to shed light on the relevance of PTHrP in the context of prostate cancer patients and to uncover the potential underlying mechanisms. The expression of PTHrP, E-cadherin, and vimentin in tumor tissues of 88 prostate cancer patients was evaluated by immunohistochemical technique. Subsequently, the associations between PTHrP and clinicopathological parameters and prognosis of patients with prostate cancer were analyzed. Immunohistochemical analysis showed that the expression rates of PTHrP, E-cadherin, and vimentin in prostate cancer tissues were 95.5%, 88.6%, and 84.1%, respectively. Patients with a high level of PTHrP had a decreased expression of E-cadherin (P = .013) and an increased expression of vimentin (P = .010) compared with patients with a low level of PTHrP. Besides, the high expression of PTHrP was significantly correlated with a higher level of initial prostate-specific antigen (P = .026), positive lymph node metastasis (P = .010), osseous metastasis (P = .004), and Gleason score (P = .026). Moreover, patients with a high level of PTHrP had shorter progression-free survival (P = .002) than patients with a low level of PTHrP. The present study indicates that PTHrP is associated with risk factors of poor outcomes in prostate cancer, while epithelial-mesenchymal transition may be involved in this process.

Preoperative prediction of metastatic pheochromocytoma and paraganglioma using clinical, genetic, and biochemical markers: A cohort study.

The prevalence of metastatic pheochromocytoma and paraganglioma (PPGL) is approximately 15%-20%. Although there are indicators to assess metastatic risks, none of them predict metastasis reliably. Therefore, we aimed to develop and validate a scoring system using clinical, genetic, and biochemical risk factors to preoperatively predict the metastatic risk of PPGL. In the cross-sectional cohort (n=180), clinical, genetic, and biochemical risk factors for metastasis were identified using multivariate logistic regression analysis, and a novel scoring system was developed. The scoring system was validated and compared with the age, size of tumor, extra-adrenal location, and secretory type (ASES) score in the longitudinal cohort (n=114). In the cross-sectional cohort, pseudohypoxia group-related gene variants (SDHB, SDHD, or VHL), methoxytyramine >0.16nmol/L, and tumor size >6.0cm were independently associated with metastasis after multivariate logistic regression. Using them, the gene variant, methoxytyramine, and size of tumor (GMS) score were developed. In the longitudinal cohort, Harrell's concordance index of the GMS score (0.873, 95% confidence interval [CI]: 0.738-0.941) was higher than that of the ASES score (0.713, 95% CI: 0.567-0.814, p=0.007). In the longitudinal cohort, a GMS score ≥2 was significantly associated with a higher risk of metastasis (hazard ratio=25.07, 95% CI: 5.65-111.20). A GMS score ≥2 (p<0.001), but not ASES score ≥2 (p=0.090), was associated with shorter progression-free survival. The GMS scoring system, which integrates gene variant, methoxytyramine level, and tumor size, provides a valuable preoperative approach to assess metastatic risk in PPGL.

Clinical outcomes in patients with non-small cell lung cancer harboring EGFR Exon20 in-frame insertions in the near-loop and far-loop: Results from LC-SCRUM-Asia

ObjectivesIn this study, we explored the clinical outcomes of non-small cell lung cancer (NSCLC) patients with EGFR Exon20 in-frame insertions (Exon20ins), and the impact of the location of Exon20ins on these clinical outcomes. Materials and methodsThe efficacies of current systemic therapies in NSCLC patients harboring Exon20ins were investigated using a large-scale clinico-genomic database of LC-SCRUM-Asia, and compared with that of amivantamab in the CHRYSALIS trial. ResultsOf the 11,397 patients enrolled in LC-SCRUM-Asia, Exon20ins were detected in 189 patients (1.7 %). Treatment with classical EGFR tyrosine-kinase inhibitors (classical TKIs) was associated with a significantly shorter progression-free survival (PFS) in NSCLC patients with Exon20ins as compared with Exon19 deletions and L858R. Post platinum-based chemotherapy, classical TKIs and immune checkpoint inhibitors (ICIs) were associated with a shorter PFS than with docetaxel in patients with Exon20ins (HR [95 % CI]; TKIs vs docetaxel, 2.16 [1.35–3.46]; ICIs vs docetaxel, 1.49 [1.21–1.84]). Patients treated with amivantamab in the CHRYSALIS trial showed a risk reduction in PFS and overall survival as compared with LC-SCRUM-Asia patients treated with docetaxel, classical TKIs, or ICIs. Among the 189 patients, Exon20ins were classified as near-loop or far-loop insertions in 115 (61 %) and 56 (30 %) patients, respectively. Treatment with osimertinib was associated with a longer PFS in patients with Exon20ins in near-loop as compared with far-loop (median, 5.6 vs. 2.0 months; HR [95 % CI], 0.22 [0.07–0.64]). ConclusionsAfter platinum-based chemotherapy, classical TKIs and ICIs are less effective in NSCLC patients with Exon20ins, and amivantamab may be a promising targeted therapy. There is a possibility that the location of Exon20ins has an impact on the efficacy of TKIs.

Prognostic impact of genetic abnormalities in 536 first-line chronic lymphocytic leukaemia patients without 17p deletion treated with chemoimmunotherapy in two prospective trials: Focus on IGHV-mutated subgroups (a FILO study).

The potential prognostic influence of genetic aberrations on chronic lymphocytic leukaemia (CLL) can vary based on various factors, such as the immunoglobulin heavy variable (IGHV) status. We conducted an integrative analysis on genetic abnormalities identified through cytogenetics and targeted next-generation sequencing in 536 CLL patients receiving first-line chemo(immuno)therapies (CIT) as part of two prospective trials. We evaluated the prognostic implications of the main abnormalities, with specific attention to their relative impact according to IGHV status. In the entire cohort, unmutated (UM)-IGHV, complex karyotype, del(11q) and ATM mutations correlated significantly with shorter progression-free survival (PFS). Focusing on the subset of mutated IGHV (M-IGHV) patients, univariate analysis showed that complex karyotype, del(11q), SF3B1 and SAMHD1 mutations were associated with significant lower PFS. The prognostic influence varied based on the patient's IGHV status, as these abnormalities did not affect outcomes in the UM-IGHV subgroup. TP53 mutations had no significant impact on outcomes in the M-IGHV subgroup. Our findings highlight the diverse prognostic influence of genetic aberrations depending on the IGHV status in symptomatic CLL patients receiving first-line CIT. The prognosis of gene mutations and cytogenetic abnormalities needs to be investigated with a compartmentalized methodology, taking into account the IGVH status of patients receiving first-line BTK and/or BCL2 inhibitors.

Predictive factors of nivolumab plus ipilimumab treatment efficacy in metastatic renal cell carcinoma patients.

Nivolumab plus ipilimumab is a recommended first-line therapy regimen for metastatic renal cell carcinoma. However, it is not clear which patient characteristics are associated with its effectiveness. We retrospectively examined 67 metastatic renal cell carcinoma patients treated with nivolumab plus ipilimumab as a first-line therapy in multiple institutions from September 2018 to August 2022. We analyzed the relationships between survival outcomes and patient-related variables, including paraneoplastic symptoms. We also analyzed the relationships between changes in symptoms and parameters and outcomes. Of the 67 patients, 32 patients had paraneoplastic symptoms. The median progression-free survival was 14.9months and median overall survival was 43.3months. The objective response rate was 49.25% (33 patients), including two patients with complete response. Patients with cytoreductive nephrectomy, bone metastasis, high C-reactive protein levels and paraneoplastic symptoms were significantly correlated with short progression-free survival in the univariate analysis. Multivariate analysis of these factors showed that the presence of paraneoplastic symptoms at treatment initiation remained an independent predictor of progression-free survival. Of the 32 patients with paraneoplastic symptoms at treatment initiation, 12 patients had symptomatic improvement and 20 did not. The 1-year progression-free survival rates were significantly longer in improved patients compared with those with no improvement. Patients without cytoreductive nephrectomy and with bone metastasis, liver metastasis, high C-reactive protein levels and paraneoplastic symptoms were significantly correlated with shorter progression-free survival. The presence of paraneoplastic symptoms was an independent predictor of progression-free survival. Improvement in paraneoplastic symptoms may reflect the treatment efficacy of nivolumab plus ipilimumab.

Real-world and clinical trial outcomes in large B-cell lymphoma with axicabtagene ciloleucel across race and ethnicity

AbstractAxicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor T-cell therapy approved for treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting the use of axi-cel for patients with LBCL, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients with R/R LBCL who received axi-cel between 2017 and 2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 clinical trials, respectively. Adjusted odds ratio (OR) and hazard ratio (HR) for race and ethnicity groups are reported. Overall survival was consistent across race/ethnicity groups. However, non-Hispanic (NH) Black patients had lower overall response rate (OR, 0.37; 95% confidence interval [CI], 0.22-0.63) and lower complete response rate (OR, 0.57; 95% CI, 0.33-0.97) than NH White patients. NH Black patients also had a shorter progression-free survival vs NH White (HR, 1.41; 95% CI, 1.04-1.90) and NH Asian patients (HR, 1.67; 95% CI, 1.08-2.59). NH Asian patients had a longer duration of response than NH White (HR, 0.56; 95% CI, 0.33-0.94) and Hispanic patients (HR, 0.54; 95% CI, 0.30-0.97). There was no difference in cytokine release syndrome by race/ethnicity; however, higher rates of any-grade immune effector cell–associated neurotoxicity syndrome were observed in NH White patients than in other patients. These results provide important context when treating patients with R/R LBCL with axi-cel across different racial and ethnic groups. ZUMA-1and ZUMA-7 (ClinicalTrials.gov identifier: NCT02348216 and NCT03391466, respectively) are both registered on ClinicalTrials.gov.

The Presence of Small-Size Circulating Tumor Cells Predicts Worse Prognosis in Non-Small Cell Lung Cancer Patients.

Most patients with non-small cell lung cancers (NSCLC) are diagnosed at advanced stages. The 5-year survival rate of patients with advanced lung cancer is less than 20%, which makes lung cancer the leading cause of cancer-related deaths worldwide. To identify indicators that can predict the prognosis of lung cancer patients. To determine the correlation between circulating tumor cells (CTCs), circulating tumor-derived endothelial cells (CTECs), and their subtypes and the prognosis of patients with NSCLC, 80 patients with lung cancer were recruited and 48 patients who met the enrollment criteria were selected in this study. Peripheral blood was collected from the enrolled patients before any treatment and analyzed by the subtraction enrichment and immunostaining-fluorescence in situ hybridization technique to determine the correlation between CTCs and CTECs and lung cancer disease progression and to identify prognostic indicators. In all patients, the positive rate of CTCs was 100% and the positive rate of CTECs was 81.3%. The CTEC positivity rate was higher in late-stage patients than in early-stage patients (P = .03). Patients with advanced or lymph node metastases had a higher rate of small-size CTC positivity than those with early or no lymph node metastases. Large-size CTEC positivity was higher in patients with advanced NSCLC than in early-stage patients. Patients with ≥1 small-size CTC had shorter progression-free survival, and it was an independent prognostic factor. Small-size CTCs are a reliable prognostic indicator and a probable predictor of the severity of disease in NSCLC patients.