Experienced Disease Recurrence Research Articles

Primary ovarian cancer combined with primary fallopian tube cancer: A case report

BACKGROUND Low grade serous carcinoma of the ovary (LGSOC) is a rare type of epithelial ovarian cancer with a low incidence rate. The origin of ovarian cancer has always been a hot topic in gynecological oncology research, and some scholars believe that the origin of ovarian malignant tumors is the fallopian tubes. Primary fallopian tube cancer is the lowest incidence of malignant tumors in the female reproductive system. There are only a few reports in the literature, but the mortality rate is very high. But in clinical practice, fallopian tube cancer is very common, but in most cases, it is classified as ovarian cancer. CASE SUMMARY We report a 54 years old postmenopausal woman who was hospitalized with a lower abdominal mass and underwent surgical treatment. The final pathological confirmation was low-grade serous carcinoma of the right ovary and low-grade serous carcinoma of the left fallopian tube. No special treatment was performed after the surgery, and the patient was instructed to undergo regular follow-up without any signs of disease progression. CONCLUSION The prognosis of LGSOC is relatively good, over 80% of patients still experience disease recurrence.

Non-Metastatic Uterine Carcinosarcoma: A Tailored Approach or One Size Fits All?

Purpose: Uterine carcinosarcomas are highly aggressive tumors of the endometrium and are associated with a poor prognosis. The optimal adjuvant treatment for both early and advanced-stage patients remains unclear. Methods: Cases of uterine carcinosarcoma were identified in our institution’s pathology database between 2000 and 2022. Kaplan–Meier estimates were calculated for the local and distant recurrence-free, disease-free and overall survival; hazard ratios were calculated using Cox proportional hazards modelling for independent prognostic factors including the stage and treatment. Results: A total of 48 patients were identified as having uterine carcinosarcoma, of whom 70.8% were surgically staged. In total, 43 patients had pelvic-confined disease, while five had positive omental or peritoneal biopsies at surgery. There were 10 pelvic (20.8%) and 19 (39.6%) distant recurrences. None of the patients with stage IA disease who received chemotherapy and brachytherapy experienced disease recurrence. The local recurrence-free survival was 54.95%, the distant recurrence-free survival was 44.7%, and the overall survival was 59.6% at 5 years. Local recurrence-free survival and overall survival were inversely associated with advanced-stage OR 1.23 (p = 0.005) and OR 1.28 (p = 0.017), respectively, and no chemotherapy was associated with OR 1.96 (p = 0.06) and OR 2.08 (p = 0.056), respectively. Conclusion: The local and distant recurrence rates were high for advanced=stage patients even when treated with aggressive adjuvant therapy regimens. Chemotherapy may improve recurrence and survival. Early-stage patients may perform well with vaginal vault brachytherapy and chemotherapy. Further prospective comparisons are required between sequential, sandwich, and concurrent approaches to chemotherapy and radiotherapy, to optimize outcomes in this high-risk population.

Advances in next-generation sequencing for relapsed pediatric acute lymphoblastic leukemia: current insights and future directions.

Leukemia is one of the most common cancers in children; and its genetic diversity in the landscape of acute lymphoblastic leukemia (ALL) is important for diagnosis, risk assessment, and therapeutic approaches. Relapsed ALL remains the leading cause of cancer deaths among children. Almost 20% of children who are treated for ALL and achieve complete remission experience disease recurrence. Relapsed ALL has a poor prognosis, and relapses are more likely to have mutations that affect signaling pathways, chromatin patterning, tumor suppression, and nucleoside metabolism. The identification of ALL subtypes has been based on genomic alterations for several decades, using the molecular landscape at relapse and its clinical significance. Next-generation sequencing (NGS), also known as massive parallel sequencing, is a high-throughput, quick, accurate, and sensitive method to examine the molecular landscape of cancer. This has undoubtedly transformed the study of relapsed ALL. The implementation of NGS has improved ALL genomic analysis, resulting in the recent identification of various novel molecular entities and a deeper understanding of existing ones. Thus, this review aimed to consolidate and critically evaluate the most current information on relapsed pediatric ALL provided by NGS technology. In this phase of targeted therapy and personalized medicine, identifying the capabilities, benefits, and drawbacks of NGS will be essential for healthcare professionals and researchers offering genome-driven care. This would contribute to precision medicine to treat these patients and help improve their overall survival and quality of life.

Disease-free survival after pancreatectomy for pancreatic neuroendocrine tumors: A 17-year single-center experience of 223 patients

BackgroundMetastasis or recurrence of pancreatic neuroendocrine tumors (pNETs) after pancreatectomy is an important source of postsurgical morbidity. This study aimed to define disease-free survival (DFS) in this population. MethodsPatients who underwent pancreatectomy for pNETs between January 2005 and January 2022 were included. Clinicopathologic and survival data were collected, and the primary endpoint was DFS. Kaplan-Meier survival analysis and Cox proportional hazards regression modeling were performed. ResultsOf the 223 patients, 144 (65%) distal/subtotal/partial pancreatectomies, 71 (32%) pancreaticoduodenectomies, 6 (3%) total pancreatectomies, and 2 (1%) enucleations were performed. Of the 223 patients, 45 (20%) experienced disease recurrence or metastasis after index pancreatectomy during the 17 years of the study. Nonfunctional pNETs (162 [73%]) were more common than hormonally functional subtypes. The 2- and 5-year DFSs were 82% and 76%, respectively. Kaplan-Meier analysis demonstrated that N1 node positive disease, size of ≥ 4 cm, lymphovascular invasion, perineural invasion, Ki-67 of ≥ 20%, and nonfunctional pNETs are significantly associated with a lower DFS (P < .05). Univariate Cox analysis identified the following predictors to be significantly associated with poorer DFS: larger tumor size (hazard ratio [HR], 1.16; 95% CI, 1.04–1.28), Ki-67 index of ≥ 20% (HR, 4.93; 95% CI, 2.00–11.44), perineural invasion (HR, 3.23; 95% CI, 1.40–7.89), open surgery (HR, 3.34; 95% CI, 1.03–1.33), node-positive disease (HR, 5.27; 95% CI, 2.28–13.26), and increased body mass index (HR, 1.10; 95% CI, 1.03–1.17) (P < .05). ConclusionOf note, 1 in 5 patients who underwent resection developed recurrence or metastasis after pancreatectomy. Prognostic predictors of DFS in pNETs could help optimize treatment and enhance follow-up protocols to improve quality and reduce morbidity.

The phase 3 INTerpath-002 study design: Individualized neoantigen therapy (INT) V940 (mRNA-4157) plus pembrolizumab vs placebo plus pembrolizumab for resected early-stage non–small-cell lung cancer (NSCLC).

TPS8116 Background: Pembrolizumab (pembro; anti–PD-1) is indicated as adjuvant monotherapy following resection and adjuvant chemotherapy in patients (pts) with stage IB (T2a ≥4 cm), II, or IIIA NSCLC (per AJCC v7). However, many pts experience disease recurrence, and have limited treatment options available. V940 (mRNA-4157) is a novel individualized neoantigen therapy that encodes up to 34 neoantigens that is specifically tailored and manufactured for each pt derived from their tumor. V940 as monotherapy and in combination with pembro has shown preliminary antitumor activity in the phase 1 KEYNOTE-603 study in several solid tumor types, including NSCLC. Additionally, in pts with completely resected, high-risk stage IIIB/C/D and IV cutaneous melanoma in the KEYNOTE-942 primary analysis, V940 plus pembro demonstrated significant improvements in recurrence-free survival (HR, 0.561 [95% CI, 0.309–1.017]; P = 0.0266) and distant metastasis-free survival (HR, 0.347 [95% CI, 0.145–0.828]; P = 0.0063) vs pembro alone. Here we present the design of the phase 3, randomized, double-blind INTerpath-002 study (NCT06077760) of adjuvant V940 plus pembro vs placebo plus pembro in pts with completely resected and chemotherapy-treated stage II–IIIB (N2) NSCLC (AJCC v8). Methods: Eligible pts aged ≥18 years with completely resected stage II, IIIA, or IIIB (N2) squamous or nonsquamous NSCLC (per AJCC v8.0) where EGFR-directed therapy is not indicated as primary therapy (ie, absence of sensitizing EGFR mutations e.g. DEL19 or L858R), who have received 1–4 doses of adjuvant platinum-doublet chemotherapy, have ECOG PS 0 or 1, and have available tumor tissue for next-generation sequencing and PD-L1 testing will be enrolled. Pts must not have received previous neoadjuvant therapy for NSCLC and must not have received or be candidates for adjuvant radiotherapy. Pts will be randomized 1:1 to receive V940 1 mg IM or placebo Q3W for up to 9 doses plus pembro 400 mg IV Q6W for up to 9 cycles or until disease recurrence, pt withdrawal, unacceptable toxicity, or an additional malignancy requiring treatment. Randomization will be stratified by histology (squamous vs nonsquamous), PD-L1 TPS ( &lt; 1% vs 1%–49% vs ≥50%), disease stage (II vs III), and geographic location (North America/Western Europe/Australia vs rest of world). The primary endpoint is disease-free survival per investigator review. Secondary endpoints include distant metastasis-free survival per investigator assessment, OS, lung cancer‒specific survival, patient-reported outcomes, and safety. Tumor imaging will occur at baseline, every 12 wk until wk 48, every 24 wk through year 3, and every 48 wk thereafter. Enrollment began in October 2023 and is ongoing globally (NCT06077760). The abstract was originally presented and published in: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT281. Clinical trial information: NCT06077760 .

Circulating tumor DNA (ctDNA) to predict response to neoadjuvant chemotherapy (NAC) and prognosis in patients (pts) with early breast cancer (BC).

e12642 Background: pCR to NAC is an important predictor of clinical recurrence. Up to 16% of patients with pCR may experience disease recurrence, 45% of patients with RD do not. Longitudinal ctDNA testing offers a minimally invasive approach for monitoring treatment response EBC patients receiving NAC. We evaluated whether ctDNA status and dynamics can predict the tumor response to NAC and the risk of recurrence in patients with EBC. Methods: We conducted an observational, retrospective, single-center study to investigate whether ctDNA can predict tumor response to NAC and prognosis in BC patients. 74 pts received standard of care NAC;g 4 patients were treated in the adjuvant setting. Blood samples were collected at diagnosis from 44 pts (baseline) and longitudinally during treatment from 34 patients. Tumor response and progression outcomes were reported. A clinically validated, tumor-informed ctDNA assay (Signatera). ctDNA status and dynamics were correlated with pathologic and radiologic outcomes. Results: 29 TNBC pts were ctDNA+ at baseline, 6 were ctDNA- Of the 29 pts, early ctDNA clearance by week 6 of NAC was observed in 10 pts, weeks 7-16 in 9 pts, clearance post-surgery in 1, 3 pts remained ctDNA+ after surgery, serial ctDNA testing is underway for the remaining 6 pts. All TNBC patients who had radiological complete response (CR) had early clearance of ctDNA . All pts with persistent ctDNA positivity levels after completion of NAC had radiological partial response (PR). Of the 9 TNBC pts with undetectable baseline ctDNA, 33% achieved CR on MRI and 43% achieved pathologic CR. Of the 19 TNBC pts with ctDNA clearance in response to NAC, 89% (17/19) remained ctDNA- and with no evidence of disease (NED) (length of follow up). 1 pt initially cleared their ctDNA on NAC, turned ctDNA+ 4 weeks prior to radiological recurrence. 1 pt with ctDNA clearance on NAC remained ctDNA post-surgery but experienced recurrence. All (n=3) TNBC pts with persistent ctDNA-positivity levels after curative treatment (NAC and surgery) had disease recurrence. The remaining 6 pts ctDNA are ongoing NAC. Of the 6 pts with undetectable baseline ctDNA, 6/6 continued to be ctDNA- regardless of their disease status. At diagnosis, 8/9 ER+ ps were ctDNA+. 3/8 (38%) ER+ pts with positive baseline ctDNA had early clearance of ctDNA after NAC. All 3 had residual disease on pathology. 2/8 (25%) remained ctDNA+ after surgery and neither achieved radiologic CR or pCR. The remaining 3 pts are ongoing NAC. Conclusions: In early TNBC, ctDNA monitoring can be used to predict tumor response to NAC and tailor therapeutic regimens. ctDNA persistence can predict early recurrence and helps identify patients in which treatment escalation or enrollment on clinical trials is necessary. In ER positive breast cancer, and despite the small number of patients, ctDNA clearance does not predict response to NAC.

Phosphorylated telomerase reverse transcriptase contributes to the progression of papillary thyroid carcinoma

Somatic mutations in the promoter region of telomerase reverse transcriptase (TERT) occur at a high frequency in several cancer types and are associated with malignancy potential and prognosis. Protein levels of TERT and phosphorylated TERT (p-TERT) are related to malignancy potential. To explore the association of TERT phosphorylation and malignancy or prognosis of thyroid cancer, we analyzed the expression of p-TERT and the clinical features of papillary thyroid carcinoma (PTC) in a cohort of 120 patients. We found that TERT and p-TERT were more abundant in tumors harboring TERT promoter mutations. During the 5-year follow-up period, nine patients experienced disease recurrence. The hazard ratio for recurrence was higher in those with abundant TERT and p-TERT levels. The Kaplan–Meier analysis indicated that the recurrence-free survival was significantly worse in TERT-positive/p-TERT-positive patients than TERT-positive/p-TERT-negative and TERT-negative/p-TERT-negative patients. Higher p-TERT levels correlated with malignant clinicopathologic features and were an independent risk factor for PTC recurrence. These findings indicated the potential role of p-TERT level as a clinically prognostic biomarker in PTC.

Clinical factors predicting objective response to bevacizumab-based chemotherapies in advanced and recurrent epithelial ovarian cancer.

Bevacizumab-based chemotherapies are commonly administered in the treatment of patients diagnosed with epithelial ovarian cancer (EOC). The primary aim of this study was to assess the factors that predict the objective response to bevacizumab-based therapies in cases of advanced and recurrent EOC. The retrospective data of 264 patients with EOC from the current study were collected between 2009 and 2022 at our clinic. Survival analyses were conducted utilizing the Kaplan-Meier method and the log-rank test. Binary logistic regression analysis was employed to assess the factors predicting the objective response. A predominant subset of patients (83%) presented with serous adenocarcinoma, exhibiting a high-grade differentiation at 87%. The vast majority (80%) of the cohort experienced disease recurrence. Three-fourths of the cases received bevacizumab in combination with platinum-based doublet chemotherapy. In the multivariate analysis, clinical factors such as a disease recurrence (P=0.031), upfront tumor debulking surgery before bevacizumab (P=0.009), doublet chemotherapy (P=0.003), and the presence of malignant pleural effusion (P=0.024) emerged as significant determinants influencing the Objective Response Rate (ORR) in patients undergoing bevacizumab-based therapy. The ORR was 67.5% (N.=178), comprising 15.2% complete responses (N.=40) and 52.1% partial responses (N.=138). The median Progression-Free Survival (PFS) and Overall Survival (OS) were estimated at 10.2 months (95% CI, 8.60-11.9) and 20.1 months (95% CI, 16.0-24.2), respectively. The responses to bevacizumab-based chemotherapies could be predict by the presence of malignant pleural effusion, disease recurrence, upfront tumor debulking surgery and doublet regimen of chemotherapy.

INTerpath-001: Pembrolizumab with V940 (mRNA-4157) versus pembrolizumab with placebo for adjuvant treatment of high-risk stage II-IV melanoma.

TPS9616 Background: The anti−PD-1 antibody pembrolizumab is approved as adjuvant therapy for stage IIB-C and stage III melanoma by AJCC 8th ed, following complete resection. Adjuvant pembrolizumab has improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with high-risk melanoma, but many patients experience disease recurrence. In the randomized phase 2b KEYNOTE-942 study, the individualized neoantigen therapy V940 showed improved RFS and DMFS when used in combination with pembrolizumab versus pembrolizumab monotherapy in patients with stage III or IV melanoma. INTerpath-001 (NCT05933577) is a double-blind phase 3 randomized controlled trial designed to evaluate the efficacy and safety of adjuvant pembrolizumab plus V940 versus pembrolizumab plus placebo in patients with resected high-risk stage II-IV melanoma. Methods: Eligible patients are aged ≥18 years with surgically resected stage IIB or IIC (pathologic or clinical), III, or IV cutaneous melanoma per AJCC 8th ed and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients are ineligible if they have received any prior systemic therapy and if more than 13 weeks has elapsed between last surgical resection and first dose of pembrolizumab. Patients with ocular or mucosal melanoma and past or current in-transit metastases or satellitosis are excluded. All patients must provide a blood sample and a formalin-fixed, paraffin-embedded tumor sample for sequencing. Patients will be stratified by risk (IIB, IIC, IIIA, and IIIB vs IIIC/D and IV) and age (&lt;65 years vs ≥65 years). Approximately 1089 patients will be randomly assigned 2:1 to receive pembrolizumab 400 mg plus V940 1 mg or pembrolizumab 400 mg with placebo. Pembrolizumab will be administered intravenously every 6 weeks and v940 or placebo will be administered intramuscularly every 3 weeks. Treatment will continue for up to 9 doses or until disease recurrence, unacceptable toxicity, or patient withdrawal. The primary end point is RFS by investigator review. Secondary end points are DMFS by investigator review, overall survival, safety and tolerability, and quality of life. Hazard ratios and 95% CIs will be estimated using a stratified Cox regression model with the Efron method of handling ties. Between-treatment differences will be evaluated using a stratified log-rank test. Enrollment is ongoing. Clinical trial information: NCT05933577 .

Reconsidering S100B: Why it is time to abandon its use in detecting disease recurrence in stage III melanoma patients

BackgroundEspecially in the era of successful systemic therapy, there is an urgent need to detect early disease recurrence in stage III melanoma patients. This study investigates if serum S100 calcium-binding protein B (S100B) can detect disease recurrence in stage III melanoma patients. MethodsA retrospective cohort study was conducted at the University Medical Center Groningen (UMCG). Adult AJCC 8th stage III melanoma patients in whom serum S100B was measured as part of follow-up from January 2010 until April 2023 were included. The association between serum S100B and disease recurrence was evaluated using standard definitions for sensitivity and positive predictive value (PPV). ResultsOverall, 147 patients were included (mean age was 60.4 years, 53.1 % were female). Most patients were classified as stage IIIB (39, 26.5 %) and IIIC (73, 49.7 %). During median follow-up of 56 months, 69 (46.9 %) patients experienced disease recurrence. Seventeen out of 18 patients with elevated serum S100B (≥0.15 μg/L) experienced disease recurrence (PPV of 94.4 %). However, 52 out of 69 patients with disease recurrence had normal serum S100B (sensitivity of 24.6 %). Eight out of 17 (47.1 %) patients were asymptomatic (P = 0.608), twelve (70.6 %) patients had at least four distant metastases (P < 0.001). ConclusionThe clinical value of serum S100B to detect disease recurrence in stage III melanoma patients is negligible since only one out of four patients with disease recurrence have elevated serum S100B. Furthermore, half of stage III melanoma patients with elevated S100B experienced symptoms, and most patients already have multiple distant metastases.

Pharmacological inhibition of the LIF/LIFR autocrine loop reveals vulnerability of ovarian cancer cells to ferroptosis

Of all gynecologic cancers, epithelial-ovarian cancer (OCa) stands out with the highest mortality rates. Despite all efforts, 90% of individuals who receive standard surgical and cytotoxic therapy experience disease recurrence. The precise mechanism by which leukemia inhibitory factor (LIF) and its receptor (LIFR) contribute to the progression of OCa remains unknown. Analysis of cancer databases revealed that elevated expression of LIF or LIFR was associated with poor progression-free survival of OCa patients and a predictor of poor response to chemotherapy. Using multiple primary and established OCa cell lines or tissues that represent five subtypes of epithelial-OCa, we demonstrated that LIF/LIFR autocrine signaling is active in OCa. Moreover, treatment with LIFR inhibitor, EC359 significantly reduced OCa cell viability and cell survival with an IC50 ranging from 5-50 nM. Furthermore, EC359 diminished the stemness of OCa cells. Mechanistic studies using RNA-seq and rescue experiments unveiled that EC359 primarily induced ferroptosis by suppressing the glutathione antioxidant defense system. Using multiple in vitro, ex vivo and in vivo models including cell-based xenografts, patient-derived explants, organoids, and xenograft tumors, we demonstrated that EC359 dramatically reduced the growth and progression of OCa. Additionally, EC359 therapy considerably improved tumor immunogenicity by robust CD45+ leukocyte tumor infiltration and polarizing tumor-associated macrophages (TAMs) toward M1 phenotype while showing no impact on normal T-, B-, and other immune cells. Collectively, our findings indicate that the LIF/LIFR autocrine loop plays an essential role in OCa progression and that EC359 could be a promising therapeutic agent for OCa.

Abstract PO5-06-13: Impact of Therapy on Sites of Metastases in Triple Negative Breast Cancer

Abstract Background: Metastatic triple negative breast cancer (TNBC) is a diverse disease with the propensity to spread to visceral organs and the central nervous system (CNS). While systemic chemotherapy is commonly used, there is a growing utilization of immune checkpoint inhibitors (ICI) and antibody drug conjugates (ADC). However, few studies have examined the impact of specific therapies on individual metastatic sites, limiting clinical guidance for solitary metastases. Objective: This study aimed to evaluate the efficacy of various systemic therapies in TNBC patients with lung, liver, and CNS metastases. Methods: We analyzed data from the Dallas Metastatic Breast Cancer Study, a retrospective cohort study that includes all patients with metastatic breast cancer treated at a single academic medical center and identified 52 TNBC patients with visceral and CNS metastases diagnosed between 2009 and 2021. We correlated the site of metastasis with and treatment response, which was assessed based on imaging findings using RECIST 1.1 criteria. Results and Discussion: The median age at diagnosis of visceral metastatic disease was 52 years. Of the patients, 60% presented with de novo metastatic disease, while 40% experienced disease recurrence. The most prevalent metastatic sites were the lung (n=28), CNS (n=28), and liver (n=9). Among patients with detectable circulating tumor DNA, the most prevalent gene mutations in lung metastases were TP53 (36%), PTEN (13%), and PIK3R1 (10%). In liver metastases, TP53 (53%) and BRCA1 (15%) mutations were the most frequently observed. Similarly, in CNS metastases, TP53 (40%) and BRCA1 (13%) mutations were again most frequently detected. The notable frequency of TP53 mutations indicates the necessity for further investigations to explore potential differences in treatment approaches for patients with these mutations. The median overall survival (OS) was 14.43 months ±15.53, with the longest survival observed in patients with lung metastases (15 months), followed by liver metastases (6 months) and CNS metastases (5 months). Patients with involvement of a single visceral or CNS site had a mean OS of 15.80±18.19 months, whereas those with two sites of involvement had a mean OS of 13.08±10.18 months. Patients with metastases in all three sites had a mean OS of 8.33±8.50 months. Treatment modalities varied among patients. For liver metastases, chemotherapy (n=6), ICI (n=2), ADC (n=1), radiation therapy (n=2), and surgery (n=1) were administered. Lung metastases were treated with chemotherapy (n=26), ICI (n=4), ADC (n=5), radiation therapy (n=4), and surgery (n=1). CNS metastases were managed with chemotherapy (n=14), ICI (n=2), ADC (n=1), radiation therapy (n=21), and surgery (n=4). Systemic therapy for liver metastases resulted in stable disease (75%) and progressive disease (25%). In lung metastases, it led to stable disease (56%), partial response (23%), complete response (13%), and progressive disease (8%). CNS metastases treated with systemic therapy demonstrated stable disease (86%) and progressive disease (14%). The most commonly used systemic therapy was paclitaxel. Immunotherapy achieved a partial response (60%), stable disease (20%), and progressive disease (20%) in metastatic lesions. Treatment with ADCs resulted in stable disease (43%), partial response (29%), and progressive disease (29%). Compared to lung metastases, liver and CNS metastases exhibited lower response rates and overall survival. CNS metastases were less likely to receive systemic therapies, indicating a need for improvement. These findings highlight the importance of personalized treatment strategies tailored to individual metastatic sites in TNBC. Citation Format: Hannah Chang, Pallavi Dev, Luise Froessl, Shao-Po Huang, Christine Hodgdon, Julia Maues, Isaac Chan. Impact of Therapy on Sites of Metastases in Triple Negative 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 PO5-06-13.

Seven-year outcomes of venetoclax-ibrutinib therapy in mantle cell lymphoma: durable responses and treatment-free remissions

AbstractIn the phase 2 clinical trial (AIM) of venetoclax-ibrutinib, 24 patients with mantle cell lymphoma (MCL; 23 with relapsed/refractory [R/R] disease) received ibrutinib 560 mg and venetoclax 400 mg both once daily. High complete remission (CR) and measurable residual disease negative (MRD-negative) CR rates were previously reported. With median survivor follow-up now exceeding 7 years, we report long-term results. Treatment was initially continuous, with elective treatment interruption (ETI) allowed after protocol amendment for patients in MRD-negative CR. For R/R MCL, the estimated 7-year progression-free survival (PFS) was 30% (95% confidence interval [CI], 14-49; median, 28 months; 95% CI, 13-82) and overall survival (OS) was 43% (95% CI, 23-62; median, 32 months; 95% CI, 15 to not evaluable). Eight patients in MRD-negative CR entered ETI for a median of 58 months (95% CI, 37-79), with 4 experiencing disease recurrence. Two of 3 reattained CR on retreatment. Time-to-treatment failure (TTF), which excluded progression in ETI for those reattaining response, was 39% overall and 68% at 7 years for responders. Beyond 56 weeks, grade ≥3 and serious adverse events were uncommon. Newly emergent or increasing cardiovascular toxicity were not observed beyond 56 weeks. We demonstrate long-term durable responses and acceptable toxicity profile of venetoclax-ibrutinib in R/R MCL and show feasibility of treatment interruption while maintaining ongoing disease control. This trial was registered at www.clinicaltrials.gov as #NCT02471391.

The molecular characteristics of recurrent/metastatic HPV-positive head and neck squamous cell carcinoma: A systematic review of the literature.

About 17% of patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC), which is mainly comprised of oropharyngeal SCC (OPSCC), will experience disease recurrence, which is often considered incurable when manifested at a metastatic and/or recurrent stage. We conducted a critical qualitative systematic review. Our objectives were to provide an overview of the molecular landscape of recurrent/metastatic HPV-positive HNSCC as well as novel molecular biomarkers. A literature review was conducted to identify studies reporting on the molecular characteristics of recurrent/metastatic HPV-positive HNSCC, novel molecular biomarkers and treatment options. The reviews of abstracts, full articles, and revision of the included studies, followed by data extraction and quality assessment were performed by three independent assessors. All primary literature, such as retrospective, prospective, and clinical trials as well as basic research studies were considered, and the final search was conducted at the end of February 2023. The level of evidence was rated using the guidelines published by the Oxford Centre for Evidence-based Medicine and quality was assessed using the Newcastle-Ottawa Scale criteria. The literature search resulted in the identification of 1991 articles. A total of 181 full articles were screened, and 66 articles were included in this analysis. Several studies reported that recurrent/metastatic HPV-positive HNSCC had higher rates of TP53 mutation and were genomically similar to HPV-negative HNSCC. The detection of circulating tumour tissue-modified HPV DNA (ctHPVDNA) as a specific biomarker has shown promising results for monitoring treatment response and recurrence in the subset of HPV-positive HNSCC. In addition, evidence for targeted therapy in recurrent/metastatic HPV-positive HNSCC has emerged, including agents that inhibit overexpressed EGFR. Studies of combination immunotherapy are also underway. Our review outlines the latest evidence on the distinct molecular profiles of recurrent/metastatic HPV-positive HNSCC as well as the clinical potential of ctHPVDNA testing in routine practice. More controlled and longitudinal studies are needed to identify additional molecular targets and to assess the performance and benefits of novel molecular biomarkers in clinical practice.

Development and validation of prediction models for papillary thyroid cancer structural recurrence using machine learning approaches

BackgroundAlthough papillary thyroid cancer (PTC) patients are known to have an excellent prognosis, up to 30% of patients experience disease recurrence after initial treatment. Accurately predicting disease prognosis remains a challenge given that the predictive value of several predictors remains controversial. Thus, we investigated whether machine learning (ML) approaches based on comprehensive predictors can predict the risk of structural recurrence for PTC patients.MethodsA total of 2244 patients treated with thyroid surgery and radioiodine were included. Twenty-nine perioperative variables consisting of four dimensions (demographic characteristics and comorbidities, tumor-related variables, lymph node (LN)-related variables, and metabolic and inflammatory markers) were analyzed. We applied five ML algorithms—logistic regression (LR), support vector machine (SVM), extreme gradient boosting (XGBoost), random forest (RF), and neural network (NN)—to develop the models. The area under the receiver operating characteristic (AUC-ROC) curve, calibration curve, and variable importance were used to evaluate the models’ performance.ResultsDuring a median follow-up of 45.5 months, 179 patients (8.0%) experienced structural recurrence. The non-stimulated thyroglobulin, LN dissection, number of LNs dissected, lymph node metastasis ratio, N stage, comorbidity of hypertension, comorbidity of diabetes, body mass index, and low-density lipoprotein were used to develop the models. All models showed a greater AUC (AUC = 0.738 to 0.767) than did the ATA risk stratification (AUC = 0.620, DeLong test: P < 0.01). The SVM, XGBoost, and RF model showed greater sensitivity (0.568, 0.595, 0.676), specificity (0.903, 0.857, 0.784), accuracy (0.875, 0.835, 0.775), positive predictive value (PPV) (0.344, 0.272, 0.219), negative predictive value (NPV) (0.959, 0.959, 0.964), and F1 score (0.429, 0.373, 0.331) than did the ATA risk stratification (sensitivity = 0.432, specificity = 0.770, accuracy = 0.742, PPV = 0.144, NPV = 0.938, F1 score = 0.216). The RF model had generally consistent calibration compared with the other models. The Tg and the LNR were the top 2 important variables in all the models, the N stage was the top 5 important variables in all the models.ConclusionsThe RF model achieved the expected prediction performance with generally good discrimination, calibration and interpretability in this study. This study sheds light on the potential of ML approaches for improving the accuracy of risk stratification for PTC patients.Trial registrationRetrospectively registered at www.chictr.org.cn (trial registration number: ChiCTR2300075574, date of registration: 2023-09-08).

Abstract CT281: The phase 3 INTerpath-002 study design: Individualized neoantigen therapy (INT) V940 (mRNA-4157) plus pembrolizumab vs placebo plus pembrolizumab for resected early-stage non-small-cell lung cancer (NSCLC)

Abstract Background: Pembrolizumab (pembro; anti-PD-1) is indicated as adjuvant monotherapy following resection and adjuvant chemotherapy in patients (pts) with stage IB (T2a ≥4 cm), II, or IIIA NSCLC (per AJCC v7). However, many pts experience disease recurrence, and have limited treatment options available. V940 (mRNA-4157) is a novel individualized neoantigen therapy that encodes up to 34 neoantigens that is specifically tailored and manufactured for each pt derived from their tumor. V940 as monotherapy and in combination with pembro has shown preliminary antitumor activity in the phase 1 KEYNOTE-603 study in several solid tumor types, including NSCLC. Additionally, in pts with completely resected, high-risk stage IIIB/C/D and IV cutaneous melanoma in the KEYNOTE-942 primary analysis, V940 plus pembro demonstrated significant improvements in recurrence-free survival (HR, 0.561 [95% CI, 0.309-1.017]; P = 0.0266) and distant metastasis-free survival (HR, 0.347 [95% CI, 0.145-0.828]; P = 0.0063) vs pembro alone. Here we present the design of the phase 3, randomized, double-blind INTerpath-002 study (NCT06077760) of adjuvant V940 plus pembro vs placebo plus pembro in pts with completely resected and chemotherapy-treated stage II-IIIB (N2) NSCLC (AJCC v8). Methods: Eligible pts aged ≥18 years with completely resected stage II, IIIA, or IIIB (N2) squamous or nonsquamous NSCLC (per AJCC v8.0) where EGFR-directed therapy is not indicated as primary therapy (ie, absence of sensitizing EGFR mutations e.g. DEL19 or L858R), who have received 1-4 doses of adjuvant platinum-doublet chemotherapy, have ECOG PS 0 or 1, and have available tumor tissue for next-generation sequencing and PD-L1 testing will be enrolled. Pts must not have received previous neoadjuvant therapy for NSCLC and must not have received or be candidates for adjuvant radiotherapy. Pts will be randomized 1:1 to receive V940 1 mg IM or placebo Q3W for up to 9 doses plus pembro 400 mg IV Q6W for up to 9 cycles or until disease recurrence, pt withdrawal, unacceptable toxicity, or an additional malignancy requiring treatment. Randomization will be stratified by histology (squamous vs nonsquamous), PD-L1 TPS (&amp;lt;1% vs 1%-49% vs ≥50%), disease stage (II vs III), and geographic location (North America/Western Europe/Australia vs rest of world). The primary endpoint is disease-free survival per investigator review. Secondary endpoints include distant metastasis-free survival per investigator assessment, OS, lung cancer‒specific survival, patient-reported outcomes, and safety. Tumor imaging will occur at baseline, every 12 wk until wk 48, every 24 wk through year 3, and every 48 wk thereafter. Enrollment began in October 2023 and is ongoing globally (NCT06077760). Citation Format: Jonathan D. Spicer, Santosh M. Nair, Adnan Khattak, Jay M. Lee, Michelle Brown, Robert S. Meehan, Nazly Shariati, Xuan Deng, Ayman Samkari, Jamie E. Chaft. The phase 3 INTerpath-002 study design: Individualized neoantigen therapy (INT) V940 (mRNA-4157) plus pembrolizumab vs placebo plus pembrolizumab for resected early-stage non-small-cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT281.

Clinicopathological Significance of Nucleosome Remodeling and Deacetylase Complex Expression in Endometrial Carcinoma.

Only a few studies have examined the expression of nucleosome remodeling and deacetylase complex in endometrial carcinoma (EC). The aim of this study was to analyze the expressions of histone deacetylase (HDAC1), HDAC2, and chromodomain helicase DNA-binding protein 4 (CHD4) in EC. Sixty cases of EC were categorized into two clusters based on the expression levels of the three proteins. Cluster 1 (C1) exhibited elevated expressions of HDAC2 and CHD4 compared with cluster 2 (C2). Notably, 75% of cases in C2 represented non-aggressive histological types, whereas 37.5% of cases in C1 manifested aggressive types. C2 exclusively comprised pathological tumor stage 1 (pT1) tumors, whereas C1 included pT2 and pT3 tumors. In C1, 25% of cases displayed aberrant p53 expression, contrasting with the absence of such expression in C2. Furthermore, only one patient in C2 experienced disease recurrence, whereas 20.8% of patients in C1 developed recurrent tumors. High HDAC2 and CHD4 expression may be associated with adverse clinicopathological characteristics in EC. Further studies are needed to validate these results.

Personalized approach to outpatient management of patients taking tamoxifen by gynecologists

BACKGROUND: 30% of women with luminal breast cancer receiving adjuvant tamoxifen experience disease recurrence within 15 years. This demonstrates the wide variability in clinical response to tamoxifen. Both nongenetic (age, gender, body mass index, duration of drug use) and genetic factors have been described to influence the high variability of response to tamoxifen. Differences in the genes encoding the enzymes CYP2D6, CYP2C, and CYP3A (CYP2D6*4, CYP3A5*3, CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3) and the ABCB1 gene (C3435T) may also be the main factors of susceptibility to the occurrence of undesirable effects when taking tamoxifen, which in turn may lead to decreased patient adherence to therapy.&#x0D; AIM: The aim of this study was to create a concept and an algorithm for a personalized approach to outpatient management of patients taking tamoxifen by a gynecologist in connection with the carriage of polymorphisms of cytochrome P450 and drug transporter genes.&#x0D; MATERIALS AND METHODS: In 2017–2018, the outpatient records of 230 patients with breast cancer were analyzed retrospectively. A single-stage pharmacogenetic study of 120 women with stage I–III luminal breast cancer taking tamoxifen was conducted prospectively for the presence of cytochrome P450 gene polymorphisms using the polymerase chain reaction method and assessing associations with adverse drug reactions, and 54 patients were interviewed after five-year follow-up to assess adherence and satisfaction with medical supervision.&#x0D; RESULTS: The likelihood of developing endometrial hyperplasia has been shown to increase while taking tamoxifen with increasing average age, body mass index, duration of tamoxifen use, and postmenopause. Significant associations have been identified between the carriage of the CYP2D6, CYP2C9, CYP2C19, CYP3A5, and ABCB1 gene polymorphisms and the development of adverse drug reactions. Predictive models have been developed to determine the risk of adverse drug reactions. All studied adverse drug reactions associated with various genetic polymorphisms predominated in the group of patients who stopped taking tamoxifen due to poor intolerance. Gynecologists regularly observed 57.4% of patients. Moreover, the higher the adherence to therapy was, the higher was the regularity of observation by a gynecologist.&#x0D; CONCLUSIONS: A plan for outpatient management of patients receiving adjuvant endocrine therapy with tamoxifen by a gynecologist has been developed.

Abstract 4150: Development of a three-dimensional spatialomics map of lethal prostate cancer driven by clinical imaging

Abstract Prostate adenocarcinoma (PCa) is the most common malignancy and the second leading cause of cancer-related mortality in United States men. Following treatment for localized PCa, up to 50% of these men can experience disease recurrence, with subsequent metastasis and death. This indicates that there is suboptimal identification of lethal PCa at the time of diagnosis, despite advancements in imaging, genomics, and biomarkers. To improve the noninvasive diagnosis of lethal PCa at initial diagnosis, we have developed a novel magnetic resonance imaging (MRI) method, diffusion basis spectrum imaging (DBSI), that noninvasively measures cancer, stromal, and immune cell contributions to the prostate tumor microenvironment (TME). To validate DBSI for PCa, we have applied novel technologies to matched prostatectomy specimens that include (i) fully automated tissue section processing with serial 2-photon tomographic (STP) imaging of the sections to generate 3D volumetric structural maps of the tumor tissue and (ii) multiplex MALDI mass spectrometry imaging of untargeted glycans and extracellular matrix (ECM) peptides and of proteins targeted with novel photocleavable-mass-tagged antibodies (MALDI-IHC) to spatially resolve hundreds of biomolecules from the TME. To establish the feasibility of this approach, we recruited a patient with an unusually aggressive prostate cancer consisting of Gleason 5+4 acinar adenocarcinoma histology with intraductal growth that was locally invasive and lymph node positive at prostatectomy (stage T3bN1). This patient also had the unusual finding of low activity on prostate specific membrane antigen positron emission tomography (PSMA-PET). Following gross sectioning of the prostate with MRI-guided 3D printed molds to co-register clinical DBSI with histology, a 5-mm thick tissue cross-section containing tumor and normal prostate was imaged with high resolution ex vivo DBSI followed by 3D structural mapping with STP imaging. Selected slides in the 3D stack were subject to multiplexed MALDI imaging to identify relationships between cellular and molecular heterogeneity with tumor structure identified with DBSI and STP imaging. We discovered unique structural differences in the prostate tumor compared with the surrounding stroma based upon collagen and glycan modifications to the ECM that were recapitulated with second harmonic maps of collagen from STP imaging as well as stromal maps generated from DBSI imaging. Additional novel protein and glycan ECM components were expressed in this tumor known to be associated with poor patient outcomes. Together, these data represent the first evidence successfully linking noninvasive in vivo clinical imaging and de novo spatialomics technologies with potential to improve PCa diagnostics. This advanced imaging workflow can be applied to any tissue type, underscoring its relevance to translational cancer research. Citation Format: Joseph E. Ippolito, David H. Ballard, Karla Bergeron, Ritesh Chidambaram, Anusha Elumalai, Tyler J. Fraum, Huaping Jing, Peter Kamelin, Eric H. Kim, Catherine Kita, Aleksandra Klim, Anthony Knesis, Mark Lim, José Marcio Luna, Hani Nakhoul, Timothy Ragan, Kenneth J. Rothschild, Sheng-Kwei Song, Kainen Utt, Cody Weimholt, Gargey Yagnik, Elijah Yew, Peggi M. Angel, Richard R. Drake. Development of a three-dimensional spatialomics map of lethal prostate cancer driven by clinical imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4150.

Abstract 5655: Association between tumor genomic variants and the long term post surgical recurrence as detected by a tumor informed ctDNA assay

Abstract Background: While surgical resection of early stage cancers is often curative, a number of patients will experience disease recurrence. Given the genomic heterogeneity of cancer, we hypothesized that different driver mutations present in a patient’s tumor may influence whether and when recurrence occurs. To investigate this, the association between the presence of driver mutations and rates of molecular residual disease (MRD) detection by circulating tumor DNA (ctDNA) was evaluated in patients with stage I-III colorectal cancer (CRC). Methods: This was a retrospective evaluation of patients who underwent commercial ctDNA testing (SignateraTM) following curative surgical resection for stage I-III CRC from 2019 to February 2023. For this analysis, patients who were ctDNA-negative post-surgery (2-12 weeks) and had ctDNA testing performed between 6-24 months after surgery were included. Patients were stratified based on the presence or absence of mutations in driver genes and the associated percentage of patients with ctDNA-positivity over time was calculated. Results: Of 11,436 patients with stage I-III CRC, 45.7% (5,230) had ctDNA testing performed between 2-12 weeks post-surgery. During this window, 81% (4,239/5,230) had a negative post-surgical ctDNA test result available. For this analysis, 78.4% (3,323/4,239), 46.7% (1,979/4,239), 24% (1,017/4,239) and 8.2% (348/4,239) had follow-up ctDNA testing performed for at least 6, 12, 18, and 24 months post-surgery, respectively. Certain driver mutations were associated with increased risk of post-surgical ctDNA-positivity rate. In patients with stage I CRC, APC mutations were associated with elevated rates of ctDNA positivity at 12 months [(APC-mutated: 13% (11/85) vs. APC-wildtype 3% (1/31); p=0.06)] and 18 months [(APC-mutated: 38% (12/32) vs. APC-wildtype: 6% (1/18); p=0.02)]. Interestingly, similar findings were not observed in stage II or stage III CRC. Similarly in patients with stage III CRC, SMAD4 mutations exhibited a substantially increased probability of ctDNA-positivity at 6 months [(SMAD4-mutated: 8% (15/194) vs. wildtype: 4% (54/1267) p=0.09)], 12 months [(SMAD4-mutated: 25% (32/129) vs. wildtype: 12.4% (102/817); p=0.0005)], and 24 months [(SMAD4-mutated: 69% (41/59) vs. wildtype: 53% (149/279); p=0.02)]. Conclusions: These findings point to several genomic alterations that may underlie cancer recurrence after a long period of undetectable disease with a differential impact across different stages. This may allow, in the future, for a personalized surveillance strategy based on driver mutations and stage of the disease. Correlation of ctDNA positivity with clinical outcomes based on driver mutational status may inform to what extent tumor-specific characteristics drive patient outcomes following a successful surgery. Citation Format: Noah Friedman, Megan Richters, J. Bryce Ortiz, Robert Burns, Sara L. Bristow, Minetta C. Liu, Alexey Aleshin, Adham Jurdi, Helio A. Costa. Association between tumor genomic variants and the long term post surgical recurrence as detected by a tumor informed ctDNA assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5655.