Curative Intent Therapy Research Articles

Abstract B007: Identification of Asporin as a HER3 ligand exposes a therapeutic vulnerability in metastatic prostate cancer

Abstract Background: Rates of prostate cancer incidence and advanced-stage diagnoses are increasing. Despite curative-intent therapies, nearly all patients with advanced disease progress to metastatic castration-resistant prostate cancer (mCRPC), a lethal form of the disease. There is an urgent unmet need to understand the mechanisms driving prostate cancer progression and identify alternative therapies for patients with mCRPC. It is well-established that cancer-associated fibroblasts (CAF) in the tumor microenvironment secrete factors that enable cancer cells to establish metastases. Asporin (ASPN) is an extracellular protein secreted by a subset of CAF and is associated with worse oncologic outcomes, yet the mechanisms remain poorly understood. In this study, we sought to identify the molecular interactions between the CAF-secreted ASPN and metastatic prostate cancer cells. Methods: ASPN-induced HER2/HER3 activation and downstream signaling was identified by RNA-sequencing and then confirmed by immunoblotting in multiple human metastatic prostate cancer cell lines. Binding interactions were assessed computationally by AlphaFOld2 with Rosetta refinement and substantiated by co-immunoprecipitation assays. CRISPR-cas9 targeting of HER2 and HER3 and therapeutic inhibition of HER2 with Tucatinib were used to determine the role of HER2/HER3 in ASPN-induced signaling and migration. The efficacy of Tucatinib and antibody-drug conjugates (ADC) targeting HER2 (Trastuzumab-deruxtecan) and HER3 (Patritumab-deruxtecan) were assessed in multiple metastatic prostate cancer cell lines in vitro. Trastuzumab-deruxtecan was assessed in PC3 xenografts in vivo. Prostate cancer metastases from 33 patients were assessed by IHC for HER2 and HER3 and by RNAscope for ASPN. Results: We report that ASPN is a novel ligand of HER3 and induces HER3 heterodimerization with its preferred dimerization partner, HER2. ASPN activates established ErbB-associated pathways including Phosphoinositide 3-kinase (PI3K), Mitogen-activated protein kinase (MAPK), and calcium signaling, in multiple metastatic prostate cancer cell lines to promote cell migration. Genetic and molecular inhibition of HER2/HER3 mitigates ASPN-induced signaling and cell migration, suggesting these receptors are required for paracrine activation by ASPN. Importantly, small molecule and ADC therapies targeting HER2/HER3 significantly diminished prostate cancer cell growth in vitro, with enzalutamide-resistant cells showing increased sensitivity. Trastuzumab-deruxtecan nearly resolved tumors in an in vivo xenograft model. Lastly, ASPN+ CAF in the TME of HER2/HER3-expressing metastatic prostate cancer is frequently observed in patient samples, supporting the clinical relevance of these findings. Conclusions: Collectively, these findings indicate ASPN functions as a HER3 ligand to induce cellular migration, and inhibition with anti-HER2/HER3 therapies highlights potential clinical utility for patients with HER2-expressing metastatic prostate cancer. Citation Format: Amanda B. Hesterberg, Hong Yuen Wong, Jorgen Jackson, Monika Antunovic, Brenda L. Rios, Evan Watkins, Riley E. Bergman, Brad A. Davidson, Sarah E. Ginther, Diana Graves, Elliott F. Nahmias, Jared A. Googel, Lillian B. Martin, Violeta Sanchez, Paula Gonzalez Ericsson, Quanhu Sheng, Benjamin P. Brown, Jens Meiler, Ben H. Park, Kerry R. Schaffer, Jennifer B. Gordetsky, Paula J. Hurley. Identification of Asporin as a HER3 ligand exposes a therapeutic vulnerability in metastatic prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B007.

Abstract PR015: Novel digital PCR ctDNA monitoring assay evaluating exceptional responders to combination immune-oncology (IO) therapy

Abstract Non-invasive monitoring of ctDNA following curative intent IO therapy has been used to build an understanding of the dynamics of clinical response. Defining clinical response for patients identified with stable disease has always been difficult with imaging. To improve the resolution of ctDNA dynamics, we examined the plasma from a set of exceptional responders to combination IO therapy. These patients did not progress by imaging, however, the measurement of ctDNA showed that there was a persistent level of disease burden throughout the time on study. By evaluating these patients, we gained a comprehensive understanding of the response dynamics including the depth of Molecular Response (MR), the level of molecular persistence and the timing of molecular progression. Current NGS based methods for evaluating ctDNA have been shown to have considerable variability particularly at lower Tumor Fractions (TF). MR dynamics of ctDNA utilize a decrease of 50% TF, which may be related to the accuracy and resolution of assay rather than being a biologically relevant limit. We describe a comprehensive monitoring ctDNA platform using a novel digital PCR assay strategy that achieves a dynamic range not achievable by any current assay. METHODS: Plasma samples from the exceptional responders were evaluated using a novel tumor informed ctDNA platform. Personalized panels, targeting 3-5 variants, were selected from patient tumor data. In total, 225 unique timepoints were extracted (avg 25 timepoints per patient). A novel PCR primer algorithm was designed which showed improved amplification for the individual reactions and optimized multiplexing of the assays. Utilizing machine learning methods, the aggregated data analysis calculates quantitative TF and an accurate percent change between each timepoint. RESULTS: By examining the entire treatment cycle of these patients, we found that the patient timeline separated into molecular response, molecular persistence, and molecular progression. The maximum decrease in TF (molecular response) was found by C4D1 with the largest decrease occurring at either C1D1 or C2D1. Molecular persistence was found in one patient to continue for 55 cycles of treatment (1381 days on trial). Molecular progression occurred in 2 of the 3 exceptional responders. One patient had progression at cycle 12, while the second occurred at cycle 43. Progression occurred very rapidly with the TF doubling from baseline value in 28 days. While patient 1 did see a decrease in the TF for 3 cycles, progression was observed, prompting the end of treatment. To our knowledge this is the first study to evaluate the complete treatment cycle of exceptional responders to IO therapy. The ddPCR assay provided a unique and expansive window into the ctDNA dynamics of treatment suggesting that longitudinal monitoring provides valuable insights. Future studies utilizing this assay will allow for better understanding of the complex tumor dynamics during treatment. Citation Format: Daniel Stetson. Novel digital PCR ctDNA monitoring assay evaluating exceptional responders to combination immune-oncology (IO) therapy [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr PR015.

Breast Cancer Disseminated Tumor Cells: Do They Stay and Fight or Run and Hide?

Many solid tumors including breast cancer can exhibit early dissemination and dormancy-in which cancer cells spread early in the disease process and survive long periods without detectable growth. These early disseminated tumor cells sometimes reactivate and lead to incurable metastatic disease years or even decades after curative-intent therapy for the primary tumor. We are just beginning to understand the role of the immune system in this process in part because of improvements in immunocompetent models as well as technological advances such as single-cell genomics and spatial transcriptomics. In this issue of Cancer Research, Bushnell and colleagues showed that NK cells are important in this context. The authors found that disseminated tumor cells and quiescent cells express higher levels of MHC 1 but are resistant to NK-cell-mediated immunity. The proposed mechanism involves the STING pathway and transcription factors Sox2 and Bach1. As other studies have highlighted the importance of T-cell immunity, this work reaffirms the importance and diversity of immune regulation of dormancy and suggests the need for future studies to flesh out mechanistic details and predict when each type of immunity is most important. See related article by Bushnell et al., p. 3337.

A standing platform for cancer drug development using ctDNA-based evidence of recurrence.

The time required to conduct clinical trials limits the rate at which we can evaluate and deliver new treatment options to patients with cancer. New approaches to increase trial efficiency while maintaining rigor would benefit patients, especially in oncology, in which adjuvant trials hold promise for intercepting metastatic disease, but typically require large numbers of patients and many years to complete. We envision a standing platform - an infrastructure to support ongoing identification and trial enrolment of patients with cancer with early molecular evidence of disease (MED) after curative-intent therapy for early-stage cancer, based on the presence of circulating tumour DNA. MED strongly predicts subsequent recurrence, with the vast majority of patients showing radiographic evidence of disease within 18 months. Such a platform would allow efficient testing of many treatments, from small exploratory studies to larger pivotal trials. Trials enrolling patients with MED but without radiographic evidence of disease have the potential to advance drug evaluation because they can be smaller (given high probability of recurrence) and faster (given short time to recurrence) than conventional adjuvant trials. Circulating tumour DNA may also provide a valuable early biomarker of treatment effect, which would allow small signal-finding trials. In this Perspective, we discuss how such a platform could be established.

Integrating the Symptom Experience in Patients with Stage I-III Breast Cancer in China: A Qualitative Study

PurposeTo develop an in-depth understanding of the meaning of symptoms in the context of how women with stage I-III breast cancer in China coped with the effects of primary and adjuvant therapies for breast cancer. MethodA qualitative descriptive approach was used. A purposive sample of women diagnosed with stage I-III breast cancer were recruited from the “Be Resilient to Breast Cancer” study between November 2023 and March 2024. Data was collected from in person interviews using a semi-structured interview guide. Interviews were audio-recorded and transcribed verbatim. The framework analysis method was used to generate codes and themes. ResultsA sample of 17 women with breast cancer agreed to participate. The average age was 50.1 years (SD=8.45), and the majority (65%) had stage III. The overarching theme was Confronting Physical and Psychological Symptoms. The four themes explaining the experience were Changed Identity, Uncertainty, Finding Meaning and Seeking Support and Solace. Changed Identity and Uncertainty reflected the challenges of coping with multiple symptoms from the treatment. The themes of Finding Meaning and Seeking Support and Solace captured how women adapted a positive perspective to cope with the experience. ConclusionsThis study contributed to the evidence of the integration of the symptom experience in coping with breast cancer treatment in the context of a collectivist Chinese culture. It enhanced the understanding of the physical and psychological symptom experience of curative intent breast cancer therapy and offered insight into how women from China cope in early survivorship.

Chemotherapy-Induced Peripheral Neuropathy in Patients With Gastroesophageal Cancer.

Chemotherapy for various stages of gastroesophageal cancer (GEC) is often neurotoxic. Chemotherapy-induced peripheral neuropathy (CIPN) impairs health-related quality of life (HRQoL). This study investigates the incidence and severity of CIPN and its association with HRQoL in patients with GEC. Patients who received chemoradiotherapy or chemotherapy for GEC were identified from the Netherlands Cancer Registry. Patient-reported data (measured using the EORTC QLQ-CIPN20 and EORTC QLQ-C30) were collected through the Prospective Observational Cohort Study of Esophageal-Gastric Cancer Patients (POCOP) at baseline and at 3, 6, 9, 12, 18, and 24 months after treatment initiation. Linear mixed effects models were constructed to assess CIPN and the correlation between CIPN and HRQoL was analyzed using Spearman's correlation. A total of 2,135 patients were included (chemoradiotherapy: 1,593; chemotherapy with curative intent: 295; palliative chemotherapy: 247). In all 3 treatment groups, CIPN significantly increased during treatment (adjusted mean score of CIPN at 6 months: chemoradiotherapy, 8.3 [baseline: 5.5]; chemotherapy with curative intent, 16.0 [baseline: 5.6]; palliative therapy, 25.4 [baseline: 10.7]). For chemoradiotherapy, the adjusted mean score continued to increase after treatment (24 months: 11.2). For chemotherapy with curative intent and palliative therapy, the adjusted mean score of CIPN decreased after treatment but did not return to baseline values. CIPN was negatively correlated with HRQoL in all treatment groups, although significance and strength of the correlation differed over time. Because of the poor prognosis of GEC, it is essential to consider side effects of (neurotoxic) treatment. The high prevalence and association with HRQoL indicate the need for early recognition of CIPN.

A randomised controlled trial of Standard Of Care versus RadioAblaTion in Early Stage HepatoCellular Carcinoma (SOCRATES HCC)

BackgroundTherapeutic options for early-stage hepatocellular carcinoma (HCC) in individual patients can be limited by tumor and location, liver dysfunction and comorbidities. Many patients with early-stage HCC do not receive curative-intent therapies. Stereotactic ablative body radiotherapy (SABR) has emerged as an effective, non-invasive HCC treatment option, however, randomized evidence for SABR in the first line setting is lacking.MethodsTrans-Tasman Radiation Oncology Group (TROG) 21.07 SOCRATES-HCC is a phase II, prospective, randomised trial comparing SABR to other current standard of care therapies for patients with a solitary HCC ≤ 8 cm, ineligible for surgical resection or transplantation. The study is divided into 2 cohorts. Cohort 1 will compromise 118 patients with tumors ≤ 3 cm eligible for thermal ablation randomly assigned (1:1 ratio) to thermal ablation or SABR. Cohort 2 will comprise 100 patients with tumors > 3 cm up to 8 cm in size, or tumors ≤ 3 cm ineligible for thermal ablation, randomly assigned (1:1 ratio) to SABR or best other standard of care therapy including transarterial therapies. The primary objective is to determine whether SABR results in superior freedom from local progression (FFLP) at 2 years compared to thermal ablation in cohort 1 and compared to best standard of care therapy in cohort 2. Secondary endpoints include progression free survival, overall survival, adverse events, patient reported outcomes and health economic analyses.DiscussionThe SOCRATES-HCC study will provide the first randomized, multicentre evaluation of the efficacy, safety and cost effectiveness of SABR versus other standard of care therapies in the first line treatment of unresectable, early-stage HCC. It is a broad, multicentre collaboration between hepatology, interventional radiology and radiation oncology groups around Australia, coordinated by TROG Cancer Research.Trial registrationanzctr.org.au, ACTRN12621001444875, registered 21 October 2021.

A phase II/III study of peri-operative nivolumab (nivo) and ipilimumab (ipi) in patients (pts) with locoregional esophageal (E) and gastroesophageal junction (GEJ) adenocarcinoma: Results of the neoadjuvant pathologic complete response (pCR) rate (ECOG-ACRIN EA2174).

4000 Background: E/GEJ adenocarcinoma has a high mortality rate despite curative intent therapy. Although the use of immune checkpoint inhibition (ICI) in combination with chemotherapy in the metastatic setting and as adjuvant monotherapy both confer survival benefits, its role in combination with neoadjuvant chemoradiation or with other ICIs in the adjuvant setting remains unclear. Here we report the impact of nivo on pCR rate in pts with E/GEJ adenocarcinoma receiving neoadjuvant chemoradiation as part of the EA2174 clinical trial. Methods: Pts with a localized T1N1-3M0 or T2-3N0-2M0 E/GEJ adenocarcinoma with an ECOG PS of 0-1 and deemed surgical candidates for an esophagectomy were eligible. In step 1, pts were randomized to neoadjuvant therapy with carboplatin AUC 2 and paclitaxel 50 mg/m2 intravenously (IV) weekly x 5 along with 41.4-50.4 Gy radiation without (Arm A) or with (Arm B) nivo 240 mg IV during weeks 1 and 3 of treatment, followed by esophagectomy. Pts underwent a second randomization (step 2) to 6-12 months of adjuvant nivo with or without 6 months of ipi. Planned accrual for step 1 was 278 pts. The primary neoadjuvant endpoint was pCR rate with H0= 23% vs HA= 38%, 90% power, one-sided α = 0.10. The primary adjuvant endpoint comparing nivo to nivo/ipi is disease free survival and will be reported separately once data are mature. Results: Between May 2019 and Dec 2022, 275 pts were enrolled to step 1 of the study (Arm A, n = 138; Arm B, n = 137). Male = 89.5%; White = 92%, Asian = 2.2%, Black 1.5%; median age 65.5 years; E = 60.4%, GEJ = 39.3%. Only 78.5% of pts proceeded to surgery (Arm A = 76.1%, Arm B 81.0%). The pCR rate in Arm A was 21.0% (95% CI, 14.5-28.8) and in Arm B was 24.8% (95% CI, 17.8-32.9), showing no statistically significant difference (p = 0.27). Surgical complication rates between the two arms were similar (Arm A = 28.7%, Arm B = 25.4%). Grade (G) 3/4 events occurring in at least 5% of pts on Arm A—anemia (n = 7), dysphagia (n = 9), esophagitis (n = 7), decreased lymphocytes (n = 80), decreased neutrophils (n = 7); decreased white blood cells (n = 20). G3/4 events occurring in at least 5% of pts on Arm B—anemia (n = 10), dysphagia (n = 8), nausea (n = 8), decreased lymphocytes (n = 84), decreased neutrophils (n = 20), decreased white blood cells (n = 31). Three treatment related deaths occurred on Arm A and two on Arm B. There were no notable differences in chemotherapy or radiation exposure between the two arms. Conclusions: The addition of nivo to neoadjuvant carboplatin, paclitaxel and radiation does not improve the pCR rate in pts with resected E/GEJ adenocarcinoma. Given the known benefit of the addition of ICI to chemotherapy, a further understanding of the impact of radiation on ICI activity is needed. Clinical trial information: NCT03604991 .

TTCC-2022-01: Niraparib and dostarlimab in locally-advanced head and neck squamous cell carcinoma treated with (chemo) radiotherapy (RADIAN).

TPS6125 Background: The prognosis of locally-advanced head and neck squamous cell carcinoma (LA-HNSCC) remains poor, with a 60% 5-year overall survival (OS) rate despite curative-intent therapies. Treatment intensification strategies with antiPD-(L)1 agents given concurrently to (chemo)radiotherapy (CRT) have failed to improve survival. New radiosensitizing agents such as PARP inhibitors have shown encouraging results in early studies, and are of special interest in cisplatin-unfit patients (pts) (Moutafi et al. 2021). Beyond radiation sensitization, PARP inhibition is predicted to trigger immune responses via STING pathway activation, and synergize with anti-PD-(L)1 agents (Sen T et al., 2019). We hypothesize that niraparib will enhance antitumor immune responses when combined with dostarlimab before and after definitive CRT and will boost RT response ultimately leading to higher disease-free survival (DFS). Methods: Trial design: RADIAN is an investigator-initiated, multi-center, non-randomized two-cohort phase 1b study of niraparib and dostarlimab in LA-HNSCC pts candidates for CRT (cohort A) or RT alone (cohort B – cisplatin unfit). Dostarlimab 500mg is given intravenously 3 weeks(w) before RT and then q/3w starting w4 post-RT for up to 14 cycles. Niraparib 200 or 300mg is given orally once daily 1w after dostarlimab until start of CRT (cohort A) or continuously until last dose of RT (Cohort B) and then continuously in 3w cycles from w4 post-RT for up to a year (14 cycles). Intensity-modulated RT (70 Grays:2Gray/fraction) and high-dose cisplatin are given as per standard-of-care. Study procedures include collection of baseline archival or fresh tumor sample for molecular profiling, PD-L1 expression and immunophenotyping; serial blood samples for circulating tumor (ct) DNA and clinical/endoscopic photographs of the tumor (baseline, pre-niraparib, pre-RT, 12w post-RT, end-of treatment, and at progression). Imaging and follow-up procedures are conducted as per standard-of-care. Key eligibility criteria: untreated, stage III to IVB laryngeal, hypopharyngeal, HPV-negative oropharyngeal SCC (stage III only if HPV-positive), and stage IVB oral cavity SCC as per TNM 8th edition;adequate organ function; no autoimmune disorders; no immunosuppressive therapy. Study objectives: primary objective is to evaluate 1-year disease free survival. Secondary objectives: safety/tolerability including RT delay/completion; locoregional and distant control, event-free survival, OS and ctDNA dynamics correlation with efficacy endpoints. Sample size: 32 evaluable pts for correlative studies are planned for enrollment (16/cohort). It is expected that experimental treatment will provide an increase of efficacy of 0.64 in terms of HR (1-year DFS of 75.9 % in cohort A and 68.2% in cohort B). Study activation: Nov 11th 2023, with 2 pts enrolled as of Feb 6th 2024. Clinical trial information: NCT05784012 .

Timeframe for lymphedema therapy for head and neck cancer survivors.

e13535 Background: More than 90% of head and neck cancer (HNC) survivors experience secondary head and neck lymphedema. Prompt identification and treatment are essential given the progressive nature of lymphedema and potential complications. Usual care includes complete decongestive therapy performed by a lymphedema therapist followed by lifelong home self-care. The ability to participate in lymphedema therapy (LT) is deleteriously impacted by numerous barriers. We are conducting a phase 3 multisite randomized trial involving HNC survivors with treatment-naïve lymphedema which compares usual lymphedema care to the use of an advanced pneumatic compression device (APCD). For patients treated on the usual care arm, data pertaining to LT delivery was collected prospectively. Herein we report the preliminary analysis from this dataset. Methods: Eligible patients were age ≥18 years, had pathologically confirmed HNC, completed curative intent cancer therapy with no evidence of active cancer, were diagnosed with internal or external head and neck lymphedema with at least one core lymphedema associated symptom and had not previously received treatment for lymphedema. Participants were randomized to either usual care with complete decongestive therapy directed by a lymphedema therapist followed by home self-care or daily self-directed use of APCD. Anatomic measurements and patient reported outcome measures were obtained at 2-, 4- and 6-month endpoints. The intervention phase lasted 6 months and therapy records were received for analysis. Key outcome measures included the time from referral to LT evaluation consultation, time from LT evaluation to treatment session and time from referral to treatment session. Results: At the time of this analysis, 87 participants randomized to usual care arm were eligible for inclusion in this assessment. Of the 87 patients, we were unable to document completion of LT consultation or therapy for 39 patients. Among the 48 participants who were referred for LT and received therapy, 72% were male and 28% were female, with 91% identifying as white, 7% as black, and 2% as other. The average age was 62. The mean time from referral by a health care provider to initial lymphedema consultation was 19.6 (σ 18.1) days. Of note, there was a wide-ranging timeframe from referral to LT treatment, varying from 0 to 93 days. The mean time from consultation to treatment was 1.7 days (σ 5.1) and referral to treatment was 21.3 (σ 17.8). Conclusions: A key finding of this study is the high rate (45%) of those referred for LT were not documented to complete a therapy consultation or to receive therapy. Of those patients who receive therapy, consultation and treatment were delay significantly in a high percentage of patients. These finding highlight the need for additional investigation into barriers to timely implementation of LT for head and neck cancer survivors. Guidelines and standards of care should be developed to guide practitioners. Clinical trial information: NCT04797390 .

Current management practices of de novo oligometastatic breast cancer: Real-world data from a physician survey.

1104 Background: De novo oligometastatic breast cancer (oligo-mBC) is generally defined as < 5 lesions at the time of diagnosis and represent a steadily increasing subset of metastatic cancers. Several retrospective studies demonstrated prolonged overall survival (OS) for select patients with oligo-mBC when treated with multimodality therapy (chemotherapy, surgery, and radiation). However, randomized trials that tested surgical resection of the primary tumor, or radiation of oligometastases (including recurrent and de novo disease) showed no OS benefit. No randomized trials to date have tested all 3 treatment modalities combined (as used with curative intent in early-stage disease). Current NCCN guidelines do not include specific recommendations for de novo oligo-mBC, the St Gallen International guidelines allow multimodality therapy for carefully selected patients. We surveyed practicing medical oncologists through the ASCO survey pool regarding their use of multimodality therapy in de novo oligo-mBC. Methods: An online survey was sent to the ASCO Research survey pool (N=999) between 11/14/23 – 12/29/23, 193 ASCO members completed the survey. Data was confidential and anonymous. Results: The majority (76-79%) of respondents recommend starting with palliative systemic chemotherapy. If patients have a response to initial chemotherapy, 42-54% recommend ablative radiation to all residual lesions, and 38-52% recommended surgical resection of the primary tumor. Overall, multimodality therapy is recommended sometimes by 29-36%, often by 19-29%, almost never by 32-41%, and never by 2-7% of respondents. Recommendations varied by disease subtype (Table). Conclusions: These survey data indicate varied practices in the treatment of de novo oligo-mBC. This highlights the need for future randomized clinical trials to investigate whether there may be survival benefit by receptor subtype in de novo oligo-mBC treated with curative intent multimodality therapy as used in locally advanced cancers. [Table: see text]

Treatment discontinuation due to toxicity for patients with acute myeloid leukemia (AML) treated on SWOG S1203.

6529 Background: Curative-intent therapy for patients with newly diagnosed AML centers on the use of cytarabine as part of an intensive multi-drug induction regimen. Treatment-related toxicity may lead to patients stopping treatment, despite the considerable risk of inadequately treated AML. We compared rates of protocol therapy discontinuation due to adverse events (AEs) in either of two standard induction regimens (7+3 or high dose cytarabine + idarubicin, IA) on the S1203 study (Garcia-Manero; Leukemia 2023). Methods: S1203 was a randomized study of patients <60 years old with newly diagnosed AML. Patients were required to have performance status (PS) <3, ejection fraction >45%, and no prolonged QTc interval or known cardiac disease. There were no exclusion criteria for kidney or liver function. On the 7+3 induction arm, subjects received daunorubicin 90 mg/m2 IV daily days 1-3 with continuous infusion cytarabine 100 mg/m2 daily days 1-7. On the IA arm, subjects received idarubicin 12 mg/m2 daily days 1-3 with continuous infusion cytarabine 1.5 g/m2 daily days 1-4. Toxicities were assessed per the Common Terminology Criteria for Adverse Events version 4.0. Rates of discontinuation were compared using Fisher’s exact test. Results: From 4/2013-11/2015, 522 subjects were randomized (261 to each arm). Treatment discontinuation due to either death or toxicity occurred in 8 vs 22 patients on 7+3 vs IA respectively (p=0.014). During induction, 0 patients on the 7+3 arm discontinued treatment due to toxicity versus 4 patients on the IA arm (0% vs 2%; p=0.12). Toxicities leading to treatment discontinuation on the IA arm included congestive heart failure (n=2, one with concurrent arrhythmia), acute kidney injury (n=1), and hypotension complicated by stroke and cardiac arrest (n=1). Two of the 4 patients who discontinued treatment due to toxicity on IA achieved a complete remission after their first cycle. For patients with PS 2-3 (n=40 on 7+3, n=27 on IA), rates of grade 3-5 AEs were 85% vs 86% and rates of grade 5 AEs were 0% vs 11% (p=0.065). Conclusions: 7+3 was well tolerated. Excluding patients from S1203 with PS 2-3 or decreased hepatic/renal function would not have prevented treatment-related toxicity. The low rate of protocol therapy discontinuation due to toxicity suggests that eligibility criteria for clinical trials could be further broadened to improve patient access. Clinical trial information: NCT0180233 . [Table: see text]

Stereotactic Body Radiotherapy in Recurrent and Oligometastatic Head and Neck Tumours.

The treatment of head and neck cancers (HNCs) encompasses a complex paradigm involving a combination of surgery, radiotherapy, and systemic treatment. Locoregional recurrence is a common cause of treatment failure, and few patients are suitable for salvage surgery. Reirradiation with conventional radiation techniques is challenging due to normal tissue tolerance limits and the risk of significant toxicities. Stereotactic body radiotherapy (SBRT) has emerged as a highly conformal modality that offers the potential for cure while limiting the dose to surrounding tissue. There is also growing research that shows that those with oligometastatic disease can benefit from curative intent local ablative therapies such as SBRT. This review will look at published evidence regarding the use of SBRT in locoregional recurrent and oligometastatic HNCs.

Practice patterns and survival outcomes for muscle-invasive bladder cancer: real-life experience in a general population setting.

Bladder cancer (BC) is a common malignancy in Europe and North America. Among BCs, muscle-invasive BCs (MIBCs) are distinguished, as they require aggressive treatment due to their spreading potential and poor prognosis. Despite its clinical relevance, little information on MIBC in a general population setting is available. This study aims to report practice patterns and survival outcomes for MIBC patients in a general population setting. MIBCs among BC incidence in 2011 and 2012 recorded in a French population-based cancer registry (810 000 inhabitants) were included in the study. Data were extracted from the medical files. Individual, tumour-related characteristics and initial management including diagnostic tools, multidisciplinary team meeting (MDT) assessment, and treatment delivered were described. Cystectomy, chemoradiation, radiotherapy, and chemotherapy were considered as specific treatments. Matching between MDT decision and the treatment provided was detailed. Management practices were discussed according to the guideline's recommendations. Overall survival (using the Kaplan-Meier method) and net survival (using the Pohar-Perme estimator) were calculated. Among 538 incident BC cases, 147 (27.3%) were MIBCs. Diagnostic practices displayed a relevant locoregional assessment of BC. Almost all cases (n = 136, 92.5%) were assessed during an uro-oncological MDT with a median time from diagnosis of 18 days (first quartile:12-third quartile:32). Discrepancies appeared between MDT decisions and treatments delivered: 71 out of 86 subjects received the recommended cystectomy or chemoradiation (with or without neoadjuvant chemotherapy); 6 out of 11 had the recommended radio- or chemotherapy; and 9 patients did not undergo any specific treatment despite the MDT decision. Cystectomy was the most common treatment performed; the time to surgery appeared consistent with the guideline's recommendations. Forty people only received supportive care. Still, the 5-year overall and net survival was poor, with 19% (13-26) and 22% (14-31), respectively. The 5-year net survival was 35% (23-48) for people who underwent curative-intent treatments. MIBC management remains challenging even for cases assessed during an MDT. Many people did not undergo any specific treatment. Prognosis was poor even when curative-intent therapies were delivered. Efforts to reduce exposure to risk factors such as tobacco smoking and occupational exposures must be maintained.

Abstract PO2-16-11: Real-World Data of Neuroendocrine Neoplasms of Breast

Abstract Background: Primary neuroendocrine neoplasms (NEN) of breast are rare and heterogeneous. WHO has classified NENs of non-endocrine organs into three distinct categories in 2022, however real-world data on outcomes of patients with NENs of non-endocrine organs under this new classification system are still sparse. Real world experience regarding demography, clinical presentation, treatment response, and prognosis can help identify potential areas of improvement in the management of breast NEN. Methods: Here, we present our findings from patients with NEN of breast in the Cleveland Clinic Foundation between 2000 and 2023. Pathology reports were reviewed to confirm NEN of breast origin. Neuroendocrine differentiation was determined by tumor histology and immunohistochemistry (IHC). For metastatic tumors at presentation, primary organ was determined by IHC and clinical presentation. Overall survival (OS) was from date of diagnosis of NEN. Recurrence is redemonstration of tumor following curative intent therapy, and progression is increase in tumor burden. T-test and log-rank test were used in statistical analyses. Results: Total of 97 patients were identified. Of these, 79 presented with localized disease, 18 were metastatic at presentation. 88 (91%) were invasive ductal carcinoma (IDC), and 64 (81%) were local disease at presentation and rest were metastatic. Gender spread was 92:5 (F:M). Patients with ER + disease was 84/96, PR + disease was 71, and 4/93 patients had overexpression of HER2. Median age was 70 at diagnosis. 11 patients underwent neoadjuvant chemotherapy, 15 patients underwent adjuvant chemotherapy (AC), and 58/84 patients underwent hormonal adjuvant therapy. For localized disease, median recurrence free survival (RFS) was 165 months (144-NA), and recurrence rate was 8/79 (10%). Recurrence rate for local IDC was 10% (6/64). Patients with metastatic disease at presentation had a median progression free survival (PFS) of 30 months, and progression rate was 7/18 (39%). For patients with metastatic disease, median lines of palliative therapy used was 2, with median duration of first line treatment being 3.5 months, and 10 months for second line. Most common surgical procedure was mastectomy, with 37% of patients undergoing management. Median duration from diagnostic biopsy to definitive surgery was 1 month. Median follow up was 28 months. Most common hormonal adjuvant option was anastrozole (58%), most common AC regimen was docetaxel and cyclophosphamide (39%), and most common first line palliative agent was letrozole (42%). Patients who underwent AC did not reach median OS, and patients who did not receive AC had a median OS of 148 months (p=0.8). Patients with grade 3 tumors had a median OS of 58.6 months, and grade 1 and 2 had a median OS of 148.1 months (p=0.5). Discussion: Current treatment strategies for NEN of breast mirror those of non-NEN of breast with similar histology and stage based on extrapolation of data. Recurrence rate was similar between IDC and SPC. In our cohort, survival was not significantly dependent on grade and use of AC. This might be due to the number of patients included in our study, as there was a non-significant trend towards lower OS in patients with high-grade neoplasms, and further limitations from retrospective design of study. Further research towards benefit of AC in NEN of breast and prognostic value of grading is necessary to explore management options in comparison to non-NEN of the breast. Citation Format: Serhan Unlu, Olisaemeka Ogbue, Gloria Lewis, Abdo Haddad, Hamed Daw, Baidehi Maiti. Real-World Data of Neuroendocrine Neoplasms of Breast [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 PO2-16-11.

Abstract PO3-18-01: Cirrhosis is associated with worse post-operative survival among patients with breast cancer: a population-based study

Abstract Background: The relationship between cirrhosis and breast cancer treatment and outcomes has not been specifically explored. We evaluated the association between cirrhosis and surgical outcomes in female patients with breast cancer. Methods: We performed a retrospective cohort study of female patients undergoing surgery for breast cancer between 2007-2018 using health administrative data from Ontario, Canada. Breast cancer surgeries were captured using Canadian Classification of Health Intervention codes. Patients with cirrhosis were identified using validated coding definitions. Overall and cancer-specific survival from time of surgery to December 2021 was compared between patients with and without cirrhosis using Kaplan-Meier survival analysis. Modified Poisson regression, chi-square and ANOVA were used to assess the association between cirrhosis and 90-day post-operative mortality, post-operative complications, length of hospital stay, intensive care unit (ICU) admission, and post-operative hepatic decompensation within 6 months. Results: A total of 83,880 females with breast cancer undergoing surgery were identified with 910 (1%) having cirrhosis. The median age at diagnosis was 65 (IQR 57-72) in patients with cirrhosis and 61 (IQR 51-71) in those without (p< 0.001). The most common etiology of cirrhosis was non-alcoholic fatty liver disease (n = 602, 66%) followed by alcohol-related (n =144, 16%) with n=27 (3%) having a history of decompensation within two years prior to surgery. Model for end stage liver disease score (MELD-Na) was available in 24% (n = 218), with a median score of 8 (IQR 6 – 11). Patients with cirrhosis had similar breast cancer stage at diagnosis as patients without cirrhosis (47% stage I, 38% stage 2, 11% stage 3, and 0.5% stage 4) with the most common type of surgical procedure being lumpectomy (71%) in both groups. Use of pre-operative chemotherapy was less common in patients with cirrhosis (5.9% vs 7.9%, p=0.026). Post-operative radiation and chemotherapy within 6-months after surgery was lower in patients with cirrhosis (56.8% vs 63.7%, p< 0.001 and 48.4% vs 52.2%, p=0.019, respectively). Patients with cirrhosis had higher 90-day post-operative mortality compared to those without (1.4% vs 0.3%, p < 0.001). After adjusting for age, income quintile, and breast cancer surgery, cirrhosis was independently associated with 90-day post-operative mortality (RR, 4.1; 95% CI 2.4-6.8). Patients with cirrhosis had a higher prevalence of incision complications (6.4% vs 4.6%, p= 0.007) and blood transfusions (2.9% vs 1.1%, p < 0.001), but similar rates of surgical site infections (6.4% vs 5.3%, p=0.138) and venous thromboembolism (0.3% vs 0.5%, p=0.5). Re-operation was slightly higher in patients without cirrhosis (3.2% vs 4.6%, p=0.05). Length of hospital stay was 2 days in patients with cirrhosis and 1.3 days for patients without (p < 0.001); ICU admission was more likely in patients with cirrhosis (1.8% vs 0.9%, p=0.008); and 18 (2%) patients with cirrhosis developed post-operative hepatic decompensation within 6 months. Survival in patients with cirrhosis was lower than those without (5-year OS 77% vs 87%, p< 0.0001); stage 0/I (83% vs 94%, p< 0.05), stage II (75% vs 87%, p< 0.05), stage III (62% vs 73%, p< 0.05), stage IV (40% vs 40%). Cancer-specific survival was also lower in patients with cirrhosis (5-year CSS 88% vs 91%, p=0.017). Conclusion: This large population-based study demonstrates that, compared to patients without cirrhosis, patients with cirrhosis are older with similar stage at diagnosis, but are somewhat less likely to receive adjuvant therapies. While they have slightly higher risks of certain post-operative complications and lower overall and cancer-specific survival, their outcomes remain favourable and should be considered for curative-intent therapies. Citation Format: Manisha Jogendran, Jennifer Flemming, Maya Djerboua, Shaila Merchant, Sean Bennett. Cirrhosis is associated with worse post-operative survival among patients with breast cancer: a population-based study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-01.

Quality of Life and Depression Symptoms After Therapy De-Escalation in HPV+ Oropharyngeal Squamous Cell Carcinoma

Despite interest in therapy de-escalation for survivors of human papillomavirus-mediated oropharyngeal squamous cell carcinoma (HPV-positive OPSCC), the association of de-escalated therapy with patient-reported quality of life (QoL) outcomes and burden of depressive symptoms remains unclear. To identify associations between clinicopathologic and therapeutic variables with patient-reported QoL outcomes and depression symptom burden in patients with HPV-positive OPSCC, who were enrolled in a therapy de-escalation trial. In this nonrandomized controlled, open-label, curative-intent therapy de-escalation clinical trial in adults with stage I, II, and III HPV-positive OPSCC, patients were recruited from a high-volume head and neck oncology practice. The main outcomes of this study included quantitative, patient-reported QoL and depression symptoms per well-validated inventories. Patient-reported QoL was based on Functional Assessment of Cancer Therapy-Head & Neck (FACT-HN) scores (range, 0-148; lower score indicates inferior QoL). Patient-reported depression-related symptom burden was based on Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) scores (range, 0-27; a higher score indicates a higher burden of depression symptoms). Baseline clinicopathologic and treatment variables were paired with FACT-HN and QIDS-SR scores at baseline, 3, 6, 12, 24, and 36 months. Linear mixed-effect models with a random intercept were used for each participant and fixed effects for other measures. Regression coefficients are reported with 95% CIs. A total of 95 patients were followed up for a median (IQR) of 2.2 (1.6-3.2) years. Of these, 93 patients (98%) were male with a mean (SD) age of 60.5 (8.2) years. Overall, 54 participants (57%) had a history of current or former smoking, 47 (50%) underwent curative-intent surgery (with or without adjuvant therapy), and 48 (50%) underwent primary radiotherapy (with or without chemotherapy). The median (IQR) radiotherapy dose was 60 (60-70) Gy. Five deaths and 2 recurrence events were observed (mean [SD] recurrence interval, 1.4 [1.5] years). A higher radiotherapy dose was the only modifiable factor associated with inferior patient-reported QoL (lower FACT-HN) (coefficient, -0.66 [95% CI, -1.09 to -0.23]) and greater burden of depression-related symptoms (higher QIDS-SR) (coefficient, 0.11 [95% CI, 0.04-0.19]). With the 70-Gy dose as reference, improvements in FACT-HN and QIDS-SR scores were identified when patients received 51 to 60 Gy (coefficient, 12.75 [95% CI, 4.58-20.92] and -2.17 [-3.49 to -0.85], respectively) and 50 Gy or lower (coefficient, 15.03 [4.36-25.69] and -2.80 [-4.55 to -1.04]). In this nonrandomized controlled, open-label, curative-intent therapy de-escalation trial, a higher radiotherapy dose was associated with inferior patient-reported QoL and a greater burden of depression-related symptoms. This suggests opportunities for improved QoL outcomes and reduced depression symptom burden with a reduction in radiotherapy dose. ClinicalTrials.gov Identifier: NCT04638465.

Survival in esophageal cancer with nonregional lymphadenopathy: a propensity score–matched analysis

BackgroundSurvival among esophageal cancer patients with stage IV non-regional lymphadenopathy treated with neoadjuvant therapy and surgical resection is not well described. This study aimed to compare the survival outcomes of patients with non-regional lymphadenopathy with a propensity matched cohort of patients with loco-regional disease. MethodsA retrospective cohort analysis of a prospectively maintained database from a regional upper gastrointestinal cancer network in Quebec, Canada was performed. From 01/2010 until 12/2022, patients with radiologically suspicious non-regional retroperitoneal or supraclavicular lymphadenopathy were identified. Using 1:1 propensity score matching, a control group without non-regional disease was created. ResultsOf the 1235 patients identified, 39 met the inclusion criteria and were allocated to the study group of whom 35/39 (89%) had adenocarcinoma. Retroperitoneal and supraclavicular lymphadenopathy occurred in 26/39 (67%) and 13/39 (33%). Thirty-four received neoadjuvant chemotherapy (87%) and 5/39 (13%) chemoradiotherapy. Following resection, ypN0 of non-regional lymph node stations occurred in 21/39 (54%). When comparing the study group with a matched non-Stage IV control group, median overall survival was similar in patients with retroperitoneal lymphadenopathy (21 months, 95% CI 8-21 vs 27.0, 95% CI 13-41 p=0.262) but not with supraclavicular disease (13 months, 95% CI 8-18,p=0.039). Median follow up was 40.1 months (95% CI 1-83) and 70.0 (95% CI 33-106) for the study and control groups. ConclusionsCompared to a matched cohort of patients with similar disease burden but not stage IV disease, retroperitoneal lymphadenopathy did not negatively affect survival outcomes. Multimodal curative intent therapy may be appropriate in select cases.

Long-Term Outcomes of dMMR/MSI-H Rectal Cancer Treated With Anti-PD-1-Based Immunotherapy as Curative-Intent Treatment.

Neoadjuvant anti-PD-1 therapy has shown encouraging efficacy in patients with deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) locally advanced rectal cancer (LARC), which suggests its potential as a curative-intent therapy and a promising treatment option for organ preservation. We aimed to investigate the long-term outcomes of patients with dMMR/MSI-H LARC who experienced clinical complete response (cCR) after anti-PD-1 therapy. We retrospectively analyzed patients with dMMR/MSI-H LARC who achieved cCR and received nonoperative management following neoadjuvant anti-PD-1-based treatment from 4 Chinese medical centers. Patients were followed up for at least 1 year after they achieved cCR, their clinical data were collected, and survival outcomes were analyzed using the Kaplan-Meier method. A total of 24 patients who achieved cCR and received nonoperative management from March 2018 to May 2022 were included, with a median age of 51.0 years (range, 19.0-77.0 years). The median treatment course to reach cCR was 6.0 (range, 1.0-12.0). Fifteen patients (62.5%) continued their treatments after experiencing cCR, and the median treatment course was 17.0 (range, 3.0-36.0). No local regrowth or distant metastasis was observed in a median follow-up time of 29.1 months (range, 12.6-48.5 months) after cCR. The 3-year disease-free and overall survivals were both 100%. Patients with dMMR/MSI-H locally advanced or low-lying rectal cancer who achieved cCR following anti-PD-1-based therapy had promising long-term outcomes. A prospective clinical trial with a larger sample size is required to further validate these findings.

Abstract 7151: Targeting metabolic pathway in triple negative breast cancer with a small molecule inhibitor

Abstract Background: Triple Negative Breast Cancer (TNBC) is the most aggressive type of breast cancer, making up 15-20% of diagnosed cases, and has high rates of metastasis and recurrence. Most women with this disease experience a recurrence after curative-intent therapy for early breast cancer, while a smaller proportions are diagnosed with distant metastases initially. Cancer cells are characterized by their reprogramming of glucose metabolism. Cancer cells show increased proliferation along with higher energy and substrate demands. Through our efforts to find effective therapies for TNBC, we have identified CET019, a new small molecule that effectively suppresses the growth of breast cancer cells. Methods: Cell viability and clonogenic assays were performed on a range of TNBC cells, including MDA-MB-231, MDA-MB-468, SUM159, HCC1395, HCC1806, EMT6, and 4T1. Cell cycle distribution was assessed through flow cytometry. LC-MS/MS analysis was performed on TMT-labeled samples for global proteome profiling. The efficacy of CET019 (30 mg/kg) was tested using tumor and patient derived xenograft studies. Results: Our studies show that CET019 suppresses the clonogenic potential and growth of various triple-negative breast cancer cells. The CET019 treatment causes cell cycle arrest in TNBC cells at the G2/M phase. Proteomics analysis suggests that CET019 specifically affects metabolic and proteosomal pathways. In vivo studies with CET019 found an inhibition of tumor growth kinetics in the mouse xenograft study with different TNBC models, as compared to the control group. We also observed that CET019 inhibited metastatic lung nodules. The results were further substantiated in three Patient Derived Xenograft (PDX) models. Conclusion: In summary, our study has identified a novel small molecule candidate CET019 as a promising lead candidate for TNBC treatment, paving the way for further development.“The complete chemical structures of the compounds used will be disclosed at the time of presentation at the meeting.” Citation Format: Arpit Dheeraj, Fernando Jose Marques, Dhanir Tailor, Abel Bermudez, Benedikt Grau, Sharon Pitteri, Sanjay V. Malhotra. Targeting metabolic pathway in triple negative breast cancer with a small molecule inhibitor [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 7151.