Developed Disease Recurrence Research Articles

Are background breast parenchymal features on preoperative breast MRI associated with disease-free survival in patients with invasive breast cancer?

To evaluate whether breast parenchymal features of the contralateral breast on preoperative MRI are associated with primary breast cancer characteristics and disease-free survival (DFS) in women with invasive breast cancer. Women with newly diagnosed invasive breast cancer who underwent preoperative breast MRI followed by surgery were retrospectively evaluated. Background parenchymal enhancement (BPE) on dynamic contrast-enhanced MRI and background diffusion signal (BDS) on diffusion-weighted MRI of the contralateral breast were qualitatively assessed using a four-category scale: minimal, mild, moderate, or marked. Primary breast cancer characteristics were compared based on the degree of BPE or BDS. Cox proportional hazards models were used to evaluate the association between MRI parenchymal features and DFS after adjusting for clinicopathologic features. A total of 515 women (mean age, 54years) were included. Of whom, 46 (8.9%) patients who developed disease recurrence at a median follow-up of 60months were observed. A high level (moderate/marked) of BPE or BDS was associated with younger age (≤ 45) and premenopausal status (all P < 0.05) compared to a low level (minimal/mild), but it was not associated with primary cancer characteristics such as tumor stage, grade, or subtype. Multivariable Cox proportional hazards analysis demonstrated that larger tumor size (> 2cm) (hazard ratio [HR], 3.877; P < . 001), triple-negative subtype (HR, 2.440; P = .013), and axillary node metastasis (HR, 1.823; P = .049) were associated with worse DFS. No associations were observed between background parenchymal features and disease outcomes. MRI parenchymal features, including BPE and BDS, of the contralateral breast showed no associations with primary breast cancer characteristics or DFS in women with invasive breast cancer.

Feasibility of ctDNA in detecting minimal residual disease and predicting recurrence for colorectal cancer liver metastases.

Approximately 50% of patients diagnosed with colorectal cancer develop colorectal cancer liver metastases (CRLM). Although curative intent liver resection provides 5-year survival of 40-50%, up to 70% of patients develop recurrence of CRLM. Detection of minimal residual disease (MRD) is essential for timely, optimized treatment. This study evaluated the feasibility and utility of using circulating tumor DNA (ctDNA) to identify MRD and predict disease recurrence. Patients with CRLM that underwent liver resection and had known KRAS or PIK3CA mutations were retrospectively identified. Serial blood samples were collected every 3 months following surgery for disease surveillance. ctDNA was isolated from the samples and analyzed with digital PCR (dPCR). KRAS and PIK3CA mutations were identified by dPCR in 29 patients over 115 timepoints. In patients with detectable ctDNA at time of liver resection, 81% (13/16) developed disease recurrence, while 46% (6/13) of the patients with undetectable ctDNA recurred (p=0.064). Presence of ctDNA was detected in 27.6% (8/29) of the initial postoperative samples. Radiologic recurrence was later diagnosed in 100% (8/8) of these patients, while 52% (11/21) who had undetectable ctDNA postoperatively recurred (p=0.026). Detectable ctDNA postoperatively was associated with a shorter disease-free survival (DFS) of 9 months vs 13 months in patients who had undetectable ctDNA (HR 2.95, 95% CI 1.16-7.49; p=0.02). Liquid biopsy using dPCR can identify low levels of ctDNA, enabling early detection of disease recurrence. Additionally, the presence of ctDNA postoperatively was predictive of recurrence. This study corroborates current literature and provides rational for moving toward a clinical trial using ctDNA and dPCR to detect MRD after CRLM resection.

Optimized biomarker evaluation and molecular testing in the era of breast cancer precision medicine

ABSTRACT Ground breaking advances in medicine, driven in part by major technologic developments in molecular biology have led us to a new model for cancer care that has been termed personalized, or precision medicine. Precision medicine is a model for making medical decisions that employs an innovative clinical approach and advanced tumor testing methods that are tailored to understanding an individual patient’s tumor biology and the molecular drivers of their disease. This medical model includes a combination of diagnostic testing and specific treatment options that can be offered to patients at presentation and in theory throughout the course of their disease as new mutations arise with the development of disease recurrence. Although the precision medicine model offers incredible potential to transform cancer care, these advances are only meaningful when they reach the correct patients. The evolving paradigm of precision medicine is changing the practice of pathology, and the pathology community needs to be mindful of these changes because every tissue specimen represents a patient’s life, and those patients are depending on the pathology community to handle their tissue correctly. The diagnostic tests performed in the pathology laboratory for precision medicine are increasingly complex, and pathologists along with the entire laboratory and clinical communities need to take steps to ensure that the right diagnosis is given to the right patient to inform the right treatment options, at the right time, along every step of the continuum of care for cancer patients. While hormone receptors and human epidermal growth factor receptor 2 (HER2) overexpression and/or amplification have been the mainstay for risk-stratification, and treatment decision making in breast cancer since the early 2000’s, the seminal work on gene expression by Perou and colleagues in the early 2000’s opened the door for molecular testing in the prognostic and predictive assessment of breast cancer. Molecular testing is now part of the standard of care in the precision medicine model for breast cancer care. In this article, the reader will gain a better understanding of how the lack of standardization of pre-analytic factors has the potential to negatively impact the quality of the tissue specimen for downstream biomarker and molecular testing, which ultimately can negatively affect patient care. The reader will also gain insight into the current climate surrounding molecular testing in breast cancer.

765. PATTERNS, TIMING, AND SURVIVAL OF RECURRENCE FOLLOWING SURGERY FOR ESOPHAGEAL ADENOCARCINOMA IN THE EUROPEAN MULTICENTRE ENSURE STUDY

Abstract Background After surgery for esophageal cancer approximately half of patients will develop disease recurrence. A more accurate and detailed understanding of the pattern, timing, treatment and prognosis of initial recurrence sites can guide improvements in surveillance and therapy. Therefore, the aim of this study was to accurately describe the pattern and timing of esophageal cancer recurrence, and to assess the distinct survival patterns of these recurrence locations. Methods This study included all patients who underwent surgical resection for esophageal and junctional adenocarcinoma registered in the ENSURE study. ENSURE was an international multicenter study of consecutive patients undergoing surgery for esophageal and esophagogastric junction cancers between 2009 and 2015 across 20 centers in Europe and Canada (NCT03461341). The first recurrence site was recorded and recurrence-free survival (RFS) was estimated using Kaplan-Meier curves. Sites of first recurrence were stratified into different groups and survival outcomes post recurrence detection were estimated using Kaplan-Meier curves. Results Of 3397 eligible patients, 1310 patients had disease recurrence with comprehensive follow-up data available (median RFS of 12.1 months). First recurrence was detected at multiple distant sites (n=469; 37.3%) or at a single distant site (n=463; 33.7%), while isolated local recurrence occurred in 189 (14.4%) patients. Liver-only recurrence occurred significantly earlier (median 9.0 months), while lung-only (15.2 months) and local-only occurred later (17.8 months). Patients with multiple-sites and liver-only recurrence had significant worse median post recurrence survival (7.4 and 8.3 months, respectively) when compared with lung- or local-only recurrence (10.4 and 15.9 months, respectively). Conclusion This study demonstrates that specific recurrence locations of esophageal cancer possess distinct RFS curves. Furthermore, specific recurrence locations result in different post recurrence survival outcomes. This information can help guide improvements in surveillance after esophageal cancer surgery and decisions regarding treatment of esophageal cancer recurrence.

Intravesical Gemcitabine for Non-Muscle Invasive Bladder Cancer after Bacillus Calmette-Guerin Treatment Failure: A Prospective Study.

We prospectively enrolled 28 patients with recurrent NMIBC after previous intravesical treatment in the last year who declined or were unsuitable for cystectomy between 2021 and 2023. Gemcitabine at 2,000 mg/100 mL was instilled weekly for 6 weeks. Patients were assessed for response after 8 weeks, with subsequent evaluations scheduled every three months to one year. The findings demonstrated that out of the 28 patients, 20 (71.4%) exhibited a complete response to intravesical gemcitabine treatment, and 8 (28.6%) had no complete response. The average age of the participants was 60.25 years. The study identified significant differences in treatment response based on age but without significant differences based on gender. Furthermore, there was no noteworthy association between tumor stage and grade and treatment response. Moreover, among patients with low-grade tumors, 66.7% achieved a complete response, while 72.7% reached a complete response among those with high-grade tumors. Of the patients who reached a complete response, 28.6% experienced no recurrence during one year of follow-up, and 42.9% developed recurrent disease within one year of treatment initiation. Ten months following treatment, a patient developed muscle-invasive bladder cancer and went on to cystectomy. In conclusion, the results suggest that intravesical gemcitabine could represent a feasible choice for NMIBC patients unresponsive to BCG therapy and ineligible for or unwilling to undergo cystectomy.

Identifying patients at high risk of recurrence by rebound of plasma Epstein-Barr virus DNA in nasopharyngeal carcinoma.

6030 Background: About 10-30% of patients with nasopharyngeal carcinoma (NPC) would develop disease recurrence following treatment. The optimal method to screen patients needing early medical intervention remains to be studied. We investigated the potential cut-off values of plasma EBV DNA in identifying patients at high risk of recurrence. Methods: From 2012 to 2020, 950 patients with detectable pre-treatment plasma EBV DNA and undetectable EBV DNA within 3 months after treatment were retrospectively reviewed. Survival outcomes of patients with different plasma EBV DNA rebound patterns were analyzed. The diagnostic performance of different cut-off values was evaluated in patients with ≥ 2 positive tests. Results: The number of patients with continuous negative plasma EBV DNA, only 1 positive test, and ≥ 2 positive tests during post-treatment surveillance were 747, 89, and 114, respectively. Patients with ≥ 2 positive plasma EBV DNA tests had worse PFS, LRRFS, and DMFS when compared with the ones with negative tests ( P &lt; 0.001, P &lt; 0.001, and P &lt; 0.001) and only 1 positive test ( P &lt; 0.001, P &lt; 0.001, and P &lt; 0.001). Superior PFS was observed for patients with negative tests compared to patients with only 1 positive test ( P = 0.006). Of 56 patients with more than 50 copies/ml plasma EBV DNA in both tests, 48 developed recurrences within 4 years. The sensitivity, specificity, PPV, and NPV of this cut-off for recurrence prediction were 35.8%, 99.0%, 85.7%, and 90.4, respectively. Then, the whole population was divided into the low-risk group (≤ 1 positive test), the intermediate-risk group (≥ 2 positive tests and at least one test had &lt; 50 copies/ml) and the high-risk group (≥ 2 positive tests and both tests had ≥ 50 copies/ml). The PFS of the high-risk group was worse than that of the low-risk group ( P &lt; 0.001) and the intermediate-risk group ( P &lt; 0.001). The PFS of the high-risk patients with and without capecitabine or tegafur/gimeracil/oteracil before clinical confirmed relapse were 59.3% and 15.0% ( P = 0.004). Conclusions: NPC patients with ≥ 2 positive tests and ≥ 50 copies/ml in both tests during follow-up were at high risk of relapse. Early medical intervention could bring survival benefits to this cohort.

HA-1–targeted T-cell receptor T-cell therapy for recurrent leukemia after hematopoietic stem cell transplantation

AbstractRelapse is the leading cause of death after allogeneic hematopoietic stem cell transplantation (HCT) for leukemia. T cells engineered by gene transfer to express T cell receptors (TCR; TCR-T) specific for hematopoietic-restricted minor histocompatibility (H) antigens may provide a potent selective antileukemic effect post-HCT. We conducted a phase 1 clinical trial using a novel TCR-T product targeting the minor H antigen, HA-1, to treat or consolidate treatment of persistent or recurrent leukemia and myeloid neoplasms. The primary objective was to evaluate the feasibility and safety of administration of HA-1 TCR-T after HCT. CD8+ and CD4+ T cells expressing the HA-1 TCR and a CD8 coreceptor were successfully manufactured from HA-1–disparate HCT donors. One or more infusions of HA-1 TCR-T following lymphodepleting chemotherapy were administered to 9 HCT recipients who had developed disease recurrence after HCT. TCR-T cells expanded and persisted in vivo after adoptive transfer. No dose-limiting toxicities occurred. Although the study was not designed to assess efficacy, 4 patients achieved or maintained complete remissions following lymphodepletion and HA-1 TCR-T, with 1 patient still in remission at >2 years. Single-cell RNA sequencing of relapsing/progressive leukemia after TCR-T therapy identified upregulated molecules associated with T-cell dysfunction or cancer cell survival. HA-1 TCR-T therapy appears feasible and safe and shows preliminary signals of efficacy. This clinical trial was registered at ClinicalTrials.gov as #NCT03326921.

Abstract PO4-17-02: A multicenter, prospective, observational study of patients receiving trastuzumab deruxtecan for the treatment of HER2-positive and HER2-low unresectable and/or metastatic breast cancer: DESTINY-Breast-RESPOND

Abstract Background: Approximately 20% of breast cancer (BC) cases are human epidermal growth factor receptor 2-positive (HER2+; immunohistochemistry [IHC] 3+, IHC 2+/in-situ hybridization [ISH]+), and up to ~50% of patients with primary or metastatic BC (mBC) have HER2-low tumors (IHC 1+, IHC 2+/ISH−), a new therapeutically targetable subset of BC. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate approved in the USA, EU, and other countries for the treatment of adult patients with unresectable or metastatic HER2+ BC who have received a prior anti-HER2-based regimen, or with unresectable or metastatic HER2-low BC who have received a prior chemotherapy (CTx) in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant CTx. Approvals followed positive results from the DESTINY-Breast03 and DESTINY-Breast04 clinical trials. In DESTINY-Breast03, T-DXd improved median progression-free survival (mPFS) compared with trastuzumab emtansine (28.8 vs 6.8 months, respectively; P&amp;lt; 0.0001) in previously treated (prior trastuzumab and taxane) patients with HER2+ mBC. In DESTINY-Breast04, T-DXd significantly improved mPFS vs physician’s choice of CTx (9.9 vs 5.1 months, respectively; P&amp;lt; 0.001) in all randomized patients with HER2-low mBC who were previously treated with one or two lines of CTx. Alongside these efficacy benefits, T-DXd has demonstrated an acceptable and generally manageable safety profile. To optimize care and maximize treatment benefit, insights into real-world T-DXd use and safety events of interest, including patient management and experience, are needed. This study aims to describe the effectiveness and tolerability of T-DXd in patients with HER2+ or HER2-low unresectable and/or mBC in a real-world setting. Trial design: DESTINY-Breast-RESPOND (NCT05592483) is a multicenter (120 sites planned as of June 2023), multi-country (HER2+ cohort: several regions globally; HER2-low cohort: North America only), prospective, observational study characterizing real-world clinical use, effectiveness, tolerability, and patient experience among adults who initiated T-DXd monotherapy, per standard of care, for HER2+ (second line or earlier) and HER2-low unresectable and/or mBC (T-DXd not provided by study sponsor). The decision to initiate T-DXd will be made by the physician prior to, and independent from, participation in this study. Approximately 750 patients with HER2+ and 250 patients with HER2-low disease will be enrolled. Patients must have received prior treatment with a trastuzumab-containing regimen in the metastatic setting or have evidence of disease progression within 6 months of neoadjuvant or adjuvant treatment (HER2+ cohort), or prior CTx in the metastatic setting or have evidence of disease progression within 6 months of adjuvant CTx (HER2-low cohort). Data will be collected via chart abstraction, patient-reported outcome questionnaires on tolerability and safety (PGI-TT, NCI PRO-CTCAE, and EORTC IL19), and a daily patient nausea/vomiting symptom diary. Endpoints will be analyzed separately for HER2+ and HER2-low cohorts. The primary endpoint of interest is time to next treatment from T-DXd initiation, a measure of real-world effectiveness. Other important endpoints include treatment patterns, safety events of interest (nausea/vomiting, fatigue, alopecia, interstitial lung disease/pneumonitis, left ventricular ejection fraction decrease) and their management, time to T-DXd discontinuation, and patient-reported tolerability. Patients will be observed until end of study (~60% of patients receive subsequent treatment or have died), withdrawal from study, or loss to follow up, whichever occurs first. Citation Format: Joyce O'Shaughnessy, Reva Basho, Maryam Lustberg, Gary H Lyman, Manoj Prahladan, Gareth D. James, Della Varghese, Flavia Lujan, Hans Tesch. A multicenter, prospective, observational study of patients receiving trastuzumab deruxtecan for the treatment of HER2-positive and HER2-low unresectable and/or metastatic breast cancer: DESTINY-Breast-RESPOND [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 PO4-17-02.

Abstract PO3-04-01: Population Pharmacokinetics of trastuzumab deruxtecan (T-DXd) in HER2-positive breast cancer subjects: analyses across 12 Phase 1-3 studies

Abstract Background: T-DXd, an antibody-drug conjugate composed of a humanized anti-HER2 monoclonal antibody and a topoisomerase I inhibitor payload, is approved for adult patients with unresectable or metastatic HER2-positive (HER2+) BC administered T-DXd 5.4 mg/kg Q3W with a prior anti-HER2–based therapy either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy. The objective of this analysis was to present pharmacokinetic (PK) characterization of T-DXd and DXd in patients with advanced/metastatic HER2-positive breast cancer from a pooled data source of 12 phase 1 to 3 clinical trials. Methods: Data from subjects with HER2-positive breast cancer and other solid tumors enrolled in studies DS8201-A-J101, DS8201-A-J102, DS8201-A-A103, DS8201-A-A104, DS8201-A-U201, DS8201-AJ202, DS8201-A-U205, DS8201-A-U204, DS8201-A-U206, DS8201-A-U301, DS8201-A-U302, and DS8201-A-U303 were used for this analysis. A population PK (PopPK) analysis was performed using nonlinear mixed effects modeling approach using NONMEM® (version 7.4.3). The effect of significant covariates was evaluated by univariate and multivariate analyses on steady-state exposure of T-DXd and DXd. Results: Data across T-DXd doses 0.8 to 8 mg/kg with 2216 subjects were included. The PK of T-DXd and DXd were adequately described by PopPK analysis based on standard model diagnostic techniques. T-DXd elimination clearance and volume of distribution of central and peripheral compartments were estimated at 0.402 L/day, 2.68 L and 5.91 L, respectively. DXd elimination clearance was estimated at 18.4 L/hour. Covariates previously detected to be statistically significant (cancer type, tumor size, albumin, race-country, body weight and sex for T-DXd; age, cancer type, AST, total bilirubin, ritonavir or itraconazole use, race-country, formulation and body weight for DXd) were retained in the PopPK model. No new covariates were identified as statistically significant in the PopPK analysis. All covariates were contained within the 0.8 to 1.25 exposure ratio interval in T-DXd and DXd steady-state area under the concentration-time curve (AUC), indicating no clinically meaningful effect, except for subjects with high body weight (90 kg; 95th percentile) showing a 28% and 26% higher T-DXd and DXd AUC, respectively, relative to a BC subject with median body weight of 60 kg. None of these changes were clinically meaningful based on exposure-response analyses of efficacy and safety endpoints. T-DXd and DXd post hoc exposure estimates in all BC subjects (HER2-positive and HER2-low) as well as BC subjects with HER2- positive were comparable across hepatic function, renal function, region, race-country and line of therapy. Conclusions: Similar T-DXd and DXd exposures were obtained for the recommended dosing of 5.4 mg/kg Q3W T-DXd in BC subjects across categories of hepatic function, renal function, region, race-country, HER2 status, and line of therapy. Citation Format: Claire Li, Stefanie henning, Kashyap Patel, Katrina Hui, Gerly van der Vleuten, malaz Abutarif, Tushar Garimella, Amit Khatri. Population Pharmacokinetics of trastuzumab deruxtecan (T-DXd) in HER2-positive breast cancer subjects: analyses across 12 Phase 1-3 studies [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 PO3-04-01.

Abstract PO2-19-06: An Open-label, Interventional, Multicenter Study of Trastuzumab Deruxtecan Monotherapy in Patients With Unresectable and/or Metastatic HER2-Low or HER2 Immunohistochemistry 0 Breast Cancer: DESTINY-Breast15

Abstract Background Approximately 50% of all breast cancer (BC) tumors express low levels of HER2, defined by HER2 immunohistochemistry (IHC) scores of 1+ or IHC 2+/in situ hybridization negative (ISH−), and are referred to as HER2-low BC. Trastuzumab deruxtecan (T-DXd), a HER2-directed antibody-drug conjugate, has been approved in the United States, European Union, and other countries for the treatment of adult patients with unresectable or metastatic HER2-low BC (IHC 1+ or IHC 2+/ISH−), regardless of hormone receptor (HR) status, who previously received chemotherapy in the metastatic setting or who have developed disease recurrence within 6 months of completing adjuvant chemotherapy. The DESTINY-Breast04 trial that formed the basis of T-DXd approval in HER2-low BC included only 63 patients who were HR–negative and patients with HER2 IHC 0 status were not enrolled. However, the phase 2 DAISY trial demonstrated clinically meaningful activity of T-DXd in patients with HER2 IHC 0 BC. Along with HER2 status, HR–positive or HR-negative tumor status could confer variation in prognosis and sensitivity to systemic therapy. Few targeted agents are available for patients with HR-negative, HER2 IHC 0 metastatic BC, particularly for patients without pathogenic BC gene mutations or programmed cell death ligand 1 expression. Therefore, there is an unmet medical need for therapeutic treatment options in this patient population. Study Description DESTINY-Breast15 is a multicenter, open-label, single-arm, phase 3b trial designed to evaluate the efficacy and safety of T-DXd in patients with HR-positive or HR-negative unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH−) or HER2 IHC 0 BC who received 1 or 2 lines of prior therapy in the metastatic setting, including (but not limited to) targeted agents or endocrine therapy per cohort. Patients must have an ECOG PS score of 0 or 1, have never previously been HER2-positive (IHC 3+ or IHC 2+/ISH+), and have never previously received anti-HER2 therapy in the metastatic setting. At least 250 patients will be enrolled from approximately 80 sites in Belgium, Brazil, China, Ireland, Italy, Netherlands, Portugal, Spain, and the United States to receive T-DXd and will be assigned to 1 of 4 cohorts according to their HR and HER2 status (tested per local practice in accordance with ASCO/CAP 2018 guidelines). The 4 cohorts are cohort 1, HR-negative, HER2-low (n ≈ 100); cohort 2, HR-negative, HER2 IHC 0 (n ≈ 50); cohort 3, HR-positive, HER2-low (n ≈ 50); and cohort 4, HR-positive, HER2 IHC 0 (n ≈ 50). Cohort 3 will specifically recruit patients with rapid disease progression, defined as recurrent disease &amp;lt; 2 years from starting adjuvant endocrine therapy, progression within 12 months of completing adjuvant CDK4/6 inhibitor, or progression within 12 months of starting CDK4/6 inhibitor therapy in the metastatic setting. T-DXd will be administered at a dose of 5.4 mg/kg intravenously once every 3 weeks until disease progression, unacceptable toxicity, or 2 years after the first dose of T-DXd. The primary end point is time from the start of T-DXd treatment to initiation of subsequent anticancer treatment or death. Secondary end points are real-world progression-free survival (defined as time from the date of first administration of T-DXd to date of first observed instance of disease progression per RECIST version 1.1 or death from any cause), time to treatment discontinuation or death, objective response rate per RECIST version 1.1, safety, and patient-reported quality-of-life–related outcomes. Time-to-event endpoints will be evaluated using Kaplan-Meier methods. Citation Format: Shanu Modi, Roberto Salgado, Valentina Guarneri, Divi Alagappan, Natalie Dennis, Amy Hanlon Newell, Aislyn Boran, Ouzna Morsli, Antonio Llombart-Cussac. An Open-label, Interventional, Multicenter Study of Trastuzumab Deruxtecan Monotherapy in Patients With Unresectable and/or Metastatic HER2-Low or HER2 Immunohistochemistry 0 Breast Cancer: DESTINY-Breast15 [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 PO2-19-06.

Abstract RF02-03: Trastuzumab deruxtecan (T-DXd) in combination with anastrozole or fulvestrant in patients with HER2-low HR+ advanced/metastatic breast cancer: a Phase 1b, open-label, multicenter, dose-expansion study (DESTINY-Breast08)

Abstract Background: Trastuzumab deruxtecan (T-DXd) is approved in over 40 countries for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-low (a score of 1+ on immunohistochemistry [IHC] analysis or an IHC score of 2+ and negative results on in-situ hybridization) breast cancer who have received prior chemotherapy in the metastatic setting or who developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. DESTINY-Breast08 (DB-08) was designed to establish the safety, tolerability, and preliminary activity of T-DXd in combination with widely used standard of care therapies in HER2-low hormone receptor (HR)+ metastatic breast cancer (mBC). Results reported here are from the dose-expansion stage of the Phase 1b, multicenter, open-label, parallel-assignment DB-08 study arms investigating T-DXd–endocrine therapy (ET) combinations [NCT04556773]. Methods: Eligible patients had centrally confirmed HER2-low advanced/mBC with measurable disease per RECIST 1.1 and were documented as HR+. Among patients with mBC, ≤1 prior line of ET ± a targeted therapy was allowed, and prior chemotherapy in the mBC setting was exclusionary. Patients received T-DXd 5.4 mg/kg intravenously (IV) every three weeks (Q3W) + anastrozole 1 mg orally daily (T-DXd + ANA) or T-DXd 5.4 mg/kg IV Q3W + fulvestrant 500 mg intramuscularly Q4W, with a 500 mg loading dose on Cycle 1 Day 15 (T-DXd + FUL). Primary endpoints were safety and tolerability; secondary endpoints included objective response rate (ORR), progression-free survival, duration of response (all evaluated by investigator per RECIST 1.1), and overall survival (OS). Data cutoff (DCO) was ~24 weeks after the last patient in each arm had received study treatment. Results: As of February 20, 2023, 21 patients in the T-DXd + ANA arm and 20 patients in the T-DXd + FUL arm had received study treatment. Median age was 55 and 66 years, 67% and 75% of patients received a prior line of ET ± a targeted therapy for mBC, 33% and 25% had no prior line of treatment for mBC, and median follow up in censored patients was 12.1 months (range 4.0, 17.3) and 8.5 months (range 1.3, 15.1) in the T-DXd + ANA and T-DXd + FUL arms, respectively. Adverse events (AEs) occurred in 95.2% (20/21) of patients in the T-DXd + ANA arm and 100% (20/20) of patients in the T-DXd + FUL arm, with AEs ≥Grade 3 occurring in 47.6% (10/21) and 55.0% (11/20) of patients in each arm, respectively. The most common any-grade AEs, occurring in ≥30% of patients in either arm, are reported in the Table. Three (15%) adjudicated drug-related interstitial lung disease/pneumonitis events were reported in the T-DXd + FUL arm (all Grade 2; at DCO, one case had resolved, one was resolving, and one was not resolved); none were reported in the T-DXd + ANA arm. AEs were manageable by drug interruption and dose reduction. Confirmed ORR was 71.4% (15/21; 95% confidence interval [CI] 47.8, 88.7) in the T-DXd + ANA arm, and 40.0% (8/20; 95% CI 19.1, 64.0) in the T-DXd + FUL arm (Table). OS data were not mature at this DCO. Conclusions: Safety profiles for T-DXd-ET combinations were generally comparable to T-DXd monotherapy and manageable with dose modification and routine clinical practice. T-DXd in combination with anastrozole or fulvestrant was active in first- or second-line treatment of patients with HER2-low HR+ mBC. Citation Format: Komal Jhaveri, Fabrice André, Erika Hamilton, Peter Schmid, Carey Anders, Laura Testa, Inna Ganshina, Yen-Shen Lu, Seock-Ah Im, Robyn Young, Magdalena Wrona, Caron Lloyd, Yiwen Zhang, Sherene Loi. Trastuzumab deruxtecan (T-DXd) in combination with anastrozole or fulvestrant in patients with HER2-low HR+ advanced/metastatic breast cancer: a Phase 1b, open-label, multicenter, dose-expansion study (DESTINY-Breast08) [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 RF02-03.

Abstract PS06-01: Results from a pilot study exploring ctDNA detection using a tumor-informed assay in the monarchE trial of adjuvant abemaciclib with endocrine therapy in HR+, HER2-, node-positive, high-risk early breast cancer

Abstract Background Two years of adjuvant abemaciclib + endocrine therapy (ET) resulted in significant and clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in patients (pts) with HR+, HER2-, node-positive, high-risk early breast cancer (EBC) in the monarchE trial (NCT03155997). The benefit of abemaciclib was sustained beyond completion of treatment and deepened in magnitude at 4 years for IDFS and DRFS. This pilot study investigated the technical feasibility of ctDNA detection beginning prior to study treatment, as well as rates of persistence and clearance in a subset of EBC pts from monarchE using the clinically validated SignateraTM ctDNA assay. Methods Samples were analyzed from a selected subset of pts (n=178; 84 from abemaciclib+ET arm; 94 ET alone) who had blood collected both before initiating protocol directed therapy, Visit 1 (V1; randomization + ≤ 3 days) and near completion of the 2-year treatment period, Visit 27 (V27; 24 months +/- 5 days from V1). This cohort of pts was enriched for overall IDFS events compared to the total monarchE study population, however pts with relapses occurring prior to V27 were excluded. Primary tumors from selected pts were subjected to whole exome sequencing (WES). Selected samples included those from pts with a range of tumor mutation burden. Cell-free DNA was extracted from 356 plasma samples. A Signatera ctDNA assay was developed for each pt based on up to 16 variants detected by WES from each baseline tumor sample. Results The IDFS event rate for the selected subset (n=178) was 39.3% (abemaciclib+ET 34.5% [29/84] and ET alone 43.6% [41/94]). Ten pts (5.6%) were initially ctDNA+ and 42 pts (23.6%) were persistently (7 pts, 3.9%) or became (35 pts, 19.7%) ctDNA+ at V27. Notably, 70% of pts who were initially ctDNA+ and 100% of pts who were either persistently ctDNA+ or became ctDNA+ experienced recurrence (see Table 1). In contrast, none of the 3 pts that cleared ctDNA+ developed recurrence. In pts persistently ctDNA negative (neg), 28 (21.1%) experienced recurrence. Overall, 10% (7/70) of pts with IDFS events were initially ctDNA+ and 50% (35/70) had detectable ctDNA at V27. Conclusions Detection of ctDNA soon after completing neoadjuvant chemotherapy was infrequent, but also associated with a high-risk of recurrence. ctDNA positivity was common at the end of the 2-year treatment period and was highly prognostic with all pts subsequently developing disease recurrence. Importantly, ~30% of pts with early ctDNA detection ultimately dropped below detection limits during the 2-year treatment period and none developed recurrence. Although some pts remained persistently ctDNA neg during this study and experienced recurrence, the delay in recurrence may indicate longitudinal benefit from remaining ctDNA neg. Future planned analysis of an expanded cohort reflective of the intent to treat population including additional timepoints within the 2-year treatment period will further define how ctDNA dynamics may identify pts at high-risk of recurrence. Table 1. Summary of Subset Positivity Rates. + positive; - negative; NA, not applicable. Citation Format: Sherene Loi, Stephen Johnston, Carlos Arteaga, Stephanie Graff, Sarat Chandarlapaty, Matthew Goetz, Christine Desmedt, Jorge Reis-Filho, Hironobu Sasano, Vanessa Rodrik-Outmezguine, Anthony Sireci, Cynthia Sandoval Rubenstein, Helen Won, Deli Liu, Lacey M. Litchfield, Nicholas Turner. Results from a pilot study exploring ctDNA detection using a tumor-informed assay in the monarchE trial of adjuvant abemaciclib with endocrine therapy in HR+, HER2-, node-positive, high-risk early 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 PS06-01.

Late-onset lymphopenia during radiation is associated with an increased risk of tumor recurrence in newly diagnosed pediatric medulloblastoma.

Recent data found a correlation between lymphopenia occurring early during craniospinal radiation therapy (RT) and risk of disease recurrence in newly diagnosed childhood medulloblastoma. However, the population included patients who received chemotherapy prior to or during RT. Here, we investigate the effect of lymphopenia during RT in patients with newly diagnosed pediatric medulloblastoma who were chemotherapy-naïve. We analyzed 79 patients with newly diagnosed medulloblastoma (ages 2-21years) treated between 1997 and 2013 with craniospinal RT. Log-rank tests were used to determine survival differences, and Cox proportional hazards regression was used to assess associations between patient characteristics and lymphopenia with disease recurrence risk. Eighty-three percent of patients (62/75) had grade ≥3 lymphopenia by RT Week 3, with 95% developing grade ≥3 lymphopenia at some point during therapy. There was no difference in incidence of lymphopenia between those who received proton beam RT (93%) versus photon (97%). Twenty-four of 79 (30%) patients developed disease recurrence at an average 27.0months after diagnosis. There was higher risk of disease recurrence in patients with grade ≥3 lymphopenia during RT Week 4 (log-rank p=.016; Cox p=.03) and Week 5 (log-rank p=.024; Cox p=.032); after adjusting for clinical risk group, only grade ≥3 lymphopenia at Week 4 remained prognostic (Cox p=.04). No correlation was found between risk of tumor recurrence and early lymphopenia (RT Weeks 0-3) or absolute lymphocyte count (ALC) below the median at any time during RT. Lymphopenia during RT Weeks 4 and 5 correlates with increased risk of tumor recurrence in pediatric patients with newly diagnosed medulloblastoma.

Current Immunotherapy Treatments of Primary Breast Cancer Subtypes.

Breast cancer receives the most funding when compared to any other cancer type, according to a global study conducted by The Lancet. Nevertheless, this malignancy remains the most diagnosed cancer among women and relies heavily on a neoadjuvant treatment regimen of chemotherapy and targeted therapy. After standard treatment, 25-30% of breast cancer patients still develop disease recurrence and must undergo cytoreductive debulking surgery followed by intensive chemotherapy. An array of targeted therapies are currently being utilized and developed to alleviate negative side effects, eradicate cancer growth, and diminish disease recurrence. Immunotherapy is a promising cancer therapy that upregulates one's immune system to stimulate a therapeutic effect and is utilized for cancer management among other ailments such as immunodeficiencies, hypersensitivity reactions, autoimmune diseases, inflammatory disorders, tissue and organ transplantation, and infectious diseases. This review highlights the five primary subtypes of breast cancer, provides a brief history of immunotherapy, evaluates the current landscape of treating breast cancer with immunotherapy, analyzes selected ongoing or recently completed immunotherapy clinical trials for hormone receptor-positive, HER2-enriched, and triple-negative breast cancer, and examines future trends for the treatment of breast cancer with immunotherapeutic techniques. This review provides a formal summary categorized by breast cancer subtype rather than types of immunotherapeutic treatment.

Terapia de conversión en cáncer gástrico: experiencia del Instituto Nacional de Cancerología de Colombia

Background: Gastric cancer (GC) represents a public health problem in Colombia and worldwide. Since most patients are at advanced stages at the time of diagnosis, it is necessary to develop management strategies as conversion therapy (CT). Objective: The aim of this study was to estimate the results of CT for treating patients with advanced and GC at Instituto Nacional de Cancerología de Colombia (INC). Material and methods: We included patients with incurable gastric cancer who underwent induction chemotherapy and intended curative surgery between 2010 and 2021. The clinical and pathological data and survival of the patients included were retrospectively reviewed. Overall survival (OS) was calculated from the time of initiation of chemotherapy until the date of death. Survival functions were estimated using the life table and Kaplan-Meier methods, and survival curves at 3 and 5 years were constructed. Results: 23 patients were analyzed; mean age was 56 years, and 17 (74%) were men. The most common criterion indicating unresectability was a T4b tumor in 13 cases (56.5%). All the patients underwent CT. Median follow-up was 28 months. Eleven patients developed disease recurrence (52%). Median survival was 41.2 months, and 3- and 5-year OS was 57.7% and 38.5%, respectively. Conclusions: CT provided an acceptable OS rate for selected patients with incurable advanced GC. This strategy requires a

DNA damage levels in peripheral blood mononuclear cells before and after first cycle of chemotherapy have comparable prognostic values in germ cell tumor patients.

Germ cell tumors (GCTs) represent the most frequent solid malignancy in young men. This malignancy is highly curable by cisplatin (CDDP)-based chemotherapy. However, there is a proportion of patients having a poor prognosis due to refractory disease or its relapse. No reliable biomarkers being able to timely and accurately stratify poor prognosis GCT patients are currently available. Previously, we have shown that chemotherapy-naïve GCT patients with higher DNA damage levels in peripheral blood mononuclear cells (PBMCs) have significantly worse prognosis compared to patients with lower DNA damage levels. DNA damage levels in PBMCs of both chemotherapy-naïve and first cycle chemotherapy-treated GCT patients have been assessed by standard alkaline comet assay and its styrene oxide (SO)-modified version. These levels were correlated with clinico-pathological characteristics. We re-confirm prognostic value of DNA damage level in chemotherapy-naïve GCT patients and reveal that this prognosticator is equally effective in GCT patients after first cycle of CDDP-based chemotherapy. Furthermore, we demonstrate that SO-modified comet assay is comparably sensitive as standard alkaline comet assay in case of patients who underwent first cycle of CDDP-based chemotherapy, although it appears more suitable to detect DNA cross-links. We propose that DNA damage levels in PBMCs before and after first cycle of CCDP-based chemotherapy are comparable independent prognosticators for progression-free and overall survivals in GCT patients. Therefore, their clinical use is highly advised to stratify GCT patients to identify those who are most at risk of developing disease recurrence or relapse, allowing tailoring therapeutic interventions to poor prognosis individuals, and optimizing their care management and treatment regimen.

Role of Mesohepatectomy for Pediatric Centrally Located Liver Tumors.

Mesohepatectomy (MH) or central hepatectomy (CH) is a recognized surgical technique for centrally located pediatric liver tumors. This technique of liver resection avoids extended liver resections and thereby helps in the preservation of liver parenchyma. In this article, we aim to analyze our experience and outcome with this technique of liver resection. A retrospective analysis of patients who underwent MH from January 2015 to June 2023 at our institute was performed. The variables analyzed include demographics, preoperative treatment, perioperative management, and postoperative outcome. A total of five patients underwent CH. Four patients had hepatoblastoma, and one patient had mesenchymal hamartoma. All four patients with hepatoblastoma received neoadjuvant chemotherapy. All five patients had negative surgical margins, and one of the five developed disease recurrences necessitating resurgery and ultimately died of metastasis. one patient sustained intraoperative major bile duct injuries, and one patient had postoperative Abnormal, well-circumscribed, extra-biliary collection of bile. MH with clear margins is feasible in the selected subset of pediatric liver tumors involving segments IV, V, and VIII with outcomes equivalent to extended hepatic resections.

Clinical characteristics and management outcomes in isolated nail lichen planus: A retrospective case series.

Background Isolated nail lichen planus (NLP) without mucocutaneous involvement is rare. Literature about the clinical profile and management is scarce. Aims/Objective We attempted to characterize the clinico-demographic profile and analyze the management outcome of patients with isolated nail lichen planus. Methods Records of 15 patients were evaluated, and their demographic profile, clinical features of the nail matrix and nail bed disease, onychoscopy findings, histopathological features, treatment given, and follow-up progress were analysed. Results Data from 15 patients were collected. The mean age of the patients was 28.6 ± 19.0 years (range 3.5 years to 56 years). The gender ratio was 0.8 with 7 males and 8 females. The average disease duration at presentation was 2.8 ± 2.6 years (6 months-9 years). The average number of nails involved was 16.4 ± 4.6 (8-20 nails). All 20 nails were involved in 9 (60%) patients. Nail matrix -involvement was seen in all, with onychorrhexis being the most common manifestation, which was seen in 11 (73.3%) patients. Nail bed involvement was seen in 11 (73.3%) patients, with onycholysis being the most common presentation. Severe nail disease was seen in 7 (46.7%) patients, and 5 (33.3%) had pterygium involving an average of 3.4 nails. Moderate to good improvement was observed in 9 (60%) patients after an average of 6.1 ± 2.4 (3-9) treatment sessions with intramuscular and intramatricial triamcinolone acetonide injection. Of these, 2/9 (22.2%) developed disease recurrence in a few nails after an interval of 1 and 1.5 years, respectively. Two patients achieved complete clinical cures that persisted beyond 2 years of follow-up. Limitations Retrospective nature of the series and the small sample size are the major limitations. Conclusion The risk of permanent disfigurement is high in NLP and calls for an early diagnosis and prompt treatment. Intralesional and intramuscular steroids are first-line therapeutic options depending upon the number of nails involved.

Analysis of enhanced CT imaging signs and clinicopathological prognostic factors in hepatoid adenocarcinoma of stomach patients with radical surgery: a retrospective study

BackgroundTo investigate the association between CT signs and clinicopathological features and disease recurrence in patients with hepatoid adenocarcinoma of stomach (HAS).MethodsForty nine HAS patients undergoing radical surgery were retrospectively collected. Association between CT and clinicopathological features and disease recurrence was analyzed. Multivariate logistic model was constructed and evaluated for predicting recurrence by using receiver operating characteristic (ROC) curve. Survival curves between model-defined risk groups was compared using Kaplan–Meier method.Results24(49.0%) patients developed disease recurrence. Multivariate logistic analysis results showed elevated serum CEA level, peritumoral fatty space invasion and positive pathological vascular tumor thrombus were independent factors for disease recurrence. Odds ratios were 10.87 (95%CI, 1.14–103.66), 6.83 (95%CI, 1.08–43.08) and 42.67 (95%CI, 3.66–496.85), respectively. The constructed model showed an area under ROC of 0.912 (95%CI,0.825–0.999). The model-defined high-risk group showed poorer overall survival and recurrence-free survival than the low-risk group (both P < 0.001).ConclusionsPreoperative CT appearance of peritumoral fatty space invasion, elevated serum CEA level, and pathological vascular tumor thrombus indicated poor prognosis of HAS patients.

Treatment Outcomes of Simultaneous Integrated Boost to Intraprostatic Lesions with External Beam Radiotherapy in Localized Prostate Cancer Patients.

To evaluate the treatment outcomes and toxicity of definitive radiotherapy (RT) for prostate cancer (PC) patients using the simultaneous integrated boost (SIB) technique to intraprostatic lesion (IPL). All the patients received 78 Gy for their prostate ± seminal vesicles and 86 Gy for the IPL using the SIB technique. High-risk patients received pelvic nodal irradiation. The pelvic lymphatic field received 46-54 Gy of radiation. Univariable and multivariable analyses were conducted of the prognostic factors for freedom from biochemical failure (FFBF), progression-free survival (PFS), and PC-specific survival (PCSS) of 619 PC patients who received definitive RT between September 2012 and August 2021. Predictors of late Grade ≥ 2 genitourinary (GU) and gastrointestinal (GI) toxicities were also identified using logistic regression. The median age of the entire cohort was 69 years (range, 47-89 years). Most of the patients (82.7%) had tumors with a GS of 6 or 7, 134 (21.6%) had PC with a GS of 3 + 4, 126 (20.4%) had PC with a GS of 4 + 3, and only 9% had clinical nodal metastasis. The median follow-up time for the entire cohort was 68.5 months (95% CI, 64.4-72.6 months). The 5-year FFBF, PFS, and PCSS rates were 93.2%, 83.2%, and 98.6%, respectively. They were predicted by the serum prostate specific antigen (PSA), Gleason score (GS), clinical nodal stage, and D'Amico risk group. Only 45 patients (7.3%) developed disease recurrence 41.9 months after RT. Of these patients, 12 (1.9% of the total) had BF only, 31 (5.3%) had both BF and distant metastasis, and 2 (0.3%) had distant metastasis only. The 5-year FFBF rates for low-, intermediate-, and high-risk disease were 98.0%, 93.1%, and 88.5%, respectively (p < 0.001). The 5-year PFS and PCSS rates according to risk groups were 91.0%, 82.1%, and 77.4% (p < 0.001), and 99.2%, 96.4%, and 95.9% (p = 0.03), and respectively. GS > 7 and lymph node metastasis negatively predicted FFBF and PCSS in multivariable analysis. Lymph node metastasis was associated with poor PFS, but only marginally (p = 0.06). Ninety (14.6%) and 44 (7.1%) patients had acute Grade ≥ 2 GU and GI toxicities, respectively, and 42 (6.8%) and 27 (4.4%) patients had late Grade ≥ 2 GU and GI toxicities, respectively. Diabetes (OR = 2.61; 95% CI = 1.29-5.26; p = 0.007) and transurethral resection of prostate (OR = 6.75; 95% CI = 3.37-13.54; p = 0.001) independently predicted late Grade ≥ 2 GU toxicity, but no significant predictor of late Grade ≥ 2 GI toxicity was found. Localized PC was effectively and safely treated with definitive RT using the SIB technique to deliver 86 Gy to the IPL in 39 fractions without severe late toxicity. This finding must be validated with long-term results.