Treatment De-escalation Research Articles

Modern Management of Gastric Neuroendocrine Neoplasms.

Gastric neuroendocrine neoplasms (G-NENs) are a heterogeneous group of tumors that broadly fall into two groups. The first group, driven by oversecretion of gastrin, are generally multifocal, small, and behave indolently with a low (but non-zero) risk of progression and metastatic spread. They are conventionally categorized into type 1, with endogenous gastric-based overproduction of gastrin, and type 2 G-NEN, with overproduction of gastrin from an extra-gastric gastrin-secreting tumor. The second group, termed type 3 G-NEN, occur spontaneously and are potentially more aggressive, having a clinical course analogous to other neuroendocrine tumors of the gastrointestinal tract. Type 1 G-NEN can be managed with endoscopic surveillance and resection of visible lesions with great success, reserving surgery for the rare high-risk lesion, whereas surgical resection of the causative gastrin-secreting tumor in type 2 G-NEN is usually curative. Type 3 G-NEN is usually managed with formal surgical resection but there is growing evidence that limited surgery or even endoscopic resection in appropriately selected patients with low risk is both safe and effective. A novel subtype of G-NEN, associated with long-term proton pump inhibitor usage, is increasing in incidence. The pathophysiology seems to parallel type 1 G-NEN. In the setting of metastatic disease, which can occur in any subtype but is most common by far in type 3 G-NEN, the lack of trial data unique to G-NEN results in extrapolation of strategies and agents for treatment of non-gastric neuroendocrine disease. The rapid pace of development in this area is likely to benefit the metastatic G-NEN patient as well. As treatment is predicate on type of G-NEN, establishing the etiology of the lesion is crucial but growing knowledge of G-NEN pathophysiology and close collaboration between pathologists, gastroenterologists, radiologists, surgeons, and oncologists have enabled a growing trend towards de-escalation and less-invasive treatment paradigms.

Genomic tests for risk stratification in patients with early human epidermal growth factor receptor 2-positive breast cancer.

The purpose of this review is to provide a comprehensive overview of human epidermal growth factor receptor 2 (HER2) genomic tests, particularly focusing on the most recent developments and looking at the future prospects of this field, yet to be thoroughly explored. HER2DX is a multifeatured assay, retrospectively proved to add prognostic information and to predict pathological complete response (pCR) in patients with HER2-positive early breast cancer (EBC) undergoing neoadjuvant treatment containing HER2-directed agents. Preliminary data have shown that the assay maintains its predictive capabilities even in the context of chemotherapy-free, anti-HER2 neoadjuvant regimens, potentially selecting patients suitable for treatment de-escalation, having highly HER2-driven malignancies. Multigene prognostic assays have become essential tools in the management of EBC, providing crucial information for risk stratification.

Demystifying the Contemporary Role of 12-Month Dual Antiplatelet Therapy After Acute Coronary Syndrome.

For almost two decades, 12-month dual antiplatelet therapy (DAPT) in acute coronary syndrome (ACS) has been the only class I recommendation on DAPT in American and European guidelines, which has resulted in 12-month durations of DAPT therapy being the most frequently implemented in ACS patients undergoing percutaneous coronary intervention (PCI) across the globe. Twelve-month DAPT was initially grounded in the results of the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial, which, by design, studied DAPT versus no DAPT rather than the optimal DAPT duration. The average DAPT duration in this study was 9 months, not 12 months. Subsequent ACS studies, which were not designed to assess DAPT duration, rather its composition (aspirin with prasugrel or ticagrelor compared with clopidogrel) were further interpreted as supportive evidence for 12-month DAPT duration. In these studies, the median DAPT duration was 9 or 15 months for ticagrelor and prasugrel, respectively. Several subsequent studies questioned the 12-month regimen and suggested that DAPT duration should either be fewer than 12 months in patients at high bleeding risk or more than 12 months in patients at high ischemic risk who can safely tolerate the treatment. Bleeding, rather than ischemic risk assessment, has emerged as a treatment modifier for maximizing the net clinical benefit of DAPT, due to excessive bleeding and no clear benefit of prolonged treatment regimens in high bleeding risk patients. Multiple DAPT de-escalation treatment strategies, including switching from prasugrel or ticagrelor to clopidogrel, reducing the dose of prasugrel or ticagrelor, and shortening DAPT duration while maintaining monotherapy with ticagrelor, have been consistently shown to reduce bleeding without increasing fatal or nonfatal cardiovascular or cerebral ischemic risks compared with 12-month DAPT. However, 12-month DAPT remains the only class-I DAPT recommendation for patients with ACS despite the lack of prospectively established evidence, leading to unnecessary and potentially harmful overtreatment in many patients. It is time for clinical practice and guideline recommendations to be updated to reflect the totality of the evidence regarding the optimal DAPT duration in ACS.

Pattern of LRR in Endometrial Cancer and Identification of Predictive Factors

Background: Tailored adjuvant treatment is key to managing endometrial cancer effectively. Understanding prognostic factors of loco-regional failure and the impact of adjuvant treatment can help in treatment de-escalation without compromising survival outcomes. The aim of this study was to assess the pattern of failure in endometrial cancer patients and to determine predicting Loco-Regional Recurrence (LRR) factors. Patients and methods: Data were collected from 214 patients treated for endometrial cancer between 2005 and 2012 in Salah Azaiez Institute in Tunisia. All patients underwent upfront surgery followed by adjuvant brachytherapy with or without external beam radiation. The median follow-up period was 44 months. Univariate and multivariate analyses were performed to identify prognostic factors for LRR. Results: The 5-year overall survival rate was 78.1%, and the 5-year progression-free survival rate was 80.1%. LRR occurred in 25 patients (11.6%), with a median recurrence time of 29 months (range 4 months - 46 months). Pelvic relapse was the most common site, occurring in 10 patients. Vaginal relapses were observed in 9 patients, and retro-peritoneal relapses were observed in 6 cases. FIGO stage, tumor grade, histologic type, Lympho-Vascular Space Invasion (LVSI), and delays in adjuvant treatment were significant predictors of LRR. Conclusion: Identifying prognostic factors for LRR in endometrial cancer is crucial for optimizing adjuvant treatment strategies. Higher FIGO stages and the presence of LVSI were independent predictive factors for LRR. Tailored adjuvant treatment, taking these prognostic factors into account, is essential to improve patient outcomes and minimize unnecessary treatment-related toxicity.

Treatment and Staging Intensification Strategies Associated with Radical Prostatectomy for High-Risk Prostate Cancer: Efficacy Evaluation and Exploration of Novel Approaches.

The management of high-risk prostate cancer (PCa) presents a significant clinical challenge, often necessitating treatment intensification due to the potential presence of micrometastases. While radical prostatectomy (RP) constitutes one of the primary treatment modalities, the integration of neoadjuvant and adjuvant therapies suggests a paradigm shift towards more aggressive treatment strategies, also guided by new imaging modalities like positron emission tomography using prostate-specific membrane antigen (PSMA-PET). Despite the benefits, treatment intensification raises concerns regarding increased side effects. This review synthesizes the latest evidence on perioperative treatment intensification and de-escalation for high-risk localized and locally advanced PCa patients eligible for surgery. Through a non-systematic literature review conducted via PubMed, Scopus, Web of Science, and ClinicalTrials.gov, we explored various dimensions of perioperative treatments, including neoadjuvant systemic therapies, adjuvant therapies, and the role of novel diagnostic technologies. Emerging evidence provides more support for neoadjuvant systemic therapies. Preliminary results from studies suggest the potential for treatments traditionally reserved for metastatic PCa to show apparent benefit in a non-metastatic setting. The role of adjuvant treatments remains debated, particularly the use of androgen deprivation therapy (ADT) and adjuvant radiotherapy in patients at higher risk of biochemical recurrence. The potential role of radio-guided PSMA lymph node dissection emerges as a cutting-edge approach, offering a targeted method for eradicating disease with greater precision. Innovations such as artificial intelligence and machine learning are potential game-changers, offering new avenues for personalized treatment and improved prognostication. The intensification of surgical treatment in high-risk PCa patients is a dynamic and evolving field, underscored by the integration of traditional and novel therapeutic approaches. As evidence continues to emerge, these strategies will refine patient selection, enhance treatment efficacy, and mitigate the risk of progression, although with an attentive consideration of the associated side effects.

Evaluation of Empiric Antibacterial Treatment and Subsequent De-escalation for Febrile Neutropenia

Background: Febrile neutropenia (FN) is the most common complication of chemotherapy-induced neutropenia that affects over 80% of patients with hematologic malignancies. National guidance and randomized controlled trial data demonstrate empiric antimicrobial therapy (EAT) can be discontinued after 72 hours of apyrexia and clinical recovery regardless of absolute neutrophil count (ANC). A 2019 internal study identified opportunity for improvement for targeted de-escalation. We aimed to reevaluate duration of EAT in patients with FN without a documented source of infection. Methods: A pharmacovigilance platform identified 110 patients from January to September 2023 without identified source of infection. Data collection was performed via manual chart review. Historic patient data from our 2019 cohort (n=50) was available in our research repository. The primary outcome was the duration of EAT in patients with at least 72 hours of apyrexia and clinical recovery, defined as normalization of vital signs. Secondary outcomes included adverse events associated with EAT, and initiation of intravenous vancomycin. Results: Baseline characteristics for 2023 were similar to historic, median age was 67.5 years, 56% were male, and median ANC at fever onset was 150 cells/μL. EAT was continued in 29 patients (58%) despite defervescence and stabilization versus 35 (70%) in 2019 (figure 1). Average duration (LOT) of EAT beyond clinical stabilization was 6 versus 7 days. Adverse effects due to EAT occurred in 13 patients in 2023 (26%) versus 4 (8%); of which, C. difficile infection (CDI) was the greatest contributor. Vancomycin was initiated in 31 patients (62%), 22 having no identifiable indication. Conclusions: Rates of EAT de-escalation for neutropenic patients after 72 hours of apyrexia and clinical stability improved by 12% as compared to 2019. Mean days of overall EAT was 3 days less in 2023. With a notable increase in CDI rates in 2023, dedicated time for antimicrobial stewardship review, clinician education and guideline driven alerts for review will be explored to help further improve practice.

Tubular Carcinoma of the Breast: The Possibility to Omit Sentinel Lymph Node Biopsy.

Tubular breast carcinoma, classified as a special type of invasive cancer, has a good prognosis. This study aimed to retrospectively investigate the clinical and pathological characteristics of 32 tubular carcinoma cases enrolled at our institution, with a focus on exploring the potential for treatment de-escalation. The study included all patients diagnosed with tubular breast carcinoma at our hospital between January 2005 and December 2021. In addition, 549 patients with ductal carcinoma in situ (DCIS) and 1,524 patients with stage I and II invasive cancers [not otherwise specified (NOS)] were selected for comparison. All participants were female, with an average age of 54.4 years. The median follow-up duration was 64 months. The median tumor diameter was 7 mm, and all cases were Luminal A type. Moreover, no lymph vascular invasion was observed in any case, and no local recurrence, distant metastasis, or death occurred. The sentinel lymph node positive rate was 0% in the tubular carcinoma group, significantly lower than that in the NOS group (25.5%, p=0.0019) and not significantly different from that in the DCIS group (0.2%). The tubular carcinoma group tended to have better overall survival (OS) and disease-free survival (DFS) than the NOS group. Furthermore, the tubular carcinoma group was not inferior in OS and DFS compared to the DCIS group. Lymph node metastasis rate, OS, and DFS of the tubular carcinoma group are comparable to those of the DCIS group. Sentinel lymph node biopsy for tubular carcinoma can be omitted with an accurate preoperative diagnosis.

Efficacy and safety of denosumab de‑escalation in giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is a locally aggressive intermediate bone tumor. Denosumab has shown effectiveness in GCTB treatment; however, the benefits of denosumab de-escalation for unresectable GCTB have not been well discussed. The present study investigated the efficacy and safety of denosumab de-escalation for GCTB. The medical records of 9 patients with unresectable GCTB or resectable GCTB not eligible for resection, who received de-escalated denosumab treatment at Okayama University Hospital (Okayama, Japan) between April 2014 and December 2021, were retrospectively reviewed. The denosumab treatment interval was gradually extended to every 8, 12 and 24 weeks. The radiographic changes and clinical symptoms during standard and de-escalated denosumab therapy were assessed. The denosumab interval was de-escalated after a median of 12 months of a standard 4-weekly treatment. Imaging showed that the re-ossification of osteolytic lesions obtained with the 4-weekly treatment were sustained with 8- and 12-weekly treatments. The extraskeletal masses reduced significantly with standard treatment, while tumor reduction was sustained during de-escalated treatment. During the 24-weekly treatment, 2 patients remained stable, while 2 patients developed local recurrence. The clinical symptoms improved significantly with standard treatment and remained improved during de-escalated treatment. There were severe adverse events including osteonecrosis of the jaw (2 patients), atypical femoral fracture (1 patient) and malignant transformation of GCTB (1 patient). In conclusion, 12-weekly de-escalated denosumab treatment showed clinical benefits as a maintenance treatment in patients with unresectable GCTB, in addition to sustained stable tumor control and improved clinical symptoms with standard treatment. A 24-weekly treatment can also be administered, with careful attention paid to detecting local recurrence.

Clinical prognostic factors to guide treatment strategy for HPV‑positive oropharyngeal cancer using treatment outcomes of induction chemotherapy: A real‑world experience.

The role of induction chemotherapy (IC) in locally advanced oropharyngeal cancer (OPC) remains debatable, and suitable candidates for de-escalation treatment in these patients have not been fully identified. Therefore, the present study aimed to identify high-risk candidates for human papillomavirus (HPV)-positive OPC by analyzing patients who underwent IC followed by chemoradiotherapy (CRT) to guide optimal treatment strategies. Patients diagnosed with stage III-IVA OPC and treated with a minimum of two cycles of IC followed by CRT, between 2004 and 2020, were retrospectively reviewed. All the patients were restaged according to the American Joint Committee on Cancer, 8th edition. The overall response rate and survival outcomes associated with clinical factors based on HPV status were analyzed using univariate and multivariate analyses. The present study analyzed 105 patients with a median age of 60 years (range, 40-76 years). Among 105 patients, 40 (38.1%) were HPV-negative and 65 (61.9%) HPV-positive. In all patients, survival outcomes were notably poorer in patients aged ≥60 years (P=0.006) and those who did not achieve complete response post-CRT (P<0.001), irrespective of the HPV status. The median relative dose intensity of IC was ≥80%, indicating adequate treatment, regardless of age. In contrast to patients with HPV-negative OPC, age ≥60 years (P=0.011) and T4 stage (P=0.019) emerged as substantial poor prognostic factors for survival outcomes in patients with HPV-positive OPC. Patients with HPV-positive OPC were categorized into three groups based on the number of clinical factors at diagnosis (such as age and T4 stage). The progression-free and overall survival showed significant stratification across each group as the number of high-risk factors increased despite IC and CRT. The findings indicated that patients with these high-risk factors require a cautious therapeutic strategy even when they are diagnosed with HPV-positive OPC, and the role of combined modality, including IC, will need to be investigated in a randomized trial to be routinely incorporated into clinical practice.

Laparoscopic Indocyanine Green-Guided Sentinel Lymph Node Biopsy for Gallbladder Neoplasms.

Surgical resection, the only potentially curative treatment for gallbladder cancer (GBC), entails an extended cholecystectomy with portal lymphadenectomy. Lymph node dissection is a key staging procedure, but its therapeutic value is unclear. Additionally, it is technically challenging and potentially harmful. Methods for better assessment of lymph node status are needed. This report presents a case of indocyanine green (ICG)-guided sentinel lymph node biopsy (SNLB) for a patient with a gallbladder mass suspicious for GBC. An 81-year-old woman consulted for abdominal discomfort. Abdominal ultrasound showed an intraluminal gallbladder mass suspicious for GBC. Staging imaging did not show liver invasion, lymphadenopathy, or distant metastasis. Given the woman's advanced age and limited extent of disease, a laparoscopic extended cholecystectomy with an ICG-guided SLNB was performed. Injection of 1 ml of ICG (0.125 mg/mL) into the gallbladder bed was performed using a 22-gauge needle, avoiding direct injection into the gallbladder wall. A near-infrared camera was used to visualize real-time ICG flow through the lymphatic vessels of the gallbladder toward the cystic node. Then, a sentinel lymph node posterolateral to the bile duct (station 12b) was identified. The node was resected and sent for permanent section. The procedure continued with an extended cholecystectomy. Pathology showed an intracholecystic papillary neoplasm with high-grade dysplasia. Cystic and sentinel lymph nodes were negative for malignancy. For patients with gallbladder neoplasms, ICG-guided SLNB is a feasible technique that could allow for treatment de-escalation. Further evaluation in clinical trials is needed.

GCT-03. MONOGERM, A NOVEL PROOF-OF-PRINCIPLE BAYESIAN PHASE II TRIAL DESIGN OF CARBOPLATIN OR VINBLASTINE MONOTHERAPY INDUCTION PRIOR TO RADIOTHERAPY FOR INTRACRANIAL GERMINOMA

Abstract BACKGROUND Current European standard-of-care for localised intracranial germinoma is multi-agent chemotherapy (carboPEI: carboplatin/etoposide/ifosfamide) followed by definitive radiotherapy, with excellent survival. MonoGerm is a de-escalation, non-inferiority trial aiming to reduce toxicity. Twelve-week carboplatin (PMID:8039122) AUC10 or vinblastine (PMIDs:32642701/34520101) induction will be evaluated to test if as effective as carboPEI from SIOP-CNS-GCT-II. A novel trial design was required to answer this question pragmatically/safely. METHODS Clinical trials in rare diseases recruit slowly, allowing continuous monitoring of efficacy outcomes. Efficacy-transition-pathways (ETP) are innovative visual tools to aid determination of trial design parameters, and an extension of the dose-transition-pathways concept introduced for dose-finding trials (PMID:28733440). RESULTS MonoGerm includes two monotherapies, with each single arm recruiting six cohorts of three patients, with interim assessment after each recruited cohort and final analysis at 18 patients (total n=36). Insufficient tumour volume response (&amp;lt;30%) at 6-week safety MRI results in 12-weeks carboPEI. Primary outcome is radiological complete response (CR) by 12-weeks of induction monotherapy. A beta-binomial conjugate analysis will generate posterior probability distributions, combining observed trial data as realisations from a binomial distribution with a minimally informative Beta (1,1) prior. Decision criteria to allow early stopping at interim analyses and go/no-go decisions at final analysis are based on probabilities from these posterior distributions. ETP visually maps out parameters used to assert decisions after each interim assessment as a pyramid decision tree. For each recruited cohort and every CR outcome, estimates of the true CR rate and probabilities with associated decisions are mapped out. ETP allows clear communication between statisticians, clinicians, and patient-public-involvement (PPI) teams, facilitating informed decisions in an efficient/realistic trial design. CONCLUSION MonoGerm, a novel Bayesian de-escalation trial, funded by Little Princess Trust (https://www.littleprincesses.org.uk/), uses ETP and continuous monitoring with built-in stopping rules to ensure patient safety in this treatment de-escalation trial.

Circulating Tumor DNA-Guided De-Escalation Targeted Therapy for Advanced Non−Small Cell Lung Cancer

Uninterrupted targeted therapy until disease progression or intolerable toxic effects is currently the routine therapy for advanced non-small cell lung cancer (NSCLC) involving driver gene variations. However, drug resistance is inevitable. To assess the clinical feasibility of adaptive de-escalation tyrosine kinase inhibitor (TKI) treatment guided by circulating tumor DNA (ctDNA) for achieving complete remission after local consolidative therapy (LCT) in patients with advanced NSCLC. This prospective nonrandomized controlled trial was conducted at a single center from June 3, 2020, to July 19, 2022, and included 60 patients with advanced NSCLC with driver variations without radiologically detectable disease after TKI and LCT. The median (range) follow-up time was 19.2 (3.8-29.7) months. Data analysis was conducted from December 15, 2022, to May 10, 2023. Cessation of TKI treatment and follow-up every 3 months. Treatment was restarted in patients with progressive disease (defined by the Response Evaluation Criteria in Solid Tumors 1.1 criteria), detectable ctDNA, or elevated carcinoembryonic antigen (CEA) levels, whichever manifested first, and treatment ceased if all indicators were negative during follow-up surveillance. Progression-free survival (PFS). Secondary end points were objective response rate, time to next treatment, and overall survival. Among the total study sample of 60 participants (median [range] age, 55 [21-75] years; 33 [55%] were female), the median PFS was 18.4 (95% CI, 12.6-24.2) months and the median (range) total treatment break duration was 9.1 (1.5-28.1) months. Fourteen patients (group A) remained in TKI cessation with a median (range) treatment break duration of 20.3 (6.8-28.1) months; 31 patients (group B) received retreatment owing to detectable ctDNA and/or CEA and had a median PFS of 20.2 (95% CI, 12.9-27.4) months with a median (range) total treatment break duration of 8.8 (1.5-20.6) months; and 15 patients (group C) who underwent retreatment with TKIs due to progressive disease had a median PFS of 5.5 (95% CI, 1.5-7.2) months. For all participants, the TKI retreatment response rate was 96%, the median time to next treatment was 29.3 (95% CI, 25.3-35.2) months, and the data for overall survival were immature. The findings of this nonrandomized controlled trial suggest that this adaptive de-escalation TKI strategy for patients with NSCLC is feasible in those with no lesions after LCT and a negative ctDNA test result. This might provide a de-escalation treatment strategy guided by ctDNA for the subset of patients with advanced NSCLC. ClinicalTrials.gov Identifier: NCT03046316.

Oncologic outcomes of de-escalating axillary treatment in clinically node-positive breast cancer patients treated with neoadjuvant systemic therapy – A two center cohort study

BackgroundThe aim of the present study was to report the 5-year axillary recurrence-free interval (aRFI) in clinically node-positive breast cancer patients treated according to a de-escalating axillary treatment protocol after neoadjuvant systemic therapy (NST). MethodsAll patients diagnosed in two hospitals between October 2014 and March 2021 were identified retrospectively. Data on diagnostic workup, treatment and follow-up was collected. Adjuvant axillary treatment was considered based on the initial staging using 18F-FDG PET/CT and the results of axillary lymph node marking with a radioactive-iodine seed protocol or a targeted axillary dissection procedure. Follow-up was updated until 27th April 2024. Kaplan-Meier curves were calculated to report the 5-year aRFI with corresponding 95 % confident intervals (95%-CI). ResultsA total of 199 patients were included. Axillary pathological complete response was reported in 66 (33.2 %). Based on the treatment protocol and initial clinical staging, no adjuvant axillary treatment was indicated in 30 patients (15 %), while 139 (70 %) received axillary radiotherapy without performance of an axillary lymph node dissection (ALND). The remaining 30 patients (15 %) underwent an ALND with additional locoregional radiotherapy. A median follow-up of 62 months (30–106) showed that 4 (2 %) patients experienced an axillary recurrence after 7, 8, 36 and 36 months, respectively. In all 4 patients, synchronous distant metastases were diagnosed. The estimated 5-year aRFI was 97.8 % (95%-CI 95.6–99.9 %) ConclusionAlthough longer follow-up should be awaited before final conclusions can be drawn regarding the oncological safety of this approach, the implementation of a de-escalating axillary treatment protocol appears to be safe since the estimated 5-year aRFI is 97.8 %.

Awareness, Knowledge, and Current Practice of Breast Cancer Among Surgeons in Jordan.

Breast cancer (BC) is the most prevalent cancer in Jordan. De-escalation in treatment reflects a paradigm shift in BC treatment. More tailored strategies and the adoption of a multidisciplinary approach are essential to apply recent changes in management. In the era of breast surgery fellowship, adopting well-structured training is essential to apply recent therapeutic guidelines and meet patients' expectations. A cross-sectional study using a customized, self-reported questionnaire was used. Data collection occurred anonymously using a link via WhatsApp in the period between February 2023 and April 2023. A total of 89 surgeons were involved in this study, and only 14 (15.7%) completed a subspecialty in breast surgery. About 58.4% considered the age of 40 years as the starting point for screening, and 84.3% reported that mammogram screening is associated with improved BC survival. Only 10.1% and 28.1% acknowledged the applicability of both tomosynthesis and breast magnetic resonance imaging in screening, respectively. A significant difference in the mean knowledge score about BC is observed between general surgeon and those with subspecialty. Varying levels of awareness concerning different risk factors and their correlation with the likelihood of BC occurrence observed. Although 56.2% of participants could offer breast conserving surgery and consider it oncological safe, only 48.3% defined it correctly. Of the participants, 61.8% and 76.4% stated that sentinel lymph node biopsy can be safely applied in clinically negative or suspicious axillary nodes, respectively, with <50% of surgeon performing it in their practice. More efforts are required to enhance the knowledge and practice of surgeons in the field of breast surgery. Adopting national guidelines can facilitate the acceptance and improvement of current practices among surgeons in Jordan.

Longitudinal circulating tumor DNA monitoring for detection of molecular residual disease in patients with advanced germ cell tumors.

e17022 Background: Germ cell malignancies, commonly manifesting as testicular cancer, is one of the most common malignancies in men 15 to 45 years of age, with the incidence doubling over the past 40 years. When identified promptly and treated with a multidisciplinary approach, germ cell tumors have an excellent prognosis with cure rate &gt;90% and 5-year survival rate &gt;95%. Treatment involves radical orchiectomy for diagnostic and therapeutic purposes. Further management includes active surveillance, adjuvant chemotherapy, retroperitoneal lymph node dissection (RLND), and radiation therapy. While AFP, B-HCG, and LDH are good biomarkers, they are not sensitive or specific for detecting molecular residual disease (MRD). B-HCG is detected in &lt;30% of individuals with seminoma and B-HCG and AFP are detected in 50–60% of patients with non-seminomatous tumors. We describe the use of circulating tumor DNA (ctDNA) for detection of MRD in advanced germ cell malignancy, especially when baseline biomarkers are negative. Methods: This is a retrospective analysis of 20 patients with testicular cancer treated at Rush University Medical Center who monitored closely for MRD. Signatera (Natera Inc.), a personalized tumor-informed ctDNA assay, was utilized for detection and quantification of ctDNA in patients’ plasma samples, measured at MRD (1-12 weeks post-orchiectomy) and regular intervals thereafter, regardless of treatment modality. Event free survival (EFS) was determined, defined as the period from radical orchiectomy to date of radiographic progression of disease. Results: There was a total of 20 patients (35% seminoma, 65% non-seminoma) with 2 of the patients having extragonadal disease. The mean age was 32.2 years old with IQR (28-36). Post operatively, 20% underwent RLND, 10% were on surveillance, 53% received post-orchiectomy chemotherapy, 6.7% of patients underwent autologous stem cell transplant. The median follow up time is 1.14 years. Two patients had positive ctDNA despite negative baseline traditional biomarkers. There were 23.3% (7/30) of patients that had evidence of radiographic progression. Of the patients with progression, serial ctDNA monitoring had high rates of concordance (85%, 6/7) of ctDNA positivity with biomarker positivity and radiographic progression. Conclusions: Overall, ctDNA correlated with, and sometimes even preceded, traditional biomarkers and radiographic findings of disease progression. The ctDNA positivity of 2 patients in this cohort despite negative baseline AFP, B-HCG, and LDH, highlights the sensitivity and specificity of ctDNA for MRD compared to more traditional biomarkers. Serial monitoring of ctDNA offers valuable insights into germ cell tumor disease status, including presence of MRD, and there is a need for prospective studies to guide treatment escalation and de-escalation in germ cell tumors.

Pathological and clinical outcomes following neoadjuvant dual HER2 therapy for early-stage breast cancer: An Australian institutional real-world experience.

There has been significant progress made in developing novel targeted therapies in the neoadjuvant setting for non-metastatic HER2-positive breast cancer, which may be used in combination with conventional chemotherapy to optimise pathological responses at surgery. However, these therapies, particularly the chemotherapeutic components, may portend significant and long-lasting toxicity. Hence, de-escalation of treatment intensity has been an area of interest and was evaluated in the phase II NeoSphere study. Herein, we report the real-world pathological and survival outcomes from neoadjuvant taxane and dual HER2 blockade recorded at our centre. This was a retrospective cohort study of patients receiving neoadjuvant pertuzumab, trastuzumab and taxane chemotherapy for non-metastatic HER2-positive breast cancer at a single centre in Sydney, Australia. We collected data pertaining to baseline demographic characteristics, pathological response rates, post-surgical prescribing patterns and also undertook survival analyses for invasive disease-free survival (iDFS) as well as exploratory analyses for correlations between pre-specified clinicopathologic factors and pathological response at surgery. Our population was largely similar at baseline to the NeoSphere study. 71 patients were included in the final analysis. 61% achieved a pathological complete response (pCR). Three patients received conventional chemotherapy in the adjuvant setting. 92% of included patients were alive and disease-free at 3 years of follow-up. Only 3 events of recurrence or death were recorded at a median follow-up of 32 months. No significant difference in iDFS was noted between patients achieving pCR and those with residual disease at surgery. This study demonstrates that de-escalated adjuvant treatment for HER2-positive early breast cancer achieved favourable pathological and long-term outcomes comparable to large trials, some utilising more intensive chemotherapeutic components.

Prediction of pathologic complete response to chemoimmunotherapy in triple-negative breast cancer using tumor-infiltrating lymphocytes: Exploiting cutoff values.

e12629 Background: Triple-negative breast cancer (TNBC) prognosis is significantly influenced by tumor-infiltrating lymphocytes (TILs), but the lack of validated cutoff values has limited their clinical applicability. In the era of neoadjuvant pembrolizumab plus chemotherapy (P+CT) as a new standard of care, the role of TILs as predictors of response to chemoimmunotherapy remains uncertain. Methods: This study aimed to assess TILs as predictors of pathologic complete response (pCR) within the Neo-Real study, a multicenter, real-world data investigation on neoadjuvant P+CT in TNBC. TILs were evaluated using the standardized methodology of the International TILs Working Group. Logistic regression and receiver operating characteristic (ROC) curve analysis were performed to evaluate the predictive ability of TILs expression and multivariable models for pCR. Results: The analysis included 128 patients (pts) treated with neoadjuvant P+CT (68% stage II, 26% stage III). The proportion of pts in each TILs’ category and results of ROC curve analysis are presented in the Table. A cutoff value of 10% demonstrated the highest accuracy in predicting pCR, while a high specificity was observed at a cutoff value of 50%. Thus, the probability of residual disease if TILs ≥ 50% is considerably low. Incorporating categorized clinical and pathological variables, a multivariable logistic regression model, using TILs (≥ 10% vs &lt; 10%), Ki67 (≥ 50% vs &lt; 50%), and tumor stage (III vs II), exhibited the highest AUC (0.688) for predicting pCR. Conclusions: Our study underscores the predictive value of TILs for pCR in TNBC following neoadjuvant P+CT. The cutoff value of ≥ 50% identified patients with a very high probability of pCR. The results reinforce TILs’ use as a biomarker for treatment de-escalation, especially for pts with TILs ≥ 50%. Further enhancement of TILs' predictive potential may be achieved through multivariable models. [Table: see text]

Predictive biomarkers for pathological complete response in early-stage triple negative breast cancer following neoadjuvant chemotherapy.

598 Background: Identifying predictive biomarkers for early-stage triple negative breast cancer (TNBC) is essential for tailoring neoadjuvant chemotherapy (NACT) strategies effectively. Methods: We investigated potential clinical and pathological biomarkers in early-stage TNBC patients who underwent NACT regimens with anthracyclines and taxanes at a single cancer center. Medical records were scrutinized for clinical and laboratory data, with categorical variables analyzed using Fisher’s exact test. Logistic regression assessed factors associated with pathological complete response (pCR). Sensitivity and specificity of the biomarkers were explored using receiver operating characteristics (ROC) curve analyses. Results: Among 110 TNBC patients receiving anthracycline- and taxane-based NACT with complete pathology data, the median age was 48 years, 60% had stage III tumors, and 30.9% achieved pCR. Stromal tumor infiltrating lymphocytes (TILs) &gt; 10% were observed in 54.5%, 32.7% had TILs ≥30%, and 90.9% had Ki67 ≥ 50%. Univariate analysis showed no association between pCR and TILs &gt;10% (p=0.5), Ki67 ≥ 50% (p=0.4), anatomic stage (p=0.06), eosinophil-to-lymphocyte ratio (p=0.3), platelet-to-lymphocyte ratio (p=0.08), age (p=0.5), grade (p=0.6), or HER2 status (p=0.6). Neutrophil-to-lymphocyte ratio (NLR) was significantly associated with pCR in both univariate (OR 3.92; 95% CI 1.67 - 9.57; p=0.002) and multivariable analyses (Table). No association was observed between NLR ≤ 1.76 and TILs, anatomic stage, or Ki67. The optimal NLR cutoff using ROC curve was 1.76, yielding 60.6% sensitivity and 71.8% specificity for pCR. NLR cutoffs of ≤ 1.43 had specificities higher than 85%. Although TILs value was not associated with pCR in the regression model, high TILs value (≥50%) yielded a specificity of 89.4% for pCR. Conclusions: NLR emerged as a significant and independent predictor of pCR in early-stage TNBC. Prospective studies should explore this readily available biomarker in assessing neoadjuvant strategy responses. Moreover, high specificities for pCR were observed with NLR ≤ 1.43 and TILs ≥ 50%, representing cutoff values that could be explored for treatment de-escalation. [Table: see text]

Prognostic genomic signatures in patients with RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC) from the phase III study of first-line FOLFIRI/cetuximab versus FOLFIRI/cetuximab followed by cetuximab (Cet) alone (ERMES study).

3590 Background: The ERMES trial did not show non-inferiority of maintenance with Cet alone versus standard treatment. However, preliminary results suggested that a strategy of de-escalation treatment with only Cet might be effective in selected patients. Here we describe preliminary data from comprehensive genomic profiling (CGP) of CRC samples from the ERMES study. Methods: Patients with untreated RAS/BRAF wt mCRC were randomly assigned (1:1) to receive either FOLFIRI/Cet until PD/toxicity (arm A) or FOLFIRI/Cet for 8 cycles followed by Cet alone (arm B). DNA from tumor tissue samples was analyzed with the Oncomine Comprehensive Assay Plus covering hot spot mutations in over 500 genes. Variant calling was performed using the Ion Reporter v5.20 software. The prognostic value of genomic signatures was assessed in the intention-to-treat (ITT) patients’ population with available sequencing data. Results: CGP has been successfully completed so far for 139 patients of the ITT population (68 in arm A and 71 in arm B). This subgroup had a median progression free survival (mPFS) of 9.3 months. The comparison of the genomic profile of cases within the 25th and the 75th mPFS percentile (34 and 36 patients, respectively), identified two signatures that were defined: RES, 14 genes with genomic alterations unique to the 25th percentile poor prognosis group; SENS, 34 genes altered only in the 75th percentile good prognosis cohort. The RES signature was significantly associated with ERBB2, IL-4 and IL-13, MET activated PI3K/AKT, ESR, PI3K and FGFR4 signalling. When the RES signature was applied to the whole cohort, patients with at least one genomic alterations in any gene of the signature showed a mPFS of 2.4 months versus 15.2 months of the wt (Hazard Ratio, HR wt versus mutant 0.07). The SENS signature was associated with pathways related to gene transcription and expression, SMAD 2/3/4 transcription, DNA repair, chromatin modification and Activin signalling. The mPFS of SENS mutant and wt patients was 16.2 and 3.2 months, respectively (HR wt versus mutant 10.09). An exploratory analysis found no significant differences in mPFS for patients with good prognosis based on genomic signatures enrolled in the standard arm (A) versus the experimental arm (B). Conclusions: These preliminary data suggest that CGP of mCRC patients can identify prognostic genomic signatures, which might allow a better stratification of patients and the identification of subgroups that might benefit a treatment de-escalation strategy.

CO117 Factors Associated with Biologic Treatment De-Escalation in Patients with Crohn’s Disease

CO117 Factors Associated with Biologic Treatment De-Escalation in Patients with Crohn’s Disease