Neoadjuvant Regimen Research Articles

Abstract I004: Systematic Discovery and Annotation of Cancer Emergent Orphan non-coding RNAs in human Cancers

Abstract We recently described orphan non-coding RNAs (oncRNAs) as a class of cancer-specific small RNAs with the potential to play functional roles in breast cancer progression1. Here, we report a systematic search to annotate and characterize cancer-emergent oncRNAs across 32 tumor types. We also leverage large-scale in vivo genetic screens in xenografted mice to functionally identify driver oncRNAs in multiple tumor types. We have not only discovered a large repertoire of oncRNAs, but also found that their presence and absence represent a digital molecular barcode that faithfully captures the types and subtypes of cancer. Importantly, we discovered that this molecular barcode is partially accessible from the cell-free space as some oncRNAs are secreted by cancer cells. In a large retrospective study across 192 breast cancer patients, we showed that oncRNAs can be reliably detected in the blood and that changes in the cell-free oncRNA burden captures both short-term and long-term clinical outcomes upon completion of a neoadjuvant chemotherapy regimen. Citation Format: Hani Goodarzi. Systematic Discovery and Annotation of Cancer Emergent Orphan non-coding RNAs in human Cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr I004.

OGC SO42 - A comparison of body composition changes between neoadjuvant FLOT and MAGIC regimes in patients with locally advanced oesophageal cancer

Abstract Background Several studies have documented the changes in body composition that can occur between pre and post neoadjuvant chemotherapy for locally advanced OGA. However, none have compared the changes between different neoadjuvant regimes following the shift in practice from MAGIC to FLOT neoadjuvant chemotherapy. Specifically, given that the FLOT regimen has been thought to be more toxic than MAGIC regimen, it is unclear whether this toxicity is measurable and clinically significant with regards to body composition. This study aims to compare the changes in body composition between these two regimens in patients with locally advanced oesophageal cancer. Method We conducted a retrospective cohort study comparing changes in body composition between patients receiving either MAGIC or FLOT neoadjuvant chemotherapy. 115 patients treated with FLOT (n = 61) or MAGIC (n = 54) who underwent an oesophagectomy for OGA between 2008 and 2020 at Queen Elizabeth Hospital, Birmingham, UK were ultimately enrolled in the study. Changes in body composition between pre- and post-neo-adjuvant chemotherapy were determined by analysis of computed tomography (CT) imaging. Slice-O-Matic is a software tool allowing segmentation of body tissues into different classes Including skeletal muscle and fat based on the Hounsfield units. Results Our findings showed a statistically significant difference in the weight loss of participants enrolled the MAGIC group compared to FLOT (FLOT -0.6 ±6.9 vs MAGIC -3.4 ±1.2, p=0.034) which was therefore also reflected in BMI differential before and after neoadjuvant chemotherapy (FLOT -0.2 ± 2.2 vs MAGIC -1.2 ± 2.7, p=0.024). However, there was no statistically significant difference in the L3 skeletal muscle index in both regimes (FLOT -2.8 ± 4.1 vs MAGIC -2.9 ± 4.1; p=0.93). Finally, changes in L3 fat index between the two cohorts did not demonstrate statistically significant difference in our study (FLOT -0.9 ± 22.6 vs MAGIC -5.6 ± 24.8; p=0.29). Conclusion Our study suggests that a large proportion of patients with locally-advanced OGA were sarcopenic prior to starting chemotherapy and this proportion increased post treatment. There was no statistically significant loss of muscle mass or fat during treatment with either MAGIC or FLOT. Despite this, weight loss and decreases in BMI were greater in the MAGIC group compared to FLOT, suggesting FLOT may have a more favourable toxicity profile with regard to body composition. Overall, our findings support the safety profile of FLOT chemotherapy with regard to body composition changes and illustrates a superior pathological response to FLOT therapy for OGA.

SOX combined with tislelizumab and low-dose radiation therapy for the neoadjuvant treatment of locally advanced gastric/gastroesophageal junction adenocarcinoma: study protocol for a prospective, multicenter, single-arm, phase Ib/II clinical trial

BackgroundRecently, the clinical benefits of neoadjuvant chemotherapy combined with immunotherapy have been observed in patients with locally advanced gastric or gastroesophageal junction (G/GEJ) cancer; however, the pathological complete response (pCR) and long-term survival rates are still unsatisfactory. The aim of this study is to investigate the efficacy and safety of chemotherapy combined with tislelizumab and low-dose radiation therapy (LDRT) for the neoadjuvant treatment of locally advanced G/GEJ cancer.MethodsThis is a prospective, multicenter, single-arm, phase Ib/II trial. In the phase Ib study, 5 patients will be enrolled in each treatment group with different radiation doses. In the phase II study, a total of 44 patients will be enrolled. Eligible patients will be registered and receive three cycles of SOX regimen chemotherapy (S-1: 40-60 mg Bid, d1-14, q3w; oxaliplatin: 130 mg/m2, iv drip, d1, q3w) plus tislelizumab (200 mg, iv drip, d1, q3w). Simultaneously, LDRT will be planned and administered after the first cycle of systemic therapy. Radical D2 gastrectomy will be performed 4-6 weeks after the last administration of chemotherapy plus tislelizumab. The primary endpoint of phase Ib study is to determine the optimal radiation dose for phase II study. The primary endpoint of phase II is the pCR rate. The secondary endpoints include R0 resection rate, major pathological response (MPR) rate, 2-year event-free survival (EFS) rate, 2-year overall survival (OS) rate and safety profile. Moreover, we will also explore potential molecular markers for predicting the benefit and safety of this neoadjuvant regimen. Written informed consent should be provided by all patients enrolled in the study. The study protocol was approved by the independent ethics committee at each institution.DiscussionThis is the first study to explore the efficacy and safety of neoadjuvant chemotherapy combined with tislelizumab and LDRT in G/GEJ cancer patients, the results of which may provide novel treatment strategy for patients with locally advanced G/GEJ adenocarcinoma.Clinical trial registrationClinicalTrials.Gov, identifier NCT06266871.

Losartan-based nanocomposite hydrogel overcomes chemo-immunotherapy resistance by remodeling tumor mechanical microenvironment

Preclinical studies demonstrating high cure rates with PD1/PD-L1 combinations have led to numerous clinical trials, but emerging results are disappointing. These combined immunotherapies are commonly employed for patients with refractory tumors following prior treatment with cytotoxic agents. Here, we uncovered that the post-chemotherapy tumor presents a unique mechanical microenvironment characterized by an altered extracellular matrix (ECM) elasticity and increased stiffness, which facilitate the development of aggressive tumor phenotypes and confer resistance to checkpoint blocking therapy. As thus, we rationally designed an in situ nanocomposite hydrogel system, LOS&FeOX@Gel, which enabled effective and specific delivery of the therapeutic payloads (losartan [LOS] and oxaliplatin [OX]) into tumor. We demonstrate that sustained release of LOS effectively remodels the tumor mechanical microenvironment (TMM) by reducing ECM deposition and its associated “solid stress”, thereby augmenting the efficacy of OX and its immunological effects. Importantly, this hydrogel system greatly sensitized post-chemotherapy tumor to checkpoint blocking therapy, showing synergistic therapeutic effects against cancer metastasis. Our study provides mechanistic insights and preclinical rationale for modulating TMM as a potential neoadjuvant regimen for tumor to optimize the benefits of chemo-immunotherapy, which lays the groundwork for leveraging “mechanical-immunoengineering” strategies to combat refractory tumors.Graphical

Update on Neoadjuvant and Adjuvant BRAF Inhibitors in Papillary Craniopharyngioma: A Systematic Review

Background/Objectives: The recent discovery of BRAF mutation in papillary craniopharyngiomas opened new avenues for targeted therapies to control tumour growth, decreasing the need for invasive treatments and relative complications. The aim of this systematic review was to summarize the recent scientific data dealing with the use of targeted therapies in papillary craniopharyngiomas, as adjuvant and neoadjuvant treatments. Methods: The PRISMA guidelines were followed with searches performed in Scopus, MEDLINE, and Embase, following a dedicated PICO approach. Results: We included 21 pertinent studies encompassing 53 patients: 26 patients received BRAF inhibitors (BRAFi) as adjuvant treatment, while 25 received them as neoadjuvant treatment. In the adjuvant setting, BRAFi were used to treat recurrent tumours after surgery or adjuvant radiation therapy. The most common regimen combined dabrafenib (BRAFi) with trametinib (MEK1 and 2 inhibitor) in 81% of cases. The mean treatment length was 8.8 months (range 1.6 to 28 months) and 32% were continuing BRAFi. A reduction of tumour volume variable from 24% to 100% was observed at cerebral MRI during treatment and volumetric reduction ≥80% was described in 64% of cases. Once the treatment was stopped, adjuvant treatments were performed to stabilize patients in remission in 11 cases (65%) or when a progression was detected in three cases (12%). In four cases no further therapies were administered (16%). Mean follow-up after the end of targeted therapy was 17.1 months. As neoadjuvant regimen, 36% of patients were treated with dabrafenib and trametinib with a near complete radiological response in all the cases with a mean treatment of 5.7 months. The neoadjuvant use of verumafenib (BRAFi) and cometinib (MEK1 inhibitor) induced a near complete response in 15 patients (94%), with a median volumetric reduction between 85% and 91%. Ten patients did not receive further treatments. Side effects varied among studies. The optimal timing, sequencing, and duration of treatment of these new therapies should be established. Moreover, questions remain about the choice of specific BRAF/MEK inhibitors, the optimal protocol of treatment, and the strategies for managing adverse events. Conclusions: Treatment is shifting to a wider multidisciplinary management, where a key role is played by targeted therapies, to improve outcomes and quality of life for patients with BRAF-mutated craniopharyngiomas. Future, larger comparative trials will optimize their protocol of use and integration into multimodal strategies of treatment.

Efficacy and safety of Anlotinib based neoadjuvant chemotherapy for locally advanced triple negative breast cancer (TNBC)

BackgroundAnlotinib, an oral multitarget tyrosine kinase inhibitor, has shown the ability to inhibit tumor angiogenesis. This study aimed to assess the effectiveness and safety of anlotinib plus docetaxel, epirubicin, and cyclophosphamide (TEC) as a neoadjuvant chemotherapy regimen for locally advanced TNBC.MethodsLocally advanced TNBC patients who had received no prior systemic treatment were eligible for this study. The enrolled patients were scheduled to undergo six cycles of anlotinib (12 mg, d1-14, q3w) plus docetaxel (75 mg/m2, d1, q3w), epirubicin (75 mg/m2, d1, q3w) and cyclophosphamide (600 mg/m2, d1, q3w) prior to surgery, unless there was disease progression or severe toxicity. The primary objective of this study was the safety of this therapeutic regimen, and the secondary objective was the tumor response. The safety of this regimen was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and the efficacy of this treatment was measured using the Response Evaluation Criteria in Solid Tumors version 1.1.ResultsA total of 18 patients were included in this study. Participants completed an average of 5.56 neoadjuvant treatment cycles. The objective response rate (ORR) was 83.33%, and the disease control rate was 100%, respectively. The pCR was 55.6%. No patients discontinued therapy because of Adverse effects (AEs). Grade 3 or 4 AEs were observed in 5 cases (27.8%), with neutropenia and palmar-plantar erythrodysesthesia syndrome being the most common.ConclusionsAnlotinib combined with TEC as neoadjuvant therapy demonstrated manageable toxicity and promising antitumor activity for locally advanced TNBC. Further investigation of this combination regimen is warranted.

Neoadjuvant Pembrolizumab Plus Chemotherapy in Early-Stage Triple-Negative Breast Cancer: A Nationwide Retrospective Turkish Oncology Group Study

Background/Objectives: Following the results of the phase 3 KEYNOTE-522 trial, the U.S. Food and Drug Administration approved pembrolizumab, a humanized IgG4 kappa monoclonal antibody, in combination with neoadjuvant chemotherapy as a new standard of care for high-risk early-stage triple-negative breast cancer (TNBC). This retrospective, multicenter study in Türkiye assessed the real-world efficacy and safety of neoadjuvant pembrolizumab combined with chemotherapy in early-stage TNBC. Methods: The study included 108 patients treated between 2021 and 2023 across 14 oncology centers. Three distinct neoadjuvant regimens incorporating pembrolizumab were administered at the discretion of the treating physicians. The primary outcomes were the pathological complete response (pCR) rate after neoadjuvant therapy and the 2-year event-free survival (EFS) and overall survival (OS) rates. Results: The observed pCR rate was 63.9%, closely mirroring the 64.8% reported in the KEYNOTE-522 trial. At the two-year mark, the EFS rate was 87.2% and the OS rate was 92.3%. Multivariable analysis identified pCR as the sole independent predictor of both EFS and OS. The safety profile was consistent with previous clinical trial data, with most adverse events being of grade 1–2 in severity. Conclusions: These findings provide valuable real-world confirmation of the efficacy and safety of neoadjuvant pembrolizumab–chemotherapy in early-stage TNBC, complementing evidence from randomized trials.

L’immunothérapie péri-opératoire des cancers bronchiques non à petites cellules (CBNPC) : standards actuels et perspectives

Surgery is the cornerstone of the treatment for stage I to IIIA NSCLC. Perioperative platinum-based chemotherapy has long been combined with surgery for patients with resectable stage II-IIIA disease, although the benefits are modest, with an increase in overall survival of approximately 5 %. Recently, immunotherapy has been integrated into neo-adjuvant, adjuvant, and perioperative treatment regimens based on data demonstrating improved event-free survival (EFS) and disease-free survival (DFS), respectively, for localized or locally advanced resectable NSCLC, without activating mutation. Two phase 3 trials have shown an adjuvant benefit and have been approved in Europe but are not supported in France. Four phase III trials Checkmate-816, Checkmate-77T, AEGEAN and KEYNOTE-671 showed a benefit from the combination of an immune checkpoint inhibitor with chemotherapy in the neoadjuvant or in perioperative setting. The results of Checkmate-816 enabled the early access authorization of Nivolumab, in combination with platinum-based chemotherapy in the neoadjuvant treatment of adult patients with resectable NSCLC at high risk of recurrence, including tumors express PD-L1 at the threshold ≥ 1 %, not EGFR mutated, nor ALK translocated.1877-1203/© 2024 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Concordance of Whole-Slide Imaging and Conventional Light Microscopy for Assessment of Pathologic Response Following Neoadjuvant Therapy for Lung Cancer

Pathologic response is an end point in many ongoing clinical trials for neoadjuvant regimens, including immune checkpoint blockade and chemotherapy. Whole-slide scanning of glass slides generates high-resolution digital images and allows for remote review and potential measurement with image analysis tools, but concordance of pathologic response assessment on digital scans compared with that on glass slides has yet to be evaluated. Such a validation goes beyond previous concordance studies, which focused on establishing surgical pathology diagnoses, as it requires quantitative assessment of tumor, necrosis, and regression. Further, as pathologic response assessment is being used as an end point, such concordance studies have regulatory implications. The purpose of this study was 2-fold, which was as follows: first, to determine the concordance between pathologic response assessed on glass slides and that assessed on digital scans, and second, to determine if pathologists benefited from using measurement tools when determining pathologic response. To that end, hematoxylin and eosin–stained glass slides from 64 non–small cell lung carcinoma specimens were visually assessed for percent residual viable tumor (%RVT). The sensitivity and specificity for digital vs glass reads of pathologic complete response (0% RVT) and major pathologic response (≤10% RVT) were all >95%. When %RVT was considered as a continuous variable, the intraclass correlation coefficient of digital vs glass reads was 0.94. The visual assessments of pathologic response were supported by pathologist annotations of residual tumor and tumor bed areas. In a separate subset of hematoxylin and eosin–stained glass slides, several measurement approaches to quantifying %RVT were performed. Pathologist estimates strongly reflected measured %RVT. This study demonstrates the high level of concordance between glass slides evaluated using light microscopy and digital whole-slide images for pathologic response assessments. Pathologists did not require measurement tools to generate robust %RVT values from slide annotations. These findings have broad implications for improving clinical workflows and multisite clinical trials.

Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial.

Mismatch repair deficiency (dMMR) is found in approximately 15% of non-metastatic colon cancers (CCs) and is characterized by a defective DNA mismatch repair system, resulting in hypermutated and highly immunogenic tumors. Although patients with dMMR CC have limited benefit from chemotherapy, these tumors have been shown to respond exceptionally well to neoadjuvant anti-PD-1 plus anti-CTLA-4, with high rates of pathologic responses. Here, based on data from melanoma studies, we postulated a high efficacy and favorable toxicity profile of anti-PD-1 plus anti-LAG-3. In the NICHE-3 study, a total of 59 patients with locally advanced dMMR CC were treated with two 4-weekly cycles of nivolumab (480 mg) plus relatlimab (480 mg) before surgery. Pathologic response was observed in 57 of 59 (97%; 95% confidence interval (CI): 88-100%) patients, meeting the primary endpoint. Responses included 54 (92%; 95% CI: 81-97%) major pathologic responses (≤10% residual viable tumor) and 40 (68%; 95% CI: 54-79%) pathologic complete responses. With a median follow-up of 8 months (range, 2-19), one patient had recurrence of disease. The treatment displayed an acceptable safety profile, with all-grade and grade 3-4 immune-related adverse events (irAEs) occurring in 80% and 10% of patients, respectively. The most common irAEs were infusion-related reactions (29%), thyroid dysfunction (22%) and fatigue (20%). In conclusion, our results show that neoadjuvant nivolumab/relatlimab induces high rates of pathologic responses and that further investigation of this treatment in larger studies is warranted. These data add to the body of evidence in support of neoadjuvant immunotherapy regimens in dMMR CC. ClinicalTrials.gov identifier: NCT03026140 .

A narrative review on advances in neoadjuvant immunotherapy for esophageal cancer: Molecular biomarkers and future directions.

Esophageal cancer has a poor prognosis and survival rate due to its high incidence in Asia, lack of early symptoms and limited treatment options. In recent years, many clinical trials have demonstrated that immunotherapy has greatly improved the survival of patients with esophageal cancer. In addition, the combination of neoadjuvant immunotherapy with other popular therapeutic regimens has shown good efficacy and safety. In this review, we summarize the progress of clinical trials and some breakthroughs in neoadjuvant immunotherapy for esophageal cancer in recent years and suggest the possibility of multimodal neoadjuvant immunotherapy regimens, as well as directions for future development.

ThP2.4 - Unveiling the Odds: Identifying the Axillary Recurrence rates in Invasive Breast Cancer Surgery in a district general hospital - Seventeen years of Surgical Performance decoded

Abstract Introduction Axillary recurrence should be minimised by effective staging and treatment where appropriate Minimum standard <5% axillary recurrence at 5 years Target <3% axillary recurrence at 5 years according to UK ABS guidelines. Methods All patients with primary cancer diagnosed at our institution between January 2004 and December 2020 were identified from a prospectively maintained database of operations obtained from the medical coding department. Demographics of the patients, pre-operative investigations, MDT discussion outcomes, operative details (and complications), post-operative pathology, neo-adjuvant and adjuvant therapy regimens and follow-up data were recorded. All patients were followed up to the censoring date of December 2021 which gave a median follow-up of 18 months (range, 12- 204). Axillary recurrence and treatment regimens were recorded. Primary outcome measures were overall axillary recurrence and disease-free. IBM SPSS Statistics (Version 26.0 (IBM Corporation, Armonk, NY, USA) was used for statistical analysis to determine patient and pre-operative pathological characteristics that were predictive of isolated axillary recurrence after completion of the primary treatment course. Significance was defined as P<0.05. Results There were 4024 women diagnosed with breast cancer in Midyorks trust between this period who were referred and had surgical intervention. Of these, 107 patients were identified with recurrences. 12 were found to have an isolated axillary recurrence (8 ANC 4 SLNB) Conclusion The 17-year isolated axillary recurrence rate of women treated was 0.3%. Multimodality management at the time of recurrence, including axillary surgery, radiation, and systemic therapy, significantly improved the morbidity

Patient-derived Organoid Pharmacotyping As A Predictive Tool for Therapeutic Selection in Pancreatic Ductal Adenocarcinoma.

We integrate a new approach to chemosensitivity data for clinically-relevant regimen matching, and demonstrate the relationship with clinical outcomes in a large PDO biobank. Pancreatic ductal adenocarcinoma (PDAC) usually recurs following potentially curative resection. Prior studies related patient-derived organoid (PDO) chemosensitivity with clinical responses. PDOs were established from pre-treatment biopsies in a multi-institution clinical trial (n=21) and clinical specimens at a high-volume pancreatectomy center (n=74, of which 48 were pre-treated). PDO in vitro chemosensitivities to standard-of-care chemotherapeutics (pharmacotypes) were matched to potential clinically-relevant regimens by a weighted nearest-neighbors analysis. Clinical outcomes were then compared for patients who had well-matched versus poorly-matched treatment according to this metric. Our function matched 91% of PDOs to a standard-of-care regimen (9% pan-resistant). PDOs poorly-matched to the neoadjuvant regimen received would have matched to an alternative in 34% of cases. Patients receiving neoadjuvant chemotherapy well-matched to their pharmacotype experienced improved CA 19-9 response (60% decreased to normal when well-matched, 29% when poorly-matched, P<0.05) and lymph node down-staging (33% N0 after poorly-matched, 69% after well-matched, P<0.05). Patients receiving both well-matched neoadjuvant and adjuvant chemotherapy experienced improved recurrence-free- and overall survival (median RFS 8.5mo poorly-matched, 15.9mo well-matched, P<0.05; median OS 19.5 vs. 30.3mo, P<0.05). In vitro PDO pharmacotyping can inform PDAC therapy selection. We demonstrate improved outcomes including survival for patients treated with regimens well-matched to their PDO chemosensitivities. A subsequent prospective study using PDO pharmacotype matching could improve oncologic outcomes and improve quality of life by avoiding therapies not expected to be effective.

357. OUTCOMES OF TWO-COURSE NEOADJUVANT CHEMOTHERAPY WITH DOCETAXEL, CISPLATIN, AND 5-FLUOROURACIL ON ADVANCED ESOPHAGEAL CANCER: A SINGLE INSTITUTION STUDY

Abstract Background The CROSS trial established neoadjuvant chemoradiotherapy (CRT) as a cornerstone in treating esophageal cancer, making it the standard approach worldwide. However, in Japan, the JCOG1109 trial, a three-arm study, redefined the standard by showing the superiority of neoadjuvant chemotherapy (NAC) with docetaxel, cisplatin, and 5-fluorouracil (DCF) over the conventional cisplatin and 5-fluorouracil (CF) regimen. Notably, it found no significant difference between neoadjuvant CRT with CF and CF. This trial adopted a 3-week cycle of 3 courses for the DCF regimen. Nonetheless, subsequent findings by Makino et al. suggested no difference in outcomes between 2-course and 3-course DCF regimens. This report presents the results of a 2-course neoadjuvant DCF regimen at our institution. Method This study included esophageal cancer patients who underwent esophagectomy after a 2-course NAC-DCF regimen at Okayama University Hospital from January 2014 to December 2019. Eligible participants were 20 to 80 years old, with a performance status of 0–1, histologically confirmed esophageal squamous cell carcinoma (ESCC), and adequate organ function. The stages ranged from cT1-4a N0-3 M0. We evaluated recurrence patterns, overall survival (OS), and recurrence-free survival (RFS) using the Kaplan-Meier method and explored histopathological factors associated with RFS through COX regression analysis. Results Out of 209 cases, 63 were eligible. The median follow-up was 71 months, with 17 instances of recurrence observed, categorized as lymphatic (6 cases), hematinic (3 cases), local (2 cases), dissemination (2 cases), and multiple (4 cases). The 5-year RFS was 64.5%, and the 5-year OS was 65.8%. Univariate analysis identified pathological T, N, Stage, and chemotherapy response grade as significant factors related to RFS, with multivariate analysis highlighting pathological N as an independent factor. Kaplan-Meier analysis demonstrated significant survival differences across N stages, particularly between N1 and N2. Conclusion Our findings from the 2-course neoadjuvant DCF regimen highlight pathological N stage as a crucial independent predictor of recurrence in ESCC patients treated with NAC-DCF. Specifically, patients above N2 exhibited notably poorer prognoses, underscoring the need for adjuvant treatment strategies.

354. NEOADJUVANT CHEMORADIOTHERAPY FOLLOWED BY SURGERY VERSUS UPFRONT SURGERY FOR ESOPHAGEAL CANCER: LONG-TERM OUTCOMES IN A CROSS TRIAL STUDY CENTER

Abstract Background Since the publication of the CROSS-trial, showing improved survival following neoadjuvant chemoradiotherapy + surgery (CRT-S) compared to upfront surgery (U-S) for esophageal cancer, this neoadjuvant regimen has become standard care in the Netherlands. Given the relatively low R0 rate in the U-S arm (69%) and lymph node yield (LNY) in both arms (15 U-S, 18 CRT-S) observed in the CROSS-trial, the present study aimed to compare survival of patients who underwent CRT-S versus U-S in a tertiary referral center that participated in the CROSS-trial, within the era that the trial was performed. Methods This retrospective study included patients, who underwent an esophagectomy between 2004-2010, and met the CROSS-trial inclusion criteria. Primary outcome was 10-year overall survival (OS), and patients with CRT-S and U-S were compared. Secondary outcomes were R0-resection rate, LNY and positive LNY. Subgroup analyses were performed for histology (adenocarcinoma [AC] and squamous cell carcinoma [SCC] and for surgical approach (transthoracic [TTE] and transhiatal [THE] esophagectomy). Results We included 288 patients: 144 after CRT-S, 144 after U-S. 112 (39%) participated in the CROSS-trial. 10-year OS was not significantly better for CRT-S (40%) versus U-S (34%; p=0.183). In SSC, OS following CRT-S was 49% and after U-S 35% (p=0.228), versus 38% and 34% in AC (p=0.396). Following TTE, OS was better compared to THE in both CRT-S and U-S groups: 44% and 39% (p=0.369) versus 32% and 29% (p=0.590). R0-rates were 96% (CRT-S) and 86% (U-S). Median LNY was equal: 23. 55 (38%) and 100 (69%) patients had positive lymph nodes after respectively CRT-S and U-S. Conclusion This study showed that, with a radical TTE, comparable OS results can be achieved, and therefore CRT may not be indicated in all patients. Further analyses are necessary to identify patients who may benefit from the additional local treatment that CRT is (e.g SCC or involved circumferential resection margin). Additionally, surgical techniques have improved since the CROSS-trial, with less surgical trauma in minimally invasive esophagectomy. This may result in better outcomes for surgery nowadays, indicating the need for further studies in the current era.

Utility of SATB2 and MOC-31 Immunostains to Distinguish Between Poorly Differentiated Rectal Adenocarcinoma and Anal Squamous Cell Carcinoma.

Colorectal adenocarcinoma and squamous cell carcinoma (SCC) can arise in the anorectum and present a significant diagnostic challenge when poorly differentiated. Accurate diagnosis can significantly influence management, as the treatments for these conditions involve distinct neoadjuvant chemoradiotherapy regimens. MOC-31 and SATB2 have been utilized as specific markers of glandular differentiation and colorectal origin, respectively, but studies have shown that they may be positive in squamous cell carcinoma of other sites. This raises the concern that MOC-31 and SATB2 may be positive in squamous cell carcinoma of the anorectum, and overreliance on these stains may be a potential diagnostic pitfall in differentiating rectal poorly differentiated adenocarcinoma (PDA) from anal nonkeratinizing SCC. We identified biopsies from 10 rectal PDA and 17 anorectal nonkeratinizing SCC cases and stained them for MOC-31 and SATB2. We found that MOC-31 was highly sensitive, being positive in 10/10 cases of rectal PDA, but not specific, as it was also positive in 11/17 SCC cases. In contrast, SATB2 was both sensitive, with positive staining in 10/10 rectal PDA cases, and specific, with negative staining in 17/17 SCC cases. This includes equivocal staining in 4 of these negative SCC cases. MOC-31 had a sensitivity of 100% and specificity of 35.3%, while SATB2 had a sensitivity of 100% and specificity of 100%. Unlike squamous mucosa of the head and neck, and esophagus, SCC of the anus does not frequently stain positively for SATB2. These data suggest that SATB2 is a reliable marker in distinguishing rectal PDA from anorectal nonkeratinizing SCC, whereas MOC-31 is commonly positive in SCC of the anus. It is also important to note that equivocal SATB2 staining may be seen in SCC.

Spatial proteomic profiling elucidates immune determinants of neoadjuvant chemo-immunotherapy in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) presents significant clinical and therapeutic challenges due to its aggressive nature and generally poor prognosis. We initiated a Phase II clinical trial (ChiCTR1900027160) to assess the efficacy of a pioneering neoadjuvant chemo-immunotherapy regimen comprising programmed death-1 (PD-1) blockade (Toripalimab), nanoparticle albumin-bound paclitaxel (nab-paclitaxel), and the oral fluoropyrimidine derivative S-1, in patients with locally advanced ESCC. This study uniquely integrates clinical outcomes with advanced spatial proteomic profiling using Imaging Mass Cytometry (IMC) to elucidate the dynamics within the tumor microenvironment (TME), focusing on the mechanistic interplay of resistance and response. Sixty patients participated, receiving the combination therapy prior to surgical resection. Our findings demonstrated a major pathological response (MPR) in 62% of patients and a pathological complete response (pCR) in 29%. The IMC analysis provided a detailed regional assessment, revealing that the spatial arrangement of immune cells, particularly CD8+ T cells and B cells within tertiary lymphoid structures (TLS), and S100A9+ inflammatory macrophages in fibrotic regions are predictive of therapeutic outcomes. Employing machine learning approaches, such as support vector machine (SVM) and random forest (RF) analysis, we identified critical spatial features linked to drug resistance and developed predictive models for drug response, achieving an area under the curve (AUC) of 97%. These insights underscore the vital role of integrating spatial proteomics into clinical trials to dissect TME dynamics thoroughly, paving the way for personalized and precise cancer treatment strategies in ESCC. This holistic approach not only enhances our understanding of the mechanistic basis behind drug resistance but also sets a robust foundation for optimizing therapeutic interventions in ESCC.

367. IMPACT OF NEOADJUVANT IMMUNOTHERAPY ON POSTOPERATIVE COMPLICATIONS IN RESECTABLE ESOPHAGEAL ADENOCARCINOMA

Abstract Background Several studies are ongoing on the use of immunotherapy in the neoadjuvant setting for esophageal and gastroesophageal junction cancer but it is unclear the effect of an increased activation of the immune system on surgery and the postoperative course. Methods This multicenter retrospective cohort study included data from 3 high-volume centers for upper-GI surgery. Only patients with esophageal adenocarcinoma who underwent neoadjuvant therapy and radical surgery between 2015 and 2022 were included. Clinical characteristics and the postoperative outcomes were compared between patients who received standard neoadjuvant therapy or chemotherapy plus immunotherapy. A 1-to-1 matched comparison was also performed. The difference in overall survival (OS) and disease free survival (DFS) between the two groups was also evaluated. Results Overall, 563 patients were included and 21 received preoperative Pembrolizumab or Trastuzumab combined with at least a couple of chemotherapy drugs. The incidence of complications was 47% in the group with immunotherapy and 40.7% in the other group (p=0.53). The matched analysis confirmed no differences in rate of complications (p&amp;gt;0.99), gravity of complications (p=0.17) and pulmonary complications (p&amp;gt;0.99). Anastomotic leak rate was 4.7% in the immunotherapy group and 19% in the other one (p=0.34). Overall survival and disease free survival were comparable (respectively p=0.4 and p=0.9) also after the matched analysis (respectively p=0.15 and p=0.52). Conclusion Neoadjuvant immunotherapy-based regimen does not affect the postoperative course, in particular it does not appear to aggravate the major complications of esophagectomy.

625. PHASE II TRIAL OF INDUCTION CHEMOTHERAPY FOLLOWED BY CHEMORADIATION AND MINIMALLY INVASIVE SURGERY FOR LOCALLY ADVANCED CARCINOMA OF THE ESOPHAGUS

Abstract Background Most patients with esophageal cancer (EC) present locally advanced disease. Currently, multimodal strategies as neoadjuvant chemoradiotherapy or perioperative chemotherapy are employed, but still have high local and distant failures rates. This study evaluated the results of a phase II protocol with induction chemotherapy (IC) and concurrent chemoradiation (CR) before surgery for locally advanced carcinoma of the esophagus and esophagogastric junction (EGJ). The primary end point was to evaluate pathological complete remission (PCR) rate at surgical specimen. A PCR ≥ 30% was considered promising for further study. Methods Patients with squamous cell carcinoma (SCC) or adenocarcinoma (AC) of the thoracic esophagus and JEG, clinical stage T1b-3, N0-2, M0, PS 0-2, underwent two cycles of IC with carboplatin and paclitaxel followed by CR with the same agents and minimally invasive esophagectomy. At the screening, 14 days after the first cycle of IC and 6-8 weeks after the CR, metabolic responses were accessed by PET-CT and classified according the PERCIST criteria. Results One hundred and twenty-nine patients were accrued from January 2017 to April 2023. Forty-seven patients started the trial and 45 completed the neoadjuvant part of the protocol. Most patients were male (73.3%), the median age of was 55 years and AC was the most prevalent histological subtype (53.3%). Grade 3/4 toxicity during IC were infrequent and included neutropenia (12.5%), anemia (6.2%) and dysphagia (10.4%). Lymphopenia (10.7%) and dysphagia (6.5%) were the most common grade 3/4 toxicity during CR. All cases received the full radiotherapy dose of 45 Gy by IMRT technique. Thirty-seven patients underwent surgery and 31 had minimally invasive MacKeown esophagectomy with complete tumor resection (R0). Sixty-four percent of all included patients completed the neoadjuvant therapy and survived for 30 days after surgery. The most prevalent postoperative complications were anastomotic fistula (29%) and pneumonia (19%). Median hospital stay was 12 (7-56) days. Six patients (19.3%) had major postoperative morbidity (Clavien-Dindo ≥ IIIb), 4 were reoperated and one (3.2%) died during hospitalization. The median number of lymph nodes retrieved was 24. Eleven patients (33.5%) had pathological positive lymph nodes. The overall pathological complete response rate was 25.8%, 41.8% for SCC and 15.8% for AC. The early metabolic evaluation by PERCIST showed that 2 cases (4.4%) had progressive disease (PD), 26 (57.7%) stable disease (SD), 15 (33.3%) partial response (PR) and 2 (4.4%) complete response (CR). All the CR were SCC. The late metabolic response analysis showed that 1 (2.4%) patient had PD, 6 (14.6%) SD, 23 (56%) PR and 11 (27%) CR. On the basis of an intention-to-treat analysis, the median overall survival was 31.4 months, whereas the five-year overall survival was 31.2%. After curative surgery, 12 patients had recurrence disease. Six (19%) patients had recurrences at distant sites, 4 (12.9%) had loco-regional recurrence and 2 (6.4%) had both patterns. Conclusion This intensified neoadjuvant regimen was efficacious and safe in patients with locally advanced EC, but failed to reach the defined efficacy goal for further investigation, especially for AC.

317. PD-L1 DYNAMICS DURING THE CISPLATIN-INDUCED ACQUIRED RESISTANCE PROCESS IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background Immunotherapy combined with chemotherapy has been the first-line treatment and the most widely-used neoadjuvant regimen in esophageal squamous cell carcinoma (ESCC). Resistance to chemotherapy is an inevitable clinical problem, however, the impact of chemoresistance on immunotherapy efficacy remains unclear. This study aimed to investigate the impact of chemoresistance formation on PD-L1 dynamic changes both in vivo and in vitro during the construction of cisplatin-resistant ESCC models, with the goal of exploring the potential influence of chemoresistance on immunotherapy. Methods For in vivo model, fluorescent-labeled ESCC cells (AKR) were implanted into C57 mice, followed by cisplatin administration for six cycles. Surviving tumor cells were isolated using flow cytometry, and reinjected to establish cisplatin-resistant model. Tumors were harvested to evaluate PD-L1 expression by immunohistochemistry. For in vitro model, ESCC cell lines (TE-1, KYSE150) received low-dose cisplatin for 48h. After three cycles, resistance index (RI, RI=IC50 of drug-expose cell/IC50 of parental cell) was determined by CCK8 assay. The process was repeated with escalating cisplatin doses until resistant cell lines were established (RI&amp;gt;5). PD-L1 expression was measured using RT-qPCR/Western-Blot after each generation. Results In vivo (Figure A), cisplatin-resistant tumor exhibited elevated PD-L1 expression compared to control group (H-score: 22.17 vs 2.09, p&amp;lt;0.001). In vitro (Figure B), PD-L1 expression exhibited an initial increase, followed by a gradual decrease during the process of cisplatin-induced resistance. Specifically, in early stages of cisplatin-resistance in TE-1 cells, PD-L1 mRNA expression rose 4.9 times, consistently paralleled by an elevation in protein level. Subsequently, PD-L1 expression gradually decreased in both mRNA and protein levels. KYSE150 cells exhibited a trend of upregulation in PD-L1 expression in the early stages of cisplatin resistance but later decreased, returning to parental cell levels. Conclusion Under in vivo conditions, acquired cisplatin-resistance in ESCC cells significantly upregulated PD-L1 expression, indicating a potential mechanism for PD-L1-mediated immune escape and its impact on immunotherapy efficacy. However, under in vitro conditions, no consistent trend in PD-L1 expression was observed during the acquisition of cisplatin resistance. This suggests a potentially crucial role of the immune system involved in the chemoresistance regulatory mechanism. Further investigations are needed to explore the impact of chemoresistance on tumor immunology.