Primary Tumor Response Research Articles

Molecular Mechanisms Driving the Formation of Brain Metastases.

Simple SummaryBrain metastases are the most common brain tumor in adults and are associated with poor prognosis. The propensity of different solid tumors to metastasize varies greatly, with lung, breast, and melanoma primary tumors commonly leading to brain metastases, while other primaries such as prostate rarely metastasize to the brain. The molecular mechanisms that predispose and facilitate brain metastasis development are poorly understood. In this review, we present the current data on the genomic landscape of brain metastases that arise from various primary cancers and also outline potential molecular mechanisms that drive the formation of distant metastases in the brain.Targeted therapies for cancers have improved primary tumor response rates, but concomitantly, brain metastases (BM) have become the most common brain tumors in adults and are associated with a dismal prognosis of generally less than 6 months, irrespective of the primary cancer type. They most commonly occur in patients with primary breast, lung, or melanoma histologies; however, they also appear in patients with other primary cancers including, but not limited to, prostate cancer, colorectal cancer, and renal cell carcinoma. Historically, molecular biomarkers have normally been identified from primary tumor resections. However, clinically informative genomic alterations can occur during BM development and these potentially actionable alterations are not always detected in the primary tumor leading to missed opportunities for effective targeted therapy. The molecular mechanisms that facilitate and drive metastasis to the brain are poorly understood. Identifying the differences between the brain and other extracranial sties of metastasis, and between primary tumors and BM, is essential to improving our understanding of BM development and ultimately patient management and survival. In this review, we present the current data on the genomic landscape of BM from various primary cancers which metastasize to the brain and outline potential mechanisms which may play a role in promoting the formation of the distant metastases in the brain.

Primary Tumor Shrinkage and the Effect on Metastatic Disease and Outcomes in Patients With Advanced Kidney Cancer With Intermediate or Poor Prognosis Treated With Nivolumab Plus Ipilimumab or Cabozantinib.

Immune checkpoint inhibitor (ICI)-based combinations have become the first-line standard of care in metastatic renal cell carcinoma (mRCC), but their activity on the primary tumor is still one of the most debated issues. The aim of our analysis was to evaluate the primary tumor's response to first-line therapy with cabozantinib or nivolumab+ipilimumab, and its correlation with metastatic response and with patient outcomes. Sixty-seven mRCC patients met the criteria for inclusion in the final analysis (30 treated with cabozantinib and 37 with nivolumab+ipilimumab). In the overall population, the primary tumor control rate (PTCR) was 90.9%; no complete responses (CR) were achieved. A significant correlation was found between the baseline size of the primary tumor's longest diameter and its response according to RECIST v1.1 criteria at the time of the second radiological assessment (rs=-0.351; P=.049). Moreover, a significant correlation between the type of primary tumor response and the response of the metastases was observed in the overall population (rs=0.50; two-sided P<0.001). There was also a significant correlation between primary tumor response and 1-year survival rate (P=.002), even when adjusted for the IMDC prognostic group and type of therapy (HR=8.70; 95%CI, 2.52-30.05; P=.001). Extension of the primary tumor did not affect patient survival, while its response was significantly related to the response on metastatic disease and survival. No significant differences in terms of primary tumor shrinkage were identified between treatment with nivolumab+ipilimumab or cabozantinib in this cohort.

Differences and Similarities in the Pattern of Early Metabolic and Morphologic Response after Induction Chemo-Immunotherapy versus Induction Chemotherapy Alone in Locally Advanced Squamous Cell Head and Neck Cancer.

Simple SummaryThere are differences and similarities when assessing the short-term therapeutic response of chemotherapy and chemotherapy plus immunotherapy using imaging techniques, which may be necessary to make treatment decisions in malignant head and neck tumors. After both chemo- and immunochemotherapy, remission becomes measurable in cross-sectional and metabolic diagnostics after only one cycle of therapy, with 18FDG-PET/CT predicting complete remission of tumor cells in a representative biopsy better than MRI/CT examination in both therapeutic modalities. While complete tumor remission is highly likely (88%) after immunochemotherapy in tumors with low residual activity (≤40% of initial SUV), this is less common after chemotherapy alone (65%). In metabolic nonresponse with more than 80% residual activity, the probability of complete remission nevertheless is low after chemotherapy alone (6%). After immunochemotherapy, these false nonresponders are common (35%), requiring additional diagnostics by deep biopsy. Cases of pseudoprogression with an increase of SUVmax of more than 125% of the baseline were not observed.Background: In head and neck cancer patients, parameters of metabolic and morphologic response of the tumor to single-cycle induction chemotherapy (IC) with docetaxel, cis- or carboplatin are used to decide the further course of treatment. This study investigated the effect of adding a double immune checkpoint blockade (DICB) of tremelimumab and durvalumab to IC on imaging parameters and their significance with regard to tumor cell remission. Methods: Response variables of 53 patients treated with IC+DICB (ICIT) were compared with those of 104 who received IC alone. Three weeks after one cycle, pathologic and, in some cases, clinical and endoscopic primary tumor responses were evaluated and correlated with a change in 18F-FDG PET and CT/MRI-based maximum-standardized uptake values (SUVmax) before (SUVmaxpre), after treatment (SUVmaxpost) and residually (resSUVmax in % of SUVmaxpre), and in maximum tumor diameter (Dmax) before (Dmaxpre) and after treatment (Dmaxpost) and residually (resD). Results: Reduction of SUVmax and Dmax occurred in both groups; values were SUVmaxpre: 14.4, SUVmaxpost: 6.6, Dmaxpre: 30 mm and Dmaxpost: 23 mm for ICIT versus SUVmaxpre: 16.5, SUVmaxpost: 6.4, Dmaxpre: 21 mm, and Dmaxpost: 16 mm for IC alone (all p < 0.05). ResSUVmax was the best predictor of complete response (IC: AUC: 0.77; ICIT: AUC: 0.76). Metabolic responders with resSUVmax ≤ 40% tended to have a higher rate of CR to ICIT (88%; n = 15/17) than to IC (65%; n = 30/46; p = 0.11). Of the metabolic nonresponders (resSUVmax > 80%), 33% (n = 5/15) achieved a clinical CR to ICIT versus 6% (n = 1/15) to IC (p = 0.01). Conclusions: ICIT and IC quickly induce a response and 18F-FDG PET is the more accurate modality for identifying complete remission. The rate of discrepant response, i.e., pCR with metabolic nonresponse after ICIT was >30%.

568. THE PROGNOSTIC EFFECT OF PATHOLOGICAL LYMPH NODE REGRESSION AFTER NEOADJUVANT CHEMOTHERAPY FOR OESOPHAGEAL ADENOCARCINOMA – A MULTICENTRE STUDY

Abstract The prognostic benefit of primary tumour and lymph node (LN) downstaging after neoadjuvant chemotherapy for oesophageal adenocarcinoma (OAC) is well described. However, there is no robust evidence regarding the prognostic effect of pathological LN regression despite emerging evidence of a discrepancy, in some patients, between tumour regression grade in the primary tumour and response in regional LNs. The aim of this study was to investigate the relationship between pathological LN regression, tumour recurrence and survival. Retrospective, multicentre cohort study including 763 patients with OAC treated with neoadjuvant chemotherapy followed by surgery at 5 high-volume tertiary referral centres in the United Kingdom. Tumour regression was assessed in the primary tumour (Mandard) and LNs retrieved from oesophagectomy specimens. Patients were classified as LN negative (no evidence of tumour or regression in any LN), complete LN-responders (evidence of regression ≥1 LN, no residual tumour in any LN), partial LN-responders (evidence of regression ≥1 LN with residual tumour ≥1 LN) and LN non-responders (no or minimal regression in any LN). Survival analysis was performed using Kaplan-Meier and Cox regression. Overall, 243 (31.8%) patients were classified as LN negative, 62 (8.1%) as complete LN-responders, 155 (20.3%) as partial LN-responders and 303 (39.7%) as LN non-responders. Some patients had a LN response in the absence of a response in the primary tumour (97/431, 22.5%). Multivariable Cox regression survival analysis (adjusting for age, gender, chemotherapy regimen, clinical stage, tumour grade, lympho-vascular invasion and primary tumour response) demonstrated improved overall survival in complete LN-responders (Hazard ratio (HR) 0.37 95% confidence interval (CI) 0.24-0.58), partial LN-responders (HR 0.70 95% CI 0.55-0.89) and LN negative patients (HR 0.34 95% CI 0.26-0.44) compared to LN non-responders. In this cohort of patients with OAC treated with neoadjuvant chemotherapy prior to surgical resection, LN regression was a strong prognostic factor independent of primary tumour response, which was discordant in a significant number of patients. Complete LN-responders had equivalent survival to those with negative LN. Complete and partial LN-responders had better survival than LN non-responders. Evaluation and documentation of LN regression should be considered during the standard pathological reporting of oesophagectomy specimens.

670P Discordant pathologic tumor response in primary tumors and lymph nodes after neoadjuvant immune checkpoint inhibition (ICI) in head and neck squamous cell carcinoma (HNSCC)

Discordant radiographic responses are described in other tumor types in response to immunotherapy with response at some anatomic sites and progression in others. Here we determined the frequency of discordant pathologic tumor response (pTR) in HNSCC patients treated with ICI in the context of neoadjuvant trials.

223P Gene expression profiles in endocrine-resistant breast cancer

Around 75% of breast cancer (BC) patients' tumors express the treatment-predictive biomarker estrogen receptor alpha (ER/ESR1) and are accordingly offered endocrine therapy. One-third of patients develop endocrine resistance, a majority with tumors that retain ER expression. For most patients, the resistance mechanism is still unknown but factors such as alterations in ER downstream signaling have been investigated. This study aims to examine the gene expression programs of endocrine-resistant tumors. A cohort of verified endocrine-resistant BC patients diagnosed in 2005-2006 and 2008-2012 was retrospectively collected at the Karolinska University Hospital in Stockholm, Sweden. Cases (N=56) were defined as patients with an ER+ and human epidermal growth factor receptor 2 (HER2)-negative primary tumor who developed an ER+/HER2- relapse during endocrine therapy. Patients with an ER+/HER2- tumor without progression or relapse at 10 years of follow-up were defined as controls (N=56). RNA was extracted from formalin-fixed paraffin-embedded tissue and analyzed using Affymetrix Clariom D microarrays. Transcriptome Analysis Console (TAC) Software, Gene Set Enrichment (GSEA) application, and R were used for gene expression data analysis. The initial analysis generated differentially expressed genes, where in general more genes were upregulated in primary tumors of cases who eventually relapse versus controls and downregulated in relapse versus primary tumors of cases. Subsequent investigation of gene sets showed upregulations in epithelial-mesenchymal transition, androgen response, MYC targets, and reactive oxygen species in primary tumors of cases versus controls. We found upregulation in metabolism-associated gene sets and downregulation of estrogen response, epithelial-mesenchymal transition, androgen response, and ESR1 regulation in relapses of cases compared to their primary tumors. This study of a unique cohort of endocrine-resistant tumors suggests that specific signaling pathways are associated with the development of endocrine resistance in BC. These gene expression signatures may guide further studies on the resistance mechanisms and develop future diagnostic tools for therapy response prediction.

MRI in the Evaluation of Locally Advanced Vulvar Cancer Treated with Chemoradiotherapy and Vulvar Cancer Recurrence: The 2021 Revision of FIGO Classification and the Need for Multidisciplinary Management.

Simple SummaryVulvar cancer is a rare gynecologic tumor (representing 4% of all gynecologic malignancies). We review the role of MRI in patients with locally advanced vulvar cancer (LAVC), highlighting the findings that influence clinical management. We also present the MRI findings of local recurrence according to its type and location.Magnetic resonance imaging (MRI) plays an essential role in the management of patients with locally advanced vulvar cancer (LAVC), who frequently benefit from a multidisciplinary approach. Accordingly, chemoradiotherapy (CRT) with radical or neoadjuvant intent seems to provide a better quality of life and less morbidity than extensive surgery alone. In this overview, we discuss the role of MRI in the post-CRT assessment of LAVC, emphasizing the evaluation of primary tumor response. In order to assess treatment response and select candidates for post-CRT local excision, the MRI findings are described according to signal intensity, restricted diffusion, enhancement, and invasion of adjacent organs. We also focus on the role of MRI in detecting vulvar cancer recurrence. It occurs in 30–50% of patients within two years after initial treatment, the majority appearing near the original resection margins or in ipsilateral inguinal or pelvic lymph nodes. Finally, we describe early and delayed complications of CRT, such as cellulitis, urethritis, vulvar edema, bone changes, myositis, and fistulization. By describing the role of MRI in assessing LAVC response to CRT and detecting recurrence, we hope to provide suitable indications for a personalized approach.

Microbeam Radiation Therapy Controls Local Growth of Radioresistant Melanoma and Treats Out-of-Field Locoregional Metastasis

Synchrotron-generated microbeam radiation therapy (MRT) represents an innovative preclinical type of cancer radiation therapy with an excellent therapeutic ratio. Beyond local control, metastatic spread is another important endpoint to assess the effectiveness of radiation therapy treatment. Currently, no data exist on an association between MRT and metastasis. Here, we evaluated the ability of MRT to delay B16F10 murine melanoma progression and locoregional metastatic spread. We assessed the primary tumor response and the extent of metastasis in sentinel lymph nodes in 2 cohorts of C57BL/6J mice, one receiving a single MRT and another receiving 2 MRT treatments delivered with a 10-day interval. We compared these 2 cohorts with synchrotron broad beam-irradiated and nonirradiated mice. In addition, using multiplex quantitative platforms, we measured plasma concentrations of 34 pro- and anti-inflammatory cytokines and frequencies of immune cell subsets infiltrating primary tumors that received either 1 or 2 MRT treatments. Two MRT treatments were significantly more effective for local control than a single MRT. Remarkably, the second MRT also triggered a pronounced regression of out-of-radiation field locoregional metastasis. Augmentation of CXCL5, CXCL12, and CCL22 levels after the second MRT indicated that inhibition of melanoma progression could be associated with increased activity of antitumor neutrophils and T-cells. Indeed, we demonstrated elevated infiltration of neutrophils and activated T-cells in the tumors after the second MRT. Our study highlights the importance of monitoring metastasis after MRT and provides the first MRT fractionation schedule that promotes local and locoregional control with the potential to manage distant metastasis.

Pathological Responses of the Primary Tumor and Locoregional Lymph Nodes After Neoadjuvant Immunochemotherapy in Esophageal Squamous Cell Cancer.

BackgroundThe current study attempted to describe the specific patterns of pathological tumor response and locoregional node metastases from surgically resected esophageal squamous cell carcinoma after neoadjuvant immunochemotherapy (NAIC), as well as to explore the association between clinicopathological characteristics and such oncological patterns.MethodsFifty-one patients with cT3 or deeper esophageal squamous cell cancer underwent subtotal esophagectomy after NAIC. The NAIC regimen included intravenous administration of platinum-based and docetaxel- and taxane-based chemotherapeutics along with a 200 mg fixed dose of one programmed death 1 (PD-1) inhibitor, given every 3 weeks. We divided patients into tumor/nodal good-responders and poor-responders based on the pathological observation of the tumor or nodal responses. We also examined the association between clinicopathological factors and tumor/nodal responses. Further, significant baseline predictors for tumor and nodal good-responders were identified using multivariate binary logistic regression.ResultsOf the 51 patients, 68.6% achieved marked primary tumor response. Notably, 21.6% of patients achieved complete pathological response. Significant differences in treatment cycles between tumor good-responders and tumor poor-responders (P = 0.019) were observed. For locoregional nodal responses, only 33.3% of patients achieved down-staged nodal disease. Of the investigated variables, neoadjuvant cycles (odds ratio (OR): 5.271, 95% confidence interval (CI): 1.278 - 21.740, P = 0.022) and pretreatment platelets (OR: 0.979, 95% CI: 0.962 - 0.996, P = 0.017) were identified as independent predictors for good tumor and nodal responses.ConclusionsWe conclusively noted that most patients receiving NAIC were tumor good-responders, whereas only one-third of patients were nodal good-responders. Furthermore, we identified that treatment cycle number and baseline platelet counts were independent predictors of combined tumor and nodal responses.

Toll-like receptor 7/8 agonist R848 alters the immune tumor microenvironment and enhances SBRT-induced antitumor efficacy in murine models of pancreatic cancer

BackgroundStereotactic body radiotherapy (SBRT) has been increasingly used as adjuvant therapy in pancreatic ductal adenocarcinoma (PDAC), and induces immunogenic cell death, which leads to the release of tumor antigen and...

Prediction of Incomplete Response of Primary Tumour Based on Clinical and Radiomics Features in Inoperable Head and Neck Cancers after Definitive Treatment.

Radical treatment of patients diagnosed with inoperable and locally advanced head and neck cancers (LAHNC) is still a challenge for clinicians. Prediction of incomplete response (IR) of primary tumour would be of value to the treatment optimization for patients with LAHNC. Aim of this study was to develop and evaluate models based on clinical and radiomics features for prediction of IR in patients diagnosed with LAHNC and treated with definitive chemoradiation or radiotherapy. Clinical and imaging data of 290 patients were included into this retrospective study. Clinical model was built based on tumour and patient related features. Radiomics features were extracted based on imaging data, consisting of contrast- and non-contrast-enhanced pre-treatment CT images, obtained in process of diagnosis and radiotherapy planning. Performance of clinical and combined models were evaluated with area under the ROC curve (AUROC). Classification performance was evaluated using 5-fold cross validation. Model based on selected clinical features including ECOG performance, tumour stage T3/4, primary site: oral cavity and tumour volume were significantly predictive for IR, with AUROC of 0.78. Combining clinical and radiomics features did not improve model’s performance, achieving AUROC 0.77 and 0.68 for non-contrast enhanced and contrast-enhanced images respectively. The model based on clinical features showed good performance in IR prediction. Combined model performance suggests that real-world imaging data might not yet be ready for use in predictive models.

Abstract CT106: Primary tumor response in T1aN0M0 renal cell carcinoma patients ineligible for surgery and treated with nivolumab and ipilimumab: Results from phase 2 pilot study

Abstract Background: Some patients with primary renal cell carcinoma (RCC) are unable to have surgery for different reasons (functional single kidney with a central, high-complexity RCC, high risk of nephrectomy and dialysis, patients with complex coagulation disorders, etc.). We hypothesize that combination of nivolumab and ipilimumab could eliminate the primary tumor in T1aN0M0 patients ineligible for surgical treatment. Methods: This is a prospective, multicenter, non-randomized phase 2 pilot study. Patients with biopsy-proven clear-cell RCC of ≤4 cm (cT1a), no evidence of any metastases, and unable to have surgery or other nephron-sparing interventions (ablation) or with preference to have no surgery or intervention for any reason received combination of ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, and nivolumab (240 mg intravenously) every 2 weeks during 16 weeks. The primary endpoint was complete response rate. Simon's two-stage design was used. The null hypothesis that the true complete response rate was 11% and was tested against a one-sided alternative. This design yields a type I error rate of 0.05 and power of 0.9 when the true complete response rate is 60% (alternative hypothesis). The null hypothesis should be rejected if 3 or more responses are observed in 8 patients. Results: Between February 2020 and June 2021, 8 patients were included. Median age was 77.9 years (range 73-89). Patients were Caucasian (100%), predominantly male (75%), 62.5% had centrally located RCC, 25% had ECOG PS 1, and 6 of 8 patients had moderate and severe comorbidities. Median follow-up was 12.7 months (95% CI 5.2-16.5). All patients received immunotherapy during 4 months without grade ≥2 adverse events. No complete responses were observed. Partial responses were found in 2 patients (25%). Median size of the primary tumor at RCC diagnosis and after immunotherapy was 3.11 cm (range 2.2-3.9) and 2.86 cm (range 1.5-4.0), respectively. Any shrinkage of the primary tumor was reported in 4 (50%) patients (change in median sum of diameters -18%). Only one patient had tumor enlargement (+0.5 cm (+13%) after 9 months. SBRT was used in this patient. All other patients are under active surveillance. Next secondary end-point of 3-year progression-free survival will be reported. Conclusions: The activity of immunotherapy against primary tumor was limited in patients with T1aN0M0 RCC ineligible for surgical treatment. Duration of stable disease will be studied with long-term follow-up of these patients. Treatment with nivolumab and ipilimumab was safe in patients with moderate and severe comorbidities. Citation Format: Ilya Tsimafeyeu, Maria Volkova, Rustem Gafanov, Igor Myslevtsev, Andrey Andrianov, Axel Bex. Primary tumor response in T1aN0M0 renal cell carcinoma patients ineligible for surgery and treated with nivolumab and ipilimumab: Results from phase 2 pilot study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT106.

Abstract 1309: Patient-derived tumor organoids as a platform to study radiation-exposed neoantigens

Abstract Focal radiation therapy (RT) can increase tumor immunogenicity and T cell-mediated tumor rejection when combined with immune checkpoint blockade (ICB). Our prior findings in patients and in preclinical studies suggest that one mechanism whereby RT increases tumor immunogenicity is by enhancing the expression of neoantigens.1,2 In response to RT, cells rapidly transcribe and translate hundreds of genes associated with the DNA damage response (DDR), protein turnover and cellular stress. Genes in these pathways are frequently mutated in cancer. Thus, we hypothesized that the presence of immunogenic mutations in genes upregulated by radiation could help predict the benefits of RT used in combination with ICB. In order to develop such a predictor, we built an in vitro system to study the RT-induced transcriptional response of primary human tumors cultured as patient-derived tumor organoids (PDO). PDOs were established from 2 breast cancer (BC), 4 non-small cell lung cancer (NSCLC) and 3 colorectal cancer (CRC) patients. PDOs were irradiated with doses of 5 to 8 Gy daily for 3 days (n=4) or left untreated (UT, n=4) and cultured for 24h prior to RNA extraction. RNA sequencing was carried out using a NovaSeq6000 sequencer (Illumina) to a depth of 30 million reads. Differential expression analysis between RT and UT samples was performed using DESeq2 and significantly perturbed genes were defined as genes with fold change greater than 1.5 and adjusted p-value cutoff of 0.05. In total we detected an average of 15,000+/-800 protein coding genes per sample and the number of genes modulated by RT was found to vary with cancer type. This ranged from an average of 3.9+/-1.6% genes upregulated by RT in NSCLC to 12.1+/-2.5% in CRC organoids. There were 104 and 490 genes commonly upregulated by RT in NSCLC and CRC, respectively. One of the BC PDOs is a triple-negative BC and the other HR+ and despite this difference, we identified 24 commonly upregulated genes. Gene Set Enrichment Analysis (GSEA), revealed enrichments in DDR and pro-inflammatory signaling pathways among the upregulated genes. Whole exome sequencing and paired normal tissue was used to determine the variants and predicted neoantigens for these PDOs. In one of the EGFR mutated NSCLC PDOs we found that among the genes transcriptionally upregulated by RT, 18 carried somatic mutations predicted to be antigenic. The presentation of these neoantigens is being investigated by mass spectrometry analysis of the immunopeptidome eluted from surface MHC-I molecules. Similar investigations are being carried out in the other models. Overall, results support the feasibility of identifying a common signature of RT upregulated genes in PDOs. This will provide a system to predict RT- exposed neoantigens. [1] Formenti et al. Nat. Med. 2018;24(12):1845-1851, [2] Lhuillier et al. J. Clin. Invest. 2021;131(5):e138740 Citation Format: Samantha J. Van Nest, Jared Capuano, Bhavneet Bhinder, Martin G. Klatt, Tuo Zhang, M. Laura Martin, Silvia C. Formenti, Olivier Elemento, Nils-Petter Rudqvist, Sandra Demaria. Patient-derived tumor organoids as a platform to study radiation-exposed neoantigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1309.

Neoadjuvant sintilimab combined with chemotherapy in patients with resectable esophageal squamous cell carcinoma (ESCC): Preliminary results from a phase II study.

e16008 Background: Although preoperative chemoradiotherapy is the standard of care for patients with resectable locally advanced esophageal cancer, prognosis still remains poor. Combining PD-1 blockade to chemotherapy has demonstrated significant clinical benefits in first line treatment of metastatic ESCC. Sintilimab, a fully human IgG4 monoclonal antibody that binds to programmed cell death receptor-1 (PD-1), has shown remarkable clinical efficacy in metastatic ESCC. We aimed to assess the activity and safety profile of the combination of sintilimab with paclitaxel and cisplatin for neoadjuvant treatment of ESCC. Methods: In this ongoing, single-arm, phase II study, we recruited patients from the First Affiliated Hospital of Henan University of Technology in China with histopathologically diagnosed resectable ESCC who had clinical cT2-4/N1-3M0 (stage II-IVA). Patients were given 2 cycles of chemotherapy (nab-paclitaxel 260 mg/m2, d1 and cisplatin 75 mg/m2, d1-3) in combination with 2 cycles of sintilimab (200mg, iv, d1, q3w), followed by esophagectomy. The primary endpoint was pathological complete response (pCR). The secondary endpoints included major pathological remission (MPR) and objective response rate (ORR). Results: Between Nov 2020 and Dec 2021, 15 patients were enrolled and commenced treatment. A total of 11 patients (75%) completed neoadjuvant and radical resection, 4 patients refused surgery. Six patients (54.5%) achieved major pathologic response (MPR), including five (45.5%) with a pathologic complete response (pCR) in primary tumor. According to RECIST v1.1, 1 of 8 patients (12.5%) achieved partial response (CR), 4 of 8 patients (50%) achieved partial response, and 3 of 8 patients (37.5%) achieved stable disease (SD). The objective response rate (ORR) and disease control rate (DCR) for 8 patients were 62.5% and 100%, respectively. The most frequent treatment-related adverse events (TRAE) included leukopenia (60%), nausea (40%) and diarrhea (20%). The grade 3 or 4 TRAE were leukopenia (26.7%), neutropenia (20%) and pneumonia (6.7%). There was no surgical delays or unexpected surgical complications related to drug toxicity. Conclusions: Neoadjuvant combination of sintilimab and chemotherapy is a safe and efficacious treatment option for patients with resectable ESCC, and 45.5% pCR rate is encouraging. Our clinical study is still enrolling, and the survival effects are under follow up. Clinical trial information: ChiCTR2000040345.

7: NEOADJUVANT CHEMORADIOTHERAPY OR CHEMOTHERAPY ALONE FOR OESOPHAGEAL CANCER: POPULATION-BASED COHORT STUDY

Abstract Background and aim Although both neoadjuvant chemoradiotherapy (nCRT) and chemotherapy (nCT) are used as neoadjuvant treatment for oesophageal cancer, it is unknown if one provides a survival advantage over the other particularly with respect to histological subtype. This study aimed to compare prognosis following nCRT and nCT in patients undergoing oesophagectomy for oesophageal adenocarcinoma (OAC) and squamous cell carcinoma (OSCC). Methods Data from the National Cancer Database (2006 to 2015) were used to identify patients with OAC (n = 11,167; nCRT 9,972 (89%), nCT 1,195 (11%)) and OSCC (n = 2,367; nCRT 2 m155 (91%), nCT 212 (9%)). Propensity score matching and Cox multivariable analyses were used to account for treatment selection biases. Results In the matched cohort for OAC, nCRT provided higher rates of complete pathological response (35% vs. 21%, P &amp;lt; 0.001) and margin-negative resections (90% vs. 86%, P &amp;lt; 0.001). However, nCRT had similar survival to nCT (Hazard ratio (HR):1.04, 95% confidence interval (CI):0.95–1.14). The corresponding 5-year survival for nCRT and nCT were 36% and 37% (P = 0.1), respectively. For OSCC, nCRT had higher rates of complete pathological response (51% vs. 30%, P &amp;lt; 0.001) and margin-negative resections (93% vs. 82%, P &amp;lt; 0.001). nCRT had a statistically significant overall survival benefit (HR: 0.78, 95% CI: 0.62–0.97). The 5-year survival for nCRT and nCT were 45% versus 38% (P = 0.026), respectively. Conclusion Despite pathological benefits including primary tumour response from nCRT, there was no prognostic benefit to nCRT compared to nCT for OAC suggesting both modalities are equally acceptable. However, for OSCC, nCRT followed by surgery appears to remain the optimal treatment approach.

Implementing subtype-specific pre-clinical models of breast cancer to study pre-treatment aspirin effects.

BackgorundPrior data suggest pre‐diagnostic aspirin use impacts breast tumour biology and patient outcome. Here, we employed faithful surgical resection models of HER2+ and triple‐negative breast cancer (TNBC), to study outcome and response mechanisms across breast cancer subtypes.MethodNOD/SCID mice were implanted with HER2+ MDA‐MB‐231/LN/2‐4/H2N, trastuzumab‐resistant HER2+ HCC1954 or a TNBC patient‐derived xenograft (PDX). A daily low‐dose aspirin regimen commenced until primary tumours reached ~250 mm3 and subsequently resected. MDA‐MB‐231/LN/2‐4/H2N mice were monitored for metastasis utilising imaging. To interrogate the survival benefit of pre‐treatment aspirin, 3 weeks post‐resection, HCC1954/TNBC animals received standard‐of‐care (SOC) chemotherapy for 6 weeks. Primary tumour response to aspirin was interrogated using immunohistochemistry.ResultsAspirin delayed time to metastasis in MDA‐MB‐231/LN/2‐4/H2N xenografts and decreased growth of HER2+/TNBC primary tumours. Lymphangiogenic factors and lymph vessels number were decreased in HER2+ tumours. However, no survival benefit was seen in aspirin pre‐treated animals (HCC1954/TNBC) that further received adjuvant SOC, compared with animals treated with SOC alone. In an effort to study mechanisms responsible for the observed reduction in lymphangiogenesis in HER2+ BC we utilised an in vitro co‐culture system of HCC1954 tumour cells and mesenchymal stromal cells (MSC). Aspirin abrogated the secretion of VEGF‐C in MSCs and also decreased the lymph/angiogenic potential of the MSCs and HCC1954 by tubule formation assay. Furthermore, aspirin decreased the secretion of uPA in HCC1954 cells potentially diminishing its metastatic capability.ConclusionOur data employing clinically relevant models demonstrate that aspirin alters breast tumour biology. However, aspirin may not represent a robust chemo‐preventative agent in the HER2+ or TNBC setting.

Targeting metabolism: A potential strategy for hematological cancer therapy.

Most hematological cancer-related relapses and deaths are caused by metastasis; thus, the importance of this process as a target of therapy should be considered. Hematological cancer is a type of cancer in which metabolism plays an essential role in progression. Therefore, we are required to block fundamental metastatic processes and develop specific preclinical and clinical strategies against those biomarkers involved in the metabolic regulation of hematological cancer cells, which do not rely on primary tumor responses. To understand progress in this field, we provide a summary of recent developments in the understanding of metabolism in hematological cancer and a general understanding of biomarkers currently used and under investigation for clinical and preclinical applications involving drug development. The signaling pathways involved in cancer cell metabolism are highlighted and shed light on how we could identify novel biomarkers involved in cancer development and treatment. This review provides new insights into biomolecular carriers that could be targeted as anticancer biomarkers.

A practical framework for the targeted use of total neoadjuvant therapy for rectal cancer

Total neoadjuvant therapy (TNT) for rectal cancer is the preoperative delivery of radiation or chemoradiotherapy as well as systemic chemotherapy for the purpose of improving treatment completion rates and decreasing toxicity, maximizing the primary tumor response, and improving survival for patients with rectal cancer. This review summarizes the data surrounding TNT, including several recent randomized controlled trials. Moreover, it reviews the literature regarding high-quality surgery and the role of radiation and chemotherapy in the treatment of rectal cancer in the modern era. Finally, it presents an evidence-based protocol for the selective use of TNT in the treatment of patients with rectal cancer.

Multifunctional profiling of triple-negative breast cancer patient-derived tumoroids for disease modeling.

3D cell models derived from patient tumors are highly translational tools that can recapitulate the complex genetic and molecular compositions of solid cancers and accelerate identification of drug targets and drug testing. However, the complexity of performing assays with such models remains a hurdle for their wider adoption. In the present study, we describe methods for processing and multi-functional profiling of tumoroid samples to test compound effects using a novel flowchip system in combination with high content imaging and metabolite analysis. Tumoroids were formed from primary cells isolated from a patient-derived tumor explant, TU-BcX-4IC, that represents metaplastic breast cancer with a triple-negative breast cancer subtype. Assays were performed in a microfluidics-based device (Pu⋅MA System) that allows automated exchange of media and treatments of tumoroids in a tissue culture incubator environment. Multi-functional assay profiling was performed on tumoroids treated with anti-cancer drugs. High-content imaging was used to evaluate drug effects on cell viability and expression of E-cadherin and CD44. Lactate secretion was used to measure tumoroid metabolism as a function of time and drug concentration. Observed responses included loss of cell viability, decrease in E-cadherin expression, and increase of lactate production. Importantly, the tumoroids were sensitive to romidepsin and trametinib, while showed significantly reduced sensitivity to paclitaxel and cytarabine, consistent with the primary tumor response. These methods for multi-parametric profiling of drug effects in patient-derived tumoroids provide an in depth understanding of drug sensitivity of individual tumor types, with important implications for the future development of personalized medicine.

Early primary tumor response in metastatic RCC patients treated with immune checkpoint inhibitors-based combinations.

349 Background: 25-30% of renal cell carcinoma presents with metastases (mRCC) at diagnosis. The activity of immune checkpoint inhibitor (ICI)-combinations on the primary tumor (PT) is debated. Patients and Methods: mRCC patients (pts) with PT who received first-line nivolumab plus ipilimumab (N/I) or pembrolizumab plus axitinib (P/A) were included. We investigated the early primary tumor response (EPTR) at the first radiological assessment. Results: 73 pts were included. The median early reduction of the PT longest diameter was 12.4% with P/A versus 6.2% with N/I (p = 0.42). We evaluated if the type of EPTR could affect the metastases response. Among pts with PT stable disease (SD), 8.3% had metastatic disease progression (PD) with P/A and 34.8% with N/I. Early PT partial response (PR) was associated with no metastatic PD with both N/I and P/A. The 2 pts with PT PD had also metastatic PD to P/A. Of the 3 PT with PD to N/I, 1 had metastatic SD and 2 PD. In the overall population, of the 94.1% without PT progression (PR+SD), 47.5% had metastatic PR, 35.6% SD, 16.9% PD. Conclusions: ICIs-combinations achieved an early PT PR in about 10-20%, without any complete responses. Only a small percentage of PT had an early PD, mainly associated with metastatic PD. However, among those PT without an early progression, metastatic PR can be achieved in approximately 50% of cases.[Table: see text]