Higher Tumor Growth Rate Research Articles

Prognostic Impact of Tumor Growth Rate During Second-line Chemotherapy in Patients With Gastric Cancer.

Despite the remarkable developments in chemotherapy for gastric cancer (GC), rapid tumor growth is sometimes experienced during chemotherapy. This study investigated the association of tumor growth rate (TGR) during second-line chemotherapy with the prognosis of patients with GC. We retrospectively reviewed 29 patients with GC treated with nab-paclitaxel plus ramucirumab as second-line chemotherapy between 2017 and 2019 at Osaka Metropolitan University. Of them, 13 cases with target lesions were classified into two groups according to TGR using a cutoff value of 0.25. Clinicopathological factors and survival outcomes were compared between the high TGR (n=5) and low TGR (n=8) groups. The median duration of first-line chemotherapy was significantly longer in the high TGR group than in the low TGR group [median 298 days vs. 72.5 days, p=0.030]. Progressive disease (PD) was observed in 60% of patients with high TGR, whereas stable disease (SD) was observed in 75% patients with low TGR. The median survival time (MST) after starting chemotherapy was 488 days in the low TGR group but was not reached in the high TGR group (log rank p=0.215). The MST after PD was 145 days in the low TGR group but was not estimated in the high TGR group (log rank p=0.345). Based on the absence of significant differences in survival outcomes between the high and low TGR groups, sequential late-line chemotherapy might be considered important, even for patients with high TGR.

Impact of environmental temperature on the survival outcomes of breast cancer: A SEER-based study

BackgroundExperimental evidence in tumor-bearing mouse models shows that exposure to cool, that is, sub-thermoneutral environmental temperature is associated with a higher tumor growth rate and an immunosuppressive tumor immune microenvironment than seen at thermoneutral temperatures. However, the translational significance of these findings in humans is unclear. We hypothesized that breast cancer patients living in warmer climates will have better survival outcomes than patients living in colder climates.MethodsA retrospective population-based analysis was conducted on 270,496 stage I-III breast cancer patients, who were retrieved from the Surveillance, Epidemiology and End Results (SEER) over the period from 1996 to 2017. The average annual temperature (AAT) was calculated based on city level data from the National Centers for Environmental Information.ResultsA total of 270, 496 patients were analyzed. Temperature as assessed in quartiles. After adjusting for potential confounders, patients who lived in the 3rd and 4th quartile temperature regions with AAT 56.7–62.5°F (3rd quartile) and > 62.5°F (4th quartile) had a 7% increase in the OS compared to patients living at AAT < 48.5°F (1st quartile) (HR 0.93, 95% CI 0.90–0.95 and HR 0.93, 95% CI 0.91–0.96, respectively). For DSS, When comparing AAT quartiles, patients living with AAT in the range of 56.7–62.5°F and > 62.5°F demonstrated a 7% increase each in DSS after adjustment (HR 0.93, 95% CI 0.90–0.96 and HR 0.93, 95% CI 0.90–0.96).ConclusionsHigher environmental temperatures are associated with significantly better OS and DSS in breast cancer patients. Future research is warranted to confirm this observation using large datasets to elucidate the underlying mechanisms and investigate novel therapeutic strategies to minimize this geographic disparity in clinical outcomes.

From molecular signatures to radiomics: tailoring neurooncological strategies through forecasting of glioma growth.

Contemporary oncological paradigms for adjuvant treatment of low- and intermediate-grade gliomas are often guided by a limited array of parameters, overlooking the dynamic nature of the disease. The authors' aim was to develop a comprehensive multivariate glioma growth model based on multicentric data, to facilitate more individualized therapeutic strategies. Random slope models with subject-specific random intercepts were fitted to a retrospective cohort of grade II and III gliomas from the database at Kepler University Hospital (n = 191) to predict future mean tumor diameters. Deep learning-based radiomics was used together with a comprehensive clinical dataset and evaluated on an external prospectively collected validation cohort from University Hospital Zurich (n = 9). Prediction quality was assessed via mean squared prediction error. A mean squared prediction error of 0.58 cm for the external validation cohort was achieved, indicating very good prognostic value. The mean ± SD time to adjuvant therapy was 28.7 ± 43.3 months and 16.1 ± 14.6 months for the training and validation cohort, respectively, with a mean of 6.2 ± 5 and 3.6 ± 0.7, respectively, for number of observations. The observed mean tumor diameter per year was 0.38 cm (95% CI 0.25-0.51) for the training cohort, and 1.02 cm (95% CI 0.78-2.82) for the validation cohort. Glioma of the superior frontal gyrus showed a higher rate of tumor growth than insular glioma. Oligodendroglioma showed less pronounced growth, anaplastic astrocytoma-unlike anaplastic oligodendroglioma-was associated with faster tumor growth. Unlike the impact of extent of resection, isocitrate dehydrogenase (IDH) had negligible influence on tumor growth. Inclusion of radiomics variables significantly enhanced the prediction performance of the random slope model used. The authors developed an advanced statistical model to predict tumor volumes both pre- and postoperatively, using comprehensive data prior to the initiation of adjuvant therapy. Using radiomics enhanced the precision of the prediction models. Whereas tumor extent of resection and topology emerged as influential factors in tumor growth, the IDH status did not. This study emphasizes the imperative of advanced computational methods in refining personalized low-grade glioma treatment, advocating a move beyond traditional paradigms.

Piezo1 facilitates optimal T cell activation during tumor challenge

ABSTRACT Functional effector T cells in the tumor microenvironment (TME) are critical for successful anti-tumor responses. T cell anti-tumor function is dependent on their ability to differentiate from a naïve state, infiltrate into the tumor site, and exert cytotoxic functions. The factors dictating whether a particular T cell can successfully undergo these processes during tumor challenge are not yet completely understood. Piezo1 is a mechanosensitive cation channel with high expression on both CD4+ and CD8+ T cells. Previous studies have demonstrated that Piezo1 optimizes T cell activation and restrains the CD4+ regulatory T cell (Treg) pool in vitro and under inflammatory conditions in vivo. However, little is known about the role Piezo1 plays on CD4+ and CD8+ T cells in cancer. We hypothesized that disruption of Piezo1 on T cells impairs anti-tumor immunity in vivo by hindering inflammatory T cell responses. We challenged mice with T cell Piezo1 deletion (P1KO) with tumor models dependent on T cells for immune rejection. P1KO mice had the more aggressive tumors, higher tumor growth rates and were unresponsive to immune-mediated therapeutic interventions. We observed a decreased CD4:CD8 ratio in both the secondary lymphoid organs and TME of P1KO mice that correlated inversely with tumor size. Poor CD4+ helper T cell responses underpinned the immunodeficient phenotype of P1KO mice. Wild type CD8+ T cells are sub-optimally activated in vivo with P1KO CD4+ T cells, taking on a CD25loPD-1hi phenotype. Together, our results suggest that Piezo1 optimizes T cell activation in the context of a tumor response.

Impact of diabetes and chronic kidney disease on active surveillance outcomes for small renal masses: A cohort study.

The American Cancer Society estimates 79,000 individuals will be diagnosed with kidney cancer in 2022, most of which are initially found as small renal masses (SRMs). Proper management of SRM patients includes careful evaluation of risk factors such as medical comorbidities and renal function. To investigate the importance of these risk factors, we examined their effect on crossover to delayed intervention (DI) and overall survival (OS) in patients undergoing active surveillance (AS) for SRMs. This is an Institutional Review Board-approved retrospective analysis of AS patients presented at kidney tumor conferences with SRMs between 2007 and 2017. Univariable and multivariable logistic regression analyses were performed to determine how factors including estimated glomerular filtration rate (eGFR), diabetes, and chronic kidney disease are associated with DI and OS. A total of 111 cases were reviewed. In general, AS patients were elderly and had significant comorbidities. On univariate analysis, intervention was more likely to occur in patients with a younger age (P = 0.01), better kidney function (P = 0.01), and higher tumor growth rates (GRs) (P = 0.02). Higher eGFR was associated with better survival (P = 0.03), while higher tumor GRs (P = 0.014), greater Charlson Comorbidity Index (P = 0.01), and larger tumors (P = 0.01) were associated with worse OS. Of the comorbidities, diabetes was found to be an independent predictor of worse OS (P = 0.01). Patient-level factors - such as diabetes and eGFR - are associated with the rate of DI and OS among SRM patients. Consideration of these factors may facilitate better AS protocols and improve patient outcomes for those with SRMs.

Abstract 6034: Characterization of a novel syngeneic cSCC mouse model to advance immunotherapy treatments

Abstract Cutaneous Squamous Cell Carcinoma (cSCC) is the second most common malignancy diagnosed in Caucasians with an incidence of about one million cases per year. TP53 and p16 are the most common mutated genes in cSCC. Previous studies of cSCC have shown that patients with both p53 and p16 mutations have lower survival rates. There are currently no syngeneic mouse preclinical models to accelerate the efficacy of immunotherapy combinations to treat cSCC. Our laboratory has generated several genetically engineered mouse models (GEMMs) containing tissue-specific p53 and p16 gene mutations. Recently, we have immortalized three murine cSCC cell lines (cSCC-5690, cSCC-8006, and cSCC-8271) derived from spontaneous skin tumors from GEMMs. Therefore, we hypothesized that the double mutant cell line cSCC-5690 enhances cell survival, tumor aggressiveness, and has lower sensitivity to antibody immunotherapy. Protein and RNA expression of the cell lines were validated by western blotting and qRT-PCR assays. Sphere and soft agar assays were used to evaluate the stem cell population and tumorigenicity of the cell lines. Then, we examined the chemosensitivity with cisplatin through clonogenic assays. To further study the tumorigenicity of cells, we evaluated in vivo tumor growth on C57BL/6J immunocompetent mice by injecting subcutaneously the tumor cell lines. The three cell lines expressed different levels of keratin 14 (K14), but cSCC 5690 and 8006 expressed high levels of genes related to oncogenic pathways as well as mesenchymal markers. The cell line cSCC-5690 expressing mutant p53 R172H with p16 gene deletion, showed an enhanced sphere, and colony tumor formation and both tumorigenic cell lines (cSCC-5690, 8006) showed different sensitivities to cisplatin treatment. A higher tumor growth rate was observed with cSCC-5690 compared to cSCC-8006, while cSCC-8271 showed no tumor growth. Immunohistochemistry studies demonstrated that both cSCC-5690 and 8006 tumors expressed vimentin but only cSCC-5690 expressed K14. The most aggressive syngeneic tumor model (cSCC-5690) was used to evaluate the anti-tumor efficiency of anti-PD1, anti-CD47 antibodies, and STING-agonist. Preliminary results revealed a significant tumor response only to STING agonist (c-di-GMP) which activates the innate and adaptive immune response. Therefore, we were able to characterize all three cell lines and established a new mouse model of cSCC as a relevant platform for immunotherapy studies. Citation Format: Alanis Enid Rodriguez Rosario, Roberto Rangel, Jeffrey Myers. Characterization of a novel syngeneic cSCC mouse model to advance immunotherapy treatments [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 6034.

Abstract 6042: Developing patient-derived organoids and tumor xenograft model for ovarian cancer for preclinical therapeutic evaluation

Abstract Purpose: Patient-derived organoid (PDO) and patient derived xenografts (PDX) models has been shown strong potential as experimental and preclinical research model which preserve original tumor characteristics. Here we represent our protocols setup process for ovarian cancer organoid establishment and PDX after data review and cell line xenograft experiments. Methods: First, we reviewed the histologic subtype of ovarian cancer of biobank in national cancer center, Korea then tried to match common subtype ovarian cancer cell line by literature review for xenograft experiments. Patient specimens were collected from histologically confirmed cancer patients under informed consent (NCC2020-0219). We obtained fresh tumor tissue from standard primary surgery of ovarian cancer patient and tissue was dissociated. Then we plated cells in matrigel with modified growth factors media. Organoids were passaged with diameter larger than 50µm and genetic analysis were performed to compare with original tumor. For PDX condition establishment, xenograft models using OVCAR3 in athymic nude and NOG mouse strains were compared, then SKOV3, SNU840, SNU251, and ES2 cell line subcutaneous xenograft growth were observed in NOG mouse. Results: Frequency of subtype of ovarian cancers (n=733) in biobank represented as following: serous adenocarcinoma (70%, n=509), endometrioid tumors (11%), clear cell tumors (10%), mucinous tumors (4%) and others (5%). After adjustment of organoid culture condition, PDOs (10 patients and 11 samples) were successfully long term cultured over 5 passages and the subtypes were including high grade serous type (n=5, 50%), clear cell carcinoma (n=2), mucinous carcinoma (n=2) and low grade serous type (n=1). The median age was 65 (28-82) years and stage III-IV (n=6) were frequent. Among them, number of recurred patients was three. Currently, the genetic information of each organoid is ongoing with CNV analysis, and the sensitivity and comparative analysis of the drug will be performed. Xenografts of OVCAR3 represented higher tumor growth rate in NOG mice than in athymic nude mice (p=0.03) then comparison of growth between cell lines in NOG mice showed fast as following in order: ES2, SKOV3, OVCAR3, SNU840, and SNU251 Conclusions: PDO from ovarian cancer were established and it might provide tools for personalized drug screening. To improve success rate we are continuing adjustment of PDO culture condition and PDX. (This work was supported by National Research Foundation of Korea grant, founded by the Korea government (MSIT) [No.2020R1A2C2010566]) Citation Format: Jihee Kim, Ji Hyeong Seo, Yun-Hee Kim, YoHan Woo, Yeon Jee Lee, Yena Kim, Wonyoung Choi, Young Ju Kim, Chong Woo Yoo, Sang Yoon Park, Myong Cheol Lim, Sun-Young Kong. Developing patient-derived organoids and tumor xenograft model for ovarian cancer for preclinical therapeutic evaluation [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 6042.

Identifying biomarkers associated with tumor growth rate: a longitudinal preoperative magnetic resonance imaging follow-up of low-grade gliomas.

BackgroundAlthough the influence of molecular biomarkers on the biological behavior of tumor cells has been investigated, their quantitative influence on the velocity of tumor growth remains unclear. This study aimed to identify the molecular biomarkers associated with tumor growth rates in World Health Organization (WHO) grade II gliomas, or low-grade gliomas (LGGs).MethodsPreoperative magnetic resonance imaging (MRI) data of patients with LGGs were retrospectively reviewed. Patients with at least 2 preoperative MRIs taken more than 90 days apart were enrolled. Patients with isocitrate dehydrogenase (IDH) wild-type tumors or with no recorded IDH status were excluded. A linear mixed-effects model was used to assess the velocity of tumor diameter expansion. The effect of biomarker expression on tumor growth rate was assessed using a multivariate linear mixed-effects regression model.ResultsData from 56 patients were used in our study. The overall velocity of diameter expansion (VDE) for LGGs was 2.1 mm/year. Higher expression level of mutant p53 were significantly associated with a higher tumor growth rate (+1.9 mm/year, P<0.01), while higher expression level of alpha-thalassemia/mental retardation syndrome X-linked protein (ATRX) were significantly associated with a lower tumor growth rate (−1.3 mm/year, P<0.01). Tumors with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation were found to grow significantly more slowly than those with no methylation (−3.1 mm/year, P<0.01). The telomerase reverse transcriptase (TERT) promoter type and expressions levels of Ki-67 and epidermal growth factor receptor (EGFR) showed no significant independent impact on tumor growth rates.ConclusionsThe status of biomarkers is significantly associated with the tumor growth rate in LGGs.

CLINICAL AND BIOLOGICAL CHARACTERISTICS OF T3N0M0 AND T4N0M0 BREAST CANCER

T3–4N0M0 breast cancer is rather rare among all breast cancers. The clinical features of these tumors and their biological nature are poorly studied in the scientific literature. In this study we showed that patients with T3N0M0 and T4N0M0 tumors revealed a number of common clinical features, comorbidities and biological characteristics of the tumor. At the same time carcinomas differed in their aggressiveness and the course of the disease. The history was shorter and the average tumor size was larger among patients from T3N0M0 group than in the T4N0M0 group, which indicates a higher tumor growth rate. Also, mean proliferation index ki-67 was higher in the T3N0M0 group than in the T4N0M0 group. The proportion of triple-negative and luminal B Her2‑negative biological subtypes was the largest in both the T3N0M0 and T4N0M0 groups. More than 50 % of women with T3–4N0M0 tumors had carcinomas with zero or low expression of hormonal receptors. Thus, such tumors were more aggressive and potentially highly sensitive to systemic chemotherapy in a significant proportion of patients with T3–4N0M0 breast cancer in our study.

Prognostic Significance of Tumor Growth Rate (TGR) in Patients with Huge Hepatocellular Carcinoma Undergoing Transcatheter Arterial Chemoembolization.

The prognostic value of the tumor growth rate (TGR) in huge hepatocellular carcinoma (HHCC) patients treated with transcatheter arterial chemoembolization (TACE) as an initial treatment remains unclear. This two-center retrospective study was conducted in 97 patients suffering from HHCC. Demographic characteristics, oncology characteristics, and some serological markers were collected for analysis. The TGR was significantly linear and associated with the risk of death when applied to restricted cubic splines. The optimal cut-off value of TGR was −8.6%/month, and patients were divided into two groups according to TGR. Kaplan–Meier analysis showed that the high-TGR group had a poorer prognosis. TGR (hazard ratio (HR), 2.06; 95% confidence interval (CI), 1.23–3.43; p = 0.006), presence of portal vein tumor thrombus (PVTT) (HR, 1.93; 95% CI, 1.13–3.27; p = 0.016), and subsequent combination therapy (HR, 0.59; 95% CI, 0.35–0.99; p = 0.047) were independent predictors of OS in the multivariate analysis. The model with TGR was superior to the model without TGR in the DCA analysis. Patients who underwent subsequent combination therapy showed a longer survival in the high-TGR group. This study demonstrated that higher TGR was associated with a worse prognosis in patients with HHCC. These findings will distinguish patients who demand more personalized combination therapy and rigorous surveillance.

Secretory NPC2 Protein-Mediated Free Cholesterol Levels Were Correlated with the Sorafenib Response in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor in the world. Sorafenib is the first-line drug for patients with advanced HCC. However, long-term treatment with sorafenib often results in reduced sensitivity of tumor cells to the drug, leading to acquired resistance. Identifying biomarkers which can predict the response to sorafenib treatment may represent a clinical challenge in the personalized treatment era. Niemann-Pick type C2 (NPC2), a secretory glycoprotein, plays an important role in regulating intracellular free cholesterol homeostasis. In HCC patients, downregulation of hepatic NPC2 is correlated with poor clinical pathological features through regulating mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) activation. This study aimed to investigate the roles of secretory NPC2-mediated free cholesterol levels as biomarkers when undergoing sorafenib treatment and evaluate its impact on acquired sorafenib resistance in HCC cells. Herein, we showed that NPC2 downregulation and free cholesterol accumulation weakened sorafenib’s efficacy through enhancing MAPK/AKT signaling in HCC cells. Meanwhile, NPC2 overexpression slightly enhanced the sorafenib-induced cytotoxic effect. Compared to normal diet feeding, mice fed a high-cholesterol diet had much higher tumor growth rates, whereas treatment with the free cholesterol-lowering agent, hydroxypropyl-β-cyclodextrin, enhanced sorafenib’s tumor-inhibiting ability. In addition, sorafenib treatment induced higher NPC2 secretion, which was mediated by inhibition of the Ras/Raf/MAPK kinase (MEK)/ERK signaling pathway in HCC cells. In both acquired sorafenib-resistant cell and xenograft models, NPC2 and free cholesterol secretion were increased in culture supernatant and serum samples. In conclusion, NPC2-mediated free cholesterol secretion may represent a candidate biomarker for the likelihood of HCC cells developing resistance to sorafenib.

Impact of tumor growth rate during preceding treatment on tumor response to nivolumab or irinotecan in advanced gastric cancer

BackgroundNivolumab (NIVO) and irinotecan (IRI) are standard treatments for refractory advanced gastric cancer (AGC); however, it is unclear which drug should be administered first or in which cases. The tumor growth rate (TGR) during preceding treatment is reported to be associated with tumor response in metastatic colorectal cancer patients treated with regorafenib or trifluridine/tipiracil, suggesting that TGR may be useful for drug selection. Therefore, we evaluated the association between TGR during preceding treatment and the tumor response to NIVO or IRI.Patients and methodsWe retrospectively evaluated consecutive AGC patients treated with NIVO or IRI and divided them into slow-growing (Slow) and rapid-growing (Rapid) groups according to TGR and the presence or absence of new lesions (NL+/NL−, respectively) during preceding treatment (Slow group: NL− with low TGR <0.30%/day; Rapid group: NL+ or high TGR ≥0.30%/day).ResultsA total of 117 patients (Rapid/Slow groups, 72/45; NIVO/IRI groups, 32/85) were eligible. All baseline characteristics except peritoneal metastases were similar between patients treated with NIVO and IRI in the Rapid and Slow groups. The response rate was significantly higher in patients treated with NIVO compared with IRI [31%/3%; odds ratio (OR), 13.8; P = 0.01; adjusted OR, 52; P = 0.002] in the Slow group, but there was no difference between patients treated with NIVO and IRI (5%/8%; OR, 0.68; P = 0.73; adjusted OR, 0.94; P = 0.96) in the Rapid group. Disease control rate, progression-free survival, and overall survival were consistent with these results.ConclusionsOur findings suggest that NIVO treatment is a more favorable option for patients with slow-growing tumors, and NIVO and IRI are similarly recommended for patients with rapid-growing tumors in refractory AGC. TGR and NL emergence during preceding treatment may be helpful for drug selection and warrant further investigation.

Model-based evaluation of image-guided fractionated whole-brain radiation therapy in pediatric diffuse intrinsic pontine glioma xenografts.

Radiation therapy (RT) is currently the standard treatment for diffuse intrinsic pontine glioma (DIPG), the most common cause of death in children with brain cancer. A pharmacodynamic model was developed to describe the radiation‐induced tumor shrinkage and overall survival in mice bearing DIPG. CD1‐nude mice were implanted in the brain cortex with luciferase‐labeled patient‐derived orthotopic xenografts of DIPG (SJDIPGx7 H3F3AWT / K27 M and SJDIPGx37 H3F3AK27M / K27M). Mice were treated with image‐guided whole‐brain RT at 1 or 2 Gy/fraction 5‐days‐on 2‐days‐off for a cumulative dose of 20 or 54 Gy. Tumor progression was monitored with bioluminescent imaging (BLI). A mathematical model describing BLI and overall survival was developed with data from mice receiving 2 Gy/fraction and validated using data from mice receiving 1 Gy/fraction. BLI data were adequately fitted with a logistic tumor growth function and a signal distribution model with linear radiation‐induced killing effect. A higher tumor growth rate in SJDIPGx37 versus SJDIPGx7 xenografts and a killing effect decreasing with higher tumor baseline (p < 0.0001) were identified. Cumulative radiation dose was suggested to inhibit the tumor growth rate according to a Hill function. Survival distribution was best described with a Weibull hazard function in which the hazard baseline was a continuous function of tumor BLI. Significant differences were further identified between DIPG cell lines and untreated versus treated mice. The model was adequately validated with mice receiving 1 Gy/fraction and will be useful in guiding future preclinical trials incorporating radiation and to support systemic combination therapies with RT.

Abstract PS17-47: Treatment naïve patient-derived xenograft model compared to the post-neoadjuvant model from the same patient diagnosed with triple negative breast cancer

Abstract Triple negative breast cancer (TNBC) is an aggressive and difficult-to-treat subtype of breast cancer that typically exhibits rapid growth rates, high rates of metastasis, and resistance to commonly used oncological drugs. Historically, cell lines have been utilized in order to study TNBC; recently, however, patient derived xenografts (PDX) models have evolved as the new standard that offers a translational approach to the research and subsequent treatment of breast cancer. Here, we characterize two novel PDX models for TNBC: TU-BcX-4QA and TU-BcX-4QAN. The former derived from a biopsy specimen prior to any therapies, and the latter derived from a mastectomy of the same patient after three rounds of AC-T therapy (doxorubicin and cyclophosphamide followed by paclitaxel). In establishing a treatment naïve and post-neoadjuvant therapy PDX model pair, we created a prime model that examines the effects of chemotherapy on tumor heterogeneity, clonal selection, and the overall characteristics of a tumor. Furthermore, we examined the evolution of the characteristics of the post-neoadjuvant therapy PDX model after continual passaging within the SCID/Beige murine models. Through serial implantation in SCID/Beige murine models for tissue propagation, we observed that TU-BcX-4QAN consistently had a higher tumor growth rate and a smaller number of metastatic lesions that developed on the lungs and liver in comparison to the TU-BcX-4QA model. In treating the tumor derived cell lines with NCI-approved oncological drugs, we distinguished the variations in their responses to various, commonly used therapies, and determined that TU-BcX-4QAN had a more resistant profile. Using qRT-PCR, we further discovered the differences between the two models in their contrasting gene expression; preliminary data indicates an increase in certain mesenchymal genes (CDH2, VIM, and ZEB2), a decrease in cell cycle genes (p21, p53), and an increase in proliferation genes (MK167) in TU-BcX-4QAN compared to TU-BcX-4QA. Additionally, serial passages are correlated with a decrease trend in human gene expression within TU-BcX-4QAN. This suggest that treatment can select for certain cancer cells within the primary tumor that allows for the growth of a different tumor altogether and illustrates both the advantages and limitations of the TU-BcX-4QA andTU-BcX-4QAN model pair in translational research. Citation Format: Gabrielle Olivia Windsor, Margarite Matossian, Maryl Wright, Steven Elliott, Khoa Nguyen, Bridgette Collins-Burow, Matthew Burow. Treatment naïve patient-derived xenograft model compared to the post-neoadjuvant model from the same patient diagnosed with triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-47.

Tumor growth rate as a prognostic factor for metastatic or recurrent adenoid cystic carcinoma of the head and neck patients treated with carboplatin plus paclitaxel.

Large prospective studies of chemotherapy for metastatic or recurrent adenoid cystic carcinoma (ACC) of the head and neck are lacking due to the rarity of ACC. The aim of this study is to evaluate the efficacy of carboplatin plus paclitaxel toward ACC and perform an exploratory investigation of the prognostic factors to investigate the optimal strategy for metastatic or recurrent ACC. We retrospectively analyzed recurrent or metastatic ACC patients treated with carboplatin plus paclitaxel between April 2007 and September 2019 in our hospital. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were evaluated, and an exploratory analysis of the prognostic factors was conducted. A total of 26 ACC patients were enrolled. ORR and DCR were 11.5 and 76.9%; the median PFS and OS were 8.1 and 22.3months, respectively. From the results of the multivariate analysis, higher (≥ 6%/month) tumor growth rate (TGR) was associated with worse PFS (hazard ratio [HR] 7.00, 95% CI 1.34-36.53, p = 0.02) and OS (HR 29.33, 95% CI 3.38-254.80, p < 0.01). The median PFS (10.6 vs. 6.6months, log-rank p < 0.05) and OS (48.5 vs. 16.9months, log-rank p < 0.01) were significantly shorter in patients with higher TGR. Carboplatin plus paclitaxel showed modest efficacy for recurrent or metastatic ACC patients. Watchful waiting may be optimal for ACC patients with lower TGR. Systemic chemotherapy should be considered when TGR increases during active surveillance.

Loss of HMGCS2 Enhances Lipogenesis and Attenuates the Protective Effect of the Ketogenic Diet in Liver Cancer.

Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor with limited treatment. The ketogenic diet (KD) emerged as a metabolic therapy for cancer; however, the antitumor effect on HCC remains controversial. We previously reported that the ketogenesis rate-limiting enzyme, 3-hydroxymethylglutaryl-CoA synthase 2 (HMGCS2), was downregulated in most patients with HCC. The knockdown of HMGCS2 enhanced the proliferation and metastasis ability of HCC cells. However, the role of HMGCS2 in affecting KD-mediated metabolic effects remains unclear. Here, we report that KD feeding upregulates HMGCS2 expression and inhibits HCC tumor growth, while a reverse correlation between tumor size and HMGCS2 expression was observed. We found that HCC cells with HMGCS2 downregulation possess altered lipid metabolism that increases fatty acid, triglyceride, and cholesterol synthesis. Under KD feeding, a higher tumor growth rate was observed in HMGCS2 knockdown tumors, which had increased lipid synthesis-related marker expression and a positive correlation between lipid quantity and tumor weight. In conclusion, these results demonstrate that the downregulation of HMGCS2 attenuates the protective effect of the KD by shifting ketone production to enhance de novo lipogenesis in HCC. Our study elucidates a new molecular mechanism underlying the crosstalk between HMGCS2 expression and the KD in cancer treatment, which provides more information for precision medicine in developing personalized treatment strategies.

Controlling the Phenotype of Tumor-Infiltrating Macrophages via the PHD-HIF Axis Inhibits Tumor Growth in a Mouse Model.

SummaryThe tumor microenvironment (TME) polarizes tumor-infiltrating macrophages toward tumor support. Macrophage-abundant tumors are highly malignant and are the cause of poor prognosis and therapeutic resistance. In this study, we show that the prolyl hydroxylase (PHD) inhibitor FG-4592 (FG) inhibits tumor growth of macrophage-abundant tumors and prolongs mouse survival. FG not only normalizes tumor vessels and improves tumor oxygenation but also directly affects macrophages and activates phagocytosis through the PHD-hypoxia-inducible factor (HIF) axis. Remarkably, FG can promote phagocytic ability of the Ly6Clo subset of tumor-infiltrating macrophages, leading to tumor growth inhibition. Moreover, Ly6Cneg macrophages contributed to blood vessel normalization. Using a malignant tumor mouse model, we characterized macrophage function and subsets. Altogether, our findings suggest that the PHD inhibitor can promote the anti-tumor potential of macrophages to improve cancer therapy.

Nivolumab and Pembrolizumab in advanced cutaneous melanoma : Results from real-life data in patients from France— Evaluation of use, current practices and medico economic approach.

e21009 Background: In 2016, Nivolumab (N) and Pembrolizumab (P) have been registred for first line ECOG PS 0-1 adult patients with non-resecable or metastatic melanoma. The Brittany and Pays de la Loire Cancer Observatory has collected data on their real-life indications, current management, safety, efficacy and medico-economics Methods: All non opposing adult patients (pts) with advanced cutaneous melanoma who initiated a treatment with N (3 mg/kg q2w) or P (2 mg/kg q3w) in 2016 and 2017 were included. Minimum follow-up for survival was 12 months. Sex, age, mutation profile, lines of treatment, toxicities, response rate, survival and treatment cost have been collected. Results: 149 pts were treated by N and 201 pts by P with a median age of respectively 68 [21-88] and 69 years [28-96]. Of the 350 patients, 34% were at least 75 years and around 30% presented a BRAF mutation. The median duration of treatment was 4.9 months [0-34.6] for N and 4.2 [0-35.8] for P (Not Significant NS). 65% of pts were treated in 1st line for N and 69% for P. 24% of the pts were treated in 2nd line for both treatments. 81% of the pts had a baseline PS of 0 or 1. All lines combined (first line for wt BRAF and first or second line for m BRAF melanoma), clinical benefit was 53% for N and 47% for P. Median OS was respectively 21.7 m for N and 22.8 m for P (NS). mPFS were respectively 6.4 m and 4.6 m (NS). 18% of pts presented grade III/IV toxicities with N and 17% with P. wt BRAF pts showed more grade III/IV toxicities than m BRAF pts (p = 0.046). For N, pts with grade III/IV toxicities showed better PFS (p = 0.051) and OS (p = 0.064). For both cohorts, PS ≥2, BRAF status and treatment line identified subgroup of pts with worsened PFS and OS 55% (24/44) of pts who stopped N or P because of death had a baseline PS of 0-1 showing PS alone is not sufficient to predict survival. Aggressive diseases (high metastasis rate, cerebro-meningeal metastasis, high tumor growth rate with any previous treatment) appear to be the worse candidates for immunotherapy. N and P courses during the 2 years costed 6.6 and 9.7 millions of euros respectively with approximatively 84% or 79% of this cost for N and P clinically benefitting pts. Conclusions: Immunotherapy in real-life setting in cutaneous advanced melanomas confirms literature’s data regarding clinical benefit, survival rate and safety profile and suggests to think about a composite predictive biomarker including BRAF status, ECOG PS, toxicity and treatment line.

Exploratory analysis of prognostic factors for lenvatinib in radioiodine-refractory differentiated thyroid cancer.

Multitarget kinase inhibitors (m-TKI), including lenvatinib, are now available as treatment options for radioiodine-refractory differentiated thyroid cancer (RR-DTC). However, the optimal timing of treatment initiation with m-TKI in these patients remains to be defined. We retrospectively reviewed the clinical records of 30 consecutive patients with RR-DTC. The relationship between clinical characteristics was evaluated, including tumor growth parameters at pretreatment/post-treatment and efficacy of lenvatinib. A total of 26 patients with RR-DTC treated with lenvatinib were evaluable for response and eligible for analysis. From the results of multivariate analysis, baseline tumor size and tumor-related symptoms were independent negative prognostic factors for overall survival (OS) and progression-free survival (PFS). Pretreatment tumor growth parameters were not prognostic for either PFS or OS. Patients with RR-DTC with a high tumor burden and tumor-related symptoms had significantly worse prognosis. Greater tumor reduction after starting lenvatinib may lead to better prognosis, irrespective of pretreatment high tumor growth rate.

Impact of tumor growth rate during preceding treatment on tumor response to nivolumab or irinotecan in advanced gastric cancer.

84 Background: Although nivolumab (NIVO) and irinotecan (IRI) are recognized as standard third-line and further treatments for patients (pts) with advanced gastric cancer (AGC), the drug that should be administered first remains unclear. Conversely, tumor growth rate (TGR) during preceding treatment was associated with tumor response to regorafenib or trifluridine/tipiracil in colorectal cancer. Methods: We retrospectively evaluated 212 pts with AGC treated with NIVO or IRI for the first time between January 2015 and June 2018 at three institutions. The main inclusion criteria were ECOG PS of 0–2, prior use of fluoropyrimidines and taxanes, and no prior use of NIVO or IRI. Pts were classified into slow- (SG) and rapid- (RG) growing groups according to TGR and presence or absence of new lesions (NL) during preceding treatment. TGR = (D1 − D0)/100D0 (CT1 − CT0), where CT1 is the date of CT at PD during preceding treatment, CT0 is the date of CT before CT1, and Dn is the sum of target lesion diameters at CTn. SG and RG were defined as NL− with low TGR and NL− with high TGR or NL+, respectively. TGR cut-off value was defined as a median TGR of 0.30%/day. Results: A total of 117 pts (RG/SG, 72/45; NIVO/IRI, 32/85) were eligible. Almost all baseline characteristics were similar between the NIVO and IRI groups among the RG or SG, whereas the proportion of pts with peritoneum metastases was higher in the NIVO group than in the IRI group among the RG. The response rate (RR) was significantly higher with NIVO than with IRI [31% vs. 3%, odds ratio (OR): 13.8, p = 0.01; adjusted OR (aOR): 52, p = 0.002] among the SG, whereas it was comparable between both drugs (5% vs. 8%, OR: 0.68, p = 0.73; aOR: 0.94, p = 0.96) among the RG. PFS was longer with NIVO than with IRI [median PFS (mPFS) 4.2 vs. 1.9 months (m), hazard ratio (HR): 0.50, p = 0.10] among the SG, whereas it was shorter with NIVO than with IRI (mPFS 1.6 vs. 2.1 m, HR: 1.37, p = 0.28) in the RG. Conclusions: RR was higher with NIVO than with IRI among slow growing tumors, whereas it was comparable between both drugs among rapid growing tumors. TGR during preceding treatment might be helpful for drug selection in pts with AGC who are considered for treatment with NIVO or IRI.