Therapy For Metastatic Cancer Research Articles

Occult metastatic thyroid cancer diagnosed during breast cancer axillary sentinel node biopsy.

SummaryIn most developed countries, breast carcinoma is the most common malignancy in women and while thyroid cancer is less common, its incidence is almost three to five times greater in women than in men. Since 1966, studies have demonstrated an association between thyroid and breast cancer and despite these studies, the mechanism/s by which they are related, remains unclear. We present a case of a 56-year-old lady who initially presented in 2014 with a screen detected left breast carcinoma but was subsequently found to have occult metastatic thyroid cancer to the axilla, diagnosed from a sentinel node biopsy from the primary breast procedure. The patient underwent a left mastectomy, left axillary dissection and total thyroidectomy followed by three courses of radioactive iodine ablation. Despite this, her thyroglobulin level continued to increase, which was secondary to a metastatic thyroid cancer parasternal metastasis. Breast and thyroid cancer presents metachronously or synchronously more often than by chance. With improving mortality in primary cancers, such as breast and differentiated thyroid cancer, it is likely that as clinicians, we will continue to encounter this association in practice.Learning points:There has been a long-standing observation of an association between breast and thyroid cancer although the exact mechanism of this association remains unclear.Our patient presented with thyroid cancer with an incidental diagnosis from a sentinel node biopsy during her primary breast operation for breast cancer and was also found to have a parasternal distant bony metastasis.Thyroid axillary metastases are generally rare.The interesting nature in which this patient’s metastatic thyroid carcinoma behaved more like a breast carcinoma highlights a correlation between these two cancers.With improving mortality in these primary cancers, clinicians are likely to encounter this association in clinical practice.Systemic therapy for metastatic breast and thyroid cancers differ and therefore a clear diagnosis of metastasis is crucial.

Abstract LB-069: TRAILing chemoresistance: Oxaliplatin resistance sensitizes colorectal cancer to TRAIL via death receptor localization

Abstract Colorectal cancer (CRC) remains the second leading cause of cancer related death in the United States. Clinical studies show combination chemotherapy cocktails increase Stage IV patient progression free survival when containing 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX). Despite an initial response rate of 40-50%, patients undergoing FOLFOX have a low median overall survival of 18-months. Treatment induced chemoresistance is in part responsible for this high morbidity, as subpopulations of surviving cells develop resistance mechanisms to induce a more aggressive, metastatic phenotype. Consequently, there exists an urgent need to develop new therapies for metastatic cancers that have become chemoresistant. We hypothesized that Tumor Necrosis factor - α Related Apoptosis Inducing Ligand (TRAIL) based therapeutics would be efficacious in treating oxaliplatin resistant CRC, providing an adjuvant for patients who have exhausted conventional treatment modalities. Four different CRC cell lines were chosen for this study: SW620, SW480, HCT116 and HT29 cells as they all have varying sensitivities to TRAIL. Briefly, oxaliplatin resistant (OxR) derivatives of these cell lines were developed by treating with oxaliplatin and subjecting surviving subpopulations to many rounds of increasing concentrations of chemotherapy. Resistant cells show increased expression of mesenchymal markers along with increased invasiveness. Metastatic CRC patient blood samples were obtained from Guthrie Clinic. Interestingly, SW620 OxR and HCT116 OxR cells show increased sensitization to soluble TRAIL compared to their parental counterparts. Flow cytometry and confocal microscopy demonstrate these sensitized cell lines have increased expression of death receptor 4 (Dr4). Previous studies have demonstrated that combination treatment with oxaliplatin and TRAIL sensitize cancer cells via localization of death receptors into lipid rafts. In our study, we observe a similar phenomenon where oxaliplatin resistant cells have a higher degree of lipid raft-Dr4 colocalization. Induction of death receptor-lipid raft complexes using resveratrol enhances parental SW620 cell sensitivity to TRAIL by 70%, whereas inhibition of lipid rafts via cholesterol sequestration using nystatin decreases sensitization of SW620 OxR cells by 30%. Circulating tumor cells (CTCs) from metastatic CRC patients who have undergone FOLOFX or oxaliplatin based chemotherapy exhibited colocalization of Dr4 and Dr5 into lipid rafts. Additionally, treating whole blood samples from patients with TRAIL-conjugated nanoparticles decreased the number of viable CTCs in circulation 4-fold compared to oxaliplatin monotherapy. These results demonstrate the utility of TRAIL based therapeutics to treat chemoresistant and metastatic CRC. Additionally, this mechanism of apoptosis signal propagation via lipid raft-death receptor complexes can be explored further to probe possible drug targets to augment receptor localization. Citation Format: Joshua Dale Greenlee, Nerymar Ortiz-Otero, Tejas Subramanian, Kevin Liu, Michael King. TRAILing chemoresistance: Oxaliplatin resistance sensitizes colorectal cancer to TRAIL via death receptor localization [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-069.

Abstract CT204: High cytotoxic T-cell or polymorphonuclear cell infiltrates in the tumor microenvironment correlate with responses to BL8040 plus pembrolizumab combination therapy in metastatic pancreatic tumors: Scientific correlates of a phase II clinical trial

Abstract Background: We recently conducted a clinical trial assessing Pembrolizumab (P) and BL-8040 (BL) in patients with pancreatic cancer. We prospectively collected serial biopsies to help understand the impact of this treatment on the tumor microenvironment (TME). Methods: Twenty patients were enrolled and were treated with BL8040 (1.25mg/kg) monotherapy for 2 weeks followed by dual therapy with BL8040 (d1, 4, 8, 11) plus Pembrolizumab (200 mg IV, d1) every 3 weeks. Biopsies were collected at baseline (T0) and during therapy. Some patients had biopsies after BL monotherapy (Tm) and some after combined therapy (Tc) due to a protocol change mid-study. Malignant cells expressing PD-L1 were assessed using immunohistochemistry (IHC) and TME was studied using 3 multiplex immunofluorescence panels including one each for T-cells subpopulations, macrophages and myeloid-derived suppressor cells (MDSCs). Median densities of the different phenotypes were analyzed in tumor and stromal compartments and correlated with serial biopsies. Results: Of 20 patients enrolled and 15 were evaluable for response of whom 2 had stability and 1 had a partial response. 17 patients had at least one viable biopsy; 4 had biopsies at T0 and Tm, 3 had biopsies at T0, Tm, and Tc, and 2 had biopsies at T0 and Tc. In general, we noted that cytotoxic T cells increased from baseline when measured at Tm or Tc. In contrast, MDSC counts and overall T cells decreased at Tm or Tc from baseline. Additionally, we saw an increase in CD 68+ and PD-L1 expressing macrophages (P=0.059 and P=0.046, respectively). Patients who had clinical benefit (PR/SD) had greater numbers of cytotoxic T-cells (CD3+CD8+, median, 226.08 cells/mm2) and regulatory T cells (CD3+FOXP3+, median, 48.20 cells/mm2) at baseline than PD patients (median, 26.15 cells/mm2, P=0.03; 13.31 cells/mm2, P=0.016, respectively). Conversely, at T0, the lowest numbers of tumor cytotoxic T-cells activated CD3+CD8+GB+ (median, 0.34 cells/mm2) and highest numbers of PMN-cells (CD66b+CD11b+, median, 16.66 cells/mm2) were observed in patients with PD when compared with PR or SD (median, 4.54 cells/mm2, P=0.097; 3.38 cells/mm2, P=0.023, respectively), suggesting that highest densities of PMN-cells may contribute to downregulation of T-cells in those cases. Conclusions: Higher cytotoxic T-cells or PMN-cell counts at T0 may predict changes in the TME and radiologic response to treatment with BL8040+Pembrolizumab therapy in metastatic pancreatic cancer. PMN-cells may play a role promoting immune suppression of T-cells, increase the risk of metastasis and interfering with the treatment. Trial Registration: NCT02907099, Ethics Approval: This study was approved by the M.D. Anderson Institutional Review Board, approval number 2016-0410. Citation Format: Carmelia M. Noia Barreto, Debora A. Ledesma, Swati Gite, Luisa M. Solis, Mei Jiang, Renganayaki K. Pandurengan, Robert Wolff, Milind Javle, Shubham Pant, Gauri Varadhachary, Rachna Shroff, Abi Vainstein-Haras, Ella Sorani, Tzipora M. Lustig, Osnat Kashtan, Yosi Gozlan, Steven M. Townson, Jeanne M. Fahey, James Yao, Ignacio I. Wistuba, Michael Overman, David Fogelman, Edwin R. Parra. High cytotoxic T-cell or polymorphonuclear cell infiltrates in the tumor microenvironment correlate with responses to BL8040 plus pembrolizumab combination therapy in metastatic pancreatic tumors: Scientific correlates of a phase II clinical trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT204.

Abstract 508: A novel orally available Wnt-pathway inhibitor for the treatment of metastatic cancers

Abstract We have developed a novel drug compound (OBD9) which blocks growth of metastatic cancer cells both in vitro and in vivo. We now identify OBD9 as an effective Wnt-signaling inhibitor targeting TNIK (TRAF2 And NCK Interacting Kinase) and we hypothesize that OBD9 represent a novel therapeutic option for patients with tumors that have an activated Wnt signaling pathway. To find novel drug candidates that selectively inhibit metastatic tumor cell viability, a drug screen was firstly performed and results of the screen identified members of the FDA-approved benzimidazole methylcarbamate family (e.g. mebendazole (MBZ) and albendazole (ALB)) as potential therapies for metastatic cancer. Earlier work also supports a role for this chemical family in the potential treatment of multiple cancers, but progress has been stalled by their poor water solubility and poor bioavailability for systemic delivery to disseminated tumors. We therefore synthesized a novel compound (OBD9) containing the scaffold of MBZ coupled to an oxetane group to enhance aqueous solubility to 361μM. OBD9 demonstrates significant cytotoxicity toward a variety of cancer cell types including colon, lung, and prostate cancers (IC50: 0.9-2μM). In a mouse xenograft model using highly aggressive PCMLN3 prostate cancer cells, OBD9 at 30 mg/kg significantly repressed growth of established tumors with no visible toxicity. In a mouse xenograft model of human A549 lung cancer cell line, orally delivered OBD9 also dramatically inhibited the growth of established tumors at 30 or 90μM without noticeable toxicity. Mechanistically, we find that OBD9 treatment significantly reduces TNIK levels as early as 4 hours at 1uM via an autophagy-dependent protein degradation pathway. TNIK functions as an activator of Wnt signaling pathway via phosphorylation of the beta-catenin/TCF4 complex that regulates Wnt downstream targets. We show that OBD9 treatment inhibits colon cancer cell growth and both qPCR and Western blot data suggest that Wnt signaling downstream targets, such as TCF4, AXIN2 and cMyc, are all significantly suppressed by OBD9 via the inhibition of TNIK. Overall, our in vitro and in vivo data suggest that OBD9 potentially represents a novel therapeutic option for multiple cancers including but not limit to colon, lung and prostate cancer. Citation Format: Kun Zhou, Jae Eun Cheong, Catherine Alix-Panabières, Lijun Sun, Bruce R. Zetter. A novel orally available Wnt-pathway inhibitor for the treatment of metastatic cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 508.

A facile and universal method to achieve liposomal remote loading of non-ionizable drugs with outstanding safety profiles and therapeutic effect

Liposomes have made remarkable achievements as drug delivery vehicles in the clinic. Liposomal products mostly benefited from remote drug loading techniques that succeeded in amphipathic and/or ionizable drugs, but seemed impracticable for nonionizable and poorly water-soluble therapeutic agents, thereby impeding extensive promising drugs to hitchhike liposomal vehicles for disease therapy. In this study, a series of weak acid drug derivatives were designed by a simplistic one step synthesis, which could be remotely loaded into liposomes by pH gradient method. Cabazitaxel (CTX) weak acid derivatives were selected to evaluate regarding its safety profiles, pharmacodynamics, and pharmacokinetics. CTX weak acid derivative liposomes were superior to Jevtana® in terms of safety profiles, including systemic toxicity, hematological toxicity, and potential central nerve toxicity. Specifically, it was demonstrated that liposomes had capacity to weaken potential toxicity of CTX on cortex and hippocampus neurons. Significant advantages of CTX weak acid derivative-loaded liposomes were achieved in prostate cancer and metastatic cancer therapy resulting from higher safety and elevated tolerated doses.

Response to multidisciplinary therapy of metastatic anaplastic thyroid cancer involving the right internal jugular vein and superior vena cava.

Response to multidisciplinary therapy of metastatic anaplastic thyroid cancer involving the right internal jugular vein and superior vena cava.

Metastatic Pancreatic Cancer: ASCO Guideline Update.

The aim of this work was to provide an update to the ASCO guideline on metastatic pancreatic cancer pertaining to recommendations for therapy options after first-line treatment. ASCO convened an Expert Panel and conducted a systematic review to update guideline recommendations for second-line therapy for metastatic pancreatic cancer. One randomized controlled trial of olaparib versus placebo, one report on phase I and II studies of larotrectinib, and one report on phase I and II studies of entrectinib met the inclusion criteria and inform the guideline update. New or updated recommendations for germline and somatic testing for microsatellite instability high/mismatch repair deficiency, BRCA mutations, and TRK alterations are provided for all treatment-eligible patients to select patients for recommended therapies, including pembrolizumab, olaparib, larotrectinib, or entrectinib, or potential clinical trials. The Expert Panel continues to endorse the remaining recommendations for second-line chemotherapy, as well as other recommendations related to treatment, follow-up, and palliative care from the 2018 version of this guideline. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Cabozantinib as a choice for platinum-refractory metastatic urothelial cancer.

In the field of systemic therapy for metastatic urothelial cancer, more than 30 years has passed without the development of any definitive subsequent-line of therapy for patients who do not respond to platinum-based combination chemotherapy. However, immune checkpoint inhibitors, such as pembrolizumab, have built a solid evidence base for a role as a second-line therapy for patients with platinum-refractory metastatic urothelial cancer. The pivotal phase 3 trial, KEYNOTE-045,1 evaluating the survival benefit of pembrolizumab in 542 patients with platinum-refractory metastatic urothelial cancer, showed that median overall survival in the pembrolizumab group was 10·3 months (95% CI 8·0–11·8), which was significantly longer than that in paclitaxel, docetaxel, or vinflunine chemotherapy group (7·4 months [6·1–8·3]).

Sterile, abscess-like cerebral lesion during trastuzumab therapy after HER2 status switch in a triple negative breast cancer patient: a case report and literature review

BackgroundBreast cancer is a global health problem – it is the most common malignancy among women. Triple negative breast cancers (TNBC) account for 10–20% of female breast cancer. Most TNBC cases confer poor prognosis. Brain metastasis appears in more than 15% in the triple negative breast cancer population, which causes serious decrease in survival. Changes of immunophenotype are not uncommon in breast cancer, offering new therapeutic options in cases where targetable proteins or pathways are being identified.Case presentationAfter five lines of chemotherapy and 82 months following the first diagnosis, our patient with brain metastatic triple negative breast cancer had human epidermal growth factor receptor 2 (HER2) genetic heterogeneity in the metastatic tissue sample interpreted as HER2 status conversion. After the removal of the metastasis, we started first line therapy for metastatic HER2 positive cancer with trastuzumab and paclitaxel. After the first cycle of trastuzumab, on day 8, she had a seizure, and neurosurgical examination showed an abscess-like lesion. The punctate proved to be sterile by microbiological and pathological examination, so we continued cytostatic therapy without the anti-HER2 antibody. 3 months later, we could not identify the previous abscess-like lesion in the control computer tomography (CT) scan, and our patient had no neurological deficits.ConclusionWe emphasize the importance of regular tissue confirmation of predictive markers in progressive tumorous disease even if our presented case is not unequivocally a “conversion case”. Tumor subtype is determined according to algorithms and definitions published in guidelines, nevertheless, use of different guidelines may lead to controversial interpretation in cases where HER2 genetic heterogeneity is present. Furthermore, we suggest that seronegative, aseptic intracranial fluid effusion after the removal of a brain metastasis may possibly be a side effect of trastuzumab.

Cisplatin, Gemcitabine, and Paclitaxel as a Salvage Second-Line Therapy for Metastatic Germ-Cell Cancer.

Second-line salvage therapy for patients with metastatic germ-cell cancer (GCC) after the first-line combination of VIP (etoposide, ifosfamide, cisplatin) therapy has not been established. This study evaluated the efficacy and tolerability of the TGP (paclitaxel, gemcitabine, cisplatin) combination chemotherapy as a second-line salvage therapy. The medical records of 16 consecutive patients with metastatic GCC who had been treated with first-line VIP therapy followed by second-line TGP therapy between 2005 and 2019 were reviewed and statistically analyzed. Ten patients, excluding the 6 patients treated with TGP without unequivocal progression, were included in the efficacy analysis. All 16 patients were included in the safety analysis. The median follow-up period from initial TGP administration was 78 months (interquartile range, 46-120 months). The estimated 5-year progression-free and overall survival rates for the 10 patients in the efficacy analysis were 70% and 100%, respectively. Grade 3/4 hematologic toxicity occurred in all 16 patients, but none developed uncontrollable infections or life-threatening bleeding. One patient died of treatment-related secondary leukemia, however. The present study is to our knowledge the first to examine the therapeutic outcomes and safety profile of second-line TGP chemotherapy. VIP followed by TGP might be an alternative first- and second-line conventional regimen for patients with metastatic GCC in this granulocyte colony-stimulating factor era, especially for patients at a high risk of bleomycin-induced pulmonary toxicity.

Cysteinyl leukotriene receptor 1 promotes 5-fluorouracil resistance and resistance-derived stemness in colon cancer cells.

Colon cancer is a therapy-resistant cancer with a low 5-year survival frequency. The drug 5-fluorouracil (5-FU) has been used as a first-line therapy in metastatic colon cancer in combination with leucovorin or oxaliplatin with a >40% resistance rate. High CysLT1R expression in tumors is associated with poor survival of colon cancer patients. We sought to examine the role of CysLT1R in 5-FU resistance and established 5-FU-resistant (5-FU-R) colon cancer cells. These 5-FU-R-cells expressed increased levels of CysLT1R and showed increased survival and migration compared to nonresistant cells. Increases in thymidylate synthase and active β-catenin were also observed in the 5-FU-R-cells. LTD4/CysLT1R signaling was further increased and abolished after CYSLTR1 CRISPR-Cas9-knockdown and reduced in CysLT1R-doxycycline-knockdown experiments and CysLT1R-antagonist montelukast/5-FU-treated cells. Montelukast and 5-FU resulted in synergistic effects by reducing HT-29cell and 5-FU-R-HT-29cell migration and zebrafish xenograft metastasis. An increase in the stem cell markers in 5-FU-R-cells and 5-FU-R-cell-derived colonospheres and in CysLT1R-Dox-knockdown cells increased colonosphere formation and stem cell markers was noticed after 5-FU treatment. IL-4-mediated stemness in both HT-29-colonospheres and 5-FU-R-cell derived colonospheres was abolished by montelukast or montelukast + 5-FU-treatment. Targeting CysLT1R signaling by montelukast might reverse drug resistance and decrease resistance-derived stemness in colon cancer patients.

Activation of p38α stress-activated protein kinase drives the formation of the pre-metastatic niche in the lungs.

Primary tumor-derived factors (TDFs) act upon normal cells to generate a pre-metastatic niche, which promotes colonization of target organs by disseminated malignant cells. Here we report that TDFs-induced activation of the p38α kinase in lung fibroblasts plays a critical role in the formation of a pre-metastatic niche in the lungs and subsequent pulmonary metastases. Activation of p38α led to inactivation of type I interferon signaling and stimulation of expression of fibroblast activation protein (FAP). FAP played a key role in remodeling of the extracellular matrix as well as inducing the expression of chemokines that enable lung infiltration by neutrophils. Increased activity of p38 in normal cells was associated with metastatic disease and poor prognosis in human melanoma patients whereas inactivation of p38 suppressed lung metastases. We discuss the p38α-driven mechanisms stimulating the metastatic processes and potential use of p38 inhibitors in adjuvant therapy of metastatic cancers.

Real-life results from the prospective QoliXane trial of the platform for outcome, quality of life, and translational research on pancreatic cancer (PARAGON) registry.

4625 Background: Gemcitabine and nab-paclitaxel (NPG) is standard first-line therapy for metastatic pancreatic cancer (mPC), but the pivotal study did not include quality of life (QoL) analyses. Methods: The QOLIXANE-PARAGON study started as a prospective, non-interventional, multicenter study conducted in Germany and transitioned into a permanent registry for pancreatic cancer patients (pts) considering all types of treatments. This report focuses on the pts enrolled into the QOLIXANE portion of the study. Pts were recruited from 95 German centers. QoL was prospectively measured via EORTC-C30 questionnaires (prior to and every month thereafter): therapy and efficacy parameters were prospectively collected. QoL and efficacy endpoints were analyzed in the intention-to-treat population (ITT). The primary endpoint was the rate of pts without deterioration of QoL/Global Health Score (QoL/GHS) at 3 months. Results: 600 pts were enrolled. Mean GHS/QoL score at baseline was low and was 46.2 (SD 22.8). Median progression-free survival was 5.85 months (95% CI, 5.23 to 6.25). Median overall survival (OS) was 8.91 months (95% CI, 7.89 to 10.19). The KM-analysis showed that 61% and 41% of pts had maintained QoL/GHS after 3 and 6 months, respectively. Median time to deterioration of QoL/GHS was 4.68 months (95% CI, 4.04 to 5.59). Mean QoL/GHS improved from 46.1 (SD 22.7) at baseline to 52.8 (SD 21.3) after 6 months. In the QoL response analysis, 34.6%, 37.4% and 28% of evaluable pts had improved, stable and worse QoL/GHS after 3 months, respectively. In the Cox regression analysis, GHS/QoL scores strongly predicted survival with a HR of 0.86 (p < 0.0001). Conclusions: QoliXane the largest study on QoL of mPC. It shows that time to deterioration of QoL is short but that a relevant group of mPC in first line have improved or maintained QoL after 3 and 6 months and that QoL is a predictor of pts outcome. Clinical trial information: NCT02691052 .

Racial disparities in utilization and effectiveness of first-line therapies in metastatic castrate-resistant prostate cancer.

e17541 Background: Prospective evidence suggests that abiraterone use is associated with improved progression-free survival in African-American (AA) men with metastatic castrate-resistant prostate cancer (mCRPC) compared to white men. It is unclear whether race-based differences in treatment utilization and effectiveness exist for men with newly diagnosed mCRPC treated in real-world clinical practice. Methods: In this retrospective cohort study, we used the Flatiron Health electronic health record-derived de-identified database to identify patients with mCRPC who received first-line (1L) systemic therapy between 2012 and 2018. We used multivariable logistic regression analysis to examine differences in utilization of abiraterone, enzalutamide, and docetaxel between AA and white men. We then used Fine-Gray models with death as a competing risk to assess treatment-specific associations between race and time to next therapy (TTNT) – a proxy for progression-free survival. Finally, we used multivariable Cox proportional hazards analyses to assess for treatment-specific racial disparities in all-cause mortality. All analyses were adjusted for age, Elixhauser comorbidity index, baseline steroid or opioid use (a proxy for disease aggressiveness), performance status, insurance status, and (if significant) an interaction term for race and age. Results: Of 3,808 mCRPC patients in the cohort, 2,165 (68.7%) were white and 404 (10.6%) were AA. At time of metastatic diagnosis, AA men were younger (69 vs. 75, p < 0.001) and more likely to have PSA value greater than 50 (57.9% vs. 42.6%, p < 0.001) compared to white men. Median follow up was 15 months. There were no significant racial differences in 1L utilization, TTNT, or all-cause mortality associated with abiraterone, enzalutamide, or docetaxel use (Table). Conclusions: In this large real-world analysis of men with mCRPC who received 1L therapy, we found no significant treatment-specific differences in utilization, TTNT, or all-cause mortality between AA and white men. Long-term prospective evidence is needed to justify differential treatment selection for AA men with mCRPC. [Table: see text]

HGCSG 1803: Single-arm phase II study evaluating efficacy of oxaliplatin, irinotecan and S-1 combination therapy (OX-IRIS) in metastatic pancreatic cancer as first-line treatment.

TPS4668 Background: Combination chemotherapy with oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) showed improved survival compared to gemcitabine monotherapy for patients with metastatic pancreatic cancer and has become the one of the standard regimens. Despite of its clinical benefit, FOLFIRNIOX needs continuous infusion of 5-FU for 46 hours, which impairs quality of life. In other gastrointestinal cancer, infuser pomp free regimens, in which oral 5-FU drug replace the continuous infusion of 5-FU, have developed as alternative regimen. Therefore, we planned to develop new combination chemotherapy with oxaliplatin, irinotecan and S-1 (OX-IRIS) for advanced pancreatic cancer. We previously conducted the phase Ⅰ study for assessing the safety and determining the recommended dose of OX-IRIS regimen. Methods: To evaluate efficacy and safety of OX-IRIS, HGCSG1803 study staeted as a multicenter, non-randomized, single arm, prospective, phase II study in December 2019. The patients with untreated metastatic or relapsed pancreatic cancer are eligible for this study. OX-IRIS is administered as follows; a 30-min intravenous infusion (IV) of antiemetic, a 2-h IV of oxaliplatin at 85 mg/m2, a 1.5-h IV of irinotecan at 150 mg/m2 on day 1 and day 15 of each 4-week cycle, and S-1 (40 mg/m2) was taken orally twice daily, from after dinner on day 1 to after breakfast on day 15, followed by a 14-day rest, and to be repeated every 2 weeks until disease progression, unacceptable toxicity, or patient refusal. The primary endpoint is response rate, and the secondary endpoints are overall survival, progression-free survival, safety, and dose intensity for each drug. A total of 40 cases are planned for registration from 18 institutions in Japan within 2.5 years. Clinical trial information: jRCTs011190008 .

Modified FOLFIRINOX as a second-line therapy following gemcitabine plus nab-paclitaxel therapy in metastatic pancreatic cancer

BackgroundThere is no established second-line treatment after failure of gemcitabine plus nab-paclitaxel (GnP) therapy for metastatic pancreatic cancer (MPC). The purpose of this study was to evaluate the efficacy and tolerability of the modified FOLFIRINOX (mFFX) as a second-line therapy for MPC and to investigate prognostic factors for survival.MethodsFrom 2015 to 2019, we retrospectively reviewed the medical records of consecutive patients receiving mFFX for MPC after failure of GnP therapy. Patients were treated every 2 weeks with mFFX (intravenous oxaliplatin 85 mg/m2, intravenous irinotecan 150 mg/m2, and continuous infusion of 5-fluorouracil 2400 mg/m2 for 46 h without bolus infusion).ResultsIn total, 104 patients received mFFX. The median overall survival (OS) was 7.0 months (95% confidence interval [CI]: 6.2–9.8) and the progression-free survival (PFS) 3.9 months (95% CI 2.8–5.0). The objective response rate was 10.6% and the disease control rate 56.7%. The median relative dose intensities of oxaliplatin, irinotecan, and infusional 5-FU were 80.0% (range 21.5–100%), 77.2% (range 38.1–100%), and 85.9% (range 36.9–100%), respectively. Grade 3–4 toxicities were reported in 57 patients (54.8%), including neutropenia, leukopenia, anemia, febrile neutropenia, and peripheral sensory neuropathy. Glasgow prognostic score and carcinoembryonic antigen level were independently associated with survival. Our prognostic model using these parameters could classify the patients into good (n = 38), intermediate (n = 47), and poor (n = 19) prognostic groups. The median OS and PFS time was 14.7 (95% CI 7.6–16.3) and 7.6 months (95% CI 4.1–10.5) for the good prognostic factors, 6.5 (95% CI 5.5–10.0) and 3.6 months (95% CI 2.7–4.8) for the intermediate prognostic factors and 5.0 (95% CI 2.9–6.6) and 1.7 months (95% CI 0.9–4.3) for the poor prognostic factors, respectively.ConclusionsThe mFFX showed to be a tolerable second-line treatment for MPC after GnP failure. Our prognostic model might be useful for deciding whether mFFX is indicated in this setting.

MON-443 SPECT/CT Localization of Incidental Diverticular Bleed After Radioiodine (i131) Therapy for Metastatic Thyroid Cancer

Background: Radioiodine therapy for patients with metastatic papillary and follicular thyroid cancer status post total thyroidectomy improves overall survival and is standard of care. Physiologic and pathologic biodistribution of I131 is dependent on tissue sodium iodine symporter expression with nonspecific radioiodine distribution seen secondary to physiologic routes of excretion. Clinical Case: Whole body scintigraphy (WBS) was performed seven days after I131 therapy in a 37-year-old male treated for metastatic papillary thyroid cancer with extension to a thyroglossal duct cyst at the time of surgery. His post-procedural course was uncomplicated with the exception of self-limited hematochezia six days after ablation. WBS images demonstrated a focus more superiorly in the neck concordant with metastatic thyroglossal duct cyst involvement. Activity was also present in the small and large bowel distribution reflecting normal routes of radioiodine excretion. WBS images depicted a discrete focus of radioiodine activity in the right lower quadrant, which SPECT/CT further localizes as activity in the sigmoid colon. Non-contrast CT images demonstrate an associated linear pattern of hyperdense hyperattenuation in the colonic lumen consistent with fresh blood. It is well established that the physiologic and pathologic biodistribution of I131 is dependent on tissue sodium-iodine symporter expression with additional distribution secondary to normal routes of excretion. Nonspecific radioiodine localization has been described at sites of inflammation secondary to vasodilation and increased vascular permeability resulting in leakage and accumulation in tissues. Sodium-iodine expression is found in many tissues, including salivary glands, lactating mammary glands, gastric mucosa, thymus, and small bowel; however, they are not expressed in the colon, nasopharyngeal mucosa, or orbital fibroblasts. I131 localization has been previously described within numerous body diverticula, such as Zenker’s and Meckel’s diverticula; however, radioiodine activity in association with an acute colonic diverticular bleed has not been reported. Conclusion: We propose that the isolated focus of radioiodine activity in the sigmoid colon associated with transient self-limited bleed could be either related to preexisting diverticulitis leading to I131 accumulation secondary to hyperemia, increased vascular capillary permeability, and subsequent aggravation of colonic mucosa resulting in a transient bleed or due to incidental nonspecific pooling of radioiodine in a colonic diverticulum resulting in secondary mucosal irritation with subsequent minor bleeding. To our knowledge this is the first reported case of SPECT/CT localization of radioiodine to an isolated colonic diverticular bleed in a patient status post I131 therapy for metastatic papillary thyroid cancer.

Real-world treatment patterns, healthcare resource use and clinical outcomes of patients receiving second line therapy for advanced or metastatic gastric cancer

BackgroundSecond-line (2 L) chemotherapies for advanced or metastatic gastric cancer have shown improved survival but there is no commonly accepted standard of care. This study examines real-world patient characteristics, treatment patterns, healthcare resource use (HCRU) and clinical outcomes in this setting.MethodsRetrospective chart reviews were performed at participating institutions from Australia, Canada, Italy and UK for adult patients receiving 2 L treatment for advanced/metastatic disease from January 2013 to July 2015. Data were collected for 12 months or until death.ResultsTwo hundred eighty patients were included, mean age was 60.9 years and 68.9% were male. Half (51.8%) received monotherapy in 2 L, of whom 69.0% received taxanes. Irinotecan monotherapy was common in Australia (30.0% of monotherapy patients) and Canada (43.8%), but infrequent in Italy and UK. Doublet chemotherapy was used in 36.4% of 2 L patients, most commonly fluoropyrimidine + irinotecan. Use of targeted therapies (trastuzumab, ramucirumab) was infrequent except in Italy. Estimated median real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) from the time of 2 L treatment initiation was 3.09 (95% CI: 2.76–3.68) and 6.54 (5.29–7.76) months, respectively, and estimated 12-month rwPFS and rwOS rate was 8 and 26%, respectively. Only a minority (26.8%) of patients were hospitalized during the follow-up period, with the lowest hospitalization in Italy (16.7%). Laboratory and imaging tests were performed for 93.2 and 70.4%, respectively.ConclusionsAbout half of patients received monotherapy as 2 L chemotherapy for advanced/metastatic gastric cancer and a third received doublets. Real-world clinical outcomes for 2 L treatment are poor and HCRU is considerable.

Targeting PD-1 or PD-L1 in Metastatic Kidney Cancer: Combination Therapy in the First-Line Setting.

Recent FDA approvals of regimens targeting programmed death 1 (PD-1) in combination with anti-CTLA-4 or with VEGF tyrosine kinase inhibitors are reshaping front-line therapy for metastatic kidney cancer. In parallel, therapeutics specific for programmed death ligand 1 (PD-L1), one of the two major ligands for PD-1, are under continued investigation. Surprisingly, not all PD-1 and PD-L1 agents lead to similar clinical outcomes, potentially due to biological differences in the cellular expression and regulation of these targets. Here, we review current clinical data on combination immune checkpoint inhibitor therapy in metastatic kidney cancer and discuss the relevant biology of PD-1 and PD-L1. The design of future rational combination therapy trials in metastatic renal cell carcinoma will rely upon an understanding of this biology, along with an evolving understanding of immune cell populations and their functional states in the tumor microenvironment.

Mechanosensing of Mechanical Confinement by Mesenchymal-Like Cells.

Mesenchymal stem cells (MSCs) and tumor cells have the unique capability to migrate out of their native environment and either home or metastasize, respectively, through extremely heterogeneous environments to a distant location. Once there, they can either aid in tissue regrowth or impart an immunomodulatory effect in the case of MSCs, or form secondary tumors in the case of tumor cells. During these journeys, cells experience physically confining forces that impinge on the cell body and the nucleus, ultimately causing a multitude of cellular changes. Most drastically, confining individual MSCs within hydrogels or confining monolayers of MSCs within agarose wells can sway MSC lineage commitment, while applying a confining compressive stress to metastatic tumor cells can increase their invasiveness. In this review, we seek to understand the signaling cascades that occur as cells sense confining forces and how that translates to behavioral changes, including elongated and multinucleated cell morphologies, novel migrational mechanisms, and altered gene expression, leading to a unique MSC secretome that could hold great promise for anti-inflammatory treatments. Through comparison of these altered behaviors, we aim to discern how MSCs alter their lineage selection, while tumor cells may become more aggressive and invasive. Synthesizing this information can be useful for employing MSCs for therapeutic approaches through systemic injections or tissue engineered grafts, and developing improved strategies for metastatic cancer therapies.