Dominant Metastatic Site Research Articles

CD24hiCD27+ Bregs within Metastatic Lymph Nodes Promote Multidrug Resistance in Breast Cancer.

Axillary lymph nodes (LN) are the primary and dominant metastatic sites in breast cancer. However, the interaction between tumor cells and immune cells within metastatic LNs (mLN) remains poorly understood. In our study, we explored the effect of CD24hiCD27+ regulatory B cells (Breg) within mLNs on orchestrating drug resistance of breast cancer cells. We collected mLN samples from patients with breast cancer who had received standard neoadjuvant therapy (NAT) and analyzed the spatial features of CD24hiCD27+ Bregs through multicolor immunofluorescence staining. The effect of CD24hiCD27+ Bregs on drug resistance of breast cancer cells was evaluated via in vitro experiments. A mouse model with mLNs was used to evaluate the strategies with blocking the interactions between Bregs and breast cancer for improving tumor regression within mLNs. In patients with breast cancer who had received NAT, there is a close spatial correlation between activated CD24hiCD27+ Bregs and residual tumor cells within mLNs. Mechanistically, CD24hiCD27+ Bregs greatly enhance the acquisition of multidrug resistance and stem-like features of breast cancer cells by secreting IL6 and TNFα. More importantly, breast cancer cells further promote the activation of CD24hiCD27+ Bregs via CD40L-dependent and PD-L1-dependent proximal signals, forming a positive feedback pattern. PD-L1 blockade significantly attenuates the drug resistance of breast cancer cells induced by CD24hiCD27+ Bregs, and addition of anti-PD-L1 antibody to chemotherapy improves tumor cell remission in mLNs. Our study reveals the pivotal role of CD24hiCD27+ Bregs in promoting drug resistance by interacting with breast cancer cells in mLNs, providing novel evidence for an improved strategy of chemoimmunotherapy combination for patients with breast cancer with mLNs.

Evaluating the utility of fluorine-18 fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET)/ computed tomography (CT) scan in cancer of unknown primary.

3062 Background: Cancer of unknown primary (CUP) represents a heterogeneous group of metastatic tumours where standardized diagnostic work-up fails to identify the tissue of origin (TOO). Small studies, to date mainly focused on cervical lymph node squamous cell CUP patients, have shown 18F-FDG-PET/CT can change patient management and identify the TOO. We aimed to describe the Peter MacCallum Cancer Centre experience with 18F-FDG PET/CT in CUP with respect to detection of a TOO and its impact on management. A secondary aim was to compare the overall survival (OS) in patients where TOO is detected with those without TOO detection. Methods: Retrospective analysis of CUP patients treated between 2014-2020. Patients were identified from medical oncology clinics and PET/CT records. Information regarding demographics, clinicopathological details, CUP subtype as per ESMO guidelines, genomic analysis (If known), suspected TOO as per clinician pre- and post-FDG PET/CT, treatment details pre- and post FDG PET/CT and follow-up were collated from electronic medical records. Clinical details and genomic analysis were used to determine the clinically suspected TOO and compared against independent blinded nuclear medicine specialist FDG-PET/CT reads to determine sensitivity, specificity, accuracy and detection rate of TOO. Results: One hundred and forty-seven patients were identified of whom 65% had undergone molecular profiling. The median age at diagnosis was 61 years (range 20-84) and the median follow-up time was 69 months (range, 26–83). The predominant histological subtype was adenocarcinoma (54%). Eighteen percent of patients had a prior cancer history and 29% had a 1st degree relative with a history of cancer. Ninety-three percent were ECOG 0-1, and the dominant metastatic site was lymph nodes (35%). Eighty-one percent were classified as unfavourable CUP subtype as per ESMO guidelines. FDG PET/CT demonstrated a TOO detection rate of 34% with high specificity (98%) and moderate accuracy (78%). FDG PET/CT resulted in a change in management in 22% of patients and identified occult disease sites in 37% of patients. The median OS for all patients was 17.8 months. Median OS was not reached and 12.5 months for favourable and unfavourable CUP subtypes, respectively (p < 0.0001). Median OS when a potential TOO was identified on an FDG-PET/CT scan was 25.4 months compared with 9.1 months when a TOO remained elusive. (p < 0.0001). Multivariable analysis of survival adjusted for age and sex remained significant for FDG-PET identification of TOO (p = 0.004), favourable CUP (p < 0.001) and ECOG ≤ 1 (p < 0.001). Conclusions: 18F-FDG PET/CT plays a complementary role in CUP diagnostic work-up and was able to determine the likely TOO in a third of cases. OS is improved with TOO identification, demonstrating the value of access to a diagnostic PET/CT scan for CUP patients.

Anaesthesia for Hepatic Resection Surgery.

This article will focus on the perioperative management of hepatic resection for colorectal cancer (CRC) liver metastases (CLRMs) (the liver is the dominant metastatic site for CRC) within the context of the Enhanced Recovery After Surgery (ERAS) paradigm. It discusses the epidemiology and outcomes along with the history of hepatic resection surgery and pertinent anatomy. The discussion of the preoperative phase includes patient selection, assessment of liver functional status, and new developments in prehabilitation. The intraoperative phase details developments in surgical and anesthetic techniques to minimize liver hemorrhage and reduce the risk of postoperative hepatic failure. Newer analgesic options are included. Management of potential complications is outlined in the postoperative section followed by a description of current evidence for ERAS and future directions.

Nationwide registry for patients with neuroendocrine neoplasm of pancreas, gastrointestinal tract, lungs, bronchi, or thymus in Japan

BackgroundNeuroendocrine neoplasm (NEN) is a comparatively rare tumor that has been considered indolent. Due to these characteristics, detailed epidemiological data have not been analyzed in Japan. To elucidate the present status of NEN diagnosis and treatment in Japan, we started a registry cohort study in January 2015.MethodsPatients pathologically diagnosed with NENs of the pancreas, gastrointestinal tract, lungs, bronchi, or thymus after January 2012 were enrolled in this registry after the date of ethics review committee approval in each hospital or institute. Follow-up was continued for enrolled patients.ResultsDuring 5 years of enrollment between January 2015 and December 2019, a total of 1526 participants from 63 departments were enrolled in this registry (mean, 305.2 participants/year), covering approximately 5.8% of the annual incidence of NENs in Japan. For pancreatic NEN, 41.9% of patients had metastasis and the dominant metastatic site was the liver, at twice the rate of lymph node metastasis in the current registry. In contrast, the frequency of lymph node metastasis from gastrointestinal (GI)-NEN was similar to that of the liver. The distribution of WHO 2019-based grades varied according to the primary site. Low-to-intermediate grade (G1–G2) was dominant for duodenal, jejunal/ileal, rectal, and pancreatic NENs, whereas high grade (G3 or NEC) was dominant for esophageal, stomach, and colon NENs. For PanNENs, G3 and NEC accounted only for 1.6% and 2.9%, respectively.ConclusionsThese cohort data provide crucial information for clinical research to clarify the characteristics of NENs in Japan.

Clinical evolution after surgery of hepatic metastases of colorectal cancer according to genomic profile.

188 Background: Hepatic metastatic disease from colorectal cancer (CRC) is a significant clinical problem, as the liver is the dominant metastatic site for patients with CRC and 25% of patients will have liver affection at diagnosis. Due to improvement in systemic therapy and locoregional treatments in the last decade, survival has increased significantly. In this regard, it is key to be able to establish several prognostic factors that significantly influence survival. Methods: We carried out a retrospective analysis of 554 patients with mCRC treated at the Gregorio Marañon Hospital (Madrid, Spain) between January 2010 and 2021. We analyzed the clinical and molecular characteristics of patients undergoing liver metastasis surgery as first metastasis surgery together with relapse patterns to progression. Results: Out of our cohort of 554 patients with mCRC we identified 169 patients that underwent liver metastasis surgery as 1st surgery, achieving a media of survival of 56.38 months [95% CI, 44.21-73.78 months]. Regarding the clinical characteristics of the population, the majority were men (63,91%) and had a PS 0-1 (90,5%); and 46 patients (27,2%) were more than 70 years old. In relation to the location of the primary tumour, 46 patients (27,2%) had it n the right colon and 120 in the left colon (71,0%). And 43 patients (25,4%) had extrahepatic disease at the time of surgery. Regarding the biomakers, we indentified the following mutations: 68 mutated KRAS (40,2%), 5 mutated NRAS (2,9%), 9 mutated BRAF (5,3%), 13 mutated PI3K (7,6%), 1 HER2 amplification (0,5%) and 4 with IMS phenotype (2,3%). After the metastasis surgery, progression was mainly hepatic (50,3%), followed by pulmonary (24,8%), peritoneal (11,8%), lymph node (12%), bones (4,7%) and cerebral (1,1%), without having significant differences in relapse patterns at the statistics when analyzed by genomic profile. When analyzing progression-free survival (PFS) and overall survival (OS) according to the genomic profile, in the BRAF mutated vs BRAF WT population, no statistically significant differences were found, obtaining therefore an evident benefit. Furthermore, we found significant differences in OS for patients with right vs left primary tumour as well as for patients with extrahepatic involvement at the time of surgery. Conclusions: Patients undergoing sequential metastatic surgery have a long survival, so it is important to analyse patterns of relapse and clinical course. There is no evidence of significant differences in the progression patterns according to the mutational status of the mCRC; but selected patients with BRAF mutations may obtain benefit in PFS and OS with locoregional approaches to their liver disease.

Analysis of patients (pts) with in-transit metastases treated with nivolumab (NIVO) or ipilimumab (IPI) in CheckMate 238.

9569 Background: In the phase 3 CheckMate 238 study, NIVO has demonstrated improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) vs IPI in pts with resected stage IIIB–C or IV melanoma, which was sustained at the 4-y analysis. Having in-transit metastases/satellites (ITM) is a poor prognostic factor, and pts with ITM are generally omitted from clinical trials. This study was the first and only adjuvant checkpoint inhibitor trial to include pts with ITM. Here, we present post hoc outcomes in this subgroup. Methods: Pts aged ≥15 y with completely resected stage IIIB–C or IV melanoma stratified by stage and tumor PD-L1 status were randomized 1:1 to NIVO (3 mg/kg Q2W; n = 453) or IPI (10 mg/kg Q3W for 4 doses, Q12W thereafter; n = 453) for a maximum of 1 y or until disease recurrence/unacceptable toxicity. Pts with ITM, with or without synchronous nodal involvement, were included. The primary study endpoint was RFS; overall survival (OS) was a secondary endpoint; and DMFS was exploratory. Results: Each of the 2 treatment groups had 164 pts with ITM. Baseline characteristics were generally similar between treatment groups in pts with or without ITM; in pts with ITM vs without ITM, tumor ulceration was less frequent in NIVO-treated pts, and fewer IPI-treated pts had PD-L1 expression ≥5%. RFS and DMFS favored NIVO vs IPI in all ITM subgroups (table). OS was similar to the intention-to-treat (ITT) population with no differences noted between treatment groups or between ITM subgroups. Among pts with or without ITM, dominant metastatic sites were lung and lymph nodes, followed by brain, liver, and soft tissue (in varying order). Similar metastasis patterns were observed in pts with ITM regardless of nodal involvement. Treatment-related adverse events (any grade and grade 3/4) in pts with ITM were similar to those of the ITT population. Conclusions: Results of this post hoc 4-y analysis of CheckMate 238 showed that safety and efficacy were similar in pts with or without ITM, supporting the use of adjuvant NIVO in pts with ITM, regardless of nodal involvement. Clinical trial information: NCT02388906. [Table: see text]

Perioperative Chemotherapy for Liver Metastasis of Colorectal Cancer.

The liver is the dominant site of metastasis for patients with colorectal cancer. For those with isolated liver metastases, surgical resection with systemic therapy has led to long-term remission in as high as 80% of patients in well-selected cohorts. This review will focus on how systemic therapy should be integrated with resection of liver metastases; in particular, the use of clinical risk scores based on clinicopathological features that help with patient selection, various approaches to the treatment of micro-metastatic disease (peri-operative versus post-operative chemotherapy), as well as conversion chemotherapy for those with initially upfront unresectable disease will be discussed.

Optimizing skeletal-related events prevention in patients with advanced prostate cancer.

In patients with metastatic castration-resistant prostate cancer (mCRPC), bone is a dominant site of metastasis. Bone metastases often lead to skeletal-related events (SREs), which include pain, spinal cord compression and fractures. The treatment of bone metastases in men with mCRPC aims to improve SRE-free survival, quality of life and clinical outcomes. Effective treatment options include antiresorptive bone-targeted agents such as zoledronic acid and denosumab, and radium-223, a bone-targeting radiopharmaceutical. Although overseas and local guidelines have widely recommended using either zoledronic acid or denosumab for the prevention of SREs in men with mCRPC and associated bone metastases, current evidence suggests that denosumab is superior to zoledronic acid in terms of longer SRE-free time and fewer total SREs observed in patients.

Fibroblast growth factors signaling in bone metastasis.

Many solid tumors metastasize to bone, but only prostate cancer has bone as a single, dominant metastatic site. Recently, the FGF axis has been implicated in cancer progression in some tumors and mounting evidence indicate that it mediates prostate cancer bone metastases. The FGF axis has an important role in bone biology and mediates cell-to-cell communication. Therefore, we discuss here basic concepts of bone biology, FGF signaling axis, and FGF axis function in adult bone, to integrate these concepts in our current understanding of the role of FGF axis in bone metastases.

Abstract P1-19-34: The role of hormone receptor (HR) status on initial treatment choices and outcomes for human epidermal growth factor receptor (HER)-2 positive advanced breast cancer: A study of the southeast Netherlands advanced breast cancer (SONABRE) registry

Abstract Background Previously, we reported that patients with HR+/HER2+ advanced breast cancer diagnosed in 2007-2009 had a better overall survival (OS) than patients with HR-/HER2+ advanced breast cancer (SONABRE Registry, Lobbezoo et al. BCRT 2013). This differential outcome suggests an impact of biology and/or used systemic therapies. The objective of the current study was to present initial palliative systemic therapy choices and its impact on OS and progression-free survival (PFS) in patients diagnosed with HER2+ advanced breast cancer in the Netherlands in 2007-2017, stratified by HR status. Patients and methods From our ongoing SONABRE Registry, we selected all consecutive patients diagnosed with HER2+ advanced breast cancer in six hospitals in the Netherlands in 2007-2017. OS and PFS by HR status were obtained using the Kaplan-Meier method and compared by the log-rank test. The multivariable Cox proportional hazards model for OS and PFS on initial systemic therapy were stratified by HR status and included the potential prognostic variables age, cardiovascular disease, metastatic-free interval, initial metastatic sites, (neo-) adjuvant therapy and (type of) initial palliative systemic therapy. Results Of the 376 patients included, 221 (59%) patients were diagnosed with HR+/HER2+ and 155 (41%) with HR-/HER2+ advanced breast cancer. Patients with HR+/HER2+ disease were most frequently diagnosed with bone metastases (74%), whereas the majority of patients with HR-/HER2+ disease were diagnosed with visceral metastases (66%) as initial dominant metastatic site. Of patients with HR+/HER2+ disease, 95% received at least one line of palliative systemic therapy among which 56% initially included HER2-targeted based therapy. Among patients with HR-/HER2+ disease, 77% received systemic therapy of which 87% initially included HER2-targeted based therapy. Median OS was 29 months (95% CI: 24-34) for HR+/HER2+ and 17 months (95% CI: 14-22) for HR-/HER2+ disease (logrank p=0.03). In patients with HR+/HER2+ disease, initial endocrine therapy without HER2-targeted therapy (n=80) did not significantly impact OS (hazard ratio: 1.12, 95% CI: 0.75-1.68), even though it was associated with a shorter initial PFS (hazard ratio: 1.48, 95% CI: 0.94-2.34) when compared with initial HER2-targeted therapy plus chemotherapy (n=81). On the other hand, in patients with HR-/HER2+ disease, receiving initial chemotherapy without HER2-targeted therapy (n=15) was associated with a shorter OS (hazard ratio:2.15, 95% CI 1.11-4.16) and PFS (hazard ratio =3.15, 95% CI 1.37-7.24) when compared with receiving initial HER2-targeted therapy plus chemotherapy (n=97). Conclusions In this extended real-life study with a long follow-up, we confirmed our previous findings that among patients with HER2+ advanced breast cancer the HR+ subtype had a more favorable outcome. We were able to show a differential metastatic pattern by HR status underlining its biological relevance. Immediate use of HER2-targeted therapy had no statistically significant positive effect on OS in the HR+ subtype, in contrast to the positive effect of immediate HER2-targeting therapy in the HR- subtype. Translational studies are warranted to shed more light on the cross-talk between the HR and HER2 pathways to improve selection for HER2-targeted therapies. Citation Format: Sandra M.E. Geurts, Khava I.E. Ibragimova, Nathalie JA Teeuwen, Frans Erdkamp, Birgit EPJ Vriens, Marien O den Boer, M Wouter Dercksen, Manon JAE Pepels, Maaike de Boer, Vivianne CG Tjan-Heijnen. The role of hormone receptor (HR) status on initial treatment choices and outcomes for human epidermal growth factor receptor (HER)-2 positive advanced breast cancer: A study of the southeast Netherlands advanced breast cancer (SONABRE) registry [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-34.

Abstract 4850: The relevance of using proper preclinical models when developing therapeutics for localized or bone metastatic prostate cancer

Abstract Early stages of prostate cancer are sensitive to androgen deprivation therapy, but upon progression the disease develops to metastatic castration-resistant prostate cancer, where bone is the dominant metastatic site. Despite of recent advances in drug development, the advanced stage is still incurable. Tumor microenvironment in metastatic locations differs from the primary site and may cause resistance to used therapy and modulate tumor properties. Therefore, it is crucial to use proper models in preclinical drug development. Aim of this study was to establish predictive preclinical in vitro and in vivo prostate cancer models that can be used in drug development when targeting cancer cells or tumor microenvironment at different stages. Androgen receptor (AR) positive human prostate cancer cell line LNCaP was used in all studies. In the in vitro assay, the effects of the antiandrogen enzalutamide on viability of LNCaP cells was determined using CellTiter Glo assay in the presence and absence of a synthetic androgen R1881. In two in vivo studies, male NMRI nude mice were used. In a subcutaneous model, part of the mice received dihydrotestosterone (DHT) supplement prior to cancer cell inoculation. In a bone metastasis model, LNCaP cells were inoculated into tibia bone marrow. The mice were randomized to treatment groups based on similar serum PSA levels and cancer-induced changes in bone determined by X-ray imaging at 6 weeks after inoculation of the cancer cells. The mice were treated with 300 kBq/kg of Radium-223 dichloride or vehicle at 6 and 10 weeks. Bone lesions were followed by X-ray imaging during the study. The study was terminated at 12 weeks after inoculation of the cancer cells and the tibias were removed for histological analysis and AR staining. In the in vitro assay, 0.1 and 0.01 nM R1881 increased LNCaP cell viability, and enzalutamide reduced cell viability in the presence of R1881 compared to the group with only R1881. In the subcutaneous model, tumors formed within 2-3 weeks after inoculation and the maximum tumor volume was reached within 10-12 weeks. LNCaP tumors grew in NMRI nude mice without DHT supplement, but DHT supplement supported tumor growth. In the bone metastasis model, LNCaP tumors induced osteoblastic-mixed bone lesions without additional androgen supplement, and immunohistochemical staining demonstrated strong AR expression. Radium-223 dichloride reduced the progression of tumor-induced bone lesions, decreased serum PSA levels, and decreased tumor area analyzed by histology. This study showcases relevant models that can be used at different phases of preclinical drug development when evaluating efficacy or safety of new therapeutics as mono- or combination therapies. The choice of a preclinical model and key readouts should be carefully selected based on whether developing therapeutics for localized or metastatic prostate cancer. Citation Format: Tiina E. Kähkönen, Jenni H.E. Mäki-Jouppila, Mari I. Suominen, Jussi M. Halleen, Jenni Bernoulli. The relevance of using proper preclinical models when developing therapeutics for localized or bone metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4850.

Abstract P6-18-28: Patterns of treatment and outcome of palbociclib plus endocrine therapy in hormone receptor-positive (HR+)/HER2 receptor-negative (HER2-) metastatic breast cancer (MBC): A real life multicenter Italian study

Abstract Background The CDK4/6 inhibitor palbociclib combined with endocrine therapy has proven to prolong progression-free survival (PFS) in previously untreated and pretreated women with HR+/HER2- MBC. Few data are available regarding the performance of such a regimen outside the clinical trials, and there is the need to understand its performances in real world. Methods We report a multicenter real-life experience aimed to verify the patterns of treatment and outcome of palbociclib plus endocrine therapy in an unselected population of MBC patients (pts). The primary endpoint was clinical benefit rate (CBR: complete response [CR], partial response [PR], or stable disease for longer than 6 months [SD]); secondary aims were median progression-free survival (mPFS) and safety of the combination. Statistical analysis was performed to identify variables potentially predictive of outcomes. Patients received P at 125 mg daily, 3 wk on/1 wk off in a 28d cycle, combined with letrozole administered orally 2.5 mg on a continuous daily dosing schedule (cohort A) or Fulvestrant 500 mg (F500) i.m. q4wks with loading dose (cohort B); treatment was given until disease progression, toxicity or patient's refusal. Results The study enrolled 150 postmenopausal pts (65 in cohort A, 85 in cohort B) treated from December 2016 to April 2018 at 4 Italian Institutions. Median age in the whole population was 62 years (range 47-79; mean age 59 years in cohort A, 64 in cohort B); 13 pts (20%) in cohort A and 23 pts (27%) in cohort B had de novo metastatic disease; 46% of pts in cohort A and 55% had visceral involvement, while 17% and 20% respectively had bone-only disease. The median number of prior lines was 2 in cohort A (range 1-3) and 3 (range 2-5) in cohort B, including ET (median 3) and chemotherapy (median 2); in cohort B 37 pts (43%) had previously received F 500, while 12% (cohort A) and 15% (cohort B) had been pretreated with everolimus. In cohort A a PR as best response was observed in 32% (20 pts), with 14 pts (23%) achieving SD lasting ≥ 6 months for a CBR of 52%. In cohort B CBR was 60%, with 25% PR, 48% SD lasting ≥ 6 months in 35 pts (41%). The most common adverse events in both cohorts were neutropenia (grade 1-2 in 67%, grade 3-4 in 35%), grade 1 anemia (52%) and thrombocytopenia (34%), requiring dose reduction in 27% of cases. At a median follow-up of 12 months (range 1-16), mPFS was 6.3 months in cohort A and 5.5 months in cohort B. In both groups a better mPFS was observed in pts treated as ≤ 3rd versus > 3rd line: 9.6 versus 5.2 in cohort A (p=0.003), 8.8 versus 4.1 months in cohort B, respectively (p= 0.002). No significant outcome differences were observed according to prior endocrine therapy with F500 or everolimus, or dominant metastatic site. Conclusions Our real life data, in line with the results of reported clinical trials, indicate that palbociclib plus letrozolo or F500 is active and safe in HR+/HER2- MBC, also suggesting a better performance of the combinations in earlier treatment lines. Citation Format: Palumbo R, Torrisi R, Quaquarini E, Sottotetti F, Gambaro A, Collovà E, Ferzi A, Fava S, Agostinetto E, Tagliaferri B, Licata L, Teragni C, Bernardo A. Patterns of treatment and outcome of palbociclib plus endocrine therapy in hormone receptor-positive (HR+)/HER2 receptor-negative (HER2-) metastatic breast cancer (MBC): A real life multicenter Italian study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-28.

EFFICACY AND SAFETY OF NANOPARTICLE ALBUMIN-BOUND PACLITAXEL VERSUS PACLITAXEL IN METASTATIC BREAST CANCER

Purpose: To compare the efficacy and safety of nab-pacitaxel versus paclitaxel in patients with metastatic breast cancer. Patients and Methods: A total of 92 patients with metastatic breast cancer received chemotherapy for nab-palitaxel versus paclitaxel at the dose of 260mg/m2 and 175mg/m2 respectively for total 8 cycles at the Hospital of Hue University of Medicine and Pharmacy and of Hue Central Hospital from February 2013 to October 2015. Results: The mean age in two groups of patients is 54 and 53 years old. The ECOG index was 0-1 in both groups. Menopausal status accounted for 73% in 2 groups. Dominant metastatic organ sites of two groups are bone, lung, liver. Multiple sites of metastasis in nab-paclitaxel and paclitaxel groups were 18% and 20%, respectively. The response rate of patients with nab-paclitaxel was 54.5% versus 31.2% in the paclitaxel group, p = 0.024. The time to progression was 8.46 months in the nab-paclitaxel group and 7.38 months in the paclitaxel group, p = 0.019. The median survival time of the nab-paclitaxel and paclitaxel groups was 28.89 and 27.79 months, respectively, p = 0.554. Neutropenia rates in the nab-pacitaxel and paclitaxel groups were 27.3% and 39.6% respectively, p = 0.033. Other toxicities were similar in both groups. Conclusion: Nab-Paclitaxel has clinical benefits over paclitaxel in metastatic breast cancer because of higher response rate, prolonged time to progression and less neutropenia. Key words: metastatic breast cancer, nab-paclitaxel, paclitaxel

Ipilimumab Activity in Advanced Uveal Melanoma: A Pooled Analysis

Uveal Melanoma (UM) is a rare tumour, with an estimated annual global incidence between 5.3-10.9 cases per million people. It accounts for less than 5% of all melanoma cases. UM arises from the vascular layers of the eye (iris, ciliary body, and choroid). It is a highly aggressive malignancy and about 50% of patients will develop metastatic disease at some stage after prior diagnosis of primary uveal melanoma. Liver is the dominant site of metastases (60-90%) followed by lungs (25%).

Dual-specificity tyrosine-regulated kinase 2 is a suppressor and potential prognostic marker for liver metastasis of colorectal cancer.

Colorectal cancer is a common cancer and a leading cause of cancer‐related death worldwide. The liver is a dominant metastatic site for patients with colorectal cancer. Molecular mechanisms that allow colorectal cancer cells to form liver metastases are largely unknown. Activation of epithelial–mesenchymal transition is the key step for metastasis of cancer cells. We recently reported that dual‐specificity tyrosine‐regulated kinase 2 (DYRK2) controls epithelial–mesenchymal transition in breast cancer and ovarian serous adenocarcinoma. The aim of this study is to clarify whether DYRK2 regulates liver metastases of colorectal cancer. We show that the ability of cell invasion and migration was abrogated in DYRK2‐overexpressing cells. In an in vivo xenograft model, liver metastatic lesions were markedly diminished by ectopic expression of DYRK2. Furthermore, we found that patients whose liver metastases expressed low DYRK2 levels had significantly worse overall and disease‐free survival. Given the findings that DYRK2 regulates cancer cell metastasis, we concluded that the expression status of DYRK2 could be a predictive marker for liver metastases of colorectal cancer.

P-324 - Mitomycin-c (mtc) as salvage therapy for patients with metastatic colorectal cancer (mCRC)

Introduction: For patients with mCRC and disease progression after the available standard cytotoxic and biologic agents, treatment options outside the context of a clinical trial are limited. Mitomycin-C is an old cytotoxic drug that has been used for a variety of solid tumor types in the past. It is still used in some instances for treatment of patients with mCRC in good performance status as salvage therapy. Methods: At the IORS, we retrospectively reviewed patients with mCRC who were treated with mitomycin-C as salvage therapy in a five-year period. All patients had previously received at least two chemotherapy regimens with or without biological agents. Data concerning demographic characteristics, previous treatment, number of cycles of mitomycin-C, toxicity and treatment outcome were analysed. Results: In the period between January 2011 and December 2016, 46 patients were treated with mitomycin-C as salvage therapy, 26 male (56.5%) and 20 female (43.5%), with median age at diagnosis 57 years, range 34 to 73. All patients had previously received oxaliplatin and irinotecan based chemotherapy, with 8 patients (17.4%) also having received bevacizumab in the first line, while 12 patients (21.4%) had treatment with cetuximab in the third line as per reimbursement availability in Serbia (K-ras wild type tumours). Mitomycin-C was administered at a dose of 8 mg/m2 every three weeks as monotherapy (10 pts, 21.7%) or in combination with fluoropyrimidines: capecitabine 1000 mg twice daily (2000 mg per day) days 1 to 14 every three weeks (11 pts, 23.9%), or infusional 5FU per DeGramont regimen (25 pts, 54.4%). ECOG performance status (PS) of our patients at the start of mitomycin-C therapy was: PS0 13 pts (28%), PS1 32 pts (70%) and PS2 1 patient (2%). Dominant metastatic sites were: liver in 35 patients, lung in 9, peritoneum in 9, ovary in 6, while 14 patients had more than one metastatic site. Median number of cycles of mitomycin-C was 4, range 1 to 12. Best response to mitomycin-C therapy was partial response in 1 patient (2%), stable disease in 15 patients (33%), and progression in 30 patients (65%). Two patients were still on mitomycin-C treatment at the cut-off time. Median progression-free survival (mPFS) during mitomycin-C treatment was 2.6 months (2.2-3.1m, CI 95%). There were no statistically significant differences in mPFS between men and women, ECOG performance status at start of MTC therapy, patients with primary left versus right colon tumors, nor depending on localisation of metastatic site(s). Median overall survival in this group of patients was 43 months (35.9-50.1m, CI 95%). Nine patients are still alive at the time of this analysis. Ten patients experienced grade 3 haematologic toxicity, all of them receiving the combination MTC-DeGramont therapy, but were able to complete treatment. There were no grade 4 toxicities. Conclusion: In this study mitomycin-C+/-fluoropyrimidines showed a modest efficacy and a favourable toxicity profile as salvage regimen in mCRC, in a population of patients with prolonged survival. It may be considered for patients with mCRC in good PS who received all available therapies and are not eligible for clinical studies.

Use and impact of selective internal radiation therapy (SIRT) in routine care patients with metastatic colorectal cancer (mCRC).

742 Background: The liver is the dominant site of metastasis in patients (pts) with mCRC. Radioembolisation is a potential option in the multidisciplinary management of these patients. Recently initial analysis of a randomised controlled trial (RCT) in the 1st line setting demonstrated no overall progression free survival (PFS) benefit from adding SIRT, but prolongation of liver PFS (HR 0.69, p=0.002) was seen. Methods: Consecutive pts with mCRC enrolled from January 2009 were identified from a prospective multi-site Australian registry. Characteristics and outcomes for pts selected for treatment with SIRT were analysed. Results: Of 1,694 pts with mCRC, 580 (34.2%) had liver only disease at diagnosis, 409/580 (70.5%) with synchronous vs 166/580 (28.6%) with metachronous disease. Of pts with liver only disease, 187 (32.2%) were considered resectable at diagnosis, 100 (17%) as potentially resectable and 293 (51%) were treated with palliative intent. Overall 47 pts received SIRT with 1stline chemotherapy (CT). SIRT treated pts were more likely to have a synchronous presentation (85% vs 68%, p=0.01), liver only disease (83.0% vs 27.3%, p=<0.01), to be ECOG 0 (51.1% vs 34.6%, p=0.01), to be younger (60.8 years vs. 65.9 years, p=0.008) and to be enrolled on a RCT (38.3% vs 7.3%, p=<0.01). In the liver only population treated with palliative intent, SIRT treated pts (n=30) vs CT only pts (n=188) had a median PFS of 10.6 months vs 9.9 months (HR 0.87, p = 0.18) and a median OS of 24.3 months vs 19.3 months (HR 0.73, p = 0.04). Conclusions: SIRT is rarely used in the 1st line treatment of mCRC in routine practice. The available data suggests that OS gains can be seen in the absence of differences in PFS. However, this observed differential effect on survival maybe due to selection biases. SIRT treated patients were significantly younger and fitter than the CT alone group. Future analyses will include a multivariate analysis and examine the impact of the recently presented SIRFLOX trial data on the use of SIRT in clinical practice.

Prevalence of vitamin D deficiency among palliative care cancer outpatients: Prospective analysis of 347 cases of single individual medical practice.

204 Background: In spite of the fact that cancer patients under palliative care represent the group of high risk for vitamin D deficiency (e.g. changed nutritional patterns and UV exposure), data reporting vitamin D levels in palliative care setting are rather scarce. Methods: Between Jan-02/2014 and June-20/2015 circulating 25-hydroxyvitamin-D (25-OH-D) levels were analyzed in 76% consecutive patients’ samples of a single individual cancer practice located in Gdansk, Poland. Three hundred forty seven patients (female: 72.5%, median age 64, range: 23-89 years; breast cancer: 57.8%, colon cancer 27.7%) were admitted for palliative care due to: disseminated cancer (18%), side effects of anticancer therapy (56.6%) or symptom control in non-cancer diseases (24.5%). Results of fast 25-OH-D blood tests were correlated with selected clinical factors. Results: The median 25-OH-D level of all our cohort patients was 15.85 ng/mL (range: 0.40 – 62.00 ng/mL); 65.0% of subjects were vitamin D deficient (25-OH-D < 20 ng/mL) and 23.5% insufficient (20-30 ng/mL); only 3.30% patients were taking vitamin D supplements before they entered the study. The univariate analysis identified the following risk factors for inadequate 25-OH-D levels: active cancer disease (median 25-OH-D: 12.50 ng/mL versus 17.86 ng/mL in patients without evidence of disease, p < 0.001) and current glucocorticoids use (at least 14 days within the last month: 11.58 ng/mL versus 17.12 ng/mL in glucocorticoids nonusers; p < 0.01). Age, gender, body mass index values, primary cancer location, dominant metastatic site and higher antibiotics use did not influence 25-OH-D levels. Conclusions: 1) Low (deficient or insufficient) 25-OH-D serum levels were highly prevalent in palliative cancer care outpatients, mostly in those with clinically active disease and using glucocorticoids; 2) the study will continue to address the correlation between 25-OH-D concentrations and symptom burden as well as the potential feasibility of vitamin D supplementation to improve symptoms management of patients in palliative care setting.

Defining the survival benchmark for breast cancer patients with systemic relapse.

BACKGROUNDOur original paper, published in 1992, reported a median overall survival after first relapse in breast cancer of 26 months. The current retrospective review concentrates more specifically on patients with first systemic relapse, recognizing that subsets of patients with local recurrence are potentially curable.METHODSRecords of 5,168 patients from a largely breast-cancer-specific oncology practice were reviewed to identify breast cancer patients with their first relapse between 1996 and 2006 after primary treatment. There were 189 patients diagnosed with metastatic disease within 2 months of being seen by our therapeutic team and 101 patients diagnosed with metastatic disease greater than 2 months. The patients were divided in order to account for lead-time bias than could potentially confound the analysis of the latter 101 patients.RESULTSMedian survival for our primary study population of 189 patients was 33 months. As expected, the median survival from first systemic relapse (MSFSR) for the 101 patients excluded because of the potential for lead-time bias was better at 46 months. Factors influencing prognosis included estrogen receptor (ER) status, disease-free interval (DFI), and dominant site of metastasis. Compared with our original series, even with elimination of local-regional recurrences in our present series, the median survival from first relapse has improved by 7 months over the past two decades.CONCLUSIONThe new benchmark for MSFSR approaches 3 years.

AFM-based dual nano-mechanical phenotypes for cancer metastasis.

An enhanced mechanical compliance is considered to be a mechanical indicator for metastatic cancer cells. Our study using atomic force microscopy (AFM) revealed that breast cancer cells agreed well with this hypothesis. However, prostate cancer cells displayed a reverse correlation; less metastatic prostate cancer cells were more mechanically compliant. Two-dimensional AFM force spectroscopy was performed to characterize dual mechanical properties-the cell-substrate adhesion as well as the mechanical compliance. Interestingly, prostate cancer cells displayed a strong positive correlation between the cell-substrate adhesion and metastatic potential. However, there was no clearly observable correlation between the cell-substrate adhesion and the metastatic potential despite variations in mechanical compliance of breast cancer cells. These results suggest that the correlation between the dual mechanical signatures and metastatic potential be uniquely identified for cancer cells originating from different organs. We postulate that this correlation could reveal which step of cancer progression is favorable in terms of physical interaction between cancer cells and micro-environments. We expect that based on the "seed and soil hypothesis", the identification of the dual mechanical phenotypes, could provide a new insight for understanding how a dominant metastatic site is determined for cancer cells originating from specific organs.