Treatment Of Distant Metastases Research Articles

The KRAS-Variant and Cetuximab in HPV-Positive Oropharyngeal Cancer in NRG/RTOG 1016

NRG/RTOG 1016 was a non-inferiority phase III trial comparing radiation with cisplatin versus cetuximab monotherapy for patients with HPV-positive oropharyngeal squamous cell carcinoma (SCC). The trial did not meet the non-inferiority criteria for overall survival (OS) and had significantly worse progression-free survival (PFS) and locoregional failure (LRF) in patients treated with cetuximab. Based on prior evidence that HNSCC patients with a germ-line mutation in KRAS (the KRAS-variant) had a positive response to radiation with cisplatin plus cetuximab without increased toxicity, samples from RTOG 1016 were used to test the protocol-specified hypothesis that KRAS-variant patients will have better outcomes when receiving IMRT + cetuximab monotherapy compared to IMRT + cisplatin. The KRAS-variant was tested in 562 samples at MiraDx, a CLIA-certified laboratory. OS, PFS, LRF, and distant metastases (DM) were as defined per the RTOG 1016 protocol, and hazard ratios (HRs) were estimated by (cause-specific) Cox models. Negative binomial regression was used to model the number of treatment-related acute and late (≤ and > 180 days from end of treatment, respectively) grade 3-5 adverse events. To assess the predictive role of the KRAS-variant, all models included KRAS, assigned treatment, and their interaction, with the interaction tested at two-sided 0.05. HRs and toxicity ratios are expressed as IMRT + cetuximab / IMRT + cisplatin. The prevalence of the KRAS-variant was 16% with similar patient and tumor characteristics and well-balanced treatment arms for variant and non-variant patients. Median follow-up was 8.6 years. There was no significant interaction between KRAS and treatment for OS (p = 0.99), PFS (p = 0.56), LRF (p = 0.09), or DM (p = 0.19) (Table 1). In KRAS-variant patients the mean acute and late toxicity ratios were 0.53 (95% CI 0.36, 0.80) and 1.62 (95% CI 0.57, 4.62). In non-variant patients, the mean acute and late toxicity ratios were 0.80 (95% CI 0.67, 0.95) and 0.55 (95% CI 0.35, 0.87), respectively. The interaction of KRAS and treatment was not significant for acute (p = 0.07) or late toxicity (p = 0.07). While this study does not directly refute prior evidence that KRAS-variant patients benefit from radiation + cisplatin and cetuximab, this study does not support the hypothesis that the KRAS-variant is a predictive biomarker of improved outcome in HPV+ oropharyngeal SCC patients treated with IMRT + cetuximab alone, and suggests that for KRAS-variant patients, potential benefits in LRF and acute toxicity with cetuximab may be offset by worse DM and worse late toxicity.

The Latest Treatment for Head and Neck Cancers: Transoral Robotic Surgery and Photoimmunotherapy

Remarkable progress has been achieved in head and neck surgery in recent years. Transoral robotic surgery (TORS) is becoming popular worldwide for the removal of less invasive tumors. TORS is used especially for oropharyngeal cancer and is minimally invasive, with a short treatment time and minimal postoperative dysfunction. The procedure is performed by inserting one endoscope and two robotic arms. The robotic arm has a 360-degree movable tip, which enables fine manipulation, even in narrow oral cavities. The endoscope also provides three-dimensional images and enables the surgeon to get close to the operative site, making it possible to check for small blood vessels and other objects while performing the operation. Photoimmunotherapy is a new treatment for distant metastasis or recurrent head and neck cancers not indicated for surgery or radiotherapy. Treatment requires the administration of a dye, IR700, one day before the procedure. This dye disrupts cell membranes when exposed to near-infrared (NIR) radiation. To deliver this dye specifically to the tumor, an antibody drug against the epidermal growth factor receptor, which is expressed relatively specifically in tumors, is used. This treatment has a strong anti-tumor effect and the tumor shrinks relatively quickly. However, because NIR irradiation is required, the lesion must be within the infrared irradiation range. In addition, because of rapid shrinkage of the tumor, post-treatment tissue defects are serous complication, and tumor invasion into the carotid artery are contraindications due to the risk for major hemorrhage caused by tumor shrinkage.

Modern diagnostics and treatment of distant metastasis of cervical cancer

Cervical cancer comprises a major female health problem worldwide. Despite population screening programmes, broad vaccination, precision pathogenesis studies and emergent diagnostics and treatment strategies, its prevalence is rising by year. We increasingly report the spread of disease, particularly of metastatic cervical cancer. The such patients’ prognosis is far from favourable. We review the literature relevant to diagnostic and treatment options in metastatic cervical cancer. The options and survival rates described vary by the locality of metastatic lesions and routes of metastasis. Patients with haematogenous metastases have a worse prognosis than patients with lymphogenous ones. From a diagnostic point of view, 2-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG PET) and PET-computed tomography remain efficacious for detecting distant metastases. Adjuvant chemotherapy and concurrent chemoradiotherapy are effective in lymphogenous metastases. Haematogenous lung metastases resection and/or chemotherapy are the tactics of choice to contain relapsed metastatic cervical cancer. Accordingly, chemoradiotherapy is the optimal choice in patients with stage IVB cervical cancer. Multimodal therapy has revealed better survival prognosis. Stereotactic radiosurgery or craniotomy is indicated in oligometastatic brain lesions, with treatment outcomes and survival rates improving for the techniques’ combination with whole-brain radiation therapy. However, in multiple metastasis to brain or extracranial metastasis, chemotherapy combined with palliative whole-brain radiation are left as the only option.

Oncocytic Papillary Thyroid Carcinoma and Oncocytic Poorly Differentiated Thyroid Carcinoma: Clinical Features, Uptake, and Response to Radioactive Iodine Therapy, and Outcome.

ObjectiveThe main objective of this study was to review the clinicopathologic characteristics and outcome of patients with oncocytic papillary thyroid carcinoma (PTC) and oncocytic poorly differentiated thyroid carcinoma (PDTC). The secondary objective was to evaluate the prevalence and outcomes of RAI use in this population.MethodsPatients with oncocytic PTC and PDTC who were treated at a quaternary cancer centre between 2002 and 2017 were retrospectively identified from an institutional database. All patients had an expert pathology review to ensure consistent reporting and definition. The cumulative incidence function was used to analyse locoregional failure (LRF) and distant metastasis (DM) rates. Univariable analysis (UVA) was used to assess clinical predictors of outcome.ResultsIn total, 263 patients were included (PTC [n=218], PDTC [n=45]) with a median follow up of 4.4 years (range: 0 = 26.7 years). Patients with oncocytic PTC had a 5/10-year incidence of LRF and DM, respectively, of 2.7%/5.6% and 3.4%/4.5%. On UVA, there was an increased risk of DM in PTC tumors with widely invasive growth (HR 17.1; p<0.001), extra-thyroidal extension (HR 24.95; p<0.001), angioinvasion (HR 32.58; p=0.002), focal dedifferentiation (HR 19.57, p<0.001), and focal hobnail cell change (HR 8.67, p=0.042). There was additionally an increased risk of DM seen in male PTC patients (HR 5.5, p=0.03).The use of RAI was more common in patients with larger tumors, angioinvasion, and widely invasive disease. RAI was also used in the management of DM and 43% of patients with oncocytic PTC had RAI-avid metastatic disease. Patients with oncocytic PDTC had a higher rate of 5/10-year incidence of LRF and DM (21.4%/45.4%; 11.4%/40.4%, respectively). Patients with extra-thyroidal extension had an increased risk of DM (HR 5.52, p=0.023) as did those with angioinvasion. Of the patients with oncocytic PDTC who received RAI for the treatment of DM, 40% had RAI-avid disease.ConclusionWe present a large homogenous cohort of patients with oncocytic PTC and PDTC, with consistent pathologic reporting and definition. Patients with oncocytic PTC have excellent clinical outcomes and similar risk factors for recurrence as their non-oncocytic counterparts (angioinvasion, large tumor size, extra-thyroidal extension, and focal dedifferentiation). Compared with oncocytic PTCs, the adverse biology of oncocytic PDTCs is supported with increased frequency of DM and lower uptake of RAI.

Radioiodine Ablation for Thyroid Cancer. Historical and Modern Aspects. Literature Review

Thyroid cancer is the most common oncological pathology of the endocrine system organs with a continuing trend towards an increase in the incidence. Radioiodine therapy (RIT) is the second stage of combined treatment, it is carried out only as an adjuvant treatment, it is an uncontested method of radio-targeted therapy for distant metastases of differentiated thyroid cancer (DTC). The method of radioiodine therapy is based on the unique natural affinity of iodine atoms for the follicular epithelium of the thyroid gland and DTC cells. Determination of indications for RIT is based on stratification of recurrence risk, persistence, and disease prevalence. Over the past 15 years, the world’s leading professional communities have repeatedly revised approaches to risk stratification. Consideration of the mutational profile of the tumor and the theranostic approach have become significant innovations.Radioiodine therapy can be presented in the form of three modes: ablation of residual thyroid tissue, treatment of residual tumor and treatment of distant metastases. These regimens differ in the administered therapeutic activity of 131I, which looks logical from the point of view of the necessary personalization of the treatment. At the same time, in scientific circles, disputes about the absence of significant differences in the used therapeutic activities of 131I prescribed for radioiodine ablation outside the personalized approach do not subside.

Surgical indications and clinical management of benign and malignant follicular thyroid tumors: An algorithmic‑based approach

The present study retrospectively reviewed the treatment courses and results of patients with follicular thyroid tumors, including carcinomas. In the 5 year study period from April 2015 to March 2020, 797 patients with differentiated thyroid carcinoma and 128 patients with follicular tumors (FTs) received surgery or treatment for distant metastases and recurrence at the Kanagawa Cancer Center (Japan). Of these patients, 73 that were diagnosed with follicular thyroid carcinoma (FTC) were included in the present study. An algorithm used for the application of treatment strategies was assessed. The aim of the present study was to examine patients with FT or FTC who were treated at the Kanagawa Cancer Center to devise appropriate treatment strategies and to evaluate the various treatment outcomes of FTC. Pre-diagnostic serum thyroglobulin and thyroid stimulating hormone levels, follow-up and overall survival (OS) were investigated in the present study. The results revealed that OS was significantly increased in patients with minimally invasive follicular thyroid cancer (MIFTC) compared with widely invasive follicular thyroid cancer (WIFTC) (log-rank test, P=0.017). Additionally, OS was significantly higher in patients without distant metastasis at the first consultation compared with those initially diagnosed with distant metastasis (log-rank test, P=0.023). Although all patients without distant metastasis at the first consultation and those with MIFTC are alive, the 10-year survival rates were 75.3% for patients with WIFTC and 75.6% for those with distant metastasis at the first consultation. The results of the present study suggested that the prognosis of WIFTC was the worst among patients with FTC and distant metastasis, and that total thyroidectomy surgery and radioactive iodine treatment are essential. Additionally, if the disease progresses, prompt inclusion of tyrosine kinase inhibitor therapy is necessary.

Hemoglobin Level during Radiotherapy Predicts Survival Outcomes after Radiochemotherapy for Stage III Non-Small Cell Lung Cancer

Low hemoglobin (Hgb) levels have been linked with poor prognosis in various malignancies including non-small cell lung cancer (NSCLC). Here we tested the hypothesis that low Hgb levels during radiochemotherapy for stage III NSCLC are associated with lower rates of overall survival (OS), disease-free survival (DFS), and distant metastasis(DM). We retrospectively reviewed Hgb levels before and during definitive radiochemotherapy (radiation dose ≥60 Gy) in 189 patients with inoperable stage III NSCLC. Seventy-nine (42%) patients were treated with 3D conformal radiotherapy (3DCRT), 85 (45%) with intensity-modulated radiotherapy (IMRT), and 24 (13%) with passive scattering proton therapy (PSPT), 1 patient received PSPT and IMRT sequentially. Eighty-one patients (43%) received induction chemotherapy. We calculated Hgb means before and during treatment and analyzed the changes in these values. Potential associations between mean Hgb levels during treatment and rates of OS, DM, and DFS were analyzed with Cox proportional hazards models. Mean Hgb levels before and during treatment for all patients were 13.2 g/dL (range 8.2−17.4) and 11.5 g/dL (range 8.6−14.7). Hgb decreased in most patients during treatment (mean difference 2.1 g/dL [range 0.5−6.9]). The median follow-up time was 21.3 months (range 2.8–121.4). In univariate analyses, mean Hgb levels were found to be associated with OS (hazard ratio [HR] 0.856, 95% confidence interval [CI] 0.750–0.977, P=0.021), DFS (HR 0.818, 95% CI 0.711–0.941,P=0.005), and DM (HR 0.786, 95% CI 0.668–0.924, P=0.004). Gross tumor volume (GTV) and tumor histology were also associated with survival outcomes and applied in multivariate analysis. Mean Hgb level was still significantly associated with OS (HR 0.871, 95% CI 0.763–0.994, P=0.041), DFS (HR 0.853, 95% CI 0.739–0.985,P=0.03), and DM (HR 0.837, 95% CI 0.709–0.988, P=0.035) after adjustment for GTV and histology. Hgb decreased during radiotherapy. Low Hgb levels during treatment predicted poorer OS, DFS, and DM in patients with stage III NSCLC. Monitoring Hgb levels during radiotherapy in large multi-center studies is recommended to validate the role of Hgb and to select threshold values.

SURGICAL TREATMENT OF REGIONAL RECURRENCE FROM GASTRIC CANCER AFTER MULTIMODAL TREATMENT WITH NEOADJUVANT CHEMORADIOTHERAPY (A CASE REPORT)

Background. Gastric cancer is the fourth most common cancer and the second leading cause of cancer-related death worldwide. Despite many advances in the diagnosis and treatment of gastric cancer, the overall five-year survival rate does not exceed 25–30 %, and distant metastases and loco-regional recurrence develop in more than 50 % of patients. Disease recurrence is not only associated with the presence of tumor micro-metastases at the time of surgery, but also with dissemination of tumor cells during mobilization of the stomach or lymph node dissection. Even after performing radical surgery, the prognosis remains extremely unfavorable. No standardized methods of treatment for isolated loco-regional recurrence have been developed yet. Cases of successful treatment of distant metastases and regional recurrence are sporadic. Case report. We present the case of a 75-year-old patient with histologically proven well-differentiated tubular adenocarcinoma of the stomach. The patient underwent neoadjuvant chemoradiation therapy (total radiotherapy dose was 45 Gy, modified Capox regimen) followed by gastrectomy and D2lymph node dissection. The control examination revealed an isolated regional recurrence of gastric cancer. It was decided to perform surgical treatment for isolated regional gastric cancer recurrence. Conclusion. There is no standardized approach to the treatment of regional recurrence of gastric cancer. Surgical treatment in such cases is a method of choice, especially for patients who previously received neoadjuvant chemoradiotherapy. According to the worldwide literature, the median survival of such patients does not exceed a few months. The key point that determines the effectiveness of neoadjuvant therapy is the achievement of complete or partial pathological response to therapy, thus demonstrating improved survival compared to surgery alone. Therefore, it is extremely important to search for immunohistochemical and molecular genetic markers for predicting tumor response to neoadjuvant therapy in order to administer it for only potential responders.

CT-Guided 125I Brachytherapy in the Treatment of Distant Metastases in the Oral Cavity and Maxillofacial Region

We aimed to evaluate the feasibility and clinical effectiveness of CT-guided 125I brachytherapy for distant oral and maxillofacial metastases.

Management of Recurrent and Metastatic HPV-Positive Oropharyngeal Squamous Cell Carcinoma after Transoral Robotic Surgery.

Objective To describe management and oncologic outcomes for patients who develop locoregional recurrence (LRR) or distant metastasis (DM) following transoral robotic surgery for human papilloma virus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC). Study Design Case series with chart review. Setting Tertiary care referral center. Subjects and Methods A total of 286 patients with HPV-positive OPSCC who underwent transoral robotic surgery-based treatment from May 2007 to May 2015. Results Of 286 patients (12.2%), 35 met inclusion criteria. Of these, 19 experienced an LRR and 16 developed a DM; 2 patients with LRR subsequently developed DM. In those patients with an LRR, 79% had T1/T2 tumors, and 47% had N0/N1 nodal disease, compared with 75% and 6% in the DM group, respectively. The median time to LRR or DM was 0.6 years (interquartile range [IQR], 0.4-1.0) and 1.8 years (IQR, 1.0-2.1), respectively. Salvage treatment with intent to cure was attempted in 23 patients (16 LRR, 7 DM). The median time from LRR or DM to last follow-up for the 18 patients who were still alive after salvage was 1.9 years (IQR, 0.4-3.8; range, 7 days-6.2 years). Estimated cancer-specific survival rates at 3 years following intent-to-cure treatment were 63% (95% CI, 39-100; number still at risk, 5) in the LRR group and 100% (95% CI, 100-100; number still at risk, 2) in the DM group. Conclusion Overall, LRR and DM for HPV-positive OPSCC following transoral robotic surgery-based therapy are infrequent. In our subset of patients who underwent intent-to-cure treatment, cancer-specific survival rates were favorable. Therefore, aggressive salvage treatment for LRR and DM for HPV-positive OPSCC should be recommended for appropriate candidates.

THE PLACE OF SURGERY IN MODERN TREATMENT OF SKIN MELANOMA

Recent breakthroughs in the treatment of melanoma are associated with the systemic therapy by drugs of new classes, however, the place of surgery remains to be the main in the management of both localized and widespread melanoma. In this literature review, there are systematized the modern concepts of local excision of the primary tumor, the value of biopsy of sentinel lymph node and possibilities of surgical treatment of distant metastases of melanoma.

Pilot Therapeutic Protocol for the Treatment of Local Advanced Disease, such as the Generalized Peritoneal Carcinomatosis and for the Treatment of Distant Metastases in Human Malignant Neoplastic Disease-Targeting the Medium

Pilot Therapeutic Protocol for the Treatment of Local Advanced Disease, such as the Generalized Peritoneal Carcinomatosis and for the Treatment of Distant Metastases in Human Malignant Neoplastic Disease-Targeting the Medium

CT-guided 125I brachytherapy in the treatment of distant metastases in the oral cavity and maxillofacial region

PURPOSE: We aimed to evaluate the feasibility and clinical effectiveness of CT-guided 125I brachytherapy for distant oral and maxillofacial metastases. MATERIALS AND METHODS: We retrospectively analyzed 65 patients with 84 distant oral and maxillofacial metastases. Thirty-one patients with 38 lesions received 125I brachytherapy (group A) and 34 with 46 lesions received external beam radiotherapy (EBRT; group B). RESULTS: Median follow-up time was 16 months. The 3-, 6-, 12-, 18-, and 24-month local control rates for group A were 83.9%, 75.9%, 66.7%, 38.4%, and 25.0%, respectively; for group B they were 76.5%, 62.5%, 43.8%, 25.0%, and 0.0%, respectively (P<.05); the median local tumor progression-free survival times were 14 and 9 months, respectively. Group A had a better local tumor progression-free survival (LTPFS) relative to group B (P<.001; HR, 6.961 [95%CI, 2.109, 9.356]). Cox proportional hazards regression analysis indicated that 125I brachytherapy, tumor size, and primary pathological type were the independent factors affecting LTPFS. Additionally, 125I brachytherapy showed better performance in relieving patient clinical symptoms relative to EBRT (P<.05). Group A also had fewer complications than group B, especially regarding grade 3/4 complications according to Radiation Therapy Oncology Group grading criteria. Mean overall survival times in groups A and B were 17.1 and 14.8 months, respectively. CONCLUSION: CT-guided 125I brachytherapy is feasible and safe for distant oral and maxillofacial metastases; it achieved a better local control rate, longer LTPFS and fewer complications without compromising overall survival compared with EBRT.

Abstract 4563: Role of ezrin in PKA dependent colorectal cancer cell fate

Abstract Introduction: Metastasis is the main cause of cancer related death in CRC. However, the molecular basis of CRC metastasis is poorly understood. Ezrin is a known cAMP dependent AKAP. We have found ezrin hyperphosphorylation at T567 is critical for CRC cell survival. In this study we evaluated the dependency of PKA activation with ezrin phosphorylation at T567 on its downstream cell survival mechanisms. Methods: Small molecule ezrin kinase inhibitor NSC668394 was used to test the effect of inhibition of ezrinT567 phosphorylation on PKA activation and its downstream cell survival signaling. A genetic knockdown approach was utilized to further confirm the result. In another approach, growth factor mediated activation of ezrin T567 phosphorylation was performed and ezrin/PKA signaling was then analyzed for its downstream cell survival effects. To further confirm the findings ezrin phospho-mimetic (T567D) and phospho-deficient (T567A) mutants were generated through site directed mutation approaches. Results: We demonstrated that dephosphorylation of ezrin at T567 activates PKA in a cAMP independent manner and leads to CRC cell death through inhibition of XIAP and survivin. Moreover, the stable knockdown of ezrin showed similar result. Interestingly, ligand mediated ezrin hyperphosphorylation at T567 has the opposite effect in which there is cAMP dependent PKA activation leading to CRC survival through upregulation of XIAP and survivin. This was further confirmed with ezrin T567 phospho-mimetic and phospho-deficient mutants which demonstrate PKA activation by cAMP dependent and independent mechanisms respectively leading to different CRC cell fates. Therefore, ezrin signaling demonstrated two opposing pathways in which both requires activation of PKA and yet result in different CRC cell fates by regulating XIAP and survivin expression. Conclusions: Two different ezrin signaling dependent pathways were identified which are dependent on the same enzymatic activity but with opposite effects on CRC cell fates. Therefore, ezrin might be a novel target that could be utilized for the development of new therapeutic strategies and further understanding the mechanism of ezrin/cAMP-PKA activation and its role in CRC cell survival could have potential impact for treatment of distant metastasis in CRC. Citation Format: Premila Leiphrakpam, Michael G. Brattain. Role of ezrin in PKA dependent colorectal cancer cell fate. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4563.

Imaging of metastases from breast cancer to uncommon sites: a pictorial review.

There are three types of breast cancer recurrence which can occur after initial treatment: local, regional, and distant. Distant metastases are more frequent than local and regional recurrences. It usually occurs several years after the primary breast cancer, although it is sometimes diagnosed at the same time as the primary breast cancer. Although the common distant metastases are bone, lung and liver, breast cancer has the potential to metastasize to almost any region of the body. Early detection and treatment of distant metastases improves the prognosis, therefore radiologists and clinicians should recognize the possibility of metastasis from breast cancer and grasp the imaging characteristics. In this report, we demonstrate the imaging characteristics of metastases from breast cancer to uncommon sites.

The role of surgery in the treatment of distant metastases of skin melanomar

The choice of tactics in the treatment of one of the most common types of cancer skin- melanomy- is currently an urgent task facing the cancer community. High activity of local growth and regional metastasis of melanoma, its capacity for dissemination and multiple distant metastases make this task extremely important factor, largely determining the course and outcome of disease. Metastatic melanoma skin requires complex treatment, one of whose components is the surgical method. This article analyzes the use of surgical treatment of distant metastases of melanoma, depending on the location, quantity and rate of growth, the nature and effectiveness of previous treatment, the patient’s general condition. The authors have shown the prospects of application of surgical treatment in the radical treatment of patients with distant metastases of melanoma, the effectiveness of this method in the palliative treatment of metastatic melanoma and important role in the treatment of distant metastases of melanoma in combination with other treatments.

Predictive factors for long-term survival in head and neck squamous cell carcinoma patients with distant metastasis after initial definitive treatment.

Distant metastasis (DM) of head and neck squamous cell carcinoma (HNSCC) is not common but remains a substantial problem. Here, we evaluated factors predictive of long-term survival in HNSCC patients presenting with DM after initial definitive treatment. The medical records of patients with HNSCC who underwent definitive treatment between 2006 and 2011 were reviewed. Univariate and multivariate analyses were performed to identify clinicopathological factors associated with long-term survival after DM. Of 779 HNSCC patients, 98 (12.6 %) had DM after completion of definitive treatment, with a median time to DM of 15 months (range 1-87 months). Overall survival (OS) rates at 1 and 2 years after DM were 43.1 and 20.5 %, respectively. In multivariate analysis, hypoalbuminemia (P < 0.001, hazard ratio [HR] 3.45, 95 % confidence interval [CI] 2.01-5.92), prior or simultaneous locoregional failure events (P < 0.001, HR 2.36, 95 % CI 1.47-3.79), multisite DM (P = 0.001, HR 2.30, 95 % CI 1.42-3.72), and no salvage treatment for DM (P = 0.003, HR 2.19, 95 % CI 1.32-3.64) were independent predictors of OS after the development of DM. Seventeen (18 %) patients survived >2 years. Patients who did not have any of these risk factors had the most favorable outcomes, with a 2-year survival of 100 %. In the absence of risk factors, long-term survival can be achieved despite the development of DM after definitive treatment.

Treatment of distant metastases from follicular cell-derived thyroid cancer.

Distant metastases from thyroid cancer of follicular origin are uncommon. Treatment includes levothyroxine administration at suppressive doses, focal treatment modalities with surgery, external radiation therapy and thermal ablation, and radioiodine in patients with uptake of 131I in their metastases. Two thirds of distant metastases will become refractory to radioiodine at some point, and when there is a significant tumor burden and documented progression on imaging, a treatment with a kinase inhibitor may provide benefits.

Follicular thyroid carcinoma with distant metastasis: outcome and prognostic factor

Follicular thyroid carcinoma (FTC) usually has a good prognosis unless there is distant metastasis (DM). In this retrospective study we evaluated the outcome of FTC patients with DM and attempted to identify prognostic factors. The subjects of this study were the 106 of FTC patients who underwent thyroidectomy at our hospital between 1989 and 2010 who had been diagnosed with DM at presentation or had developed DM after the initial surgery. Their cumulative cause-specific survival (CSS) rate from diagnosis of DM to date of last follow-up was calculated by the Kaplan-Meier method. Prognostic factors were identified by univariate analysis (the log-rank test) and multivariate analysis (Cox's proportional hazards model). The site of the DM was the lung in 36 patients, bone in 33 patients, both lung and bone in 28 patients and other sites in 9 patients. During the follow-up period, 22 patients died of their disease. The DMs were treated by radioactive iodine (RI) therapy in 80 patients, by surgical treatment in 36 patients and by external beam radiation therapy (EBRT) in 27 patients. The CSS rates at 5, 10, and 15 years after the first DM was diagnosed were 82.2%, 63.8%, and 23.9%, respectively. Univariate analyses and multivariate analysis identified age at diagnosis of DM and primary tumor size as significant factors related to CSS. In this study, we could not show RI therapy, EBRT or surgical treatment for DM had an impact on the outcome.

Abstract B260: Wnt signaling, triple-negative breast cancer, and green tea.

Abstract Background and Goals: Triple negative breast cancer (TNBC) represents 15-20% of sporadic breast cancers, lacks ER, PR, and HER2 overexpression - and thus has no targeted treatment options. TNBC is a clinically challenging subtype with exceptionally poor prognosis, high recurrence and metastases and currently represents an unmet medical need. A critical aspect to improving the outcome for TNBC and other breast cancer patients is the prevention and/or treatment of distant metastases, especially to brain. Another major limitation of TNBC treatment is that most current drugs do not cross the blood-brain barrier to target fatal brain metastases, so novel therapeutic approaches are urgently needed. Results: TNBC have a Wnt signaling etiology and our recent work shows that HBP1 (a transcriptional repressor that suppresses Wnt signaling) was decreased in TNBC. Specifically, we showed that the HBP1 gene was mutated or reduced in invasive breast cancers. The under-expression of two Wnt pathways inhibitors (SFRP1 and HBP1) predicted an exceptionally poor prognosis. We sought to identify new therapeutic strategies aimed at TNBC and at decreasing Wnt signaling. Here, we investigated a combined regimen of the green tea polyphenol epigallocatechin gallate (EGCG) and of decitabine (DAC) that we reasoned might be effective at elevating SFRP1 and HBP1 to reverse a poor prognosis. We reported that EGCG decreased Wnt signaling in vitro by elevating HBP1. EGCG is in numerous clinical trials for breast and other cancers. Decitabine is an inhibitor of DNA methylation and is FDA-approved for hematologic malignancies. Thus, new pre-clinical studies have excellent potential to re-purpose existing drugs for TNBC. The combined regimen of EGCG/DAC significantly reduced TNBC tumorigenesis in two orthotopic TNBC tumor xenograft models (MDA-MB231 and Sum149). The inhibition by EGCG/DAC treatment correlated with reduced Wnt signaling and with the elevated SFRP1 and HBP1 gene expression. Importantly, a stable knockdown of either HBP1 or SFRP1 resulted in larger TNBC tumors that were now refractory to EGCG/DAC treatment. These data suggests that the decreased Wnt signaling and elevation of HBP1 or SFRP1 were critical factors to the efficacy of EGCG/DAC. Finally, EGCG/DAC treatment was effective at reducing brain metastases initiated from the mammary orthotopic site in a variant MDA-MB231TNBC tumor model. Conclusions: Our studies indicated that a combined regimen of EGCG and DAC decreased Wnt signaling and reduced TNBC tumorigenesis and resulting brain metastases in pre-clinical models. Thus, EGCG/DAC appears to uniquely cross the blood-brain barrier to reduce the otherwise fatal brain metastases, likely by reducing Wnt signalling. Together, EGCG/DAC may be an excellent therapeutic combination for clinical trials aimed at improving TNBC patient outcomes. (Supported by NIH, AICR, the Komen Foundation, and DOD to ASY, GES, and JB. MC was supported by NIH Hematology-Oncology Training Grant to Tufts Medical Center). Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B260. Citation Format: Amy S. Yee, Kurtz Eric Paulson, Maricel Castaner, Helen Uong, Nora Minerva, Kai Wang, Kelsey Gilchrist, Maria Choi, Gail E. Sonenshein, Jim Baleja. Wnt signaling, triple-negative breast cancer, and green tea. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B260.