Purpose: To compare overall survival in high-risk patients with primary uveal melanoma who received adjuvant sunitinib with institutional controls. Design: Retrospective cohort. Participants: Selection criteria were (1) monosomy 3 and 8q amplification by cytogenetic or DecisionDx-UM Class 2 and (2) monosomy 3 and large tumor size (T3-4 by American Joint Committee on Cancer classification). Exclusion criteria were date of diagnosis before 2007 or after 2013 and age < 18 years. Methods: A cohort of patients who intended to receive adjuvant sunitinib for 6 months was compared with institutional historical controls with the same risk factors. Kaplane-Meier and Cox proportional hazards models were used to analyze the outcome. Propensity score was used to adjust for nonrandom assignment to sunitinib. Main Outcome Measures: Overall survival. Results: From the Wills Eye Hospital Oncology Service Uveal Melanoma Cytogenetic Database (N = 1172), 128 patients fulfilled the selection and exclusion criteria. Median follow-up was 52.7 months (range, 0.26e108 months). A total of 54 patients received sunitinib. Their median age was 56 years (range, 29-81 years), and 48% were men. A total of 74 historical controls in the same risk category were identified. Their median age was 62 years (21-80 years), and 48% were men. Patients in the sunitinib group had worse cytogenetic or molecular features (monosomy 3 and 8q amplification or class 2 87% vs. 57%; P < 0.001), had smaller tumor sizes (T3-4 56% vs. 83%; P = 0.001), and were younger. There were 51 deaths, 14 (26%) in the sunitinib group and 37 (50%) in the control group. In the univariate analysis, the sunitinib group had longer overall survival (hazard ratio, 0.53; 95% confidence interval, 0.29-0.99; P - 0.041). In multivariate Cox regression analysis, interaction between use of sunitinib and age as a dichotomous variable was highly significant (P = 0.003). The following variables were statistically associated with prediction of overall survival: cytogenetic/ molecular status (P = 0.015), T-size category (P - 0.022), gender (P - 0.040), and adjuvant sunitinib in patients aged < 60 years (P - 0.004). Results were confirmed by propensity score analysis. Conclusions: In this retrospective study, the use of sunitinib in the adjuvant setting was associated with better overall survival. (C) 2017 by the American Academy of Ophthalmology

Colon cancer is a leading cause of cancer related mortality. Until very recently the only existing options that medical oncologists had to treat metastatic colon cancer were a combination of chemotherapy, anti-EGFR and anti-angiogenic agents. We currently have the first proof that immune therapies could be an effective approach to battle colorectal cancers that carry a mismatch repair machinery deficient phenotype. It is expected that as our knowledge of the different mechanisms of immune-resistance grows, this therapeutic modality might soon be applicable to all patients. However, due to the continuous increase in the cost of oncological drugs, some treatment overheads may soon become prohibitive for many. In this review we will examine the current evidence related to this topic with the objective to provide the reader with concise but practical information about the potential role of immunotherapy in CRC.

The combination of immune checkpoint inhibitors ipilimumab and nivolumab has been recently been FDA approved for first line treatment of unresectable and metastatic BRAF wild type melanoma. The approval came following the impressive results of the CheckMate 067, where the combination of ipilimumab and nivolumab appeared to outperform each as a single agent in regards to response rate and progression free survival. Though we await final overall survival data, the combination will likely be adapted by many oncologists and integrated into the ever changing melanoma treatment algorithm. In this article we aim to summarize the data leading up to the recent FDA approval and publication by Larkin et al. that presents the results from the CheckMate 067 trial. We will also further explore the feasibility, challenges, and applicability of combination immune checkpoint inhibitor therapy.

Lung cancer is a major public health problem worldwide and the leading cause of cancerrelated mortality in developed countries. Significant advances have been made especially with the discovery of targeted agents. However, only a small proportion of patients carry activating mutations; until recently conventional chemotherapy and angiogenesis inhibitors were the preferred treatment for the vast majority of patients. Now, the successful experience of anti-PD-1 agents may have opened the door to a novel and previously unexplored dimension in the treatment of lung cancer: immunotherapy. In this mini-review we will discuss the current applications and future consequences related this topic, paying special attention to the clinical studies that constitute the scientific evidence to supports its use.

Metastatic melanoma represents an aggressive tumor with overall poor prognosis. Targeted agents and immunotherapy have become the standard of care. Approximately 50-60 % of melanomas harbor BRAF mutations. Vemurafenib and dabrafenib are BRAF inhibitors, a group of drugs that will certainly expand, and obtained FDA approval after showing increased response rate (ORR), progression free survival (PFS) and overall survival (OS) when compared to chemotherapy. Trametinib was the first MEK inhibitor approved as single agent in 2013, but when combined with BRAF inhibition, results are even improved. Immunotherapy with IL-2 received approval in 1999 based on phase II data mainly due to its potentially long term response but proved to be quite toxic. Check point inhibitors can block CTLA-4 (ipilimumab) or PD-1 (nivolumab and pembrolizumab) thus interrupting the brakes that stop the immune system against malignant cells. Long duration of response resembles that of IL-2 but with more acceptable toxicity. Given the complexity of this rapidly evolving field we will try to provide the reader with a summary of the key clinical aspects derived from the use of these new agents in daily practice. Keywords: Melanoma, immune therapy, targeted agents, anti-CTL-4, anti-PD-1, BRAF inhibitors, MEK inhibitors.

Mucosal melanomas are rare and associated with poor prognosis. Importantly, primary mucosal melanoma is clinically and biologically different from cutaneous melanoma. Complete surgical resection is the standard of care treatment for localized melanoma. However, given the usual anatomic locations where mucosal melanomas arise, including head and neck and anorectal mucosa, resection with optimal margins is challenging and post-surgical local recurrences are not uncommon. Adjuvant radiation therapy diminishes local recurrence rate but does not seem to improve overall survival in multiple retrospective series. Although significant progress has been achieved in term of systemic treatment for patients with metastatic cutaneous and uveal melanomas, there are still no groundbreaking results for patients with mucosal melanoma. In that sense, metastatic mucosal melanoma is indeed an orphan disease. Chemotherapy in general has shown poor results. The efficacy of ipilimumab is not established yet. Targeted agents, such as imatinib or sunitinib could be a promising treatment option for patients with KIT mutations. In this review we will try to update the reader with some key points of this rare disease, especially those related to its particular clinical features, some recently discovered and potential molecular targets as well as the small number of clinical trials that support a rational approach to this disease. Keywords: Mucosal melanoma, KIT, imatinib, sunitinib, ipilimumab.

Treatment of advanced and metastatic melanoma is a rapidly changing field. Over the past 10 years, there have been six new drugs approved by the FDA for the treatment of metastatic melanoma. These approved drugs include a number of immune checkpoint inhibitors and MAPK-pathway-targeted therapies. The discovery of such agents as ipilimumab, pembrolizumab, nivolumab, vemurafenib, trametininb and dabrafenib have revolutionized the way in which melanoma in managed. While these agents have succeeded in both early and later phase clinical trials, a large number of investigational therapies have not yet been developed or researched past Phase I clinical studies. Furthermore, there are dozens of potential agents in Phase I and Phase II clinical development that appear promising and are currently being explored. The field currently aims to determine the optimal sequence and combination of these therapies to best overcome such setbacks as toxicity and resistance and build upon the successes previously seen.

Treatment of advanced and metastatic melanoma is a rapidly changing field. Over the past 10 years, there have been six new drugs approved by the FDA for the treatment of metastatic melanoma. These approved drugs include a number of immune checkpoint inhibitors and MAPK-pathway-targeted therapies. The discovery of such agents as ipilimumab, pembrolizumab, nivolumab, vemurafenib, trametininb and dabrafenib have revolutionized the way in which melanoma in managed. While these agents have succeeded in both early and later phase clinical trials, a large number of investigational therapies have not yet been developed or researched past Phase I clinical studies. Furthermore, there are dozens of potential agents in Phase I and Phase II clinical development that appear promising and are currently being explored. The field currently aims to determine the optimal sequence and combination of these therapies to best overcome such setbacks as toxicity and resistance and build upon the successes previously seen.

Purpose: To investigate the effects of immunoembolization with granulocyte macrophage colony-stimulating factor (GM-CSF) in patients With uveal melanoma (UM) with liver-only metastasis.Materials and Methods: In this double-blind phase II clinical trial, patients were randomized to undergo immunoembolization or bland embolization (BE). Lobar treatment was performed with GM-CSF or nottual saline solution mixed with ethiodized oil followed by embolization with gelatin sponge emulsified with iodinated contrast medium. Fifty-two patients (immunoembolization, n = 25; BE, n 27) were enrolled. Response was assessed after every two treatments. The primary endpoint was overall response rate (ORR) of liver metastases. Progression-free survival (PFS); overall survival (OS), and immunologic responses were secondary endpoints.Results: There were five partial responses in the immutoembolization group (ORR, 21.2%; 90% confidence interval [CI], 10.3%- 30.5%) and three in the BE group (ORR, 16.7%; 90% CI, 6.3%-26.9%). Stable disease Was seen in 12 patients in the immunoembolization group and 19 in the BE group. OS times were 21.5 months (95% CI, 18.5-24.8 mo) with immunoembolization and 17.2 months (95% CI, 11.9-22.4 mo) with BE. The degree of proinflammatory cytokine production was more robust after immunoembolization and correlated with time to "systemic" extrahepatic progression. In the immunoembolization group, interleukin (IL)-6 levels at 1 hour (P =.001) and IL-8 levels at. 18 hours after the procedure (P <.001) were Significant predictors of longer systemic PFS. Moreover, a dose response pattern was evident between posttreatment serum cytokine concentrations and systemic PFS.Conclusions: Immunoembolization induced more robust inflammatory responses, which correlated with the delayed progression of extrahepatic systemic metastases.

Between 20-25% of all breast cancers are diagnosed in patients younger than 50 years of age, most of whom are still premenopausal. Currently, tamoxifen is considered the standard of care for adjuvant treatment in these cases. However, in postmenopausal women, aromatase inhibitors (AIs) are a better choice. Given the superiority of AIs over tamoxifen in postmenopausal women, multiple investigators explored the potential role of AIs in premenopausal patients receiving ovarian suppression. Until very recently, available data derived from the ABCSG-12 clinical trial argued against the combination of AIs and ovarian suppression. This idea, however, may have changed with the release of the combined analysis of two clinical trials: SOFT and TEXT which evaluated the use of ovarian suppression in combination therapy. Clinicians will soon reconsider the possibility of using this strategy for premenopausal patients. Given the availability of this new data this review will analyze the consequences derived from this study, contextualize this new information within the vast available literature of anti-hormonal therapy, and discuss potential arguments in favor of and against the use of this approach.

Triple negative breast cancer (TNBC) is more prevalent in younger patients and those carrying BRCA mutations. Although the incidence of breast cancer in general has dropped during the last years, TNBC has shown a relative increase. It is recognized as a breast cancer subtype with a high risk of tumor relapse and mortality. However, patients who achieve pathological complete response (pCR) with the use of neoadjuvant treatments have better prognosis and may attain cure. The lack of effective targeted therapies makes the use of conventional chemotherapy the only alternative available to fight this disease. Since many TNBCs share at least some phenotypic characteristics with germline BRCA-mutated tumors (BRCAness) cross-linking agents, such platinum salts, are particularly useful. Recently, two randomized phase 2 clinical trials support this presumption. However, improvement in pCR rates does not come free of toxicity. Given the potential change in practice associated with the generalized use of carboplatin in the neoadjuvant setting for TNBC patients, the aim of this review is to discuss the benefits as well as the potential drawbacks linked with the use of this strategy.

e20046 Background: Patients with high-risk uveal melanoma have up to 70% chances of developing distant metastases. There is no US FDA-approved adjuvant treatment able to reduce that risk and prolong survival. We aimed to compare overall survival (OS) in high-risk patients who received adjuvant sunitinib with institutional historical controls. Methods: A cohort of patients who received adjuvant sunitinib for at least 6 months was compared with institutional historical controls patients who had similar demographic as well as high-risk features, including: A) – monosomy-3 and 8q amplification (M3-8qA) in the primary tumor by cytogenetic analysis or class II by molecular analysis; B) – monosomy-3 and large tumor size (T3 or 4 by AJCC TNM). Patients in the control group were diagnosed during the same period of time (2007 - 2013) but did not receive any adjuvant treatment. Primary endpoint was OS and was evaluated using Kaplan-Meier survival curves and Cox proportional hazards model. Results: A total of 105 Caucasian patients were included; median follow-up was 34.5 months (range 0.25 – 82 months). There were 50 patients who received sunitinib. Median age was 55 (29 – 69 years old) and 46% were males. Fifty five historical controls, with the same high risk factors, were found in our database. The median age was 58 (21 – 70 years old) and 51% were males. Patients in the sunitinib group had worse cytogenetic features (M3-8qA 78% vs. 47%; P = .001) but smaller tumor sizes (T3-4 56% vs. 80%; P = .01). There were a total of 19 deaths; 3 (6%) in the sunitinib and 16 (29%) in the control group, respectively. Estimated 5-year survival rate was 91% (95% CI: 82 –100%) in the sunitinib group and 61% (95% CI: 47 – 79%) in the non-adjuvant control group. OS was significantly longer in the sunitinib group (HR = 0.267, 95% CI: 0.077 – 0.925, P = 0.037) and this remained significant after being individually adjusted by cytogenetic status, tumor size, age and gender. No meaningful interactions were detected. Conclusions: In this retrospective study, the use of sunitinib in the adjuvant setting was associated with better OS. Current ongoing clinical trials are testing this hypothesis.

Breast cancer continues to be a major health problem. Both patients and clinicians demand faster access to drugs that could result in better outcomes. In part motivated by this necessity, there has been a change in the dominant paradigm regarding how drugs become approved. Complete pathological response (pCR), understood as the absence of remanent and viable tumor after a neoadjuvant treatment, is now considered by a large proportion of the medical community as a valid surrogate. The presumption is that patients achieving pCR are less likely to develop tumor recurrence. Consequently, if a drug can improve the number of patients achieving pCR it could then obtain approval by the regulatory agencies. Pertuzumab, an anti-HER- 2 monoclonal antibody, was granted accelerated approval based on this principle. The unprecedented approval of this drug is now an example that can help us to understand the advantages but also the potential risks associated with this new approach. In this review, we will discuss the results of the two clinical trials leading to the FDA-approval of pertuzumab in the neo-adjuvant setting. We will also analyze the outcomes from long term follow up of two important neoadjuvant clinical trials, the NeoALTTO and the NOAH studies. These last ones had provided further insights regarding the magnitude, the quality as well as some limitations of the relationship between pCR and harder endpoints such as event-free or overall survival. It seems evident that the acknowledgement of pCR as a potential surrogate endpoint represents an important step in the right direction. However, it still remains controversial whether this is applicable to all subtypes of breast cancers. Additional investigations may be necessary to safely generalize this concept.

Uveal melanoma represents the most common primary intraocular tumor in adults. However, it remains a relatively infrequent malignancy where large clinical trials are difficult to accomplish. However, during the last couple of years we have witnessed an unprecedented expansion of our understanding of this disease. New genetic and molecular pathways were found to play key roles in the development of uveal melanoma and they represent potential targets for future therapies. At the same time there were some improvements in the delineation of prognostic features as well as treatment options for metastatic disease, with both liver-directed strategies as well as targeted agents. In this review we will try to summarize and update the reader with the most relevant information in terms of its pathogenesis, clinical presentation, prognostic factors– cytogenetic and genetic profiling –, state of the art management of liver only as well as systemic metastatic disease. Finally we will also discuss current ongoing clinical trials as well as future directions in terms of research and clinical investigation. Keywords: Uveal melanoma, immune therapy, targeted agents, BAP1, GNAQ, GNA11, chemoembolization, immunoembolization, selumetinib and sunitinib.

During the last decade we have witnessed an unprecedented outburst of new treatment approaches for the management of metastatic colon cancer.Anti-angiogenic drugs, epidermal growth factor receptor blockers and multi-kinase inhibitors have all resulted in small but consistent improvement in clinical outcomes.However, this progress has paradoxically leaded us into new challenges.In many cases the clinical development was done in parallel and the lack of head-to-head comparison evolved into circumstances where several valid new "standards of care" are available.Even though desirable in essence, the availability of many options as well as different possible combinations frequently leaves the busy clinician in the difficult situation of having to choose between one or the other, sometimes without solid evidence to support each decision.In addition, progress never stops and new agents are continuously tested.For these reason this review will try to summarize all the clinical trials that constitute the theoretical framework that support our daily practice but will also procure the reader with rational answers to common clinical dilemmas by critically appraising the current literature.Lastly, we will provide with a compilation of promising new agents that may soon become our next line of defense against this deadly disease.