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Background The efficacy of FOLFIRINOX for metastatic pancreatic cancer has led to its use in patients with earlier stages of disease. This study retrospectively analyzed a cohort of patients with locally-advanced pancreatic cancer (LAPC) treated with FOLFIRINOX. Methods Between 2008 and 2013, 51 treatment-naive patients with LAPC at a single institution received first-line FOLFIRINOX with neoadjuvant intent, at the full dose as described in the PRODIGE 4/ACCORD 11 study. Combined chemoradiation was administered for those who remained unresectable after maximum response to chemotherapy. The primary outcome measure was overall survival (OS), and secondary outcomes were progression-free survival (PFS) and margin-negative (R0) resection rate, and toxicity profile. Results A total of 429 cycles of FOLFIRINOX were given with a median of 8 cycles (range 2–29) per patient; 66% of cycles were full dose. After chemotherapy, 27 (53%) received chemoradiation. The median OS was 35.4 months (95% CI 25.8–45). Ten (4 borderline resectable and 6 unresectable) patients had successful R0 resections; those who had R0 resections had a significantly longer survival than those who did not (3-year OS rate 67% versus 21%, log rank p = 0.042). Increasing number of full-dose cycles was significantly associated with increased survival. The toxicity profile was similar to previous reports of this regimen. Conclusions FOLFIRINOX is feasible as neoadjuvant therapy for LAPC. Although the R0 resection rate was only 20%, the median OS of almost 3 years appears promising. Dose intensity and duration were associated with increased survival in this study, arguing against dose attenuated versions of this regimen.

Summary Background The oral AKT inhibitor ipatasertib is being investigated in cancers with a high prevalence of PI3K/AKT pathway activation, including triple-negative breast cancer. The LOTUS trial investigated the addition of ipatasertib to paclitaxel as first-line therapy for triple-negative breast cancer. Methods In this randomised, placebo-controlled, double-blind, phase 2 trial, women aged 18 years or older with measurable, inoperable, locally advanced or metastatic triple-negative breast cancer previously untreated with systemic therapy were recruited from 44 hospitals in South Korea, the USA, France, Spain, Taiwan, Singapore, Italy, and Belgium. Enrolled patients were randomly assigned (1:1) to receive intravenous paclitaxel 80 mg/m 2 (days 1, 8, 15) with either ipatasertib 400 mg or placebo once per day (days 1–21) every 28 days until disease progression or unacceptable toxicity. Randomisation was by stratified permuted blocks (block size of four) using an interactive web-response system with three stratification criteria: previous (neo)adjuvant therapy, chemotherapy-free interval, and tumour PTEN status. The co-primary endpoints were progression-free survival in the intention-to-treat population and progression-free survival in the PTEN-low (by immunohistochemistry) population. This ongoing trial is registered with ClinicalTrials.gov (NCT02162719). Findings Between Sept 2, 2014, and Feb 4, 2016, 166 patients were assessed for eligibility and 124 patients were enrolled and randomly assigned to paclitaxel plus ipatasertib (n=62) or paclitaxel plus placebo (n=62). Median follow-up was 10·4 months (IQR 6·5–14·1) in the ipatasertib group and 10·2 months (6·0–13·6) in the placebo group. Median progression-free survival in the intention-to-treat population was 6·2 months (95% CI 3·8–9·0) with ipatasertib versus 4·9 months (3·6–5·4) with placebo (stratified hazard ratio [HR] 0·60, 95% CI 0·37–0·98; p=0·037) and in the 48 patients with PTEN-low tumours, median progression-free survival was 6·2 months (95% CI 3·6–9·1) with ipatasertib versus 3·7 months (1·9–7·3) with placebo (stratified HR 0·59, 95% CI 0·26–1·32, p=0·18). The most common grade 3 or worse adverse events were diarrhoea (14 [23%] of 61 ipatasertib-treated patients vs none of 62 placebo-treated patients), neutrophil count decreased (five [8%] vs four [6%]), and neutropenia (six [10%] vs one [2%]). No colitis, grade 4 diarrhoea, or treatment-related deaths were reported with ipatasertib. One treatment-related death occurred in the placebo group. Serious adverse events were reported in 17 (28%) of 61 patients in the ipatasertib group and nine (15%) of 62 patients in the placebo group. Interpretation Progression-free survival was longer in patients who received ipatasertib than in those who received placebo. To our knowledge, these are the first results supporting AKT-targeted therapy for triple-negative breast cancer. Ipatasertib warrants further investigation for the treatment of triple-negative breast cancer. Funding F Hoffmann-La Roche.

Objective: To evaluate the effectiveness and tolerability of neoadjuvant chemotherapy with weekly paclitaxel in combination with weekly carboplatin area under curve 2 followed by anthracycline chemotherapy. Patients and methods: This is a retrospective review of electronic medical records of patients (N = 32) with stage 1c–III triple-negative breast cancer. Patients received neoadjuvant chemotherapy with paclitaxel 80 mg/m2 once per week for 12 weeks in combination with carboplatin area under curve 2 once per week for 12 weeks (wP + wCb), followed by a standard anthracycline regimen including either doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2 or 3 weeks, or epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks for four cycles with myeloid growth factor support. Results: Most patients (91%) received all 12 cycles of wP + wCb, and 88% received all four planned cycles of anthracycline chemotherapy. Of the patients, 84% completed all planned therapies. The complete pathologic response rate was 60%. In terms of hematologic toxicity, 96% of the patients experienced grade ≥3 leucopenia, 40% grade ≥3 anemia, and 15% grade ≥3 thrombocytopenia, and neutropenic fever was seen in 22% of the patients. Conclusion: The combination of neoadjuvant chemotherapy with wP + wCb before anthracycline chemotherapy can be tolerated by patients with triple-negative breast cancer. Complete pathologic response rates were comparable with those historically seen. Careful selection of patients is fundamental as this regimen is associated with a high incidence of hematologic toxicity. Keywords: Triple negative breast cancer, Neoadjuvant chemotherapy

The large knowledge learned in molecular biology specifically in the oncology field during the last ten years has resulted in fruitful results for the treatment of non-small cell lung cancer. The first pathway to be effectively targeted in lung cancer was the epidermal growth factor receptor. The acceptance of epidermal growth factor receptor mutation as a strong predictive biomarker in non-small cell lung carcinoma has encouraged the search for more targets. In 2011, regulatory entities granted conditional approval to an anaplastic lymphoma kinase inhibitor (crizotinib) based on an impressive overall response rate in previously treated non-small cell lung cancer patients whose tumors harbored EML4/ALK translocations. The landmark approval of crizotinib based on early promising clinical data highlights the remarkable success of molecular medicine in lung cancer therapeutics. The cumulative data developed after that approval has confirmed the appropriateness of this decision as recently reported phase III has now demonstrated. Unfortunately, resistance to this agent invariably develops and we now face the challenge of understanding several resistance pathways and overcoming them with new and more potent compounds. New agents in clinical development such as alectinib, LDK378, AP26113, and AUY922 have not only demonstrated promising activity in crizotinib resistant patients, but also crossing new pharmacokinetic boundaries in ALK inhibition as potent CNS penetration.

SUMMARY We know how important antiangiogenesis therapy can be in cancer treatment. However, it took some time before the first compound became approved. Currently, several agents are approved and used against cancer. Moreover, the possible number of clinical indications and agents that are in development is extraordinary. A lot of questions regarding angiogenesis in cancer still remain unanswered. One of the major weaknesses is the fact that most of the approved agents do not have a predictive or prognostic biomarker that can be used to tailor these novel agents in terms of inducing the best possible antitumor effect. Many of these new targeted agents inhibit several tumorigenesis pathways, but most of the time only one of these pathways is the main driver for cancer proliferation. In this article, we present the most current clinical information available in antiangiogenic therapy and the potential development in non-small-cell lung cancer.

Lung cancer research has incorporated molecular medicine into the management of this disease during the last 5 years. Several novel tumorigenesis pathways associated with lung cancer development and proliferation have been discovered and further developed as targets. The idea behind this is to deliver individualized therapy for each patient based on his/her tumor phenotype, which may involve the overexpression or lack of certain proteins, receptors, mutations and other factors. To date, many of these characteristics have been shown to have a potential role as prognostic or predictive biomarkers, with most of the available data being obtained from retrospective analyses, various laboratory platforms, and data sets used for comparison. However, well-designed prospective randomized clinical trials are underway to validate the significance and future role of these novel biomarkers, allowing us to sort out the best personalized management for an individual with lung cancer diagnosis. Nevertheless, one of these features, the EGF receptor (EGFR) gene mutation, has emerged as a prognostic and strongly predictive biomarker when EGFR inhibition is used as a therapy for tumors that harbor the mutation. Our article displays the most recently developed data related to this biomarker and what have we learned based on the analyses of clinical trials that have studied different agents in the clinical arena.

e15013Background: Analysis ofcell-free circulating tumor RNA (cfRNA) extracted from plasma of cancer patients (pts) provides a means of measuring dynamic changes in gene expression as well as level...

For many decades, the use of chemotherapy as second-line therapy in non-small-cell lung cancer relied upon disease progression. Several studies have shown that four to six cycles of chemotherapy administered as front-line therapy treatment offers a survival advantage to patients; however, further chemotherapy beyond this initial treatment was more associated with side effects and no benefit in survival. Until 2009, second-line treatment for lung cancer was well established for three therapeutic agents: docetaxel, pemetrexed and erlotinib. Currently, the timeframe to use these agents has been challenged by two large randomized clinical trials in which pemetrexed (JMEN trial) and erlotinib (Sequential Tarceva in Unresectable NSCLC [SATURN] trial) were used as 'maintenance' therapy and shown to impact progression-free survival and overall survival. This review focuses on the actual dilemma that medical oncologists face in clinical practice in terms of when and to whom maintenance therapy should be applied or if the 'watch and wait' approach prior to start second-line therapy is still advisable.

11550 Background: There is an unmet need to evaluate tumor response by other means than radiology tests. Changes in gene expression, allele-fractions of mutations, PDL-1 expression and levels of cell free DNA [DNA] or RNA [RNA] in plasma might be useful for monitoring disease state and predicting outcome to anti-tumoral therapy. Methods: We measured serial levels of plasma DNA/RNA in metastatic patients (pts) with NSCLC and breast cancers undergoing treatment and correlated them with response (CR/PR/SD/PD) seen by CT scans. We also monitored PD-L1 expression in NSCLC pts treated with immunotherapy. DNA/RNA were extracted from plasma. RNA was reverse transcribed with random primers to cDNA. Levels of DNA/RNA were determined by RT-qPCR. Results: 52 pts were enrolled (28 breast/24 NSCLC). Breast group: 39% (11/28) were Caucasian (NHW) and 36% (10/28) Hispanic (H). 20 pts completed first two cycles of therapy: 2 pts had PR and showed no change (NC) or decrease (DEC) in levels of DNA/RNA. 11pts achieved SD, 9 had NC levels of DNA/RNA. Pts with PD: 5/6 underwent significant increase (INC) in DNA/RNA levels. Overall, among breast pts, there was an 84% (16/19) agreement between response and levels of DNA/RNA. These were correlated with one another ( r = 0.7002, p< 0.0001). NSCLC group: 71% (16/24) were NHW and 25% (6/24) H. Non-SQCC were 87% (21/24). 20 pts had CT scans. One pt had PR with DEC levels of DNA/RNA. 10 pts achieved SD, all showed DEC or NC levels of DNA/RNA. 8 pts had PD, 6 of them had INC in DNA/RNA levels even 7 weeks prior to PD. Among NSCLC pts, there was a 90% (17/19) agreement in response and levels of DNA/RNA. These were correlated with one another ( r= 0.6231, p< 0.0001). In 5 pts PD-L1 expression remained stable when CT scans showed SD or PR. Conclusions: There is a strong correlation between clinical responses with changes in plasma levels of DNA/RNA in pts with NSCLC (90%) and breast cancer (84%). Some of these were documented weeks before imaging was done. cfRNA is as effective as cfDNA as predictive tool for response. Plasma PDL-1 expression is a new tool to monitor immunotherapy response.

PURPOSE OF REVIEW: This article reviews the most recent developments and implications in regard to isocitrate dehydrogenase mutations in chondrosarcoma, a disease in which currently available systemic therapies have proven inefficacious, with an emphasis on how disruption in normal cellular metabolism plays a role in oncogenesis. RECENT FINDINGS: The development of acquired isocitrate dehydrogenase-1/isocitrate dehydrogenase-2 mutations has been described in multiple tumors and more recently in chondrosarcomas. The impact of these mutations has been the focus of multiple research efforts during the last years, allowing us to better understand the impact of the mutation, including its interaction with other proteins, changes in expression of genes involved in tumor genesis, the oncogenic potential of 2-hydroxyglutarate, the impact on cellular proliferation and differentiation, and the influence on the epigenetic state of cells owing to changes in DNA and histone methylation patterns. New compounds targeting the mutation have been developed. SUMMARY: This mutation is the first of its kind described in chondrosarcoma, serving as an identifying marker of chondroid differentiation, and becoming the first molecular target with potential anticancer effect, translating into the development of therapies targeting these mutations currently being tested further in preclinical models and clinical trials.

The hedgehog (Hh) pathway is a critical regulator of vertebrate embryonic development and is involved in the function of processes such as stem cell maintenance and differentiation, tissue polarity and cell proliferation. Given how critical these functions are, it is not surprising that mutations in Hh pathway components are often implicated in the tumorigenesis of a variety of human cancers. Promotion of tumor growth has recently been shown by activated Hh signaling in the tumor itself, as well as by pathway activation within surrounding cells comprising the tumor microenvironment. Targeted disruption of various Hh pathway proteins has been successfully employed as an anticancer strategy with several synthetic Hh antagonists now available. Here, the molecular basis of Hh signaling, the therapeutic rationales for targeting this pathway and the current status of Hh pathway inhibitors in the clinic are reviewed.

Thyroid cancer incidence continues to increase, remaining the most common endocrine malignancy. The need for effective systemic therapies combined with high incidence of driver mutations and overexpression of molecular pathways make refractory thyroid cancer an ideal candidate for treatment with novel agents. Multikinase inhibitors have caused a paradigm shift in the treatment of patients with advanced iodine-refractory thyroid cancer. These agents have shown to be the most effective systemic therapy for this disease not only causing prolonged responses but also improving survival. The activity of these agents inhibiting several pathways simultaneously, such as rearranged during transfection protooncogene, mitogen-activated protein kinase, and angiogenesis, can probably explain the effectiveness in controlling the progression of this malignancy. Several of these agents are currently on clinical studies in patients with differentiated and medullary thyroid cancer and most of them are showing promising clinical activity. With the approval of vandetanib for the treatment of medullary thyroid cancer, a new era in the management of this disease has begun. The molecular rationale for the use of these drugs for thyroid cancer is discussed as well as their promising clinical results.

There has not been a more exciting time in lung pathology than now. Because of new developments in tumor biology research and molecular pathology, the entire treatment algorithm of non small cell lung cancer has completely changed. Not too long ago, we still considered “carcinoma compatible with non small cell lung cancer” as a valid histopathologic diagnosis, good enough to start a patient on chemotherapy. Advances in pathology such as immunohistochemistry, gene expression profile, and the implementation of laboratory techniques like polymerase chain reaction, fluorescent in situ hybridization, and others have moved forward this field not only to identify a more accurate classification of this disease but also to identify new tumorigenesis pathways or active mutations which could serve as biomarkers with predictive and/or prognostic power to tailor our therapeutic agents. The fact that pathologists can accurately determine tumor histology as an adenocarcinoma or squamous cell carcinoma has a tremendous impact in the treatment selection. To date, the histologic subtype of non small cell lung cancer is the first step in customization of lung cancer therapy allowing us to choose among several chemotherapeutic agents. However, tumor biology has shown to be a stronger tool to personalized medicine, and pathology plays a crucial role in developing and improving these novel techniques. In this article, we will review the well established and most promising gene abnormalities as well as upregulated pathways recently found in lung cancer patients with the goal to use them to better classify these tumors and to identify new treatments for this disease.

Lung cancer therapy with current available chemotherapeutic agents is mainly palliative. For these and other reasons there is now a great interest to find targeted therapies that can be effective not only palliating lung cancer or decreasing treatment-related toxicity, but also giving hope to cure these patients. It is already well known that the ubiquitin-proteasome system like other cellular pathways is critical for the proliferation and survival of cancer cells; thus, proteosome inhibition has become a very attractive anticancer therapy. There are several phase I and phase II clinical trials now in non-small cell lung cancer and small cell lung cancer using this potential target. Most of the trials use bortezomib in combination with chemotherapeutic agents. This paper tends to make a state-of-the-art review based on the available literature regarding the use of bortezomib as a single agent or in combination with chemotherapy in patients with lung cancer.

1048 Background: A preferred NAC regimen for HER2-negative BC is DDAC for 4 cycles followed by 12 weeks of T. RDI of 1 indicates that all intended doses are given at the scheduled interval. While l...

Aim: In a retrospective study of 18 pts with unresectable (UR) or borderline resectable (BR) LAPC, neoadjuvant therapy with FOLFIRINOX with or without subsequent chemoradiation (CCRT) resulted in an R0 resection rate (RR) of 44% (Hosein et al, BMC Cancer 2012). The reported 1-year progression-free survival (PFS) was 83 % and the 1-year overall survival (OS) was 100 %. Toxicity profile was tolerable. In order to confirm these preliminary results, we analyzed a large cohort of pts treated in a similar fashion with mature follow-up. Methods: Between 2008 and 2013, 51 treatment-naive pts with LAPC were treated with first-line FOLFIRINOX with neoadjuvant intent. Pts were categorized as BR or UR using the NCCN criteria. Pts received FOLFIRINOX chemotherapy (at the full dose as described in the ACCORD-11 trial) until maximum response or tolerability, and then underwent surgery if their imaging suggested resectability. Pts then received CCRT if they were still UR or BR after FOLFIRINOX. The end points of this retrospective analysis were OS, PFS, R0 RR and toxicity profile. Results: A total of 429 cycles were given with a median of 8 (range 2-29); 27 (53%) went on to receive CCRT. After a median follow-up of 17 mo (range 2-56), the Kaplan-Meier median OS was 35 mo (95% CI 26-45), the 3-yr OS rate was 42% and the median PFS was 14 mo (95% CI 11 – 16). By imaging criteria, 13 (26%) were converted to resectability and 10 (4 BR and 6 UR) of these had successful R0 resections. Pts who had R0 resections had a significantly longer survival than pts who did not (3-yr OS rate 67% vs 21%, log rank p = 0.042). Grade 1&2/3&4 chemotherapy-related toxicities were neutropenia (39%/20%), neutropenic fever (0%/12%), thrombocytopenia (53%/16%), anemia (63%/10%), fatigue (76%/6%), nausea (57%/4%) vomiting (22%/4%), neuropathy (53%/4%) and diarrhea (37%/10%). Conclusions: FOLFIRINOX followed by chemoradiotherapy is feasible as neoadjuvant therapy in patients with unresectable LAPC. Although the resection rate was only 20%, the median OS of almost 3 years is appreciably longer than historical survival rates for this population. Prospective controlled trials testing this algorithm in LAPC are ongoing. Disclosure: All authors have declared no conflicts of interest.

e15197 Background: Although no prospective data are available for the use of FOLFIRINOX in LAPC, in a retrospective study of 18 pts with UR or BR LAPC, neoadjuvant therapy with FOLFIRINOX with or w...

e17564 Background: Pemetrexed (Pem) is commonly used as frontline +/- maintenance chemotherapy (MCTx) in patients (pts) with advanced non-squamous (ns) NSCLC. Due to Pem toxicity profile, pts can remain on therapy (tx) for prolonged periods of time. We are reporting an increase in the erythrocyte MCV without apparent clinical significance. Methods: 54 ns-NSCLC pts previously treated with Pem-based tx either as initial treatment followed by MCTx Pem alone or Pem/bevacizumab (Bev) or second line tx were analyzed for elevation of MCV from a normal baseline (80-98 fl). All pts were on daily folic acid (FA) and vitamin B12 (vitB12) supplementation at least every 3 cycles of Pem. Co-factors such as FA, vitB12, homocysteine (Hom), and methylmalonic acid (MMA) were measured on those pts still alive, on active MCTx, and available who had high MCV. Results: 54 pts were evaluable; 50 pts received platinum/Pem/Bev triplet as initial tx followed by Pem/Bev or Pem MCTx and 2 pts with Pem/Bev and Pem alone as second line, respectively. Median age: 63 yrs old (34-84); 32 pts were male and 31 pts (56%) Hispanic. 32 pts (58%) developed an elevated MCV (range: 98.1-114). For the entire cohort, median # cycles of Pem given 11 (range: 2-38). In those pts who had high MCV, the median # of Pem cycles given was 12 (range: 5-38). All pts had normal or low MCV prior to tx, but one. Unfortunately, 33 pts had progressed and are no longer on MCTx. 12 pts out of the 19 still on MCTx had high MCV. In 5/12 pts, we were able to measure their co-factor levels. All values were within normal limits. The MCVs of these 5 pts were: 101.6, 100, 102.1, 102.2, and 104.8 from baseline values of: 74.4, 89.3, 92.8, 89.7, and 89.6, respectively. Their Hbg levels were: 12.2, 13.2, 15.4, 11.4, and 11 g/dL, respectively with normal WBC (and differential) and platelets. Conclusions: Pem is an antifolate agent that is associated with folate depletion (due to TS inhibition) and macrocytosis. We are reporting here patients treated with Pem for long time with proper FA and vitB12 supplementation that have an increased MCV with no apparent signs of folate, vitB12, MMA, and Hom deficiency. This observation needs a lengthened follow-up.

Lung cancer incidence continues to rise and is the number one cause of cancer death in both men and women worldwide with projected 221,130 new cases and 156,940 deaths in the United States in 2011. 1 Non-small cell lung cancer (NSCLC) represents more than 85% of the cases with most patients having either locally advanced or metastatic disease at the time of initial diagnosis, and approximately 60%–70% of them have an adenocarcinoma histologic subtype. In the last three years, we have seen several advances in the management of NSCLC, with several factors playing an important role in the treatment decision making process. Maintenance therapy has been added to the algorithm of NSCLC management and Pemetrexed has been studied as single agent or in combination in this setting with recent studies showing safety and improved progression free survival (PFS) and/or overall survival (OS), still the disease for the most part has a dismal outcome. More research work needs to be done to identify which patients truly benefit from these approaches, and to whom we should offer maintenance or switch maintenance vs. close observation.