Adjuvant Approach Research Articles

Adjuvant Immunotherapy with Surgery Improves Survival in Murine Models of Thoracic Malignancies

Abstract Objectives Immunotherapy is an alternative therapy for thoracic malignancies, but results in humans have not been as impressive as anticipated. We hypothesized that adjuvant immunotherapy with surgery debulking can improve efficacy and long term response rates. Methods We retrospectively reviewed our group’s experience with human immunotherapy trials for NSCLC and mesothelioma. We developed murine models of NSCLC and mesothelioma surgery to evaluate clinically applicable immunotherapy approaches (tumor vaccination and checkpoint inhibitors) and optimized regimen. Outcomes were assessed for overall survival and tumor progression. Flow Cytometry, ELISA, PCR and in vivo neutralization assays were utilized to determine immune responses. Results The most important predictor of immunotherapy response in human trials was minimal disease at the time of immunotherapy. Surgery generates a state of minimum disease, thus we used a murine cancer surgery model to evaluate clinically available adjuvant immunotherapy approaches in a controlled setting. Adjuvant vaccination strategies were associated with decreased tumor volumes (p<0.01) and were associated with an increase in postoperative survival (42 days vs 24 days, p=0.03). In vivo lymphocyte assays demonstrated only partial cytotoxic activity of CD8+ T-cells postoperatively. The addition of checkpoint inhibitor (CTLA4i) with tumor vaccination improved potency and nearly tripled post-operative survival (54 days vs 19 days; p=0.004). Additionally, 34% of mice receiving combination immunotherapy with surgery were cured (p=0.03). Conclusion This evidence supports a new approach to thoracic malignancies including multi modal immunotherapy with surgical resection.

Semiconductor diode laser device adjuvanting intradermal vaccine

A brief exposure of skin to a low-power, non-tissue damaging laser light has been demonstrated to augment immune responses to intradermal vaccination. Both preclinical and clinical studies show that this approach is simple, effective, safe and well tolerated compared to standard chemical or biological adjuvants. Until now, these laser exposures have been performed using a diode-pumped solid-state laser (DPSSL) devices, which are expensive and require labor-intensive maintenance and special training. Development of an inexpensive, easy-to-use and small device would form an important step in translating this technology toward clinical application.Here we report that we have established a handheld, near-infrared (NIR) laser device using semiconductor diodes emitting either 1061, 1258, or 1301nm light that costs less than $4000, and that this device replicates the adjuvant effect of a DPSSL system in a mouse model of influenza vaccination. Our results also indicate that a broader range of NIR laser wavelengths possess the ability to enhance vaccine immune responses, allowing engineering options for the device design.This small, low-cost device establishes the feasibility of using a laser adjuvant approach for mass-vaccination programs in a clinical setting, opens the door for broader testing of this technology with a variety of vaccines and forms the foundation for development of devices ready for use in the clinic.

Neurocognitive impact of cranial radiation in adults with cancer: an update of recent findings.

Radiation to the brain is associated with adverse effects on cognition in cancer patients. Advances in technology have improved treatment efficacy, while new or adjuvant approaches continue to be developed. The long-term impact of both established and newer treatments on cognition is an active area of research. The article reviews the 15 studies published between January 2015 and October 2016 that include data on neurocognitive functions following radiation to the brain in adults with brain metastases, primary brain tumors, or other cancers. These studies examine neurocognitive outcomes in relation to radiation treatment delivery, pharmacological interventions, and biomarkers of brain injury. Advances in radiotherapy protocols have reduced neurotoxic side-effects. Implementation of standardized, validated neurocognitive measures and biomarkers of brain injury provide new insights into the impact of cranial radiation on cognitive functions. Several promising new lines of research will benefit from further study to address common challenges in the field, including high rates of attrition in longitudinal trials, absence of control groups, small sample sizes, and heterogeneous patient groups.

Potent Immune Stimulation from Nanoparticle Carriers Relies on the Interplay of Adjuvant Surface Density and Adjuvant Mass Distribution.

Development of novel adjuvant delivery approaches which provide safe and effective immune stimulation are critical for prophylactic and therapeutic advances in a wide range of diseases. Toll-like receptor agonists (TLRas) have been identified as potent stimulators of antigen presenting cells (APCs) and are capable of inducing proinflammatory immune responses desirable for vaccine and immunostimulatory applications. Although TLRas have been successfully incorporated into nanoparticle platforms, minimal work has been done to evaluate the direct role of the adjuvant incorporation in these formulations in directing the immune response. Here, we developed a series of nanoparticle carriers with controlled surface densities of two TLRas, lipopolysaccharide (LPS), corresponding to TLR-4, and CpG oligodeoxynucleotide, corresponding to TLR-9. The proinflammatory cytokine production and expression of costimulatory molecules on APCs were evaluated following a 24 h particle incubation period in vitro using bone marrow derived macrophages and in vivo following particle instillation in the airway of mice. Results demonstrate that proinflammatory cytokine production is predominantly driven by the distribution of the adjuvant dose to a maximal number of cells, whereas the upregulation of costimulatory molecules needed to drive APC maturation and promote adaptive responses indicate the requirement of an optimal density of TLRa on the particle surface. These results indicate that adjuvant surface density is an important parameter for tight control of immune stimulation and provide a foundation for pathogen mimicking particle (PMP) vaccines and immunostimulatory therapeutics.

Abstract P5-16-09: Overall survival of patients with non-metastatic triple negative breast cancer who received neoadjuvant vs adjuvant chemotherapy: Cohort analysis of National cancer data base (NCDB) 2010 - 2011

Abstract Background: One of the benefits of neoadjuvant approach to the treatment of breast cancer is early microscopic disease control, which should translate to improved survival. However, clinical trials have not yet shown a survival benefit for neoadjuvant approach in even high risk patients, such as triple negative cases. Few studies have been performed outside of clinical trials. Purpose: The objective of our study was to compare the overall survival of Stage I-III triple negative breast cancer patients who received neoadjuvant vs adjuvant chemotherapy within the NCDB, a prospectively collected, large, nationwide, hospital-based cancer outcomes database which contains information for more than 1,500 Commission on Cancer-accredited cancer programs in the U.S. Patient and Method: We identified a cohort of women, aged > 18 year-old at diagnosis, with clinical stage I-III triple negative breast cancer diagnosed in 2010-2011, who received either neoadjuvant chemotherapy only or adjuvant chemotherapy only. Patients with incomplete or missing vital status, receptors status and treatment information were excluded. Demographic (age at diagnosis, race, ethnicity, comorbidities, insurance, median income, urbanicity), tumor (clinical stage, histology, grade) and treatment (breast surgery, surgical margin, radiation) factors were examined. Stabilized inverse proportion weights were developed and assigned to balance the neoadjuvant and adjuvant groups on all demographic, tumor and treatment covariates. Unadjusted and adjusted overall survival was calculated using the Kaplan-Meier method and compared using the log-rank test. Results: Among the 15,483 women with triple negative breast cancer, 4,335 (28%) received neoadjuvant chemotherapy and 11,148 (72%) received adjuvant chemotherapy. Most of the demographic, tumor and treatment factors were similarly distributed among neoadjuvant and adjuvant groups except age at diagnosis and clinical stage. Compared to patients received adjuvant chemotherapy, patients received neoadjuvant chemotherapy were more likely to be younger (45% vs. 31% < 50 year-old, p<0.0001) and have a higher clinical stage (35% vs. 6% stage III, p<0.0001). The unadjusted 4-year overall survival of patients received neoadjuvant vs adjuvant approach was 75.8% (95% CI 74.4%-77.4%) and 87.5% (95% CI 87.1%-87.9%), respectively. After adjusting for demographic, tumor and treatment factors, the 4-year overall survival of patients received neoadjuvant vs adjuvant approach was 81.9% (95% CI 79.5%-84.3%) and 85.3% (95% CI 85.2%-85.4%), respectively. Conclusion: In this NCDB study, the overall survival of triple negative breast cancer patients received neoadjuvant chemotherapy was inferior to those received adjuvant chemotherapy, even after adjusting for demographic, tumor and treatment factors. However, information regarding the chemotherapy regimen used and whether a full course of chemotherapy was delivered (2 factors that affect disease response and outcome) was not available. Patient and tumor factors at the time of disease presentation that are important in determining which triple negative patients will benefit from neoadjuvant approach remain to be defined. Citation Format: Cheng YC, Smith E, Yen T. Overall survival of patients with non-metastatic triple negative breast cancer who received neoadjuvant vs adjuvant chemotherapy: Cohort analysis of National cancer data base (NCDB) 2010 - 2011 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-09.

Dual Functional Mesoporous Silicon Nanoparticles Enhance the Radiosensitivity of VPA in Glioblastoma

Radiotherapy is a critical strategy and standard adjuvant approach to glioblastoma treatment. One of the major challenges facing radiotherapy is to minimize radiation damage to normal tissue without compromising therapeutic effects on cancer cells. Various agents and numerous approaches have been developed to improve the therapeutic index of radiotherapy. Among them, radiosensitizers have attracted much attention because they selectively increase susceptibility of cancer cells to radiation and thus enhance biological effectiveness of radiotherapy. However, clinical translation of radiosensitizers has been severely limited by their potential toxicity to normal tissue. Recent advances in nanomedicine offer an opportunity to overcome this hindrance. In this study, a dual functional mesoporous silica nanoparticle (MSN) formulation of the valproic acid (VPA) radiosensitizer was developed, which specifically recognized folic acid–overexpressing cancer cells and released VPA conditionally in acidic turmeric microenvironment. The efficacy of this targeted and pH-responsive VPA nanocarrier was evaluated as compared to VPA treatment approach in two cell lines: rat glioma cells C6 and human glioma U87. Compared to VPA treatment, targeted VPA-MSNs not only potentiated the toxic effects of radiation and led to a higher rate of cell death but also enhanced inhibition on clonogenic assay. More interestingly, these effects were further accentuated by VPA-MSNs at low pH values. Western blot analysis showed that the effects were mediated via enhanced apoptosis-inducing effects. Our results suggest that the adjunctive use of VPA-MSNs may enhance the effectiveness of radiotherapy in glioma treatment by lowering the radiation doses required to kill cancer cells and thereby minimize collateral damage to healthy adjacent tissue.

Nanomolar concentration of blood-soluble drag-reducing polymer inhibits experimental metastasis of human breast cancer cells.

Metastasis is the leading cause of cancer mortality. Extravasation of cancer cells is a critical step of metastasis. We report a novel proof-of-concept study that investigated whether non-toxic blood-soluble chemical agents capable of rheological modification of the near-vessel-wall blood flow can reduce extravasation of tumor cells and subsequent development of metastasis. Using an experimental metastasis model, we demonstrated that systemic administration of nanomolar concentrations of so-called drag-reducing polymer dramatically impeded extravasation and development of pulmonary metastasis of breast cancer cells in mice. This is the first proof-of-principle study to directly demonstrate physical/rheological, as opposed to chemical, way to prevent cancer cells from extravasation and developing metastasis and, thus, it opens the possibility of a new direction of adjuvant interventional approach in cancer.

Phytotherapy and Nutritional Supplements on Breast Cancer.

Breast cancer is the most frequent type of nonskin malignancy among women worldwide. In general, conventional cancer treatment options (i.e., surgery, radiotherapy, chemotherapy, biological therapy, and hormone therapy) are not completely effective. Recurrence and other pathologic situations are still an issue in breast cancer patients due to side effects, toxicity of drugs in normal cells, and aggressive behaviour of the tumours. From this point of view, breast cancer therapy and adjuvant methods represent a promising and challenging field for researchers. In the last few years, the use of some types of complementary medicines by women with a history of breast cancer has significantly increased such as phytotherapeutic products and nutritional supplements. Despite this, the use of such approaches in oncologic processes may be problematic and patient's health risks can arise such as interference with the efficacy of standard cancer treatment. The present review gives an overview of the most usual phytotherapeutic products and nutritional supplements with application in breast cancer patients as adjuvant approach. Regardless of the contradictory results of scientific evidence, we demonstrated the need to perform additional investigation, mainly well-designed clinical trials in order to establish correlations and allow for further validated outcomes concerning the efficacy, safety, and clinical evidence-based recommendation of these products.

Lidocaine Infusion: A Promising Therapeutic Approach for Chronic Pain.

Opioid abuse is a national epidemic in the United States, where it is estimated that a prescription drug overdose death occurs every 19 minutes. While opioids are highly effective in acute and subacute pain control, their use for treatment of chronic pain is controversial. Chronic opioids use is associated with tolerance, dependency, hyperalgesia. Although there are new strategies and practice guidelines to reduce opioid dependence and opioid prescription drug overdose, there has been little focus on development of opioid-sparing therapeutic approaches. Lidocaine infusion has been shown to be successful in controlling pain where other agents have failed. The opioid sparing properties of lidocaine infusion added to its analgesic and antihyperalgesic properties make lidocaine infusion a viable option for pain control in opioid dependent patients. In this review, we provide an overview of the opioid abuse epidemic, and we outline current evidence supporting the potential use of lidocaine infusion as an adjuvant therapeutic approach for management of chronic pain.

Presence and Quantity of COX-2 in Lymph Node Metastases of Patients with Head and Neck Cancer

COX-2 expression in primary lesions, as well as lymph node metastases, appears to identify HNSCC patients at higher risk in all tumor sites. Adjuvant therapeutic approaches targeting COX-2 might be a promising tool in this patient population.

Prospects of cytological cervical cancer screening in India: Exploring adjuvant approaches.

Prospects of cytological cervical cancer screening in India: Exploring adjuvant approaches.

Potassium Ascorbate with Ribose: Promising Therapeutic Approach for Melanoma Treatment.

While surgery is the definitive treatment for early-stage melanoma, the current therapies against advanced melanoma do not yet provide an effective, long-lasting control of the lesions and a satisfactory impact on patient survival. Thus, research is also focused on novel treatments that could potentiate the current therapies. In the present study, we evaluated the effect of potassium ascorbate with ribose (PAR) treatment on the human melanoma cell line, A375, in 2D and 3D models. In the 2D model, in line with the current literature, the pharmacological treatment with PAR decreased cell proliferation and viability. In addition, an increase in Connexin 43 mRNA and protein was observed. This novel finding was confirmed in PAR-treated melanoma cells cultured in 3D, where an increase in functional gap junctions and a higher spheroid compactness were observed. Moreover, in the 3D model, a remarkable decrease in the size and volume of spheroids was observed, further supporting the treatment efficacy observed in the 2D model. In conclusion, our results suggest that PAR could be used as a safe adjuvant approach in support to conventional therapies for the treatment of melanoma.

Conduita tratamentului conservator în sindromul ovarelor polichistice la adolescente

Polycystic ovary syndrome (PCOS) is a common endocrine and heterogeneous dysfunction, characterized by chronic anovulation and androgen excess, affecting 6-10% of women of childbearing age. It is the most common cause of anovulatory infertility. It seems that the key element in the pathophysiology of PCOS is increased insulin resistance. The correction of infertility in teens is not a priority. They can receive treatment to normalize menstrual cycles, with the reduction of symptoms and improvement of metabolic disorders. Many overweight teens have increased insulinemia, which may play a role in the development of PCOS. Standard treatment is oral estroprogestative, used to perform regular menstrual cycles. Normalize menstrual cycles can be done with oral contraceptives or oral antidiabetic agents that improve metabolic dysfunctions. An adjuvant approach of the utmost importance for teens is lifestyle modification and diet. Teen treatment should be individualized depending on a number of peculiarities that have to be taken into account: menstruation disorders, mastopathies and ovarian dystrophies, hyperandrogenism syndrome, sexually transmitted diseases and other associated disorders. In obese women with PCOS, weight loss improves hyperandrogenism, reduces metabolic disturbances, reduces insulin resistance and insulinemia, improves fertility rate, stimulates ovulation.

Making the Most of Cancer Surgery with Neoadjuvant Immunotherapy.

Surgery remains our strongest treatment pillar against early stages of cancer. In a number of instances, the curative potential of surgery can be enhanced by treatments given before (neoadjuvant) or after (adjuvant) surgical procedures. Immunomodulation has emerged as a powerful tool to fight metastatic disease across cancer histologies and goes now to be tested at earlier surgically amenable stages. The work by Liu and colleagues in this issue provides solid preclinical evidence in support of neoadjuvant immunotherapy over adjuvant approaches. Cancer Discov; 6(12); 1312-4. ©2016 AACRSee related article by Liu and colleagues, p. 1382.

Adjuvant chemotherapy versus chemoradiotherapy in the management of patients with surgically resected duodenal adenocarcinoma: A propensity score-matched analysis of a nationwide clinical oncology database.

To the authors' knowledge, optimal adjuvant approaches for resected duodenal adenocarcinoma are not well established. Given the significant risk of locoregional disease recurrence, there may be a subset of patients who demonstrate an improvement in overall survival (OS) from the addition of radiotherapy (chemoradiotherapy [CRT]) to an adjuvant chemotherapy regimen. Patients with resected, nonmetastatic duodenal adenocarcinoma who received chemotherapy (694 patients) or CRT (550 patients) were identified in the National Cancer Data Base (1998-2012). Cox regression identified covariates associated with OS. The chemotherapy and CRT cohorts were matched (1:1) by propensity scores based on the likelihood of receiving CRT or the survival hazard from Cox modeling. OS was compared using Kaplan-Meier estimates. CRT was more frequently used for patients who underwent positive-margin surgical resection (15.9% vs 9.1%; P<.001). At a median follow-up of 79.2 months (interquartile range, 52.9-114.9 months), the median OS of the propensity score-matched cohort was 46.7 months (interquartile range, 18.9 months to not reached). No survival advantage was observed for patients who were treated with adjuvant CRT compared with those treated with adjuvant chemotherapy (median OS: 48.9 months vs 43.5 months [HR, 1.04; 95% confidence interval, 0.88-1.22 (P = .669)]). CRT was not found to be associated with a significant improvement in the median OS after positive-margin surgical resection (133 patients; 27.6 months vs 18.5 months [P = .210]) or in the presence of T4 classification (461 patients; 30.6 months vs 30.4 months [P = .844]) inadequate lymph node staging (584 patients; 40.5 months vs 43.2 months [P = .707]), lymph node positivity (647 patients; 38.3 months vs 34.1 months [P = .622]), or poorly differentiated histology (429 patients; 46.6 months vs 35.7 months [P = .434]). The addition of radiation to adjuvant therapy does not appear to significantly improve survival, even in high-risk cases. Cancer 2017;123:967-76. © 2016 American Cancer Society.

Improving efficacy of the adjustable gastric band: studies of the use of adjuvant approaches in a rodent model

BackgroundThe laparoscopic adjustable gastric band (AGB) has been effective in reducing excess weight by approximately 50% for at least 16 years. However, as with all weight loss approaches, reduction in weight resulting from bariatric surgery is associated with a compensatory reduction in energy expenditure, which may confound and limit weight loss. Adjuvant therapies that reduce food intake and increase energy expenditure may be used to improve weight loss outcomes by ameliorating, or even reversing, this reduction in energy expenditure. MethodsRats were either fitted with an AGB or were sham operated and received one of 2 adjunctive pharmacologic treatments, (1) thyroxine or (2) bupropion/naltrexone (Contrave), at a range of doses and matched with vehicle controls (n = 6–8/group) over a 4-week period of combined treatments. Metabolic parameters including food intake, weight, fat mass, and energy expenditure in brown adipose tissue (BAT), whole body calorimetry, and physical activity were assessed. ResultsInflation of the AGB caused a reduction in weight gain that was further enhanced by cotreatment with either thyroxine or Contrave (P<.05). Thyroxine completely ameliorated the reduction in AGB-induced BAT thermogenesis and significantly improved weight loss, particularly in fat mass. Contrave also augmented the loss of weight and fat mass associated with the AGB and increased BAT thermogenesis in banded rats even at doses below that required to change food intake. ConclusionAdjuvant therapies can improve the efficacy of the AGB, at least in part by negating the compensatory reduction in energy expenditure, but also via a combined effect on food intake.

Long‐term decision regret after post‐prostatectomy image‐guided intensity‐modulated radiotherapy

Decision regret (DR) may occur when a patient believes their outcome would have been better if they had decided differently about their management. Although some studies investigate DR after treatment for localised prostate cancer, none report DR in patients undergoing surgery and post-prostatectomy radiotherapy. We evaluated DR in this group of patients overall, and for specific components of therapy. We surveyed 83 patients, with minimum 5years follow-up, treated with radical prostatectomy (RP) and post-prostatectomy image-guided intensity-modulated radiotherapy (IG-IMRT) to 64-66Gy following www.EviQ.org.au protocols. A validated questionnaire identified DR if men either indicated that they would have been better off had they chosen another treatment, or they wished they could change their mind about treatment. There was an 85.5% response rate, with median follow-up post-IMRT 78months. Adjuvant IG-IMRT was used in 28% of patients, salvage in 72% and ADT in 48%. A total of 70% of patients remained disease-free. Overall, 16.9% of patients expressed DR for treatment, with fourfold more regret for the RP component of treatment compared to radiotherapy (16.9% vs 4.2%, P=0.01). DR for androgen deprivation was 14.3%. Patients were regretful of surgery due to toxicity, not being adequately informed about radiotherapy as an alternative, positive margins and surgery costs (83%, 33%, 25% and 8% of regretful patients respectively). Toxicity caused DR in the three radiotherapy-regretful and four ADT-regretful patients. Patients were twice as regretful overall, and of surgery, for salvage vs adjuvant approaches (both 19.6% vs 10.0%). Decision regret after RP and post-prostatectomy IG-IMRT is uncommon, although patients regret RP more than post-operative IG-IMRT. This should reassure urologists referring patients for post-prostatectomy IG-IMRT, particularly in the immediate adjuvant setting. Other implications include appropriate patient selection for RP (and obtaining clear margins), and ensuring adequately discussing definitive radiotherapy as an alternative to surgery.

Adjuvant Therapy of Resected Non-small Cell Lung Cancer: can We Move Forward?

Twenty years ago, an individual patient data meta-analysis of eight cisplatin-based adjuvant chemotherapy (AC) studies in completely resected early stage non-small cell lung cancer (NSCLC) demonstrated a 13% reduction of the risk of death favoring chemotherapy that was of borderline statistical significance (p=0.08). This marginal benefit boosted a new generation of randomized trials to evaluate the role of modern platinum-based regimens in resectable stages of NSCLC and, although individual studies generated conflicting results, overall they contributed to confirm the role of AC which is now recommended for completely resected stage II and III NSCLC, mostly 4cycles, while subset analyses suggested a benefit in patients with large IB tumors. Cisplatin-based therapy was the core regimen of those adjuvant clinical trials and even if a substitution with other platinum-derived was also suggested, mainly based on extrapolated data from studies in advanced disease, cisplatin was confirmed to be slightly superior to carboplatin and is still the drug of choice in the adjuvant setting. Currently, any attempt to improve efficacy of cisplatin-based chemotherapy through antiangiogenic drugs association or pharmacogenomics approaches have failed, while results of additional studies are eagerly awaited. In the context of promising targeted therapies, even if several randomized trials in the advanced setting evaluated tyrosine kinase inhibitors (TKis) versus platinum-based chemotherapy and showed impressive results, clinical experience with TKIs in the adjuvant setting is still limited and most of the trials have not required patients to be molecularly tested for the drug-specific molecular predictive factor. At the present time, the role of targeted agents as adjuvant approaches remains largely not investigated. Finally, with the negative experience of the use of vaccines in this setting, the integration of immunotherapy (mainly immunocheckpoint inhibitors) in platinum-based schedules has just started to be evaluated, representing a potential future clinical option, but still far from clinical practice.

Abstract CT077: PRECISION (Profiling Early Breast Cancer for Radiotherapy Omission): a phase II study of breast-conserving surgery without adjuvant radiotherapy for favorable-risk breast cancer

Abstract Background: Radiation therapy (RT) following breast conserving surgery (BCS) is well-known to improve outcomes for patients with invasive breast cancer. However, RT poses an inconvenience to patients and confers a small, yet real, risk of long-term adverse effects. In addition, reports have suggested that not all patients stand to benefit equally from RT, with certain disease features portending an excellent prognosis regardless of the adjuvant treatment approach. Specifically, favorable luminal A cancers exhibit a 10-year locoregional recurrence (LRR) rate of 2% following BCS and RT, suggesting very low putative risk in the absence of RT. While luminal A breast cancers are the most favorable among subtypes, robustly distinguishing them from luminal B tumors is a challenge. This trial seeks to employ a molecular profiling approach to identify favorable-risk, early-stage breast cancer patients who may feasibly omit RT following BCS. Methods: To identify a low-risk, luminal A cohort of breast cancer patients, we will employ well-characterized clinicopathologic parameters in addition to molecular profiling. Eligible patients will be 50-75 years of age and must have invasive breast cancer ?2 cm (T1), that is estrogen receptor positive, low- or intermediate-grade, without HER2 amplification, and with negative margins (no ink on tumor) following BCS. Following resection, tumor samples will undergo prediction analysis of microarray 50 (PAM50) profiling via the NanoString Prosigna assay to characterize intrinsic biologic subtype. Patients with tumors classified as luminal A (low-risk score) will be eligible for the omission of RT. The trial is a single-arm prospective cohort study designed to assess the viability of RT omission in this favorable population. The primary endpoint will be LRR at 5 years and a rate of &amp;lt;5% will be considered of interest. Projected accrual will be 345 patients to be enrolled over 4 years. Using this design, the study has 90% power to distinguish a 5-year LRR rate of 1% from 5% using a one-sample exponential test with one-sided type I error of 0.025. Secondary endpoints include 5- and 10-year recurrence rates of any type (local, regional and/or distant), disease-free survival, invasive-disease-free survival and overall survival, in addition to rates of salvage mastectomy and radiotherapy. (ClinicalTrials.gov: NCT02653755) Citation Format: Lior Z. Braunstein, Alphonse G. Taghian, Jay R. Harris. PRECISION (Profiling Early Breast Cancer for Radiotherapy Omission): a phase II study of breast-conserving surgery without adjuvant radiotherapy for favorable-risk breast cancer. [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 CT077.

Abstract 742: A novel multidrug metronomic chemotherapy significantly delays tumor growth in mice

Abstract The tumor immunosuppressive microenvironment represents a major obstacle to an effective tumor-specific cellular immune response. We have previously shown that a novel multi-drug chemotherapy administered in a metronomic fashion was able to increase immune response to peptides. The chemotherapy consisted of a cocktail including taxanes (paclitaxel and docetaxel) and alkylating (cyclophosphamide) agents. The newly designed strategy was shown to be safe, well tolerated and significantly efficacious (Tagliamonte et al., CII 2015). In the present study, the effect on the immunosuppressive tumor microenvironment by the same multi-drug cocktail was evaluated in a mouse model upon sub-cutaneous ectopic implantation of B16 melanoma cells. Treated animals showed a remarkable delay in tumor growth and prolonged survival as compared to control group. Such an effect was directly correlated with CD4+ T cell reduction and CD8+ T cell increase. A significant reduction in the percentage of both CD25+FoxP3+ and CD25+CD127low regulatory T cell population was found in the spleens as well as in the tumor lesions. An intrinsic CD8+ T cell response specific to B16 naturally expressed Trp2 TAA was observed. The same metronomic chemotherapy combined to a vaccine based on mutated antigens, was subsequently shown to increase immune response to vaccine resulting in a significant delay of B16 tumor growth as well as animal survival. The novel multi-drug daily metronomic chemotherapy evaluated in the present study was very effective in counterbalancing the immunosuppressive tumor microenvironment and enhancing vaccine efficacy. Consequently, the intrinsic as well as vaccine-induced anti-tumor T cell immunity could exert its function containing tumor growth. Overall, the described metronomic chemotherapy may represent a promising adjuvant approach to enhance anti-tumor cellular immunity and amplify the biological effects of therapeutic cancer vaccines. Citation Format: Maria Tagliamonte, Annacarmen Petrizzo, Maria Lina Tornesello, Antonio Luciano, Domenica Rea, Antonio Barbieri, Claudio Arra, Maria Napolitano, Gennaro Ciliberto, Franco M. Buonaguro, Luigi Buonaguro. A novel multidrug metronomic chemotherapy significantly delays tumor growth in mice. [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 742.