6-11 Benefit of trastuzumab in the adjuvant setting for early- stage breast cancer has also been demonstrated. Four large trials, and several smaller studies, conducted in the adjuvant setting showed significant improvements in disease-free survival (DFS) (36%-52% reduction in DFS events) and overall survival (OS) (33% to 37% reduction in deaths), independent of patient age, tumor size, nodal status, or hormone receptor status. 12-16 Two of these trials, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B- 31 and North Central Cancer Treatment Group (NCCTG) N9831 trials were conducted in North America. In these two studies, patients with HER2-positive breast cancer were randomized to adriamycin and cyclophosphamide followed by paclitaxel with or without trastuzumab. Because they were similar in design, the trials were analyzed jointly. At the most recent report, after 3.9 years of median follow-up, women in the trastuzumab arm had significantly increased DFS (p<.001; stratified hazard ratio [HR], 0.52; 95% CI, 0.45 to 0.60) and OS (p<.001; stratified hazard ratio [HR], 0.61; 95% CI, 0.50 to 0.75) compared with women in the control arm. 12 On the basis of these data and the data from the other adjuvant trials, trastuzumab has become a critical component of standard therapy for HER2-positive early breast cancer. More recently, the efficacy of trastuzumab administered in combination with chemotherapy in the neoadjuvant (preoperative) setting has been evaluated. In the first randomized trial to evaluate this approach, Buzdar et al. reported a 67% pathologic complete response (pCR) rate, defined as no residual invasive disease in the breast or axilla, among patients receiving neoadjuvant chemotherapy plus trastuzumab versus a pCR rate of 25% among patients receiving noadjuvant chemotherapy alone (p=.02).17 Subsequent to this, the GeparQuattro,18 NOAH,19 NeoALTTO,20 NeoSphere21, American College of Surgeons Oncology Group (ACOSOG) Z1041 22 and Cancer and Leukemia Group B (CALGB) 40601 23 trials, have also demonstrated improved pCR rates among patients receiving trastuzumab in 6 Protocol: 2014-0443 Version 2.1 Version Date: 11 April 2016 addition to chemotherapy (table 1). These trials all used different chemotherapy backbones but are consistent in demonstrating high pCR rates in HER2-positive patients receiving neoadjuvant chemotherapy plus trastuzumab. There has been recent interest in using dual HER2-targeted therapy to increase pCR rates. In the NeoSphere trial, in addition to the arm adding trastuzumab to docetaxel where the pCr rate was 29% (31 out of 107), there was another arm that added pertuzumab, a monoclonal antibody that binds to HER2 and inhibits dimerization of HER2 with other members of the EGFR family of receptors. The addition of pertuzumab to trastuzumab and docetaxel increased the pCR rate to 46% (49 out of 107). 21 The addition of pertuzumab did not significantly increase the rate of grade 3 or higher adverse events (AE). The NeoALTTO and CALGB trials evaluated the addition of lapatinib, a HER2-targeted receptor tyrosine kinase inhibitor. 20,23 In the NeoALTTO trial, the pCR rate in patients receiving trastuzumab plus paclitaxel was 30%; a rate that increased to 51% with the addition of lapatinib. 20 In the CALGB trial, the pCR rate for patients receiving paclitaxel plus trastuzumab was 40% versus 51% when lapatinib was added. 23 In both trials, the addition of lapatinib led to increased greater than grade 3 toxicities including diarrhea, neutropenia and liver enzyme alterations. 20,23 In an initial report from MD Anderson, it was shown that patients achieving a pCR have improved outcomes when compared to patients not achieving a pCR after neoadjuvant chemotherapy plus trastuzumab. In this study, which included 142 patients with HER2-positive breast cancer that received neoadjuvant chemotherapy with a taxane, anthracycline and concomitant trastuzumab, a pCR was achieved in 72 (51%). The 3-year Kaplan-Meier estimates of recurrence- free survival (RFS) were 96% (95% CI, 91% to 100%) for patients achieving a pCR versus 80% (95% CI, 70.8% to 90.5%) for those not achieving a pCR (p=.02). 24 In a subsequent report from MD Anderson that evaluated 229 patients with HER2-positive breast cancer, a pCR was achieved in 114 (50%). Compared to patients achieving < pCR, those with pCR had higher five-year rates of local recurrence-free survival (100% versus 95%, P=0.011), distant metastasis (96% versus 80%, P<0.001), RFS (96% versus 79%, P<0.001), and OS (95% versus 84%, P=0.006). Improvements in RFS and OS were seen with decreasing post- treatment stage. Failure to achieve a pCR was the strongest independent predictor of recurrence (HR=4.09, 95% CI, 1.67-10.04, P=0.002) and death (HR=4.15, 95% CI, 1.39-12.38, P=0.011). 25 These data are consistent with those reported from the TECHNO trial, a phase II non-randomized study of 217 patients with HER2-positive breast cancer who received 6 months of neoadjuvant epirubicin and paclitaxel-based chemotherapy and trastuzumab. 26 In this study, 39% of patients achieved a pCR. Three-year DFS was 88% for patients achieving a pCR versus 73% for patients not achieving a pCR (p=.01). Three- year OS rates were 96% for patients achieving a pCR versus 86% for patients 7 Protocol: 2014-0443 Version 2.1 Version Date: 11 April 2016 not achieving a pCR (p=.03). pCR was the strongest prognostic factor for relapse and death. Disease-free survival outcomes for patients failing to achieve a pCR are summarized in table 2. Taken together, these data show that achieving a pCR is a strong predictor of long-term outcome and that novel therapeutic strategies are needed for patients failing to achieve a pCR. Also shown in table 2 are survival outcomes for patients enrolled on the BCIRG- 006 trial that evaluated trastuzumab in the adjuvant setting. These data demonstrate that patients who undergo surgery as an initial intervention and are found to have pathologically node-positive disease also represent a high-risk population. Data from the combined analyses of the NSABP B-31 and N9831 adjuvant trastuzumab trials showed that the 5-year recurrence free-survival rates were higher for those patients with hormone receptor-positive patients (89.4%) compared to those with hormone receptor-negative patients (81.6%).27 Taken together, these data suggest that patients with HER2-positive breast cancer that receive neoadjuvant chemotherapy with HER2-targeted therapy as well as those that undergo upfront surgery and are found to have ≥ 4 positive lymph nodes or 1-3 positive lymph nodes and are hormone receptor negative are a high-risk group in which novel therapeutic strategies are needed. 8 Protocol: 2014-0443 Version 2.1 Version Date: 11 April 2016 1.3 Nelipepimut-S Interest in the development of cancer vaccines increased after advances in the molecular characterization of human tumors led to the identification of tumor- associated antigens (TAA) that can be recognized by T lymphocytes.