IMPORTANCEApproximately 25% of patients with early-stage breast cancer who receive (neo)adjuvant chemotherapy experience a recurrence within 5 years. Improvements in therapy are greatly needed.OBJECTIVE To determine if pembrolizumab plus neoadjuvant chemotherapy (NACT) in early-stage breast cancer is likely to be successful in a 300-patient, confirmatory randomized phase 3 neoadjuvant clinical trial. DESIGN, SETTING, AND PARTICIPANTSThe I-SPY2 study is an ongoing open-label, multicenter, adaptively randomized phase 2 platform trial for high-risk, stage II/III breast cancer, evaluating multiple investigational arms in parallel. Standard NACT serves as the common control arm; investigational agent(s) are added to this backbone. Patients with ERBB2 (formerly HER2)-negative breast cancer were eligible for randomization to pembrolizumab between November 2015 and November 2016.INTERVENTIONS Participants were randomized to receive taxane-and anthracycline-based NACT with or without pembrolizumab, followed by definitive surgery. MAIN OUTCOMES AND MEASURESThe primary end point was pathologic complete response (pCR). Secondary end points were residual cancer burden (RCB) and 3-year event-free and distant recurrence-free survival. Investigational arms graduated when demonstrating an 85% predictive probability of success in a hypothetical confirmatory phase 3 trial. RESULTSOf the 250 women included in the final analysis, 181 were randomized to the standard NACT control group (median [range] age, 47 [24.77] years). Sixty-nine women (median [range] age, 50 [27-71] years) were randomized to 4 cycles of pembrolizumab in combination with weekly paclitaxel followed by AC; 40 hormone receptor (HR)-positive and 29 triple-negative. Pembrolizumab graduated in all 3 biomarker signatures studied. Final estimated pCR rates, evaluated in March 2017, were 44% vs 17%, 30% vs 13%, and 60% vs 22% for pembrolizumab vs control in the ERBB2-negative, HR-positive/ERBB2-negative, and triple-negative cohorts, respectively. Pembrolizumab shifted the RCB distribution to a lower disease burden for each cohort evaluated. Adverse events included immune-related endocrinopathies, notably thyroid abnormalities (13.0%) and adrenal insufficiency (8.7%). Achieving a pCR appeared predictive of long-term outcome, where patients with pCR following pembrolizumab plus chemotherapy had high event-free survival rates (93% at 3 years with 2.8 years' median follow-up).CONCLUSIONS AND RELEVANCE When added to standard neoadjuvant chemotherapy, pembrolizumab more than doubled the estimated pCR rates for both HR-positive/ERBB2negative and triple-negative breast cancer, indicating that checkpoint blockade in women with early-stage, high-risk, ERBB2-negative breast cancer is highly likely to succeed in a phase 3 trial. Pembrolizumab was the first of 10 agents to graduate in the HR-positive/ERBB2-negative signature.

Janus kinase 2 (JAK2) signal transduction is a critical mediator of the immune response. JAK2 is implicated in the onset of graft-versus-host disease (GVHD), which is a significant cause of transplant-related mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Transfer of JAK2 donor T cells to allogeneic recipients leads to attenuated GVHD yet maintains graft-versus-leukemia. Th1 differentiation among JAK2 T cells is significantly decreased compared with wild-type controls. Conversely, iTreg and Th2 polarization is significantly increased among JAK2 T cells. Pacritinib is a multikinase inhibitor with potent activity against JAK2. Pacritinib significantly reduces GVHD and xenogeneic skin graft rejection in distinct rodent models and maintains donor antitumor immunity. Moreover, pacritinib spares iTregs and polarizes Th2 responses as observed among JAK2 T cells. Collectively, these data clearly identify JAK2 as a therapeutic target to control donor alloreactivity and promote iTreg responses after allo-HCT or solid organ transplantation. As such, a phase I/II acute GVHD prevention trial combining pacritinib with standard immune suppression after allo-HCT is actively being investigated (https://clinicaltrials.gov/ct2/show/NCT02891603).

The indications and benefits of postmastectomy radiation therapy (PMRT) continue to evolve. Advances in systemic adjuvant therapy and targeted therapy for breast cancer are likely to play an increasingly important role in control of locoregional as well as distant disease. Ongoing scrutiny of patterns of chest wall failure will be required to define the net benefit derived from PMRT. This article discusses the 2001 American Society of Clinical Oncology guidelines for PMRT and current practices using PMRT in selected groups of patients who have breast cancer.

National Comprehensive Cancer Network (NCCN) guidelines for female breast cancer treatment and surveillance are well established, but similar guidelines on male breast cancers are less recognized. As an NCCN institution, our objective was to examine practice patterns and follow-up for male breast cancer compared to established guidelines for female patients. After Institutional Review Board approval, a prospective breast database from 1990 to 2009 was queried for male patients. Medical records were examined for clinico-pathological factors and follow-up. The 5-year survival rates with 95% confidence intervals were estimated using Kaplan-Meier method and Greenwood formula. Of the 19,084 patients in the database, 73 (0.4%) were male patients; 62 had complete data. One patient had bilateral synchronous breast cancer. The median age was 68.8 years (range 29-85 years). The mean/median invasive tumor size was 2.2/1.6 cm (range 0.0-10.0 cm). All cases had mastectomy (29 with axillary node dissection, 23 with sentinel lymph node biopsy only, 11 with sentinel node biopsy followed by completion axillary dissection). Lymph node involvement occurred in 25/63 (39.7%). Based on NCCN guidelines, chemotherapy, hormonal therapy, and radiation are indicated in 34 cases, 62 cases, and 14 cases, respectively. Only 20/34 (59%) received chemotherapy, 51/62 (82%) received hormonal therapy, and 10/14 (71%) received post-mastectomy radiation. Median follow-up was 26.2 months (range: 1.6-230.9 months). The 5-year survival estimates for node positive and negative diseases were 68.5% and 87.5%, respectively (p = 0.3). Despite the rarity of male breast cancer, treatment options based on current female breast tumors produce comparable results to female breast cancer. Increased awareness and a national registry for patients could help improve outcomes and tailor treatment recommendations to the male variant.

Acute graft- vs. -host disease (GVHD) is an important cause of morbidity and death after allogeneic hematopoietic cell transplantation (HCT). We identify a new approach to prevent GVHD that impairs monocyte-derived dendritic cell (moDC) alloactivation of T cells, yet preserves graft- vs.-leukemia (GVL). Exceeding endoplasmic reticulum (ER) capacity results in a spliced form of X-box binding protein-1 (XBP-1s). XBP-1s mediates ER stress and inflammatory responses. We demonstrate that siRNA targeting XBP-1 in moDCs abrogates their stimulation of allogeneic T cells. B-I09, an inositol-requiring enzyme-1α (IRE1α) inhibitor that prevents XBP-1 splicing, reduces human moDC migration, allo-stimulatory potency, and curtails moDC IL-1β, TGFβ, and p40 cytokines, suppressing Th1 and Th17 cell priming. B-I09-treated moDCs reduce responder T cell activation via calcium flux without interfering with regulatory T cell (Treg) function or GVL effects by cytotoxic T lymphocytes (CTL) and NK cells. In a human T cell mediated xenogeneic GVHD model, B-I09 inhibition of XBP-1s reduced target-organ damage and pathogenic Th1 and Th17 cells without impacting donor Tregs or anti-tumor CTL. DC XBP-1s inhibition provides an innovative strategy to prevent GVHD and retain GVL.