Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.

Background Median overall survival for patients with metastatic soft tissue sarcoma is 12 to 16 months. Olaratumab is a human anti–platelet-derived growth factor receptor α monoclonal antibody which has antitumour activity in human sarcoma xenografts. Methods We conducted an open-label phase 1b, randomised, phase 2 study of doxorubicin ± olaratumab in patients with unresectable/metastatic soft tissue sarcoma. The phase 1b primary endpoint was safety; the phase 2 primary endpoint was progression-free survival using a two-sided alpha level of 0·2 and statistical power of 0·8. This study was registered with ClinicalTrials.gov, number NCT01185964. Findings Fifteen patients were enrolled and treated with olaratumab+doxorubicin in the phase 1b portion; 133 patients were randomised (66 to olaratumab+doxorubicin; 67 to doxorubicin) in the phase 2 portion, 129 of whom (97%) received at least one dose of study treatment (64 olaratumab+doxorubicin; 65 doxorubicin). Median progression-free survival in phase 2 was 6·6 months (95% confidence interval [CI], 4·1–8·3) with olaratumab+doxorubicin and 4·1 months (95% CI, 2·8–5·4) with doxorubicin (stratified hazard ratio [HR], 0·672; 95% CI, 0·442–1·021; p=0·0615). Median overall survival was 26·5 months (95% CI, 20·9–31·7) with olaratumab+doxorubicin and 14·7 months (95% CI, 9·2–17·1) with doxorubicin (stratified HR, 0·463; 95% CI, 0·301–0·710; p=0·0003). Adverse events more frequent with olaratumab+doxorubicin vs doxorubicin alone included neutropenia (38 [59%] vs 25 [39%]), mucositis (34 [53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [19%]), and diarrhea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade ≥3 was similar in both groups (olaratumab plus doxorubicin 8 (13%) vs doxorubicin 9 (14%). Interpretation This study of olaratumab with doxorubicin in patients with advanced soft tissue sarcoma met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement of 11·8 months in median overall survival (P=0·0003; HR 0·46). Funding Eli Lilly and Company.

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.

Introduction: The androgen receptor (AR) is widely expressed in breast cancers and has been proposed as a therapeutic target in estrogen receptor alpha (ER) negative breast cancers that retain AR. However, controversy exists regarding the role of AR, particularly in ER + tumors. Enzalutamide, an AR inhibitor that impairs nuclear localization of AR, was used to elucidate the role of AR in preclinical models of ER positive and negative breast cancer.

These NCCN Guidelines Insights highlight the important updates/changes to the surgical axillary staging, radiation therapy, and systemic therapy recommendations for hormone receptor-positive disease in the 1.2017 version of the NCCN Guidelines for Breast Cancer. This report summarizes these updates and discusses the rationale behind them. Updates on new drug approvals, not available at press time, can be found in the most recent version of these guidelines at NCCN.org.