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Gayathri Nagaraj and Cynthia X. Ma

Decisions regarding adjuvant chemotherapy for patients with estrogen receptor (ER)-positive, HER2-negative, lymph node-negative breast cancer have traditionally relied on clinical and pathologic parameters. However, the molecular heterogeneity and the complex tumor genome demand more sophisticated approaches to the problem. Several multigene-based assays have been developed to better prognosticate the risk of recurrence and death and predict benefit of therapy in this patient population. Oncologists are often faced with the challenge of incorporating these various complex genome-based biomarkers along with the traditional biomarkers in clinical decision-making. The NCCN Clinical Practice Guidelines in Oncology for Breast Cancer are helpful in providing a general recommendation. However, uncertainty remains in the absence of definitive data for various clinical scenarios. This case report describes a postmenopausal woman with stage I breast cancer that is low-grade and ER-rich, and has an intermediate Oncotype DX recurrence score of 28.

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Noa Efrat Ben-Baruch, Ron Bose, Shyam M. Kavuri, Cynthia X. Ma and Matthew J. Ellis

Activating mutations in the HER2 tyrosine kinase have been identified in human breast cancers that lack HER2 gene amplification. These patients are not candidates for HER2-targeted drugs under current standards of care, but preclinical data strongly suggest that these patients will benefit from anti-HER2 drugs. This case report describes a young woman with metastatic breast cancer whose tumor was found to carry a HER2 L755S mutation, which is in the kinase domain of HER2. Treatment with the second-generation HER2/EGFR tyrosine kinase inhibitor neratinib resulted in partial response and dramatic improvement in the patient's functional status. This partial response lasted 11 months, and when the patient's cancer progressed, she was treated with neratinib plus capecitabine and her cancer again responded. This second response parallels the benefit seen with continuing trastuzumab in HER2-amplified breast cancer after disease progression. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-mutated breast cancer. Two clinical trials of neratinib for HER2-mutated metastatic breast cancer are currently enrolling patients. Further, data from The Cancer Genome Atlas project have identified HER2 mutations in a wide range of solid tumors, including bladder, colorectal, and non–small cell lung cancers, suggesting that clinical trials of neratinib or neratinib-based combinations for HER2-mutated solid tumors is warranted.

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Cynthia Z. Qi, Min Huang, Amin Haiderali, Jipan Xie, Zheng-Yi Zhou, Eric Q. Wu and Peter Fasching

Objective: Pathological complete response (pCR) has been a commonly used endpoint in neoadjuvant trials for breast cancer (BC). A pooled analysis of 12 neoadjuvant BC trials by Cortazar et al (2014) reported a positive association between pCR and long-term survival outcomes among patients with general BC and certain subtypes including triple negative BC (TNBC). To update and extend the evidence to assess the association of pCR and survival outcomes in TNBC, this study reviewed and summarized cohort studies and recent clinical trials in the literature. Methods: English publications reporting association between pCR and survival outcomes among TNBC patients receiving neoadjuvant chemotherapy were searched in MEDLINE, EMBASE, Cochrane CENTRAL, and Northern Light Sciences Conference Abstracts. Full-text publications from all years and conference abstracts since year 2016 were identified. Relevant clinical trials, real-world evidence (RWE) studies, and meta-analyses were included for review and extraction. Results: Of total 1,880 publications retrieved, 35 reported association between pCR and survival outcomes for neoadjuvant TNBC (9 clinical trials, 21 RWE studies, and 5 pooled/meta-analyses). The sample size of TNBC patients varied between 25 and 1,645. Different pCR definitions were used across studies, of which absence of tumor in the breast and axillary nodes was most common (N=29). The prognostic impact of pCR was evaluated for multiple survival outcomes: overall survival (OS; N=19), disease-free survival (DFS; N=14), relapse-free survival (RFS; N=7), event-free survival (N=5), distant DFS (N = 4), and local RFS (N=2). Kaplan-Meier analysis was used to assess the association between pCR and these outcomes in 31 studies. Clear separation of survival curves in favor of pCR was observed in all the studies. Log-rank tests were conducted in 18 studies, and statistically significant association was reported in majority of them, except for 1 RWE study with small sample size (N=35) and 1 pooled analysis with a different pCR definition (absence of tumor in the breast) than most of the others. Cox proportional hazards model was used in 17 studies, wherein hazard ratios of survival outcomes comparing pCR vs non-pCR ranged from 0.08 to 0.53. Conclusions: Despite divergent study designs and pCR definitions, evidence from both clinical and real-world settings consistently suggest that pCR is a strong predictor of OS and other survival outcomes among TNBC patients.

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Prashant Gabani, Emily Merfeld, Amar J. Srivastava, Ashley A. Weiner, Laura L. Ochoa, Dan Mullen, Maria A. Thomas, Julie A. Margenthaler, Amy E. Cyr, Lindsay L. Peterson, Michael J. Naughton, Cynthia Ma and Imran Zoberi

Background: This study evaluated factors predictive of locoregional recurrence (LRR) in women with triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy who do not experience pathologic complete response (pCR). Methods: This is a single-institution retrospective review of women with TNBC treated with neoadjuvant chemotherapy, surgery, and radiation therapy in 2000 through 2013. LRR was estimated between patients with and without pCR using the Kaplan-Meier method. Patient-, tumor-, and treatment-specific factors in patients without pCR were analyzed using the Cox proportional hazards method to evaluate factors predictive of LRR. Log-rank statistics were then used to compare LRR among these risk factors. Results: A total of 153 patients with a median follow-up of 48.6 months were included. The 4-year overall survival and LRR were 70% and 15%, respectively, and the 4-year LRR in patients with pCR was 0% versus 22.0% in those without (P<.001). In patients without pCR, lymphovascular space invasion (LVSI; hazard ratio, 3.92; 95% CI, 1.64–9.38; P=.002) and extranodal extension (ENE; hazard ratio, 3.32; 95% CI, 1.35–8.15; P=.009) were significant predictors of LRR in multivariable analysis. In these patients, the 4-year LRR with LVSI was 39.8% versus 15.0% without (P<.001). Similarly, the 4-year LRR was 48.1% with ENE versus 16.1% without (P=.002). In patients without pCR, the presence of both LVSI and ENE were associated with an even further increased risk of LRR compared with patients with either LVSI or ENE alone and those with neither LVSI nor ENE in the residual tumor (P<.001). Conclusions: In patients without pCR, the presence of LVSI and ENE increases the risk of LRR in TNBC. The risk of LRR is compounded when both LVSI and ENE are present in the same patient. Future clinical trials are warranted to lower the risk of LRR in these high-risk patients.

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Jing Xi, Aabha Oza, Shana Thomas, Foluso Ademuyiwa, Katherine Weilbaecher, Rama Suresh, Ron Bose, Mathew Cherian, Leonel Hernandez-Aya, Ashley Frith, Lindsay Peterson, Jingqin Luo, Jairam Krishnamurthy and Cynthia X. Ma

Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors are now the standard of care for hormone receptor–positive (HR+), HER2-negative (HER–) metastatic breast cancer (MBC). However, guidelines are lacking regarding their optimal sequencing with other available agents. This study examines physician practice patterns and treatment outcomes of palbociclib and subsequent therapies in a real-world setting. Methods: A retrospective chart review was conducted for consecutive patients with MBC who received palbociclib between February 2015 and August 2017 at the Alvin J. Siteman Cancer Center. Kaplan-Meier method was used to generate time-to-event curves and estimate median progression-free survival (mPFS). Log-rank test was used to compare differences. Results: A total of 200 patients, with a median age of 59.4 years and a follow-up of 19.5 months, were included. Palbociclib was most frequently combined with letrozole (73.5%), followed by fulvestrant (25%), anastrozole (1%), and tamoxifen (0.5%). Most patients received palbociclib in the endocrine-resistant setting (n=42, n=50, and n=108 in the first-, second-, and subsequent-line settings, respectively), and the fraction of patients receiving palbociclib as first- or second-line therapy increased in recent months (P=.0428). mPFS was 20.7, 12.8, and 4.0 months with palbociclib administered in the first-, second-, and subsequent-line settings, respectively (P<.0001). Incidences of grade 3/4 neutropenia (41.5%) and dose reductions (29%) were comparable to reports in the literature. Among patients whose disease progressed on palbociclib (n=104), the most frequent next-line treatment was capecitabine (n=21), followed by eribulin (n=16), nab-paclitaxel (n=15), and exemestane + everolimus (n=12). mPFS with hormone therapy alone or in combination with targeted agents (n=32) after first-, second-, and subsequent-line palbociclib was 17.0, 9.3, and 4.2 months, respectively (P=.04). mPFS with chemotherapy (n=70) was not reached, 4.7, and 4.1 months after first-, second-, and subsequent-line palbociclib, respectively (P=.56). Conclusions: Palbociclib is effective for HR+/HER2– MBC in real-world practice. Hormone therapy alone or in combination with targeted agents remains an effective option after palbociclib progression.

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Michael J. Berger, David S. Ettinger, Jonathan Aston, Sally Barbour, Jason Bergsbaken, Philip J. Bierman, Debra Brandt, Dawn E. Dolan, Georgiana Ellis, Eun Jeong Kim, Steve Kirkegaard, Dwight D. Kloth, Ruth Lagman, Dean Lim, Charles Loprinzi, Cynthia X. Ma, Victoria Maurer, Laura Boehnke Michaud, Lisle M. Nabell, Kim Noonan, Eric Roeland, Hope S. Rugo, Lee S. Schwartzberg, Bridget Scullion, John Timoney, Barbara Todaro, Susan G. Urba, Dorothy A. Shead and Miranda Hughes

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Antiemesis address all aspects of management for chemotherapy-induced nausea and vomiting. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Antiemesis, specifically those regarding carboplatin, granisetron, and olanzapine.