Systematic Immunotherapy Target Discovery Using Genome-Scale In Vivo CRISPR Screens in CD8 T Cells.

CD8 T cells play essential roles in anti-tumor immune responses. Here, we performed genome-scale CRISPR screens in CD8 T cells directly under cancer immunotherapy settings and identified regulators of tumor infiltration and degranulation. The in vivo screen robustly re-identified canonical immunotherapy targets such as PD-1 and Tim-3, along with genes that have not been characterized in T cells. The infiltration and degranulation screens converged on an RNA helicase Dhx37. Dhx37 knockout enhanced the efficacy of antigen-specific CD8 T cells against triple-negative breast cancer in vivo. Immunological characterization in mouse and human CD8 T cells revealed that DHX37 suppresses effector functions, cytokine production, and T cell activation. Transcriptomic profiling and biochemical interrogation revealed a role for DHX37 in modulating NF-κB. These data demonstrate high-throughput in vivo genetic screens for immunotherapy target discovery and establishes DHX37 as a functional regulator of CD8 T cells.

Association of Medicaid Expansion with Post-mastectomy Reconstruction Rates.

BACKGROUND: The Affordable Care Act sought to improve access to health care for low-income individuals. This study aimed to assess whether expansion of Medicaid coverage increased rates of post-mastectomy reconstruction (PMR) for patients who had Medicaid or no insurance. METHODS: A retrospective analysis performed through the National Cancer Database examined women who underwent PMR and were uninsured or had Medicaid, private insurance, or Medicare, and whose race/ethnicity, age, and state expansion status were known. Trends in the use of PMR after passage of Medicaid expansion in 2014 were evaluated. RESULTS: In all states and at all time periods, patients with private insurance were about twice as likely to undergo PMR as patients who had Medicaid or no insurance. In 2016, only 28.7 % of patients with Medicaid or no insurance in nonexpansion states underwent PMR (p < 0.001) compared with 38.5 % of patients in expansion states (p < 0.001). Patients in expansion states also have higher levels of education, higher income, and greater likelihood of living in metropolitan areas. Additionally, patients in all states saw an increase in early-stage disease, with a concomitant reduction in late disease, but this change was greater in expansion states than in non-expansion states. CONCLUSIONS: Expansion states have larger proportions of patients undergoing PMR than non-expansion states. This difference stems from significant differences in income, education, comorbidities, race, and location. Large metropolitan areas have the largest number of patients undergoing PMR, whereas rural areas have the least.

Assessing Interobserver Variability of Cosmetic Outcome Assessment in Breast Cancer Patients Undergoing Breast-Conservation Surgery.

BACKGROUND: Inter-rater reliability between breast surgical oncologists and reconstructive surgeons using cosmesis scales, and the correlation between their observations and patients' own subjective assessments, is poorly understood. METHODS: Patients undergoing BCS in a prospective trial rated their cosmetic outcome on a Likert scale (poor/fair/good/excellent) at the postoperative and 1-year time points; photographs were also taken. Three breast surgical oncologists (not involved in these cases) and two reconstructive surgeons were asked to independently rate cosmesis using the Harvard/NSABP/RTOG scale. RESULTS: Overall, 55 and 17 patients had photographs and Likert self-evaluations at the postoperative and 1-year time points, respectively. There was poor agreement between surgeon and patient ratings postoperatively [kappas - 0.042 (p = 0.659), 0.069 (p = 0.226), and 0.076 (p = 0.090) for the breast surgical oncologists; and 0.018 (p = 0.689) and 0.112 (p = 0.145) for the reconstructive surgeons], and poor interobserver agreement between surgeons of the same specialty (kappa - 0.087, 95% confidence interval [CI] - 0.091 to - 0.082, p = 0.223 for breast surgical oncologists; and kappa - 0.150, 95% CI - 0.157 to - 0.144, p = 0.150, for reconstructive surgeons). At 1 year, the interobserver agreement between breast surgical oncologists was better (kappa 0.507, 95% CI 0.501-0.512, p < 0.001); however, there was still poor correlation between the reconstructive surgeons (kappa - 0.040, 95% CI - 0.049 to - 0.031, p = 0.772). Agreement between surgeon and patient ratings remained poor at this time point [kappas - 0.115 (p = 0.477), 0.177 (p = 0.245), and 0.101 (p = 0.475) for breast surgical oncologists; and 0.335 (p = 0.037) and -0.118 (p = 0.221) for reconstructive surgeons]. CONCLUSION: Despite gradation scales for measuring cosmesis after BCS, high levels of agreement between surgeons is lacking and these do not always reflect patients' subjective assessments.

Characteristics and Long-Term Risk of Breast Angiosarcoma.

BACKGROUND: Angiosarcoma of the breast is rare and aggressive. It can occur as a de novo tumor or secondary to breast cancer treatment. The purpose of this study is to analyze differences between patients with primary and secondary angiosarcoma of the breast and investigate potential risk factors for its development. PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Results program of the National Cancer Institute database was queried to identify patients with angiosarcoma of the breast, trunk, shoulder, and upper arm. The population-based incidence was analyzed. Primary and secondary angiosarcoma cases were identified and compared. Breast cancer characteristics of secondary angiosarcoma patients were compared with all breast cancer patients in the database who did not develop angiosarcoma. RESULTS: Overall, 904 patients were included, and 65.4% were secondary angiosarcomas. These patients had worse survival, were older, more likely to be White, more likely to have regionally advanced disease, and had angiosarcoma tumors of higher pathologic grade. Independent factors associated with development of secondary angiosarcoma among breast cancer patients included White race, older age, invasive tumor, lymph node removal, lumpectomy, radiation treatment, and left-sided tumor. Although the mean time to develop angiosarcoma after breast cancer diagnosis was 8.2 years, the risk continues to increase up to 30 years after breast cancer treatment. CONCLUSION: Angiosarcoma is rare but increasing in incidence. Secondary angiosarcomas are more common and exhibit more aggressive behavior. Several factors for angiosarcoma after breast cancer treatment could be identified, which may help us counsel and identify patients at risk.

Apocrine Breast Cancer: Unique Features of a Predominantly Triple-Negative Breast Cancer.

INTRODUCTION: Invasive apocrine carcinoma is a rare breast cancer that is frequently triple negative. Little is known about the characteristics of its molecular subtypes. We compared the incidence, demographics, and clinicopathologic features of this cancer with non-apocrine carcinomas stratified by molecular subtype. METHODS: Women with invasive apocrine cancer were retrospectively identified from the Surveillance, Epidemiology, and End Results (SEER) database. Clinicopathologic and demographic features were compared with non-apocrine carcinomas, both overall using data from 2004 to 2017 and stratified by molecular subtypes using data from 2010 to 2017. The life table method was used to determine the 7-year breast cancer-specific survival. RESULTS: Compared with non-apocrine cancers, apocrine cancers presented at a younger age, with larger, higher-grade tumors that were much more likely to be triple negative (50% vs. 11%) or human epidermal growth factor receptor 2 (HER2)-positive (28% vs. 15%) and less likely to be luminal (22% vs. 74%); however, the 7-year survival was the same at 85%. The characteristics varied dramatically by molecular type. Compared with non-apocrine triple-negative, apocrine triple-negative patients were less likely to be African American and were much older, with smaller, lower-grade tumors and much better survival (86% vs. 74%). In contrast, compared with luminal non-apocrine, apocrine luminal patients had larger, higher-grade tumors and worse survival (79% vs. 89%). CONCLUSIONS: Invasive apocrine carcinomas have more aggressive features than non-apocrine carcinomas but the breast cancer-specific survival is the same. Half of these apocrine tumors are triple negative but these have more favorable features and much better survival than non-apocrine triple-negative cancers.

Surgical Outcomes of Mastectomy with Immediate Autologous Reconstruction Followed by Radiation.

INTRODUCTION: Timing of autologous reconstruction relative to postmastectomy radiation therapy (PMRT) is debated. Benefits of immediate reconstruction must be weighed against a possibly heightened risk of complications from flap irradiation. We reviewed flap outcomes after single operation plus PMRT in a large institutional cohort. METHODS: Medical records were reviewed for women who underwent simultaneous mastectomy-autologous reconstruction with PMRT from 2007 to 2016. Primary endpoints were rates and types of radiation-related flap complications and reoperations, whose predictors were assessed by multivariable analysis. A p value < 0.10 was deemed significant to avoid type II error. Non-parametric logistic regression generated a model of PMRT timing associated with probabilities of complications and reoperations. RESULTS: One-hundred and thirty women underwent 208 mastectomy reconstruction operations, with a median follow up of 35.1 months (interquartile range 23.6-56.5). Forty-seven (36.2%) women experienced radiation-related complications, commonly fat necrosis (44.1%) and chest wall asymmetry (28.8%). Complications were higher among women who received PMRT < 3 months after surgery (46.8% for < 3 months vs. 29.3% for ≥ 3 months; p = 0.06), most of whom received neoadjuvant chemotherapy, and among women treated with internal mammary nodal (IMN) radiation (65.2% vs. 26.4%; p < 0.01); IMN radiation remained strongly associated in multivariable analysis (odds ratio [OR] 5.24; p < 0.01). Thirty-two (24.6%) women underwent 70 reoperations, commonly fat grafting (51.9%) and fat necrosis excision (17.1%). Reoperations were higher among women who received PMRT < 3 months after surgery (48.9 for < 3 months vs. 36.6 for ≥ 3 months; p = 0.19), which was significantly associated in multivariable analysis (OR 0.42; p = 0.08 for ≥ 3 months). The probabilities of complications and reoperations were lowest when PMRT was administered ≥ 3 months after surgery. CONCLUSIONS: Among a large institutional cohort, immediate autologous reconstruction was associated with similar rates of adverse flap outcomes as historically reported alternatively sequenced protocols. IMN radiation increased risk, while PMRT ≥ 3 months after surgery decreased risk. Additional studies are needed to elaborate the impact of IMN radiation and early PMRT in immediate versus delayed autologous reconstruction.

Management of recurrent bilateral multifocal pseudoangiomatous stromal hyperplasia (PASH).

Pseudoangiomatous stromal hyperplasia (PASH) is a benign hyperplastic condition of the breast that can lead to macromastia. The standard treatment for PASH is focal excision or rarely reduction mammoplasty. We present a rare case of postpartum bilateral rapid breast enlargement and axillary growth that was refractory to reduction mammoplasty. Ultimately, the patient required bilateral mastectomy and two-stage implant-based breast reconstruction. This more extensive form along with its management represents one of the few reported cases in the literature. The decision to pursue bilateral mastectomy was undertaken after exhausting more conservative options. Excellent aesthetic outcome and pain relief was obtained following definitive extirpative and reconstructive surgery.

The impact of communication style on patient satisfaction.

BACKGROUND: Communication between patients and health providers influences patient satisfaction, but it is unknown whether similarity in communication styles results in higher patient satisfaction. METHODS: This study was conducted in the Smilow Cancer Hospital Breast Center. During routine follow-up visits, patients completed a Communication Styles Assessment (CSA), health survey (SF-12), Princess Margaret Hospital Satisfaction with Doctor Questionnaire, and brief demographic form. Physicians and Advanced Practice Providers were also asked to complete the CSA. Patients and providers were blinded to each other's responses. A communication styles concordance score was calculated as the Pearson correlation between 80 binary CSA items for each provider/patient pair. Factors affecting patient satisfaction scores were assessed in mixed-effects models. RESULTS: In total, 330 patients were invited to participate; of these 289 enrolled and 245 returned surveys. One hundred seventy-four completed all survey components, and 18 providers completed the CSA. Among the factors considered, physical health score (effect size = 0.0058, 95% CI 0.00051 to 0.0011, p = 0.032) and employment status (0.12, 95% CI - 0.0094 to 0.25, p = 0.069) had the greatest impact on patient satisfaction. However, patients who were not employed and less physically healthy had significantly elevated satisfaction scores when their communication style was more similar to their provider's (1.52, 95% CI 0.66 to 2.38, p = 0.0016). CONCLUSIONS: Patients who were physically healthy and employed were generally more satisfied with their care. The similarity in communication styles of patients and providers had a greater impact on patient satisfaction for patients who were less physically healthy and not employed.

A Randomized, Controlled Trial of Cavity Shave Margins in Breast Cancer.

BACKGROUND: Routine resection of cavity shave margins (additional tissue circumferentially around the cavity left by partial mastectomy) may reduce the rates of positive margins (margins positive for tumor) and reexcision among patients undergoing partial mastectomy for breast cancer. METHODS: In this randomized, controlled trial, we assigned, in a 1:1 ratio, 235 patients with breast cancer of stage 0 to III who were undergoing partial mastectomy, with or without resection of selective margins, to have further cavity shave margins resected (shave group) or not to have further cavity shave margins resected (no-shave group). Randomization occurred intraoperatively after surgeons had completed standard partial mastectomy. Positive margins were defined as tumor touching the edge of the specimen that was removed in the case of invasive cancer and tumor that was within 1 mm of the edge of the specimen removed in the case of ductal carcinoma in situ. The rate of positive margins was the primary outcome measure; secondary outcome measures included cosmesis and the volume of tissue resected. RESULTS: The median age of the patients was 61 years (range, 33 to 94). On final pathological testing, 54 patients (23%) had invasive cancer, 45 (19%) had ductal carcinoma in situ, and 125 (53%) had both; 11 patients had no further disease. The median size of the tumor in the greatest diameter was 1.1 cm (range, 0 to 6.5) in patients with invasive carcinoma and 1.0 cm (range, 0 to 9.3) in patients with ductal carcinoma in situ. Groups were well matched at baseline with respect to demographic and clinicopathological characteristics. The rate of positive margins after partial mastectomy (before randomization) was similar in the shave group and the no-shave group (36% and 34%, respectively; P=0.69). After randomization, patients in the shave group had a significantly lower rate of positive margins than did those in the no-shave group (19% vs. 34%, P=0.01), as well as a lower rate of second surgery for margin clearance (10% vs. 21%, P=0.02). There was no significant difference in complications between the two groups. CONCLUSIONS: Cavity shaving halved the rates of positive margins and reexcision among patients with partial mastectomy. (Funded by the Yale Cancer Center; ClinicalTrials.gov number, NCT01452399.).

Single-arm, neoadjuvant, phase II trial of pertuzumab and trastuzumab administered concomitantly with weekly paclitaxel followed by 5-fluoruracil, epirubicin, and cyclophosphamide (FEC) for stage I-III HER2-positive breast cancer.

PURPOSE: The purpose of this two-cohort Phase II trial was to estimate the pathologic complete response (pCR: ypT0/is ypN0) rate when trastuzumab plus pertuzumab are administered concurrently during both the taxane and anthracycline phases of paclitaxel and 5-fluorouracil/epirubicin/cyclophosphamide (FEC) neoadjuvant chemotherapy. METHODS: The pCR rates were assessed separately in hormone receptor (HR) positive and negative cases following Simon's two-stage design, aiming to detect a 20% absolute improvement in pCR rates from 50 to 70 and 70 to 90% in the HR-positive and HR-`negative cohorts, respectively. RESULTS: The HR-negative cohort completed full accrual of 26 patients; pCR rate was 80% (95% CI 60-91%). The HR+ cohort was closed early after 24 patients due to lower than expected pCR rate of 26% (95% CI 13-46%) at interim analysis. Overall, 44% of patients (n = 22/50) experienced grade 3/4 adverse events. The most common were neutropenia (n = 10) and diarrhea (n = 7). There was no symptomatic heart failure, but 28% (n = 14) had ≥ 10% asymptomatic decrease in LVEF; in one patient, LVEF decreased to < 50%. Cardiac functions returned to baseline by the next assessment in 57% (8/14) of cases. CONCLUSIONS: Eighty percent of HR-negative, HER2-positive breast cancers achieve pCR with paclitaxel/FEC neoadjuvant chemotherapy administered concomitantly with pertuzumab and trastuzumab. These results are similar to pCR rates seen in trials using HER2-targeted therapy during the taxane phase only of sequential taxane-anthracycline regimens and suggest that we have reached a therapeutic plateau with HER2-targeted therapies combined with chemotherapy in the neoadjuvant setting.

Effect of neoadjuvant chemotherapy on tumor-infiltrating lymphocytes and PD-L1 expression in breast cancer and its clinical significance.

BACKGROUND: The effects of neoadjuvant chemotherapy on immune markers remain largely unknown. The specific aim of this study was to assess stromal tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) protein expression in a cohort of breast cancer patients treated with neoadjuvant chemotherapy. METHODS: Using quantitative immunofluorescence, we investigated stromal TILs and PD-L1 protein expression in pre-treatment and residual breast cancer tissue from a Yale Cancer Center patient cohort of 58 patients diagnosed with breast cancer from 2003 to 2009 and treated with neoadjuvant chemotherapy. We compared the TIL count and PD-L1 status in paired pre-treatment and residual cancer tissues and correlated changes and baseline levels with survival. RESULTS: Of the 58 patients, 46 (79.3%) had hormone-positive and 34 (58.6%) had node-positive breast cancer. Eighty-six percent of residual cancer tissues had TIL infiltration and 17% had PD-L1 expression. There was a trend for higher TIL counts in postchemotherapy compared to prechemotherapy samples (p = 0.09). Increase in TIL count was associated with longer 5-year recurrence-free survival (p = 0.02, HR = 3.9, 95% CI = 1.179-15.39). PD-L1 expression (both stromal and tumor cells) was significantly lower in post-treatment samples (p = 0.001). Change in PD-L1 expression after therapy or TILs and PD-L1 expression in the posttreatment samples did not correlate with survival. CONCLUSIONS: Increase in stromal TILs in residual cancer compared to pretreatment tissue is associated with improved recurrence-free survival. Despite a trend for increasing TIL counts, PD-L1 expression decreased in residual disease compared to pretreatment samples.

Economic Impact of Routine Cavity Margins Versus Standard Partial Mastectomy in Breast Cancer Patients: Results of a Randomized Controlled Trial.

OBJECTIVE: The aim of the study was to compare costs associated with excision of routine cavity shave margins (CSM) versus standard partial mastectomy (PM) in patients with breast cancer. BACKGROUND: Excision of CSM reduces re-excision rates by more than 50%. The economic implications of this is, however, unclear. METHODS: Between October 21, 2011 and November 25, 2013, 235 women undergoing PM for Stage 0-III breast cancer were randomized to undergo either standard PM ("no shave", n = 116) or have additional CSM taken ("shave", n = 119). Costs from both a payer and a hospital perspective were measured for index surgery and breast cancer surgery-related care through subsequent 90 days. RESULTS: The 2 groups were well-matched in terms of baseline characteristics. Those in the "shave" group had a longer operative time at the initial surgery (median 76 vs 66 min, P < 0.01), but a lower re-excision rate for positive margins (13/119 = 10.9% vs 32/116 = 27.6%, P < 0.01). Actual direct hospital costs associated with operating room time ($1315 vs. $1137, P = 0.03) and pathology costs ($1195 vs $795, P < 0.01) were greater for the initial surgery in patients in the "shave" group. Taking into account the index surgery and the subsequent 90 days, there was no significant difference in cost from either the payer ($10,476 vs $11,219, P = 0.40) or hospital perspective ($5090 vs $5116, P = 0.37) between the "shave" and "no shave" groups. CONCLUSIONS: Overall costs were not significantly different between the "shave" and "no shave" groups due to significantly fewer reoperative surgeries in the former.

Association of LN Evaluation with Survival in Women Aged 70 Years or Older With Clinically Node-Negative Hormone Receptor Positive Breast Cancer.

BACKGROUND: Some suggest that lymph node (LN) evaluation not be performed routinely in women aged ≥70 years with clinically (c) LN-negative (-), hormone receptor (HR)-positive (+) breast cancer. We sought to determine the association of omission of LN evaluation on survival. METHODS: Patients who met the above criteria and were diagnosed from 2004 to 2012 were identified in the NCDB and SEER databases. Overall survival (OS) and breast cancer-specific survival (BCSS) were determined. RESULTS: Using the NCDB, we identified 157,584 cLN- HR+ patients aged ≥70 years in whom survival and LN evaluation data were available. A total of 126,638 patients (80.2%) had regional LN surgery. With a median follow-up of 41.6 months, there was a significant difference in OS between those who had LN evaluation and those who did not (median OS: 100.5 vs. 70.9 months, respectively, p < 0.001). After adjusting for patient age, race, insurance, income, comorbidities, tumor characteristics and treatment, patients who had undergone LN evaluation still had a lower hazard rate for death than those who had not (hazard ratio = 0.633; 95% confidence interval [CI] 0.613-0.654, p < 0.001). We then did a parallel analysis using SEER data that showed LN evaluation was associated with a lower hazard rate for both BCSS (hazard ratio = 0.452; 95% CI 0.427-0.479, p < 0.001) and non-BCSS (hazard ratio = 0.465; 95% CI 0.447-0.482, p < 0.001). CONCLUSIONS: Roughly 20% of patients older than aged 70 years with cLN-, HR+ breast cancer did not have LN evaluation. Those who did had better OS controlling for sociodemographic, pathologic, and treatment variables; however, this may be due to patient selection.

Brief-exposure to preoperative bevacizumab reveals a TGF-ß signature predictive of response in HER2-negative breast cancers.

To best define biomarkers of response, and to shed insight on mechanism of action of certain clinically important agents for early breast cancer, we used a brief-exposure paradigm in the preoperative setting to study transcriptional changes in patient tumors that occur with one dose of therapy prior to combination chemotherapy. Tumor biopsies from breast cancer patients enrolled in two preoperative clinical trials were obtained at baseline and after one dose of bevacizumab (HER2-negative), trastuzumab (HER2-positive) or nab-paclitaxel, followed by treatment with combination chemo-biologic therapy. RNA-Sequencing based PAM50 subtyping at baseline of 46 HER2-negative patients revealed a strong association between the basal-like subtype and pathologic complete response (pCR) to chemotherapy plus bevacizumab (p ≤ 0.0027), but did not provide sufficient specificity to predict response. However, a single dose of bevacizumab resulted in down-regulation of a well-characterized TGF-ß activity signature in every single breast tumor that achieved pCR (p ≤ 0.004). The TGF-ß signature was confirmed to be a tumor-specific read-out of the canonical TGF-ß pathway using pSMAD2 (p ≤ 0.04), with predictive power unique to brief-exposure to bevacizumab (p ≤ 0.016), but not trastuzumab or nab-paclitaxel. Down-regulation of TGF-ß activity was associated with reduction in tumor hypoxia by transcription and protein levels, suggesting therapy-induced disruption of an autocrine-loop between tumor stroma and malignant cells. Modulation of the TGF-ß pathway upon brief-exposure to bevacizumab may provide an early functional readout of pCR to preoperative anti-angiogenic therapy in HER2-negative breast cancer, thus providing additional avenues for exploration in both preclinical and clinical settings with these agents.

Racial Differences in Utilization of Breast Conservation Surgery: Results from the National Cancer Data Base (NCDB).

BACKGROUND: Whether rates of breast-conservation surgery (BCS) vary based on race and ethnicity has not been clearly elucidated on a national leve. METHODS: The National Cancer Data Base (NCDB) was used to identify women who underwent surgery for invasive breast cancer during 2010 and 2011. The effect of race and ethnicity on BCS rates was determined, independent of patient demographics, tumor-related variables, and geographic region. RESULTS: There were 299,827 patients with known race and ethnicity who underwent definitive breast surgery. BCS rates by race were as follows: 135,065/241,236 (56.0 %) for whites, 17,819/33,301 (53.5 %) for blacks, 4,722/9,508 (49.7 %) for Asian/Pacific Islanders, and 7,919/15,782 (50.2 %) for Hispanics (p < 0.001). Mean tumor size differed among the racial groups: 2.07 cm in whites, 2.54 cm in blacks, 2.23 cm in Asians, and 2.48 cm in Hispanics (p < 0.001). When stratified by tumor size, BCS was most common in blacks and least common in Asians for all tumors >2 cm (p < 0.001). On multivariable analysis adjusted for age, tumor size, nodal status, grade, molecular type, geographic area, urban/rural residence, insurance status, and census-derived median income and education for the patient's zip code, the odds ratio for BCS for blacks compared to whites was 1.23 (95 % confidence interval [CI] 1.20-1.27, p < 0.001), for Asians was 0.84 (95 % CI 0.80-0.88, p < 0.001), and for Hispanics was 1.00 (95 % CI 0.96-1.05, p = 0.885). CONCLUSIONS: When adjusted for patient demographics, tumor-related variables, and geographic area, BCS rates are higher in blacks and lower in Asians compared to whites.

Use of neoadjuvant chemotherapy for patients with stage I to III breast cancer in the United States.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is the standard of care for patients with locally advanced breast cancer and can yield clinical advantages in individuals with lower stage cancers as well. To the authors' knowledge, the extent and patterns of use of NAC remain unknown. The objective of the current study was to assess temporal trends in NAC use and to examine what clinical, demographic, and treatment site characteristics influence its use. METHODS: Data from the National Cancer Data Base regarding 395,486 patients with stage I to stage III breast cancer who received adjuvant or neoadjuvant chemotherapy in the United States from 2003 through 2011 were analyzed. Chi-square tests and logistic regression analyses were used to assess the association between NAC use and patient, tumor, and facility characteristics. RESULTS: Overall, 17.4% of patients received NAC, including 4% of patients with stage I disease, 17.8% of patients with stage II disease, and 41.6% of patients with stage III disease. NAC use increased over time from 12.2% to 24.0%, particularly among patients with more advanced cancers. Rates increased from 12.9% to 39.3% in patients with stage IIIA, from 72.3% to 86.4% in patients with stage IIIB, and from 30.1% to 59.3% in patients with stage IIIC cancers. On multivariate analysis, patients aged <60 years, African American individuals, and those treated in academic centers were more likely to receive NAC. NAC use also varied by geographic region and was the highest in the West South Central region (21%) and lowest in the Midwest (15.2%). CONCLUSIONS: Although NAC use increased between 2003 and 2011, <50% of all patients with stage III breast cancer were treated with NAC. Substantial regional and practice-related variations exist.