Exosome RNA Unshielding Couples Stromal Activation to Pattern Recognition Receptor Signaling in Cancer.

Interactions between stromal fibroblasts and cancer cells generate signals for cancer progression, therapy resistance, and inflammatory responses. Although endogenous RNAs acting as damage-associated molecular patterns (DAMPs) for pattern recognition receptors (PRRs) may represent one such signal, these RNAs must remain unrecognized under non-pathological conditions. We show that triggering of stromal NOTCH-MYC by breast cancer cells results in a POL3-driven increase in RN7SL1, an endogenous RNA normally shielded by RNA binding proteins SRP9/14. This increase in RN7SL1 alters its stoichiometry with SRP9/14 and generates unshielded RN7SL1 in stromal exosomes. After exosome transfer to immune cells, unshielded RN7SL1 drives an inflammatory response. Upon transfer to breast cancer cells, unshielded RN7SL1 activates the PRR RIG-I to enhance tumor growth, metastasis, and therapy resistance. Corroborated by evidence from patient tumors and blood, these results demonstrate that regulation of RNA unshielding couples stromal activation with deployment of RNA DAMPs that promote aggressive features of cancer. VIDEO ABSTRACT.

Guideline-Concordant Surgical Care for Lobular Versus Ductal Inflammatory Breast Cancer.

INTRODUCTION: Quality of surgical care is understudied for lobular inflammatory breast cancer (IBC), which is less common, more chemotherapy-resistant, and more mammographically occult than ductal IBC. We compared guideline-concordant surgery (modified radical mastectomy [MRM] without immediate reconstruction following chemotherapy) for lobular versus ductal IBC. METHODS:  Female individuals with cT4dM0 lobular and ductal IBC were identified in the National Cancer Database (NCDB) from 2010-2019. Modified radical mastectomy receipt was identified via codes for "modified radical mastectomy" or "mastectomy" and "≥10 lymph nodes removed" (proxy for axillary lymph node dissection). Descriptive statistics, chi-square tests, and t-tests were used. RESULTS: A total of 1456 lobular and 10,445 ductal IBC patients were identified; 599 (41.1%) with lobular and 4859 (46.5%) with ductal IBC underwent MRMs (p = 0.001). Patients with lobular IBC included a higher proportion of individuals with cN0 disease (20.5% lobular vs. 13.7% ductal) and no lymph nodes examined at surgery (31.2% vs. 24.5%) but were less likely to be node-negative at surgery (12.7% vs. 17.1%, all p < 0.001). Among those who had lymph nodes removed at surgery, patients with lobular IBC also had fewer lymph nodes excised versus patients with ductal IBC (median [interquartile range], 7 (0-15) vs. 9 (0-17), p = 0.001). CONCLUSIONS: Lobular IBC patients were more likely to present with node-negative disease and less likely to be node-negative at surgery, despite having fewer, and more frequently no, lymph nodes examined versus ductal IBC patients. Future studies should investigate whether these treatment disparities are because of surgical approach, pathologic assessment, and/or data quality as captured in the NCDB.

Breast Conservation Surgery and Mastectomy Have Similar Locoregional Recurrence After Neoadjuvant Chemotherapy: Results From 1462 Patients on the Prospective, Randomized I-SPY2 Trial.

Neoadjuvant chemotherapy (NAC) increases rates of successful breast-conserving surgery (BCS) in patients with breast cancer. However, some studies suggest that BCS after NAC may confer an increased risk of locoregional recurrence (LRR). We assessed LRR rates and locoregional recurrence-free survival (LRFS) in patients enrolled on I-SPY2 (NCT01042379), a prospective NAC trial for patients with clinical stage II to III, molecularly high-risk breast cancer. Cox proportional hazards models were used to evaluate associations between surgical procedure (BCS vs mastectomy) and LRFS adjusted for age, tumor receptor subtype, clinical T category, clinical nodal status, and residual cancer burden (RCB). In 1462 patients, surgical procedure was not associated with LRR or LRFS on either univariate or multivariate analysis. The unadjusted incidence of LRR was 5.4% after BCS and 7.0% after mastectomy, at a median follow-up time of 3.5 years. The strongest predictor of LRR was RCB class, with each increasing RCB class having a significantly higher hazard ratio for LRR compared with RCB 0 on multivariate analysis. Triple-negative receptor subtype was also associated with an increased risk of LRR (hazard ratio: 2.91, 95% CI: 1.8-4.6, P < 0.0001), regardless of the type of operation. In this large multi-institutional prospective trial of patients completing NAC, we found no increased risk of LRR or differences in LRFS after BCS compared with mastectomy. Tumor receptor subtype and extent of residual disease after NAC were significantly associated with recurrence. These data demonstrate that BCS can be an excellent surgical option after NAC for appropriately selected patients.

Temporal Trends and Factors Associated with Receipt of Post-mastectomy Radiation After Neoadjuvant Chemotherapy in Women with cT3 Breast Cancer.

INTRODUCTION: Given the potential impact of increasingly effective neoadjuvant chemotherapy (NACT) on post-mastectomy radiotherapy (PMRT) recommendations, we examined temporal trends in post-NACT PMRT for cT3 breast cancer. METHODS: We identified women ≥ 18 years in the National Cancer Database (NCDB) diagnosed 2004-2019 with cT3N0-1M0 breast cancer treated with chemotherapy and mastectomy. Multivariable logistic regression and Cox proportional hazards models were used to estimate associations between pathologic NACT response [complete response (CR), partial response (PR), or no response (NR); or disease progression (DP)] and PMRT and between PMRT and overall survival (OS), respectively. RESULTS: We identified 39,901 women (Asian/Pacific Islander 1731, Black 5875, Hispanic 3265, White 27,303). Among cN0 patients with CR, PMRT rates declined from 67% in 2004 to 35% in 2019 but remained unchanged for patients with DP. Relative to NR, CR [odds ratio (OR) 0.36, 95% confidence interval (CI) 0.29-0.46] and PR (OR 0.44, 95% CI 0.36-0.55) in cN0 patients were associated with lower odds of PMRT while DP (OR 1.33, 95% CI 1.05-1.69) was associated with higher odds. Among cN1 patients, PMRT rates decreased from 90% to 73% for CR between 2005 and 2019 and increased from 76% to 82% for DP between 2004 and 2019. Relative to NR, CR (OR 0.78, 95% CI 0.63-0.95) was associated with lower odds of PMRT while DP (OR 1.93, 95% CI 1.58-2.37) was associated with higher odds. PMRT was associated with improved OS among cN1 patients (hazard ratio (HR) 0.77, 95% CI 0.67-0.88). CONCLUSION: CR was associated with decreased PMRT receipt over time, while temporal trends following PR and DP differed by cN status, suggesting that nodal involvement guided PMRT receipt more than in-breast disease.

Impact of Patient Comorbidities on Presentation Stage of Breast and Colon Cancers.

BACKGROUND: While patients with multiple comorbidities may have frequent contact with medical providers, it is unclear whether their healthcare visits translate into earlier detection of cancers, specifically breast and colon cancers. METHODS: Patients diagnosed with stage I-IV breast ductal carcinoma and colon adenocarcinoma were identified from the National Cancer Database and stratified by comorbidity burden, dichotomized as a Charlson Comorbidity Index (CCI) Score of <2 or ≥2. Characteristics associated with comorbidities were analyzed by univariate and multivariate logistic regression. Propensity-score matching was performed to determine the impact of CCI on stage at cancer diagnosis, dichotomized as early (I-II) or late (III-IV). RESULTS: A total of 672,032 patients with colon adenocarcinoma and 2,132,889 with breast ductal carcinoma were included. Patients with colon adenocarcinoma who had a CCI ≥ 2 (11%, n = 72,620) were more likely to be diagnosed with early-stage disease (53% vs. 47%; odds ratio [OR] 1.02, p = 0.017), and this finding persisted after propensity matching (CCI ≥ 2 55% vs. CCI < 2 53%, p < 0.001). Patients with breast ductal carcinoma who had a CCI ≥ 2 (4%, n = 85,069) were more likely to be diagnosed with late-stage disease (15% vs. 12%; OR 1.35, p < 0.001). This finding also persisted after propensity matching (CCI ≥ 2 14% vs. CCI < 2 10%, p < 0.001). CONCLUSIONS: Patients with more comorbidities are more likely to present with early-stage colon cancers but late-stage breast cancers. This finding may reflect differences in practice patterns for routine screening in these patients. Providers should continue guideline directed screenings to detect cancers at an earlier stage and optimize outcomes.

Changes in Surgical Management of the Axilla Over 11 Years - Report on More Than 1500 Breast Cancer Patients Treated with Neoadjuvant Chemotherapy on the Prospective I-SPY2 Trial.

BACKGROUND: Axillary surgery after neoadjuvant chemotherapy (NAC) is becoming less extensive. We evaluated the evolution of axillary surgery after NAC on the multi-institutional I-SPY2 prospective trial. METHODS: We examined annual rates of sentinel lymph node (SLN) surgery with resection of clipped node, if present), axillary lymph node dissection (ALND), and SLN and ALND in patients enrolled in I-SPY2 from January 1, 2011 to December 31, 2021 by clinical N status at diagnosis and pathologic N status at surgery. Cochran-Armitage trend tests were calculated to evaluate patterns over time. RESULTS: Of 1578 patients, 973 patients (61.7%) had SLN-only, 136 (8.6%) had SLN and ALND, and 469 (29.7%) had ALND-only. In the cN0 group, ALND-only decreased from 20% in 2011 to 6.25% in 2021 (p = 0.0078) and SLN-only increased from 70.0% to 87.5% (p = 0.0020). This was even more striking in patients with clinically node-positive (cN+) disease at diagnosis, where ALND-only decreased from 70.7% to 29.4% (p < 0.0001) and SLN-only significantly increased from 14.6% to 56.5% (p < 0.0001). This change was significant across subtypes (HR-/HER2-, HR+/HER2-, and HER2+). Among pathologically node-positive (pN+) patients after NAC (n = 525) ALND-only decreased from 69.0% to 39.2% (p < 0.0001) and SLN-only increased from 6.9% to 39.2% (p < 0.0001). CONCLUSIONS: Use of ALND after NAC has significantly decreased over the past decade. This is most pronounced in cN+ disease at diagnosis with an increase in the use of SLN surgery after NAC. Additionally, in pN+ disease after NAC, there has been a decrease in use of completion ALND, a practice pattern change that precedes results from clinical trials.

Transforming growth factor ß-mediated suppression of antitumor T cells requires FoxP1 transcription factor expression.

Tumor-reactive T cells become unresponsive in advanced tumors. Here we have characterized a common mechanism of T cell unresponsiveness in cancer driven by the upregulation of the transcription factor Forkhead box protein P1 (Foxp1), which prevents CD8⁺ T cells from proliferating and upregulating Granzyme-B and interferon-γ in response to tumor antigens. Accordingly, Foxp1-deficient lymphocytes induced rejection of incurable tumors and promoted protection against tumor rechallenge. Mechanistically, Foxp1 interacted with the transcription factors Smad2 and Smad3 in preactivated CD8⁺ T cells in response to microenvironmental transforming growth factor-ß (TGF-ß), and was essential for its suppressive activity. Therefore, Smad2 and Smad3-mediated c-Myc repression requires Foxp1 expression in T cells. Furthermore, Foxp1 directly mediated TGF-ß-induced c-Jun transcriptional repression, which abrogated T cell activity. Our results unveil a fundamental mechanism of T cell unresponsiveness different from anergy or exhaustion, driven by TGF-ß signaling on tumor-associated lymphocytes undergoing Foxp1-dependent transcriptional regulation.

Awareness of link between obesity and breast cancer risk is associated with willingness to participate in weight loss intervention.

PURPOSE: To assess knowledge of obesity-associated cancer risk, self-awareness of BMI status, and willingness to engage in weight loss intervention in breast cancer survivors with overweight and obesity as a companion study for a novel weight loss program using a telehealth platform (NCT04855552). METHODS: Breast cancer survivors with BMI ≥ 25 kg/m2 were surveyed to assess self-perception of BMI, knowledge of obesity-related cancer risk, and willingness to participate in weight loss programs. Multivariable logistic regression was used to assess factors associated with willingness to participate. RESULTS: Of the 122 participants, 73 (59.8%) had BMI 25.0-29.9 kg/m2 (overweight) and 49 (40.2%) had BMI ≥ 30 (obesity). Patients with obesity were more likely to underestimate their BMI than those with overweight, 40.8% vs. 23.3% (p = 0.03). The majority (82.0%) indicated awareness that obesity increases breast cancer risk and 57.4% expressed interest in a weight loss program. Patients with knowledge of obesity-related breast cancer risk (91.4% willing vs. 69.2% not willing, p < 0.01) were more willing to participate in a weight loss program on univariable and multivariable analyses (p < 0.01). CONCLUSION: Our results underscore the importance of raising patients' awareness of obesity-related health risks and individual BMI category. Future work in the development of better education and communication tools to improve awareness will likely improve the adoption rate of healthy lifestyles in at-risk patients.

Preoperative MRI and Its Impact on Surgical Outcomes in Patients with Triple Negative Breast Cancer Treated with Primary Surgery: Did New Margin Guidelines or Cavity Shave Margins Practice Diminish the Role of Preoperative MRI?

BACKGROUND: Results of an earlier retrospective study from our institution suggested that patients with triple negative breast cancer (TNBC) who had preoperative MRI may have had an improved local recurrence rate (LRR) after breast conserving surgery (BCS). We aimed to clarify the impact of preoperative MRI on surgical outcomes in an expanded TNBC cohort treated by BCS in a contemporary era. METHODS: Our study cohort comprised 648 patients with TNBC who underwent BCS between 2009 and 2018. Demographic and clinical characteristics were compared between those with (n = 292, 45.1%) and without (n = 356, 54.9%) preoperative MRI. Multivariable logistic regression was performed to assess the association of preoperative MRI with surgical outcomes. RESULTS: The crude LRR of 3.5% was lower than previously reported. Univariable analyses demonstrated that the LRR and re-excision rates in the MRI and no-MRI groups were 3.4 and 3.7%, 21.6% and 27.2%, p = 0.876 and p = 0.10, respectively. Multivariable logistic regression analyses demonstrated that preoperative MRI was not associated with a lower LRR: odds ratio (OR) = 1.42 (p = 0.5). During our study period, new margin guidelines and shave margins practice were adopted in 2014 and 2015. To account for their effects, the year of diagnosis/surgery and other clinical variables were adjusted in multivariable logistic regression and inverse probability weighting models to demonstrate that preoperative MRI remained associated with a lower re-excision risk, OR 0.56, p = 0.04l; and a lower re-excision rate, 23.15% versus 36.0%, p < 0.01, respectively. CONCLUSIONS: Our findings suggested that patients with TNBC anticipating BCS may benefit from preoperative MRI.

New Operative Reporting Standards: Where We Stand Now and Opportunities for Innovation.

BACKGROUND: The American College of Surgeons Commission on Cancer's (CoC) new operative standards for breast cancer, melanoma, and colon cancer surgeries will require that surgeons provide synoptic documentation of essential oncologic elements within operative reports. Prior to designing and implementing an electronic tool to support synoptic reporting, we evaluated current documentation practices at our institution to understand baseline concordance with these standards. METHODS: Applicable procedures performed between 1 January 2018 and 31 December 2018 were included. Two independent reviewers evaluated sequential operative notes, up to a total of 100 notes, for documentation of required elements. Complete concordance (CC) was defined as explicit documentation of all required CoC elements. Mean percentage CC and surgeon-specific CC were calculated for each procedure. Interrater reliability was assessed via Cohen's kappa statistic. RESULTS: For sentinel lymph node biopsy, mean CC was 66% (n = 100), with surgeon-specific CC ranging from 6 to 100%, and for axillary dissection, mean CC was 12% (n = 89) and surgeon-specific CC ranged from 0 to 47%. The single surgeon performing melanoma wide local excision had a mean CC of 98% (n = 100). For colon resections, mean CC was 69% (n = 96) and surgeon-specific CC ranged from 39 to 94%. Kappa scores were 0.77, 0.78, -0.15, and 0.78, respectively. CONCLUSIONS: We identified heterogeneity in current documentation practices. In our cohort, rates of baseline concordance varied across surgeons and procedures. Currently, documentation elements are interspersed within the operative report, posing challenges to chart abstraction with resulting imperfect interrater reliability. This presents an exciting opportunity to innovate and improve compliance by introducing an electronic synoptic documentation tool.

PTGES3 is a Putative Prognostic Marker in Breast Cancer.

BACKGROUND: The COX/prostaglandin (COX/PG) pathway plays a role in cancer pathogenesis via the production of prostaglandin E2 (PGE2). In breast cancer, the expression patterns of the COX/PG pathway enzymes involved in PGE2 synthesis are not well defined. MATERIALS AND METHODS: Using the Cancer Genome Atlas data, we analyzed the expression patterns of cyclooxygenases, COX1 (PTGS1) and COX2 (PTGS2), and four downstream enzymes of the COX/prostaglandin pathway - PTGS3 (PTGDS), PTGES1, PTGES2 and PTGES3 - in invasive breast cancer. The Clinical Proteomic Tumor Analysis Consortium database was used to determine the expression of these six genes at the protein level. Existing single-cell RNA sequencing data were used to evaluate the expression of the six COX/PG genes in luminal and basal epithelial cells from normal breast tissues. Cox regression Kaplan-Meier adjusted survival analyses were performed to evaluate the association of COX/PG pathway genes in overall survival using the TCGA data. Finally, we utilized the Tumor Immune Estimation Resource to correlate the expression of these six COX/PG genes with tumor infiltrating immune cell number. RESULTS: COX1, COX2 and PTGES3 were significantly upregulated at the protein level in breast cancer compared to normal tissues (P < 0.005). However, only PTGES3 expression was elevated at both the mRNA and protein level in breast cancer (P < 0.0005). PTGES3 is the most highly expressed enzymes within the COX/PG pathway in both luminal and basal epithelial cells in normal breast tissues. Using Cox Regression Kaplan-Meier survival analysis, PTGES3 expression had a significant inverse prognostic association with breast cancer survival [HR >1.43, P = 0.0057]. Elevated PTGES3 expression within the tumor microenvironment significantly correlated with CD8+ T cell abundance, suggesting a possible immunomodulatory role of PTGES3 in the tumor microenvironment. CONCLUSIONS: PTGES3, a terminal synthetase in the COX/prostaglandin pathway, is a putative prognostic marker in breast cancer.

Effectiveness of a Short Duration of Neoadjuvant Endocrine Therapy in Patients with HR+ Breast Cancer-An NCDB Analysis (2004-2016).

BACKGROUND: National medical/surgical organizations have recommended the use of neoadjuvant endocrine therapy (NET) to bridge surgery delay of weeks to months for patients with hormone receptor positive (HR+) breast cancer during the ongoing coronavirus disease 2019 (COVID-19) pandemic. The effects of NET of varying durations on pathologic response are unclear. Using the National Cancer Database (NCDB), we evaluated objective response to short (< 9 weeks), moderate (9-27 weeks), and long (> 27 weeks) duration of NET. PATIENTS AND METHODS: The study cohort included female patients diagnosed with nonmetastatic invasive HR+ breast cancer, stratifying by those who received NET versus no NET between 2004 and 2016. Pathologic response was grouped into four categories (complete, downstaged, stable, upstaged) by comparing clinical and pathologic staging data. Objective response to NET included complete, downstaged, and stable pathologic response. Clinical characteristics were compared using χ2 and analysis of variance (ANOVA) tests. Multivariable logistic regression was used to determine factors associated with NET use and objective response according to NET duration. RESULTS: A minority (1.2%) received NET in our cohort. Factors associated with NET use included older age, non-Black patients, more advanced clinical stage, higher comorbidity score, government insurance, and lobular histology. Objective response rate (ORR) was 56.7%, 52.1%, and 49.0% after short, moderate, and long NET duration, respectively. CONCLUSION: Short NET duration did not result in an inferior ORR. Future study to evaluate the interaction between surgery delay and NET use on clinical outcome will provide insights into the safety of NET to bridge potential surgery delay in patients with HR+ breast cancer.

Immediate Breast Reconstruction for Inflammatory Breast Cancer: Trends in Use and Clinical Outcomes 2004-2016.

INTRODUCTION: National guidelines specify against immediate breast reconstruction (IBR) among inflammatory breast cancer (IBC) patients. However, limited data exist regarding this practice. We report practice patterns and oncologic outcomes among nonmetastatic IBC patients receiving trimodality therapy, with or without IBR. METHODS: Using the National Cancer Database, we identified nonmetastatic IBC patients treated with trimodality therapy from 2004 to 2016. Primary outcome was overall survival (OS), assessed on unadjusted analysis using Kaplan-Meier estimates and on adjusted analysis using multivariable Cox proportional hazards and inverse probability weighting (IPW) models. OS analysis was also conducted with propensity score matched (PSM) cohorts. Secondary outcomes included IBR utilization rates, time to postmastectomy radiotherapy (PMRT), and surgical outcomes. RESULTS: 6589 women were included, including 5954 (90.4%) non-reconstructed and 635 (9.6%) IBR. Among IBR recipients, 250 (39.4%) underwent autologous reconstruction, 171 (26.9%) underwent implant-based reconstruction, and 214 (33.7%) unspecified. IBR utilization increased from 6.3% to 10.1% from 2004 to 2016 at a 4% average annual growth rate (P < 0.001). Median follow-up was 43 and 45 months for IBR and non-reconstructed patients, respectively (P = 0.29). On Cox multivariable analysis, IBR was associated with improved OS (HR 0.63, 95% CI 0.44-0.90, P = 0.01), but this association was not significant on IPW analysis (P = 0.06). In PSM cohorts, this association remained significant (HR 0.60, 95% CI 0.40-0.92, P = 0.02). Margin status, time to PMRT, 30-day readmission, and 30-/90-day mortality did not differ between groups (all P > 0.05). CONCLUSION: Although not endorsed by national guidelines, IBR is increasing among IBC patients; however, more granular data are needed to determine oncologic safety.

CDH2/N-cadherin and early diagnosis of invasion in patients with ductal carcinoma in situ.

PURPOSE: This proof-of-concept study investigates gene expression in core needle biopsies (CNB) to predict whether individuals diagnosed with ductal carcinoma in situ (DCIS) on CNB were affected by invasion at the time of diagnosis. METHODS: Using a QuantiGene Plex 2.0 assay, 14 gene expression profiling was performed in 303 breast tissue samples. Preoperative diagnostic performance of a gene was measured by area under receiver-operating characteristic curve (AUC) with 95% confidence interval (CI). The gene mRNA positivity cutoff was computed using Gaussian mixture model (GMM); protein expression was measured by immunohistochemistry; DNA methylation was evaluated by targeted bisulfite sequencing. RESULTS: mRNA from 69% (34/49) mammoplasties, 72% (75/104) CNB DCIS, and 89% (133/150) invasive breast cancers (IBC) were analyzed. Based on pre-and post-surgery DCIS chart reviews, 21 cases were categorized as DCIS synchronous with invasion and 54 DCIS were pure DCIS without pathologic evidence of invasive disease. The ectopic expression of neuronal cadherin CDH2 was probable in 0% mammoplasties, 6% pure DCIS, 29% synchronous DCIS, and 26% IBC. The CDH2 mRNA positivity in preoperative biopsies showing pure DCIS was predictive of a final diagnosis of invasion (AUC = 0.67; 95% CI 0.53-0.80; P = 0.029). Site-specific methylation of the CDH2 promoter (AUC = 0.76; 95% CI 0.54-0.97; P = 0.04) and measurements of N-cadherin, a pro-invasive cell-cell adhesion receptor encoded by CDH2 (AUC = 0.8; 95% CI 0.66-0.99; P < 0.005) had a discriminating power allowing for discernment of CDH2-positive biopsy. CONCLUSIONS: Evidence of CDH2/N-cadherin expression, predictive of invasion synchronous with DCIS, may help to clarify a diagnosis and direct the course of therapy earlier in a patient's care.

Utility of Oncotype DX in Male Breast Cancer Patients and Impact on Chemotherapy Administration: A Comparative Study with Female Patients.

BACKGROUND: Use of the Oncotype DX recurrence score (RS) has been widely adopted in women with early-stage hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER-) breast cancer (BC). Validation studies on the use of RS in male BC (MBC) are lacking. OBJECTIVE: The aim of this study was to identify the utilization of RS and association with chemotherapy recommendations in early-stage MBC compared with female BC (FBC). METHODS: Using the National Cancer Database (NCDB), a retrospective review was performed for patients with T1/T2, node-negative, HR+/HER2- BC between 2010 and 2014. Patients were stratified by demographics, tumor characteristics, RS, and chemotherapy use comparing MBC with FBC over the allotted time period. RESULTS: A total of 358,497 patients-3068 (0.8%) males and 355,429 (99.1%) females-met the inclusion criteria. A smaller proportion of MBC patients received RS testing compared with FBC patients (32% vs. 35%, p < 0.001). Male patients who had RS were younger, had T2 tumors, lymphovascular invasion, and private insurance. The distribution of RS was similar in both groups. Only 4% of MBC patients with low RS received adjuvant chemotherapy, compared with 4.9% of FBC patients. Overall chemotherapy rates were similar in MBC and FBC patients. CONCLUSIONS: Our results showed that RS has not been completely embraced in the management of MBC, although when performed in MBC, chemotherapy recommendations vary based on RS. Whether the use of RS affects the clinical outcomes of MBC is unknown. A prospective registry would help clarify and evaluate the impact of RS on clinical outcomes in MBC.

Impact of 21-Gene Expression Assay on Clinical Outcomes in Node-Negative ≤ T1b Breast Cancer.

BACKGROUND: Prior to the advent of Oncotype DX 21-gene recurrence score (oDX) assay, the National Comprehensive Cancer Network (NCCN) guideline supported omission of adjuvant chemotherapy in patients with ≤ 1 cm (T1b) hormone receptor-positive (HR +), human epidermal growth factor receptor 2 (HER2-) node tumors. However, around 30% of these patients would have an oDX recurrence score that warrants consideration of adjuvant chemotherapy. To clarify the potential benefit of oDX in these patients, we performed a retrospective analysis comparing clinical outcomes of women with T1a or T1b, N0 HR + HER2- according to performance of oDX. PATIENTS AND METHODS: After receiving institutional review board (IRB) approval, an institutional database was queried to identify patients with HR + HER2- ≤ T1bN0 tumors (n = 2307) diagnosed between 2009 and 2018. Patients were further stratified by recurrence score (RS) defined as low (< 18), intermediate (18-30), or high (> 30). Log-rank, Kaplan-Meier, and inverse probability of treatment weighting (IPW) analyses were used to compare disease-free survival (DFS) and overall survival (OS) across groups. RESULTS: Performance of oDX (n = 1149, 49.8%) was associated with larger tumors, younger age, and White race. On univariate analysis, performance of oDX was associated with improved OS (P < 0.01). On multivariate IPW analysis, performance of oDX lengthened DFS by an average of 16.5 months, while OS was similar between groups (P < 0.01 and P = 0.73). The improved DFS was mainly driven by those with tumors ≥ T1b. CONCLUSIONS: Overall, outcomes were excellent regardless of oDX testing. Performance of oDX testing was associated with improved DFS in patients with tumors ≥ T1b. Our results support routine use of oDX testing in patients with tumors ≥ T1b.

Refining the indications for neoadjuvant chemotherapy for patients with HER2+ breast cancer: A single institution experience.

BACKGROUND: We aim to compare the clinical outcomes of patients with early-stage HER2+ breast cancer treated with adjuvant chemotherapy (AC) and neoadjuvant chemotherapy (NAC). METHODS: Patients with non-metastatic HER2+ breast cancer treated from 2009 to 2018 at our institution comprised our study cohort (n = 1254). Pathologic complete response (pCR) was defined as the absence of invasive disease in the breast and axilla after NAC. Log-rank, Kaplan-Meier, and inverse probability of treatment weighting were used to assess differences in disease-free and overall survival between groups stratified by AC vs. NAC and pCR vs. non-pCR. RESULTS: The majority received AC (n = 787 or 62.8%) while 467 (37.2%) patients received NAC. Median follow up for AC and NAC groups was 46 and 28 months, respectively. The crude disease-free survival and overall survival of our study cohort were 92.2% and 89.1% for AC, 89.1% and 82.2% for NAC pCR, and 68.1% and 60.0% for NAC non-pCR, respectively. For clinical stage ≥IIB patients, NAC conferred a positive but statistically nonsignificant treatment effect over AC in multivariate analysis. CONCLUSIONS: After adjusting for imbalances in our subgroups, we found that, regardless of the sequence of chemotherapy (AC vs. NAC), patients with early-stage HER2+ breast cancer had excellent outcomes.

Changing practice patterns of adjuvant radiation among elderly women with early stage breast cancer in the United States from 2004 to 2014.

Randomized controlled trials (RCTs) have challenged the need for routine radiation therapy (RT) in women ≥ age 70 with favorable early stage breast cancer (BC) due to modest improvement in local control and no survival benefit. We studied practice patterns in RT among elderly women in the United States. We analyzed data from the National Cancer Database (NCDB) of women ≥age 70 diagnosed with T1 or T2 and N0 invasive BC treated with breast conservation surgery (BCS) between 2004 and 2014. Patients were divided into four groups: (1) no RT, (2) partial breast irradiation (PBI); (3) hypofractionation (HF); and (4) conventional whole breast RT (CWBI). Univariable and multivariable analyses (MVA) were performed to compare characteristics among the four RT groups. A subgroup analysis of women with favorable disease (T1N0 ER + HER2-) was also performed with similar statistical comparisons. Of the 66,126 meeting eligibility, 9,570 (14.5%) had PBI, 16,340 (24.7%) had HF, and 40,117 (60.7%) had CWBI. Only 99 patients (0.15%) had RT omitted. Omission of RT increased marginally from 0.04% in 2004 to 0.24% in 2014. MVA identified older age (OR 1.18, CI 1.08-1.28), more comorbidities (Charlson-Deyo Score of 1) (OR 3.36, CI 1.29-8.72), and no hormone therapy (OR 22.07, CI 5.79-84.07) as more likely to have RT omitted. The use of HF increased from 3.9% to 47.0%, P < .001 with a concomitant decrease in CWBI from 88% to 41%, P < .001. MVA identified older age, treatment location, and omission of chemotherapy as associated with HF. No significant differences from the larger cohort were found among the T1N0 subgroup analysis. Despite RCT evidence, omission of RT was rare in the United States, suggesting that more effective outreach methods to disseminate clinical guideline information may be needed.

Impact of long-term lipid-lowering therapy on clinical outcomes in breast cancer.

INTRODUCTION: The use of statins has been associated with improved survival in patients with breast cancer in several studies but results have been mixed. This study evaluates the impact of duration of statin use on breast cancer patient outcomes. METHODS: This is a single-institution, retrospective cohort, examining the impact of statin use on the outcomes of 1523 women diagnosed with operable breast cancer between1995 and 2015. Clinical variables were compared using Student's t test, Fisher's exact and Chi square tests. Overall (OS) and disease-free (DFS) survival were performed using Kaplan-Meier and Cox-Proportional Hazard (Cox-PH) analysis in the statistical software R. RESULTS: Patients were grouped by duration of statin use: never-statin user [N] (n = 1092), short (< 3 years) [S] (n = 115), moderate [M] (3-5 years) (n = 109) and long [L] (> 5 years) (n = 207) term. Over a median follow-up of 70.2 months, 138 women died (84 died of breast cancer) and 125 had disease recurrence. On multivariable Cox-PH analysis adjusting for clinical variables including metabolic comorbidities using the Charlson comorbidity index, OS in the [S] and [M] subgroups did not differ [N], while OS was improved in [L] (adjusted hazard ratio (AHR) 0.38, confidence interval (CI) 0.17-0.85, p < 0.018). DFS was also significantly improved in the [L] subgroup (adjusted HR 0.15, CI 0.05-0.48, p < 0.001). Subanalysis stratified by receptor status showed a trend towards improved DFS in all tumor subtypes including triple-negative breast cancer. CONCLUSIONS: Our retrospective analyses suggest that long-term statin use (> 5 years) was associated with improved OS and DFS in women with breast cancer regardless of receptor subtype, even after adjusting for metabolic comorbidities.

Does time to adjuvant chemotherapy (TTC) affect outcomes in patients with triple-negative breast cancer?

PURPOSE: A recent study reported that time to adjuvant chemotherapy (TTC) > 30 days was significantly associated with worse OS and DFS in triple-negative breast cancer (TNBC). Earlier studies, however, found that worse outcomes were associated with TTC > 60 days or > 90 days. As the trend for mastectomy with reconstruction continues to rise, TTC of < 30 days is often not feasible due to wound-healing issues in some of these patients. To elucidate the impact of TTC, we sought to evaluate the clinical outcomes associated with TTC in a contemporary cohort treated for TNBC at a single institution. METHODS: A single-institution database was queried to identify nonmetastatic TNBC patients who received adjuvant chemotherapy from 2009 to 2018. TTC was defined as interval between date of surgery and adjuvant chemotherapy start date. Median TTC was used to divide our cohort into four quartiles; ≤ 31, 32-42, 43-56, and > 56 days. Logrank, Kaplan-Meier, and inverse probability weighting (IPW) tests were used to analyze disease-free (DFS) and overall survival (OS). RESULTS: The mean TTC of our study cohort (n = 724) was 48 days (median TTC = 42 days). Black race, mastectomy without adjuvant radiation, and mastectomy with immediate reconstruction were associated with delayed TTC (all p-values < 0.01). In multivariate IPW analysis, TTC > 56 (n = 173) days did not impact DFS or OS compared to TTC ≤ 31 (n = 198) days (p = 0.27 and p = 0.21, respectively). Similar results were seen during subgroup analysis for groups identified as higher risk for delayed TTC. CONCLUSION: Our results demonstrated that TTC was not significant or significantly associated with DFS or OS in patient receiving chemotherapy for operable TNBC. Our results were reassuring for patients electing mastectomy with immediate reconstruction, who may experience a longer TTC.