Immune Phenotype and Postoperative Complications After Elective Surgery.

OBJECTIVES: To characterize and quantify accumulating immunologic alterations, pre and postoperatively in patients undergoing elective surgical procedures. BACKGROUND: Elective surgery is an anticipatable, controlled human injury. Although the human response to injury is generally stereotyped, individual variability exists. This makes surgical outcomes less predictable, even after standardized procedures, and may provoke complications in patients unable to compensate for their injury. One potential source of variation is found in immune cell maturation, with phenotypic changes dependent on an individual's unique, lifelong response to environmental antigens. METHODS: We enrolled 248 patients in a prospective trial facilitating comprehensive biospecimen and clinical data collection in patients scheduled to undergo elective surgery. Peripheral blood was collected preoperatively, and immediately on return to the postanesthesia care unit. Postoperative complications that occurred within 30 days after surgery were captured. RESULTS: As this was an elective surgical cohort, outcomes were generally favorable. With a median follow-up of 6 months, the overall survival at 30 days was 100%. However, 20.5% of the cohort experienced a postoperative complication (infection, readmission, or system dysfunction). We identified substantial heterogeneity of immune senescence and terminal differentiation phenotypes in surgical patients. More importantly, phenotypes indicating increased T-cell maturation and senescence were associated with postoperative complications and were evident preoperatively. CONCLUSIONS: The baseline immune repertoire may define an immune signature of resilience to surgical injury and help predict risk for surgical complications.

The impact of chemotherapy sequence on survival in node-positive invasive lobular carcinoma.

BACKGROUND AND OBJECTIVES: We sought to evaluate the impact of chemotherapy sequence on survival by comparing node-positive invasive lobular carcinoma (ILC) patients who received neoadjuvant (NACT) and adjuvant (ACT) chemotherapy. METHODS: cT1-4c, cN1-3 ILC patients in the National Cancer Data Base (2004-2013) who underwent surgery and chemotherapy were divided into NACT and ACT cohorts. Kaplan-Meier curves and Cox proportional hazards modeling were used to estimate unadjusted and adjusted overall survival (OS), respectively. RESULTS: Five thousand five hundred fifty-one (35.6%) of 15 573 ILC patients treated with chemotherapy received NACT. NACT patients had similar rates of pT3/4 disease (26.6% vs 26.2%), nodal involvement (median 3 vs 4), and number of lymph nodes examined (median 13 vs 14) but higher rates of mastectomy (81.8% vs 74.5%, P < 0.001) vs ACT patients. 3.4% of NACT patients experienced pathologic complete response (pCR). Unadjusted 10-year OS was worse for NACT vs ACT patients (65.1% vs 54.4%, log-rank P < 0.001). After adjustment for known covariates, NACT continued to be associated with worse OS (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.25-1.52). CONCLUSIONS: In node-positive ILC, NACT yielded low rates of pCR, was not associated with lower rates of mastectomy or less extensive axillary surgery, and was associated with worse survival vs ACT, suggesting limited benefit for these patients.

Trends and variations in postmastectomy radiation therapy for breast cancer in patients with 1 to 3 positive lymph nodes: A National Cancer Data Base analysis.

BACKGROUND: High-level evidence is lacking to guide treatment decisions about postmastectomy radiation therapy (PMRT) in patients who have breast cancer with 1 to 3 positive lymph nodes who receive contemporary systemic therapies, leading to potential variations in PMRT delivery. The objective of this study was to examine nationwide trends in PMRT use in this group. METHODS: The National Cancer Data Base (NCDB) was used to identify 93,372 women who had T1-T2N1 breast cancer diagnosed between 2003 and 2012. Patients who received neoadjuvant chemotherapy or radiation therapy (RT) and those who had bilateral breast cancers were excluded. Time trends were evaluated using the Cochrane-Armitage test and correlated the receipt of PMRT with various patient demographic, facility, clinicopathologic, and treatment variables using multivariable logistic regression. A second analysis was performed for patients who were diagnosed during 2010 and included radiation oncologist density as an additional covariate. P values < .0001 were considered statistically significant. RESULTS: Overall, 22.5% of the study population received PMRT, representing an increase from 19.1% in 2003 to 30.3% in 2012. Factors associated with greater PMRT use included younger age, lower Charlson-Deyo comorbidity scores, shorter distance to the treating facility, treatment at a comprehensive cancer program, facility location in the New England Census division, and higher density of radiation oncologists. Increased PMRT use was associated with later year of diagnosis, receipt of chemotherapy, receipt of hormone therapy, higher grade disease, larger tumor size, greater numbers of positive lymph nodes, positive margins, and absence of immediate breast reconstruction (all P < .0001). CONCLUSIONS: The receipt of PMRT by patients with breast cancer who have 1 to 3 positive lymph nodes has increased over time, with wide variability in practice patterns in the United States. Cancer 2018;124:482-90. © 2017 American Cancer Society.

Intra-tumor molecular heterogeneity in breast cancer: definitions of measures and association with distant recurrence-free survival.

PURPOSE: The purpose of the study was to define quantitative measures of intra-tumor heterogeneity in breast cancer based on histopathology data gathered from multiple samples on individual patients and determine their association with distant recurrence-free survival (DRFS). METHODS: We collected data from 971 invasive breast cancers, from 1st January 2000 to 23rd March 2014, that underwent repeat tumor sampling at our institution. We defined and calculated 31 measures of intra-tumor heterogeneity including ER, PR, and HER2 immunohistochemistry (IHC), proliferation, EGFR IHC, grade, and histology. For each heterogeneity measure, Cox proportional hazards models were used to determine whether patients with heterogeneous disease had different distant recurrence-free survival (DRFS) than those with homogeneous disease. RESULTS: The presence of heterogeneity in ER percentage staining was prognostic of reduced DRFS with a hazard ratio of 4.26 (95% CI 2.22-8.18, p < 0.00002). It remained significant after controlling for the ER status itself (p < 0.00062) and for patients that had chemotherapy (p < 0.00032). Most of the heterogeneity measures did not show any association with DRFS despite the considerable sample size. CONCLUSIONS: Intra-tumor heterogeneity of ER receptor status may be a predictor of patient DRFS. Histopathologic data from multiple tissue samples may offer a view of tumor heterogeneity and assess recurrence risk.

How to Navigate the Treatment Spectrum from Multimodality Therapy to Observation Alone for ductal carcinoma in situ.

DCIS detection has increased dramatically since the introduction of screening mammography. Current guidance concordant care recommends surgical intervention for all patients with DCIS, followed by radiation and/or endocrine therapy for some. Adjuvant therapies after surgical excision have reduced recurrence rates but not breast cancer mortality. Given the lack of evidence of current treatment regimens and the morbidity associated with these treatments, there is concern that DCIS is over-treated. Active surveillance may be a favorable alternative for selected patients and is currently being investigated through four international clinical trials.

Adaptive stress response genes associated with breast cancer subtypes and survival outcomes reveal race-related differences.

Aggressive breast cancer variants, like triple negative and inflammatory breast cancer, contribute to disparities in survival and clinical outcomes among African American (AA) patients compared to White (W) patients. We previously identified the dominant role of anti-apoptotic protein XIAP in regulating tumor cell adaptive stress response (ASR) that promotes a hyperproliferative, drug resistant phenotype. Using The Cancer Genome Atlas (TCGA), we identified 46-88 ASR genes that are differentially expressed (2-fold-change and adjusted p-value < 0.05) depending on PAM50 breast cancer subtype. On average, 20% of all 226 ASR genes exhibited race-related differential expression. These genes were functionally relevant in cell cycle, DNA damage response, signal transduction, and regulation of cell death-related processes. Moreover, 23% of the differentially expressed ASR genes were associated with AA and/or W breast cancer patient survival. These identified genes represent potential therapeutic targets to improve breast cancer outcomes and mitigate associated health disparities.

Prediction of Upstaged Ductal Carcinoma In Situ Using Forced Labeling and Domain Adaptation.

OBJECTIVE: The goal of this study is to use adjunctive classes to improve a predictive model whose performance is limited by the common problems of small numbers of primary cases, high feature dimensionality, and poor class separability. Specifically, our clinical task is to use mammographic features to predict whether ductal carcinoma in situ (DCIS) identified at needle core biopsy will be later upstaged or shown to contain invasive breast cancer. METHODS: To improve the prediction of pure DCIS (negative) versus upstaged DCIS (positive) cases, this study considers the adjunctive roles of two related classes: atypical ductal hyperplasia (ADH), a non-cancer type of breast abnormity, and invasive ductal carcinoma (IDC), with 113 computer vision based mammographic features extracted from each case. To improve the baseline Model A's classification of pure vs. upstaged DCIS, we designed three different strategies (Models B, C, D) with different ways of embedding features or inputs. RESULTS: Based on ROC analysis, the baseline Model A performed with AUC of 0.614 (95% CI, 0.496-0.733). All three new models performed better than the baseline, with domain adaptation (Model D) performing the best with an AUC of 0.697 (95% CI, 0.595-0.797). CONCLUSION: We improved the prediction performance of DCIS upstaging by embedding two related pathology classes in different training phases. SIGNIFICANCE: The three new strategies of embedding related class data all outperformed the baseline model, thus demonstrating not only feature similarities among these different classes, but also the potential for improving classification by using other related classes.

Pediatric phyllodes tumors: A review of the National Cancer Data Base and adherence to NCCN guidelines for phyllodes tumor treatment.

BACKGROUND: Phyllodes tumors are fibroepithelial breast lesions that are uncommon in women and rare among children. Due to scarcity, few large pediatric phyllodes tumor series exist. Current guidelines do not differentiate treatment recommendations between children and adults. We examined national guideline adherence for children and adults. METHODS: We queried the NCDB (2004-2014) for female patients with phyllodes tumor histology, excluding patients with missing age or survival data. Patients were stratified by age (pediatric <21, adult ≥21), and compared based on patient characteristics, treatment patterns, and survival. RESULTS: We identified 2787 cases of phyllodes tumor (2725 adult, 62 pediatric). Median age was 17years in children and 52years in adults. Margin positivity rates and median tumor size were similar between adults and children. Treatment was discordant with NCCN guidelines in 28.6% of adults and 14.5% of children through use of axillary staging, chemotherapy, adjuvant endocrine therapy, and radiotherapy. Five-year and ten-year survival were comparable between both groups. CONCLUSION: Children and adults present with similarly sized phyllodes tumors. Trends reveal high margin positivity rates, and overtreatment with regional axillary staging and systemic adjuvant therapies. Particularly in children, treatment decisions must consider risks of adjuvant therapy including radiation-related second primary cancers, given uncertain benefit. TYPE OF STUDY: Retrospective Comparative Study. LEVEL OF EVIDENCE: Level III.

Genetic and phenotypic characteristics of pleomorphic lobular carcinoma in situ of the breast.

The clinical, pathologic, and molecular features of pleomorphic lobular carcinoma in situ (PLCIS) and the relationship of PLCIS to classic LCIS (CLCIS) are poorly defined. In this study, we analyzed 31 cases of PLCIS (13 apocrine and 18 nonapocrine subtypes) and compared the clinical, pathologic, immunophenotypic, and genetic characteristics of these cases with those of 24 cases of CLCIS. Biomarker expression was examined using immunostaining for E-cadherin, gross cystic disease fluid protein-15, estrogen, progesterone, androgen receptor, human epidermal growth factor receptor2, CK5/6, and Ki67. Array-based comparative genomic hybridization to assess the genomic alterations was performed using microdissected formalin-fixed paraffin-embedded samples. Patients with PLCIS presented with mammographic abnormalities. Histologically, the tumor cells were dyshesive and showed pleomorphic nuclei, and there was often associated necrosis and microcalcifications. All lesions were E-cadherin negative. Compared with CLCIS, PLCIS showed significantly higher Ki67 index, lower estrogen receptor and progesterone receptor expression, and higher incidence of HER2 gene amplification. The majority of PLCIS and CLCIS demonstrated loss of 16q and gain of 1q. Apocrine PLCIS had significantly more genomic alterations than CLCIS and nonapocrine PLCIS. Although lack of E-cadherin expression and the 16q loss and 1q gain-array-based comparative genomic hybridization pattern support a relationship to CLCIS, PLCIS has clinical, mammographic, histologic, immunophenotypic, and genetic features that distinguish it from CLCIS. The histologic features, biomarker profile, and genomic instability observed in PLCIS suggest a more aggressive phenotype than CLCIS. However, clinical follow-up studies will be required to define the natural history and most appropriate management of these lesions.