Citations

Abstract Purpose: Prevention of chemotherapy-induced nausea and vomiting (CINV) is essential to preserve quality of life in cancer patients receiving highly emetogenic chemotherapy (HEC) such as doxorubicin-cyclophosphamide (AC) or cisplatin. Recently, new drugs (e.g. fosaprepitant and newer neurokinin 1 receptor antagonists [NK1RAs], rolapitant and netupitant) and updated guidelines for antiemetic use (e.g. adding olanzapine) have emerged. However, trends in real world antiemetic use are understudied. Methods: We performed a retrospective study using the OptumLabs Data Warehouse (OLDW), which includes administrative claims for privately insured and Medicare Advantage enrollees in the U.S. We identified 34,236 patients age 18 years or older treated with either AC or cisplatin between January 2006 and June 2016. Data collected included baseline demographics (age, gender, census region and race), chemotherapy administered, and presence/absence of a central intravenous access device. Trends of anti-emetic use were presented overall and separately for 5-HT receptor antagonists (5HT3RAs) and NK1RAs. Results: 23,030 patients (67.3%) received an anthracycline-based regimen (AC with or without docetaxel or paclitaxel), and 11,206 (32.7%) patients received cisplatin. Approximately two thirds of patients were female (n= 23,392). Dexamethasone use was stable over the decade (used by 85-90% in all years). Use of 5HT3RAs, primarily palonosetron and ondansetron, occurred in at least 95% of patients in all study years, consistent with guideline recommendations. NK1RAs were underutilized early on compared with guideline recommendations, but use increased to approximately 80% in the most recently evaluated year. Fosaprepitant use rose precipitously starting in 2009, preceding a sharp fall in aprepitant use beginning in 2011. The use of olanzapine, rolapitant and netupitant was minimal throughout the study period. Conclusions: Dexamethasone and 5-HT3RAs were used in the vast majority of patients receiving HEC, in accordance with guideline recommendations. Less compliance with guidelines was seen with NK1RA use. Citation Format: O'Sullivan CC, Van Houten HK, Sangaralingham L, Leal AD, Shinde S, Liu H, Ettinger D, Loprinzi CL, Ruddy KJ. Ten year trends in antiemetic prescribing in cancer patients receiving highly emetogenic chemotherapy (HEC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-11-18.

Abstract This abstract was withdrawn by the authors.

Abstract Background:Late recurrence (emergence from dormancy) is characteristic of ER+ breast cancers. Despite adjuvant endocrine therapy, many breast cancers recur decades after their initial diagnosis and treatment. Why this occurs is poorly understood. Methods: We studied 2 independent datasets of endocrine treated, ER+ breast cancers with up to 20 years follow-up. The 1st comprised matched samples from the primary tumor pretreatment at diagnosis and the first recurrence after or during adjuvant endocrine therapy (all FFPE). The 2nd dataset comprised pretreatment biopsies only (all snap frozen). For both datasets, high quality RNA was amplified, labelled, and subjected to transcriptome analysis using the Affymetrix technology (U133 Plus 2.0). Low quality data were identified using 'simpleaffy' and 'ffpe', and removed; all tools were from the R package unless otherwise noted. Remaining data were normalized using 'frma'. Genes differentially expressed between early (≤3 years) and late (≥ 5 years) were selected using limma. Unsupervised hierarchical clustering and PCA explored the structure of the data. A similar molecular analysis was done on the 2nd dataset. A classification scheme that robustly separated early from late recurrences was validated in an independent public dataset of comparable patients, array platform, and frozen tissues. We also explored features in pretreatment samples that predetermined response duration. Results: Genes that separated pretreatment specimens by recurrence time did not separate posttreatment specimens. Specimens did not cluster in patient pairs or by site of recurrence. 8245 genes were differentially expressed between early and late recurrences in the FFPE samples, while 2400 genes were significantly different in the same comparison in the frozen samples. Initial pathway analysis was done on each dataset independently using IPA (Ingenuity® Systems, www.ingenuity.com). 70 canonical pathways were identified in common between the two datasets (pretreatment). We then looked for genes regulated in both datasets (ignores FFPE and frozen tissue as source). There were 279 genes in common that differentially regulated in the same direction (upregulated; downregulated). IPA analysis of these genes identified 49 canonical pathways. We also explored the differentially expressed gene sets using 'GSEA' (www.software.broadinstitute.org/gsea/index.jsp). Pathways consistently associated with early vs. late recurrence include integrin signaling, the unfolded protein response, endoplasmic reticulum stress, actin-based motility, and estrogen biosynthesis. Conclusion: Analysis of pretreatment tumors can predict early recurrences from those that will remain dormant and recur much later. Recurrent tumors exhibit a remodeled molecular landscape that likely reflects the effects of treatments and/or a recreation of a niche with potentially common features at the site of recurrence. Changes in molecular signaling associated with duration of recurrence are consistent with our experimental model studies in vitro implicating UPR signaling as a major integrator of response to endocrine therapy and duration of survival. Additional data sets are being arrayed and more detailed molecular signaling studies are in progress. Citation Format: Clarke R, Dixon MJ, Jin L, Turnbull A, Hu R, Zwart A, Wang Y, Xuan J, Sengupta S, Renshaw L, Sims A, Liu MC. Molecular features of dormancy in ER+ breast cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-10.

Abstract Background: While TNBC remains the most aggressive type of breast cancer (BC), substantial heterogeneity in biology and outcomes exists among TNBC subtypes. Historically, risk stratification of TNBC has been based on anatomic factors such as tumor size, nodal involvement and presence of distant metastases. However, these features alone fail to accurately predict outcomes. Tumor immune infiltration (sTILs) and distribution of immune cell subsets in the perip heral blood (NLR) have emerged as variables reported to be associated with outcomes in TNBC. We sought to evaluate whether NLR and sTILs provided independent prognostic information in TNBC. Methods: From a cohort of 9,982 women who underwent BC surgery at Mayo Clinic, Rochester, MN between Jan 1985 and Dec 2012, we identified 605 centrally-confirmed TNBC tumors. Patients (pts) with prior BC, bilateral BC, non-invasive disease, stage IV, neoadjuvant therapy, endocrine therapy, or adenoid cystic histology were excluded. For eligible tumors, clinical and pathologic variables were evaluated, including peripheral blood NLR and central assessment of sTILs per the 2014 International TILs Working Group recommendations. We calculated the Pearson correlation coefficient (PCC) between NLR and sTILs and constructed Cox Proportional Hazards Models to evaluate their association with invasive-disease free (IDFS) and overall survival (OS). NLR and sTILs were both analyzed as continuous variables. Results: Most pts had T1-2 (95%) and N0-1 disease (86%). Median OS follow-up was 10.6yrs. Median IDFS was 12yrs (95%CI 10.2-16.7) and median OS was 18.8yrs (95%CI 15.6-20.8). NLR and sTILs were available in 408 and 599 pts, respectively. The median NLR and sTIL content were 2.29 (0.14-10.50) and 20% (0-90%), respectively. NLR and sTILs were poorly correlated (PCC 0.0237). On univariate analysis (UVA), a higher NLR was associated with worse IDFS (HR 1.13; 95%CI 1.02-1.26, p=0.02) and OS (HR 1.17; 95%CI 1.04-1.31, p=0.01). Each 1% increment in sTILs was associated with improved IDFS (HR 0.99; 95%CI 0.98-0.99, p<0.001) and OS (HR 0.99, 95%CI 0.98-1.00, p<0.001). Among pts with high sTILs (≥20%), a higher NLR remained significantly associated with worse IDFS (HR 1.21; 95%CI 1.05-1.38, p=0.007) and OS (HR 1.25; 95%CI 1.09-1.44, p=0.001). In contrast, among pts with low sTILs (<20%), NLR was not associated with IDFS (HR 1.07; 95%CI 0.89-1.28, p=0.49) or OS (HR 1.07; 95%CI 0.88-1.30, p=0.49). The interaction test between NLR and sTILs did not reach statistical significance. A multivariate analysis (MVA; including age, menopausal status, histologic subtype, grade, tumor size, nodal stage, Ki-67, NLR, sTILs, adjuvant chemotherapy, type of surgery and adjuvant radiation) showed that sTILs remained independently associated with IDFS (HR 0.99, 95%CI 0.97-1.0, p=0.019) and OS (HR 0.99, 95% CI 0.97-1.0, p=0.044), whereas NLR did not. Conclusions: A lower NLR and a higher sTIL content were each associated with improved IDFS and OS among pts with nonmetastatic TNBC on UVA. However, when evaluated on a MVA, only sTILs remained independently associated with IDFS and OS. Our data suggest that the effect of sTILs on outcomes may not be modified by the NLR. Citation Format: Leon-Ferre RA, Polley M-Y, Liu H, Gilbert J, Cafourek V, Hillman D, Negron V, Boughey JC, Liu MC, Ingle JN, Kalari K, Couch FJ, Visscher DW, Goetz MP. Prognostic value of the neutrophil-to-lymphocyte ratio (NLR) and its relation to stromal tumor infiltrating lymphocytes (sTILs) in triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-05-06.

Abstract Purpose: Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with substantial risks of disease recurrence. While cytotoxic chemotherapy is commonly administered and reduces recurrence, disease outcomes vary considerably and few prognostic tools are available for risk stratification for TNBC patients. We constructed and validated clinical calculators for invasive-disease free survival (IDFS) and overall survival (OS) for TNBC and compared their performance against AJCC-based models which include only tumor size and nodal status. Methods: From a surgical cohort of 9,982 patients who underwent breast cancer surgery at Mayo Clinic between January 1985 and December 2012, 605 centrally reviewed TNBC patients were identified and used to construct Cox models for IDFS and OS. Patients treated with neoadjuvant chemotherapy were excluded. Variables considered included age, menopausal status, tumor size, nodal status, Nottingham grade, type of breast surgery (mastectomy vs. lumpectomy), adjuvant radiation therapy, adjuvant chemotherapy, Ki67, stromal tumor infiltrating lymphocytes (sTILs), and neutrophil-to-lymphocyte ratio (NLR). Missing values were imputed using single imputation with all variables (including outcomes) included in the imputation model. Backward step-down procedure was used for model selections. The final models were internally validated for calibration and discrimination using bootstrapping methods and compared with AJCC-based models. Results: For both IDFS and OS, higher sTIL's, less extensive nodal involvement, use of adjuvant chemotherapy, and lower NLR were significant predictors of improved clinical outcomes. Premenopausal status and younger age were additionally predictive of improved IDFS and OS, respectively. Models for IDFS and OS have good calibration and are associated with bias-corrected C-indices of 0.68 and 0.71, respectively, as compared with C-indices of 0.59 and 0.62 for AJCC-based models. Conclusions: Our data indicate that a clinical calculator that includes sTIL's, NLR, menopausal status, age, nodal involvement as well as chemotherapy use can provide significantly greater prediction of clinical risk than tumor size and nodal status alone. These tools may be used to identify TNBC patients at elevated risk of disease relapse and to aid physician's communication with patients regarding their long-term disease outlook and planning treatment strategies. External validation is required to further evaluate broader applicability of this tool, which was developed utilizing a single-institutional experience. Citation Format: Polley M-YC, Leon-Ferre RA, Liu H, Gilbert J, Cafourek V, Hillman DW, Negron V, Boughey JC, Liu MC, Ingle JN, Kalari K, Couch F, Visscher DW, Goetz MP. Mayo clinic TNBC outcome calculator: A clinical calculator to predict disease relapse and survival in women with triple-negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-06-07.

Abstract Background: Mammography (digital 2D or digital 3D/tomosynthesis) is the cornerstone of current screening strategies for breast cancer, but new approaches are needed to further reduce the proportion of cancers diagnosed at advanced stages and more effectively identify those women in need of additional testing and biopsies. Circulating cell-free nucleic acids (cfNAs) shed from tumors, isolated from peripheral blood, and analyzed with ultra-deep and broad sequencing of cancer-associated genes, have great potential for early cancer detection. The ultimate goal is to develop blood cfNA cancer screening tests for use in conjunction with established risk factors and/or radiographic features for improved cancer detection. Development of these tests requires large, well-annotated cohorts of asymptomatic participants with adequate volumes of prediagnostic blood. The STRIVE Study cohort was recently established to train and validate cfNA-based tests for early detection of breast cancer. Eligibility criteria and trial design: The STRIVE Study is a new prospective, multi-ethnic mammography cohort that will recruit 120,000 subjects from 15+ US breast cancer screening centers (including Mayo Clinic and Sutter Health sites). Eligibility criteria require only that a participant has a scheduled routine screening mammogram at a participating center and has not received a biopsy prior to the research blood draw. Participants are recruited within 28 days of screening mammography (digital or tomosynthesis), consent electronically, provide blood samples, and complete an on-line risk factor questionnaire. Participants will be followed for all cancer diagnoses, cancer recurrences, and death for at least 5 years. Pertinent medical record information, imaging findings (including breast density), and follow-up data will be transferred electronically to a central database throughout the study period. Additional blood samples will be collected from participants with abnormal mammogram results, or who are diagnosed with cancer, to document and better understand the evolution of cfNA signals. Recruitment began in February 2017. Primary Aims: To train and validate a cfNA blood-based test to identify breast cancer overall in a cohort of women undergoing screening mammography. Statistical Methods: The study will be divided into a training phase (1/3 of participants) and an independent clinical validation phase (remaining 2/3 of participants). In the training phase, statistical machine learning techniques will be used to develop algorithms incorporating cfNA signals, clinical characteristics, or radiological features. In the validation phase, the prespecified locked algorithm developed from the training phase will be clinically validated in an independent group of women. Contact information for people with a specific interest in the trial: Additional details regarding the STRIVE Study are available on the ClinicalTrials.gov website (NCT03085888). For site-specific questions, please call 844-366-9738 for the Mayo Clinic and 1-855-578-7483 for Sutter Health. Citation Format: Liu MC, Cummings S, Vachon CM, Kerlikowske K, Couch FJ, Morris EA, Olson JE, Polley EC, Conners AL, Ellis RL, Patel B, Maimone IV S, Zhang N, Hamilton S, Clarke CA, Allen BA, Maddala T, Hartman A-R. Development of cell-free nucleic acid-based tests for early detection of breast cancer: The STRIVE study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-02-01.

Abstract Background: Patients with breast cancer (BC) and chest wall disease have limited treatment options. We hypothesize that checkpoint inhibition may be an effective treatment approach due to the inflammatory nature of chest wall infiltration, and the association of PD-1 expression with lymphocytic infiltration. Platinum chemotherapy may facilitate anti-tumor immunity in a synergistic manner, and clinical studies of the PD-1 inhibitor pembrolizumab with platinum combinations have been effective in the treatment of advanced lung cancer. In this study, we will evaluate the combination of carboplatin and pembrolizumab in BC patients with chest wall disease. Methods: This is a randomized phase II multicenter study in the TBCRC including patients with advanced, unresectable BC with hormone resistant or triple negative chest wall disease. Patients may have had prior surgery, prior chest wall radiation is not required, and other sites of distant metastases are allowed. Eighty-four patients at TBCRC sites will be randomized 2:1 to receive pembrolizumab and carboplatin (n=56, Arm A) or carboplatin alone (n=28, Arm B) until disease progression. Patients randomized to Arm B may cross-over following progression to pembrolizumab alone (Arm Bx). Patients in Arm A will be treated with pembrolizumab 200 mg IV and carboplatin AUC 5 IV every 3 weeks for at least 6 cycles followed by maintenance pembrolizumab 200 mg IV every 3 weeks if stable or responding disease. Patients in Arm B will be treated with carboplatin AUC 5 IV every 3 weeks until progression, then may cross-over to pembrolizumab 200 mg IV every 3 weeks alone (Arm Bx). An interim analysis for futility will be performed after 18 patients are enrolled into Arm B to allow early closure of that arm for lack of efficacy. The primary endpoint is disease control rate at 18 weeks of treatment; the study is powered to detect a 20% difference in disease control rates between arms (hazard ratio 0.52, α= 0.10, β= 0.20). Secondary endpoints include progression free survival, toxicity, and response based on PD-L1 expression and irRECIST. Exploratory endpoints include association of response with a number of biomarkers including tumor PD-L1 gene expression, tumor and peripheral blood immune composition and cytokine expression, peripheral T-cell PD-1 expression, circulating tumor DNA, circulating tumor cells, and tumor MYC genomic expression using tumor biopsy and peripheral blood testing before and after treatment. This study should be open to accrual by August of 2017. (NCT03095352) Citation Format: Vidula N, Goga A, Krummel M, Hwang J, Liu M, Park BH, Nanda R, Pohlmann P, Storniolo AM, Van Poznak C, Brufsky A, Abramson V, Wolff A, Rugo HS. TBCRC 044: A randomized phase II study of pembrolizumab in combination with carboplatin versus carboplatin alone in breast cancer patients with chest wall disease [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-02-03.

Abstract Stereotactic Radiosurgery ( SRS ) is considered standard of care for patients with 1–3 brain metastases ( BM ). Recent observational studies have shown equivalent OS in patients with 5+ BM compared to those with 2–4, suggesting SRS alone may be appropriate in these patients. We aim to review outcomes of patients treated with SRS with 2–4 versus 5+ BM . This analysis included consecutive patients from 1994 to 2015 treated with SRS . Of 1017 patients, we excluded patients with a single BM and patients without adequate survival data, resulting in 391 patients. All risk factors were entered into univariate analysis using Cox proportional hazards model, and significant factors were entered into multivariate analysis ( MVA ). We additionally analyzed outcomes after excluding patients with prior surgery or whole‐brain radiotherapy ( WBRT ). Median follow‐up was 7.1 months. Median KPS was 90, mean age was 59, and most common histologies were melanoma and lung. Median tumor volume was 3.41 cc. Patients with 2–4 BM had a median OS of 8.1 months compared to 6.2 months for those with 5+ BM ( P = 0.0136). On MVA , tumor volume, KPS , and histology remained significant for OS , whereas lesion number did not. Similar results were found when excluding patients with prior surgery or WBRT . Rather than lesion number, the strongest prognostic factors for patients undergoing SRS were tumor volume >10 cc, KPS , and histology. BM number may therefore not be the most important criterion for candidacy for SRS . Patients with 5 or more BM should be considered for SRS .

Abstract Background Physical therapy is an important treatment option for patients with low back pain (LBP). However, whether to refer patients for physical therapy and the timing of initiation remain controversial. Objective The objective of this study was to evaluate the impact of receiving physical therapy and the timing of physical therapy initiation on downstream health care utilization and costs among patients with acute LBP. Design The design was a retrospective cohort study. Methods Patients who had a new onset of LBP between January 1, 2009, and December 31, 2013, in New York State were identified and grouped into different cohorts on the basis of whether they received physical therapy and the timing of physical therapy initiation. The probability of service use and LBP-related health care costs over a 1-year period were analyzed. Results Among 46,914 patients with acute LBP, 40,246 patients did not receive physical therapy and 6668 patients received physical therapy initiated at different times. After controlling for patient characteristics and adjusting for treatment selection bias, health care utilization and cost measures over the 1-year period were the lowest among patients not receiving physical therapy, followed by patients with immediate physical therapy initiation (within 3 days), with some exceptions. Among patients receiving physical therapy, those receiving physical therapy within 3 days were consistently associated with the lowest health care utilization and cost measures. Limitations This study was based on commercial insurance claims data from 1 state. Conclusions When referral for physical therapy is warranted for patients with acute LBP, immediate referral and initiation (within 3 days) may lead to lower health care utilization and LBP-related costs.

Abstract Tumor-associated macrophages (TAM) play a critical role in cancer development and progression. However, the heterogeneity of TAM presents a major challenge to identify clinically relevant markers for protumor TAM. Here, we report that expression of adipocyte/macrophage fatty acid–binding protein (A-FABP) in TAM promotes breast cancer progression. Although upregulation of A-FABP was inversely associated with breast cancer survival, deficiency of A-FABP significantly reduced mammary tumor growth and metastasis. Furthermore, the protumor effect of A-FABP was mediated by TAM, in particular, in a subset of TAM with a CD11b+F4/80+MHCII−Ly6C− phenotype. A-FABP expression in TAM facilitated protumor IL6/STAT3 signaling through regulation of the NFκB/miR-29b pathway. Collectively, our results suggest A-FABP as a new functional marker for protumor TAM. Significance: These findings identify A-FABP as a functional marker for protumor macrophages, thus offering a new target for tumor immunotherapy. Cancer Res; 78(9); 2343–55. ©2018 AACR.