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Chemotherapy is the most commonly prescribed treatment for patients with aggressive and lethal triple negative breast cancers (TNBCs), which often develop chemoresistance. A recent study combined single nucleus sequencing, single cell RNA sequencing, and evolutionary biology to understand how tumor cells use genetic and phenotypic diversity to evade the selective pressures of neoadjuvant chemotherapy.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Extent of response to neoadjuvant chemotherapy, tumor size, and patient age are important prognostic variables for patients with osteosarcoma, but applying information from these continuous variables in survival models is difficult. Dichotomization is usually inappropriate and alternative statistical techniques should be considered instead. Nonlinear multivariable regression methods (restricted cubic splines and fractional polynomials) were applied to data from the National Cancer Database to model continuous prognostic factors for overall survival from localized, high-grade osteosarcoma of the appendicular and nonspinal skeleton following neoadjuvant chemotherapy and surgical resection (N=2493). The assumption that log hazard ratios were linear in relation to these continuous prognostic factors was tested using likelihood ratio tests of model deviance and Wald tests of spline coefficients. Log hazard ratios for increasing patient age were linear over the range of 4 to 80 years, but showed evidence for variation in the coefficient over elapsed follow-up time. Tumor size also showed a linear relationship with log hazard over the range of 1 to 30 cm. Hazard ratios for chemotherapy effect profoundly deviated from log-linear (P<0.004), with significantly decreased hazard for death from baseline for patients with ≥90% tumor necrosis (hazard ratio, 0.32; 95% confidence interval, 0.20-0.52; P<0.0001). Important implications of these results include: (1) ≥90% tumor necrosis defines good chemotherapy response in a clinically useful manner; (2) staging osteosarcoma by dichotomizing tumor size is inappropriate; and (3) patient age can be modeled as a linear effect on the log hazard ratio in prognostic models with the caveat that risk may change over duration of the analysis.
BACKGROUND - A subset of patients with rectal cancer who undergo neoadjuvant chemoradiation therapy will develop a complete pathologic tumor response. Complete nodal response is not universal in these patients and is difficult to assess clinically. Quantifying the risk of nodal disease would allow for targeted therapy with either radical resection or "watchful waiting."
OBJECTIVE - This study aimed to identify risk factors for residual nodal disease in ypT0 rectal adenocarcinoma.
DESIGN - This is a retrospective case control study.
SETTINGS - The National Cancer Database 2006 to 2014 was used to identify patients for this study.
PATIENTS - Patients with stage II/III rectal adenocarcinoma who completed chemoradiation therapy followed by resection and who had ypT0 tumors were included. Patients with metastatic disease and <2 lymph nodes evaluated were excluded. Patients were divided into 2 groups: node positive and node negative.
MAIN OUTCOME MEASURES - The main outcome was nodal disease. The secondary outcome was overall survival.
RESULTS - A total of 42,257 patients with stage II/III rectal cancer underwent chemoradiation therapy and radical resection; 4170 (9.9%) patients had ypT0 tumors and 395 (9.5%) were node positive. Of patients with clinically node-negative disease (ie, pretreatment imaging), 6.2% were node positive after chemoradiation therapy and resection. In multivariable analysis, factors predictive of nodal disease included increasing (pretreatment) clinical N-stage, high tumor grade (3/4), perineural invasion, and lymphovascular invasion. Higher clinical T-stage was inversely associated with residual nodal disease. Overall 5-year survival was significantly different between patients with ypN0, ypN1, and ypN2 disease (87.4%, 82.2%, and 62.5%, p = 0.002).
LIMITATIONS - This study was limited by the lack of clinical detail in the database and the inability to assess recurrence.
CONCLUSIONS - Ten percent of patients with ypT0 tumors had positive nodes after chemoradiation therapy and resection. Factors associated with residual nodal disease included clinical nodal disease at diagnosis and poor histologic features. Patients with any of these features should consider radical resection regardless of tumor response. Others could be suitable for "watchful waiting" strategies. See Video Abstract at http://links.lww.com/DCR/A458.
PURPOSE - Anorectal gastrointestinal stromal tumors (GISTs) are exceedingly rare, and management remains controversial in regard to local resection (LR) and preoperative chemotherapy.
METHODS - The National Cancer Data Base was queried from 1998 to 2012 for cases of GIST resection in the rectum or anus. Patient demographics, type of surgery (LR vs. radical excision [RE]), short-term outcomes, and overall survival (OS) were analyzed. Preoperative chemotherapy was recorded following the US FDA approval of imatinib in 2002.
RESULTS - Overall, 333 patients with resection of anorectal GISTs were included. Mean age at presentation was 62.3 years (range 22-90), and median tumor size was 4.0 cm (interquartile range 2.2-7.0). Five-year OS for all patients was 77.6%. In a multivariable survival analysis, only age and tumor size >5 cm (hazard ratio 2.48, 95% confidence interval 1.50-4.01; p = 0.004) were associated with increased mortality. One hundred and sixty-three (49.0%) patients underwent LR, compared with 158 (47.4%) who underwent RE. For tumors smaller than 5 cm, no difference in 5-year survival by surgical approach was observed (LR 82.3% vs. RE 82.6%; p = 0.71). Fifty-nine patients (17.7%) received preoperative chemotherapy; for patients undergoing RE with tumors >5 cm, there was decreased mortality in the group who received preoperative chemotherapy (5-year OS with chemotherapy 79.2% vs. no chemotherapy 51.2%; p = 0.03).
CONCLUSIONS - Size is the most important determinant in survival following resection. Local excision is common, with resection split between LR and RE. For smaller tumors, LR may be adequate therapy. Preoperative chemotherapy may result in improved survival for large tumors treated with radical resection, but the data are imperfect.
Triple-negative breast cancer (TNBC) is a heterogeneous disease that can be classified into distinct molecular subtypes by gene expression profiling. Considered a difficult-to-treat cancer, a fraction of TNBC patients benefit significantly from neoadjuvant chemotherapy and have far better overall survival. Outside of BRCA1/2 mutation status, biomarkers do not exist to identify patients most likely to respond to current chemotherapy; and, to date, no FDA-approved targeted therapies are available for TNBC patients. Previously, we developed an approach to identify six molecular subtypes TNBC (TNBCtype), with each subtype displaying unique ontologies and differential response to standard-of-care chemotherapy. Given the complexity of the varying histological landscape of tumor specimens, we used histopathological quantification and laser-capture microdissection to determine that transcripts in the previously described immunomodulatory (IM) and mesenchymal stem-like (MSL) subtypes were contributed from infiltrating lymphocytes and tumor-associated stromal cells, respectively. Therefore, we refined TNBC molecular subtypes from six (TNBCtype) into four (TNBCtype-4) tumor-specific subtypes (BL1, BL2, M and LAR) and demonstrate differences in diagnosis age, grade, local and distant disease progression and histopathology. Using five publicly available, neoadjuvant chemotherapy breast cancer gene expression datasets, we retrospectively evaluated chemotherapy response of over 300 TNBC patients from pretreatment biopsies subtyped using either the intrinsic (PAM50) or TNBCtype approaches. Combined analysis of TNBC patients demonstrated that TNBC subtypes significantly differ in response to similar neoadjuvant chemotherapy with 41% of BL1 patients achieving a pathological complete response compared to 18% for BL2 and 29% for LAR with 95% confidence intervals (CIs; [33, 51], [9, 28], [17, 41], respectively). Collectively, we provide pre-clinical data that could inform clinical trials designed to test the hypothesis that improved outcomes can be achieved for TNBC patients, if selection and combination of existing chemotherapies is directed by knowledge of molecular TNBC subtypes.
BACKGROUND - Osteosarcomas arising in the proximal femur, humerus, and tibia appear to have poorer outcomes than those arising in distal long bones. However, the strength of this association is uncertain, particularly in light of other prognostic factors. Therefore, this retrospective cohort study was performed to compare patient outcomes between proximal and distal tumor location within extremity long bones.
MATERIAL AND METHODS - A total of 153 patients with conventional high-grade osteosarcoma of the extremity long bones, pelvis, or axial skeleton who had undergone neoadjuvant chemotherapy and surgical resection between 1985 and 2010 were identified in the Surgical Pathology files at Vanderbilt Medical Center. Effect of anatomic location within a proximal long bone was assessed using multivariable Cox proportional hazard regression.
RESULTS - Proximal tumor location was a strong predictor of poor prognosis in univariate survival analysis. Multivariate regression analysis showed that after controlling for American Joint Committee on Cancer (AJCC) stage, histologic response to chemotherapy, surgical resection margin status, and histologic type, location in the proximal femur, tibia, and humerus were independent risk factors for death due to osteosarcoma, but not event-free survival.
CONCLUSION - Osteosarcomas of the proximal extremity long bones are associated with decreased disease-specific survival compared to tumors of the distal long bones, even after accounting for other key prognostic covariates.
BACKGROUND - Recently, a gene expression algorithm, TNBCtype, was developed that can divide triple-negative breast cancer (TNBC) into molecularly-defined subtypes. The algorithm has potential to provide predictive value for TNBC subtype-specific response to various treatments. TNBCtype used in a retrospective analysis of neoadjuvant clinical trial data of TNBC patients demonstrated that TNBC subtype and pathological complete response to neoadjuvant chemotherapy were significantly associated. Herein we describe an expression algorithm reduced to 101 genes with the power to subtype TNBC tumors similar to the original 2188-gene expression algorithm and predict patient outcomes.
METHODS - The new classification model was built using the same expression data sets used for the original TNBCtype algorithm. Gene set enrichment followed by shrunken centroid analysis were used for feature reduction, then elastic-net regularized linear modeling was used to identify genes for a centroid model classifying all subtypes, comprised of 101 genes. The predictive capability of both this new "lean" algorithm and the original 2188-gene model were applied to an independent clinical trial cohort of 139 TNBC patients treated initially with neoadjuvant doxorubicin/cyclophosphamide and then randomized to receive either paclitaxel or ixabepilone to determine association of pathologic complete response within the subtypes.
RESULTS - The new 101-gene expression model reproduced the classification provided by the 2188-gene algorithm and was highly concordant in the same set of seven TNBC cohorts used to generate the TNBCtype algorithm (87%), as well as in the independent clinical trial cohort (88%), when cases with significant correlations to multiple subtypes were excluded. Clinical responses to both neoadjuvant treatment arms, found BL2 to be significantly associated with poor response (Odds Ratio (OR) =0.12, p=0.03 for the 2188-gene model; OR = 0.23, p < 0.03 for the 101-gene model). Additionally, while the BL1 subtype trended towards significance in the 2188-gene model (OR = 1.91, p = 0.14), the 101-gene model demonstrated significant association with improved response in patients with the BL1 subtype (OR = 3.59, p = 0.02).
CONCLUSIONS - These results demonstrate that a model using small gene sets can recapitulate the TNBC subtypes identified by the original 2188-gene model and in the case of standard chemotherapy, the ability to predict therapeutic response.
Although there are considerable data on the use of mathematical modeling to describe tumor growth and response to therapy, previous approaches are often not of the form that can be easily applied to clinical data to generate testable predictions in individual patients. Thus, there is a clear need to develop and apply clinically relevant oncologic models that are amenable to available patient data and yet retain the most salient features of response prediction. In this study we show how a biomechanical model of tumor growth can be initialized and constrained by serial patient-specific magnetic resonance imaging data, obtained at two time points early in the course of therapy (before initiation and following one cycle of therapy), to predict the response for individual patients with breast cancer undergoing neoadjuvant therapy. Using our mechanics coupled modeling approach, we are able to predict, after the first cycle of therapy, breast cancer patients that would eventually achieve a complete pathologic response and those who would not, with receiver operating characteristic area under the curve (AUC) of 0.87, sensitivity of 92%, and specificity of 84%. Our approach significantly outperformed the AUCs achieved by standard (i.e., not mechanically coupled) reaction-diffusion predictive modeling (0.75), simple analysis of the tumor cellularity estimated from imaging data (0.73), and the Response Evaluation Criteria in Solid Tumors (0.71). Thus, we show the potential for mathematical model prediction for use as a prognostic indicator of response to therapy. The work indicates the considerable promise of image-driven biophysical modeling for predictive frameworks within therapeutic applications.
©2015 American Association for Cancer Research.
OBJECTIVES - Neoadjuvant chemotherapy (NAC) before radical cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC). Many patients are referred to an academic medical center (AMC) for cystectomy but receive NAC in the community setting. This study examines if administration of NAC in the community is associated with differences in type of NAC received, pathologic response rate (pT0), and time to cystectomy as compared to NAC administered at an AMC.
METHODS - We performed a retrospective study of patients with MIBC (cT2a-T4-Nx-M0) referred to a single AMC between 1/2012 and 1/2014 who received NAC. We analyzed chemotherapy received, time to cystectomy, pT0, and survival in patients who received NAC in our AMC compared to those treated in the community.
RESULTS - In all, 47 patients were analyzed. A similar total dose of cisplatin (median: 280 mg/m(2) for both groups, P = 0.82) and pT0 rate (25% vs. 29%, P = 0.72) were seen in patients treated in our AMC and the community. However, administration of NAC in the community was associated with a prolonged time to cystectomy compared with that in our AMC (median number of days 162 vs. 128, P<0.01). This remained significant after adjusting for stage, comorbidity status, and distance to the AMC (P = 0.02). Disease-free survival and overall survival did not differ.
CONCLUSION - Patients with MIBC treated with NAC in the community as compared to an AMC received similar chemotherapy and achieved comparable pT0 rates, indicating effective implementation of NAC in the community. However, NAC in the community was associated with longer time to cystectomy, suggesting a delay in the transition of care between settings.
Copyright © 2015 Elsevier Inc. All rights reserved.
OBJECT - This pilot study evaluated the utility of 3'-deoxy-3'[18F]-fluorothymidine ([(18)F]-FLT) positron emission tomography (PET) to predict response to neoadjuvant therapy that included cetuximab in patients with wild-type KRAS rectal cancers.
METHODS - Baseline [(18)F]-FLT PET was collected prior to treatment initiation. Follow-up [(18)F]-FLT was collected after three weekly infusions of cetuximab, and following a combined regimen of cetuximab, 5-FU, and radiation. Imaging-matched biopsies were collected with each PET study.
RESULTS - Diminished [(18)F]-FLT PET was observed in 3/4 of patients following cetuximab treatment alone and in all patients following combination therapy. Reduced [(18)F]-FLT PET following combination therapy predicted disease-free status at surgery. Overall, [(18)F]-FLT PET agreed with Ki67 immunoreactivity from biopsy samples and surgically resected tissue, and was predictive of treatment-induced rise in p27 levels.
CONCLUSION - These results suggest that [(18)F]-FLT PET is a promising imaging biomarker to predict response to neoadjuvant therapy that included EGFR blockade with cetuximab in patients with rectal cancer.