Primary Tumor Response Research Articles

Prognostic value of neoadjuvant treatment response in locally advanced rectal cancer

BackgroundFor locally advanced rectal cancer, response to neoadjuvant radiation has been associated with improved outcomes but has not been well characterized in general practice. The goals of this study were to describe disease response rates after neoadjuvant treatment and to evaluate the association between disease response and survival. Materials and methodsRetrospective cohort study of patients aged 18-80 y with clinical stage II and III rectal adenocarcinoma in the National Cancer Database (2006-2012). All patients underwent radical resection after neoadjuvant treatment. Treatment responses were defined as follows: no tumor response; intermediate—T and/or N downstaging with residual disease; and complete—ypT0N0. Multivariable, multinomial regression was used to evaluate the association between neoadjuvant radiation use and disease response. Multivariable Cox regression was used to evaluate the association between disease response and overall risk of death. ResultsAmong 12,024 patients, 12% had a complete and 30% an intermediate response. Neoadjuvant chemotherapy alone was less likely to achieve an intermediate (relative risk ratio: 0.70 [0.56-0.88]) or a complete response (relative risk ratio: 0.59 [0.41-0.84]) relative to neoadjuvant radiation. Tumor response was associated with improved 5-y overall survival (complete = 90.2%, intermediate = 82.0%, no response = 70.5%; log-rank, P < 0.001). Complete and intermediate pathologic responses were associated with decreases in risk of death (hazard ratio: 0.40 [0.34-0.48] and 0.63 [0.57-0.69], respectively) compared to no response. Primary tumor and nodal response were independently associated with decreased risk of death. ConclusionsNeoadjuvant radiation is associated with treatment response, and pathologic response is associated with improved survival. Pathologic response may be an early benchmark for the oncologic effectiveness of neoadjuvant treatment.

Results of neoadjuvant chemoradiotherapy with docetaxel, cisplatin, and 5-fuluorouracil for advanced esophageal cancer.

171 Background: We previously reported a phase I study of neoadjuvant chemoradiotherapy (CRT ) with docetaxel, cisplatin, and 5-fuluorouracil (DCF) for advanced esophageal cancer. After that, we continued to conduct neoadjuvant CRT with DCF as phase II study and here, we report the results of this study including phase I. Methods: We performed neoadjuvant CRT with DCF chemotherapy and concurrent radiation therapy (40Gy including irradiation field) in patients with advanced esophageal squamous cell carcinoma. Dose of chemotherapy were as follows: docetaxel 25mg/m2 (level 1 n=17), or 30mg/m2 (level 2 n=4) on day 1,15,29 and 43 and cisplatin 70mg/m2 on day 1,29 and 5-fuluorouracil on day 1-4 and 29-32. The tumors were resected during weeks 10-13. Results: From Dec 2009 to Aug 2012, 21patients were enrolled and 19 patients underwent thoracic surgery. There were 17 male and four female subjects of ages ranging from 38 to 72 years (median, 61 years). Of these, 6 patients had stage IIIA esophageal cancer and two had stage IIIB esophageal cancer. All the patients had squamous cell carcinoma. Pathological complete response of primary tumor was achieved in 12 patients (63%) and complete pathological response of both primary tumor and lymph node was seen in eight patients (42%). During CRT, the most common grade 3/4 non-hematological toxicity were anorexia (29%) and esophagitis (29%). During CRT, septic shock caused by infection via catheter was observed and re-operation was performed in one patient with reconstructed gastric tube necrosis.One patient developed recurrent gastric tube ulcer in the anastomotic part 4years after esophagectomy. 10 patients are alive more than 5 years and 5-year overall survival is 47.6% and three of them were level II cases. Conclusions: This preoperative CRT regimen using triplets result in favorite prognosis, but treatment plan should be reconsidered because of relative high toxicity. Because high complete response rate of primary tumor were observed and long-term survival has been obtained at a high rate in the case of level II, we planned new phase I/II study of CRT with DCF without preventive irradiation field. Clinical trial information: R000002555.

Response monitoring of breast cancer patients receiving neoadjuvant chemotherapy using quantitative ultrasound, texture, and molecular features.

BackgroundPathological response of breast cancer to chemotherapy is a prognostic indicator for long-term disease free and overall survival. Responses of locally advanced breast cancer in the neoadjuvant chemotherapy (NAC) settings are often variable, and the prediction of response is imperfect. The purpose of this study was to detect primary tumor responses early after the start of neoadjuvant chemotherapy using quantitative ultrasound (QUS), textural analysis and molecular features in patients with locally advanced breast cancer.MethodsThe study included ninety six patients treated with neoadjuvant chemotherapy. Breast tumors were scanned with a clinical ultrasound system prior to chemotherapy treatment, during the first, fourth and eighth week of treatment, and prior to surgery. Quantitative ultrasound parameters and scatterer-based features were calculated from ultrasound radio frequency (RF) data within tumor regions of interest. Additionally, texture features were extracted from QUS parametric maps. Prior to therapy, all patients underwent a core needle biopsy and histological subtypes and biomarker ER, PR, and HER2 status were determined. Patients were classified into three treatment response groups based on combination of clinical and pathological analyses: complete responders (CR), partial responders (PR), and non-responders (NR). Response classifications from QUS parameters, receptors status and pathological were compared. Discriminant analysis was performed on extracted parameters using a support vector machine classifier to categorize subjects into CR, PR, and NR groups at all scan times.ResultsOf the 96 patients, the number of CR, PR and NR patients were 21, 52, and 23, respectively. The best prediction of treatment response was achieved with the combination mean QUS values, texture and molecular features with accuracies of 78%, 86% and 83% at weeks 1, 4, and 8, after treatment respectively. Mean QUS parameters or clinical receptors status alone predicted the three response groups with accuracies less than 60% at all scan time points. Recurrence free survival (RFS) of response groups determined based on combined features followed similar trend as determined based on clinical and pathology.ConclusionsThis work demonstrates the potential of using QUS, texture and molecular features for predicting the response of primary breast tumors to chemotherapy early, and guiding the treatment planning of refractory patients.

Is neoadjuvant chemoradiation with dose-escalation and consolidation chemotherapy sufficient to increase surgery-free and distant metastases-free survival in baseline cT3 rectal cancer?

Patients with cT3 rectal cancer are less likely to develop complete response to neoadjuvant chemoradiation (nCRT) and still face significant risk for systemic relapse. In this setting, radiation (RT) dose-escalation and consolidation chemotherapy in “extended” nCRT regimens have been suggested to improve primary tumor response and decrease the risks of systemic recurrences. For these reasons we compared surgery-free and distant-metastases free survival among cT3 patients undergoing standard or extended nCRT. MethodsPatients with distal and non-metastatic T3 rectal cancer managed by nCRT were retrospectively reviewed. Patients undergoing standard CRT (50.4 Gy and 2 cycles of 5FU-based chemotherapy) were compared to those undergoing extended CRT (54 Gy and 6 cycles of 5FU-based chemotherapy). Patients were assessed for tumor response at 8–10 weeks. Patients with complete clinical response (cCR) underwent organ-preservation strategy (Watch & Wait). Patients were referred to salvage surgery in the event of local recurrence during follow-up. Cox's logistic regression was performed to identify independent features associated with improved surgery-free survival after cCR and distant-metastases-free survival. Results155 patients underwent standard and 66 patients extended CRT. Patients undergoing extended CRT were more likely to harbor larger initial tumor size (p = 0.04), baseline nodal metastases (cN+; p < 0.001) and higher tumor location (p = 0.02). Cox-regression analysis revealed that the type of nCRT regimen was not independently associated with distinct surgery-free survival after cCR or distant-metastases-free survival (p > 0.05). ConclusionsDose-escalation and consolidation chemotherapy are insufficient to increase long-term surgery-free survival among cT3 rectal cancer patients and provides no advantage in distant metastases-free survival.

Evaluation of Discordance in Primary Tumor and Lymph Node Response After Neoadjuvant Therapy in Breast Cancer

BackgroundNeoadjuvant therapy (NAT) offers a unique opportunity to assess tumor response to systemic agents. However, a discrepancy may exist between the response of the primary tumor and involved nodes. We report on the frequency of response discordance after NAT in breast cancer. Patients and MethodsAll consecutive node-positive patients receiving NAT in our department from 2009 to 2014 were identified. Patient demographics, and radiologic and pathologic features were tabulated. Tumor response was estimated by magnetic resonance imaging of the breast. Lymph node (LN) response was estimated from pathologic treatment response measurements. Statistical analysis was performed. ResultsA total of 108 node-positive patients treated with NAT were eligible for inclusion. Median age was 51.73 years (range, 20-87 years). All patients underwent axillary clearance, and 62% underwent mastectomy. A 40% mean reduction in tumor size was observed. Statistically, a positive correlation between tumor and LN response after NAT was observed (Spearman correlation coefficient, r = 0.46, P < .001). Complete pathologic response was observed in 17 patients (15.7%). However, 21 patients experienced complete LN response, with only 81% of these patients (n = 17) experiencing a complete response in tumor also. A complete response was observed in tumor in 20 patients, and this predicted complete nodal response in 85% of cases (n = 17). Fifteen percent of primary tumors with complete pathologic response had persistently positive LNs. ConclusionA significant discordance exists between the primary tumor and LN response, representing a concern for the lack of response of occult regional or systemic metastases due to potential biologic heterogeneity.

Association between gene expression profile of the primary tumor and chemotherapy response of metastatic breast cancer

BackgroundTo better predict the likelihood of response to chemotherapy, we have conducted a study comparing the gene expression patterns of primary tumours with their corresponding response to systemic chemotherapy in the metastatic setting.MethodsmRNA expression profiles of breast carcinomas of patients that later developed distant metastases were analyzed using supervised and non-supervised classification techniques to identify predictors of response to chemotherapy. The top differentially expressed genes between the responders and non-responders were identified and further explored. An independent dataset which was generated to predict response to neo-adjuvant CT was utilized for the purpose of validation. Response to chemotherapy was also correlated to the clinicopathologic characteristics, molecular subtypes, metastatic behavior and survival outcomes.ResultsAnthracycline containing regimens were the most common first line treatment (58.4%), followed by non-anthracycline/non-taxane containing (25.8%) and taxane containing (15.7%) regimens. Response was achieved in 41.6% of the patients to the first line CT and in 21.8% to second line CT. Response was not found to be significantly correlated to tumour type, grade, lymph node status, ER and PR status. Patients with HER2+ tumours showed better response to anthracycline containing therapy (p: 0.002). Response to first and second line chemotherapy did not differ among gene expression based molecular subtypes (p: 0.236 and p: 0.20). Using supervised classification, a 14 gene response classifier was identified. This 14-gene predictor could successfully predict the likelihood of better response to first and second line CT (p: <.0001 and p: 0.761, respectively) in the training set. However, the predictive value of this gene set in data of response to neoadjuvant chemotherapy could not be validated.ConclusionsTo our knowledge, this is the first study revealing the relation between gene expression profiles of the primary tumours and their chemotherapy responsiveness in the metastatic setting. In contrast to the findings for neoadjuvant chemotherapy treatment, there was no association of molecular subtype with response to chemotherapy in the metastatic setting. Using supervised classification, we identified a classifier of chemotherapy response; however, we could not validate this classifier using neoadjuvant response data.Trial registrationNon applicable. Subjects were retrospectively registered.

Intensified preoperative chemoradiation by adding oxaliplatin in locally advanced, primary operable (cT3NxM0) rectal cancer

PurposeThe major goals of preoperative treatment for locally advanced rectal cancers (LARCs) are improvement of local tumor control, tumor downsizing, and downstaging. Modifications with respect to standardized chemoradiation protocol, e. g., integrating oxaliplatin, are realized with the aim of improving primary tumor response and patient outcome.Patients and methodsIn this phase II multicenter study, patients with LARC of the mid- or lower rectum, cT3cNxcM0 as staged by MRI, were included and treated preoperatively with a combination of capecitabine and oxaliplatin following a standardized protocol during radiation. The focus of this long-term analysis was overall (OS) and disease-free survival (DFS).ResultsA total of 60 patients (19 women, 41 men, median age 60.5 years) were initially enrolled, 1 patient was excluded (violation of study protocol), and 1 was patient lost of follow-up, leading to a total of 58 patients for long-term analysis. The 3‑year OS was 85.5%; 3‑year DFS 71.2%. Over time, 15 patients (25.9%) developed tumor recurrence (1 locoregional, 6.7%; 11 distant, 73.3%; 3 locoregional+distant, 20%). Recurrence-specific therapy was planned in the majority of patients, in 9 of 15 patients (60%) with a radical surgical approach. Of these, 4 patients (44.4%) are again tumor-free at the end of investigation. While tumor downsizing (T level) or pathologically complete response did not influence patient survival, lymph node negativity (LNneg) after preoperative chemoradiation showed significant influence.ConclusionLNneg after preoperative treatment for LARC significantly influences patient survival. A radical surgical approach for recurrent LARC (locoregional, distant) should be contemplated when possible as we were able to clearly demonstrate its importance and efficacy.

Inter- and intra-observer reproducibility of ADC measurements in esophageal carcinoma primary tumors.

The apparent diffuse coefficient (ADC) may correlate with the treatment response to chemotherapy/radiotherapy in solid tumors. Our aim was to determine the inter- and intra-observer reproducibility of ADC measurements in primary esophageal squamous cell carcinoma (ESCC). ADCs were blindly measured in 31 patients diagnosed with ESCC by two observers before treatment (pre-ADC) and after 5th fraction radiotherapy (intra-ADC) twice with a 2-week interval. The mean pre-ADC of primary tumors was 1.25±0.22 and 1.27±0.23 (in 10−3mm2/s) from observer A for measurements 1 and 2, respectively, and the intra-observer measurements were -0.02 bias vs. -0.13-0.09 limits of agreement. From observer B, the mean pre-ADC varied between 1.25±0.23 and 1.27±0.23 (in 10−3mm2/s) for measurements 1 and 2, respectively, and intra-observer measurements were -0.02 bias vs. -0.17∼0.16 limits of agreement. The mean pre-ADC of primary tumors was 1.26±0.24 (in 10−3mm2/s) from observers A and B, and inter-observer measurements were 0.01 bias vs. -0.09-0.09 limits of agreement, revealing a low inter-observer variance. Similar measurements of the intra-SD parameters showed that the pre- and intra-ADC of primary tumors differed significantly. Thus ADC measurements may have sufficient inter-observer and intra-observer reproducibility to measure primary tumor responses to treatment, and the ADCs before and during treatment differed.

The Role of Postmastectomy Radiation Therapy for Clinical Stage II-III Breast Cancer Patients With Pathological Complete Remission of Axillary Lymph Nodes After Neoadjuvant Chemotherapy

With the increasing use of neoadjuvant chemotherapy (NAC), patients with pathologically involved nodes had a great chance to be found as pathologically node negative at the time of definitive surgery. Several retrospective studies addressed that there were no survival benefits in those patient with pathologically complete remission (pCR) of axillary lymph node who treated with postmastectomy radiotherapy (PMRT) after NAC. We aim to retrospectively evaluate the role of PMRT in clinical stage II-III breast cancer patients with pathological nodes negative (ypN0) after NAC. We retrospectively identified 946 breast cancer patients with clinical stage II-III who underwent NAC in our center between 2003 and 2013. There were 290 patients achieved ypN0 after mastectomy and the clinical outcomes of the patients had been elucidated. The effects of PMRT on locoregional recurrence-free survival (LRRFS), disease-free survival (DFS) and overall survival (OS) were evaluated by Kaplan-Meier method and compared using the log-rank test. Prognostic factors associated with survival were evaluated by univariate and multivariate analysis. The median age was 50 years old (range, 25-80 years). All patients received 2-8 cycles (median, 4 cycles) of preoperative chemotherapy contained with anthracycling and paclitaxel and mastectomy. Of the 290 patients, 217 (74.8%) underwent PMRT and 73 (25.2%) did not. With a median follow-up time of 63 month, 12 patients developed LRR and 39 developed distant metastasis. The 5-year LRRFS, DFS and OS was 94.2%, 79.3% and 91.8% in no-PMRT group and 95.9%, 84.3% and 92.4% in PMRT group, respectively (p=NS). There was no significant difference between the patients with PMRT and without PMRT in terms of survival outcome, even for the subgroup of patients with clinical stage III disease or with residual disease in breast after NAC. On univariate and multivariate analysis, there were no benefits of PMRT on LRRFS (hazard ratio [HR], 0.714; 95% confidence interval [CI], 0.193-2,634; p =0.612), DFS (HR 0.908; 95%[CI], 0.477-1.734; p = 0.773) or OS (HR, 0.829; 95% [CI], 0.291-2.359; p =0.725). Age at diagnosis，ER and LVI status, adjuvant chemotherapy were independent prognostic factors for LRRFS （p＜0.01）, primary tumor response to NAC was marginally significant with poor LRRFS (hazard ratio [HR] 0.109; 95% CI, 0.011-1.098; p=0.06). Advanced Clinical T stage (T3-T4) was independently associated with decreased DFS and OS. Patients who achieved ypN0 after NAC without PMRT had similar outcomes compared with patients treated with PMRT, regardless of clinical stage and primary tumor response. PMRT might not be necessary for ypN0 patients. Prospective randomized study is needed to identify whether it is safe to omit PMRT in patients with clinical stage II-III disease and achieved ypN0 after NAC and mastectomy

Plerixafor Improves Primary Tumor Response and Reduces Nodal Metastasis in Cervical Cancer Treated With Radio-Chemotherapy

Plerixafor Improves Primary Tumor Response and Reduces Nodal Metastasis in Cervical Cancer Treated With Radio-Chemotherapy

Outcome of neoadjuvant chemotherapy in locally advanced breast cancer: A tertiary care center experience

Breast cancer is the most common cancer among Bangladeshi women. Almost all present with palpable lump and 40% of them are with locally advanced breast cancer. Neoadjuvant chemotherapy is the standard choice of treatment for the patients.This prospective study was done involving 220 newly diagnosed locally advanced breast cancer (LABC) patients from January 2010 to December 2014 in the National Institute of Cancer Research &amp; Hospital (NICRH), Mohakhali, Dhaka to observe the clinical and pathological response of locally advanced breast cancer after four cycles of chemotherapy and surgery. Chemotherapy schedule with Cyclophosphamide 600mg/m2 and Doxorubicine 60mg/m2 (AC) was prescribed and carried out three weekly for four cycles. Primary tumor size and axillary nodal size was measured and compared with the previous record. After three weeks of chemotherapy the patients undergone mastectomy and axillary dissection. Histopathology was done to see the pathological response of primary tumor and axillary node. Other biological marker such as estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth receptor (HER-2) were done. After four cycles of chemotherapy with AC, 194 patients (88%) responded clinically, 29 patients (13%) showed complete clinical response (cCr) and 165 patients (75%) partial response (pCr). Surgical specimen showed complete pathological response (cPr) in 22 patients (10%). Neoadjuvant chemotherapy with AC is the standard chemotherapy schedule for locally advanced breast cancer and radical surgery was possible in 75% of the patients.Bangladesh Med J. 2016 Sep; 45 (3): 141-146

FDG-PET/CT for response evaluation of invasive bladder cancer following neoadjuvant chemotherapy.

We investigated the accuracy of FDG-PET/CT response identification following neoadjuvant or induction chemotherapy (NAIC) for invasive bladder cancer (BC) as to better select patients for radical cystectomy (RC). Between 2010 and 2014, 37 cT1-4N1-3 BC patients received a FDG-PET/CT before and after NAIC followed by RC. Metabolic lymph node (LN) response was evaluated according to EORTC recommendations. Additionally, primary tumor response was evaluated for 23 patients by means of delayed pelvic imaging after forced diuresis. Gold standard was response on pathologic analysis of RC specimens. Response was defined as partial response (pPR, any pathologic downstaging) or complete response (pCR,<ypT1N0). Cancer-specific survival (CSS) was correlated with pCR and metabolic CR. Twenty-four cN+patients achieved LN pCR. FDG-PET/CT identified pCR with 67% sensitivity and 46% specificity. Primary tumor response was evaluable for 17/23 patients, of whom 12 were responders. Tumor downstaging (pPR or pCR) was identified with 83% sensitivity and 80% specificity. Tumor pCR was detected with 70% sensitivity and 71% specificity. pCR of overall disease (primary tumor and LNs, n=17) was detected with 67% sensitivity and 75% specificity. CSS was positively associated with pathologic CR (HR 0.16, p=0.027), but not with metabolic CR (HR 0.560, p=0.612). FDG-PET/CT can accurately distinguish primary tumor downstaging from non-response, which suggests that response monitoring (in cN0 patients) might be used to adjust neoadjuvant treatment. pCR identification is less accurate, especially for LN metastases, which suggests that FDG-PET/CT cannot be used to select patients for RC.

Abstract 4603: Protocol optimization combining activatable nanodelivery with immunotherapy in a murine breast cancer model

Abstract Activatable nanotherapeutics provide the opportunity to deliver anthracyclines to a well-controlled region of interest and therefore to locally stimulate immunogenic cell death. Such a strategy can be combined with immunotherapy for both local tumor control and creation of an abscopal effect. Our group previously reported that combining local administration of a CpG oligonucleotide with local release of doxorubicin from a temperature-sensitive liposomal nanoparticle (TSL) led to the elimination of directly treated lesions in a syngeneic murine model of mammary adenocarcinoma.1 While this therapeutic approach increased the numbers of tumor infiltrating CD8+ T lymphocytes in distant lesions and extended survival, distant tumors returned with a growth delay of approximately 14 days and T-regulatory cells were not reduced by treatment. Therefore, checkpoint blockade of the programmed death-1 (PD-1) pathway (anti-PD-1) was incorporated in the protocol. CuDox-TSL were prepared from DPPC:MPPC:DSPE-PEG2k (86:10:4) in the presence of copper (II) gluconate and triethanolamine at 0.2 mg-drug/mg-lipid. A complex between doxorubicin and copper was created to enhance the circulation and stability of TSL and to reduce systemic toxicity. On day 21, mice with bilateral invasive neu deletion (NDL) tumors (~4 mm) were treated with i.v. administration of CuDox-TSL at 6 mg doxorubicin/kg body weight. Ultrasound (US) hyperthermia (1.1 MPa, 1.5 MHz, achieving 42°C for 5 min before and 20 min after drug injection) triggered drug release. Immediately after US, 100 µg of CpG-ODN 1826 was administered intratumorally to the insonified tumor; anti-PD-1 (200 µg, i.p.) was administrated three days later. Flow cytometry and immunohistochemistry were performed on day 28 after one treatment with each component and survival was assessed after treatment was repeated for three weeks. While control mice survived 35 days, 50% of treated mice were tumor-free after 100 days. All primary tumors and 50% of the contralateral tumors regressed and were eliminated by day 63. With the incorporation of immunotherapy, three doses of chemotherapy were sufficient to eliminate all directly treated tumors, as compared with 8 doses without immunotherapy. After a single treatment with each component, a substantial change was observed in systemic immune cells, including a significant increase in natural killer and dendritic cells in distant lymph nodes, in CD8+ T cells in tumors and associated lymph nodes and in IFNγ-secreting CD4+ T cells in the treated tumor and distant lymph nodes. The results demonstrate that activatable chemotherapy can be paired with an immune adjuvant and PD-1 blockade to generate a curative response in primary and distant tumors. Further, local chemotherapy, as potentiated by activatable liposomes does not impede a systemic CD8+ T cell response. [1] Journal of Controlled Release (2015); 220: 253-264. Citation Format: Azadeh Kheirolomoom, Matthew Silvestrini, Lisa Mahakian, Elizabeth Ingham, Josquin Foiret, Spencer Tumbale, Sarah Tam, Neil Hubbard, Alexander Borowsky, Katherine Ferrara. Protocol optimization combining activatable nanodelivery with immunotherapy in a murine breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4603. doi:10.1158/1538-7445.AM2017-4603

Early primary renal tumor response predicts clinical outcome in patients with primary unresectable renal cell carcinoma with synchronous distant metastasis receiving molecularly targeted therapies.

The aim of the present study was to investigate the prognostic factors for patients with primary unresectable renal cell carcinoma (RCC) with synchronous distant metastasis receiving molecularly targeted therapies. A total of 26 patients with primary unresectable RCC with synchronous distant metastasis underwent molecularly targeted therapies at the Kurume University Hospital (Kurume, Japan) between March 2008 and March 2016. Early primary renal tumor response was evaluated at 8-12 weeks after the introduction of molecularly targeted therapy and a 10% decrease in the diameter of primary renal tumor was used as the cut-off value. The median overall survival from the initiation of first-line molecularly targeted therapy was 18.3 months. Univariate analyses for various factors identified early primary renal tumor response (P=0.0004) and best response to first-line treatment (P=0.0002) as prognostic variables. Multivariate analyses also identified early primary renal tumor response (P=0.0099) and best response to first-line treatment (P=0.0054) as independent prognostic factors. A comparison of clinical characteristics between the group with ≥10% shrinkage and the group with disease progression or <10% shrinkage revealed that the number of metastatic sites and pretreatment monocyte-to-lymphocyte ratio tended to be predictive factors for primary renal tumor response. These results suggest that early primary renal tumor shrinkage is highly variable for patients with primary unresectable RCC with synchronous distant metastasis receiving molecularly targeted therapies.

High expression of endoglin in primary breast cancer may predict response to neoadjuvant chemotherapy

Neoadjuvant chemotherapy (NAC) is a widely-used treatment for breast cancer, as it may render unresectable breast tumors to become resectable. In addition, NAC provides the unique opportunity to assess response to treatments within months rather than years of follow-up. However, predictive markers of tumor response to NAC are lacking. Therefore, the present study aimed to investigate the expression of endoglin, a marker of angiogenesis, and its association with pathologic responses to NAC. Samples from 34 breast cancer patients were obtained prior to and following NAC treatment. Immunohistochemical staining for endoglin and the mechanistic target of rapamycin (mTOR) was performed, and the correlation between the expression of these markers and pathologic response was examined. The overall response rate to NAC of these 34 patients was 67.6%. A mean microvascular density value of 14 served as a threshold score for the increased expression of endoglin. Increased expression of endoglin in primary tumors prior to NAC correlated with improved response in primary tumors (P=0.019) or in primary tumors and regional lymph nodes (P=0.014), when compared with reduced expression of endoglin. Increased expression of mTOR following NAC was additionally correlated with improved response to NAC. The results of the present study demonstrated that the expression of endoglin in breast tumor samples prior to NAC may be a predictor of treatment response. Long-term follow-up of clinical outcome is required to explain the elevation of mTOR expression levels following NAC treatment in responsive tumors.

Ex Vivo Explant Cultures of Non-Small Cell Lung Carcinoma Enable Evaluation of Primary Tumor Responses to Anticancer Therapy.

To improve treatment outcomes in non-small cell lung cancer (NSCLC), preclinical models that can better predict individual patient response to novel therapies are urgently needed. Using freshly resected tumor tissue, we describe an optimized ex vivo explant culture model that enables concurrent evaluation of NSCLC response to therapy while maintaining the tumor microenvironment. We found that approximately 70% of primary NSCLC specimens were amenable to explant culture with tissue integrity intact for up to 72 hours. Variations in cisplatin sensitivity were noted with approximately 50% of cases responding ex vivo Notably, explant responses to cisplatin correlated significantly with patient survival (P = 0.006) irrespective of tumor stage. In explant tissue, cisplatin-resistant tumors excluded platinum ions from tumor areas in contrast to cisplatin-sensitive tumors. Intact TP53 did not predict cisplatin sensitivity, but a positive correlation was observed between cisplatin sensitivity and TP53 mutation status (P = 0.003). Treatment of NSCLC explants with the targeted agent TRAIL revealed differential sensitivity with the majority of tumors resistant to single-agent or cisplatin combination therapy. Overall, our results validated a rapid, reproducible, and low-cost platform for assessing drug responses in patient tumors ex vivo, thereby enabling preclinical testing of novel drugs and helping stratify patients using biomarker evaluation. Cancer Res; 77(8); 2029-39. ©2017 AACR.

Plerixafor Improves Primary Tumor Response and Reduces Metastases in Cervical Cancer Treated with Radio-Chemotherapy.

Purpose: There is an important need to improve the effectiveness of radio-chemotherapy (RTCT) for cervical cancer. The CXCL12/CXCR4 pathway can influence RT response by recruiting normal myeloid cells to the tumor microenvironment that in turn can exert radioprotective effects, and may promote metastases. The objective of this study was to explore the efficacy and toxicity of combining RTCT with CXCL12/CXCR4 inhibition in cervical cancer.Experimental Design: CXCR4 expression was measured in 115 patients with cervical cancer. Two primary orthotopic cervical cancer xenografts (OCICx) with different levels of CXCR4 expression were treated with RT (30 Gy: 15 daily fractions) and weekly cisplatin (4 mg/kg), with or without the CXCR4 inhibitor Plerixafor (5 mg/kg/day). The endpoints were tumor growth delay and lymph node metastases. Acute intestinal toxicity was assessed using a crypt cell assay.Results: There was a fivefold variation in CXCR4 mRNA expression in the patient samples, and good correlation between the expression in patients and in the xenografts. The combination of RTCT and Plerixafor produced substantial tumor growth delay and reduced lymph node metastases compared with RTCT alone in both of the xenograft models. There was a trend toward reduced acute intestinal toxicity with the addition of Plerixafor to RTCT. There were no changes in normal organ morphology to suggest increased late toxicity.Conclusions: This study demonstrates that the addition of Plerixafor to standard RTCT improves primary tumor response and reduces metastases in cervical cancer with no increase in toxicity. This combination warrants further investigation in phase I/II clinical trials. Clin Cancer Res; 23(5); 1242-9. ©2016 AACR.

Abstract P4-06-12: Murine radical mastectomy model for preclinical study of adjuvant systemic therapies

Abstract Background: Current standard of care of breast cancer is removal of primary tumor followed by systemic adjuvant therapy to reduce recurrence and to prolong survival. However, vast majority of the preclinical studies that use murine models evaluate the drug response of primary tumors either in mammary pads or subcutaneous tissues. Lately it has been shown that the genetic profiles of metastatic lung tumors are significantly different from that of their primary mammary tumors, let alone subcutaneous tumors. Therefore we hypothesized that the responses of metastatic tumors rather than primary mammary tumors need to be evaluated for a systemic therapy. However there are few reports of murine mastectomy models used for preclinical study. Methods: Murine mammary adenocarcinoma 4T1-luc2 cells were inoculated into #2 right mammary fat pad under direct vision as previously described (Katsuta et al, JSR 2016). The tumor burden was quantified by bioluminescence IVIS imaging system. Novel platinum drug, Triplatin, or Vehicle was administrated every 4 days for 3 times from the day after inoculation. Amount of lung metastases were quantified ex vivo by IVIS imaging. Then we compared the growth of metastatic tumors between two methods of radical mastectomy; midline incision method and Halsted incision method, which were performed 8 days after inoculation. Triplatin or Vehicle was administered 2 days after mastectomies. Results: First we compared the two methods of chest mammary tumor removal; midline incision method and Halsted incision method. There was no significant difference in weight of resected tumors between these two techniques (p=0.751), however, the bioluminescence in midline incision model was significantly higher than Halsted incision model at the first day after operations (p=0.003). Only 1 out of 7 cases (14%) after Halsted incision method developed local recurrence, whereas all (100%) the animals that underwent midline incision method developed recurrence within 30 days after operation (p&amp;lt;0.001). No mice developed respiratory failure due to wound closure of wide skin defect. We then examined the effect of Triplatin on chest mammary tumor and lung metastasis. There was no significant difference in bioluminescence from chest mammary tumors between treatment group and non-treatment, however, ex vivo bioluminescence of lung metastases demonstrated that treatment group mice had significantly less tumor burden in lung than non-treatment group. Utilizing Halsted incision method with less local recurrence, we found that lung metastases were significantly less in treatment group than non-treatment group in live animals monitored by bioluminescence. Conclusion: We have established an improved murine chest mammary tumor resection model. Effects on metastases, as opposed to primary tumor should be evaluated for the preclinical study of adjuvant systemic therapy, since they may not be the same. Citation Format: Katsuta E, Takabe K. Murine radical mastectomy model for preclinical study of adjuvant systemic therapies [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-06-12.

Abstract OT2-02-03: Pilot study of zirconium-89 bevacizumab positron emission tomography for imaging angiogenesis in patients with inflammatory breast carcinoma receiving preoperative chemotherapy

Abstract Background: Inflammatory breast cancer (IBC) continues to have a poor prognosis despite standard tri-modality treatment with chemotherapy, mastectomy and radiation. Current methods of assessing primary tumor response (i.e., clinical exam and breast magnetic resonance imaging [MRI]) are limited for distinguishing residual tumor from responsive disease because of persistent morphologic changes in the breast. Therefore, the inability to accurately assess tumor response during treatment often results in the continuation of ineffective systemic chemotherapy until definitive pathologic evaluation at mastectomy. IBC has a highly angiogenic phenotype which is believed to play a role in this tumor's aggressiveness. The novel radiotracer Zirconium-89 (89Zr)-bevacizumab was developed for imaging tumor angiogenesis with PET. We hypothesize that, as an imaging biomarker of angiogenesis, 89Zr-bevacizumab-PET/CT is a more specific noninvasive functional imaging modality for detecting the presence of tumor angiogenesis compared to current diagnostic methods and will serve as a predictor of response to therapy in patients (pts) with IBC. Methods: Pts with newly diagnosed HER2neg IBC who will receive preoperative chemotherapy are eligible for this pilot study. 89Zr-bevacizumab-PET/CT, breast MRI and FDG-PET/CT are performed before, after 2 cycles, and at the completion of preoperative therapy. Biopsies of primary IBC tumors are obtained prior to and after 2 cycles of preoperative therapy. At the completion of preoperative therapy, pts proceed to mastectomy or biopsy if ineligible to proceed to mastectomy based on current standards for assessing primary tumor response, i.e., clinical exam, breast MRI and lack of systemic progression. At the time of mastectomy, standard evaluation of the surgical specimen will determine pathologic response of IBC to preoperative chemotherapy. A research sample will be collected if residual cancer is present at the time of mastectomy for histologic evaluation of tumor angiogenesis. Objectives/Correlatives: The primary objective is to determine feasibility of 89Zr-bevacizumab-PET/CT imaging in pts with IBC. The primary endpoint is assessment of radiolabeling of chelated bevacizumab and number of successfully acquired 89Zr-bevacizumab-PET/CT scans. Correlative studies will be performed on IBC tissue to assess extent of angiogenesis including microvessel density, vessel diameter, vascular pericyte coverage and tumor VEGF levels. Secondary objectives are: 1) To determine if 89Zr-bevacizumab accumulation in primary IBC tumors correlates with the extent of angiogenesis determined by correlative analysis on IBC tissue; 2) To assess the predictive value of 89Zr-bevacizumab-PET/CT after 2 cycles and at the end of preoperative therapy for determining pathologic response at mastectomy as given by residual cancer burden. Statistics: This is an accrual, not statistical based, feasibility justification. Planned sample size is 10 in order to make a preliminary statement about feasibility and ability for 89Zr-bevacizumab-PET/CT to serve as a surrogate in vivo biomarker of tumor angiogenesis and response to preoperative chemotherapy. Clinical Trial Information: NCT01894451. Citation Format: Jacene HA, Overmoyer B, Schlosnagle EJ, Abbott A, Yeh E, Paolino J, Goel S, Culhane A, Bellon JR, Nakhlis F, Hirshfield-Bartek J, Van den Abbeele A. Pilot study of zirconium-89 bevacizumab positron emission tomography for imaging angiogenesis in patients with inflammatory breast carcinoma receiving preoperative chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-02-03.

Unidimensional measurement may be superior to assess primary tumor response after neoadjuvant chemotherapy for nasopharyngeal carcinoma.

Application of current response evaluation criteria in solid tumors (RECIST 1.1) for assessment of irregularly shaped nasopharyngeal carcinoma (NPC) is a gray area with much ambiguity. Our aim was to compare unidimensional measurements (UDM) and bidimensional measurements (BDM) on magnetic resonance images in alternative planes for measurement of tumor response after neoadjuvant chemotherapy (NACT) in patients with locally advanced NPC. 59 patients with untreated non-metastatic NPC were prospectively enrolled. The size or change in size of the primary tumor and retropharyngeal nodes was assessed by UDM and BDM on axial and coronal planes before and after 2 cycles of NACT. Tumor volume was considered as the reference standard. Correlation between volume and diameter was analyzed using a general linear model. The degree of agreement and discordance of response classification based on different measures were evaluated with κ statistic and McNemar's test, respectively. Both axial UDM (RECIST 1.1) and axial BDM (WHO) showed a significant association with volumetric standard. However, the agreement of axial UDM with VM was better than that of axial BDM (κ value: 0.514 to 0.372). In addition, when increasing coronal planes to evaluate tumor response with UDM and BDM, an inferior agreement between coronal BDM and VM was still observed. Notably, coronal UDM showed the best consistency with volume (κ = 0.585). Hence, axial UDM showed better correlation with volumetric measurements than axial BDM. Since coronal UDM showed high correlation to VM, we suggest further research to assess its use for response assessment of NPC after NACT.