Marker Of Tumor Response Research Articles

P-219 - Gemcitabine and nab-paclitaxel based regimen in advanced pancreatic carcinoma at tertiary cancer centre, Bangalore

Introduction: Pancreatic ductal adenocarcinoma is associated with the worst prognosis of all gastrointestinal malignancies, mainly due to late and nonspecific symptoms, an aggressive tumor biology, and resistance to most therapies. Only 10–20% of patients are resectable at presentation. For many of these remaining patients were subjected to systemic chemotherapy either to down stage in borderline resectable cases or to prolong the survival. Depending on the patient’s performance status and preferences, more or less aggressive regimens can be chosen. This study was to evaluate the efficacy and safety of Gemcitabine with Nab-paclitaxel regimen in advanced carcinoma of pancreas. Methods: We analyze the patients with ECOG performance status 0-2 in advanced pancreatic cancer who were treated with gemcitabine and Nab-Paclitaxel regimen from Jan2014 to April 2016 in our center. The patients those who failed to Folfirinox or Gemcitabine + Platinum based chemotherapy in first line setting were enrolled to receive gemcitabine and Nab-Paclitaxel regimen. The schedule of gemcitabine and Nab-Paclitaxel regimen was Gemcitabine 1000 mg/m2 and Nab-Paclitaxel 125mg/m2 on Day 1 and Day8 of each cycle every 3weeks. Primary prophylaxis with Growth factor support was given in age > 60 years. The efficacy and toxicity of above regimen were analyzed. Results: 37 patients with advanced Pancreas and good ECOG Performance status 0-2 were enrolled. The median age was 66 (range 48 to 75 years). Male: female ratio was 1.46:1. The tumor marker CA19-9 was elevated at baseline in 59.45% of patients. The efficacy of this regimen as follows Efficacy Gemcitabine and Nab-Paclitaxel regimen in First line therapy (n 16) versus Second line therapy (n 21) in advanced pancreatic cancer were shown in the following order: Complete response 6.25% vs 0), Partial response (31.25% vs 28.57%), Stable disease (37.5% vs 33.3%), Progressive disease (25% vs 38%), Median PFS in months (5.5 vs 3.5), Median OS in months(10.5m vs 8m) and 1 year survival (37.5% vs 23.8%) respectively. Tumor marker response (CA 19-9) >50% drop from baseline at 3 months was seen 40.9% of patients. Hematological toxicity: Anemia (27%), Neutropenia (37.8%), Febrile neutropenia (10.8%), Thrombocytopenia (29.7%). Nonhematological toxicity: Nausea/vomiting 18.9%, Diarrhea 21.6%, Peripheral neuropathy (27%), Mucositis 13.5%, Fatigue 37.8%, Median number of cycles completed by patients were 3 and dose reductions were required in 18.75% of first line and 33.3% in second line settings. Conclusion: Gemcitabine and Nab- Paclitaxel regimen is easily tolerable and efficacious regimen in both first and second line therapy of an advanced pancreatic cancer. The further studied are required to compare above regimen with Gemcitabine with platinum based combinations and to assess quality of life.

Very early molecular marker of tumor response to PD-1 inhibition in plasma of patients with advanced non-small cell lung cancer (NSCLC).

3030 Background: Nivolumab shows a durable tumor response in 20 % of advanced NSCLC patients. While a PD-L1 immunohistochemistry complementary diagnostic has been approved, there is a need to identify a predictive biomarker with greater diagnostic accuracy. Methods: In an ongoing study of patients, treated with nivolumab every 2 weeks for advanced recurrent NSCLC and a known KRAS mutation in the primary tumor, liquid biopsies were taken by a simple blood draw at baseline (before treatment), 1, 2, 4, 6 and thereafter every 12 weeks until disease progression. Circulating tumor DNA (ctDNA) was extracted from cell free plasma and tested with a specific digital droplet PCR (ddPCR)-KRAS G12/G13 screenings assay (BIORAD). Mutation levels in plasma were compared with tumor response on CT scans by RECIST v.1.1. CT scans were performed at baseline and thereafter every 6 weeks until disease progression. Results: Patient characteristics are shown in table 1. In this prospective analysis specific patterns could be demonstrated in plasma ctDNA testing of KRAS mutation levels. All 4 responders showed an increase of mutant copies/ml plasma in the first week followed by a clear drop to non-detectable KRAS mutations at all CT evaluated tumor responses. The 2 non-responders however, did not show the increase in mutant copies/ml at one week and showed a gradual increase in mutant copies/ml in the following weeks. Conclusions: Specific plasma ctDNA testing seems a very promising early biomarker (1 week) for tumor response to PD-1 therapy. [Table: see text]

Serum HMGB1 concentrations at 4\xa0weeks is a useful predictor of extreme poor prognosis for advanced hepatocellular carcinoma treated with sorafenib and hepatic arterial infusion chemotherapy

BackgroundBiomarkers predicting the response to the anticancer treatment and prognosis in patients with advanced hepatocellular carcinoma (HCC) are required. Recently, high mobility group box 1 (HMGB1) was reported to promote HCC progression and be associated with poor prognosis for patients with HCC. The purpose of this study was to assess serum HMGB1 concentrations before and during sorafenib treatment or hepatic arterial infusion chemotherapy (HAIC) and to explore the ability of serum HMGB1 concentrations to predict prognosis.MethodsSerum HMGB1 concentrations were measured in 71 and 72 patients with advanced HCC treated with sorafenib and HAIC, respectively, to assess their usefulness for prediction of the response to the treatment and prognosis.ResultsMultivariate analysis identified high HMGB1 at 4 weeks (P = 0.001), high α-fetoprotein (AFP) at baseline (P = 0.025), tumor liver occupying rate (P = 0.009) and modified RECIST (mRECIST, P < 0.0001) as independent predictors of poor overall survival in sorafenib treatment. High HMGB1 at 4 weeks (P = 0.025), vascular invasion to the hepatic vein (Vv) (P = 0.009), mRECIST (P < 0.0001) and Child-Pugh B (P = 0.004) were identified as independent predictors of poor overall survival in HAIC treatment. The concentrations of HMGB1 at baseline and 4 weeks were not correlated with conventional tumor markers and progressive disease assessed by mRECIST at 8 weeks.ConclusionsThese results suggest that serum HMGB1 at 4 weeks after the start of treatment might be a useful biomarker with added value to the conventional tumor marker and radiologic responses to predict poor overall survival in patients with advanced HCC treated with sorafenib or HAIC.

The role of quantitative estrogen receptor status in predicting tumor response at surgery in breast cancer patients treated with neoadjuvant chemotherapy.

Estrogen receptor (ER) negative (-) breast cancer (BC) patients have better tumor response rates than ER-positive (+) patients after neoadjuvant chemotherapy (NCT). We conducted a retrospective review using the institutional database "Biomatrix" to assess the value of quantitative ER status in predicting tumor response at surgery and to identify potential predictors of survival outcomes. Univariate followed by multivariable regression analyses were conducted to assess the association between quantitative ER and tumor response assessed as tumor size reduction and pathologic complete response (pCR). Predictors of recurrence-free survival (RFS) were identified using a cox proportional hazards model (CPH). A log-rank test was used to compare RFS between groups if a significant predictor was identified. 304 patients were included with a median follow-up of 43.3months (Q1-Q3 28.7-61.1) and a mean age of 49.7years (SD 10.9). Quantitative ER was inversely associated with tumor size reduction and pCR (OR 0.99, 95% CI 0.99-1.00, p=0.027 and 0.98 95% CI 0.97-0.99, p<0.0001, respectively). A cut-off of 60 and 80% predicted best the association with tumor size reduction and pCR, respectively. pCR was shown to be an independent predictor of RFS (HR 0.17, 95% CI 0.07-0.43, p=0.0002) in all patients. At 5years, 93% of patients with pCR and 72% of patients with residual tumor were recurrence-free, respectively (p=0.0012). Quantitative ER status is inversely associated with tumor response in BC patients treated with NCT. A cut-off of 60 and 80% predicts best the association with tumor size reduction and pCR, respectively. Therefore, patients with an ER status higher than the cut-off might benefit from a neoadjuvant endocrine therapy approach. Patients with pCR had better survival outcomes independently of their tumor phenotype. Further prospective studies are needed to validate the clinical utility of quantitative ER as a predictive marker of tumor response.

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.

Abstract P5-16-21: The association of higher tumor HER2 load with treatment response to neoadjuvant therapy in HER2 positive breast cancer patients

Abstract Background: Neoadjuvant therapy for HER2 positive invasive breast cancer is used to downstage tumor prior to surgery, objectively measure response, and evaluate novel therapies in clinical trials. Residual Cancer Burden (RCB) established by pathologic evaluation of post-treatment surgical specimens is a marker of tumor response to chemotherapy as well as predictor of recurrence-free survival in HER2 positive breast cancer. The relationship between the HER2 tumor load and the response to chemotherapy in not known. Specific Aims: To evaluate RCB after neoadjuvant chemotherapy and HER2-targeted treatment for HER2-positive breast cancer, and to determine clinicopathologic factors associated with treatment response as represented by RCB. Methods: This retrospective chart review included all HER2-positive breast cancer patients, stage I – III, receiving neoadjuvant chemotherapy and HER2-targeted therapy with post-treatment surgical resection at an Allina Health hospital from 2013-2016. Review of clinicopathologic variables included HER2/CEP17 ratio, HER2 absolute copies, ER/PgR status (using the H score calculation), patient age, baseline tumor size, and gross and microscopic pathology review of breast tissue specimens with RCB evaluation completed by breast pathologists. To compare factors related to response, chi-square with Monte-Carlo simulation was used to analyze dichotomous variables, and Mann Whitney U-tests were used for continuous variables. Findings: The study included 97 patients. Upon surgical resection, complete pathologic response (RCB-0) was found in 47% (46/97 patients), and partial pathologic response (RCB-I) in 15% (15/97 patients). As compared to non-responders (RCB-2 and RCB-3) the complete and partial responders (RCB-0 and RCB-1) were associated with greater HER2/CEP17 ratios (10.2 vs. 6.5; p=0.003), and greater HER2 absolute copies (25 vs. 15.8; p &amp;lt;0.001). Complete responders were associated with lower ER expression (H scores of 89.2 vs. 171.8; p=0.005) than non-responders, with RCB-1 responders associated with ER H-scores between RCB-0 and non-responders (H score=145.9). No significant differences were noted between responders and non-responders on age at diagnosis, pre-treatment tumor size, PgR expression, or the percentage of tumor infiltrating lymphocytes. Conclusions: The majority of patients with HER2 positive tumors show considerable benefit with neoadjuvant chemotherapy and HER2-targeted treatment (63% in our study) based on RCB assessment. Predictors of response as measured by RCB include high HER2/CEP17 ratios, high absolute copies of HER2 signals by FISH, and lower ER expression. Citation Format: Lillemoe TJ, Susnik B, Grimm E, Kang S-HL, Swenson KK, Krueger JL, Finkelstein MJ, Tsai ML. The association of higher tumor HER2 load with treatment response to neoadjuvant therapy in HER2 positive breast cancer patients [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 P5-16-21.

MRE11 and ATM Expression Levels Predict Rectal Cancer Survival and Their Association with Radiotherapy Response.

BackgroundAberrant expression of DNA repair proteins is associated with poor survival in cancer patients. We investigated the combined expression of MRE11 and ATM as a predictive marker of response to radiotherapy in rectal cancer.MethodsMRE11 and ATM expression were examined in tumor samples from 262 rectal cancer patients who underwent surgery for rectal cancer, including a sub-cohort of 54 patients who were treated with neoadjuvant radiotherapy. The relationship between expression of the two-protein panel and tumor regression grade (TRG) was assessed by Mann–Whitney U test and receiver operating characteristics area under curve (ROC-AUC) analysis. The association between expression of the two-protein panel and clinicopathologic variables and survival was examined by Kaplan-Meier methods and Cox regression analysis.ResultsA high score for two-protein combined expression in the tumor center (TC) was significantly associated with worse disease-free survival (DFS) (P = 0.035) and overall survival (OS) (P = 0.003) in the whole cohort, and with DFS (P = 0.028) and OS (P = 0.024) in the neoadjuvant subgroup (n = 54). In multivariate analysis, the two-protein combination panel (HR = 2.178, 95% CI 1.115–4.256, P = 0.023) and perineural invasion (HR = 2.183, 95% CI 1.222–3.899, P = 0.008) were significantly associated with DFS. Using ROC-AUC analysis of good versus poor histological tumor response among patients treated preoperatively with radiotherapy, the average ROC-AUC was 0.745 for the combined panel, 0.618 for ATM alone, and 0.711 for MRE11 alone.ConclusionsThe MRE11/ATM two-protein panel developed in this study may have clinical value as a predictive marker of tumor response to neoadjuvant radiotherapy, and a prognostic marker for disease-free and overall survival.

Performance of 177Lu-DOTATATE-based peptide receptor radionuclide therapy in metastatic gastroenteropancreatic neuroendocrine tumor: a multiparametric response evaluation correlating with primary tumor site, tumor proliferation index, and dual tracer imaging characteristics.

To assess the performance of Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in metastatic gastroenteropancreatic neuroendocrine tumor (GEP-NET) and correlate it with primary tumor site, tumor proliferation index, and dual tracer imaging characteristics. Fifty patients (M : F 33 : 17, age: 26-71 years) with histopathologically confirmed metastatic/inoperable NETs who had undergone at least three cycles of PRRT with Lu-DOTATATE were included in the analysis. As part of the pretreatment evaluation, they underwent either Tc-HYNIC TOC (n=40)/Ga-DOTATATE PET (n=10) or fluorine-18-fluorodeoxyglucose (F-FDG) PET-computed tomography (CT). Response was assessed after three and five cycles PRRT on the basis of three parameters: (a) symptomatic and subjective scale, (b) biochemical tumor marker level, and (c) objective imaging (F-FDG/Ga DOTATATE PET/CT, Tc-HYNIC TOC, ceCT), and was categorized using predefined criteria (detailed in methods). Stable disease on imaging assessment with response on symptomatic or biochemical tumor marker scales or both were included in the responder group. The study population was broadly classified into (a) metastatic GEP-NET with known primary (n=43 i.e. 86%), which was further subclassified according to the site of primary and (b) those with unknown primary (n=7 i.e. 14%). Symptomatic response: 96% of patients showed a symptomatic response or improvement in health-related quality of life, irrespective of tumor proliferation index, dual tracer imaging characteristics, and response or progression of disease in the scan. Biochemical tumor marker response: 83% of scan responders showed a decrease, 10% showed a stable value, and 7% showed an increase in tumor marker levels. Among the scan nonresponders, 67% patients showed a corresponding increase in the tumor marker level, 22% patient showed a decrease, whereas 11% showed stable values. Scan response: 31 out of total 50 patients (62%) showed a partial scan response with either a decrease in the number of somatostatin receptor (SSTR)-positive lesions or metabolic activity in F-FDG/Ga-DOTATATE PET-CT or both, 10 patients (20%) showed stable disease, and nine patients (18%) showed progressive disease. The higher objective partial scan response documented can be explained by the introduction of the F-FDG-PET/CT parameter as a determinant criterion. Among the responders category (n=41), 32 (78.04%) showed discordance between F-FDG-PET/CT-based and SSTR-based imaging, whereas eight out of nine patients with nonresponse category (88.89%) showed concordance between SSTR-based imaging and F-FDG-PET/CT. Conversely, 32 of 33 patients (96.97%) with SSTR/F-FDG discordance and nine out of 17 (52.94%) with concordance were finally classified as responders, whereas the remaining, that is, 1/33 (3.03%) in the 'discordant' category and 8/17 (47.06%) with imaging concordance were classified as nonresponders, respectively. Our data show that high pretherapy F-FDG maximum standardized uptake values were associated with increased chances of treatment refractoriness in GEP-NETs. However, symptomatic improvement was observed in most cases irrespective of grade and F-FDG uptake. High pretherapy F-FDG maximum standardized uptake value in both low-grade and high-grade NET predicted a poor outcome and was associated with disease progression. Introduction of F-FDG-PET/CT parameter as a determinant of response classification increases the percentage of objective scan responders among patients with grades I and II GEP-NETs as F-FDG activity was observed to decrease before SSTR-based imaging and more frequently compared with the latter.

Abstract 3996: KA2237 and KA2507: Novel, oral cancer immunotherapeutics targeting PI3K-p110β/p110δ and HDAC6 with single-agent and combination activity

Abstract Two de novo-designed classes of orally-active immunotherapeutics - selectively targeting the PI3K-p110β/p110δ and HDAC6 enzymes - for solid and hematological cancer treatment will be described. The former, exemplified by the clinical candidate KA2237, are uniquely-selective inhibitors of the PI3K-p110β/p110δ isoforms, displaying immunotherapeutic activity and inhibiting primary tumor growth and metastasis. The latter, for which KA2507 is the candidate compound, are HDAC6-specific inhibitors, which inhibit tumor growth through regulation of aggresome formation, and inhibition of PD-L1 expression via decrease of STAT3 phosphorylation. In both cases, selectivity has been achieved over other enzyme superfamily members, with the aim being to minimize mechanism-related toxicity, thereby potentially providing opportunities to enable elevated single dose levels - and broad combination modalities not possible with pan-inhibitors of both enzymes - to be investigated. The PI3K-p110β/p110δ and HDAC6 inhibitors display potent oral activity as single agents in in vivo tumor syngeneic models, impacting on growth inhibition, PD and tumor marker responses; the PI3K-p110β/p110δ inhibitors also inhibit metastatic spread and, following surgical removal of primary tumor, confer promising inhibition of tumor regrowth. Crucially, the inhibitors work in combination with one another, making this co-therapy approach unique in oncology, and potentially important clinically in overcoming resistance mechanisms in both solid and hematological cancer. The rationale for this combination is based upon immunotherapeutic and cell signalling mechanisms, which will be described. KA2237 is entering Phase I studies in patients with lymphoma as a single agent in Q1 2016, with KA2507 scheduled to follow in Q3 to treat multiple myeloma. Further clinical investigations into solid tumor immunotherapy - both single agent- and combination-studies - are planned. Citation Format: Stephen J. Shuttleworth. KA2237 and KA2507: Novel, oral cancer immunotherapeutics targeting PI3K-p110β/p110δ and HDAC6 with single-agent and combination activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3996.

Focal adhesion kinase: predictor of tumour response and risk factor for recurrence after neoadjuvant chemoradiation in rectal cancer.

Rectal cancer represents about 30% of colorectal cancers, being around 50% locally advanced at presentation. Chemoradiation (CRT) followed by total mesorectal excision is the standard of care for these locally advanced stages. However, it is not free of adverse effects and toxicity and the complete pathologic response rate is between 10% and 30%. This makes it extremely important to define factors that can predict response to this therapy. Focal adhesion kinase (FAK) expression has been correlated with worse prognosis in several tumours and its possible involvement in cancer radio‐ and chemosensitivity has been suggested; however, its role in rectal cancer has not been analysed yet. To analyse the association of FAK expression with tumour response to CRT in locally advanced rectal cancer. This study includes 73 patients with locally advanced rectal cancer receiving standard neoadjuvant CRT followed by total mesorectal excision. Focal adhesion kinase protein levels were immunohistochemically analysed in the pre‐treatment biopsies of these patients and correlated with tumour response to CRT and patients survival. Low FAK expression was significantly correlated with local and distant recurrence (P = 0.013). Low FAK expression was found to be a predictive marker of tumour response to neoadjuvant therapy (P = 0.007) and patients whose tumours did not express FAK showed a strong association with lower disease‐free survival (P = 0.01). Focal adhesion kinase expression predicts neoadjuvant CRT response in rectal cancer patients and it is a clinically relevant risk factor for local and distant recurrence.

Sialoblastoma of the cheek: A case report and review of the literature.

Sialoblastoma is a rare salivary gland tumor that recapitulates the primitive salivary gland anlage. The authors herein report a case of sialoblastoma of a minor salivary gland, clinically presenting with progressive enlargement of a mass in the cheek of a 1-year-old female infant. Histopathologically, the mass consisted of tight clusters of basaloid cells and partially formed ductal and pseudo-ductal spaces separated by thin fibrous bands. Immunohistchemical studies demonstrated the presence of cytokeratin AE1/AE3, p63, CD99, α-fetoprotein (AFP) and Hep Par-1 expression in a considerable number of tumor cells. The clinical and pathological characteristics are presented and relevant literature is reviewed. Early complete surgical excision is recommended for the treatment of sialoblastoma. Radiation may be considered in cases with incomplete resection of the tumor. Chemotherapy may play a vital role in extensive, metastatic, or relapsed cases, or in cases with inadequate excision. The follow-up treatment should be frequent and prolonged. To the best of our knowledge, this is the first reported case of sialoblastoma of the cheek with immunoreactivity for AFP and Hep Par-1, which may be associated with the embryonic origin of the tumor. AFP may be a useful marker of tumor response in patient with sialoblastoma.

MP06-05 PRECYSTECTOMY EPITHELIAL TUMOR MARKER RESPONSE TO NEOADJUVANT CHEMOTHERAPY AND ITS EFFECT ON ONCOLOGICAL OUTCOMES IN UROTHELIAL BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Epidemiology & Evaluation II1 Apr 2016MP06-05 PRECYSTECTOMY EPITHELIAL TUMOR MARKER RESPONSE TO NEOADJUVANT CHEMOTHERAPY AND ITS EFFECT ON ONCOLOGICAL OUTCOMES IN UROTHELIAL BLADDER CANCER Soroush T Bazargani, Thomas G. Clifford, Hooman Djaladat, Anne Schuckman, Sarmad Sadeghi, Tanya Dorff, David Quinn, and Siamak Daneshmand Soroush T BazarganiSoroush T Bazargani More articles by this author , Thomas G. CliffordThomas G. Clifford More articles by this author , Hooman DjaladatHooman Djaladat More articles by this author , Anne SchuckmanAnne Schuckman More articles by this author , Sarmad SadeghiSarmad Sadeghi More articles by this author , Tanya DorffTanya Dorff More articles by this author , David QuinnDavid Quinn More articles by this author , and Siamak DaneshmandSiamak Daneshmand More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2166AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We have previously reported that elevated pre-cystectomy serum levels of epithelial tumor markers predict worse oncological outcome in patients with invasive urothelial bladder cancer (UBC). Herein, we evaluated the effect of neoadjuvant chemotherapy (NAChT) on elevated tumor marker levels and their association with oncological outcomes. METHODS Under IRB approval, serum levels of Carbohydrate Antigen 125 (CA-125), Carbohydrate Antigen 19-9 (CA 19-9) and Carcinoembryonic Antigen (CEA) were prospectively measured in 368 patients with invasive UBC from August 2011 through August 2015. In the subgroup undergoing NAChT, markers were measured prior to the first and after the last cycle of chemotherapy (before cystectomy). RESULTS 93 (25%) patients underwent NAChT, of whom 51 had a complete tumor marker profile before and after therapy and 24 (47%) of them had one or more elevated pre-NAChT tumor markers (3 missing post NAChT markers). The mean age was 67 years (range: 33-82), with 12 (57%) males. After completion of chemotherapy, 9/21 (43%) patients normalized their tumor markers, while 12/21 (57%) had one or more persistently elevated markers (p=0.004). There was no difference in pathological stage between groups (p=0.16). Median serum level of CA19-9 was significantly different before and after NAChT (137 vs. 19.3. respectively; p=0.03), while CA125 and CEA were not (Figure 1). Further analysis showed that tumor marker response is strongly correlated with disease recurrence/progression (45% in responders vs. 91% in non-responders at a median time 111 vs. 71 days respectively; p=0.01). Two patients that died in the normalized tumor marker group had tumor marker relapse at recurrence prior to their death. CONCLUSIONS To our knowledge, this is the first pilot study showing tumor marker response to NAChT. The results of this cohort suggest that patients with persistently elevated markers following NAChT have a very poor prognosis following cystectomy. There may be a promising role for these markers in identifying patients whose tumor is resistant to chemotherapy. A larger, controlled study with longer follow up is needed to determine their role in predicting survival. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e68 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Soroush T Bazargani More articles by this author Thomas G. Clifford More articles by this author Hooman Djaladat More articles by this author Anne Schuckman More articles by this author Sarmad Sadeghi More articles by this author Tanya Dorff More articles by this author David Quinn More articles by this author Siamak Daneshmand More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

CYFRA 21-1 as an Instant Prognostic Marker of Tumor Response on Radiation With or Without Chemotherapy in Patients With Larynx and Hypopharynx Squamous Cell Carcinoma

CYFRA 21-1 as an Instant Prognostic Marker of Tumor Response on Radiation With or Without Chemotherapy in Patients With Larynx and Hypopharynx Squamous Cell Carcinoma

Possible role of the systemic inflammatory reaction in defining tumor responder vs. nonresponder in cancer macrobead therapy.

572 Background: Peritoneal implantation of mouse renal adenocarcinoma cell-containing (RENCA) Macrobead (MB) represents a cell-system-based approach to the treatment of advanced, mCRC that has been evaluated to date in Phase IIa trials. The data indicate that there are “responders” (R) and “non-responders”(NR) as reflected in overall survival (OS), where “response” is defined as a &gt;20% decrease in either/both CEA or CA19-9 during the first 30 days after MB implantation. We analyzed whether the “response” is due to a post-implant systemic inflammatory response (SIR) or rather a direct inhibitory effect of the MB. Methods: Thirty-four treatment-resistant mCRC patients (pts) were implanted laparoscopically at least once with RENCA MB. Pts were considered R (n=25), or NR (n=9), based on tumor marker responses within the first 30 days. CRP, IL-6, TNF-alpha, and ESR, as measures of SIR, were measured at Day 14 and 30. Results: All 34 pts showed SIR to MB implantation, as indicated by transient rises in CRP, IL-6, TNF-a, and ESR. Baseline CRP values (R, mean 3.24+/-4.39 vs. NR, 2.96+/-3.43; t-test, p=0.86), Day 14 CRP values (R, mean 20.97 +/- 7.21 vs. NR, 14.5+/-8.78; t-test, p=0.04), Day 30 CRP values (R, mean 8.21+/-5.43 vs. NR, 10.76+/-6.92; t-test, p=0.27) and mean changes in IL-6 (baseline p=0.28; Day 14 p=0.36; Day 30 p=0.54), TNF-a (baseline p=0.37; Day 14 p=0.32; Day 30 p=0.29) did not show statistically significant differences between R and NR groups. Conclusions: Data suggest that early tumor marker decreases in R of RENCA MB are likely not due to the induced SIR, but rather a possibly direct anti-tumor-cell effect by factors released by MB. This supports the importance of the MB-induced changes in the MEF-2 pathway in the target colorectal cancer cell/tumor reported previously. Studies of clinical efficacy of MB continue in a Phase IIb clinical trial. Clinical trial information: NCT01053013.

Abstract IA19: Targeting the BCL-2 family in breast cancer

Abstract The steps taken to evade cell death are a recognized hallmark of cancer. Intense efforts over the last three decades have provided important insights into the molecular mechanisms that govern programmed cell death and how tumors recalibrate key survival pathways to sustain their growth. The pro-survival protein BCL-2 is overexpressed in approximately 75% of breast cancer, where it is has emerged as an important prognostic marker. Indeed, BCL-2 expression is a key component of the Oncotype DX assay. BCL-2 overexpression is even more prominent in luminal tumors (~85%), reflecting its estrogen-responsiveness. Other key pro-survival family members, MCL-1 and BCL-XL, are also commonly expressed across breast cancer subtypes. This group of pro-survival guardian proteins play a critical role in keeping pro-apoptotic effector proteins (such as BAX and BAK) in check. The effector proteins are essential for commitment to apoptosis, which occurs following mitochondrial cytochrome c release and caspase activation, resulting in cell death. BCL-2 guardian proteins also neutralize a group of sensor proteins (such as BIM). The sensor proteins are triggered by distinct cytotoxic stimuli (such as chemotherapy) to activate the effectors BAX and BAK. The sensor proteins are termed BH3 only proteins, as they lack the BCL-2 Homology (BH) domains BH1, BH2 and BH4 found in the two other subgroups. While BCL-2 is an important prognostic marker in breast cancer, its precise role as a predictive marker of tumor response has yet to be properly clarified. Nevertheless, there is increasing evidence that augmented levels of pro-survival BCL-2 proteins can prime tumors for death induced by conventional chemotherapy or endocrine therapy. This is due to the high occupation of pro-survival BCL-2 proteins by pro-apoptotic BH3 proteins, which can be activated by therapy, thereby committing tumor cells to apoptosis. Small molecule inhibitors termed BH3 mimetics that bind and neutralize BCL-2 pro-survival proteins have recently been described. These are showing considerable promise in early phase studies of lymphoid malignancies. We recently explored the feasibility of targeting luminal B tumors in combination therapy comprising endocrine therapy (tamoxifen) and a BH3 mimetic (ABT-737 or ABT-199) using patient derived xenograft (PDX) models of primary breast cancer. Tumor response and overall survival were significantly improved by combination therapy, when compared to tamoxifen alone. Moreover, synergy between BH3 mimetics and PI3K/mTOR inhibitors could be exploited by concomitant targeting of both survival pathways, a strategy that appeared both safe and effective. Since the potent and selective BCL-2 inhibitor ABT-199 was effective in these models (despite abundant BCL-XL expression), BCL-2 may be a crucial target for some luminal tumors, where we speculate it could provide a suitable companion biomarker for patient selection. This work has formed the basis for a Phase 1b study of BCL-2 inhibition with ABT-199 (venetoclax) in combination with tamoxifen in metastatic ER-positive breast cancer (ISRCTN98335443). The prospects for the development of BCL-XL and MCL-1 inhibitors will also be discussed. Citation Format: Geoffrey J. Lindeman, Delphine Merino, François Vaillant, James R. Whittle, Sheau Wen Lok, Kylie Shackleton, Jane E. Visvader. Targeting the BCL-2 family in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr IA19.

Updated overall survival analysis of NAPOLI-1: Phase III study of nanoliposomal irinotecan (nal-IRI, MM-398), with or without 5-fluorouracil and leucovorin (5-FU/LV), versus 5-FU/LV in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy.

417 Background: NAPOLI-1 is a global, randomized Phase 3 study evaluating nal-IRI—a nanoliposomal irinotecan—with or without 5-FU/LV in 417 patients with mPAC previously treated with gemcitabine-based therapy. Primary survival analysis was based on 313 events. Nal-IRI+5FU/LV significantly improved overall survival (OS, primary endpoint), 6.1 months (mo) vs 4.2 mo; with 5-FU/LV (unstratified hazard ratio [HR] = 0.67; P = 0.012). Primary endpoint was supported by improved progression-free survival, time to treatment failure, objective response and CA19-9 tumor marker response rates, and manageable toxicities. An updated analysis of OS, 6- and 12-month-survival estimates, and safety is presented. Methods: The updated descriptive analysis of OS, based on 378 events (25 May 2015), includes data from all randomized patients across the 3 arms. Results: After 378 OS events, nal-IRI+5-FU/LV (n = 117) retained an OS advantage relative to 5-FU/LV (n = 119): 6.2 mo (95% confidence interval [CI], 4.8–8.4) vs 4.2 mo (95% CI, 3.3–5.3) with an unstratified HR of 0.75 (P = 0.0417). In contrast, there was no OS advantage with nal-IRI monotherapy (n = 151) vs 5-FU/LV (n = 149): 4.9 mo [95% CI, 4.2–5.6] vs 4.2 mo [95% CI, 3.6–4.9], HR = 1.08; P = 0.5. Six-month survival estimates were 53% (95% CI, 44–62%) for nal-IRI+5-FU/LV vs 38% (95% CI, 29–47%) for 5-FU/LV; 12-month survival estimates were 26% (95% CI, 18-35%) for nal-IRI+5-FU/LV vs 16% (95% CI, 10–24%) for 5-FU/LV. With events in nearly all patients, the OS curves converge at ~20 mo with 19 patients (16.2%) surviving beyond 20 mo. This is a reason for attenuation of the HR estimate and unstratified log rank p-value. The most common grade 3+ adverse events occurring at a ≥ 2% incidence in the nal-IRI-containing arms were neutropenia, diarrhea, vomiting, and fatigue. Conclusions: In an updated analysis, the median OS benefit for nal-IRI+5FU/LV over 5-FU/LV was maintained, with a similar safety profile. Nal-IRI+5-FU/LV may be a new standard of care for patients with mPAC previously treated with gemcitabine-based therapy. Clinical trial information: NCT01494506.

Deletions of multidrug resistance gene loci in breast cancer leads to the down-regulation of its expression and predict tumor response to neoadjuvant chemotherapy.

Neoadjuvant chemotherapy (NAC) is intensively used for the treatment of primary breast cancer. In our previous studies, we reported that clinical tumor response to NAC is associated with the change of multidrug resistance (MDR) gene expression in tumors after chemotherapy. In this study we performed a combined analysis of MDR gene locus deletions in tumor DNA, MDR gene expression and clinical response to NAC in 73 BC patients. Copy number variations (CNVs) in biopsy specimens were tested using high-density microarray platform CytoScanTM HD Array (Affymetrix, USA). 75%–100% persons having deletions of MDR gene loci demonstrated the down-regulation of MDR gene expression. Expression of MDR genes was 2–8 times lower in patients with deletion than in patients having no deletion only in post-NAC tumors samples but not in tumor tissue before chemotherapy. All patients with deletions of ABCB1 ABCB 3 ABCC5 gene loci – 7q21.1, 6p21.32, 3q27 correspondingly, and most patients having deletions in ABCC1 (16p13.1), ABCC2 (10q24), ABCG1 (21q22.3), ABCG2 (4q22.1), responded favorably to NAC. The analysis of all CNVs, including both amplification and deletion showed that the frequency of 13q14.2 deletion was 85% among patients bearing tumor with the deletion at least in one MDR gene locus versus 9% in patients with no deletions. Differences in the frequency of 13q14.2 deletions between the two groups were statistically significant (p = 2.03 ×10−11, Fisher test, Bonferroni-adjusted p = 1.73 × 10−8). In conclusion, our study for the first time demonstrates that deletion MDR gene loci can be used as predictive marker for tumor response to NAC.

Abstract B10: Noninvasive pharmacodynamic markers of the dual mTORC1/2 inhibitor AZD2014 in combination with paclitaxel, in cisplatin-resistant ovarian carcinoma xenografts

Abstract Background: The PI3K/AKT/mTOR pathway is known to regulate glucose metabolism, proliferation and apoptosis, hence the inhibition of mTOR is expected have impact on these important mechanisms of tumor growth and survival. Studies of cancer metabolism following mTOR inhibition reported to date have only been carried out on allosteric mTOR inhibitors which selectively inhibit the activity of mTORC1. The metabolic changes associated with dual mTORC1 and 2 inhibitions remain unknown. AZD2014 is a dual mTORC1/2 inhibitor. The aims of this study are to (i) examine the effects on tumor metabolism following mTORC1/2 inhibition alone and in combination with paclitaxel, (ii) to develop a non-invasive pharmacodynamic (PD) biomarker for tumor response. Methods: We investigated the effects of AZD2014 alone (A: 50mg/kg/3 days/week po), paclitaxel alone (P: 20mg/kg/1 day/week ip) and the combination of AZD2014 and paclitaxel (A+P: same doses) on tumor growth, signal transduction (pSer473-AKT, pSer240/244-S6) and apoptosis (cleaved PARP) in a cisplatin resistant ovarian (A2780CisR) carcinoma xenograft model following 2 weeks of treatment. Metabolic profiles of A2780CisR tumor extracts after 2 weeks of treatment were also measured by high resolution in vitro 1H- and 31P-MRS. In order to develop early non-invasive PD markers of tumor response, in vivo 1H-MRS before and after 3 days of treatment were also performed. Results: Growth and molecular response- Following two weeks of treatment, tumor volumes of the A2780CisR xenografts increased by 280±100% in A+P (p&amp;lt;0.05; compared to vehicle-controls (V)), 420±160% in A (not significant compared to V (ns)), 730±180% in P (ns) and 560±20% in V. Reduced pSer473-AKT and pSer240/244-S6 protein levels and increased cleaved-PARP expression were observed in A- and A+P-treated xenografts consistent with mTORC1/2 inhibition and induction of apoptosis, respectively. In vitro 1H- and 31P-MRS of tumor extracts- Similar significant increases in branched-chain amino acids (p&amp;lt;0.03), glutamine (p&amp;lt;0.002), tyrosine (p&amp;lt;0.0001), phenylalanine (p&amp;lt;0.02) and glucose (p&amp;lt;0.03) were found in A- and A+P-treated tumors when compared with V. Significant decreases in phosphocholine (PC, p&amp;lt;0.002), glycero-phosphocholine (GPC, p&amp;lt;0.002), phosphoethanolamine (PE, p&amp;lt;0.02) and ATP (p&amp;lt;0.003), together with reduced expression of choline kinase, were only seen in A+P-treated tumors. An increase in threonine (p&amp;lt;0.03) was only observed in P- and A+P-treated tumors compared with V. In vivo 1H-MRS- The reduction in phospholipid metabolites (PC, GPC and PE) following A+P treatment was confirmed in vivo with a significant decrease in the ratio of total choline/water signal (p=0.04) observed at the early time-point of 3 days of treatment. Conclusions: A+P is effective in preclinical ovarian tumors, with additive growth inhibition and increased apoptosis. Very few metabolic changes were observed in P-treated tumors compared with V. The non-phospholipid changes in the metabolic profiles of A- and A+P-treated tumors are consistent with previous findings where similar metabolic profiles were found following mTOR inhibition (1). A+P treatment also caused decreases in PC (associated with reduced choline kinase expression) and other choline-related metabolites and these phospholipid changes may have potential as surrogate non-invasive markers for determining tumor response following AZD2014 and paclitaxel combination treatment. (1) Lin et al. Cell Symposia: Angiogenesis, Metabolic Regulation, and Cancer Biology in association with VIB, Belgium 2012. This work is supported by the CR-UK and EPSRC Cancer Imaging Centre in association with the MRC and Department of Health (England) grants C1060/A10334 and C1060/A16464, NHS funding to the NIHR Biomedical Research Centre. MOL is an NIHR Senior Investigator. Citation Format: Anne-Christine LF Wong Te-Fong, Efthymia Papaevangelou, Martin O. Leach, Udai Banerji, Yuen-Li Chung. Noninvasive pharmacodynamic markers of the dual mTORC1/2 inhibitor AZD2014 in combination with paclitaxel, in cisplatin-resistant ovarian carcinoma xenografts. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B10.

Non-invasive in vivo imaging of early metabolic tumor response to therapies targeting choline metabolism.

The cholinic phenotype, characterized by elevated phosphocholine and a high production of total-choline (tCho)-containing metabolites, is a metabolic hallmark of cancer. It can be exploited for targeted therapy. Non-invasive imaging biomarkers are required to evaluate an individual's response to targeted anticancer agents that usually do not rapidly cause tumor shrinkage. Because metabolic changes can manifest at earlier stages of therapy than changes in tumor size, the aim of the current study was to evaluate (1)H-MRS and diffusion-weighted MRI (DW-MRI) as markers of tumor response to the modulation of the choline pathway in mammary tumor xenografts. Inhibition of choline kinase activity was achieved with the direct pharmacological inhibitor H-89, indirect inhibitor sorafenib and down-regulation of choline-kinase α (ChKA) expression using specific short-hairpin RNA (shRNA). While all three strategies significantly decreased tCho tumor content in vivo, only sorafenib and anti-ChKA shRNA significantly repressed tumor growth. The increase of apparent-diffusion-coefficient of water (ADCw) measured by DW-MRI, was predictive of the induced necrosis and inhibition of the tumor growth in sorafenib treated mice, while the absence of change in ADC values in H89 treated mice predicted the absence of effect in terms of tumor necrosis and tumor growth. In conclusion, (1)H-choline spectroscopy can be useful as a pharmacodynamic biomarker for choline targeted agents, while DW-MRI can be used as an early marker of effective tumor response to choline targeted therapies. DW-MRI combined to choline spectroscopy may provide a useful non-invasive marker for the early clinical assessment of tumor response to therapies targeting choline signaling.

Seizure reduction is a prognostic marker in low-grade glioma patients treated with temozolomide.

We aimed to analyze the value of seizure reduction and radiological response as prognostic markers of survival in patients with low-grade glioma (LGG) treated with temozolomide (TMZ) chemotherapy. We retrospectively reviewed adult patients with a progressive LGG and uncontrolled epilepsy in two hospitals (VUmc Amsterdam; MCH The Hague), who received chemotherapy with TMZ between 2002 and 2014. End points were a ≥50 % seizure reduction and MRI response 6, 12 and 18 months (mo) after the start of TMZ, and their relation with progression-free survival (PFS) and overall survival (OS). We identified 53 patients who met the inclusion criteria. Seizure reduction was an independent prognostic factor for both PFS (HR 0.38; 95 % CI 0.19–0.73; p = 0.004) and OS (HR 0.39; 95 % CI 0.18–0.85; p = 0.018) after 6mo, adjusting for age and histopathological diagnosis, as well as after 12 and 18mo. Patients with an objective radiological response showed a better OS (median 87.5mo; 95 % CI 62.0–112.9) than patients without a response (median 34.4mo; 95 % CI 26.1–42.6; p = 0.046) after 12mo. However, after 6 and 18mo OS was similar in patients with and without a response on MRI. Seizure reduction is an early and consistent prognostic marker for survival after treatment with TMZ, that seems to precede the radiological response. Therefore, seizure reduction may serve as a surrogate marker for tumor response.Electronic supplementary materialThe online version of this article (doi:10.1007/s11060-015-1975-y) contains supplementary material, which is available to authorized users.