Negative Predictive Factor For Response Research Articles

The influence of metastatic patterns and tumor load on therapeutic efficacy of immunotherapy in patients with metastatic melanoma as determined by quantitative PET-parameters using [ 18 F]-fluorodeoxyglucose PET/computed tomography.

The introduction of immunotherapy was a revolution in the treatment of metastatic melanoma. Nevertheless, there are only few clinical parameters to predict response to immunotherapy. The purpose of this study was to identify metastatic patterns that can predict response by using noninvasive 18 F-FDG PET/CT imaging. In 93 immunotherapy-treated patients, total metabolic tumor volume (MTV) was measured before and after treatment. The differences were compared to quantify therapy response. Patients were divided into seven subgroups regarding the affected organ systems. The results as well as clinical factors were evaluated in multivariate analyses. No subgroup of metastatic patterns had a significant difference in response rates, but with a trend towards poorer response regarding osseous and hepatic metastases. Osseous metastases presented with significant lower disease-specific survival (DSS) ( P = 0.001). Sole lymph node metastases were the only subgroup with MTV reduction and with significant higher DSS (57.6 months; P = 0.033). Patients, who ever developed brain metastases, showed a high progression of MTV of 201 ml ( P = 0.583) and poor DSS of 49.7 months ( P = 0.077). Lower numbers of affected organs indicated significantly higher DSS (hazard ratio, 1.346; P = 0.006). Osseous metastases represented a negative predictive factor for response to immunotherapy and survival. Cerebral metastases, especially when nonresponsive to immunotherapy, predicted poor survival and high increase of MTV. A high number of affected organ systems was identified as a negative factor for response and survival. Patients with only lymph node metastases showed a better response and survival.

Diabetes Mellitus as a Prognostic Factor for Locally Advanced Rectal Cancer.

Currently, the impact of diabetes mellitus (DM) on rectal cancer patients is complex and just partly elucidated. The purpose of this study was to investigate the impact of diabetes mellitus on rectal cancer patients focusing on tumor differentiation grade, neoadjuvant chemoradiotherapy (NACRT) response, disease-free (DFS) and overall (OS) survival. Our study's population consisted of a group of 53 patients diagnosed with locally advanced rectal cancer, who underwent NACRT, followed by radical oncological surgery. This patient population was further divided into two groups according to diabetes presence. Downstaging rates, local control, DFS, and OS were lower in the DM subgroup compared to the non-DM locally advanced rectal cancer patients. The presence of DM at the time of diagnosis of locally advanced rectal cancer patients may be a negative predictive factor for response to neoadjuvant therapy, distant metastases, and local recurrences rates.

OA02.07 Characterization of the Tumor Microenvironment and Investigation of Immune Checkpoint Expression in Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive cancer with a poor prognosis and an increasing incidence, for which novel therapeutic strategies are urgently required. Since the immune system has been described to play a role in protection against MPM, characterization of its tumor immune microenvironment (TME) and immune checkpoints might help to identify new immunotherapeutic targets and their predictive and/or prognostic value. Immunohistochemistry (IHC) was performed on tissue samples of untreated (n=40) and chemotherapy-pretreated (n=14) MPM patients. Different subsets if immune cells were identified based on staining for CD4, CD8, FoxP3, CD68, CD45RO and granzyme B. The expression of the immune checkpoints TIM-3, LAG-3, PD-1 and its ligand PD-L1 was also investigated. The relationship between the immunological parameters and survival, as well as response to chemotherapy was analyzed using the R statistical software. All patients had CD8+ tumor infiltrating lymphocytes (TILs), CD68+ histiocytes and macrophages and CD45RO+ T cells in their stroma, with CD8+ TILs being the predominant cell type of the immune infiltrate. Stromal CD4+ TILs were found in 75% of the untreated and 71% of the pretreated samples. A subset of those cells was also FoxP3+ and these CD4+FoxP3+ cells were positively correlated with stromal CD4 expression (p<0.001). Less than half of the samples showed positivity for granzyme B. Both, untreated and pretreated patients had PD-1+ TILs, while only 10% of the untreated patients also had PD-1+ tumor cells. PD-L1 positivity on lymphocytes and/or tumor cells was observed for more than half of the patients, with significant differences according to the histological subtype (p<0.001). Patients with a sarcomatoid histology showed the most PD-1 expression. TIM-3 was expressed in tumor cells, stromal lymphocytes and plasma cells, less often in pretreated samples compared to untreated samples. All samples were negative for LAG-3. After multivariate analysis stromal CD45RO expression was found to be an independent negative predictive factor for response to chemotherapy (p=0.017) and expression of CD4 and TIM-3 in lymphoid aggregates were good prognostic factors (p=0.008; p=0.001). Our data reveal the diversity of immune cells present in MPM and point to TIM-3 as a new target in mesothelioma. Administering chemotherapy before or together with PD-1/PD-L1/TIM-3 blocking agents may not be the best combination sequence and further research on the predictive value of CD45RO in the stroma might guide patient selection for chemotherapy.

Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma

ABSTRACTMalignant pleural mesothelioma (MPM) is an aggressive cancer with a poor prognosis and an increasing incidence, for which novel therapeutic strategies are urgently required. Since the immune system has been described to play a presumed role in the protection against MPM, characterization of its tumor immune microenvironment (TME) and immune checkpoints can identify new immunotherapeutic targets and their predictive and/or prognostic value.To characterize the TME and the immune checkpoint expression profile, we performed immunohistochemistry (IHC) on formalin-fixed paraffin embedded (FFPE) tissue sections from 54 MPM patients (40 at time of diagnosis; 14 treated with chemotherapy). We stained for PD-1, PD-L1, TIM-3, LAG-3, CD4, CD8, CD45RO, granzyme B, FoxP3 and CD68. Furthermore, we analyzed the relationship between the immunological parameters and survival, as well as response to chemotherapy. We found that TIM-3, PD-1 and PD-L1 were expressed on both immune and tumor cells. Strikingly, PD-1 and PD-L1 expression on tumor cells was only seen in unpretreated samples. No LAG-3 expression was observed. CD45RO expression in the stroma was an independent negative predictive factor for response on chemotherapy, while CD4 and TIM-3 expression in lymphoid aggregates were independent prognostic factors for better outcome. Our data propose TIM-3 as a promising new target in mesothelioma. Chemotherapy influences the expression of immune checkpoints and therefore further research on the best combination treatment schedule is required.

The role of antiangiogenic agents in the treatment of patients with advanced colorectal cancer according to K-RAS status.

Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer worldwide. Recently, it has been found that about 40 % of patients with CRC have mutations in the K-RAS gene. Several clinical trials have showed that patients with metastatic colorectal cancer (mCRC) who present tumour-promoting mutations in signalling pathways involving the epidermal growth factor receptor (EGFR), which includes activating K-RAS mutations, do not respond to anti-EGFR drugs such as panitumumab and cetuximab. Hence, K-RAS status is now considered an important negative predictive factor for response to anti-EGFR drugs. Moreover, K-RAS status seems to have also a prognostic role in CRC, but this fact is somewhat controversial. Activity of antiangiogenic agents seems not to be influenced by K-RAS gene status. Tumour angiogenesis has attracted interest in attempts to improve the management of mCRC. The vascular endothelial growth factor (VEGF) pathway is fundamental to the regulation of angiogenesis, and research has focused on developing agents that selectively target it. In this way, the anti-VEGF antibody bevacizumab in combination with chemotherapy has provided important clinical benefits in terms of response rate, progression-free survival and overall survival to patients with mCRC. Efficacy data of bevacizumab in K-RAS wild-type patients seem to be comparable with the efficacy data observed with anti-EGFR therapies in a cross-trial comparison. Although there is a lack of prospective and randomized data in this setting, the combination of chemotherapy plus antiangiogenic agents could be considered as an effective alternative for the treatment of mCRC with independence of K-RAS gene status. Here, we review the available data we have in the literature of the use of antiangiogenic strategies in the treatment of mCRC nowadays.

Prognostic and predictive value of liver volume in colorectal cancer patients with unresectable liver metastases.

PurposeTo determine the prognostic and predictive value of liver volume in colorectal cancer patients with unresectable liver metastases.Materials and MethodsSixteen patients received whole liver radiotherapy (WLRT) between January 1997 and June 2013. A total dose of 21 Gy was delivered in 7 fractions.ResultsThe median survival time after WLRT was 9 weeks. In univariate analysis, performance status, serum albumin and total bilirubin level, liver volume and extrahepatic metastases were associated with survival. The mean liver volume was significantly different between subgroups with and without pain relief (3,097 and 4,739 mL, respectively; p = 0.002).ConclusionA larger liver volume is a poor prognostic factor for survival and also a negative predictive factor for response to WLRT. If patients who are referred for WLRT have large liver volume, they should be informed of the poor prognosis and should be closely observed during and after WLRT.

O2-033 - Antibody-Dependent Cellular Cytotoxicity of Cetuximab Against Colorectal Cancer Cell Lines with Wild-Type and Mutant KRAS

ABSTRACT Cetuximab is a chimeric IgG1 monoclonal antibody (mAb) that targets the epidermal growth factor receptor (EGFR). In addition to direct EGFR inhibition, antibody-dependent cellular cytotoxicity (ADCC) is considered to be an important mechanism of action of cetuximab. Recently, KRAS mutations in tumors have been shown to be a negative predictive factor for response to cetuximab treatment of colorectal cancer (CRC). KRAS mutations potentially contribute to the resistance to the direct inhibitory effect of cetuximab. However, the influence of KRAS mutations on cetuximab-induced ADCC is not fully understood. In this study, we investigated cetuximab-mediated ADCC against human CRC lines, HCT116 and DLD-1, which carry mutated KRAS, and their derivative cell lines, HKh2 and DKO-4, respectively, in which the mutated KRAS allele was deleted by targeted disruption (KRAS wild-type). Peripheral blood mononuclear cells (PBMCs) from healthy volunteers and NK92, a natural killer cell line, exogenously expressing FcγR3A (CD16a) were used as effector cells. We first determined the growth-inhibitory effect of cetuximab alone. Growth inhibition was observed only in KRAS wild-type cell lines, but its effect was only slight. In a standard short-term (4 h) ADCC assay that mainly evaluated lytic activity via perforin/granzyme, ADCC activities were exhibited to a similar extent against CRC cell lines regardless of the KRAS mutation status. We also examined a long-term (24 h) ADCC assay under the perforin-inhibited condition to evaluate the death receptor ligand-induced apoptosis, which is another major mechanism of ADCC. In this assay, cetuximab-mediated ADCC was induced in wild-type but not mutant KRAS cell lines. Similar to a previous report, Hkh2 and DKO-4 displayed a higher sensitivity to recombinant human Fas ligand (FasL) and TRAIL than did HCT116 and DLD-1, respectively. Furthermore, blocking experiments with neutralizing antibodies revealed that induction of apoptosis via Fas–FasL interaction is involved in perforin-independent cetuximab-mediated ADCC against KRAS wild-type cells. In conclusion, these results suggest that mutated KRAS may contribute to the resistance to the antitumor effects of cetuximab not only through direct receptor inhibition but also through ADCC mediated by Fas–FasL interaction.

Abstract 2527: Antibody-dependent cellular cytotoxicity of cetuximab against colorectal cancer cells with wild-type and mutant KRAS

Abstract Cetuximab is a chimeric IgG1 monoclonal antibody (mAb) that targets the extracellular domain of epidermal growth factor receptor (EGFR). In addition to direct EGFR inhibition, antibody-dependent cellular cytotoxicity (ADCC) is considered to be an important mechanism of action of cetuximab. Recently, KRAS mutations in tumors have been shown to be a negative predictive factor for response to cetuximab treatment for colorectal cancer (CRC). KRAS activating mutations constitutively transduce RAS/RAF/MEK/ERK pathway signaling, which theoretically cannot be suppressed by inhibition of the upstream receptor through the use of cetuximab. Thus, KRAS mutations potentially contribute to the resistance to the direct inhibitory effect of cetuximab. However, the influence of KRAS mutations on cetuximab induced ADCC is not fully understood. In this study, we investigated cetuximab-mediated ADCC against human CRC lines, HCT116 and DLD-1, which carry mutated KRAS, and their derivative cell lines, HKh2 and DKO-4 respectively, in which the mutated KRAS allele was deleted by targeted disruption (KRAS wild-type). Peripheral blood mononuclear cells (PBMCs) from healthy volunteers and NK92, a natural killer cell line, exogenously expressing Fcα3A (CD16a) were used as effector cells. We first determined the growth-inhibitory effect of cetuximab alone using a WST-8 assay. Growth inhibition was observed only in KRAS wild-type cell lines, but its effect was only slight. In a standard short-term (4hr) ADCC assay that mainly evaluated lytic activity via perforin/granzyme, ADCC activities were exhibited to a similar extent against CRC cell lines regardless of the KRAS mutation status. We also examined a long-term (24hr) ADCC assay under the perforin-inhibited condition to evaluate the death receptor ligand-induced apoptosis, which is another major mechanism of ADCC. In this assay, cetuximab-mediated ADCC was induced in wild-type but not mutant KRAS cell lines. Similar to a previous report, Hkh2 and DKO-4 displayed a higher sensitivity to recombinant human Fas ligand (FasL) and TRAIL than did HCT116 and DLD-1, respectively. Furthermore, blocking experiments with neutralizing antibodies revealed that induction of apoptosis via Fas-FasL interaction is involved in perforin-independent cetuximab-mediated ADCC against KRAS wild-type cells. In conclusion, these results suggest that mutated KRAS may contribute to the resistance to the antitumor effects of cetuximab not only through direct receptor inhibition but also through ADCC mediated by Fas-FasL interaction. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2527. doi:1538-7445.AM2012-2527

Is chronic opioid use a negative predictive factor for response to cervical epidural steroid injections?

Cervical epidural steroid injections (ESIs) are often used to treat patients with neck and upper extremity pain associated with a cervical radiculopathy. The effect of chronic opioid use in cervical radiculopathy patients managed with ESIs is unknown; past studies suggest that these patients may behave differently than opioid naïve patients. The purpose of this study is to determine the effect of chronic (greater than 6 months) opioid use on the immediate outcome of cervical ESIs. A two year retrospective chart review identified 22 consecutive patients with cervical radiculopathy who underwent a single level interlaminar cervical ESI, main outcome variable was > 50% pain relief on VAS at follow up. Inclusion factors were unilateral disc protrusion, exclusion factors were severe central canal or foraminal stenosis, spondylolithesis, spinal instability, cord edema, or with multi-level disc protrusions. Using a linear logistic regression analysis on both patient demographics and physical exam measures, the most significant explanatory model was the use of opiates at the time of injection; 70% of opioid naïve patients had a favorable outcome while only 20% of patients managed with chronic opioids had relief (p= 0.06). Patients managed with opioids chronically may respond in a different manner to ESIs when compared to opioid naïve patients.

CXCR4 as a Predictor of Response in Acute Myeloid Leukemia

The expression of CXCR4 (CD184) has been associated with poor prognosis in Acute Myeloid Leukemia (AML) and it has also been suggested that the CXCL12(SDF-1a)/CXCR4 interaction contributes to the resistance of leukemia cells to chemotherapy-induced apoptosis. Inhibition of CXCR4 was found to enhance chemotherapy-induced apoptosis in a subset of leukemic myeloblasts that carry Flt3 mutations and to overcome chemoresistance associated with stromal activity. NPM variants with a cytoplasmic localization represent the most common mutation detected in myeloid malignancies and are associated with a favourable clinical outcome. A recent study provides biological evidence for a novel role for NPM as a negative regulator of CXCR4 signalling induced by CXCL12: suppression of NPM expression enhanced chemotactic responses to CXCL12, and conversely, over-expression of a cytosolic NPM mutant reduced chemotaxis induced by CXCL12. We investigated whether CD184 expression is a negative predictor factor for response to chemotherapy and if there is clinical evidence that NPM mutations could overcome chemoresistance to induction therapy in this subset of patients. The expression of CD184 was analyzed by flow cytometric methods in a group of 70 cases of adult AML at onset of disease, diagnosed at our Institution since January 2006. The diagnosis was performed according to FAB/WHO criteria; all patients received intensive chemotherapy according to institutional protocols. There were 34 males and 36 females and median age was 46 years (range 18–65). AML cells were gated based upon their CD45 expression and samples were considered positive if CD184 was expressed by more than 20% of blasts. CD184 was positive in 45 and negative in 25 cases. There was no significant difference between the two groups in terms of sex, age, Hb level, WBC and Plt counts, percentage of blasts, and occurrence of the NPM mutation. The CR rate was 45% in CD184+ and 82% in CD184- (p=0.03); among CD184+ cases, the CR rate was significantly higher in NPMc+ cases, (p=0.03). Our results show that CD184 expression is associated with a lower rate of CR after induction therapy and this association is stronger in NPM unmutated cases, suggesting that CD184 expression is a negative predictive factor for response to chemotherapy. Further data are needed to verify if the biological role of the cytosolic NPM mutant as a negative regulator of CXCR4 signalling induced by CXCL12 could have a clinical role contributing to overcome the resistance of leukemic cells to induction chemotherapy.

When is a tumor marker ready for prime time? A case study of c-erbB-2 as a predictive factor in breast cancer.

c-erbB-2 (HER-2, c-neu) might play a role as a predictive factor in breast cancer. However, the clinical utility of the marker in this disease is still not established. We conducted a critical analysis of the literature, in which we reviewed the factors that contribute to the lack of acceptance of c-erbB-2 for clinical use and attempted to determine the predictive role of c-erbB-2 for response to specific therapies. We conducted a MEDLINE literature search using the keywords c-erbB-2, HER2, neu, and breast cancer, reviewed the references included in each publication, and reviewed abstracts that have been reported in the 1997-2000 proceedings to the American Association of Cancer Research and American Society for Clinical Oncology annual meetings. The preclinical and clinical data reported to date suggest that amplification or overexpression of c-erbB-2 is a weak to moderate negative pure prognostic factor. c-erbB-2 seems to be a weak to moderate negative predictive factor for response to endocrine therapy. The marker is also a moderate negative predictive factor for response to alkylating agents and a moderate positive predictive factor for response to anthracyclines. The data regarding response to taxanes or radiotherapy are not sufficient to make recommendations regarding treatment decision making. Finally, c-erbB-2 is a strong predictive factor for response to trastuzumab. We conclude that, in the adjuvant setting, c-erbB-2 status should not be used to determine whether a woman should receive adjuvant systemic therapy (weak prognostic factor). In addition, c-erbB-2 status should not be used to determine whether a patient should receive endocrine therapy. When adjuvant chemotherapy is recommended, anthracycline-based therapy should be the preferred regimen for c-erbB-2-positive patients. However, when anthracyclines are contraindicated, alkylating agent-based therapy should not be withheld. To determine the true predictive role and strength of the marker for response to each therapy, prospective randomized clinical trials or formal meta-analyses are required.

Lung-Resistance–Related Protein Expression Is a Negative Predictive Factor for Response to Conventional Low but not to Intensified Dose Alkylating Chemotherapy in Multiple Myeloma

AbstractThis study was undertaken to assess the significance of lung-resistance related protein (LRP) expression in plasma cells from untreated multiple myeloma (MM) patients and to determine whether LRP was associated with a poor response and survival in patients treated with different dose regimens of melphalan. Seventy untreated patients received conventional oral dose melphalan (0.25 mg/kg, day 1 to 4) combined with prednisone (MP) or intravenous intermediate-IDM; 70 mg/m2) or high- (140 mg/m2) dose Melphalan (HDM). LRP expression was assessed with immunocytochemistry using the LRP-56 monoclonal antibody. LRP expression was found in 47% of patients. In the MP treated patients, LRP expression was a significant prognostic factor regarding response induction (P < .05), event free survival (P < .003), and overall survival (P < .001). In the intensified dose melphalan treated patients LRP did not have a prognostic value. The response rates of LRP-positive patients to MP and IDM/HDM were 18% versus 81%, respectively (P < .0001). We conclude that LRP is frequently expressed in untreated MM patients and is an independent predictor for response and survival in patients treated with MP. Pretreatment assessment of LRP identifies a subpopulation of patients with a poor probability of response to conventional dose melphalan. Dose intensification of melphalan is likely to overcome LRP-mediated resistance.

Lung-Resistance–Related Protein Expression Is a Negative Predictive Factor for Response to Conventional Low but not to Intensified Dose Alkylating Chemotherapy in Multiple Myeloma

This study was undertaken to assess the significance of lung-resistance related protein (LRP) expression in plasma cells from untreated multiple myeloma (MM) patients and to determine whether LRP was associated with a poor response and survival in patients treated with different dose regimens of melphalan. Seventy untreated patients received conventional oral dose melphalan (0.25 mg/kg, day 1 to 4) combined with prednisone (MP) or intravenous intermediate-IDM; 70 mg/m2) or high- (140 mg/m2) dose Melphalan (HDM). LRP expression was assessed with immunocytochemistry using the LRP-56 monoclonal antibody. LRP expression was found in 47% of patients. In the MP treated patients, LRP expression was a significant prognostic factor regarding response induction (P &lt; .05), event free survival (P &lt; .003), and overall survival (P &lt; .001). In the intensified dose melphalan treated patients LRP did not have a prognostic value. The response rates of LRP-positive patients to MP and IDM/HDM were 18% versus 81%, respectively (P &lt; .0001). We conclude that LRP is frequently expressed in untreated MM patients and is an independent predictor for response and survival in patients treated with MP. Pretreatment assessment of LRP identifies a subpopulation of patients with a poor probability of response to conventional dose melphalan. Dose intensification of melphalan is likely to overcome LRP-mediated resistance.