Adenosine Triphosphate-based Chemotherapy Response Assay Research Articles

Adenosine triphosphate-based chemotherapy response assay predicts long-term survival of primary epithelial ovarian cancer.

The aim of this study is to analyze the long-term relapse-free survival and overall survival outcomes of primary ovarian cancer patients using adenosine triphosphate-based chemotherapy response analysis. In total, 162 primary epithelial ovarian cancer patients who underwent chemotherapy response assay for carboplatin, cisplatin, and paclitaxel by adenosine triphosphate-based chemotherapy response analysis prior to chemotherapy between December 2006 and November 2016 were retrospectively reviewed. Chemosensitivity with single or combined three agents and clinical characteristics of patients were studied to understand their correlation with long-term relapse-free survival and overall survival. Median follow-up time was 61.4 (range 1 - 130) months. Univariate analysis showed the paclitaxel-sensitive group (HR = 0.625, 95%CI = 0.393 to 0.994), combined carboplatin and paclitaxel-sensitive group (HR = 0.574, 95%CI = 0.352 to 0.937), and combined carboplatin, cisplatin, and paclitaxel-sensitive group (HR = 0.489, 95%CI = 0.295 to 0.810) were highly associated with better relapse-free survival than their corresponding non-sensitive groups. The carboplatin-sensitive group (HR = 0.533, 95%CI = 0.303 to 0.939), cisplatin-sensitive group (HR = 0.433. 95%CI = 0.251 to 0.748), and combined carboplatin- and cisplatin-sensitive group (HR = 0.286, 95%CI = 0.142 to 0.576) were highly associated with better overall survival than their corresponding non-sensitive groups. Combined carboplatin, cisplatin, and paclitaxel chemosensitivity, together with International Federation of Gynecology and Obstetrics (FIGO) stage were independent predictors for relapse-free survival. Single or combined chemosensitivity of cisplatin and/or carboplatin, together with residual tumor size and FIGO stage, were significant independent predictors for overall survival on a multivariate hazard model. Paclitaxel sensitivity is a prognostic factor of long-term relapse-free survival in patients with epithelial ovarian cancer, but platinum sensitivity is a more important prognostic factor for long-term overall survival.

Clinical value of an adenosine triphosphate-based chemotherapy response assay in resectable stage III colorectal cancer.

PurposeATP-based chemotherapy response assay (ATP-CRA) is a well-documented and validated technology that can individualize chemotherapy. This study was undertaken to assess the usefulness of ATP-CRA in advanced colorectal cancer (CRC) patients receiving adjuvant chemotherapy.MethodsA total of 136 patients with curative resection between January 2006 and April 2014 were evaluated using ATP-CRA. Patients received either the FOLFOX or Mayo clinic regimen chemotherapy following assay results. The sensitive-group (S-group) was defined as a drug-producing ≥ 40% reduction in ATP, and the resistant-group (R-group) as an ATP reduction of < 40%. These 2 groups were further subdivided to produce 4 subgroups: the FOLFOX sensitive subgroup (the FS subgroup [n = 65]), the Mayo sensitive subgroup (the MS subgroup [n = 40]), the FOLFOX resistant subgroup (the FR subgroup [n = 10]), and the Mayo resistant subgroup (the MR subgroup [n = 21]). Clinical responses and survival results were compared for both treatment regimens.ResultsThe FS and MS subgroups showed a better disease-free survival rate (29% vs. 40%, 35% vs. 47.6%) and overall survival rate (92.3% vs. 80.0%, 87.5% vs. 76.2%) than FR and MR subgroups. The FS and MS subgroups showed a longer time to relapse (20.2 months vs. 9.5 months, 17.6 months vs. 16.4 months) than the FR and MR subgroups.ConclusionATP-CRA tailored-chemotherapy has the potential to provide a survival benefit in resectable advanced CRC.

Correlation of Early Recurrence With In Vitro Adenosine Triphosphate Based Chemotherapy Response Assay in Pancreas Cancer With Postoperative Gemcitabine Chemotherapy.

Gemcitabine-based regimens represent the standard systemic first line treatment in patients after pancreatic resection. However, the clinical impact of gemcitabine varies significantly in individuals because of chemoresistance. An in vitro adenosine triphosphate based chemotherapy response assay (ATP-CRA) was designed to evaluate the sensitivity of cancer cells to various chemotherapeutic agents. This study investigated the correlation between in vitro gemcitabine sensitivity of tumor cells and early recurrence after curative resection. From January 2007 to December 2010, the ATP-CRA for gemcitabine was tested in 64 patients surgically treated for pancreas cancer at Gangnam Severance Hospital, Seoul, Korea. We analyzed the relationship between chemosensitivity and early systemic recurrence in patients with pancreas cancer to predict disease-free survival (DFS) after curative resection in pancreas cancer. The mean cell death rate (CDR) was 20.0 (±14.5) and divided into two groups according to the mean values of the CDR. Lymphovascular invasion was more frequently shown in gemcitabine resistance group without statistical significance. In univariate and multivariate analysis, advanced tumor stage and gemcitabine sensitive group (CDR ≥ 20) were identified as independent prognostic factors for DFS. Gemcitabine sensitivity measured by ATP-CRA was well correlated with in vivo drug responsibility to predict early recurrence following gemcitabine-based adjuvant chemotherapy in patients with pancreas cancer.

Clinical correlation between &amp;lt;i&amp;gt;in vitro&amp;lt;/i&amp;gt; chemoresponse assay and first line chemotherapy for metastatic colorectal cancer patients

Purpose: The study investigated correlations between adenosine triphosphate-based chemotherapy response assay (ATP-CRA) and clinical response after first line chemotherapy for metastatic colorectal cancer patients. Methods: From June 2009 to June 2012, 24 patients were enrolled in this study. ATP-CRA was performed to evaluate the chemosensitivities of three combination anticancer drugs such as 5-fluorouracil (FU)+oxaliplatin and irinotecan, and capecitabine+oxaliplatin for metastatic colorectal cancer. A sensitive group (SG) and resistant group (RG) for chemotherapy regimen (oxaliplatin+5-FU+leucovorin [FOLFOX], n = 14; oxaliplatin+capecitabine [CapeOx], n = 2; irinotecan+5-FU+leucovorin [FOLFIRI], n = 8) was defined as cut-off value 30%. The outcomes were a correlation between the ATP-CRA results and the clinical response and progression-free survival. Results: Patients were dichotomized into the SG (19 patients) and RG (5 patients) groups. There was no difference between groups, in terms of regimen, frequency and interval of chemotherapy. The disease control rate after first response evaluation was not shown statistically difference (89.5% in SG and 60.0% in RG, respectively, P = 0.15). And there was also no significance in second and third response evaluation. The median progression-free month were 7.0 (range, 2–27 month) and 5.0 (range, 3–12 month), respectively and shown marginal significance. However, there was no statistical difference in progression-free survival curve (P = 0.16). Sensitivity, specificity, positive prediction rate and negative prediction rage for disease control after first response was 85.0%, 50.0%, 89.5%, and 40.0%. Conclusion: Although ATP-CRA may be helpful in predicting chemotherapy response in metastatic colorectal cancer, there was not conclusive. Therefore, we recommend further clinical studies to confirm the efficacy of chemoresponse assay for metastatic colorectal cancer. Keywords: Colorectal cancer, Metastasis, Chemotherapy, Response

In Vitro Adenosine Triphosphate-Based Chemotherapy Response Assay as a Predictor of Clinical Response to Fluorouracil-Based Adjuvant Chemotherapy in Stage II Colorectal Cancer.

PurposeWe evaluated the usefulness of the in vitro adenosine triphosphate-based chemotherapy response assay (ATP-CRA) for prediction of clinical response to fluorouracil-based adjuvant chemotherapy in stage II colorectal cancer.Materials and MethodsTumor specimens of 86 patients with pathologically confirmed stage II colorectal adenocarcinoma were tested for chemosensitivity to fluorouracil. Chemosensitivity was determined by cell death rate (CDR) of drug-exposed cells, calculated by comparing the intracellular ATP level with that of untreated controls.ResultsAmong the 86 enrolled patients who underwent radical surgery followed by fluorouracil-based adjuvant chemotherapy, recurrence was found in 11 patients (12.7%). The CDR ≥ 20% group was associated with better disease-free survival than the CDR < 20% group (89.4% vs. 70.1%, p=0.027). Multivariate analysis showed that CDR < 20% and T4 stage were poor prognostic factors for disease-free survival after fluorouracil-based adjuvant chemotherapy.ConclusionIn stage II colorectal cancer, the in vitro ATP-CRA may be useful in identifying patients likely to benefit from fluorouracil-based adjuvant chemotherapy.

Abstract 4676: In-vitro adenosine triphosphate-based chemotherapy response assay (ATP-CRA) results comparison between primary and recurrent gynecologic cancer using a unique cohort

Abstract Purpose: The standard chemotherapy regimen in gynecologic cancer treatment is not established, particularly in cases of recurrence. The objective of this study is to evaluate the role of in vitro adenosine triphosphate-based chemotherapy response assay (ATP-CRA) in recurrent gynecologic cancer. Methods: We examined 20 matched primary and recurrent tumor pairs of each patient with recurrent gynecologic cancer, using ATP-CRA. Tumor samples were obtained from primary and secondary debulking or palliative surgery. Inhibition rates of the chemotherapeutic agents were compared. Results: The diseases of patients analyzed in this study were composed of ovarian/peritoneal cancer [11 patients (55%)], uterine cancer [7 patients (35%)], and cervical cancer [3 patients (15%)]. The average of inhibition rate was 36.3% in samples obtained from primary surgery and 33.6% in samples from secondary debulking or palliative surgery (P&amp;gt;0.1). In the primary surgery cases, the drugs showing high inhibition rate were ifosfamide (56.4%), cisplatin (52.6%), and irinotecan (43.3%) in the following order, and in the secondary operation cases, ifosfamide (54.3%), cisplatin (44.3%), and Topotecan (39.9%). The number of cases in which the ATP-CRA result had actual influence in choosing the regimen, were 0 (0%) in primary surgery cases, and 7 (35%) in secondary surgery cases (P&amp;lt;0.05). Conclusion: The drug inhibition rate did not decrease in the recurrent tumors compared to the primary tumors. The actual influence of ATP-CRA results increase significantly in the secondary surgery compared to the primary one. Note: This abstract was not presented at the meeting. Citation Format: Eun Ji Nam, Young Tae Kim, Sang Wun Kim, Sunghoon Kim, Ga Won Yim. In-vitro adenosine triphosphate-based chemotherapy response assay (ATP-CRA) results comparison between primary and recurrent gynecologic cancer using a unique cohort. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4676. doi:10.1158/1538-7445.AM2014-4676

ATP-based chemotherapy response assay in primary or recurrent ovarian and peritoneal cancer.

PurposeTo investigate chemosensitivity with an adenosine triphosphate-based chemotherapy response assay in patients with epithelial ovarian or peritoneal cancer according to tumor histology, grade, and disease status.Materials and MethodsOne hundred specimens were collected during primary or secondary debulking from 67 patients with primary ovarian cancer, 24 patients with recurrent ovarian cancer, 5 patients with primary peritoneal cancer, and 4 patients with recurrent peritoneal cancer; samples were collected between August 2006 and June 2009. Tumor cells were isolated and cultured for 48 hours in media containing chemotherapy. The chemosensitivity index (CI) was calculated as 300 minus the sum of the cell death rate at 0.2×, 1×, and 5× drug concentrations, and the CI values were compared.ResultsCI values were obtained from 93 of 100 patients. The most active agents against primary disease were ifosfamide and paclitaxel. For primary serous adenocarcinoma, paclitaxel and irinotecan were the most active, followed by ifosfamide. For clear cell carcinoma, ifosfamide was the most active, followed by paclitaxel and irinotecan. Although not statistically significant, the CIs of cisplatin, carboplatin, paclitaxel, and docetaxel decreased as tumor grade increased. In 14 cases of recurrent disease, paclitaxel was the most active, followed by ifosfamide and cisplatin.ConclusionIfosfamide and paclitaxel were the most active drugs for primary and recurrent disease. Therefore, we recommend further clinical studies to confirm the efficacy of paclitaxel, ifosfamide, and cisplatin combination chemotherapy for recurrent and primary ovarian cancer.

Correlation between the molecular subtype of breast cancer and thein vitroadenosine triphosphate-based chemosensitivity assay

PurposeThe empirical use of a chemotherapy regimen shows different results in individual breast cancer patient treatment. Recent studies showed the effectiveness of the adenosine triphosphate-based chemotherapy response assay (ATP-CRA). However, little is known about the correlation between chemosensitivity and breast cancer molecular subtypes. Therefore, we investigated whether the result of ATP-CRA is associated with a molecular subtype of breast cancer.MethodsTwo hundred eighty-seven patients diagnosed with breast cancer and receiving ATP-CRA at Mokdong Hospital, Ewha Womans University between September 2007 and December 2010 were enrolled in this study. Hormone receptor status, HER2/neu expression, and results of chemosensitivity tests of the patients was analyzed.ResultsIn all of four subtypes, the combination of two agents showed significant higher mean cell death rate than a single agent. Within the breast cancer cell lines in this study, the range of chemosensitivity response was very wide and varied for each patient. For this reason, the molecular subtype of breast cancer is inconclusive in choosing an effective chemotherapeutic agent and in vitro chemosensitivity test, prior to therapy, could be a useful method for planning chemotherapy for each patient.ConclusionChemosensitivity response to anticancer agents was found to vary depending on the individual breast cancer patients. The molecular subtype of breast cancer is inconclusive to choose the effective chemotherapeutic agent and the in vitro chemosensitivity test, prior to therapy, could be more useful for planning chemotherapy for each patient.

Abstract P4-03-11: SUVmax of FDG-PET/CT is Associated with Chemotherapy Response Assay Test Results and Prognostic Factors in Breast Cancer Patients

Abstract Backgrounds:18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET/CT) is widely used for cancer evaluation and there are several studies which suggested maximum standard uptake value (SUVmax) may reflect the cancer patients' prognosis. Adenosine triphosphate-based chemotherapy response assay (ATP-CRA) is commonly used as a chemosensitivity assay modality for the treatment of various cancers in clinical settings and there have been several studies on its usefulness in breast cancer. We previously reported chemosensitivity (ATP-CRA) results might reflect patients' prognosis. So we supposed that SUVmax could reflect chemosenitivity (ATP-CRA) results of patients, so performed this study to analyze the relationship between PET/CT SUVmax and chemosenstivity (ATP-CRA) results of these drugs. Furthermore, we evaluated prognostic factors for breast cancer according to SUVmax. Materials and Methods: 102 breast cancer patients, who underwent PET/CT and chemosensitive (ATP-CRA) test between December 2010 and April 2012, were enrolled in this study. We analyzed, retrospectively, the correlation between SUVmax of PET/CT and chemosenitivity (ATP-CRA) results of doxorubicin/paclitaxel. SUVmax according to prognostic factors were also assessed. Results: Chemosensitivity (ATP-CRA) results of doxorubicin and paclitaxel have significant positive correlation with SUVmax. Their correlation coefficient were 0.236 (p = 0.020) and 0.216 (p = 0.030), respectively. Patients with larger tumor size, higher histologic and nuclear grade, estrogen receptor negative, progesterone receptor negative, HER2 positive, and Ki67 positive (≥14%) have higher mean SUVmax values (p &amp;lt; 0.05). In molecular subgroup analysis, triple negative group showed higher mean SUVmax values than luminal A group (p &amp;lt; 0.001). Conclusion: Higher SUVmax values of PET/CT is correlated with better chemosensitive (ATP-CRA) results of doxorubicin and paclitaxel, and poor prognostic factors of breast cancer. However, examination of additional cases might be needed. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-03-11.

Sa1659 The ATP-Based Doublet Chemotherapy Response Assay for Un-Resectable Advanced Gastric Cancer; A Single Center, Prospective, Randomized Controlled Study

Adenosine triphosphate based chemotherapy response assay (ATP-CRA) showed positive correlation with treatment response and survival in some human cancers. However, it is not certain whether this test can be applicable to gastric cancer as most studies used ATP-CRA based on single anticancer drug sensitivity. Therefore, we prospectively conducted ATP-CRA based on doublet chemotherapeutic regimens in unresectable AGC.

Innovative In Vitro Chemo-Hormonal Drug Therapy for Refractory Thyroid Carcinomas

More than 95% of the thyroid carcinomas are well differentiated types showing favorable prognosis. However, only a few therapeutic options are available to treat the patients with undifferentiated thyroid carcinomas, especially with refractory thyroid carcinomas that are not amenable to surgery or radioiodine ablation. We investigated the anticancer effects of 20 chemotherapy and hormonal therapy drugs on 8 thyroid carcinoma cell lines. In vitro chemosensitivity was tested using the adenosine-triphosphate-based chemotherapy response assay (ATP-CRA). The tumor inhibition rate (TIR; or cell death rate) or half maximal inhibitory concentration (IC50) was analyzed to interpret the results. Of the 12 chemotherapy drugs, etoposide (178.9 index value in follicular carcinoma cell line) and vincristine (211.7 in Hürthle cell carcinoma cell line) were the most active drugs showing the highest chemosensitivity, and of the 8 additional drugs, trichostatin A (0.03 µg/mL IC50 in follicular carcinoma cell line) showed favorable outcome having the anticancer effect. In our study, the result of etoposide and vincristine show evidence as active anticancer drugs in thyroid carcinoma cell lines and trichostatin A seems be the next promising drug. These drugs may become an innovative therapy for refractory thyroid carcinomas in near future.

Adenosine triphosphate-based chemotherapy response assay-guided chemotherapy in unresectable colorectal liver metastasis

Background:This study aims to evaluate the effectiveness of adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided neoadjuvant chemotherapy for increasing resectability in patients with unresectable colorectal liver metastasis.Patients and methods:Patients were randomised into two groups: Group A was treated by conventional chemotherapy regimen and Group B was treated by chemotherapy regimen according to the ATP-CRA. Three chemotherapeutic agents (5-fluorouracil, oxaliplatin and irinotecan) were tested by ATP-CRA and more sensitive agents were selected. Either FOLFOX or FOLFIRI was administered. Between Group A and B, treatment response and resectability were compared.Results:Between November 2008 and October 2010, a total 63 patients were randomised to Group A (N=32) or Group B (N=31). FOLFOX was more preferred in Group A than in Group B (26 out of 32 (81.3%) vs 20 out of 31 (64.5%)). Group B showed better treatment response than Group A (48.4% vs 21.9%, P=0.027). The resectability of hepatic lesion was higher in Group B (35.5% vs 12.5%, P=0.032). Mean duration from chemotherapy onset to the time of liver resection was 11 cycles (range 4–12) in Group A and 8 cycles (range 8–16) in Group B.Conclusion:This study showed that tailored-chemotherapy based on ATP-CRA could improve the treatment response and resectability in initially unresectable colorectal liver metastasis.

Predictive Value of In Vitro Adenosine Triphosphate-Based Chemotherapy Response Assay in Advanced Gastric Cancer Patients Who Received Oral 5-Fluorouracil after Curative Resection

PurposeTo assess the usefulness of adenosine triphosphate-based chemotherapy response assay (ATP-CRA) results in advanced gastric cancer patients receiving adjuvant chemotherapy.Materials and MethodsSixty-two patients underwent curative surgical resection between January, 2006 and December, 2008. Their highly purified surgical specimens were evaluated by ATP-CRAs. Of the 62, 49 had successful assay results and they received either oral 5-fluorouracil or other chemotherapies. We retrospectively analyzed data for 24 patients who were treated with oral 5-fluorouracil and whose assays were successful.ResultsThe median observation time was 24.6 months (range, 10.1 to 40.9 months). The median treatment time was 11.2 months (range, 1.2 to 17.7 months). The median age was 66 years (range, 30 to 81 years). Patients were grouped into sensitive- and resistant-groups according to adenosine triphosphate-based chemotherapy response results for fluorouracil. The sensitive-group showed a significantly longer time to relapse (not reached in the sensitive-group vs. 24.8 months in the resistant-group, p=0.043) and longer overall survival compared to the resistant-group (not reached in the sensitive-group vs. 35.7 months in the resistant-group, p=0.16, statistically insignificant).ConclusionPatients who receive curative surgical resection significantly benefit from sensitive adjuvant chemotherapy according to ATP-CRA results for time to relapse.

Correlation of Early Systemic Recurrence withIn VitroAdenosine Triphosphate-Based Chemotherapy Response Assay in Stage II and III Breast Cancer Patients Treated with Doxorubicin-Based Chemotherapy

(EBCTCG)의메타분석을통해50세이하의유방암환자에서15년 Purpose: An in vitro adenosine triphosphate-based chemotherapy response assay (ATP-CRA) was designed to require only a limited number of cells and shorten test turnaround time with a high success rate. This study investigated the correlation between in vitro doxorubicin sensitivity of tumor cells and early systemic recurrence, defined as recurrence within 2 years after surgery. Methods: From January 2004 to March 2007, the ATP-CRA for doxorubicin was tested in 128 patients among breast cancer patients treated at Gangnam Severance Hospital, Seoul, Korea. The American Joint Committee on Cancer stages for all patients were II and III. All patients received doxorubicin-based chemotherapy. Selected patients were divided into a chemosensitive group and a non-chemosensitive group, according to a 40% cell death rate as a cut-off value. We analyzed the relationship between chemosensitivity and early systemic recurrence in patients with breast cancer. Results: The mean age of the patients investigated was 44.6-years-old, the mean follow-up period was 39.9 months, and recurrence free survival was 38.6 months. Thirteen recurrences were observed during follow-up. Among 13 patients with a recurrence, eight had a recurrence within 2 years (early recurrence). All of the early recurring patients belonged to the non-sensitive group. Doxorubicin sensitivity results measured by ATP-CRA were related with early recurrence free survival in patients with breast cancer (p=0.030). The mean cell death rate derived from the ATP-CRA for the early recurrence group tended to be lower than that of the non-early recurrence group, but the difference was not statistically significant (p=0.05). Conclusion: Doxorubicin sensitivity measured by ATP-CRA was well correlated with in vivo drug responsibility to predict early recurrence against doxorubicinbased adjuvant chemotherapy in patients with breast cancer.

Metastatic Lymph Node Targeted Chemosensitivity Test for Gastric Cancer

The objective of this study was to compare the chemosensitivity of primary tumor and metastasized lymph node from patient with gastric adenocarcinoma. We studied 26 gastric cancer patients with lymph node metastasis who underwent gastric resection at the Korea University Guro Hospital from Feb 2007 to July 2008. The chemosensitivity of primary tumor and metastatic lymph node were studied using an adenosine triphosphate-based chemotherapy response assay (ATP-CRA). The concordance rate of the ATP-CRA test was 30.8% (8/26). The concordance rate between primary tumor and metastatic N2 group lymph node was only 9.1% (1/11). The metastatic tumor inhibition rates with 5-fluorouracil, cisplatin, doxorubicin, and oxaliplatin were higher than the inhibition rates for primary tumor. Tumor inhibition rates was significantly different between primary tumor and metastatic tumor after doxorubicin treatment (27.734±20.95 versus 38.403±26.87, P=0.021). We detected simple correlations of tumor inhibition rates between primary and metastatic tumors with cisplatin (r=0.661, P<0.001) and doxorubicin (r=0.475, P=0.031). We observed differences between first choice chemotherapeutic agents based on ATPCRA tests of primary tumor and metastatic tumor in lymph node. Therefore, chemotherapeutic agents should be carefully selected for adjuvant chemotherapy using a chemosensitivity test.

T1166 ATP-Based Chemotherapy Response Assay Based Combination Chemotherapy for Unresectable Advanced Gastric Cancer: Interim Report of Prospective Controlled Study

Background: Although, chemotherapy is one of the main treatment modalities for patients with unresectable advanced gastric cancer, it is difficult to find a universally applicable regimen. Recently, adenosine triphosphate based chemotherapy response assay (ATP-CRA) showed positive correlation with treatment response and survival in some human cancers. It is not certain whether this test can be applicable to gastric cancer, yet. Also, most studies used ATP-CRA on single anticancer drug while combination regimen is commonly used in practice.We prospectively conducted ATP-CRA based on doublet chemotherapeutic regimens in unresectable gastric cancer. Methods: Fifty-five patients with gastric cancer (with written informed consents) were consecutively enrolled between April 2007 and June 2009. ATPCRAs were tested to tumor cells obtained through endoscopic biopsy, using paclitaxel/ cisplatin [DDP], docetaxel/DDP, and irinotecan/DDP as well as single regimen including 5FU, cisplatinum, paclitaxel, docetaxel and irinotecan. All patients were randomly treated with one of above DDP-based doublet regimens into either tailored group where the doublet regimens showing the highest inhibition rate in ATP-CRAs using 3 combinations were administered, or empirical group where blindly chosen combinations were given regardless of ATP-CRA results. Results: The overall success rate of ATP-CRA was 96.4% (53/55). Evaluable thirty-two cases were analzyed (male:female=26:6, mean age: 57.9 years). Median follow up duration was 7.8 months (1.9-24.9). 18 cases and 14 cases were randomly assigned in tailored and empirical group, respectively. The disease control rate was 55.6% and 64.3%, respectively. The median progression-free survival (PFS) and overall survivals (OS) were 120 and 274 days, respectively in tailored group and 148 and 312 days in empirical group (p>0.05). Also, median PFS andOS inmatched group (where administered regimens included the drug with the highest inhibition rate in ATP-CRAs using paclitaxel, docetaxel and irinotecan, 10 cases) were 120 and 177days, respectively and 122 and 312days in unmatched group (remainings beside matched group, 22cases) (p>0.05). Conclusion: ATP-CRA was successfully performed with high success rate in gastric cancer with small amounts of tissue taken endoscopically. Prediction of response to combined chemotherapeutic agents by ATPCRA was not superior to that of empirical combined chemotherapy in advanced gastric cancer. A further study with larger number of patient will be required to confirm the clinical significance of combination chemotherapy assessed by ATP-CRA in unresectable gastric cancer.

Individualized Tumor Response Testing for Prediction of Response to Paclitaxel and Cisplatin Chemotherapy in Patients with Advanced Gastric Cancer

The purpose of our study was to determine the most accurate analytic method to define in vitro chemosensitivity, using clinical response as reference standard in prospective clinical trial, and to assess accuracy of adenosine triphosphate-based chemotherapy response assay (ATP-CRA). Forty-eight patients with chemo-naïve, histologically confirmed, locally advanced or metastatic gastric cancer were enrolled for the study and were treated with combination chemotherapy of paclitaxel 175 mg/m2 and cisplatin 75 mg/m2 for maximum of six cycles after obtaining specimen for ATP-CRA. We performed the receiver operator characteristic curve analysis using patient responses by WHO criteria and ATP-CRA results to define the method with the highest accuracy. Median progression free survival was 4.2 months (95% confidence interval [CI]: 3.4-5.0) and median overall survival was 11.8 months (95% CI: 9.7-13.8) for all enrolled patients. Chemosensitivity index method yielded highest accuracy of 77.8% by ROC curve analysis, and the specificity, sensitivity, positive and negative predictive values were 95.7%, 46.2%, 85.7%, and 75.9%. In vitro chemosensitive group showed higher response rate (85.7% vs. 24.1%) (P=0.005) compared to chemoresistant group. ATP-CRA could predict clinical response to paclitaxel and cisplatin chemotherapy with high accuracy in advanced gastric cancer patients. Our study supports the use of ATP-CRA in further validation studies.

In VitroAdenosine Triphosphate Based Chemotherapy Response Assay in Gastric Cancer

PurposeThe purpose of this study was to investigate the reliability and the clinical applicability of the adenosine-triphosphate-based chemotherapy response assay (ATP-CRA) as a method of determining in vitro chemosensitivity in patients with gastric cancer.Materials and MethodsA total of 243 gastric cancer tissue samples were obtained from gastrectomies performed between February 2007 and January 2010. We evaluated the effectiveness of the ATP-CRA assay in determining the chemosensitivity of gastric cancer specimens using eleven chemotherapeutic agents - etoposide, doxorubicin, epirubicin, mytomicin, 5-fluorouracil, oxaliplatin, irinotecan, docetaxel, paclitaxel, methotraxate, and cisplatin - for chemosensitivity studies using ATP-CRA. We assessed the failure rate, the cell death rate, and the chemosensitivity index.ResultsThe failure rate of ATP-CRA was 1.6% (4/243). The mean coefficient of variation for triplicate ATP measurements was 6.5%. Etoposide showed the highest cell death rate (35.9%) while methotrexate showed the lowest (16.6%). The most active chemotherapeutic agent was etoposide, which most frequently ranked highest in the chemosensitivity test: 31.9% (51/160). Oxaliplatin was more active against early gastric cancers than advanced gastric cancers, whereas docetaxel was more active against advanced cancers. The lymph node negative group showed a significantly higher cell death rate than the lymph node positive group when treated with doxorubicin, epirubicin, and mitomycin.ConclusionsATP-CRA is a stable and clinically applicable in vitro chemosensitivity test with a low failure rate. The clinical usefulness of ATP-CRA should be evaluated by prospective studies comparing the regimen guided by ATP-CRA with an empirical regimen.

Heterogeneity of Adenosine Triphosphate-Based Chemotherapy Response Assay in Colorectal Cancer - Secondary Publication

PurposeAdenosine triphosphate-based chemotherapy response assay (ATP-CRA) is a well-documented and validated technology that can individualize chemotherapy for patients with lung, stomach, or breast cancer. This study explored the feasibility of ATP-CRA as a chemosensitivity test in patients with colorectal cancer.Materials and MethodsA total of 118 patients who underwent surgical resection for colorectal adenocarcinoma were analyzed for chemosensitivity to 6 anticancer drugs using ATP-CRA. We calculated the cell death rate (CDR) by measuring intracellular ATP levels of drug-exposed cells and untreated controls.ResultsInterpretable results were available for 85.5% (118/138) of patients. The mean coefficient of variation for triplicate ATP measurements was 9.2%. The highest CDR was observed in irinotecan (34.0%) and the lowest CDR in etoposide (21.0%). Paclitaxel had the broadest range of CDR (0-86.7%) and 5-FU had the narrowest range of CDR (0-56.8%). The overall highest responsiveness was seen most prevalently in irinotecan (24.7%, 23/93 patients). Irinotecan had the greatest responsiveness in patients with well differentiated and moderately differentiated carcinoma.ConclusionOur study suggests that ATP-CRA could be used to identify patients with colorectal cancer who might benefit from treatment with a specific chemotherapeutic agent.

Impact of Grade, Hormone Receptor, and HER-2 Status in Women with Breast Cancer on Response to Specific Chemotherapeutic Agents by in vitro Adenosine Triphosphate-based Chemotherapy Response Assay

This study was designed to assess whether histological and biological factors of breast cancer can predict chemoresponse to specific agents. Adenosine triphosphate-based chemotherapy response assay (ATP-CRA) was employed to retrieve chemoresponse to 5-fluorouracil (5-FU), doxetaxel, doxorubicin, epirubicin, and paclitaxel in 49 patients. Tumors with high histologic and nuclear grade have higher response rate to doxorubicin (P<0.05) and palitaxel (P<0.05). Estrogen receptor (ER)-negative tumors respond well to doxorubicin (P=0.038), and progesterone receptor (PR)-negative tumors to 5-FU (P=0.039), doxetaxel (P=0.038), doxorubicin (P=0.000), epirubicin (P=0.010), and paclitaxel (P=0.003). Among the breast cancer subtypes determined by ER, PR, and HER-2 immunohistochemical stains, the HER-2+/ER- subtype has a higher response rate to doxorubicin (P=0.008). This in vitro result suggests that the combination of histologic and nuclear grade, hormone receptor, and HER-2 status can be a predictive factor of response to specific chemotherapy agents. Further in vivo study should be followed for clinical trials.