MGMT expression correlates with response rate and survival in patients with inoperable glioblastoma (GBM) treated with neoadjuvant temozolomide (TMZ)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1574-1574
Author(s):  
M. Barrie ◽  
N. Eudes ◽  
P. Metellus ◽  
S. Fuentes ◽  
S. Honore ◽  
...  
Keyword(s):  
Response Rate ◽  
Alkylating Agents ◽  
Objective Response ◽  
Neoadjuvant Treatment ◽  
Antigen Retrieval ◽  
Repair Gene ◽  
Mgmt Expression ◽  
Therapeutic Decisions ◽  
Dna Repair Gene ◽  
Number Of Patients

1574 Background: Methylation of the promotor of O6-alkylguanine alkyltransferase (MGMT), a DNA repair gene, may enhance chemosensitivity to alkylating agents. In GBM, this methylation has been correlated to survival as well as to the benefit of adding TMZ concomitant and adjuvant to radiotherapy (RT) (Hegi, NEJM, 2005). We examine the relationship between MGMT expression and objective response rate to dose intense TMZ schedule administered as neoadjuvant treatment before RT in inoperable GBM, as previously presented (Chinot, ASCO, 2005). Methods: Thirty patients were included in this phase II trial that tested TMZ (150 mg/m2/day) on days 1 to 7 and 15 to 21 of each 28 days cycle for up to 4 cycles prior to RT. We analysed retrospectively MGMT expression by immunochemistry (streptavidin-peroxydase) after antigen retrieval using anti-MGMT antibody (Abcys, 1/100) in 25 formalin-fixed paraffin embedded samples from the study population. Results: In the eligible population (n = 28) response rates (RR) were of 25% (95% CI, 8.63% to 41.37%); SD 32%; PD 43%. Median progression free survival (PFS) and overall survival (OS) were 3.8 and 5.8 months, respectively. MGMT expression was analysed in 25 pts while material was considered as inadequate in 3 pts because of insufficient tumor material. The median percentage of cells that expressed MGMT in tumor nuclei was 35% and so was chosen as cut-off. Low MGMT expression was significantly associated with a high RR (55%) while tumor that exhibit high MGMT expression was associated to a RR of 9% (chi-2 p=0.004). MGMT was also strongly correlated to PFS (log rank p=0.009) and OS (log rank p=0.003). Conclusion: Despite limited number of patients, our study strongly supports the predictive value of MGMT expression for objective response to TMZ in addition to its prognostic value for PFS and OS in GBM. If confirmed in prospective study, MGMT expression may help to guide therapeutic decisions as well as more targeted trial design. [Table: see text] No significant financial relationships to disclose.

Phase 2 biomarker-driven study of ipilimumab plus nivolumab (Ipi/Nivo) for ARV7-positive metastatic castrate-resistant prostate cancer (mCRPC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5035-5035 ◽  
Author(s):  
Karim Boudadi ◽  
Daniel L. Suzman ◽  
Brandon Luber ◽  
Hao Wang ◽  
John Silberstein ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Response Rate ◽  
Objective Response ◽  
Gene Mutations ◽  
Immune Checkpoint Blockade ◽  
Phase 2 ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Castrate Resistant

5035 Background: ARV7+ mCRPC is an aggressive phenotype with a median PFS of 3-4 mo and OS of 7-9 mo. We hypothesized that ARV7+ tumors would be enriched for DNA repair mutations, rendering them more responsive to combined immune checkpoint blockade. Methods: We enrolled 15 mCRPC pts with ARV7+ CTCs (using a CLIA-certified assay) into a single arm phase 2 study. Pts received Nivo 3 mg/kg plus Ipi 1 mg/kg every 3 wk x 4 doses, then maintenance Nivo 3 mg/kg every 2 wk. Targeted sequencing for DNA repair defects was performed on pretreatment tumor biopsies (n=11) or cell-free DNA (n=4). Primary endpoint: PSA50response rate. Secondary endpoints: objective response rate (ORR) in pts with measurable disease, durable PFS (lack of progression ≥24 wk), PSA‐PFS, radiographic (r)PFS, overall survival (OS), and frequency/intensity of AEs. Results: 15 ARV7+ men were enrolled, with median f/u 8.4 (range 1.9–10.5) mo. Median age was 65, 47% had ECOG ≥1, median PSA was 115 ng/mL, 67% had visceral/nodal mets, all had bone mets, and 60% had ≥4 prior regimens for mCRPC. Mean ARV7/AR ratio was 23% (range 3–75%). 6/15 men (40%) had pathogenic DNA repair gene mutations ( BRCA2, ATM, MSH6, FANCM, FANCA, POLH). Overall, the PSA50rate was 1/15 (7%), ORR was 2/8 (25%), durable PFS rate was 3/15 (20%), PSA-PFS was 3.0 (95%CI 2.1–4.9) mo, rPFS was 3.9 (95%CI 2.8–5.5) mo, and OS was 9.5 (95%CI 7.2–NA) mo. Outcomes appeared better in DNA repair deficient (DRD+) tumors vs. DNA repair proficient (DRD–) tumors (TABLE). 15 grade 3-4 treatment-related AEs occurred in 7/15 (46%) men (including 2 hepatitis, 2 colitis, 1 pneumonitis); there were no treatment-related deaths. Conclusions: In this first study targeting ARV7+ mCRPC, treatment with Ipi/Nivo had acceptable safety and encouraging efficacy, particularly in men with DRD+ tumors. DNA repair mutations may be enriched in ARV7+ prostate cancer. Clinical trial information: NCT02601014. [Table: see text]

scholarly journals 363 Vactosertib and durvalumab as second or later line treatment for PD-L1 positive non-small cell lung cancer: interim result

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A388-A388
Author(s):  
Byoung Chul Cho ◽  
Ki Hyeong Lee ◽  
Ji-Youn Han ◽  
Byoung Yong Shim ◽  
Hye Ryun Kim ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Objective Response Rate ◽  
Immune Checkpoint Inhibitors ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Platinum Based Chemotherapy ◽  
Number Of Patients ◽  
Anti Tumor Activity

BackgroundTargeting transforming growth factor-β (TGF-β) is reported to augment the efficacy of immune checkpoint inhibitors (ICIs) through either enhanced anti-tumor immunity or the correction of tumor microenvironment (TME). Therefore, the combination of vactosertib, a highly selective TGF-β RI kinase inhibitor, and durvalumab is anticipated to improve anti-tumor activity of the ICI. A phase 1b/2a study was conducted to evaluate the combination of vactosertib and durvalumab in patients with advanced NSCLC who progressed after platinum-based chemotherapy.MethodsPatients were treated with vactosertib at a dose of 200 mg twice daily (five days on and two days off) and durvalumab at a dose of 1500 mg every four weeks. Eligible patients were ≥19 years old with good performance status (ECOG 0–1) and have no prior exposure to immune checkpoint inhibitors or other TGF- β R1 kinase inhibitors. The objectives of this analysis were to evaluate the safety, antitumor activity including objective response rate (ORR), duration of response (DOR), and time to response (TTR) as well as circulating pharmacodynamic biomarkers related to TGF-β signaling. Response was assessed per RECIST (v1.1).ResultsBy August 4 2020, twenty-six PD-L1 positive (SP263 assay) patients were analyzed. Median age was 61.5 years (range 48–83), 69.2% were male, median number of previous lines of chemotherapy was 1 (range 1–4), and all patients were PD-L1 positive (15 patients with PD-L1≥25% and 11 patients with PD-L1 1–24%). The most frequently reported treatment-related adverse events (TRAE) were itching (38.5%) and skin rash (34.6%), but no Gr≥3 itching and rash were observed. Each case of the following was reported as Grade 3 TRAEs: adrenal insufficiency, anemia, and pneumonitis; Grade 4 TRAE, CPK increase, was observed in one patient. Objective response rate was 30.8% and 40.0% in patients with PD-L1≥1% and ≥25% respectively. Circulating PAI-1 and CTGF evaluated in 15 patients decreased significantly on Cycle 1 day 5. Ongoing biomarker results will be presented.ConclusionsThe combination of vactosertib and durvalumab has demonstrated a manageable safety profile and encouraging anti-tumor activity as a potential therapeutic strategy in patients with advanced NSCLC. The efficacy outcomes of this combination in a larger number of patients with advanced NSCLC will be followed.Trial RegistrationNCT03732274Ethics ApprovalThe study was approved by Ethics Board of Severance Hospital (4-2018-0892), National Cancer Center (NCC2019-0057), St. Vincent’s Hospital (VC19MDDF0205), and Chungbuk National University Hospital (2019-08-015).

TRITON3: An international, randomized, open-label, phase III study of the PARP inhibitor rucaparib vs. physician’s choice of therapy for patients with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination deficiency (HRD).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS389-TPS389 ◽  
Author(s):  
Charles J. Ryan ◽  
Wassim Abida ◽  
Alan Haruo Bryce ◽  
Arjun Vasant Balar ◽  
Igor Dumbadze ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Radiographic Progression ◽  
Objective Response ◽  
Phase Iii ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Patient Reported ◽  
Brca1 Brca2

TPS389 Background: Recent data have shown that up to 25% of patients with advanced prostate cancer, including mCRPC, have a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM, or another homologous recombination DNA repair gene. Such mutations can be used as a molecular marker to select patients for targeted treatment with poly(ADP-ribose) polymerase inhibitors (PARPis), which are lethal to cells with HRD. Treatment with PARPis has shown preliminary evidence of antitumor activity in patients with mCRPC and a mutation in a homologous recombination DNA repair gene (Mateo et al. N Engl J Med. 2015;373:1697-708). These data provide a compelling rationale for evaluating rucaparib, a potent inhibitor of PARP1, PARP2, and PARP3, in patients with mCRPC associated with HRD. Methods: TRITON3 (NCT02975934) is a randomized, phase 3 study evaluating rucaparib 600 mg BID vs physician’s choice of abiraterone, enzalutamide, or docetaxel in patients with mCRPC and a deleterious germline or somatic BRCA1, BRCA2, or ATM mutation (identified by prior local testing or central testing during screening). Patients must have progressed on androgen receptor signaling–directed therapy in the mCRPC setting; prior PARPi treatment or chemotherapy for mCRPC are exclusion criteria. Patients will be randomly assigned in a 2:1 ratio to either rucaparib or physician’s choice, with the possibility for cross over from the comparator treatment to rucaparib upon radiographic progression confirmed by independent radiology review. The primary endpoint is radiographic progression-free survival (modified RECIST v1.1/PCWG3 criteria) assessed by independent radiology review. Secondary endpoints include objective response rate, duration of response, patient-reported outcomes, overall survival, and safety. Pretreatment blood samples collected from all patients will enable development of a noninvasive plasma-based companion diagnostic to select patients who may benefit from rucaparib treatment. Patients (≈400) will be enrolled at > 100 sites worldwide. Clinical trial information: NCT02975934.

Niraparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD): Correlative measures of tumor response in phase II GALAHAD study.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 118-118 ◽  
Author(s):  
Matthew Raymond Smith ◽  
Karim Fizazi ◽  
Shahneen Kaur Sandhu ◽  
William Kevin Kelly ◽  
Eleni Efstathiou ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Duration Of Treatment ◽  
Brca Mutations ◽  
Repair Gene ◽  
Recist 1.1 ◽  
Dna Repair Gene ◽  
Breakthrough Designation

118 Background: Niraparib, a highly potent and selective poly (ADP-ribose) polymerase inhibitor (PARPi) received breakthrough designation by US FDA for treatment of pts with BRCA1,2 mutant mCRPC who progressed on taxane and androgen receptor-targeted therapy. Circulating tumor cells (CTC) detection associates with poor outcomes, with declining counts consistent with improved survival [1,2]. Methods: GALAHAD study assessed niraparib (300 mg daily) in pts with mCRPC+DRD (NCT02854436). Patients with non-measurable soft tissue disease by RECIST 1.1 were required to have a baseline CTC count ≥1 cell/7.5 mL blood. CTC response was defined as CTC conversion to <5 for pts with baseline CTC≥5 and CTC drop to 0 post-baseline for pts with ≥1 baseline CTC. Alkaline phosphatase (ALP) was collected at each monthly cycle. Results: For primary efficacy population of pts with BRCA1/2 mutations, the objective response rate (ORR) by RECIST 1.1 criteria was 41.4%. CTC response rates for this population were as high as ORR regardless of measurability (Table). Time to CTC response for each CTC responder will be shown. Radiographic progression-free survival (rPFS) durations were similar for patients with a measurable disease response and patients with CTC conversion. Median duration of treatment for responders of any type was 6.7mo (range: 2–27). DRD status, both BRCA and non- BRCA, for each responder will also be discussed. Trends in disease burden and markers of bone metabolism will also be quantitatively explored including 24% pts who were on treatment for at least one cycle who had ≥25% decreased unfractionated ALP from baseline. Conclusions: Niraparib showed clinical activity with CTC response and decline in ALP levels in mCRPC pts having biallelic BRCA mutations, which further supports its recent breakthrough designation. Clinical trial information: NCT02854436. [Table: see text]

Effectiveness of neoadjuvant chemotherapy including bevacizumab in patients with resectable colorectal cancer liver metastases

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4060-4060 ◽  
Author(s):  
B. Gruenberger ◽  
W. Scheithauer ◽  
D. Tamandl ◽  
C. Zielinski ◽  
J. Schueller ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Response Rate ◽  
Objective Response ◽  
Neoadjuvant Treatment ◽  
High Response Rate ◽  
Curative Surgery ◽  
Colorectal Cancer Liver Metastases ◽  
End Points ◽  
Response To Chemotherapy

4060 Background: Chemotherapy including bevacizumab has become the new standard in the first line treatment of patients with metastatic colorectal cancer (mCRC). Response to chemotherapy has been assessed as major prognostic factor for RFS in resectable mCRC patients, but safety concerns have been raised. We conducted a phase II trial to evaluate the safety of neoadjuvant chemotherapy including bevacizumab (Bev). Methods: Patients with resectable mCRC received six cycles (3 months) of neoadjuvant XELOX (capecitabine 3,500mg/m2/day days 1–7 plus oxaliplatin 85mg/m2 day 1) with bevacizumab (5mg/kg) every 2 weeks. The sixth cycle did not include Bev resulting in a gap of 5 weeks between last Bev and surgery. Primary end points were feasibility of neoadjuvant treatment with this regimen and response rate; secondary end points were feasibility of curative liver resection and perioperative morbidity of the surgical procedure. Results: 54 patients (32 male, 22 female) with a median age of 61 years (SD ± 10.6) were included. The median number of preoperative cycles was 6 (SD ± 2). Grade 3/4 side effects were PNP in 13%, H&F in 3%, diarrhea in 38%, anaemia in 3% and neutropenia in 12% of our patients. Thromboembolic events occurred in 4 patients (7%), hypertension grade III in 2 (4%) and perforation in 1 (2%) patients. A dose reduction of chemotherapy was required in 43%. There were no treatment related deaths. The overall objective response rate for all 54 patients was 74% (40 patients) including 11% pCR. 11 additional patients (20%) had stable disease and only 3 (6%) progressed. Potential curative surgery was performed in all but 5 patients (91%). 2 patients were not resected due to PD, 2 because of pulmonary embolism during chemotherapy and 1 patient because of positive hilar lymph nodes. Conclusions: These data provide evidence that neoadjuvant chemotherapy including bevacizumab can be safely administered in patients with resectable mCRC. A high response rate and a disease control rate of 94% suggest that XELOX + Bev is an effective regimen in this treatment setting. No significant financial relationships to disclose.

Paclitaxel in relapsed squamous cell carcinoma of head and neck (SSCHN): Retrospective study of a single institution

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e17047-e17047
Author(s):  
J. Fayette ◽  
A. Montella ◽  
T. Bachelot ◽  
P. Pommier ◽  
D. Girodet ◽  
...  
Keyword(s):  
Overall Survival ◽  
Response Rate ◽  
Objective Response ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Phase Iii ◽  
Second Line ◽  
Single Institution ◽  
First Line ◽  
Line P

e17047 Background: For relapse or metastatic SCCHN the standard treatment is the combination of cisplatin and 5FU that showed higher response rate than methotrexate but similar overall survival. Cetuximab demonstrated in a phase III (N Engl J Med. 2008;359:1116) its efficacy and paclitaxel showed efficacy in a phase II study (Cancer. 1998;82:2270). The objective of this study was to evaluate paclitaxel (P) in our institution in various situations. Methods: We retrospectively reviewed 56 pts with relapse or metastatic SSCHN treated with P in a single institution in Lyon (France) between June 2002 and February 2008. P was administered in first line for locally advanced disease, in first line for relapsed or metastatic disease, or in second or more line. P was administered q1w or q3w, alone or in combination with carboplatin or cetuximab. Results: Median age was 59 years (36–84) at the beginning of paclitaxel. Localizations of primitive tumor: oral cavity (14%), oropharynx (30%), hypopharynx (39%) larynx (7%), rhinopharynx (4%), or other (6%). All patients received adequate initial treatment with surgery and/or radiotherapy, 47% had have neoadjuvant chemotherapy (71% with cddp-5fu, but 5 pts received P). Five patients received P as neoadjuvant treatment. Among 52 evaluable patients, 33 received P in first line of treatment after relapse, 12 in second line. Monotherapy was administered to 20 patients and 22 received P combined with carboplatin, and 1 with cetuximab. For all patients, objective response rate (OR) was 30.8% (95% CI 18.7–45.1%). In first line of relapse, OR was 39.4% (95% CI 22.9–57.9%) and 16.7% (95% CI 2.1–18.4%) in second line. In monotherapy OR was 30.0% (95% CI 11.9–54.3%) and 36.4% (95% CI 17.2–59.3%) in combination with carboplatin. The overall survival (OS) of all patients was 6.3 months (95% CI 3.9–7.9 m), and 7.7 m (95% CI 3.9–11 m) and 5.2 m (95% CI 2.8–7.9 m) in first and second line, respectively. There is no difference in OS between monotherapy and combination: 6.1 m (95% CI 3.9–7.9 m) and 5.3 m (95% CI 3.9–7.9 m), respectively. Conclusions: P did not improve overall survival but showed interesting response rate in relapsed patients who are often symptomatic. Recent studies suggest high potentialities in combination with EGFR inhibitors. No significant financial relationships to disclose.

5-day dosing schedule of temozolomide in relapsed sensitive or refractory small cell lung cancer (SCLC) and methyl-guanine-DNA methyltransferase (MGMT) analysis in a phase II trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7052-7052
Author(s):  
Alexander Edward Dela Cruz Drilon ◽  
Kadota Kyuichi ◽  
Kety H Huberman ◽  
Camelia S. Sima ◽  
John Joseph Fiore ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Response Rate ◽  
Alkylating Agents ◽  
Parp Inhibitor ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Dosing Schedule ◽  
Mgmt Expression ◽  
Mgmt Promoter

7052 Background: MGMT promoter methylation and loss of MGMT activity are associated with improved sensitivity to alkylating agents. We recently reported that the oral alkylating agent temozolomide is active in 2nd- and 3rd-line treatment of relapsed SCLC at 75mg/m2/day for 21 out of 28 days (Pietanza et al, Clin Can Res 2012). Here we evaluate the 5-day dosing schedule of temozolomide in a second cohort of patients and analyze MGMT activity in both cohorts of patients on the same study. Methods: Patients with disease progression after 1 or 2 prior chemotherapy regimens received temozolomide at 200mg/m2/day for 5 out of 28 days (n=25). Those with sensitive (S-SCLC, n=16) and refractory (R-SCLC, n=9) disease were enrolled to assess safety. Available tumor tissue from patients treated according to either schedule was assessed for MGMT promoter methylation status by PCR and MGMT expression by immunohistochemistry (IHC). Results: An overall response rate of 12% was noted (3 partial responses: 1 S-SCLC, 2 R-SCLC). 4 patients had stable disease for at least 3 cycles. Median progression-free survival and overall survival for all patients were 1.3 months and 7.9 months, respectively. Grade ≥3 thrombocytopenia and neutropenia was observed in 20% with a shorter mean duration of myelosuppression compared to the 21-day schedule. Results from MGMT evaluation of tumor samples from both dosing schedules were combined. Promoter methylation of MGMT was not significantly associated with response (p=0.23). However, patients that lacked MGMT expression by IHC had a higher response rate compared to those with MGMT-positive tumors (43% vs. 13%, p = 0.052; see table). Conclusions: The 5-day dosing schedule of temozolomide is both active and safe in patients with relapsed SCLC. A strong trend toward increased response was demonstrated in patients with MGMT-negative tumors compared to patients with MGMT-positive tumors by IHC. A trial combining temozolomide with the PARP inhibitor, ABT888, is planned. [Table: see text]

TRITON2: An international, multicenter, open-label, phase II study of the PARP inhibitor rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination deficiency (HRD).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS388-TPS388 ◽  
Author(s):  
Wassim Abida ◽  
Alan Haruo Bryce ◽  
Arjun Vasant Balar ◽  
Gurkamal S. Chatta ◽  
Nancy Ann Dawson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Objective Response ◽  
Specific Antigen ◽  
Nodal Disease ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Platinum Based Chemotherapy ◽  
Brca1 Brca2

TPS388 Background: Up to 25% of patients with advanced prostate cancer, including mCRPC, have a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM or another homologous recombination (HR) DNA repair gene that can serve as a molecular marker to select those who may respond to poly(ADP-ribose) polymerase inhibitors (PARPis). PARPis are lethal to cells with HRD, and PARPi treatment has shown preliminary evidence of an antitumor effect in patients with mCRPC who harbor a mutation in an HR DNA repair gene (Mateo et al. N Engl J Med. 2015;373:1697-708). These data provide a compelling rationale for evaluating rucaparib, a potent PARP1, PARP2 and PARP3 inhibitor, in patients with mCRPC associated with HRD. Methods: TRITON2 (NCT02952534) is a phase 2 study evaluating rucaparib 600 mg BID in patients with mCRPC. Patients with a deleterious germline or somatic BRCA1, BRCA2 or ATM mutation (per prior local test or central test during screening) will be enrolled into 1 of 2 cohorts based on the presence or absence of measurable visceral and/or nodal disease. An exploratory cohort will enroll patients with an alteration in any of 12 other prespecified HR genes (eg, RAD51C, RAD51D and PALB2), with or without measurable visceral and/or nodal disease. Patients must have progressed on androgen receptor signaling–directed therapy and 1 prior taxane-based chemotherapy for mCRPC. Patients who received prior treatment with a PARPi, mitoxantrone, cyclophosphamide or platinum-based chemotherapy are excluded. The primary endpoint is objective response rate measured using modified RECIST v1.1/PCWG3 for patients with soft-tissue disease and prostate-specific antigen response for patients with nonmeasurable disease. Secondary endpoints include duration of response, radiographic progression-free survival, overall survival, clinical benefit rate and safety. Pretreatment blood samples collected from all patients will enable development of a plasma-based companion diagnostic to select patients who may benefit from rucaparib treatment. Patients (≈160) will be enrolled at > 100 sites worldwide. Clinical trial information: NCT02952534.

Relationship between neutrophils/lymphocytes and tumor infiltrating lymphocytes stroma in patients with invasive muscle bladder cancer and the response to treatment.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16513-e16513
Author(s):  
Martin Eduardo Richardet ◽  
Maria gimena Ferreira ◽  
Martin Paradelo ◽  
Luciana Paola Acosta ◽  
Matias Molina ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Predictive Factor ◽  
Objective Response ◽  
Neoadjuvant Treatment ◽  
High Body Mass Index ◽  
Response To Treatment ◽  
Number Of Patients ◽  
The Difference ◽  
Tract Infections ◽  
Infiltrating Lymphocytes

e16513 Background: The bladder cancer is a malignant disease. It has been related to tobacco consumption, fat diet, high body mass index (BMI) and urinary tract infections. As a result of the activation the pro-inflammatory pathways. Neutrophil to lymphocyte radio (NLR) and the infiltrating lymphocytes of the tumor stroma (TILs) have been shown to have a significant prognostic value in different tumors. The primary aim is to analyze the role of TILs and RNL as a predictive factor, in patients with MIBC and objective response rate (ORR). The secondary aim is to evaluate the relationship beteween BMI, tabaquism and ORR, in the same group of pts. Methods: A total of 35 pts with MIBC was included. All pts received neoadjuvant treatment, with cisplatin and gemcitabine. Also, TILs was determined as the percentage of mononuclear inflammatory cells in the total stromal area counted in 5 high-power fields (CGA, X 400), on the invasive front of the tumor. The NLR was obtained before treatment and value of cut-off was 2.6. the evaluation of ORR was calculated used the T-Test and Chi Square test. Results: Of the total of 35 patients. 15 patients obtained complete response (CR), 6 pts partial response (PR), 5 pts stable disease (SD) and 9 pts disease progression (DP). In 21 tumor sample was observed an intense TILS. These patients obtained a better ORR 42.6 % vs 21.7% with low TILs in his tumor samples. The difference was statistically significant (p: 0.001). Regarding NLR, only 9 pts presented response with NLR > 2,6 vs 12 pts with response and RNL < 2.6. The difference was not statistically significant. When analyzing the smoking and response. We could observe response of 69.6% in smoking pts vs Non- smoking the response was 41.7%. Regarding BMI, 21 pts with response of 27% and 14 patient without response 25.9%. But the differences were not significant in any groups. Conclusions: We conclude that the presence of TILS in tumor samples, in patients with MIBC, could be a predictive factor against the response to neoadjuvant treatment. With the other variables, smoking and BMI, we did not observed influence in ORR. We will keep working to obtain a greater number of patients. Then we could have a better analysis and statistical power.

scholarly journals Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents N Engl J Med 343:1350–1354, 2000

2001 ◽  
Vol 10 (2) ◽  
pp. 1
Author(s):  
Michael F. Stiefel ◽  
M. Sean Grady
Keyword(s):  
Dna Repair ◽  
Dna Methyltransferase ◽  
Alkylating Agents ◽  
Performance Status ◽  
Disease Free Survival ◽  
Tumor Grade ◽  
Molecular Data ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Mgmt Promoter

The DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) inhibits the killing of tumor cells by alkylating agents. MGMT activity is controlled by a promoter; methylation of the promoter silences the gene in cancer, and the cells no longer produce MGMT. We examined gliomas to determine whether methylation of the MGMT promoter is related to the responsiveness of the tumor to alkylating agents. METHODS: We analyzed the MGMT promoter in tumor DNA by a methylation-specific polymerase-chain-reaction assay. The gliomas were obtained from patients who had been treated with carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, or BCNU). The molecular data were correlated with the clinical outcome. RESULTS: The MGMT promoter was methylated in gliomas from 19 of 47 patients (40 percent). This finding was associated with regression of the tumor and prolonged overall and disease-free survival. It was an independent and stronger prognostic factor than age, stage, tumor grade, or performance status. CONCLUSIONS: Methylation of the MGMT promoter in gliomas is a useful predictor of the responsiveness of the tumors to alkylating agents.

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