Pembrolizumab and Monoclonal Antibody Therapy in Advanced Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Gastric Cancer,Colorectal Cancer,Esophageal Cancer,Advanced Cancer,Breast Cancer,Neoplasms
PROVIDER: 2180426 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:The CHER-LOB randomized phase II study showed that the combination of lapatinib and trastuzumab plus chemotherapy increases the pathologic complete remission (pCR) rate as compared to chemotherapy plus either trastuzumab or lapatinib. An extensive biomarker programme was prospectively planned to identify potential predictors of sensitivity to different treatments and evaluate treatment effect on tumor biomarkers. A mutation in PIK3CA exon 20 or 9 was documented in 20% of the cases. Overall, the pCR rates were similar in PIK3CA wild type and PIK3CA mutated patients (33.3% vs 22.7%; p=0.323). However, for patients receiving trastuzumab plus lapatinib, the probability of pCR was higher in PIK3CA wild type tumors (48.4% vs 12.5%; p=0.06). Ki67, pAKT and apoptosis measured on the residual disease were significantly reduced from baseline. The degree of Ki67 inhibition was significantly higher in patients receiving the dual anti-HER2 blockade. In conclusion, PIK3CA mutations seem to identify patients less likely to benefit from dual anti-HER2 inhibition. p95-HER2 and markers of PI3K pathway deregulation are not confirmed as markers of different sensitivity to trastuzumab or lapatinib.
2015-10-06 | GSE66398 | GEO
Project description:The CHER-LOB randomized phase II study showed that the combination of lapatinib and trastuzumab plus chemotherapy increases the pathologic complete remission (pCR) rate as compared to chemotherapy plus either trastuzumab or lapatinib. An extensive biomarker programme was prospectively planned to identify potential predictors of sensitivity to different treatments and evaluate treatment effect on tumor biomarkers. A mutation in PIK3CA exon 20 or 9 was documented in 20% of the cases. Overall, the pCR rates were similar in PIK3CA wild type and PIK3CA mutated patients (33.3% vs 22.7%; p=0.323). However, for patients receiving trastuzumab plus lapatinib, the probability of pCR was higher in PIK3CA wild type tumors (48.4% vs 12.5%; p=0.06). Ki67, pAKT and apoptosis measured on the residual disease were significantly reduced from baseline. The degree of Ki67 inhibition was significantly higher in patients receiving the dual anti-HER2 blockade. In conclusion, PIK3CA mutations seem to identify patients less likely to benefit from dual anti-HER2 inhibition. p95-HER2 and markers of PI3K pathway deregulation are not confirmed as markers of different sensitivity to trastuzumab or lapatinib.
2015-10-06 | GSE66305 | GEO
Project description:We studied the effect on tumour response to neoadjuvant therapy of the substitution of lapatinib for trastuzumab in combination with weekly paclitaxel after doxorubicin plus cyclophosphamide treatment, and of the addition of lapatinib and trastuzumab combined after doxorubicin plus cyclophosphamide treatment in patients with HER2-positive operable breast cancer to determine whether there would be a benefit of dual HER2 blockade in these patients.
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Project description:Faratian2009 - Role of PTEN in Trastuzumab
resistance
This model is described in the article:
Systems biology
reveals new strategies for personalizing cancer medicine and
confirms the role of PTEN in resistance to trastuzumab.
Faratian D, Goltsov A, Lebedeva G,
Sorokin A, Moodie S, Mullen P, Kay C, Um IH, Langdon S, Goryanin
I, Harrison DJ.
Cancer Res. 2009 Aug; 69(16):
6713-6720
Abstract:
Resistance to targeted cancer therapies such as trastuzumab
is a frequent clinical problem not solely because of
insufficient expression of HER2 receptor but also because of
the overriding activation states of cell signaling pathways.
Systems biology approaches lend themselves to rapid in silico
testing of factors, which may confer resistance to targeted
therapies. Inthis study, we aimed to develop a new kinetic
model that could be interrogated to predict resistance to
receptor tyrosine kinase (RTK) inhibitor therapies and directly
test predictions in vitro and in clinical samples. The new
mathematical model included RTK inhibitor antibody binding,
HER2/HER3 dimerization and inhibition, AKT/mitogen-activated
protein kinase cross-talk, and the regulatory properties of
PTEN. The model was parameterized using quantitative
phosphoprotein expression data from cancer cell lines using
reverse-phase protein microarrays. Quantitative PTEN protein
expression was found to be the key determinant of resistance to
anti-HER2 therapy in silico, which was predictive of unseen
experiments in vitro using the PTEN inhibitor bp(V). When
measured in cancer cell lines, PTEN expression predicts
sensitivity to anti-HER2 therapy; furthermore, this
quantitative measurement is more predictive of response
(relative risk, 3.0; 95% confidence interval, 1.6-5.5; P <
0.0001) than other pathway components taken in isolation and
when tested by multivariate analysis in a cohort of 122 breast
cancers treated with trastuzumab. For the first time, a systems
biology approach has successfully been used to stratify
patients for personalized therapy in cancer and is further
compelling evidence that PTEN, appropriately measured in the
clinical setting, refines clinical decision making in patients
treated with anti-HER2 therapies.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000424.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2011-08-18 | BIOMD0000000424 | BioModels
Project description:To assess pathologic complete response (pCR), clinical response, feasibility, safety, and potential predictors of response to preoperative trastuzumab plus vinorelbine in patients with operable, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. EXPERIMENTAL DESIGN: 48 patients received preoperative trastuzumab and vinorelbine weekly for 12 weeks. Single and multigene biomarker studies were done in an attempt to identify predictors of response. RESULTS: 8 of 40 (20%) patients achieved pCR (95% confidence interval, 9-36%). Of 9 additional patients recruited for protocol-defined toxicity analysis, 8 were evaluable; 42 of 48 (88%) patients had clinical response (16 patients, clinical complete response; 26 patients, clinical partial response). T(1) tumors more frequently exhibited clinical complete response (P = 0.05) and showed a trend to exhibit pCR (P = 0.07). 5 (13%) patients experienced grade 1 cardiac dysfunction during preoperative treatment. Neither HER2 nor estrogen receptor status changed significantly after exposure to trastuzumab and vinorelbine. RNA profiling identified three top-level clusters by unsupervised analysis. Tumors with extremes of response [pCR (n = 3) versus nonresponse (n = 3)] fell into separate groups by hierarchical clustering. No predictive genes were identified in pCR tumors. Nonresponding tumors were more likely to be T(4) stage (P = 0.02) and express basal markers (P < 0.00001), growth factors, and growth factor receptors. Insulin-like growth factor-I receptor membrane expression was associated with a lower response rate (50% vs 97%; P = 0.001). CONCLUSIONS: Preoperative trastuzumab plus vinorelbine is active and well tolerated in patients with HER2-positive, operable, stage II/III breast cancer. HER2-overexpressing tumors with a basal-like phenotype, or with expression of insulin-like growth factor-I receptor and other proteins involved in growth factor pathways, are more likely to be resistant to this regimen. harri-00137 Assay Type: Gene Expression Provider: Affymetrix Array Designs: HG-U133_Plus_2 Organism: Homo sapiens (ncbitax)
2015-06-25 | E-GEOD-70233 | biostudies-arrayexpress
Project description:This is a Phase II multi-center 2-sequential cohorts trial, designed to assess the objective response rate of two anti HER2 combination in advanced disease CRC patients harbouring an amplified HER2 tumor assessed according to HERACLES Diagnostic Criteria by FISH/SISH.
Cohort A: monoclonal antibody trastuzumab, used in combination with the small molecule tyrosine kinase inhibitor lapatinib.
Cohort B, monoclonal antibody pertuzumab, used in combination with the antibody drug conjugate trastuzumab-emtansine.
Please note that cohort A accrual has been closed and endpoint already reached.
| 2249965 | ecrin-mdr-crc
Project description:To assess pathologic complete response (pCR), clinical response, feasibility, safety, and potential predictors of response to preoperative trastuzumab plus vinorelbine in patients with operable, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. EXPERIMENTAL DESIGN: 48 patients received preoperative trastuzumab and vinorelbine weekly for 12 weeks. Single and multigene biomarker studies were done in an attempt to identify predictors of response. RESULTS: 8 of 40 (20%) patients achieved pCR (95% confidence interval, 9-36%). Of 9 additional patients recruited for protocol-defined toxicity analysis, 8 were evaluable; 42 of 48 (88%) patients had clinical response (16 patients, clinical complete response; 26 patients, clinical partial response). T(1) tumors more frequently exhibited clinical complete response (P = 0.05) and showed a trend to exhibit pCR (P = 0.07). 5 (13%) patients experienced grade 1 cardiac dysfunction during preoperative treatment. Neither HER2 nor estrogen receptor status changed significantly after exposure to trastuzumab and vinorelbine. RNA profiling identified three top-level clusters by unsupervised analysis. Tumors with extremes of response [pCR (n = 3) versus nonresponse (n = 3)] fell into separate groups by hierarchical clustering. No predictive genes were identified in pCR tumors. Nonresponding tumors were more likely to be T(4) stage (P = 0.02) and express basal markers (P < 0.00001), growth factors, and growth factor receptors. Insulin-like growth factor-I receptor membrane expression was associated with a lower response rate (50% vs 97%; P = 0.001). CONCLUSIONS: Preoperative trastuzumab plus vinorelbine is active and well tolerated in patients with HER2-positive, operable, stage II/III breast cancer. HER2-overexpressing tumors with a basal-like phenotype, or with expression of insulin-like growth factor-I receptor and other proteins involved in growth factor pathways, are more likely to be resistant to this regimen.
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2016-03-31 | E-GEOD-62327 | biostudies-arrayexpress
Project description:The use of trastuzumab and pertuzumab in combination with docetaxel for initial treatment of HER2-positive breast cancer patients has resulted in notable clinical benefits in comparison to docetaxel administered with trastuzumab alone. Nevertheless, although therapeutic success is evident at the outset, the majority of tumours eventually advance, rendering metastatic disease and subsequent recurrence in patients who have developed acquired resistance. There is an urgent requirement to enhance our comprehension of the mechanisms governing resistance, enabling us to develop targeted therapeutic approaches to improve efficacy. We produced four HER2-positive-derived cell lines through prolonged exposure to trastuzumab and pertuzumab, determining their resistance rates. We confirmed long-term resistance through a notable increase in colony formation capacity of the derived cells. We confirmed the molecular identity of the new cell lines using immunohistochemistry of their receptors and profiling of point mutations. We detected HER2 overexpression in all cell lines and resistance to trastuzumab and pertuzumab did not result in variations in ER, PR and HER2 receptor expression. Finally, a study using proteomics analysis confirmed a significant alteration in the abundance patterns of over 600 proteins. This has implications for various vital biological processes such as ribosome creation, mitochondrial functionality, and metabolism. These mechanisms may play a crucial role in developing resistance in HER2-positive breast cancer. We conclude that these BCCLs resistant to trastuzumab plus pertuzumab-based anti-HER2 therapy could be a useful resource to enhance comprehension of resistance acquisition mechanisms.
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Project description:Efficacy of a selective MEK (trametinib) and BRAFV600E (dabrafenib) inhibitors associated with radioactive iodine (RAI) for the treatment of refractory metastatic differentiated thyroid cancer with RAS (current cohort) or BRAFV600E mutation. To evaluate the objective response rate according to RECIST criteria in thyroid cancer patients with metastatic radioactive iodine (RAI) refractory disease, 6 months after a treatment combining in each arm of the phase II trial (patients with RAS mutation or patients with BRAFV600E mutation): - Arm A: 6 weeks of trametinib followed by RAI treatment (5.5 GBq following rhTSH) in patients with RAS mutation - Arm B: 6 weeks of trametinib plus dabrafenib followed by RAI treatment (5.5 GBq following rhTSH) in patients with BRAFV600E mutation
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