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BioMed Research International 2020The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a promising treatment target for patients with breast cancer (BC). Our study aimed to evaluate the most... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a promising treatment target for patients with breast cancer (BC). Our study aimed to evaluate the most effective and safe PI3K inhibitor for patients with BC, especially in PIK3CA mutation.
METHODS
Electronics databases were systematically searched from their inception to June 2020 for published randomized controlled trials (RCTs) comparing PI3K inhibitor therapy versus non-PI3K inhibitor therapy in patients with BC that mentioned or reported data of PIK3CA-mutated patient subgroups. Eligible RCTs had to report at least one of the following clinical outcomes: objective response rate (ORR), progression-free survival (PFS), or adverse events (AE).
RESULTS
Nine eligible RCTs involving 3872 BC patients and four PI3K inhibitor therapy arms (i.e., alpelisib, buparlisib, pictilisib, and taselisib) were included. In evaluating ORR, beneficial significant results of PI3K inhibitors could be found in the PIK3CA mutated group (1.952, 1.012 to 3.766); analogous results could also be found in 6m-PFS (1.519, 1.144 to 2.018) and PFS from HR data (-0.346, -0.525 to -0.168). From pairwise and network meta-analyses, buparlisib showed the most favorable ORR, as it was significantly different from fulvestrant in the PIK3CA-mutated patient group (2.80, 1.56 to 5.03). Alpelisib ranked first in the assessment of 6m-PFS and was significantly different from fulvestrant in the PIK3CA-mutated group (2.33, 1.45 to 3.44). The above PI3K inhibitors had good safety with few serious AEs. PROSPERO registration CRD42020193932.
CONCLUSION
The PI3K inhibitors alpelisib and buparlisib appear to have superior efficacy and safety therapeutic choices for patients with BC, especially in PIK3CA-mutated patients.
Topics: Aminopyridines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Class I Phosphatidylinositol 3-Kinases; Clinical Trials as Topic; Female; Humans; Morpholines; Mutation; Network Meta-Analysis; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Progression-Free Survival; Signal Transduction; Thiazoles; Treatment Outcome
PubMed: 33376736
DOI: 10.1155/2020/7451576 -
Advances in Therapy Apr 2022Tazemetostat is an enhancer of zeste homolog 2 (EZH2) inhibitor recommended for patients with relapsed/refractory (R/R) follicular lymphoma (FL) after demonstrating...
A Matching-Adjusted Indirect Comparison of Single-Arm Trials in Patients with Relapsed or Refractory Follicular Lymphoma Who Received at Least Two Prior Systemic Treatments: Tazemetostat was Associated with a Lower Risk for Safety Outcomes Versus the PI3-Kinase Inhibitors Idelalisib, Duvelisib,...
INTRODUCTION
Tazemetostat is an enhancer of zeste homolog 2 (EZH2) inhibitor recommended for patients with relapsed/refractory (R/R) follicular lymphoma (FL) after demonstrating single-agent, antitumor activity in patients with wild-type or mutant EZH2. The phosphoinositide 3-kinase (PI3K) inhibitors idelalisib, copanlisib, umbralisib and (formerly) duvelisib are indicated for third-line, fourth-line, and later (3L/4L+) treatment of R/R FL. The objective of this analysis was to provide an indirect treatment comparison of tazemetostat with each PI3K inhibitor for 3L/4L+ R/R FL treatment.
METHODS
A systematic literature review was conducted to identify trials for idelalisib (DELTA), duvelisib (DYNAMO), copanlisib (CHRONOS-1 Part B), and umbralisib (UNITY-NHL) in 3L+ R/R FL. Matching-adjusted indirect comparisons were conducted by weighting tazemetostat individual patient data with available baseline characteristics from each comparator trial: age, Eastern Cooperative Oncology Group performance status, disease stage, histology, prior treatment lines, prior stem cell therapy, progression within 24 months, and refractory status to last therapy. Only the tazemetostat trial included patients with grade 3b or transformed FL, or recorded EZH2 mutation status. Primary safety outcomes included risk of grade ≥ 3 treatment-emergent adverse events (TEAEs); primary efficacy outcomes included objective response rate (ORR).
RESULTS
Matched patients treated with tazemetostat had lower relative risk (RR) for all grouped safety outcomes, including any grade ≥ 3 TEAEs, compared with idelalisib (RR = 0.45), duvelisib (RR = 0.35), copanlisib (RR = 0.37), and umbralisib (RR = 0.65; all, p < 0.01), any serious TEAE, and any TEAE leading to dose reduction, drug discontinuation, or interruption. The ORR was not significantly different for tazemetostat versus other treatments (idelalisib 43% vs 56%, p = 0.16; duvelisib 48% vs 47%, p = 0.91; copanlisib 49% vs 61%, p = 0.11; and umbralisib 57% vs 47%, p = 0.10).
CONCLUSIONS
In this statistically adjusted comparison, tazemetostat was associated with lower RR for safety outcomes versus idelalisib, duvelisib, copanlisib, and umbralisib, while achieving similar efficacy outcomes.
Topics: Benzamides; Biphenyl Compounds; Child, Preschool; Heterocyclic Compounds, 4 or More Rings; Humans; Isoquinolines; Lymphoma, Follicular; Morpholines; Neoplasm Recurrence, Local; Phosphatidylinositol 3-Kinases; Purines; Pyridones; Pyrimidines; Quinazolines; Quinazolinones; Risk
PubMed: 35157216
DOI: 10.1007/s12325-022-02054-z -
International Journal of Clinical and... 2015PTEN (10q23.3) is a negative regulator of the phosphatidylinositol 3-kinase (PIK3)/Akt survival pathway and a tumor suppressor frequently deleted in prostate cancer....
UNLABELLED
PTEN (10q23.3) is a negative regulator of the phosphatidylinositol 3-kinase (PIK3)/Akt survival pathway and a tumor suppressor frequently deleted in prostate cancer. PTEN genomic deletion is among the most common genetic aberrations in human prostate cancer. At present, the prognostic value of PTEN genomic deletion is unclear. We performed a systematic review and meta-analysis to clarify the association between PTEN genomic deletion and a higher Gleason score or a higher possibility of capsular penetration. A comprehensive, computerized literature search of PubMed was carried out until May 27, 2014. Studies were included according to specific inclusion criteria. Pooled hazard ratio was estimated using the fixed effects model or random effects model according to heterogeneity between studies. Seven eligible studies meeting the specific inclusion criteria were selected for further analysis; all were retrospective studies. Overall meta-analysis demonstrated that PTEN genomic deletion was associated with a higher Gleason score (OR 0.319; 95% confidence interval: 0.153-0.666; P = 0.000) and a higher possibility of capsular penetration (OR 0.393; 95% confidence interval: 0.185-0.837; P = 0.015). None of the studies materially altered the original results and no evidence of publication bias was found.
CONCLUSION
PTEN genomic deletion in operable localized prostate cancer indicates a higher Gleason score and a higher probability of capsular penetration, indicating a worse prognosis. Further studies should be conducted in order to investigate the effect of PTEN genomic deletion on clinical outcomes in different histological types of prostate cancer or its function in castration-resistant prostate cancer.
PubMed: 26131120
DOI: No ID Found -
Brain Pathology (Zurich, Switzerland) Jul 2019Malformations of cortical development (MCD) comprise a broad spectrum of developmental brain abnormalities. Patients presenting with MCDs often suffer from...
Malformations of cortical development (MCD) comprise a broad spectrum of developmental brain abnormalities. Patients presenting with MCDs often suffer from drug-resistant focal epilepsy, and some become candidates for epilepsy surgery. Their likelihood of achieving freedom from seizures, however, remains uncertain, and depends in a major part on the underlying pathology. Tissue samples obtained in epilepsy surgery form the basis of definite histopathological diagnosis; however, new molecular genetic methods have not yet been implemented in diagnostic processes for MCD cases. Furthermore, it has not been completely understood how the underlying pathology affects patients' outcomes after epilepsy surgery. We performed a systematic literature review of studies describing both histopathological and molecular genetic findings in MCD, along with studies on epilepsy surgery outcomes. We aimed to correlate the genetic causes with the underlying morphological abnormalities in focal cortical malformations and to stress the importance of the underlying biology for patient management and counseling. From the summarized findings of multiple authors, it is obvious that MCD may have a diverse genetic background despite a similar or even identical histopathological picture. Even though most of their molecular genetic findings converge on various levels of the PI3K/AKT/mTOR pathway, the exact mechanisms underlying MCD formation have not yet been completely described or indeed how this pathway generates a diverse range of histological abnormalities. Based on our findings, we therefore propose that all patients diagnosed and operated for drug-resistant epilepsy should have an integrated molecular and pathological diagnosis similar to the current practice in brain tumor diagnostic processes that might lead to more accurate diagnosis and effective stratification of patients undergoing epilepsy surgery.
Topics: Brain; Brain Diseases; Cerebral Cortex; Drug Resistant Epilepsy; Epilepsy; Genetic Association Studies; Humans; Malformations of Cortical Development; Phosphatidylinositol 3-Kinases; Seizures; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 30485578
DOI: 10.1111/bpa.12686 -
BioMed Research International 2020To evaluate the impact of mutation status on clinical outcomes of breast cancer treated with inhibitors. (Meta-Analysis)
Meta-Analysis
AIM
To evaluate the impact of mutation status on clinical outcomes of breast cancer treated with inhibitors.
METHODS
A comprehensive literature search was conducted in online databases from inception to December 31, 2019. The main characteristics and prognostic data of each eligible study were extracted. The odds ratio (OR) for the overall response rate (ORR) and hazard ratio (HR) for progression-free survival (PFS) were estimated using the fixed-effects Mantel-Haenszel model.
RESULTS
A total of 8 studies involving 2670 patients were included for analysis. Overall, the clinical outcomes of inhibitors were significantly influenced by mutation status in breast cancer. After the treatment of inhibitors, breast cancer patients with mutations presented better ORR (mutated group: OR = 1.98 [95% CI, 1.46 to 2.70]; wild-type group: OR = 1.09 [95% CI, 0.78 to 1.53]) and better PFS (-mutated group: HR = 0.65 [95% CI, 0.55 to 0.76]; wild-type group: HR = 0.87 [95% CI, 0.70 to 1.09]). No publication bias was detected for ORR and PFS in our analysis.
CONCLUSION
In this meta-analysis, it suggests that the association between clinical outcomes of inhibitors and mutation status is dramatic. mutations were a favorable factor in the clinical outcomes of breast cancer treated with inhibitors.
Topics: Antineoplastic Agents; Breast Neoplasms; Class I Phosphatidylinositol 3-Kinases; Female; Humans; Mutation; Prognosis; Receptors, Steroid
PubMed: 32461963
DOI: 10.1155/2020/1598037 -
Cancer Cell International 2015Tumour cells show greater dependency on glycolysis so providing a sufficient and rapid energy supply for fast growth. In many breast cancers, estrogen, progesterone and...
BACKGROUND
Tumour cells show greater dependency on glycolysis so providing a sufficient and rapid energy supply for fast growth. In many breast cancers, estrogen, progesterone and epidermal growth factor receptor-positive cells proliferate in response to growth factors and growth factor antagonists are a mainstay of treatment. However, triple negative breast cancer (TNBC) cells lack receptor expression, are frequently more aggressive and are resistant to growth factor inhibition. Downstream of growth factor receptors, signal transduction proceeds via phosphatidylinositol 3-kinase (PI3k), Akt and FOXO3a inhibition, the latter being partly responsible for coordinated increases in glycolysis and apoptosis resistance. FOXO3a may be an attractive therapeutic target for TNBC. Therefore we have undertaken a systematic review of FOXO3a as a target for breast cancer therapeutics.
METHODS
Articles from NCBI were retrieved systematically when reporting primary data about FOXO3a expression in breast cancer cells after cytotoxic drug treatment.
RESULTS
Increased FOXO3a expression is common following cytotoxic drug treatment and is associated with apoptosis and cell cycle arrest. There is some evidence that metabolic enzyme expression is also altered and that this effect is also elicited in TNBC cells. FOXO3a expression serves as a positive prognostic marker, especially in estrogen (ER) receptor positive cells.
DISCUSSION
FOXO3a is upregulated by a number of receptor-dependent and -independent anti-cancer drugs and associates with apoptosis. The identification of microRNA that regulate FOXO3a directly suggest that it offers a tangible therapeutic target that merits wider evaluation.
PubMed: 25678856
DOI: 10.1186/s12935-015-0156-6