The Role of PI3K Inhibition in the Treatment of Breast Cancer, Alone or Combined With Immune Checkpoint Inhibitors.
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ABSTRACT:
SUBMITTER: Zhang Z
PROVIDER: S-EPMC8139556 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectivesInhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI.MethodsC57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS.ResultsTreatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8+ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8+ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8+ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors.ConclusionPI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.
| S-EPMC8156389 | biostudies-literature
Project description:BackgroundWe indirectly compared the effects of immune checkpoint inhibitors alone (ICI) and ICI-combined chemotherapy (chemo-ICI) in patients with non-small cell lung cancer who had high programmed death-ligand 1 (PD-L1) expression (defined as tumour proportion score ≥50% or TC3/IC3) through network meta-analyses.MethodsThrough literature searches, we shortlisted 22 randomised controlled trials encompassing 4289 patients, with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) set as the primary outcomes. The dichotomous data for ORR and hazard ratios (HRs) and their 95% confidence intervals (CIs) for OS and PFS were extracted.ResultsWe found that chemo-ICI had significantly improved ORR (OR 1.7, 95% CI 1.1-2.5) and PFS (HR 0.59, 95% CI: 0.48-0.74) relative to ICI. Although no significant difference in OS was observed, the analyses revealed that the chemo-ICI patients tended to undergo fewer progression events than ICI patients (HR 0.82, 95% CI 0.6-1.1). In subgroup analysis, the non-squamous, PD-1 inhibitor and first-line treatment cohorts exhibited significant differences in ORR and PFS, but not in OS. However, in the squamous, PD-L1 inhibitor, and previously treated cohorts, PFS, OS and ORR were not different between chemo-ICI and ICI patients.ConclusionsIn conclusion, for non-squamous NSCLC patients, accepting PD-1 as the first-line treatment may be a relatively better option.
| S-EPMC9427994 | biostudies-literature
Project description:IntroductionBreast cancer has traditionally been viewed as immunogenically 'cold,' but two immune checkpoint inhibitors have been approved in combination with chemotherapy for PD-L1 positive advanced triple-negative breast cancer (TNBC), and pembrolizumab was also recently approved for early stage TNBC. As the landscape is rapidly evolving, a comprehensive review of checkpoint inhibitors in breast cancer is needed to aid clinicians in selecting appropriate candidates for therapy, and to highlight ongoing promising studies in this area and topics in need of further investigation.Area coveredThis review summarizes the latest evidence from completed and ongoing trials of immune checkpoint inhibitors. Ongoing studies were identified using a search of ClinicalTrials.gov with the term 'breast cancer' along with specific checkpoint inhibitor agents.Expert opinionA number of novel combination strategies are under investigation to enhance response and overcome resistance to immunotherapy, with promising preliminary data from checkpoint inhibitors targeting TIGIT, combinations with small molecule inhibitors such as lenvatinib, and injectable agents directly influencing the immune microenvironment. As immunotherapy enters into the curative setting, biomarkers predictive of immunotherapy benefit are needed, as PD-L1 status has not been a helpful discriminator in completed trials in early-stage breast cancer.
| S-EPMC8995399 | biostudies-literature
Project description:Breast cancer is the most prevalent non-skin cancer diagnosed in females and developing novel therapeutic strategies to improve patient outcomes is crucial. The immune system plays an integral role in the body's response to breast cancer and modulating this immune response through immunotherapy is a promising therapeutic option. Although immune checkpoint inhibitors were recently approved for the treatment of breast cancer patients, not all patients respond to immune checkpoint inhibitors as a monotherapy, highlighting the need to better understand the biology underlying patient response. Additionally, as radiotherapy is a critical component of breast cancer treatment, understanding the interplay of radiation and immune checkpoint inhibitors will be vital as recent studies suggest that combined therapies may induce synergistic effects in preclinical models of breast cancer. This review will discuss the mechanisms supporting combined approaches with radiotherapy and immune checkpoint inhibitors for the treatment of breast cancer. Moreover, this review will analyze the current clinical trials examining combined approaches of radiotherapy, immunotherapy, chemotherapy, and targeted therapy. Finally, this review will evaluate data regarding treatment tolerance and potential biomarkers for these emerging therapies aimed at improving breast cancer outcomes.
| S-EPMC9643771 | biostudies-literature
Project description:BackgroundIt is still controversial whether immune checkpoint inhibitors (ICIs) can improve the curative effect when added to original standard chemotherapy treatment for triple-negative breast cancer (TNBC). We compared their antitumor efficacy and adverse effects (AEs) to make a better clinical decision.MethodsSeven databases were searched for eligible articles. Progression-free survival (PFS), overall survival (OS), and AEs were measured as the primary outcomes.ResultsNine randomized controlled trials (RCTs) involving 4,501 patients were included. ICI+chemotherapy treatment achieved better PFS (hazard ratio [HR]: 0.78, [0.70-0.86], p < 0.00001), OS (HR: 0.86, [0.74-0.99], p = 0.04), and complete response (584/1,106 vs. 341/825, risk ratio [RR]: 1.38, [1.01-1.89], p = 0.04). With the prolongation of survival, the survival advantage of ICI+chemotherapy increased compared with chemotherapy. Subgroup analysis suggested that the addition of ICIs might not have a better effect in Asian patients, patients with locally advanced disease, or patients with brain metastases. In the toxicity analysis, more Grade 3-5 AEs and serious AEs were found in the ICI+chemotherapy group. For Grade 3-5 AEs, more cases of diarrhea, severe skin reactions, pneumonitis, hepatitis, and adrenal insufficiency were related to the ICI+chemotherapy group.ConclusionsICI+chemotherapy appears to be better than chemotherapy alone for TNBC treatment, with better OS and PFS. However, its high rates of serious AEs need to be taken seriously.Systematic review registrationPROSPERO Registration: CRD42021276394.
| S-EPMC8716854 | biostudies-literature
Project description:UnlabelledTraditional treatment modalities for advanced cancer (radiotherapy, chemotherapy, or targeted agents) act directly on tumors to inhibit or destroy them. Along with surgery, these modalities are predominantly palliative, with toxicity and only modest improvements in survival in patients with advanced solid tumors. Accordingly, long-term survival rates for most patients with advanced cancer remain low, thus there is a need for cancer treatments with favorable benefit and toxicity profiles that can potentially result in long-term survival. The immune system plays a critical role in the recognition and eradication of tumor cells ("immune surveillance"), and immunotherapies based on this concept have been used for decades with some success against a few tumor types; however, most immunotherapies were limited by a lack of either substantial efficacy or specificity, resulting in toxicity. We now have a greater understanding of the complex interactions between the immune system and tumors and have identified key molecules that govern these interactions. This information has revitalized the interest in immunotherapy as an evolving treatment modality using immunotherapeutics designed to overcome the mechanisms exploited by tumors to evade immune destruction. Immunotherapies have potentially complementary mechanisms of action that may allow them to be combined with other immunotherapeutics, chemotherapy, targeted therapy, or other traditional therapies. This review discusses the concepts and data behind immunotherapies, with a focus on the checkpoint inhibitors and their responses, toxicities, and potential for long-term survival, and explores promising single-agent and combination therapies in development.Implications for practiceImmunotherapy is an evolving treatment approach based on the role of the immune system in eradicating cancer. An example of an immunotherapeutic is ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4) to augment antitumor immune responses. Ipilimumab is approved for advanced melanoma and induced long-term survival in a proportion of patients. The programmed death-1 (PD-1) checkpoint inhibitors are promising immunotherapies with demonstrated sustained antitumor responses in several tumors. Because they harness the patient's own immune system, immunotherapies have the potential to be a powerful weapon against cancer.
| S-EPMC4492230 | biostudies-literature
Project description:The management of breast cancer brain metastases (BCBM) has historically involved local therapies. However, as novel systemic treatments have become more effective in controlling visceral disease, BCBM have also been better controlled. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in brain metastases in patients with lung cancer and melanoma and represent a promising option for patients with triple-negative BCBM, a group with limited systemic therapy options. In this review we summarize current data about the role of ICIs in the treatment BCBM. We identified 15 clinical trials that evaluated ICIs ± chemotherapy in patients with breast cancer. The studies were mostly focused on triple-negative breast cancer (TNBC). Of these trials, 4 excluded patients with BCBM, while 11 allowed patients with stable, treated or asymptomatic BCBM. In total, 2692 patients were enrolled in the identified clinical trials, but only 91 trial patients (3.3%) had BCBM. Furthermore, only 2 of these clinical trials reported BCBM-specific outcomes and none of the clinical trials reported BCBM-specific adverse events. Up to 45% of patients with TNBC will develop BCBM; however, only 3.3% of the patients included in the clinical trials that led to the U.S. Food and Drug Administration approvals for ICIs in advanced breast cancer had brain metastases. This review reinforces that efficacy data are greatly needed for patients with BCBM-this is an area of unmet need in oncology. More inclusive clinical trials and real-world data that evaluate the safety and efficacy of ICIs in patients with BCBM are greatly needed.
| S-EPMC9256020 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is one of most common cancers and the fourth leading cause of death worldwide. Commonly, HCC development occurs in a liver that is severely compromised by chronic injury or inflammation. Liver transplantation, hepatic resection, radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), and targeted therapies based on tyrosine protein kinase inhibitors are the most common treatments. The latter group have been used as the primary choice for a decade. However, tumor microenvironment in HCC is strongly immunosuppressive; thus, new treatment approaches for HCC remain necessary. The great expression of immune checkpoint molecules, such as programmed death-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte activating gene 3 protein (LAG-3), and mucin domain molecule 3 (TIM-3), on tumor and immune cells and the high levels of immunosuppressive cytokines induce T cell inhibition and represent one of the major mechanisms of HCC immune escape. Recently, immunotherapy based on the use of immune checkpoint inhibitors (ICIs), as single agents or in combination with kinase inhibitors, anti-angiogenic drugs, chemotherapeutic agents, and locoregional therapies, offers great promise in the treatment of HCC. This review summarizes the recent clinical studies, as well as ongoing and upcoming trials.
| S-EPMC8160723 | biostudies-literature
Project description:Hepatocellular Carcinoma (HCC) is one of the most common cancers and a leading cause of cancer related death worldwide. Until recently, systemic therapy for advanced HCC, defined as Barcelona Clinic Liver Cancer (BCLC) stage B or C, was limited and ineffective in terms of long-term survival. However, over the past decade, immune check point inhibitors (ICI) combinations have emerged as a potential therapeutic option for patients with nonresectable disease. ICI modulate the tumor microenvironment to prevent progression of the tumor. Radiotherapy is a crucial tool in treating unresectable HCC and may enhance the efficacy of ICI by manipulating the tumor microenvironment and decreasing tumor resistance to certain therapies. We herein review developments in the field of ICI combined with radiotherapy for the treatment of HCC, as well as look at challenges associated with these treatment modalities, and review future directions of combination therapy.
| S-EPMC10405730 | biostudies-literature
Project description:BACKGROUND:Single agent immune checkpoint inhibitors (ICIs) improve survival outcomes compared to chemotherapy for advanced non-small cell lung cancer (NSCLC), but treatment efficacy widely varies. The combination of ICIs with chemotherapy has shown promising efficacy over chemotherapy alone; however, whether this strategy is superior to single agent ICIs for the treatment of advanced NSCLC remains unknown. METHODS:The records of 109 patients with advanced NSCLC who were administered at least one cycle of ICIs were retrospectively reviewed. Patients were grouped based on the presence or absence of a chemotherapy treatment combination. Efficacy and survival outcomes were analyzed. RESULT:Sixty-nine (58.0%) patients received single agent ICIs (ICI group) and 50 (42.0%) received ICIs and chemotherapy (ICC group). The median (3.2 vs. 3.0?months; P?=?0.025) and one-year (34.5 vs. 9.6%; P?=?0.026) progression-free survival (PFS) rates were significantly better in the ICC than in the ICI group. The superior efficacy of ICC remained in the propensity score matched pairs (median PFS 3.2 vs. 2.6?months, P?=?0.032; 1-year PFS 35.2 vs. 7.6%; P?=?0.035). Eastern Cooperative Oncology Group performance status 0-1 (HR 0.37, 95% CI 0.22-0.62; P < 0.001) and the ICC group (HR 0.56, 95% CI 0.34-0.94; P = 0.028) were predictive of PFS. Subgroup-to-chemotherapy interaction revealed improved risk reduction for adenocarcinoma and EGFR mutation. CONCLUSION:Combing chemotherapy with ICIs improved treatment efficacy over ICIs alone. The additional efficacy of chemotherapy may differ between histological subtypes and EGFR mutation status.
| S-EPMC6501017 | biostudies-literature