Showing papers on "Lapatinib published in 2021"

Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial

Abstract: Summary Background Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab Methods This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18–70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1–14 of each 21-day cycle Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease The primary endpoint was progression-free survival according to masked independent central review Efficacy and safety were assessed in all patients who received at least one dose of the study drugs Results presented here are from a prespecified interim analysis This study is registered with ClinicalTrialsgov, NCT03080805 Findings Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7–not reached]) than with lapatinib plus capecitabine (6·8 months [5·4–8·1]; hazard ratio 0·39 [95% CI 0·27–0·56]; one-sided p Interpretation Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy Funding Jiangsu Hengrui Medicine and National Key R&D Program of China Translations For the Chinese translation of the abstract see Supplementary Materials section

HER2-positive breast cancer and tyrosine kinase inhibitors: the time is now.

Abstract: Human epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for 20–25% of all breast cancers. Multiple HER2-targeted therapies have been developed over the last few years, including the tyrosine kinase inhibitors (TKI) lapatinib, neratinib, tucatinib, and pyrotinib. These drugs target HER2 and other receptors of the epidermal growth factor receptor family, therefore each has unique efficacy and adverse event profile. HER2-directed TKIs have been studied in the early stage and advanced settings and have shown promising responses. There is increasing interest in utilizing these drugs in combination with chemotherapy and /or other HER2-directed agents in patients with central nervous system involvement, TKIs have shown to be effective in this setting for which treatment options have been previously limited and the prognosis remains poor. The aim of this review is to summarize currently approved TKIs for HER2+ breast, key clinical trials, and their use in current clinical practice.

Trastuzumab-induced cardiotoxicity: a review of clinical risk factors, pharmacologic prevention, and cardiotoxicity of other HER2-directed therapies

Abstract: Despite great success as a targeted breast cancer therapy, trastuzumab use may be complicated by heart failure and loss of left ventricular contractile function. This review summarizes the risk factors, imaging, and prevention of cardiotoxicity associated with trastuzumab and other HER2-targeted therapies. Cardiovascular disease risk factors, advanced age, and previous anthracycline treatment predispose to trastuzumab-induced cardiotoxicity (TIC), with anthracycline exposure being the most significant risk factor. Cardiac biomarkers such as troponins and pro-BNP and imaging assessments such as echocardiogram before and during trastuzumab therapy may help in early identification of TIC. Initiation of beta-adrenergic antagonists and angiotensin converting enzyme inhibitors may prevent TIC. Cardiotoxicity rates of other HER2-targeted treatments, such as pertuzumab, T-DM1, lapatinib, neratinib, tucatinib, trastuzumab deruxtecan, and margetuximab, appear to be significantly lower as reported in the pivotal trials which led to their approval. Risk assessment for TIC should include cardiac imaging assessment and should incorporate prior anthracycline use, the strongest risk factor for TIC. Screening and prediction of cardiotoxicity, referral to a cardio-oncology specialist, and initiation of effective prophylactic therapy may all improve prognosis in patients receiving HER2-directed therapy. Beta blockers and ACE inhibitors appear to mitigate risk of TIC. Anthracycline-free regimens have been proven to be efficacious in early HER2-positive breast cancer and should now be considered the standard of care for early HER2-positive breast cancer. Newer HER2-directed therapies appear to have significantly lower cardiotoxicity compared to trastuzumab, but trials are needed in patients who have experienced TIC and patients with pre-existing cardiac dysfunction.

Brain Metastases in HER2-Positive Breast Cancer: Current and Novel Treatment Strategies

Abstract: Development of brain metastases can occur in up to 30-50% of patients with breast cancer, representing a significant impact on an individual patient in terms of survival and quality of life. Patients with HER2-positive breast cancer have an increased risk of developing brain metastases; however, screening for brain metastases is not currently recommended due to the lack of robust evidence to support survival benefit. In recent years, several novel anti-HER2 agents have led to significant improvements in the outcomes of HER2-positive metastatic breast cancer. Despite these advances, brain and leptomeningeal metastases from HER2-positive breast cancer remain a significant cause of morbidity and mortality, and their optimal management remains an unmet need. This review presents an update on the current and novel treatment strategies for patients with brain metastases from HER2-positive breast cancer and discusses the open questions in the field.

EGFR/ErbB2-Targeting Lapatinib Therapy for Aggressive Prolactinomas.

Abstract: Context Approximately 10% to 20% of prolactinomas are resistant to dopamine agonist therapy. The ErbB signaling pathway may drive aggressive prolactinoma behavior. Objective We evaluated lapatinib, an ErbB1-epidermal growth factor receptor (EGFR)/ErbB2 or human EGFR2 (HER2) tyrosine kinase inhibitor (TKI), in aggressive prolactinomas. Design A prospective, phase 2a multicenter trial was conducted. Setting This study took place at a tertiary referral pituitary center. Patients Study participants included adults with aggressive prolactinomas showing continued tumor growth despite maximally tolerated dopamine agonist therapy. Intervention Intervention included oral lapatinib 1250 mg/day for 6 months. Main outcome measures The primary end point was 40% reduction in any tumor dimension assessed by magnetic resonance imaging at study end; tumor response was assessed by Response Evaluation Criteria in Solid Tumors criteria. Secondary end points included prolactin (PRL) reduction, correlation of response with EGFR/HER2 expression, and safety. Results Owing to rigorous inclusion criteria, of 24 planned participants, only 7 consented and 4 were treated. None achieved the primary end point but 3 showed stable disease, including 2 with a 6% increase and 1 with a 16.8% decrease in tumor diameter. PRL response was not always concordant with tumor response, as 2 showed 28% and 59% increases in PRL. The fourth participant had a PRL-secreting carcinoma and withdrew after 3 months of lapatinib because of imaging and PRL progression. EGFR/HER2 expression did not correlate with treatment response. Lapatinib was well tolerated overall, with reversible grade 1 transaminitis in 2 patients, grade 2 rash in 2 patients, and grade 1 asymptomatic bradycardia in 2 patients. Conclusions An oral TKI such as lapatinib may be an effective option for a difficult-to-treat patient with an aggressive prolactinoma.

Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors.

Abstract: Human epidermal growth factor 2 (HER2/ERBB2) is frequently amplified/mutated in cancer. The tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib are FDA-approved for the treatment of HER2-positive breast cancer. Direct comparisons of the preclinical efficacy of the TKIs have been limited to small-scale studies. Novel biomarkers are required to define beneficial patient populations. In this study, the anti-proliferative effects of the three TKIs were directly compared using a 115 cancer cell line panel. Novel TKI response/resistance markers were identified through cross-analysis of drug response profiles with mutation, gene copy number and expression data. All three TKIs were effective against HER2-amplified breast cancer models; neratinib showing the most potent activity, followed by tucatinib then lapatinib. Neratinib displayed the greatest activity in HER2-mutant and EGFR-mutant cells. High expression of HER2, VTCN1, CDK12, and RAC1 correlated with response to all three TKIs. DNA damage repair genes were associated with TKI resistance. BRCA2 mutations were correlated with neratinib and tucatinib response, and high expression of ATM, BRCA2, and BRCA1 were associated with neratinib resistance. Neratinib was the most effective HER2-targeted TKI against HER2-amplified, -mutant, and EGFR-mutant cell lines. This analysis revealed novel resistance mechanisms that may be exploited using combinatorial strategies.

Efficacy of Neratinib Plus Capecitabine in the Subgroup of Patients with Central Nervous System Involvement from the NALA Trial

Abstract: Author(s): Hurvitz, Sara A; Saura, Cristina; Oliveira, Mafalda; Trudeau, Maureen E; Moy, Beverly; Delaloge, Suzette; Gradishar, William; Kim, Sung-Bae; Haley, Barbara; Ryvo, Larisa; Dai, Ming-Shen; Milovanov, Vladimir; Alarcon, Jesus; Kalmadi, Sujith; Cronemberger, Eduardo; Souza, Cristiano; Landeiro, Luciana; Bose, Ron; Bebchuk, Judith; Kabbinavar, Fairooz; Bryce, Richard; Keyvanjah, Kiana; Brufsky, Adam M | Abstract: BackgroundNeratinib has efficacy in central nervous system (CNS) metastases from HER2-positive metastatic breast cancer (MBC). We report outcomes among patients with CNS metastases at baseline from the phase III NALA trial of neratinib plus capecitabine (Nn+nC) versus lapatinib plus capecitabine (Ln+nC).Materials and methodsNALA was a randomized, active-controlled trial in patients who received two or more previous HER2-directed regimens for HER2-positive MBC. Patients with asymptomatic/stable brain metastases (treated or untreated) were eligible. Patients were assigned to Nn+nC (neratinib 240 mg per day, capecitabine 750 mg/m2 twice daily) or Ln+nC (lapatinib 1,250 mg per day, capecitabine 1,000 mg/m2 twice daily) orally. Independently adjudicated progression-free survival (PFS), overall survival (OS), and CNS endpoints were considered.ResultsOf 621 patients enrolled, 101 (16.3%) had known CNS metastases at baseline (Nn+nC, nn= 51; Ln+nC, nn= 50); 81 had received prior CNS-directed radiotherapy and/or surgery. In the CNS subgroup, mean PFS through 24 months was 7.8 months with Nn+nC versus 5.5 months with Ln+nC (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.41-1.05), and mean OS through 48 months was 16.4 versus 15.4 months (HR, 0.90; 95% CI, 0.59-1.38). At 12 months, cumulative incidence of interventions for CNS disease was 25.5% for Nn+nC versus 36.0% for Ln+nC, and cumulative incidence of progressive CNS disease was 26.2% versus 41.6%, respectively. In patients with target CNS lesions at baseline (nn= 32), confirmed intracranial objective response rates were 26.3% and 15.4%, respectively. No new safety signals were observed.ConclusionThese analyses suggest improved PFS and CNS outcomes with Nn+nC versus Ln+nC in patients with CNS metastases from HER2-positive MBC.Implications for practiceIn a subgroup of patients with central nervous system (CNS) metastases from HER2-positive breast cancer after two or more previous HER2-directed regimens, the combination of neratinib plus capecitabine was associated with improved progression-free survival and CNS outcomes compared with lapatinib plus capecitabine. These findings build on previous phase II and III studies describing efficacy of neratinib in the prevention and treatment of CNS metastases, and support a role for neratinib as a systemic treatment option in the management of patients with HER2-positive brain metastases following antibody-based HER2-directed therapies.

Exosomal annexin A6 induces gemcitabine resistance by inhibiting ubiquitination and degradation of EGFR in triple-negative breast cancer.

Abstract: Exosomes are carriers of intercellular information that regulate the tumor microenvironment, and they have an essential role in drug resistance through various mechanisms such as transporting RNA molecules and proteins. Nevertheless, their effects on gemcitabine resistance in triple-negative breast cancer (TNBC) are unclear. In the present study, we examined the effects of exosomes on TNBC cell viability, colony formation, apoptosis, and annexin A6 (ANXA6)/EGFR expression. We addressed their roles in gemcitabine resistance and the underlying mechanism. Our results revealed that exosomes derived from resistant cancer cells improved cell viability and colony formation and inhibited apoptosis in sensitive cancer cells. The underlying mechanism included the transfer of exosomal ANXA6 from resistant cancer cells to sensitive cancer cells. Isobaric peptide labeling-liquid chromatography-tandem mass spectrometry and western blotting revealed that ANXA6 was upregulated in resistant cancer cells and their derived exosomes. Sensitive cancer cells exhibited resistance with increased viability and colony formation and decreased apoptosis when ANXA6 was stably overexpressed. On the contrary, knockdown ANXA6 restored the sensitivity of cells to gemcitabine. Co-immunoprecipitation expression and GST pulldown assay demonstrated that exosomal ANXA6 and EGFR could interact with each other and exosomal ANXA6 was associated with the suppression of EGFR ubiquitination and downregulation. While adding lapatinib reversed gemcitabine resistance induced by exosomal ANXA6. Moreover, ANXA6 and EGFR protein expression was correlated in TNBC tissues, and exosomal ANXA6 levels at baseline were lower in patients with highly sensitive TNBC than those with resistant TNBC when treated with first-line gemcitabine-based chemotherapy. In conclusion, resistant cancer cell-derived exosomes induced gemcitabine resistance via exosomal ANXA6, which was associated with the inhibition of EGFR ubiquitination and degradation. Exosomal ANXA6 levels in the serum of patients with TNBC might be predictive of the response to gemcitabine-based chemotherapy.

Effects of HER Family–targeting Tyrosine Kinase Inhibitors on Antibody-dependent Cell-mediated Cytotoxicity in HER2-expressing Breast Cancer

Abstract: Purpose: Antibody-dependent cell-mediated cytotoxicity (ADCC) is one mechanism of action of the monoclonal antibody (mAb) therapies trastuzumab and pertuzumab. Tyrosine kinase inhibitors (TKIs), like lapatinib, may have added therapeutic value in combination with mAbs through enhanced ADCC activity. Using clinical data, we examined the impact of lapatinib on HER2/EGFR expression levels and natural killer (NK) cell gene signatures. We investigated the ability of three TKIs (lapatinib, afatinib, and neratinib) to alter HER2/immune-related protein levels in preclinical models of HER2-positive (HER2+) and HER2-low breast cancer, and the subsequent effects on trastuzumab/pertuzumab-mediated ADCC. Experimental Design: Preclinical studies (proliferation assays, Western blotting, high content analysis, and flow cytometry) employed HER2+ (SKBR3 and HCC1954) and HER2-low (MCF-7, T47D, CAMA-1, and CAL-51) breast cancer cell lines. NCT00524303 provided reverse phase protein array–determined protein levels of HER2/pHER2/EGFR/pEGFR. RNA-based NK cell gene signatures (CIBERSORT/MCP-counter) post-neoadjuvant anti-HER2 therapy were assessed (NCT00769470/NCT01485926). ADCC assays utilized flow cytometry–based protocols. Results: Lapatinib significantly increased membrane HER2 levels, while afatinib and neratinib significantly decreased levels in all preclinical models. Single-agent lapatinib increased HER2 or EGFR levels in 10 of 11 (91%) tumor samples. NK cell signatures increased posttherapy (P = 0.03) and associated with trastuzumab response (P = 0.01). TKI treatment altered mAb-induced NK cell–mediated ADCC in vitro, but it did not consistently correlate with HER2 expression in HER2+ or HER2-low models. The ADCC response to trastuzumab and pertuzumab combined did not exceed either mAb alone. Conclusions: TKIs differentially alter tumor cell phenotype which can impact NK cell–mediated response to coadministered antibody therapies. mAb-induced ADCC response is relevant when rationalizing combinations for clinical investigation.

An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer.

Abstract: Poly (ADP-ribose)-polymerase inhibitors (PARPi) have been approved for cancer patients with germline BRCA1/2 (gBRCA1/2) mutations, and efforts to expand the utility of PARPi beyond BRCA1/2 are ongoing. In preclinical models of triple-negative breast cancer (TNBC) with intact DNA repair, we have previously shown an induced synthetic lethality with combined EGFR inhibition and PARPi. Here, we report the safety and clinical activity of lapatinib and veliparib in patients with metastatic TNBC. A first-in-human, pilot study of lapatinib and veliparib was conducted in metastatic TNBC (NCT02158507). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rates and pharmacokinetic evaluation. Gene expression analysis of pre-treatment tumor biopsies was performed. Key eligibility included TNBC patients with measurable disease and prior anthracycline-based and taxane chemotherapy. Patients with gBRCA1/2 mutations were excluded. Twenty patients were enrolled, of which 17 were evaluable for response. The median number of prior therapies in the metastatic setting was 1 (range 0–2). Fifty percent of patients were Caucasian, 45% African–American, and 5% Hispanic. Of evaluable patients, 4 demonstrated a partial response and 2 had stable disease. There were no dose-limiting toxicities. Most AEs were limited to grade 1 or 2 and no drug–drug interactions noted. Exploratory gene expression analysis suggested baseline DNA repair pathway score was lower and baseline immunogenicity was higher in the responders compared to non-responders. Lapatinib plus veliparib therapy has a manageable safety profile and promising antitumor activity in advanced TNBC. Further investigation of dual therapy with EGFR inhibition and PARP inhibition is needed. ClinicalTrials.gov , NCT02158507 . Registered on 12 September 2014

A phase II study of dose-dense temozolomide and lapatinib for recurrent low-grade and anaplastic supratentorial, infratentorial, and spinal cord ependymoma.

Abstract: Background No standard medical treatment exists for adult patients with recurrent ependymoma, and prospective clinical trials in this population have not succeeded because of its rarity and challenges in accruing patients. The Collaborative Ependymoma Research Network conducted a prospective phase II clinical trial of dose-dense temozolomide (TMZ) and lapatinib, targeting the unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status and increased expression of ErbB2 (human epidermal growth factor receptor 2) and ErbB1 (epidermal growth factor receptor) in ependymomas. Methods Patients age 18 or older with histologically proven and progressive ependymoma or anaplastic ependymoma were eligible and received dose-dense TMZ and daily lapatinib. The primary outcome measure was median progression-free survival (PFS). Landmark 6- and 12-month PFS and objective response were measured. Serial assessments of symptom burden using the MD Anderson Symptom Inventory Brain Tumor (MDASI-BT)/MDASI-Spine Tumor modules were collected. Results The 50 patients enrolled had a median age of 43.5 years, median Karnofsky performance status of 90, and a median of 2 prior relapses. Twenty patients had grade III, 16 grade II, and 8 grade I ependymoma. Half had spinal cord tumors; 15 had a supratentorial tumor, 8 infratentorial, and 2 had disseminated disease. Treatment was well tolerated. The median PFS was 7.8 months (95% CI: 5.5,12.2); the 6- and 12-month PFS rates were 55% and 38%, with 2 complete and 6 partial responses. Measures of symptom burden showed reduction in moderate-severe pain and other disease-related symptoms in most patients. Conclusions This treatment, with demonstrated clinical activity with objective responses and prolonged disease control associated with disease-related symptom improvements, is an option as a salvage regimen for adult patients with recurrent ependymoma.

Tweaking EMT and MDR dynamics to constrain triple-negative breast cancer invasiveness by EGFR and Wnt/β-catenin signaling regulation.

Abstract: Due to a lack of effective targeted therapies, patients with metastatic triple-negative breast cancer (TNBC) have poor clinical outcomes. Epithelial to mesenchymal transition (EMT) is known to contribute to cancer progression, invasiveness and multidrug resistance (MDR). There is a strong correlation between various drug efflux mechanisms, cancer stem cells and tumor microenvironments, which in turn is synchronized by complex signaling crosstalk between EMT and MDR. We hypothesize that combining these regulatory connections with targeted combinatorial therapies may be an effective approach to annihilate the progression/metastasis of TNBC. AlamarBlue assays were used to depict TNBC cell viability, whereas flow cytometry was used to detect apoptotic cell populations, reactive-oxygen species (ROS) levels as well as mitochondrial depolarization. qRT-PCR, Western blotting and confocal microscopy were used to provide molecular-level information of the genes and proteins involved. Our initial analyses showed that targeting EGFR by either erlotinib (EGFR inhibitor) or lapatinib (EGFR/HER-2 inhibitor) alone was ineffective against TNBC. Interestingly, we subsequently found that a low dose of lapatinib did act as a substrate rather than as an inhibitor facilitating EMT and MDR, leading to metastasis. Additional gene expression studies indicated that co-targeting the EGFR and Wnt/β-catenin pathways with lapatinib and XAV939 (a tankyrase inhibitor) promoted mesenchymal to epithelial transition (MET). Application of these inhibitors led to a 5.62-fold increase in the epithelial marker E-cadherin and a 3.33-fold decrease in the stemness marker EpCAM, with concomitant 1.5-fold and 3.22-fold reductions in the ABC transporters ABCB1 and ABCG2, respectively. These co-targeting effects resulted in overcoming EMT and MDR, which in turn was highlighted by reduced levels of pEGFR, pAKT, pMAPK, pSTAT-3, pGSK-3β and β-catenin. Our data indicate that the synergistic action of targeting both the EGFR and Wnt/β-catenin signaling pathways in TNBC cells may open up new avenues for combatting this disease.

Targeting the PI3K and MAPK pathways to improve response to HER2-targeted therapies in HER2-positive gastric cancer.

Abstract: Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear. Using mass spectrometry-based genotyping we analysed 105 hotspot, non-synonymous somatic mutations in PIK3CA and ERBB-family (EGFR, ERBB2, ERBB3 and ERBB4) genes in gastric tumour samples from 69 patients. A panel of gastric cell lines (N87, OE19, ESO26, SNU16, KATOIII) were profiled for anti-proliferative response to the PI3K inhibitor copanlisib and the MEK1/2 inhibitor refametinib alone and in combination with anti-HER2 therapies. Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months). Mutations in PIK3CA were only identified in HER2-negative tumours, while ERBB-family mutations were identified in HER2-positive and HER2-negative tumours. Copanlisib had anti-proliferative effects in 4/5 cell lines, with IC50s ranging from 23.4 (N87) to 93.8 nM (SNU16). All HER2-positive cell lines except SNU16 were sensitive to lapatinib (IC50s 0.04 µM–1.5 µM). OE19 cells were resistant to trastuzumab. The combination of lapatinib and copanlisib was synergistic in ESO-26 and OE-19 cells (ED50: 0.83 ± 0.19 and 0.88 ± 0.13, respectively) and additive in NCI-N87 cells (ED50:1.01 ± 0.55). The combination of copanlisib and trastuzumab significantly improved growth inhibition compared to either therapy alone in NCI-N87, ESO26 and OE19 cells (p < 0.05). PI3K or MEK inhibition alone or in combination with anti-HER2 therapy may represent an improved treatment strategy for some patients with HER2-positive GC, and warrants further investigation in a clinical trial setting.

Radiotherapy and Receptor Tyrosine Kinase Inhibition for Solid Cancers (ROCKIT): A Meta-Analysis of 13 Studies.

Abstract: Background We hypothesized that the addition of receptor tyrosine kinase inhibitors (RTKis, e.g., lapatinib, erlotinib, cetuximab, bevacizumab, panitumumab) to radiotherapy-based treatment for solid tumors does not increase overall survival but may increase toxicity. Methods Population, Intervention, Control, Outcome, Study Design; Preferred Reporting Items for Systematic Reviews and Meta-Analyses; and Meta-analysis of Observational Studies in Epidemiology methods were used to identify prospective randomized studies including patients with solid tumor cancers treated with radiotherapy with or without RTKis. Extracted variables included use of radiotherapy vs chemoradiotherapy, RTKi type (antibody vs small molecule), outcomes, and toxicities. The primary endpoint was overall survival; the secondary endpoint was grade 3+ toxicity. Random-effects meta-analyses were performed for each outcome measure. All statistical tests were 2-sided. Results A total of 405 studies met the initial search criteria, of which 13 prospective randomized trials of radiotherapy with or without RTKi met the inclusion criteria, encompassing 5678 patients. The trials included cancers of the head and neck (6 trials, 3295 patients), esophagus (3 trials, 762 patients), lung (2 trials, 550 patients), and brain (2 trials, 1542 patients). Three studies evaluated a small molecule and radiotherapy in 949 patients, and 10 studies evaluated antibodies and radiotherapy in 4729 patients. The addition of RTKis to radiotherapy-based treatment did not improve overall survival (hazard ratio = 1.02, 95% confidence interval = 0.90 to 1.15, P = .76) but increased grade 3+ toxicity (relative risk = 1.18, 95% confidence interval = 1.06 to 1.33, P = .009). Conclusions The addition of RTKis to radiotherapy does not improve survival and worsens toxicity.

MicroRNA in combination with HER2-targeting drugs reduces breast cancer cell viability in vitro

Abstract: HER2-positive (HER2 +) breast cancer patients that do not respond to targeted treatment have a poor prognosis. The effects of targeted treatment on endogenous microRNA (miRNA) expression levels are unclear. We report that responsive HER2 + breast cancer cell lines had a higher number of miRNAs with altered expression after treatment with trastuzumab and lapatinib compared to poorly responsive cell lines. To evaluate whether miRNAs can sensitize HER2 + cells to treatment, we performed a high-throughput screen of 1626 miRNA mimics and inhibitors in combination with trastuzumab and lapatinib in HER2 + breast cancer cells. We identified eight miRNA mimics sensitizing cells to targeted treatment, miR-101-5p, mir-518a-5p, miR-19b-2-5p, miR-1237-3p, miR-29a-3p, miR-29c-3p, miR-106a-5p, and miR-744-3p. A higher expression of miR-101-5p predicted better prognosis in patients with HER2 + breast cancer (OS: p = 0.039; BCSS: p = 0.012), supporting the tumor-suppressing role of this miRNA. In conclusion, we have identified miRNAs that sensitize HER2 + breast cancer cells to targeted therapy. This indicates the potential of combining targeted drugs with miRNAs to improve current treatments for HER2 + breast cancers.

An update on the role of long non-coding RNAs in the pathogenesis of breast cancer.

Abstract: Breast cancer is the most frequent female malignancy This malignancy has diverse clinical and molecular subtypes with different prognoses Dysregulation of long non-coding RNAs (lncRNAs) not only participates in the development of breast cancer, but also affects the clinical course and prognosis of this type of cancer Hundreds of studies have shown up-regulation or down-regulation of lncRNAs in breast cancer samples or serum samples of affected individuals suggesting these RNA molecules as diagnostic markers for breast cancer Different anticancer agents such as trastuzumab, lapatinib, doxorubicin, hydroxyurea, docetaxel, 5-fluorouracil and 6-thioguanine affect expression profile of lncRNAs In the present article, we review the results of investigations about the role of lncRNAs in the evolution of breast cancer

A Novel Ferroptosis-Related Gene Signature Predicts Overall Survival of Breast Cancer Patients.

Abstract: Breast cancer is the second leading cause of death in women, thus a reliable prognostic model for overall survival (OS) in breast cancer is needed to improve treatment and care. Ferroptosis is an iron-dependent cell death. It is already known that siramesine and lapatinib could induce ferroptosis in breast cancer cells, and some ferroptosis-related genes were closely related with the outcomes of treatments regarding breast cancer. The relationship between these genes and the prognosis of OS remains unclear. The data of gene expression and related clinical information was downloaded from public databases. Based on the TCGA-BRCA cohort, an 8-gene prediction model was established with the least absolute shrinkage and selection operator (LASSO) cox regression, and this model was validated in patients from the METABRIC cohort. Based on the median risk score obtained from the 8-gene model, patients were stratified into high- or low-risk groups. Cox regression analyses identified that the risk score was an independent predictor for OS. The findings from CIBERSORT and ssGSEA presented noticeable differences in enrichment scores for immune cells and pathways between the abovementioned two risk groups. To sum up, this prediction model has potential to be widely applied in future clinical settings.

Effectiveness and safety of pyrotinib-based therapy in patients with HER2-positive metastatic breast cancer: A real-world retrospective study.

Abstract: The previous studies had demonstrated the promising effectiveness and acceptable safety of pyrotinib in patients with HER2-positive metastatic breast cancer. We aimed to investigate the real-world data of pyrotinib in complex clinical practice and complement the findings of clinical trials. Two hundred and eighteen patients were included for effectiveness analysis. A total of 62.0% had received two or more lines of systematic therapy, and 95.4% had been exposed to prior anti-HER2 therapy, with 95.4% receiving trastuzumab, 5.0% receiving pertuzumab, and 40.8% receiving lapatinib. The median progression-free survival (PFS) was 9.3 months and the objective response rate (ORR) was 44.0%. Patients treated with pyrotinib-based therapy as first, second, or later line had a median PFS of 15.0, 10.3, and 6.8 months, respectively. Patients treated with pyrotinib and trastuzumab received significant benefit in terms of median PFS compared with pyrotinib alone (10.7 (9.1-12.3) vs. 8.8 (8.1-9.5), p = 0.016). Patients pretreated with lapatinib had a median PFS of 6.9 months. The median PFS time was 7.0 months in patients with brain metastasis. Multivariate Cox regression analyses showed that lines of pyrotinib-based therapy (1 vs. 2 vs. ≥3), prior treatment with lapatinib, and combination treatments with trastuzumab proved to be independent predictors of PFS. Two hundred and forty-eight patients were included in the safety analysis, and the results showed that the toxicity of pyrotinib was tolerable, with the most common grade 3/4 adverse event being diarrhea (19.8%). Pyrotinib-based therapy demonstrated promising efficacy and tolerable toxicity in first-, second-, and later-line treatments and in lapatinib-treated patients. The combination of pyrotinib and trastuzumab showed advantages in PFS, even for patients resisting trastuzumab. Pyrotinib-based therapy could be the preferred choice for brain metastasis patients, especially when combined with brain radiotherapy.

Pyrotinib Combined With Vinorelbine in HER2-Positive Metastatic Breast Cancer: A Multicenter Retrospective Study.

Abstract: Introduction Pyrotinib plus capecitabine has been approved in China for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Meanwhile, vinorelbine is another important chemotherapy option for MBC available in oral and intravenous forms. Thus, pyrotinib plus vinorelbine may represent a new treatment option, particularly for patients with failed capecitabine treatment. This study reported the first real-world data for pyrotinib plus vinorelbine therapy in HER2+ MBC. Methods HER2+ MBC patients (n = 97) treated with pyrotinib plus vinorelbine in six institutions across China from May 2018 to June 2020 were enrolled. Progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and toxicity profiles were determined. Results Sixty-seven percent of patients received more than two lines of systematic therapy. Nearly all patients (97.9%) had received trastuzumab and 50.5% were administered lapatinib. When combined with pyrotinib, 74.2% received oral and 25.8% received intravenous vinorelbine. Median PFS (mPFS) was 7.8 (range, 4.7-10.8) months for all patients. The mPFS in patients administered pyrotinib as second-line therapy and third-or-higher-line therapy were 12.0 and 6.4 months, respectively. Patients who received pyrotinib plus oral or intravenous vinorelbine had similar mPFS (7.8 vs. 6.4 months, p = 0.871). The 23 patients with brain metastases had mPFS of 6.3 (range, 3.4-9.2) months. Lapatinib-naive patients had significantly longer PFS than lapatinib-treated patients (10.8 months vs. 5.6 months, p = 0.020). Median OS was not achieved. The ORR for 96 patients was 34.3%. Common grade 3 and 4 adverse events were diarrhea (22.7%), neutropenia (7.2%), and leukopenia (4.1%). Conclusions Pyrotinib plus vinorelbine therapy demonstrated promising effects in HER2+ MBC with tolerable toxicity, particularly in patients with second-line treatment and without prior lapatinib treatment, as well as in patients with brain metastases. Oral vinorelbine is a useful alternative to the intravenous form when combined with pyrotinib. Clinical trial registration [ClinicalTrials.gov], identifier [NCT04517305].

Circular RNA circ-MMP11 Contributes to Lapatinib Resistance of Breast Cancer Cells by Regulating the miR-153-3p/ANLN Axis.

Abstract: Background: Chemo-resistance is a major obstacle to the treatment of breast cancer. Circular RNA (circRNA) circ-MMP11 has been reported to be promoting the progression of breast cancer. This study is designed to explore the role and mechanism of circ-MMP11 in lapatinib resistance in breast cancer. Methods: Circ-MMP11, microRNA-153-3p (miR-153-3p), and Anillin (ANLN) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell viability, number of colonies, apoptosis, migration, and invasion were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), colony formation, flow cytometry, and transwell assays, respectively. Exosomes were exerted and detected by differential centrifugation and a transmission electron microscope. The protein levels of CD63, CD9, and ANLN were assessed by western blot assay. The binding relationship between miR-153-3p and circ-MMP11 or ANLN was predicted by circinteractome or starbase, and then verified by a dual-luciferase reporter assay and RNA pull-down assay. The biological role of circ-MMP11 on breast cancer tumor growth and drug resistance was detected by the xenograft tumor model in vivo. Results: Circ-MMP11 and ANLN were highly expressed, and miR-153-3p was decreased in LR breast cancer tissues and cells. Circ-MMP11 could be transported by exosomes. Furthermore, circ-MMP11 knockdown promoted lapatinib sensitivity by repressing cell viability, colony number, migration, invasion, and boosting apoptosis in LR breast cancer cells. And circ-MMP11 deficiency improved the drug sensitivity of breast cancer in vivo. Mechanically, circ-MMP11 could regulate ANLN expression through sponging miR-153-3p. Conclusion: Circ-MMP11 could be transferred by exosomes in breast cancer cells. And circ-MMP11 functioned as a sponge of miR-153-3p to regulate ANLN expression, thereby promoting lapatinib resistance in breast cancer cells, providing therapeutic targets for the treatment of breast cancer.

Quinazoline Derivatives as Potential Therapeutic Agents in Urinary Bladder Cancer Therapy.

Abstract: Cancer diseases remain major health problems in the world despite significant developments in diagnostic methods and medications. Many of the conventional therapies, however, have limitations due to multidrug resistance or severe side effects. Bladder cancer is a complex disorder, and can be classified according to its diverse genetic backgrounds and clinical features. A very promising direction in bladder cancer treatment is targeted therapy directed at specific molecular pathways. Derivatives of quinazolines constitute a large group of chemicals with a wide range of biological properties, and many quinazoline derivatives are approved for antitumor clinical use, e.g.,: erlotinib, gefitinib, afatinib, lapatinib, and vandetanib. The character of these depends mostly on the properties of the substituents and their presence and position on one of the cyclic compounds. Today, new quinazoline-based compounds are being designed and synthesized as potential drugs of anticancer potency against bladder cancers.

Biomarker Analysis of the Phase III NALA Study of Neratinib + Capecitabine versus Lapatinib + Capecitabine in Patients with Previously Treated Metastatic Breast Cancer.

Abstract: PURPOSE Neratinib plus capecitabine (N+C) demonstrated significant progression-free survival (PFS) benefit in NALA (NCT01808573), a randomized phase III trial comparing N+C with lapatinib + capecitabine (L+C) in 621 patients with HER2-positive (HER2+) metastatic breast cancer (MBC) who had received ≥2 prior HER2-directed regimens in the metastatic setting. We evaluated correlations between exploratory biomarkers and PFS. PATIENTS AND METHODS Somatic mutations were evaluated by next-generation sequencing on primary or metastatic samples. HER2 protein expression was evaluated by central IHC, H-score, and VeraTag/HERmark. p95 expression (truncated HER2) was measured by VeraTag. HRs were estimated using unstratified Cox proportional hazards models. RESULTS Four hundred and twenty samples had successful sequencing: 34.0% had PIK3CA mutations and 5.5% had HER2 (ERBB2) mutations. In the combined patient populations, PIK3CA mutations trended toward shorter PFS [wild-type vs. mutant, HR = 0.81; 95% confidence interval (CI), 0.64-1.03], whereas HER2 mutations trended toward longer PFS [HR = 1.69 (95% CI, 0.97-3.29)]. Higher HER2 protein expression was associated with longer PFS [IHC 3+ vs. 2+, HR = 0.67 (0.54-0.82); H-score ≥240 versus <240, HR = 0.77 (0.63-0.93); HERmark positive vs. negative, HR = 0.76 (0.59-0.98)]. Patients whose tumors had higher HER2 protein expression (any method) derived an increased benefit from N+C compared with L+C [IHC 3+, HR = 0.64 (0.51-0.81); H-score ≥ 240, HR = 0.54 (0.41-0.72); HERmark positive, HR = 0.65 (0.50-0.84)], as did patients with high p95 [p95 ≥2.8 relative fluorescence (RF)/mm2, HR = 0.66 (0.50-0.86) vs. p95 < 2.8 RF/mm2, HR = 0.91 (0.61-1.36)]. CONCLUSIONS PIK3CA mutations were associated with shorter PFS whereas higher HER2 expression was associated with longer PFS. Higher HER2 protein expression was also associated with a greater benefit for N+C compared with L+C.