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1.
Cancers (Basel) ; 13(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34638434

RESUMO

BRAF-activating mutations are the most frequent driver mutations in papillary thyroid cancer (PTC). Targeted inhibitors such as dabrafenib have been used in advanced BRAF-mutated PTC; however, acquired resistance to the drug is common and little is known about other effectors that may play integral roles in this resistance. In addition, the induction of PTC dedifferentiation into highly aggressive KRAS-driven anaplastic thyroid cancer (ATC) has been reported. We detected a novel RAC1 (P34R) mutation acquired during dabrafenib treatment in a progressive metastatic lesion with ATC phenotype. To identify a potential functional link between this novel mutation and tumor dedifferentiation, we developed a cell line derived from the metastatic lesion and compared its behavior to isogenic cell lines and primary tumor samples. Our data demonstrated that RAC1 mutations induce changes in cell morphology, reorganization of F-actin almost exclusively at the cell cortex, and changes in cell adhesion properties. We also established that RAC1 amplification, with or without mutation, is sufficient to drive cell proliferation and resistance to BRAF inhibition. Further, we identified polyploidy of chromosome 7, which harbors RAC1, in both the metastatic lesion and its derived cell line. Copy number amplification and overexpression of other genes located on this chromosome, such as TWIST1, EGFR, and MET were also detected, which might also lead to dabrafenib resistance. Our study suggests that polyploidy leading to increased expression of specific genes, particularly those located on chromosome 7, should be considered when analyzing aggressive thyroid tumor samples and in further treatments.

2.
Target Oncol ; 16(5): 569-589, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34559360

RESUMO

BACKGROUND: The checkpoint kinase 1 (CHK1) inhibitor prexasertib exhibited modest monotherapy antitumor activity in prior trials, suggesting that combination with chemotherapy or other targeted agents may be needed to maximize efficacy. OBJECTIVES: The aim of this study was to determine the recommended phase II dose and schedule of prexasertib in combination with either cisplatin, cetuximab, pemetrexed, or 5-fluorouracil in patients with advanced and/or metastatic cancer, and to summarize preliminary antitumor activity of these combinations. PATIENTS AND METHODS: This phase Ib, nonrandomized, open-label study comprised dose-escalation phase(s) with multiple sub-arms evaluating different prexasertib-drug combinations: Part A, prexasertib + cisplatin (n = 63); Part B, prexasertib + cetuximab (n = 41); Part C, prexasertib + pemetrexed (n = 3); Part D, prexasertib + 5-fluorouracil (n =8). Alternate dose schedules/regimens intended to mitigate toxicity and maximize dose exposure and efficacy were also explored in sub-parts. RESULTS: In Part A, the maximum tolerated dose (MTD) of prexasertib in combination with cisplatin (75 mg/m2) was declared at 80 mg/m2, with cisplatin administered on Day 1 and prexasertib on Day 2 of a 21-day cycle. The overall objective response rate (ORR) in Part A was 12.7%, and 28 of 55 evaluable patients (50.9%) had a decrease in target lesions from baseline. The most frequent treatment-related adverse events (AEs) in Part A were hematologic, with the most common being white blood cell count decreased/neutrophil count decreased, experienced by 73.0% (any grade) and 66.7% (grade 3 or higher) of patients. In Part B, an MTD of 70 mg/m2 was established for prexasertib administered in combination with cetuximab (500 mg /m2), both administered on Day 1 of a 14-day cycle. The overall ORR in Part B was 4.9%, and 7 of 31 evaluable patients (22.6%) had decreased target lesions compared with baseline. White blood cell count decreased/neutrophil count decreased was also the most common treatment-related AE (56.1% any grade; 53.7% grade 3 or higher). In Parts A and B, hematologic toxicities, even with the addition of prophylactic granulocyte colony-stimulating factor, resulted in frequent dose adjustments (> 60% of patients). In Part C, evaluation of prexasertib + pemetrexed was halted due to dose-limiting toxicities in two of the first three patients; MTD was not established. In Part D, the MTD of prexasertib in combination with 5-fluorouracil (label dose) was declared at 40 mg /m2, both administered on Day 1 of a 14-day cycle. In Part D, overall ORR was 12.5%. CONCLUSIONS: This study demonstrated the proof-of-concept that prexasertib can be combined with cisplatin, cetuximab, and 5-fluorouracil. Schedule was a key determinant of the tolerability and feasibility of combining prexasertib with these standard-of-care agents. Reversible hematologic toxicity was the most frequent AE and was dose-limiting. Insights gleaned from this study will inform future combination strategies for the development of prexasertib and next-generation CHK1 inhibitors. CLINICALTRIALS. GOV IDENTIFIER: NCT02124148 (date of registration 28 April 2014).

3.
Invest New Drugs ; 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34562230

RESUMO

BACKGROUND: Carboplatin and paclitaxel (CT) is one of the standard chemotherapy regimens used in various tumor types. Preclinical models have suggested that selinexor, a first-in-class oral potent selective inhibitor of nuclear export Exportin-1, and CT exerts antitumor activity in multiple malignancies. METHODS: This was a single-center, multi-arm phase Ib study utilizing a "basket type" expansion. CT and selinexor was employed as one of the 13 parallel arms. Advanced relapsed/refractory solid tumors following standard therapy or where the addition of selinexor to standard regimens deemed appropriate, were eligible. RESULTS: Of 13 patients treated, 12 patients were evaluable for response. The most common cancers were breast (n = 4), esophageal (n = 2), ovarian (n = 2) and non-small cell lung cancers (n = 2). All 13 patients had at least one treatment-related adverse events (TRAEs) and the most common were neutropenia (85%), leukopenia (85%), thrombocytopenia (85%), anemia (69%), nausea (54%), vomiting (46%), and fatigue (46%). One patient at 60 mg QW experienced DLT with grade 3 nausea and vomiting lasting 3 days. Unconfirmed partial response (uPR) was observed in 3 patients; one patient each with esophageal, breast, and ovarian cancer. One patient with esophageal adenocarcinoma had confirmed PR, however, was discontinued from the study due to clinical progression. Five patients achieved stable disease (SD). Disease control rate was 8%. Majority of patients (77%), including two patients who had uPR, had prior exposure to carboplatin and/or paclitaxel. Time-to-treatment failure (TTF) ranged from 1 to 153 weeks. CONCLUSION: The RP2D of selinexor was 60 mg QW in combination with CT. The combination conferred viable clinical activity with durable objective responses which should further be explored in tumor types for which CT is used as standard of care. Trial information. ClinicalTrials.gov Identifier: NCT02419495. Sponsor(s): Karyopharm Therapeutics. (Trial registration: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495 ).

4.
Cancer Discov ; 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34551969

RESUMO

Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, was evaluated in a large multihistology phase I dose-expansion trial that enrolled 197 patients with advanced solid tumors. Futibatinib demonstrated an objective response rate (ORR) of 13.7%, with responses in a broad spectrum of tumors (cholangiocarcinoma and gastric, urothelial, central nervous system, head and neck, and breast cancer) bearing both known and previously uncharacterized FGFR1-3 aberrations. The greatest activity was observed in FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma (ORR, 25.4%). Some patients with acquired resistance to a prior FGFR inhibitor also experienced responses with futibatinib. Futibatinib demonstrated a manageable safety profile. The most common treatment-emergent adverse events were hyperphosphatemia (81.2%), diarrhea (33.5%), and nausea (30.4%). These results formed the basis for ongoing futibatinib phase II/III trials and demonstrate the potential of genomically selected early-phase trials to help identify molecular subsets likely to benefit from targeted therapy.

5.
Cancer Res ; 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34518211

RESUMO

Oxidative phosphorylation (OXPHOS) is an active metabolic pathway in many cancers. RNA from pre-treatment biopsies from patients with triple negative breast cancer (TNBC) who received neoadjuvant chemotherapy demonstrated that the top canonical pathway associated with worse outcome was higher expression of an OXPHOS signature. In multiple TNBC patient-derived xenografts (PDXs), treatment with IACS-10759, a novel inhibitor of OXPHOS, stabilized tumor growth. Gene expression profiling revealed that all sensitive models displayed a basal-like 1 TNBC subtype, and expression of mitochondrial genes was significantly higher in sensitive PDXs. An in vivo functional genomics screen in tumors treated with IACS-10759 found several potential synthetic lethal targets, including CDK4. A combination of palbociclib, a CDK4/6 inhibitor, and IACS-10759 exhibited significant anti-tumor efficacy in vitro and in vivo. In addition, the combination of IACS-10759 and multi-kinase inhibitor cabozantinib had improved antitumor efficacy compared to either single agent. Taken together, these data suggest that OXPHOS is a metabolic vulnerability in TNBC that may be leveraged with novel therapeutics in combination regimens.

6.
Hepatology ; 2021 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-34510503

RESUMO

Cholangiocarcinoma is a deadly and highly therapy-refractory cancer of the bile ducts, with early results from immune checkpoint blockade trials showing limited responses. While recent molecular assessments have made bulk characterizations of immune profiles and their genomic correlates, spatial assessments may reveal novel actionable insights. Here, we have integrated immune checkpoint-directed immunohistochemistry with next-generation sequencing of resected intrahepatic cholangiocarcinoma (iCCA) samples from 96 patients. We find that both T-cell and immune checkpoint markers are enriched at the tumor margins compared to the tumor center. Using two approaches, we identify high PD-1 or LAG3 and low CD3/CD4/ICOS specifically in the tumor center as associated with poor survival. Moreover, loss-of-function BAP1 mutations are associated with and cause elevated expression of the immunosuppressive checkpoint marker B7H4. In conclusion, this study provides a foundation on which to rationally improve and tailor immunotherapy approaches for this difficult-to-treat disease.

7.
Invest New Drugs ; 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34559346

RESUMO

INTRODUCTION: Clinical observations of cancer patients treated with selinexor have reported high incidence of nausea and anorexia. The study objective was to investigate the adoption of prophylactic olanzapine for the prevention of nausea, vomiting and anorexia in cancer patients receiving selinexor and standard chemotherapy. METHODS: We retrospectively reviewed supportive care interventions in patients receiving selinexor and recorded frequency of adverse events (NCI-CTAE). Association between categorical variables were analyzed using Fisher's exact tests; repeated measures analysis was performed to assess weight changes over time. RESULTS: Of 124 evaluable patients, 83 (66.9%) were female, 93 were white (75.0%), and the most common cancer was ovarian (N = 30, 24.2%). One hundred and four patients (83.9%) received olanzapine, of which 93 (89.4%) were prophylactically treated, the majority (86.5%) receiving low 2.5 mg daily dose. Other anti-emetics included ondansetron in 90 patients (72.6%), dexamethasone prescribed in 50 patients (40.3%) and metoclopramide in 49 patients (39.5%), while aprepitant/fosaprepitant (N = 2, 1.6%) were prescribed infrequently. Cancer patients receiving prophylactic olanzapine (N = 93) compared to patients who never received olanzapine (N = 20) had more Grade 1 + anorexia (31.2% vs 20.0%), less nausea (53.8% vs 70.0%), less vomiting (33.3% vs 40.0%), and increased hyperglycemia (29.0% vs 10.0%), but differences were non-statistically significant. In addition, there was minimal weight loss over time in both groups and no statistically significant differences in weight loss between groups. CONCLUSION: Prophylactic olanzapine decreased nausea, vomiting and maintained weight over 3 months but did not prevent anorexia in patients receiving selinexor and chemotherapy. Low dose olanzapine was well tolerated but associated with hyperglycemia.

8.
Nat Commun ; 12(1): 5086, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34429404

RESUMO

Development of candidate cancer treatments is a resource-intensive process, with the research community continuing to investigate options beyond static genomic characterization. Toward this goal, we have established the genomic landscapes of 536 patient-derived xenograft (PDX) models across 25 cancer types, together with mutation, copy number, fusion, transcriptomic profiles, and NCI-MATCH arms. Compared with human tumors, PDXs typically have higher purity and fit to investigate dynamic driver events and molecular properties via multiple time points from same case PDXs. Here, we report on dynamic genomic landscapes and pharmacogenomic associations, including associations between activating oncogenic events and drugs, correlations between whole-genome duplications and subclone events, and the potential PDX models for NCI-MATCH trials. Lastly, we provide a web portal having comprehensive pan-cancer PDX genomic profiles and source code to facilitate identification of more druggable events and further insights into PDXs' recapitulation of human tumors.


Assuntos
Xenoenxertos , Neoplasias/genética , Neoplasias/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Genoma , Genômica , Humanos , Masculino , Camundongos , Modelos Biológicos , Mutação , Transcriptoma
9.
Lancet Oncol ; 22(9): 1290-1300, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34339623

RESUMO

BACKGROUND: Systemic therapies for metastatic biliary tract cancers are few, and patients have a median overall survival of less than 1 year. MyPathway evaluates the activity of US Food and Drug Administration-approved therapies in non-indicated tumours with potentially actionable molecular alterations. In this study, we present an analysis of patients with metastatic biliary tract cancers with HER2 amplification, overexpression, or both treated with a dual anti-HER2 regimen, pertuzumab plus trastuzumab, from MyPathway. METHODS: MyPathway is a non-randomised, multicentre, open-label, phase 2a, multiple basket study. Patients aged 18 years and older with previously treated metastatic biliary tract cancers with HER2 amplification, HER2 overexpression, or both and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled from 23 study sites in the USA and received intravenous pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) plus trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). The primary endpoint was investigator-assessed objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary outcome and adverse events were analysed in all patients who received at least one dose of pertuzumab and trastuzumab. This trial is registered with ClinicalTrials.gov, NCT02091141, and is ongoing. FINDINGS: 39 patients enrolled in the MyPathway HER2 biliary tract cancer cohort between Oct 28, 2014, and May 29, 2019, were evaluable for anti-tumour activity by the March 10, 2020, data cutoff date. Median follow-up was 8·1 months (IQR 2·7-15·7). Nine of 39 patients achieved a partial response (objective response rate 23% [95% CI 11-39]). Grade 3-4 treatment-emergent adverse events were reported in 18 (46%) of 39 patients, most commonly increased alanine aminotransferase and increased aspartate aminotransferase (each five [13%] of 39). Treatment-related grade 3 adverse events were reported in three (8%) of 39 patients, including increased alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, and blood bilirubin. Serious treatment-emergent adverse events were observed in ten (26%) of 39 patients, of which only abdominal pain occurred in more than one patient (two [5%] of 39). There were no treatment-related serious adverse events, treatment-related grade 4 events, or deaths. INTERPRETATION: Treatment was well tolerated in patients with previously treated HER2-positive metastatic biliary tract cancer. The response rate is promising for the initiation of randomised, controlled trials of pertuzumab plus trastuzumab in this patient population. FUNDING: F Hoffmann-La Roche-Genentech.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico , Idoso , Neoplasias do Sistema Biliar/metabolismo , Neoplasias do Sistema Biliar/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Intervalo Livre de Progressão , Receptor ErbB-2/antagonistas & inibidores , Critérios de Avaliação de Resposta em Tumores Sólidos , Taxa de Sobrevida , Estados Unidos
10.
Artigo em Inglês | MEDLINE | ID: mdl-34362693

RESUMO

INTRODUCTION: Enrolling patients with metastatic urothelial carcinoma (mUC) in phase I trials provides an opportunity to identify biological drug activity. Developing prognostic scores may aid in patient selection for phase 1 trials. PATIENTS AND METHODS: We analyzed records of patients with mUC who participated in targeted therapy and immunotherapy phase I clinical trials at MD Anderson Cancer Center (MDACC). The Bellmunt and Bajorin scores were calculated as bladder cancer-specific prognostic scores. The Royal Marsden Hospital (RMH) and MDACC scores were calculated as phase I prognostic scores. Hazard ratios (HR) were calculated using the Cox proportional hazard model. The prognostic value of the Bellmunt, Bajorin, RMH, and MDACC scores were assessed using the Likelihood ratio (LR) χ2 test and the c-index. RESULTS: Between 2015 and 2019, 43 patients were enrolled in phase I trials and 12 were enrolled in >I trial leading to a total of 57 trial participants (TPs). Ninty-seven percent of TPs received prior platinum therapy and 60% received a prior checkpoint inhibitor. Median overall survival (OS) and progression-free survival (PFS) were significantly shorter with increasing Bajorin, RMH, or MDACC scores, but not with increasing Bellmunt score. The RMH (c-index=0.658, LR χ2=11.8, P=.008) and MDACC scores (c-index =0.66, LR χ2=12.76, P=.01) outperformed the Bajorin score (c-index=0.522, LR χ2=1.22, P=.5) and the Bellmunt score (c-index=0.537, LR χ2=0.36, P=.9) in predicting overall survivalover. The Bajorin, RMH, and MDACC scores, but not the Bellmunt score, were also predictive of progression-free survival (PFS)prog. The RMH and MDACC scores again outperformed the Bajorin scoreand the Bellmunt score for predicting PFS. CONCLUSION: The RMH and MDACC phase I prognostic scores accurately predicted survival in patients with mUC and outperformed the bladder cancer-specific scores at time of enrollment on phase 1 clinical trials. The RMH and MDACC scores could optimize selection of patients with mUC for phase I clinical trials.

11.
Clin Cancer Res ; 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34301750

RESUMO

PURPOSE: We describe the first-in-human dose-escalation trial for ALRN-6924, a stabilized, cell-permeating peptide that disrupts p53 inhibition by MDM2 and MDMX to induce cell cycle arrest or apoptosis in TP53 wild-type tumors. METHODS: Two schedules were evaluated for safety, pharmacokinetics, pharmacodynamics, and anti-tumor effects in patients with solid tumors or lymphomas: In arm A, patients received ALRN-6924 by intravenous infusion once-weekly for 3 weeks every 28 days; arm B, was twice-weekly for 2 weeks every 21 days. RESULTS: Seventy-one patients were enrolled: 41 in arm A (0.16-4.4 mg/kg), 30 in arm B (0.32-2.7 mg/kg). ALRN-6924 showed dose-dependent pharmacokinetics and increased serum levels of MIC-1, a biomarker of p53 activation. The most frequent treatment-related adverse events were gastrointestinal side effects, fatigue, anemia, and headache. In arm A, at 4.4 mg/kg, dose-limiting toxicities (DLTs) were Grade 3 (G3) hypotension, G3 alkaline phosphatase elevation, G3 anemia, and G4 neutropenia in one patient each. At the maximum tolerated dose in arm A of 3.1 mg/kg, G3 fatigue was observed in one patient. No DLTs were observed in arm B. No G3/G4 thrombocytopenia was observed in any patient. Seven patients had infusion-related reactions; three discontinued treatment. In 41 efficacy-evaluable patients with TP53 wild-type disease across both schedules the disease control rate was 59%. Two patients had confirmed complete responses, two had confirmed partial responses, 20 had stable disease. Six patients were treated for >1 year. The recommended phase 2 dose was schedule A, 3.1 mg/kg. CONCLUSION: ALRN-6924 was well tolerated and demonstrated anti-tumor activity.

12.
Clin Cancer Res ; 27(18): 4994-5003, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34285061

RESUMO

PURPOSE: Glutamine is a critical fuel for solid tumors. Interference with glutamine metabolism is deleterious to neoplasia in preclinical models. A phase I study of the oral, first-in-class, glutaminase (GLS) inhibitor telaglenastat was conducted in treatment-refractory solid tumor patients to define recommended phase II dose (RP2D) and evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. PATIENTS AND METHODS: Dose escalation by 3 + 3 design was followed by exploratory tumor-/biomarker-specific cohorts. RESULTS: Among 120 patients, fatigue (23%) and nausea (19%) were the most common toxicity. Maximum tolerated dose was not reached. Correlative analysis indicated >90% GLS inhibition in platelets at plasma exposures >300 nmol/L, >75% tumoral GLS inhibition, and significant increase in circulating glutamine. RP2D was defined at 800 mg twice-daily. Disease control rate (DCR) was 43% across expansion cohorts (overall response rate 5%, DCR 50% in renal cell carcinoma). CONCLUSIONS: Telaglenastat is safe, with a favorable PK/PD profile and signal of antitumor activity, supporting further clinical development.

13.
Adv Ther ; 38(8): 4581-4591, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34241781

RESUMO

INTRODUCTION: Patients with advanced cutaneous squamous cell carcinoma (CSCC) have a poor prognosis. Blocking the PD-1-PD-L1 axis has shown promising activity in this patient population. We assessed the safety and antitumor activity of PD-1 inhibitor pembrolizumab in patients with refractory advanced CSCC. METHODS: This was a prespecified subgroup analysis of patients with advanced CSCC who enrolled in an open-label, phase II clinical trial for pembrolizumab in patients with refractory rare cancers during 2016-2018. Patients received pembrolizumab 200 mg intravenously every 21 days until progressive disease, unacceptable adverse event, or completion of 24 months of treatment. The primary endpoint was nonprogression rate (NPR) at 27 weeks; secondary endpoints included safety, objective response rate (ORR) per irRECIST, clinical benefit rate (CBR), progression-free survival, and overall survival. RESULTS: Twenty patients with refractory CSCC enrolled; 19 were evaluable for efficacy. Median follow-up time was 44.1 months. The NPR at 27 weeks was 37% (95% CI 0.16-0.62). Three patients had a complete response (CR), three had a partial response, and one had stable disease, for an ORR of 32% and a CBR of 37%; median duration of response was 27.3 months. All three patients with a CR remained free of recurrence at the time of writing. Severe treatment-related adverse events (grade ≥ 3) occurred in 10% of patients (2/20). PD-L1 expression was not correlated with response to pembrolizumab. CONCLUSION: A long-term follow-up confirms pembrolizumab's antitumor activity and safety profile in patients with refractory CSCC. Patients with a CR may experience cure. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02721732, Registered March 29, 2016.


Assuntos
Antineoplásicos Imunológicos , Carcinoma de Células Escamosas , Neoplasias Cutâneas , Anticorpos Monoclonais Humanizados , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma de Células Escamosas/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico
14.
Ann Surg Oncol ; 28(10): 5477-5485, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34247335

RESUMO

BACKGROUND: Neoadjuvant systemic therapy (NST) is standard for locally advanced breast cancer and is now frequently considered for those with early-stage and node-positive disease. We aimed to evaluate the treatment course and outcomes in patients with disease progression during NST. METHODS: Patients diagnosed with unilateral stage I-III breast cancer between 2005 and 2015 with documented local-regional progression while receiving NST, by clinical examination and/or imaging after two or more cycles of chemotherapy, were identified from a prospective database, stratified by receipt of surgery and outcomes analyzed. RESULTS: Of 6362 patients treated with NST during the study period, 124 (1.9%) developed disease progression. At a median live follow-up of 71 months, 23.4% were alive without disease and 70.2% had died from breast cancer. Median overall survival (OS) time for patients with progression was 26 months and median distant disease-free survival (DFS) was 14 months. Triple-negative breast cancer was associated with a higher likelihood of death (p < 0.001) and development of distant metastasis (p = 0.002). Among patients who had surgery (104, 89.3%), 40 (38.5%) developed local-regional recurrence, 67 (64.4%) developed distant metastasis, and 69 (66.3%) died from breast cancer. Median OS and median distant DFS in this subgroup was 31 and 16 months, respectively. CONCLUSIONS: High rates of local-regional and distant failure were seen following disease progression while receiving NST. This suggests aggressive tumor biology and the need to study novel systemic therapies. Poor survival outcomes despite surgical management highlight the importance of careful patient selection when considering operative intervention after progression while receiving NST.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Terapia Neoadjuvante , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia
15.
Oncogene ; 40(26): 4425-4439, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34108622

RESUMO

Molecular alterations in the PI3K/AKT pathway occur frequently in hormone receptor-positive breast tumors. Patients with ER-positive, HER2-negative metastatic breast cancer are often treated with CDK4/6 inhibitors such as palbociclib in combination with endocrine therapy. Although this is an effective regimen, most patients ultimately progress. The purpose of this study was identifying synthetic lethality partners that can enhance palbociclib's antitumor efficacy in the presence of PIK3CA/AKT1 mutations. We utilized a barcoded shRNA library to determine critical targets for survival in isogenic MCF7 cells with PIK3CA/AKT1 mutations. We demonstrated that the efficacy of palbociclib is reduced in the presence of PIK3CA/AKT1 mutations. We also identified that the downregulation of discoidin domain receptor 1 (DDR1) is synthetically lethal with palbociclib. DDR1 knockdown and DDR1 pharmacological inhibitor decreased cell growth and inhibited cell cycle progression in all cell lines, while enhanced the sensitivity of PIK3CA/AKT1 mutant cells to palbociclib. Combined treatment of palbociclib and 7rh further induced cell cycle arrest in PIK3CA/AKT1 mutant cell lines. In vivo, 7rh significantly enhanced palbociclib's antitumor efficacy. Our data indicates that DDR1 inhibition can augment cell cycle suppressive effect of palbociclib and could be effective strategy for targeted therapy of ER-positive, HER2-negative breast cancers with PI3K pathway activation.

16.
Onco Targets Ther ; 14: 3037-3049, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33994796

RESUMO

Background: Crizotinib inhibits ALK, MET and ROS1 tyrosine kinases but the development of resistance to monotherapy is an issue. The anti-angiogenic properties of pazopanib could overcome crizotinib drug resistance. Additionally, the anti-angiogenic properties of crizotinib could augment the clinical efficacy of pazopanib. Methods: We evaluated the safety and responses in patients with advanced solid tumors treated with crizotinib and pazopanib. Results: Eighty-two patients (median age 53 years, range 18-78 years) were enrolled. The median number of prior systemic therapies was 3 (range, 0-8). We were able to dose escalate to dose level 8 (crizotinib 250 mg twice daily and pazopanib 800 mg daily) with no MTD identified. Grade 3 or 4 toxicities were seen in 32% of patients with the highest prevalence being fatigue (n=9, 11%), diarrhea (n=6, 7%), vomiting (n=3, 4%), anemia (n=2, 2%) and ALT increased (n=2, 2%). Of the 82 patients, 61 (74%) had measurable disease by RECISTv1.1 and reached first restaging (6 weeks). Partial response (PR) was observed in 6/61 (10%) patients, and stable disease (SD) lasting ≥6 months was observed in 10/61 patients (16%) (total = 16/61 (26%) of patients with SD ≥6 months/PR). Conclusion: Dose level 6 (crizotinib 200 mg twice daily and pazopanib 600 mg daily) was the most tolerable dosing of the combination and can be used in future studies. We also observed moderate clinical activity in patients with advanced solid tumors that had received numerous prior therapies.

17.
Invest New Drugs ; 39(5): 1357-1365, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33909232

RESUMO

Background Selinexor, a first-in-class, oral selective inhibitor of nuclear export (SINE) compound inhibits Exportin-1(XPO1), had demonstrated synergistic activity with many chemotherapies and conferred in vivo antitumor efficacy in hematologic as well as solid tumors. Methods This open-label, single-center, multi-arm phase 1b study used a standard 3 + 3 design and a "basket type" expansion. Selinexor with intravenous topotecan was given in one of the 13 parallel arms. Patients with advanced or metastatic relapsed/refractory solid tumors following prior systemic therapy, or in whom the addition of selinexor to standard chemotherapy deemed appropriate, were eligible. Results Fourteen patients with the median age of 61 years (range, 22-68years) were treated, and the most common cancer types were gynecological cancers; ovarian (n = 5), endometrial (n = 2), and 1 each with fallopian tube and vaginal cancers. Of the 14 patients treated, 12 (86 %) had at least one treatment-related adverse event (TRAE). The most common TRAEs were anemia (71 %), thrombocytopenia (57 %), hyponatremia (57 %), vomiting (57 %), fatigue (50 %), nausea (50 %), and neutropenia (36 %). Two patients had dose limiting toxicities. One patient dosed at selinexor 80 mg had grade 3 nausea and vomiting and one patient dosed at selinexor 60 mg experienced grade 4 neutropenia and thrombocytopenia. Of the 13 efficacy evaluable patients, one (8 %) with endometrial cancer achieved unconfirmed partial response (uPR) and the time-to-treatment failure (TTF) was 48 weeks, whereas 6 of the 13 (46 %) patients had stable disease (SD) contributing to the clinical benefit rate of 46 %. The median TTF for all patients was 9 weeks (range, 2-48weeks). Conclusions Once weekly selinexor in combination with topotecan was viable and showed some preliminary tumor efficacy. The recommend phase 2 dose of selinexor was 60 mg once weekly in combination with IV topotecan.Trial registration: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495.

18.
NPJ Breast Cancer ; 7(1): 44, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863913

RESUMO

Five to ten percent of ER+ metastatic breast cancer (MBC) tumors harbor somatic PTEN mutations. Loss of function of this tumor-suppressor gene defines a highly aggressive, treatment-refractory disease for which new therapies are urgently needed. This Phase I multipart expansion study assessed oral capivasertib with fulvestrant in patients with PTEN-mutant ER+ MBC. Safety and tolerability were assessed by standard methods. Plasma and tumor were collected for NGS and immunohistochemistry analyses of PTEN protein expression. In 31 eligible patients (12 fulvestrant naive; 19 fulvestrant pretreated), the 24-week clinical benefit rate was 17% in fulvestrant-naive and 42% in fulvestrant-pretreated patients, with objective response rate of 8% and 21%, respectively. Non-functional PTEN was centrally confirmed in all cases by NGS or immunohistochemistry. Co-mutations occurred in PIK3CA (32%), with less ESR1 (10% vs 72%) and more TP53 (40% vs 28%) alterations in fulvestrant-naive versus fulvestrant-pretreated patients, respectively. PTEN was clonally dominant in most patients. Treatment-related grade ≥3 adverse events occurred in 32% of patients, most frequently diarrhea and maculopapular rash (both n = 2). In this clinical study, which selectively targeted the aggressive PTEN-mutant ER+ MBC, capivasertib plus fulvestrant was tolerable and clinically active. Phenotypic and genomic differences were apparent between fulvestrant-naive and -pretreated patients.Trial registration number for the study is NCT01226316.

19.
Artigo em Inglês | MEDLINE | ID: mdl-33928209

RESUMO

This trial assessed the utility of applying tumor DNA sequencing to treatment selection for patients with advanced, refractory cancer and somatic mutations in one of four signaling pathways by comparing the efficacy of four study regimens that were either matched to the patient's aberrant pathway (experimental arm) or not matched to that pathway (control arm). MATERIALS AND METHODS: Adult patients with an actionable mutation of interest were randomly assigned 2:1 to receive either (1) a study regimen identified to target the aberrant pathway found in their tumor (veliparib with temozolomide or adavosertib with carboplatin [DNA repair pathway], everolimus [PI3K pathway], or trametinib [RAS/RAF/MEK pathway]), or (2) one of the same four regimens, but chosen from among those not targeting that pathway. RESULTS: Among 49 patients treated in the experimental arm, the objective response rate was 2% (95% CI, 0% to 10.9%). One of 20 patients (5%) in the experimental trametinib cohort had a partial response. There were no responses in the other cohorts. Although patients and physicians were blinded to the sequencing and random assignment results, a higher pretreatment dropout rate was observed in the control arm (22%) compared with the experimental arm (6%; P = .038), suggesting that some patients may have had prior tumor mutation profiling performed that led to a lack of participation in the control arm. CONCLUSION: Further investigation, better annotation of predictive biomarkers, and the development of more effective agents are necessary to inform treatment decisions in an era of precision cancer medicine. Increasing prevalence of tumor mutation profiling and preference for targeted therapy make it difficult to use a randomized phase II design to evaluate targeted therapy efficacy in an advanced disease setting.

20.
Nature ; 592(7853): 302-308, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33762732

RESUMO

Our knowledge of copy number evolution during the expansion of primary breast tumours is limited1,2. Here, to investigate this process, we developed a single-cell, single-molecule DNA-sequencing method and performed copy number analysis of 16,178 single cells from 8 human triple-negative breast cancers and 4 cell lines. The results show that breast tumours and cell lines comprise a large milieu of subclones (7-22) that are organized into a few (3-5) major superclones. Evolutionary analysis suggests that after clonal TP53 mutations, multiple loss-of-heterozygosity events and genome doubling, there was a period of transient genomic instability followed by ongoing copy number evolution during the primary tumour expansion. By subcloning single daughter cells in culture, we show that tumour cells rediversify their genomes and do not retain isogenic properties. These data show that triple-negative breast cancers continue to evolve chromosome aberrations and maintain a reservoir of subclonal diversity during primary tumour growth.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células , Células Clonais/metabolismo , Células Clonais/patologia , Evolução Molecular , Sequência de Bases , Linhagem Celular Tumoral , Linhagem da Célula , Aberrações Cromossômicas , Variações do Número de Cópias de DNA/genética , Análise Mutacional de DNA , Instabilidade Genômica/genética , Humanos , Perda de Heterozigosidade/genética , Modelos Genéticos , Taxa de Mutação , Imagem Individual de Molécula , Análise de Célula Única , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
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