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1.
Clin Adv Hematol Oncol ; 18(3): 157-159, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32609664
2.
Clin Pharmacol Ther ; 2020 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-32562552

RESUMO

Microtubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genome-wide association studies (GWAS) from two clinical cohorts treated with MTAs (CALGB 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR1 ; e.g., rs74497159, ßCALGB 40101 per allele log hazard ratio (95% CI) = 0.591 (0.254 - 0.928), ßCALGB 40502 per allele log hazard ratio (95% CI) = 0.693 (0.334 - 1.053); PMETA = 3.62x10-7 ) were the most highly ranked associations based on P-values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in iPSC-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.

3.
Clin Cancer Res ; 2020 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-32586939

RESUMO

PURPOSE: We evaluated the prognostic and predictive value of circulating tumor cells (CTCs) hormone-receptor positive (HR+) metastatic breast cancer (MBC) patients randomized to letrozole (Let) alone or letrozole plus bevacizumab (Let+Bev) in the first-line setting (CALGB 40503). EXPERIMENTAL DESIGN: Blood samples were collected at pretreatment and three additional time points during therapy. The presence of ≥5 CTCs per 7.5 mLs of blood was considered CTC-positive. Association of CTCs with progression-free survival (PFS) and overall survival (OS) was assessed using Cox regression models. RESULTS: Of 343 patients treated, 294 had CTC data and were included in this analysis. Median follow-up was 39 months. In multivariable analysis, CTC-positive patients at baseline (31%) had significantly reduced PFS (HR=1.49; 95%CI: 1.12-1.97) and OS (HR=2.08; 95%CI: 1.49-2.93) compared to CTC-negative. Failure to clear CTCs during treatment was associated with significantly increased risk of progression (HR=2.2; 95%CI: 1.58-3.07) and death (HR=3.4; 95% CI: 2.36-4.88). CTC-positive patients who received only Let had the worse PFS (HR=2.3; 95% CI: 1.54-3.47) and OS (HR=2.6; 95% CI: 1.59-4.40). Median PFS in CTC-positive patients was significantly longer (18.0 versus 7.0 months) in Let+Bev versus Let arm (p=0.0009). Restricted mean survival time analysis further revealed that addition of Bev was associated with PFS benefit in both CTC-positive and CTC-negative patients, but OS benefit was only observed in CTC-positive patients. CONCLUSIONS: CTCs were highly prognostic for the addition of Bev to first-line Let in patients with HR+ MBC. Further research to determine the potential predictive value of CTCs in this setting is warranted.

4.
Clin Cancer Res ; 2020 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-32571790

RESUMO

The 2019 Accelerating Anticancer Agent Development (AAADV) Workshop assembled a panel of experts for an in-depth discussion session to present "Novel Therapeutic Interventions Early in the Disease Trajectory." The panel reviewed the limitations of evaluating investigational cancer therapeutics solely in advanced metastatic and relapsed/refractory disease settings, and recommended strategies for drug evaluation earlier in the disease course, including in the first line in combination with standard chemotherapy and in the maintenance and neoadjuvant disease settings. Advantages of earlier drug evaluation were discussed, including expanding the population of evaluable patients, earlier response assessment via surrogate endpoints, earlier clinical benefit in the disease course, tailoring of therapies based on response, and furthering our understanding of biomarker-driven therapies.

5.
Adv Ther ; 37(7): 3059-3082, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32445185

RESUMO

Epigenetic processes are essential for normal development and the maintenance of tissue-specific gene expression in mammals. Changes in gene expression and malignant cellular transformation can result from disruption of epigenetic mechanisms, and global disruption in the epigenetic landscape is a key feature of cancer. The study of epigenetics in cancer has revealed that human cancer cells harbor both genetic alterations and epigenetic abnormalities that interplay at all stages of cancer development. Unlike genetic mutations, epigenetic aberrations are potentially reversible through epigenetic therapy, providing a therapeutically relevant treatment option. Histone methyltransferase inhibitors are emerging as an epigenetic therapy approach with great promise in the field of clinical oncology. The recent accelerated approval of the enhancer of zeste homolog 2 (EZH2; also known as histone-lysine N-methyltransferase EZH2) inhibitor tazemetostat for metastatic or locally advanced epithelioid sarcoma marks the first approval of such a compound for the treatment of cancer. Many other histone methyltransferase inhibitors are currently in development, some of which are being tested in clinical studies. This review focuses on histone methyltransferase inhibitors, highlighting their potential in the treatment of cancer. We also discuss the role for such epigenetic drugs in overcoming epigenetically driven drug resistance mechanisms, and their value in combination with other therapeutic approaches such as immunotherapy.

6.
J Clin Oncol ; : JCO2000611, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32432946

RESUMO

PURPOSE: To provide evidence-based guidance on the clinical management of cancer cachexia in adult patients with advanced cancer. METHODS: A systematic review of the literature collected evidence regarding nutritional, pharmacologic, and other interventions, such as exercise, for cancer cachexia. PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) and systematic reviews of RCTs published from 1966 through October 17, 2019. ASCO convened an Expert Panel to review the evidence and formulate recommendations. RESULTS: The review included 20 systematic reviews and 13 additional RCTs. Dietary counseling, with or without oral nutritional supplements, was reported to increase body weight in some trials, but evidence remains limited. Pharmacologic interventions associated with improvements in appetite and/or body weight include progesterone analogs and corticosteroids. The other evaluated interventions either had no benefit or insufficient evidence of benefit to draw conclusions on efficacy. Limitations of the evidence include high drop-out rates, consistent with advanced cancer, as well as variability across studies in outcomes of interest and methods for outcome assessment. RECOMMENDATIONS: Dietary counseling may be offered with the goals of providing patients and caregivers with advice for the management of cachexia. Enteral feeding tubes and parenteral nutrition should not be used routinely. In the absence of more robust evidence, no specific pharmacological intervention can be recommended as the standard of care; therefore, clinicians may choose not to prescribe medications specifically for the treatment of cancer cachexia. Nonetheless, when it is decided to trial a drug to improve appetite and/or improve weight gain, currently available pharmacologic interventions that may be used include progesterone analogs and short-term (weeks) corticosteroids.

7.
Am Soc Clin Oncol Educ Book ; 40: e292-e308, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32453634

RESUMO

Recent advances in the understanding of underlying molecular signaling mechanisms of cancer susceptibility and progression have led to an increase in the use of targeted therapies for cancer treatment. Despite improvements in survival with new treatment options in oncology, resistance to therapy is a major obstacle to the long-term effectiveness of targeted agents in metastatic cancer treatment, culminating in insensitivity to treatment and tumor outgrowth. Adaptive resistance can play an important role in primary and upfront resistance to therapy as well as in secondary or acquired resistance. By focusing on colorectal and breast tumors, we discuss how therapeutic combinations based on specific drivers of tumor biology can be used to overcome resistance. We present how monitoring tumor dynamics over time may allow early adaptation of treatment. Breast cancer is the most common malignancy in women worldwide, and the majority of these cancers are sensitive to endocrine therapy (ET) blocking the production of or response to estrogen. However, primary and acquired resistance limits efficacy. Recent combinations of agents targeted to pathways that drive tumor growth resistance with ET have resulted in remarkable improvements in disease response and control, improving survival in some settings. In this review, we summarize adaptive resistance mechanisms, approaches to combination strategies, and dynamic tumor monitoring to improve efficacy and overcome resistance. We provide examples of combination therapy to enhance the efficacy of targeted therapies in breast and colorectal tumors.

8.
Breast Cancer Res Treat ; 181(3): 623-633, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32378051

RESUMO

PURPOSE: Capecitabine is important in breast cancer treatment but causes diarrhea and hand-foot syndrome (HFS), affecting adherence and quality of life. We sought to identify pharmacogenomic predictors of capecitabine toxicity using a novel monitoring tool. METHODS: Patients with metastatic breast cancer were prospectively treated with capecitabine (2000 mg/m2/day, 14 days on/7 off). Patients completed in-person toxicity questionnaires (day 1/cycle) and automated phone-in assessments (days 8, 15). Correlation of genotypes with early and overall toxicity was the primary endpoint. RESULTS: Two hundred and fifty-nine patients were enrolled (14 institutions). Diarrhea and HFS occurred in 52% (17% grade 3) and 69% (9% grade 3), respectively. Only 29% of patients completed four cycles without dose reduction/interruption. In 39%, the highest toxicity grade was captured via phone. Three single nucleotide polymorphisms (SNPs) associated with diarrhea-DPYD*5 (odds ratio [OR] 4.9; P = 0.0005), a MTHFR missense SNP (OR 3.3; P = 0.02), and a SNP upstream of MTRR (OR 3.0; P = 0.03). GWAS elucidated a novel HFS SNP (OR 3.0; P = 0.0007) near TNFSF4 (OX40L), a gene implicated in autoimmunity including autoimmune skin diseases never before implicated in HFS. Genotype-gene expression analyses of skin tissues identified rs11158568 (associated with HFS via GWAS) with expression of CHURC1, a transcriptional activator controlling fibroblast growth factor (beta = - 0.74; P = 1.46 × 10-23), representing a previously unidentified mechanism for HFS. CONCLUSIONS: This is the first cancer pharmacogenomic study to use phone-in self-reporting, permitting augmented toxicity characterization. Three germline toxicity SNPs were replicated, and several novel SNPs/genes having strong functional relevance were discovered. If further validated, these markers could permit personalized capecitabine dosing.

9.
Int J Cancer ; 2020 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-32359091

RESUMO

We present data from patients with advanced biliary tract cancer (BTC) receiving pembrolizumab in the KEYNOTE-158 (NCT02628067; phase 2) and KEYNOTE-028 (NCT02054806; phase 1b) studies. Eligible patients aged ≥18 years from both studies had histologically/cytologically confirmed incurable BTC that progressed after standard treatment regimen(s), measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status 0/1, and no prior immunotherapy. Programmed death ligand 1 (PD-L1)-positive tumors were required for eligibility in KEYNOTE-028 only. Patients received pembrolizumab 200 mg every three weeks (KEYNOTE-158) or 10 mg/kg every two weeks (KEYNOTE-028) for ≤2 years. Primary efficacy endpoint was objective response rate (ORR) by RECIST v1.1. Response assessed by independent central review is reported. KEYNOTE-158 enrolled 104 patients and KEYNOTE-028 enrolled 24 patients. Median (range) follow-up was 7.5 months (0.6-34.3) in KEYNOTE-158 and 5.7 months (0.6-55.4) in KEYNOTE-028. In KEYNOTE-158, ORR was 5.8% (6/104; 95% CI, 2.1%-12.1%); median duration of response (DOR) was not reached (NR) (range, 6.2-26.6+ months). Median (95% CI) OS and PFS were 7.4 (5.5-9.6) and 2.0 (1.9-2.1) months. Among PD-L1-expressers (n = 61) and PD-L1-nonexpressers (n = 34), respectively, ORR was 6.6% (4/61) and 2.9% (1/34). In KEYNOTE-028, ORR was 13.0% (3/23; 95% CI, 2.8%-33.6%); median DOR was NR (range, 21.5-53.2+ months). Median (95% CI) OS and PFS were 5.7 (3.1-9.8) and 1.8 (1.4-3.1) months. Grade 3 to 5 treatment-related adverse events occurred in 13.5% of patients in KEYNOTE-158 (no grade 4; grade 5 renal failure, n = 1) and 16.7% in KEYNOTE-028 (no grade 4/5). In summary, pembrolizumab provides durable antitumor activity in 6% to 13% of patients with advanced BTC, regardless of PD-L1 expression, and has manageable toxicity.

10.
J Natl Compr Canc Netw ; 18(4): 452-478, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32259783

RESUMO

Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.

11.
Future Oncol ; 16(12): 705-715, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32223649

RESUMO

Patients with HR+/HER2- metastatic breast cancer (MBC) whose cancers have progressed despite conventional therapies represent an unmet clinical need. Trop-2, a transmembrane calcium signal transducer, is highly expressed in MBC and plays a role in tumor growth and progression. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate comprising an Trop-2 antibody coupled to SN-38, the active metabolite of irinotecan, via a unique hydrolyzable linker. SG has demonstrated promising activity in a Phase I/II IMMU-132-01 basket study in heavily pretreated solid tumors, including HR+/HER2- MBC. We describe the registrational Phase III TROPiCS-02 study (NCT03901339), evaluating SG versus treatment of physician's choice in HR+/HER2- MBC. Trial registration number: NCT03901339.

12.
Technol Cancer Res Treat ; 19: 1533033819896331, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32129154

RESUMO

BACKGROUND: More than 30% of estrogen receptor-positive breast cancers are resistant to primary hormone therapy, and about 40% that initially respond to hormone therapy eventually acquire resistance. Although the mechanisms of hormone therapy resistance remain unclear, aberrant DNA methylation has been implicated in oncogenesis and drug resistance. PURPOSE: We investigated the relationship between methylome variations in circulating tumor DNA and exemestane resistance, to track hormone therapy efficacy. METHODS: We prospectively recruited 16 patients who were receiving first-line therapy in our center. All patients received exemestane-based hormone therapy after enrollment. We collected blood samples at baseline, first follow-up (after 2 therapeutic cycles) and at detection of disease progression. Disease that progressed within 6 months under exemestane treatment was considered exemestane resistance but was considered relatively exemestane-sensitive otherwise. We obtained circulating tumor DNA-derived methylomes using the whole-genome bisulfide sequencing method. Methylation calling was done by BISMARK software; differentially methylated regions for exemestane resistance were calculated afterward. RESULTS: Median follow-up for the 16 patients was 19.0 months. We found 7 exemestane resistance-related differentially methylated regions, located in different chromosomes, with both significantly different methylation density and methylation ratio. Baseline methylation density and methylation ratio of chromosome 6 [32400000-32599999] were both high in exemestane resistance. High baseline methylation ratios of chromosome 3 [67800000-67999999] (P = .013), chromosome 3 [140200000-140399999] (P = .037), and chromosome 12 [101200000-101399999] (P = .026) could also predict exemestane resistance. During exemestane treatment, synchronized changes in methylation density and methylation ratio in chromosome 6 [32400000-32599999] could accurately stratify patients in terms of progression-free survival (P = .000033). Cutoff values of methylation density and methylation ratio for chromosome 6 [149600000-149799999] were 0.066 and 0.076, respectively. CONCLUSION: Methylation change in chromosome 6 [149600000-149799999] is an ideal predictor of exemestane resistance with great clinical potential.

13.
Oncologist ; 25(3): e439-e450, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32162822

RESUMO

BACKGROUND: In the EMBRACA phase III study (NCT01945775), talazoparib was associated with a significantly prolonged progression-free survival (PFS) compared with physician's choice of chemotherapy (PCT) in germline BRCA1/2-mutated HER2-negative advanced breast cancer (ABC). Herein, the safety profile of talazoparib is explored in detail. MATERIALS AND METHODS: Overall, 412 patients received ≥1 dose of talazoparib (n = 286) or PCT (n = 126). Adverse events (AEs) were evaluated, including timing, duration, and potential overlap of selected AEs. The relationship between talazoparib plasma exposure and grade ≥3 anemia was analyzed. Time-varying Cox proportional hazard models assessed the impact of dose reductions on PFS. Patient-reported outcomes (PROs) in patients with common AEs and health resource utilization (HRU) were assessed in both treatment arms. RESULTS: The most common AEs with talazoparib were hematologic (195 [68.2%] patients) and typically occurred within the first 3-4 months of receiving talazoparib. Grade 3-4 anemia lasted approximately 7 days for both arms. Overlapping grade 3-4 hematologic AEs were infrequent with talazoparib. Higher talazoparib exposure was associated with grade ≥3 anemia. Permanent discontinuation of talazoparib due to hematologic AEs was low (<2%). A total of 150 (52.4%) patients receiving talazoparib had AEs associated with dose reduction. Hematologic toxicities were managed by supportive care medication (including transfusion) and dose modifications. Among patients with anemia or nausea and/or vomiting AEs, PROs favored talazoparib. After accounting for the treatment-emergent period, talazoparib was generally associated with a lower rate of hospitalization and supportive care medication use compared with chemotherapy. CONCLUSION: Talazoparib was associated with superior efficacy, favorable PROs, and lower HRU rate versus chemotherapy in gBRCA-mutated ABC. Toxicities were manageable with talazoparib dose modification and supportive care. IMPLICATIONS FOR PRACTICE: Talazoparib was generally well tolerated in patients with germline BRCA-mutated HER2-negative advanced breast cancer in the EMBRACA trial. Common toxicities with talazoparib were primarily hematologic and infrequently resulted in permanent drug discontinuation (<2% of patients discontinued talazoparib due to hematologic toxicity). Hematologic toxicities typically occurred during the first 3-4 months of treatment and were managed by dose modifications and supportive care measures. A significant efficacy benefit, improved patient-reported outcomes, lower rate of health resource utilization and a tolerable safety profile support incorporating talazoparib into routine management of germline BRCA-mutated locally advanced/metastatic breast cancer.

14.
Clin Breast Cancer ; 20(3): e251-e260, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32139271

RESUMO

Expression of human epidermal growth factor receptor 2 (HER2) in breast cancer defines a subset of patients (∼15%-20%) who are candidates for anti-HER2 therapies, most notably, trastuzumab, pertuzumab, antibody drug conjugates (eg, T-DM1), and tyrosine kinase inhibitor (TKI) drugs (eg, lapatinib and neratinib), all of which have dramatically changed the prognosis for this aggressive subtype of breast cancer. A roundtable meeting of the Breast Cancer Therapy Expert Group (BCTEG) was convened in March 2018 in an effort to discuss and clarify, from the perspective of the practicing community oncologist, recent developments in the diagnosis and treatment of HER2-positive (HER2+) breast cancer. Members of the group selected 4 key topics for discussion prior to the meeting, including diagnosis of HER2+ disease, and its treatment in the neoadjuvant, adjuvant, and metastatic settings. Approved testing methods, such as immunohistochemistry and fluorescence in situ hybridization, are used to demonstrate overexpression and/or amplification of HER2 in breast tumors, and established clinical guidelines are used to appropriately define treatment plans for patients with HER2+ disease. The panel acknowledges a range of treatment options now available for treatment of HER2+ breast cancer in the neoadjuvant, adjuvant, and advanced/metastatic settings, although it is noted that many controversies remain, including the optimal sequence of therapies, the most appropriate treatment(s) for subsets of patients with HER2+ disease (eg, hormone receptor-negative or -positive/HER2+), and uncertainties surrounding the diagnosis and definition of HER2+ disease. The current report summarizes the discussion of the BCTEG panel on this topic.

15.
Cell Rep ; 30(10): 3368-3382.e7, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32160543

RESUMO

Tumors that overexpress the MYC oncogene are frequently aneuploid, a state associated with highly aggressive cancers and tumor evolution. However, how MYC causes aneuploidy is not well understood. Here, we show that MYC overexpression induces mitotic spindle assembly defects and chromosomal instability (CIN) through effects on microtubule nucleation and organization. Attenuating MYC expression reverses mitotic defects, even in established tumor cell lines, indicating an ongoing role for MYC in CIN. MYC reprograms mitotic gene expression, and we identify TPX2 to be permissive for spindle assembly in MYC-high cells. TPX2 depletion blocks mitotic progression, induces cell death, and prevents tumor growth. Further elevating TPX2 expression reduces mitotic defects in MYC-high cells. MYC and TPX2 expression may be useful biomarkers to stratify patients for anti-mitotic therapies. Our studies implicate MYC as a regulator of mitosis and suggest that blocking MYC activity can attenuate the emergence of CIN and tumor evolution.

16.
Breast Cancer Res ; 22(1): 27, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164785

RESUMO

BACKGROUND: Palbociclib improves outcomes for women with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC). Dose reductions are recommended for the management of hematologic toxicities. A previous pooled analysis from the PALOMA clinical trials showed that 36.9% of patients required dose reduction, predominantly during the first 6 months of treatment and with decreasing frequency during subsequent 28-day treatment cycles (C). Previous data have shown that palbociclib dose reductions do not affect efficacy. This pooled, post hoc analysis evaluated the frequency of hematologic adverse events (AEs) before and after palbociclib dose reduction in PALOMA-1, PALOMA-2, and PALOMA-3. METHODS: This analysis evaluated the frequency of hematologic AEs 30 days before dose reduction and during each subsequent treatment from C1 to C6 among patients who required palbociclib dose reduction. Data were pooled from 3 randomized studies. PALOMA-1 was a phase 2, open-label study of postmenopausal patients untreated for ABC receiving palbociclib plus letrozole or letrozole alone. PALOMA-2 was a phase 3, double-blind study of postmenopausal patients untreated for ABC receiving palbociclib plus letrozole or placebo plus letrozole. PALOMA-3 was a phase 3, double-blind study of pre/perimenopausal or postmenopausal patients, whose disease progressed on prior endocrine therapy, receiving palbociclib plus fulvestrant or placebo plus fulvestrant. RESULTS: A total of 311 (35.5%) patients with HR+/HER2- ABC required a palbociclib dose reduction (93.6% due to AEs) from 125 to 100 mg. Mean patient age was 59.9 years, and 46.9% of patients had visceral disease. Median time to dose reduction was 70 days. The majority of dose reductions occurred within 3 months of starting palbociclib treatment. Incidences of all-grade and grades 3/4 hematologic AEs were lower following dose reduction. CONCLUSIONS: A decrease in frequency and severity of hematologic AEs, including febrile neutropenia, following palbociclib dose reduction was observed, supporting the recommended use of dose reduction in AE management. TRIAL REGISTRATION: These studies were sponsored by Pfizer. ClinicalTrials.gov: NCT00721409; registration date July 24, 2008. ClinicalTrials.gov: NCT01740427; registration date December 4, 2012. ClinicalTrials.gov: NCT01942135; registration date September 13, 2013.

17.
Breast Cancer Res ; 22(1): 22, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32070401

RESUMO

BACKGROUND: In preclinical studies, the expression of vascular endothelial growth factor (VEGF) in hormone receptor-positive breast cancer is associated with estrogen-independent tumor growth and resistance to endocrine therapies. This study investigated whether the addition of bevacizumab, a monoclonal antibody against VEGF, to letrozole enhanced the antitumor activity of the letrozole in the preoperative setting. METHODS: Postmenopausal women with newly diagnosed stage 2 or 3 estrogen and/or progesterone receptor-positive, HER2-negative breast cancer were randomly assigned (2:1) between letrozole 2.5 mg PO daily plus bevacizumab 15 mg/kg IV every 3 weeks (Let/Bev) and letrozole 2.5 mg PO daily (Let) for 24 weeks prior to definitive surgery. Primary objective was within-arm pathologic complete remission (pCR) rate. Secondary objectives were safety, objective response, and downstaging rate. RESULTS: Seventy-five patients were randomized (Let/Bev n = 50, Let n = 25). Of the 45 patients evaluable for pathological response in the Let/Bev arm, 5 (11%; 95% CI, 3.7-24.1%) achieved pCR and 4 (9%; 95% CI, 2.5-21.2%) had microscopic residual disease; no pCRs or microscopic residual disease was seen in the Let arm (0%; 95% CI, 0-14.2%). The rates of downstaging were 44.4% (95% CI, 29.6-60.0%) and 37.5% (95% CI, 18.8-59.4%) in the Let/Bev and Let arms, respectively. Adverse events typically associated with letrozole (hot flashes, arthralgias, fatigue, myalgias) occurred in similar frequencies in the two arms. Hypertension, headache, and proteinuria were seen exclusively in the Let/Bev arm. The rates of grade 3 and 4 adverse events and discontinuation due to adverse events were 18% vs 8% and 16% vs none in the Let/Bev and Let arms, respectively. A small RNA-based classifier predictive of response to preoperative Let/Bev was developed and confirmed on an independent cohort. CONCLUSION: In the preoperative setting, the addition of bevacizumab to letrozole was associated with a pCR rate of 11%; no pCR was seen with letrozole alone. There was additive toxicity with the incorporation of bevacizumab. Responses to Let/Bev can be predicted from the levels of 5 small RNAs in a pretreatment biopsy. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov (Identifier: NCT00161291), first posted on September 12, 2005, and is completed.

18.
Oncologist ; 25(2): e214-e222, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32043771

RESUMO

BACKGROUND: Limited data exist describing real-world treatment of de novo and recurrent HER2-positive metastatic breast cancer (MBC). MATERIALS AND METHODS: The Systemic Therapies for HER2-Positive Metastatic Breast Cancer Study (SystHERs) was a fully enrolled (2012-2016), observational, prospective registry of patients with HER2-positive MBC. Patients aged ≥18 years and ≤6 months from HER2-positive MBC diagnosis were treated and assessed per their physician's standard practice. The primary endpoint was to characterize treatment patterns by de novo versus recurrent MBC status, compared descriptively. Secondary endpoints included patient characteristics, progression-free and overall survival (PFS and OS, by Kaplan-Meier method; hazard ratio [HR] and 95% confidence interval [CI] by Cox regression), and patient-reported outcomes. RESULTS: Among 977 eligible patients, 49.8% (n = 487) had de novo and 50.2% (n = 490) had recurrent disease. A higher proportion of de novo patients had hormone receptor-negative disease (34.9% vs. 24.9%), bone metastasis (57.1% vs. 45.9%), and/or liver metastasis (41.9% vs. 33.1%), and a lower proportion had central nervous system metastasis (4.3% vs. 13.5%). De novo patients received first-line regimens containing chemotherapy (89.7%), trastuzumab (95.7%), and pertuzumab (77.8%) more commonly than recurrent patients (80.0%, 85.9%, and 68.6%, respectively). De novo patients had longer median PFS (17.7 vs. 11.9 months; HR, 0.69; 95% CI, 0.59-0.80; p < .0001) and OS (not estimable vs. 44.5 months; HR, 0.55; 95% CI, 0.44-0.69; p < .0001). CONCLUSION: Patients with de novo versus recurrent HER2-positive MBC exhibit different disease characteristics and survival durations, suggesting these groups have distinct outcomes. These differences may affect future clinical trial design. Clinical trial identification number. NCT01615068 (clinicaltrials.gov). IMPLICATIONS FOR PRACTICE: SystHERs was an observational registry of patients with HER2-positive metastatic breast cancer (MBC), which is a large, modern, real-world data set for this population and, thereby, provides a unique opportunity to study patients with de novo and recurrent HER2-positive MBC. In SystHERs, patients with de novo disease had different baseline demographics and disease characteristics, had superior clinical outcomes, and more commonly received first-line chemotherapy and/or trastuzumab versus those with recurrent disease. Data from this and other studies suggest that de novo and recurrent MBC have distinct outcomes, which may have implications for disease management strategies and future clinical study design.

19.
Clin Breast Cancer ; 20(3): 183-193, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32014370

RESUMO

In addition to classical clinicopathologic factors, such as hormone receptor positivity, human epidermal growth factor receptor 2 (HER2) status, and tumor size, grade, and lymph node status, a number of commercially available genomic tests may be used to help inform treatment decisions for early breast cancer patients. Although these tests improve our understanding of breast cancer and help to individualize treatment decisions, clinicians face challenges when deciding on the most appropriate test to order, and the advantages, if any, of one test over another. The Breast Cancer Therapy Expert Group (BCTEG) recently convened a roundtable meeting to discuss issues surrounding the use of genomic testing in early breast cancer, with the goal of providing practical guidance on the use of these tests by the community oncologist, for whom breast cancer may be only one of many tumor types they treat. The group recognizes that genomic testing can provide important prognostic (eg, risk for recurrence), and in some cases predictive, information (eg, benefit of chemotherapy, or extended adjuvant endocrine therapy), which can be used to help guide treatment decisions in breast cancer. The available tests differ in the types of information they provide, and in the patient populations and clinical trials that were conducted to validate them. We summarize the discussion of the BCTEG on this topic, and we also consider several patient cases and clinical scenarios in which genomic testing may, or may not, be useful to guide treatment decisions for the practicing community oncologist.

20.
J Clin Oncol ; 38(10): 1059-1069, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32031889

RESUMO

PURPOSE: The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer. PATIENTS AND METHODS: I-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week. RESULTS: MK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform). CONCLUSION: The Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.

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