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1.
Clin Cancer Res ; 29(15): 2781-2790, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37261814

RESUMO

PURPOSE: GDC-0927 is a novel, potent, nonsteroidal, orally bioavailable, selective estrogen receptor (ER) degrader that induces tumor regression in ER+ breast cancer xenograft models. PATIENTS AND METHODS: This phase I dose-escalation multicenter study enrolled postmenopausal women with ER+/HER2- metastatic breast cancer to determine the safety, pharmacokinetics, and recommended phase II dose of GDC-0927. Pharmacodynamics was assessed with [18F]-fluoroestradiol (FES) PET scans. RESULTS: Forty-two patients received GDC-0927 once daily. The MTD was not reached. The most common adverse events (AE) regardless of causality were nausea, constipation, diarrhea, arthralgia, fatigue, hot flush, back pain, and vomiting. There were no deaths, grade 4/5 AEs, or treatment-related serious AEs. Two patients experienced grade 2 AEs of special interest of deep vein thrombosis and jugular vein thrombosis, both considered unrelated to GDC-0927. Following dosing, approximately 1.6-fold accumulation was observed, consistent with the observed half-life and dosing frequency. There were no complete or partial responses. Pharmacodynamics was supported by >90% reduction in FES uptake and an approximately 40% reduction in ER expression, suggesting ER degradation is not the mechanistic driver of ER antagonism. Twelve patients (29%) achieved clinical benefit; 17 patients (41%) showed a confirmed best overall response of stable disease. Baseline levels of ER and progesterone receptor protein and mutant ESR1 circulating tumor DNA did not correlate with clinical benefit. CONCLUSIONS: GDC-0927 appeared to be well tolerated with pharmacokinetics supporting once-daily dosing. There was evidence of target engagement and preliminary evidence of antitumor activity in heavily pretreated patients with advanced/metastatic ER+/HER2- breast cancer with and without ESR1 mutations.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptores de Estrogênio/genética , Pós-Menopausa , Antagonistas do Receptor de Estrogênio , Tomografia por Emissão de Pósitrons
2.
Int J Cancer ; 150(2): 279-289, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34528705

RESUMO

Germline variants might predict cancer progression. Bevacizumab improves overall survival (OS) in patients with advanced cancers. No biomarkers are available to identify patients that benefit from bevacizumab. A meta-analysis of genome-wide association studies (GWAS) was conducted in 1,520 patients from Phase III trials (CALGB 80303, 40503, 80405 and ICON7), where bevacizumab was randomized to treatment without bevacizumab. We aimed to identify genes and single nucleotide polymorphisms (SNPs) associated with survival independently of bevacizumab treatment or through interaction with bevacizumab. A cause-specific Cox model was used to test the SNP-OS association in both arms combined (prognostic), and the effect of SNPs-bevacizumab interaction on OS (predictive) in each study. The SNP effects across studies were combined using inverse variance. Findings were tested for replication in advanced colorectal and ovarian cancer patients from The Cancer Genome Atlas (TGCA). In the GWAS meta-analysis, patients with rs680949 in PRUNE2 experienced shorter OS compared to patients without it (P = 1.02 × 10-7 , hazard ratio [HR] = 1.57, 95% confidence interval [CI] 1.33-1.86), as well as in TCGA (P = .0219, HR = 1.58, 95% CI 1.07-2.35). In the GWAS meta-analysis, patients with rs16852804 in BARD1 experienced shorter OS compared to patients without it (P = 1.40 × 10-5 , HR = 1.51, 95% CI 1.25-1.82) as well as in TCGA (P = 1.39 × 10-4 , HR = 3.09, 95% CI 1.73-5.51). Patients with rs3795897 in AGAP1 experienced shorter OS in the bevacizumab arm compared to the nonbevacizumab arm (P = 1.43 × 10-5 ). The largest GWAS meta-analysis of bevacizumab treated patients identified PRUNE2 and BARD1 (tumor suppressor genes) as prognostic genes of colorectal and ovarian cancer, respectively, and AGAP1 as a potentially predictive gene that interacts with bevacizumab with respect to patient survival.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Estudo de Associação Genômica Ampla , Neoplasias/tratamento farmacológico , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Cetuximab/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/patologia , Paclitaxel/administração & dosagem , Prognóstico , Taxa de Sobrevida
3.
Breast Cancer Res Treat ; 189(1): 15-23, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34218359

RESUMO

PURPOSE: Endocrine therapy (ET) is an effective strategy to treat hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) but nearly all patients eventually progress. Our goal was to develop and validate a web-based clinical calculator for predicting disease outcomes in women with HR+ABC who are candidates for receiving first-line single-agent ET. METHODS: The meta-database comprises 891 patient-level data from the control arms of five contemporary clinical trials where patients received first-line single-agent ET (either aromatase inhibitor or fulvestrant) for ABC. Risk models were constructed for predicting 24-months progression-free survival (PFS-24) and 24-months overall survival (OS-24). Final models were internally validated for calibration and discrimination using ten-fold cross-validation. RESULTS: Higher number of sites of metastases, measurable disease, younger age, lower body mass index, negative PR status, and prior endocrine therapy were associated with worse PFS. Final PFS and OS models were well-calibrated and associated with cross-validated time-dependent area under the curve (AUC) of 0.61 and 0.62, respectively. CONCLUSIONS: The proposed ABC calculator is internally valid and can accurately predict disease outcomes. It may be used to predict patient prognosis, aid planning of first-line treatment strategies, and facilitate risk stratification for future clinical trials in patients with HR+ABC. Future validation of the proposed models in independent patient cohorts is warranted.


Assuntos
Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/tratamento farmacológico , Feminino , Fulvestranto/uso terapêutico , Humanos , Receptor ErbB-2 , Receptores de Estrogênio
4.
Breast Cancer Res Treat ; 185(1): 165-173, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32930927

RESUMO

PURPOSE: To determine the longitudinal impact of adjuvant chemotherapy and tamoxifen-only treatments on the reproductive potential of women with breast cancer by using a sensitive ovarian reserve marker anti-Mullerian hormone (AMH) as a surrogate. METHODS: One-hundred-and-forty-two women with a primary diagnosis of breast cancer were prospectively followed with serum AMH assessments before the initiation, and 12, 18 and 24 months after the completion of adjuvant chemotherapy or the start of tamoxifen-only treatment. The chemotherapy regimens were classified into Anthracycline-Cyclophosphamide-based (AC-based) and Cyclophosphamide-Methotrexate + 5-Fluorouracil (CMF). Longitudinal data were analyzed by mixed effects model for treatment effects over time, adjusting for baseline age and BMI. RESULTS: Both chemotherapy regimens resulted in significant decline in ovarian reserve compared to the tamoxifen-only treatment (p < 0.0001 either regimen vs. tamoxifen for overall trend). AMH levels sharply declined at 12 months but did not show a significant recovery from 12 to 18 and 18 to 24 months after the completion of AC-based or CMF regimens. The degree of decline did not differ between the two chemotherapy groups (p = 0.53). In contrast, tamoxifen-only treatment did not significantly alter the age-adjusted serum AMH levels over the 24-month follow up. Likewise, the use of adjuvant tamoxifen following AC-based regimens did not affect AMH recovery. CONCLUSIONS: Both AC-based regimens and CMF significantly compromise ovarian reserve, without a recovery beyond 12 months post-chemotherapy. In contrast, tamoxifen-only treatment does not seem to alter ovarian reserve. These data indicate that the commonly used chemotherapy regimens but not the hormonal therapy compromise future reproductive potential.


Assuntos
Neoplasias da Mama , Reserva Ovariana , Hormônio Antimülleriano , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Feminino , Humanos , Tamoxifeno/efeitos adversos
5.
Support Care Cancer ; 29(1): 311-322, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32358778

RESUMO

PURPOSE: To assess the feasibility and efficacy of a non-hormonal hyaluronic acid (HLA) vaginal gel in improving vulvovaginal estrogen-deprivation symptoms in postmenopausal women with a history of hormone receptor-positive (HR+) cancer. METHODS: For this single-arm, prospective longitudinal trial, we identified disease-free patients with a history of HR+ breast cancer treated with aromatase inhibitors or HR+ endometrial cancer treated with surgery and postoperative radiation. Participants used HLA daily for the first 2 weeks, and then 3×/week until weeks 12-14; dosage was then increased to 5×/week for non-responders. Vulvovaginal symptoms and pH were assessed at 4 time points (baseline [T1], 4-6 weeks [T2], 12-14 weeks [T3], 22-24 weeks [T4]) with clinical evaluation, the Vaginal Assessment Scale (VAS), Vulvar Assessment Scale (VuAS), Female Sexual Function Index (FSFI), and Menopausal Symptom Checklist (MSCL). RESULTS: Of 101 patients, mean age was 55 years (range, 31-78), 68% (n = 69) were partnered, and 60% (n = 61) were sexually active. In linear mixed models, VAS/VuAS scores significantly improved at all assessment points (all p < 0.001). MSCL scores similarly improved (all p < 0.001). FSFI scores significantly improved from T1 to T2 (p < 0.03), T3 (p < 0.001), and T4 (p < 0.001). Severe vaginal pH (> 6.5) decreased from 26% at T1 to 19% at T4 (p = 0.18). CONCLUSIONS: HLA moisturization improved vulvovaginal health/sexual function of cancer survivors. While HLA administration 1-2×/week is recommended for women in natural menopause, a 3-5×/week schedule appears to be more effective for symptom relief in cancer survivors.


Assuntos
Inibidores da Aromatase/uso terapêutico , Sobreviventes de Câncer , Ácido Hialurônico/uso terapêutico , Vagina/patologia , Doenças Vaginais/tratamento farmacológico , Vulva/patologia , Adulto , Idoso , Atrofia , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/terapia , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Pós-Menopausa/fisiologia , Estudos Prospectivos , Cremes, Espumas e Géis Vaginais/uso terapêutico
6.
Nat Cancer ; 1(4): 382-393, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32864625

RESUMO

Alpelisib is a selective inhibitor of PI3Kα, shown to improve outcomes for PIK3CA mutant, hormone receptor positive (HR+) metastatic breast cancers (MBC) when combined with antiestrogen therapy. To uncover mechanisms of resistance, we conducted a detailed, longitudinal analysis of tumor and plasma circulating tumor DNA among such patients from a phase I/II trial combining alpelisib with an aromatase inhibitor (AI) (NCT01870505). The trial's primary objective was to establish safety with maculopapular rash emerging as the most common grade 3 adverse event (33%). Among 44 evaluable patients, the observed clinical benefit rate was 52%. Correlating genetic alterations with outcome, we identified loss-of-function PTEN mutations in 25% of patients with resistance. ESR1 activating mutations also expanded in number and allele fraction during treatment and were associated with resistance. These data indicate that genomic alterations that mediate resistance to alpelisib or antiestrogen may promote disease progression and highlight PTEN loss as a recurrent mechanism of resistance to PI3Kα inhibition.


Assuntos
Inibidores da Aromatase , Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/farmacologia , Neoplasias da Mama/tratamento farmacológico , Moduladores de Receptor Estrogênico/uso terapêutico , Feminino , Humanos , PTEN Fosfo-Hidrolase/genética , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Tiazóis
7.
Breast Cancer Res Treat ; 184(1): 161-172, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32789591

RESUMO

PURPOSE: In MONARCH 1 (NCT02102490), single-agent abemaciclib demonstrated promising efficacy activity and tolerability in a population of heavily pretreated women with refractory HR+, HER2- metastatic breast cancer (MBC). To help interpret these results and put in clinical context, we compared overall survival (OS) and duration of therapy (DoT) between MONARCH 1 and a real-world single-agent chemotherapy cohort. METHODS: The real-world chemotherapy cohort was created from a Flatiron Health electronic health records-derived database based on key eligibility criteria from MONARCH 1. The chemotherapies included in the cohort were single-agent capecitabine, gemcitabine, eribulin, or vinorelbine. Results were adjusted for baseline demographics and clinical differences using Mahalanobis distance matching (primary analysis) and entropy balancing (sensitivity analysis). OS and DoT were analyzed using the Kaplan-Meier method and Cox proportional hazards regression. RESULTS: A real-world single-agent chemotherapy cohort (n = 281) with eligibility criteria similar to the MONARCH 1 population (n = 132) was identified. The MONARCH 1 (n = 108) cohort was matched to the real-world chemotherapy cohort (n = 108). Median OS was 22.3 months in the abemaciclib arm versus 13.6 months in the matched real-world chemotherapy cohort with an estimated hazard ratio (HR) of 0.54. The median DoT was 4.1 months in MONARCH 1 compared to 2.9 months in the real-world chemotherapy cohort with HR of 0.76. CONCLUSIONS: This study demonstrates an approach to create a real-world chemotherapy cohort suitable to serve as a comparator for trial data. These exploratory results suggest a survival advantage and place the benefit of abemaciclib monotherapy in clinical context.


Assuntos
Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Capecitabina/uso terapêutico , Feminino , Humanos , Modelos de Riscos Proporcionais , Receptor ErbB-2 , Vinorelbina/uso terapêutico
8.
Fertil Steril ; 113(6): 1251-1260.e1, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32331767

RESUMO

OBJECTIVE: To assess whether woman who have BRCA mutations (WBM) experience more declines in ovarian reserve after chemotherapy treatment, as it induces oocyte death by deoxyribonucleic acid (DNA) damage, and BRCA mutations result in DNA damage repair deficiency. DESIGN: Longitudinal cohort study. SETTING: Academic centers. PATIENT(S): The 108 evaluable women with breast cancer were stratified into those never tested (negative family history; n = 35) and those negative (n = 59) or positive (n = 14) for a pathogenic BRCA mutation. INTERVENTION(S): Sera were longitudinally obtained before and 12-24 months after chemotherapy treatment, assayed for antimüllerian hormone (AMH), and adjusted for age at sample collection. MAIN OUTCOME MEASURE(S): Ovarian recovery, defined as the geometric mean of the after chemotherapy age-adjusted AMH levels compared with baseline levels. RESULT(S): Compared with the controls, the before chemotherapy treatment AMH levels were 24% and 34% lower in those negative or positive for BRCA mutations, consistent with accelerated ovarian aging in WBM. The WBM had a threefold difference in AMH recovery after chemotherapy treatment (1.6%), when compared with BRCA negative (3.7%) and untested/low risk controls (5.2%). Limiting the analysis to the most common regimen, doxorubicin and cyclophosphamide followed by paclitaxel, showed similar results. These findings were mechanistically confirmed in an in vitro mouse oocyte BRCA knockdown bioassay, which showed that BRCA deficiency results in increased oocyte susceptibility to doxorubicin. CONCLUSION(S): Women who have pathogenic BRCA mutations are more likely to lose ovarian reserve after chemotherapy treatment, suggesting an emphasis on fertility preservation. Furthermore, our findings generate the hypothesis that DNA repair deficiency is a shared mechanism between aging, infertility, and cancer. CLINICAL TRIAL REGISTRATION NUMBER: NCT00823654.


Assuntos
Antineoplásicos/efeitos adversos , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/tratamento farmacológico , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Mutação em Linhagem Germinativa , Oócitos/efeitos dos fármacos , Reserva Ovariana/efeitos dos fármacos , Insuficiência Ovariana Primária/induzido quimicamente , Adulto , Animais , Hormônio Antimülleriano/sangue , Biomarcadores/sangue , Neoplasias da Mama/genética , Feminino , Humanos , Estudos Longitudinais , Camundongos , Oócitos/patologia , Reserva Ovariana/genética , Insuficiência Ovariana Primária/sangue , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/fisiopatologia , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
9.
Science ; 366(6466): 714-723, 2019 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-31699932

RESUMO

Activating mutations in PIK3CA are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (PI3Kα) inhibitors have been approved for therapy. To characterize determinants of sensitivity to these agents, we analyzed PIK3CA-mutant cancer genomes and observed the presence of multiple PIK3CA mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double PIK3CA mutations are in cis on the same allele and result in increased PI3K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased p110α membrane lipid binding. Double PIK3CA mutations predict increased sensitivity to PI3Kα inhibitors compared with single-hotspot mutations.


Assuntos
Carcinogênese/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias/genética , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/química , Classe Ia de Fosfatidilinositol 3-Quinase/química , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Feminino , Humanos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Ligação Proteica , Domínios Proteicos , Tiazóis/farmacologia
11.
Cancer Cell ; 34(3): 427-438.e6, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30205045

RESUMO

We integrated the genomic sequencing of 1,918 breast cancers, including 1,501 hormone receptor-positive tumors, with detailed clinical information and treatment outcomes. In 692 tumors previously exposed to hormonal therapy, we identified an increased number of alterations in genes involved in the mitogen-activated protein kinase (MAPK) pathway and in the estrogen receptor transcriptional machinery. Activating ERBB2 mutations and NF1 loss-of-function mutations were more than twice as common in endocrine resistant tumors. Alterations in other MAPK pathway genes (EGFR, KRAS, among others) and estrogen receptor transcriptional regulators (MYC, CTCF, FOXA1, and TBX3) were also enriched. Altogether, these alterations were present in 22% of tumors, mutually exclusive with ESR1 mutations, and associated with a shorter duration of response to subsequent hormonal therapies.


Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama Masculina/genética , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Sistema de Sinalização das MAP Quinases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama Masculina/patologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , Estudos Prospectivos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Adulto Jovem
12.
Eur J Cancer ; 101: 12-19, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30007894

RESUMO

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially dose-limiting side-effect of neurotoxic chemotherapy for cancer patients. We evaluated the preliminary efficacy of acupuncture in preventing worsening CIPN in patients receiving paclitaxel. METHODS: In this phase IIA single-arm clinical trial, we screened stage I-III breast cancer patients receiving neoadjuvant/adjuvant weekly paclitaxel for development of CIPN. The primary objective was to assess acupuncture's efficacy in preventing the escalation of National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.0, grade II CIPN to higher grades. Acupuncture was deemed worthy of further study if 23 or more of the 27 enrolled patients did not develop grade III CIPN. Outcome measures (NCI-CTCAE CIPN grade, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity [FACT/GOG-Ntx], Neuropathic Pain Scale [NPS]) were obtained weekly during the intervention. RESULTS: Of 104 patients screened, 37 developed grade II CIPN (36%), and 28 (27%) enrolled into the intervention phase; one was removed due to protocol violation. Of the 27 patients receiving acupuncture, 26 completed paclitaxel treatment without developing grade III CIPN, meeting our prespecified success criteria for declaring acupuncture worthy of further study. FACT/GOG-Ntx and NPS scores remained stable during the intervention while continuing weekly paclitaxel. Acupuncture treatment was well tolerated; 4 of 27 (15%) patients reported grade I bruising. CONCLUSIONS: Acupuncture was safe and showed preliminary evidence of effectiveness in reducing the incidence of high grade CIPN during chemotherapy. A follow-up randomised controlled trial is needed to establish definitive efficacy in CIPN prevention for patients at risk.


Assuntos
Terapia por Acupuntura/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/terapia , Terapia por Acupuntura/efeitos adversos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Contusões/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia , Índice de Gravidade de Doença , Resultado do Tratamento
13.
Curr Oncol Rep ; 20(7): 51, 2018 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-29713831

RESUMO

PURPOSE OF REVIEW: The treatment landscape for many cancers has dramatically changed with the development of checkpoint inhibitors. This article will review the literature concerning the use of checkpoint inhibitors in breast cancer. RECENT FINDINGS: The histological subtype of BC with the strongest signal of efficacy has been triple-negative breast cancer (TNBC). Early trials of single-agent checkpoint inhibitors did not demonstrate a uniformly positive signal. Clinical studies suggest response rates between 5 and 10% in pretreated patients and roughly 20-25% for untreated advanced TNBC. However, in the small subset of patients who do respond, the response is often durable. More encouraging results have been reported with their use in combination with chemotherapy in the neoadjuvant setting. Larger phase III studies are underway to confirm these earlier findings. An immune-directed therapeutic approach for the management of BC is underway, and it is likely that combination therapy will be required to achieve a level of efficacy worthy of use in the BC treatment paradigm. These agents are not without both economic and clinical toxicity; therefore, it is imperative that we identify patients most likely to benefit from these therapies through well-designed biologically plausible clinical studies and by evaluating novel combinatorial approaches with informative biomarker driven correlative studies.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Imunoterapia/métodos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/metabolismo , Feminino , Humanos , Terapia Neoadjuvante , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Receptor ErbB-2/metabolismo
14.
Clin Cancer Res ; 24(18): 4380-4387, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-29793946

RESUMO

Purpose: This single-arm, open-label phase II study evaluated the safety and efficacy of taselisib (GDC-0032) plus fulvestrant in postmenopausal women with locally advanced or metastatic HER2-negative, hormone receptor (HR)-positive breast cancer.Patients and Methods: Patients received 6-mg oral taselisib capsules daily plus intramuscular fulvestrant (500 mg) until disease progression or unacceptable toxicity. Tumor tissue (if available) was centrally evaluated for PIK3CA mutations. Adverse events (AE) were recorded using NCI-CTCAE v4.0. Tumor response was investigator-determined using RECIST v1.1.Results: Median treatment duration was 4.6 (range: 0.9-40.5) months. All patients experienced ≥1 AE, 30 (50.0%) had grade ≥3 AEs, and 19 (31.7%) experienced 35 serious AEs. Forty-seven of 60 patients had evaluable tissue for central PIK3CA mutation testing [20 had mutations, 27 had no mutation detected (MND)]. In patients with baseline measurable disease, clinical activity was observed in tumors with PIK3CA mutations [best confirmed response rate: 38.5% (5/13; 95% CI, 13.9-68.4); clinical benefit rate (CBR): 38.5% (5/13; 95% CI, 13.9-68.4)], PIK3CA-MND [best confirmed response rate: 14.3% (3/21; 95% CI, 3.0-36.3); CBR: 23.8% (5/21; 95% CI, 8.2-47.2)], and unknown PIK3CA mutation status [best confirmed response rate: 20.0% (2/10; 95% CI, 2.5-55.6); CBR: 30.0% (3/10; 95% CI, 6.7-65.2)].Conclusions: Taselisib plus fulvestrant had clinical activity irrespective of PIK3CA mutation status, with numerically higher objective response rate and CBR in patients with PIK3CA-mutated (vs. -MND) locally advanced or metastatic HER2-negative, HR-positive breast cancer. No new safety signals were reported. A confirmatory phase III trial is ongoing. Clin Cancer Res; 24(18); 4380-7. ©2018 AACR.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/genética , Imidazóis/administração & dosagem , Oxazepinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Fulvestranto/administração & dosagem , Fulvestranto/efeitos adversos , Humanos , Imidazóis/efeitos adversos , Pessoa de Meia-Idade , Mutação , Oxazepinas/efeitos adversos , Receptor ErbB-2/genética , Receptores de Estrogênio/genética
15.
Breast Cancer Res Treat ; 171(2): 325-334, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29789969

RESUMO

BACKGROUND: In hormone receptor-positive advanced breast cancer, a progression-free survival benefit was reported with addition of bevacizumab to first-line letrozole. However, increased toxicity was observed. We hypothesized that functional age measures could be used to identify patients at risk for toxicity while receiving letrozole plus bevacizumab for hormone receptor-positive advanced breast cancer. METHODS: CALGB 40503 was a phase III trial that enrolled patients with hormone receptor-positive advanced breast cancer randomized to letrozole with or without bevacizumab. Patients randomized to bevacizumab were approached to complete a validated assessment tool evaluating physical function, comorbidity, cognition, psychological state, social support, and nutritional status. The relationship between pretreatment assessment measures and the incidence of grade ≥ 3 (National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0) adverse events was determined. RESULTS: One hundred thirteen (58%) of 195 patients treated with letrozole plus bevacizumab completed the pretreatment assessment questionnaire. One patient was excluded due to missing adverse event data. The median age of patients was 56. Frequently reported grade ≥ 3 adverse events were hypertension (26%), pain (20%), and proteinuria (7%). Two hemorrhagic events (one grade 5) and 1 thrombosis event occurred. Age ≥ 65 years (p < 0.01), decreased vision (p = 0.04), and poorer pretreatment physical function measures (p < 0.05) were found on univariate analysis to be significantly associated with increased incidence of grade ≥ 3 adverse events. Upon multivariate analysis, age ≥ 65 years (p = 0.01) and decreased vision (p = 0.04) remained significant. Univariable and multivariable logistic regression models demonstrated associations between age, vision, the ability to walk up flights of stairs, and grade ≥ 3 adverse events. CONCLUSIONS: Age (≥ 65 years), decreased vision, and impairments in physical function correlated with increased incidence of toxicity in patients receiving first-line letrozole plus bevacizumab. When evaluating therapy likely to increase toxicity, functional assessment measures can identify patients at increased risk for side effects who may benefit from closer monitoring.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Neoplasias da Mama/patologia , Feminino , Humanos , Incidência , Letrozol/administração & dosagem , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco
16.
Cancer ; 124(12): 2552-2560, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29624641

RESUMO

BACKGROUND: The investigation of exercise training in metastatic breast cancer has received minimal attention. This study determined the feasibility and safety of aerobic training in metastatic breast cancer. METHODS: Sixty-five women (age, 21-80 years) with metastatic (stage IV) breast cancer (57% were receiving chemotherapy, and >40% had ≥ 2 lines of prior therapy) were allocated to an aerobic training group (n = 33) or a stretching group (n = 32). Aerobic training consisted of 36 supervised treadmill walking sessions delivered thrice weekly between 55% and 80% of peak oxygen consumption (VO2peak ) for 12 consecutive weeks. Stretching was matched to aerobic training with respect to location, frequency, duration, and intervention length. The primary endpoint was aerobic training feasibility, which was a priori defined as the lost to follow-up (LTF) rate (<20%) and attendance (≥70%). Secondary endpoints were safety, objective outcomes (VO2peak and functional capacity), and patient-reported outcomes (PROs; quality of life). RESULTS: One of the 33 patients (3%) receiving aerobic training was LTF, whereas the mean attendance rate was 63% ± 30%. The rates of permanent discontinuation and dose modification were 27% and 49%, respectively. Intention-to-treat analyses indicated improvements in PROs, which favored the attention control group (P values > .05). Per protocol analyses indicated that 14 of 33 patients (42%) receiving aerobic training had acceptable tolerability (relative dose intensity ≥ 70%), and this led to improvements in VO2peak and functional capacity (P values < .05). CONCLUSIONS: Aerobic training at the dose and schedule tested is safe but not feasible for a significant proportion of patients with metastatic breast cancer. The acceptable feasibility and promising benefit for select patients warrant further evaluation in a dose-finding phase 1/2 study. Cancer 2018;124:2552-60. © 2018 American Cancer Society.


Assuntos
Neoplasias da Mama/reabilitação , Terapia por Exercício/métodos , Exercício Físico/fisiologia , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Adulto , Idoso , Neoplasias da Mama/patologia , Terapia por Exercício/efeitos adversos , Estudos de Viabilidade , Feminino , Humanos , Pessoa de Meia-Idade , Consumo de Oxigênio/fisiologia , Resultado do Tratamento , Adulto Jovem
17.
Oncologist ; 23(5): 528-539, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29352052

RESUMO

Advancements in molecular profiling and endocrine therapy (ET) have led to more focused clinical attention on precision medicine. These advances have expanded our understanding of breast cancer (BC) pathogenesis and hold promising implications for the future of therapy. The estrogen receptor-α is a predominant endocrine regulatory protein in the breast and in estrogen-induced BC. Successful targeting of proteins and genes within estrogen receptor (ER) nuclear and nonnuclear pathways remains a clinical goal. Several classes of antiestrogenic agents are available for patients with early, advanced, or metastatic BC, including selective ER modulators, aromatase inhibitors, and a selective ER degrader. Clinical development is focused upon characterizing the efficacy and tolerability of inhibitors that target the phosphatidylinositol 3 kinase (PI3K)/akt murine thymoma viral oncogene (AKT)/mammalian target of rapamycin inhibitor (mTOR) signaling pathway or the cyclin-dependent kinase 4/6 (CDK4/6) cell cycle pathway in women with hormone receptor-positive, human epidermal growth receptor 2-negative BC who have demonstrated disease recurrence or progression. De novo and acquired resistance remain a major challenge for women with BC receiving antiestrogenic therapy. Therefore, sequential combination of targeted ET is preferred in these patients, and the ever-increasing understanding of resistance mechanisms may better inform the selection of future therapy. This review describes the intricate roles of the PI3K/AKT/mTOR and CDK4/6 pathways in intracellular signaling and the use of endocrine and endocrine-based combination therapy in BC. IMPLICATIONS FOR PRACTICE: The foundational strategy for treating hormone receptor-positive, human epidermal growth receptor 2-negative, advanced breast cancer includes the use of endocrine therapy either alone or in combination with targeted agents. The use of combination therapy aims to downregulate cell-signaling pathways with the intent of minimizing cellular "crosstalk," which can otherwise result in continued tumorigenesis or progression through redundant pathways. This review provides the clinician with the molecular rationale and clinical evidence for these treatments and refers to evidence-based guidelines to inform the decision-making process.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Receptores de Estrogênio/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Transdução de Sinais
18.
Gynecol Oncol ; 147(3): 621-625, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28969913

RESUMO

OBJECTIVE: Bevacizumab, a monoclonal antibody to VEGF, has shown efficacy in ovarian, cervical and endometrial cancer in addition to several other solid tumors. Serious side effects include hypertension, proteinuria, bowel perforation, and thrombosis. We tested the hypothesis that genetic variation in hypertension-associated genes is associated with bevacizumab-induced hypertension (BIH). METHODS: Patients with solid tumors treated with bevacizumab in combination with other therapy were identified from six clinical trials. Haplotype-tagging (ht) SNPs for 10 candidate genes associated with hypertension were identified through the International Hapmap Project. Germline DNA was genotyped for 103 htSNPs using mass spectrometry. Bevacizumab toxicities were identified from clinical trial reports. Haplotypes were reconstructed from diploid genotyping data and frequencies were compared using standard two-sided statistical tests. RESULTS: The study included 114 patients with breast, lung, ovarian, or other cancers, of whom 38 developed BIH. WNK1, KLKB1, and GRK4 were found to contain single loci associated with BIH. Haplotype analysis of WNK1, KLKB1, and GRK4 identified risk haplotypes in each gene associated with grade 3/4 BIH. A composite risk model was created based on these haplotypes. Patients with the highest risk score were the most likely to develop grade 3/4 BIH (OR=6.45; P=0.005; 95%CI, 1.86-22.39). CONCLUSIONS: We concluded that genetic variation in WNK1, KLKB1, and GRK4 may be associated with BIH. These genes are biologically plausible mediators due to their role in blood pressure control, regulating sodium homeostasis and vascular tone. This preliminary risk model performed better than population-based risk models and when further validated may help risk-stratify patients for BIH prior to initiating therapy.


Assuntos
Bevacizumab/efeitos adversos , Hipertensão/induzido quimicamente , Hipertensão/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Estudos de Casos e Controles , Feminino , Quinase 4 de Receptor Acoplado a Proteína G/genética , Predisposição Genética para Doença , Haplótipos , Humanos , Calicreínas/genética , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Proteína Quinase 1 Deficiente de Lisina WNK/genética
19.
JAMA ; 318(9): 825-835, 2017 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-28873162

RESUMO

Importance: Guidelines for cancer genetic testing based on family history may miss clinically actionable genetic changes with established implications for cancer screening or prevention. Objective: To determine the proportion and potential clinical implications of inherited variants detected using simultaneous sequencing of the tumor and normal tissue ("tumor-normal sequencing") compared with genetic test results based on current guidelines. Design, Setting, and Participants: From January 2014 until May 2016 at Memorial Sloan Kettering Cancer Center, 10 336 patients consented to tumor DNA sequencing. Since May 2015, 1040 of these patients with advanced cancer were referred by their oncologists for germline analysis of 76 cancer predisposition genes. Patients with clinically actionable inherited mutations whose genetic test results would not have been predicted by published decision rules were identified. Follow-up for potential clinical implications of mutation detection was through May 2017. Exposure: Tumor and germline sequencing compared with the predicted yield of targeted germline sequencing based on clinical guidelines. Main Outcomes and Measures: Proportion of clinically actionable germline mutations detected by universal tumor-normal sequencing that would not have been detected by guideline-directed testing. Results: Of 1040 patients, the median age was 58 years (interquartile range, 50.5-66 years), 65.3% were male, and 81.3% had stage IV disease at the time of genomic analysis, with prostate, renal, pancreatic, breast, and colon cancer as the most common diagnoses. Of the 1040 patients, 182 (17.5%; 95% CI, 15.3%-19.9%) had clinically actionable mutations conferring cancer susceptibility, including 149 with moderate- to high-penetrance mutations; 101 patients tested (9.7%; 95% CI, 8.1%-11.7%) would not have had these mutations detected using clinical guidelines, including 65 with moderate- to high-penetrance mutations. Frequency of inherited mutations was related to case mix, stage, and founder mutations. Germline findings led to discussion or initiation of change to targeted therapy in 38 patients tested (3.7%) and predictive testing in the families of 13 individuals (1.3%), including 6 for whom genetic evaluation would not have been initiated by guideline-based testing. Conclusions and Relevance: In this referral population with selected advanced cancers, universal sequencing of a broad panel of cancer-related genes in paired germline and tumor DNA samples was associated with increased detection of individuals with potentially clinically significant heritable mutations over the predicted yield of targeted germline testing based on current clinical guidelines. Knowledge of these additional mutations can help guide therapeutic and preventive interventions, but whether all of these interventions would improve outcomes for patients with cancer or their family members requires further study. Trial Registration: clinicaltrials.gov Identifier: NCT01775072.


Assuntos
DNA de Neoplasias/análise , Mutação em Linhagem Germinativa , Neoplasias/genética , Idoso , Biomarcadores Tumorais/genética , Análise Mutacional de DNA/métodos , Feminino , Predisposição Genética para Doença , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos
20.
Breast Cancer Res Treat ; 165(1): 77-84, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28547655

RESUMO

PURPOSE: To assess sexual/vaginal health issues and educational intervention preferences in women with a history of breast or gynecologic cancer. METHODS: Patients/survivors completed a cross-sectional survey at their outpatient visits. Main outcome measures were sexual dysfunction prevalence, type of sexual/vaginal issues, awareness of treatments, and preferred intervention modalities. Descriptive frequencies were performed, and results were dichotomized by age, treatment status, and disease site. RESULTS: Of 218 eligible participants, 109 (50%) had a history of gynecologic and 109 (50%) a history of breast cancer. Median age was 49 years (range 21-75); 61% were married/cohabitating. Seventy percent (n = 153) were somewhat-to-very concerned about sexual function/vaginal health, 55% (n = 120) reported vaginal dryness, 39% (n = 84) vaginal pain, and 51% (n = 112) libido loss. Many had heard of vaginal lubricants, moisturizers, and pelvic floor exercises (97, 72, and 57%, respectively). Seventy-four percent (n = 161) had used lubricants, 28% moisturizers (n = 61), and 28% pelvic floor exercises (n = 60). Seventy percent (n = 152) preferred the topic to be raised by the medical team; 48% (n = 105) raised the topic themselves. Most preferred written educational material followed by expert discussion (66%, n = 144/218). Compared to women ≥50 years old (41%, n = 43/105), younger women (54%, n = 61/113) preferred to discuss their concerns face-to-face (p = 0.054). Older women were less interested in online interventions (52%, p < 0.001), despite 94% having computer access. CONCLUSION: Female cancer patients/survivors have unmet sexual/vaginal health needs. Preferences for receiving sexual health information vary by age. Improved physician-patient communication, awareness, and educational resources using proven sexual health promotion strategies can help women cope with treatment side effects.


Assuntos
Neoplasias dos Genitais Femininos/terapia , Conhecimentos, Atitudes e Prática em Saúde , Educação de Pacientes como Assunto/métodos , Preferência do Paciente , Disfunções Sexuais Fisiológicas/terapia , Disfunções Sexuais Psicogênicas/terapia , Saúde Sexual , Adulto , Idoso , Estudos Transversais , Feminino , Neoplasias dos Genitais Femininos/diagnóstico , Neoplasias dos Genitais Femininos/epidemiologia , Neoplasias dos Genitais Femininos/psicologia , Pesquisas sobre Atenção à Saúde , Necessidades e Demandas de Serviços de Saúde , Humanos , Pessoa de Meia-Idade , Avaliação das Necessidades , Prevalência , Comportamento Sexual , Disfunções Sexuais Fisiológicas/diagnóstico , Disfunções Sexuais Fisiológicas/epidemiologia , Disfunções Sexuais Fisiológicas/psicologia , Disfunções Sexuais Psicogênicas/diagnóstico , Disfunções Sexuais Psicogênicas/epidemiologia , Disfunções Sexuais Psicogênicas/psicologia , Resultado do Tratamento , Vagina/fisiopatologia , Adulto Jovem
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