PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer

Breast Care, Journal Year: 2016, Volume and Issue: 11(6), P. 385 - 390

Published: Jan. 1, 2016

Immune checkpoint inhibition represents a major recent breakthrough in the treatment of malignant diseases including breast cancer. Blocking programmed death receptor-1 (PD-1) and its ligand, PD-L1, has shown impressive antitumor activity may lead to durable long-term disease control, especially triple-negative subtypes cancer (TNBC). Although immune blockade is generally well tolerated, specific immune-related adverse events (irAEs) occur. This review summarizes clinical efficacy, perspectives, future challenges using PD-1/PD-L1-directed antibodies

Language: Английский

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2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer

Thyroid, Journal Year: 2015, Volume and Issue: 26(1), P. 1 - 133

Published: Oct. 14, 2015

Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Association's (ATA's) guidelines for management of these disorders were revised in 2009, significant scientific advances have occurred field. The aim to inform clinicians, patients, researchers, health policy makers on published evidence relating diagnosis cancer. Methods: specific questions addressed based prior versions guidelines, stakeholder input, input task force members. Task panel members educated knowledge synthesis methods, including electronic database searching, review selection relevant citations, critical appraisal selected studies. Published English language articles adults eligible inclusion. College Physicians Guideline Grading System was used grading strength recommendations therapeutic interventions. We developed similarly formatted system appraise quality such studies resultant recommendations. guideline had complete editorial independence from ATA. Competing interests regularly updated, managed, communicated ATA Results: include regarding initial evaluation, ultrasound criteria fine-needle aspiration biopsy, interpretation biopsy results, use molecular markers, benign nodules. Recommendations those screening cancer, staging risk assessment, surgical management, radioiodine remnant ablation therapy, thyrotropin suppression therapy using levothyroxine. related long-term surveillance recurrent disease imaging serum thyroglobulin, hormone metastatic disease, consideration trials targeted as well directions future research. Conclusions: evidence-based decision-making They represent, our opinion, contemporary optimal care patients with disorders.

Language: Английский

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Evaluation of Factors Related to Late Recurrence - Later than 10 Years after the Initial Treatment - in Primary Breast Cancer

Oncology, Journal Year: 2013, Volume and Issue: 85(2), P. 100 - 110

Published: Jan. 1, 2013

Tumors can recur years after treatment, and breast cancer is especially noted for long periods of dormancy. The status the during this period poorly understood. As a model to study mechanisms dormancy, we used murine D2.0R mammary carcinoma cells, which are metastatic but form occasional metastases in liver other organs latency. Highly D2A1 cells provided positive, control. Our goals were learn how cell lines differ survival kinetics secondary site seek evidence source In spontaneous metastasis assays from fat pad injections, found dormancy because persistence large numbers solitary liver. To quantify fate arrival liver, experimental used. permit identification that had not divided, labeled before injection with fluorescent nanospheres, diluted undetectable levels by division. Cancer injected i.v. target them coinjected reference microspheres monitor survival. Dormancy was defined as retention nanosphere fluorescence vivo, well negative staining proliferation marker Ki67. A proportion persisted dormant cells. No formed, viable could be recovered 11 weeks injection. Large solitary, dormant, Ki67-negative also detected against background progressively growing metastases. Thus, identified possible contributor tumor dormancy: persist tissue. If such present patients, they contribute recurrence would susceptible current therapeutic strategies targeting proliferating

Language: Английский

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The blockade of immune checkpoints in cancer immunotherapy

Nature reviews. Cancer, Journal Year: 2012, Volume and Issue: 12(4), P. 252 - 264

Published: March 22, 2012

Language: Английский

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Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer

New England Journal of Medicine, Journal Year: 2015, Volume and Issue: 373(17), P. 1627 - 1639

Published: Sept. 27, 2015

Nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, disrupts PD-1-mediated signaling and may restore antitumor immunity.

Language: Английский

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PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

New England Journal of Medicine, Journal Year: 2015, Volume and Issue: 372(26), P. 2509 - 2520

Published: May 30, 2015

Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic due mismatch-repair defects may be susceptible immune checkpoint blockade.We conducted phase 2 study evaluate clinical activity pembrolizumab, an anti-programmed death 1 inhibitor, in 41 patients progressive metastatic carcinoma or without deficiency. Pembrolizumab was administered intravenously at dose 10 mg per kilogram body weight every 14 days mismatch repair-deficient colorectal cancers, repair-proficient and cancers were not colorectal. The coprimary end points immune-related objective response rate 20-week progression-free survival rate.The 40% (4 patients) 78% (7 9 patients), respectively, for 0% (0 18 11% (2 cancers. median overall reached cohort cancer but 2.2 5.0 months, (hazard ratio disease progression death, 0.10 [P<0.001], hazard 0.22 [P=0.05]). Patients noncolorectal had responses similar those (immune-related rate, 71% [5 7 patients]; 67% [4 6 patients]). Whole-exome sequencing revealed mean 1782 tumor tumors, as compared 73 (P=0.007), high mutation loads associated prolonged (P=0.02).This showed status predicted benefit blockade pembrolizumab. (Funded by Johns Hopkins University others; ClinicalTrials.gov number, NCT01876511.).

Language: Английский

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Nivolumab versus Docetaxel in Advanced Squamous-Cell Non–Small-Cell Lung Cancer

New England Journal of Medicine, Journal Year: 2015, Volume and Issue: 373(2), P. 123 - 135

Published: May 31, 2015

Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared docetaxel in this patient population.We randomly assigned 272 patients to receive at dose mg per kilogram body weight every 2 weeks, docetaxel, 75 square meter body-surface area weeks. The primary end point was overall survival.The median survival 9.2 months (95% confidence interval [CI], 7.3 13.3) nivolumab versus 6.0 CI, 5.1 7.3) docetaxel. risk 41% lower than (hazard ratio, 0.59; 95% 0.44 0.79; P<0.001). At year, rate 42% 34 50) 24% 17 31) response 20% 9% (P=0.008). progression-free 3.5 2.8 ratio for progression, 0.62; 0.47 0.81; expression PD-1 ligand (PD-L1) neither prognostic nor predictive benefit. Treatment-related adverse events grade 4 were reported 7% group 55% those group.Among advanced, previously treated NSCLC, survival, rate, significantly better regardless PD-L1 level. (Funded by Bristol-Myers Squibb; CheckMate 017 ClinicalTrials.gov number, NCT01642004.).

Language: Английский

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Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma

New England Journal of Medicine, Journal Year: 2015, Volume and Issue: 373(1), P. 23 - 34

Published: May 31, 2015

Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4] have been shown to complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or plus was compared with patients

Language: Английский

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Cancer Genome Landscapes

Science, Journal Year: 2013, Volume and Issue: 339(6127), P. 1546 - 1558

Published: March 28, 2013

Over the past decade, comprehensive sequencing efforts have revealed genomic landscapes of common forms human cancer. For most cancer types, this landscape consists a small number "mountains" (genes altered in high percentage tumors) and much larger "hills" infrequently). To date, these studies ~140 genes that, when by intragenic mutations, can promote or "drive" tumorigenesis. A typical tumor contains two to eight "driver gene" mutations; remaining mutations are passengers that confer no selective growth advantage. Driver be classified into 12 signaling pathways regulate three core cellular processes: cell fate, survival, genome maintenance. better understanding is one pressing needs basic research. Even now, however, our knowledge genomes sufficient guide development more effective approaches for reducing morbidity mortality.

Language: Английский

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Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer

Science, Journal Year: 2015, Volume and Issue: 348(6230), P. 124 - 128

Published: March 13, 2015

Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response this therapy, we used whole-exome sequencing non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated molecular smoking signature, neoantigen burden, DNA repair pathway mutations; each factor burden. one responder, neoantigen-specific CD8+ responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances reactivity. Our results suggest landscape shapes therapy.

Language: Английский

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