The matrix metalloproteinases (MMP) are a family of proteolytic enzymes that degrade multiple components of the extracellular matrix. A large body of experimental and clinical evidence has implicated ...MMPs in tumor invasion, neoangiogenesis, and metastasis, and therefore they represent ideal pharmacologic targets for cancer therapy. From the 1990s to early 2000s, synthetic inhibitors of MMPs (MMPI) were studied in various cancer types. Unexpectedly, despite strongly promising preclinical data, all trials were unsuccessful in reducing tumor burden or improving overall survival; in addition, MMPIs had unforeseen, severe side effects. Two main reasons can explain the failure of MMPIs in clinical trials. It has now become apparent that some MMPs have antitumor effects; therefore, the broad-spectrum MMPIs used in the initial trials might block these MMPs and result in tumor progression. In addition, although MMPs are involved in the early stages of tumor progression, MMPIs were tested in patients with advanced disease, beyond the stage when these compounds could be effective. As more specific MMPIs are now available, MMP targeting could be reconsidered for cancer therapy; however, new trials should be designed to test their antimetastatic properties in early-stage tumors, and endpoints should focus on parameters other than decreasing metastatic tumor burden.
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The importance of integrating biomarkers into the TNM staging has been emphasized in the 8
Edition of the American Joint Committee on Cancer (AJCC) Staging system. In a pooled analysis of 2148 ...TNBC-patients in the adjuvant setting, TILs are found to strongly up and downstage traditional pathological-staging in the Pathological and Clinical Prognostic Stage Groups from the AJJC 8
edition Cancer Staging System. This suggest that clinical and research studies on TNBC should take TILs into account in addition to stage, as for example patients with stage II TNBC and high TILs have a better outcome than patients with stage I and low TILs.
A message from ASCO'S President. It has been forty years since President Richard Nixon signed the National Cancer Act of 1971, which many view as the nation's declaration of the "War on Cancer." The ...bill has led to major investments in cancer research and significant increases in cancer survival. Today, two-thirds of patients survive at least five years after being diagnosed with cancer compared with just half of all diagnosed patients surviving five years after diagnosis in 1975. The research advances detailed in this year's Clinical Cancer Advances demonstrate that improvements in cancer screening, treatment, and prevention save and improve lives. But although much progress has been made, cancer remains one of the world's most serious health problems. In the United States, the disease is expected to become the nation's leading cause of death in the years ahead as our population ages. I believe we can accelerate the pace of progress, provided that everyone involved in cancer care works together to achieve this goal. It is this viewpoint that has shaped the theme for my presidential term: Collaborating to Conquer Cancer. In practice, this means that physicians and researchers must learn from every patient's experience, ensure greater collaboration between members of a patient's medical team, and involve more patients in the search for cures through clinical trials. Cancer advocates, insurers, and government agencies also have important roles to play. Today, we have an incredible opportunity to improve the quality of cancer care by drawing lessons from the real-world experiences of patients. The American Society of Clinical Oncology (ASCO) is taking the lead in this area, in part through innovative use of health information technology. In addition to our existing quality initiatives, ASCO is working with partners to develop a comprehensive rapid-learning system for cancer care. When complete, this system will provide physicians with personalized, real-time information that can inform the care of every patient with cancer as well as connect patients with their entire medical teams. The rapid learning system will form a continuous cycle of learning: securely capturing data from every patient at the point of care, drawing on evidence-based guidelines, and evaluating quality of care against those standards and the outcomes of other patients. Clinical trials are another area in which collaboration is critical. Increasing clinical trial participation will require commitment across the cancer community from physicians, patients, insurers, hospitals, and industry. A 2010 report by the Institute of Medicine described challenges to participation in trials by both physicians and patients and provided recommendations for revitalizing clinical trials conducted through the National Cancer Institute's Cooperative Group Program. ASCO has pledged its support for the full implementation of these recommendations. More broadly, ASCO recently outlined a bold vision for translational and clinical cancer research for the next decade and made recommendations to achieve that vision. Accelerating Progress Against Cancer: ASCO's Blueprint for Transforming Clinical and Translational Research, released in November, calls for a research system that takes full advantage of today's scientific and technologic opportunities and sets a high-level agenda for policy makers, regulators, and advocates. Cancer research has transformed cancer care in the past forty years, and this year's Clinical Cancer Advances illustrates how far we have come in the past year alone. We now have a tremendous opportunity to use today's knowledge and collaborate across all facets of cancer care to conquer this deadly disease. Michael P. Link, MD President American Society of Clinical Oncology.
COVID‐19 can be especially dangerous in vulnerable populations such as those with cancer undergoing treatment. When it is discovered in an asymptomatic patient through imaging, there is a paucity of ...evidence‐based treatment recommendations.
COVID‐19 can be especially dangerous in vulnerable populations such as those with cancer undergoing treatment. When it is discovered in an asymptomatic patient through imaging, there is a paucity of evidence‐based treatment recommendations.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
BackgroundMagrolimab is a monoclonal antibody that blocks the macrophage inhibitory immune checkpoint CD47, which is present on tumor cells. Overexpression of prophagocytic signals makes cells more ...susceptible to CD47 blockade. Taxanes are known to enhance expression of prophagocytic signals on tumor cells and therefore may synergize with magrolimab. These Phase 2 studies (ELEVATE TNBC: NCT04958785; ELEVATE Lung&UC: NCT04827576) are evaluating safety, tolerability, and recommended Phase 2 dose (RP2D) of magrolimab in combination with taxanes in locally advanced/metastatic triple-negative breast cancer (mTNBC), locally advanced/metastatic non-small cell/small cell lung cancers (mNSCLC/mSCLC), and locally advanced/metastatic urothelial cancer (mUC) (figure 1). We report data from 2 safety run-ins (SRIs) from these studies.MethodsPatients with mTNBC in SRI1 received magrolimab and nanoparticle albumin-bound-paclitaxel or paclitaxel. Patients with mNSCLC/mSCLC or mUC in SRI2 received magrolimab+docetaxel. Magrolimab was started as a 1 mg/kg priming dose, followed by 30 mg/kg weekly (7 weeks in SRI1; 5 weeks in SRI2), and then a maintenance dose of 30 mg/kg Q2W for SRI1 and 60 mg/kg Q3W for SRI2. Chemotherapy was given per standard of care. Safety was assessed in patients who received ≥1 dose of any study drug. Dose-limiting toxicities (DLTs) were assessed in patients who experienced a DLT during the DLT evaluation period or did not experience a DLT and completed ≥3 (SRI1) or ≥2 (SRI2) magrolimab doses and ≥2 (SRI1) or ≥1 (SRI2) taxane doses. To select an RP2D, ≤2 of 6 DLT-evaluable patients could experience a DLT, or the magrolimab dose would be de-escalated and a new cohort assessed.ResultsSix patients from each SRI were considered DLT-evaluable. The safety analysis population consisted of 8 and 9 patients in SRI1 and SRI2, respectively. No DLTs were observed during the DLT assessment period. Treatment-emergent adverse events (TEAEs) were observed in 8/8 (SRI1) and 9/9 (SRI2) patients (table 1). The most common TEAEs in SRI1 were anemia, vomiting, and headache (5/8 each); in SRI2, fatigue (5/9) and hyponatremia (3/9) were the most common. In SRI2, 2/9 patients experienced TEAEs resulting in discontinuation of magrolimab (fatal gastrointestinal bleed deemed unrelated to treatment and grade 3 neuritis). No additional deaths were reported.ConclusionsThe observed safety profile was as expected based on the known toxicity profiles of the individual agents, and magrolimab appears tolerable in these combinations. No DLTs, magrolimab-related deaths, or unexpected safety signals were observed across indications. Magrolimab RP2D was determined at the initial dose level tested.Trial RegistrationNCT04827576, NCT04958785Ethics ApprovalThe protocol and proposed informed consent form were reviewed and approved by all relevant Institutional Review Boards, Independent Ethics Committees and/or Research Ethics Boards prior to study commencement. There is no number provided as we did not receive one. Participants gave informed consent to participate in the study before taking part.ConsentThe protocol and proposed informed consent form were reviewed and approved by all relevant Institutional Review Boards, Independent Ethics Committees and/or Research Ethics Boards prior to study commencement. There is no number provided as we did not receive one. Participants gave informed consent to participate in the study before taking part.Abstract 698 Figure 1ELEVATE TNBC and ELEVATE Lung&UC Study Design.Abstract 698 Table 1TEAEs occurring in ≥2 patients in either of the SRI cohorts.
Providing HIV Pre-Exposure Prophylaxis Trent-Adams, Sylvia, PhD; Cheever, Laura W., MD
American journal of preventive medicine,
2013, January 2013, 2013-1-00, Volume:
44, Issue:
1
Journal Article
Peer reviewed
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A MESSAGE FROM ASCO'S PRESIDENT
Like many health professionals who care for people with cancer, I entered the field because of specific patients who touched my heart. They still do. In an effort to ...weave together my personal view of what the American Society of Clinical Oncology (ASCO) stands for and the purpose the organization serves, my presidential theme this year is “Patients. Pathways. Progress.” Patients come first. Caring for patients is the most important, rewarding aspect of being an oncology professional. At its best, the relationship between doctor and patient is compassionate and honest—and a relationship of mutual respect. Many professional organizations have an interest in cancer, but no other society is so focused on the entire spectrum of cancer care, education, and research. Nor is any other society as particularly interested in bringing new treatments to our patients through clinical trials as ASCO is. Clinical trials are the crux for improving treatments for people with cancer and are critical for continued progress against the disease. “Pathways” has several meanings. Some pathways are molecular—like the cancer cell's machinery of destruction, which we have only begun to understand in recent years. But there are other equally important pathways, including the pathways new therapies follow as they move from bench to bedside and the pathways patients follow during the course of their diseases. Improved understanding of these pathways will lead to new approaches in cancer care, allowing doctors to provide targeted therapies that deliver improved, personalized treatment. The best pathway for patients to gain access to new therapies is through clinical trials. Trials conducted by the National Cancer Institute's Cooperative Group Program, a nationwide network of cancer centers and physicians, represent the United States' most important pathway for accelerating progress against cancer. This year, the Institute of Medicine released a report on major challenges facing the Cooperative Group Program. Chief among them is the fact that funding for the program has been nearly flat since 2002. ASCO has called for a doubling of funding for cooperative group research within five years and supports the full implementation of the Institute of Medicine recommendations to revitalize the program. ASCO harnesses the expertise and resources of its 28,000 members to bring all of these pathways together for the greater good of patients. Progress against cancer is being made every day—measurable both in our improved understanding of the disease and in our ability to treat it. A report issued in December 2009 by the National Cancer Institute, the Centers for Disease Control and Prevention, the American Cancer Society, and the North American Association of Central Cancer Registries found that rates of new diagnoses and rates of death resulting from all cancers combined have declined significantly in recent years for men and women overall and for most racial and ethnic populations in the United States. The pace of progress can be and needs to be hastened. Much remains to be done. Sustained national investment in cancer research is needed to bring better, more effective, less toxic treatments to people living with cancer. Pathways to progress continue in the clinic as doctors strive to find the right treatments for the right patients, to understand what represents the right treatments, and to partner with patients and caregivers for access to those treatments. This report demonstrates that significant progress is being made on the front lines of clinical cancer research. But although our nation's investment in this research is paying off, we must never forget the magnitude of what lies ahead. Cancer remains the number two killer of Americans. Future progress depends on continued commitment, from both ASCO and the larger medical community. George W. Sledge Jr, MD President American Society of Clinical Oncology
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Background: Standard first-line treatment for mTNBC is chemotherapy. However, outcomes are poor, and new treatment options are needed. Cohort B of KEYNOTE-086 (NCT02447003) ...assessed the safety and antitumor activity of pembrolizumab as first-line therapy for patients (pts) with PD-L1–positive mTNBC. Methods: Men and women with centrally confirmed mTNBC, no prior systemic anticancer therapy for metastatic disease, ECOG PS 0-1, and a tumor PD-L1 combined positive score (CPS) ≥1% received pembrolizumab 200 mg Q3W for 24 mo or until disease progression, intolerable toxicity, or investigator or pt decision. Tumor imaging was performed Q9W for 12 mo and Q12W thereafter. Clinically stable pts with PD could remain on pembrolizumab until PD was confirmed on subsequent assessment. Primary end point was safety. Secondary end points included ORR, DOR, and PFS (RECIST v1.1, central review). Planned enrollment was 80 pts. This analysis included all pts who had ≥18 wk of follow-up as of Nov 10, 2016. Results: 79 of the first 137 pts with PD-L1–evaluable tumors (58%) had PD-L1 CPS ≥1%. Of the first 52 pts enrolled, 100% were women, median age was 53 y, 40% had elevated LDH, 69% had visceral metastases, and 87% received prior (neo)adjuvant therapy. After a median follow-up of 7.0 mo (range 4.4-12.5), 15 (29%) pts remained on pembrolizumab. Treatment-related AEs occurred in 37 (71%) pts, most commonly fatigue (31%), nausea (15%), and diarrhea (13%). 4 (8%) pts experienced 5 grade 3-4 treatment-related AEs: back pain, fatigue, hyponatremia, hypotension, and migraine (n = 1 each). No pts died or discontinued pembrolizumab due to an AE. ORR was 23% (95% CI 14%-36%). Best overall response was CR in 4%, PR in 19%, SD in 17%, PD in 58%, and not assessed in 2%. Median time to response was 8.7 wk (range 8.1-17.7). Median DOR was 8.4 mo (range, 2.1+ to 8.4), with 8 (67%) responses ongoing at cutoff. Median PFS was 2.1 mo (95% CI, 2.0-3.9); estimated 6-mo PFS rate was 29%. Conclusions: Data from the first 52 pts enrolled in KEYNOTE-086 cohort B suggest that pembrolizumab monotherapy has a manageable safety profile and promising antitumor activity as first-line therapy for PD-L1–positive mTNBC. Clinical trial information: NCT02447003.
The huge communities of residential microbes, including bacteria, viruses, Archaea, and Eukaryotes, that colonize humans are increasingly recognized as playing important roles in health and disease. ...A complex populous ecosystem, the human gastrointestinal (GI) tract harbors up to 10(11) bacterial cells per gram of luminal content, whose collective genome, the gut metagenome, contains a vastly greater number of individual genes than the human genome. In health, the function of the microbiome might be considered to be in dynamic equilibrium with the host, exerting both local and distant effects. However, 'disequilibrium' may contribute to the emergence of disease, including malignancy. In this review, we discuss how the intestinal bacterial microbiome and in particular how an 'estrobolome,' the aggregate of enteric bacterial genes capable of metabolizing estrogens, might affect women's risk of developing postmenopausal estrogen receptor-positive breast cancer. Estrobolome composition is impacted by factors that modulate its functional activity. Exploring variations in the composition and activities of the estrobolome in healthy individuals and in women with estrogen-driven breast cancer may lead to development of microbiome-based biomarkers and future targeted interventions to attenuate cancer risk.
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