A meta-analysis on the prophylactic use of macrolide antibiotics for the prevention of disease exacerbations in patients with Chronic Obstructive Pulmonary Disease

SummaryIntroductionMacrolides are of unique interest in preventing COPD exacerbations because they possess a variety of antibacterial, antiviral and anti-inflammatory properties. Recent research has generated renewed interest in prophylactic macrolides to reduce the risk of COPD exacerbations. Little is known about how well these recent findings fit within the context of previous research on this subject. The purpose of this article is to evaluate, via exploratory meta-analysis, whether the overall consensus favors prophylactic macrolides for prevention of COPD exacerbations.MethodsEMBASE, Cochrane and Medline databases were searched for all relevant randomized controlled trials (RCTs). Six RCTs were identified. The primary endpoint was incidence of COPD exacerbations. Secondary endpoints including mortality, hospitalization rates, adverse events and likelihood of having at least one COPD exacerbation were also examined.ResultsThere was a 37% relative risk reduction (RR = 0.63, 95% CI: 0.45–0.87, p value = 0.005) in COPD exacerbations among patients taking macrolides compared to placebo. Furthermore, there was a 21% reduced risk of hospitalization (RR = 0.79, 95% CI: 0.69–0.90, p-value = 0.01) and 68% reduced risk of having at least one COPD exacerbation (RR = 0.34, 95% CI 0.21–0.54, p-value = 0.001) among patients taking macrolides versus placebo. There was also a trend toward decreased mortality and increased adverse events among patients taking macrolides but these were not statistically significant.ConclusionsProphylactic macrolides are an effective approach for reducing incident COPD exacerbations. There were several limitations to this study including a lack of consistent adverse event reporting and some degree of clinical and statistical heterogeneity between studies

Genomic complexity predicts resistance to endocrine therapy and CDK4/6 inhibition in hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer

PURPOSE: Clinical biomarkers to identify patients unlikely to benefit from CDK4/6 inhibition (CDK4/6i) in combination with endocrine therapy (ET) are lacking. We implemented a comprehensive circulating tumor DNA (ctDNA) analysis to identify genomic features for predicting and monitoring treatment resistance. EXPERIMENTAL DESIGN: ctDNA was isolated from 216 plasma samples collected from 51 patients with hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) on a phase II trial of palbociclib combined with letrozole or fulvestrant (NCT03007979). Boosted whole-exome sequencing (WES) was performed at baseline and clinical progression to evaluate genomic alterations, mutational signatures, and blood tumor mutational burden (bTMB). Low-pass whole-genome sequencing was performed at baseline and serial timepoints to assess blood copy-number burden (bCNB). RESULTS: High bTMB and bCNB were associated with lack of clinical benefit and significantly shorter progression-free survival (PFS) compared with patients with low bTMB or low bCNB (all P \u3c 0.05). Dominant APOBEC signatures were detected at baseline exclusively in cases with high bTMB (5/13, 38.5%) versus low bTMB (0/37, 0%; P = 0.0006). Alterations in ESR1 were enriched in samples with high bTMB (P = 0.0005). There was a high correlation between bTMB determined by WES and bTMB determined using a 600-gene panel (R = 0.98). During serial monitoring, an increase in bCNB score preceded radiographic progression in 12 of 18 (66.7%) patients. CONCLUSIONS: Genomic complexity detected by noninvasive profiling of bTMB and bCNB predicted poor outcomes in patients treated with ET and CDK4/6i and identified early disease progression before imaging. Novel treatment strategies including immunotherapy-based combinations should be investigated in this population

Chemotherapy principles of managing stage IV breast cancer in the United States

The therapeutic landscape for metastatic breast cancer (MBC) has expanded greatly over the last three decades with an increasing availability of targeted therapies for specific breast cancer subtypes. However, cytotoxic chemotherapy remains an essential component for the management of endocrine refractory or triple negative MBC. Multiple chemotherapy agents have demonstrated activity in MBC as single agents and in combination. While taxanes are frequently recommended as the initial treatment of metastatic disease, capecitabine is a convenient oral therapy with well received toxicity profile. Eribulin is the only agent that demonstrated overall survival (OS) benefit in a phase III clinical trial when compared to treatment of physician choice in heavily pre-treated patients. Ixabepilone, gemcitabine, vinorelbine and platinum agents have demonstrated activity and, therefore, constitute additional therapeutic options. In this review, we will discuss the data supporting the use of different cytotoxic agents and the general principles in guiding the use of chemotherapy

Treatment response as predictor for brain metastasis in triple negative breast cancer: A score‐based model

Background Triple negative breast cancer (TNBC) has worse prognosis than other subtypes of breast cancer, and many patients develop brain metastasis (BM). We developed a simple predictive model to stratify the risk of BM in TNBC patients receiving neo‐adjuvant chemotherapy (NAC), surgery, and radiation therapy (RT). Methods Patients with TNBC who received NAC, surgery, and RT were included. Cox proportional hazards method was used to evaluate factors associated with BM. Significant factors predictive for BM on multivariate analysis (MVA) were used to develop a risk score. Patients were divided into three risk groups: low, intermediate, and high. A receiver operating characteristic (ROC) curve was drawn to evaluate the value of the risk group in predicting BM. This predictive model was externally validated. Results A total of 160 patients were included. The median follow‐up was 47.4 months. The median age at diagnosis was 49.9 years. The 2‐year freedom from BM was 90.5%. Persistent lymph node positivity, HR 8.75 (1.76‐43.52, P = 0.01), and lack of downstaging, HR 3.46 (1.03‐11.62, P = 0.04), were significant predictors for BM. The 2‐year rate of BM was 0%, 10.7%, and 30.3% (P < 0.001) in patients belonging to low‐, intermediate‐, and high‐risk groups, respectively. Area under the ROC curve was 0.81 (P < 0.001). This model was externally validated (C‐index = 0.79). Conclusions Lack of downstaging and persistent lymph node positivity after NAC are associated with development of BM in TNBC. This model can be used by the clinicians to stratify patients into the three risk groups to identify those at increased risk of developing BM and potentially impact surveillance strategies

Targeting the Phosphatidylinositol 3-Kinase Signaling Pathway in Breast Cancer

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) network plays a key regulatory function in cell survival, proliferation, migration, metabolism, angiogenesis, and apoptosis. Genetic aberrations found at different levels make this pathway one of the most commonly disrupted in human breast cancer. Because the PI3K pathway has divergent downstream effects, the identification of the key effectors of the pathway and their presence in the different subtypes of breast tumors will allow the development of ideal targeted therapies with meaningful clinical efficacy

Long-Term Outcomes with 3-Dimensional Conformal External Beam Accelerated Partial Breast Irradiation

Purpose: Long-term tumor control and cosmetic outcomes for accelerated partial breast radiation (APBI) delivered with 3-dimensional conformal external beam radiation (3D-CRT) remain limited. We seek to address these concerns by reporting our experience of 3D-CRT APBI with extended follow-up. Methods and Materials: All patients treated with APBI delivered with 3D-CRT from January 2006 through December 2012 at a single institution were identified. Those with more than a year of follow-up were analyzed for ipsilateral breast tumor recurrence (IBTR), progression-free survival (PFS), cosmesis, and pain. Disease outcomes were analyzed by margin status (\u3c2 mm, ≥2 mm), total radiation dose prescribed, presence of invasive disease, and American Society for Radiation Oncology (ASTRO) 2016 updated consensus groupings (suitable, cautionary, and unsuitable). Results: Two hundred ninety-three patients were identified, of whom 266 had \u3e1 year of follow-up. Median follow-up was 87 months (range, 13-156). Of the 266, 162 (60.9%) were ASTRO “suitable,” 87 (32.7%) were “cautionary,” and 17 (6.4%) were “unsuitable.” Seven-year rates of IBTR and PFS were 1.8% and 95.2%, respectively. Margin status, invasive versus in situ disease, prescribed dose, and ASTRO grouping were not prognostic for either IBTR or PFS on univariate analysis. Cosmesis was good to excellent in 75.2%. Two patients (0.8%) had subsequent plastic surgery owing to poor cosmesis. Narcotic medication for treatment site pain was needed by 6 (2.3%). Conclusions: External beam APBI results in excellent long-term disease control. Good to excellent cosmetic outcomes are achieved in most patients, although increasing dose per fraction and greater percentage of irradiated breast were predictive of adverse posttreatment cosmetic outcomes. Select patients in “cautionary” and “unsuitable” consensus groupings do not appear to have inferior outcomes

Triple-Negative Breast Cancer Is Not a Contraindication for Breast Conservation

Background. Triple-negative breast cancer (TNBC) is an aggressive subtype shown to have a high risk of locoregional recurrence (LRR). The purpose of this study was to determine the impact of operation type on LRR in TNBC patients. Methods. A total of 1325 patients with TNBC who underwent breast-conserving therapy (BCT) or mastectomy from 1980 to the present were identified. Clinical and pathological factors were compared by the chi-square test. LRR-free survival (LRRFS), distant metastasis-free survival, and overall survival were estimated by the Kaplan-Meier method. Multivariate analysis was performed by the Cox proportional hazard models. Results. BCT was performed in 651 patients (49%) and mastectomy in 674 (51%). The mastectomy group had larger tumors, a higher incidence of lymphovascular invasion, and higher pathologic N stage (all P < 0.001). At 62-month median follow-up, LRR was seen in 170 (26%) in the BCT group and 203 (30%) in the mastectomy group. Five-year LRRFS rates were higher in the BCT group (76% vs. 71%, P = 0.032), as was distant metastasis-free survival (68% vs. 54%, P < 0.0001) and overall survival (74% vs. 63%, P < 0.0001). On multivariate analysis, T stage (hazard ratio [HR] 1.37, P = 0.006), high nuclear grade (HR 1.92, P = 0.002), lymphovascular invasion (HR 1.93, P < 0.0001), close/positive margins (HR 1.89, P < 0.0001), and use of non-anthracycline or taxane-based adjuvant chemotherapy (HR 2.01, P < 0.0001) increased the LRR risk, while age [ 50 years was protective (HR 0.73, P = 0.007). Operation type (mastectomy vs. BCT, HR 1.07, P = 0.55) was not statistically significant. Conclusions. BCT is not associated with increased LRR rates compared to mastectomy. TNBC should not be considered a contraindication for breast conservation

Nodal Status and Clinical Outcomes in a Large Cohort of Patients With Triple-Negative Breast Cancer

Purpose To evaluate the clinical outcomes and relationship between tumor size, lymph node status, and prognosis in a large cohort of patients with confirmed triple receptor–negative breast cancer (TNBC). Patients and Methods We reviewed 1,711 patients with TNBC diagnosed between 1980 and 2009. Patients were categorized by tumor size and nodal status. Kaplan-Meier product limit method was used to calculate overall survival (OS) and relapse-free survival (RFS). A Sidak adjustment was used for multiple group comparisons. Cox proportional hazards models were fit to determine the association of tumor size and nodal status with survival outcomes after adjustment for other patient and disease characteristics. Results Median age was 48 years (range, 21 to 87 years). At a median follow-up of 53 months (range, 0.7 to 317 months), there were 614 deaths and 747 recurrences. The 5-year OS was 80% for node-negative patients (N0), 65% for one to three positive lymph nodes (N1), 48% for four to nine positive lymph nodes (N2), and 44% for ≥ 10 positive lymph nodes (N3; P < .0001). The 5-year RFS rates were 67% for N0, 52% for N1, 36% for N2, and 33% for N3 (P < .0001). Pairwise comparison by nodal status showed that when comparing N0 with node-positive disease, there was a significant difference in OS and RFS (P < .001 all comparisons). However, when comparing N1 with N2 and N3 disease regardless of tumor size, there were no significant differences in OS or RFS. Conclusion In patients with TNBC, once there is evidence of lymph node metastasis, the prognosis may not be affected by the number of positive lymph nodes