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PurposeThere is uncertainty about outcomes differences between partial breast irradiation (PBI) and whole breast irradiation (WBI) for early-stage breast cancer.MethodsProspective randomized trials comparing adjuvant PBI to WBI in early-stage invasive breast cancer were identified using PubMed. Odds ratios (OR), 95% confidence intervals and absolute risks were computed for pre-specified efficacy and toxicity outcomes including cosmesis. Subgroup analysis evaluated the effect of PBI modality (external beam radiation treatment [EBRT], intraoperative radiation treatment [IORT] or brachytherapy) on efficacy. Meta-regression analysis explored the influence of median follow-up, patient and tumor characteristics on results.ResultsNine trials comprising 14514 patients were included. While PBI was associated with increased odds of local recurrence compared to WBI (OR 1.69, P < 0.001), it was associated with reduced odds of death without breast cancer recurrence (OR 0.55, P < 0.001) and with improvement in overall survival (OS) that approached, but did not meet statistical significance (OR 0.84, P = 0.06). Subgroup analysis for PBI modality showed significant differences in the odds of local recurrence, based on method of PBI with EBRT showing the lowest magnitude of inferiority. Nodal involvement was associated with higher local recurrence risk, while larger tumors were associated with lesser improvement in death without breast cancer recurrence and OS. PBI was associated with higher odds of fat necrosis (OR 1.72, P = 0.002). Worse cosmetic outcome with PBI approached statistical significance (OR 1.23, P = 0.06).ConclusionsCompared to WBI, PBI is associated with higher odds for local recurrence and toxicity, but less death without breast cancer recurrence. The balance between benefit and risk of PBI appears optimal for women with smaller hormone receptor positive tumors, without nodal involvement and treated with EBRT.

Data suggest that for newly approved cancer drugs safety and tolerability are worse than in control arms of registration trials. Less is known about the balance between efficacy and toxicity of drugs studied in unselected phase 3 randomized controlled trials (RCTs) including those not resulting in regulatory approval. We searched Clinicaltrials.gov to identify phase 3 RCTs in patients with advanced breast, colorectal, lung, or prostate cancer completed between January 2005 and October 2016. We extracted efficacy and safety data from publications. For efficacy hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were extracted. For safety, we computed odds ratios (ORs) and 95% confidence intervals (CIs) for toxic death, treatment discontinuation without progression and commonly reported grade 3/4 adverse events (AEs). Data were then pooled in a meta-analysis. Of 377 RCTs identified initially, 143 RCTs comprising 88,603 patients were included in the analysis. Of these, 79 (57%) trials met their primary endpoint. Compared to control groups, both PFS (HR 0.80; 95% CI 0.78–0.82) and OS (HR 0.87; 95% CI 0.85–0.89) were improved with experimental drugs. Toxic death (OR 1.14; 95% CI 1.03–1.27), treatment discontinuation without progression (OR 1.64; 95% CI 1.56–1.71) and grade 3/4 AEs were also more common with experimental drugs compared to respective control group therapy. Just over half of phase 3 RCTs in common solid tumors met their primary endpoint and in nearly half, experimental therapy had worse safety compared to control arms.

Several targeted therapies have been approved in recent years for second-line treatment of immune thrombocytopenic purpura (ITP), providing an alternative to rituximab and splenectomy. The extent to which these drugs reduce bleeding risk has not been well defined. Targeted therapies recently approved for the treatment of ITP in adults were identified through a search of recently published professional guidelines. Randomized controlled trials (RCTs) supporting regulatory approval were identified through a search of drug labels on FDA@gov. Odds ratios (ORs) and associated 95% confidence intervals (CIs) were computed for pre-specified efficacy outcomes including platelet recovery to ≥ 50,000/µL, major and minor bleeding events, and survival. ORs for all adverse events were also computed. Four targeted therapies were identified, including three thrombopoietin receptor agonists and one tyrosine kinase inhibitor. Six RCTs, comprising 752 patients, were included in the meta-analysis. More patients treated with targeted therapies for ITP as compared to placebo achieved platelet counts over ≥ 50,000/µL (OR 8.29, 95% CI 5.59–12.29). Compared to placebo, targeted therapies for ITP were associated with significantly lower odds for major bleeding (OR 0.43, 95% CI 0.21–0.91), minor bleeding (OR 0.66, 95% CI 0.45–0.97), and with numerically lower mortality rates (OR 0.24, 95% CI 0.05–1.07). The odds for adverse events were comparable between the two arms (OR 1.43 95% CI 0.76–2.67). Compared to placebo, targeted therapies for ITP increase platelet counts, decrease bleeding events, and show a trend towards lower mortality, without increased toxicity. These findings support their use as a second-line ITP treatment.

PurposeResults from clinical trials of adjuvant dose-dense chemotherapy in patients with breast cancer are inconsistent.MethodsA systematic search of MEDLINE identified studies comparing the efficacy of dose-dense adjuvant chemotherapy to a standard treatment. The primary analysis included studies that used identical regimens in the experimental and control groups, but varied only dose density. A secondary analysis included studies that used either different drugs or doses in the experimental and the control groups. Hazard ratios (HRs) and 95% confidence intervals were computed for disease-free survival (DFS) and overall survival (OS) and pooled in a meta-analysis. Subgroup analyses and meta-regression explored drug schedules utilized in control groups and the influence of clinicopathologic variables on benefit from dose-dense therapy.ResultsThe primary analysis included 5 studies comprising 9819 patients while the secondary analysis included 6 studies comprising 9679 patients. Dose-dense treatment significantly improved DFS (HR 0.85, p < 0.001) and OS (HR 0.86, p = 0.008) in the primary analysis. Similar results were observed in the secondary analysis. Dose-dense schedule was important primarily in studies utilizing paclitaxel every 3 weeks as the control group (interaction p = 0.04 for DFS interaction p = 0.001 for OS). A significantly greater relative magnitude of benefit was observed in pre-menopausal women and those with nodal involvement, but there was no influence of hormone receptor status on results.ConclusionsAdjuvant dose-dense regimens improve breast cancer outcomes. It remains uncertain whether the observed benefit reflects the impact of dose density or the inferiority of paclitaxel every 3 weeks as a control group.

Background De-intensification of anti-cancer therapy without significantly affecting outcomes is an important goal. Omission of axillary surgery or breast radiation is considered a reasonable option in elderly patients with early-stage breast cancer and good prognostic factors. Data on avoidance of both axillary surgery and radiation therapy (RT) is scarce and inconclusive. Methods A retrospective cohort study comprising all women aged 70 years and older diagnosed with early, hormone receptor (HR) positive, HER2-negative breast cancer treated with breast-conserving surgery (BCS) without sentinel lymph node biopsy (SLNB) and RT in a large tertiary center (between 2016 and 2021). Data on patient and tumor characteristics as well as outcomes including local recurrence, loco-regional recurrence, distant metastases, and death were extracted. Disease free survival (DFS) was assessed by Kaplan-Meier analysis. The Cox proportional hazard regression model was performed to identify factors (demographic and clinical characteristics of the patients) that predict the disease recurrence or death. Results A total of 100 women were included, median age of patients was 81. All patients had clinically node-negative disease with a median tumor size was 13 mm. Five (5%) women had lymphovascular invasion. At a median follow-up of 3.9 years, there were 7 (7%) recurrences, 4 local, 2 local-regional, and one distant. The median DFS for the entire group was 42 months (11–128). Eight patients (8%) died, 5 of them for reasons unrelated to breast cancer (3 of unknown reason). Tumor size larger than 13 mm was associated with significantly worse DFS (HR = 4.02, 95% CI 1.08–14.99, p  = 0.04). Conclusion Omission of both SLNB and adjuvant RT is feasible in elderly, early breast cancer patients with small luminal tumors.

Background Adjuvant endocrine therapy is a gold standard in early-stage, hormone receptor positive breast cancer. In postmenopausal women, aromatase inhibitors (AIs) are associated with improved outcome compared to tamoxifen monotherapy. Differences in the toxicity profiles of these drugs are described; however, little is known about whether the risk of adverse events changes over time. Methods Sequential reports of large, randomized, adjuvant endocrine therapy trials comparing AIs to tamoxifen were reviewed. Data on pre-specified adverse events were extracted including cardiovascular events, bone fractures, cerebrovascular disease, endometrial cancer, secondary malignancies excluding breast cancer, venous thrombosis and death without recurrence. Odds ratios (ORs) were calculated for each adverse event at each time over the course of follow-up. The change in the ORs for adverse events over time was evaluated using weighted linear regression. Results Analysis included 21 reports of 7 trials comprising 30,039 patients and reporting outcomes between 28 and 128 months of follow-up. Compared to tamoxifen, AIs use was associated with a significant reduction in the magnitude of increased odds of bone fracture over time ( β  = − 0.63, p  = 0.013). There was a non-significant decrease in the magnitude of reduced odds of secondary malignancies over time ( β  = 0.448, p  = 0.094). The differences in other toxicity profiles between AIs and tamoxifen did not change significantly over time. Conclusions The increased risk of bone fractures associated with adjuvant AIs falls over time and after discontinuation of treatment. Differences in other toxicities between AIs and tamoxifen do not change significantly over time including a persistently elevated risk of cardiovascular events .

Background Smoking is associated with an increased incidence of hormone receptor positive breast cancer. Data regarding worse breast cancer outcome in smokers are accumulating. Current literature regarding the impact of smoking on breast cancer characteristics is limited. We evaluated the impact of smoking on breast cancer characteristics and outcome. Methods This was a retrospective single center study. All women diagnosed from 4/2005 through 3/2012 and treated in our institute for early, estrogen receptor positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer, whose tumors were sent for Oncotype DX analysis were included. Medical records were reviewed for demographics, clinico-pathological parameters, treatment and outcome. Data regarding smoking were retrieved according to patients’ history at the first visit in the oncology clinic. Patients were grouped and compared according to smoking history (ever smokers vs. never smokers), smoking status (current vs. former and never smokers) and smoking intensity (pack years ≥30 vs. the rest of the cohort). Outcomes were adjusted in multivariate analyses and included age, menopausal status, ethnicity, tumor size, nodal status and grade. Results A total of 662 women were included. 28.2% had a history of smoking, 16.6% were current smokers and 11.3% were heavy smokers. Smoking had no impact on tumor size, nodal involvement and Oncotype DX recurrence score. Angiolymphatic and perineural invasion rates were higher in current smokers than in the rest of the cohort (10.4% vs. 5.1%, p  = 0.045, 8.3% vs. 3.5%, p  = 0.031, respectively). Smoking had no other impact on histological characteristics. Five-year disease free survival and overall survival rates were 95.7% and 98.5%, respectively. Smoking had no impact on outcomes. Adjusted disease free survival and overall survival did not influence the results. Conclusions Smoking had no clinically significant influence on tumor characteristics and outcome among women with estrogen receptor positive, HER2 negative, early breast cancer. As the study was limited to a specific subgroup of the breast cancer population in this heterogeneous disease and since smoking is a modifiable risk factor for the disease, further research is required to clarify the possible impact of smoking on breast cancer.

Purpose To evaluate the total biopsy and positive biopsy rates in women at high risk of breast cancer compared to the general population. Methods The study group consisted of 330 women with pathogenic variants (PVs) in BRCA1/2 attending the dedicated multidisciplinary breast cancer clinic of a tertiary medical center in Israel. Clinical, genetic, and biopsy data were retrieved from the central healthcare database and the medical files. Patients aged 50 years or older during follow-up were matched 1:10 to women in the general population referred for routine breast cancer screening at the same age, as recommended by international guidelines. The groups were compared for rate of biopsy studies performed and percentage of positive biopsy results. Matched analysis was performed to correct for confounders. Results The total biopsy rate per 1000 follow-up years was 61.7 in the study group and 22.7 in the control group ( p  < 0.001). The corresponding positive biopsy rates per 1000 follow-up years were 26.4 and 2.0 ( p  < 0.001), and the positive biopsy percentages, 42.9% and 8.7% ( p  < 0.0001). Conclusion Women aged 50 + years with PVs in BRCA1/2 attending a dedicated clinic have a 2.7 times higher biopsy rate per 1000 follow-up years, a 13.2 times higher positive biopsy rate per 1000 follow-up years, and a 4.9 times higher positive biopsy percentage than same-aged women in the general population.

Background Efficacy of immune checkpoint inhibitors (ICIs) in metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma is inconsistent. Whether the efficacy of ICIs is comparable across different subgroups remains unknown. Methods We identified randomized controlled trials (RCTs) that compared standard treatment for metastatic gastric/GEJ adenocarcinoma to ICIs. Hazard ratios (HRs) and 95% confidence intervals (CI) for overall survival (OS) were extracted and pooled in a meta‐analysis. Prespecified subgroups were included as follows: age at randomization (65 years), gender (female vs male), ethnicity (Asians vs non‐Asians), performance‐status (0 vs 1), tumor location (gastric vs GEJ), and histological subtype (diffuse vs others). OS in patients with programmed death ligand (PD‐L1) positive and with microsatellite instability‐high (MSI‐H) were also extracted and pooled in a meta‐analysis. Results Five RCTs comprising 2,264 patients were analyzed. Compared to standard therapy, ICIs did not improve OS (HR = 0.86, 95% CI 0.71‐1.03, P = .10) and the effect of ICIs on OS was similar in all subgroups. Nonsignificantly greater effect sizes were seen in older patients (HR = 0.85 vs 0.88, P = .81), male (HR = 0.82 vs 0.99, P = .16), Asians (HR = 0.86 vs 0.96, P = .55), performance‐status 0 (HR = 0.84 vs 0.88, P = .81), GEJ tumors (HR = 0.78 vs 0.90, P = .37), and nondiffuse subtype (HR = 0.71 vs 0.79, P = .62). ICIs were associated with significantly improved OS in patients with MSI‐H (HR = 0.33, P = .001), but not in PD‐L1 positive disease (HR = 0.86, P = .06). Conclusions Compared to standard treatment, ICIs in metastatic gastric/GEJ adenocarcinoma did not improve OS. None of the evaluated subgroups has shown increased magnitude of effect to ICIs, aside of the small group with MSI‐H tumors. Compared to standard treatment, ICIs in metastatic gastric/GEJ adenocarcinoma did not improve OS. None of the evaluated subgroups including, age, gender, ethnicity, performance status, primary tumor location, and histological subtype, has shown increased magnitude of effect from ICIs. In exploratory analysis for small group with MSI‐H tumors, treatment with ICIs was associated with significant OS improvement compared to the control group.

BackgroundThe combination of a taxane with trastuzumab and pertuzumab is standard of care for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The combination of vinorelbine with trastuzumab and pertuzumab showed anti-tumor activity in a phase 2 trial.Patients and methodsThe databases of two tertiary medical centers were retrospectively searched for patients with HER2-positive metastatic breast cancer who underwent first-line treatment in 2013–2019 with a taxane or vinorelbine in combination with trastuzumab and pertuzumab. Groups were compared for progression-free survival (PFS), overall survival (OS), and toxicity profile.ResultsThe study included 87 patients in the taxane group and 65 in the vinorelbine group. Overall median PFS was significantly longer in the taxane group [HR 0.56 (0.36–0.88), P = 0.01], but on multivariate analysis the difference was not statistically significant [HR 0.68 (0.4–1.1, P = 0.11)]. PFS was comparable in both groups of patients with recurrent disease [HR 0.94 (0.5–1.79), P = 0.85]. However, in patients with de novo metastatic disease, the difference in favor of the taxane group was pronounced [HR 0.4 (0.2–0.78), P = 0.007] and maintained significance on multivariate analysis [HR 0.46 (0.2–0.97, P = 0.04)]. There was no statistical significant difference in OS in the whole cohort [HR 0.69 (0.39–1.23)] or the subgroups.ConclusionsPatients with HER2-positive metastatic breast cancer had similar survival with first-line treatment of taxane or vinorelbine combined with trastuzumab and pertuzumab. When the analysis was adjusted for prognostic factors, there was no PFS benefit for taxanes except in the subgroup with de novo disease.