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IMPORTANCE: Aurora A kinase (AURKA) activation, related in part to AURKA amplification and variants, is associated with downregulation of estrogen receptor (ER) α expression, endocrine resistance, and implicated in cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) resistance. Alisertib, a selective AURKA inhibitor, upregulates ERα and restores endocrine sensitivity in preclinical metastatic breast cancer (MBC) models. The safety and preliminary efficacy of alisertib was demonstrated in early-phase trials; however, its activity in CDK 4/6i–resistant MBC is unknown. OBJECTIVE: To assess the effect of adding fulvestrant to alisertib on objective tumor response rates (ORRs) in endocrine-resistant MBC. DESIGN, SETTING, AND PARTICIPANTS: This phase 2 randomized clinical trial was conducted through the Translational Breast Cancer Research Consortium, which enrolled participants from July 2017 to November 2019. Postmenopausal women with endocrine-resistant, ERBB2 (formerly HER2)–negative MBC who were previously treated with fulvestrant were eligible. Stratification factors included prior treatment with CDK 4/6i, baseline metastatic tumor ERα level measurement (<10%, ≥10%), and primary or secondary endocrine resistance. Among 114 preregistered patients, 96 (84.2%) registered and 91 (79.8%) were evaluable for the primary end point. Data analysis began after January 10, 2022. INTERVENTIONS: Alisertib, 50 mg, oral, daily on days 1 to 3, 8 to 10, and 15 to 17 of a 28-day cycle (arm 1) or alisertib same dose/schedule with standard-dose fulvestrant (arm 2). MAIN OUTCOMES AND MEASURES: Improvement in ORR in arm 2 of at least 20% greater than arm 1 when the expected ORR for arm 1 was 20%. RESULTS: All 91 evaluable patients (mean [SD] age, 58.5 [11.3] years; 1 American Indian/Alaskan Native [1.1%], 2 Asian [2.2%], 6 Black/African American [6.6%], 5 Hispanic [5.5%], and 79 [86.8%] White individuals; arm 1, 46 [50.5%]; arm 2, 45 [49.5%]) had received prior treatment with CDK 4/6i. The ORR was 19.6%; (90% CI, 10.6%-31.7%) for arm 1 and 20.0% (90% CI, 10.9%-32.3%) for arm 2. In arm 1, the 24-week clinical benefit rate and median progression-free survival time were 41.3% (90% CI, 29.0%-54.5%) and 5.6 months (95% CI, 3.9-10.0), respectively, and in arm 2 they were 28.9% (90% CI, 18.0%-42.0%) and 5.4 months (95% CI, 3.9-7.8), respectively. The most common grade 3 or higher adverse events attributed to alisertib were neutropenia (41.8%) and anemia (13.2%). Reasons for discontinuing treatment were disease progression (arm 1, 38 [82.6%]; arm 2, 31 [68.9%]) and toxic effects or refusal (arm 1, 5 [10.9%]; arm 2, 12 [26.7%]). CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that adding fulvestrant to treatment with alisertib did not increase ORR or PFS; however, promising clinical activity was observed with alisertib monotherapy among patients with endocrine-resistant and CDK 4/6i–resistant MBC. The overall safety profile was tolerable. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02860000

IMPORTANCE: Whether racial and ethnic disparities in locoregional recurrence (LRR) exist among patients with similar access to care treated in randomized clinical trials is unknown. OBJECTIVE: To examine racial and ethnic differences in LRR among patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (ERBB2 [formerly HER2 or HER2/neu])–negative, node-negative breast cancer enrolled in the Trial Assigning Individualized Options for Treatment (TAILORx). DESIGN, SETTING, AND PARTICIPANTS: This unplanned retrospective post hoc analysis examined a prospective multicenter clinical trial population of women with breast cancer enrolled between 2006 and 2010, with 9 years of follow-up. The TAILORx investigators randomized patients to treatment based on their Oncotype DX recurrence score, including endocrine therapy alone (recurrence score <11), endocrine therapy alone vs chemotherapy followed by endocrine therapy (recurrence score 11-25), or chemotherapy followed by endocrine therapy (recurrence score >25). Patients with unknown race and ethnicity or lack of follow-up were excluded from this analysis. Data analysis was performed between December 2021 and March 2022. MAIN OUTCOME AND MEASURES: Locoregional recurrence was defined as ipsilateral in breast, skin, chest wall, or regional nodal recurrence without concurrent distant recurrence, and was stratified by racial and ethnic group. Unadjusted Kaplan-Meier and adjusted Cox proportional hazards regression models were used for survival analyses. RESULTS: Of the 10 273 women enrolled in TAILORx, this analysis included 9369 with T1-2N0 HR-positive, ERBB2-negative breast cancer. Of these patients, 428 (4.6%) were Asian, 886 (9.4%) were Hispanic, 676 (7.2%) were non-Hispanic Black (hereinafter Black), and 7406 (78.8%) were non-Hispanic White (hereinafter White). Assigned treatment receipt was high, with a 9.3% (n = 870) crossover of treatment groups and a median endocrine therapy duration of longer than 60 months, ranging from 61.1 to 65.9 months, across racial and ethnic groups. A total of 6818 patients (72.6%) received radiation (6474 [96.1%] after breast-conserving surgery and 344 [13.0%] after mastectomy). At a median follow-up of 94.8 months (range, 1-138 months), 8-year LRR rates were 3.6% (95% CI, 1.6%-5.6%) in Asian patients, 3.9% (95% CI, 2.2%-5.4%) in Black patients, 3.1% in Hispanic patients (95% CI, 1.7%-4.5%), and 1.8% (95% CI, 1.5%-2.3%) in White patients (P < .001). In survival analyses adjusted for patient, tumor, and treatment factors, Asian race (hazard ratio, 1.91 [95% CI, 1.12-3.29]) and Black race (1.78 [1.15-2.77]) were independently associated with LRR. In adjusted survival analyses for breast cancer mortality, LRR was independently associated with increased breast cancer mortality (hazard ratio, 5.71 [95% CI, 3.50-9.31]). CONCLUSIONS AND RELEVANCE: In this post hoc analysis, racial and ethnic differences in LRR were observed among patients with T1-2N0 HR-positive, ERBB2-negative breast cancer despite high rates of treatment receipt in this clinical trial population, with the highest LRR rates in Asian and Black patients. Further study is needed to understand whether failure to rescue after LRR may contribute to racial disparities in breast cancer mortality. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00310180

Detecting mutations from single DNA molecules is crucial in many fields but challenging. Next-generation sequencing (NGS) affords tremendous throughput but cannot directly sequence double-stranded DNA molecules (‘single duplexes’) to discern the true mutations on both strands. Here we present Concatenating Original Duplex for Error Correction (CODEC), which confers single duplex resolution to NGS. CODEC affords 1,000-fold higher accuracy than NGS, using up to 100-fold fewer reads than duplex sequencing. CODEC revealed mutation frequencies of 2.72 × 10−8in sperm of a 39-year-old individual, and somatic mutations acquired with age in blood cells. CODEC detected genome-wide, clonal hematopoiesis mutations from single DNA molecules, single mutated duplexes from tumor genomes and liquid biopsies, microsatellite instability with 10-fold greater sensitivity and mutational signatures, and specific tumor mutations with up to 100-fold fewer reads. CODEC enables more precise genetic testing and reveals biologically significant mutations, which are commonly obscured by NGS errors.

Adenopathy related to COVID-19 vaccination is a frequent imaging finding that may lead to a diagnostic conundrum in patients with manifest or suspected cancer, in whom it may be indistinguishable from malignant nodal involvement.

Supplemental Digital Content is available in the text.

Genomic profiling of ER+/HER2−breast tumors after short-term estrogen deprivation revealed alterations associated with intrinsic resistance and provided mechanistic insights.

Objective -Platelets, which are mainly known for their role in hemostasis, are now known to play a crucial role in tumor metastasis and neovascularization. Metastatic disease is the cause of roughly 90% of all cancer-related deaths and understanding the mechanisms leading to dissemination of tumor cells to distant sites remains one of the main challenges of cancer research. Platelets carry a plethora of potent angiogenic and metastatic mediators within their alpha-granules and exposure to breast tumor cells induces platelet activation, leading to release of these mediators. Tamoxifen is a selective estrogen receptor modulator that is widely used for the treatment and prevention of breast cancer; its use is associated with a 50% reduction in the risk of invasive and noninvasive breast cancer in women who utilized the drug for at least 5 years. Interestingly, tamoxifen has demonstrated anti-cancer efficacy in estrogen negative breast cancers suggesting that this drug has additional mechanisms of action. Previously tamoxifen and its metabolites have been shown to directly impact platelet function. Because platelets are critical for metastatic spread, we posited that tamoxifen or its metabolites may exert anti-tumor effects through direct platelet inhibition. To test this hypothesis, we examined the impact of tamoxifen on platelet activation, angiogenic potential and metastasis both ex vivoand in breast cancer patients utilizing tamoxifen therapy.

No relevant conflicts of interest to declare.

Elevated numbers of circulating bloodborne tissue factor antigen-bearing microparticles represent a significant risk factor for the development of venous thromboembolic events in cancer patients. We recently demonstrated the efficacy of low molecular weight heparin to prevent thrombosis in cancer patients with high levels of circulating tissue factor bearing microparticles. Enthusiasm for prophylactic anticoagulation in cancer cohorts is tempered by the requirement for daily self-injection and potential risk for hemorrhage. Statins significantly reduce the incidence of venous thromboembolic events in healthy individuals by an uncertain mechanism. Statins reduce the generation of tissue factor bearing microparticles in vitro and in animal models. Whether statins affect tissue factor bearing microparticles in cancer patients has not been previously assessed. We performed a randomized phase II study to evaluate whether rosuvastatin reduces the number of circulating tissue factor bearing microparticles in women with metastatic breast cancer.Eligibility requirements included women with metastatic breast cancer on stable endocrine therapy (no changes within previous 6 weeks) with preserved bone marrow function. Patients were excluded if actively receiving chemotherapy (within prior 5 weeks) or currently taking statins. Baseline laboratory testing was performed at days 0 and 28 following enrollment. Study subjects were randomized to rosuvastatin 20 mg or 40 mg to be initiated from days 28 to 56. Repeat laboratory testing was performed on days 42 and 56 to assess for a reduction of tissue factor bearing microparticles and D-dimer. The number of circulating tissue factor bearing microparticles was measured by impedance-based flow cytometry and tissue factor activity was measured by a chromogenic Xa assay. Two-sided Wilcoxon signed rank test was used to compare the median levels at baseline and post treatment of laboratory endpoints within group, and Fisher exact test and Wilcoxon rank sum test to compare baseline characteristics between groups.A total of 19 women have been enrolled. Nine women were randomized to rosuvastatin 20 mg and ten were randomized to 40 mg. There were no significant differences between the two groups in baseline characteristics (e.g. age, body mass index, performance status, blood counts, renal function or number of tissue factor bearing microparticles). For the group randomized to rosuvastatin 20 mg, we observed no change in the number of tissue factor bearing microparticles (1576/μl vs 1888/μl , P= 0.55), microparticle-associated tissue factor activity, D-dimer or C-reactive protein (CRP), (P>0.05). In the group of women who received 40 mg rosuvastatin, the median decrease in the number of circulating tissue factor bearing microparticles per patient was -28%, with a median baseline value of 1763/μl versus a post-treatment value of 1216/μl (P=0.047). The group receiving 40mg rosuvastatin also demonstrated a non-significant median change in D-dimer of -21% (P=0.44), microparticle-associated tissue factor activity of -2% (P=0.84), and CRP of -10% (P= 0.81).In a randomized phase II study in women with metastatic breast cancer, we observed a statistically significant 28% decrease in circulating tissue factor bearing microparticles following initiation of rosuvastatin 40 mg. Furthermore, these results emphasize that assay of tissue factor antigen-bearing microparticles does not correlate with assay of tissue factor activity. Based on the association between tissue factor-antigen bearing microparticles and cancer-associated thrombosis, these data provide additional support for a large scale clinical trial to assess the efficacy of statins to prevent thrombosis in cancer patients.Off Label Use: rosuvastatin to lower tissue factor bearing microparticles.

Elevated numbers of circulating bloodborne tissue factor antigen-bearing microparticles represent a significant risk factor for the development of venous thromboembolic events in cancer patients. We recently demonstrated the efficacy of low molecular weight heparin to prevent thrombosis in cancer patients with high levels of circulating tissue factor bearing microparticles. Enthusiasm for prophylactic anticoagulation in cancer cohorts is tempered by the requirement for daily self-injection and potential risk for hemorrhage. Statins significantly reduce the incidence of venous thromboembolic events in healthy individuals by an uncertain mechanism. Statins reduce the generation of tissue factor bearing microparticles in vitro and in animal models. Whether statins affect tissue factor bearing microparticles in cancer patients has not been previously assessed. We performed a randomized phase II study to evaluate whether rosuvastatin reduces the number of circulating tissue factor bearing microparticles in women with metastatic breast cancer.