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IMPORTANCE: Oral tamoxifen citrate benefits women with ductal carcinoma in situ (DCIS), but concern about toxic effects has limited acceptance. Previous pilot studies have suggested transdermal 4-hydroxytamoxifen gel has equivalent antiproliferative efficacy to oral tamoxifen, with low systemic exposure. OBJECTIVE: To demonstrate that 4-hydroxytamoxifen gel applied to the breast skin is noninferior to oral tamoxifen in its antiproliferative effect in DCIS lesions. DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, phase 2 preoperative window trial was performed at multicenter breast surgery referral practices from May 31, 2017, to January 27, 2021. Among 408 women with estrogen receptor–positive DCIS who were approached, 120 consented and 100 initiated study treatment. The most common reasons for nonparticipation were surgical delay, disinterest in research, and concerns about toxic effects. Data were analyzed from January 26, 2021, to October 5, 2022. INTERVENTION: Random assignment to oral tamoxifen citrate, 20 mg/d, and gel placebo or 4-hydroxytamoxifen gel, 2 mg/d per breast, and oral placebo, for 4 to 10 weeks, followed by DCIS resection. MAIN OUTCOMES AND MEASURES: The primary end point was absolute change in DCIS Ki-67 labeling index (Ki67-LI). Secondary end points included 12-gene DCIS Score, breast tissue tamoxifen metabolite concentrations, tamoxifen-responsive plasma protein levels, and patient-reported symptoms. Noninferiority of Ki67-LI reduction by 4-hydroxytamoxifen gel was tested using analysis of covariance; within- and between-arm comparisons were performed with paired t tests for mean values or the Wilcoxon rank sum test for medians. RESULTS: Of 90 participants completing treatment (mean [SD] age, 55 [11] years; 8 [8.9%] Asian, 16 [17.8%] Black, 8 [8.9%] Latina, and 53 [58.9%] White), 15 lacked residual DCIS in the surgical sample, leaving 75 evaluable for the primary end point analysis (40 in the oral tamoxifen group and 35 in the 4-hydroxytamoxifen gel group). Posttreatment Ki67-LI was 3.3% higher (80% CI, 2.1%-4.6%) in the 4-hydroxytamoxifen gel group compared with the oral tamoxifen group, exceeding the noninferiority margin (2.6%). The DCIS Score decreased more with oral tamoxifen treatment (−16 [95% CI, −22 to −9.4]) than with 4-hydroxytamoxifen gel (−1.8 [95% CI, −5.8 to 2.3]). The median 4-hydroxytamoxifen concentrations deep in the breast were nonsignificantly higher in the oral tamoxifen group (5.7 [IQR, 4.0-7.9] vs 3.8 [IQR, 1.3-7.9] ng/g), whereas endoxifen was abundant in the oral tamoxifen group and minimal in the 4-hydroxytamoxifen gel group (median, 13.0 [IQR, 8.9-20.6] vs 0.3 [IQR, 0-0.3] ng/g; P < .001). Oral tamoxifen caused expected adverse changes in plasma protein levels and vasomotor symptoms, with minimal changes in the transdermal group. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, antiproliferative noninferiority of 4-hydroxytamoxifen gel to oral tamoxifen was not confirmed, potentially owing to endoxifen exposure differences. New transdermal approaches must deliver higher drug quantities and/or include the most potent metabolites. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02993159

Neoadjuvant chemotherapy is now considered standard of care for most of the patients with clinically node-positive disease, and for a large proportion of triple-negative breast cancer and HER2-positive tumors. Here we reviewed the benefit of neoadjuvant chemotherapy on surgical de-escalation, the prognostic role of pathologic complete response, new therapeutic strategies across subtypes, and ongoing studies assessing locoregional treatment de-escalation according to treatment response. Thanks to the integration of new biomarkers, new ways to detect minimal residual disease after neoadjuvant chemotherapy, and new targeted therapies, the landscape of neoadjuvant therapy is evolving rapidly, and our ability to personalize breast cancer treatment is improving.

Characterizing macrophysical properties of deep convective systems on a global scale is a precursor to understanding their influence on Earth's Energy Budget and Water Cycle. This study documents the properties of global convective objects (COs) in the early afternoon (1:30 p.m. local time; LT) and overnight (1:30 a.m. LT) measurements from the A‐Train satellite constellation. CloudSat measurements are used to identify convective cores and establish their intensity, while other A‐Train data sets define cloud structure, storm spatial extent, rainfall yield, and radiative effects of each CO. Global distributions of storm characteristics are consistent with previous studies in which the most intense convection is located over tropical land, particularly over the Amazon and Congo Basin, while the largest COs occur over the Maritime Continent. Despite their limited twice‐daily sampling, A‐Train measurements capture that early afternoon convection over tropical land is both more intense and produces heavier rainfall than nighttime land‐based convection, while the day‐night differences are minimal over the tropical ocean. High‐resolution estimates of updraft cores reveal that CO size increases as the number of distinct cores in a CO increases owing to an increase in nonconvective rain and anvil cloud area. Convective objects generally cool the environment, which is strongest over the Northern Hemisphere midlatitudes, but cooling weakens as the nonconvective cloud fraction increases such that 30% of COs actually exert a net warming effect. These results suggest that A‐Train measurements may capture bulk connections between deep convective cloud features, precipitation, and radiative effects despite a lack of complete diurnal sampling. Storm clouds have a large impact on Earth's weather and climate. They produce a large fraction of global rainfall in short intense downpours and can both cool and warm the environment by reflecting sunlight and reducing emitted thermal radiation. Whether they cool or warm the atmosphere depends on cloud size and thickness as well as rainfall amount. These features impact the moisture and energy transfer within local and large‐scale environments, which influence weather patterns. Yet, it is difficult to represent the influences that storms have on a global scale in climate and weather forecasting models. This work provides a global perspective of early afternoon and late night storm signatures and their energy and rainfall contributions. Using global satellite observations, storms are the strongest and produce the heaviest rainfall over tropical land during early afternoon, but they are the largest over tropical ocean. Storms generally cool the Earth at this time of day, but cooling weakens as the amount of nonraining cloud within the storm grows. This work may help improve storm representation in numerical models by connecting properties, such as the cloud size, strength, and frequency, to rain rates and energy output to better assess features that have the largest impact on weather and climate. The A‐Train observes several thousand convective objects (COs) to link cloud, rainfall, and radiative features despite limited diurnal samplingConvection is the most intense over land, but the largest systems with the strongest radiative effects occur over tropical oceanCOs generally cool the tropics at 1:30 p.m./a.m. local time but this effect weakens as the number of embedded cores increases The A‐Train observes several thousand convective objects (COs) to link cloud, rainfall, and radiative features despite limited diurnal sampling Convection is the most intense over land, but the largest systems with the strongest radiative effects occur over tropical ocean COs generally cool the tropics at 1:30 p.m./a.m. local time but this effect weakens as the number of embedded cores increases