Laura J. Esserman

The Women Informed to Screen Depending on Measures of risk (WISDOM) Study (clinicaltrials.gov NCT02620852, 2016-08-31) is pragmatic randomized controlled trial evaluating risk assessment to inform the age to start, frequency and modality of breast cancer screening and risk reduction. The WISDOM Study uses a preference-tolerant design, enabling women who decline randomization to self-select their screening arm. The risk-based arm included comprehensive breast cancer risk assessment using the Breast Cancer Surveillance Consortium (BCSC) model and genetics. From August 2016 to February 2023, WISDOM enrolled a large, diverse, nationwide cohort of 46,403 participants - 77% non-Hispanic (NH) White, 9% Hispanic, 6% (NH) Black, and 5% (NH) Asian; demographic diversity increased over time. Mean age at baseline was 54 years. 28,372 (61%) were randomized, while 89% of those who self-selected their screening arm chose risk-based screening. The preference-tolerant design captured real-world screening preferences while maintaining scientific rigor and demonstrated strong preference for risk-based screening.

Dynamic biomarkers of therapy response are critical for precision oncology but often rely on serial tissue biopsies, which are invasive and not always feasible. In contrast, peripheral blood offers a minimally invasive, dynamic window into the evolving systemic immune landscape. Leveraging this, we performed RNA sequencing on 546 peripheral blood samples from 160 patients with high-risk stage II/III human epidermal growth factor receptor 2 (HER2)–negative breast cancer treated with either chemotherapy alone or in combination with immunotherapy (chemoimmunotherapy). Our analysis uncovered immune correlates of tumor subtype and treatment response. For example, samples from patients with triple-negative breast cancer exhibited elevated T cell receptor clonality and robust immune activation profiles. Among patients receiving chemoimmunotherapy, early responders demonstrated high baseline T cell receptor diversity, followed by rapid clonal expansion and activation of T cells after just one treatment cycle. We developed a multiparametric peripheral immune biomarker that integrated baseline and early on-treatment features to predict response to pembrolizumab, which was successfully validated in an independent cohort of 59 patients with breast cancer treated with neoadjuvant dostarlimab. These findings reveal the potential of blood-based immune monitoring to predict immunotherapy benefit, offering an accessible tool for tailoring treatment strategies in breast cancer.

Importance: Individual breast cancer risk can guide screening initiation, frequency, use of supplemental imaging, and preventive measures to improve breast cancer screening by shifting resources from low-risk women to high-risk women. Objective: To determine whether risk-based breast cancer screening is a feasible alternative to annual mammography. Design, Setting, and Participants: Parallel-group, pragmatic, multicenter randomized clinical trial comparing risk-based (n = 14 212) with annual (n = 14 160) breast cancer screening. Women aged 40 to 74 years without prior diagnoses of breast cancer or ductal carcinoma in situ, or prophylactic bilateral mastectomy, were recruited from all 50 US states from September 2016 to February 2023, with follow-up through September 5, 2025 (median follow-up, 5.1 years). Statistical analysis was conducted between July and November 2025. All study procedures were conducted via an online platform. Women who declined randomization were enrolled in an observational cohort. Interventions: Risk assessment included sequencing of 9 susceptibility genes, polygenic risk score, and the Breast Cancer Surveillance Consortium version 2 model. The risk-based group received 1 of 4 recommendations: (1) highest risk (≥6% 5-year risk, high-penetrance pathogenic variant): alternating mammography and magnetic resonance imaging (MRI) every 6 months and counseling; (2) elevated risk (top 2.5 risk percentile by age): annual mammography and risk-reduction counseling; (3) average risk: biennial mammography; and (4) low risk (aged 40-49 years and <1.3% 5-year risk): no screening until risk is 1.3% or greater or age 50 years. Main Outcomes and Measures: The coprimary outcomes included noninferiority for stage ≥IIB cancers and superiority in reducing biopsy rates. Secondary outcomes included identification of stage ≥IIA cancers, mammogram rates, uptake of prevention strategies in higher risk cohorts, preference for screening group in the observational cohort, ductal carcinoma in situ, MRI, and stage-specific cancer rates. Results: A total of 28 372 women were randomized. The mean (SD) age was 54 (9.6) years and the majority were non-Hispanic White (77%). The rate of stage ≥IIB cancers was noninferior in the risk-based compared with the annual group (risk-based: 30.0 [95% CI, 16.3-43.8] vs annual: 48.0 [95% CI, 30.1-65.5] per 100 000 person-years; rate difference, −18.0 per 100 000 person-years [95% CI, −40.2 to 4.1]). The rate of breast biopsies was not lower in the risk-based group (rate difference, 98.7 per 100 000 person-years [95% CI, −17.9 to 215.3]) despite fewer mammograms (rate difference, −3835.9 [95% CI, −4516.8 to −3154.9]). The cumulative incidence of cancer, biopsy, mammogram, and MRI increased as risk category increased. In the observational cohort, 89% of participants (15 980/18 031) chose risk based. Conclusions: Risk-based breast cancer screening that includes population-based genetic testing safely stratified risk and screening intensity, but did not reduce biopsy rates. Trial Registration: ClinicalTrials.gov Identifier: NCT02620852

RISE UP (Revolutionizing Investigations to StEp Up Prevention) for breast cancer brought together leading cancer specialists, women’s health providers, basic and population scientists, regulators, politicians, industry leaders, patient advocates, and more from around the world to discuss and chart a radical rethinking of breast cancer prevention and risk reduction through a lens of hormonal management across a woman’s life course. The presentations at RISE UP were organized to outline a path forward by leveraging what we know about breast cancer biology, early detection, treatment, and endocrine therapy toward a better and sustainable approach for breast cancer prevention. Important conference considerations were to expand our thinking about prevention by broadly considering how the hormonal environment during different life phases or common benign conditions could be better managed to minimize breast cancer risk. This set the stage for transitioning to advances in risk prediction, promising risk-reducing agents, and biomarker-driven trials to test them. Biomarker-based trials discussed focused on 1) lower or intermittent doses of standard prevention agents, 2) drugs already approved for other health purposes, and 3) maximizing benefits from lifestyle interventions alone or in combination. Throughout RISE UP, there was a strong focus on promoting health equity, including comprehensive reproductive health access, equitable representation in clinical trials, and strategies to educate women, providers, and advocates about disparities in care and how to successfully reduce them. The meeting concluded with a competition for innovative approaches to breast cancer prevention that could be integrated into hormonal and women’s health interventions. RISE UP was an innovative conference that provided a forum for cross-cutting topics in women’s health that do not currently exist. The insights shared at RISE UP will be paradigm shifting in breast cancer prevention and women’s health space in the years to come.

Purpose of Review: Tailoring treatment strategies to the biological features of invasive disease and the individual needs and preference of each patient has transformed the way we manage breast cancer. This article calls for a similar shift in the management paradigm of ductal carcinoma in situ (DCIS) from a uniform treatment model toward a risk-stratified stepwise approach that aligns with the heterogeneous nature of the disease to avoid overtreatment. Recent Findings: Most DCIS lesions are hormone receptor positive, and only a subset have a risk for progression to invasive cancer. Early results from observational and clinical studies indicate that active surveillance is a safe and feasible alternative to upfront surgical treatment for low-risk DCIS. Ongoing clinical trials like RECAST will further inform and refine strategies for optimal management of this condition. Summary: The integration of risk-adapted management strategies, endocrine risk-reducing interventions, and advanced imaging modalities into active surveillance protocols hold significant potential to reduce overtreatment and personalize care for patients with DCIS. Early data from clinical trials support the notion that providing a period of active surveillance is safe and offers a critical assessment window during which DCIS treatment can be individualized. Strengthening the evidence base to support the adoption of active surveillance as an initial approach in the management of DCIS is an important clinical priority.

Importance: The current ocular Common Terminology Criteria for Adverse Events (CTCAE) mix eye signs with symptoms and lack standardized clinical photographs and experimental oncology drug dose modification recommendations. Robust reporting of ocular adverse events (AEs) is important to maintain patient safety and to guide the development of novel efficacious drugs. Objective: To develop improved ocular AE grading scales to reliably evaluate and grade ocular AEs in patients on experimental oncology drug therapy and to provide clear drug dose modification recommendations. Design, Setting, and Participants: A collaborative multicenter interspecialty working group consisting of oncologists and academic ophthalmologists from 11 academic centers in the US and ophthalmologists from the US Food and Drug Administration was assembled in February 2023 to form a consensus on new experimental oncology drug–related ocular AE grading scales. The grading scales were released in June 2023. Main Outcomes and Measures: Expert consensus on novel experimental oncology drug–related ocular AE grading scales. Results: Six experimental oncology drug–related ocular AE grading scales were developed with agreement from ophthalmologists and oncologists for use in antibody-drug conjugate clinical trials: visual acuity, eye symptoms, cornea, conjunctiva/sclera, anterior chamber, and retina/posterior segment. Conclusions and Relevance: The new experimental oncology drug–related ocular AE grading scales developed by the consensus panel were developed to be more concise, containing photographs where applicable, and to provide clear drug dose modification recommendations compared with the previous CTCAE. Use of these ocular AE grading scales may allow for more objective and consistent incidence measurements of ocular AEs throughout clinical trials and postmarketing, potentially facilitating safe testing of novel agents that may cause eye toxicity.

Early-stage breast cancers resistant to neoadjuvant therapy (NAT), characterized by high residual cancer burden (RCB) after treatment, have an increased risk of metastatic recurrence. Here, we show that circulating tumor DNA (ctDNA) detected using a tumor-informed test (1) can improve risk stratification of patients with NAT-resistant tumors (RCB-II/RCB-III) and (2) predict response to NAT. Stratification using ctDNA status at pretreatment or post-NAT and ctDNA dynamics identified NAT-resistant tumors with a significantly decreased risk of metastatic recurrence. ctDNA clearance as early as week 3 across receptor subtypes predicted favorable responses to NAT, including immunotherapies. Interestingly, less than a fifth of patients with NAT-resistant tumors were ctDNA-positive post-NAT. Serial mutation profiling of NAT-resistant tumors revealed that patient-specific ctDNA assay variants remained detectable over time, including in tumors of patients ctDNA-negative post-NAT. Refining risk stratification for NAT-resistant tumors using ctDNA and understanding ctDNA shedding in these tumors could guide treatment decisions to prevent or delay metastatic recurrence.

Supplementary Table 1. ILC patient and tumor characteristics, including cases with missing data.