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Sara M Tolaney

Publications and source records attributed to Sara M Tolaney.

7 recordsLinked to original sources
PubMed2026

Association of immune and proliferation gene signatures and stromal tumor-infiltrating lymphocytes with clinical outcomes in patients with stage I triple-negative breast cancer.

BACKGROUND: One-third of patients with triple-negative breast cancer (TNBC) are diagnosed with stage I tumors. Biomarkers to stratify prognosis in this setting remain a major unmet need. METHODS: Tissue samples and clinicopathologic data were retrieved from consecutive patients with stage I TNBC (defined as ER <10% and HER2-negative) who underwent upfront breast surgery and received standard of care adjuvant systemic therapy at Dana-Farber/Brigham Cancer Center between 2016 and 2021. The TNBC-DX assay (Core Immune Gene [CIG] signature, proliferation signature) was applied to tumor tissue, and stromal tumor-infiltrating lymphocytes (sTILs) were centrally reviewed. Both biomarkers were tested for association with clinical outcomes using the Kaplan-Meier method. RESULTS: A total of 253 patients with stage I TNBC were included. Most tumors were ductal (88.9%) and high-grade (73.1%); 65.2% of patients received adjuvant chemotherapy. With 18 recurrence events observed, the 3-year recurrence-free survival (RFS) in the overall cohort was 95.0% (95% confidence interval [CI]: 92.1% - 98.1%) and the 3-year overall survival was 97.9% (95% CI: 95.9% - 100.0%). No significant differences in RFS were observed by TNBC-DX (n&#x202f;=&#x202f;117 patients) or sTILs (n&#x202f;=&#x202f;123 patients) category. However, a 3-year RFS of 100% (95% CI: 100% - 100%) was observed among the 29 patients with the highest CIG score quartile. A favorable prognosis was also observed in patients with high sTILs (>20%), who experienced a 3-year RFS of 97.0% (95% CI: 90% - 100%). Conversely, a high TNBC-DX proliferation score was numerically associated with poor outcomes, with a 3-year RFS of 83% (95% CI: 68% - 100%). CONCLUSIONS: In this retrospective study, immune and proliferative features showed opposing prognostic trends in stage I TNBC. Their integration may improve risk stratification and warrants further investigation.

Stromal tumor infiltrating lymphocytes (sTILs)↗
PubMed2026

Molecular and immune profiling of HER2-low, HER2 ultra-low, and HER2-null male breast cancer.

BACKGROUND: HER2 expression is described along a biological continuum from null to positive and serves as a critical biomarker for therapeutic guidance in breast cancer (BC). While HER2-low and ultra-low categories have emerged as actionable targets for antibody-drug conjugates (ADCs) in female BC, their molecular and immune characteristics remain largely unexplored in male breast cancer. METHODS: We profiled 214 male breast tumors using next-generation sequencing and whole-transcriptome sequencing to assess mutational, transcriptomic, and immune landscapes. Tumor mutational burden (TMB) was defined as high if&#x202f;>&#x202f;10 mutations/Mb. Immune cell fractions were inferred using Quantiseq deconvolution. RESULTS: Among 214 samples, 66 (30.8%) were HER2-null, 53 (24.8%) HER2 ultra-low, 80 (37.4%) HER2-low, and 15 (7.0%) HER2-positive. HER2 ultra-low tumors exhibited a higher prevalence of PIK3CA mutations (39.2% vs 22.6%, p&#x202f;&#x2264;&#x202f;0.05) compared to HER2-null. No significant differences were observed in TMB-high frequency or PD-L1 expression across subgroups. Immune composition differed primarily between HER2-null and HER2-expressing subgroups: HER2-ultra-low tumors showed higher B-cell infiltration, whereas HER2-null tumors were enriched in neutrophils. Transcriptomic analysis revealed upregulation of selected stemness-associated genes (NANOG, KLF4, POU5F1) and CEACAM1 in HER2-null tumors, while HER2-low and HER2-ultra-low tumors were largely similar across most molecular and immune readouts in this cohort. CONCLUSIONS: HER2-null male breast cancer appears to represent the most biologically divergent subgroup within the HER2-negative spectrum, whereas HER2-low and HER2-ultra-low tumors were largely similar in this cohort. These findings support further investigation of HER2-null disease as a distinct biological state and provide hypothesis-generating data for biomarker development in this rare population.

Male↗
PubMed2026

Neoadjuvant Paclitaxel, Trastuzumab, and Pertuzumab for Stage II to III, ERBB2-Positive Breast Cancer: A Secondary Analysis of the DAPHNe Trial.

IMPORTANCE: The neoadjuvant combination of paclitaxel, trastuzumab, and pertuzumab (THP) represents a promising abbreviated regimen for early-stage ERBB2-positive breast cancer, but long-term outcomes and the role of ultrasensitive circulating tumor DNA (ctDNA) monitoring remain incompletely defined. OBJECTIVE: To assess 5-year outcomes and characterize ctDNA dynamics with an ultrasensitive assay in patients with ERBB2-positive breast cancer receiving neoadjuvant THP. DESIGN, SETTING, AND PARTICIPANTS: This study was a prespecified secondary analysis of the prospective, single-arm, investigator-initiated phase 2 DAPHNe nonrandomized clinical trial. Patients were enrolled in the DAPHNe trial from November 2018 to January 2020. The trial took place at a multicenter academic cancer center and affiliated community practices. Participants included patients with stage II to III ERBB2-positive breast cancer receiving neoadjuvant THP for 12 weeks. Ultrasensitive ctDNA analyses were performed in patients with available tumor tissue and serial plasma samples. The secondary analysis was conducted between between March 2023 and April 2025. INTERVENTIONS: Neoadjuvant THP administered for 12 weeks, followed by surgery and adjuvant therapy guided by pathologic response. MAIN OUTCOMES AND MEASURES: Main outcomes included 5-year event-free survival, recurrence-free interval (RFI), distant RFI, and overall survival. ctDNA detection and clearance were assessed using a whole-genome-based, tumor-informed ultrasensitive assay at 4 predefined time points (baseline, preoperative, postoperative, and late adjuvant). RESULTS: The overall trial cohort included 98 patients (median [IQR] age, 49.5 years [24.0-78.0 years]; 97 female patients [99.0%]; 1 male patient [1.0%]), with mostly stage 2 disease (91 patients [92.9%]) and hormone receptor-positive tumors (65 patients [66.3%]). With a median (IQR) follow-up of 5.2 (5.0-5.4) years, the 5-year event-free survival was 99% (95% CI, 97%-100%), the 5-year RFI was 98% (95% CI, 93%-100%), the 5-year distant RFI was 100% (95% CI, 100%-100%), and the 5-year overall survival was 99% (95% CI, 97%-100%). Among 57 patients included in ctDNA analyses, baseline ctDNA was detected in 51 individuals (89.5%). After neoadjuvant therapy, ctDNA clearance occurred in 49 of 51 patients (96.1%), with only 2 individuals (3.9%) remaining ctDNA-positive preoperatively; detectability remained low (<10%) during postoperative follow-up. One single patient experienced a local recurrence, with ctDNA detected at time of recurrence and cleared following surgical resection. CONCLUSIONS AND RELEVANCE: In this secondary analysis of the DAPHNe nonrandomized clinical trial, neoadjuvant THP was associated with excellent long-term outcomes in patients with early-stage ERBB2-positive breast cancer. Ultrasensitive ctDNA analyses demonstrated high baseline detection rates and near-universal clearance after abbreviated neoadjuvant therapy, supporting further investigation of ctDNA-guided de-escalation strategies in this setting. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03716180.

Humans↗
PubMed2026

Patient-reported outcomes from the TBCRC 022 study of neratinib and ado-trastuzumab emtansine for HER2-positive breast cancer brain metastases.

PURPOSE: In TBCRC 022 (NCT01494662), neratinib and ado-trastuzumab emtansine (T-DM1) demonstrated intracranial activity among patients with HER2-positive breast cancer brain metastases. However, gastrointestinal (GI) toxicities-particularly diarrhea-were common, potentially impacting quality of life. Clinician-reported adverse event (CTCAE) grading may underestimate the patient experience. We report GI toxicities using patient-reported outcomes (PROs) in TBCRC's neratinib-T-DM1 cohort. METHODS: Patients received neratinib (160&#x202f;mg daily) and T-DM1 (3.6&#x202f;mg/kg IV every 21 days). A pre-planned analysis assessed patient-reported GI toxicities during Cycles 1-4 using the Patient-reported Outcomes Measurement Information System (PROMIS) GI Diarrhea scale, Systemic Therapy-Induced Diarrhea Assessment Tool (STIDAT), and PRO-CTCAE. Descriptive statistics and linear mixed effects models evaluated symptom trajectories over time. We evaluated agreement for PRO and clinician-reported data. RESULTS: Forty-four patients enrolled; all completed &#x2265;1 PRO. GI symptom burden increased over Cycles 1-3. PROMIS scores worsened significantly by Cycle 2, with a peak mean increase of 6.62 (95% confidence interval (CI): 2.67-10.59; p&#x202f;=&#x202f;0.002) at Cycle 3. STIDAT scores also worsened by Cycle 3 (mean change 0.50; 95%CI: 0.11-0.90; p&#x202f;=&#x202f;0.015). Based on maximum PRO-CTCAE scores, moderate-to-severe symptoms were reported by 20.5% (diarrhea), 24.4% (appetite loss), and 41.0% (constipation). Agreement between PRO-CTCAE and clinician-reported CTCAE was low (kappa <0.2) with clinicians reporting less toxicity. PROMIS and STIDAT scores were significantly correlated. CONCLUSION: This GI-focused PRO analysis highlights the value of PROs in capturing patient-experienced toxicities that impact quality of life yet are underestimated by clinicians. Incorporating PROs into clinical trials can inform supportive care and prophylactic strategies.

Humans↗
PubMed2025

Detection of heterogeneous resistance mechanisms to tyrosine kinase inhibitors from cell-free DNA.

Though there has been substantial progress in the development of anti-human epidermal growth factor receptor 2 (HER2) therapies to treat HER2-positive metastatic breast cancer (MBC) within the past two decades, most patients still experience disease progression and cancer-related death. HER2-directed tyrosine kinase inhibitors can be highly effective therapies for patients with HER2-positive MBC; however, an understanding of resistance mechanisms is needed to better inform treatment approaches. We performed whole-exome sequencing on 111 patients with 73 tumor biopsies and 120 cell-free DNA samples to assess mechanisms of resistance. In 11 of 26 patients with acquired resistance, we identified alterations in previously characterized genes, such as PIK3CA and ERBB2, that could explain treatment resistance. Mutations in growing subclones identified potential mechanisms of resistance in 5 of 26 patients and included alterations in ESR1, FGFR2, and FGFR4. Additional studies are needed to assess the functional role and clinical utility of these alterations in driving resistance.

Humans↗
PubMed2025

Integration of Gene Expression and Digital Histology to Predict Treatment-Specific Responses in Breast Cancer.

Deep learning models applied to digital histology can predict gene expression signatures (GES) and offer a low-cost, rapidly available alternative to molecular testing at the time of diagnosis. We optimized transformer-based models to infer GES results and applied this approach to pre-treatment H&E-stained biopsies from 1,940 breast cancer patients treated with neoadjuvant chemotherapy in clinical trial and real-world cohorts. The most predictive histology-derived GES for pathologic complete response (pCR) in the I-SPY2 trial was validated in four external cohorts: CALGB 40601, CALGB 40603, a trial of durvalumab plus CT, and standard-of-care CT-treated patients from the University of Chicago. Among HER2-negative patients, a transformer-based model trained using a signature composed of estrogen-regulated genes, proliferation, apoptosis, and interferon response genes predicted pCR with an AUC of 0.794, outperforming models based on clinical features alone (AUC 0.704, p = 0.001), pathologist TIL assessment, and a model trained directly to predict response from I-SPY2 cases. Tertiles of this signature stratify patients into clinically relevant groups with increasing likelihood of complete response, with pCR rates &#x2265;50% in the top tertile regardless of treatment or hormone receptor status. Additional transformer-based signature models predicted response to specific therapies (but not chemotherapy alone), including a HER2 signaling signature in IO-treated patients, and a claudin-low signature in bevacizumab treated patients. In HER2- cohorts with available gene expression data and histology, models trained on expression data performed similarly to digital histology predictions, but the combination of gene expression and histology outperformed histology alone. These findings suggest that histology-based GES provides additive information to RNA sequencing data and can inform precision treatment selection across breast cancer subtypes.

Journal Article↗