Angela DeMichele

PURPOSE: EA1181 (ClinicalTrials.gov identifier: NCT04266249 ) is a single-arm trial evaluating neoadjuvant taxane, trastuzumab, and pertuzumab (THP) in patients with clinical stage II/IIIa human epidermal growth factor receptor 2 (HER2)–positive breast cancer. This report focuses on the secondary end points of pathologic complete response (pCR) rates and associated factors. The primary end point—3-year recurrence-free survival among patients achieving a pCR (ypT0/Tis, ypN0)—will be reported when data mature. Methods: Patients received four cycles of trastuzumab and pertuzumab (HP) with either once per week paclitaxel (12 weeks) or docetaxel (every 3 weeks for four cycles), followed by surgery. Clinicopathologic characteristics were assessed in all patients. The HER2DX pCR score was determined using diagnostic biopsy samples in a representative subset. Logistic regression models identified factors associated with pCR. RESULTS: A total of 2,175 patients were enrolled (781 HER2+/estrogen receptor‑negative [ER–]; 1,394 HER2+/ER+). Of 2,141 patients who initiated THP, the overall pCR rate was 43.8%: 63.7% in HER2+/ER– and 32.4% in HER2+/ER+ tumors. Higher pCR rates were observed in tumors that were ER-negative or low ER expressing, progesterone receptor-negative or low expressing, HER2 immunohistochemistry (IHC) 3+, and in patients treated with once per week paclitaxel. T3 disease was associated with a lower pCR rate in HER2+/ER– tumors; otherwise, tumor (T) and nodal (N) stage did not significantly affect pCR. Among 569 patients assessed for HER2DX pCR scores, a high score was independently associated with higher pCR rates, after adjustment for clinicopathologic variables. CONCLUSION: Neoadjuvant THP achieved pCR in nearly two-thirds of patients with HER2+/ER– and one third with HER2+/ER+ breast cancer. Low hormone receptor expression, HER2 IHC 3+ status, once per week paclitaxel use, and a high HER2DX pCR score were independent predictors of pCR. These findings should help optimize risk stratification and treatment personalization for patients with HER2-positive breast cancer.

To evaluate the functional relevance of mutations newly detected in breast cancer metastases, we analyzed genomic data from 662 paired and ~6,000 unpaired primary and metastatic tumors. These analyses indicate that metastasis-specific mutations are frequently acquired post-dissemination, with a disproportionate contribution from APOBEC-mediated mutagenesis. Metastasis-specific mutations converged on a set of pathways that were highly recurrent, distinct from those altered in primary tumors, and dependent on metastatic site. 95% of patients harbored metastasis-specific mutations within a minimum set of 10 pathways. Remarkably, more than half the variation in metastatic latency across patients was explained by the relative timing of mutation acquisition within implicated pathways before versus after dissemination. These findings support a “mutability-dependent” model of metastasis in which functionally consequential mutations accumulate after primary tumor dissemination and contribute to metastatic outgrowth, with latency reflecting the time required for DTCs to acquire the remaining driver mutations needed to achieve metastatic competence.

Background: In adjuvant HR+/HER2− breast cancer, tolerability and persistence with long-term therapy are critical. In PALLAS, adding palbociclib to endocrine therapy (ET) did not improve invasive disease-free or overall survival. We investigated factors associated with treatment intolerance and early discontinuation.Patients and methods: This exploratory analysis evaluated early palbociclib discontinuation among patients initiating planned two-year palbociclib plus ET in PALLAS. Competing-risks methods and cause-specific hazard models assessed associations between baseline demographic, clinical, and patient-reported outcome (PRO) measures and discontinuation for reasons other than recurrence or death. Dose reductions, treatment-emergent toxicities, and longitudinal PRO trajectories were also evaluated.Results: Among 2,840 patients initiating palbociclib plus ET, 1,171 (41.3%) discontinued palbociclib early. Dose reductions to 100 mg and 75 mg occurred in 55.2% and 33.6%, respectively. In multivariable analysis, higher nodal stage was associated with lower discontinuation risk (N3 versus N0: HR 0.59, 95% CI 0.45–0.79), whereas poor baseline overall quality of life (HR 1.87, 95% CI 1.10–3.19) and financial difficulties (HR 1.27, 95% CI 1.05–1.54) were independently associated with increased risk. Similar patterns were observed for dose reductions. Patients discontinuing within three months were older, less likely to have received chemotherapy, and had more baseline PRO impairments, particularly anxiety. Baseline PRO impairment was also associated with treatment-emergent toxicities, particularly non-haematological events. Longitudinally, fatigue and nausea were more prominent with palbociclib.Conclusions: Baseline patient-reported health status, nodal stage, and socioeconomic factors are important determinants of adjuvant palbociclib discontinuation. Integrating PROs into treatment decision-making and monitoring may help identify patients at increased risk of treatment intolerance and support more individualised management of prolonged adjuvant therapy.

PURPOSE: Patients with stage II/III human epidermal growth factor receptor 2 (HER2)–positive or triple-negative breast cancer (TNBC) frequently receive neoadjuvant therapy (NAT). Although pathologic complete response (pCR) correlates with improved outcomes, many non-pCR patients have long-term survival. Circulating tumor-DNA (ctDNA) minimal residual disease (MRD) assessment may provide additional or superior risk stratification. METHODS: Pathologic Response Evaluation and Detection in Circulating Tumor-DNA is a prospective, multicenter study evaluating ctDNA as a biomarker of treatment response using a tumor-informed, ultrasensitive (P = .001), independent of pCR. Additionally, detectable ctDNA after surgery identified patients at extremely high recurrence risk (HR, 128 [95% CI, 15 to 1,083]; P < .001), while ctDNA-negative patients after surgery had 94% 5-year IDFS. CONCLUSION: In HER2-positive breast cancer and TNBC, ctDNA after NAT does not discriminate pCR from non-pCR. However, ctDNA provides markedly superior prognostic stratification, identifying patients with exceptional outcomes and those at extreme risk. These findings support ctDNA-guided therapeutic de-escalation and escalation strategies.

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.

A higher incidence of triple-negative breast cancer (TNBC) and worse social determinants of health both contribute to racial survival disparities among Black women diagnosed with breast cancer. A post hoc analysis of the ECOG-ACRIN EA1131 study (adjuvant platinum v capecitabine in stage II-III TNBC with residual disease after neoadjuvant chemotherapy) evaluated racial disparities in disease-free survival (DFS) and overall survival (OS) among Black and White patients. Of the 415 patients enrolled in EA1131, 376 were included in this analysis (308 White [82%] and 68 Black [18%]). Common characteristics included basal-subtype TNBC (77%), grade 3 disease (71%), residual stage II disease (49%), private insurance (70%), and a BMI ≥30 (49%). There were no racial differences in grade and clinical or pathologic stage. Black patients were more likely to have basal-subtype TNBC (89% v 75%; P = .009), a BMI ≥30 (62% v 46%; P = .026), to reside within the lowest neighborhood socioeconomic index quartile (39% v 22%; P = .008), and have Medicaid (32% v 13%; P < .001) compared with White patients. Despite these differences, there were no significant differences in DFS or OS by race (hazard ratio [HR], 0.99 [95% CI, 0.62 to 1.57] and HR, 0.60 [95% CI, 0.32 to 1.12], respectively) among Black and White patients.

Mutation identification via circulating tumor DNA (ctDNA) to select appropriate therapy has demonstrated clinical utility in metastatic breast cancer (MBC). SERENA-6 demonstrated the efficacy and tolerability of camizestrant in HR + /HER2-, ESR-1 mutated MBC after an AI/CDK 4/6 inhibitor. However, it remains unclear whether switching therapy at the time of ctDNA-detected emergence of ESR-1 mutations (“molecular progression”) improves long-term outcomes over switching therapy at the time of traditional anatomic/clinical progression.

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.

Representativeness of Study Participants

The presence of bone marrow (BM) disseminated tumor cells (DTC_bm) identifies early-stage breast cancer patients at increased risk of recurrence and poorer overall survival. However, limitations in detecting DTC_bm by standard immunohistochemical approaches have hampered clinical application. To address this gap, we developed a flow cytometry-based method, DTC-Flow, that enables the sensitive and efficient detection and molecular characterization of breast cancer DTC_bm. Our analysis identified HER2 as a sensitive marker for detecting breast cancer cells, including those lacking HER2 amplification are claudin-low. DTC-Flow using a HER2/EpCAM/CD45 marker panel enabled >90% cancer cell recovery and sensitivity of one cancer cell per million nucleated BM cells across a range of breast cancer subtypes. Molecular analyses of DTC-Flow-sorted DTC_bm from metastatic patients suggested a quiescent state and demonstrated their close genomic relationship to primary/metastatic tumors, as well as continued genetic evolution. In early-stage breast cancer patients, DTC-Flow detected DTC_bm with greater sensitivity than cytokeratin-based immunohistochemical approaches. Our data support the development of DTC-Flow as a sensitive and specific platform to identify breast cancer patients harboring DTC_bm and better understand the biology of minimal residual disease. Ultimately, this platform could enable the selection of personalized therapeutic approaches based on molecular features of DTC_bm, monitoring of DTC_bm to assess the efficacy of such therapies, and the development of novel therapeutic approaches targeting unique biological vulnerabilities of DTCs in order to eradicate these cells before they can give rise to lethal recurrent cancers.