Treatment patterns and clinical outcomes in patients with metastatic triple-negative breast cancer: a large-scale data analysis using the Japanese claims database.

PURPOSE: This study evaluated treatment patterns and clinical outcomes among patients with metastatic triple-negative breast cancer (mTNBC) in real-world clinical settings in Japan. METHODS: The treatment patterns, time to next treatment or death (TTNTD), time to treatment discontinuation, adverse events of interest, and medical costs of treating patients with mTNBC in first-, second-, and third-line settings were investigated using data of patients meeting the inclusion criteria between January 2017 and March 2022 in a Japanese medical claims database. The treatment regimens for mTNBC were defined according to the Japanese Breast Cancer Society Clinical Practice Guidelines. RESULTS: In this study, 2236 patients with mTNBC (median age 66.0 years; 99.8% female) were included in the first-line cohort. Of these, 46.6% and 20.8% were included in the second- and third-line cohorts, respectively. The two most frequently used treatments were capecitabine (19.1%) and S-1 (tegafur-gimeracil-oteracil) (14.5%) in the first-line cohort, eribulin (18.3%) and bevacizumab/paclitaxel (14.4%) in the second-line cohort, and eribulin (19.4%) and bevacizumab/paclitaxel (17.5%) in the third-line cohort. The TTNTD shortened as the line of therapy progressed (median 8.0, 6.5, and 5.2 months for the first-, second-, and third-line treatments, respectively). Nausea/vomiting and neutropenia/leukopenia occurred in 62.8% and 18.3% of all patients, respectively. The medical total costs per day were 6.7, 10.2, and 12.9 thousand yen during the first-/second-/third-line treatments, respectively. CONCLUSION: This study provides insight into current treatment patterns for mTNBC in Japan. The cost-benefit balance worsens with later-line treatment and a high unmet need for mTNBC drug treatment remains.

The Japanese breast cancer society clinical practice guidelines for radiation treatment of breast cancer, 2022 edition.

The Breast Cancer Clinical Practice Guidelines, organized by the Japanese Breast Cancer Society (JBCS), were published in 2022. We present the English version of the Radiation Therapy (RT) section of the guidelines. The JBCS formed a task force to update the 2018 version of the JBCS Clinical Practice Guidelines. The Background Questions (BQs) contain the standard treatments for breast cancer in clinical practice, whereas the Clinical Questions (CQs) address daily clinical questions that remain controversial. Future Research Questions (FRQs) explore the subjects that are considered important issues, despite there being insufficient data for inclusion as CQs. The task force selected the 12 BQs, 8 CQs, and 6 FRQs for the RT section. For each CQ, systematic literature reviews and meta-analyses were conducted according to the Minds Manual for Guideline Development 2020, version 3.0. The recommendations, strength of recommendation, and strength of evidence for each CQ were determined based on systematic reviews and meta-analyses, and finalized by voting at the recommendation decision meeting.

Real-world data of HER2-negative early breast cancer patients treated with anthracycline and/or taxane regimens in Japan.

BACKGROUND: Anthracycline- and taxane-based chemotherapy regimens are established treatments for human epidermal growth factor receptor (HER)2-negative early-stage breast cancer with high risk of recurrence. This study examined the prevalence of these chemotherapy regimens as perioperative therapy, the patterns of retreatment, and factors influencing prescription choices in Japan. METHODS: This observational cohort study focused on high-risk early-stage breast cancer patients not undergoing anti-HER2 therapy, utilizing data from a hospital-based claims database in Japan spanning from April 2008 to September 2021. RESULTS: Of 42,636 high-risk patients who underwent breast cancer surgery, 32,133 (75.4%) were categorized as having luminal-type (received endocrine therapy) and 10,503 (24.6%) as having triple-negative cancer (not receiving any endocrine therapies). Most patients (98.7%) with luminal-type breast cancer received perioperative therapy, and 40.3% of those received anthracycline/taxane. In the triple-negative group, 57.0% of all patients received perioperative therapy and of those, 93.4% received anthracycline/taxane. Being over 40 years old, having an early stage (clinical stage ≤ II), and receiving treatment in non-specialized facilities were associated with less use of anthracycline/taxane in the luminal-type group. For the triple-negative group, associated factors with less use of anthracycline/taxane included being over 60 years old, treatment in small hospital (capacity < 200 beds), and treatment in non-specialized facilities. CONCLUSIONS: Approximately half the patients in both the luminal-type and triple-negative groups were prescribed anthracycline and/or taxane for perioperative chemotherapy. The choice was associated with patient age, cancer stage, and the scale and specialization of the treatment facilities. This study sheds light on the current state of breast cancer treatment practices in Japan.

The Japanese Breast Cancer Society Clinical Practice Guidelines for Breast Cancer, 2022 Edition: changes from the 2018 edition and general statements on breast cancer treatment.

The Japanese Breast Cancer Society Clinical Practice Guidelines for Breast Cancer, 2022 Edition was published in June 2022. The guidelines were prepared while conforming as much as possible to the "Minds Manual for Guideline Development 2020 ver. 3.0." edited by the Minds Manual Development Committee of the Japan Council for Quality Health Care in 2021. In addition, a survey of Japanese Breast Cancer Society members on the 2018 edition of the guidelines was conducted from February 19 to March 4, 2021. Based on the responses from over 600 members, original innovations were made to make the guidelines more user-friendly. The 2018 edition of the guidelines was developed to provide support tools for physicians and patients to utilize shared decision-making. The 2022 guidelines consist of two volumes: (1) an "Epidemiology and Diagnosis" section covering "Screening and Diagnosis", "Radiological diagnosis", and "Pathological diagnosis", and (2) a "Treatment" section covering "Surgical therapy", "Radiation therapy", and "Systemic therapy". We believe that this concise summary of the guidelines will be useful to physicians and researchers in Japan and overseas.

Trastuzumab deruxtecan for human epidermal growth factor receptor 2-low advanced or metastatic breast cancer: recommendations from the Japanese Breast Cancer Society Clinical Practice Guidelines.

The Japanese Breast Cancer Society Clinical Practice Guidelines are published as timely guidance on clinical issues in breast cancer treatment in Japan. In the recent edition of these guidelines, we addressed a new clinical question 34 (CQ 34, systemic treatment part) "Is trastuzumab deruxtecan recommended for patients with unresectable or metastatic HER2-low breast cancer?" and a new future research question 7 (FRQ 7, pathological diagnosis part) "How is HER2-low breast cancer diagnosed for the indication of trastuzumab deruxtecan?". These questions address use of trastuzumab deruxtecan in patients with unresectable or metastatic HER2-low breast cancer who have previously received chemotherapy for metastatic disease. The strengths of evidence and recommendation were determined through a quantitative and qualitative systematic review using multiple outcomes, including efficacy and safety. We conclude that trastuzumab deruxtecan is recommended for this patient population (strength of recommendation: 1; strength of evidence: moderate; CQ34) and that HER2-low expression for the indication of trastuzumab deruxtecan should be diagnosed using companion diagnostics based on appropriate criteria (FRQ7).

Protecting the Brain: Novel Strategies for Preventing Breast Cancer Brain Metastases through Selective Estrogen Receptor ß Agonists and In Vitro Blood-Brain Barrier Models.

Breast cancer brain metastasis (BCBM) is a challenging condition with limited treatment options and poor prognosis. Understanding the interactions between tumor cells and the blood-brain barrier (BBB) is critical for developing novel therapeutic strategies. One promising target is estrogen receptor ß (ERß), which promotes the expression of key tight junction proteins, sealing the BBB and reducing its permeability. In this study, we investigated the effects of 17ß-estradiol (E2) and the selective ERß agonist diarylpropionitrile (DPN) on endothelial and cancer cells. Western blot analysis revealed the expression patterns of ERs in these cell lines, and estrogen treatment upregulated claudin-5 expression in brain endothelial cells. Using in vitro models of the BBB, we found that DPN treatment significantly increased BBB tightness about suppressed BBB transmigration activity of representative Her2-positive (BT-474) and triple-negative (MDA-MB-231) breast cancer cell lines. However, the efficacy of DPN treatment decreased when cancer cells were pre-differentiated in the presence of E2. Our results support ERß as a potential target for the prevention and treatment of BCBM and suggest that targeted vector-based approaches may be effective for future preventive and therapeutic implications.

[Improved Outcomes in Advanced Metastatic Breast Cancer].

In stage Ⅳ breast cancer or recurrent breast cancer diagnosed after a curative treatment and later exhibiting distant metastasis, treatment aims are extending overall survival and improving/maintaining quality of life(QOL). The primary focus of treatment is to control systemic tumor volume, and in this regard, the introduction of novel drug treatment by years is expected to contribute to improvement of survival. However for instance, registration cohort data from France diagnosed between 2008 and 2016, categorized by diagnosis year, revealed improvements in survival only in HER2-positive breast cancer, with no such improvements observed in other subtypes. This variation appears to coincide with the introduction of novel anti-HER2 therapy, suggesting the essential need for the introduction of drugs that clearly demonstrate an extension of overall survival. Significant impacts from introduced new drugs have also been observed in other subtypes since 2017, and examining future data may confirm their reflections. Advances not only in drug development but also in cancer/host genome analysis and molecular diagnostics are allowing for more precise treatment selection and treatment changes. Enhancing treatment strategies, including proper local therapies such as surgery and radiation therapy, remains a crucial challenge.

Treatment patterns, healthcare resource utilization and outcomes for early stage triple-negative breast cancer in Japan.

Aim: There is limited information regarding the treatment and outcomes of early stage triple-negative breast cancer (esTNBC) in real-world settings in Japan. Materials & methods: Retrospective analyses of the Medical Data Vision database assessed treatment patterns, healthcare resource utilization (HCRU), patient characteristics, outcomes and prognostic factors among four groups (neoadjuvant therapy+surgery+adjuvant therapy; neoadjuvant therapy+surgery; surgery+adjuvant therapy; surgery only) of esTNBC patients. Results: Treatment patterns, HCRU and demographics varied among the four groups. HCRU was greater and prognosis tended to be worse in the neoadjuvant+surgery+adjuvant therapy group. Conclusion: Our results provide insights into the treatment practices, HCRU and prognosis of esTNBC in Japan. The treatment practices were heterogeneous, reflecting the decision-making process in Japan during the study period.

Triple-negative breast cancer (TNBC) is a cancer type that does not express three biomarkers (estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2), which results in a lack of targeted treatment strategies. Early stage TNBC (esTNBC) is mainly treated by anticancer drugs before (neoadjuvant) and/or after (adjuvant) surgery and adjuvant radiotherapy. New therapies including an immune checkpoint inhibitor which helps better immune system and a PARP inhibitor which helps repair DNA damage were approved for esTNBC in 2022 in Japan, and they are expected to change the treatment options for TNBC. However, there are limited data about the treatment patterns, healthcare resource utilization (HCRU) and outcomes for esTNBC in real-world clinical practice in Japan. Therefore, a hospital-based administrative database was analyzed to understand the treatment patterns for patients with esTNBC in Japan, the HCRU, treatment outcomes (overall survival and event free survival), and the associated factors. Patients received a large variety of treatments before and after surgery. Patients who received both neoadjuvant and adjuvant therapies tended to have more severe disease and required greater HCRU, and their outcomes were worse than patients who received neoadjuvant treatment only, adjuvant treatment only or neither neoadjuvant nor adjuvant treatment. Our findings will help us understand how new treatments will impact the treatment practices and patient outcomes in the future.

Survival trends and patient characteristics between 2004 and 2016 for breast cancer in Japan based on the National Clinical Database-Breast Cancer Registry.

This is a prognostic report by the Japanese Breast Cancer Society on breast cancer extracted from the National Clinical Database-Breast Cancer Registry of Japan. Here, we present a summary of 457,878 breast cancer cases registered between 2004 and 2016. The median follow-up duration was 5.6 years. The median age at the start of treatment was 59 years (5-95%: 38-82 years) and increased from 57 years between 2004 and 2008 to 60 years between 2013 and 2016. The proportion of patients with Stage 0-II disease increased from 74.5% to 78.3%. The number of cases with estrogen and progesterone receptor positivity increased from 74.8% to 77.9% and 60.5% to 68.1%, respectively. Regarding (neo-)adjuvant chemotherapy, the taxane (T) or taxane-cyclophosphamide (C) regimen increased by 2.4% to 8.2%, but the (fluorouracil (F)) adriamycin (A)-C-T/(F) epirubicin (E)C-T and (F)AC/(F)EC regimens decreased by 18.6% to 15.2% and 13.5% to 5.0%, respectively. Regarding (neo-)adjuvant anti-human epidermal growth factor-2 (HER2)-targeted therapy, the use of trastuzumab increased from 4.6% to 10.5%. The rate of sentinel lymph node biopsy increased from 37.1% to 60.7%, while that of axillary dissection decreased from 54.5% to 22.6%. Improvements in disease-free and overall survival were observed in patients with HER2-positive breast cancer, but there was no apparent trend in patients with hormone receptor-positive, HER2-negative, or triple-negative breast cancers.

2020 Annual Report of National Clinical Database-Breast Cancer Registry: 10-year mortality of elderly breast cancer patients in Japan.

The Japanese Breast Cancer Society initiated the breast cancer registry in 1975, which transitioned to the National Clinical Database-Breast Cancer Registry in 2012. This annual report presents data from 2020 and analyzes the ten-year mortality rates for those aged 65 and older. We analyzed data from 93,784 breast cancer (BC) cases registered in 2020 and assessed 10-year mortality rates for 36,279 elderly patients diagnosed between 2008 and 2012. In 2020, 99.4% of BC cases were females with a median age of 61. Most (65%) were diagnosed at early stages (Stage 0 or I). Breast-conserving surgery rates varied with stages: 58.5% at cStage I, 30.8% at cStage II, and 13.1% at cStage III. Sentinel lymph node biopsy was done in 73.6% of cases, followed by radiotherapy in 70% of those post-conserving surgery and chemotherapy in 21.1% post-surgery. Pathology showed that 63.4% had tumors under 2.0 cm, 11.7% had pTis tumors, and 77.3% had no axillary lymph node metastasis. ER positivity was seen in 75.1%, HER2 in 14.3%, and 30% had a Ki67 positivity rate above 30%. Across all stages and subtypes, there was a trend where the 10-year mortality rates increased for individuals older than 65 years. In Stage I, many deaths were not directly linked to BC and, for those with HER2-type and triple-negative BC, breast cancer-related deaths increased with age. Within Stage II, patients older than 70 years with luminal-type BC often experienced deaths not directly linked to BC, whereas patients below 80 years with HER2-type and triple-negative BC, likely had breast cancer-related deaths. In Stage III, breast cancer-related deaths were more common, particularly in HER2 and triple-negative BC. Our prognostic analysis underscores distinct mortality patterns by stage, subtype, and age in elderly BC patients. It highlights the importance of personalized treatment strategies, considering subtype-specific aggressiveness, age-related factors, and comorbidities.

First-Line Ipatasertib, Atezolizumab, and Taxane Triplet for Metastatic Triple-Negative Breast Cancer: Clinical and Biomarker Results.

PURPOSE: To evaluate a triplet regimen combining immune checkpoint blockade, AKT pathway inhibition, and (nab-) paclitaxel as first-line therapy for locally advanced/metastatic triple-negative breast cancer (mTNBC). PATIENTS AND METHODS: The single-arm CO40151 phase Ib study (NCT03800836), the single-arm signal-seeking cohort of IPATunity130 (NCT03337724), and the randomized phase III IPATunity170 trial (NCT04177108) enrolled patients with previously untreated mTNBC. Triplet therapy comprised intravenous atezolizumab 840 mg (days 1 and 15), oral ipatasertib 400 mg/day (days 1-21), and intravenous paclitaxel 80 mg/m2 (or nab-paclitaxel 100 mg/m2; days 1, 8, and 15) every 28 days. Exploratory translational research aimed to elucidate mechanisms and molecular markers of sensitivity and resistance. RESULTS: Among 317 patients treated with the triplet, efficacy ranged across studies as follows: median progression-free survival (PFS) 5.4 to 7.4 months, objective response rate 44% to 63%, median duration of response 5.6 to 11.1 months, and median overall survival 15.7 to 28.3 months. The safety profile was consistent with the known toxicities of each agent. Grade ≥3 adverse events were more frequent with the triplet than with doublets or single-agent paclitaxel. Patients with PFS >10 months were characterized by NF1, CCND3, and PIK3CA alterations and increased immune pathway activity. PFS <5 months was associated with CDKN2A/CDKN2B/MTAP alterations and lower predicted phosphorylated AKT-S473 levels. CONCLUSIONS: In patients with mTNBC receiving an ipatasertib/atezolizumab/taxane triplet regimen, molecular characteristics may identify those with particularly favorable or unfavorable outcomes, potentially guiding future research efforts.

Changes in cell-free DNA after short-term palbociclib and fulvestrant treatment for advanced or metastatic hormone receptor-positive and human epidermal growth factor 2-negative breast cancer.

PURPOSE: Here, we investigated the potential predictive and elucidating efficacy of cell-free DNA (cfDNA) changes on clinical outcomes and biological effects, respectively, after short-term palbociclib and fulvestrant treatment for patients with hormone receptor (HR)-positive and human epidermal growth factor 2 (HER2)-negative advanced or metastatic breast cancer (ABC). METHODS: In this secondary analysis of the Japan Breast Cancer Research Group-M07 (FUTURE) trial, blood cfDNA was obtained before palbociclib treatment and on day 15 of cycle one (28-day cycle). Target enrichment was performed using next-generation sequencing; progression-free survival (PFS) was compared based on cfDNA changes between baseline and day 15 of cycle one after combination therapy. RESULTS: Fifty-six patients (112 paired blood samples) were examined. The median follow-up time was 8.9 months. PIK3CA (30.4%, 17/56), FOXA1 (30.4%, 17/56), and ESR1 (28.6%, 16/56) were most frequently mutated at baseline. The number of mutated genes was significantly decreased on day 15 compared with that at baseline (paired t test: P value = 0.025). No significant difference was observed in PFS (decrease group, 7.9 m vs the others, 9.3 m; log-rank P value = 0.75; hazard ratio, 1.13; 95% confidence interval, 0.53-2.41). Among patients without previous aromatase inhibitor treatment (n = 15), three (20%) had ESR1 mutations after progression to fulvestrant. CONCLUSION: No significant association was observed between changes in mutated genes after short-term palbociclib and fulvestrant treatment and disease progression; a significant reduction in cfDNA mutation level was observed on day 15 of cycle one. Clinical meanings of cfDNA should be investigated in the future trials.

Annual report of the Japanese Breast Cancer Registry for 2019.

This is an annual report by the Japanese Breast Cancer Society regarding the clinical data on breast cancer extracted from the National Clinical Database-Breast Cancer Registry (NCD-BCR) of Japan. Here, we present an updated summary of 98,300 breast cancer cases registered in 2019. The median age at cancer diagnosis was 61 years (interquartile range 49-72 years), and 30.6% of the breast cancer patients were premenopausal. Of the 93,840 patients without distant metastases, 14,118 (15.0%) and 42,047 (44.8%) were diagnosed with stage 0 and I disease, respectively. Breast-conserving surgery was performed in 42,080 (44.8%) patients. Regarding axillary procedures, 62,677 (66.8%) and 7371 (7.9%) patients underwent sentinel node biopsy and axillary node dissection after biopsy, respectively. Whole breast irradiation was administered to 29,795 (70.8%) of the 42,080 patients undergoing breast-conserving surgery. Chest wall irradiation was administered to 5524 (11.1%) of the 49,637 patients who underwent mastectomy. Of the 6912 clinically lymph node-negative patients who received preoperative therapy, 5250 (76.0%) and 427 (6.2%) underwent sentinel node biopsy and axillary node dissection after biopsy, respectively; however, 602 (8.7%) patients initially underwent axillary node dissection without biopsy.

Risk factors for late recurrence and postrelapse survival in estrogen receptor (ER)-positive, human epidermal growth factor receptor (HER) 2-negative breast cancer after 5 years of endocrine therapy.

It is unclear which patients with ER-positive, HER2-negative breast cancer benefit from extended endocrine therapy beyond 5 years. Prognostic factors for late-recurring breast cancer postrelapse survival have been reported. We retrospectively analyzed data from 892 patients with ER-positive and HER2-negative invasive breast cancer who were disease-free after completing a 5-year adjuvant endocrine therapy. Patients were then classified as high-risk (positive lymph nodes, large tumor size, high tumor grade) or low-risk. High-risk patients were divided into extended endocrine therapy and stop groups. Comparisons were made using propensity score matching, and the benefits of extended endocrine therapy for high-risk patients and prognostic factors for postrelapse survival were assessed. The high- and low-risk groups comprised 444 and 448 patients, respectively. The 10-year distant disease-free survival (DDFS) rates were 96.3 % (95 % confidence interval [CI] 0.912-0.985) and 86.5 % (95 % CI 0.798-0911) in the extended and stop groups, respectively (P = 0.00382). Cox proportional hazards model revealed that extended endocrine therapy promoted greater reduction in distant metastasis risk than 5-year endocrine therapy in high-risk populations (hazard ratio [HR] 0.27; 95 % CI 0.11-0.68; P = 0.0054). Postrelapse survival was significantly different in patients with DDFS ≥7 years (HR 0.24; 95 % CI 0.072-0.81; P = 0.021) and those with better response to first-line treatment (HR 0.072; 95 % CI, 0.058-0.90; P = 0.041). Patients with risk factors for late recurrence should be considered for extended endocrine therapy. Longer DDFS and response to first-line treatment may be a prognostic factor for postrelapse survival after late recurrence.

The Japanese Breast Cancer Society Clinical Practice Guidelines for surgical treatment of breast cancer, 2022 edition.

The 2022 revision of the Japanese Breast Cancer Society (JBCS) Clinical Practice Guidelines for surgical treatment of breast cancer was updated following a systematic review of the literature using the Medical Information Network Distribution Service (MINDS) procedure, which focuses on the balance of benefits and harms for various clinical questions (CQs). Experts in surgery designated by the JBCS addressed five areas: breast surgery, axillary surgery, breast reconstruction, surgical treatment for recurrent and metastatic breast cancer, and other related topics. The revision of the guidelines encompassed 4 CQs, 7 background questions (BQs), and 14 future research questions (FRQs). A significant revision in the 2022 edition pertained to axillary management after neoadjuvant chemotherapy in CQ2. The primary aim of the 2022 JBCS Clinical Practice Guidelines is to provide evidence-based recommendations to empower patients and healthcare professionals in making informed decisions regarding surgical treatment for breast cancer.

The Japanese Breast Cancer Society clinical practice guidelines for epidemiology and prevention of breast cancer, 2022 edition.

The Japanese Breast Cancer Society Clinical Practice Guidelines for Epidemiology and Prevention of Breast Cancer, 2022 Edition.

The Japanese Breast Cancer Society Clinical Practice Guidelines for systemic treatment of breast cancer, 2022 edition.

The Japanese Breast Cancer Society (JBCS) Clinical Practice Guidelines for systemic treatment of breast cancer were updated to the 2022 edition through a process started in 2018. The updated guidelines consist of 12 background questions (BQs), 33 clinical questions (CQs), and 20 future research questions (FRQs). Multiple outcomes including efficacy and safety were selected in each CQ, and then quantitative and qualitative systematic reviews were conducted to determine the strength of evidence and strength of recommendation, which was finally determined through a voting process among designated committee members. Here, we describe eight selected CQs as important updates from the previous guidelines, including novel practice-changing updates, and recommendations based on evidence that has emerged specifically from Japanese clinical trials.

Patritumab Deruxtecan (HER3-DXd), a Human Epidermal Growth Factor Receptor 3-Directed Antibody-Drug Conjugate, in Patients With Previously Treated Human Epidermal Growth Factor Receptor 3-Expressing Metastatic Breast Cancer: A Multicenter, Phase I/II Trial.

PURPOSE: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in breast cancer; high expression is associated with an adverse prognosis. Patritumab deruxtecan (HER3-DXd) is an investigational HER3-targeted antibody-drug conjugate that is being evaluated as a novel treatment in HER3-expressing advanced breast cancer in the U31402-A-J101 study. METHODS: Adults with disease progression on previous therapies were eligible. Patients in the dose-escalation, dose-finding, and dose-expansion parts received HER3-DXd 1.6-8.0 mg/kg intravenously once every 3 weeks or one of two alternative dosing regimens. In the dose-escalation part, the primary objectives were to determine the maximum tolerated dose and recommended dose for expansion (RDE). The safety and efficacy of the RDE were assessed during dose expansion. RESULTS: One hundred eighty-two enrolled patients received ≥1 dose of HER3-DXd. Patients had a median of five previous therapies for advanced disease. Efficacy results are reported across clinical subtypes: hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-negative) breast cancer (n = 113; objective response rate [ORR], 30.1%; median progression-free survival [mPFS], 7.4 months), triple-negative breast cancer (n = 53; ORR, 22.6%; mPFS, 5.5 months), and HER2-positive breast cancer (n = 14; ORR, 42.9%; mPFS, 11.0 months). Objective responses were observed in cancers with HER3-high and HER3-low membrane expression. Dose-limiting toxicities observed during dose selection were decreased platelet count and elevated aminotransferases. In dose expansion, GI and hematologic toxicities were the most common treatment-emergent adverse events (TEAEs) observed. Grade ≥3 TEAEs were observed in 71.4% of patients, and 9.9% discontinued treatment because of TEAEs. Three grade 3 and one grade 5 treatment-related interstitial lung disease events occurred. CONCLUSION: HER3-DXd demonstrated a manageable safety profile and durable efficacy in heavily pretreated patients across clinical subtypes. These data warrant further evaluation of HER3-DXd in patients with HER3-expressing metastatic breast cancer.