Pathological response and safety of albumin-bound paclitaxel as a neoadjuvant treatment for HER2-positive breast cancer compared to docetaxel combined with anti-HER2 therapy: a real-world study.

Background: This study aimed to retrospectively analyse the pathological response and safety of combining albumin-bound paclitaxel (nab-paclitaxel) or docetaxel with anti-HER2 therapy as a neoadjuvant treatment for HER2-positive breast cancer. Methods: From June 2020 to August 2023, 225 HER2-positive breast cancer patients who underwent radical surgery following neoadjuvant treatment were enrolled in this study. The patients were divided into two groups based on the drugs they received: the nab-paclitaxel group (n=166, receiving nab-paclitaxel + platinum along with trastuzumab and pertuzumab) and the docetaxel group (n=59, receiving docetaxel + platinum along with trastuzumab and pertuzumab). The pathological response and adverse events related to the drugs were collected and evaluated in both groups. Results: In the nab-paclitaxel group, the rates of breast and total pathological complete response (bpCR and tpCR) were significantly greater than those in the docetaxel group (69.27% vs. 47.45%, P=0.003; 68.67% vs. 45.76%, P=0.002). For patients who did not achieve pCR after chemotherapy, the pathological response of chemotherapy was analysed using MP grading and RCB grading. The results showed that there was a statistically significant difference between the two groups (P<0.05). Multivariate analysis revealed that therapeutic drugs, clinical stage, ER status, and Ki-67 level were independent predictors of pCR. The nab-paclitaxel group had a significantly greater proportion of patients with peripheral sensory neuropathy than did the docetaxel group (58.43% vs. 38.98%, P=0.035), while the docetaxel group had a greater proportion of patients with allergies and elevated ALT (31.93% vs. 69.49%, P=0.000; 23.49% vs. 40.68%, P=0.021). Conclusions: Our real-world study revealed that nab-paclitaxel combined with anti-HER2 therapy was an effective neoadjuvant therapy for HER2-positive breast cancer. The multivariate analysis revealed that chemotherapy drugs, clinical stage, ER status, and Ki-67 level was the significant factor influencing treatment outcome. These findings offer a valuable reference for the neoadjuvant treatment of patients with HER2-positive breast cancer.

A Pooled Analysis of Trastuzumab Deruxtecan in Patients With HER2-Positive Metastatic Breast Cancer With Brain Metastases.

BACKGROUND: This exploratory pooled analysis investigated the efficacy and safety of trastuzumab deruxtecan (T-DXd) versus comparator treatment in patients with HER2-positive metastatic breast cancer (mBC) with brain metastases (BMs) at baseline, categorized according to previous local treatment. PATIENTS AND METHODS: T-DXd data were pooled from DESTINY-Breast01/-02/-03. Comparator data, from patients receiving physician's choice therapy and trastuzumab emtansine, were pooled from DESTINY-Breast02 and -03, respectively. Baseline BM status was assessed according to US Food and Drug Administration criteria. Endpoints included intracranial objective response rate (ORR; complete or partial response in brain) per blinded independent central review (BICR) by RECIST v1.1, time to intracranial response, intracranial duration of response (DoR), central nervous system progression-free survival (CNS-PFS) by BICR, overall survival (OS), and safety. RESULTS: 148 patients who received T-DXd and 83 patients who received comparator treatment had BMs at baseline. In those who were treated with T-DXd, the intracranial ORR of patients with treated/stable and untreated/active BMs was 45.2% and 45.5%, respectively. The median (range) time to intracranial response was 2.8 months (1.1-13.9 months) and 1.5 months (1.2-13.7 months) in patients with treated/stable and untreated/active BMs, respectively. For those with treated/stable BMs, the median (95% CI) intracranial DoR was 12.3 months (9.1-17.9 months), and for those with untreated/active BMs it was 17.5 months (13.6-31.6 months). The median (95% CI) CNS-PFS and OS was 12.3 months (11.1-13.8 months) and not reached (22.1 months-not estimable [NE]) in those with treated/stable BMs, and 18.5 months (13.6-23.3 months) and 30.2 months (21.3 months-NE) in those with untreated/active BMs, respectively. Drug-related TEAEs grade ≥3 were experienced by 43.2% of patients with BMs and 46.4% without BMs with T-DXd. CONCLUSIONS: T-DXd demonstrated meaningful intracranial efficacy and clinical benefit in OS, with an acceptable and manageable safety profile in patients with HER2-positive mBC with treated/stable and untreated/active BMs.

Elacestrant in ESR1-mutant, endocrine-responsive metastatic breast cancer: should health authorities consider post hoc data to inform priority access?

For patients with hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) metastatic breast cancer (mBC) progressed on first-line endocrine therapy plus a cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i), fulvestrant, a selective estrogen receptor degrader (SERD) administered intramuscularly, represented the only monotherapy option until the approval of elacestrant. This oral SERD has been approved for patients with ESR1-mutant HR+/HER2- mBC by the European Medicines Agency, the Food and Drug Administration, and the UK Medicines and Healthcare products Regulatory Agency, according to the results of the randomized phase III EMERALD trial, which demonstrated elacestrant superiority over standard endocrine monotherapy. Consequently, elacestrant has been incorporated in the European Society for Medical Oncology and American Society of Clinical Oncology guidelines. However, in Europe, the access to this recommended drug depends on the decision of the National Health Authorities of each state. In this communication, we describe the main results and implications of the EMERALD trial, in the context of the biomarker-driven algorithm for patients with HR+/HER2- mBC progressed on CDK4/6i, and conclude that a subgroup of patients with ESR1-mutant tumors and specific clinical features can really derive a clinically meaningful benefit from elacestrant, sparing access to more toxic combination approaches and preserving the quality of life.

Efficacy and safety of different regimens of neoadjuvant therapy in patients with hormone receptor-positive, her2-negative breast cancer: a network meta-analysis.

Introduction: The objective of this systematic review and network meta-analysis (NMA) is to assess the effectiveness and safety of various neoadjuvant treatment protocols in individuals diagnosed with hormone receptor-positive, her2 negative(HR+/HER2-) breast cancer. Materials and methods: A systematic search was conducted in four databases (Medline, Embase, Web of Science, and CENTRAL) from the inception of the databases to January 16, 2024, to identify randomized controlled trials (RCTs) to various neoadjuvant therapy options in patients diagnosed with hormone receptor-positive, HER2-negative breast cancer. A network meta-analysis was conducted to evaluate pathological complete response (pCR). Results: There were 17 randomized controlled trials (RCTs) included in the analysis. These trials examined 16 different treatment regimens and involved a total of 5752 participants. The analysis revealed that the six most effective neoadjuvant treatment regimens for HR+/HER2- breast cancer were: CT(A)+olaparib (82.5%), CT(A)+nivolumab (76.5%), Com (74.9%), CT (72.1%), Mono+eribulin (72.0%), and CT(A)+pembrolizumab (70.4%).Paired meta-analysis for pathological complete response (pCR) found no statistically significant distinction between treatment regimens that included both anthracycline and immunosuppressants and regimens that relied solely on anthracycline chemotherapy(OR:1.14, 95%ci 0.79-1.64, I2 = 71%, P=0.50). Similarly, there was no significant difference between platinum-based chemotherapy and anthracycline-basedchemotherapy(OR:1.37, 95%ci 0.53- 3.56, I2 = 11%, P=0.52). With regards to safety, adverse effects of grade 3-5 were observed, which included haematological toxicity, gastrointestinal reactions, skin and mucous membrane reactions, neuropathy, hepatotoxicity, and cardiac disorders. Conclusions: The CT(A)+Olaparib and CT(A)+nivolumab groups demonstrated superior efficacy in neoadjuvant therapy for HR+/HER2- breast cancer. Furthermore, it is crucial to focus on effectively managing the adverse effects of the treatment plan to enhance patient's ability to tolerate it. Given the constraints of the current research, additional well-executed and suitable RCTs are necessary to validate the findings of this investigation. Although pCR is valuable in assessing the effect of neoadjuvant therapy in some cases, prognostic prediction and efficacy assessment in patients with HR+/HER2- breast cancer should be based on a combination of broader clinical and biological characteristics. Systematic review registration: PROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024534539, CRD42024501740.

Trastuzumab deruxtecan in patients with previously treated HER2-low advanced breast cancer and active brain metastases: the DEBBRAH trial.

BACKGROUND: Trastuzumab deruxtecan (T-DXd) is approved for human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). T-DXd has shown encouraging intracranial activity in HER2-positive ABC patients with stable or active brain metastases (BMs); however, its efficacy in patients with HER2-low ABC with BMs is not well established yet. METHODS: DEBBRAH is a single-arm, five-cohort, phase II study evaluating T-DXd in patients with central nervous system involvement from HER2-positive and HER2-low ABC. Here, we report results from patients with heavily pretreated HER2-low ABC and active BMs, enrolled in cohorts 2 (n = 6, asymptomatic untreated BMs) and 4 (n = 6, progressing BMs after local therapy). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was intracranial objective response rate per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) for both cohorts. RESULTS: Intracranial objective response rate per RANO-BM was 50.0% [3/6 patients; 95% confidence interval (CI) 11.8% to 88.2%] and 33.3% [2/6 patients; 95% CI 4.3% to 77.7%; P = 0.033 (one-sided)] in cohorts 2 and 4, respectively. All responders had partial responses. Median time to intracranial response was 2.3 months (range, 1.5-4.0 months) and median duration of intracranial response was 7.2 months (range, 2.8-16.8 months). Median progression-free survival per RECIST v.1.1. was 5.4 months (95% CI 4.1-10.0 months). Treatment-emergent adverse events occurred in all patients included (16.7% grade 3). Three patients (25.0%) had grade 1 interstitial lung disease/pneumonitis. CONCLUSIONS: T-DXd demonstrated promising intracranial activity in pretreated HER2-low ABC patients with active BMs. Further studies are needed to validate these results in larger cohorts. This trial is registered with ClinicalTrials.gov, NCT04420598.

HER2 expression in upper tract urothelial carcinoma and the relationship with clinicopathological characteristics-an analysis of 155 patients in Southwest China.

OBJECTIVE: We aimed to evaluate the expression of HER2 in patients with upper tract urothelial carcinoma (UTUC) in Southwest China by using a relatively large cohort, and to determine the relationship between HER2 expression and clinicopathological characters. MATERIALS AND METHODS: We retrospectively enrolled the clinical data of 155 UTUC patients who have undergone radical nephroureterectomy (RNU) from March 2019 to September 2022. HER2 expression was assessed using immunohistochemistry and scored according to the HercepTest (Scores of 0 or 1 + were considered as negative and 2 + or 3 + as positive). Tumor molecular phenotype was classified by the panel of CK20, CK5/6, and CD44. RESULTS: HER2 was overexpressed in 55 (35.5%) patients. It was associated with pathologic characteristics such as grade (p = 0.017), tumor molecular phenotype (p < 0.001) and Ki-67 expression (p = 0.017). On univariate and multivariable logistic regression analysis, HER2 overexpression remained associated with higher grade (HR, 10.6; 95% CI 1.0-112.6; p = 0.050) and luminal molecular phenotype (HR, 8.0; 95% CI 1,6-38.4; p = 0.010). During disease progression after nephroureterectomy, the phenotype of the tumor might change and a switch phenomenon in phenotype after recurrence in the bladder was reported. CONCLUSION: According to our study, in Southwest China, one-third of UTUC patients overexpressed HER2. Tumors with high grade or luminal phenotype tended to be HER2 positive. HER2 may represent a promising target for therapy in UTUC.

Clinicopathologic and molecular characterization of stages II-IV gastric cancer with Claudin 18.2 expression.

BACKGROUND: Claudin 18.2 (CLDN18.2) is a promising target for targeted therapies in gastric cancer (GC). This study investigated the prevalence of CLDN18.2 expression in patients with stages II-IV GC or gastroesophageal junction (GEJ) adenocarcinoma and its correlation with clinicopathologic features and other crucial GC biomarkers. METHODS: We enrolled 1000 patients diagnosed with stages II-IV GC after surgical treatment. Immunohistochemistry for CLDN18 (43-14A clone), PD-L1 (22C3 pharmDx), HER2, and FGFR2 was performed. CLDN18.2 positivity was defined as moderate-to-strong (2+/3+) membranous staining in ≥75% of tumor cells. CLDN18.2 expression was compared with biomarker expression, Epstein-Barr virus (EBV) association and microsatellite instability status, and clinicopathologic features. RESULT: CLDN18.2 was positive in 34.4% of the patients. CLDN18.2 positivity was significantly higher in the middle and upper thirds than in the lower third gastric location (P < .001), but there was no correlation with age, sex, or stage (P > .05). CLDN18.2 positivity was rare (2.8%) in mucinous adenocarcinoma but frequent (90.9%) in a majority of gastric carcinomas with lymphoid stroma. CLDN18.2 positivity was higher in EBV-associated (P < .001) and PD-L1-positive (PD-L1 CPS ≥ 5) GC (P = .014) but lower in HER2 positive GC (P = .005). CLDN18.2 positivity was not significantly associated with overall survival and disease-free survival. CONCLUSION: This study provides a comprehensive evaluation of CLDN18.2 status and its correlation with the clinicopathologic characteristics of patients with stages II-IV GC in Korea and with crucial biomarkers. It may be valuable for guiding future drug development, expanding treatment options, and ultimately improving patient outcomes in GC.

Comparative Analysis and Future Prospects of Human Epidermal Growth Factor Receptor 2 (HER2) and Trophoblast Cell-Surface Antigen 2 (Trop-2) Targeted Antibody-Drug Conjugates in Breast Cancer Treatment.

Breast cancer remains the most prevalent malignancy among women globally, presenting significant challenges in therapeutic strategies due to tumor heterogeneity, drug resistance, and adverse side effects. Recent advances in targeted therapies, particularly antibody-drug conjugates (ADCs), have shown promise in addressing these challenges by selectively targeting tumor cells while sparing normal tissues. This study provides a comprehensive analysis of two innovative ADCs targeting HER2 and Trop-2, which are critical markers in various breast cancer subtypes. These conjugates combine potent cytotoxic drugs with specific antibodies, leveraging the antigens' differential expression to enhance therapeutic efficacy and reduce systemic toxicity. Our comparative analysis highlights the clinical applications, efficacy, and safety profiles of these ADCs, drawing on data from recent clinical trials. In addition, the paper discusses the potential of these ADCs in treating other types of cancers where HER2 and Trop-2 are expressed, as well as the toxicity risks associated with targeting these antigens in normal cells. Additionally, the paper discusses novel synthetic drugs that show potential in preclinical models, focusing on their mechanisms of action and therapeutic advantages over traditional chemotherapy. The findings underscore the transformative impact of targeted ADCs in breast cancer treatment, noting significant advancements in patient outcomes and management of side effects. However, ongoing issues such as resistance mechanisms and long-term safety remain challenges. The conclusion offers a forward-looking perspective on potential improvements and the future trajectory of ADC research. This study not only elucidates the current landscape of ADCs in breast cancer but also sets the stage for the next generation of oncological therapeutics. This study not only elucidates the current landscape of ADCs in breast cancer but also sets the stage for the next generation of oncological therapeutics, with particular attention to their broader applications and associated risks.

Unveiling the mysteries of HER2-low expression in breast cancer: pathological response, prognosis, and expression level alterations.

BACKGROUND: The novel anti-HER2 antibody drug conjugates (ADCs) can effectively improve the long-term survival of patients with HER2-low expression breast cancer. However, pathological responses to neoadjuvant therapy (NAT) within HER2-low expression breast cancer, the relationship between pathological response and prognosis and the transformation of HER2 status are all now poorly understood. METHODS: The patients with HER2-0 and HER2-low expression breast cancer receiving NAT at Harbin Medical University Cancer Hospital between Jan. 2014 and Nov. 2018 were retrospectively explored. HER2 low expression refers to the IHC 1 + or 2 + and FISH negative. The Kappa test was utilized for analyzing the consistency rate of HER2 expression. To evaluate disease-free survival (DFS) and overall survival (OS), this research employed both the Kaplan-Meier analysis and the Cox regression. RESULTS: In this study, 178 patients with HER2-0 and 344 patients with HER2-low expression breast cancer were included. In comparison with the HER2-0 group, it is shown that patients in the HER2-low group have more possibility to be younger compared to those 50 years old (P < 0.014), have more premenopausal patients (P < 0.001), a higher proportion of hormone receptor (HR) positive patients (P < 0.001), and less proportion of stage III V patients (P < 0.034). When NAT was finished, the pCR rate became 23.6% in the HER2-0 group while 22.1% in the HER2-low group, and there was also a higher pCR rate in HR- patients in comparison with that in HR + patients (P < 0.01). Considering HER2 expression inconsistency, the overall HER2 inconsistency rate was 30.4% (Kappa = 0.431, P < 0.01). Among patients initially diagnosed as HER2-0, 34% (N = 61) were re-diagnosed as HER2-low after NAT. After stratification by HR expression status, HR+/HER2-0 patients transformed to HER2-low after NAT in 37%, and 32% of HR- patients changed from HER2-0 to HER2-low. In this survival analysis, there were both better DFS rates (P = 0.009) and OS rates (P = 0.026) in the HR-/HER2-low patients in comparison with the HR-/HER2-0 patients, while the HER2-0 and HER2-low patients in the HR + group had no significant survival difference. Additionally, for non-pCR patients, there was better DFS (P = 0.029) and OS (P = 0.038) in the HER2-low group in comparison with that of the HER2-0 group, while no significant survival difference exists between pCR patients. CONCLUSION: After HR stratification, there are unique clinical characteristics and prognostic outcomes in HER2-low expression breast cancer, which indicates the potential to become a specific molecular subtype of breast cancer. The significant instability of HER2-low expression status between primary tumor and residual invasive disease suggests that multiple detections of HER2 status should be emphasized in NAT strategies.

The Impact of Pembrolizumab as a Salvage Therapy Based on HER2 Expression in Advanced Gastric Cancer.

Immune checkpoint inhibitors (ICIs) are used as salvage treatments for advanced gastric cancer (AGC) regardless of HER2 status. This study assessed the efficacy of ICIs based on HER2 expression in AGC patients who received pembrolizumab as salvage monotherapy at Samsung Medical Center from November 2017 to March 2023. HER2 status was determined via immunohistochemistry, and tumor response and survival outcomes were compared accordingly. Among the 113 patients analyzed, with a median age of 61 years and 64.6% being male, 12 patients (10.6%) were HER2-positive, and 101 patients (89.4%) were HER2-negative. Of 92 evaluable patients, none had a complete response. However, 50% of HER2-positive patients had a partial response, compared to 4.9% of HER2-negative patients (p < 0.001). The disease control rate was 70% in HER2-positive and 37.8% in HER2-negative patients (p = 0.086). Median progression-free survival was 5.53 months for HER2-positive patients versus 1.81 months for HER2-negative patients (p = 0.037). Pembrolizumab as a salvage chemotherapy for the treatment of AGC demonstrated superior effectiveness in HER2-positive patients compared with HER2-negative patients.

The RAL Small G Proteins Are Clinically Relevant Targets in Triple Negative Breast Cancer.

Breast cancer (BC) is the most frequent cancer and second-leading cause of cancer deaths in women in the United States. While RAS mutations are infrequent in BC, triple-negative (TN) and HER2-positive (HER2+) BC both exhibit increased RAS activity. Here, we tested the RAS effectors RALA and RALB, which are overexpressed in BC, as tractable molecular targets in these subtypes. While analysis of the breast cancer patient sample data suggests that the RALs are associated with poor outcome in both TNBC and HER2+ BC, our in vivo and in vitro experimental findings revealed the RALs to be essential in only the TNBC cell lines. While testing the response of the BC cell lines to the RAL inhibitors RBC8 and BQU57, we observed no correlation between drug efficacy and cell line dependency on RAL expression for survival, suggesting that these compounds kill via off-target effects. Finally, we report the discovery of a new small molecule inhibitor, OSURALi, which exhibits strong RAL binding, effectively inhibits RAL activation, and is significantly more toxic to RAL-dependent TNBC cells than RAL-independent HER2+ and normal cell lines. These results support the RALs as viable molecular targets in TNBC and the further investigation of OSURALi as a therapeutic agent.

New Advances in Metastatic Urothelial Cancer: A Narrative Review on Recent Developments and Future Perspectives.

The standard of care for advanced or metastatic urothelial carcinoma (mUC) was historically identified with platinum-based chemotherapy. Thanks to the advances in biological and genetic knowledge and technologies, new therapeutic agents have emerged in this setting recently: the immune checkpoint inhibitors and the fibroblast growth factor receptor inhibitors as the target therapy for patients harboring alterations in the fibroblast growth factor receptor (FGFR) pathway. However, chasing a tumor's tendency to recur and progress, a new class of agents has more recently entered the scene, with promising results. Antibody-drug conjugates (ADCs) are in fact the latest addition, with enfortumab vedotin being the first to receive accelerated approval by the U.S. Food and Drug Administration in December 2019, followed by sacituzumab govitecan. Many other ADCs are still under investigation. ADCs undoubtedly represent the new frontier, with the potential of transforming the management of mUC treatment in the future. Therefore, we reviewed the landscape of mUC treatment options, giving an insight into the molecular basis and mechanisms, and evaluating new therapeutic strategies in the perspective of more and more personalized treatments.

HER2 status and response to neoadjuvant anti-HER2 treatment among patients with breast cancer and Li-Fraumeni syndrome.

BACKGROUND: Breast cancer (BC) is the most common cancer among females with Li-Fraumeni syndrome (LFS), but available data on LFS-related BC characteristics are derived from small retrospective cohorts. Prior work has demonstrated a high proportion of HER2-positive BCs, but our understanding of how HER2-positive LFS BCs respond to anti-HER2 treatments is limited. METHODS: BCs diagnosed in patients with germline TP53 variants between 2002-2022 were assembled from three institutions. Hormone receptor (HR) and HER2 expression were retrieved from pathology records. Pathologic complete response (pCR) was defined as ypT0/is ypN0. RESULTS: A total of 264 BCs were identified among 232 patients with LFS: 211 (79.9 %) were invasive carcinomas, of which 106 were HER2-positive. Among HER2-positive BCs, most tumors co-expressed HRs (72.6 %) and were more frequent among those diagnosed at younger age (p < 0.001). Mastectomy was the preferred surgical approach among women with nonmetastatic cancers (77.8 %) and most received anti-HER2 targeted therapy (74.7 %). Among 38 patients receiving neoadjuvant therapy with available post-treatment pathology reports, 27 (71.1 %) achieved pCR: 18/26 (69.2 %) among HR-positive and 7/10 (70.0 %) HR-negative. The rate of pCR was 84.6 % among patients treated with an anthracycline-free regimen (all received trastuzumab). Among classifiable HER2-negative BCs (n = 77), 31 (40.3 %) were HER2-low and 46 (59.7 %) HER2-zero. CONCLUSIONS: Among females with LFS and BC, HER2-positive subtype was associated with younger age at diagnosis and a predominant HR-positivity. Favorable pCR rates were observed among those receiving neoadjuvant HER2-directed therapies, for both HR-positive and negative tumors. These data may inform the counseling and care of patients with LFS.

The DEBBRAH trial: Trastuzumab deruxtecan in HER2-positive and HER2-low breast cancer patients with leptomeningeal carcinomatosis.

BACKGROUND: Leptomeningeal disease (LMD) is associated with poor survival and diminished quality of life. Trastuzumab deruxtecan (T-DXd) has shown remarkable intracranial and extracranial activity in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). The DEBBRAH trial was designed to evaluate its efficacy and safety in patients with HER2-positive and HER2-low ABC with a history of brain metastases (BMs) and/or LMD. Here, we report results from cohort 5, which specifically included patients with pathologically confirmed LMD. METHODS: This single-arm, open-label, five-cohort, phase 2 trial enrolled seven patients in cohort 5 who received 5.4 mg/kg T-DXd intravenously every 21 days until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Key secondary endpoints included progression-free survival (PFS) and safety profile. FINDINGS: At data cutoff (April 4, 2023), the median duration of follow-up was 12.0 months (range, 2.5-18.6). The median OS was 13.3 months (95% confidence interval [CI], 5.7-NA, p < 0.001), meeting the primary endpoint. The median PFS was 8.9 months (95% CI, 2.1-NA). Two (28.6%) of seven patients remained on treatment after 18.6 and 11.9 months, respectively. Of the five patients who progressed and died, none had intracranial progression or clinical worsening of leptomeningeal symptoms. Notably, 71.4% (95% CI, 29.0-96.3) achieved prolonged stabilization (≥24 weeks) by response evaluation criteria in solid tumors (RECIST) v.1.1. No unexpected safety signals and no treatment-related deaths were observed. CONCLUSIONS: T-DXd showed promising antitumor activity in patients with HER2-positive and HER2-low ABC with previously untreated, pathologically confirmed LMD. These encouraging data warrant further investigation to address the unmet need in this difficult-to-treat condition. FUNDING: This work was funded by Daiichi Sankyo/AstraZeneca. This trial is registered with ClinicalTrials.gov: NCT04420598.

Inetetamab-based therapy in real-world treatment patterns with HER2-positive advanced breast cancer patients: a retrospective single-center study.

Background: Inetetamab is a novel antibody targeting human epidermal growth factor receptor 2 (HER2) developed in China. Due to its optimized antibody-dependent cell-mediated cytotoxicity effect compared with trastuzumab, it has shown good efficacy and safety in the treatment of HER2-positive advanced breast cancer (ABC). Objectives: This study aimed to investigate the efficacy and safety of inetetamab combination therapy in the treatment of HER2-positive ABC in real-world clinical practice. Design: Retrospective study. Methods: A total of 133 patients with HER2-positive ABC who were treated with inetetamab-based regimens between March 2020 and January 2024 were retrospectively included in this study. The main endpoint was median progression-free survival (mPFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Results: The study included 133 HER2-positive ABC patients, and the median age was 55 years. The mPFS was 8.0 (6.7-9.3) months. The ORR was 50.4%, while the DCR was 88.7%. The mPFS for patients receiving inetetamab-based therapy as first to second, third to fourth, and later lines of metastatic treatment were 14.0, 7.0, and 6.0 months, respectively. Patients treated with inetetamab plus pyrotinib plus chemotherapy, especially with capecitabine, had the best outcomes (mPFS = 14.0 months). Multivariate analysis revealed that prior HER2-TKI treatment was significantly associated with worse PFS (hazard ratios 2.829, 95% confidence interval 1.265-6.328, p = 0.011). Subgroup analysis indicated that patients without visceral metastases had significantly better PFS (14.0 months vs 8.0 months, p = 0.003). The overall incidence of any grade adverse events (AEs) was 100%, with most being grades 1-2. Severe complications included neutropenia (37.6%) and leukopenia (33.1%). Conclusions: Inetetamab-based combination therapy shows promising efficacy and good safety in patients with HER2-positive ABC. It is one of the late-line treatment options for Chinese patients with HER2-positive ABC.

Survival outcomes of neoadjuvant versus adjuvant therapy in patients with T1c, node-negative, human epidermal growth factor receptor 2-positive breast cancer: A Surveillance, Epidemiology, and End Results population-based study.

BACKGROUND: Persistent debates exist regarding the superiority of neoadjuvant therapy (NAT) over adjuvant therapy (AT) for patients with T1c, node-negative, human epidermal growth factor receptor 2-positive (HER2+) breast cancer, and relevant guidelines for these patients are lacking. METHODS: Data on patients with T1cN0M0-stage HER2+ breast cancer who received chemotherapy and surgery were extracted from 2010 to 2020 from the Surveillance, Epidemiology, and End Results database. Propensity score matching (PSM) was used to create well-balanced cohorts for the NAT and AT groups. Kaplan-Meier (KM) analysis and Cox proportional hazards models were used to assess the differences between NAT and AT in terms of overall survival (OS) and breast cancer-specific survival (BCSS). Additionally, logistic regression models were used to explore factors associated with response to NAT. RESULTS: After PSM, 2140 patient pairs were successfully matched, which achieved a balanced distribution between the NAT and AT groups. KM curves revealed similar OS and BCSS between patients receiving NAT and those undergoing AT. A multivariate Cox model identified achieving pathological complete response (pCR) after NAT, compared with AT, as a protective prognostic factor for OS (hazard ratio, 0.52; 95% CI, 0.35-0.77; p < .001) and BCSS (hazard ratio, 0.60; 95% CI, 0.37-0.98; p = .041). A logistic regression model revealed that White race and hormone receptor-negative status independently predicted pCR. CONCLUSIONS: For patients with T1cN0M0-stage HER2+ breast cancer, NAT demonstrated comparable OS and BCSS to AT. Patients who achieved pCR after NAT exhibited significantly better survival outcomes compared with those who received AT.

QL1701 (a proposed trastuzumab biosimilar) versus reference trastuzumab plus docetaxel as first-line therapy for HER2-positive metastatic breast cancer: a multicenter, randomized, double-blinded, parallel-controlled, phase III equivalence trial.

BACKGROUND: QL1701 is a proposed biosimilar to the reference trastuzumab (Herceptin®). This trial compared the efficacy and safety of QL1701 with the reference trastuzumab in first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. MATERIALS AND METHODS: This randomized, double-blinded, parallel-controlled, phase III equivalence trial was conducted in 73 centers in China. Eligible patients with histologically or cytologically diagnosed HER2-positive metastatic breast cancer were randomly assigned (1 : 1) to receive either QL1701 or reference trastuzumab in combination with docetaxel (every 3 weeks) for eight cycles as the first-line treatment. Then, in patients with objective responses or stable disease, the QL1701 or reference trastuzumab with or without docetaxel was maintained for totally up to 12 months if tolerated. The primary endpoint was 24-week objective response rate (ORR) assessed by an independent review committee (IRC). The equivalence margin was 0.80-1.25 with a 90% confidence interval (CI) for the ORR ratio (QL1701 to reference trastuzumab). RESULTS: Between 29 April 2020 and 15 March 2022, 474 patients were randomized, and 473 received either QL1701 (n = 236) or reference trastuzumab (n = 237). The risk ratio for 24-week ORR was 1.07 (90% CI 0.94-1.21). The 90% CI fell within the pre-specified equivalence margin of 0.80-1.25. The 24-week ORR assessed by IRC was 59.7% (95% CI 53.2% to 66.1%) versus 56.1% (95% CI 49.5% to 62.5%) in QL1701 and the reference trastuzumab, respectively. As of 12 April 2023, there were no notable differences in progression-free survival (median: 8.3 versus 8.4 months) and overall survival (1-year rate: 95.1% versus 93.3%) between the two groups. Safety, pharmacokinetic (PK), and immunogenicity profiles were similar between the two groups. CONCLUSION: QL1701 demonstrated equivalent efficacy and similar safety to the reference trastuzumab when combined with docetaxel in the first-line treatment of patients with HER2-positive metastatic breast cancer, with similar PK and immunogenicity profiles.

Excavating regulated cell death signatures to predict prognosis, tumor microenvironment and therapeutic response in HR+/HER2- breast cancer.

Regulated cell death (RCD) has been documented to have great potentials for discovering novel biomarkers and therapeutic targets in malignancies. But its role and clinical value in HR+/HER2- breast cancer, the most common subtype of breast cancer, are obscure. In this study, we comprehensively explored 12 types of RCD patterns and found extensive mutations and dysregulations of RCD genes in HR+/HER2- breast cancer. A prognostic RCD scoring system (CDScore) based on six critical genes (LEF1, SLC7A11, SFRP1, IGFBP6, CXCL2, STXBP1) was constructed, in which a high CDScore predicts poor prognosis. The expressions and prognostic value of LEF1 and SFRP1were also validated in our tissue microarrays. The nomogram established basing on CDScore, age and TNM stage performed satisfactory in predicting overall survival, with an area under the ROC curve of 0.89, 0.82 and 0.8 in predicting 1-year, 3-year and 5-year overall survival rates, respectively. Furthermore, CDScore was identified to be correlated with tumor microenvironments and immune checkpoints by excavation of bulk and single-cell sequencing data. Patients in CDScore high group might be resistant to standard chemotherapy and target therapy. Our results underlined the potential effects and importance of RCD in HR+/HER2- breast cancer and provided novel biomarkers and therapeutic targets for HR+/HER2- breast cancer patients.

Real-world treatment patterns and outcomes in patients with HR+/HER2- metastatic breast cancer treated with chemotherapy in the United States.

BACKGROUND: Until recently, treatment options for patients with hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) and resistance to endocrine therapy were limited to chemotherapy. This real-world study describes treatment patterns and outcomes in patients treated with chemotherapy in the United States before approval of antibody-drug conjugates. PATIENTS AND METHODS: This retrospective, observational study included adults with HR+/HER2- mBC from the ConcertAI Patient360™ Breast Cancer dataset who initiated their first chemotherapy in the metastatic setting between January 2011 and June 2021. Treatment patterns were described; real-world overall survival, time to next treatment or death, and real-world progression-free survival were evaluated for all eligible patients and patients treated with subsequent chemotherapy. Index dates were the start date of each chemotherapy treatment. RESULTS: Among 1545 eligible patients, 76% were white, 12% had Eastern Cooperative Oncology Group performance status ≥2, 38% had de novo mBC, and median age was 61 years (range, 52-69 years). Within the index period, capecitabine was used the most as the first chemotherapy agent and decreased in later treatments, while the use of eribulin increased between first and fourth chemotherapies. Median (95% confidence interval) real-world overall survival was 23.3 months (21.3-25.4 months) from start of first chemotherapy, time to next treatment or death was 6.5 months (5.9-7.1 months), and real-world progression-free survival was 6.9 months (6.4-7.6 months); median times from second, third, and fourth chemotherapies decreased with each additional chemotherapy treatment. CONCLUSIONS: This real-world study demonstrates that for patients with HR+/HER2- mBC, chemotherapy provides relatively limited survival benefit which decreases with each additional chemotherapy line, and highlights the need for improved treatment options.

Absolute lymphocyte count predicts efficacy of palbociclib in patients with metastatic luminal breast cancer.

BACKGROUND: Absolute lymphocyte count (ALC) is a predictive and prognostic factor for various tumor types, including breast cancer. Palbociclib is a CDK4/6 inhibitor widely used for the treatment of metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer. However, predictive biomarkers of the efficacy of palbociclib remain unelucidated. We conducted a retrospective study to examine the predictive value of the baseline ALC in patients treated with palbociclib. METHODS: The medical records of patients with ER-positive, HER2-negative breast cancer treated with palbociclib plus hormonal therapy between December 2017 and December 2021 were analyzed retrospectively. The cutoff value of ALC was set at 1800 cells/µL at the initiation of palbociclib treatment. The clinical benefit rate (CBR) was defined as the rate of complete or partial response or stable disease for at least 6 months. Progression-free survival (PFS) rates were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards regression. RESULTS: All of the 202 patients were women, with a median age of 59 years and a performance status (PS) of ≤ 2. The median numbers of lines of chemotherapy and endocrine therapy before palbociclib treatment were 0 (range, 0-9) and 1 (range, 0-7), respectively. Fifty-one patients had liver metastases. Forty-six patients tested negative for progesterone receptor (PgR) expression. The median follow-up time was 9.1 months. The CBR was significantly higher in the ALC-high group than in the ALC-low group (79% vs. 60%; P = 0.018). The median PFS was significantly longer in the ALC-high group than in the ALC-low group (26.8 months vs. 8.4 moths, respectively; P = 0.000013). ALC, age, PS, PgR status, prior chemotherapy, prior endocrine therapy, and liver metastasis were entered into the multivariate analysis. ALC was identified as an independent factor for PFS (P = 0.00085), along with liver metastasis (P = 0.0020), PS (P = 0.026), and prior endocrine therapy (P = 0.019). CONCLUSION: ALC can serve as a predictor of palbociclib efficacy in patients with metastatic ER-positive, HER2-negative breast cancer.