HER2-targeted therapies for HER2-positive early-stage breast cancer: present and future.

Breast cancer (BC) has the second highest incidence among cancers and is the leading cause of death among women worldwide. The human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20%-30% of BC patients. The development of HER2-targeted drugs, including monoclonal antibodies (mAbs), tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs), has improved the operation rate and pathological remission rate and reduced the risk of postoperative recurrence for HER2-positive early-stage BC (HER2+ EBC) patients. This review systematically summarizes the mechanisms, resistance, therapeutic modalities and safety of HER2-targeted drugs and helps us further understand these drugs and their use in clinical practice for patients with HER2+ EBC.

Investigating the Efficacy and Safety of a Dose-Dense Paclitaxel, Cyclophosphamide With Trastuzumab in Stage I-II Human Epidermal Growth Factor Receptor 2 (HER2) Positive Breast Cancer.

BACKGROUND: The evolution of systemic therapies has improved outcomes for patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer. Nonetheless, the tolerability and safety profile of systemic therapies represent an area for further improvement. Here we report the results of a phase 2 trial evaluating a nonanthracycline, nonplatinum adjuvant treatment regimen for patients following initial surgical resection. METHODS: We enrolled patients with stage I or II HER2+ breast cancer who underwent upfront surgery to receive adjuvant treatment with 6 cycles of dose-dense Paclitaxel, cyclophosphamide and Trastuzumab (PC-H) every 2 weeks, followed by 13 cycles of maintenance trastuzumab every 3 weeks to complete 52 weeks of treatment (compromising 19 cycles). The primary objective was to determine the safety and feasibility of adjuvant PC-H, measured by the completion rate frequency and the grade of adverse events, using National Cancer Institute Common Terminology Criteria. The secondary objective was to estimate relapse-free survival and overall survival. RESULTS: Between 2010 and 2019, a total of 39 patients were enrolled. Of those, 34 patients (87.18%) completed the planned treatment. Severe adverse events of grade 3 or 4 occurred in 27 patients (69.23%), including 3 patients (7.69%) with grade 3-4 decrease in ejection fraction. At median follow up of 5.6 years, all 39 patients were alive. The 5-year relapse-free survival was 94.30% (95% CI: 75.3-100). CONCLUSIONS: PC-H demonstrated overall safety and efficacy, yielding high rates of relapse-free survival among patients with early stage (HER2+) breast cancer.

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 combined with sirolimus and chemotherapy for the treatment of HER2-positive metastatic breast cancer patients with abnormal activation of the PI3K/Akt/mTOR pathway after trastuzumab treatment.

Background: We explored the efficacy and safety of inetetamab combined with sirolimus and chemotherapy for the treatment of human epidermal factor receptor 2 (HER2)-positive metastatic breast cancer patients with abnormal activation of the PI3K/Akt/mTOR (PAM) pathway after trastuzumab treatment. Methods: For this prospective multicenter clinical study, HER2-positive metastatic breast cancer patients with PAM pathway mutations confirmed by histology or peripheral blood genetic testing were enrolled from July 2021 to September 2022. Patients were randomly assigned to a trial or control group. The patients in the trial group received inetetamab combined with sirolimus and chemotherapy, while the control group patients received pyrotinib and chemotherapy. The RECIST v1.1 standard was used to evaluate efficacy. Descriptive statistics were used to summarize the clinicopathological features, and the Kaplan-Meier method was used to generate survival curves. The log-rank test was used to compare progression-free survival (PFS) between the two groups. Results: A total of 59 HER2-positive metastatic breast cancer patients with abnormal activation of the PAM pathway were included, of which 37 received inetetamab combined with sirolimus and chemotherapy treatment and 22 received pyrotinib and chemotherapy treatment. The median PFS was 4.64 months in the inetetamab group and 5.69 months in the pyrotinib group, with no statistically significant difference (p = 0.507). The objective response rates were 27.3% for the inetetamab group and 29.4% for the pyrotinib group. The safety assessment indicated that the adverse event (AE) incidences were 86.1% (31/36) in the inetetamab group and 78.9 (15/19) in the pyrotinib group, with 9 (25%) and four (21.1%) Grade 3/4 AEs in the inetetamab and pyrotinib groups, respectively. Conclusions: For metastatic HER2-positive breast cancer patients with abnormal PAM pathway activation and previous trastuzumab treatment, the combination of inetetamab with sirolimus and chemotherapy is equivalent to the combination of pyrotinib and chemotherapy. Therefore, this regimen could be a treatment option for PAM pathway-activated metastatic HER2-positive breast cancer patients.

Clinicopathological characteristics, treatment patterns and outcomes in patients with HER2-positive breast cancer based on hormone receptor status: a retrospective study.

BACKGROUND: Different hormone receptor (HR) expression patterns have significant biological and therapeutic implications in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, the distinction between HR-positive /HER2-positive (HR+/HER2+) and HR-negative/HER2-positive (HR-/HER2+) subtypes remains unclear. METHODS: This retrospective study analyzed 828 patients with HER2-positive breast cancer at the First Affiliated Hospital of Xi'an Jiaotong University from 2012 to 2022. Baseline characteristics were compared by chi-square test. Survival outcomes were estimated by Kaplan-Meier method. RESULTS: In total, 56.3% (n = 466) had HR-positive and 43.7% (n = 362) had HR-negative disease. Comparatively, HR+/HER2 + breast cancers presented favorable clinicopathological features. At a median follow-up of 49 months, 199 disease-free survival (DFS) events and 99 deaths were observed. HR+/HER2 + patients had significantly better survival outcomes than HR-/HER2 + patients. HR-positive status was an independent protective factor for overall survival (OS) [P = 0.032; hazard ratio, 0.61; 95% confidence interval (CI), 0.39-0.96] and DFS (P = 0.001; hazard ratio, 0.61; 95% CI, 0.46-0.81). HR+/HER2 + patients were significantly less sensitive to neoadjuvant therapy than HR-/HER2 + patients. In the first-line treatment for HR+/HER2 + advanced breast cancer, receiving endocrine therapy significantly improved advanced-OS (P < 0.001; hazard ratio, 0.33; 95% CI, 0.18-0.59) and progression-free survival (PFS) (P < 0.001; hazard ratio, 0.38; 95% CI, 0.25-0.58) compared with not receiving endocrine therapy. Moreover, maintenance endocrine therapy after HER2-targeted therapy and chemotherapy is associated with significant advanced-OS and PFS benefits compared with no maintenance endocrine therapy (advanced-OS: P < 0.001; hazard ratio, 0.05; 95% CI, 0.03-0.12; PFS: P < 0.001; hazard ratio, 0.35; 95% CI, 0.21-0.57). CONCLUSIONS: This study reveals the high heterogeneity of HER2-positive breast cancer related to HR status in clinicopathological features, metastasis patterns, and outcomes. Large randomized controlled trials are warranted to optimize treatment strategies for the HER2-positive breast cancer population.

Shifting the Paradigm: The Transformative Role of Neoadjuvant Therapy in Early Breast Cancer.

The use of neoadjuvant systemic therapy (NST) has become increasingly important in the treatment of breast cancer because of its various advantages. These include the ability to downstage tumors without compromising locoregional control and the potential to obtain valuable information about clinical and biological response to therapy with implications for individual prognoses. Surgical response assessment paves the way for response-adapted therapy, and pathological complete response (pCR; defined as ypT0/is ypN0) serves as an additional endpoint for drug development trials. Recommended NST regimens commonly consist of anthracyclines and taxane, with dose-dense anthracyclines and weekly paclitaxel often preferred, whenever feasible. For patients with human epidermal growth factor receptor-2 (HER2)-positive tumors, dual anti-HER2 therapy (trastuzumab and pertuzumab) is indicated together with NST in case of elevated risk of recurrence. For patients with triple-negative breast cancer (TNBC), adding carboplatin to NST correlates with improved pCR and survival rates, as does the addition of immune checkpoint inhibitors. For hormone receptor (HR)-positive/HER2-negative cancers, emerging data on NST including immune checkpoint inhibitors may elevate the significance of NST in high-risk luminal breast cancer. Here, we present a synthesis of the results from neoadjuvant clinical trials that aim at optimizing treatment options for patients with high-risk breast cancer.

Sonodynamic Therapy for HER2+ Breast Cancer with Iodinated Heptamethine Cyanine-Trastuzumab Conjugate.

The first example of sonodynamic therapy (SDT) with a cyanine dye-antibody conjugate is reported. The aim of this study was to evaluate the sonodynamic efficacy of a trastuzumab-guided diiodinated heptamethine cyanine-based sensitizer, 2ICy7-Ab, versus its non-iodinated counterpart, Cy7-Ab, in a human epidermal growth factor receptor 2-positive (HER2+) xenograft model. In addition, the combined sonodynamic and photodynamic (PDT) effects were investigated. A single intravenous injection of 2ICy7-Ab followed by sonication or combined sonication and photoirradiation in mice resulted in complete tumor growth suppression compared with the nontreated control and showed no detectable toxicity to off-target tissues. In contrast, Cy7-Ab provided only a moderate therapeutic effect (~1.4-1.6-fold suppression). SDT with 2ICy7-Ab resulted in a 3.5-fold reduction in tumor volume within 45 days and exhibited 13-fold greater tumor suppression than PDT alone. In addition, 2ICy7-Ab showed more durable sonostability than photostability. The sonotoxicity of the iodinated versus noniodinated counterparts is attributed to the increased generation of hydroxyl radicals, superoxide, and singlet oxygen. We observed no significant contribution of PDT to the efficacy of the combined SDT and PDT, indicating that SDT with 2ICy7-Ab is superior to PDT alone. These new findings set the stage for the application of cyanine-antibody conjugates for fluorescently monitored targeted sonodynamic treatment of cancer.

HER-2 Receptor and αvß3 Integrin Dual-Ligand Surface-Functionalized Liposome for Metastatic Breast Cancer Therapy.

Human epidermal growth factor receptor-2 (HER2)-positive breast cancer metastasis remains the primary cause of mortality among women globally. Targeted therapies have revolutionized treatment efficacy, with Trastuzumab (Trast), a monoclonal antibody, targeting HER2-positive advanced breast cancer. The tumor-homing peptide iRGD enhances the intratumoral accumulation and penetration of therapeutic agents. Liposomes serve as versatile nanocarriers for both hydrophilic and hydrophobic drugs. Gefitinib (GFB) is a potential anticancer drug against HER2-positive breast cancer, while Lycorine hydrochloride (LCH) is a natural compound with anticancer and anti-inflammatory properties. This study developed TPGS-COOH-coated liposomes co-loaded with GFB and LCH, prepared by the solvent injection method, and surface-functionalized with Trast and iRGD. The dual surface-decorated liposomes (DSDLs) were characterized for their particle size (PS), polydispersity index (PDI), zeta potential (ZP), surface chemistry, surface morphology, and their crystallinity during in-vitro drug release, drug encapsulation, and in-vitro cell line studies on SK-BR-3 and MDA-MB-231 breast cancer cells. The half-maximum inhibitory concentration (IC-50) values of single decorated liposomes (SDLs), iRGD-LP, and Trast-LP, as well as DSDLs (iRGD-Trast-LP) on SK-BR-3 cells, were 6.10 ± 0.42, 4.98 ± 0.36, and 4.34 ± 0.32 µg/mL, respectively. Moreover, the IC-50 values of SDLs and DSDLs on MDA-MB-231 cells were 15.12 ± 0.68, 13.09 ± 0.59, and 11.08 ± 0.48 µg/mL, respectively. Cellular uptake studies using confocal laser scanning microscopy (CLSM) showed that iRGD and Trast functionalization significantly enhanced cellular uptake in both cell lines. The wound-healing assay demonstrated a significant reduction in SDL and DSDL-treated MDA-MB-231 cell migration compared to the control. Additionally, the blood compatibility study showed minimal hemolysis (less than 5% RBC lysis), indicating good biocompatibility and biosafety. Overall, these findings suggest that TPGS-COOH-coated, GFB and LCH co-loaded, dual-ligand (iRGD and Trast) functionalized, multifunctional liposomes could be a promising therapeutic strategy for treating HER2-positive metastatic breast cancer.

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.

Survival following adjuvant trastuzumab-based treatment among older patients with HER2-positive early invasive breast cancer: A national population-based cohort study using routine data.

BACKGROUND: Randomised controlled trials (RCTs) reported adjuvant trastuzumab-based treatment improved overall survival (OS) among patients with HER2-positive early invasive breast cancer (EIBC). Few RCTs included older patients or those with comorbidity/frailty. This study aimed to determine whether the effect of adjuvant trastuzumab-based treatment on survival outcomes varies by patient age and fitness, using national data from routine care. METHODS: Women (50+ years) newly-diagnosed with HER2-positive EIBC between 2014 and 2019 were identified from England Cancer Registry data. Registration records were linked to Systemic Anti-Cancer Therapy data for treatment details and ONS death register for mortality details. A propensity score analysis employing the inverse probability of treatment weighting method was used to balance the patient variables across treatment groups. Cox models were used to evaluate whether the effect of treatment on OS was associated with patient age and fitness; competing risks regression models were used for breast cancer-specific survival (BCSS). RESULTS: 5238 women initiated adjuvant trastuzumab-based treatment. Median follow-up was 56.7 months. Comparison with 3421 women who did not receive adjuvant trastuzumab highlighted differences at diagnosis in relation to age, fitness, grade, nodal involvement, surgery type and use of radiotherapy. Weighted survival analysis found trastuzumab was associated with improved OS (hazard ratio HR 0.56, 95 %CI: 0.45-0.70) and improved BCSS (subHR 0.62, 95 %CI: 0.47-0.82). We found no evidence of a difference in effect by age or patient fitness for either outcome. CONCLUSION: In this national dataset, adjuvant trastuzumab was associated with improvements in survival, with an OS effect size similar to RCT evidence. The effect size was not found to vary by patient age or fitness. Chronological age and fitness alone should not be barriers to receipt of effective adjuvant targeted treatment.

Development and Validation of a Prognostic Nomogram Model for HER2-Positive Male Breast Cancer Patients.

BACKGROUND: HER2-positive male breast cancer (MBC) is a rare condition that has a poor prognosis. The purpose of this study was to establish a nomogram model for predicting the prognosis of HER2-positive MBC patients. METHODS: 240 HER2-positive MBC patients from 2004 to 2015 were retrieved from the surveillance, epidemiology, and end results (SEER) database. All HER2-positive MBC patients were divided randomly into training (n = 144) and validation cohorts (n = 96) according to a ratio of 6:4. Univariate and multivariate Cox regression analyses were used to determine the prognostic factors associated with HER2-positive MBC patients. A clinical prediction model was constructed to predict the overall survival of these patients. The nomogram model was assessed by using receiver operating characteristics (ROC) curves, calibration plots and decision curve analysis (DCA). RESULTS: The Cox regression analysis showed that T-stage, M-stage, surgery and chemotherapy were independent risk factors for the prognosis of HER2-positive MBC patients. The model could also accurately predict the Overall survival (OS) of the patients. In the training and validation cohorts, the C indexes of the OS nomograms were 0.746 (0.677-0.815) and 0.754 (0.679-0.829), respectively. Calibration curves and DCA verified the reliability and accuracy of the clinical prediction model. CONCLUSION: In conclusion, the predictive model constructed had good clinical utility and can help the clinician to select appropriate treatment strategies for HER2-positive MBC patients.

Targeted multimodal synergistic therapy of drug-resistant HER2-positive breast cancer by pyrotinib-ICG self-assembled nanoparticles.

Neoadjuvant targeted therapy combining targeted agents with chemotherapy significantly improve survival rates of patients suffering from human epidermal receptor (HER2)-positive breast cancer (BC) in early or locally advanced stages. However, approximately 50% of patients fail to achieve a pathological complete response. In response, targeted photothermal therapy (PTT) and photodynamic therapy (PDT) have emerged as effective strategies to bolster primary tumors treatment. In this context, we developed a novel nanodrug, referred to as "P/ICG", which comprised of a tyrosine-kinase inhibitor pyrotinib and the photosensitizer indocyanine green (ICG). This formulation was created for the targeted and multimodal synergistic therapy of HER2-positive BC. Upon irradiation with near-infrared light, ICG generates high levels of intracellular reactive oxygen species and elevated temperature, enhancing chemotherapy effects of pyrotinib. This synergistic action boosts a highly effective anticancer effect promoting the ferroptosis pathway, providing an efficient therapeutic strategy for treating HER2-positive BC.

Predictors of pathological complete response to neoadjuvant treatment in invasive breast cancer with different human epidermal growth factor receptor 2 (HER2) subcategories.

Background: Among human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients who receive anti-HER2 treatment, a noteworthy correlation between pathological complete response (pCR) and longer survival has been observed. The rate of pCR varies with the tumor's degree of HER2 protein expression. The aim of this study was to assess the correlations between clinicopathological characteristics, magnetic resonance imaging (MRI) parameters, and pCR in breast cancer with different HER2 subcategories. Methods: A total of 281 invasive breast cancer patients diagnosed with HER2-positivity were included. HER2-positive translated to immunohistochemistry (IHC) 3+ or IHC 2+/fluorescence in situ hybridization (FISH)(+). All enrolled patients underwent baseline MRI examination and received neoadjuvant chemotherapy, dual anti-HER2 therapy, and subsequent therapeutic surgery from January 2021 to May 2022. A logistic regression model was used to evaluate the effects of covariates on pCR. Results: Compared to the IHC 2+/FISH(+) group, patients with IHC 3+ tumors had a higher pCR rate (58.1% vs. 26.7%, P<0.001), clinical stage (58.6% vs. 40%, P=0.038), apparent diffusion coefficient (ADC) value (0.96 vs. 0.88 mm2/s, P=0.004), and were more likely to be estrogen receptor (ER) negative (55.9% vs. 31.1%, P=0.002) and progesterone receptor (PR) negative (72.5% vs. 46.7%, P=0.001). In both groups, univariate analysis showed that the pCR group more often had ER-negative and PR-negative status than the non-pCR group (P<0.001). The final multivariable analysis showed that ER-negativity was associated with pCR in the IHC 2+/FISH(+) group (P=0.004). ER-negativity and the longest diameter were two independent predictors of pCR in the IHC 3+ group (P<0.001 for ER, P=0.026 for longest diameter). Conclusions: The IHC 3+ group had a higher pCR rate than the IHC 2+/FISH(+) group. Along with clinicopathological characteristics, MRI parameters were supplemental predictors of pCR, particularly in IHC 3+ patients.

Exceptional Response to Pembrolizumab in HER2-Positive Gallbladder Carcinoma with High Tumor Mutational Burden.

PURPOSE: Patients with advanced cholangiocarcinoma, including gallbladder cancer, typically have a poor prognosis owing to limited effective chemotherapy options. The field of genotype-directed therapy in patients with cholangiocarcinoma is advancing. However, limited clinical data are currently available to evaluate the efficacy of molecularly targeted therapy. METHODS: Herein, we report the case of a 67-year-old man diagnosed with human epidermal growth factor receptor-2 (HER2)-positive and tumor mutation burden-high (TMB-H) cholangiocarcinoma. The HER2-positive and TMB-H characteristics were identified using comprehensive genomic profiling after showing resistance to gemcitabine and S-1 therapy. In the absence of clinical trials for HER2-positive cancer at that time, the patient was treated with pembrolizumab, which is used for TMB-H solid tumors in clinical practice. RESULTS: After receiving pembrolizumab, the patient experienced significant shrinkage in the primary tumor and liver metastases. Thus far, the patient has been receiving pembrolizumab for approximately 10 months. CONCLUSION: To our knowledge, this is the first report showing the efficacy of pembrolizumab in a patient with cholangiocarcinoma harboring both HER2-positive and TMB-H.

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.

Correlation of preoperative sonographic staging and postoperative histopathologic staging in patients with invasive breast cancer.

PURPOSE: To assess the accuracy of preoperative sonographic staging in patients with primary invasive breast cancer. METHODS: We retrospectively analyzed a prospectively kept service database of patients with newly diagnosed, unifocal, cT1-3, invasive breast cancer. All patients were diagnosed at a single center institution between January 2013 and December 2021. Clinical T stage was assessed preoperatively by ultrasound and correlated with the definite postoperative pathologic T stage. Demographics, clinical and pathological characteristics were collected. Factors influencing accuracy, over- and underdiagnosis of sonographic staging were analyzed with multivariable regression analysis. RESULTS: A total of 2478 patients were included in the analysis. Median patients' age was 65 years. 1577 patients (63.6%) had clinical T1 stage, 864 (34.9%) T2 and 37 (1.5%) T3 stage. The overall accuracy of sonography and histology was 76.5% (n = 1896), overestimation was observed in 9.1% (n = 225) of all cases, while underestimation occurred in 14.4% (n = 357) of all cases. Accuracy increased when clinical tumor stage cT was higher (OR 1.23; 95% CI 1.10-1.38, p ≤ 0.001). The highest accuracy was seen for patients with T2 stage (82.8%). The accuracy was lower in Luminal B tumors compared to Luminal A tumors (OR 0.71; 95% CI 0.59-0.87, p ≤ 0.001). We could not find any association between sonographic accuracy in HER2 positive patients, and demographic characteristics, or tumor-related factors. CONCLUSION: Our unicentric study showed a high accuracy of sonography in predicting T stage, especially for tumors with clinical T2 stage. Tumor stage and biological tumor factors do affect the accuracy of sonographic staging.

Olaparib plus trastuzumab in HER2-positive advanced breast cancer patients with germline BRCA1/2 mutations: The OPHELIA phase 2 study.

PURPOSE: To evaluate the efficacy and safety of the combination of olaparib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC) and germinal BRCA mutations (gBRCAm). METHODS: OPHELIA (NCT03931551) was a single-arm, open-label, phase 2 clinical trial. Patients aged ≥18 years diagnosed with HER2-positive ABC with germinal deleterious mutations in BRCA1 or BRCA2 who had received at least one prior systemic regimen for advanced disease were enrolled. Patients received olaparib plus trastuzumab until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was investigator-assessed clinical benefit rate for at least 24 weeks as per RECIST v.1.1. Key secondary endpoints included overall response rate (ORR) and safety profile. RESULTS: A total of 68 pre-treated HER2-positive ABC patients were screened. Due to slow accrual the trial was stopped after enrolling 5 patients instead of the planned sample size of 20. Four patients achieved clinical benefit (80.0 %, 95 % CI; 28.4-99.5, p < 0.001) and the primary endpoint was met. The ORR was 60.0 % (95 % CI; 14.7-94.7), including one complete response. Four (80.0 %) patients experienced at least one treatment-related treatment-emergent adverse event (TEAE). Most TEAEs were grade 1 or 2. There were no treatment-related deaths and no new safety signals were identified. CONCLUSIONS: This study suggests that the combination of olaparib plus trastuzumab may be effective and safe in pre-treated patients with HER2-positive gBRCAm ABC. This ABC patient population should be further studied and not be pre-emptively excluded from clinical trials of targeted therapy for BRCA1/2-driven cancers.

Additional statin treatment enhances the efficacy of HER2 blockade and improves prognosis in Rac1-high/HER2-positive breast cancer.

The prognosis of HER2-positive breast cancer (BC) has improved with the development of anti-HER2 therapies; however, the problem remains that there are still cases where anti-HER2 therapies do not respond well. We found that the expression of SREBF2, a master transcriptional factor in the mevalonate pathway, was correlated with ERBB2 (HER2) expression and a poor prognosis in HER2-positive BC. The target gene expressions of SREBF2 were associated with higher expression of ERBB2 in HER2-positive BC cells. Statins, anti-hypercholesterolemia drugs that inhibit the mevalonate pathway, enhanced the efficacy of HER2-targeting agents with inducing apoptosis in a geranylgeranylation-dependent manner. Mechanistically, statins specifically inhibited membrane localization of Rac1, a target protein of geranylgeranylation, and suppressed the activation of HER2 downstreams AKT and ERK pathways. Consistently, retrospective analysis showed a longer recurrence-free survival in Rac1-high/HER2-positive BC patients treated with HER2-targeting agents with statins than without statins. Our findings thus suggest that Rac1 expression could be used as a biomarker to stratify HER2-positive BC patients that could benefit from dual blockade, i.e., targeting HER2 with inhibition of geranylgeranylation of Rac1 using statins, thereby opening avenues for precision medicine in a new subset of Rac1-high/HER2-positive BC.

Patterns in use and tolerance of adjuvant neratinib in patients with hormone receptor (HR)-positive, HER2-positive early-stage breast cancer.

PURPOSE: One year of neratinib therapy is known to derive a significant invasive disease-free survival (iDFS) benefit in early-stage, hormone receptor-positive (HR +), HER2 + , node-positive breast cancer after trastuzumab-based adjuvant therapy. Limitations to neratinib use include significant gastrointestinal side effects, which often result in treatment discontinuation. In this study, we aimed to identify clinicopathologic features associated with adjuvant neratinib use and factors impacting treatment completion. METHODS: We performed a retrospective review of patients with early-stage HR + HER2 + breast cancer who were prescribed neratinib from 2017 to 2023 at our institution. We used the electronic medical record to extract information on patient characteristics, clinical features, and treatment information. Patients were identified as high risk based on definitions adapted from the standard high-risk definition in HR + HER2- breast cancer combined with studies correlating high Ki67 or high tumor grade with lower recurrence-free survival. Statistical analysis was performed using two-sided T-tests and chi-square tests. RESULTS: We identified 62 eligible patients of whom 55% completed 1 year of neratinib and 45% did not. Sixty percent (N = 37) of patients offered neratinib were considered high risk at diagnosis. The most common reason for neratinib discontinuation was inability to tolerate side effects (54%) followed by pill burden (18%). The most common side effect experienced by patients was diarrhea despite anti-diarrheal prophylaxis (56%), followed by rash (8%). Patients who received an up-titration of neratinib were more likely to complete the full course of neratinib when compared to those who did not (76% vs. 40.5% p = 0.013). The median starting dose of those who completed neratinib treatment was 140 vs. 240 mg in those who did not (p = 0.016). Neither group experienced a statistically significant greater likelihood of treatment holds or dose reductions. In terms of outcomes, 10 patients had progression of disease of whom 7 did not complete neratinib treatment (p = 0.169). Interestingly, those 7 patients developed metastatic disease and 57% (N = 4) had central nervous system metastases. CONCLUSION: Patients are more likely to complete 1 year of adjuvant neratinib with dose up-titration. Dose reductions and interruptions did not affect neratinib adherence in our patient population. Seven patients (11%) in our study developed metastatic disease, all of whom did not complete adjuvant neratinib treatment.

Characteristics of sphingomyelin metabolism in the MCF7 and BT474 radiotherapy­resistant HER2­positive breast cancer cell lines.

Breast cancer is the most common cancer globally in terms of incidence. This cancer is classified into subtypes based on histological or immunological characteristics. HER2-positive cases account for 15-25% of breast cancer cases, and one of the first events in breast carcinogenesis is HER2 upregulation. Furthermore, HER2 expression increases the detection rate of metastatic or recurrent breast cancers by 50-80%. The epidermal growth factor receptor family includes HER2, which is a transmembrane receptor protein. In our previous case report, patients who were resistant to anti-HER2 monoclonal antibody therapy, chemotherapy and radiotherapy had higher concentrations of phospholipid metabolites such as phosphatidylcholine and sphingomyelin (SM), which was associated with cancer recurrence progression. To better understand the relationship between radiotherapy resistance and SM expression, breast cancer cell lines with and without HER2 expression (MCF7 and BT474) after exposure to ionizing radiation (IR) were examined. In the cell culture supernatant, similar levels of SM in MCF7 cells were identified after 1-4 Gy exposure. However, SM levels in BT474 cells were upregulated compared with those of in the control group. Intracellular SM levels were upregulated in BT474 cells exposed to 1 and 4 Gy compared with the non-irradiated control group. Furthermore, significantly increased mRNA expression levels of sphingomyelin synthase 2 (SGMS2) in BT474 cells exposed to IR were observed compared with those in nonirradiated cells; however, the SGMS2 levels in MCF7 cells did not differ significantly among the 0, 2 and 4 Gy groups. These findings suggested that a higher dose of IR induced the secretion of SM and its associated gene expression in HER2-positive breast cancer cells.