HER2-positive Early Breast Cancer Research Articles

Impact of Pertuzumab and Ado-Trastuzumab Emtansine on Cumulative Avoidance of Recurrence Among Women Treated for Locally Advanced, Inflammatory, or Early-Stage Nonmetastatic HER2-Positive Breast Cancer in the United States.

We assessed the impact of HER2-positive early breast cancer (EBC) treatment landscape changes following the introduction of pertuzumab and ado-trastuzumab emtansine (T-DM1) on cumulative population-level recurrences avoided since 2013 (first pertuzumab approval for EBC in the United States; US). We constructed a multi-year epidemiologic population treatment-impact model to estimate annual recurrences between 2013 and 2031. Parameters were: BC incidence; stage I-III proportion; HER2-positive disease proportion; treatment proportions for neoadjuvant-only, adjuvant-only, and neoadjuvant-adjuvant continuation; and therapeutic agent proportions within each of those settings (chemotherapy only, trastuzumab±chemotherapy, pertuzumab with trastuzumab±chemotherapy, or T-DM1). The primary endpoint was cumulative recurrences, estimated by incorporating extrapolated clinical trial data for each regimen of interest into the model under four scenarios. Approximately 889,057 women were predicted to be diagnosed with stage I-III HER2-positive BC from 2006 to 2031 in the US and potentially indicated for HER2-targeted treatment. In steady-state equilibrium, the model estimated that real-world utilization of pertuzumab and T-DM1 will reduce the population-level number of recurrences by approximately 32%, with 7226 recurrences predicted in 2031 based on current utilization rates. In different modeled scenarios, use of neoadjuvant pertuzumab, continuation of pertuzumab in the adjuvant setting, and T-DM1 in the adjuvant setting in women with residual disease after neoadjuvant treatment were all predicted to reduce the number of recurrences. Given the improvement of HER2-targeted treatments, alongside increases in BC disease burden, we expect that the population-level impact of HER2-targeted treatments will accelerate over the next decade. Our results suggest that utilization of HER2-targeted treatments in the US has the potential to change the epidemiology of HER2-positive EBC by preventing a substantial number of women from experiencing disease recurrence. These improvements may help to inform our understanding of the future disease and economic burden of HER2-positive BC in the US.

Monocyte-to-lymphocyte ratio as predictor of cancer therapy-related cardiotoxicity in patients with breast cancer: a pilot cohort study.

Elevated pre-treatment baseline inflammation has been associated with cancer therapy-related cardiac dysfunction (CTRCD) in patients with breast cancer. Monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio and systemic immune-inflammation index (NLR × platelets) have emerged in clinical context as markers of disease-related inflammation. To evaluate development of CTRCD according to pre-treatment blood inflammatory biomarkers in patients with breast cancer. Pilot cohort study including consecutive female patients ≥ 18years with HER2-positive early breast cancer who consulted at the institution's breast oncology outpatient clinic between march/2019 and march/2022. CTRCD: absolute reduction in LVEF > 10% to below 53% (2D-echocardiogram). Survival analysis was performed using Kaplan-Meier curves, compared by the log-rank test, and discrimination ability was evaluated through AUC-ROC. Forty-nine patients (53.3 ± 13.3y) were included and followed-up for a median of 13.2months. CTRCD was observed in 6 (12.2%) patients. Patients with high blood inflammatory biomarkers had lower CTRCD-free survival (P < 0.050 for all). MLR showed statistically significant AUC (0.802; P = 0.017). CTRCD was observed in 27.8% of patients with high MLR versus 3.2% with low MLR (P = 0.020); negative predictive value was 96.8% (95%CI 83.3-99.4%). In patients with breast cancer, elevated pre-treatment inflammatory markers were associated with increased risk of cardiotoxicity. Among these markers, MLR had good discriminatory performance and high negative predictive value. The incorporation of MLR might improve risk evaluation and selection of patients for follow-up during cancer therapy.

Combined role of the neutrophil/lymphocyte ratio and Neo-Bioscore in neoadjuvant therapy in HER2-positive early breast cancer.

e12613 Background: High neutrophil/lymphocyte ratio (NLR) is considered a poor prognostic factor in triple negative breast cancer but its role in HER2-positive early breast cancer (eHBC) and its relationship with Neo-Bioscore (Nb) scale (NbS) in neoadjuvant therapy (NeoT) has not been established. They could be predictive factors of response to double antiher2 blocking with Pertuzumab (Pz) and Trastuzumab (Tz). Methods: The efficacy of Chemo-trastuzumab (ChTz) versus Chemo-trastuzumab-pertuzumab (ChTzPz) was assessed in patients with eHBC treated at our center. We performed a comparative analysis of the pathological complete response (pCR) according to pre-treatment NLR and clinical NbS (Grade + clinical stage + estrogen receptor (ER) previous to NeoT) Univariate and multivariate retrospective study were performed using xi-square and binary logistic regression (v21 SPSS software). Results: 150 patients (Pts) with stage IIA to IIIC HBC were treated from 2014 to 2022. Mean age 52 years. 83 Pts (55.3%) received Chem-Tz and 67 Pts (44.7%) Chem-Tz-Pz. In the overall sample, the pCR was higher in the Tz-Pz group, 60% Vs 40%; OR 3.05 (95% CI 1.5-5.9). In the NLR &gt;2 subgroup, pCR was higher in Pts treated with Pz-Tz, 66.7% vs 33.3%; OR 4.2 (95% CI 1.5 – 11.07) If we combine Pts with both NLR ≥2 and clinical Nb ≥2, the pCR was significantly higher in the Tz-Pz group, 68.4% vs 11.8%; OR 16.25 (95% CI 2.7-94.8). In the multivariate analysis, Nb≥2, NLR ≥2 and double blockade with Pz are related to an increase in pCR (OR 1.29, OR 1.076 and OR 2.90 respectively), with significance for Pz (p=0.001). Conclusions: In our review, the combined use of Pz-Tz proves to be a more effective treatment than simple Tz blockade in the treatment of poor prognosis breast cancer. High NLR, despite being a poor prognostic factor, seems to be a predictor factor of pCR in Pts treated with Pz-Tz. The increase in NLR and clinical NbS are factors to take into account to predict the efficacy of NeoT in eHBC Pts. [Table: see text]

A meta-analysis of cardiac toxicity of concurrent epirubicin and trastuzumab in early breast cancer.

e12583 Background: The concurrent use of doxorubicin and trastuzumab has been limited due to the increased risk of cardiac toxicity. Epirubicin is a less cardiotoxic alternative to doxorubicin, and the change in ejection fraction occurs until its cumulative dose doubles that with doxorubicin. This study aims to evaluate the cardiotoxicity and pathological complete response (pCR) rate associated with concurrent usage of epirubicin and trastuzumab in patients with HER2 positive early breast cancers (EBC). Methods: A literature search was conducted on NCBI/PubMed, and Cochrane database for phase II or III randomized controlled trials of concurrent use of epirubicin and trastuzumab in HER2 positive EBC between January 1, 2000 and February 28, 2021.The definition of adverse cardiac events varied among these trials, including changes in left ventricular systolic function and clinical heart failure. To compare the risk of cardiotoxicity and the odds of pCR rate between concurrent and non-concurrent regimens, a meta-regression analysis utilizing fixed-effects and mixed-effects linear models was conducted to investigate the relationship between various covariates. Results: Seven trials containing concurrent use of epirubicin and trastuzumab involving 1797 patients were analyzed. All of them are neoadjuvant studies. The median cumulative dose of epirubicin used was 300mg/m2 and there were a total of 96 reported cardiac adverse events. The concurrent use of epirubicin and trastuzumab did not result in a statistically significant increase in cardiotoxicity compared to non-concurrent regimens (risk ratio = 1.18, 95% CI: 0.68-2.05). Meanwhile, there was a significant increase in pCR rate with the concurrent regimens (odds ratio = 1.48, 95% CI: 1.04-2.12). Mixed-effects meta-regression analysis showed that in trials with higher proportion of hormone receptor-positive EBC patients, the risk ratio of cardiotoxicity significantly increased with concurrent regimens and pathological complete response rate became less significant. Conclusions: The concurrent use of a limited dose of epirubicin and trastuzumab demonstrated a positive impact on pCR rate without a significant increase in cardiotoxicity. Further research is necessary to fully comprehend the long-term safety profile in individuals with metastatic breast cancer. [Table: see text]

Association of HER2/CEP17 ratio with pCR after HER2-directed neoadjuvant treatments in the phase III NeoALTTO trial.

600 Background: HER2-directed therapies are approved for the treatment of patients with HER2-positive invasive breast cancer as defined by HER2 protein overexpression, or HER2 gene amplification based on HER2/chromosome enumeration probe (CEP17) ratio ≥ 2.2. Above this accepted HER2 status determination, however, it is still unknown whether the efficacy of HER2-directed therapy in early breast cancer increases with increasing HER2/CEP17 ratios. Therefore, the purpose of the presented work is to evaluate whether quantitative assessment of the HER2/CEP17 ratio predicts pathological complete response (pCR) and event-free survival (EFS) of patients treated with neo-adjuvant HER2-based regimen in the prospective phase III NeoALTTO trial. Methods: 455 women with HER2-positive early breast cancer, who had received neo-adjuvant trastuzumab and/or lapatinib for 6 weeks and then together with 12 cycles of weekly paclitaxel were included in this analysis. The HER2/CEP17 ratio in the primary tumor samples was correlated with pCR and survival outcome. Results: The Median HER2/CEP17 ratio in NeoALTTO was 5.1 (range: 1.1 – 100.0), and ratios were not associated with age, hormone receptor status, or any of the other clinicopathological variables analyzed. The log HER2/CEP17 ratio significantly predicted for pCR in both uni-variate (OR: 1.83; 95% CI: 1.11 - 3.01, p = 0.0176) and multivariate analysis (OR: 1.79; 95% CI: 1.07 - 2.99, p = 0.0257). Higher HER2/CEP17 ratios were, however, not associated with improved EFS (adjusted HR = 0.79; p = 0.3537). A pCR prediction model which included HER2/CEP17 ratio, treatment arm, and hormone receptor status improved the predictive strength of treatment arm alone from a ROC AUC value of 0.60 to 0.69. Conclusions: In patients treated with HER2-based neoadjuvant therapy, quantitative analysis of the readily available pre-treatment HER2/CEP17 ratio by FISH is predictive of pCR but not EFS.

A multicenter phase II study of vaccines to prevent recurrence in patients with HER-2–positive breast cancer.

532 Background: Patients (pts) with early stage HER2-positive breast cancer are commonly treated with neoadjuvant HER2-targeted therapy. Pts who have residual invasive disease have a less favorable outcome and increased risk of recurrent disease than pts with a complete pathologic response (pCR). It also has been observed that pts who do not achieve a pCR have low or absent anti-HER-2 CD4 Th1 responses. We hypothesized that correcting anti-HER-2 CD4 Th1 response using vaccines will be safe, induce anti-tumor immunity in HER2-positive breast cancer and reduce the risk of recurrence. We conducted a multi-center, phase 2, randomized study to determine the safety, immunogenicity and recurrence free survival of two HER2 vaccines (multivalent anti-oncodriver DNA vaccine (WOKVAC) or HER-2-pulsed dendritic cell vaccine (DC1)). Methods: Pts with HER2-positive early breast cancer were eligible if they had residual invasive disease at surgery after receiving neoadjuvant chemotherapy plus HER2-targeted therapy. Patients were randomly assigned in a 1:1 ratio, with stratification according to residual cancer burden (RCB) (1+2 vs 3) to receive adjuvant HER2 vaccination with either DC1 or WOKVAC. For the initial vaccination phase, DC1 was delivered via US guided inguinal lymph node administration, weekly x 6 weeks and WOKVAC was given intradermally on weeks 1, 4, and 7. Booster vaccines were given at months 6, 9 and 12. The primary end point is to evaluate the safety and tolerability of each vaccine and assess immune response rate as measured by ELISPOT. Each treatment arm will be assessed separately. Secondary endpoints include recurrence-free survival. Exploratory analyses include the assessment of prognostic and predictive biomarkers including circulating tumor cells, serum HER2 levels, and other immune correlative biomarkers. Here we are reporting the initial safety results. Results: Total of 110 eligible pts (55 WOKVAC vs 55 DC1) were enrolled from 2/2018 to 12/2022 and received at least one dose of treatment and 38 pts pending completion of the booster phase. Most pts had clinical stage II/III 56/35 (82%) and 50% had positive node disease at diagnosis. 82% had hormone receptor positive disease. 37/38/8 patients had RCB 1/2/3. For patients without known RCB status, ypTNM was used to randomize (yp stage I/II/III = 13/13/1 pts). The most frequently observed treatment related adverse events (TRAE) were injection site pain/reaction (38%) and chills (34%), fever (25%) and fatigue (40%) for DC1 arm. For WOKVAC, the most common toxicities included injection site reaction (68%) and fatigue (37%). All of these were grade 1 and 2. Nine patients had events including new primary cancer (1), local recurrence (2), metastatic disease recurrence (6). Conclusions: Both DC1 and WOKVAC HER2 vaccines were well tolerated without significant toxicities. Updated results will be presented at the meeting including correlatives. Clinical trial information: NCT03384914 .

Lowering the bar for consideration of neoadjuvant chemotherapy in early-stage HER2-positive breast cancers.

e12534 Background: The use of neoadjuvant chemotherapy (NAC) has contributed to increased rates of disease-free survival (DFS) as well as overall survival in breast cancer patients, specifically those with HER2-positive disease. Stage 2 patients with HER2-positive disease including tumors &gt; 2cm as well as node positive disease receive neoadjuvant chemotherapy as per current NCCN guidelines. The aim of our study was to understand outcomes in patients with early breast cancer receiving chemotherapy. Methods: We extracted data on patients with initial clinical stages IA-IB breast cancer who had HER2-positive status on initial biopsy and received chemotherapy plus anti-HER2 therapy in the Henry Ford Health System between January 2016 to June 2020. Patients with T2 or above and/or node positive disease were excluded. Results: Of the 229 total patients that met eligibility criteria, 159 (71%) were white, 65 (28%) were African American. 99% were females. The median age at diagnosis was 61 years. Estrogen receptor positivity was noted in 85% (196/229) of the patients. NAC was given to 56 patients (24%) of which 26 (46%) were African American and 45 (80%) were hormone receptor positive. 5 (9%) patients achieved pathological complete remission (CR). Remaining 51 patients (91%) did not have pathological CR. Of these, 17 (33%) patients had the same stage at surgery after NAC and 34 (66%) were upstaged on final pathological evaluation. 21 patients with residual disease (41%) underwent treatment change in the form of either ado-trastuzumab emtasine (TDM-1) or additional radiation therapy or repeat surgery. Of note, 34 of the 51 patients were treated for residual disease after 2019 with TDM-1. 54 (95%) patients are alive currently. Of the 173 patients that received adjuvant chemotherapy (76%), 39 (23%) were African American and 150 (87%) had hormone receptor positive disease. 19 of these (11%) were upstaged at surgery compared to the initial biopsy requiring treatment change. 163 (94%) are alive currently with no disease recurrence. Conclusions: Our study results suggest that NAC is used in minority of breast cancer patients, especially with stages 1A and 1B. Pathological CR rate in our study population was low and majority of patients who got NAC as well as a small percent of those who received adjuvant chemotherapy had disease upstaged based on surgical pathology results. We believe that this could be because of inaccurate initial staging due to limitations of imaging techniques and our population being mostly hormone receptor positive. With approval of TDM-1 in patients with residual disease post NAC, we may be able to improve outcomes in terms of recurrences and survival in these patients. Thus, consideration of NAC for early stage HER2-positive breast cancers appears attractive and data like our study may support ongoing prospective clinical trials.

Defendor special: Interim analysis of TCHP with primary empegfilgrastim prophylaxis (long-acting G-CSF) for treatment outcomes in early HER2+ breast cancer.

e12586 Background: TCHP is the standard regimen for neoadjuvant therapy (NAT) of HER2-positive early breast cancer (HER2+ eBC) and requires primary G-CSF prophylaxis (PP). Pathological complete response (pCR) after NAT reflects better pts outcomes. Long-acting G-CSF presents more balanced neutrophils (NEU) count vs short G-CSF. Preclinical data show tumor-associated neutrophils (TANs) as anti-tumor effector cells in eBC. There are limited data on the clinical benefit of TCHP in the subset of patients with HER2 amplification by ISH in the low-moderate of HER2 protein expression. This sub-group analysis of multicenter prospective study was designed to evaluate the pCR after TCHP with PP by empegfilgrastim (E) or filgrastim (F) in pts with HER2+ eBC. Methods: HER2+ eBC pts (n=199) with II-III stages are getting NAТ: 6 docetaxel/ carboplatin/ trastuzumab + pertuzumab + empegfilrastim/ filgrastim (TCHP+E/F). Short G-CSF (F) uses according to routine clinical practice, long-acting G-CSF (E) - 24h after each NAT cycle. This descriptive analyse were performed for pts who completed the whole NAT regimen. The study endpoints: pCR (ypT0/is, ypN0) in intention-to-treat (ITT) population and according to HER2 status: 3+ vs 2+ ISH positive (+). ClinicalTrials.gov No NCT04905329. Results: At the data cut-off (01’2023) 199 pts with HER2+ BC completed planned NAT and surgery (71 pts – TCHP+E; 128 pts – TCHP+F). pCR rate according to HER2 status and in ITT population in 2 G-CSF groups is presented. In TCHP+E group pCR rate exceeds KRISTINE trial data despite a more enriched pts’ population with poor prognosis (34% pts with IIIB - IIIC vs 17% pts in KRISTINE trial) while TCHP+F showed comparable results with historical control. The superior pCR rate under PP with E was also observed in HER2 (3+) pts sub-group vs PP with F. However, in HER2 (2+ ISH+) the results are similar in 2 G-CSF groups. The mature data are awaited. Conclusions: TCHP+E shows superior pCR rate vs TCHP+F in the ITT and HER2 (3+) population. The obtained results affirm data of preclinical research on the ability of G-CSF to switch tumor immunity from “cold” to “hot” in the eBC. We assumed that balanced NEU count under long-acting G-CSF stimulation enhances TANs infiltration is increasing therapy efficiency. In HER2 (2+ ISH+) population pCR results were comparable in 2 G-CSF groups. Discrepancies between gene amplification and protein overexpression resulted in declined amount of HER2-inhibitors-HER2 receptor active complexes. It can be TANs failure to kill anti-HER2-antibody-opsonized cancer cells by a trogoptosis. Our hypothesis requires further confirmation with translational research. Clinical trial information: NCT04905329 . [Table: see text]

Body Mass Index As A Prognostic Factor In HER-2 Positive Early Breast Cancer Patients And Its Effect On Duration Of Treatment With Trastuzumab: A Retrospective Study.

To evaluate prognostic value of body mass index in human epidermal growth factor receptor 2-positive early breast cancer, and to evaluate the duration of trastuzumab administration. The retrospective study was conducted from March 2020 to December 2021 at Kafrelsheikh University Hospital and Zagazig University Hospital, Egypt, and comprised data of women diagnosed between 2015 and 2017 with stage III human epidermal growth factor receptor 2-positivebreast cancer, who were treated with adjuvant chemotherapy and trastuzumab for a year. Body massindex had been calculated at the time of diagnosis, and data was divided into 3 groups: average weight group A, overweight group B and obese group C. Disease-free survival, distant disease-free survival and overall survival were estimated for all the three groups. Data was analysed using SPSS 26. The mean age of 160 cases was 44.99±11.35 years(range: 25-66 years). There were 93(58.1) postmenopausal women, 60(37.5%) had positive family history and 128 (80%) underwent modified radical mastectomy. There were 60(37.5%) patients in group A, 49(30.6%) in group B and 51(31.9%) in group C. There was significant association of body mass index with disease-free survival and distant disease-free survival (p<0.05), but not with overall survival (p>0.05). Significant difference was noted between body mass index and duration of trastuzumab (p<0.001). Body massindex wasfound to be an independent prognostic factor for human epidermal growth factor receptor 2-positiveearly breast cancer.

The amount of surgery in patients with early breast cancer and complete clinical response to neoadjuvant systemic therapy

BACKGROUND: Neoadjuvant systemic therapy for triple-negative and HER2-positive breast cancer can achieve a complete pathologic response in approximately 60% of patients. Pathological complete response to neoadjuvant systemic therapy is a predictive factor consistent with a positive prognosis which can be accurately determined by percutaneous vacuum aspiration biopsy.&#x0D; AIM: To evaluate the amount of surgery in the group of patients with triple-negative and HER2-positive early breast cancer whose complete pathologic response was confirmed by vacuum aspiration biopsy and who did not undergo standard surgery.&#x0D; MATERIALS AND METHODS: The following single-centre study has been conducted in the Russian Federation. Women aged 18 years old and older with unicentric (cT1-2N0-1M0 by classification TNM) triple-negative or HER2-positive breast cancer with complete clinical response after neoadjuvant systemic therapy according to imaging diagnostic methods. The patients underwent vacuum aspiration biopsy on the mammary gland under ultrusound control with standard amount of surgical intervention on the axillary region. In case when no invasive or in situ disease was detected, no further breast surgery was performed and the patients underwent standard radiation therapy. The survival with no tumor relapse in the ipsilateral mammary gland was assessed as the primary endpoint. The study is registered on сlinicaltrials.gov, NCT04293796.&#x0D; RESULTS: Between June 2020 and May 2022, twenty-seven (84.4%) patients (all women; mean age 47.5 (3268) years) were enrolled in the study and underwent visually controlled vacuum aspiration biopsy. The average initial tumor size was 20.5 (735) mm. 7 (25.9%) patients initially had metastases in the axillary lymph nodes confirmed by puncture biopsy; 15 (55.6%) patients had HER2-positive breast cancer, and 12 (44.4%) had triple-negative breast cancer. A study of vacuum aspiration biopsy samples showed that 6 (22.2%) patients had a residual tumor, and 21 (77.8%) patients achieved complete pathologic response (95% confidence interval 53.2 to 81.4). At a median follow-up of 12.4 months, there were no tumor relapses in the ipsilateral mammary gland in 21 patients with complete pathologic response confirmed by vacuum aspiration biopsy after neoadjuvant systemic therapy, as well as other relapses or progression of the disease.&#x0D; CONCLUSIONS: The patients with a complete pathologic response, which is confirmed by the vacuum aspiration biopsy method, who refused to perform surgery on the mammary gland do not demonstrate worse results with a short period of observation. However, additional prospective clinical studies are needed.

Real world evidence of adjuvant trastuzumab in HER2 positive early breast cancer

Adjuvant trastuzumab in HER2+ breast cancer reduces recurrence and mortality, and has been the standard treatment since 2006. The objective was to analyze health outcomes in the real world. Observational, retrospective study of patients with HER2+ breast cancer, stages I–III, treated with adjuvant trastuzumab in the past 15 years in only one center and for the first time in Spain. Survival was analyzed according to the number of cycles and cardiotoxicity. Two hundred and seventy-five HER2positive patients (18.60%) out of 1479 received adjuvant (73%) or neoadjuvant/adjuvant (26%) trastuzumab, concomitantly (90%) or sequentially (10%) with chemotherapy. The probability of overall and disease-free survival (OS and DFS) at 5 years was 0.93 (95% CI 0.89–0.96), and 0.88 (95% CI 0.83–0.92). The number of cases with a significant and asymptomatic decrease in ventricular ejection fraction and heart failure were 54 (19.64%) and 12 (4.36%), respectively. Sixty-eight patients (24.70%) received 16 or fewer cycles, especially those older than 65 (OR 0.371, 95% CI 0.152–0.903; p = 0.029) and with cardiotoxicity (OR 15.02, 95% CI 7.437–30.335; p < 0.001). The risk of cardiotoxicity was associated with having received radiotherapy (OR 0.0362, 95% CI 0.139–0.938; p = 0.037). Arterial hypertension (HR 0.361, 95% CI 0.151–0.863, p = 0.022), neoadjuvant treatment (HR 0.314, 95% CI 0.132–0.750, p = 0.009) and cardiotoxicity (HR 2.755, 95% CI 1.235–6.143, p = 0.013) maintained significant association with OS. Only neoadjuvant treatment maintained a significant association with DFS (HR 0.437, 95% CI 0.213–0.899, p = 0.024). The effectiveness of neoadjuvant and adjuvant trastuzumab can be considered comparable to those of clinical trials. In the real world, factors such as age, hypertension, radiotherapy, neoadjuvant treatment, and cardiotoxicity should be taken into consideration to optimize outcomes.

123O Randomized phase II trial of neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin in early HER2-positive breast cancer (ABCSG-52/ATHENE)

For most HER2-positive early breast cancer (EBC) patients (pts), neoadjuvant dual HER2 blockade with trastuzumab (T) and pertuzumab (P) plus poly-chemotherapy is standard of care. To improve the balance between toxicity burden and treatment outcomes, chemotherapy de-escalation has been a major focus in recent years. Among other immunogenic properties, anthracyclines can trigger an immunogenic cell death that engages the adaptive immune system. Within the ABCSG-52 trial we investigated a chemotherapy de-escalation immunotherapy regimen in HER2-positive EBC. Pts with previously untreated, histologically confirmed HER2-positive EBC (clinical prognostic stage cT1c-4a-d, N0–3,M0) were randomized 1:1 to two 3-weekly cycles of a chemotherapy-free induction phase (part 1) with TP plus 1200mg atezolizumab (TP+A) or TP alone. Afterwards, all pts received 4 cycles of TP+A in combination with epirubicin (part 2). The primary endpoint was pathological complete response (pCR; ypT0/Tis ypN0) in the overall study population. A pCR rate of ≥ 40% was considered as a positive trial result. Overall, 58 pts were randomized to TP-A (n=29) or TP (n=29) in 9 Austrian study centers. Median age was 57 (range 33-82), 16 pts (27.6%) had hormone-receptor (HR)-negative and 42 (72.4%) had HR-positive tumors. 45 pts (77.6%) had stage ≤ IIA and 13 (22.4%) ≥ IIB. In 35 pts a pCR was observed (60.3%; 95%CI 47.5% - 71.9%), 19 (65.5%) in the TP-A group and 16 (55.2%) in TP group (Δ 10.3%; 95%CI -14.7% - 35.4%). Residual cancer burden (RCB) class 0 or I was seen in 44 out of 55 pts (80%) with valid RCB assessment. Treatment emergent adverse events (AEs) grade ≥ 3 were reported in 17 pts (29.3%), 9 in TP-A group (31.0%) and 8 (27.6%) in TP group. No AEs of special interest (immune-related AEs, cardiac disorders grade ≥ 2, or infusion-related reactions) grade ≥ 3 were detected. Outcome according to PD-L1 expression status is currently analyzed and will also be presented at the meeting. For HER2-positive EBC, a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab and epirubicin is highly effective and safe and merits further investigation.

97P Efficacy and safety of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer: Long-term data from the PHranceSCa study

97P Efficacy and safety of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer: Long-term data from the PHranceSCa study

119TiP A multicenter, open-label, single-arm, non-interventional real-world study to investigate the treatment patterns of neratinib in HER2-positive early breast cancer (EBC) in China: NER-Tree study

119TiP A multicenter, open-label, single-arm, non-interventional real-world study to investigate the treatment patterns of neratinib in HER2-positive early breast cancer (EBC) in China: NER-Tree study

8P First decision impact study of HER2DX in patients (pts) with HER2-positive (HER2+) early breast cancer

8P First decision impact study of HER2DX in patients (pts) with HER2-positive (HER2+) early breast cancer

10P HER2 loss and PAM50 dynamics after neoadjuvant therapy (NAT) in HER2-positive (HER2+) early breast cancer (BC)

10P HER2 loss and PAM50 dynamics after neoadjuvant therapy (NAT) in HER2-positive (HER2+) early breast cancer (BC)

116P Time and motion randomised study of a subcutaneous (SC) pertuzumab and trastuzumab fixed-dose combination (PH FDC) for the treatment of HER2-positive early breast cancer (HER2 EBC): PHaTiMa

In oncologic monotherapy, SC compared to intravenous (IV) route brings advantages like patients’ (Pts) and healthcare professionals (HCP) preference and improved healthcare efficiency, thanks to reductions of both time and use of resources. During adjuvant dual blockade for HER2 EBC, trained observers measured time used in various treatment activities for 3 cycles (2nd to 4th) of pertuzumab (Perjeta or P) IV and trastuzumab (Herceptin® or H) IV or SC (Group A: P-IV+H-IV; Group B: P-IV+H-SC) and later for subsequent 3 cycles (5th to 7th) of PH FDC SC (Phesgo). The objectives were to assess time saved by Pts and HCP and what resources were used with PH FDC SC versus P-IV+H-IV or P-IV+H-SC. In 10 Spanish centres, 34 women were randomised (n=17 in Groups A and B). Per cycle, PH FDC SC saved 71% and 63% of Pts time in treatment room (-119 and -87 min, both p<0.0001) and 75% and 69% in chair (-121 and -90 min, both p<0.0001) compared with P-IV+H-IV and P-IV+H-SC, respectively. Active HCP time was reduced by 49% and 48% (-22.9 and -23.0 min, both p<0.0001), including preparation (-6.05 min p<0.0001 and -2.05 min p=0.1112) and administration (-16.9 min p=0.0006 and -20.8 min p<0.0001). Active times were reduced both for pharmacists (-2.10 min p=0.0185 and -1.46 min p=0.0488) and nurses (-18.3 min p=0.0004 and -20.0 min p<0.0001). PH FDC SC reduced use of consumables and avoided drug waste. Safety data up to cycle 7 (in 2025 ends 3-year follow-up) reported 20 Pts with 38 adverse events related to study treatments (only 2 Grade 3: diarrhoea and a serious [SAE] drug hypersensitivity). PH FDC SC significantly saved Pts and HCP times and reduced use of healthcare resources. In dual therapies, the advantages of the SC route are added to those of fixed dose combination, versus administering drugs separately. Preliminary safety data indicated that the study treatments were overall well tolerated. Together with previous findings showing comparable efficacy and safety profiles and Pts preference of PH FDC SC versus P-IV+H-IV in (neo)adjuvant settings, these results encourage the use of PH FDC SC for dual blockade treatments.

Pathologic Complete Response and Individual Patient Prognosis After Neoadjuvant Chemotherapy Plus Anti–Human Epidermal Growth Factor Receptor 2 Therapy of Human Epidermal Growth Factor Receptor 2–Positive Early Breast Cancer

The achievement of pathologic complete response (pCR) is strongly prognostic for event-free survival (EFS) and overall survival (OS) in patients with early breast cancer (EBC), and adapting postneoadjuvant therapy improves long-term outcomes for patients with HER2-positive disease not achieving pCR. We sought to investigate prognostic factors for EFS and OS among patients with and without pCR after neoadjuvant systemic treatment consisting of chemotherapy plus anti-HER2 therapy. We used individual data from 3,710 patients randomly assigned in 11 neoadjuvant trials for HER2-positive EBC with ≥100 patients enrolled, available data for pCR, EFS, and OS, and follow-up ≥3 years. We assessed baseline clinical tumor size (cT) and clinical nodal status (cN) as prognostic factors using stratified (by trial and treatment) Cox models separately for hormone receptor-positive versus hormone receptor-negative disease, and for patients who had pCR (pCR+; ypT0/is, ypN0) versus patients who did not achieve a pCR (pCR-). The median follow-up overall was 61.2 months. In pCR+ patients, cT and cN were significant independent prognostic factors for EFS, whereas only cT was a significant predictor for OS. In pCR- patients, cT, cN, and hormone receptor status were significant independent predictors for both EFS and OS. Regardless of hormone receptor status, cT, and cN, the 5-year EFS/OS rates were higher in pCR+ patients than in pCR- patients. In most subsets with regards to hormone receptor and pCR status, cT and cN were independent prognostic factors for both EFS and OS, including pCR+ patients. These results confirm that patients achieving pCR have far better survival outcomes than patients who do not. The traditional poor prognostic features, namely tumor size and nodal status, remain important even after a pCR.

Abstract 1873: D3L-001, a novel bispecific antibody targeting HER2 and CD47, demonstrates potent preclinical efficacy in solid tumors

Abstract Background: HER2 is overexpressed in different solid tumors, including 10-20% breast and gastric cancers. Many HER2-targeted drugs, including trastuzumab, pertuzumab, lapatinib, trastuzumab emtansine (T-DM1), and trastuzumab deruxtecan (T-DXd), have been approved for treatment of HER2-positive early and metastatic breast cancer (BC). However, trials involving pertuzumab, lapatinib and T-DM1 have failed to provide significant clinical improvements in patients with HER2-positive gastric cancer (GC), suggesting differences in HER2 mediated disease biology between HER2-positive BC and GC. Recent studies have suggested efficacy of HER2 antibodies could be further enhanced by antibody-dependent cellular phagocytosis (ADCP) principally regulated by “don’t-eat-me” CD47 signals, which is overexpressed in many HER2-positive cancers and suppresses phagocytosis through binding to SIRPα. Methods: BC and GC cell lines were used. Monocytes were isolated from human PBMC and differentiated into macrophages, which were used for in vitro ADCP assays. In in vivo animal experiments, D3L-001 and comparator antibodies were examined for efficacy in solid tumor xenograft models. Results: D3L-001 was designed to have higher HER2 affinity (KD &amp;lt; 1 nM) than that of CD47 (KD &amp;gt;10 nM). With this unique design, D3L-001 showed preferential binding to HER2/CD47 double positive tumor cells as compared to CD47 single positive cells. D3L-001 showed better anti-tumor effect than trastuzumab in a panel of solid tumor models, including but not limited to BC and GC cell lines or patient derived xenografts. Immunohistochemistry (IHC) analysis was performed in tumor FFPE slides to evaluate expression of HER2 and CD47 in the efficacy tested models, and we observed that D3L-001 showed broad tumor growth inhibition in HER2 or CD47 high/low expression models. In both in vitro and in vivo studies using breast cancer HCC1954, JIMT-1 and gastric cancer N87 models, we observed a synergistic effect in the combination of Trastuzumab with Magrolimab. Moreover, D3L-001 showed a trend of better efficacy than the combination of Trastuzumab and Magrolimab. These results confirm the synergistic effect of dual-targeting HER2 and CD47 simultaneously and suggest advantage of using bispecific antibodies to confer such effect. D3L-001 also displayed potent and comparable in vivo efficacy as Enhertu in gastric N87 model, and it showed synergistic in vivo efficacy, when combining with Pertuzumab or Paclitaxel, in breast HCC1954, JIMT-1 and gastric cancer N87 models. Conclusion: D3L-001, a novel HER2×CD47 bsAb, demonstrated potent anti-tumor effect in a variety of solid tumor models via HER2 guided CD47 co-blocking. It also showed synergistic efficacy when combining with other anti-tumor agents. D3L-001 will be further evaluated in clinic for its potential as a novel treatment option in HER2-positive BC, GC and other solid tumors. Citation Format: Haopeng Rui, Xiaofeng Yang, Jiahao Chen, Jia Wang, Zhiqiang Zheng, Zhiqiang Chen, Jingtao Lu, Peggy Wu, Janet Chen, Allison Wang, George Chen. D3L-001, a novel bispecific antibody targeting HER2 and CD47, demonstrates potent preclinical efficacy in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1873.

P123 Optimal Regimen of Neoadjuvant Systemic Therapy for HER2 Positive Early Breast Cancer

P123 Optimal Regimen of Neoadjuvant Systemic Therapy for HER2 Positive Early Breast Cancer