HER2 Therapy Research Articles

Comparison of two anthracycline regimens for treatment of breast cancer and the incidence of cardiac injury

Abstract Background Anthracycline based breast cancer treatment regimens have evolved over time. Whether the risk of myocardial injury is different between regimens is unclear. Purpose To compare the incidence and significance of high sensitivity troponin-I (TpI) levels immediately post anthracycline therapy in women with breast cancer treated with two different anthracycline regimens. Methods We prospectively recruited women with early-stage breast cancer who received either dose-dense doxorubicin and cyclophosphamide (ddAC) or 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) with or without subsequent HER2 therapy. The ddAC regimen comprises 4 cycles of doxorubicin given every 2 weeks (240mg/m2), whereas FEC consists of 3 cycles of epirubicin given every 3 weeks (total epirubicin dose of 300mg/m2, which is doxorubicin equivalent dose of 240mg/m2 using a cardiovascular toxicity dose ratio of 0.80 as per the 2022 ESC Cardio-oncology guidelines). Clinical characteristics were collected and TpI levels were measured before anthracyclines and 4-6 weeks post last dose. Comprehensive echocardiograms were conducted at baseline and post-therapy. Results 236 female participants were enrolled; 103 (43.6%) received ddAC and 133 (56.4%) received FEC. Compared to FEC, patients receiving ddAC were older (mean age 58.1±10.2 vs 51.0±9.3 years; p < 0.001) received similar cumulative doxorubicin equivalent dose (237.4±23.4 vs 239.9 ± 11.9 mg/m2; p=0.30), had similar baseline LVEF (62.1 ± 4.8 vs 61.3 ± 3.6%, p=0.14), and TpI levels (median (IQR) 2.0 (2.0-2.0) vs 2 (2.0-3.0) ng/L, p=0.12) respectively. Baseline risk factors were similar (hypertension 21% vs 17%, p=0.34; diabetes 7% vs 5%, p=0.44; dyslipidemia 15% vs. 8%, p=0.12). Post-anthracycline, the ddAC group had higher TpI level compared to patients in the FEC group (median (IQR) 12 (7-29) vs 6 (4-11) ng/L; p<0.001). The proportion of patients with abnormal TpI levels (>99th percentile, >16.0 ng/L) was higher in the ddAC group (43.7% vs 15.0%; p < 0.001). In a multivariable linear regression model that included age, treatment regimen, baseline TpI, hypertension, diabetes mellitus and dyslipidemia, ddAC remained significantly associated with higher post anthracycline TpI levels (β=15.5, 95%CI: 8.7-22.3; p<0.001). There was no significant difference in the mean LVEF post-anthracycline (59.9 ± 5.1 vs 60.0 ± 3.8; p=0.91). No patients developed clinical heart failure. Conclusion Despite similar doxorubicin equivalent doses, the incidence of abnormal TpI levels was ~3 fold higher with DD-AC than FEC. Given that DD-AC is now more commonly used especially with immunotherapy this knowledge is clinically relevant. The difference in proportion with troponin elevation could be due to differences in the number of cycles (3 vs 4) and the frequency of chemotherapy administration (every 2 vs 3 weeks) between the regimens. However, this did not translate into a larger reduction in LVEF. But longer-term follow-up is needed.

LC-HRMS-based global metabolomics profiling unravels the distinct metabolic signature of lapatinib-resistant and trastuzumab-resistant HER2+ breast cancer cells

The effectiveness of lapatinib (LAP) and trastuzumab (TRZ), the first-line therapies for HER2+ breast cancer, has been limited owing to the development of acquired resistance in patients with HER2+. This study aimed to investigate the alterations in metabolic signatures in LAP-resistant HCC1954 and TRZ-resistant HCC1954 and pathways in human HER2+ breast cancer cells using liquid chromatography–high-resolution mass spectrometry (LC-HRMS) and enrichment analysis. The HCC1954 parental cells were sequentially treated 13 rounds with LAP or TRZ to develop resistant cells and then tested for their cytotoxicity using the MTT assay. Metabolites were prepared from HCC1954 parental (MBXWT), HCC1954-LAP (MBXLAP), and HCC1954-TRZ (MBXTRZ) cells prior to LC-HRMS, chemometric, enrichment, and joint pathway analyses. LAP- and TRZ-resistant cells were successfully developed from HCC1954, and 29 and 17 differentially expressed metabolites (DEMs) were identified between MBXWT-MBXLAP and MBXWT-MBXTRZ, respectively. The analysis of DEMs between MBXWT and MBXLAP revealed significant enrichment in D-amino acid metabolism, while MBXWT and MBXTRZ identified valine, leucine, isoleucine biosynthesis, ascorbate, and aldarate metabolism. Joint pathway enrichment analysis of LAP-resistant DEMs and differentially expressed genes (DEGs) showed enrichment in glutathione metabolism, while that of TRZ-resistance and DEGs showed enrichment in carbohydrate metabolism, namely pentose and glucuronate interconversions, starch and sucrose metabolism, and galactose metabolism. The findings from this study indicate considerable metabolic changes in LAP- and TRZ-resistant HCC1954 cells, which are crucial for understanding the resistance mechanisms and developing strategies to overcome these problems.

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.

Proteomics based selection achieves complete response to HER2 therapy in HER2 IHC 0 breast cancer

Recent trials have shown the efficacy of trastuzumab deruxtecan (T-DXd) in HER2-negative patients, but there is not yet a way to identify which patients will best respond, especially with the inability of current HER2 IHC and FISH assays to accurately determine HER2 expression in the unamplified setting. Here, we present a heavily pre-treated patient with triple-negative breast cancer (HER2 IHC 0 who had a complete response to T-DXd. In this case, we used a CLIA-certified reverse-phase protein array-based proteomic assay (RPPA) to determine that the patient had moderate HER2 protein expression (HER2Total 2+, 42%) and activation (HER2Y1248 1+, 23%). Using these results, we determined that the patient may benefit from T-Dxd despite being traditionally qualified as HER2 IHC 0. These findings highlight the potential for proteomics-based assays that may more accurately quantitate HER2 and (its activation) in the HER2 unamplified/IHC 0 setting to better select patients whose tumors are classically molecularly defined as HER2 IHC 0, but still could respond to HER2-directed therapy, and give patients access to therapies which for which they otherwise would not be eligible.

Immunotherapy as a new perspective for the therapy of esophageal cancer

Abstract The therapeutic landscape in nearly every therapeutic line in advanced/metastatic patients with squamous cell carcinoma (SCC) and esophagogastric adenocarcinoma (EGC) is enriched by recent approvals of immune checkpoint inhibitors (ICIs). In curative intended therapy, patients without pathological residual disease of SCC or GEJ (esophagogastric junction) cancer after preoperative chemoradiation and complete resection have access to adjuvant immunotherapy (independent of PD-L1 (programmed cell death protein 1) status, nivolumab, CHECKMATE 577). For metastatic SCC in the first-line, nivolumab combined with chemotherapy or with ipilimumab (TPS (tumor proportion score) ≥1 %, SCC, CHECKMATE 648) are approved, as well as second-line nivolumab alone regardless of PD-L1 status (ATTRACTION 03). For both, locally advanced or metastatic SCC and EGC, chemotherapy with pembrolizumab is available for patients with CPS (combined positive score) ≥10 (KEYNOTE 590) and for adenocarcinoma with nivolumab (CPS ≥5, CHECKMATE 649). Recent added approvals are chemotherapy with pembrolizumab in CPS ≥1 patients (KEYNOTE 859) and the addition of trastuzumab for personalized therapy in HER-2 positive/CPS ≥1 gastric and GEJ patients (KEYNOTE 811).

PDL1/HER2-Targeted Lipid-Encapsulated Oxygen Nanobubbles Combined with Photodynamic Therapy for HER2+ Breast Cancer Immunotherapy.

Programmed death (PD) 1/PD ligand 1 (PDL1) inhibitors are immune checkpoint inhibitors (ICIs) that may facilitate HER2-positive breast cancer treatment; however, their clinical efficacy remains elusive. Oxygen-enhanced photodynamic therapy (PDT) increases immunogenic cell death (ICD), providing a promising strategy to render the tumor microenvironment more sensitive to the ICIs. Lipid-encapsulated oxygen nanobubbles (Lipo-NBs-O2) obtained using nanobubbles (NBs) water for oxygen delivery in vivo can facilitate enhanced PDT. Here, dual-receptor targeted Lipo-NBs-O2 (DRT@Lipo-NBs-O2) is prepared by modifying Lipo-NBs-O2 with anti-PDL1 scFv and the fusion protein anti-HER2 scFv-tandem-repeat cytochrome c (anti-HER2-nCytc). Copper phthalocyanine is the photosensitizer (PS). DRT@Lipo-PS-NBs-O2 plus near-infrared irradiation leads to robust ICD induction, increasing DC activation and CD8+ T-cell numbers. Modification with anti-PDL1 scFv improves tumor distribution of DRT@Lipo-PS-NBs-O2 and plays the ICI role, invigorating CD8+ T cells and boosting the effects of immunotherapy. Oxygen supplied through DRT@Lipo-PS-NBs-O2 reduces P-glycoprotein expression. Enhanced PDT and Cytc can cause tumor cell death, thereby reducing the immune burden. Under dual receptor targeting and laser local irradiation, tumor cells become subject to the combination effects of PDT, ICD, ICIs, and apoptosis; this effectively suppresses tumor growth and metastasis. Lipo-NBs-O2 affords a combination of oxygen delivery and multidrug therapy to alleviate HER2-positive breast cancer.

Pathologic complete response to KEYNOTE522 and HER2-directed therapy for synchronous TNBC and HER2+ breast cancer

Simultaneous presentation of two separate primary breast cancers of differing histology at initial diagnosis is an uncommon phenomenon; it is even rarer to find these pathologically distinct populations within the same biopsy. Here we report the case of a patient diagnosed with clearly demarcated, pathologically heterogenous triple negative breast cancer (TNBC) and HER2+ breast cancer that was treated with a hybrid chemoimmunotherapy regimen combining elements of Keynote-522 and a standard HER2-directed neoadjuvant regimen, yielding apathologic complete response by the time of surgery with no notable adverse events. Molecular analysis of the histologically distinct tumor populations confirmed molecular evidence of differential HER2 expression but also suggested clonal relatedness of the two tumor populations based upon mutational profile, with phenotypic divergence potentially resulting from copy number alterations in NF1. Overall, this case highlights a rare histologic phenomenon that was successfully treated by combining both TNBC and HER2 directed neoadjuvant therapies.

Surface-Available HER2 Levels Alone Are Not Indicative of Cell Response to HER2-Targeted Antibody-Drug Conjugate Therapies.

HER2-targeting therapies have advanced breast cancer treatment over the past decade. Clinically, eligibility for HER2 therapies is determined by assessing HER2 levels on tumor cell surfaces through immunohistochemistry or by gene regulation through fluorescence in situ hybridization. HER2 therapies are not always effective in patients with elevated levels of HER2, questioning whether the amount of HER2 is sufficiently predictive of patient outcomes. Additionally, the HER2-targeting antibody-drug conjugate (ADC) Enhertu® was recently approved for metastasized HER2-low cancers, confirming the benefits of HER2 treatment for patients with low HER2 levels. To evaluate the correlation between HER2 levels and treatment efficacy, we quantified HER2 on eight cell lines using flow cytometry while simultaneously determining the toxicity of two HER2-targeting ADCs. Both HER2-high cell lines and HER2-low cell lines had significant toxicity responses to ADCs. We quantified HER2 internalization and found no correlation between HER2 levels and the percentage of internalization. We found a useful metric suggesting that a minimum number of HER2 receptors trafficked to lysosomes is sufficient to provide effective treatment. Our results indicate that the current standards of determining eligibility for HER2 therapy could limit patients' access to effective treatment. In conclusion, HER2 levels are not wholly adequate to determine the response to ADC treatment.

Trastuzumab, pertuzumab and nab-paclitaxel plus pyrotinib or not in neoadjuvant treatment of HER2-positive breast cancer: A multi-center, randomized, open-label, phase II study.

e12634 Background: Trastuzumab plus pertuzumab (TP) combined with chemotherapy is the standard neoadjuvant treatment regimen for HER2+ breast cancer. Anti-HER2 tyrosine kinase inhibitor, pyrotinib, shows great efficacy in HER2+ metastatic breast cancer, but lacking efficacy data on the basis of TP and chemotherapy in the neoadjuvant setting. This study aims to evaluate the efficacy and safety of TP plus nab-paclitaxel with or without pyrotinib as neoadjuvant treatment in HER2+ breast cancer. Methods: Stage II-III HER2+ breast cancer patients, stratified by disease stage (II vs. III) and hormone receptor (HR) status (positive vs. negative), were randomized 1:1 into the pyrotinib group or the control group. Both groups received a combination of 3-weekly TP and weekly nab-paclitaxel for 12 weeks. The pyrotinib group was concurrent given 320mg pyrotinib once daily. Primary endpoint was the total pathological complete remission (tpCR), defined as no invasive cancer in the breast and axillary lymph node. Results: From Nov 2020 to Apr 2023, a total of 109 patients were enrolled, with 108 receiving treatment: 55 in the pyrotinib group and 53 in the control group.The tpCR rate was 65.5% (95% CI: 51.4%, 77.8%) in the pyrotinib group, which shows no significant difference with the control group [60.4% (95% CI: 46.0%,73.5), P = 0.585). The breast pathological complete response (bpCR) rates were 70.9% (95% CI: 57.1%,82.4%) and 64.2%(95% CI: 49.8%,76.9%) in the pyrotinib and control group, respectively (P = 0.453). In the pyrotinib group, 52 (94.5%), 31 (56.4%), and 23 (41.8%) patients experienced dose-interruption, dose-reduction, and discontinuation of pyrotinib, respectively. The most common grade ≥3 adverse events in the pyrotinib and control groups were diarrhea (58.1% vs. 0%), decreased neutrophil count (23.6% vs. 15.1%), and decreased white blood cell count (16.4% vs. 7.5%). Conclusions: Our study showed pyrotinib didn’t significantly improve tpCR rate with pyrotinib on the basis of TP and nab-paclitaxel neoadjuvant therapy of HER2+ breast cancer. Concurrent pyrotinib treatment with TP was associated with a high rate of severe diarrhea. Further biomarker analyses are needed to identify which population would receive great benefit with neoadjuvant pyrotinib therapy in HER2+ breast cancer. Clinical trial information: NCT04398914 .

Peony exploratory analyses of biomarker changes: From baseline to surgical samples in patients with HER2+ breast cancer.

e15136 Background: PEONY (NCT02586025) is a randomized, multicenter, double-blind, placebo-controlled, phase III trial evaluating neoadjuvant and adjuvant pertuzumab/placebo with trastuzumab and docetaxel in HER2-positive early/locally advanced breast cancer. We previously reported that pertuzumab showed an improved efficacy vs. placebo in terms of total pathological complete response (tpCR), event-free survival and disease-free survival (DFS), as well as in pre-defined biomarker subgroups. Limited data are available on biomarker changes after neoadjuvant treatment in the Asian population. Thus, we aim to (1) describe the biomarker changes from baseline to surgical samples after HER2 targeted neoadjuvant therapy, and (2) explore the association of surgical biomarkers and DFS. Methods: This study will focus on biomarkers of tumor tissue samples collected at baseline and surgery among 218 non-tpCR patients, due to limited samples collected at disease progression. Samples were tested using Immunohistochemistry (IHC) for HER3, PTEN, CD8 and PD-L1. Both HER2/HER3 mRNA expression and PIK3CA mutation were assessed using a PCR based methodology. The statistical analyses were using R (4.1.3). Biomarkers were categorized as high/low either by median derived from baseline samples, or with well-established cutoffs, e.g. HER2 IHC of 3+ vs. 1/2+ and PD-L1 at 1%. The changes of biomarkers were examined among the paired samples using Fisher’s exact test and depicted by alluvial plots. Cox proportional hazard regression analysis was performed to examine the association between surgical biomarkers and DFS in pooled arms. Results: Since the surgical biomarkers are only evaluable among patients with residual disease, patients in this analysis had a higher stage, and were more likely to be node+. Of 166 paired samples, more patients show a decrease in HER2 and HER3 mRNA/IHC, PTEN IHC from baseline to surgery. PIK3CA mutation status remained the same among the majority of patients (n = 154, 95%). Immune-related biomarkers, PD-L1 and CD8, are more enriched in surgical samples compared to baseline. All these observations are similar between the two arms. No clear association has been shown in most of the biomarkers, except for PIK3CA, with DFS. Surgical tumor samples with PIK3CA mutation detected trended with a worse DFS than those with no PIK3CA mutation detected [HR: 1.81 (95% CI: 0.94 – 3.49)]. Conclusions: Of baseline and surgery paired samples, most biomarkers showed a change, except for PIK3CA mutation status. In pooled analyses, we only observed a trend of PIK3CA mutation detected in surgical samples with a worse DFS, which is in line with the association observed with baseline PIK3CA mutation status. No other associations were found between surgical biomarkers and DFS. These findings may suggest that despite biomarker changes patients continue to benefit From HER2 therapies and dual blockade. Clinical trial information: NCT02586025 .

Is early inclusion of neratinib with HER blockers possible in the treatment of stage 4 HER2 positive cancer?

e13019 Background: The management of the patients with breast cancer and choosing the most effective therapy still remains a challenge, but an achievable goal. 30-50% of the patients with stage IV HER2-positive breast cancer have an increased risk of developing brain metastases. In most patients, effective therapy for Her2+ BC does not reach the CNS due to the blood-brain barrier, which, in turn, can lead to cancer metastasis to the brain. Trastuzumab, Pertuzumab poorly penetrates the BBB, however the treatment regimens with the inclusion of trastuzumab increase life expectancy in patients with HER2+ BC with CNS metastases, mainly due to controlling of extracranial lesions. In contrast, neratinib penetrates the BBB well, and its combination with capecitabine produces responses in intensively pretreated patients, especially in cases where the only site of disease progression is the CNS. Our study was to directly compare the efficacy and safety of Neratinib plus Trastuzumab and Docetaxel(N+TDtx) and Pertuzumab plus Trastuzumab. Methods: This study involved 43 patients, among which 28 received (N+TDtx) -1st group and 15 received (N+TDtx) - 2nd group. A median number of 6 cycles were delivered in the two treatment arms, followed by Trastuzumab. Results: The primary endpoint was RFS and EFS. The median RFS was not reached in 2nd group at a median follow-up of 18.7 months, because of brain metastasis, disease progression and death of 23 (82%) patients. However, the 12-month RFS rate was significantly higher in the 1st group than in the 2nd 98% and 65%, respectively (hazard ratio [HR], 0.72; 95% CI, 0.56-0.93; P =.012). With median follow up of 36.4 months, neoadjuvant N+TDtx reduced the risk of disease recurrence, brain metastasis, progression or death by 98%, demonstrating a landmark three-year event-free survival (EFS) rate of 57% with N+TDtx, followed by trastuzumab compared to 17% with TDtx, followed by trastuzumab (Hazard Ratio [HR], 0.68; 95% Confidence Interval [CI], 0.49 to 0.93). The most frequent adverse event in the Neratinib arm was diarrhea, which was manageable with prophylactic treatment with loperamide. Conclusions: Neratinib, has shown that it was able to prevent brain metastases and demonstrated benefit in recurrence - free survival and event-survival in combination with Trastuzumab and Docetaxel over (PT+Dtx) for patients without brain metastases.

Pathological and clinical outcomes following neoadjuvant dual HER2 therapy for early-stage breast cancer: An Australian institutional real-world experience.

There has been significant progress made in developing novel targeted therapies in the neoadjuvant setting for non-metastatic HER2-positive breast cancer, which may be used in combination with conventional chemotherapy to optimise pathological responses at surgery. However, these therapies, particularly the chemotherapeutic components, may portend significant and long-lasting toxicity. Hence, de-escalation of treatment intensity has been an area of interest and was evaluated in the phase II NeoSphere study. Herein, we report the real-world pathological and survival outcomes from neoadjuvant taxane and dual HER2 blockade recorded at our centre. This was a retrospective cohort study of patients receiving neoadjuvant pertuzumab, trastuzumab and taxane chemotherapy for non-metastatic HER2-positive breast cancer at a single centre in Sydney, Australia. We collected data pertaining to baseline demographic characteristics, pathological response rates, post-surgical prescribing patterns and also undertook survival analyses for invasive disease-free survival (iDFS) as well as exploratory analyses for correlations between pre-specified clinicopathologic factors and pathological response at surgery. Our population was largely similar at baseline to the NeoSphere study. 71 patients were included in the final analysis. 61% achieved a pathological complete response (pCR). Three patients received conventional chemotherapy in the adjuvant setting. 92% of included patients were alive and disease-free at 3 years of follow-up. Only 3 events of recurrence or death were recorded at a median follow-up of 32 months. No significant difference in iDFS was noted between patients achieving pCR and those with residual disease at surgery. This study demonstrates that de-escalated adjuvant treatment for HER2-positive early breast cancer achieved favourable pathological and long-term outcomes comparable to large trials, some utilising more intensive chemotherapeutic components.

Decision-making concordance: A comparative analysis between a multidisciplinary tumor board and a large language model (ChatGPT) in breast cancer management.

e13648 Background: Advances in breast cancer management have led to more tailored therapies, increasing the complexity of decision-making. Establishing multidisciplinary tumor boards (MTB) is crucial for optimizing patient care, challenging healthcare teams intellectually. The integration of expertise, deep understanding, and clinical judgment is crucial. Artificial intelligence (AI), particularly through rapid developments and Large Language Models (LLM) offers opportunities to revolutionize healthcare by processing complex ideas and integrating medical evidence into decisions. This study evaluates ChatGPT-4 concordance with a Breast MTB. Methods: This study included 124 patients discussed at our Tumor Board from March 2023 to January 2024, treatment decisions from ChatGPT-4 were compared with those made by the MTB. Results: The median age was 52 years (24-85), with 98% female and 51% premenopausal. In 36% of the patients, the diagnosis followed a screening, while 64% were diagnosed due to symptoms like a palpable nodule or skin changes. 33% of patients meet the NCCN criteria for a family history of cancer. The distribution of clinical stages at diagnosis was 0 (15%), I (35%), II (31%), III (10%), and IV (8%). Most cases were left-sided (52%), followed by right-sided (43%), and bilateral in 5%. The phenotype was Luminal A-like (35%), Luminal B-like HER2 positive (23%), Luminal B-like HER2 negative (15%), and triple negative (10%). The overall concordance between the LLM and MTB rate achieved was 80.65% in patient profiles, including ductal carcinoma in situ. Concordance rates for treatment option indications were high: surgery (96%), radiotherapy (98%), chemotherapy (97%) and endocrine therapy (100%). For additional evaluations (PET/CT or oncogeriatric assessment), the concordance rate was 99%, for indicating genomic signatures was 96%, and for referrals for genetic evaluation, it was 93%. The lowest concordance was observed in type of anti HER2 therapy at 68%. Overall management concordance for patients in stage IV was 50%. Conclusions: AI is seeking ways to integrate into clinical routines by identifying individualized and personalized therapy option for our patients. We explore the concordance and feasibility of employing the LLM ChatGPT-4 in executing one of the most complex tasks in patient care, achieving high rates of concordance. Currently, AI is not capable of replacing medical professionals, but the use of LLM such as ChatGPT as an assistance and support tool for clinicians is likely to expand and evolve. Its capabilities could make it a valuable support tool for therapeutic management in the near future. All authors confirm that this abstract was not thought of or written by ChatGPT.

Trastuzumab-emtansine versus other anti-HER2 regimens in early or unresectable or metastatic HER-2 positive breast cancer: systematic review and network meta-analysis.

Motivation for the study. Treatment options for HER2-positive breast cancer were evaluated, focusing on the efficacy and safety of trastuzumab-emtansine (T-DM1) compared to other anti-HER2 therapies. Main findings. Trastuzumab-deruxtecan (T-DXd) and PyroCap emerged as promising alternatives, showing substantial improvements in progression-free survival for locally advanced or metastatic breast cancer. T-DM1 showed superior efficacy to the other treatments. Implications. Our findings could inform healthcare decision-making processes to optimize strategies for HER2-positive breast cancer, and potentially improve health outcomes and quality of life. We aimed to study the efficacy and safety of trastuzumab-emtansine (T-DM1) versus other anti-HER2 therapies in HER2+ breast cancer (BC). We performed a network meta-analysis (NMA) of randomized controlled trials (RCTs). Our study focused on patients undergoing treatment for unresectable locally advanced breast cancer (LABC) or metastatic breast cancer (mBC), which included regimens involving trastuzumab and taxanes. Additionally, we considered cases within the first 6 months of treatment for HER2+ early breast cancer (EBC). A total of 23 RCTs and 41 reports were included in our analysis. LABC and mBC showed no statistically significant difference in any of the comparisons of T-DM1 versus the other anti-HER2+ therapies. When assessing progression-free survival (PFS), trastuzumab-deruxtecan (T-DXd) and PyroCap demonstrated greater efficacy compared to other treatments (Hazard Ratio [HR]: 3.57; 95% confidence interval [CI]: 2.75-4.63 and HR: 1.82; 95% CI: 1.35-2.44; respectively), while T-DM1 alone exhibited superior effectiveness compared to LapCap (HR: 0.65; 95% CI: 0.55-0.77), TrasCap (HR: 0.65; 95% CI: 0.46-0.91), LapCapCitu (HR: 0.60; 95% CI: 0.33-1.10), Nera (HR: 0.55; 95% CI: 0.39-0.77), and Cap (HR: 0.37; 95% CI: 0.28-0.49). NMA allows a ranking based on the comparative efficacy and safety among the interventions available. Although superior to other schemes, T-DM1 showed a lower efficacy performance in PFS and overall response rate and a trend towards worse overall survival than T-DXd.

Evaluation of the Efficacy of Postoperative Adjuvant Therapy for HER2-Positive Ductal Carcinoma in Situ with Microinvasion

A retrospective study on 90 eligible HER2+ ductal carcinoma in situ with microinvasion (DCIS-MI) patients was performed with a median follow-up time of 57 months. The baseline was consistent between the 4-cycle and 6-cycle chemotherapy groups. There were more patients with multiple foci of micrometastasis in the target therapy group in the two groups with or without target therapy (p < 0.01). Postoperative chemotherapy with a 4-cycle regimen can achieve the expected therapeutic effect in patients with HER2+ DCIS-MI, but the role of target therapy in HER2+ DCIS-MI patients has not been confirmed.

Ingenious designed a HER2-Specific macrophage biomimetic multifunctional nanoplatform for enhanced bio-photothermal synergistic therapy in HER2 positive breast cancer

Photothermal therapy (PTT) has garnered extensive attention as an efficient strategy for cancer therapy. Unfortunately, there are currently no suitable photothermal agents (PTAs) capable of effectively treating HER2-positive breast cancer (HER2+ BC) due to the challenges in addressing blood circulation and tumor accumulation. Here, we propose a HER2-specific macrophage biomimetic nanoplatform IR820@ZIF-8@EM (AMBP) for enhanced bio-photothermal therapy of HER2+ BC. An anti-HER2 antibody was expressed in engineered macrophages using the transmembrane expression technique. As an efficient PTAs, IR820 dyes were assembled into ZIF-8 as to develop a “nano-thermal-bomb”. Homology modeling methods support that the expressed anti-HER2 antibody can specifically recognize the HER2 receptor. Moreover, antibody-dependent cell-mediated cytotoxicity can also be induced in HER2+ BC cells by AMBP. In vitro fluorescence confocal imaging showed that AMBP promoted the uptake of HER2+ cancer cells while in vivo anti-tumor experiments demonstrated that AMBP efficiently accumulates in the tumor regions. Finally, under spatiotemporally controlled near-infrared (NIR) irradiation, three of the six tumors were eradicated in AMBP-treated mice, demonstrating a safe and effective strategy. In conclusion, our research opens a new paradigm for antibody-specific macrophage, and it is expected that these characteristics will have substantial clinical translation potential for BC treatment.

Comprehensive molecular profiling identifies actionable biomarkers for patients from Thailand and the United Arab Emirates with advanced malignancies.

Comprehensive molecular profiling of tissue samples that can help guide therapy management is not widely available across the globe. Comprehensive molecular profiling through Caris Molecular Intelligence involves the analysis of DNA through next-generation sequencing, chromogenic or fluorescent in situ hybridization, pyrosequencing, and copy number alterations; RNA through whole-transcriptome sequencing and multiplex PCR of RNA; and protein through immunohistochemistry. Here we describe the experience of molecular profiling of tumor tissue samples from patients diagnosed with advanced solid tumors and treated in two countries, the United Arab Emirates and Thailand. Tumor cancer cases submitted to Caris Life Sciences (Phoenix, Arizona, USA) for molecular profiling from the UAE and Thailand were retrospectively analyzed (data accessed between 2019 and 2020) for their molecular alterations and clinical biomarkers, without regard to ethnicity. A total of 451 samples from 35 distinct types of advanced cancers were examined for mutations, amplifications, overexpression, exon copy number alterations, microsatellite instability, deficient mismatch repair, tumor mutational burden, and fusions. Interrogating each step of the biological pathway, from DNA to RNA to distinct protein, identified an alteration with an associated therapy for 75% of these tumor samples. The most common alterations identified included elevated PDL-1 that can be targeted with an immune checkpoint inhibitors and amplification of HER2 for which a variety of anti HER2 therapies are available. Comprehensive molecular profiling in patients with advanced malignancies can help optimize therapeutic management allowing for improved prognostic outcome.

Abstract PO1-10-04: Racial and Ethnic Disparities in Anthracycline and HER2-targeted Cardiotoxicity in Patients With Breast Cancer Using Global Longitudinal Strain Imaging Techniques

Abstract Purpose: Studies of global longitudinal strain (GLS) as a predictor of cancer treatment-related cardiac dysfunction (CTRCD) have been limited in racial/ethnic minority populations who are more likely to have risk factors associated with CTRCD. Our aim was to assess the utilization of GLS and development of CTRCD in a racially and ethnically diverse population of patients at an academic center in New York City. Methods: Patients were included if they had a breast cancer diagnosis and began treatment with anthracycline or HER2-directed therapies at Columbia University Irving Medical Center (CUIMC) from February 1, 2020-July 31, 2022. All patients and variables were identified via the electronic health record. Cardiovascular comorbidities including obesity, hypertension, diabetes, hyperlipidemia, coronary artery disease, congestive heart failure, and other cardiac disease, were recorded. Receipt of transthoracic echocardiogram(s) (TTE) with/without GLS were recorded, along with GLS and left ventricular ejection fraction (LVEF) values. CTRCD was defined as LVEF decrease of ≥10% to a LVEF value &amp;lt; 53% or GLS decrease of ≥ 15% from baseline or GLS &amp;lt; -18%. Analyses included descriptive statistics and univariable and multivariable logistic regression models to evaluate predictors of CTRCD by either LVEF or GLS definition. Results: We identified 270 eligible patients. Mean age was 51.8 years (standard deviation 13.0), 85 (31.5%) identified as White, 47 (17.4%) as Black/African, and 16 (5.9%) as Asian; 135 (50.0%) identified as Non-Hispanic/Latino, and 79 (29.2%) as Hispanic/Latino. Approximately half of the patient cohort, n=137 (50.7%) had a TTE with GLS during the study period. Of the TTEs done at CUIMC (n=658), 270 (41%) were ordered with GLS assessment, of which 184 (68%) reported a GLS value and 86 (32%) were not assessable due to image quality. Forty-three (16%) patients developed CTRCD: 20 (7%) by GLS criteria, 13 (5%) by LVEF criteria, and 10 (4%) by both GLS and LVEF criteria. In univariable analyses, race (OR 5.78, 95%CI 1.62-20.4 Asian compared to White), treatment with HER2 therapy without anthracycline versus anthracycline (OR 2.78, 95%CI 1.34-6.23), and prescription for cardiac medication prior to systemic therapy (OR 2.27, 95%CI 1.08-4.63) were predictors of CTRCD by any definition. In multivariable analysis, race (OR 7.86, 95%CI 1.71-38.50 Asian compared to White), and receipt of HER2 therapy without anthracycline compared to anthracycline (OR 5.13, 95%CI 1.42-25.00) were predictors of CTRCD. In multivariable analysis of CTRCD by GLS criteria only, race (OR 78.47, 95%CI 1.47-53.96 Asian compared to White), and treatment (OR 11.23, 95%CI 1.85-219 HER2 therapy compared to anthracycline; OR 58.7, 95%CI 1.05-60.59 HER2 therapy and anthracycline compared to anthracycline). Conclusions: In this retrospective analysis of a racially and ethnically diverse patient population, more than a third of Asian patients developed CTRCD, although the study is limited by small sample sizes. Asian race and receipt of anti-HER2 therapy were independent risk factors for CTRCD. Asian race was especially a predictor of CTRCD by GLS definition. Detection bias may explain the differences in CTRCD by drug class, as patients complete serial TTEs while receiving HER2-directed therapy, while patients who receive an anthracycline without HER2-directed therapy typically only receive a baseline TTE. Future research to better characterize racial differences in CTRCD incidence and develop interventions to reduce this disparity is an area warranting further investigation. Demographic and Tumor Related Factors Associated with CTRCD (n=270) Univariable and multivariable analysis of CTRCD by LVEF or GLS definition. Multivariable analysis was adjusted for all variables listed. Citation Format: Amanda Wang, Jayant Raikhelkar, Rohit Raghunathan, Julia McGuinness, Neil Vasan, Meghna Trivedi, Kevin Kalinsky, Katherine Crew, Melissa Beauchemin, Jason Wright, Dawn Hershman, Melissa Accordino. Racial and Ethnic Disparities in Anthracycline and HER2-targeted Cardiotoxicity in Patients With Breast Cancer Using Global Longitudinal Strain Imaging Techniques [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-10-04.

Abstract PS09-01: Individual patient data meta-analysis of clinical and translational biomarkers for prediction of pathological complete response (pCR) after de-escalated therapy in HER2+ breast cancer in four trials of the West German Study Group

Abstract Background Introduction of anti-HER2 therapies substantially improved outcomes for HER2-positive early breast cancer (HER2+ eBC). However, a considerable proportion of patients (pts) may still be overtreated with systemic chemotherapy (CTx) combinations. Establishing safe de-escalation strategies to avoid toxicities requires precise patient selection. Therefore, we set out to determine predictors for efficacy and survival in the unique setting of four de-escalation trials investigating short (12-week) neoadjuvant treatments (NAT) in HER2+ eBC. We investigated the prognostic ability of clinical and translational biomarkers for pCR to identify pts with the best prognosis after de-escalated systemic CTx-free NAT. Methods 756 pts who received de-escalated NAT were analyzed: trastuzumab + pertuzumab (T + P, n=92) and T + P + paclitaxel (pac, n=42) in ADAPT-HR-/HER2+ (NCT01817452); trastuzumab emtansine (T-DM1, n=118), T-DM1 + endocrine therapy (ET, n=125), and T + ET (n=129) in ADAPT-HR+/HER2+ (NCT01779206), T + P + pac (n=107) and T + P + ET (n=100) in TP-II (NCT03272477); and T + P + pembrolizumab (n=43) in Keyriched-1 (NCT03988036) in HER2-enriched (HER2-E) subtype by PAM50. The primary endpoint of each trial was pCR (ypT0/is ypN0). Survival was a secondary endpoint in all trials but Keyriched-1; survival data for TP-II are pending. Baseline gene expression was analyzed by BC360 assay; intrinsic molecular subtypes were determined using the PAM50 predictor. Stromal tumor infiltrating lymphocytes (sTILs) were evaluated at baseline and at week 3 of NAT. sTILs were categorized using a 30% threshold and the low cellularity category ( &amp;lt; 500 invasive tumor cells) at week 3. Prognostic markers for pCR were identified with univariate and multivariable logistic regression models with backstep algorithm excluding variables with p≥0.1; considered variables included age, sTILs (baseline, 3-weeks), cT, cN, grade, hormone receptor and HER2 status, intrinsic subtype, and standardized ERBB2 and ESR1 gene expression. These analyses were performed separately for NAT involving systemic CTx (i.e. containing pac, n=149) and systemic CTx-free NAT (n=607). Results Overall pCR rate was 39.1% (CTx: 66.4%; CTx-free: 32.5%). Multivariable analysis identified predictors of pCR after CTx-free NAT: low cellularity at week 3 (vs &amp;lt; 30% sTILs: OR 3.21, 95%CI 1.85-5.57), ERBB2 (OR 1.90, 95%CI 1.41-2.55), HER2 3+ (vs 1+/2+ and ISH+: OR 8.01, 95%CI 1.65-38.99), LumA/LumB/Basal subtype (vs HER2-E: OR 0.57, 95%CI 0.34-0.97), cT2 (vs 1: OR 0.54, 95%CI 0.33-0.89), and cN1-3 (vs 0, OR 0.46, 95%CI 0.27-0.78). In CTx-containing NAT, only ERBB2 (OR 2.08, 95%CI 1.28-3.40) and additionally ESR1 (OR 0.38, 95%CI 0.23-0.61) were prognostic for pCR. Updated analysis including expanded gene expression data from ADAPT-HR+/HER2+ and a prognostic score for pCR after CTx-free NAT developed using machine learning methods will be presented at the meeting. Conclusions This pooled analysis demonstrated a 66% pCR rate after a short (12-week) de-escalated NAT in HER2+ eBC. In one-third of patients (with mainly stage I cancer, higher HER2 expression by immunohistochemistry and gene expression analysis, and low cellularity at 3 weeks), pCR can be achieved without systemic CTx. Identified biomarkers could pave the way for developing new patient selection strategies to spare CTx-associated acute and late toxicities in a clinically meaningful number of patients. Citation Format: Monika Graeser, Oleg Gluz, Christine zu Eulenburg, Sherko Küemmel, Raquel von Schumann, Matthias Christgen, Rachel Wuerstlein, Enrico Pelz, Hans-Heinrich Kreipe, Peter Schmid, Marc Thill, Michael Braun, Jochem Potenberg, Claudia Schumacher, Joke Tio, Andreas Hartkopf, Marianne Just, Christian Schem, Kerstin Lüdtke-Heckenkamp, Eva-Maria Grischke, Felix Hilpert, Angela Kentsch, Ronald Kates, Ulrike Nitz, Nadia Harbeck. Individual patient data meta-analysis of clinical and translational biomarkers for prediction of pathological complete response (pCR) after de-escalated therapy in HER2+ breast cancer in four trials of the West German Study Group [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS09-01.

Abstract PO3-14-05: Integration of metabolomics and transcriptomics to Reveal Potential Biomarkers Associated with Treatment Response of Neoadjuvant Therapy in HER2+ Breast Cancer

Abstract Background: Neoadjuvant therapy (NAT) has become the standard treatment for early human epidermal growth factor receptor 2 positive (HER2+) breast cancer. For patients with HER2+ breast cancer, achieving a pathologic complete response (pCR) is highly indicative of their prognosis. However, not all HER2+ breast cancer patients could benefit from the NAT, about 40%-50% patients could not achieve pCR at surgery, even if they used the present standard neoadjuvant regime of TCbHP (taxane, carboplatin, trastuzumab and pertuzumab). This study was conducted to explore potential indicators associated with neoadjuvant efficacy of TCbHP in HER2+ breast cancer. Methods: Consecutive HER2+ breast cancer patients, who received and completed NAT with TCbHP regime and subsequent surgery at Chongqing University Cancer Hospital were prospectively enrolled. LC-MS and GC-MS platform-based untargeted metabolomics were performed to determine the metabolic profiles of plasma samples from these patients at different time points during treatment period. Random forest (RF) was used to establish predictive models based on pre-therapeutic metabolic traits. The potential monitors for the treatment response were obtained by time series analysis. Transcriptome analysis was performed in available samples to identify differentially expressed genes (DEGs) before treatment. qRT-pCR was used to detect DEGs in tastuzumab-sensitive and -resistant cell lines. Metabolic and transcriptomic data were integrated to explore substantially altered pathways that might be responsible for drug resistance. Results: From July 20, 2020 to May 28, 2021, a total of 40 HER2+ breast cancer patients with 120 plasma samples were eligible and recruited for this study. Of whom 21 (52.5%) patients achieved pCR and 19 (47.5%) achieved non-pCR, there are no significant difference in baseline clinicopathological features between pCR and non-pCR patients. There were significant differences in plasma metabolic profiles between non-pCR and pCR groups before and during treatment. A total of 100 differential metabolites were identified between pCR and non-pCR patients at pre-therapeutic period, which were markedly enriched in 40 metabolic pathways. Four key metabolites [sophorose, N-(2-acetamido)iminodiacetic acid, taurine and 6-hydroxy-2-aminohexanoic acid] were selected by RF analysis. The AUC value to discriminate pCR and non-PCR group to NAT of the single potential metabolite or combined panel of these metabolites were more than 0.910. 18 metabolites exhibit a potential for monitoring efficacy. Among 163 DEGs identified by RNA-seq, some genes might associate with trastuzumab resistance detected by qRT-PCR in cell lines. 39 altered pathways were found abnormally expressed at both the transcriptional and metabolic levels, including ABC transporters, protein digestion and absorption, mineral absorption, et al. Conclusion: By metabolomics analysis, we have both offered a road map of the molecular alterations underlying NAT of TCbHP regime in HER2+ breast cancer and a preliminary analysis of a unique metabolic signature that might be used to distinguish non-pCR from pCR patients. Metabolomics integrated with transcriptomics analysis could assist for gaining new insights into biochemical pathophysiology and might facilitate the development of new treatment targets for insensitive patients. Citation Format: Ningning Zhang, Yuxin Huang, Guanwen Wang, Yimei Xiang, Zhouhong Jing, Junjie Zeng, Feng Yu, Xianjun Pan, Wenqi Zhou, Xiaohua Zeng. Integration of metabolomics and transcriptomics to Reveal Potential Biomarkers Associated with Treatment Response of Neoadjuvant Therapy in HER2+ Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-14-05.