anti-HER2 Therapy Research Articles

Off-label use of fam-trastuzumab deruxtecan-nxki with early activity in a cohort of patients with desmoplastic small round cell tumor.

11584 Background: Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive sarcoma occurring predominantly in pediatric, adolescent and young adult biologic males, and is molecularly characterized by the pathognomonic EWSR1-WT1 fusion. Despite aggressive multi-modality therapy outcomes for those with DSRCT remain poor, and more effective therapies are urgently required. Prior pre-clinical data and transcriptomic analyses of DSRCT patients has suggested the relevance of the ERBB2 pathway in this disease, prompting the off-label use of fam-trastuzumab deruxtecan-nxki (T-DXd) in the treatment of patients of DSRCT patient with relapsed and refractory disease. Methods: Patients with relapsed/refractory DSRCT received T-DXd 5.4 mg/kg intravenously in 21-day cycles. Whole body PET and CT of the chest, abdomen and pelvis were used for monitoring. Response was correlated with HER2 immunohistochemistry (IHC) status and transcriptomic analysis by RNA sequencing (RNAseq) when available. Results: Seven patients received the agent, and at the time of submission 3 patients had at least one follow up imaging test after receiving between 6 and 9 cycles of T-DXd. Treatment was overall well tolerated with the only grade 3 toxicity of transaminitis (in patients with known liver metastases), which self-resolved. All other toxicities including constipation, nausea, and fatigue were grade 2 or less. All 3 patients have experienced clinical benefit including one patient with a RECIST 1.1 partial response and two patients with stable disease. Additionally, favorable responses were noted by PET imaging. Four additional patients with relapsed/refractory DSRCT have initiated off-label treatment with T-DXd and are pending imaging responses. 7/7 and 4/7 patients have available IHC and ERBB2 RNA expression data available respectively. All ERBB2 RNA expression data is elevated when compared with the median across all evaluated pediatric tumors in our institutional series. Conclusions: The use of anti-HER2 therapy in a limited and unselected group of heavily pre-treated DSRCT patients is demonstrating an early signal of activity with minimal toxicity and suggests that formal assessment as monotherapy or in other relevant combinations in clinical trials is warranted. Further correlation with IHC and RNAseq expression data may help optimize correlatives and/or generate biomarkers for future clinical trials.

Phase III study to evaluate the efficacy and safety of GLSI-100 (GP2 + GM-CSF) in patients with breast cancer with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy: Flamingo-01.

TPS617 Background: GP2 is a biologic nine amino acid peptide of the HER2/ neu protein delivered in combination with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) that stimulates an immune response targeting HER2/neu expressing cancers, the combination known as GLSI-100. Of the 146 patients that have been treated with GLSI-100 over 4 clinical trials, GLSI-100 was well-tolerated and no serious adverse events observed were considered related to the immunotherapy. Methods: This Phase III trial is a prospective, randomized, double-blinded, multi-center study. After 1 year of trastuzumab-based therapy, 6 intradermal injections of GLSI-100 or placebo will be administered over the first 6 months and 5 subsequent boosters will be administered over the next 2.5 years for a total of 11 injections over 3 years. The participant duration of the trial will be 3 years treatment plus 1 additional year follow-up for a total of 4 years following the first year of treatment with trastuzumab-based therapy. Patients will be stratified based on residual disease status at surgery, hormone receptor status and region. Study size, interim analysis: Approximately 498 patients will be enrolled. To detect a hazard ratio of 0.3 in invasive breast cancer free survival (IBCFS), 28 events will be required. An interim analysis for superiority and futility will be conducted when at least 14 events have occurred. This sample size provides 80% power if the annual rate of events in placebo patients is 2.4% or greater. Up to 100 non-HLA-A*02 subjects will be enrolled in an open-label arm. The patient population is defined by these key eligibility criteria: HER2/neu positive and HLA-A*02; residual disease or high risk pCR (Stage III at presentation) post neo-adjuvant therapy; exclude Stage IV; completed at least 90% of planned trastuzumab-based therapy. Trial objectives: To determine if GP2 therapy increases IBCFS; to assess the safety profile of GP2; and to monitor immunologic responses to treatment and assess relationship to efficacy and safety. Study status: The study has been initiated at a number of sites in the US. The study is also expected to be opened in Spain, France, Germany, Italy, and Poland. Clinical trial information: NCT05232916 .

Coping with inter-observer variability when assessing AI for scoring of HER2-stained whole slides.

e12571 Background: Around 15% of breast carcinomas exhibit Human Epidermal growth factor receptor 2 (HER2) overexpression due to gene amplification. HER2 protein levels are assessed by Immunohistochemistry (IHC) with 4 scores (0, 1+, 2+, 3+). Only score 3+ (IHC) cases and score 2+ (IHC) with proven HER2 gene amplification are eligible for targeted anti-HER2 therapies; others are HER2-negative. However, tumors with score 1+ and 2+ not amplified could benefit from treatment with the new HER2-based antibody-drug conjugates, requiring an accurate HER2 scoring, which is challenged by interobserver variability. This drawback is challenging for AI-based HER2 scoring assessment, and it is thus important to understand this inter-variability and then be able to propose a probabilistic framework which quantifies and explains the discrepancy between the AI analysis and the pathologist scoring. Methods: We introduce a novel probabilistic framework designed to assign probabilities to scores generated by AI algorithms. To the best of our knowledge, this represents the pioneering effort to quantify the uncertainty surrounding AI predictive models for HER2 scores. The methodology relies on a high-dimensional multivariate Gaussian approximation of the HER2 scoring process, hinting on the precise identification of marked cells to a specified category based on membrane completeness and staining intensity. Introducing uncertainty in the categorical identification enables the quantification of uncertainty in the overall AI-scoring at the whole slide image (WSI) level. Consequently, instead of offering a singular score, we can allocate a probability of belonging to a particular category (0, 1+, 2+, or 3+) for the global score. This approach enables a comparison of the predicted likelihood with the distribution of scores among pathologists, rather than relying on a "hypothetical" ground truth, often determined by a majority-voting which can be noise-sensitive or which excludes ambiguous cases when an agreement is hard to reach. Results: For illustration, we use the Kwant HER2 algorithm developed by DiaDeep on a validation set of 68 HER2 cases, previously scored by three expert pathologists. The framework allows us to understand the discrepancy between pathologists as we introduce nuance to the AI scoring and underlines narrow probability margins in borderline cases, therefore depicting the inherent challenge for pathologists to draw a clear demarcation between closely aligned scores categories. Conclusions: The proposed framework underscores the intrinsic variability of HER2 scoring between pathologists and allows to analyze the AI predictions for HER2 scoring with more nuance, consequently enabling a more critical analysis of the results compared to a singular raw output. As we enter a new era of AI-assisted diagnosis, such a method could improve the way of assessing new AI tools and help interpret their results.

Phase 2 study of novel HER2-targeting, TLR7/8 immune-stimulating antibody conjugate (ISAC) BDC-1001 (trastuzumab imbotolimod) +/- pertuzumab (P) in patients (pts) with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab deruxtecan (T-DXd).

TPS1121 Background: Therapies to manage pts with HER2+ MBC have significantly improved, but better agents are still needed. BDC-1001 (trastuzumab imbotolimod) is being studied for MBC and other HER2+ cancers. The ISAC BDC-1001 consists of a trastuzumab biosimilar conjugated to a cell membrane impermeable TLR7/8 agonist via a non-cleavable linker and is given IV every 2 wks. Designed to trigger the innate immune system, BDC-1001 causes a durable tumor-targeted adaptive immune response. Early studies show that HER2-targeted ISACs elicit potent and durable immune-mediated antitumor efficacy, and tumor regression, in a TLR- and Fc receptor-dependent manner (1). Preclinical studies with a murine surrogate of BDC-1001 (trastuzumab-T785 ISAC) show better efficacy with trastuzumab-T785 compared to trastuzumab + P. In the BDC-1001 dose-escalation trial (BBI-20201001), 6 PRs and 12 SDs ≥ 24 weeks in 8 tumor types were observed, particularly in 20mg/kg q2w dose cohorts. The most frequent drug-related AE was low grade (grade 1/2) infusion-related reactions (29%) (2). We showed the combination of a surrogate ISAC (trastuzumab-T785) + P significantly enhances efficacy in multiple HER2-expressing tumors, including those with lower HER2 expression (1). The addition of P lowered the quantity of ISAC required for anti-tumor activity in the JIMT-1 HER2 IHC2+ model. The combination of P with the ISAC significantly increased the tumor cytokine and chemokine concentration compared to monotherapy or antibody-alone, indicating enhanced tumor myeloid activation suggesting this combination may enhance the clinical activity of trastuzumab-based ISACs. Methods: The Phase 2 multicenter, open-label, randomized study (BBI-20231001) is enrolling up to 66 patients with HER2-positive (ASCO/CAP 2018) MBC previously treated with 2 or more anti-HER2 therapies including T-DXd. Patients must be > 18 years, have measurable disease, and have ECOG performance status of 0 or 1. Patients will be randomized 1:1 to receive BDC-1001 20mg/kg every 2 weeks with or without P (840mg initial dose, followed by 420mg IV q 3w). Each arm has a Simon 2 stage design. The primary objective is anti-tumor activity of BDC-1001 alone and in combination with P. Secondary objectives will evaluate safety, PK, and immunogenicity of BDC-1001 alone and in combination with P. Exploratory objectives will include PD biomarkers in tumor tissue and in peripheral blood to elucidate the MOA and biomarkers associated with BDC-1001 activity with or without P. This study began accrual in Nov 2023. 1. Ackerman S, et al. Nature Cancer. 2021. 2. Li B, et al. ASCO 2023, Abstract 2538. Clinical trial information: NCT05954143 .

Phase II/III study of paclitaxel/carboplatin alone or combined with either trastuzumab and hyaluronidase-oysk or pertuzumab, trastuzumab, and hyaluronidase-zzxf in HER2 positive, stage I-IV endometrial serous carcinoma or carcinosarcoma (NRG-GY026).

TPS5641 Background: Uterine serous carcinoma and uterine carcinosarcoma are rare, high-risk uterine cancer subtypes that overexpress HER2 in up to 40% and 10% of cases, respectively. Phase II data demonstrated a benefit in adding trastuzumab in HER2 positive advanced and recurrent uterine serous carcinoma. Dual anti-HER2 therapy has the potential for further improvement in survival. Methods: This is a non-blinded, three-arm randomized phase II/III study. The primary objective is to evaluate the efficacy of trastuzumab and hyaluronidase-oysk (HERCEPTIN HYLECTA) or a fixed dose combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO) in combination with paclitaxel/carboplatin in patients with HER2 positive uterine serous carcinoma or carcinosarcoma. The primary outcome of the phase II component is PFS. Depending on the phase II results, the study will progress to a phase III study of either two or three study arms. Patients in the control arm (Arm 1) receive carboplatin and paclitaxel every 3 weeks for 6 cycles. Patients on Arm 2 receive carboplatin and paclitaxel with trastuzumab and hyaluronidase-oysk every 3 weeks for 6 cycles plus one year of maintenance trastuzumab and hyaluronidase-oysk. Patients enrolled on Arm 3 receive carboplatin and paclitaxel with trastuzumab, pertuzumab, and hyaluronidase-zzxf every 3 weeks for 6 cycles plus one year of maintenance trastuzumab, pertuzumab, and hyaluronidase-zzxf . Those with an ongoing partial response may continue maintenance therapy for up to three years. Patients are eligible if they are diagnosed with chemo-naïve, non-recurrent stage IA-IVB myoinvasive uterine serous or carcinosarcoma. All tumors must be HER2 positive as defined by the ASCO/CAP Breast Cancer 2018 guidelines (testing performed locally). Tumors may also be HER2 positive based on next generation sequencing testing. Patients may have measurable, non-measurable, or no measurable disease and may have a plan for vaginal brachytherapy . Key exclusion criteria include severe heart disease or interstitial lung disease. The phase II portion of this study is open and enrolling. Clinical trial information: NCT05256225 .

Phase II study to evaluate safety and efficacy of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, and trastuzumab biosimilar in patients with HER2 mutated advanced solid tumors (KCSG AL20-17).

3134 Background: Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has single agent clinical activity in HER2 mutated cancer. This open-label single arm phase 2 trial investigated the efficacy and safety of the dual anti-HER2 therapy, neratinib plus trastuzumab in heavily pretreated patients with HER2 mutated solid tumors excluding HER2 amplifications. Methods: Neratinib was administered 240mg p.o. daily with trastuzumab biosimilar (Herzuma) every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Secondary endpoints were duration of response (DoR), progression free survival (PFS), and safety. An exploratory biomarker study was also conducted. Results: Forty patients were enrolled with a median follow-up of 11.08 months (range, 0.39-21.63 months) and a median of 3 (range 1-9) lines of prior systemic therapy. Tumor types included lung (42.5%), colorectal (20%) biliary (12.5%), and breast (7.5%). Sixty percent (60%) of patients (n=24) had HER2 mutation in the kinase domain. Among evaluable patients (n=39), the ORR was 23.1% (CR=0, PR=9) with a median DoR of 11.18 months (95% CI 0-22.63). Median PFS was 3.42 months (95% CI 1.57-5.27) and median overall survival was 9.47 months (95% CI 2.93-16.01). Grade ≥3 adverse events (AEs) occurred in 47.5% of patients (n=19) and diarrhea was the most frequently reported AE (n=10; 25%) followed by bilirubin elevation (n=2; 5%), and anemia (n=2; 5%). Conclusions: In heavily pretreated patients with HER2 mutated solid tumors, neratinib plus trastuzumab showed a moderate response rate, with a durable duration of response. Most AEs were manageable, highlighting the need for prophylactic diarrhea management. Exploratory biomarker results will be presented at the upcoming meeting. Clinical trial information: NCT06083662 .

Prognostic significance of ctDNA mutation analysis in patients with HER2-positive breast cancer undergoing neoadjuvant chemotherapy.

e12654 Background: Neoadjuvant chemotherapy (NACT) combined with dual anti-HER2 agents followed by surgical resection is the standard treatment for stage II-III HER2- positive breast cancer (BC). Despite the availability of effective therapies such as ado-trastuzumab emtansine (T-DM1) and neratinib, identifying patients at high risk of disease recurrence remains challenging. To evaluate whether circulating tumor DNA (ctDNA) can be used as a biomarker to assess treatment response in patients with HER2-positive EBC treated with neoadjuvant anti-HER2 therapy. ctDNA burden can serve as a useful determinant for escalating or de-escalating (neo)adjuvant strategy in EBC patients. This study aimed to assess the role of ctDNA mutation analysis using low-pass whole-genome sequencing (lpWGS) and whole exome sequencing (WES) in evaluating blood copy-number burden (bCNB), genomic alterations, mutational signatures, blood tumor mutational burden (bTMB), and minimal residual disease (MRD) monitoring. Methods: A total of 46 HER2-positive BC patients who underwent NACT combined with dual anti-HER2 agents and surgical resection were enrolled, including 28 clinical stage II and 17 III patients. Plasma samples were collected at four time points: before NACT, after 3 cycles, at the completion of NACT, and after surgery. lpWGS was utilized to assess bCNB, while WES was performed to evaluate genomic alterations, mutational signatures, and bTMB. Mutations selected from the baseline sample were monitored for MRD. In cases where lpWGS yielded negative results, targeted NGS sequencing was conducted. Somatic mutations are identified by whole exome sequencing across 20,000 genes (with boosted sequencing coverage for 600 cancer-related genes). Between 4-50 personalized somatic mutations or fusions are selected for each patient. This personalized panel together with a fixed MRD core panel is utilized for MRD detection and monitoring. Results: Among the enrolled patients, nodal metastasis was observed in 29 patients and 29 were hormone receptor-positive, and 36 achieved pCR (78.2%). Positive ctDNA was detected 58.8% of patients. Higher nodal stage was associated with ctDNA positivity at baseline. MRD positivity after chemotherapy was observed in 4 patients and 2 patients achieved pCR TP53 was the most frequently altered gene, followed by PIK3CA, MAP3K1, REV3L, MYC, MAP2K4, ERBB3, ATRX, ATM and ALK. This pattern is comparable to that observed in previous studies on BC. Non-PCR patients commonly exhibit MAP3K1 and MAP2K4 alteration is their ctDNA. Conclusions: The identification of MRD, regardless of pCR status, can be valuable for risk stratification and personalized treatment decision-making. Further studies are warranted to validate these findings and explore the clinical implications of ctDNA mutation analysis in HER2-positive BC management.

Comprehensive genomic profiling and therapeutic implications for Taiwanese patients with treatment-naïve breast cancer.

Breast cancer is a heterogeneous disease categorized based on molecular characteristics, including hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression levels. The emergence of profiling technology has revealed multiple driver genomic alterations within each breast cancer subtype, serving as biomarkers to predict treatment outcomes. This study aimed to explore the genomic landscape of breast cancer in the Taiwanese population through comprehensive genomic profiling (CGP) and identify diagnostic and predictive biomarkers. Targeted next-generation sequencing-based CGP was performed on 116 archived Taiwanese breast cancer specimens, assessing genomic alterations (GAs), including single nucleotide variants, copy number variants, fusion genes, tumor mutation burden (TMB), and microsatellite instability (MSI) status. Predictive variants for FDA-approved therapies were evaluated within each subtype. In the cohort, frequent mutations included PIK3CA (39.7%), TP53 (36.2%), KMT2C (9.5%), GATA3 (8.6%), and SF3B1 (6.9%). All subtypes had low TMB, with no MSI-H tumors. Among HR + HER2- patients, 42% (27/65) harbored activating PIK3CA mutations, implying potential sensitivity to PI3K inhibitors and resistance to endocrine therapies. HR + HER2- patients exhibited intrinsic hormonal resistance via FGFR1 gene gain/amplification (15%), exclusive of PI3K/AKT pathway alterations. Aberrations in the PI3K/AKT/mTOR and FGFR pathways were implicated in chemoresistance, with a 52.9% involvement in triple-negative breast cancer. In HER2+ tumors, 50% harbored GAs potentially conferring resistance to anti-HER2 therapies, including PIK3CA mutations (32%), MAP3K1 (2.9%), NF1 (2.9%), and copy number gain/amplification of FGFR1 (18%), FGFR3 (2.9%), EGFR (2.9%), and AKT2 (2.9%). This study presents CGP findings for treatment-naïve Taiwanese breast cancer, emphasizing its value in routine breast cancer management, disease classification, and treatment selection.

Preliminary safety and efficacy of TQB2930, a HER2-targeted bispecific antibody in patients with advanced breast cancer: Results from a phase 1b study.

1026 Background: TQB2930 is a HER2-targeted bispecific antibody, binding to two distinct HER2 epitopes, the same domain as trastuzumab (ECD4) and pertuzumab (ECD2). This study aims to evaluate the safety and efficacy of TQB2930 for patients with advanced breast cancer after failure of standard therapy. Methods: This phase 1b, dose-escalation and expansion trial included patients preferred HER2-expressing or HER2-amplified breast cancer who had received standard therapy. In the dose-escalation phase, TQB2930 was given weekly (10mg/kg, QW), biweekly (20mg/kg, Q2W), or triweekly (30mg/kg, Q3W). After the dose-escalation phase, eligible patients were enrolled and dosed biweekly or triweekly in the expansion cohort. The primary endpoints were safety, maximum tolerated or maximum administered dose, and the secondary endpoints were immunogenicity, pharmacokinetics, and tumor response per RECIST v1.1. Results: As of Dec 20, 2023, 34 patients(pts) have received TQB2930 weekly (n=3), biweekly (n=16), and triweekly (n=15). All pts were female, the median age was 59. 22 pts had HER2 expression of ICH3+ or ICH2+ with FISH+, and the others had ICH2+ with FISH- or ICH1+. The median prior lines of therapies were 3 (range: 0-8), with one pt intolerance to first-line treatment enrolled, and the median prior lines of HER2-targeted therapies were 2 (range: 0-8). No dose-limited toxicity was observed. The main treatment-related adverse events (TRAEs) were infusion reaction, occult blood of urine, leukopenia, and neutropenia. 3 pts were reported grade≥3 TRAEs, including neutropenia, anemia, and hypokalemia. Of 31 response-evaluable pts, the objective response rate (ORR) was 25.8% with 8 partial responses (PRs) were observed (including 5 confirmed PRs and 3 PRs awaiting confirmation). The disease control rate was 80.6%. Moreover, 5 pts achieved PR at 30mg/kg (ORR 41.7%), including one with prior exposure to trastuzumab, pyrotinib, tucatinib, ARX788, and the other one prior to trastuzumab, pertuzumab, lapatinib, MRG002. The median progression-free survival for all pts was 5.5 months (95%CI 3.58-NE). Additionally, Pharmacokinetic analysis showed exposure (Cmax and AUC0-t) of TQB2930 increased linearly with doses within 10~30mg/kg. After dosing, the mean peak concentration reached at 2.5-4.3 h, and the elimination half-life of TQB2930 was 109-161 h. Conclusions: TQB2930 is well tolerated and has demonstrated promising single-agent anti-tumor activity in HER2-positive breast cancer who have failed standard anti-HER2 therapies, including multiple lines of prior HER2 targeted agents. These early signs of activity support the further exploration of combination therapy of TQB2930 and the study is ongoing. Clinical trial information: NCT06202261 .

Defining low-HER2 cancers using RNA quantification by next generation sequencing.

e13044 Background: The recent success of treatment with HER2-directed antibody-drug conjugate T-DXd (trastuzumab-deruxtecan) in treating low-HER2 expression breast cancer raises the possibility of similar success in other tumors that express similarly low levels of HER2. HER2 amplification has been reported in various types of tumors at relatively low frequency. However, “low-HER2” expression in various types of tumors remains undefined. In this study, we utilized next generation sequencing to explore the levels of ERBB2 (HER2), ERBB3, ERBB4, PIK3CA, and ERS1 mRNA in various types of cancers and attempted to set limits reflecting distinct biology of tumors based of level of ERBB2 expression. Methods: RNA was extracted from FFPE samples from patients with cancers of breast (N=203), ovary (N=95), endometrium (N=75), and esophagus/stomach (N=46). RNA was sequenced via a 1408 gene panel using a standard hybrid capture approach. Results: Based on previous data correlating gene amplification with gene expression (DOI: 10.1002/imed.1051), we defined ERBB2 expression as high, low, and very-low when ERBB2 expression measured >1500 TPM (transcripts per million), 800-1500 TPM, and <800 TPM, respectively. ERBB2 high, low, and very-low were detected in 20%, 32%, and 48% of breast cancer; 5%, 29%, and 65% of endometrial cancer; 9%, 26%, and 65% of ovarian cancer; 12%, 16%, and 72% of esophageal/stomach cancer; and 8%, 19%, and 73% of lung cancer. With minor exceptions, cases classified as ERBB2 high and low from the five tumor types showed no correlation with levels of PIK3CA, ESR1, or ERBB4 mRNA. In contrast, cases with relatively very-low ERBB2 showed significant correlation with PIK3CA, ESR1, and ERBB4 mRNA. Endometrial cancer was an exception and showed no correlation with PIK3CA mRNA in very-low ERBB2 cases. Activation of PIK3CA has been reported to be associated with resistance to anti-HER2 therapy. These findings suggest that cases showing high or low ERBB2 are independent of PIK3CA and likely less influenced by the negative effects of PIK3CA on response to HER2 inhibitors. Cases classified as ERBB2 high or low showed significantly higher (P<0.0001) PIK3CA mutations as compared with ERBB2 very-low cases (27% vs 14%). ERBB2 mutations were relatively rare, detected in only 7%, 8%, 14%, 1%, and 4% of breast, endometrial, esophageal/stomach, ovarian, and lung cancers, respectively. However, significantly (P=0.001) higher mutation rate is detected in ERBB2-high and -low as compared with very-low ERBB2 cases (8% vs 6%). Conclusions: ERBB2/HER2 RNA quantification in cancers can define a biologically distinct group of patients. Patients defined as very-low ERBB2 as classified in this approach appear to be biologically distinct and more likely to be resistant to anti-HER2 therapy. Clinical trials using this approach in selecting patients for treatment with antibody-drug conjugates are justified and needed.

Metastatic breast cancer in elderly women: A retrospective cohort study in Morocco.

e13073 Background: Breast cancer (BC) stands as the predominant malignancy among women worldwide, presenting a significant global public health problem. In Morocco, it is the leading cause of cancer-related mortality in females. However, there exists a limited understanding of outcomes and treatment patterns for elderly patients with metastatic breast cancer (MBC) in our context. Methods: We conducted a retrospective cohort study at the Department of Medical Oncology, Hassan II University Hospital of Fez, focusing on 92 female patients aged 65 years or older diagnosed with MBC, between January 2012 and December 2016. The primary objectives were to estimate overall survival (OS) and progression-free survival (PFS), describe treatment patterns, and characterize the clinicopathological, and prognostic aspects of MBC in elderly women in Morocco. Results: The cohort’s median age was 70.88 (range, 65-88years) with 45.6% of patients aged of 65 to 69 years, 34.8% between 70 to 74 years old, and 19.6% over 75. Most patients (77.2%) had an Eastern Cooperative Oncology Group (ECOG) score of 0 to 1, and only 33.7% had comorbidities. De novo stage IV constituted 59.8% of all cases. Metastatic recurrences represent 40.2% with 16.2% having recurrence within 12 months, and 83.8% having a recurrence interval exceeding 12 months. The median time to recurrence was 45.5 months. Invasive ductal carcinoma (IDC) was the predominant histological type (81.1%), with SBR grade II (51%) and grade III (21.7%). Metastases were observed in pleuropulmonary (78.3%), bone (56.5%), lymph nodes (33.7%) and liver (30.4%). With 71.7% having metastases in fewer than three sites, while 28.3% had metastases in three or more sites. Molecular profiling showed Luminal A (38%) and Luminal B (26.1%) subtypes as the most prevalent, followed by triple-negative (17.4%) and HER2+ (15.2%). Treatment modalities included chemotherapy (50%), hormone therapy (15.2%) or a combination of the two (17.4%), and anti-HER2 targeted (14.1%). Median OS was 37 months (95% CI: 16.86 - 57.13 months), and median PFS was 33.16 ± 4.1 months. Anti-HER2 therapy showed a significant association with survival (p = 0,05). Conclusions: This study highlights the characteristics, survival, and treatment modalities of elderly patients with MBC in Morocco. Despite the predominance of luminal BC an intriguing observation was the frequent use of chemotherapy as first line modality.

The efficacy and safety of trastuzumab biosimilar HLX02 compared with reference trastuzumab plus pertuzumab in combination with chemotherapy as the first-line treatment for HER2 positive metastatic breast cancer: A real-world study in China.

e13016 Background: Dual-targeted anti-HER2 therapy with trastuzumab (H) and pertuzumab (P) significantly improves outcomes in HER2-positive breast cancer and has become the first-line standard treatment for patients with advanced HER2-positive breast cancer in China in 2019 based on the results of the CLEOPATRA and PUFFIN study. HLX02 (Zercepac) was the first trastuzumab biosimilar manufactured in China. Here, we present the first real-world comparison of HLX02 versus reference trastuzumab (RTZ) and pertuzumab with chemotherapy as the first-line treatment for HER2-positive metastatic China.Between January 2019 and August 2023, 121 patients with HER2-positive MBC patients were enrolled at Beijing Cancer Hospital in China. These patients received HLX02 or RTZ in combination with pertuzumab and various chemotherapies as first-line treatment. We retrospectively analyzed survival outcomes, efficacy, and adverse events. Methods: Between January 2019 and August 2023, 121 patients with HER2-positive MBC patients were enrolled at Beijing Cancer Hospital in China. These patients received HLX02 or RTZ in combination with pertuzumab and various chemotherapies as first-line treatment. We retrospectively analyzed survival outcomes, efficacy, and adverse events. Results: Both groups, 68 received RTZ and 53 received HLX02, showed similar characteristics of age, disease status (de novo or recurrent), metastatic sites (visceral or non-visceral), and treatment history. A total of 118 (97.5%) received trastuzumab plus pertuzumab combined with chemotherapy as the first-line palliative therapy, with a median number of 6 cycles in each group. Taxanes were the most commonly used chemotherapy regimen in both groups (91.2 vs. 92.5%), including nab-paclitaxel (44.1 vs. 45.3%), docetaxel (41.2 vs. 17.0%), paclitaxel (5.9 vs. 30.2%). With a median follow-up of 15.0 months (range 1.0 - 58.0), the results showed no significant difference in PFS between the RTZ and HLX02 arms (median PFS: 22.0 vs. 19.0 months, p=0.900). Additionally, the efficacy outcomes, including objective response rate (ORR), disease control rate (DCR), and safety profiles did not show significant differences between the two groups. Among 121 patients, 20 patients (16.5%) experienced CNS progression. For these patients, the median time from the first-line therapy to the CNS progression was 15.0 months (95% CI 12.8 - 17.2). Conclusions: The real-world data suggest similar efficacy and safety of HLX02 and RTZ plus pertuzumab with different chemotherapy regimens as the first-line treatment for patients with HER2-positive advanced breast cancer patients in China. Overall, the PFS was consistent with the CLEOPATRA trial in both groups, and there was no new safety signal.

Efficacy of first-line dual oral pyrotinib plus capetabine therapy in HER2-positive metastatic breast cancer: A real-world retrospective study.

The combination of dual-targeted human epidermal growth factor receptor 2 (HER2) therapy and chemotherapy is the standard first-line regimen for recurrent/metastatic breast cancer (mBC). However, the toxicity of such combination therapy can lead to some patients being unable to tolerate adverse events or bear treatment costs. As a novel irreversible pan-ErbB receptor TKI (pyrotinib), can the dual oral administration of pyrotinib plus capetabine (PyroC) provide first-line survival benefits and serve as a more affordable treatment option? This real-world retrospective study included patients diagnosed with HER2-positive mBC who received PyroC as a first-line treatment at West China Hospital between May 2018 and July 2023. The survival data and toxicity profiles were reported in this study. A total of 64 patients received PyroC as first-line therapy. The median progression-free survival (PFS) was 19.6 months (95% CI 15.0-27.2), while overall survival (OS) has not yet been reached. Kaplan-Meier analysis indicated that age (≥60, p = 0.03) and metastasis sites (p = 0.004) were related to poor efficacy of PyroC, while there was no relationship between effectiveness and menstrual status, hormone receptor (HR) status or previous treatment with anti-HER2 therapy. Furthermore, the objective response rate (ORR) and disease control rate (DCR) were 79.7% and 98.4%, respectively. Of the patients, 78.1% reported treatment-related adverse events (TRAEs). The predominant adverse events were diarrhea (n = 46, 71.9%) and hand-foot syndrome (n = 10, 15.6%). The dual oral administration regimen (PyroC) has a promising ORR or PFS in HER2-positive mBC patients, with an acceptable safety profile and convenience.

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.

Characteristics of her2-positive breast cancer, and the current use of anti-her2 therapy and its related factors

ABSTRACT Objective: To describe the characteristics of patients with HER2-positive breast cancer and to identify the proportion of patients using anti-HER2 therapy, and treatment-making related factors. Methods: An analytical cross-sectional study was conducted on 79 patients with BC and HER2-positive diagnosed by immunohistochemistry (IHC) or with FISH at the Oncology Department of Hue University of Medicine and Pharmacy Hospital and Oncology Center of Hue Central Hospital from 1/2021 to 12/2022. Clinical and pathological features, type of drug, number of cycles using anti-Her2 therapy were recorded using medical documents. The decision-making related factors were recorded by questionnaire interviewing patients and relatives. Exclusion criteria included recurrent or previously treated tumors; having contraindications with anti-HER2 therapy; not being willing to participate in the study. SPSS 22.0 was used for the analysis. Results: Mean age was 54.14 ± 11.03. Patients with right-sided BC accounted for 53.1%. 60.8% of tumors were located in the upper right quadrant of the breast. Patient’s self-report of lumps was the most common cause of hospitalization (77.2%). By ultrasound, 60.2% of participants had a tumor size of 2 - 5cm. Abnormal lymph nodes were identified in 40.8% of patients. Histopathologically, invasive ductal carcinoma was found in the majority of tumors (75.9%). Stage II was predominant with 59.5% and 7.6% of patients with stage IV. The rate of treatment with Trastuzumab in our study was 27.8%. The main reason that patients refused anti-HER-2 therapy was financial problems (96.5%). The awareness of anti-HER2 therapy among patients and their relatives was significantly associated with the treatment decision (p = 0.007). Conclusion: Regarding the positive-HER2 BC patients, invasive ductal carcinoma was the major histopathological finding. More than half of the patients were classified as stage II of the disease. The rate of patients undergoing antiHER2 therapy was 27.8%. Financial problems were found to be the main reason for refusal of treatment. Awareness of anti-HER2 therapy is significantly associated with the patient’s decision on treatment.

The HER2 flip-HER2 amplification of tumor cells in the cerebrospinal fluid of breast cancer patients with leptomeningeal disease: implications for treating the LM tumor with anti-HER2 therapy.

CNSide is a platform that detects and characterizes tumor cells in the cerebrospinal fluid (CSF) of patients with leptomeningeal disease (LMD). The platform was validated per College of American Pathologists (CAP) and Clinical Laboratories Improvement Amendment (CLIA) guidelines and run as a commercial Laboratory Developed Test (LDT) at Biocept in San Diego, CA. The platform allows CSF tumor cell (CSF-TC) enumeration and biomarker characterization by fluorescent in situ hybridization (FISH). We performed a multicenter retrospective chart review of HER2 FISH CNSide test results that were commercially ordered on 26 patients by physicians for LMD breast cancer patients between April 2020 and October 2022. We show that HER2 is amplified on CSF tumor cells in 62% (16/26) of LMD breast cancer patients. 10/26 (38%) patients had discordant HER2-positivity between the primary tumor tissue and CSF-TC; of these, 35% (9/26) of the patients displayed HER2 amplification on the CSF-TCs, however were categorized as HER2 negative on the primary tumor. Of the 27% (7/26) patients with a HER2 positive primary tumor, one patient showed a HER2 negative LMD tumor. Two patients, 8% (2/26) had a HER2 equivocal primary tumor; of these, one demonstrated a HER2 negative, and one a HER2 positive LMD tumor. Serial analysis (at least 4 longitudinal tests) of HER2 status of the CSF-TC throughout therapy was available for 14 patients and demonstrated that HER2 status of the LMD changed in 29% (4/14) during their treatment course and impacted care decisions. Our data suggests that CSF-TC HER2 FISH analysis in LMD breast cancer patients may be discordant to the primary tumor sample and the discovery of HER2 positivity in the CSF may open doors to anti-HER2 targeted therapy options for LMD patients.

GDF-15 is a potential candidate biomarker for an elevated risk of cardiotoxicity in breast cancer patients receiving neoadjuvant dual anti-HER2 therapy.

Growth differentiation factor 15 (GDF-15) is a stress-responsive cytokine that regulates myocardial injury, cardiac overloading pressure, and inflammation and is related to the risk of cardiovascular diseases and events. The current study aimed to investigate the correlation of GDF-15 levels with clinical features, biochemical indices, and especially the risk of cardiotoxicity in breast cancer patients receiving neoadjuvant dual anti-HER2 therapy. A total of 103 HER2-positive breast cancer patients who underwent neoadjuvant dual anti-HER2 therapy (trastuzumab and pertuzumab plus chemotherapy) were included. Serum GDF-15 levels before neoadjuvant treatment were detected by enzyme-linked immunosorbent assay. Cardiotoxicity was evaluated during neoadjuvant therapy by referring to a decline of ≥10 percentage points in the left ventricular ejection fraction from baseline to an absolute level less than 50%. GDF-15 exhibited a skewed distribution, with a median level of 714 (range: 207-1805) pg/mL. GDF-15 was positively correlated with age (p = 0.037), diabetes (p = 0.036), and the N-terminal pro-brain natriuretic peptide level (p = 0.013) and positively correlated with the total cholesterol level (p = 0.086) and troponin T level (p = 0.082), but these correlations were not statistically significant. A total of 6.8% of patients experienced cardiotoxicity during neoadjuvant therapy. By comparison, the GDF-15 level was greater in patients who experienced cardiotoxicity than in those who did not (p = 0.008). A subsequent receiver operating characteristic curve revealed that GDF-15 predicted cardiotoxicity risk, with an area under the curve of 0.803 (95% CI: 0.664-0.939). After multivariate adjustment, GDF-15 independently predicted a greater risk of cardiotoxicity (p = 0.020). GDF-15 is a candidate biomarker for increased risk of cardiotoxicity in breast cancer patients receiving neoadjuvant dual anti-HER2 therapy.

Novel approach to HER2 quantification using phosphor-integrated dots in human breast invasive cancer microarray.

HER2 expression in breast cancer is evaluated to select patients for anti-HER2 therapy. With the advent of newly approved HER2-targeted drugs for low HER2 expression breast cancer, more solid evidence on the whole spectrum of HER2 expression is needed. In this study, we quantitatively assessed HER2 expression from the whole core by combining high-intensity phosphor-integrated dot (PID) immunostaining and whole slide imaging (WSI) analysis. Two types of staining were performed using a 170-core tissue microarray of invasive breast cancer. First, HER2 was stained by immunohistochemistry (IHC), and IHC scores were determined by two practicing pathologists according to the ASCO/CAP HER2 guideline. Second, HER2 was stained with PID, and tentative PID scores were determined by quantitative analysis. The results show that PID can numerically classify HER2 expression status into scores 3+, 2+, 1+, and 0. The HER2 value quantified by PID strongly correlated with the 3, 3'-diaminobenzidine (DAB) IHC score determined by pathologists (R2 = 0.93). PID IHC score 1+ cases included both DAB IHC score 1+ and 0 cases, and low HER2 expression cases appeared to be often evaluated as DAB IHC score 0. Therefore, digital image analysis by PID and WSI can help stratify HER2 IHC. It may also help classify low HER2 expression.

Assessment of HER2 status in extramammary Paget disease and its implication for disitamab vedotin, a novel humanized anti-HER2 antibody-drug conjugate therapy.

Assessment of HER2 status in extramammary Paget disease and its implication for disitamab vedotin, a novel humanized anti-HER2 antibody-drug conjugate therapy.

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.