HER2-positive Advanced Breast Cancer Research Articles

Elderly patients with advanced HER2-positive breast cancer with liver metastases benefit from low dose disitamab vedotin (RC48): case series and literature review.

Currently, although some antibody-drug conjugates have been shown to be safe and effective in the treatment of drug-resistant relapsed human epidermal growth factor receptor 2 (HER2)-positive (IHC 3+ or IHC 2+/fluorescence in situ hybridization+) breast cancer, they are already approved for clinical use in China. But the clinical needs of advanced HER2-positive patients cannot be met due to adverse reactions, drug resistance, drug accessibility and other problems, thus affecting the prognosis of patients. In particular, the representation of elderly and frail patients in randomized clinical trials is significantly under-represented. We report on two elderly women with breast cancer who developed recurrent metastatic lesions after breast cancer surgery and were again confirmed HER2-positive by histopathology and immunohistochemistry. They all developed multiple metastases in the liver after second- or third-line anti-HER2 therapy. Subsequent treatment with RC48 produced good responses and tolerable adverse reactions. One patient obtained progression-free survival for more than 7 months. Based on preliminary evidence, this study shows that RC48 in HER2-positive breast cancer with liver metastases can achieve rapid remission, thereby reducing tumor load and improving patients' quality of life. In particular, RC48 has low side effects and can be well tolerated by elderly patients after dose adjustment, providing them with treatment opportunities. It needs to be further discussed in the future research.

Abstract PO4-04-02: Real-world first line use of trastuzumab biosimilar (HLX02), pertuzumab and chemotherapy for Chinese patients with HER2-positive metastatic breast cancer

Abstract Background: HLX02 (Zercepac®) is the first manufactured trastuzumab biosimilar in China. Its similar efficacy, safety, and immunogenicity compared with Herceptin was confirmed in phase III clinical trials in patients with HER2-positive advanced breast cancer. Nevertheless, the real-world evidence of HLX02 combined with pertuzumab and chemotherapy in HER2-positive advanced breast cancer in China is still warranted. Methods: In this real world observational study, patients with HER2-positive advanced breast cancer who received HLX02, pertuzuamb and chemotherapy as first line treatment at Beijing Cancer Hospital from April 2020 to April 2023 were retrospectively and prospectively included. The primary outcome was progression-free survival (PFS), and secondary outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and adverse events (AEs). Results: A total of 55 patients (including one male) were included in this study and analyzed. The median age was 57 (range: 49, 62) years. Nearly one-third of tumors were estrogen receptor-positive (n=20, 36.4%). Thirty patients (54.5%) had newly-diagnosed stage IV disease. Visceral metastasis was reported in 40 patients (72.7%), most commonly observed in liver (n=22, 40%) and lung (n=19, 34.5%). Seven patients received prior anti-HER2 therapy during (neo-) adjuvant therapy (n=7, 12.7%). Taxane was the most commonly administrated chemotherapy regimen (n=51, 92.7%), including 56.4% albumin-bound paclitaxel, 20% liposomal paclitaxel and 18.2% docetaxel. Objective response was observed in 44 patients, leading to an ORR of 80%, and the DCR achieved 100%. HLX02 and pertuzumab was continued as maintenance therapy in 50 patients (90.9%), among which 17 combined with endocrine therapy (30.9%) and 6 combined with oral chemotherapy (10.9%). With a median follow-up of 9.8 months (range: 0.6-38.2). Progressive disease (PD) occurred in 12 of 55 patients (21.8%) and no deaths occurred. The median PFS was 24.8 months (95% confidence interval [CI]: 16.9- not estimated). The 12-month and 18-month PFS rate was 84.0% (95%CI: 72.9-96.9) and 58.8% (95%CI: 41.5 ~ 83.2), respectively. OS cannot be estimated yet due to immature data. HLX02-related diarrhea and infusion-related reaction was reported in 2 (3.6%) and 1 (1.8%) patients, respectively. LVEF values were monitored before and after drug administration, no clinical significant decline in LVEF and cardiac toxicity was observed. Conclusions: The trastuzumab biosimilar HLX02 demonstrated comparable efficacy and safety to Herceptin when combined with pertuzumab and chemotherapy for Chinese patients with HER2-positive advanced breast cancer in real world first-line treatment, which suggested that HLX02 may provide another option of Her2-targeted therapy combined with pertuzumab for Chinese patients. The benefit regarding long-term survival need to be further verified. Table 1. Effectiveness Citation Format: Ruyan Zhang, Guohong Song, Xiaoran Liu, Hui-Ping Li. Real-world first line use of trastuzumab biosimilar (HLX02), pertuzumab and chemotherapy for Chinese patients with HER2-positive metastatic 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 PO4-04-02.

Abstract PO2-04-07: Efficacy and Safety of First-line Therapy in Patients with HER-2 positive Advanced Breast Cancer:A network Meta-analysis of Randomized Controlled Trials

Abstract Background: The numerous but conflicting first-line treatment regimens for Her-2 positive advanced breast cancer necessitate a comprehensive evaluation to inform clinical decision-making. In this study, we conducted a Bayesian network meta-analysis (NMA) to compare the efficacy and safety of different interventions. Methods: We systematically searched for relevant randomized controlled trials (RCTs) in Pubmed, Embase, Cochrane Library and online abstracts published by ASCO, SABCS. NMA was performed using R software, STATA and Review Manager 5.4 to calculate and analyze the primary endpoint progression free survival (PFS), as well as the secondary endpoints of overall survival (OS), objective response rate (ORR) and adverse events (AE) higher than grade 3. Results: Out of the 8,603 manuscripts retrieved, we included 30 RCTs involving 12,045 patients in our analysis. Regarding PFS, the combination of trastuzumab with TKI was more favorable than dual-target therapy (hazard ratio=0.54, 95% [CI]: 0.40–0.72), and combination chemotherapy was superior to monotherapy (HR=0.66, 0.53-0.83). It is important to note that the addition of anthracycline did not result in improved PFS (HR=1.27, 0.87-1.86). For the HR+HER2+ population, dual-target plus endocrine therapy was more effective than single-target plus endocrine therapy (HR=0.65, 0.53-0.80). Monotherapy combined with dual-target therapy significantly improved OS and ORR compared to monotherapy with single-target therapy (HR=0.69, 0.56-0.84; OR=1.89, 1.34-2.65). A comprehensive analysis of both PFS and AE higher than grade 3 indicated that monotherapy plus dual-target therapy struck a balanced approach between effectiveness and toxicity compared to other regimens. Conclusions: Monotherapy plus dual-target therapy remains the optimal choice among all first-line treatment options for advanced breast cancer. The combination of trastuzumab with TKI demonstrated a significant improvement in PFS, but further data are warranted to confirm the survival benefit. Figure 1. Network diagrams of PFS, OS, ORR and adverse events higher than grade 3 in eligible experimental arms. Figure 2. Forest plot of PFS, OS, ORR and adverse events higher than grade 3 in eligible experimental arms. (A): PFS of HER2+ for experimental arms. (B): PFS of HR+ and HER2+ for experimental arms. (C): OS of HER2+ for experimental arms. (D): ORR of HER2+ for experimental arms. (E): Adverse events higher than grade 3 of HER2+ for experimental arms. Figure 3. Each endpoint ranking for experimental arms. (SUCRA, surface under the cumulative ranking) (A): PFS ranking for experimental arms. (B): OS ranking for experimental arms. (C): ORR ranking for experimental arms. (D): Adverse events higher than grade 3 ranking for experimental arms. (E): Experimental arms ordered by their overall probability as the best treatment in terms of both efficacy and safety Citation Format: Junxiao Wang, Yushuai Yu, Jie Zhang, Chuangui Song. Efficacy and Safety of First-line Therapy in Patients with HER-2 positive Advanced Breast Cancer:A network Meta-analysis of Randomized Controlled Trials [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 PO2-04-07.

Abstract PO2-19-09: INAVO122: a Phase III study of maintenance inavolisib or placebo + pertuzumab + trastuzumab following induction with pertuzumab + trastuzumab + a taxane in patients with PIK3CA-mutated, HER2-positive advanced breast cancer

Abstract Background The PI3K pathway plays a crucial role in HER2 signaling. Somatic mutations of PIK3CA, the gene that encodes the PI3K p110α subunit, may induce resistance to HER2-targeted therapies and are associated with poorer clinical outcomes (Swain SM, et al. SABCS 2022; P2-11-07). Inavolisib, a potent p110α-selective inhibitor that induces degradation of mutant p110α, has shown antitumor activity in PIK3CA-mutated HER2-positive breast cancer (HER2+ BC) and long-term tolerability with early intervention for common on-class toxicities, including hyperglycemia, diarrhea, and stomatitis (Bedard P, et al. ASCO 2022; 1052). The current study will assess the efficacy and safety of maintenance inavolisib + fixed-dose combination of pertuzumab + trastuzumab for subcutaneous injection (PH FDC SC) after first-line induction treatment in patients with PIK3CA-mutated, HER2+, advanced BC (aBC). Trial design INAVO122 is a multicenter, randomized, international, double-blind, placebo-controlled study. Patients will be enrolled for: first-line induction treatment if they are receiving/will receive PH + a taxane; or maintenance treatment completing induction treatment. In the maintenance phase, patients will be randomized 1:1 to receive inavolisib (9 mg orally once daily; Days 1–21 of 21-day cycles) + PH FDC SC (every 3 weeks), or placebo + PH FDC SC. Study treatment will continue until disease progression, unacceptable toxicity, death, consent withdrawal, or at the investigator’s discretion. ELIGIBILITY Enrolled patients must have centrally determined HER2+, PIK3CA-mutated tumors, with documented hormone receptor status per local assessment, and be disease-free for ≥ 6 months from completion of neoadjuvant/adjuvant systemic non-hormonal treatment. They must not have received any treatment for aBC prior to induction, and, at screening, fasting glucose must be < 126 mg/dL and HbA1c < 6.4%. To be randomized, patients must have completed induction therapy per standard of care without progression of disease and show left ventricular ejection fraction ≥ 50%. AIMS The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints are overall survival; investigator-assessed objective response rate, duration of response, clinical benefit rate, and time to second disease progression; health-related quality of life; safety; and pharmacokinetics. STATISTICAL METHODS The primary endpoint analysis will utilize a two-sided stratified log-rank test at a two-sided significance level of 5%. A stratified Cox proportional hazards model will be used to estimate the hazard ratio between the two treatment arms and its 95% confidence intervals. ACCRUAL Target randomization is ~230 patients; recruitment began in July 2023. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number NCT05894239. Citation Format: Sandra Swain, Carlos Barrios, Reva Basho, Giuseppe Curigliano, Nadia Harbeck, Chiun-Shen Huang, Sherene Loi, Nicholas Turner, Jessica Chen, Volkmar Henschel, Simon Warburton, Fabiola Amair-Pinedo, Javier Cortés. INAVO122: a Phase III study of maintenance inavolisib or placebo + pertuzumab + trastuzumab following induction with pertuzumab + trastuzumab + a taxane in patients with PIK3CA-mutated, HER2-positive advanced 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 PO2-19-09.

Abstract PO3-04-06: A comparison of the efficacy of trastuzumab deruxtecan in advanced HER2-positive breast cancer: active brain metastasis versus progressive extracranial disease alone

Abstract Background Trastuzumab deruxtecan (T-DXd) has demonstrated efficacy in patients with brain metastasis (BM), a group historically with poor outcomes. The prevalence of BMs in patients commencing T-DXd is currently unknown. To date, no direct comparisons have been made of the activity of T-DXd in patients with active BM versus those with extracranial progression alone. This real-world study explored the prevalence of BMs at commencement of T-DXd, the efficacy of T-DXd in active BM versus extracranial progression alone and the safety of T-DXd. Methods Patients with HER2-positive advanced breast cancer treated with T-DXd between June 2021 and February 2023 at our specialist cancer hospital were identified and notes reviewed. Clinico-pathological information, prior treatment, the presence or absence of CNS disease, outcomes and treatment-emergent adverse events (TEAE) were recorded. Data cut-off was 28th February 2023. Results 29 female patients: 16 extracranial disease alone, 12 BM and 1 LMD were identified. Prevalence of BM at commencement of T-DXd was 41% (12 of 29). Median age was 52 (IQR 44-62), with a median 2 (range 2-6) prior lines of HER2 directed and chemotherapy:86% (25 of 29) had received prior trastuzumab and pertuzumab, 100% (29 of 29) T-DM1 and 3% (1 of 29) patient trastuzumab duocarmazine. At a median follow-up of 13.8 months, median progression free survival (PFS) for overall population was 13.9 months (95% CI: 12.4-NE), 16.1 months (95% CI: 15.1-NE) for active BMs, and 12.4 months (95% CI: 8.3-NE) for progressive extracranial disease alone (P=0.106). 12-month OS rate was 74% (95% CI: 59-95) in the overall population, 83% (95% CI: 58-100) and 66% (95% CI: 45-96) for active BMs, and extracranial only disease respectively (P=0.678). Objective response rates: overall population was 69% (95% CI: 52-86), active BMs was 60% (95% CI: 30-90), and progressive extracranial disease alone was 69% (95% CI: 46-91). 6% (1 of 16) with extracranial disease alone developed BM during treatment with T-DXd. Reasons for treatment discontinuation: 67% (10 of 15) disease progression or death; 33% (5 of 15) toxicity. 48% (14 of 29) remain on treatment. Most common TEAEs were fatigue (97%; 28 of 29), alopecia (76%; 22 of 29), and constipation (72%; 21 of 29). Pneumonitis occurred in 9 patients (31%, included 2 deaths). 1 pathologically confirmed case of radionecrosis was documented. An updated analysis with an additional 9 patients who commenced T-DXd since February 2023 will be presented. Conclusion In this real-world study a significant number of patients had BM at the commencement of T-DXd. We demonstrate that in advanced HER2 positive breast cancer that T-DXd is as effective, in terms of PFS and OS, in active BMs as it is in progressive extracranial disease alone. These data provide the first evidence that in contrast to the historical data that active BM may no longer be a detriment to survival as compared to progressive extracranial disease alone when treated with T-Dxd. These observations warrant further investigations in larger series. The high rate of pneumonitis warrants further consideration. Citation Format: James Pearson, Adeel Khan, Talvinder Bhogal, Helen Wong, Andrea Law, Samantha Mills, Nuria Santamaria, Joanne Cliff, Douglas Errington, Allison Hall, Clare Hart, Zafar Malik, Raj Sripadam, Helen Innes, Helen Flint, Gabriella Langton, Eliyaz Ahmed, Jill Bishop, Richard Jackson, Carlo Palmieri. A comparison of the efficacy of trastuzumab deruxtecan in advanced HER2-positive breast cancer: active brain metastasis versus progressive extracranial disease alone [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 PO3-04-06.

Abstract PO5-12-12: Implementation of a comprehensive monitoring protocol for the prevention and treatment of interstitial lung disease in patients undergoing treatment with trastuzumab deruxtecan

Abstract Background: In the DESTINY-BREAST studies, Trastuzumab deruxtecan (T-DXd) demonstrated significant antitumor activity in heavily pretreated patients (pts) with HER2-positive and HER2-low advanced breast cancer (ABC). T-DXd is associated with an increased risk of interstitial lung disease (ILD), which occurs in 10-15% of patients with a 2.2% rate of fatal events. Increased monitoring for ILD within DESTINY-BREAST03 showed a reduction in grade 3-5 events. Patients with a history of clinically significant lung disease were excluded from this study, however this may not be reflective of the standard community patient population treated with T-DXd. There are currently no standardized monitoring protocols for ILD/pneumonitis for pts treated with T-DXd. We conducted a retrospective chart review to assess the benefit of implementing an ILD monitoring protocol in a cohort of patients receiving treatment with T-DXd at the Duke Cancer Institute. Methods: Patients with HER2-positive or HER2-low ABC who received ≥ five cycles of T-DXd between Jan 1, 2020- April 30, 2022 were included. Imaging with CT chest ILD protocol and pulmonary function testing with diffusing capacity for carbon monoxide (DLCO) were performed at baseline prior to initiation of T-DXd, prior to cycle 3 and cycle 5 in conjunction with ILD chest CT and then every 6 weeks to monitor for ILD. DLCO was corrected for hemoglobin. Clinical symptoms including cough, shortness of breath, dyspnea, and new or worsening respiratory symptoms were recorded. For pts that experienced more than a 10% decrease in corrected DLCO (DLCOc), a pulmonology consult was recommended. DLCOc was reviewed in combination with chest imaging and clinical history to evaluate for ILD and guidance was provided for continuation or cessation of T-DXd. Results: A total of 33 patients with HER2-positive (N=27) and HER2-low (N=6) ABC were monitored as per the predefined ILD monitoring protocol. There were 5 confirmed cases of ILD/pneumonitis within the pt cohort. 16 patients (48%) experienced DLCOc decreases >10% warranting a pulmonology consult or further review. Upon further assessment, ILD/pneumonitis was ruled out based on chest imaging and/or asymptomatic presentation in 11 patients and therapy continued without treatment delay or discontinuation. There were 5 confirmed cases of ILD/pneumonitis within the patient cohort. 3 of the 5 patients diagnosed with ILD experienced DLCOc decreases ≥10%, while 2 of the 5 diagnosed patients had DLCOc changes of < 10% but had concern for ILD on ILD/chest CT and were diagnosed after pulmonology consult. Additional results to be presented at meeting. Conclusion: For patients receiving T-DXd, implementation of a comprehensive protocol to monitor and assess for ILD secondary to treatment may allow patients with suspected ILD to begin treatment sooner or prevent permanent discontinuation by excluding ILD diagnosis. While PFT monitoring can be helpful for some patients to monitor for ILD, continuous PFT monitoring is not recommended for all patients given inconsistency. However, baseline PFTs prior to initiation and with suspected ILD in combination with imaging warrants further investigation. The use of a multidisciplinary team including pulmonologists experienced with T-DXd-induced ILD may assist in diagnosing or excluding ILD and allow for continuation of T-DXd therapy. Citation Format: Heather Moore, Kelly Westbrook, Thomas Bagwell, Scott Shofer, Carey Anders, Amy Guisinger, Olivia White, Susan Dent. Implementation of a comprehensive monitoring protocol for the prevention and treatment of interstitial lung disease in patients undergoing treatment with trastuzumab deruxtecan [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 PO5-12-12.

Abstract PO4-01-02: High throughput analysis in HER2 positive locally advanced breast cancer: pCR and mutational status

Abstract Background Pathologic complete response (pCR) after neoadjuvant treatment (NAD) is a strong prognostic biomarker associated with improved survival in breast cancer patients, especially with HER2-positive and Triple negative subtypes. PIK3CA is mutated in up to 20% of HER2 positive breast cancers, contributes to anti-HER-2 resistance and may be predictive of the lack of response to anti HER2 NAD. PIK3CA mutations in breast cancer occur primarily at hotspots E545K at exon 9 and H1047R at exon 20. Next generation sequencing has improved our knowledge regarding the biology of the mechanisms behind treatment resistance. The aim of this study is to evaluate the genomic landscape of tissue samples obtained from locally advanced breast cancer patients treated in an neoadjuvant setting, in order to correlate the genomic analysis to response and clinical outcome. Methods DNA extracted from the archival 84 formalin-fixed paraffin-embedded (FFPE) samples from core needle biopsies was subjected to deep sequencing using the TruSight Oncology (TSO) 500 panel (Illumina, San Diego, USA; 523 genes, size: 1.94 Mb), following the manufacturer’s protocol, which assesses microsatellite instability (MSI) status, tumor mutation burden (TMB), recurrent somatic copy number variations (sCNV), somatic single nucleotide variants (SNVs). Libraries were sequenced on a NovaSeq 6000 instrument (Illumina) to reach a minimum of 500 × read depth. All samples were evaluated for RNA single cell transcriptional profile. 73 of 84 patients were treated with traditional neoadjuvant chemotherapy plus trastuzumab meanwhile 13 of 84 received neoadjuvant chemotherapy plus trastuzumab and pertuzumab. Statistical analysis was performed to detect the genes whose mutation involved in the progression and/or non-response of the disease using the Statistical Package for Social Science (SPSS), release 23.0. Continuous variables were expressed as mean ± SD or median [range], categorical variables were displayed as frequencies and the appropriate parametric (Student‘s t-test) non-parametric test (X2-test or Mann-Whitney test) was used to assess significance of the differences between subgroups (patients with or without pCR). Results In total we analyzed samples of 84 patients. The median age was 48 years. 64 of 84 (76.2%) were triple positive, 66 (78.6%) with G3 and 29 (34.5%) with stage III. The most common frequently mutated genes were PIK3CA (16/84, 19%) and BRCA1 (7/84, 8.3%). The pathogenic variant of BRCA1 (sBRCA1) had a significant association with resistance to treatment: we found a pCR in only 14.3% of sBRCA1 versus 62.3% in sBRCA1 wild type (wt) patients (p=0.014). We also identified 11 somatic mutations in hereditary genes (ATM, BRCA1, BRCA2, PALB2, CHEK2, RAD51C, RAD51D). From a germline standpoint we detected 7 pathogenic variants (two affecting BRCA1, two affecting CHEK2, one affecting PALB2, 7/84, 8.3%), which will be clinically confirmed. Among patients with a mutated PI3KCA, 43.8% obtained a pCR versus 61.8% of patients with PI3KCA wt (p=0.19). This data probably presents an imbalance due to the sample size A PTEN mutation was identified in 2% of pts (2/84) which obtained no benefit in terms of pCR after NAD versus 59.8% in wt patients (p=0.09). Conclusions In this preliminary report, genetic drivers such as BRCA1 status may have a clinical implication for prognosis and treatment response after NAD in locally advanced HER2 positive breast cancer. More samples are needed to evaluate the significance of PI3K and PTEN mutations in this patient setting. We are waiting for the results of the RNA single cell transcriptional profile of these samples. Event free survival data is not yet mature at this moment. We would like to acknowledge the contribution of Multi-specialistic Biobank Research Core Facility G-STeP, Fondazione Policlinico Universitario “A. Gemelli” IRCCS (Biobank-FPG) who provided the bio-resources. Citation Format: Ida Paris, Angelo Minucci, Daniele Generali, simona Nanni, Tatiana D'angelo, Francesco Pavese, Alessandra Fabi, Maria De Bonis, Katia Cannita, Alessia Piermattei, Giordana Tiberi, Paola Fuso, Luisa Carbognin, Silvia Rotondaro, Camilla Nero, Flavia Giacomini, Tina Pasciuto, Maria Marrazzo, Luciano Giaco', Antonino Mulè, Riccardo Masetti, Gianluca Franceschini, Giorgia Garganese, Diana Giannarelli, Giovanni Scambia. High throughput analysis in HER2 positive locally advanced breast cancer: pCR and mutational status [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 PO4-01-02.

Abstract PO1-17-03: Real-world evidence of Trastuzumab biosimilars in HER2-positive breast cancer: Evaluating utilization, efficacy, and safety in Taiwan

Abstract Purpose Biosimilars have emerged as a promising alternative to reference biologic products for the treatment of cancers and immunological diseases. With regard to breast cancer, trastuzumab, a reference monoclonal antibody biologic, has been the standard of care for early and advanced HER2-positive breast cancer since 1998. Trastuzumab biosimilars, which provide comparable efficacy at a lower cost, have the potential to reduce financial burden on patients and healthcare systems and improve patient access to HER2-targeted therapy. This study aimed to evaluate the utilization, efficacy, and safety of trastuzumab biosimilars in HER2-positive breast cancer patients at Kaohsiung Veterans General Hospital. Methods A total of 113 HER2-positive breast cancer patients were enrolled between February 2020 and December 2022 and treated with trastuzumab biosimilars (OGIVRI®, trastuzumab-dkst). Of these, 44 were in the neoadjuvant group, 27 in the adjuvant group, and 42 in the metastatic group. Clinical outcomes were evaluated, including pathological complete response (pCR) rate in the neoadjuvant group, objective response rate (ORR) and clinical benefit rate (CBR) in the metastatic group, and safety profile in all groups. Results In the neoadjuvant group, 18 out of 44 evaluable patients achieved pathological complete response after surgery, resulting in a pCR rate of 40.90%. In the metastatic group , the ORR was 57.14% and the CBR was 90.47%. Furthermore, in the metastatic group, treatment with dual blockade using biosimilars resulted in an better ORR of 62.96%. No adverse events of cardiac toxicity were reported in any group. In the adjuvant group, longer follow-up is needed to assess efficacy. Conclusions Our real-world experience suggests that trastuzumab biosimilars are a safe and cost-effective alternative to reference trastuzumab in the treatment of HER2-positive breast cancer. Biosimilar trastuzumab demonstrated efficacy in the neoadjuvant setting, while dual blockade with biosimilars resulted in better disease control in the metastatic setting. Further follow-up is necessary to evaluate the efficacy of trastuzumab biosimilars in the adjuvant setting. Citation Format: Yi-Hung Lo, Yen-Dun Tzeng. Real-world evidence of Trastuzumab biosimilars in HER2-positive breast cancer: Evaluating utilization, efficacy, and safety in Taiwan [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 PO1-17-03.

Abstract PO3-04-05: Efficacy and safety of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive or HER2-low expressing, metastatic breast cancer: a single-arm phase II study

Abstract Background: Current treatment options for HER2-positive (IHC 3+, or IHC 2+/FISH+) advanced or metastatic breast cancer at third-line and above have shown limited clinical benefit. There is no recommended HER2-targeting treatment for HER2-low expressing (IHC 2+/FISH-, or IHC 1+) population. RC48 (Disitamab vedotin), a newly developed antibody-drug conjugate (ADC), is comprised of three well-defined components: hertuzumab against the prominent tumor target-HER2, monomethyl auristatin E (MMAE) and a cleavable linker, with a bystanding effect in tumor cell killing. There is a lack of data on the administration of RC48 in the Chinese population. Here, we report the efficacy and safety of RC48-ADC in the advanced or metastatic breast cancer. Methods: Patients with HER2-positive or HER2-low expressing, locally advanced or metastatic breast cancer were eligible and received RC48 2.5 mg/kg every two weeks alone or combined with drugs with different anti-tumor mechanisms, such as immune checkpoint inhibitors (ICIs), tyrosine kinase inhibitors (TKIs) and antiangiogenic compounds. The primary endpoint was the objective response rate (ORR) assessed by the primary researcher. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), time to progression, and safety. Results: At the time of data cutoff (June 30, 2023), 120 chinese female breast cancer patients were enrolled and treated with RC48-ADC. 82 patients (68.3%) were HER2-positive and 38 patients (31.7%) were HER2-low expressing. At baseline, 52 patients (43.3%) had liver metastases, 40 patients (33.3%) had brain metastases, 70 patients (58.3%) had ≥3 metastases lesions, and 84 patients (70.0%) had received ≥3 prior chemotherapy regimens. In the overall population, the ORR was 38.3% (95% confidence interval [CI]: 30.0%-47.3%). The median PFS was 5.7 months (95% CI: 4.6-6.9 months). The DCR was 64.2% (95% CI: 54.9%-72.6%). In the HER2-positive subgroup, the ORR and mPFS were 42.7% (95% CI: 32.0%-54.1%) and 6.3 months (95% CI: 4.9-7.6 months). In the HER2-low expressing subgroup, the ORR and mPFS were 29.0% (95% CI: 16.0%-46.1%) and 3.6 months (95% CI: 2.0-5.3 months). In addition, the mPFS in the dual drug combination-treated group were longer than those in the single drug treatment group, with mPFS of 7.1 months (95% CI: 5.0-9.2 months) and 4.6 months (95% CI: 3.5-5.8 months), respectively. The most frequently reported treatment-related adverse events (TRAEs) were increased AST (45.8%), increased ALT (41.7%), decreased white blood cell count (25.0%), and fatigue (25%), most were grade 1-2 in severity. Conclusions: RC48-ADC showed consistent efficacy in HER2-positive and HER2-low expressing subgroups. No new safety signals were observed. Coadministration with ICIs, TKIs and antiangiogenic compounds demonstrated substantially enhanced efficacy compared to the monotherapies and could be a future direction in development of ADC. Citation Format: Fei Qu, Wei Li, Yongmei Yin, Qian Liu. Efficacy and safety of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive or HER2-low expressing, metastatic breast cancer: a single-arm phase II study [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 PO3-04-05.

Abstract PO2-20-05: Onco-Genome Brazil: Mapping Breast and Prostate Cancer in the Brazilian Public Health System

Abstract Background: Breast and prostate cancers are the most common malignancies diagnosed in women and men respectively, and present with great clinical heterogeneity, even in tumors with the same phenotypic characteristics. Somatic and germline molecular alterations in DNA may have prognostic and predictive impact, influencing response to therapies and overall survival. In addition, the evaluation of germline mutations can help identify individuals and families at higher risk for developing cancer. Aims: Our aim is to characterize the somatic and germline genomic landscape of women with locally advanced HER2-positive breast cancer and men with metastatic prostate cancer from Brazil. Secondarily, we aim to identify genetic variants associated with tumor prognosis and treatment response, identify patients carrying pathogenic alterations in cancer-predisposing genes, and characterize the genetic ancestry of the population included in the study. Trial design: This observational multicenter cohort study (NCT05306600) will include 550 adult patients from the five macro-regions of Brazil, divided into two arms: 1) breast cancer and 2) prostate cancer. Clinical and pathological data will be collected, as well as DNA samples from peripheral blood and tumor tissue. Whole-exome sequencing (WES) will be performed to identify variants that may be drivers and/or actionable in a specific patient or tumor. These variants will be interpreted and classified according to their population frequencies, in silico predictors, functional studies, and literature data, following international guidelines proposed by expert societies. This trial is supported by the Ministry of Health in Brazil and includes patients of the Public Health System. Eligibility criteria: In arm 1, the inclusion criteria are patients with a histological diagnosis of breast carcinoma with overexpression of HER-2, clinical stage II or III, and undergoing neoadjuvant treatment with chemotherapy plus trastuzumab. In arm 2, the criteria are patient with histological diagnosis of prostate adenocarcinoma, currently in clinical stage IV. Patients without availability of biological material collection are excluded from the study, as well as patients in whom there was no central confirmation of required histology. Statistical methods: Univariate and multivariate analyses will be conducted to evaluate the possible effect of specific genes or mutations on the investigated outcomes, including tumor prognosis and treatment response. Discussion: Currently, 265 participants have already been included in the study, 150 in arm 1 and 115 in arm 2. This trial will contribute to the construction of a robust database that should provide a better understanding of the genomic profile of patients with breast and prostate cancer in Brazil. For more information about the trial, please contact Daniela Rosa (daniela.rosa@hmv.org.br). Citation Format: Jaqueline Schuch, Cláudia Bordignon, Mahira Rosa, Angélica de Baumont, Marina Bessel, Gabriel Macedo, Daniela Rosa. Onco-Genome Brazil: Mapping Breast and Prostate Cancer in the Brazilian Public Health System [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 PO2-20-05.

Abstract PO2-04-06: Investigation of the genomic evolution of HER2-positive breast cancer following progression on dual HER2-targetted therapy with Trastuzumab and Tucatinib

Abstract Background: Advanced HER2-positive breast cancer remains an incurable and highly morbid condition. One of the key challenges has been treatment of central nervous system (CNS) metastases, commonly seen in those with HER2-positive disease. Tucatinib is a recently approved treatment HER2-targetting tyrosine kinase inhibitor with proven CNS activity. There has been little analysis of potential genomic mechanisms of drug resistance. Method: We retrospectively identified patients that were treated with tucatinib, capecitabine and trastuzumab. We collated baseline clinical data and treatment history and all tumour and plasma samples available were obtained for testing. DNA was extracted from plasma samples using the QIAamp DNA Mini Kit (Qiagen) on 4ml plasma samples. Targeted next generation sequencing (NGS) of serial tumour and plasma samples was performed using a custom hybrid capture assay that covered 180 genes known to be recurrently mutated in breast cancer focusing on the known genomic landscape of metastatic disease as well as the inclusion of specific actionable targets. Survival analyses was performed using Cox regression models. Results: We identified 11 patients at our institution. Plasma samples were available for all 11 patients with a total of 107 serial samples across multiple time points, with a median of 8 (range 2-19) samples per patient. All 11 patients had baseline and End of Treatment (EOT) samples. In addition, 6/11 (54%) patients had tumour sequenced on the same NGS platform prior to commencement of therapy, with 12 individual tumour samples tested. The median PFS of our cohort was 9.6 months (4.0 - NR) with a median OS of 36.2 months (10.4-NR). 7/11 (64%) patients had CNS disease at baseline with their median PFS being 13.5 months (3.9-24.4) and median OS of 36.2months (10.4-NR). Overall, we observed an average of 18.4 (4-35) mutations per patient in tumour, 5.1 (1-15) in baseline plasma and 5.8 (2-14) in EOT plasma. The most frequent mutations seen in baseline tumour samples were ERBB2 (92%), KMT2C (67%) and NCOR1 (58%) compared with KMT2C (64%), NOTCH4 (36%) and PIK3CA (27%) in baseline plasma. Patients with a lower number of ctDNA mutations at baseline showed a trend towards improved survival (PFS 14 months vs 7.5 months). In this small cohort of patients we identified a higher than expected rates of KMT2C mutations. A KMT2C mutation was identified in 67% of samples which is higher than previously described rates of 7-15% in TCGA and METABRIC cohorts respectively. The presence of a concordant ctDNA KMT2C mutation in baseline and progression samples was a poor prognostic indicator (mPFS 7.5 months) when compared with no KMT2C mutation (mPFS 15.5 months) p =0.14 suggesting a possible mechanism of resistance to tucatinib. Conclusions: In this retrospective analysis of patients treated with Tucatinib, Trastuzumab and Capecitabine we established the genomic landscape of heavily pre-treated, advanced HER2-positive disease is complex. We observed there may be a correlation with KMT2C mutations and poorer clinical outcomes, however given the very small number of patients this data remains hypothesis generating, requiring validation with larger datasets. Citation Format: Elizabeth Blackley, Courtney van Geelen, Yi-An Ko, Stephen Wong, Miriam Yeung, Stephen Luen, Sarah-Jane Dawson, Sherene Loi. Investigation of the genomic evolution of HER2-positive breast cancer following progression on dual HER2-targetted therapy with Trastuzumab and Tucatinib [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 PO2-04-06.

Abstract PO1-15-05: Gene expression signature as a predictor of pathological complete response to neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab treatment in locally advanced HER2-positive breast cancer

Abstract Background: Neoadjuvant pertuzumab and trastuzumab in combination with chemotherapy can achieve pathological complete response (pCR, defined as ypT0/is ypN0) in approximately 40–60% of patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC). Patients who achieve pCR have significantly improved survival. Therefore, the prediction of pCR is crucial for optimizing neoadjuvant therapy. Methods: To identify a gene expression signature that could predict pCR in patients with HER2+ BC, we used the nCounter Breast Cancer 360TM V2 panel to quantify the expression of 758 genes in 104 HER2+ BC samples from patients who received neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) chemotherapy and subsequent curative breast surgery. Data normalization, differentially expressed gene (DEG) analysis, and gene set enrichment analysis (GSEA) were performed using the NanoTube Bioconductor package. Using the elastic net logistic regression model with optimal hyperparameters determined by 5-fold cross-validation (5-CV), we developed a chemosensitivity score based on the expression of significant DEGs (genes with absolute log2-fold-change ≥0.5 and q-value < 0.1). We tested its predictive value for pCR using multivariable logistic regression analysis. Results: The median age at diagnosis was 49.5 years. The clinical stage was II in 53 (51%) patients and III in 51 (49%) patients at diagnosis. Ninety (86.5%) patients had a HER2 immunohistochemistry (IHC) score of 3+, while the remaining 14 (13.5%) patients had HER2 IHC 2+ but HER2 amplification detected by in situ hybridization. Pathological evaluation of surgical specimens revealed that 55 (52.9%) patients achieved pCR. Menopausal status (p = 0.01), PAM50 intrinsic subtype (p = 0.002), hormone receptor (HR) status (p < 0.001), and HER2 IHC score (p = 0.019) were significantly correlated with the pCR rate. DEG analysis using the PAM50 intrinsic subtype, HR status, and HER2 IHC score as covariates revealed 6 downregulated DEGs and 33 upregulated DEGs in patients who achieved pCR compared to patients who did not (Table 1). The 39 DEGs were significantly enriched in nine preselected MSigDB hallmark gene sets representing immunological processes (p < 0.001). The optimal elastic net logistic regression model containing 39 DEGs achieved the mean 5-CV area under the receiver operating characteristic curve of 0.81. The chemosensitivity score calculated using the optimal model parameters was significantly correlated with pCR after adjustment for the PAM50 intrinsic subtype, HR status, and HER2 IHC score (p < 0.001). GSEA revealed eight hallmark gene sets that were significantly up- or downregulated in samples with pCR, including epithelial-mesenchymal transition (normalized enrichment score [NES] = -2.16; q < 0.001), late estrogen response (NES = -2.01; q = 0.004), early estrogen response (NES = -1.972; q = 0.005), and inflammatory response (NES = 1.53; q = 0.06). Conclusion: Our findings demonstrate that gene expression patterns can predict the response to neoadjuvant TCHP chemotherapy in HER2+ BC. The functional characterization of 39 DEGs suggests that the tumor microenvironment, including adjacent immune cells, plays a significant role in modulating the response to neoadjuvant chemotherapy in HER2+ BC. Table 1. Significant DEGs Citation Format: Junghoon Shin, Ji-Yeon Kim, Eun Yoon Cho, Seok Won Kim, Jeong Eon Lee, Hyunwoo Lee, Yeon Hee Park, Jin Seok Ahn, Young-Hyuck Im. Gene expression signature as a predictor of pathological complete response to neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab treatment in locally advanced HER2-positive 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 PO1-15-05.

Abstract PO2-18-12: Updated Results of a Phase II Study: Neoadjuvant Inetetamab Combined with Pertuzumab, Paclitaxel and Carboplatin for Locally Advanced HER2-Positive Breast Cancer

Abstract Background: Inetetamab is a neotype HER2-targeted monoclonal antibody with amino acids modified Fc segment which optimizes the antibody-dependent cellular cytotoxicity effect. However, robust evidence evaluating the combination of inetetamab combined with pertuzumab, paclitaxel and carboplatin (TCbIP) for neoadjuvant therapy is still lacking. This study aimed to evaluate the efficacy and safety of TCbIP as a neoadjuvant therapy for patients with locally advanced HER2-positive breast cancer. We now present the updated results of this trial. Methods: This phase II trial included female patients with histologically confirmed stage IIA to IIIC HER2-positive primary invasive breast cancer. Eligible patients received TCbIP treatment every three weeks for a maximum of six cycles followed by surgery. The primary endpoint was pathologic complete response (pCR, ypT0/is ypN0) rate. Key secondary endpoints included near pCR (npCR, residual breast disease < 1cm) rate, objective response rate (ORR) and safety. Results: From November 2021 to July 2023, 40 patients were enrolled in the trial. One patient received one cycle of the study treatment but was lost to follow-up without surgery, and five patients received one cycle of the study treatment and were still undergoing treatment, leaving 34 patients in the intention-to-treat (ITT) population. Among these 34 patients (82.4% in stage III), 22 patients completed the study treatment and surgery (per-protocol [PP] population) and 12 patients were still undergoing neoadjuvant treatment. The ORR was 91.2% (31/34) in the ITT population and 86.4% (19/22) in the PP population. Among the 22 patients in the PP population, 12 patients (54.5%) achieved pCR, and18 patients (81.8%) achieved npCR. The pCR rates for patients with hormone receptor (HR) negative and positive tumors were 80.0% (8/10) and 33.3% (4/12), respectively. The most common grade 3 adverse event was neutropenia (17.6%). No significant reduction in the left ventricular ejection fraction was observed in any patient. Conclusions: Neoadjuvant therapy with TCbIP demonstrated promising efficacy and manageable toxicity in patients with HER2-positive locally advanced breast cancer. Registration number: NCT05749016 (www.clinicaltrials.gov). Citation Format: Yue Chai, Jiaxuan Liu, Mingxia Jiang, Maiyue He, Xin Wang, Yipeng Wang, Xue Yang, Jing Wang, Binghe Xu, Qiao Li. Updated Results of a Phase II Study: Neoadjuvant Inetetamab Combined with Pertuzumab, Paclitaxel and Carboplatin for Locally Advanced HER2-Positive 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 PO2-18-12.

Safety and efficacy of pyrotinib for HER‑2‑positive breast cancer in the neoadjuvant setting: A systematic review and meta‑analysis.

As a novel tyrosine kinase inhibitor (TKI), pyrotinib can irreversibly block dual pan-ErbB receptors and has been used in the treatment of advanced or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, there are limited data on the use of pyrotinib in early breast cancer. Therefore, the present meta-analysis was conducted to evaluate the safety and efficacy of pyrotinib in the neoadjuvant setting for patients with early-stage or locally advanced HER2-positive breast cancer. Online databases (Pubmed, Web of Science, Embase and Cochrane Library) were comprehensively searched for eligible prospective clinical trials on August 17, 2023. The primary endpoint was the treatment-related adverse events (TRAEs), and the secondary endpoint was pathological complete response (pCR) rate. In total, seven trials with a total enrolment of 407 patients were included. A total of seven studies evaluated pyrotinib in combination with trastuzumab and chemotherapy in the neoadjuvant setting. The median age ranged from 47-50 years. The most common TRAEs were diarrhea [98% of patients; 95% confidence interval (CI): 92-100%], followed by anemia (71%; 95% CI: 55-89%), vomiting (69%; 95% CI: 55-82%), and leucopenia (66%; 95% CI: 35-91%). No treatment-related deaths occurred. The pooled pCR rate was 57% (95% CI: 47-68%). It was concluded that pyrotinib-containing neoadjuvant therapy could be an effective treatment strategy in patients with early-stage or locally advanced HER2-positive breast cancer; however, the management of adverse events should be a key consideration. The management of adverse events should be paid great attention to, during pyrotinib therapy, although pyrotinib-contained neoadjuvant therapy could be an effective treatment for patients with early-stage or locally advanced HER2-positive breast cancer. Head-to-head randomized clinical trials are warranted to further confirm the benefits and risks associated with pyrotinib therapy in patients with breast cancer.

Efficacy and safety of Trastuzumab Emtansine in treating human epidermal growth factor receptor 2-positive metastatic breast cancer in Chinese population: a real-world multicenter study.

Trastuzumab emtansine (T-DM1) has been approved worldwide for treating metastatic breast cancer (mBC) in patients who have received first-line therapy, shown disease progression, and are human epidermal growth factor receptor 2 (HER2)-positive. T-DM1 received approval in China to treat early-stage breast cancer (BC) in 2020 and for mBC in 2021. In March 2023, T-DM1 was included in medical insurance coverage, significantly expanding the eligible population. This post-marketing observational study aimed to assess the safety and effectiveness of T-DM1 in real-world clinical practice in China. This study enrolled 31 individuals with HER2-positive early-stage BC and 70 individuals with HER2-positive advanced BC from 8 study centers in Shandong Province, China. The T-DM1 dosage was 3.6 mg/kg injected intravenously every 3 weeks until the disease advanced or the drug toxicity became uncontrollable, whichever occurred earlier. Additionally, efficacy and safety information on T-DM1 were collected. During the 7-month follow-up period, no recurrence or metastases were observed in patients who had early-stage BC. The disease control rate was 31.43% (22/70) in patients with advanced BC. The most common adverse effect of T-DM1 was thrombocytopenia, with an incidence of 69.31% (70/101), and the probability of Grade ≥ 3 thrombocytopenia was 11.88% (12/101). This real-world study demonstrated that T-DM1 had good efficacy and was well tolerated by both HER2-positive early-stage BC and mBC patients.

Pyrotinib and Trastuzumab Plus Chemotherapy Serve as an Acceptable Neoadjuvant Regimen Exhibiting Good Efficacy and Tolerance in HER2-Positive Breast Cancer Patients.

Objective: Pyrotinib, a new irreversible dual pan-human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase inhibitor blocking EGFR and HER2, has achieved a promising efficacy for advanced HER2-positive (HER2+) breast cancer. This study intended to further investigate the efficacy and safety of neoadjuvant pyrotinib and trastuzumab plus chemotherapy for HER2+ breast cancer treatment. Methods: Thirty-eight HER2+ breast cancer patients who received neoadjuvant pyrotinib and trastuzumab plus chemotherapy (docetaxel and carboplatin) were retrospectively reviewed. Clinical response by Response Evaluation Criteria in Solid Tumors (RECIST), pathological complete response (pCR), and adverse events data was retrieved. Results: According to the RECIST, the complete response rate was 0.0%, 10.5%, and 15.8% after second-cycle, fourth-cycle, and sixth-cycle therapy, respectively; whereas the objective response rate was 76.3%, 92.1%, and 100.0%, accordingly. The total pCR (tpCR) rate was 52.6%, the pCR rate of the breast was also 52.6%, and the pCR rate of lymph nodes was 86.8%. The tpCR rate was lower in patients with HER2 immunohistochemistry (IHC)++ and amplification by fluorescent in situ hybridization (FISH) than in those with HER2 IHC+++ (14.3% vs. 61.3%, p = 0.024), which was also lower in patients with Ki-67 expression ≥30% than in those with Ki-67 expression <30% (40.0% vs. 76.9%, p = 0.031). The common adverse events included diarrhea (84.2%), anemia (73.7%), nausea and vomiting (63.2%), fatigue (50.0%), hypomagnesemia (44.7%), leukopenia (42.1%), thrombocytopenia (39.5%), elevated transaminase (36.8%), and pruritus (31.6%). Conclusions: Pyrotinib and trastuzumab plus chemotherapy serve as an acceptable neoadjuvant regimen exhibiting good efficacy and tolerance in HER2+ breast cancer patients, while further large-scale validation is warranted.

Mapping breast and prostate cancer in the Brazilian public health system: study protocol of the Onco-Genomas Brasil.

Breast and prostate cancers are the most common malignancies diagnosed in women and men respectively, and present with great clinical heterogeneity, even in tumors with the same histology and same site of origin. Somatic and germline molecular alterations in DNA may have prognostic and predictive impact, influencing response to therapies and overall survival. Our aim is to characterize the somatic and germline genomic landscape of women with locally advanced HER2-positive breast cancer and men with metastatic prostate cancer in Brazil. Secondarily, we aim to identify genetic variants associated with tumor prognosis and treatment response, identify patients carrying pathogenic alterations in cancer-predisposing genes, and characterize the genetic ancestry of the population included in the study. This observational multicenter cohort study will include 550 adult patients from the five macro-regions of Brazil, divided into two arms: 1) breast cancer and 2) prostate cancer. Clinical and pathological data will be collected, as well as DNA samples from peripheral blood and tumor samples. In arm 1, the inclusion criteria are a histological diagnosis of breast carcinoma with overexpression of HER-2, clinical stage II or III, and current neoadjuvant treatment with chemotherapy plus trastuzumab. In arm 2, the criterion is a histological diagnosis of prostate adenocarcinoma, clinical stage IV. Whole-exome sequencing (WES) will be performed to identify variants that may be drivers and/or actionable in a specific patient or tumor. These variants will be interpreted and classified according to their population frequencies, in silico predictors, functional studies, and literature data, following international guidelines proposed by expert societies. This trial will contribute to the construction of a robust database that should provide a better understanding of the genomic profile of patients with breast and prostate cancer in Brazil. Considering the miscegenation of the Brazilian population, knowledge generated from these data will have implications for future studies of this specific population. [clinicaltrial.gov], identifier [NCT05306600].

High HER2 Intratumoral Heterogeneity Is a Predictive Factor for Poor Prognosis in Early-Stage and Locally Advanced HER2-Positive Breast Cancer.

Breast cancer tumors frequently have intratumoral heterogeneity (ITH). Tumors with high ITH cause therapeutic resistance and have human epidermal growth factor receptor 2 (HER2) heterogeneity in response to HER2-targeted therapies. This study aimed to investigate whether high HER2 heterogeneity levels were clinically related to a poor prognosis for HER2-targeted adjuvant therapy resistance in primary breast cancers. This study included patients with primary breast cancer (n = 251) treated with adjuvant HER2-targeted therapies. HER2 heterogeneity was manifested by the shape of HER2 fluorescence in situ hybridization amplification (FISH) distributed histograms with the HER2 gene copy number within a tumor sample. Each tumor was classified into a biphasic grade graph (high heterogeneity [HH]) group or a monophasic grade graph (low heterogeneity [LH]) group based on heterogeneity. Both groups were evaluated for disease-free survival (DFS) and overall survival (OS) for a median of ten years of annual follow-up. Of 251 patients with HER2-positive breast cancer, 46 (18.3%) and 205 (81.7%) were classified into the HH and LH groups, respectively. The HH group had more distant metastases and a poorer prognosis than the LH group (DFS: p < 0.001 (HH:63% vs. LH:91% at 10 years) and for the OS: p = 0.012 (HH:78% vs. LH:95% at 10 years). High HER2 heterogeneity is a poor prognostic factor in patients with HER2-positive breast cancer. A novel approach to heterogeneity, which is manifested by the shape of HER2 FISH distributions, might be clinically useful in the prognosis prediction of patients after HER2 adjuvant therapy.

135 (PB-135) Poster - A Prospective, Single arm, Multicentre, Post-marketing Study (Phase IV) to evaluate safety and immunogenicity of Dr. Reddy’s Trastuzumab (DRL_TZ) in Patients with HER2-Positive Advanced Breast Cancer

135 (PB-135) Poster - A Prospective, Single arm, Multicentre, Post-marketing Study (Phase IV) to evaluate safety and immunogenicity of Dr. Reddy’s Trastuzumab (DRL_TZ) in Patients with HER2-Positive Advanced Breast Cancer

Comparison of trastuzumab emtansine, trastuzumab deruxtecan, and disitamab vedotin in a multiresistant HER2-positive breast cancer lung metastasis model

Human epidermal growth factor 2 (HER2)-positive breast cancer with lung metastases resistant to targeted agents is a common therapeutic challenge. Absence of preclinical lung metastasis models that are resistant to multiple anti-HER2 targeted drugs hampers the development of novel therapies. We established a novel HER2-positive breast cancer cell line (L-JIMT-1) with a high propensity to form lung metastases from the parenteral JIMT-1 cell line by injecting JIMT-1 cells into immunodeficient SCID mice. Lung metastases developed in all mice injected with L-JIMT-1 cells, and more rapidly and in greater numbers compared with the parental JIMT-1 cells. L-JIMT-1 cells expressed more epidermal growth factor receptor and HER2 than JIMT-1 cells. L-JIMT-1 cells were resistant to all five tyrosine kinase inhibitors tested in vitro (afatinib, erlotinib, lapatinib, sapitinib, and tucatinib). When we compared JIMT-1 and L-JIMT-1 sensitivity to three HER2-targeting antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and disitamab vedotin (DV) in vitro, JIMT-1 cells were resistant T-DXd, partially sensitive to T-DM1, and sensitive to DV, while L-JIMT-1 cells were resistant to both T-DM1 and T-DXd, but moderately sensitive to DV. In a mouse model, all three ADCs inhibited the growth of L-JIMT-1 lung metastases compared to a vehicle, but DV and T-DXd more strongly than T-DM1, and DV treatment led to the smallest tumor burden. The L-JIMT breast cancer lung metastasis model developed may be useful in the evaluation of anti-cancer agents for multiresistant HER2-positive advanced breast cancer.