Guidelines for managing adverse reactions to antibody-drug conjugates in breast cancer (2025 edition)

Trastuzumab Beyond Progression in Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: UK Practice now and in the Future

To investigate the immunohistochemical expression of p85 in a cohort of trastuzumab-treated HER2-positive and HER2-negative metastatic breast cancer patients. The medical records of all patients with metastatic breast cancer treated with trastuzumab-based regimens between 1998 and 2010 were reviewed and clinical information was obtained. Formalin-fixed paraffin-embedded tumor tissue samples with adequate material were retrospectively collected from 183 patients. Samples were evaluated by immunohistochemistry for p85, estrogen receptors (ER), progesterone receptors (PgR), HER2, Ki67, PTEN and phosphorylated Akt (S473 and T308). HER2 status was studied by fluorescence in situ hybridization, as well. PIK3CA mutational status was also evaluated. Median follow-up for all patients was 72 months. Central re-evaluation for HER2 revealed only 111 HER2-positive cases, with the remaining 72 patients being HER2-negative. Median survival was longer in HER2-positive patients (50.7 months) compared to HER2-negative patients (36.6 months) both treated with trastuzumab, but this difference has not reached significance (p = 0.068). In total, 62% of the patients were found positive for p85, however the p85 protein was not found to be differentially expressed in HER2-positive versus HER2-negative cases. There were no significant associations between protein expression of p85 and any of the markers under study, or with time to progression. Positive p85 protein expression was however associated with poor survival in trastuzumab-treated HER2-positive patients. In our cohort of trastuzumab-treated HER2-positive breast cancer patients, positive p85 protein expression appears to be a prognostic factor of poor survival and, if validated, might have important implications in the treatment of such patients.

Tucatinib approval by EMA expands options for HER2-positive locally advanced or metastatic breast cancer

Systemic therapy for metastatic HER2-positive breast cancer

This case report evaluates the efficacy of fam-trastuzumab deruxtecan-nxki (T-DXd) in a 59-year-old woman with hormone receptor-negative, HER2-3+ breast cancer. Following initial treatment with the TCHP chemotherapy regimen (docetaxel, carboplatin, trastuzumab, and pertuzumab), the patient experienced disease progression. T-DXd was subsequently administered, resulting in significant tumor regression. This response enabled successful surgical resection and completion of adjuvant radiation therapy, marking a notable clinical outcome. Introduction: Breast cancer in hormone receptor-negative, HER2-positive patients presents substantial treatment challenges. T-DXd, an antibody-drug conjugate (ADC), has shown promise for these patients, particularly those who have undergone prior anti-HER2 therapies. T-DXd is indicated for metastatic or recurrent HER2-positive breast cancer within 6 months of initial treatment. The frontline regimen of TCHP achieves overall response rates (ORR) of 70-80%. However, T-DXd has demonstrated superior efficacy to trastuzumab emtansine (T-DM1) in the DESTINY-Breast03 trial, making it a viable option for patients with disease progression. According to updated assessment data, out of 246 patients treated with T-DXd, 240 (97.6%) achieved disease control. This includes: Complete Response (CR): 21.1% (52 patients)Partial Response (PR): 61.0% (150 patients)Stable Disease (SD): 15.4% (38 patients) Case Presentation: A 59-year-old woman with hormone receptor-negative, HER2-positive stage IIIB left breast cancer presented with large-volume disease. She commenced the first cycle of TCHP (docetaxel, carboplatin, trastuzumab, and pertuzumab), completing five cycles. However, subsequent ultrasound imaging of the left breast revealed extensive breast edema, skin thickening, and a pathologic right axillary lymph node, which, although slightly smaller than before, indicated ongoing disease activity. A biopsy of a left breast periareolar lesion and a left flank lesion confirmed invasive ductal carcinoma involving the dermis with dermal lymphatic invasion. Immunohistochemistry (IHC) results showed ER-negative, HER2 IHC 2+, and HER2 FISH-positive status for both specimens, consistent with invasive ductal carcinoma. The left breast showed massive involvement with progressive cancer, indicating significant worsening of the disease. Consequently, the patient began second-line chemotherapy with fam-trastuzumab deruxtecan-nxki (T-DXd), completing twelve cycles. An ultrasound indicated a 0.5 cm possible malignancy in the 3 o'clock position of the left breast and macrocalcifications or areas of fat necrosis in the 10 o'clock position. PET-CT scans showed that previously observed hypermetabolic lesions in the left breast and axilla were no longer seen, with improved soft tissue swelling and skin thickening, suggesting a significant reduction in disease burden, thereby facilitating the possibility of curative resection. Following this regimen, the patient underwent bilateral mastectomy. Pathology revealed the right breast to have sclerosing adenosis and cysts with no malignancy, while the left breast contained two distinct foci of invasive ductal carcinoma (9 mm and 10 mm), with all margins negative and no skin involvement. Reactive lymph nodes indicated fibrosis and calcifications consistent with neoadjuvant therapy, with no metastatic carcinoma present (ypT1bpN0). The patient experienced common side effects such as nausea and fatigue, which were manageable. However, the risk of interstitial lung disease (ILD) or pneumonitis necessitated regular CT scans and readiness to intervene with corticosteroids like prednisone. The patient subsequently completed adjuvant radiation treatment. Despite an overall satisfactory outcome, she remains at high risk for potential future relapse, necessitating close follow-up. Discussion: This case illustrates T-DXd's potential as an effective salvage therapy for hormone receptor-negative, HER2-positive breast cancer post-failure of first-line treatments. The patient's significant tumor regression facilitated surgical resection, previously unfeasible due to extensive disease. ADCs like T-DXd offer targeted delivery of cytotoxic agents, reducing systemic exposure and side effects, as seen in this patient's response. The EMILIA trial further reinforces T-DXd’s role as a critical option following T-DM1 progression. This case adds to the growing evidence supporting T-DXd’s role in treating specific breast cancer subpopulations. Broader studies are necessary to validate these findings and refine patient selection. Exploring combination therapies with T-DXd could enhance treatment efficacy and outcomes. Conclusion: Fam-trastuzumab deruxtecan-nxki (T-DXd) shows significant potential in treating hormone receptor-negative, HER2-positive breast cancer, achieving substantial tumor regression and clinical improvement. Advances in ADCs like T-DXd have transformed the therapeutic landscape, offering targeted, effective treatments with manageable side effects. While the results are promising, ongoing research and close follow-up are crucial to optimize treatment strategies and monitor for relapse in high-risk patients. Citation Format: Aliya Khan, Evan Landau, Alan B Grosset, Samuel A. Kareff. Efficacy of Fam-Trastuzumab Deruxtecan-nxki (T-DXd) in Hormone Receptor-Negative, HER2-3+ Metastatic Breast Cancer: A Case Study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-05-20.

Recent advances in bioengineering and manufacturing have catapulted Antibody–drug conjugates (ADCs) to broader clinical applications. ADCs take advantage of the exquisite specificity of monoclonal antibodies (mAb) to deliver a highly potent cytotoxic agent to a specifically targeted cell expressing a selected antigen. HER2-positive breast cancer has served as a testing ground for ADC development in solid tumors that over-express HER2/neu by linking trastuzumab to a payload agent. With the current advances, ADCs leverage the selective targeting of monoclonal antibodies to deliver highly potent agents which otherwise have a narrow therapeutic index. Ado-trastuzumab emtansine (T-DM1) was the first ADC approved for patients with HER2-postive metastatic breast cancer (MBC) and fam-trastuzumab deruxtecan-nxki (T-DXd) was recently approved as well. Sacituzumab govitecan-hziy (SG) was approved in 2020 for patients with triple negative breast cancer (TNBC). Studies focusing on utilizing ADCs in earlier stages of breast cancer in the neoadjuvant or adjuvant setting, and central nervous system (CNS) disease are in progress. New ADCs and bispecific antibodies (bAbs) are also in development.

Background: BL-B01D1 is a potentially first-in-class novel antibody drug conjugate (ADC) consisting of an EGFRxHER3 bispecific antibody bounded to a novel topoisomerase I inhibitor payload via a cleavable linker. We now present updated safety/efficacy data from phase I study of BL-B01D1 in breast cancer (BL-B01D1-104). Methods: This study included Chinese patients (pts) with locally advanced or metastatic breast cancer (BC) and other solid tumors. BC pts were enrolled in dose-expansion (D-EXP) at 2.5mg/kg D1D8 Q3W regimen regardless of EGFR/HER3 and HER2 expression levels. Results: As of May 31, 2024, a total of 158 BC pts (156 were previously treated) have been treated with at least one dose of BL-B01D1. Among the 158 pts, 44 pts had triple negative breast cancer (TNBC) including 27 HER2 0 pts; 77 pts had HR+HER2- BC including 28 HER2 0 pts; 37 pts had HER2 positive BC. The most common TRAEs (>25%, all grade/≥G3) were anemia (90.5%/39.9%), leukopenia (88.0%/42.4%), neutropenia (85.4%/51.3%), thrombocytopenia (67.7%/25.3%), nausea (58.2%/3.8%), stomatitis (48.7%/3.8%), aspartate aminotransferase increased (45.6%/0%), alanine aminotransferase increased (42.4%/0%), asthenia (42.4%/8.9%), vomiting (40.5%/0.6%), hypertriglyceridemia (36.7%/0.6%), alopecia (32.9%/0%), hypokalemia (31.6%/3.8%), decreased appetite (31.0%/0.6%), hyperglycemia (30.4%/0%), constipation (27.2%/0.6%), hyponatremia (25.9%/1.3%). Among 158 BC pts, 1 patient was dead due to febrile neutropenia that was assessed to be related to BL-B01D1. No ILD was observed. Among the 158 pts, 147 pts were efficacy evaluable (shown in the table). Note: 1. 1 pt with HER2+ BC and 1pt with HR+HER2- BC who didn’t receive standard treatment because of poor economic condition were enrolled. 2. NE, Not evaluable. Including pts who had no post-baseline scan and already off treatment. 3. The median follow up time of PFS is 8.5 months, and the mOS of all sub-group pts are not reached. 4. NR, Not reached. Conclusions: BL-B01D1 has demonstrated encouraging efficacy in previously treated patients with metastatic and locally advanced breast cancer subtypes, particularly in earlier lines of therapy. The safety and tolerability of BL-B01D1 are consistent with previously published data. Clinical trial information: NCT05470348. Citation Format: Jiong Wu, Jian Zhang, Yiqun Du, Yanchun Meng, Sa Xiao, Hai Zhu, Yi Zhu. BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate, in patients with Locally Advanced or Metastatic Breast Cancer and other Solid Tumor: Updated results from a phase 1 study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-07-27.

Background: Antibody drug conjugates (ADCs) are composed of a monoclonal antibody with a cytotoxic payload designed to deliver targeted therapy with minimal damage to non-cancerous cells.1 Recent trials of ADCs in the metastatic breast cancer (MBC) setting have demonstrated significantly improved clinical outcomes.2-5 Sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd) are FDA approved in patients with hormone receptor positive (HR+), human epidermal growth factor 2 (HER2) negative, HER2-low, and triple negative MBC. Many of the developed ADCs share similar targets and cytotoxic payloads with similar mechanism of action; little is known regarding acquired resistance and impact on subsequent lines of therapy. There is limited data available assessing the efficacy, safety, and optimal sequencing of ADCs in this setting including patients (pts) with brain metastases (BrM) or leptomeningeal disease (LMD). Retrospective data suggests a reduction in response rates with subsequent ADC treatment in pts with MBC. This retrospective study aims to assess the efficacy, safety, and tolerability of sequential ADCs in MBC inclusive of both intracranial and extracranial disease, and to determine if the efficacy of subsequent cytotoxic chemotherapy may be impacted by ADC use. Methods: This is a single-center, retrospective, cohort study in pts with HER2 negative or low MBC (immunohistochemistry (IHC) test of 0 (as negative), 1, or 2 and fluorescence in-situ (FISH) negative (as HER2 low) who received T-DXd and/or SG at the Duke Cancer Institute (DCI) from 04/2021 to 10/2023. Eligible pts were ≥ 18 years of age with a diagnosis of HR+, HER2 low, or triple-negative locally advanced or MBC. Adverse events (AEs) were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v5. Results: A total of 112 patients with HR+/HER2- or triple negative breast cancer (TNBC) who had received T-DXd and/or SG were included. A total of 59 (52.6%) pts had HR+ MBC, and 43 (38.3 %) TNBC. Approximately 22.3% and 2.7% of patients had brain and/or LMD metastases. Pts were divided into three cohorts: pts who received ADCs sequentially (cohort A, n=13), ADC then chemotherapy (CTX) thereafter (did not receive second ADC) (cohort B, n=46), or one line of CTX in between two ADCs (cohort C, n=13). The mPFS (mPFS) in the cohort A was 4.4 months in the SG immediately prior to T-DXd group and 3.0 months for T-DXd immediately prior to SG group. In cohort B, those who received CTX following T-DXd group, the mPFS was 3.1 months. Pts who received CTX following SG, the mPFS for chemotherapy was 2.5 months, whereas in pts who received both ADCs, PFS was 2.1 months with subsequent chemotherapy. In cohort C, the mPFS was 2.1 months for SG following T-DXd and CTX and 3.3 months for T-DXd following SG and CTX. The mPFS for ADC1 was longer than ADC2 regardless of sequence order. The mPFS for first ADC was 5.5 months for SG and 3.4 months for T-DxD. In both groups, those with BrM and/or LMD all demonstrated stable disease with extracranial response after the administration of an ADC. AEs were consistent with real-world data, and. Conclusion: The administration of a second ADC following prior ADC therapy results in a shorter PFS. The efficacy of chemotherapy is impacted with the use of multiple lines of ADC therapy prior to administration. Outcomes for pts with BrM and LMD who receive ADCs do not differ for those without recurrence to the brain. Sequencing of ADCs plays a role in efficacy of treatment and can likely confer a pattern of resistance. Additional prospective data is needed to further assess ideal sequencing. Citation Format: Heather Moore, Sara Nezirevic, Carey Anders, Susan Dent, Rani Bansal, Lexie Zidanyue, Alaattin Erkanli. Evaluation of efficacy and safety of sequential antibody drug conjugates (ADCs) in human epidermal growth factor 2 (HER2) negative metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-08-15.

Background: There is no uniform standard of care for HER2-positive breast cancer (BC) after disease progression on ado-trastuzumab emtansine (T-DM1). DS-8201a is a novel HER2-targeted antibody-drug conjugate (ADC) with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload by a cleavable peptide-based linker, and with a drug-to-antibody ratio of 7 to 8. It is designed with the goal of improving critical attributes of an ADC. In an ongoing phase 1 trial, DS-8201a showed promising antitumor activity in HER2-positive BC previously treated with T-DM1 (confirmed objective response rate [ORR] of 54.5%; April 2018 data cutoff; Iwata et al, ASCO 2018). Based on preliminary results from the phase 1 trial, DS-8201a received FDA breakthrough therapy and fast track designations for metastatic BC that progressed after prior treatment with T-DM1. The pivotal, phase 2 DESTINY-BREAST01 trial in this population with HER2-positive BC who received prior T-DM1 is ongoing (Baselga et al, ASCO 2018). Study Description: This multicenter, open-label, phase 3 trial will assess the efficacy and safety of DS-8201a in subjects with HER2-positive (IHC 3+ or IHC 2+/ISH+; confirmed by centralized testing) unresectable and/or metastatic BC whose disease progressed on or after T-DM1 (NCT03523585, DESTINY-BREAST02). Approximately 600 subjects will be randomized (2:1) to DS-8201a or investigator's choice of treatment (trastuzumab plus capecitabine or lapatinib plus capecitabine). Randomization is stratified by hormone receptor status, prior pertuzumab treatment, and history of visceral disease. DS-8201a (5.4 mg/kg) will be administered IV once every 3 weeks. Progression free survival (PFS) based on blinded, independent central review using RECIST v1.1 criteria is primary efficacy endpoint; overall survival (OS) is the key secondary endpoint. Other secondary efficacy endpoints are ORR, duration of response, clinical benefit rate, and PFS based on investigator assessment. Safety assessments include serious and treatment-emergent adverse events, physical examinations, vital signs, and clinical laboratory parameters. Health-related quality of life will also be measured. The primary analysis for PFS will occur when approximately 372 PFS events have been observed; providing 90% power to detect a hazard ratio of 0.70 in PFS (a 43% improvement in median PFS from 3.3 months with investigator's choice to 4.7 months with DS-8201a) with a 1-sided alpha of 0.025. An interim OS analysis is planned at the time of the PFS analysis. Final OS analysis will occur when approximately 428 OS events have been observed. Long-term follow-up will continue after the primary analysis every 3 months until death, withdrawal of consent, loss to follow-up, or study closure. Efficacy analyses will include all randomized subjects, and safety analyses will include all randomized subjects who received ≥1 dose of study treatment. The study will enroll subjects from approximately 160 sites including in North and South America, Europe, and Asia. For further information on this trial, contact Fabrice André at FABRICE.ANDRE@gustaveroussy.fr or visit clinicaltrials.gov. Citation Format: André F, Shahidi J, Lee C, Wang K, Krop IE. Trastuzumab deruxtecan (DS-8201a) vs investigator's choice of treatment in subjects with HER2-positive, unresectable and/or metastatic breast cancer who previously received T-DM1: A randomized, phase 3 study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-02.

Background: Ado-trastuzumab emtansine (T-DM1), a HER2-targeted antibody drug conjugate (ADC), is approved for patients with HER2-positive metastatic breast cancer (BC) after disease progression on a trastuzumab-based regimen. Approval of T-DM1 was based on the EMILIA trial in which T-DM1 demonstrated an objective response rate (ORR) of 43.6%, a median progression-free survival (PFS) of 9.6 months, and an overall survival (OS) of 30.9 months (Verma S, et al. NEJM. 2012). DS-8201a is a novel HER2-targeted ADC with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload by a cleavable peptide-based linker, and with a high drug-to-antibody ratio of 7 to 8. In an ongoing phase 1 trial, DS-8201a showed a manageable safety profile and promising antitumor activity in HER2-positive BC previously treated with T-DM1 (confirmed ORR of 54.5%; April 2018 data cutoff) (Iwata et al, ASCO 2018). The pivotal, phase 2 DESTINY-BREAST01 trial in this population with HER2-positive BC who received prior T-DM1 is ongoing (Baselga et al, ASCO 2018). Study Description: This multicenter, open-label, phase 3 trial will assess the efficacy and safety of DS-8201a vs T-DM1 in subjects with HER2-positive (IHC 3+ or IHC 2+/ISH+; confirmed by centralized testing) unresectable and/or metastatic BC previously treated with trastuzumab and a taxane (NCT03529110, DESTINY-BREAST03). Subjects who previously received a HER2-targeted ADC are excluded. Approximately 500 eligible subjects will be randomized (1:1) to receive DS-8201a (5.4 mg/kg) or T-DM1 (3.6 mg/kg) IV once every 3 weeks. Randomization will be stratified by hormone receptor status, prior pertuzumab treatment, and history of visceral disease. For subjects randomized to T-DM1, the treatment will be in accordance with the approved label. The primary efficacy endpoint is PFS based on blinded, independent central review using RECIST v1.1 criteria. Secondary efficacy endpoints include OS, ORR, duration of response, clinical benefit rate, and PFS based on investigator assessment. Safety assessments include serious and treatment-emergent adverse events, physical examinations, vital signs, and clinical laboratory parameters. Health related quality of life will also be measured. The primary analysis for PFS will be performed when approximately 331 PFS events have been observed. This will provide 90% power to detect a hazard ratio of 0.70 for PFS with a 1-sided alpha of 0.025, assuming a median PFS with T-DM1 of 9.6 months and that PFS follows an exponential distribution. Long-term follow-up will continue after the primary analysis every 3 months until death, withdrawal of consent, loss to follow-up, or study closure. Efficacy analyses will include all randomized subjects, and safety analyses will include all randomized subjects who received ≥1 dose of study treatment. The study will enroll subjects from approximately 150 sites851468 including in North America, Europe, and Asia. Citation Format: Verma S, Shahidi J, Lee C, Wang K, Cortes J. Trastuzumab deruxtecan (DS-8201a) vs ado-trastuzumab emtansine (T-DM1) for subjects with HER2-positive, unresectable and/or metastatic breast cancer who previously received trastuzumab and a taxane: A phase 3, randomized study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-03.

Purpose: Achieving pathologic complete response (pCR) following neoadjuvant chemotherapy is associated with better prognosis for HER2 positive breast cancer. However, clinical and biological heterogeneity of HER2 positive disease significantly affect prognosis and treatment response. Early prediction of treatment benefit could enable tailored anti-HER2 therapy. Next-generation sequencing (NGS) based genomic tests including copy number (CN) detection are widely used in breast cancer patients. We aim to evaluate the association of HER2 copy number detected by NGS with pCR rate of HER2 positive breast cancer after neoadjuvant chemotherapy. Methods: HER2 positive breast cancer patients underwent neoajuvant chemotherapy in Henan Cancer Hospital From January 2022 to March 2023 were included in the study. Pretreatment tumour specimens were subjected to pan-cancer 1021-gene panel genomic sequencing. Copy number of HER2 was obtained from the panel. Copy number of >=4 was classified as HER2 amplified and HER2 copy number <4 was classified as HER2 non-amplified. All patients underwnt definitive surgery after receieveing neoadjuvant chemotherapy containing taxanes, trastuzumab and pertuzumab. pCR was defined as pathological stage ypT0/Tis ypN0. Results: In total, 299 HER2 positive breast cancer patients were eligible for the analysis. 87 were classified as HER2 non-amplified (29.1%) by copy number and 212 patients were classified as amplified group (70.9%). The HER2 non-amplified group tends to have a higher proportion of hormone receptor positive (HR+) patients (71.3% vs. 50.5%, p=0.002). Other clinicopathological parameters were well distributed between the groups. 91.3% of patients in HER2 amplified group had strong positive HER2 expression (IHC 3+), while only 10.5% of patients in HER2 non-amplified group had HER2 expression of IHC 3+. Patients with HER2 IHC 3+ had a PCR rate of 75.8% and Patients with HER2 IHC 2+ had a pCR rate of 20.0% (20.0% vs. 75.8% p<0.001). Patients in the amplified group had a pCR rate of 76.9% and pCR rate of the non-amplified group was12.6% (12.6% vs. 76.9% p<0.001). In a multivariable logistic regression with HER2 copy number by NGS, HR status and HER2 IHC, the HER2 copy number predicted pCR rate independently of HER2 IHC and HR status. Conclusions: NGS based detection of HER2 copy number could predict response to neoadjuvant therapy in HER2 positive patients. The discordance between IHC/FISH and NGS based detection of HER2 amplification may reflect HER2 heterogeneity. HER2 heterogeneity promotes resistance to anti-HER2 therapy. Noval antibody-drug conjugates (ADC) with bystander effect, such as Trastuzumab deruxtecan, have shown anti-tumor effect even in HER2 low expression tumors. Thus, prospective study is needed to optimize anti-HER2 therapy for patients with HER2 heterogeneity. Citation Format: Hao Dai, Dechuang Jiao, Xuhui Guo, Jianghua Qiao, anfang Li, Zhenduo Lu, Xiuchun Chen, Chengzheng Wang, Min Yan, Zhenzhen Liu. Next-generation sequencing based detection of HER2 copy number predicts pathological response to neoadjuvant therapy in HER2 positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6439.

Background: The clinical activity of antibody-drug conjugates (ADCs) when used sequentially remains uncertain. Given the increasing utilization of ADCs in both HER2-positive and HER2-negative metastatic breast cancer, our aim was to assess the efficacy of sequential ADC treatments in metastatic breast cancer patients across subtypes. Methods: We conducted a retrospective analysis using data from the Dallas Metastatic Breast Cancer Study, which encompasses all metastatic breast cancer patients treated at multiple hospitals within a single academic medical center. Clinical data were gathered through retrospective chart reviews. Progression-free survival (PFS) was defined from the initiation of ADC treatment to disease progression or death. Results: At our institution, 156 metastatic breast cancer patients were treated with ADCs between March 21, 2013 and March 29, 2024. Among these, 35 patients received sequential ADC treatments. In our analysis, we included 32 patients who switched to a second ADC after disease progression on their first ADC. Patients who switched ADCs due to side effects were excluded from our analysis. The median age at metastatic diagnosis was 52 years (range: 34-75 years). The cohort consisted of 21 patients with HER2-positive breast cancer and 13 patients with HER2-negative breast cancer. Of the patients with HER2-negative disease, six patients had hormone receptor positive disease and 12 had HER2-low disease. Overall survival for the entire cohort was 17 months (range: 6-78 months). In the HER2-positive subgroup, 15 patients initially treated with trastuzumab emtansine (T-DM1) had a median PFS of 4 months (95% CI: 0.44-7.55). Subsequent treatment with trastuzumab deruxtecan (T-DXd) resulted in a median PFS of 8 months (95% CI: 3.41-12.58). Four patients initially treated with T-DXd had a median PFS of 4.5 months (95% CI: 0-26.67) and subsequent treatment with T-DM1 resulted in a median PFS of 4 months (95% CI: 0-11.98). In the HER2-negative subgroup, eight patients initially treated with sacituzumab govitecan (SG) had a median PFS of 7.5 months (95% CI: 3.84-11.15). Subsequent T-DXd treatment resulted in a median PFS of 4.5 months (95% CI: 2.01-6.98). Looking closer specifically within the HER2-low subset, the median PFS of SG remained at 7.5 months (95% CI: 3.31-11.68), while subsequent PFS on T-DXd was slightly higher at 5 months (95% CI: 1.65-8.34). Five patients initially treated with T-DXd had a median PFS of 5 months (95% CI: 0-11.00) and subsequent treatment with SG resulted in a median PFS of 2 months (95% CI: 0-14.70). Conclusions: Our findings indicate that in the HER2-positive metastatic setting, treatment with T-DXd, despite sequential use after disease progression on T-DM1, results in a longer PFS compared to the initial T-DM1 treatment. This suggests that T-DXd retains its efficacy even after disease progression on T-DM1 despite both treatments targeting the same HER2 antigen. Conversely, in the HER2-negative metastatic setting, the sequential use of SG and T-DXd, which share the same payload, resulted in a lower PFS compared to initial treatment with SG or T-DXd. These data suggest and contribute to growing evidence that payload resistance may reduce clinical benefit across subtypes instead of antigen resistance. Future studies into novel ADC development should focus on using different payloads. Citation Format: Hannah Chang, Katherine Lei, Flavia Soares Fernandes, Mayuri Vaish, Sai Movva, Christine Hodgdon, Julia Maues, Isaac Chan. Sequential ADC Treatments in Metastatic Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-09-30.

Background: Targeted therapies have largely improved prognosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Yet, disease can still progress rapidly for some patients in the first two years after diagnosis. Our study aimed to establish a nomogram model to predict 2-year breast cancer-specific survival (BCSS) in early HER2-positive breast cancer patients. Patients and Methods: A total of 32,481 HER2-positive patients derived from Surveillance, Epidemiology, and End Results (SEER) database were included in the construction of nomogram. Concordance index (C-index) and calibration curve were used to evaluate the discrimination ability and predictive accuracy. We also tested the model in 804 patients from Shanghai Jiao Tong University Breast Cancer Data Base (SJTU-BCDB).Results: Age, estrogen receptor (ER) status, progesterone receptor (PR) status, histologic type, T stage and N stage were selected to construct the nomogram according to multivariable analysis. The 2-year BCSS rate was 95% and 60% for patients at low risk (<8 points) and high risk (>13 scores) respectively. The C-index of model derived from SEER database is 0.81 (95%CI 0.79-0.83). Sensitivity analysis was performed in patients undergoing breast surgeries with the C-index of 0.81 (95%CI 0.79-0.83). Validation in 804 patients from SJTU-BCDB showed respective C-index of 0.77 (95%CI, 0.62-0.92) in total population, 0.67 (95%CI 0.44-0.90) in patients receiving anti-HER2 therapy and 0.90 (95%CI 0.81-0.90) in those without targeted therapy.Conclusions: The novel nomogram can predict 2-year survival outcome in HER2-positive patients independent of receiving anti-HER2 therapy or not and help clinicians to adjust therapeutic strategies for those patients with higher risk. Citation Format: Li Zhu, Mengdi Chen, Jiayi Wu. A novel prognostic nomogram for 2-year survival in HER2-positive patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-39.

Background: A phase 1 dose escalation study of TAA013, an antibody drug conjugate linking trastuzumab to a cytotoxic small molecule, DM1, through an SMCC linker, in previously treated recurrent Her2 positive breast cancer patients. Material and Methods: This phase I study follows the traditional 3+3 design, dosing started at 0.6mg/kg, followed by 1.2, 2.4, 3.6, 4.8mg/kg, one intravenous infusion was given every 3 weeks, the initial infusion had to be over 90 minutes, infusion times were later shortened if treatment was well tolerated. The subsequent recommended dose would be expanded to include at least 10 patients. Patients were observed for dose-limiting toxicity (DLT) during a 21-day DLT observation period. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Maximum-tolerated dose (MTD) was defined as the highest dose level that resulted in a DLT in no more than 1 of 6 patients. Study endpoints included safety and tolerability, pharmacokinetic and immunogenicity parameter evaluation, with preliminary evaluation of efficacy. Results: The study enrolled 22 female patients with histologically confirmed Her-2 positive metastatic breast cancer, median age of 50yrs (25-67), median time from initial diagnosis to TAA013 dosing was 39 months (5-99), median prior treatment regimen was 4 (2-10), all had received trastuzumab for a mean of 8.2 months (2-10), alone or in combination with chemotherapy, other prior Her2 targeting drugs given included pertuzumab (2), lapatinib (7), and pyrotinib (8). All patients received at least 2 (median of 6 infusions, range of 1-15) infusions, except for the last 4.8mg/kg patient, but all patients passed the dose limiting toxicity (DLT) observation period of 21 days. There were no dose limiting toxicities, no serious adverse events, nor that resulting in mortality, the maximum tolerated dose was not reached. The most common treatment emergent adverse events (TEAE) included 9 (40.9%) grade 1-2 infusion reactions associated with fever(5) and/or chills(1), the reaction often abated in subsequent cycles. There were no grade 4 TEAE, but there were 3 grade 3 thrombocytopenia, one grade 3 neutropenia, and one grade 3 hyperbilirubinemia which all recovered for the patients to continue treatment, there was also one grade 3 dermatitis in a patient with a history of chronic dermatitis. Antibody drug antibodies were not detected emanating from the TAA013 therapy. Pharmacokinetic studies included evaluation of TAA013, trastuzumab and DM1. Preliminary efficacy evaluation in the 2.4-4.8mg/kg dosing group of heavily pretreated patients resulted in 2 partial responses, including patients who had previously received pyrotinib therapy. Conclusion: TAA013 is a Her2 targeting antibody drug conjugate that is safe and tolerable, with efficacy demonstrated in heavily pretreated Her2 positive breast cancer patients. Keywords: breast cancer, antibody drug conjugates, TAA013. Citation Format: J M Liu, Y M Yin, Hao Wu, W Li, X Huang, XX Li. TAA013 a trastuzumab antibody drug conjugate phase I dose escalation study in recurrent her2 positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-51.

FISH in triple-negative breast cancer: a possible strategy for the future?