HER2-positive Breast Research Articles

Misconception on the duration of ado-trastuzumab emtansine treatment for HER2-positive early breast cancer.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

CircCDYL2 promotes trastuzumab resistance via sustaining HER2 downstream signaling in breast cancer

BackgroundApproximate 25% HER2-positive (HER2+) breast cancer (BC) patients treated with trastuzumab recurred rapidly. However, the mechanisms underlying trastuzumab resistance remained largely unclear.MethodsTrastuzumab-resistant associated circRNAs were identified by circRNAs high-throughput screen and qRT-PCR in HER2+ breast cancer tissues with different trastuzumab response. The biological roles of trastuzumab-resistant associated circRNAs were detected by cell vitality assay, colony formation assay, Edu assay, patient-derived xenograft (PDX) models and orthotopic animal models. For mechanisms research, the co-immunoprecipitation, Western blot, immunofluorescence, and pull down assays confirmed the relevant mechanisms of circRNA and binding proteins.ResultsWe identified a circRNA circCDYL2, which was overexpressed in trastuzumab-resistant patients, which conferred trastuzumab resistance in breast cancer cells in vitro and in vivo. Mechanically, circCDYL2 stabilized GRB7 by preventing its ubiquitination degradation and enhanced its interaction with FAK, which thus sustained the activities of downstream AKT and ERK1/2. Trastuzumab-resistance of HER2+ BC cells with high circCDYL2 could be reversed by FAK or GRB7 inhibitor. Clinically, HER2+ BC patients with high levels of circCDYL2 developed rapid recurrence and had shorter disease-free survival (DFS) and overall survival (OS) following anti-HER2 therapy compared to those with low circCDYL2.ConclusionscircCDYL2-GRB7-FAK complex plays a critical role in maintaining HER2 signaling, which contributes to trastuzumab resistance and circCDYL2 is a potential biomarker for trastuzumab-resistance in HER2+ BC patients.

High score of LDH plus dNLR predicts poor survival in patients with HER2-positive advanced breast cancer treated with trastuzumab emtansine

ObjectiveTo investigate the prognostic value of derived neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) in patients with advanced HER2 positive breast cancer treated with trastuzumab emtansine.MethodsFifty one patients with advanced HER2 positive breast cancer who received T-DM1 treatment in Harbin Medical University Cancer Hospital were selected. The clinical data and blood test indexes were collected, and the ROC curve determined the optimal cut-off value. Kaplan-Meier survival curve and Cox regression model was used to analyze the effect of different levels of dNLR,LDH,LNI (dNLR combined with LDH index) before and after T-DM1 treatment on the survival of patients.ResultsThe median PFS and OS of the patients with advanced HER2 positive breast cancer who received T-DM1 treatment were 6.9 months and 22.2 months, respectively. The optimal cut-off value of LDH and dNLR before T-DM1 treatment was 244 U / L (P = 0.003) and 1.985 (P = 0.013), respectively. Higher LDH and dNLR were significantly correlated with shorter median PFS and OS (P < 0.05). The median PFS of patients with LNI (0), LNI (1) and LNI (2) were 8.1 months, 5.5 months and 2.3 months, respectively, P = 0.007. Univariate and multivariate analysis showed that LDH > 244 U / L, dNLR > 1.985, LNI > 0, ECOG ≥1 and HER-2 (IHC2 +, FISH+) before the T-DM1 treatment were the poor prognostic factors. LDH uptrend after the T-DM1 treatment also predicted poor prognosis.ConclusionSerum LDH > 244 U / L and dNLR > 1.985 before the T-DM1 treatment were prognostic risk factors for patients with advanced HER2 positive breast cancer receiving T-DM1 treatment. The higher LNI score was significantly associated with shorter PFS and OS. LDH uptrend after T-DM1 treatment was also related to the poor prognosis.

HER2-targeted dual radiotracer approach with clinical potential for noninvasive imaging of trastuzumab-resistance caused by epitope masking.

Rationale: The decreased HER2-accessibility by epitope masking is a primary trastuzumab-resistance mechanism. In this study, we developed a HER2-targeted dual radiotracer approach to predict the HER2-trastuzumab engagement noninvasively.Methods: Two novel HER2-specific VHHs, MIRC208 and MIRC213, were acquired by immunizing alpaca with human HER2 protein, and were site-specifically labeled with 99mTc. Biodistribution and SPECT/CT imaging studies were performed in mice bearing HER2-positive and HER2-negative tumors. The HER2 binding sites of 99mTc-MIRC208 and 99mTc-MIRC213 were investigated by cell binding and SPECT/CT imaging studies. We evaluated the therapeutic predictive ability of our dual-radiotracer imaging approach for trastuzumab treatment in mice bearing MUC4-positive tumors (trastuzumab-resistant JIMT-1 and 87MUC4) and MUC4-negative tumors (trastuzumab-sensitive 7HER2 and NCI-N87). The preliminary clinical studies of 99mTc-MIRC208 were performed in two patients with HER2-positive breast tumors.Results: 99mTc-MIRC208 and 99mTc-MIRC213 clearly visualized HER2-positive tumors, but not HER2-negative tumors. 99mTc-MIRC208 competes with trastuzumab for HER2-binding while 99mTc-MIRC213 recognizes HER2 on an epitope that is not masked by MUC4. The SPECT/CT studies with 99mTc-MIRC208 and 99mTc-MIRC213 clearly showed that the MUC4-negative and trastuzumab-sensitive 7HER2 and NCI-N87 tumors had very similar tumor uptake with the SUV208/SUV213 (2 h) ratios of 1.11 ± 0.17 in 7HER2 and 1.25 ± 0.22 in NCI-N87. However, the MUC4-positive JIMT-1 tumors showed the decreased SUV208/SUV213 (2 h) ratio (0.63 ± 0.07), which correlated well with the low response rate to trastuzumab therapy. The SUV208/SUV213 (2 h) ratio was reduced to 0.72 ± 0.02 in MUC4-expressing NCI-N87 cells, and resulting in the decreased trastuzumab sensitivity, further supporting the correlation between the SUV208/SUV213 (2 h) ratio and trastuzumab-sensitivity. The primary and metastatic HER2-positive lesions of patients were clearly visualized by 99mTc-MIRC208 SPECT at 2 h post injection.Conclusion: Overall, we demonstrated that the dual radiotracer imaging strategy is a valid noninvasive approach for the cancer patient selection before trastuzumab therapy. 99mTc-MIRC213 SPECT is utilized to quantify the tumor HER2 expression and screen HER2-positive cancer patients, while 99mTc-MIRC208 SPECT is used to determine the HER2-accessibility of trastuzumab. The SUV208/SUV213 (2 h) ratio is an important biomarker to determine the responsiveness of trastuzumab therapy.

Demographic, tumour, and treatment characteristics of female patients with breast cancer in Sri Lanka; results from a hospital-based cancer registry

BackgroundAlthough breast cancer is the most common cancer among Sri Lankan women, there is little published data on patient characteristics and treatment in the local context. We aimed to describe disease characteristics and management in a large contemporary cohort of women with breast cancer at the National Cancer Institute of Sri Lanka (NCISL).MethodsAll women with invasive primary breast cancers diagnosed during 2016–2020 were identified from the NCISL breast cancer registry. The NCISL sees approximately 40% of all cancer patients in Sri Lanka. Cancer stage at diagnosis was defined according to the Tumour, Node, and Metastasis (TNM) staging system and the Estrogen (ER) and progesterone (PR) receptor status was determined based on the results of immunohistochemistry tests. Descriptive statistics were used to describe the study cohort and treatment patterns.ResultsOver 5100 patients were diagnosed with breast cancer during the study period at the NCISL. The mean age of the women was 56 (SD 12) years. Common co-morbidities were hypertension (n = 1566, 30%) and diabetes mellitus (n = 1196, 23%). Two thirds (66%) of the cancers were early stage (stage I & II) at diagnosis. ER/PR positivity rate was 72% and HER-2 positivity rate was 22%. Two thirds of the women had undergone mastectomy while 68% had undergone axillary clearance. The rate of chemotherapy delivery was 91% for women with node positive disease while 77% of eligible women (i.e., after wide local excision or with > 3 positive lymph nodes) had received adjuvant radiotherapy. Endocrine therapy was initiated in 88% of eligible women with hormone receptor positive disease while rate of trastuzumab use was 59% among women with HER2 positive breast cancer.ConclusionsHigh percentage of advanced breast cancer at diagnosis and high prevalence of comorbidities are some of the major challenges faced in the management of breast cancer in Sri Lanka. Given that stage at diagnosis is the most important prognostic factor determining survival, greater efforts are needed to promote early diagnosis of breast cancer. Considerable lapses in the concordance between guideline recommendations and the delivery of cancer care warrants closer assessment and intervention.

UK's NICE does not recommend tucatinib for HER2-positive metastatic breast cancer

UK's NICE does not recommend tucatinib for HER2-positive metastatic breast cancer

Preclinical Assessment of Paclitaxel- and Trastuzumab-Delivering Magnetic Nanoparticles Fe3O4 for Treatment and Imaging of HER2-Positive Breast Cancer.

Objective: The purpose of this study was to investigate the anticancer activity and the potential imaging use of the innovative combination of magnetic nanoparticles (MNPs)-Fe3O4, paclitaxel (PTX), and trastuzumab (Herceptin) in HER2-positive breast cancer.Methods: MNPs-Fe3O4 was synthesized and underwent water phase transfer and hydrophobic molecular loading, and its surface was then coupled with Herceptin mono-antibody. The morphological characteristics of MNPs-Fe3O4 were observed under transmission electron microscopy (TEM). Effects of PTX-Herceptin-MNPs-Fe3O4 on breast cancer cells were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,4-diphenyltetrazolium bromide assay and the flow cytometric apoptosis assay. To establish a xenograft model, we injected breast cancer SK-BR-3 cells into the left thighs of nude mice. We measured the effect of PTX-Herceptin-MNPs-Fe3O4 on tumor growth by measuring tumor size and calculating inhibition rate with immunohistochemistry analysis further performed, and analyzed MNPs-Fe3O4 accumulation in tumor lesions using in vivo magnetic resonance imaging and in vivo fluorescence imaging.Results: Most MNPs were in spherical shape of about 10 nm in diameter observed under TEM. PTX-Herceptin-MNPs-Fe3O4 showed greater cytotoxic effects, and induced a higher apoptosis rate of SK-BR-3 cells than all the other groups, with corresponding changes of apoptosis-related proteins. Meanwhile, the in vivo tumor xenograft model showed that tumor inhibition rate in the PTX-Herceptin-MNPs-Fe3O4 group was higher than in the PTX-Herceptin group. Furthermore, PTX-Herceptin-MNPs-Fe3O4 enhanced the T2 imaging contrast enhancement effect on tumors in tumor-bearing mice.Conclusion: The novel PTX-Herceptin-MNPs-Fe3O4 combination may represent a promising alternative breast cancer treatment strategy and may facilitate tumor imaging.

Dendritic Cells Pulsed with Cytokine-Adjuvanted Tumor Membrane Vesicles Inhibit Tumor Growth in HER2-Positive and Triple Negative Breast Cancer Models.

Dendritic cells (DCs) are the most effective antigen presenting cells for the development of T cell responses. The only FDA approved DC-based immunotherapy to date is Sipuleucel-T, which utilizes a fusion protein to stimulate DCs ex vivo with GM-CSF and simultaneously deliver the antigen PAP for prostate cancer. This approach is restricted by the breadth of immunity elicited to a single antigen, and to cancers that have a defined tumor associated antigen. Other multi-antigen approaches have been restricted by poor efficacy of vaccine adjuvants. We have developed a vaccine platform that consists of autologous DCs pulsed with cytokine-adjuvanted tumor membrane vesicles (TMVs) made from tumor tissue, that encapsulate the antigenic landscape of individual tumors. Here we test the efficacy of DCs pulsed with TMVs incorporated with glycolipid-anchored immunostimulatory molecules (GPI-ISMs) in HER2-positive and triple negative breast cancer murine models. Pulsing of DCs with TMVs containing GPI-ISMs results in superior uptake of vesicles, DC activation and cytokine production. Adaptive transfer of TMV-pulsed DCs to tumor bearing mice results in the inhibition of tumor growth, reduction in lung metastasis, and an increase in immune cell infiltration into the tumors. These observations suggest that DCs pulsed with TMVs containing GPI-GM-CSF and GPI-IL-12 can be further developed to be used as a personalized immunotherapy platform for cancer treatment.

Imaging-Guided Therapy Simultaneously Targeting HER2 and EpCAM with Trastuzumab and EpCAM-Directed Toxin Provides Additive Effect in Ovarian Cancer Model.

Simple SummaryTargeted therapeutics provide cytostatic or cytotoxic action selectively to tumor cells while reducing the toxicity to normal cells. Targeting two molecular receptors overexpressed on tumor cells is a way to overcome heterogeneity of expression and improve therapeutic efficacy. Combining drugs with different modes of action might also increase the cytotoxic effect and decrease the chance for the cancer cells to develop resistance to treatment. In this work, we investigated a combination of the clinically used monoclonal antibody trastuzumab with a potent targeting protein–toxin fusion, directed at two different targets present in a large fraction of ovarian cancers. Co-targeted treatment provided a significant reduction in tumor growth and extended the survival of mice compared with the control and monotherapy groups. Our findings support further development of targeted combination therapies for treatment of aggressive and resistant cancer types.Efficient treatment of disseminated ovarian cancer (OC) is challenging due to its heterogeneity and chemoresistance. Overexpression of human epidermal growth factor receptor 2 (HER2) and epithelial cell adhesion molecule (EpCAM) in approx. 30% and 70% of ovarian cancers, respectively, allows for co-targeted treatment. The clinical efficacy of the monoclonal antibody trastuzumab in patients with HER2-positive breast, gastric and gastroesophageal cancers makes it readily available as the HER2-targeting component. As the EpCAM-targeting component, we investigated the designed ankyrin repeat protein (DARPin) Ec1 fused to a truncated variant of Pseudomonas exotoxin A with reduced immunogenicity and low general toxicity (LoPE). Ec1-LoPE was radiolabeled, evaluated in ovarian cancer cells in vitro and its biodistribution and tumor-targeting properties were studied in vivo. The therapeutic efficacy of Ec1-LoPE alone and in combination with trastuzumab was studied in mice bearing EpCAM- and HER2-expressing SKOV3 xenografts. SPECT/CT imaging enabled visualization of EpCAM and HER2 expression in the tumors. Co-treatment using Ec1-LoPE and trastuzumab was more effective at reducing tumor growth and prolonged the median survival of mice compared with mice in the control and monotherapy groups. Repeated administration of Ec1-LoPE was well tolerated without signs of hepatic or kidney toxicity. Co-treatment with trastuzumab and Ec1-LoPE might be a potential therapeutic strategy for HER2- and EpCAM-positive OC.

Abstract 1005: The bispecific antibody zanidatamab's (ZW25's) unique mechanisms of action and durable anti-tumor activity in HER2-expressing cancers

Abstract HER2-directed therapies have improved clinical outcomes for many patients with HER2-positive breast and gastric cancer. Despite these successes, there remains a need to develop improved HER2-targeted therapies for these and other HER2-expressing tumors, particularly in the setting of recurrent or metastatic disease. Zanidatamab (ZW25) is a humanized, bispecific, immunoglobulin (Ig) G1-like antibody directed against the juxtamembrane extracellular domain (ECD4) and the dimerization domain (ECD2) of human epidermal growth factor receptor 2 (HER2), the same domains targeted by trastuzumab (T) and pertuzumab (P), respectively. Data from the ongoing phase 1 study (NCT02892123) demonstrate that zanidatamab is well tolerated and has single agent activity in patients with advanced HER2-expressing cancers that have progressed after standard of care (SOC) therapies, including HER2-targeted agents such as T, P, and trastuzumab emtansine.1,2 We have previously shown that the unique design and bispecific binding of zanidatamab results in multiple mechanisms of action including increased antibody binding density, potent effector function, improved receptor internalization and HER2 downregulation relative to T.3 To better understand the mechanism by which zanidatamab differentiates itself from T, P and T+P, we recently expanded our mechanistic evaluations including cell surface HER2 aggregation, complement-dependant cytotoxicity (CDC) and inhibition of both tumor cell growth and intracellular signaling. Single molecule-sensitive direct stochastic optical reconstruction microscopy (dSTORM) was used to map HER2 receptor distribution and quantitate the size, density, and frequency of receptor clusters induced by antibody binding. In vitro assessments were performed in a panel of HER2-expressing cell lines using standard assays including CDC with human complement serum and inhibition of both tumor cell growth and intracellular signaling. Using dSTORM, we observed that zanidatamab binding resulted in enhanced HER2 aggregation and distinct HER2 capping on the tumor cell surface compared to T, P or T+P. Evaluation of CDC activity in HER2-overexpressing tumor cells demonstrated that zanidatamab, but not T, P or T+P, elicited CDC suggesting that the enhanced HER2 aggregation and capping on the tumor cell surface provides high avidity docking sites to which C1 binds and is activated. Zanidatamab showed further differentiation in the inhibition of both tumor growth and intracellular signaling of HER2-overexpressing cells compared to T, P and T+P. Zanidatamab has novel cell surface binding and additional mechanisms of action compared to T, P and T+P. Zanidatamab is actively being evaluated in clinical trials in multiple HER2-expressing solid tumors, including a registration-enabling clinical trial in HER2 gene amplified biliary tract cancer (NCT04466891). Citation Format: Nina E. Weisser, Grant Wickman, Libin Abraham, Jason O'Toole, Bryant Harbourne, Joy Guedia, Chi Wing Cheng, Peter Chan, Duncan Browman, Michael R. Gold, Neil Josephson, Surjit Dixit, Gerry Rowse. The bispecific antibody zanidatamab's (ZW25's) unique mechanisms of action and durable anti-tumor activity in HER2-expressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1005.

Abstract 337: p16INK4A-deficiency predicts for response to combined HER2 and CDK4/6 inhibition in HER2+ breast cancer brain metastases

Abstract Approximately 50% of patients with metastatic HER2-positive (HER2+) breast cancer develop brain metastases (BCBMs). To identify predictors of response and resistance to brain-penetrant, small molecule targeted therapies, we performed whole exome sequencing, RNAseq and quantitative immunohistochemistry of HER2+ BCBM tissues from 21 patients. We found that the tumor suppressor p16INK4A (p16) was deficient in the majority of HER2+ BCBMs. Orthotopic HER2+ BCBM patient-derived xenograft (PDX) models with p16 deficiency were resistant to the brain-penetrant HER2 inhibitor, tucatinib or the brain penetrant CDK4/6 inhibitor, abemaciclib, when used as single agents. However, p16-deficiency predicted response to combined tucatinib and abemaciclib in orthotopic HER2+ BCBM PDX models. These data establish the rationale for a biomarker-driven clinical trial of combined CDK4/6- and HER2-targeted agents for patients with HER2+ BCBM. Citation Format: Jing Ni, Sheheryar Kabraji, Shaozhen Xie, Yanzhi Wang, Peichen Pan, Xiaofang He, Zongming Liu, Henry Long, Myles Brown, Eric P. Winer, Deborah Dillon, Nancy Lin, Jean Zhao. p16INK4A-deficiency predicts for response to combined HER2 and CDK4/6 inhibition in HER2+ breast cancer brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 337.

Abstract 1401: MYC mediates retinoic acid resistance by suppressing cellular retinoic acid-binding protein (CRABP2) transcription in HER2-enriched breast cancers

Abstract Introduction: HER2-positive (HER2+) breast cancers express high levels of the growth-promoting HER2 protein. The development of a targeted drug, trastuzumab, has greatly improved clinical outcome for HER2+ patients. However, intrinsic and acquired resistance to trastuzumab are common. Clearly, additional therapeutic interventions are required for the clinical management of HER2-enriched breast cancers. Retinoic acid (RA) is a vital signaling molecule that regulates multiple biological processes, including cell proliferation, differentiation, and death. RA has been successfully used in the treatment of acute promyelocytic leukemia. RA also holds promise for the treatment of solid cancers like breast cancer. RA action is mediated through transcription factor RARα and the RA binding protein CRABP2, which deliver RA to RARα in the nucleus. The HER2 gene (ERBB2) is frequently co-amplified with the gene encoding RARα, a key determinant of RA sensitivity. It seems surprising, therefore, that HER2+ breast cancers are refractory to RA treatment. MYC is an oncogene that inhibits RARα activity in leukemia cells. Importantly, MYC is preferentially amplified and overexpressed in HER2+ breast cancers. My research aims to elucidate the mechanism underlying RA resistance in HER2+ breast cancers, with a special focus on the role of MYC. Hypothesis: MYC attenuates RA action by inhibiting the CRABP2-RARα pathway. Results: RNA levels of MYC are negatively correlated with CRABP2 RNA levels. Depletion of MYC upregulates CRABP2 at both the RNA and protein levels. Furthermore, we found that MYC binds to the CRABP2 promoter region suggesting that MYC may directly suppress CRABP2 gene transcription activity. Our results show that ectopic expression of MYC inhibits, whereas depletion of MYC activates RAR activity. Consistently, ectopic expression of MYC increases RA resistance, whereas depletion of MYC sensitizes cells to RA treatment. When CRABP2 is depleted along with MYC-knockdown, cell proliferation is rescued, suggesting that MYC mediates RA resistance, at least partially through downregulation of CRABP2. We also found that RA treatment enhances trastuzumab responsiveness in HER2+ breast cancer cells. Significance: This study sheds light on the role and mechanism of MYC in governing RA resistance in HER2+ breast cancer cells. Our results support the use of RA and trastuzumab for the treatment of subsets of patients with HER2+/low MYC breast cancers. Citation Format: Won-Shik Choi, Rong-Zong Liu, Roseline Godbout. MYC mediates retinoic acid resistance by suppressing cellular retinoic acid-binding protein (CRABP2) transcription in HER2-enriched breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1401.

Population pharmacokinetic and exploratory exposure\u2013response analysis of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer in the FeDeriCa study

PurposeTo characterize pertuzumab pharmacokinetics (PK) in FeDeriCa (NCT03493854: fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] versus intravenous pertuzumab plus trastuzumab); derive individual pertuzumab exposures in the PH FDC SC arm for subsequent pertuzumab exposure–response (ER) analyses; compare observed trastuzumab PK with predicted exposures from a previous SC trastuzumab model; assess whether pertuzumab affects trastuzumab PK; evaluate pertuzumab exposure–efficacy and –safety relationships and support the approved SC dosing regimen.MethodsPopulation pharmacokinetic modeling and simulations were used to describe the data. Standard goodness-of-fit diagnostics and prediction-corrected visual predictive checks were used for model performance assessment. Covariates were included from previously reported models. ER analysis was conducted using logistic regression.ResultsSC pertuzumab PK was described adequately by a two-compartment model with first-order absorption; significant covariates included in the final model were albumin, lean body weight, and Asian region; however, these appeared not to be clinically relevant. Trastuzumab concentrations were described adequately by the previous model; there was no evidence of a pertuzumab effect on trastuzumab PK as part of PH FDC SC and higher model-predicted pertuzumab exposure was not associated with differences in pathologic complete response rate or an increased probability of selected grade ≥ 3 adverse events of interest.ConclusionThe approved PH FDC SC dose [loading: 1200/600 mg pertuzumab/trastuzumab (15 mL); maintenance: 600 mg pertuzumab/trastuzumab (10 mL) and 2000 U/mL recombinant human hyaluronidase every 3 weeks] provides a positive benefit–risk profile with comparable efficacy and safety to intravenous pertuzumab plus trastuzumab.

Phase I study of LZM005, a HER2 antibody, as monotherapy or in combination with trastuzumab and docetaxel in patients with HER2-positive metastatic breast cancer.

1042 Background: LZM005 is a novel anti-HER2 antibody that binds with elevated affinity to the domain II of HER2. This phase I study assessed the safety, tolerability, pharmacokinetics (PK) and activity of LZM005, as monotherapy or combined with trastuzumab and docetaxel in patients with HER2-positive metastatic breast cancer. Methods: The phase I trial included phase Ia and Ib. Phase Ia was the monotherapy dosage escalation design. LZM005 was administered intravenously with 5mg/kg, 10mg/kg, 15mg/kg and 20mg/kg. The endpoints were dose limited toxicity (DLT) and maximum-tolerated dose (MTD), safety, tolerability and PK analysis. In phase Ib, LZM005 was combined with trastuzumab and docetaxel with MTD. The endpoints included safety and tolerability, response, PK and biomarker analysis. Results: From Jan 2017 to Feb 2020, 35 patients received LZM005 (15 monotherapy, 20 combination). No DLT was observed from 5mg/kg to 20mg/kg. In phase Ib two arms were set: 420mg arm and 525mg arm. The pharmacokinetics of LZM005 were similar to pertuzumab (Table). Common adverse events included increased transaminases, diarrhea and anemia in monotherapy and combination therapy. The common AE in phase Ia trial included diarrhea (21.4%), anemia (14.3%), elevated transaminase (14.3%). The common AE in phase Ib trial included anemia (44.1%), diarrhea (41.2%), fatigue (26.5%), elevated transaminases (23.5%), nausea (20.6%), rash (17.6%) and asymptomatic urinary tract infection (11.7%). All adverse events were manageable. No treatment-related death occurred. The clinical benefit rate and objective response rate was respectively 42.90% (6/14) and 7.14% (1/14) with monotherapy, with combination cohort was 100% (8/8) and 62.5% (5/8) in trastuzumab-naive, 83.3% (11/12) and 41.7% (5/12) in trastuzumab-pretreated patients. The median progression free survival was 22.5 weeks. Conclusions: LZM005 was well tolerated and showed potent activity in patients with HER2-positive metastatic breast cancer. Further evaluation was warranted. Clinical trial information: CTR20191921 .[Table: see text]

Potential non-drug cost differences associated with the use of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC) in the treatment of HER2-positive early breast cancer patients in Western Europe and the United States.

544 Background: In patients with HER2-positive early breast cancer (BC), pertuzumab (P) added to trastuzumab (T) and chemotherapy has been recognized as a standard-of-care, improving the risk of recurrence. P and T treatments can be given intravenously (PT IV) or, more recently, subcutaneously − via PH FDC SC. Both methods are comparable in terms of efficacy and safety profiles. However, PH FDC SC allows for a faster infusion than that of PT IV, and this can be associated with lower costs. The aim of this study is to estimate the incremental difference in non-drug costs between PH FDC SC and PT IV for a typical patient receiving treatment for HER2-positive early BC in Western Europe and the United States. Methods: A model-based cost-minimization analysis was performed to quantify mean non-drug cost differences per patient over a full course of therapy (18 cycles). Western Europe: costs in the analysis are based on an archetypal country, and explicitly include estimates for costs for patient chair time, active healthcare professional (HCP) time, usage of non-drug consumables, port-a-cath placement surgeries and patients’ productivity losses. Costs are calculated by multiplying the resource use by its corresponding unit price. Costing data were obtained from literature sources on T SC time and cost savings for Western European countries, and assumptions on PH FDC SC and PT IV times and costs. United States: non-drug costs for the two strategies were estimated using average net reimbursement amounts for relevant procedure codes for intravenous and SC therapy administration among commercial payers in the MarketScan databases. Results: PH FDC SC is estimated to reduce non-drug costs by 73% − 80% in Western Europe, and 75% in the United States. Total monetary non-drug savings per patient over 18 cycles of treatment are estimated in the range of €2,474 − €8,975 in Western Europe, and at $10,138 in the United States. In Western Europe, where the analysis allows for a disaggregation by cost category, cost savings related to savings in patient chair time (excluding patients’ productivity losses) are estimated to account for up to 62% of overall non-drug cost savings. Patients’ productivity losses are estimated to explain up to 11% of non-drug cost differences. Conclusions: The use of PH FDC SC for the treatment of HER2-positive BC can potentially result in substantial non-drug cost savings. These savings could easily derive in overall net cost savings to the healthcare system, contributing to the long-term sustainability of the healthcare spending, while still providing a safe and effective therapy.[Table: see text]

A phase II trial of trastuzumab plus modified-FOLFOX for gemcitabine/cisplatin refractory HER2-positive biliary tract cancer (BTC): Multi-institutional study of the Korean Cancer Study Group (KCSG-HB19-14).

TPS4161 Background: Biliary tract cancer (BTC), one of the most fatal cancers with limited treatment options, is generally rare in most high-income countries, but is relatively prevalent in South Korea. Recent genomic profilings have provided druggable molecular targets including HER2 amplification, which accounts for about 15% of total BTC patients. Trastuzumab is a humanized monoclonal antibody against HER2 with known efficacy in patients with HER2-positive breast and gastric cancer, and has not been tested prospectively in patients with HER2-positive BTC. The modified-FOLFOX regimen is currently being tested as a second-line therapy of BTC in phase III ABC-06 trial. This phase II study is investigating the combination of trastuzumab and modified-FOLFOX as second- or third-line treatment in HER2-postivie BTC. Methods: This study (KCSG-HB19-14; NCT04722133) is a phase II, multi-institutional, single arm trial to evaluate the efficacy and safety of trastuzumab plus modified-FOLFOX in gemcitabine/cisplatin refractory patients with HER2-positive BTC. The main inclusion criteria are HER2-positive (defined as IHC3+, or IHC2+/ISH+; ISH+ defined as HER2/CEP17 ≥2.0, or ERBB2 gene copy number ≥ 6.0 by NGS) BTC (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer and ampulla of vater cancer) patients who progressed on gemcitabine/cisplatin containing chemotherapy (one or two previous cytotoxic chemotherapy lines permitted), ECOG 0 or 1, and adequate organ function. Patients receive trastuzumab-pkrb 4mg/kg (after 6mg/kg load) D1, oxaliplatin 85mg/m2 D1, leucovorin 200mg/m2 D1, 5-FU 400mg/m2 bolus D1, and 5-FU 2400mg/m2 infusion D1-2 every 2 weeks until unacceptable toxicities or disease progression. The study has a Simon's two-stage design, with objective response rate (ORR) per RECIST v1.1 as primary endpoint. Secondary endpoints included progression-free survival, disease control rate, overall survival, safety, quality of life and correlative biomarker exploration. Additional patients were to be recruited if pre-specified thresholds for ORR are met at the first stage. The study will enroll up to 34 patients and is currently recruiting at eight sites in South Korea. As of February 2021, 16 patients have been enrolled. The pre-specified activity goal for the first stage of accrual was met; second stage accrual began in February 2021. Clinical trial information: NCT04722133.

Risk for SARS-CoV-2 infection in patients with breast cancer treated with chemotherapy, biologic therapy or active surveillance: Patient outcomes from multicenter institution in New York.

1513 Background: In high-risk estrogen-receptor positive, HER2 positive, or triple negative breast cancer (BC), chemotherapy can increase cure rates in early-stage disease and prolong survival in setting of advanced disease. Real world data specific to BC is needed to counsel patients (pts) with BC on their risk for SARS-CoV-2 infection and mortality in the context of the SARS-CoV-2 pandemic. Methods: In this retrospective study, we abstracted clinical data including demographics, tumor histology, cancer treatment, and COVID-19 testing results status from the electronic medical record of 3778 BC patients who received cancer care from 02/01/2020 – 05/01/2020 in New York City at our cancer center. The primary endpoint of the study was incidence of SARS-CoV-2 infection by treatment type (cytotoxic chemotherapy (CT) vs non-cytotoxic therapies (endocrine and/or HER2 directed therapy (E/H)) diagnosed by either serology, RT-PCR, or documented clinical diagnosis. Probability of Treatment Weighting (IPTW) and Mann-Whitney Test were used to assess risk of SARS-CoV-2 infection by treatment and assess outcomes based on oncologic and non-oncologic risk factors respectively. Results: 3062 patients met inclusion criteria with 379 pts in CT, 2343 pts in E/H and 340 in NT groups. During study period 641 patients (20.9%) were tested by either PCR or serology with 64 patients (2.1%) diagnosed with COVID-19. All pts who tested positive by PCR and subsequently had serology testing were positive for IgG. The weighted risk of SARS-COV-2 infection was 3.5% in CT vs. 2.7% in E/H (p=0.523). 27 patients (0.9%) expired over follow up, with 10 deaths attributed to SARS-CoV-2 infection. The weighted risk for death was 0.7% with CT vs. 0.1% with E/H, p=0.24 (Table A). Age, BMI,CCI and advanced cancer stage were associated with increased mortality following SARS-CoV-2 infection (Table). Conclusions: CT was not associated with increased risk of infection with SARS-CoV-2 infection or death following infection. BC cancer treatment, including CT, can be safely administered with enhanced infectious precautions and should not be withheld particularly when given for curative intent.[Table: see text]

Phase II prospective open label study of neoadjuvant pertuzumab, trastuzumab, and nab-paclitaxel in patients with HER-2 positive advanced breast cancer.

583 Background: HER2 overexpression occurs in 20-25% of breast cancers (BC) and is associated with poor prognosis. The addition of trastuzumab (trast) to chemotherapy significantly improves disease-free (DFS) and overall survival (OS) in the adjuvant setting. Pertuzumab (pert) inhibits ligand-activated signaling and in combination with trast has synergistic inhibition of BC cells overexpressing HER2. In the neoadjuvant therapy (NT) setting, the combination of trast, pert, and docetaxel can improve the pCR rate. PCR may predict for improved DFS and OS. De-escalation with weekly paclitaxel combined with trast and pert appeared to be safe and efficacious but requires steroid premedication, whereas nab-paclitaxel (nab) does not require steroid premedication. To decrease treatment-associated toxicity in patients with HER2+ BC, we utilized a non-anthracycline regimen with pert, trast, and nab as NT. The objectives of this study were to evaluate the safety and efficacy of pert added to trast and nab in HER2+ locally advanced BC (LABC) to determine the pCR, as well as DFS and OS. Methods: A total of 45 patients with biopsy-confirmed HER2+ LABC or inflammatory BC were enrolled from 2013-2017, and were treated with 6 cycles of neoadjuvant pert (840 mg loading dose, then 420 mg IV day 1 every 21 days), weekly trast (4 mg/kg loading dose, then 2 mg/kg), and weekly nab (100 mg/m2 IV). Patient characteristics, including age, race, menopausal status, grade, stage, and prior surgery and radiation were recorded. Median treatment cycles determined, and events (AE) were identified for each arm. PCR rate, DFS and OS were calculated. Results: Median age was 56 (31-78) years. 1/45 (2%) was stage I, 30/45 (67%) were stage II, 14/45 (31%) were stage III. pCR rate was 29/45 (64.4%). The initial primary tumor size was similar in pCR and non-pCR patients (mean 4.1 cm vs. 3.2 cm, respectively). Median follow-up was 36.1 months (95% CI [27.1, 41.8]). Median treatment cycles completed was 6 (1-6). A total of 4/45 (9%) patients had &gt;1 cycle delayed, and 32/45 (71%) patients had &gt;1 cycle modified. For the patients achieving pCR, the DFS (95% CI) at 3 years was 85.9% (66.7%, 94.4%) and for those without pCR, it was 87.5% (58.6%, 96.7%). OS was not reached (95% CI [NR, NR]). Grade 3 AEs (&gt; 2 patients) included 7/45 (16%) of patients with hypertension; 4/45 (9%) with anemia; and 2/45 (4%) with diarrhea, ALT, fatigue, or rash. Conclusions: This anthracycline-free regimen which included nab achieved great pCR rate of 64.4% in HER2+ BC patients with fewer treatment-related toxicities. The pCR rate is comparable with docetaxel, carboplatin, trast, and pert (TCHP) therapy in NT setting, but without the treatment-associated toxicities. This suggests we may be able to safely avoid anthracyclines and carboplatin for NT in HER2+ BC patients. The improved pCR did not translate into DFS benefit. Clinical trial information: NCT01730833.

Clinical outcomes in HER2-positive and triple-negative breast cancer: Assessing racial disparities.

e18624 Background: Triple negative breast cancer (TNBC) &amp; HER2 positive breast cancer (Her2BC), are aggressive breast cancer subtypes. Both are associated with higher mortality in Non-Hispanic Black (NHB) compared to Non-Hispanic White women (NHW). Factors attributed to this racial disparity include socioeconomic status, insurance status, diagnosis(dx)/ treatment delays &amp; comorbidities. We examined the association between race &amp; clinical outcomes (pathological complete response, pCR; recurrence free survival, RFS &amp; overall survival, OS) in patients (pts) dxed with TNBC/Her2BC treated with neoadjuvant chemotherapy (NAC) at Roswell Park Comprehensive Cancer Center. Methods: Pts dxed with Stage I-III TNBC/Her2BC who received NAC from 2000-2018 were included. pCR was defined as absence of residual invasive cancer in the breast &amp; lymph nodes after NAC. Association of race with pCR &amp; survival outcomes was evaluated using logistic &amp; Cox regression models, respectively. Multivariate (MV) models were used to evaluate the association between race &amp; pCR or survival while controlling for relevant confounders including age, BMI, insurance, comorbidities, clinical stage, grade &amp; time from dx to chemotherapy(chemo)/surgery. Analysis was conducted using SAS v9.4 at a significance level of 0.05. Results: 174 TNBC (49 NHB, 125 NHW) &amp; 80 Her2BC (13 NHB, 67 NHW) pts were analyzed. Among TNBC pts, NHB pts had higher baseline BMI(34.3 vs 28.6 kg/m2; p&lt;0.001), higher incidence of hypertension (HTN) (45% vs. 24%; p&lt;0.01), diabetes mellitus (20% vs 8%; p&lt;0.05) &amp; higher Medicare/Medicaid use (M/M) (55% vs. 28%; p&lt;0.01). Among Her2BC pts, NHB pts had higher incidence of HTN (54% vs 25%; p&lt;0.05). There was no statistically significant difference in mean chemo relative dose intensity by race. Among TNBC pts, those with pCR were younger (47 vs 53 yrs; p=0.002) &amp; had more grade 3 tumors (96% vs 80.5%; p&lt;0.05) at dx compared to pts without pCR. Similarly, among Her2BC pts, those with pCR had more grade 3 tumors (64% vs 36%; p&lt;0.05) at dx compared to pts without pCR. Among TNBC pts, advanced age, higher clinical stage &amp; longer time from dx to surgery were associated with worse RFS &amp; OS (p&lt;0.05). Among Her2BC pts, M/M use &amp; advanced clinical stage were associated with worse RFS &amp; OS (p&lt;0.05). There were no significant associations between race &amp; pCR/RFS/OS on MV analysis (table below). Conclusions: Similar outcomes were noted between races for TNBC/Her2BC pts treated at a single academic center in Buffalo, NY. Given the known genetic diversity of African American ancestry in the US, further studies investigating the interplay between race, geography &amp; clinical outcomes are warranted.[Table: see text]

Phase Ib/II study of capecitabine 7/7 schedule with neratinib in patients with HER2-positive metastatic breast cancer (MBC).

e15016 Background: Neratinib (N) is a potent irreversible inhibitor of HER1, HER2, and HER4. Capecitabine (X) at optimal dose of 7 days on and 7 days off schedule (7/7) is well-tolerated with low rates of ≥ grade (G3) diarrhea. Methods: We conducted phase Ib/II study of N with X (7/7) with loperamide and colestipol prophylaxis in patients (pts) with pretreated HER2+ MBC (NCT03377387). Eligible pts had normal left ventricular ejection fraction (≥ 50%), any and &lt; 4 prior chemotherapy-based treatments in phase Ib and II, respectively. Primary endpoint of phase Ib is maximum tolerated dose (MTD) and phase II is response rate. Secondary endpoints are safety, tolerability, and progression-free survival. Exploratory endpoint is to quantify cell-free DNA (cfDNA), correlating with response. Phase Ib follows traditional 3+3 design with 4 dose levels. In phase II, if &gt; 3/9 respond, study is expanded to 24. If &gt; 10/24 respond, study is deemed successful. Results: As of 2-4-2021, 10 pts were enrolled in phase Ib. 4 pts were treated at dose level 1 (X at 1500 mg BID at 7/7 and N at 240 mg daily); 2/4 pts experienced with G3 diarrhea during cycle 1. Six pts were treated at dose level -1 (X at 1000 mg BID 7/7 and N at 240 mg daily); 1 (17%) developed G3 diarrhea. The MTD is X at 1000 mg BID 7/7 and N at 240 mg daily. Twenty-two of 24 pts have been enrolled in phase II. Of 22 pts, data show 6 with partial response, 8 with stable disease, 3 with progressive disease, and 5 have not been assessed radiographically. Overall, 6/22 (27.3%) and 1/22 (4.5%) had all G and G3 diarrhea, respectively. Other significant toxicities at MTD included G2 hand foot syndrome (n = 1, 4.5%), G1 fatigue (n = 1, 4.5%) and G1 nausea (n = 4, 18%). Conclusions: The MTD is X at 1000 mg BID at 7/7 and N at 240 mg daily. This combination is safe and well tolerated with G3 diarrhea rate of 4.5%, which is significantly lower than the X 14/7 schedule in NALA study. The phase II portion of the study is near completion and updated result will be presented. Analysis of cfDNA, to correlate with response for phase II portion, is ongoing. Clinical trial information: NCT03377387.