anti-HER2 Monoclonal Antibody Research Articles

Dose-finding and -expansion studies of trastuzumab deruxtecan in combination with other anti-cancer agents in patients (pts) with advanced/metastatic HER2+ (DESTINY-Breast07 [DB-07]) and HER2-low (DESTINY-Breast08 [DB-08]) breast cancer (BC).

3025 Background: Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate composed of a humanized anti-HER2 monoclonal antibody and a topoisomerase I inhibitor payload, is approved for pts with unresectable or metastatic HER2+ BC with ≥2 prior anti-HER2–based therapies. T-DXd showed improved progression-free survival vs trastuzumab emtansine (T-DM1) as an earlier-line treatment (tx) for pts with HER2+ metastatic BC in the phase 3 DESTINY-Breast03 trial (Cortes J, et al. Ann Oncol. 2021;32:S1283-S1346. Abstract LBA1). Preliminary antitumor activity of T-DXd was shown in heavily pretreated pts with HER2-low advanced/metastatic BC in the phase 1 DS8201-A-J101 trial (Modi S, et al. J Clin Oncol. 2020;38:1887-1896). We report preliminary results from the dose-finding phase of 2 trials investigating T-DXd combination tx in HER2+ or HER2-low metastatic BC. Methods: DB-07 (phase 1b/2; NCT04538742) and DB-08 (phase 1b; NCT04556773) are 2-part, modular, open-label, multicenter trials of T-DXd combined with other anticancer tx in pts with advanced/metastatic BC that is HER2+ (DB-07) or HER2 low (DB-08). Part 1 of each study is an ongoing dose-finding phase; pts must have ≥1 prior tx for metastatic BC. Part 2 of each study is a dose-expansion phase; pts must have no (DB-07) or ≤1 (DB-08) prior tx for metastatic BC. We report preliminary results from the T-DXd + pertuzumab module of DB-07 part 1 (data cutoff: Oct 15, 2021) and T-DXd + anastrozole and T-DXd + fulvestrant modules of DB-08 part 1 (data cutoff: Sep 27, 2021); pts in the DB-08 modules must be hormone receptor positive. The part 1 primary objective was to assess safety and tolerability and determine the recommended phase 2 dose (RP2D) according to the modified toxicity probability interval-2 algorithm. Pts were followed up beyond the 21-day dose-limiting toxicity (DLT) period (28 days for T-DXd + fulvestrant) for safety events. Results: In DB-07, 7 pts were enrolled and received T-DXd 5.4 mg/kg + pertuzumab 420 mg (loading dose: 840 mg) every 3 wk (q3w; not evaluable for DLTs, n = 1). In DB-08, 6 pts were enrolled and received T-DXd 5.4 mg/kg q3w + anastrozole 1 mg daily (not evaluable for DLTs, n = 1); another 6 pts were enrolled and received T-DXd 5.4 mg/kg q3w + fulvestrant 500 mg every 4 wk (loading dose: 500 mg cycle 1 days 1 and 15). For all 3 modules, no DLTs were reported in any DLT-evaluable pts; the dose levels used in part 1 were approved to be the RP2Ds for use in the dose-expansion part of each corresponding module. No deaths on study or cases of interstitial lung disease/pneumonitis were reported to date. Conclusions: The RP2Ds for the T-DXd combinations were the standard doses for BC of each individual drug. These studies are ongoing, with additional T-DXd combinations being evaluated and further follow-up underway. Clinical trial information: NCT04538742; NCT04556773.

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing unresectable or recurrent biliary tract cancer (BTC): An investigator-initiated multicenter phase 2 study (HERB trial).

4006 Background: BTCs have an aggressive tumor biology with limited treatment options. With a HER2-positivity rate of 5–20% in BTCs, case series and small clinical trials have shown signs of activity for HER2 blockade in these pts. T-DXd is an antibody-drug conjugate composed of a humanized monoclonal anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor. The HERB trial is an investigator-initiated, multicenter, single-arm phase 2 trial of T-DXd in pts with HER2-expressing BTCs. Methods: Centrally confirmed HER2-expressing (HER2-positive: IHC3+ or IHC2+/ISH+, and HER2-low-expressing [HER2-low]: IHC/ISH status of 0/+, 1+/-, 1+/+, or 2+/-) pts with BTCs who were refractory or intolerant to gemcitabine containing regimen received 5.4 mg/kg of T-DXd every 3 weeks. The primary endpoint was the confirmed objective response rate (ORR) in HER2-positive pts by independent central review. The sample size of 22 had 80% power with one-sided alpha error of 5%; threshold ORR, 15%; and expected ORR, 40%. The ORR, disease control rate (DCR), progression-free survival (PFS), overall survival (OS) in HER2-positive/-low pts, and incidence of treatment-emergent adverse events (TEAEs) were assessed as secondary endpoints. Results: A total of 32 pts, 24 with HER2-positive and 8 with HER2-low BTCs, received T-DXd. Twenty-two pts with HER2-positive, excluding 2 ineligible pts, were identified for primary efficacy analysis. Among the 22 pts, IHC3+ and IHC2+/ISH+ were 45.5% and 54.5%, primary sites: gallbladder/extrahepatic/intrahepatic/Vater were 11/6/3/2, median number of prior regimens was 2 (range, 1–4). The confirmed ORR in HER2-positive pts was 36.4% (8/22; 2 CR and 6 PR; 90% CI, 19.6–56.1), indicating statistically significant improvement in ORR (P = 0.01). The DCR, median (m) PFS, mOS were 81.8% (95% CI, 59.7–94.8), 4.4 months (mo) (95% CI, 2.8–8.3), 7.1 mo (95% CI, 4.7–14.6), respectively. In addition, encouraging efficacy were seen even in HER2-low pts; ORR, DCR, mPFS, and mOS were 12.5% (1/8; 1 PR; 95% CI, 0.3–52.7), 75.0% (95% CI, 34.9–96.8), 4.2 mo (95% CI, 1.3–6.2), and 8.9 mo (95% CI, 3.0–12.8), respectively. In the safety analysis set (n = 32), TEAEs of > = grade (G) 3 occurred in 81.3% (26/32); the common TEAEs were anemia (53.1%), neutropenia (31.3%), and leukopenia (31.3%). TEAEs leading to drug discontinuation occurred in 8 pts (25.0%). Eight pts (25.0%) had interstitial lung disease (ILD; G1/G2/G3/G5 were 3/1/2/2) not adjudicated by an independent committee. Conclusions: T-DXd showed promising activity in pts with HER2-expressing BTCs. Although the safety profile was generally consistent with other T-DXd studies, ILD, an important identified risk of T-DXd, requires more careful monitoring and intervention. These results support further exploration of T-DXd in this patient population. Clinical trial information: JMA-IIA00423.

Multicenter phase II trial of trastuzumab deruxtecan for HER2-positive unresectable or recurrent biliary tract cancer: HERB trial.

Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of a humanized monoclonal anti-HER2 antibody, a cleavable tetrapeptide-based linker and a potent topoisomerase I inhibitor. The drug's efficacy has been proven in HER2-positive breast and gastric cancers. The rate of HER2 positivity in biliary tract cancer (BTC) has been reported to be 5-20%, and case reports and clinical trials have suggested that HER2 inhibitors might be active in HER2-positive BTC. Here we describe the rationale and design of the phase II HERB trial that will evaluate the efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing unresectable or recurrent BTC. The primary end point will be the centrally assessed objective response rate in HER2-positive patients.

Disitamab vedotin: a novel antibody-drug conjugates for cancer therapy

Human epidermal growth factor receptor 2 (HER2) regulates cell mitosis, proliferation, and apoptosis. Trastuzumab is a HER2-targeted monoclonal antibody (mAB), which can prolong the overall survival rate of patients with HER2 overexpression in later periods of gastric cancer and breast cancer. Although anti-HER2 monoclonal antibody has a curative effect, adjuvant chemotherapy is still necessary to upgrade the curative effect maximumly. Antibody-drug conjugate (ADC) is a kind of therapeutic drug that contains antigen-specific antibody and cytotoxic payload, which can improve the survival time of tumor patients. To date, there are several HER2-ADC products on the market, for which two anti-HER2 ADC (trastuzumab emtansine and trastuzumab deruxtecan) have been authorized by the FDA for distinct types of HER2-positive carcinoma in the breast. Disitamab vedotin (RC48) is a newly developed ADC drug targeting HER2 that is comprised of hertuzumab coupling monomethyl auristatin E (MMAE) via a cleavable linker. This paper aims to offer a general insight and summary of the mechanism of action and the currently completed and ongoing clinical studies of RC-48 in HER-2 positive solid tumors.

Listeriosis in a Metropolitan Hospital: Is Targeted Therapy a Risk Factor for Infection?

Targeted therapies are widely used for treatment of autoimmune diseases as well as solid organ and hematological malignancies. Various opportunistic infections have been described in patients on targeted therapies. Although case reports or a few case series of listeriosis have been reported to be associated with targeted therapy, most of the cases were related to anti-tumor necrosis factor-α monoclonal antibody. In this study, we describe the epidemiological and clinical profiles of listeriosis in a tertiary hospital in Shenzhen, a Southern Chinese metropolitan city in China. During the 9-year-and-6-month study period, a total of five cases of listeriosis were recorded and all of them had Listeria monocytogenes bacteremia. All five patients had predisposing factors, including corticosteroid (n = 3), targeted therapy (n = 2), pregnancy (n = 2) and anti-interferon gamma autoantibody (n = 1). The two patients who had targeted therapy during their course of cancer treatment received inhibitors of the epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) pathway. The first one was a 52-year-old woman with metastatic adenocarcinoma of the lung. She was given gefitinib (EGFR tyrosine kinase inhibitor), osimertinib (third-generation EGFR tyrosine kinase inhibitor) and afatinib (tyrosine kinase inhibitor that can bind to EGFR, HER2 and HER4). The second one was a 40-year-old woman with carcinoma of the breast with brain metastasis. She was given trastuzumab (anti-HER2 monoclonal antibody) and lapatinib (dual tyrosine kinase inhibitor of the EGFR/HER2 pathway). These two patients represent the second and third reports of listeria infections associated with EGFR/HER2 pathway inhibitors in the literature. Targeted therapy is an important predisposing factor for listeriosis. Listeria infection is an important differential diagnosis in patients on targeted therapy who present with sepsis and/or central nervous system infection, and the use of antibiotic regimens that cover listeria is crucial for empirical treatment. Avoidance of high-risk food items in these patients is important for the prevention of listeriosis.

NRG1/ERBB3/ERBB2 Axis Triggers Anchorage-Independent Growth of Basal-like/Triple-Negative Breast Cancer Cells.

Simple SummaryBreast cancer is a heterogeneous disease, categorized into distinct subgroups with different clinical prognoses and treatment strategies. This study aimed to evaluate the role of ERBB3 in different molecular subtypes of breast cancers. Despite ERBB3/HER3 and its partner ERBB2/HER2 showing low expression levels in basal-like/triple-negative breast cancers, stratification of basal-like patients according to ERBB3 mRNA expression levels highlighted a correlation between higher ERBB3 levels and shorter relapse-free patients’ survival. In vitro analyses unveiled that the activation of the NRG1/ERBB3/ERBB2 axis robustly induces anchorage-independent growth of basal-like/triple-negative breast cancer cellular models, without significant effects on cell proliferation, differentiation, and migration in adhesion. Overall, our data suggest that ERBB2/ERBB3 plays an oncogenic role in basal-like/triple-negative breast cancer patients, suggesting its neutralization as a therapeutic strategy for these breast cancer subtypes, which today have very limited treatment opportunities.ERBB3, also known as HER3, is a tyrosine kinase transmembrane receptor of the ERBB family. Upon binding to neuregulin 1 (NRG1), ERBB3 preferentially dimerizes with HER2 (ERBB2), in turn inducing aggressive features in several cancer types. The analysis of a dataset of breast cancer patients unveiled that higher ERBB3 mRNA expression correlates with shorter relapse-free survival in basal-like breast cancers, despite low ERBB3 expression in this breast cancer subtype. Administration of neuregulin 1 beta (NRG1β) significantly affected neither cellular proliferation nor the basal migratory ability of basal-like/triple-negative quasi-normal MCF10A breast cells, cultured in mono-layer conditions. Furthermore, no significant regulation in cell morphology or in the expression of basal/myoepithelial and luminal markers was observed upon stimulation with NRG1β. In non-adherent conditions, NRG1β administration to MCF10A cells did not significantly influence cell survival; however, it robustly induced cell growth as spheroids (3D growth). Intriguingly, a remarkable upregulation of ERBB3 and ERBB2 protein abundance was observed in 3D compared to 2D cell cultures, and NRG1β-induced 3D cell growth was efficiently prevented by the anti-HER2 monoclonal antibody pertuzumab. Similar results were obtained by the analysis of basal-like/triple-negative breast cancer cellular models, MDA-MB-468 and MDA-MB-231 cells, in which NRG1β induced anchorage-independent cell growth that in turn was prevented or reduced by the simultaneous administration of anti-HER2 neutralizing antibodies. Finally, the ability of pertuzumab in suppressing NRG1β-induced 3D growth was also evaluated and confirmed in MCF10A engineered with HER2-overexpression. We suggest that the NRG1/ERBB3/ERBB2 pathway promotes the anchorage-independent growth of basal-like breast cancer cells. Importantly, we provide evidence that ERBB2 neutralization, in particular by pertuzumab, robustly inhibits this process. Our results pave the way towards the development of novel anticancer strategies for basal-like breast cancer patients based on the interception of the NRG1/ERBB3/ERBB2 signaling axis.

Ultralow Limit Detection of Soluble HER2 Biomarker in Serum with a Fiber-Optic Ball-Tip Resonator Assisted by a Tilted FBG.

An optical-fiber biosensor has been developed for the detection of the breast cancer biomarker soluble human epidermal growth factor receptor-2 (sHER2). The sensor was fabricated by combining a tilted fiber Bragg grating (TFBG) with a ball resonator, allowing us to achieve an excellent sensitivity compared to other optical-fiber-based sensors. The sensor exhibits a resonance comb excited by the TFBG and the spectral profile of the ball resonator. The detection of sHER2 at extremely low concentrations was carried out by tracking the amplitude change of selected resonances. The therapeutic anti-HER2 monoclonal antibody Trastuzumab has been used to functionalize the biosensor with silane surface chemistry. The sensor features a sensitivity of 4034 dB/RIU with a limit of detection (LoD) in buffer and in a 1/10 diluted serum of 151.5 ag/mL and 3.7 pg/mL, respectively. At relatively high protein concentrations (64 ng/mL) binding to sHER (7.36 dB) as compared to control proteins (below 0.7 dB) attested the high specificity of sHER2 detection.

Potential Ameliorating Role of Spironolactone in Trastuzumab-induced Cardiotoxicity: A Narrative Review

Background: Around 20% of breast cancers (BCs) overexpress Human Epidermal Growth Factor Receptor 2 (HER-2). HER-2 overexpression is associated with increased tumor aggressiveness and poor prognosis. Trastuzumab (an anti-HER2 monoclonal antibody) has been reported to improve overall survival in early-stage and metastatic BCs, but at the expense of increasing cardiac morbidity. In the current review study, we aims to discuss the pathogenesis of trastuzumab-induced cardiotoxicity and the potential ameliorating role of spironolactone in this regard. Methods: The search strategy aimed to identify both published and unpublished studies. First off, we identified keywords and index terms, including trastuzumab, cardiotoxicity, heart failure, and spironolactone to conduct a broad search in PubMed, Embase, Scopus, and Web of Science, using the aforementioned keywords either individually or in combination. Lastly, the reference list of all identified articles was also evaluated. Our study included observational and interventional studies, case-reports, and systematic reviews and meta-analyses. Results: Trastuzumab could deteriorate mitochondrial function and subsequently leads to the accumulation of Reactive Oxygen Species (ROS) in cardiomyocytes. Published clinical studies offered conflicting results regarding the efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in respect of trastuzumab-induced cardiotoxicity. On the other hand, spironolactone was found to have both antioxidant and anti-inflammatory properties. Recent in-vivo studies supported the cardioprotective effect of spironolactone through maintaining mitochondrial ultrastructure and reducing ROS production. Conclusion: Although spironolactone mitigates oxidative stress and mitochondrial dysfunction, there is a lack of clinical evidence to support the effectiveness of spironolactone in trastuzumab-induced cardiotoxicity. Design and implementation of clinical trials are recommended to determine the potential beneficial effects of spironolactone on trastuzumab-induced cardiotoxicity.

Potential Ameliorating Role of Spironolactone in Trastuzumab-induced Cardiotoxicity: A Narrative Review

Background: Around 20% of breast cancers (BCs) overexpress Human Epidermal Growth Factor Receptor 2 (HER-2). HER-2 overexpression is associated with increased tumor aggressiveness and poor prognosis. Trastuzumab (an anti-HER2 monoclonal antibody) has been reported to improve overall survival in early-stage and metastatic BCs, but at the expense of increasing cardiac morbidity. In the current review study, we aims to discuss the pathogenesis of trastuzumab-induced cardiotoxicity and the potential ameliorating role of spironolactone in this regard. Methods: The search strategy aimed to identify both published and unpublished studies. First off, we identified keywords and index terms, including trastuzumab, cardiotoxicity, heart failure, and spironolactone to conduct a broad search in PubMed, Embase, Scopus, and Web of Science, using the aforementioned keywords either individually or in combination. Lastly, the reference list of all identified articles was also evaluated. Our study included observational and interventional studies, case-reports, and systematic reviews and meta-analyses. Results: Trastuzumab could deteriorate mitochondrial function and subsequently leads to the accumulation of Reactive Oxygen Species (ROS) in cardiomyocytes. Published clinical studies offered conflicting results regarding the efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in respect of trastuzumab-induced cardiotoxicity. On the other hand, spironolactone was found to have both antioxidant and anti-inflammatory properties. Recent in-vivo studies supported the cardioprotective effect of spironolactone through maintaining mitochondrial ultrastructure and reducing ROS production. Conclusion: Although spironolactone mitigates oxidative stress and mitochondrial dysfunction, there is a lack of clinical evidence to support the effectiveness of spironolactone in trastuzumab-induced cardiotoxicity. Design and implementation of clinical trials are recommended to determine the potential beneficial effects of spironolactone on trastuzumab-induced cardiotoxicity.

Abstract P2-13-27: Infusion-related reactions in patients receiving pertuzumab and trastuzumab: A retrospective study

Abstract BACKGROUND: The use of two anti-HER2 monoclonal antibodies (mAbs) (pertuzumab and trastuzumab) combined with taxanes is the standard of care for first line treatment in HER2-positive metastatic breast cancer (mBC). Infusion related reactions (IRR) during first administration of anti-HER2 mAb have been reported. Reintroduction of the causal drugs is often possible, but there is no data to identify patients at highest risk of developing IRR and modalities of safe reintroduction. The aim of this study was to report patients who experienced IRR during anti-HER2 mAbs infusions at Institut Curie Hospitals (ICH) and to describe these reactions. METHODS: All IRR cases must be reported to the ICH pharmacies. We retrospectively inspected the electronic record of patients who experienced an IRR during pertuzumab (Pmab) and trastuzumab (Tmab). We collected patients’ characteristics, grade of IRR and outcomes. RESULTS: From January 2013 to December 2020, a total of 223 patients had at least one Pmab+Tmab infusion as part of their BC treatment. Among them, 28 patients (8%) with anti-HER2 mAb IRR were identified. All patients but one had an HER2-positive BC; the HER2-negative case was a HER3-mutant mBC. Twelve patients (43%) had de novo mBC. Twenty-six patients (93%) received Pmab+Tmab as first line treatment for mBC. Ten patients were previously exposed to Tmab and three to Pmab+Tmab for (neo)adjuvant treatment. At IRR onset, 21 patients (75%) had liver metastasis, with more than five liver metastases for 19 of them. Fifteen patients (55%) had liver enzymes upper normal limit. IRR occurred during first anti-HER2-mAb infusion in 22 patients (79%) despite pre-treatment with antihistaminic and/or glucosteroids for taxanes. The other IRR were reported at the 2nd, 5th, 6th, 8th and > 10th cycle of Pmab+Tmab. Sixteen IRR (57%) were attributed to Pmab infusion, 9 (32%) to Tmab infusion and 3 (11%) to Tmab and/or Pmab. Al IRR were declared to the pharmacovigilance agency. Majority of reactions were mild to moderate (54% of grade 2). Most frequent symptoms associated with IRR were: thrills (68%), hyperthermia (64%); low oxygen saturation (36%), pain (25%), hypotension (21%), cutaneous (18%) and digestive (18%) reaction. Three patients were transferred to ICU. One death was attributed to anti-HER2 mAb IRR (death was attributed to respiratory distress during the first Tmab infusion). Reintroduction off Pmab+Tmab was performed in 18 patients, after pre-treatment with antihistaminic and/or glucosteroids and with vital function monitoring in conventional hospitalization. No recurrence of IRR was observed in 15/18 patients. For the 3 patients with recurrent IRR, symptoms were mild to moderate. Objective response to anti-HER2 treatments was observed in twenty three patients (82%; 8 complete responses; 15 partial responses). Median PFS was 16 months. CONCLUSIONS: Most anti-Her2-mAb IRR occurs during first infusion, are mild to moderate and do not require a transfer in ICU. Our study suggests that patients with high liver burden might be over-represented among those experiencing an IRR. Reintroduction of Pmab+Tmab was safe in most patients, allowing the continuation of the anti-HER2 dual blockade. Citation Format: Delphine Loirat, Juliette Logeart, Pauline Vaflard, Aurélien Noret, Mathilde Saint-Ghislain, Edith Borcoman, Audrey Hurgon, Cyrille Cros, Thomas Genevee, Audrey Bellesoeur, Francesco Ricci, Florence Lerebours, Laurence Escalup, Marie-Paule Sablin, François-Clément Bidard, Paul H. Cottu, Jean-Yves Pierga. Infusion-related reactions in patients receiving pertuzumab and trastuzumab: A retrospective study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-27.

Abstract P2-08-09: Investigation of autoantibodies (AAbs) in HER2+ breast cancer (BC) patients treated in the neo-adjuvant setting

Abstract Background: HER2+ breast cancer is treated with anti-HER2 IgG monoclonal antibody therapies such as trastuzumab and pertuzumab. These antibodies inhibit HER2-driven intracellular signaling and can also be described as a form of passive immunotherapy, engaging effector immune cells in antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP). Tumor-associated autoantibodies (AAbs) to tumor neo-antigens can be generated by the adaptive immune response before, or in response to, therapy. There is growing evidence of a functional role for tumor-associated AAbs in the immune response to tumors, with IgG and IgA AAbs capable of mediating ADCC and ADCP. Using the innovative Nucleic Acid-Programmable Protein Array (NAPPA) platform we examined the levels and targets of circulating AAbs to ~1700 human proteins before, during and after treatment in HER2+ breast cancer treated in the neo-adjuvant setting. . Methods: Pre-treatment, On-treatment (pre- Cycle 2) and Post-treatment (post-Cycle 6) serum samples were obtained from HER2+ breast cancer patients (n=19) treated on the ICORG 10-05 clinical trial. Patients were treated with neo-adjuvant chemotherapy (docetaxel (T)/carboplatin (C)) +/- trastuzumab (H), lapatinib (L) or HL, TCH n=9, TCHL n= 7, TCL n=3. Patients were classified as having a pathological complete response (pCR, n=6), a partial response (PR, n=6) or a non-response (NR, n=7) to treatment. IgG and IgA autoantibody levels were determined using the HD-NAPPA system, focussing on a subset of ~ 1700 human protein targets. A normalised intensity score of &gt 5 was utilised as a cut-off for detection. Results: 92 IgG AAbs and 29 IgA AAbs were detected in all samples, across all timepoints (n=57). When IgG AAbs were divided by patient response, 26 AAbs unique to pCR, 26 AAbs unique to PR and 16 AAbs unique to NR were detected. 5 IgG AAbs (BCL11B, MAP6, PRDM8, SYTL2, TP53BP2) were common to all HER2+ breast cancer patients. When IgA AAbs were divided by patient response, 11 AAbs unique to pCR, 6 AAbs unique to PR and 7 AAbs unique to NR were detected. 2 IgA AAbs (TDP1 and MAP6) were common to all HER2+ breast cancer patients. Treatment-induced AAbs were detected in On-treatment and Post- treatment samples in 16/19 patients examined. Conclusions: Our results suggest HER2+ BC patients have unique circulating AAbs associated with treatment response and AAb levels change in response to treatment. Further investigation of AAb levels as biomarkers of response in HER2+ BC is warranted in a larger cohort of patients. Citation Format: Denis Martin Collins, Ji Qiu, Jaine Blayney, Nuala McCabe, Richard Kennedy, Joshua LaBaer, John Crown. Investigation of autoantibodies (AAbs) in HER2+ breast cancer (BC) patients treated in the neo-adjuvant setting [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-08-09.

Abstract P4-01-12: Short-term trastuzumab treatment increases oncogenic fitness in HER2 overexpressing breast cancer models

Abstract Overexpression of Human EGF Receptor 2 (HER2) is found in up to 20% of primary invasive breast cancers and is a marker of aggressive metastatic disease and poor prognosis. HER2 is a member of the transmembrane tyrosine kinase receptors family which includes EGFR (HER1), HER3 and HER4. Phosphorylation of tyrosine residues in the cytoplasmic domain upon homo- or heterodimerization results in stimulation of cellular proliferation, migration, angiogenesis, and inhibition of apoptosis. HER2 is deemed a preferred heterodimer partner and presents an excellent target for personalized medicine. Anti-HER2 monoclonal antibody trastuzumab (TZM) has been used in the clinic over the last decades and it is considered as one of the most successful targeted anti-cancer therapies. However, a large fraction of eligible patients displays either primary or acquired resistance to TZM treatment. In this study, we report that even relatively short 24h TZM exposure (TZM-priming) of AU565 HER2-overexpressing breast cancer cells results in rapid and profound alterations in HER receptors’ expression level and signaling, as well as upregulation of markers associated with drug resistance. We provide several lines of evidence to support this claim: Firstly, Western blot analysis of both monolayer AU565 cells incubated in the presence or absence of 20 μg/mL TZM (TZM priming) or human IgG (control), as well as of liquid overlay AU565 spheroids generated from TZM-primed or control cells, consistently shows significant increase of HER3 and pHER2 levels in the TZM-primed samples. Secondly, immunofluorescent analysis strongly indicates that TZM priming substantially upregulates HER3 and pHER2 levels both in 2D and 3D (spheroids) models. Importantly, this process is accompanied by rearrangement of endocytic markers Rab4, CD63, Sorl1 as well as Extra domain B fibronectin, found at the cells’ surface together with HER2 and HER3 upon TZM priming. A similar trend was also found in HER2-overexpressing ovarian cancer cells SKOV-3 subjected to short-term TZM treatment. Furthermore, spheroids made with TZM-primed AU565 cells display significantly faster cell proliferation compared to IgG-primed or untreated control counterparts, as measured via optical coherent tomography imaging and Imaris 3D rendering software. Finally, tumor xenografts implanted in athymic nude mice using TZM-primed AU565 cells display continuous growth in contrast to those generated from untreated cells. These results suggest that short-term TZM treatment may inadvertently increase oncogenic fitness via adaptation to TZM-HER2 cellular binding and subsequent disruption of dimerization and signaling. These results are consistent with reports indicating that regional HER2 expression heterogeneity appears to increase with TZM treatment. Moreover, these observations are especially concerning because radiolabeled TZM probes have been employed in PET imaging in HER2+ cancer patients. In summary, our results suggest that short-term TZM treatment may result in priming and selection for more aggressive cancer phenotype. Citation Format: Alena Rudkouskaya, Cassandra L Roberge, Lauren Elder, Kailie Matteson, David T Corr, Margarida Barroso. Short-term trastuzumab treatment increases oncogenic fitness in HER2 overexpressing breast cancer models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-01-12.

Abstract P2-13-33: Preclinical development of DHES0815A: A HER2-directed antibody-drug conjugate comprised of a reduced potency PBD dimer linked to a domain I binding HER2 antibody

Abstract Background: Many HER2-directed antibody-drug conjugates (ADCs) in early development employ trastuzumab linked to tubulin binding agents as the cytotoxic drug. DHES0815A is an ADC consisting of a THIOMABTM humanized IgG1 anti-HER2 monoclonal antibody (hu7C2), which binds domain 1 of the HER2 ECD, conjugated via a disulfide linker to PBD-monoamide (MA), a DNA mono-alkylating agent. The reduced potency of the PBD-MA payload compared to PBD dimers and the stability of the conjugation site and linker were designed to improve tolerability, whereas the binding of hu7C2 to a HER2 epitope distinct from trastuzumab and pertuzumab allows combination with existing HER2 therapies. . Methods: Modifications at one imine in the PBD (pyrrolobenzodiazepine) dimer produced mono-alkylating PBDs that were assessed for DNA binding, permeability and cell potency. Each modified PBD was conjugated to hu7C2 LC K149C via a disulfide linker and assessed in HER2-positive models in vitro and in vivo. Safety studies were performed in female and male cynomolgus monkey treated every 3 weeks X 5, with a 7-week follow-up. Assessments included hematology, clinical chemistry, anti-drug antibody, standard clinical, neurological and ophthalmic exams and histopathology. Results: Our goal was design of a reduced potency PBD dimer ADC to achieve dosing in the linear PK range for optimal exposure, efficacy and safety. PBD dimers contain 2 reactive imines that bis-alkylate and crosslink DNA. Mono-alkylating PBD dimers were assessed in DNA binding, potency and permeability assays to select the optimal mono-alkylator, PBD-MA, for further investigation. hu7C2-disulfide-PBD-MA, or DHES0815A, was potent across HER2-positive breast and gastric cancer models in vitro and in vivo, with little effect on HER2-negative tumors or normal primary cells in vitro. DHES0815A was more potent than T-DM1 in HER2-positive and HER2-low breast and gastric cancer PDX models and demonstrated combination activity with standard of care agents T-DM1 or docetaxel. Mechanistically, treatment of HER2-positive cells with DHES0815A resulted in late S-phase cell cycle arrest; induction of DNA damage markers γH2AX, phospho-p53, phospho-CHK2, induction of apoptosis, and bystander activity. Pharmacokinetic analysis showed dose-proportional PK, with linear biphasic PK >/= 4mg/kg in cynomolgus monkey. Safety studies in cynomolgus monkey treated with 4, 8 or 12 mg/kg demonstrated that findings were non-adverse, monitorable and manageable. All doses were tolerated with few clinical observations and minimal to mild clinical pathology changes. Target organs were skin, bone marrow, lung and eye. The HNSTD (highest non-severely toxic dose) was 12 mg/kg. This dose enabled a starting dose of 0.6 mg/kg for phase 1 testing. Conclusions: DHES0815A is a HER2-directed ADC comprised of a domain I binding antibody linked to a reduced potency PBD dimer, PBD-MA, via a reducible disulfide linker. The antibody does not interfere with trastuzumab or pertuzumab binding, allowing combination with existing HER2 therapies. The reduced potency payload allows dosing in the linear PK range, supporting our hypothesis. DHES0815A demonstrated dose-dependent anti-tumor efficacy in multiple HER2+ breast and gastric cancer models, and showed efficacy in HER2-low models, where T-DM1 was inactive. Enhanced anti-tumor activity was observed combining DHES0815A with T-DM1, trastuzumab/pertuzumab or docetaxel. Studies in cynomolgus monkey demonstrated a safety profile compatible with initiating a phase 1 clinical trial. The phase 1 data will be presented in a separate presentation. Citation Format: Gail Lewis Phillips, Guangmin Li, Jun Guo, Shang-Fan Yu, Genee Lee, Donglu Zhang, Peter Dragovich, Thomas Pillow, Binqing Wei, M. Violet Lee, Ola Saad, Shab Masih, Douglas Leipold, Lisa Crocker, Melissa Schutten. Preclinical development of DHES0815A: A HER2-directed antibody-drug conjugate comprised of a reduced potency PBD dimer linked to a domain I binding HER2 antibody [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-33.

Abstract P2-13-25: A phase I dose-escalation study of DHES0815A, a HER2-targeting antibody-drug conjugate with a DNA monoalkylator payload, in patients with HER2-positive breast cancer

Abstract Background: Despite the success of multiple HER2-targeted agents in HER2+ breast cancer (BC), resistance remains a challenge and novel therapies are needed. DHES0815A is a THIOMABTM antibody-drug conjugate consisting of a humanized IgG1 anti-HER2 monoclonal antibody (mAb) conjugated to the DNA alkylating agent PBD-MA. The reduced potency of PBD-MA compared to PBD dimers and the stability of the conjugation site and linker were designed to improve tolerability, whereas the binding of the mAb to a HER2 epitope distinct from trastuzumab and pertuzumab was designed to enable combination therapy with existing HER2 therapies. Methods: This first-in-human, Phase I, open-label, multicenter, dose escalation study used a 3+3 dose escalation design to assess the safety, pharmacokinetics (PK), and preliminary anti-tumor activity of DHES0815A in patients with metastatic HER2-positive BC refractory to established therapies (NCT03451162). DHES0815A (0.6-6.0 mg/kg) was administered intravenously every 3 weeks (Q3W) until intolerable toxicity or disease progression. Results: A total of 14 patients were treated with DHES0815A; all had ≥3 prior lines of therapy. Thirteen patients discontinued treatment due to progressive disease (43%), adverse events (AE; [29%]) symptomatic deterioration (14%) or other (7%); 1 patient remains on treatment. DHES0815A was initially well-tolerated for doses up to 2.4 mg/kg. At 4.0 mg/kg and 6.0 mg/kg, the first dose was also well-tolerated with no dose limiting toxicities, however, following 3 or more cycles at 4.0 mg/kg or 2 or more cycles at 6.0 mg/kg, safety events involving skin, eyes, and lung emerged. Skin events were reported in 50% of patients (all doses) and related events occurring in n≥2 patients included pruritus (36%), rash (36%), and skin hyperpigmentation (21%). Ocular toxicities were reported in 57% and related events occurring in n≥2 patients included photophobia (21%), conjunctivitis, eye pain, and dry eye (each 14%). Lung toxicities were reported in 36% of patients; events occurring in n≥2 included pneumonitis (14%). Other related skin, ocular, and pulmonary events occurring in 1 patient (7%) included palmar-plantar erythrodysaesthesia, macular rash, blurred vision, eyelid edema, periorbital edema, blepharitis, punctate keratitis, wheezing, allergic rhinitis, and pneumothorax. Most events were grade 1 or 2 although 3 patients experienced grade 3 ocular events (blepharitis, eye pain, photophobia). Due to these AEs, DHES0815A dose was decreased to 2.4 mg/kg Q3W for all enrolled patients and accrual was stopped. All 5 patients receiving doses of 4.0 mg/kg and 6.0 mg/kg discontinued due to AEs. At lower doses, 1 patient receiving 2.4 mg/kg developed grade 2 rash at Cycle 21 and 1 patient receiving 1.2 mg/kg developed grade 1 rash, pruritis, and skin hyperpigmentation between Cycles 28-30. Nonlinear PK of antibody-conjugated PBD-MA (acPBD-MA) was observed due to target mediated drug disposition at 0.6, 1.2, and 2.4 mg/kg; PK approached linear at 4.0 mg/kg. Minimal systemic exposure of unconjugated PBD-MA was observed. Overall, 1 patient (7%) in the 1.2 mg/kg cohort achieved a confirmed complete response. As of 10Jun21, this patient remains on study after more than 32 months on treatment. Ten patients (86%) showed a confirmed best overall response of stable disease (86%). Conclusion: Despite some anti-tumor activity observed with DHES0815A, development in HER2-positive BC has been discontinued due to safety concerns and the narrow therapeutic window. Toxicities observed in skin, lung, and eyes are clinically apparent only after repeated dose administration. If future exploration of PBD-MA-based constructs is performed in the clinic, close monitoring for delayed toxicities is warranted. Citation Format: Ian Krop, Erika Hamilton, Kyung Hae Jung, Shanu Modi, Kevin M Kalinsky, Gail Phillips, Rong Shi, Sharareh Monemi, Michael Mamounas, Ola Saad, Voleak Choeurng, Renee Commerford, Eunpi Cho, Alexander Ungewickell, Patricia LoRusso. A phase I dose-escalation study of DHES0815A, a HER2-targeting antibody-drug conjugate with a DNA monoalkylator payload, in patients with HER2-positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-25.

Abstract P5-01-04: Correlation of HER2 receptor expression and in vivo activity of the HER2-targeting therapies trastuzumab deruxtecan (DS-8201a) and T-DM1 activity in a panel of breast XPDX models

Abstract Background: 15-20% of metastatic breast cancers are characterized by overexpression or amplification of human epidermal growth factor receptor 2 (HER2). First-line treatment for HER2-positive metastatic breast cancer includes the anti-HER2 monoclonal antibodies trastuzumab and pertuzumab in combination with chemotherapy. Second-line therapy includes T-DM1, an antibody-drug conjugate (ADC) consisting of trastuzumab conjugated to maytansinoid (DM1). Until recently, patients who progress on T-DM1 were left with few treatment options. Trastuzumab deruxtecan (DS-8201a) is an antibody-drug conjugate (ADC) consisting of an anti-HER2 (human epidermal growth factor receptor 2) antibody linked to a novel topoisomerase I inhibitor payload using a cleavable tetrapeptide-based linker and was recently approved for unresectable or T-DM1-refractory HER2+ breast cancer. In addition, DS-8201a is currently being evaluated as a treatment in breast cancers with low and medium expression of HER2. To better understand the potential for DS-8201a as a treatment in these cancer types, we evaluated this therapy in a panel of ER+/- XPDX models with differential HER2 expression. In addition, we compared DS-8201a activity to T-DM1 and benchmarked efficacy of the topoisomerase I inhibitor irinotecan in all tested models. Methods: One hundred (50ER+/50ER-) breast XPDX models were evaluated in this study. Models were established and characterized for estrogen receptor and HER2 expression by IHC and profiled using WES and RNAseq. For in vivo studies, DS-8201a and T-DM1 were administered IV at 3 mg/kg and irinotecan IP at 100 mg/kg on a weeklyx3 schedule. In vivo study endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a %T/C of ≤ 20 versus control was considered sensitive. Results: Models were grouped by ER positivity (+/-) and model HER2 score and designated as null (0), low (1+), medium (2+) or high (3+); models established from clinically HER2+ patients were also noted. In the ER+ group, HER2 low and medium expressing models accounted for over 80% of the total, while 15% were categorized as high and less than 5% as null. All models with high and 30% with medium HER2 staining were from clinically HER2+ patients, no low or null models were established from breast cancer assigned HER2+ clinically. In the ER- group, HER2 low and medium expressing models accounted for 75% of the total, while 12% were categorized as high and 13% as null. All models with high and 13% with medium HER2 staining were from clinically HER2+ patients; 5% of low or null models were established from breast cancer assigned HER2+ clinically. In vivo, 65% of the ER+ group reported sensitivity to DS-8201a versus 25% to T-DM1; 10% of DS-8201a, and 40% of T-DM1 sensitive models were high expression models and the remaining low and medium with no null models reporting sensitivity to either agent. 35% of tested ER+ models were sensitive to both HER2 therapies and 50% of models sensitive to DS-8201a were also sensitive to irinotecan. In the ER- group, 70% reported sensitivity to DS-8201a versus 25% to T-DM1; 20% of DS-8201a and 25% of T-DM1 sensitive models were high expression models and the remaining low and medium with one null model (ST069) sensitive to both agents. 25% of tested ER- models were sensitive to both HER2 therapies and 40% of models sensitive to DS-8201a were also sensitive to irinotecan. Conclusion: We have compared activity of DS-8201a, T-DM1 and irinotecan in a panel of ER+/- XPDX models and correlated activity based on HER2 expression. This data and panel can be utilized as a valuable tool in better understanding the potential for DS-8201a and other HER2-targeting therapies as a treatment in cancers driven by HER2 expression. Citation Format: Alyssa Simonson, Peter Forofontov, Johnnie R Flores, Kimberly Hernandez, April Cabang, Amy Lang, Gladys Rodriguez, Kyriakos Papadopoulos, Murali Beeram, Arthur Rosenthal, Brittany DeBerry, Lon Smith, Ronald Drengler, Amita Patnaik, Drew Rasco, Luis Rodriguez, Steven Abbate, Scott Ulmer, Michael Wick. Correlation of HER2 receptor expression and in vivo activity of the HER2-targeting therapies trastuzumab deruxtecan (DS-8201a) and T-DM1 activity in a panel of breast XPDX models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-01-04.

Autophagy and intracellular product degradation genes identified by systems biology analysis reduce aggregation of bispecific antibody in CHO cells

Aggregation of therapeutic bispecific antibodies negatively affects the yield, shelf-life, efficacy and safety of these products. Pairs of stable Chinese hamster ovary (CHO) cell lines produced two difficult-to-express bispecific antibodies with different levels of aggregated product (10–75% aggregate) in a miniaturised bioreactor system. Here, transcriptome analysis was used to interpret the biological causes for the aggregation and to identify strategies to improve product yield and quality. Differential expression- and gene set analysis revealed upregulated proteasomal degradation, unfolded protein response and autophagy processes to be correlated with reduced protein aggregation. Fourteen candidate genes with the potential to reduce aggregation were co-expressed in the stable clones for validation. Of these, HSP90B1, DDIT3, AKT1S1, and ATG16L1, were found to significantly lower aggregation in the stable producers and two (HSP90B1 and DNAJC3) increased titres of the anti-HER2 monoclonal antibody trastuzumab by 50% during transient expression. It is suggested that this approach could be of general use for defining aggregation bottlenecks in CHO cells.

Dose-escalation and dose-expansion study of trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with advanced/metastatic HER2+ gastric cancer (GC)/gastroesophageal junction adenocarcinoma (GEJA): DESTINY-Gastric03.

295 Background: T-DXd is an antibody-drug conjugate composed of a humanized anti-HER2 monoclonal antibody, a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload. T-DXd is approved for HER2+ advanced/metastatic GC/GEJA after a prior trastuzumab-based regimen (US/Israel) and GC after chemotherapy (Japan). In DESTINY-Gastric01, T-DXd showed improved efficacy vs standard chemotherapy in Japanese and Korean pts (≥2 prior therapies) with advanced HER2+ GC/GEJA. Preclinical data of T-DXd combinations suggest encouraging antitumor activity. DESTINY-Gastric03 is the first study of T-DXd combinations in GC/GEJA. Methods: DESTINY-Gastric03 (NCT04379596) is a 2-part, phase 1b/2, multicenter, open-label, 3+3 dose-escalation (part 1) and -expansion (part 2) study in advanced/metastatic HER2+ GC/GEJA. In part 1, pts with locally confirmed HER2+ GC/GEJA (IHC 3+ or IHC 2+/ISH+) who progressed on/after ≥1 prior therapy including a trastuzumab-containing regimen received T-DXd intravenously (IV) every 3 weeks + assigned combination. Primary objectives were safety and recommended phase 2 dose (RP2D). Preliminary antitumor activity was a secondary objective; confirmed objective response rate (ORR) was a secondary endpoint. We report the T-DXd + fluoropyrimidine cohorts. Results: In part 1, 15 pts were assigned to T-DXd + IV 5-fluorouracil (5-FU) and 10 pts to T-DXd + oral capecitabine (Cap). In addition to trastuzumab, all pts had received prior treatment with 5-FU and/or Cap and a median of 2 (range, 1-5) prior lines of therapy. The most common grade ≥3 AEs (%) were anemia (33), decreased neutrophil count (33), nausea (13), and stomatitis (13) with T-DXd + 5-FU and decreased neutrophil count (40), anemia (30), and nausea (20) with T-DXd + Cap. Starting doses were T-DXd 5.4 mg/kg + 5-FU 800 mg/m2 and T-DXd 5.4 mg/kg + Cap 1000 mg/m2 twice daily (BID). There were 2 dose-limiting toxicities of grade 3 stomatitis with T-DXd 6.4 mg/kg + 5-FU 800 mg/m2; this exceeded the maximum tolerated dose and was discontinued. RP2Ds were T-DXd 6.4 mg/kg + 5-FU 600 mg/m2 and T-DXd 6.4 mg/kg + Cap 1000 mg/m2 BID. Preliminary confirmed and confirmed + unconfirmed ORR at the RP2D for T-DXd + Cap were 3/7 and 5/7, respectively; 3/3 pts at the starting dose of T-DXd + Cap had confirmed ORR. ORR data for T-DXd + 5-FU are not yet mature. Conclusions: In the first T-DXd + fluoropyrimidine combination study in HER2+ GC/GEJA, preliminary part 1 results suggest tolerability and feasibility of the RP2Ds for T-DXd + 5-FU and T-DXd + Cap. Preliminary ORR with the T-DXd + Cap RP2D (n = 7) showed efficacy with this combination in heavily pretreated, trastuzumab- and fluoropyrimidine-refractory, HER2+ GC/GEJA. This study is ongoing, with further combinations and follow-up planned. Clinical trial information: NCT04379596.

Breast Cancer Vaccines: Disappointing or Promising?

Breast cancer has become the most commonly diagnosed cancer globally. The relapse and metastasis of breast cancer remain a great challenge despite advances in chemotherapy, endocrine therapy, and HER2 targeted therapy in the past decades. Innovative therapeutic strategies are still critically in need. Cancer vaccine is an attractive option as it aims to induce a durable immunologic response to eradicate tumor cells. Different types of breast cancer vaccines have been evaluated in clinical trials, but none has led to significant benefits. Despite the disappointing results at present, new promise from the latest study indicates the possibility of applying vaccines in combination with anti-HER2 monoclonal antibodies or immune checkpoint blockade. This review summarizes the principles and mechanisms underlying breast cancer vaccines, recapitulates the type and administration routes of vaccine, reviews the current results of relevant clinical trials, and addresses the potential reasons for the setbacks and future directions to explore.

The benefits of trastuzumab in the treatment of HER2+ breast cancer as a function of exposure time.

BackgroundBreast cancer is a heterogeneous disease with overexpression of several receptors, such as human epidermal receptor 2 (HER2), which is a prognostic and predictive biomarker for treatment with the anti-HER2 monoclonal antibody trastuzumab. This study aimed to test the contribution of this regimen in patients with overexpression/amplification of HER2 for periods shorter than the 1-year treatment recommendation.MethodsA retrospective single-centre study involving 155 patients with non-metastatic (stages I–III) invasive ductal HER2+ breast carcinoma, with a median follow-up of 48.9 months after completion of adjuvant therapy, except endocrine therapy.ResultsAbout 60% of patients received trastuzumab therapy for a median time of 365 days. Although the use of trastuzumab for a short period has provided some benefit, analyses of survival with a continuous dependent variable have revealed a minimum time for improved survival. In the multivariate analysis by Cox regression, trastuzumab use duration exceeding 9 weeks resulted in protection against distant metastasis (adjusted HR: 0.307 (0.139–0.678), p = 0.004), disease progression (adjusted hazard ratio (HR) 0.353 (0.175–0.714), p = 0.004) and death (adjusted HR: 0.267 (0.105–0.678), p = 0.005), being superior to multimodal systemic therapy with chemotherapy and to endocrine therapy without trastuzumab, but inferior to almost 1 year of administration of this monoclonal antibody, especially regarding overall survival (adjusted HR: 0.203 (0.069–0.596), p = 0.004).ConclusionDespite showing some benefits, the protective effect derived from a suboptimal time of trastuzumab exposure is inferior to the standard course of 1 year.

Predictors of pathologic complete response to neoadjuvant treatment in HER2-overexpressing breast cancer: a retrospective analysis using real-world data

The human epidermal growth factor receptor 2 (ERBB2, HER2 or HER2/neu) is a transmembrane tyrosine kinase receptor that is overexpressed in approximately 20% of breast cancers. The use of the anti-HER2 monoclonal antibodies Pertuzumab and Trastuzumab in association with chemotherapy has achieved a higher percentage of pathologic complete response (pCR) than conventional chemotherapy. The purpose of our study was to identify factors that could affect the therapeutic response of patients with breast cancer and HER2 overexpression treated with cytotoxic chemotherapy plus double HER2 blockade in neoadjuvant setting at Fundación Arturo López Pérez (FALP). A case–control study was designed to evaluate the effect of clinical and histopathological variables on the response to neoadjuvant therapy. Ninety-four women with non-metastatic breast cancer and HER2 overexpression received neoadjuvant combination chemotherapy with Trastuzumab and Pertuzumab at FALP during the period 2017–2020. Seventy percent of patients achieved pCR, and in the group of hormone receptor negative patients, 89% of patients achieved pCR. Different variables were analysed trying to look for clinicopathological predictors of complete response. This study provides us with real-world data on the efficacy of using this treatment combination in our population of HER2-overexpressing breast cancer patients.