Factor Receptor 2-positive Breast Cancer Research Articles

Mixed lineage kinase 3 and CD70 cooperation sensitize trastuzumab-resistant HER2+ breast cancer by ceramide-loaded nanoparticles

Trastuzumab is the first-line therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but often patients develop acquired resistance. Although other agents are in clinical use to treat trastuzumab-resistant (TR) breast cancer; still, the patients develop recurrent metastatic disease. One of the primary mechanisms of acquired resistance is the shedding/loss of the HER2 extracellular domain, where trastuzumab binds. We envisioned any new agent acting downstream of the HER2 should overcome trastuzumab resistance. The mixed lineage kinase 3 (MLK3) activation by trastuzumab is necessary for promoting cell death in HER2+ breast cancer. We designed nanoparticles loaded with MLK3 agonist ceramide (PPP-CNP) and tested their efficacy in sensitizing TR cell lines, patient-derived organoids, and patient-derived xenograft (PDX). The PPP-CNP activated MLK3, its downstream JNK kinase activity, and down-regulated AKT pathway signaling in TR cell lines and PDX. The activation of MLK3 and down-regulation of AKT signaling by PPP-CNP induced cell death and inhibited cellular proliferation in TR cells and PDX. The apoptosis in TR cells was dependent on increased CD70 protein expression and caspase-9 and caspase-3 activities by PPP-CNP. The PPP-CNP treatment alike increased the expression of CD70, CD27, cleaved caspase-9, and caspase-3 with a concurrent tumor burden reduction of TR PDX. Moreover, the expressions of CD70 and ceramide levels were lower in TR than sensitive HER2+ human breast tumors. Our invitro and preclinical animal models suggest that activating the MLK3-CD70 axis by the PPP-CNP could sensitize/overcome trastuzumab resistance in HER2+ breast cancer.

Crossover in Adjuvant Trastuzumab Trials: Sparing Toxicity in Patient Care.

Design and reporting of randomized control trials for drug therapies in the adjuvant setting require a nuanced consideration of patient crossover. Adjuvant trials can be susceptible to the misuse of crossover and may distort the interpretation of findings. We sought to investigate and describe crossover and/or postprogression access to trastuzumab within adjuvant trastuzumab randomized control trials for human epidermal growth factor receptor 2-positive breast cancer patients. Seven clinical trials for adjuvant trastuzumab in human epidermal growth factor receptor 2-positive breast cancer were identified through a meta-analysis published in the Lancet . Primary study publications were located through MEDLINE, Google Scholar, and trials were identified, when possible, using Clincialtrials.gov. Sixteen publications, describing 7 studies, were reviewed. Four (57%) trials reported offering patients within the control arm the opportunity to crossover and receive trastuzumab in the adjuvant setting. Two (29%) trials did not report nor discuss crossover within the publication. Five (71%) trials reported the total number of patients who crossed over among the control arms. No trials specified the proportion of control patients who received trastuzumab at recurrence. Trials for adjuvant trastuzumab did not disambiguate between crossover (1) in the adjuvant setting or (2) at recurrence. Due to the low reported rate of crossover, it is questionable if participants received the standard of care.

Clinical Profile and Outcome of Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer With Brain Metastases: Real-World Experience.

There are sparse data in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer with brain metastases from real-world settings, especially where access to newer targeted therapies is limited. This was a single institution, retrospective cohort study of patients with HER2-positive breast cancer diagnosed between January 2013 and December 2017 to have brain metastases and treated with any HER2-targeted therapy. The main objectives were to estimate progression-free survival (PFS) and overall survival (OS) from the time of brain metastases. A total of 102 patients with a median age of 52 (interquartile range, 45-57) years were included, of whom 63 (61.8%) had received one line and 14 (13.7%) had received two lines of HER2-targeted therapies before brain metastasis, 98 (96.1%) were symptomatic at presentation, 22 (25.3%) had solitary brain lesion, 22 (25.3%) had 2-5 lesions, and 43 (49.4%) had ≥ 5 lesions. Local treatment included surgical resection in nine (8.9%) and radiotherapy in all (100%) patients. The first HER2-targeted therapy after brain metastasis was lapatinib in 71 (68.6%), trastuzumab in 19 (18.6%), lapatinib and trastuzumab in three (2.9%), trastuzumab emtansine in four (3.9%), and intrathecal trastuzumab in five (4.9%) patients. At a median follow-up of 13.9 months, the median PFS and OS were 8 (95% CI, 6.2 to 9.8) months and 14 (95% CI, 10.8 to 17.2) months, respectively, with a 2-year OS of 25% (95% CI, 16.7 to 34.4). The median PFS in patients who received lapatinib-capecitabine regimen (n = 62) was 9.0 (95% CI, 7.3 to 10.7) months. There was a substantial clinical benefit of local and systemic therapy in patients with brain metastases and HER2-positive disease in a real-world setting with limited access to newer HER2-targeted drugs.

Novel peptide-based vaccine targeting heat shock protein 90 induces effective antitumor immunity in a HER2+ breast cancer murine model

BackgroundHeat shock protein 90 (HSP90) is a protein chaperone for most of the important signal transduction pathways in human epidermal growth factor receptor 2-positive (HER2+) breast cancer, including human epidermal...

254P Real-world clinical scenarios during introduction of trastuzumab biosimilar for HER2-positive breast cancer

Trastuzumab (tras)-anns (KANJINTI™) is one of the first biosimilars of reference product (RP) Herceptin® approved in the European Union (EU) in May 2018, also approved in the United States in June 2019, for treatment of human epidermal growth factor receptor 2-positive (HER2+) early and metastatic breast cancer (BC) as well as metastatic gastric cancer. Study objectives were to define real-world characteristics of BC patients (pts) receiving tras-anns, their prior tras treatment patterns, and tras-anns safety.

Quantifying the Effects of Combination Trastuzumab and Radiation Therapy in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.

Simple SummaryIn vitro, combination trastuzumab and single-dose radiotherapy induces an additive effect. In vivo, combination trastuzumab and single-dose radiotherapy induces greater tumor kill than a higher single dose of radiotherapy, suggesting that combination therapy can be considered to achieve a similar reduction in tumor burden as traditional radiotherapy, with fewer adverse effects.Background: Trastuzumab induces cell cycle arrest in HER2-overexpressing cells and demonstrates potential in radiosensitizing cancer cells. The purpose of this study is to quantify combination trastuzumab and radiotherapy to determine their synergy. Methods: In vitro, HER2+ cancer cells were treated with trastuzumab, radiation, or their combination, and imaged to evaluate treatment kinetics. In vivo, HER2+ tumor-bearing mice were treated with trastuzumab and radiation, and assessed longitudinally. An additional cohort was treated and sacrificed to quantify CD45, CD31, α-SMA, and hypoxia. Results: The interaction index revealed the additive effects of trastuzumab and radiation in vitro in HER2+ cell lines. Furthermore, the results revealed significant differences in tumor response when treated with radiation (p < 0.001); however, no difference was seen in the combination groups when trastuzumab was added to radiotherapy (p = 0.56). Histology revealed increases in CD45 staining in tumors receiving trastuzumab (p < 0.05), indicating potential increases in immune infiltration. Conclusions: The in vitro results showed the additive effect of combination trastuzumab and radiotherapy. The in vivo results showed the potential to achieve similar efficacy of radiotherapy with a reduced dose when combined with trastuzumab. If trastuzumab and low-dose radiotherapy induce greater tumor kill than a higher dose of radiotherapy, combination therapy can achieve a similar reduction in tumor burden.

Systemic Therapy for Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: ASCO Guideline Update Q and A.

Systemic Therapy for Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: ASCO Guideline Update Q and A.

Evaluation of Safety and Clinically Relevant Drug-Drug Interactions with Tucatinib in Healthy Volunteers.

Background and ObjectiveTucatinib is approved for treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer. Understanding potential drug–drug interactions (DDIs) informs proper dosing when co-administering tucatinib with other therapies. The aim of this study was to evaluate DDIs between tucatinib and metabolizing enzymes and transporters in healthy volunteers.MethodsParts A–C assessed the impact of itraconazole (cytochrome P450 [CYP] 3A4 inhibitor), rifampin (CYP3A4/CYP2C8 inducer), or gemfibrozil (CYP2C8 inhibitor) on the pharmacokinetics of a single 300 mg dose of tucatinib administered orally and its primary metabolite, ONT-993. Parts D and E assessed the effect of steady-state tucatinib on the pharmacokinetics of repaglinide (CYP2C8 substrate), tolbutamide (CYP2C9 substrate), midazolam (CYP3A4 substrate), and digoxin (P-glycoprotein substrate).ResultsTucatinib area under the concentration–time curve from time 0 extrapolated to infinity (AUC0–inf) increased by ~ 1.3- and 3.0-fold with itraconazole and gemfibrozil, respectively, and decreased by 48% with rifampin, indicating that tucatinib is metabolized primarily by CYP2C8, and to a lesser extent via CYP3A. Tucatinib was a strong inhibitor of CYP3A (midazolam AUC0–inf increased 5.7-fold), a weak inhibitor of CYP2C8 and P-glycoprotein, and had no impact on CYP2C9-mediated metabolism in humans. Tucatinib was well tolerated, alone and with co-administered drugs.ConclusionThe potential DDIs identified here may be mitigated by avoiding concomitant use of tucatinib with strong CYP3A inducers, moderate CYP2C8 inducers, CYP3A substrates with a narrow therapeutic window (modifying substrate dose where concomitant use is unavoidable), and strong CYP2C8 inhibitors (decreasing tucatinib dose where concomitant use is unavoidable), or by reducing the dose of P-glycoprotein substrates with a narrow therapeutic window.Trial RegistrationThis trial (NCT03723395) was registered on October 29, 2018.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-022-01144-z.

ABL kinases regulate translation in HER2+ cells through Y-box-binding protein 1 to facilitate colonization of the brain.

SUMMARYPatients with human epidermal growth factor receptor 2-positive (HER2+/ERBB2) breast cancer often present with brain metastasis. HER2-targeted therapies have not been successful to treat brain metastases in part due to poor blood-brain barrier (BBB) penetrance and emergence of resistance. Here, we report that Abelson (ABL) kinase allosteric inhibitors improve overall survival and impair HER2+ brain metastatic outgrowth in vivo. Mechanistically, ABL kinases phosphorylate the RNA-binding protein Y-box-binding protein 1 (YB-1). ABL kinase inhibition disrupts binding of YB-1 to the ERBB2 mRNA and impairs translation, leading to a profound decrease in HER2 protein levels. ABL-dependent tyrosine phosphorylation of YB-1 promotes HER2 translation. Notably, loss of YB-1 inhibits brain metastatic outgrowth and impairs expression of a subset of ABL-dependent brain metastatic targets. These data support a role for ABL kinases in the translational regulation of brain metastatic targets through YB-1 and offer a therapeutic target for HER2+ brain metastasis patients.

Breast cancer brain metastasis: Current evidence and future directions.

Breast cancer is the most common cancer in women and the second leading cause of cancer-related deaths after lung cancer. Metastasis of the central nervous system is a terrible event for breast cancer patients, affecting their survival and quality of life. Compared with hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer patients, brain metastases are more likely to affect patients with triple-negative breast cancer and human epidermal growth factor receptor 2-positive breast cancer. The treatment of breast cancer has improved greatly in the last two decades. However, brain metastases from breast cancer remain the leading cause of morbidity and mortality. Patients with breast cancer brain metastasis have been in an inferior position due to the lack of clinical research in this field, and they are often explicitly excluded from almost all clinical trials. The occurrence and progression of brain metastases will result in severe cognitive impairment and adverse physical consequences, so we must have a good understanding of the molecular mechanisms of breast cancer brain metastasis. In this article, we have retrieved the latest literature of molecules and pathways associated with breast cancer brain metastasis, summarized common therapy strategies, and discussed the prospects and clinical implications of targeting the molecules involved.

Targeted Therapeutic Options and Future Perspectives for HER2-Positive Breast Cancer.

Simple SummaryThe development of several antiHuman Epidermal Growth Factor Receptor 2 (HER2) treatments over the last few years has improved the landscape of HER2-positive breast cancer. Despite this, relapse is still the main issue in HER2-positive breast cancer. The reasons for therapeutic failure lie in the heterogeneity of the disease itself, as well as in the drug resistance mechanisms. In this review, we intended to understand the milestones that have had an impact on this disease up to their implementation in clinical practice. In addition, understanding the underlying molecular biology of HER2-positive disease is essential for the optimization and personalization of the different treatment options. For this reason, we focused on two relevant aspects, which are triple-positive disease and the role that modulation of the immune response might play in treatment and prognosis.Despite the improvement achieved by the introduction of HER2-targeted therapy, up to 25% of early human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients will relapse. Beyond trastuzumab, other agents approved for early HER2+ BC include the monoclonal antibody pertuzumab, the antibody-drug conjugate (ADC) trastuzumab-emtansine (T-DM1) and the reversible HER2 inhibitor lapatinib. New agents, such as trastuzumab-deruxtecan or tucatinib in combination with capecitabine and trastuzumab, have also shown a significant improvement in the metastatic setting. Other therapeutic strategies to overcome treatment resistance have been explored in HER2+ BC, mainly in HER2+ that also overexpress estrogen receptors (ER+). In ER+ HER2+ patients, target therapies such as phosphoinositide-3-kinase (PI3K) pathway inhibition or cyclin-dependent kinases 4/6 blocking may be effective in controlling downstream of HER2 and many of the cellular pathways associated with resistance to HER2-targeted therapies. Multiple trials have explored these strategies with some promising results, and probably, in the next years conclusive results will succeed. In addition, HER2+ BC is known to be more immunogenic than other BC subgroups, with high variability between tumors. Different immunotherapeutic agents such as HER-2 therapy plus checkpoint inhibitors, or new vaccines approaches have been investigated in this setting, with promising but controversial results obtained to date.

The effectiveness and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early-stage human epidermal growth factor receptor 2-positive breast cancer: Turkish Oncology Group study.

In our study, we aimed to evaluate the pathological response rates and side effect profile of adding pertuzumab to the treatment of HER2+ locally advanced, inflammatory, or early-stage breast cancer. This study was conducted by the Turkish Oncology Group (TOG) with data collected from 32 centers. Our study was multicentric, and a total of 364 patients were included. The median age of the patients was 49 years (18-85 years). Two hundred fifteen (60%) of the cases were hormone receptor/HER2+ positive(ER+ or PR+, or both), and 149 (40%) of them were HER2-rich (ER and PR negative). The number of complete responses was 124 (54%) in the docetaxel+trastuzumab+pertuzumab arm and 102 (45%) in the paclitaxel+trastuzumab+pertuzumab arm, and there was no difference between the groups in terms of complete response. In 226 (62%) patients with complete response, a significant correlation was found with DCIS, tumor focality, removed lymph node, and ER status P < 0.05. Anemia, nausea, vomiting, myalgia, alopecia, and mucosal inflammation were significantly higher in the docetaxel arm, P < 0.05. In our study, no statistical difference was found between the before-after echocardiography values. DCIS positivity in biopsy before neoadjuvant chemotherapy, tumor focality; the number of lymph nodes removed and ER status were found to be associated with pCR. In conclusion, we think that studies evaluating pCR-related clinicopathological variables and radiological imaging features will play a critical role in the development of nonsurgical treatment approaches.

Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB-05, trial in progress).

TPS1108 Background: The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients (pts) progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in pts with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in pts with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods: HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 pts will be enrolled. Eligible pts will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, ECOG Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Pts will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Pts with HR+ disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, with additional sites planned. Clinical trial information: NCT05132582.

Real-world outcomes among patients with HER2+ metastatic breast cancer with brain metastases.

BACKGROUND: Among patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC), incidence of brain metastases (BMs) is relatively high and increasing. Despite the high unmet need for patients with HER2+ MBC and BMs, real-world data on treatment patterns and outcomes for these patients are limited. OBJECTIVE: To compare treatment patterns and overall survival (OS) among patients with HER2+ MBC with and without BMs in the United States. METHODS: This was a real-world retrospective cohort study in which adults diagnosed with HER2+ MBC between January 1, 2016, and May 31, 2019, were identified in the Flatiron Health electronic health records database. The cohort was stratified by presence of BMs at MBC diagnosis (baseline) and before the initiation of each line of therapy (LOT). Key outcomes were OS and systemic therapy/regimen used within each LOT. An adjusted Cox proportional hazards model was used to evaluate the impact of BMs on OS. RESULTS: Of 1,755 included patients, 173 (9.9%) had BMs at baseline. Trastuzumab+ pertuzumab-based regimens were the most common first- (n = 689, 44.3%) and second-line (n = 316, 35.3%) treatments for all patients. Among patients with BMs, trastuzumab emtansine was the most common third-line regimen (n = 18, 23.4%). Lapatinib-based regimens were used more frequently among patients with BMs but were used by less than 20% of patients with BMs within any LOT. Median OS was 22.3 and 37.3 months for patients with and without BMs at baseline, respectively. Patients with BMs had a higher risk of death compared with patients without BMs (HR, 3.2; 95% CI = 2.6-3.8). CONCLUSIONS: BMs are associated with an increased risk of mortality among patients with HER2+ MBC. Further studies are needed to evaluate the extent to which novel systemic therapies for HER2+ MBC address the unmet need among patients with BMs. DISCLOSURES: This study was funded by Seagen Inc. Andres Forero-Torres is an employee of and owns stock in Seagen Inc. Kendra DeBusk is an employee of Seagen Inc. and owns stock in Seagen Inc. and Roche. Andy Surinach and Yutong Liu are employees of Genesis Research, which received funding from Seagen Inc. in connection with this study. At the time of this study, Chimeka Ike was an employee of Seagen Inc. and owns stock in Seagen Inc. At the time of this study, Nicolas Lindegger was an employee of Seagen Inc., Seagen International GmbH, and owns stock in Seagen Inc. and Roche. At the time of this study, Naomi Schwartz was a paid consultant to Seagen Inc.; she currently is an employee of and owns stock in Seagen Inc.

Association Between Imaging Features Using the BI-RADS and Tumor Subtype in Patients with Invasive Breast Cancer.

Different molecular breast cancer subtypes present different biologic features, treatment options, and clinical prognoses. The breast cancer imaging phenotype may help precisely classify breast cancer in a non-invasive manner. To identify the association between the imaging and clinicopathologic features of invasive breast cancer according to the molecular subtype. We retrospectively reviewed the electronic medical records of 313 consecutive women with breast cancer who underwent surgery between March 2018 and February 2019. Preoperative imaging studies were also reviewed and the association between the clinicopathologic and imaging features was evaluated according to the molecular subtype. On mammography, the presence of microcalcifications was correlated with the human epidermal factor receptor 2-positive subtype (67%, 14/21). Luminal A and B tumors were more likely to have a spiculated margin (57% [63/110] and 41% [34/81]), while human epidermal factor receptor 2-positive and triple-negative breast cancers were more likely to have an indistinct margin (56% [10/18] and 35% [17/48]). On ultrasonography, luminal A tumors were likely to be depicted as masses with an irregular shape (85%, 115/136) and spiculated margin (49%, 66/136). On magnetic resonance imaging, triple-negative breast cancer appeared as a mass (n=13) that frequently had an irregular shape (62%, 8/13) but was more likely to be oval or round (39%, 5/13) than other subtypes. Some imaging features on mammography, ultrasonography, and magnetic resonance imaging could be useful predictors of the molecular subtype of breast cancer and may aid precision medicine development for patients with breast cancer according to the subtype.

Comparison of adverse effects of trastuzumab with other drug combinations for the treatment of breast cancer: A review

Objectives: This study compares the adverse effects (AEs) associated with trastuzumab in the treatment of human epidermal growth factor receptor 2-positive breast cancer (HER-2 + BC) when used alone or in combination with chemotherapy or with tyrosine kinase inhibitors, so as to aid in rational treatment choices. Materials and Methods: An electronic search was conducted on PubMed using the Mesh terms ‘BC’, ‘HER-2 positive’, ‘metastasis BC, ‘trastuzumab’, and ‘safety’. Data from 32 studies regarding AEs were extracted and categorised as trastuzumab + chemotherapy (T+C), trastuzumab biosimilar (Tb), trastuzumab + tyrosine kinase inhibitors+ chemotherapy (T+TKi+C), and trastuzumab + tyrosine kinase inhibitors (T+TKi). The data are presented as the mean percentage of AEs. The statistical comparison was represented by a box and whisker plot of the interquartile range value of AEs. Results: AEs related to the gastrointestinal tract, skin, nervous, blood, and lymph were reported to be the most common in T+C, T+TKi+C, and T+TKi. Nausea, vomiting, diarrhoea, constipation, neuropathy peripheral, alopecia, rash, anaemia, leucopenia, raised aspartate transaminase and alanine transaminase were the most common complaints. AEs such as myalgia, nasopharyngitis, hypertension, and ejection fraction decrease was reported to be the most common in Tb. Conclusion: This study concluded that biosimilar of trastuzumab is safest for the treatment of HER-2-positive BC. Cardiovascular disorder is often reported in the biosimilar group, but this group has fewer AEs reported as compared with chemotherapy, and tyrosine kinase inhibitors groups related to other systems such as digestive, nervous, and respiratory. The choice of combination is depending on the type of BC and the condition of the patients. The patients must monitor for cardiotoxicity when the biosimilar of trastuzumab is used.

Characteristics of patients with brain metastases from human epidermal growth factor receptor 2-positive breast cancer: subanalysis of Brain Metastases in Breast Cancer Registry

BackgroundUp to 40% of patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer develop brain metastases (BMs). Understanding of clinical features of these patients with HER2-positive breast cancer and BMs is vital.Patients and methodsA total of 2948 patients from the Brain Metastases in Breast Cancer registry were available for this analysis, of whom 1311 had primary tumors with the HER2-positive subtype.ResultsPatients with HER2-positive breast cancer and BMs were—when compared with HER2-negative patients—slightly younger at the time of breast cancer and BM diagnosis, had a higher pathologic complete response rate after neoadjuvant chemotherapy and a higher tumor grade. Furthermore, extracranial metastases at the time of BM diagnosis were less common in HER2-positive patients, when compared with HER2-negative patients. HER2-positive patients had more often BMs in the posterior fossa, but less commonly leptomeningeal metastases. The median overall survival (OS) in all HER2-positive patients was 13.2 months (95% confidence interval 11.4-14.4). The following factors were associated with shorter OS (multivariate analysis): older age at BM diagnosis [≥60 versus <60 years: hazard ratio (HR) 1.63, P < 0.001], lower Eastern Cooperative Oncology Group status (2-4 versus 0-1: HR 1.59, P < 0.001), higher number of BMs (2-3 versus 1: HR 1.30, P = 0.082; ≥4 versus 1: HR 1.51, P = 0.004; global P = 0.015), BMs in the fossa anterior (HR 1.71, P < 0.001), leptomeningeal metastases (HR 1.63, P = 0.012), symptomatic BMs at diagnosis (HR 1.35, P = 0.033) and extracranial metastases at diagnosis of BMs (HR 1.43, P = 0.020). The application of targeted therapy after the BM diagnosis (HR 0.62, P < 0.001) was associated with longer OS. HER2-positive/hormone receptor-positive patients showed longer OS than HER2-positive/hormone receptor-negative patients (median 14.3 versus 10.9 months; HR 0.86, P = 0.03), but no differences in progression-free survival were seen between both groups.ConclusionsWe identified factors associated with the prognosis of HER2-positive patients with BMs. Further research is needed to understand the factors determining the longer survival of HER2-positive/hormone receptor-positive patients.

A prospective trial of treatment de-escalation following neoadjuvant paclitaxel/trastuzumab/pertuzumab in HER2-positive breast cancer

De-escalating adjuvant therapy following pathologic complete response (pCR) to an abbreviated neoadjuvant regimen in human epidermal growth factor receptor 2-positive (HER2+) breast cancer is the focus of international research efforts. However, the feasibility of this approach and its appeal to patients and providers had not been formally investigated. We aimed to assess adherence to de-escalated adjuvant antibody doublet therapy (trastuzumab and pertuzumab [HP], without chemotherapy) among patients with pCR following neoadjuvant paclitaxel/HP (THP). In this single-arm prospective trial, patients with treatment-naïve stage II-III HER2+ breast cancer received neoadjuvant weekly paclitaxel ×12 and HP every 3 weeks ×4. The primary endpoint was receipt of adjuvant non-HER2-directed cytotoxic chemotherapy. Ninety-eight patients received ≥1 dose of THP on study. Patients had median age of 50 years, 86% had stage II tumors, and 34% were hormone receptor-negative. Five patients had incomplete clinical response following THP and received doxorubicin and cyclophosphamide before surgery; they were classified as non-pCR and censored from further analyses. The overall pCR rate was 56.7%. Among patients with pCR, the adherence rate to de-escalated antibody-only therapy (HP) was 98.2% (95% CI 90.3–100.0%), and the primary feasibility endpoint was reached. The majority of patients felt positive or neutral about their adjuvant treatment plans. With brief follow-up (median 19.1 months), there were no breast cancer recurrences. De-escalation of adjuvant chemotherapy among patients who experience pCR in early-stage HER2+ breast cancer is a practicable approach for both patients and physicians. Planned and ongoing prospective trials will determine the long-term efficacy of this approach.Trial registration clinicaltrials.gov, NCT03716180, https://clinicaltrials.gov/ct2/show/NCT03716180.

180P A doubling in overall survival of patients with de novo HER2+ advanced breast cancer in the Netherlands

To determine whether the real-world overall survival (OS) has increased since the market release of pertuzumab and T-DM1 in 2013 in patients with de novo human epidermal growth factor receptor 2-positive (HER2+) advanced breast cancer (ABC).

207TiP Phase III study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB-05, trial in progress)

The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients (pts) progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in pts with HER2+ MBC and was well tolerated.