HER2-positive Advanced Breast Cancer Patients Research Articles

Olaparib plus trastuzumab in HER2-positive advanced breast cancer patients with germline BRCA1/2 mutations: The OPHELIA phase 2 study

PurposeTo evaluate the efficacy and safety of the combination of olaparib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC) and germinal BRCA mutations (gBRCAm). MethodsOPHELIA (NCT03931551) was a single-arm, open-label, phase 2 clinical trial. Patients aged ≥18 years diagnosed with HER2-positive ABC with germinal deleterious mutations in BRCA1 or BRCA2 who had received at least one prior systemic regimen for advanced disease were enrolled. Patients received olaparib plus trastuzumab until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was investigator-assessed clinical benefit rate for at least 24 weeks as per RECIST v.1.1. Key secondary endpoints included overall response rate (ORR) and safety profile. ResultsA total of 68 pre-treated HER2-positive ABC patients were screened. Due to slow accrual the trial was stopped after enrolling 5 patients instead of the planned sample size of 20. Four patients achieved clinical benefit (80.0 %, 95 % CI; 28.4–99.5, p < 0.001) and the primary endpoint was met. The ORR was 60.0 % (95 % CI; 14.7–94.7), including one complete response. Four (80.0 %) patients experienced at least one treatment-related treatment-emergent adverse event (TEAE). Most TEAEs were grade 1 or 2. There were no treatment-related deaths and no new safety signals were identified. ConclusionsThis study suggests that the combination of olaparib plus trastuzumab may be effective and safe in pre-treated patients with HER2-positive gBRCAm ABC. This ABC patient population should be further studied and not be pre-emptively excluded from clinical trials of targeted therapy for BRCA1/2-driven cancers.

Monitoring changing patterns in HER2 addiction by liquid biopsy in advanced breast cancer patients

BackgroundDuring targeted treatment, HER2-positive breast cancers invariably lose HER2 DNA amplification. In contrast, and interestingly, HER2 proteins may be either lost or gained. To longitudinally and systematically appreciate complex/discordant changes in HER2 DNA/protein stoichiometry, HER2 DNA copy numbers and soluble blood proteins (aHER2/sHER2) were tested in parallel, non-invasively (by liquid biopsy), and in two-dimensions, hence HER2-2D.MethodsaHER2 and sHER2 were assessed by digital PCR and ELISA before and after standard-of-care treatment of advanced HER2-positive breast cancer patients (n=37) with the antibody-drug conjugate (ADC) Trastuzumab-emtansine (T-DM1).ResultsAs expected, aHER2 was invariably suppressed by T-DM1, but this loss was surprisingly mirrored by sHER2 gain, sometimes of considerable entity, in most (30/37; 81%) patients. This unorthodox split in HER2 oncogenic dosage was supported by reciprocal aHER2/sHER2 kinetics in two representative cases, and an immunohistochemistry-high status despite copy-number-neutrality in 4/5 available post-T-DM1 tumor re-biopsies from sHER2-gain patients. Moreover, sHER2 was preferentially released by dying breast cancer cell lines treated in vitro by T-DM1. Finally, sHER2 gain was associated with a longer PFS than sHER2 loss (mean PFS 282 vs 133 days, 95% CI [210-354] vs [56-209], log-rank test p=0.047), particularly when cases (n=11) developing circulating HER2-bypass alterations during T-DM1 treatment were excluded (mean PFS 349 vs 139 days, 95% CI [255-444] vs [45-232], log-rank test p=0.009).ConclusionsHER2 gain is adaptively selected in tumor tissues and recapitulated in blood by sHER2 gain. Possibly, an increased oncogenic dosage is beneficial to the tumor during anti-HER2 treatment with naked antibodies, but favorable to the host during treatment with a strongly cytotoxic ADC such as T-DM1. In the latter case, HER2-gain tumors may be kept transiently in check until alternative oncogenic drivers, revealed by liquid biopsy, bypass HER2. Whichever the interpretation, HER2-2D might help to tailor/prioritize anti-HER2 treatments, particularly ADCs active on aHER2-low/sHER2-low tumors.Trial registrationNCT05735392 retrospectively registered on January 31, 2023 https://www.clinicaltrials.gov/search?term=NCT05735392

The efficacy and safety of trastuzumab biosimilar HLX02 compared with reference trastuzumab plus pertuzumab in combination with chemotherapy as the first-line treatment for HER2 positive metastatic breast cancer: A real-world study in China.

e13016 Background: Dual-targeted anti-HER2 therapy with trastuzumab (H) and pertuzumab (P) significantly improves outcomes in HER2-positive breast cancer and has become the first-line standard treatment for patients with advanced HER2-positive breast cancer in China in 2019 based on the results of the CLEOPATRA and PUFFIN study. HLX02 (Zercepac) was the first trastuzumab biosimilar manufactured in China. Here, we present the first real-world comparison of HLX02 versus reference trastuzumab (RTZ) and pertuzumab with chemotherapy as the first-line treatment for HER2-positive metastatic China.Between January 2019 and August 2023, 121 patients with HER2-positive MBC patients were enrolled at Beijing Cancer Hospital in China. These patients received HLX02 or RTZ in combination with pertuzumab and various chemotherapies as first-line treatment. We retrospectively analyzed survival outcomes, efficacy, and adverse events. Methods: Between January 2019 and August 2023, 121 patients with HER2-positive MBC patients were enrolled at Beijing Cancer Hospital in China. These patients received HLX02 or RTZ in combination with pertuzumab and various chemotherapies as first-line treatment. We retrospectively analyzed survival outcomes, efficacy, and adverse events. Results: Both groups, 68 received RTZ and 53 received HLX02, showed similar characteristics of age, disease status (de novo or recurrent), metastatic sites (visceral or non-visceral), and treatment history. A total of 118 (97.5%) received trastuzumab plus pertuzumab combined with chemotherapy as the first-line palliative therapy, with a median number of 6 cycles in each group. Taxanes were the most commonly used chemotherapy regimen in both groups (91.2 vs. 92.5%), including nab-paclitaxel (44.1 vs. 45.3%), docetaxel (41.2 vs. 17.0%), paclitaxel (5.9 vs. 30.2%). With a median follow-up of 15.0 months (range 1.0 - 58.0), the results showed no significant difference in PFS between the RTZ and HLX02 arms (median PFS: 22.0 vs. 19.0 months, p=0.900). Additionally, the efficacy outcomes, including objective response rate (ORR), disease control rate (DCR), and safety profiles did not show significant differences between the two groups. Among 121 patients, 20 patients (16.5%) experienced CNS progression. For these patients, the median time from the first-line therapy to the CNS progression was 15.0 months (95% CI 12.8 - 17.2). Conclusions: The real-world data suggest similar efficacy and safety of HLX02 and RTZ plus pertuzumab with different chemotherapy regimens as the first-line treatment for patients with HER2-positive advanced breast cancer patients in China. Overall, the PFS was consistent with the CLEOPATRA trial in both groups, and there was no new safety signal.

Real-world analysis of inetetamab combined with pyrotinib plus chemotherapy for the treatment of HER2-positive advanced breast cancer: A multi-center retrospective study.

e13012 Background: Inetetamab combined with tyrosine kinase inhibitors exhibited stronger antitumor effects than inetetamab alone. At present, there was few studies on the efficacy and safety of inetetamab combined with pyrotinib in the treatment of advanced breast cancer (ABC) patients. The study aims to investigate the efficacy and safety of inetetamab combined with pyrotinib plus chemotherapy for HER2-positive ABC patients. Methods: We retrospectively investigated the medical records of eligible women who aged 18 years or older with pathologically confirmed HER2-positive recurrent or metastatic invasive breast cancer, and received at least two cycles of inetetamab combined with pyrotinib plus chemotherapy treatment regimens in multicenters in China between July 2020 and December 2022. The primary endpoint was progression-free survival (PFS) estimated by the Kaplan-Meier method. The secondary endpoints were the objective response rate (ORR), disease control rate (DCR), and safety. Cox regression model was used to identify predictive factors for PFS. Results: A total of 99 patients were included. Overall patient's median PFS was 12.3 (95% CI: 10.9-13.6) months. Of 99 evaluable patients, 53 (53.5%) patients achieved objective response, including 9 (9.1%) complete response and 44 (44.4%) partial response. The remaining 45 patients achieved stable disease as the best response, thus, the DCR was 99.0%. Patients who received Inetetamab combined with pyrotinib plus chemotherapy as first-line treatment (15.0 months [95% CI: 13.6-15.8]) provided longer median PFS than that as second-line treatment (10.3 months [95% CI:9.6-10.9], p&lt;0.001). Furtherly, the Cox multivariate regression analysis indicated that patients who received inetetamab combined with pyrotinib plus albumin-bound paclitaxel for first-line treatment achieved longer median PFS. Grade 1-2 diarrhea (59.6%), vomiting (29.3%) and nausea (28.3%), hand-foot syndrome (23.2%) were the top four most common adverse events (AEs). The most common grade ≥3 AEs were leukopenia (19.2%), diarrhea (18.2%), myelosuppression (7.1%) and neutromenia (4.0%). Conclusions: The first-line treatment of inetetamab combined with pyrotinib plus chemotherapy was an effective and safe treatment for HER2-positive ABC patients. Inetetamab combined with pyrotinib plus albumin-bound paclitaxel might be the most effective combination therapies. All AEs were controllable and tolerable.

Association between platelet-to-lymphocyte ratio and outcomes in HER2-positive advanced breast cancer patients treated with pyrotinib: a retrospective study

Association between platelet-to-lymphocyte ratio and outcomes in HER2-positive advanced breast cancer patients treated with pyrotinib: a retrospective study

Stereotactic Radiotherapy or Whole Brain Radiotherapy Combined with Pyrotinib and Capecitabine in HER2-Positive Advanced Breast Cancer Patients with Brain Metastases (BROPTIMA): A Prospective, Phase Ib/II Single-Arm Clinical Study

Approximately half of patients with advanced HER2-positive breast cancer (BC) will develop brain metastases (BM) over time. Local therapy including stereotactic radiotherapy (SRT) and whole brain radiotherapy (WBRT) is the main initial treatment in malignant tumor patients with BM. However, more than 50% patients after radiotherapy in one year suffered intracranial recurrence. Pyrotinib, a small molecule, irreversible, pan-ErbB receptor tyrosine kinase inhibitor (TKI), has a high potency for controlling BM and reducing the occurrence of brain metastases in advanced HER2-positive BC patients. We hypothesized that SRT or WBRT combined with pyrotinib and capecitabine could decrease intracranial progression in HER2 positive BC with newly diagnosed BM. In this prospective single-arm phase Ib/II trial (NCT04582968), eligible patients were assigned to either fractionated stereotactic radiotherapy (FSRT) or whole-brain radiation therapy (WBRT), combined with pyrotinib and capecitabine. The primary endpoint was one-year CNS progression-free survival (PFS) rate. Secondary endpoints included intracranial objective response rate (IC-ORR) according to RANO-BM criteria, progression-free survival (PFS), overall survival (OS) and evaluation of safety and neurocognitive function. From January 2020 to August 2022, 40 patients were enrolled. Twenty-nine patients were treated with FSRT in 8 Gy per fraction with 3 to 5 fractions and 11 were treated with WBRT in 3 Gy per fraction with 10 fractions, and then received chemotherapy in a time frame starting from 0 to 7 days after radiotherapy. At a median follow-up of 17.3 months, 1-year CNS-PFS rate was 74.9% (95% CI 61.9-90.7%) and median CNS-PFS was 18 months (95% CI, 15.5 to NA months). One-year PFS rate was 66.9% (53.1-84.2%) and median PFS time was 17.6 months (95% CI 12.8-34.1 months). The best intracranial response rate (IC-ORR: complete response and partial response) was 92.5% (37/40). The most common grade 3 or worse toxicity was diarrhea (7.5%) and asymptomatic radiation necrosis was detected in 4 of 67(6.0%) lesions treated with FSRT. No differences of neurocognitive function evaluated by MMSE (Mini-Mental State Exam) were observed between different groups at any time point. Radiotherapy combined with pyrotinib and capecitabine resulted in a promising efficacy that crossed the pre-specified boundary in patients with HER2-positive advanced breast cancer with brain metastases. This is the first prospective study showing the efficacy and safety of CNS radiotherapy concurrent with pyrotinib and capecitabine in patients with BM from HER2-positive breast cancer. Further investigation in a randomized controlled study is warranted.

Pyrotinib plus capecitabine for trastuzumab-resistant, HER2-positive advanced breast cancer (PICTURE): a single-arm, multicenter phase 2 trial

BackgroundPatients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer and primary resistance to trastuzumab have a poor clinical outcome and lack good evidence to inform clinical decision. This study investigated the efficacy and safety of pyrotinib plus capecitabine in this population.MethodsThis phase 2 trial was conducted at 16 sites in China. Patients received oral pyrotinib 400 mg once daily and capecitabine 1000 mg/m2 twice a day on days 1–14 of each 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS).ResultsBetween June 2019 and September 2021, 100 patients were enrolled with a median age of 51 years (range, 24–69). All patients had been treated with trastuzumab and 21 (21.0%) patients had prior use of pertuzumab. As of August 31, 2022, the median follow-up duration was 20.1 months (range, 1.3–38.2). The median PFS was 11.8 months (95% confidence interval [CI], 8.4–15.1), which crossed the pre-specified efficacy boundary of 8.0 months. The objective response rate was 70.0% (70/100), with a median duration of response of 13.8 months (95% CI, 10.2–19.3). The disease control rate was 87.0% (87/100). The median overall survival was not reached. The most common grade ≥ 3 treatment-emergent adverse event was diarrhea (24 [24.0%]). No treatment-related deaths occurred.ConclusionsPyrotinib plus capecitabine can be considered to be a treatment option in HER2-positive advanced breast cancer patients who have shown primary resistance to trastuzumab. Even in the era of modern anti-HER2 treatments, this clinical setting warrants more investigations to meet unmet needs.Trial registrationClinicalTrials.gov, NCT04001621. Retrospectively registered on June 28, 2019.

Updated results from a phase 2 study on dalpiciclib and pyrotinib, a dual-oral chemotherapy-free regimen in HER2-positive advanced breast cancer (DAP-HER-01).

1045 Background: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown synergistic effect with anti-HER2 therapy on hormone receptor (HR)-positive and HER2-positive breast cancer from preclinical models and several clinical studies, while data of this combination in HR-negative and HER2-positive diseases are limited so far. DAP-HER-01 (NCT04293276) was aimed at evaluate the efficacy and safety of the novel dual-oral, chemotherapy-free regimen of CDK4/6 inhibitor dalpiciclib and pan-HER tyrosine kinase inhibitor pyrotinib in HER2-positive advanced breast cancer (ABC) regardless of HR status, and reported to meet the primary endpoints previously (overall ORR 70%), in which HR-negative patients achieved a higher ORR (81.8%, vs 55.6% in HR-positive patients; Min Yan, et al. ESMO 2021, Poster 276P). Here we reported the updated results of this trial. Methods: DAP-HER-01 was a single-arm, phase 2 study conducted in HER2-positive ABC patients with no more than one prior systemic treatment at advanced setting. Enrolled patients received dalpiciclib and pyrotinib until progression, unaccepted toxicity, or no further benefit. The primary endpoint was ORR as per RECIST 1.1, and secondary endpoints included progression-free survival (PFS), overall survival and safety. Results: Between April 9, 2020, and May 19, 2021, 41 patients were enrolled and received study treatment, and 40 of them were assessable for efficacy. With a median follow-up of 19.2 months, the median progression-free survival (PFS) was 11.0 months (95% CI 7.3-19.3). Considering HR status, the PFS in HR-negative patients was not matured (estimated median: 16.6 months; 95% CI: 7.3- NA), but still showed a tendency to be longer than that in HR-positive patients (median: 9.1 months; 95% CI: 5.4-11.0). Patients with brain metastases at baseline could also benefit from this treatment (median PFS: 11.0; 95% CI: 5.4-NA). Consistent with the safety data reported before, the most common grade 3 or 4 treatment-related adverse events were leukopenia (68.3%), neutropenia (65.9%) and diarrhea (19.5%). Most adverse events were tolerable, and no study-related death reported. Conclusions: Combined with previous reports, our findings suggest dalpiciclib combined with pyrotinib achieved promising efficacy and manageable toxicity in the treatment of HER2-positive ABC, including patients with HR-negative disease or brain metastases. This combination could be considered as a completely oral, chemo-free regimen for patients with HER2-positive ABC and is worthy of further study. Clinical trial information: NCT04293276 .

Construction of a prognostic hierarchical model for patients with HER2 positive breast cancer with brain metastases.

e13030 Background: Brain metastasis occurs in about 50% of advanced HER2-positive breast cancer patients. In clinical practice, we need accurate model to predict the patients’ survival time. According to survival time, we can arrange reasonable treatment strategy for HER2 positive breast cancer with brain metastases. Methods: The study recruited HER2-positive breast cancer brain metastasis (BCBM) patients who attended the Fifth Medical Center of PLA General Hospital from June 2003 to June 2022.All statistics were performed using SPSS version 22.0 and R version 3.4.3 software. Results: This study included 300 patients with HER2-positive BCBM. The median age at Brain Metastases diagnosis was 48.5 years, and the median Brain Metastases Overall Survival time (BMOS) was 18.0 months (95% CI: 14.6-21.4). A single-factor analysis of BMOS revealed that age, number of brain metastasis lesions, number of extracranial lesions during BCBM, radiotherapy after BCBM, anti-HER2 therapy after BCBM, and survival prognosis after BCBM were associated with survival prognosis after diagnosis of BCBM. According to a multi-factor analysis, the age, the number of brain metastases, radiotherapy after BCBM, and anti-HER2 therapy after BCBM were all independent factors influencing survival after diagnosis of BCBM. Different independent prognostic factors comprised the patient hierarchical evaluation model. Patients' warning scores range from 0 to 7. We divided the patients into three groups with obvious differences in prognosis： Low- intermediate-risk (score≥1), stroke group (score≥3) and high-risk group (score≥6). The patient prognosis was worse when the warning score was high. The results of Kaplan-Meier survival curve analysis showed significant prognosis differences between the three groups of patients (P &lt; 0.0001). The mean Area Under Curve of the receiver operating characteristic curve for 1-yeasr, 2-year, and 3-year prognosis prediction was 0.69,0.71, and 0.67, respectively. For low-risk patients, the prognosis was significantly improved by using any anti-HER2 medications (P&lt;0.05). Trastuzumab + Pertuzumab can significantly improve the prognosis of patients at intermediate risk (P&lt;0.001, HR=0.24,95%CI: 0.13-0.43). Patients in the intermediate-risk group received both anti-HER2 medication and combined radiotherapy significantly prolonged BMOS in patients who received only drug therapy or radiotherapy (P=0.0132). Conclusions: A survival and prognostic stratification model was constructed based on the clinicopathological characteristics and treatment pattern of a large cohort of HER2-positive breast cancer patients with brain metastases, and the patients were divided into the low-risk group, intermediate-risk group and high-risk group. The optimal individualized treatment strategy was recommended according to different groups.

Abstract P1-04-01: High HER2/CEP17 ratio is associated with better treatment outcomes in advanced HER2-positive breast cancer treated with pertuzumab, trastuzumab, and docetaxel regardless of HER2 2+ or 3+ results

Abstract Background: Dual HER2 blockade with trastuzumab and pertuzumab combined with docetaxel (DHP) is the standard first-line treatment option for patients with HER2-positive metastatic breast cancer. However, HER2 positivity alone often fails to predict treatment outcome of HER2 targeted therapy. The magnitude of HER2 immunohistochemical staining (IHC) and HER2/CEP17 ratio from in situ hybridization (ISH) is a well-known predictive biomarker for HER2 targeted therapy. In the neo-adjuvant setting, patients with HER2 IHC 3+ have higher pathologic complete response (pCR) rate compared to HER2 IHC&amp;lt; 3+ with HER2 ISH positive. In addition, higher HER2/CEP17 ratio is associated with higher pCR rate in HER2-positive breast cancer patients treated with dual HER2 blockade regimens. However, there is no data whether there is an association between HER2/CEP17 ratio and treatment outcome of DHP regimen in patients with advanced of metastatic breast cancer especially among those with HER2 IHC 3+. Methods: We performed a retrospective cohort study with patients with locally advanced or metastatic HER2-positive breast cancer who were treated with first-line palliative DHP regimen between August 2008 and January 2021 at Seoul National University Hospital. In the clinical setting, HER2 IHC 3+ is defined as HER2 positive and no further ISH testing is required. Additional ISH was performed in patients with HER2 IHC 3+ without archival HER2 ISH results. The association between HER2/CEP17 ratio and treatment outcome was assessed. Results: In total, 165 patients were included with a median follow-up duration of 28.0 months. Among the 165 patients, 35 patients had archival ISH result and additional ISH was performed in 53 patients. The correlation between HER2/CEP17 ratio and treatment outcome was assessed in 88 patients. Cox proportional hazard analysis revealed that HER2/CEP17 ratio is correlated with PFS (HR 0.23, 95% CI 0.11-0.49, p &amp;lt; 0.001). When dichotomized by the median HER2/CEP17 ratio of 4.17, patients with higher HER2/CEP17 ratio had significantly longer PFS (37.5 vs. 17.4 months, p = 0.003) and numerically higher ORR (54.5% vs. 34.1%, p = 0.085). Multivariate analysis revealed that HER2/CEP17 ratio is an independent prognostic factor for PFS (HR 0.72, p = 0.001). Of 88 patients with ISH results, 25 had HER2 IHC 1+ or 2+ and 63 had HER2 IHC 3+. HER2/CEP17 ratio was associated with PFS in both HER2 IHC 1+/2+ patients (HR 0.12, 95% CI 0.02-0.88, p = 0.037) and HER2 IHC 3+ patients (HR 0.18, 95% CI 0.07-0.49, p = 0.001). Patients with higher HER2/CEP17 ratio had longer PFS in both HER2 IHC 1+/2+ patients (28.6 vs. 12.9 months, p = 0.003) and HER2 IHC 3+ patients (Not reached vs. 18.3 months, p = 0.005) when dichotomized by the median HER2/CEP17 of 2.95 and 4.75, respectively. Conclusion: This is the first study to report that higher HER2/CEP17 ratio is associated with longer PFS in HER2-positive advanced breast cancer patients treated with palliative first-line DHP. The strength of this study is that we identified prognostic role of ISH even in patients with HER2 IHC 3+. It would be helpful to perform ISH not only in patients whose HER2 IHC is ambiguous, but also in patients with HER2 IHC 3+ to make better prediction of treatment outcome. Table 1. Patient characteristics. Citation Format: Jeongmin Seo, Jiwon Koh, Dae-Won Lee, Han Suk Ryu, Kyung-Hun Lee, Tae-Yong Kim, Seock-Ah Im. High HER2/CEP17 ratio is associated with better treatment outcomes in advanced HER2-positive breast cancer treated with pertuzumab, trastuzumab, and docetaxel regardless of HER2 2+ or 3+ results [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-04-01.

Integrin αvβ3 Is a Master Regulator of Resistance to TKI-Induced Ferroptosis in HER2-Positive Breast Cancer

Human epidermal growth factor receptor-2 (HER2)-targeting therapies provide clinical benefits for patients with HER2-positive breast cancer. However, the resistance to monotherapies invariably develops and leads to disease relapse and treatment failure. Previous studies have demonstrated a link between the potency of HER2-targeting tyrosine kinase inhibitors (TKIs) and their ability to induce an iron-dependent form of cell death called ferroptosis. The aim of this study was to understand the mechanisms of resistance to TKI-induced ferroptosis and identify novel approaches to overcome treatment resistance. We used mouse and human HER2-positive models of acquired TKI resistance to demonstrate an intimate link between the resistance to TKIs and to ferroptosis and present the first evidence that the cell adhesion receptor αvβ3 integrin is a critical mediator of resistance to TKI-induced ferroptosis. Our findings indicate that αvβ3 integrin-mediated resistance is associated with the re-wiring of the iron/antioxidant metabolism and persistent activation of AKT signalling. Moreover, using gene manipulation approaches and pharmacological inhibitors, we show that this "αvβ3 integrin addiction" can be targeted to reverse TKI resistance. Collectively, these findings provide critical insights into new therapeutic strategies to improve the treatment of advanced HER2-positive breast cancer patients.

Survival outcomes of beta-blocker usage in HER2-positive advanced breast cancer patients: a retrospective cohort study.

Clinical trials investigating the effects of beta-blockers (BBs) on cancer are underway. Evidence from preclinical research suggests that BBs could serve as anticancer agents and immune boosters. There is conflicting evidence regarding the effect of BB use on clinical outcomes in patients with breast cancer. The study aimed to determine whether BB use is associated with progression-free survival (PFS) and overall survival (OS) in patients receiving anti-human epidermal growth factor receptor 2 (HER2) treatment for advanced breast cancer. Retrospective hospital-based study. The participants enrolled were breast cancer patients with advanced HER2-positive status who initiated trastuzumab monotherapy or concomitant therapy with trastuzumab and any dose of BB. The patients were enrolled between January 2012 and May 2021 and divided into three groups based on whether they received a BB or not in the therapeutic regimen: BB-/trastuzumab+, BB+ (non-selective)/trastuzumab+, and BB+ (selective)/trastuzumab+. PFS and OS were the primary and secondary endpoints, respectively. The estimated median PFS in the BB-/trastuzumab+, BB+ (non-selective)/trastuzumab+, and BB+ (selective)/trastuzumab+ groups was 51.93, 21.50, and 20.77 months, respectively. The corresponding OS was 56.70, 29.10, and 27.17 months. The intergroup differences in these durations were significant. Both PFS [adjusted hazard ratio (HR): 2.21, 95% confidence interval (CI): 1.56-3.12; p < 0.001]) and OS (adjusted HR: 2.46, 95% CI: 1.69-3.57; p < 0.001) were worse when BBs were used. Our study provides important evidence that BB use potentially has a negative effect on patients with HER2-positive advanced breast cancer. Nevertheless, despite the study's results, cardiovascular disease (CVD) should be appropriately treated in patients with HER2-positive advanced breast cancer. Other types of drugs can be used to treat CVD, but BB use should be avoided. Large real-world database and prospective studies should be conducted to validate the results of this study.

Therapeutic landscape of advanced HER2-positive breast cancer in 2022.

HER2-positive breast cancer is an aggressive subtype of breast cancer with five-year survival rates of 30% for the advanced stage. The development of anti-HER2 treatments has led to a paradigm shift in the management and clinical outcomes of advanced HER2-positive breast cancer patients. The standard first-line treatment consists of taxane-based chemotherapy plus dual anti-HER2 therapies with trastuzumab and pertuzumab. The antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) has been a second-line therapeutic standard, but the second-line treatment approach is rapidly evolving. Given a substantial advantage of another ADC, Fam-trastuzumab deruxtecan (T-DXd), compared to T-DM1 in a recent randomized trial in the second-line setting, T-DXd is currently the preferred second-line option. Optimal third-line treatment strategies are still not established, and multiple approaches have been used including combinations based on capecitabine, trastuzumab, or both with oral anti-HER2 tyrosine kinase inhibitors. Tucatinib plus capecitabine and trastuzumab, lapatinib plus trastuzumab, neratinib or lapatinib plus capecitabine are some of the FDA approved combinations. Another newer agent approved for third- or later-line therapy in the metastatic setting ismargetuximab, an Fc-engineered anti-HER2 monoclonal antibody, in combination with chemotherapy. Other novel agents currently under clinical trials are the drugs that indirectly target HER2, including immune cell cycle inhibitors, PI3K/mTOR inhibitors, and immunotherapy agents.

Comparative review of pharmacological therapies in individuals with HER2-positive advanced breast cancer with focus on hormone receptor subgroups.

Breast cancer is the fifth leading cause of cancer-related deaths worldwide. The randomized controlled trials (RCTs) of targeted therapies in human epidermal receptor 2 (HER2)–positive advanced breast cancer (ABC) have provided an evidence base for regulatory and reimbursement agencies to appraise the use of cancer therapies in clinical practice. However, a subset of these patients harbor additional biomarkers, for example, a positive hormone receptor status that may be more amenable to therapy and improve overall survival (OS). This review seeks to explore the reporting of evidence for treatment effects by the hormone receptor status using the RCT evidence of targeted therapies for HER2-positive ABC patients. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed to identify published RCTs. Extracted data were synthesized using network meta-analysis to obtain the relative effects of HER2-positive-targeted therapies. We identified a gap in the reporting of the effectiveness of therapies by the hormone receptor status as only 15 out of 42 identified RCTs reported hormone receptor subgroup analyses; the majority of which reported progression-free survival but not OS or the overall response rate. In conclusion, we recommend that future trials in ABC should report the effect of cancer therapies in hormone receptor subgroups for all outcomes.

Maintenance endocrine therapy prolonged progression-free survival of first-line chemotherapy with trastuzumab in advanced HR-positive, HER2-positive breast cancer patients.

e13023 Background: Human epidermal growth factor receptor-2 (HER2) positive breast cancer is a growing concern due to the boom in anti-HER2 therapy. Trastuzumab as the most classic anti-HER2 therapy drug, combined with chemotherapy has become the standard first-line treatment for advanced HER2-positive (HER2+) patients. Although some real-world studies of trastuzumab have been reported, less is known about the role of hormone receptors (HR) in first-line combined therapy. For maintenance therapy after chemotherapy combined with anti-HER2 therapy, the guidance given by clinical trials is the maintenance of targeted therapy. However, for those with HER2+/HR-positive (HR+) breast cancer, whether adding endocrine maintenance therapy can benefit progression-free survival (PFS) in addition to anti-HER2 therapy still needs more research. Thus, the purpose of this study was to retrospectively analyze real-world data, determine the factors that influence the trastuzumab-based therapy in advanced HER2-positive breast cancer patients. Methods: We retrospectively collected the treatment information of advanced breast cancer patients underwent first-line chemotherapy with trastuzumab from 2012 to 2021 in Zhejiang Cancer Hospital. Kaplan–Meier analysis and Cox regression methods were used to calculate and compare the PFS. Results: The study finally enrolled 285 patients meeting the requirement, including 150 HER2+/HR-negative (HR-) and 135 HER2+/HR+ (triple-positive) patients. The median chemotherapy treatment cycles and trastuzumab cycles were 7 (6-8) and 12 (7-17) cycles, respectively. For triple-positive breast cancer, maintenance endocrine therapy was aslo given concurrently with trastusumab in 75 patients after chemotherapy and trastusumab. Overally, the median PFS of first-line treatment was 11.73 (10.16-13.30) months, which was consistent with literature reports. Multivariate analysis revealed that HR positive [hazard ratio, 0.69; 95% confidence interval (CI), 0.52–0.92; P= 0.010], and non-brain metastasis (hazard ratio, 0.54; 95% CI, 0.29–0.99; P= 0.048) were independent prognostic factors. Further Kaplan–Meier analysis demonstrated triple-positive patients with maintenance endocrine therapy significantly had longer PFS than triple-positive patients without maintenance endocrine therapy and HER2+/HR- patients (21.33m vs. 10.13m vs. 9.53m, respectively, P &lt; 0.001). Conclusions: HR-positive was an independent prognostic factor for HER2-positive advanced breast cancer patients receiving first-line chemotherapy with trastuzumab. And endocrine therapy combined trastuzumab as Maintenance after chemotherapy prolonged PFS in HR-positive subgroup patients.

Incidence and management of pyrotinib-associated diarrhea in HER2-positive advanced breast cancer patients.

The PHOEBE study showed that pyrotinib is an alternative treatment option for patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer after trastuzumab and chemotherapy. Diarrhea was a common adverse event that could compromise or modify treatment administration. We conducted a retrospective cohort study of HER2-positive advanced breast cancer patients receiving a pyrotinib-based regimen between August 2018 and January 2021. The risk of diarrhea with 95% confidence limits (CLs) was calculated and management was analyzed. A total of 46 HER2-positive advanced breast cancer patients were enrolled. Diarrhea of any grade occurred in 100% of patients, and grade 3 diarrhea was observed in 52.2% (n=24) of patients. Treatment dose modification was implemented in 39.1% (n=18) of advanced breast cancer patients. Compared with other treatment regimens, patients receiving pyrotinib plus vinorelbine suffered the highest risk of diarrhea (60%), though no significant difference was confirmed (P=0.77). Antidiarrheal agents were commonly used and loperamide-based regimens achieved an ideal antidiarrheal effect (95.3-100%), while non-loperamide-based regimens (such as montmorillonite powder) had a lower control rate (78.6%). Diarrhea was a common adverse event of pyrotinib-based treatment, and approximately 50% of patients suffered high grade diarrhea. Loperamide-based antidiarrheal agents could commendably manage most episodes.

Evaluation of the Preventive Effects of Carvedilol on Trastuzumab-Induced Cardiotoxicity in Early-Stage and Locally Advanced HER2-Positive Breast Cancer Patients.

Background: Trastuzumab is an efficient monoclonal antibody used in the treatment of Her2-positive breast cancer. Despite its prominent effect on Her2-positive patients’ disease-free Survival. Trastuzumab-induced cardiotoxicity is still one of the main challenges. Angiotensin-converting enzyme inhibitors (ACE inhibitors) are one of the most potent agents used in heart failure, which also showed confirmed cardioprotective effects against anthracycline and doxorubicin. We aimed to assess the cardioprotective effects of Carvedilol in a randomized clinical trial study. Materials and Methods: sixty non-metastatic Her-2 positive patients (30 cases; 30 controls) were entered into the study via a simple randomization method.Carvedilol was administered for the patients with the starting dose of 3.125 mg twice a day and started 7 days before trastuzumab administration. The dose has been increased in a three-week period to reach 12.5 mg twice a day and continued until the end of therapy. All the patients underwent an echocardiography after receiving Adriamycin and Cyclophosphamide in order to measure basal Ejection Fraction (EF) and Pulmonary Artery Pressure (PAP). Each patient underwent a follow-up echocardiography in 3,6,9 and 12 months after initiation of the treatment. Finally, all the patients went through the last episode of echocardiography 1 month after the end of treatment. All the Measured PAP and EF has been recorded and analyzed Results: EF and PAP changes for both groups had no significant changes during the course of treatment with Trastuzmab (p-value = 0.628 and p-value = 0.723, respectively). Seven patients in the intervention group and 2 patients in the control group presented with EF decrease. Also, 8 patients in the intervention and 9 patients in the control groups showed PAP increase. Conclusion: According to our results, in patients with HER2-positive breast cancer treated with trastuzumab, Carvedilol showed no significant protective effect on trastuzumab-induced cardiotoxicity.

155P The addition of pyrotinib in early or locally advanced HER2-positive breast cancer patients with no response to two cycles of neoadjuvant therapy: A prospective, multicenter study

Early assessment of clinical response to treatment would facilitate individualized therapy, with ineffective therapy changed. Pyrotinib is a new oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor that targets human epidermal growth factor receptor (HER) 1, HER2, and HER4. Whether the addition of pyrotinib to TCH (trastuzumab, docetaxel, carboplatin) regimen can bring benefit to non-responder after 2 neoadjuvant cycles of TCH is unclear. This prospective, open-label, multicenter study (NCT03847818) explored the efficacy and safety of neoadjuvant pyrotinib + TCH in patients with early or locally advanced HER2-positive breast cancer who did not respond after 2 neoadjuvant cycles of TCH.

Efficacy and Side Effects in HER2-Positive Advanced Breast Cancer Patients Treated with Pyrrotinib: A Real-World Study in China

Background: Pyrotinib is a molecular and irreversible tyrosine kinase inhibitor independently developed in China, and its efficacy against HER2- positive breast cancer in the real world is not clear. In this study, we evaluated the efficacy and safety of pyrotinib in the treatment of HER2-positive advanced breast cancer based on real-world evidence. Materials and Methods: We designed a prospective observational study. Thirty-six patients with HER2-positive advanced breast cancer from a single medical center were included in the study from December 2018 to February 2021. All patients received the oral HER2 receptor inhibitor pyrotinib and received concurrent chemotherapy or endocrinotherapy. The follow-up endpoint is set as April 1, 2021. The primary endpoint is Objective Response Rate (ORR) and Disease Control Rate (DCR), and the secondary endpoint is Progression- Free Survival (PFS) and related side effects. Results: By the end point of follow-up, a total of 17 patients had progressed (including 6 deaths), and the progression-free survival rate was 52.78%. The median PFS was 13months (PFS range: 3-22 months). As the best response, 4 patients achieved CR, 20 patients achieved PR, 9 patients achieved SD, and 3 patient developed PD. The ORR was 66.67% and DCR was 91.67%. In the analysis, first-line pyrotinib treatment appeared to have higher ORR (88.88% vs 59.26%), but there was no significant difference. In addition, pyrotinib showed significant efficacy in patients with brain metastases, with an ORR of 42.85%. In terms of safety, the incidence of diarrhea was 80.55%, but only 4 patients had grade 3 diarrhea, which was tolerable after the drug dose was reduced; 1 patient had grade 4 neutropenia and grade 3 and thrombocytopenia, which were considered to be related to the chemotherapy drugs. The incidence of other adverse reactions was low, and all were grade 1 to 2. Conclusion: Pyrotinib combined with chemotherapy has a significant effect on HER2-positive breast cancer, and there is still a high ORR in patients who fail multiple lines of treatment. Side effects are overall controllable and safe.

PANHER study: a 20-year treatment outcome analysis from a multicentre observational study of HER2-positive advanced breast cancer patients from the real-world setting.

Background:The evolution of therapeutic landscape of human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) has led to an unprecedented outcome improvement, even if the optimal sequence strategy is still debated. To address this issue and to provide a picture of the advancement of anti-HER2 treatments, we performed a large, multicenter, retrospective study of HER2-positive BC patients.Methods:The observational PANHER study included 1,328 HER2-positive advanced BC patients treated with HER2 blocking agents since June 2000 throughout July 2020. Endpoints of efficacy were progression-free survival (PFS) and overall survival (OS).Results:Patients who received a first-line pertuzumab-based regimen showed better PFS (p < 0.0001) and OS (p = 0.004) than those receiving other treatments. Median PFS and mOS from second-line starting were 8 and 28 months, without significant differences among various regimens. Pertuzumab-pretreated patients showed a mPFS and a mOS from second-line starting not significantly affected by type of second line, that is, T-DM1 or lapatinib/capecitabine (p = 0.80 and p = 0.45, respectively). Conversely, pertuzumab-naïve patients receiving second-line T-DM1 showed a significantly higher mPFS compared with that of patients treated with lapatinib/capecitabine (p = 0.004). Median OS from metastatic disease diagnosis was higher in patients treated with trastuzumab-based first line followed by second-line T-DM1 in comparison to pertuzumab-based first-line and second-line T-DM1 (p = 0.003), although these data might be partially influenced by more favorable prognostic characteristics of patients in the pre-pertuzumab era. No significant differences emerged when comparing patients treated with ‘old’ or ‘new’ drugs (p = 0.43), even though differences in the length of the follow-up between the two cohorts should be taken into account.Conclusion:Our results confirmed a relevant impact of first-line pertuzumab-based treatment and showed lower efficacy of second-line T-DM1 in trastuzumab/pertuzumab pretreated, as compared with pertuzumab-naïve patients. Our findings may help delineate a more appropriate therapeutic strategy in HER2-positive metastatic BC. Prospective randomized trials addressing this topic are awaited.