HER2-positive Cancer Research Articles

Clinical Efficacy of Pyrotinib Combined with Capecitabine in the Second-Line or Above Treatment for HER-2 Positive Advanced Breast Cancer and Its Association with Cell-Free DNA.

Purpose To evaluate the clinical efficacy of pyrotinib combined with capecitabine in the treatment of HER-2 positive breast cancer in real world and its correlation with cfDNA. Methods From September 2020 to June 2021, 181 cases of HER-2 positive advanced breast cancer patients who were treated in Jiangsu Cancer Hospital and Nantong Cancer Hospital were analyzed. Patients were given pyrotinib combined with capecitabine or trastuzumab combined with capecitabine. Eighty-one patients who received pyrotinib+capecitabine second-line or above treatment were included in the pyrotinib group, and 100 patients who received trastuzumab+capecitabine second-line or above treatment were included in the trastuzumab group. The objective response rate (ORR) and clinical benefit rate (CBR) of the two groups were compared. The follow-up results of the patients were analyzed, and the progression-free survival (PFS) and adverse reactions were compared between the two groups. Plasma cfDNA was detected by real-time fluorescence quantitative PCR. The cfDNA levels of patients before and after treatment were compared, and the change of cfDNA levels in patients with different curative effects over time was recorded. The patients were further divided into high cfDNA expression and low cfDNA expression groups, and the PFS of patients with different cfDNA levels was analyzed. COX univariate and multivariate analysis of factors influencing posttreatment survival in patients with HER-2-positive breast cancer were performed. Results The ORR of the pyrotinib group (58.02%) was significantly higher than that of the trastuzumab group (42.00%, P = 0.0369). Similarly, the CBR of the pyrotinib group (65.43%) was significantly higher than that of the trastuzumab group (49.00%, P = 0.0347). The incidence of adverse reactions between the two groups was not statistically significant (P > 0.05). The results of survival analysis showed that the PFS of the pyrotinib group was 8.02 ± 3.05 months, the PFS of the trastuzumab group was 7.11 ± 3.06 months, and the PFS of the pyrotinib group was significantly longer than that of the trastuzumab group (P = 0.035). The comparison of cfDNA levels between the two groups showed that on the 28th and 56th day of treatment, the cfDNA levels in the pyrotinib group were significantly lower than those in the trastuzumab group (P < 0.05). Long-term follow-up results showed that compared with patients with high cfDNA expression, the PFS of patients with low cfDNA expression was significantly prolonged (P < 0.05). The level of cfDNA is an independent risk factor affecting the prognosis of patients with HER-2-positive breast cancer. Conclusion The combined use of pyrotinib and capecitabine has good clinical efficacy and high safety in patients with HER-2 positive breast cancer. The combined use of pyrotinib and capecitabine prolongs the PFS of patients and reduces the level of plasma cfDNA. Changes in cfDNA levels can reflect the therapeutic efficacy of patients with HER-2-positive breast cancer to a certain extent and can be used as a potential indicator for evaluating the prognosis of patients with HER-2-positive breast cancer.

Magnetic resonance imaging correlation with molecular and epigenetic markers in assessment of breast cancer

BackgroundBreast cancer is a heterogeneous disease with a wide range of clinical behavior, histologic subtypes, therapeutic options, and outcomes. The different biology and histology of breast cancer display different tumor morphology at breast magnetic resonance imaging (MRI). However, few studies have examined the relationship between the MRI morphological, kinetic features and molecular and epigenetic markers in breast cancer assessment. The study aimed to evaluate the correlation between MRI morphological and kinetic features, molecular and an epigenetic marker (linc-ITGB1) in breast cancer cases. A total of 115 women (80 cases and 35 controls) with BIRAD 4 category breast lesions were included. The association between the MRI morphological & kinetic features, apparent diffusion coefficient (ADC) values, and molecular and the epigenetic marker (linc-ITGB1) was evaluated using Mann–Whitney and Chi-square tests.ResultsThe shape (p = 0.009), size of the lesion (p = 0.003), and pattern of enhancement (p ≤ 0.001) were significantly correlated with the molecular markers. Luminal subtypes are more likely to be presented with irregular shaped and non-circumscribed margin masses (97% for luminal A and 94.1% for luminal B). Triple-negative cancers are frequently presented with regular masses, circumscribed margins, and peripheral rim enhancement (50% of TN tumors). HER2-positive cancers are more likely to be multifocal/multicentric and are more associated with non-mass pattern of enhancement as compared to HER2-negative cancers. Perilesional edema was also significantly correlated with HER2-positive lesions (p = 0.009). Although the epigenetic marker linc-ITGB1 was overexpressed by 4.85-folds in breast cancer cases compared to benign controls, we could not find any significant correlation between its expression level and the MRI features or molecular subtypes (p = 0.948).ConclusionsMRI features can be a reliable predictor of breast cancer molecular subtypes. The epigenetic marker linc-ITGB1 has a potential role in breast cancer pathogenesis but with no significant correlation with either the MRI features or molecular subtypes of the lesions.

Site-Selective Lysine Acetylation of Human Immunoglobulin G for Immunoliposomes and Bispecific Antibody Complexes.

Site-selective acetylation of a single lysine residue in a protein that reaches a lysine acetyltransferase's accuracy, precision, and reliability is challenging. Here, we report a peptide-guided, proximity-driven group transfer reaction that acetylates a single lysine residue, Lys 248, of the fragment crystallizable region (Fc region) in the heavy chain of the human Immunoglobulin G (IgG). An Fc-interacting peptide bound with the Fc domain and positioned a phenolic ester close to Lys 248, which induced a nucleophilic reaction and resulted in the transfer of an acetyl group to Lys 248. The acetylation reaction proceeded to a decent yield under the physiological condition without the need for deglycosylation, unnatural amino acids, or catalysts. Along with acetylation, functional moieties such as azide, alkyne, fluorescent molecules, or biotin could also be site-selectively installed on Lys 248, allowing IgG's further derivatization. We then synthesized an antibody-lipid conjugate and constructed antibody-conjugated liposomes (immunoliposomes), targeting HER2-positive (HER2+) cancer cells. We also built a bispecific antibody complex (bsAbC) covalently linking an anti-HER2 antibody and an anti-CD3 antibody. The bsAbC showed in vitro effector-cell-mediated cytotoxicity at nanomolar concentrations. Compared with bispecific antibodies (bsAbs), bsAbCs are constructed based on native IgGs and contain two antigen-binding sites to each antigen, twice that of bsAbs. Altogether, this work reports a method of site-selective acetylation of native antibodies, highlights a facile way of site-selective IgG functionalization, and underscores the potential of bsAbCs in cancer immunotherapy.

Discovery of potent and selective HER2 PROTAC degrader based Tucatinib with improved efficacy against HER2 positive cancers

HER2 is a validated therapeutic target for HER2 positive breast cancer and gastric cancer. TKIs have significantly improved the prognosis of patients with HER2 positive cancer. However, the pan-HER TKIs always caused gastrointestinal and skin side effects, and acquired drug resistance inevitable compromised their therapeutic efficacy. Herein, we describe the discovery of the first potent and selective HER2 PROTAC degrader based Tucatinib with improved antitumor activity in vitro and in vivo. The preferred selective HER2 PROTAC, CH7C4, efficiently degraded HER2 with DC50 of 69 nM and Dmax of 96%, and inhibited the proliferation of BT-474 cells with IC50 of 0.047 ± 0.006 nM via long lasting HER2 degradation and strong repression of downstream pathway. Moreover, CH7C4 had acceptable pharmacokinetic profiles with a half-life of 5.31 h, and significantly inhibited the growth of BT-474 xenografts in vivo with TGI of 73%. As the first selective HER2 PROTAC degrader with better activity in vitro and in vivo than Tucatinib, CH7C4 provides new insights into the development of new therapeutic strategy for HER2 positive cancer.

High in-vivo stability in preclinical and first-in-human experiments with [18F]AlF-RESCA-MIRC213: a 18F-labeled nanobody as PET radiotracer for diagnosis of HER2-positive cancers.

[18F]AlF-RESCA was introduced as a core particularly useful for 18F-labeling of heat-sensitive biomolecules. However, no translational studies have been reported up to now. Herein, we reported the first-in-human evaluation of an 18F-labeled anti-HER2 nanobody MIRC213 as a PET radiotracer for imaging HER2-positive cancers. MIRC213 was produced by E. coli and conjugated with ( ±)-H3RESCA-Mal. [18F]AlF-RESCA-MIRC213 was prepared at room temperature. Its radiochemical purity and stability of were determined by radio-HPLC with the size-exclusion chromatographic column. Cell uptake was performed in NCI-N87 (HER2 +) and MCF-7 (HER2-) cells and the cell-binding affinity was verified in SK-OV-3 (HER2 +) cells. Small-animal PET/CT was performed using SK-OV-3, NCI-N87, and MCF-7 tumor-bearing mice at 30min, 1h, and 2h post-injection. For blocking experiment, excess MIRC213 was co-injected with radiotracer. Biodistribution were performed on SKOV-3 and MCF-7 tumor-bearing mice at 2h post-injection. For clinical study, PET/CT images were acquired at 2h and 4h after injection of [18F]AlF-RESCA-MIRC213 (1.85-3.7MBq/kg) in six breast cancer patients (3 HER2-positive and 3 HER2-negative). All patients underwent [18F]-FDG PET/CT within a week for tissue selection purpose. Distribution and dosimetry were calculated. Standardized uptake values (SUV) were measured in tumors and normal organs. MIRC213 was produced with > 95% purity and modified with RESCA to obtain RESCA-MIRC213. [18F]AlF-RESCA-MIRC213 was prepared within 20min at room temperature with the radiochemical yield of 50.48 ± 7.6% and radiochemical purity of > 98% (n > 10), and remained stable in both PBS (88%) and 5% HSA (92%) after 6h. The 2h cellular uptake of [18F]AlF-RESCA-MIRC213 in NCI-N87 cells was 11.22 ± 0.60 AD%/105 cells. Its binding affinity Kd value was determined to be 1.23 ± 0.58nM. Small-animal PET/CT with [18F]AlF-RESCA-MIRC213 can clearly differentiate SK-OV-3 and NCI-N87 tumors from MCF-7 tumors and background with a high uptake of 4.73 ± 1.18 ID%/g and substantially reduced to 1.70 ± 0.13 ID%/g for the blocking group (p < 0.05) in SK-OV-3 tumors at 2h post-injection. No significant bone radioactivity was seen in the tumor-bearing animals. In all six breast cancer patients, there was no adverse reaction during study. The uptake of [18F]AlF-RESCA-MIRC213 was mainly in lacrimal gland, parotid gland, submandibular gland, thyroid gland, gallbladder, kidneys, liver, and intestines. There was no significant bone radioactivity accumulation in cancer patients. [18F]AlF-RESCA-MIRC213 had significantly higher tumor uptake in lesions from HER2-positive patients than that lesions from HER2-negative patients (SUVmax of 3.62 ± 1.56 vs. 1.41 ± 0.41, p = 0.0012) at 2h post-injection. The kidneys received the highest radiation dose of 2.42 × 10-1mGy/MBq, and the effective dose was 1.56 × 10-2mSv/MBq. [18F]AlF-RESCA-MIRC213 could be prepared with high radiolabeling yield under mild conditions. [18F]AlF-RESCA-MIRC213 has relatively high stability both in vitro and in vivo. The results from clinical transformation suggest that [18F]AlF-RESCA-MIRC213 PET/CT is a safe procedure with favorable pharmacokinetics and dosimetry profile, and it is a promising new PET radiotracer for noninvasive diagnosis of HER2-positive cancers.

Efficacy and Risk Factors of Pyrrotinib in Second- and Third-Line Treatments for HER2-Positive Advanced Breast Cancer.

A study to examine the efficacy and risk factors associated with pyrrotinib in the second- and third-line treatment of advanced breast cancer with Human epidermal growth factor receptor 2- (HER2-) positive cells was conducted. Progression-free survival (PFS) was assessed as the primary endpoint, and the objective response rate (ORR), overall survival (OS), and safety were secondary endpoints. Across all the patients, the ORR was 48.57%, and the disease control rate (DCR) was 94.29%. In the follow-up period, the median PFS was 15 months, and second-line treatment had significantly longer PFS than third-line treatment (P = 0.027). The OS among all the patients was up to 28 months, but the median OS has not yet been reached. Diarrhea (69.57%) was the most important AE, mainly in grades 1 and 2. According to the COX regression analysis, brain metastasis was a risk factor for PFS, while second-line treatment and capecitabine chemotherapy were relevant to a longer PFS correlation among patients. In the second- and third-line treatment, pyrrotinib is still highly effective and safe. Pyrrotinib is a potential ideal salvage treatment plan for patients who failed in first-line treatments.

Pertuzumab, trastuzumab, and chemotherapy in HER2-positive gastric/gastroesophageal junction cancer: end-of-study analysis of the JACOB phase III randomized clinical trial

BackgroundDual-targeted anti-HER2 therapy significantly improves outcomes in HER2-positive breast cancer and could be beneficial in other HER2-positive cancers. JACOB’s end-of study analyses aimed to evaluate the long-term efficacy and safety of pertuzumab plus trastuzumab and chemotherapy for previously untreated HER2-positive metastatic gastric or gastroesophageal junction cancer.MethodsEligible patients were randomized 1:1 to pertuzumab/placebo plus trastuzumab and chemotherapy every 3 weeks. Primary endpoint: overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety.ResultsThe intention-to-treat population comprised 388 patients in the pertuzumab arm and 392 in the placebo arm. The safety population comprised 385 and 388 patients, respectively. Median follow-up was ≥ 44.4 months. Median OS was increased by 3.9 months (hazard ratio 0.85 [95% confidence intervals, 0.72–0.99]) and median PFS by 1.3 months (hazard ratio 0.73 [95% confidence intervals, 0.62–0.85]) in the pertuzumab vs. the placebo arm. ORR was numerically higher (57.0% vs. 48.6%) and median DoR 1.8 months longer with pertuzumab treatment. There was a trend for more favorable hazard ratios in certain subgroups related to HER2 amplification/overexpression. Safety was comparable between arms, except for serious and grade 3–5 adverse events, and any-grade diarrhea, which were more frequent with pertuzumab.ConclusionsJACOB did not meet its primary endpoint. Nonetheless, the study continues to demonstrate some, albeit limited, evidence of treatment activity and an acceptable safety profile for pertuzumab plus trastuzumab and chemotherapy in previously untreated HER2-positive metastatic gastric or gastroesophageal junction cancer after long-term follow-up.Trial registration NCT01774786; https://clinicaltrials.gov/ct2/show/NCT01774786.

Novel treatment approaches for HER2 positive solid tumors (excluding breast cancer).

Human epidermal growth factor 2 (HER2) alterations (protein overexpression, gene amplification and mutation) play a key role in oncogenesis and are more likely correlated to poorer outcome in solid tumors. We reviewed recently published studies in the last 18 months on novel treatment approaches for HER2 positive solid tumors (excluding breast cancer). Results of clinical studies assessing anti-HER2 therapies have been recently issued.One of the most promising drugs is transtuzumab deruxtecan, an antibody-drug conjugate which demonstrated clinically meaningful activity in gastric or gastroesophageal junction cancer and colorectal cancers.Small molecules such as poziotinib, pyrotinib, neratinib, which target both epidermal growth factor receptor (EGFR) and HER2 also showed promising activity, especially in heavily pretreated ERRB2-mutated non-small cell lung cancer (NSCLC) cancer patients. Yet, these findings need to be confirmed in confirmatory randomized trials with larger cohorts.Trastuzumab-based combinations with chemotherapy or immune checkpoint inhibitors are under development with promising results, but not in all HER2 tumors. Emerging adverse events with anti-HER2 are interstitial pneumopathy and diarrhea. Tyrosine kinase inhibitors, antibody drug conjugate in monotherapy and combinations are emerging strategies in many HER2-positive cancers; HER2 therapies are now part of standard of care of HER2-amplified gastric or gastroesophageal junction cancer. Data are pending on several unmet medical needs.

1210P The preliminary efficacy and safety of KN026 combined with KN046 treatment in HER2-positive locally advanced unresectable or metastatic gastric/gastroesophageal junction cancer without prior systemic treatment in a phase II study

KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes. KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD-1 and CTLA-4 interaction with CD80/CD86. An IIT study (KN046-IST-02) had proved efficacy and safety of KN026 combined with KN046 for late line HER2 positive gastrointestinal cancer.

1705P HER2 intratumoral genetic and non-genetic heterogeneity in metastatic colorectal cancer

HER2-positive metastatic colorectal cancer (mCRC) is a distinct subtype for which HER2-targeted therapy is established. HER2 intratumoral heterogeneity (ITH), containing two types of heterogeneity–genetic heterogeneity (GH, a mixture of HER2 positive and negative tumor cells) and non-genetic heterogeneity (NGH, a mixture of HER2 positive tumor cells and amplified HER2 gene tumor cells without HER2 protein expression)– is a predictor of response to HER2-targeted treatment in breast cancer (BC). Here, using samples with mCRC, we evaluated the diagnostic accuracy of the Gene-Protein Assay (GPA), an assay assessing HER2 ITH by a combined HER2 immunohistochemistry (IHC) and bright-field HER2 in situ hybridization (ISH) on the same tissue section, and the frequency of HER2 ITH and heterogeneous patterns.

376P Impact of anti-EGFR therapies on HER2-positive metastatic colorectal cancer (HER2+ mCRC): A systematic literature review and meta-analysis of clinical outcomes

HER2 overexpression/amplification in patients with RAS wild-type (WT) mCRC may be associated with resistance to standard of care anti-EGFR therapies. However, there are no meta-analyses investigating this association. Our objective was to assess the predictive effect of HER2 amplification/overexpression on anti-EGFR treatment outcomes.

361P Tucatinib plus trastuzumab in patients (Pts) with HER2-positive metastatic colorectal cancer (mCRC): Patient-reported outcomes (PROs) from ph II study MOUNTAINEER

HER2 amplification/overexpression (HER2-positive [HER2+]) is reported in ∼3-5% of all pts with mCRC. Treatment strategies for mCRC focus on prolonging survival, delaying tumor progression, and maintaining health-related quality of life (HRQoL). Tucatinib (TUC) is a highly selective, HER2-directed, tyrosine kinase inhibitor. Results from the MOUNTAINEER (NCT03043313) study demonstrated that dual HER2 inhibition with TUC and trastuzumab (T) in pts with HER2+ RAS WT mCRC is well tolerated with durable clinical benefit. Here we report the impact of TUC + T on HRQoL in pts from MOUNTAINEER. MOUNTAINEER is a global, multi-center, open-label, phase 2 trial that enrolled pts with HER2+ RAS WT mCRC previously treated with fluoropyrimidine, oxaliplatin, irinotecan, and anti-VEGF mAb. Overall, 117 pts were enrolled or randomized to receive TUC + T (cohorts A [n=45] and B [n=41]) or TUC monotherapy (cohort C [n=31]). HRQoL was assessed with EQ-5D-5L and EORTC QLQ-C30 for cohorts B and C. Cohort A was not assessed for HRQoL. Questionnaires were administered at predose on Cycle 1 Day 1 (C1 D1), C1 D8, C1 D15, then every D1 of C2-4 and every 3 following cycles until end of treatment. HRQoL data for cohorts B and C were analyzed using descriptive statistics. Thirty-seven pts in cohort B and 28 pts in cohort C had ≥1 dose of study treatment and completed baseline and at least 1 follow-up HRQoL assessment. For both cohorts, the mean changes from baseline during the treatment period for EORTC QLQ-C30 generally remained stable across all scales, including global health status/QoL and functional domains. Descriptive analyses showed some fluctuations in observed individual domain scores; however, global health status/QoL remained stable over time. EQ-5D-5L VAS scores also remained similar over time. HRQoL was maintained for pts treated with TUC + T or TUC monotherapy throughout the treatment period. These results, together with the primary efficacy and safety data from MOUNTAINEER, further support the overall tolerability profile of TUC + T and suggest this regimen may be an important treatment option for pts with HER2+ mCRC.

Efficacy of Trastuzumab + Cisplatin Combined with Irinotecan on the Quality of Life of Patients with Advanced Her-2 Positive Gastric Cancer.

Objective To observe the effect of trastuzumab and cisplatin combined with irinotecan in the treatment of advanced Her-2 positive gastric cancer and its influence on disease control rate. Methods From January 2018 to January 2021, 120 patients with advanced Her-2 positive gastric cancer admitted to our hospital were selected as the research subjects. According to the treatment plan of the patients, they were divided into a control group and a joint group, with 60 cases in each group; the control group was given trastuzumab + cisplatin, the joint group was treated with irinotecan on this basis, and the clinical effects and disease control rate of the two groups were observed. Results After treatment, there were 4 patients with CR in the joint group and 0 patients with CR in the control group. The ORR and DCR of the joint group were significantly higher than those of the control group (P < 0.05). The expression levels of CA199, CEA, and CA724 after treatment in the two groups were significantly reduced (P < 0.05), and the reduction in the joint group after treatment was more evident as compared with the control group (P < 0.05). The joint group witnessed better memory function, physical function, behavioral function, emotional function, and communication function than the control group (P < 0.05), and the scores of all dimensions of the two groups of patients after treatment were superior to those before treatment (P < 0.05). The occurrence of side effects was not statistically different between the two groups of patients (P > 0.05). The 1-year survival rate of the control group was 41.67%, the PFS was 6.33 ± 1.02 months, and the OS was 15.51 ± 2.16 months; the 1-year survival rate of the joint group was 43.33%, and the PFS was 8.05 ± 1.07 months, and OS was 16.03 ± 2.44 months; there was no significant difference in the 1-year survival rate between the two groups (P > 0.05), the difference in PFS between the groups was significant (t = 9.013, P < 0.001), and the difference in OS between the groups was not significant (t = 1.236, P=0.219). Conclusion Trastuzumab + cisplatin combined with irinotecan yields a promising result in the treatment of advanced gastric cancer. It can effectively regulate the expression level of tumor markers, delay disease progression, and improve the quality of life of patients. Moreover, irinotecan will not bring more toxic side effects.

Safety and efficacy profile of Trastuzumab deruxtecan in solid cancer: pooled reanalysis based on clinical trials

PurposeThis study aimed to explore the efficiency and safety of the new generation antibody-drug conjugate Trastuzumab deruxtecan (DS-8201a) in treating HER2-positive solid cancers.MethodBy searching PubMed, Medline and Ovid for all clinical trials related to the safety and efficacy of DS-8201a. Event rates were calculated for all adverse events (AEs) to evaluate the safety of DS-8201a. Objective response rate (ORR) and progression-free survival (PFS) were summarized to assess the potency of DS-8201a.ResultThe AEs with event rates greater than 30% regardless of grades were nausea, decreased appetite, vomiting, fatigue, anemia, decreased neutrophil count, alopecia and diarrhea. In the grade 3 or more, decreased neutrophil count, anemia and decreased white blood cell count were the only three AEs with event rates greater than 10% (20.3, 15.0 and 10.3%). The median PFS of patients with breast cancer, gastric cancer and other HER2-positive solid cancers were 9.0-22.1, 3.0-8.3 and 4.1-11.9 months. The median ORR was 37-79.9% in patients with breast and gastric cancer and 28.3-55% in patients with other HER2-positive cancers.ConclusionDS-8201a plays an active role in treating HER2-positive cancers, especially breast and gastric cancer, which have HER2 amplification. The most common AEs of DS-8201a were related to gastrointestinal and hematological system. Decreased white blood cell count and appetite were the AEs occurred with high grades.

HER2 status is positively associated with vessel invasion of colorectal cancer: a retrospective large cohort study

PurposeHER2-positive colorectal cancer was drawn increasing attention in recent years. Accumulating evidence showed HER2-positive metastatic colorectal cancer could benefit from HER2-targeted therapy. While HER2 expression and the relationship between HER2 status and clinicopathological characteristics of overall colorectal cancer remains largely unknown. The aim of this study was to evaluate HER2 expression in colorectal cancer and compare the clinicopathological features between HER2-positive and HER2-negative colorectal cancer.MethodsWe retrospectively analyzed 3910 primary colorectal cancer patients treated in our institution from January 2016 to December 2019. Medical records and pathology reports after surgery were collected to provide information about HER2 status and other clinicopathological characteristics.ResultsWe identified 3347 HER2-negative and 79 HER2-positive colorectal cancer patients in our cohort. The chi-square test showed that vessel invasion was significantly more common in HER2-positive colorectal cancer patients. Crude analysis showed HER2 positive was associated with vessel invasion in colorectal cancer [OR and 95% CI 0.534 (0.341, 0.835), p = 0.006]. After adjusting for N stage, a significant association was still observed between HER2 status and vessel invasion in colorectal cancer [OR and 95% CI 0.550 (0.322, 0.941), p = 0.029]. Survival analysis showed that there was no significant difference in 3-year overall survival rate between HER2 positive and HER2 negative group (p = 0.603).ConclusionOur findings indicate that the rate of HER2 positivity in colorectal cancer was relatively low, and HER2 status was strongly associated with vessel invasion while having no significant influence on the 3-year overall survival rate in colorectal cancer patients.

Design, Synthesis, and Bioevaluation of a Novel Hybrid Molecular Pyrrolobenzodiazepine-Anthracenecarboxyimide as a Payload for Antibody-Drug Conjugate.

A novel series of hybrid molecules combining pyrrolobenzodiazepine (PBD) and anthracenecarboxyimide pharmacophores were designed, synthesized, and tested for in vitro cytotoxicity against various cancer cell lines. The most potent compound from this series, 37b3, exhibited a subnanomolar level of cytotoxicity with an IC50 of 0.17-0.94 nM. 37b3 induced DNA damage and led to tumor cell cycle arrest and apoptosis. We employed 37b3 as a payload to conjugate with trastuzumab to obtain the antibody-drug conjugate (ADC) T-PBA. T-PBA maintained its mode of target and internalization ability of trastuzumab. We demonstrated that T-PBA could be degraded through the lysosomal pathway to release the payload 37b3 after internalization. T-PBA showed a powerful killing effect on Her2-positive cancer cells in vitro. Furthermore, T-PBA significantly inhibited tumor growth in gastric and ovarian cancer xenograft mouse models without overt toxicity. Collectively, these studies suggest that T-PBA represents a promising new ADC that deserves further investigation.

Multifunctional Nanoparticles Based on Iron Oxide and Gold-198 Designed for Magnetic Hyperthermia and Radionuclide Therapy as a Potential Tool for Combined HER2-Positive Cancer Treatment.

Iron oxide nanoparticles are commonly used in many medical applications as they can be easily modified, have a high surface-to-volume ratio, and are biocompatible and biodegradable. This study was performed to synthesize nanoparticles designed for multimodal HER2-positive cancer treatment involving radionuclide therapy and magnetic hyperthermia. The magnetic core (Fe3O4) was coated with a gold-198 layer creating so-called core-shell nanoparticles. These were then further modified with a bifunctional PEG linker and monoclonal antibody to achieve the targeted therapy. Monoclonal antibody—trastuzumab was used to target specific breast and nipple HER2-positive cancer cells. The nanoparticles measured by transmission electron microscopy were as small as 9 nm. The bioconjugation of trastuzumab was confirmed by two separate methods: thermogravimetric analysis and iodine-131 labeling. Synthesized nanoparticles showed that they are good heat mediators in an alternating magnetic field and exhibit great specific binding and internalization capabilities towards the SKOV-3 (HER2 positive) cancer cell line. Radioactive nanoparticles also exhibit capabilities regarding spheroid degradation without and with the application of magnetic hyperthermia with a greater impact in the case of the latter. Designed radiobioconjugate shows great promise and has great potential for in vivo studies regarding magnetic hyperthermia and radionuclide combined therapy.

The Nrf2 inhibitor brusatol synergistically enhances the cytotoxic effect of lapatinib in HER2-positive cancers

The dual tyrosine kinase (EGFR/HER2) inhibitor lapatinib is currently used to clinically treat HER2-positive breast cancer. However, a majority of patients do not respond to lapatinib therapy within 6 months. Therefore, potentiating the anti-tumor effect of lapatinib by combination treatment has a great potential to overcome the obstacle. Herein, we aim to investigate the anti-tumor activity of lapatinib in combination with brusatol and explore the potential mechanism involved in the combinatorial treatment. Our findings revealed that the Nrf2 inhibitor brusatol potently enhanced the anti-tumor effect of lapatinib against SK-BR-3, SK-OV-3 and AU565 cancer cells in a synergistic manner. Furthermore, we found that lapatinib plus brusatol more effectively decreased Nrf2 level and induced ROS generation in both SK-BR-3 and SK-OV-3 cells. Moreover, we also observed a significant reduction on the phosphorylation of HER2, EGFR, AKT and ERK1/2 in SK-BR-3 and SK-OV-3 cells when treated with lapatinib plus brusatol compared to either agent alone. More importantly, brusatol significantly augmented the anti-tumor effects of lapatinib in the SK-OV-3 xenograft model. In summary, these data provide a potential rationale for the combination of brusatol and lapatinib on the treatment of HER2-positive cancers.

HER2-low breast cancers: incidence, HER2 staining patterns, clinicopathologic features, MammaPrint and BluePrint genomic profiles

AbstractRecently, clinical trials have demonstrated promising efficacy for novel HER2-targeted therapies in HER2-low breast cancers, raising the prospect of including a HER2-low category (immunohistochemical [IHC] score of 1+, or 2+ with non-amplified in-situ hybridization [ISH]) in the HER2 evaluation of breast cancers. In order to better understand this newly-proposed HER2 category, we investigated the incidence, HER2 staining patterns, clinicopathologic features, and genomic profile of HER2-low breast cancers. HER2-stained slides of 281 consecutive breast cancers were re-reviewed and the clinicopathologic information, MammaPrint, and BluePrint results of these cases were retrospectively analyzed. HER2-low breast cancers were identified in 31% of cases and were more common in estrogen receptor (ER)-positive than ER-negative breast cancers (33.6% vs 15%, p = 0.017). HER2-low cancers were generally clinical stages I–II (79%), ER-positive (93.1%), had homogenous HER2 staining (59.2%), HER2 IHC score of 1+ (87.4%), ductal phenotype (81.6%), histologic grades of 1 or 2 (94.2%) and luminal molecular subtypes (94.3%). Three HER2-low patients received neoadjuvant chemotherapy and none of them achieved pathologic complete response. When compared to HER2-negative (IHC of 0+) and HER2-positive (IHC of 3+ or IHC of 2+ with amplified ISH) cancers, HER2-low breast cancers had significantly lower Ki-67 (p = 0.03 and p < 0.01, respectively) and higher ER positivity (p = 0.01 and p = 0.03, respectively). HER2-low breast cancers were less likely to be basal molecular subtype when compared to HER2-negative cancers (p < 0.01) and were less likely to have a HER2 molecular subtype when compared to HER2-positive cancers (p < 0.01). When adjusted for ER status, there was no significant difference on all the examined variables between HER2-low and HER2-negative groups. Our study provides valuable baseline characteristics of HER2-low breast cancers deriving from consecutive, real-world cases with a consensus confirmation of HER2 status, and would help to increase our understanding of this newly-proposed HER2 category in breast cancers.

Optimize the combination regimen of Trastuzumab and Nab-paclitaxel in HER2-positive tumors via modulating Caveolin-1 expression by lovastatin

The combination regimen of trastuzumab (Tras) plus Nab-paclitaxel (Nab) is recommended to treat HER2-positive (HER2+) cancers. However, they exert effects in different mechanisms: Tras need to stay on cell membranes, while Nab need to be endocytosed, therefore the concurrent combination regimen may not be the best one in HER2+ tumors treatment. Caveolin-1 (Cav-1) is a key player in mediating their endocytosis and is associated with their efficacy, but few researches noticed the opposite effect of Cav-1 expression on the combination efficacy. Herein, we systematically studied the Cav-1 expression level on the combination efficacy and proposed an optimized and clinically feasible combination regimen for HER2+ Cav-1High tumor treatment. In the regimen, lovastatin (Lova) was introduced to modulate the Cav-1 expression and the results indicated that Lova could downregulate Cav-1 expression, increase Tras retention on cell membrane and enhance the in vitro cytotoxicity of Tras in HER2+ Cav-1High cells but not in HER2+ Cav-1Low cells. Therefore, by exchanging the dosing sequence of Nab and Tras, and by adding Lova at appropriate time points, the precise three-drug-sequential regimen (PTDS, Nab(D1)-Lova(D2)-Lova & Tras(D2+12 h)) was established. Compared with the concurrent regimen, the PTDS regimen exhibited a higher in vitro cytotoxicity and a stronger tumor growth inhibition in HER2+ Cav-1High tumors, which might be a promising combination regimen for these patients in clinics.