Human epidermal growth factor receptor-2 expression and subsequent dynamic changes in patients with ovarian cancer.

Human epidermal growth factor receptor-2 (HER2)-targeting drugs are increasingly being incorporated into therapeutic paradigms for non-breast cancers, yet studies on HER2 expression in ovarian cancer (OC) are inadequate. Here, we studied the HER2 status and dynamic changes in OC by reviewing the records of patients who underwent HER2 testing at a single institution. Clinical parameters, including histology, BRCA status, and immunohistochemistry (IHC), were evaluated alongside HER2 expression, timing, and anatomical location. Among 200 patients, 28% and 6% exhibited expression scores of 2+ and 3+, respectively. HER2 3+ scores were observed in 23%, 11%, 9%, and 5% of mucinous, endometrioid, clear cell, and high-grade serous tumors, respectively, and were exclusively identified in BRCA-wildtype, mismatch repair-proficient, or PD-L1-low-expressing tumors. The TP53 mutation rate was low, whereas ARID1A, KRAS, and PIK3CA mutations were relatively more prevalent with HER2 scores of 2+ or 3+ than with 0 or 1+. Four of the five tumors with an HER2 3+ score exhibited ERBB2 amplification. Among 19 patients who underwent multiple time-lagged biopsies, 11 showed increased HER2 expression in subsequent biopsies. Patients with HER2-overexpressing OC exhibited distinct histological, IHC, and genomic profiles. HER2-targeting agents are potential options for BRCA-wildtype patients, particularly as later lines of treatment.

[Comparative immunohistochemistry study of different antibodies clones for detection of breast cancer markers (estrogen receptor, progesterone receptor, HER2/neu, Ki-67)]. / Sravnitel'noe issledovanie antitel razlichnykh klonov dlya vyyavleniya markerov raka molochnoi zhelezy (retseptorov estrogenov, progesterona, HER2/neu, Ki-67) immunogistokhimicheskim metodom.

OBJECTIVE: A comparative study of detection of breast cancer markers (estrogen receptors, progesterone receptors, HER2/neu, Ki-67) by immunohistochemical method with antibodies produced by PrimeBioMed (Russia) and antibodies produced by Roche Ventana (USA). MATERIAL AND METHODS: Surgical specimens and biopsies from 37 patients with invasive breast cancer were used. Sections were stained with antibodies of clones ER SP1 and GM030, PR 1E2 and PBM-5B8, HER2/neu 4B5 and PBM-46A6, Ki-67 30-9 and GM010. RESULTS: There was a high positive and significant correlation between the immunohistochemistry results and antibodies of the clones ER-SP1 and GM030, PR1E2 and PBM-5B8, HER2/neu4B5 and PBM-46A6, Ki-67 30-9 and GM010. CONCLUSION: The study showed the possibility of using antibodies of clones GM030, HER2/neu 4B5, PBM-46A6, GM010 (PrimeBioMed) on the Ventana Bench Marck Ultra automatic immunostainer using the detection system UltraView Universal DAB Detection Kit.

Lapatinib antitumor effect is associated with PI3K and MAPK pathway: An analysis in human and canine prostate cancer cells.

The aberrant activation of HER2 has a pivotal role in bone metastasis implantation and progression in several tumor types, including prostate cancer (PC). Trastuzumab and other anti-HER2 therapies, such as lapatinib, have been used in human breast cancer HER2 positive. Although HER2 overexpression has been reported in PC, anti-HER2 therapy response has revealed conflicting results. We investigated the potential of lapatinib in inhibiting cell migration and inducing apoptosis in two human (LNCaP and PC3) and two canine PC cell lines (PC1 and PC2). Cell migration and apoptosis were evaluated by Annexin V/PI analysis after lapatinib treatment. The transcriptome analysis of all cell lines before and after treatment with lapatinib was also performed. We found increased apoptosis and migration inhibition in LNCaP cells (androgen-sensitive cell line), while PC1, PC2, and PC3 cells showed no alterations after the treatment. The transcriptome analysis of LNCaP and PC3 cell lines showed 158 dysregulated transcripts in common, while PC1 and PC2 cell lines presented 82. At the doses of lapatinib used, we observed transcriptional modifications in all cell lines. PI3K/AKT/mTOR pathway were enriched in human PC cells, while canine PC cells showed enrichment of tyrosine kinase antitumor response and HER2-related pathways. In canine PC cells, the apoptosis failed after lapatinib treatment, possibly due to the downregulation of MAPK genes. Prostate cancer cells insensitive to androgens may be resistant to lapatinib through PI3K gene dysregulation. The association of lapatinib with PI3K inhibitors may provide a more effective antitumor response and clinical benefits to PC patients.

Tucatinib Combination Treatment After Trastuzumab-Deruxtecan in Patients With ERBB2-Positive Metastatic Breast Cancer.

Importance: Little is known regarding the outcomes associated with tucatinib combined with trastuzumab and capecitabine (TTC) after trastuzumab-deruxtecan exposure among patients with ERBB2 (previously HER2)-positive metastatic breast cancer (MBC). Objective: To investigate outcomes following TTC treatment in patients with ERBB2-positive MBC who had previously received trastuzumab-deruxtecan. Design, Setting, and Participants: This cohort study included all patients with MBC who were treated in 12 French comprehensive cancer centers between August 1, 2020, and December 31, 2022. Exposure: Tucatinib combined with trastuzumab and capecitabine administered at the recommended dose. Main Outcomes and Measures: Clinical end points included progression-free survival (PFS), time to next treatment (TTNT), overall survival (OS), and overall response rate (ORR). Results: A total of 101 patients with MBC were included (median age, 56 [range, 31-85] years). The median number of prior treatment lines for metastatic disease at TTC treatment initiation was 4 (range, 2-15), including 82 patients (81.2%) with previous trastuzumab and/or pertuzumab and 94 (93.1%) with previous ado-trastuzumab-emtansine) exposure. The median duration of trastuzumab-deruxtecan treatment was 8.9 (range, 1.4-25.8) months, and 82 patients (81.2%) had disease progression during trastuzumab-deruxtecan treatment, whereas 18 (17.8%) had stopped trastuzumab-deruxtecan for toxic effects and 1 (1.0%) for other reasons. Tucatinib combined with trastuzumab and capecitabine was provided as a third- or fourth-line treatment in 37 patients (36.6%) and was the immediate treatment after trastuzumab-deruxtecan in 86 (85.1%). With a median follow-up of 11.6 (95% CI, 10.5-13.4) months, 76 of 101 patients (75.2%) stopped TTC treatment due to disease progression. The median PFS was 4.7 (95% CI, 3.9-5.6) months; median TTNT, 5.2 (95% CI, 4.5-7.0) months; and median OS, 13.4 (95% CI, 11.1 to not reached [NR]) months. Patients who received TTC immediately after trastuzumab-deruxtecan had a median PFS of 5.0 (95% CI, 4.2-6.0) months; median TTNT of 5.5 (95% CI, 4.8-7.2) months, and median OS of 13.4 (95% CI, 11.9-NR) months. Those who received TTC due to trastuzumab-deruxtecan toxicity-related discontinuation had a median PFS of 7.3 (95% CI, 3.0-NR) months. Best ORR was 29 of 89 patients (32.6%). Sixteen patients with active brain metastasis had a median PFS of 4.7 (95% CI, 3.0-7.3) months, median TTNT of 5.6 (95% CI, 4.4 to NR), and median OS of 12.4 (95% CI, 8.3-NR) months. Conclusions and Relevance: In this study, TTC therapy was associated with clinically meaningful outcomes in patients with ERBB2-positive MBC after previous trastuzumab-deruxtecan treatment, including those with brain metastases. Prospective data on optimal drug sequencing in this rapidly changing therapeutic landscape are needed.

Comparative Preclinical Evaluation of HYNIC-Modified Designed Ankyrin Repeat Proteins G3 for the 99mTc-Based Imaging of HER2-Expressing Malignant Tumors.

HER2 status determination is a necessary step for the proper choice of therapy and selection of patients for the targeted treatment of cancer. Targeted radiotracers such as radiolabeled DARPins provide a noninvasive and effective way for the molecular imaging of HER2 expression. This study aimed to evaluate tumor-targeting properties of three 99mTc-labeled DARPin G3 variants containing Gly-Gly-Gly-Cys (G3C), (Gly-Gly-Gly-Ser)3-Cys ((G3S)3C), or Glu-Glu-Glu-Cys (E3C) amino acid linkers at the C-terminus and conjugated to the HYNIC chelating agent, as well as to compare them with the clinically evaluated DARPin G3 labeled with 99mTc(CO)3 using the (HE)3-tag at the N-terminus. The labeling of DARPin G3-HYNIC variants provided radiochemical yields in the range of 50-80%. Labeled variants bound specifically to human HER2-expressing cancer cell lines with affinities in the range of 0.5-3 nM. There was no substantial influence of the linker and HYNIC chelator on the binding of 99mTc-labeled DARPin G3 variants to HER2 in vitro; however, [99mTc]Tc-G3-(G3S)3C-HYNIC had the highest affinity. Comparative biodistribution of [99mTc]Tc-G3-G3C-HYNIC, [99mTc]Tc-G3-(G3S)3C-HYNIC, [99mTc]Tc-G3-E3C-HYNIC, and [99mTc]Tc-(HE)3-G3 in healthy CD1 mice showed that there was a strong influence of the linkers on uptake in normal tissues. [99mTc]Tc-G3-E3C-HYNIC had an increased retention of activity in the liver and the majority of other organs compared to the other conjugates. The tumor uptake of [99mTc]Tc-G3-(G3S)3C-HYNIC and [99mTc]Tc-(HE)3-G3 in Nu/j mice bearing SKOV-3 xenografts was similar. The specificity of tumor targeting in vivo was demonstrated for both tracers. [99mTc]Tc-G3-(G3S)3C-HYNIC provided comparable, although slightly lower tumor-to-lung, tumor-to spleen and tumor-to-liver ratios than [99mTc]Tc-(HE)3-G3. Radiolabeling of DARPin G3-HYNIC conjugates with 99mTc provided the advantage of a single-step radiolabeling procedure; however, the studied HYNIC conjugates did not improve imaging contrast compared to the 99mTc-tricarbonyl-labeled DARPin G3. At this stage, [99mTc]Tc-(HE)3-G3 remains the most promising candidate for the clinical imaging of HER2-overexpressing cancers.

Breast cryoablation for the palliative treatment of indolent subtype of multicentric triple-negative breast cancer.

Breast cryoablation for palliative and curative treatment of breast cancer has been performed for decades. Although there is a recent resurgence of interest in breast cryoablation with curative intent for unifocal, hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, this report highlights the essential role that cryoablation can play in the palliative treatment of multicentric oestrogen and progesterone receptor-negative and human epidermal growth factor receptor 2-negative (triple-negative) breast cancer, meeting the select pretreatment objectives such as breast or nipple pain relief and prevention of tumour erosion through the skin or nipple in patients who have failed or cannot tolerate the standard of care treatment.

Significance of Estrogen/Progesterone Receptor Expression in Metaplastic Breast Carcinoma.

Introduction: Metaplastic breast carcinoma (MBC) is a rare subgroup of breast neoplasms associated with adverse outcomes because of its aggressive nature. Typically, MBCs show triple-negative hormone receptor (HR) status. Determining the HR status of breast cancer is an integral part because it is an important prognostic factor and helps in the treatment course of the disease. This study aimed to determine the HR status of MBC, its significance, and its association with various clinicopathological parameters. Methods: This was a retrospective study conducted at the Department of Histopathology, Liaquat National Hospital. A total of 140 biopsy-proven cases of MBC were enrolled in the study. Clinical and pathological data were retrieved from the institutes' archives. Immunohistochemical studies were conducted to determine the estrogen receptor (ER) and progesterone receptor (PR) status. Results: The mean age of MBC in our population was found to be 52.18 ± 12.19 years. The HR positivity rate in our population was found to be 32.9%. A significant association was found between HR status and tumor laterality, tumor size, tumor grade, tumor stage, and recurrence. ER/PR-negative MBCs were most probably associated with higher grade and higher tumor stage and were larger in size (6.62 ± 3.43 cm) than ER/PR-positive MBCs (4.20 ± 1.88 cm). Moreover, ER/PR-positive MBCs showed a higher recurrence rate than ER/PR-negative MBCs (43.5% vs. 25.5%, respectively). No statistically significant relationship was found between HR status and patient age, histological subtype, or survival rate. Conclusion: MBC is a rare breast neoplasm. MBC was found to be triple negative in most cases, but a significant percentage were HR (ER/PR) positive. Moreover, we found an association between HR status and various clinicopathological features, indicating that HR status is a significant predictor of MBC prognosis.

Universal CAR T cells targeted to HER2 with a biotin-trastuzumab soluble linker penetrate spheroids and large tumor xenografts that are inherently resistant to trastuzumab mediated ADCC.

CAR T cell therapies face challenges in combating solid tumors due to their single-target approach, which becomes ineffective if the targeted antigen is absent or lost. Universal CAR T cells (UniCAR Ts) provide a promising solution by utilizing molecular tags (linkers), such as biotin conjugated to monoclonal antibodies, enabling them to target a variety of tumor antigens. Recently, we showed that conventional CAR T cells could penetrate the extracellular matrix (ECM) of ADCC-resistant tumors, which forms a barrier to therapeutic antibodies. This finding led us to investigate whether UniCAR T cells, targeted by soluble antibody-derived linkers, could similarly tackle ADCC-resistant tumors where ECM restricts antibody penetration. We engineered UniCAR T cells by incorporating a biotin-binding monomeric streptavidin 2 (mSA2) domain for targeting HER2 via biotinylated trastuzumab (BT). The activation and cytotoxicity of UniCAR T cells in the presence or absence of BT were evaluated in conventional immunoassays. A 3D spheroid coculture was set up to test the capability of UniCAR Ts to access ECM-masked HER2+ cells. For in vivo analysis, we utilized a HER2+ xenograft model in which intravenously administered UniCAR T cells were supplemented with intraperitoneal BT treatments. In vitro, BT-guided UniCAR T cells showed effective activation and distinct anti-tumor response. Upon target recognition, IFNγ secretion correlated with BT concentration. In the presence of BT, UniCAR T cells effectively penetrated HER2+ spheroids and induced cell death in their core regions. In vivo, upon intravenous administration of UniCAR Ts, circulating BT linkers immediately engaged the mSA2 domain and directed effector cells to the HER2+ tumors. However, these co-treated mice died early, possibly due to the lung infiltration of UniCAR T cells that could recognize both native biotin and HER2. Our results suggest that UniCAR T cells guided with soluble linkers present a viable alternative to conventional CAR T cells, especially for patients resistant to antibody therapy and those with solid tumors exhibiting high antigenic variability. Critical to their success, however, is the choice of an appropriate binding domain for the CAR and the corresponding soluble linker, ensuring both efficacy and safety in therapeutic applications.

Establishment of a Novel Cancer-Specific Anti-HER2 Monoclonal Antibody H2Mab-250/H2CasMab-2 for Breast Cancers.

Overexpression of human epidermal growth factor receptor 2 (HER2) in breast and gastric cancers is an important target for monoclonal antibody (mAb) therapy. All therapeutic mAbs, including anti-HER2 mAbs, exhibit adverse effects probably due to the recognition of antigens expressed in normal cells. Therefore, tumor-selective or specific mAbs can be beneficial in reducing the adverse effects. In this study, we established a novel cancer-specific anti-HER2 monoclonal antibody, named H2Mab-250/H2CasMab-2 (IgG1, kappa). H2Mab-250 reacted with HER2-positive breast cancer BT-474 and SK-BR-3 cells. Importantly, H2Mab-250 did not react with nontransformed normal epithelial cells (HaCaT and MCF 10A) and immortalized normal epithelial cells in flow cytometry. In contrast, most anti-HER2 mAbs, such as H2Mab-119 and trastuzumab reacted with both cancer and normal epithelial cells. Immunohistochemical analysis demonstrated that H2Mab-250 possesses much higher reactivity to the HER2-positive breast cancer tissues compared with H2Mab-119, and did not react with normal tissues, including heart, breast, stomach, lung, colon, kidney, and esophagus. The epitope mapping demonstrated that the Trp614 of HER2 domain IV mainly contributes to the recognition by H2Mab-250. H2Mab-250 could contribute to the development of chimeric antigen receptor-T or antibody-drug conjugates without adverse effects for breast cancer therapy.

Real-World Evidence of Ribociclib Plus Aromatase Inhibitors as First-Line Treatment in Advanced Breast Cancer: The BrasiLEEira Study.

PURPOSE: Cyclin inhibitors plus endocrine therapy represent the reference standard for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) locally advanced or metastatic breast cancer (ABC). Efficacy results on hard end points such as overall survival come from well-designed randomized clinical trials (RCTs). However, a limitation of RCTs is the low external results validity, and their extrapolation to a broader population may not be appropriate. Real-world studies can overcome these limitations, also increasing the reliability of RCTs. MATERIALS AND METHODS: The BrasiLEEira was an observational, longitudinal, retrospective, multicenter study to evaluate the effectiveness and safety of ribociclib plus nonsteroidal aromatase inhibitors in Brazilian women age 18 years or older with HR+/HER2- ABC. The study was approved by the institutional review boards of all 11 hospitals. Data were collected anonymously from medical records using an electronic case report form designed by an independent academic research organization, which conducted the study considering all recommendations of international guidelines. The primary end point was 1-year progression-free survival (PFS) rate. Secondary end points included mortality, dose reduction, and safety. RESULTS: The mean age of 76 patients was 57 years, and 28.9% were Black/Brown. The most prevalent comorbidity was arterial hypertension (34.7%). About 26.0% had endocrine-resistant disease, and 54.1% had more than three metastatic sites. The PFS rate was 77.6%. Three patients died (3.9%). Dose reductions occurred in 37.7% of patients. The most common adverse event was neutropenia (68.4%). CONCLUSION: The high-quality evidence from the BrasiLEEira study corroborates the RCTs' findings, expanding its validity to a broader spectrum and underrepresented population who may benefit from ribociclib treatment.

Adjuvant Chemotherapy in Premenopausal Patients With Hormone-Positive Breast Cancer With a Recurrence Score of 16-25: A Retrospective Analysis Using the National Cancer Database.

PURPOSE: Results from the TAILORx trial revealed that the use of adjuvant chemotherapy along with endocrine therapy had no survival advantage in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2-negative (HER2-), node-negative (N0) breast cancer (BC) with an intermediate (11-25) 21-gene recurrence score (RS) in the overall population. However, in patients under age 50 years, adjuvant chemotherapy demonstrated a progression-free survival benefit when the RS ranged from 16-25. We studied this cohort with the population-based national database. METHODS: The 2010-2018 National Cancer Database was used to include patients with BC age 18-50 years, N0, M0, RS 16-25, ER+/progesterone receptor±, and HER2-. Patients were divided into two groups on the basis of adjuvant chemotherapy use, and the survival between them was compared. RESULTS: Adjuvant chemotherapy use was noted in 4,808/15,792 (30.45%) patients. Median RS was 18 and 21 in patients without and with adjuvant chemotherapy, respectively. Factors associated with adjuvant chemotherapy use were higher T stage, poor and moderately differentiated tumors, age <40 years, care at an academic center, Caucasian race, patients undergoing mastectomy, regional lymph node surgery, and radiation therapy. Kaplan-Meier survival at 10 years was better with adjuvant chemotherapy (96.2% v 91.6%). Patients without adjuvant chemotherapy had more adverse outcomes (hazard ratio [HR], 1.683 [95% CI, 1.392 to 2.036]; P < .0001). Subgroup analysis showed that the benefit was significant in patients with RS scores 21-25 (HR, 1.953 [95% CI, 1.295 to 2.945]), ductal histology (HR, 1.521 [95% CI, 1.092 to 2.118]), Caucasian race (HR, 1.655 [95% CI, 1.180 to 2.322]), and 41-50 years age group (HR, 1.732 [95% CI, 1.244 to 2.411]). CONCLUSION: Our study showed an overall survival benefit for adjuvant chemotherapy use in patients with ER-positive, N0 premenopausal BC patients, age less than 50 years, with an intermediate RS score, particularly 21-25.

Survival outcomes in HER2-low versus HER2-zero breast cancer after neoadjuvant chemotherapy: a meta-analysis.

BACKGROUND: The survival outcomes in HER2-low versus HER2-zero breast cancer (BC) after neoadjuvant chemotherapy (NACT) remain unclear. The meta-analysis was conducted to summarize current evidence about the survival outcomes in HER2-low versus HER2-zero BC. METHODS: We conducted a systematic search in PubMed and EMBASE databases to identify relevant studies. RESULTS: A total of 14 studies with 53,714 patients were included. Overall, 34,037 patients (63.37%) were HER2-low, and 19,677 patients (36.63%) were HER2-zero. Patients with HER2-low tumors had a significantly lower pathological complete response (pCR) rate than patients with HER2-zero tumors, regardless of the hormone receptor status. Compared with HER2-zero breast cancer, the overall survival (OS) and disease-free survival (DFS) of HER2-low BC were longer in the overall cohort (HR = 0.72; 95% CI = 0.61-0.85; P < 0.0001; HR = 0.83; 95% CI = 0.75-0.92; P = 0.0002); however, no differences were observed in terms of OS and DFS between HER2-low and HER2-zero BC in the HR-negative group. In the HR-positive group, HER2-low status had no significant impact on OS, while significantly associated with increased DFS (HR = 0.85; 95% CI = 0.76-0.96; P = 0.007). CONCLUSION: These results suggest that although HER2-low BC has a poor response to NACT, it is correlated with favorable OS and DFS after NACT in the overall cohort as well as longer DFS in the HR-positive group.

Neoadjuvant pertuzumab plus trastuzumab in combination with chemotherapy for human epidermal growth factor receptor 2 positive breast cancer: a real-world retrospective single-institutional study in China.

INTRODUCTION: Real-world studies on neoadjuvant dual anti-HER2 therapy combined with chemotherapy for breast cancer (BC) are scarce in China. This study aimed to evaluate the efficacy and safety of neoadjuvant dual anti-HER2 therapy combined with chemotherapy in a real-world setting. Moreover, differences in estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and proliferation cell nuclear antigen (Ki-67) expression pre- and post-neoadjuvant therapy were analyzed. METHODS: Clinical and pathological data of patients with HER2-positive BC who received neoadjuvant dual anti-HER2 therapy combined with chemotherapy at Liaoning Cancer Hospital & Institute, China, between September 2021 and September 2023, were retrospectively reviewed. RESULTS: Among 179 included patients, a pathologic complete response (pCR) was achieved in 109 patients (60.9%). The univariate analysis results indicated that the hormone receptor (HR) status (P = 0.013), HER2 status (P = 0.003), and cycles of targeted treatment (P = 0.035) were significantly correlated with pCR. Subsequent multivariable analysis showed that HR negative and HER2 status 3 + were independent predictive factors of pCR. Anemia was the most common adverse event (62.0%), and the most common grade 3-4 adverse event was neutropenia (6.1%). The differences in HER2 (34.5%) and Ki-67 (92.7%) expression between core needle biopsy and the residual tumor after neoadjuvant therapy were statistically significant, whereas the differences were insignificant in terms of ER or PR status. CONCLUSIONS: The combination of neoadjuvant trastuzumab and pertuzumab with chemotherapy showed good efficiency, and the toxic side effects were tolerable in patients with BC. In cases where pCR was not achieved after neoadjuvant therapy, downregulation of HER2 and Ki-67 expressions was observed.

Exploring the effectiveness of molecular subtypes, biomarkers, and genetic variations as first-line treatment predictors in Asian breast cancer patients: a systematic review and meta-analysis.

BACKGROUND: Breast cancer incidence has been on the rise significantly in the Asian population, occurring at an earlier age and a later stage. The potential predictive value of molecular subtypes, biomarkers, and genetic variations has not been deeply explored in the Asian population. This study evaluated the effect of molecular subtype classification and the presence or absence of biomarkers and genetic variations on pathological complete response (pCR) after neoadjuvant treatment in Asian breast cancer patients. METHODS: A systematic search was conducted in MEDLINE (PubMed), Science Direct, Scopus, and Cochrane Library databases. Studies were selected if they included Asian breast cancer patients treated with neoadjuvant chemotherapy and contained data for qualitative or quantitative analyses. The quality of the included studies was assessed using the Newcastle Ottawa Scale. Following the random effects model, pooled odds ratios or hazard ratios with 95% confidence intervals for pCR were analysed using Review Manager Software. Heterogeneity between studies was assessed using Cochran's Q-test and I2 test statistics. RESULTS: In total, 19,708 Asian breast cancer patients were pooled from 101 studies. In the neoadjuvant setting, taxane-anthracycline (TA) chemotherapy showed better pCR outcomes in triple-negative breast cancer (TNBC) (p<0.0001) and human epidermal growth factor receptor 2 enriched (HER2E) (p<0.0001) than luminal breast cancer patients. Similarly, taxane-platinum (TP) chemotherapy also showed better pCR outcomes in TNBC (p<0.0001) and HER2E (p<0.0001). Oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative, HER2-positive and high Ki-67 were significantly associated with better pCR outcomes when treated with either TA or TP. Asian breast cancer patients harbouring wildtype PIK3CA were significantly associated with better pCR outcomes when treated with TA in the neoadjuvant setting (p=0.001). CONCLUSIONS: In the neoadjuvant setting, molecular subtypes (HER2E and TNBC), biomarkers (ER, PR, HER2, HR, Ki-67, nm23-H1, CK5/6, and Tau), and gene (PIK3CA) are associated with increased pCR rates in Asian breast cancer patients. Hence, they could be further explored for their possible role in first-line treatment response, which can be utilised to treat breast cancer more efficiently in the Asian population. However, it needs to be further validated with additional powered studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021246295.

PRaG 3.0 therapy for human epidermal growth factor receptor 2-positive metastatic pancreatic ductal adenocarcinoma: A case report.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease with limited effective treatment especially after first-line chemotherapy. The human epidermal growth factor receptor 2 (HER-2) immunohistochemistry (IHC) positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC. CASE SUMMARY: We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn't have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment. A novel combination therapy PRaG 3.0 of RC48 (HER2-antibody-drug conjugate), radiotherapy, PD-1 inhibitor, granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month. She had not developed any grade 2 or above treatment-related adverse events at any point. Percentage of peripheral CD8+Temra and CD4+Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy. CONCLUSION: PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.

Telangiectasias induced by combination tucatinib and ado-trastuzumab emtansine in a patient with metastatic breast cancer.

BACKGROUND: Tucatinib is a tyrosine kinase inhibitor currently used in salvage therapy for human epidermal growth factor receptor 2 (HER2)-positive breast and colorectal cancer. The use of tucatinib alone or in combination with ado-trastuzumab emtansine (T-DM1) in the treatment of advanced HER2-positive cancers is rapidly expanding. OBJECTIVE/METHODS: We report the case of a 66-year-old female who presented to the dermatology clinic with a one-year history of widespread telangiectasias that began after initiation of combination chemotherapy with tucatinib and T-DM1 for metastatic HER2-positive invasive ductal carcinoma. RESULTS: The patient's lesions regressed upon cessation of combination therapy and reappeared in the setting of tucatinib re-initiation, with gradual improvement over the following four months following electrocautery to the affected regions. CONCLUSIONS: We postulate that telangiectasias may be a previously unreported dermatologic side effect of combination treatment with tucatinib and T-DM1. Electrocautery is a safe and effective procedure to reduce the appearance of telangiectasias and improve patient satisfaction during chemotherapy.

Comprehensive evaluation of the relationship between biomarker profiles and neoadjuvant chemotherapy outcomes for breast cancer patients.

BACKGROUND: Accurately predicting the response to neoadjuvant chemotherapy (NAC) in breast cancer patients is crucial for guiding treatment strategies and enhancing clinical outcomes. Current studies have primarily focused on a limited set of biomarkers. More importantly, the results of many studies are in conflict. To address this, we conducted a comprehensive evaluation of the predictive value of a diverse range of clinically available molecular biomarkers in breast cancer, including HER2, ER, PR, TOPO II, EGFR, Ki67, CK5/6, AR, and p53. Additionally, we assessed changes in these biomarkers after NAC administration. METHODS: Our study involved 189 patients with invasive breast cancer who underwent NAC at our institute. We examined biomarker profiles in core-needle biopsies taken before NAC and in surgical specimens obtained after NAC. We examined the association between these biomarkers and NAC outcomes, focusing on two main aspects: the rate of pathological complete response (pCR) and the reduction in tumor size. We used Chi-square and Mann-Whitney U tests to compare biomarker status changes between pCR and non-pCR patients. Linear regression analysis was employed to evaluate the relationship between biomarker status and tumor shrinkage rate. Additionally, we compared the expression status of these biomarkers before and after NAC using Chi-square and Wilcoxon signed-rank tests. RESULTS AND CONCLUSIONS: Our results demonstrated significant differences in the expression levels of HER2, ER, PR, TOPO II, EGFR, and Ki67 between pCR and non-pCR patients, underscoring their potential as predictive markers for NAC outcomes. Importantly, our results have shed light on the contentious issue surrounding TOPO II in NAC outcome prediction. We have provided evidence that establishes a significantly positive association between TOPO II expression level and the pCR rate. Notably, tumor size was identified as a relevant predictive factor for achieving pCR. Regarding biomarker profiles, only Ki67 levels and TOPO II status exhibited changes following NAC, resolving previous controversies. While the ER and PR status remained unchanged, their expression values exhibited a slight but significant decrease post-NAC. Our results provide clarity and insights into the value and potential of using these biomarkers to predict NAC responses and prognosis in breast cancer patients.

A Cell-Penetrating Peptide Improves Anti-HER2 Single-Chain Variable Fragment Internalization and Antitumor Activity against HER2-Positive Breast Cancer In Vitro and In Vivo.

Cell-penetrating peptides (CPPs) are invaluable tools for delivering various substances into cells by crossing biological membranes. However, the effects of cell-penetrating peptide fusion proteins on the biological activity of antibodies remain to be fully understood. Here, we engineered a recombinant protein, LP-scFv, which combines the single-chain variable region of anti-human epidermal growth factor receptor-2 with a novel and non-oxic cell-penetrating peptide as a leader peptide. The introduction of this leader peptide led to a more than twofold increase in the internalization efficiency of the single-chain antibody, as confirmed using microscopic analysis and flow cytometry. The effects of the single-chain antibodies and LP-scFv on cell viability were evaluated using the MTT assay. Both the single-chain antibodies and LP-scFv reduced the viability of BT474 and NCI-N87 cells in a dose-dependent manner while exhibiting minimal toxicity towards MCF-7 and MCF-10A cells. Further investigation into LP-scFv's mechanism revealed that the induced leader peptide does not alter the MAPK-ERK1/2 and PI3K/AKT pathways of single-chain antibodies. An enhanced antitumor activity was also confirmed in an NCI-N87 tumor xenograft model in mice with a reduction of 45.2% in tumor growth inhibition (vs. 23.1% for scFv) with a 50 mg/kg dose after orthotopic injection administration, which was equivalent to that of trastuzumab (vs. 55.7% for trastuzumab). Overall, these results indicate that LP-scFv exhibits significant permeation activity in HER2-positive cells to enhance the intracellular dose effect on antitumor activity in vitro and in vivo. This research lays the foundation for designing novel antibody-based therapies for cancer.

Intracranial Efficacy of Pyrotinib and Capecitabine Combination Therapy in HER2-Positive Breast Cancer with Brain Metastases.

Aim: Approximately 50% of patients diagnosed with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (BC) are estimated to develop brain metastases (BMs). This study was aimed to assess the intracranial efficacy and survival benefits of pyrotinib and capecitabine combination therapy in the treatment of BMs in patients with HER2-positive BC. Methods: A total of 56 HER2-positive BC patients with BMs were treated with 400 mg pyrotinib once daily along with 1000 mg/m2 capecitabine twice daily for 14 days in 21-day cycles. The patients were allocated into three cohorts: (1) Cohort A composed of patients with newly diagnosed BMs without prior local radiotherapy, (2) Cohort B included patients with stable post-local radiotherapy, and (3) Cohort C composed of patients with progression following local radiotherapy. The primary endpoint was the intracranial objective response rate (CNS-ORR), while secondary endpoints included intracranial disease control rate (CNS-DCR), progression-free survival (PFS), overall survival (OS), safety, as well as QoL. Results: The observed CNS-ORR CNS-ORR of 72.73% (95% CI 51.85-86.85%) in cohort A, 55% (95% CI 34.21-74.18%) in cohort B, and 42.86% (95% CI 21.38-67.41%) in cohort C. The mPFS was 11 months, 8.4 months, and 5.2 months in cohorts A, B, and C, respectively. Diarrhea, accounting for 23.21% of all the patients, was the most common grade 3/4 adverse event related with treatments (6/22 [27.3%] in cohort A, 4/20 [20.0%] in cohort B, and 3/14 [21.4%] in cohort C). However, there were no deaths related with treatments observed. Importantly, the QoL was efficiently maintained throughout the treatment duration. Conclusion: Pyrotinib and capecitabine combination therapy proved significant effectiveness as well as tolerability in treating HER2-positive BC with BMs, yielding satisfactory results, especially in radiotherapy-naive population.

Outcomes of the patients with metastatic male breast cancer.

BACKGROUND: The goal of this research is to investigate the clinical characteristics and prognosis of men with metastatic breast cancer (mMBC). METHODS: A retrospective analysis of the data of 28 patients was conducted. Kaplan-Meier and Cox regression analyses were used to assess overall survival (OS) and prognostic variables. RESULTS: At the time of diagnosis, the median age was 57 years (range 26-86). The most prevalent pathological subtype was invasive ductal carcinoma (92.6%). HER2 positivity was 21.6% in patients, with estrogen and progesterone receptor positivity at 96.4% and 71.4%, respectively. Bone-75%, lung-39.3%, brain-21.4%, and adrenal gland-10.7% were the most prevalent metastatic sites. Trastuzumab-based chemotherapy was given to six patients. During the study period, 14 patients (or half) died. All patients had a median OS of 42.6 months (range: 21.6-63.7). The OS rates after 1, 3, and 5 years were 95.7%, 54.2%, and 36.6%, respectively. The number of metastatic locations (P = 0.045), brain metastasis (P = 0.033), and a history of regular alcohol intake (P = 0.008) were all shown to be statistically significant factors affecting OS in univariate analysis. However, multivariate analysis did not support the findings. In addition, we discovered that trastuzumab-based therapy and de-novo metastatic disease had no effect on OS for mMBC. CONCLUSIONS: The data on mMBC is restricted because of its rarity. The prognosis of mMBC was shown to be poor in this investigation. Despite the small number of patients, we discovered that in univariate analysis, having brain metastases, the number of metastatic locations, and a history of alcohol intake may be prognostic factors.