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Breast Cancer Research and Treatment Apr 2024Thymidine kinase 1 (TK1) plays a pivotal role in DNA synthesis and cellular proliferation. TK1 has been studied as a prognostic marker and as an early indicator of... (Randomized Controlled Trial)
Randomized Controlled Trial
The role of serum thymidine kinase 1 activity in neoadjuvant-treated HER2-positive breast cancer: biomarker analysis from the Swedish phase II randomized PREDIX HER2 trial.
BACKGROUND
Thymidine kinase 1 (TK1) plays a pivotal role in DNA synthesis and cellular proliferation. TK1 has been studied as a prognostic marker and as an early indicator of treatment response in human epidermal growth factor 2 (HER2)-negative early and metastatic breast cancer (BC). However, the prognostic and predictive value of serial TK1 activity in HER2-positive BC remains unknown.
METHODS
In the PREDIX HER2 trial, 197 HER2-positive BC patients were randomized to neoadjuvant trastuzumab, pertuzumab, and docetaxel (DPH) or trastuzumab emtansine (T-DM1), followed by surgery and adjuvant epirubicin and cyclophosphamide. Serum samples were prospectively collected from all participants at multiple timepoints: at baseline, after cycle 1, 2, 4, and 6, at end of adjuvant therapy, annually for a total period of 5 years and/or at the time of recurrence. The associations of sTK1 activity with baseline characteristics, pathologic complete response (pCR), event-free survival (EFS), and disease-free survival (DFS) were evaluated.
RESULTS
No association was detected between baseline sTK1 levels and all the baseline clinicopathologic characteristics. An increase of TK1 activity from baseline to cycle 2 was seen in all cases. sTK1 level at baseline, after 2 and 4 cycles was not associated with pCR status. After a median follow-up of 58 months, 23 patients had EFS events. There was no significant effect between baseline or cycle 2 sTK1 activity and time to event. A non-significant trend was noted among patents with residual disease (non-pCR) and high sTK1 activity at the end of treatment visit, indicating a potentially worse long-term prognosis.
CONCLUSION
sTK1 activity increased following neoadjuvant therapy for HER2-positive BC but was not associated with patient outcomes or treatment benefit. However, the post-surgery prognostic value in patients that have not attained pCR warrants further investigation.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT02568839. Registered on 6 October 2015.
Topics: Humans; Female; Breast Neoplasms; Neoadjuvant Therapy; Sweden; Receptor, ErbB-2; Biomarkers, Tumor; Antineoplastic Combined Chemotherapy Protocols; Trastuzumab; Ado-Trastuzumab Emtansine; Thymidine Kinase
PubMed: 38175448
DOI: 10.1007/s10549-023-07200-x -
Heliyon Jan 2024In the last couple of decades substantial therapeutic improvements deeply influenced the treatment of HER2-positive metastatic breast cancer. The most impactful... (Review)
Review
In the last couple of decades substantial therapeutic improvements deeply influenced the treatment of HER2-positive metastatic breast cancer. The most impactful advancements were obtained especially in the first-line setting, with the trastuzumab/pertuzumab anti-HER2 double blockade, and in the second line, with the advent of the potent antibody-drug conjugate trastuzumab deruxtecan. Nevertheless, a careful observation of the patterns of early-progression and long-term effects on overall survival of the most novel agents and combinations, highlights the challenges represented by the emergence of therapeutic resistance and optimal drug sequencing. The integration of sequence studies, tumor-related biomarker development/implementation and understanding of primary mechanisms of resistance to novel anti-HER2 agents, will be the way to move forward to effectively tackle these novel unmet needs.
PubMed: 38163142
DOI: 10.1016/j.heliyon.2023.e23367 -
Bladder (San Francisco, Calif.) 2023Urothelial carcinoma (UC) represents a common malignancy of the urinary system that can involve the kidneys, ureter, bladder, and urethra. Advanced/metastatic UC (mUC)... (Review)
Review
Urothelial carcinoma (UC) represents a common malignancy of the urinary system that can involve the kidneys, ureter, bladder, and urethra. Advanced/metastatic UC (mUC) tends to have a poor prognosis. UC ranks third in terms of human epidermal growth factor receptor 2 (HER2) overexpression among all tumors. However, multiple studies found that, unlike breast cancer, variable degrees of HER2 positivity and poor consistency between HER2 protein overexpression and gene amplification have been found. Trials involving trastuzumab, pertuzumab, lapatinib, afatinib, and neratinib have failed to prove their beneficial effect in patients with HER2-positive mUC, and a clinical trial on T-DM1 (trastuzumab emtansine) was terminated prematurely because of the adverse reactions. However, a phase II trial showed that RC48-ADC was effective. In this review, we provided an in-depth overview of the advances in the research regarding HER2-targeted therapy and the role of HER2 in mUC. Furthermore, we also discussed the prospects of potential strategies aimed at overcoming anti-HER2 resistance, and summarize the novel anti-HER2 approaches for the management of mUC used in recent clinical trials.
PubMed: 38155921
DOI: 10.14440/bladder.2023.871 -
Frontiers in Endocrinology 2023Pyrotinib and pertuzumab are effective treatment options for HER2-positive metastatic breast cancer (HER2+ MBC). Our study was to directly compare the efficacy and...
OBJECTIVE
Pyrotinib and pertuzumab are effective treatment options for HER2-positive metastatic breast cancer (HER2+ MBC). Our study was to directly compare the efficacy and safety of pyrotinib plus trastuzumab (PyroH) and pertuzumab plus trastuzumab (HP) in patients with HER2+ MBC.
METHODS
We conducted a retrospective examination of HER2+ MBC patients who received PyroH plus chemotherapy or HP plus chemotherapy between 2017 and 2022 at five institutions in China. Our primary endpoint was progression-free survival (PFS).
RESULTS
This study involved 333 patients, among which 161 received PyroH and 172 received HP. The utilization of PyroH as a first-line therapy for MBC was more prevalent among older patients, those with a shorter duration of disease-free interval, or those who had previously been treated with trastuzumab. Although in the first-line advanced treatment HP cohort showed numerically longer PFS (median PFS: 14.46 vs. 22.90 months, =0.057), in the second-line or later treatments, there was no significant difference in PFS between the PyroH and HP groups (median PFS: 8.67 vs. 7.92 months, =0.286). Despite HP showing a longer PFS in the overall cohort (median PFS: 9.30 vs. 13.01 months, =0.005), it did not serve as an independent predictor of PFS in the multivariate analysis (HR 1.134, 95% CI 0.710-1.811, p=0.598). Without taxane, PyroH demonstrated a longer PFS than HP (median PFS: 10.12 vs. 8.15 months, =0.017). PyroH group displayed a numerically longer median PFS in patients with brain metastases compared to the HP group, though not statistically significant (median PFS: 9.03 vs. 8.15 months, =0.976). PyroH had higher incidence of grade 3/4 diarrhea (34.3% vs. 3.0%) but similar overall adverse events.
CONCLUSION
In conclusion, PyroH is comparable in second-line or later treatment and during brain metastasis, even having superior efficacy without taxane in real-world setting. Toxicities were tolerable in both groups. (ClinicalTrials.gov: NCT05572645).
Topics: Humans; Female; Trastuzumab; Breast Neoplasms; Retrospective Studies; Receptor, ErbB-2; Taxoids
PubMed: 38149099
DOI: 10.3389/fendo.2023.1325540 -
Cancer Research and Treatment Dec 2023This study aims to evaluate the efficacy and safety of trastuzumab biosimilar (HLX02) in combination with pertuzumab and chemotherapy in patients with HER2-positive...
Trastuzumab Biosimilar (HLX02), Pertuzumab Plus Chemotherapy in Patients with HER2-Positive Metastatic Breast Cancer after Progression of Trastuzumab: A Prospective, Phase II Study.
PURPOSE
This study aims to evaluate the efficacy and safety of trastuzumab biosimilar (HLX02) in combination with pertuzumab and chemotherapy in patients with HER2-positive metastatic breast cancer (MBC) after progression of trastuzumab.
MATERIALS AND METHODS
In this prospective, single-arm, phase II study, patients with HER2-positive MBC after progression of tratuzumab received pertuzuamb, HLX02 and chemotherapy (PTC) in Beijing Cancer Hospital from March 2020 to December 2022. The primary endpoint was progression free survival (PFS), and secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. The study was registered with ClinicalTrials.gov (NCT05188495).
RESULTS
A total of 45 patients were included in this study. 12(26.7%) patients were treated in second line and 33(73.3%) patients were in third-line and later setting. 80% and 15.5% patients had previously received pyrotinib/lapatinib and T-DM1, respectively. With a median follow-up of 24.4 months (range: 1.2-43.9), the median PFS was 7.6 months (95% confidence interval [CI],4.3- 10.9m), OS was not reached, the ORR was 31.1%, and DCR was 91.1%. The treatment was well tolerated.
CONCLUSION
The combination of trastuzumab biosimilar HLX02, pertuzumab, and chemotherapy exhibited promising efficacy and a favorable safety profile as second- and beyond line treatment in HER2-positive metastatic breast cancer.
PubMed: 38147816
DOI: 10.4143/crt.2023.1151 -
Breast Cancer Research : BCR Dec 2023The role of HER2 amplification level in predicting the effectiveness of HER2-directed therapies has been established. However, its association with survival outcomes in...
HER2 amplification level by in situ hybridization predicts survival outcome in advanced HER2-positive breast cancer treated with pertuzumab, trastuzumab, and docetaxel regardless of HER2 IHC results.
BACKGROUND
The role of HER2 amplification level in predicting the effectiveness of HER2-directed therapies has been established. However, its association with survival outcomes in advanced HER2-positive breast cancer treated with dual HER2-blockade remains unexplored.
METHODS
This is a single-center retrospective study of patients with advanced HER2-positive breast cancer treated with first-line pertuzumab, trastuzumab, and docetaxel. The primary objective was to ascertain the relationship between treatment outcomes and the level of HER2 amplification by in situ hybridization (ISH).
RESULTS
A total of 152 patients were included with a median follow-up duration of 50.0 months. Among the 78 patients who received ISH, a higher HER2/CEP17 ratio correlated significantly with longer PFS (HR 0.50, p = 0.022) and OS (HR 0.28, p = 0.014) when dichotomized by the median. A higher HER2 copy number also correlated significantly with better PFS (HR 0.35, p < 0.001) and OS (HR 0.27, p = 0.009). In multivariate analysis, the HER2/CEP17 ratio was an independent predictive factor for PFS (HR 0.66, p = 0.004) and potentially for OS (HR 0.64, p = 0.054), along with HER2 copy number (PFS HR 0.85, p = 0.004; OS HR 0.84, p = 0.049). Furthermore, the correlation between HER2 amplification level by ISH with PFS and OS was consistent across the HER2 IHC 1+/2+ and 3+ categories.
CONCLUSIONS
This is the first study to report that a higher level of HER2 amplification by ISH is associated with improved PFS and OS in advanced HER2-positive breast cancer treated with dual HER2-blockade. Notably, HER2 amplification level had a predictive role regardless of IHC results. Even in patients with HER2 protein expression of 3+, treatment outcome to HER2-directed therapy was dependent on the level of HER2 gene amplification.
Topics: Humans; Female; Trastuzumab; Docetaxel; Receptor, ErbB-2; Retrospective Studies; Breast Neoplasms; In Situ Hybridization; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38098054
DOI: 10.1186/s13058-023-01746-w -
Cureus Nov 2023The addition of pertuzumab to trastuzumab in neoadjuvant chemotherapy (NAC) for anti-human epidermal receptor 2 (HER2) positive breast cancer has shown a significant...
The Add-On Effect of Fluorouracil, Epirubicin, and Cyclophosphamide Regimens for Neoadjuvant Chemotherapy in Human Epidermal Receptor 2 (HER2)-Positive Breast Cancer: A Single-Center Retrospective Study.
BACKGROUND
The addition of pertuzumab to trastuzumab in neoadjuvant chemotherapy (NAC) for anti-human epidermal receptor 2 (HER2) positive breast cancer has shown a significant improvement in the pathologic complete response (pCR) rate. However, the add-on effect of an anthracycline-based regimen (standard-of-care regimen) remains unclear. In this retrospective, observational study, participants received pertuzumab combination therapy as NAC for HER2-positive primary breast cancer.
METHODS
This study was conducted from January 1, 2020, to December 31, 2022. Patients who had not received at least three courses of pertuzumab owing to adverse events or those who had received preoperative radiotherapy were excluded.
RESULTS
The pCR rate was 35.3% (12/34 patients). The pCR group had a significantly higher percentage of histopathologic grade III (1/11 patients, p=0.030) and a significantly higher percentage of hormone receptor-negative patients (7/12 patients, p=0.015) than the non-pCR group. The non-pCR group had a significantly higher incidence of vascular invasion than the pCR group (7/22 patients, p=0.036). Menopausal status, stage, and ki-67 values were not significantly different between the two groups.
CONCLUSIONS
This study suggests an unlikely add-on effect of an anthracycline-based regimen for NAC in HER2-positive breast cancer. Moreover, our results support that the pCR rate is high in patients with hormone receptor-negative, HER2-positive breast cancer.
PubMed: 38054134
DOI: 10.7759/cureus.48255 -
Technology in Cancer Research &... 2023This study aimed to compare the efficacy and safety of docetaxel + trastuzumab + pertuzumab and docetaxel + carboplatin + trastuzumab + pertuzumab...
This study aimed to compare the efficacy and safety of docetaxel + trastuzumab + pertuzumab and docetaxel + carboplatin + trastuzumab + pertuzumab for treating HER2-positive breast cancer. HER2-positive breast cancer from patients diagnosed between January 2020 and September 2022 were included in this retrospective study. Docetaxel + trastuzumab + pertuzumab or docetaxel + carboplatin + trastuzumab + pertuzumab was selected as the neoadjuvant regimen. The primary endpoint was a complete pathological remission rate. Secondary endpoints were toxicity during neoadjuvant treatment, adjustment of the neoadjuvant therapy scheme, and adjuvant medication. A total of 81 patients were included in this study (38 in the docetaxel + carboplatin + trastuzumab + pertuzumab treatment group and 43 in the docetaxel + trastuzumab + pertuzumab group). The complete pathological remission rates in the docetaxel + carboplatin + trastuzumab + pertuzumab and docetaxel + trastuzumab + pertuzumab groups were 44.7% (95% confidence interval: 30.2%-60.3%) and 51.2% (95% confidence interval: 36.8%-65.4%), respectively. The incidence of grade 3 or higher toxicity in the docetaxel + carboplatin + trastuzumab + pertuzumab group was significantly higher than that in the docetaxel + trastuzumab + pertuzumab group (68.4% vs 39.5%, = .009). Neutropenia and asthenia were the most common grade 3 or higher toxicities. The incidence of neoadjuvant scheme adjustment was significantly higher in the docetaxel + carboplatin + trastuzumab + pertuzumab group than in the docetaxel + trastuzumab + pertuzumab group (26.3% vs 7.0%, = .039). The proportion of patients who received <6 cycles of neoadjuvant therapy was significantly higher in the docetaxel + carboplatin + trastuzumab + pertuzumab group than in the docetaxel + trastuzumab + pertuzumab group (31.6% vs 4.7%, = .004). Patients in the docetaxel + carboplatin + trastuzumab + pertuzumab group received higher doses of granulocyte-macrophage colony-stimulating factor. In the neoadjuvant treatment of HER2-positive breast cancer, the docetaxel + trastuzumab + pertuzumab regimen might be more tolerated than the docetaxel + carboplatin + trastuzumab + pertuzumab regimen and did not show a lower complete pathological remission rate. However, our findings require further validation through prospective studies.
Topics: Humans; Female; Breast Neoplasms; Docetaxel; Neoadjuvant Therapy; Carboplatin; Retrospective Studies; Prospective Studies; Receptor, ErbB-2; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Trastuzumab
PubMed: 38031361
DOI: 10.1177/15330338231218152 -
Case Reports in Oncology 2023Metaplastic breast carcinoma (MBC) is a rare histologic subtype of breast carcinoma, which is usually negative for estrogen receptor, progesterone receptor, and HER2....
INTRODUCTION
Metaplastic breast carcinoma (MBC) is a rare histologic subtype of breast carcinoma, which is usually negative for estrogen receptor, progesterone receptor, and HER2. HER2-positive MBC is therefore extremely rare. Most MBCs have poor response to chemotherapy. HER2-targeted neoadjuvant chemotherapy (NAC) is widely performed and has high efficacy in treating HER2-positive breast cancer. We report an atypical case of HER2-positive breast cancer that had poor response to NAC and was diagnosed with MBC after the surgery.
CASE PRESENTATION
A 73-year-old woman noticed a mass in her right breast and visited our hospital. The mass was diagnosed as hormone receptor-negative, HER2-positive invasive ductal carcinoma, T2N0M0 stage IIA. She received HER2-targeted NAC comprising trastuzumab + pertuzumab + docetaxel. Despite three courses, we observed disease progression. The next NAC regimen was composed of two courses of epirubicin + cyclophosphamide, but the cancer continued to grow. She stopped receiving NAC and underwent a unilateral mastectomy and sentinel lymph node biopsy. Although the preoperative pathological result of core needle biopsy specimen showed invasive ductal carcinoma, the postoperative pathological result of the surgical specimen was MBC.
CONCLUSION
In this case, when the patient had undergone three courses of trastuzumab + pertuzumab + docetaxel, it would have been appropriate to review the result of the core needle biopsy with pathologists or to perform vacuum-assisted breast biopsy. This case suggests the importance of considering the possibility of special histologic subtypes such as MBC when a tumor with the diagnosis of invasive ductal carcinoma is resistant to NAC.
PubMed: 38028581
DOI: 10.1159/000534847 -
Immune microenvironment dynamics of HER2 overexpressing breast cancer under dual anti-HER2 blockade.Frontiers in Immunology 2023The clinical prognosis of the HER2-overexpressing (HER2-OE) subtype of breast cancer (BC) is influenced by the immune infiltrate of the tumor. Specifically, monocytic...
INTRODUCTION
The clinical prognosis of the HER2-overexpressing (HER2-OE) subtype of breast cancer (BC) is influenced by the immune infiltrate of the tumor. Specifically, monocytic cells, which are promoters of pro-tumoral immunosuppression, and NK cells, whose basal cytotoxic function may be enhanced with therapeutic antibodies. One of the standards of care for HER2 BC patients includes the combination of the anti-HER2 antibodies trastuzumab and pertuzumab. This dual combination was a breakthrough against trastuzumab resistance; however, this regimen does not yield complete clinical benefit for a large fraction of patients. Further therapy refinement is still hampered by the lack of knowledge on the immune mechanism of action of this antibody-based dual HER2 blockade.
METHODS
To explore how the dual antibody challenge influences the phenotype and function of immune cells infiltrating the HER2-OE BC microenvironment, we developed 3D heterotypic cell models of this subtype. The models comprised aggregates of HER2 BC cell lines and human peripheral blood mononuclear cells. Cells were co-encapsulated in a chemically inert alginate hydrogel and maintained in agitation-based culture system for up to 7 days.
RESULTS
The 3D models of the HER2-OE immune microenvironment retained original BC molecular features; the preservation of the NK cell compartment was achieved upon optimization of culture time and cytokine supplementation. Challenging the models with the standard-of-care combination of trastuzumab and pertuzumab resulted in enhanced immune cytotoxicity compared with trastuzumab alone. Features of the response to therapy within the immune tumor microenvironment were recapitulated, including induction of an immune effector state with NK cell activation, enhanced cell apoptosis and decline of immunosuppressive PD-L1 immune cells.
CONCLUSIONS
This work presents a unique human 3D model for the study of immune effects of anti-HER2 biologicals, which can be used to test novel therapy regimens and improve anti-tumor immune function.
Topics: Humans; Female; Breast Neoplasms; Leukocytes, Mononuclear; Cell Line, Tumor; Trastuzumab; Antineoplastic Agents; Tumor Microenvironment
PubMed: 38022643
DOI: 10.3389/fimmu.2023.1267621