Epidermal Growth Factor 2-positive Breast Research Articles

Cost-effectiveness analysis of trastuzumab monotherapy versus adjuvant chemotherapy plus trastuzumab in elderly patients with HER2-positive early breast cancer.

In elderly patients with human epidermal growth factor 2-positive breast cancer, adjuvant chemotherapy was associated with decreased quality of life, with relatively small benefits for prognosis. We examined the cost-effectiveness of trastuzumab monotherapy versus adjuvant chemotherapy plus trastuzumab in elderly patients with human epidermal growth factor 2-positive breast cancer. A Markov model was developed to evaluate the costs and benefits of trastuzumab monotherapy over adjuvant chemotherapy plus trastuzumab for elderly patients with human epidermal growth factor 2-positive breast cancer. We built the model with a yearly cycle over a 20-year time horizon and five health states: disease-free, relapse, post-relapse, metastasis and death. The parameters in the model were based on a previous randomized controlled trial and a nationwide administrative database in Japan. The incremental cost-effectiveness ratio, expressed as Japanese yen per the quality-adjusted life-years, was estimated from the perspective of health care payers. One-way deterministic sensitivity analysis and probabilistic sensitivity analysis with Monte-Carlo simulations of 10 000 samples were conducted. The incremental cost-effectiveness ratio of trastuzumab monotherapy over adjuvant chemotherapy plus trastuzumab was $\sim$1.8 million Japanese yen /quality-adjusted life-year. The one-way deterministic sensitivity analysis showed that transition probability from disease-free to metastasis status and cost of metastasis status had the greatest influence on the incremental cost-effectiveness ratio. More than half the estimates in the probabilistic sensitivity analysis were located below a threshold of willingness-to-pay of 5 million Japanese yen /quality-adjusted life-year. In this first comparative cost-effectiveness analysis of adjuvant chemotherapy plus trastuzumab versus trastuzumab monotherapy in the elderly, the latter was found favorable for elderly patients with human epidermal growth factor 2-positive breast cancer.

Biologic Drug Quality Assurance to Optimize HER2 + Breast Cancer Treatment: Insights from Development of the Trastuzumab Biosimilar SB3.

SB3 is a biosimilar of trastuzumab that has been approved for use in the treatment of human epidermal growth factor 2-positive breast cancer and human epidermal growth factor 2-positive gastric cancer. Antibody-dependent cellular cytotoxicity is one of several critical quality attributes of trastuzumab. Data from the development of SB3 support the hypothesis of a relationship between antibody-dependent cellular cytotoxicity activity and clinical outcomes in terms of the response rate and long-term survival. Current analytic methods utilizing advanced technology allow the detection of small changes in other quality attributes that influence antibody-dependent cellular cytotoxicity, such as glycosylation and FcγRIIIa binding. Use of such methods to monitor batch-to-batch consistency enables production of trastuzumab biosimilars with consistent quality. Trastuzumab biosimilars such as SB3 therefore have the potential to increase accessibility to trastuzumab-based therapy without compromising efficacy or safety.

Granulocyte-colony stimulating factor-associated aortitis in a woman with advanced breast cancer: a case report and review of the literature

BackgroundGranulocyte-colony stimulating factor (G-CSF) is increasingly been used to prevent febrile neutropenia (FN) associated with the administration of chemotherapy for various cancers. The most common adverse effects of G-CSF are bone pain and injection-site reactions and aortitis has rarely been reported. We report herein a rare case of G-CSF associated with aortitis in a woman with advanced breast cancer.Case presentationA 72-year-old woman with estrogen receptor-negative human epidermal growth factor 2-positive breast cancer with distant metastases in the lung was admitted. Her treatment was initiated with docetaxel in combination with trastuzumab and pertuzumab followed by the supportive use of a long-acting G-CSF, pegfilgrastim. After administration of pegfilgrastim on day 5, the patient had an intermittent fever (body temperature up to 39.6 °C) on day 9 which continued irrespective of taking levofloxacin. She visited our outpatient clinic on day 13 with no objective symptoms other than fever. Laboratory tests revealed a high neutrophil count (15,000/μl) and a high C-reactive protein (CRP) level (46.35 mg/dl) without any other abnormalities. There was no response upon administration of antimicrobial agents. An 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) revealed thickening of the wall of the descending thoracic aorta and left pleural effusion. Therefore, thoracic aortitis induced by pegfilgrastim was suspected. On day 19, the fever resolved spontaneously followed by a gradual reduction in the neutrophil count and CRP level. In the follow-up CT, the aortic wall thickness and pleural effusion had disappeared.ConclusionsG-CSF may cause aortitis due to stimulation of the production of inflammatory cytokines. In case of high continuous fever after administration of pegfilgrastim, aortitis should be suspected unless there are other infectious findings.

Abstract P2-05-03: Clinical implication of APOBEC3A and 3B in Korean patients with breast cancer

Abstract Background: Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) family is known to function in innate immune system that protects against retrovirus by deaminating cytosine to uracil in single-stranded DNA. APOBEC family has emerged as an endogenous mutator to contribute to the mutation burden in many cancers. We aimed to evaluate the expression of APOBEC3A (A3A), 3B (A3B) mRNA and APOBEC3A-3B deletion polymorphism in Korean breast cancer patients and investigate the correlation between their expression and clinicopathological characteristics. Methods: One hundred thirty-eight patients who underwent surgery for breast cancer in Uijeongbu St. Mary's Hospital between January 2013 and December 2016 were evaluated. RNA and DNA were extracted from 138 breast cancer tissues and 10 adjacent normal breast tissues. The levels of A3A and A3B mRNA transcripts were determined using real-time quantitative PCR. Insertion and deletion PCR assays were performed to detect the APOBEC3A-3B deletion allele. Mutation hotspots in exon 2-11 of TP53 and exon 9/20 of PIK3CA were evaluated using direct sequencing method. Results: The expression of A3B was increased in breast cancer tissues than in normal breast tissues. The median A3B mRNA expression levels in both triple-negative breast cancer and human epidermal growth factor 2-positive breast cancer were significantly higher than in hormone receptor-positive breast cancer. Old age and high ki-67 expression were associated with increased expression of A3A and A3B. Advanced stage, presence of lymph node involvement, and high histological grade were associated with increased expression of A3A. The APOBEC3B deletion allele was found in 78 (56%) tumor samples. There was no significant association between A3A, A3B mRNA levels and the presence of APOBEC3B deletion allele. There was no difference in clinicopathological characteristics according to the presence of APOBEC3B deletion allele except histological grade. The frequency of high histological grade was significantly higher in tumors with APOBEC3B deletion allele than tumors without APOBEC3B deletion allele. TP53 mutations were identified in 12 (8.7%) cases and PIK3CA mutations were identified in 31 (22.5%) cases. There were no significant differences in the levels of A3A and A3B mRNA expression by TP53 mutation status. The presence of a PIK3CA mutation was significantly associated with lower A3A expression. Conclusions: The levels of A3B mRNA expression showed a difference according to breast cancer subtype, and triple-negative breast cancer showed the highest levels of A3B mRNA expression. The high levels of A3A and A3B mRNA expression were associated with an aggressive phenotype including high proliferation index. The APOBEC3A-3B deletion polymorphism was found in about half of the patients, but there was no difference in clinicopathological factors according to the presence of APOBEC3B deletion allele except histological grade. Citation Format: Won HS, Sun DS, Ko YH, You SH, Kim YS, Kim JS. Clinical implication of APOBEC3A and 3B in Korean patients with breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-05-03.

Human Epidermal Growth Factor 2-positive Breast Cancer with Mammographic Microcalcification: Relationship to Pathologic Complete Response after Neoadjuvant Chemotherapy.

Purpose To determine the relationship between the presence or absence of mammographic calcifications in human epidermal growth factor receptor 2 (HER2)-positive breast cancers and pathologic complete response (pCR) to neoadjuvant chemotherapy and to determine other tumor and clinical characteristics that may be predictive of such a response. Materials and Methods A database of all patients with HER2-positive breast cancer who underwent neoadjuvant chemotherapy between 2007 and 2015 was retrospectively reviewed. Patient demographic characteristics, mammographic appearance, molecular subtype of cancer (luminal or nonluminal), radiologic response (based on breast magnetic resonance images), surgery, and pathologic response to treatment were recorded. Inter- and subgroup comparison was performed for presence of mammographic microcalcification and cancer subtype by using Mann-Whitney and χ2 tests and logistic regression. Results A total of 111 patients with a median age of 49 years (interquartile range, 40-57 years) were evaluated. Of these, 64.9% (72 of 111) had mammographic microcalcifications, 63.1% (70 of 111) had luminal B cancer, and 36.9% (41 of 111) had nonluminal HER2-positive cancer. Radiologic response to neoadjuvant chemotherapy was observed in 70.3% (78 of 111) of patients. Surgery was performed in 97.3% (108 of 111) of patients, and 30.6% (34 of 111) of patients underwent breast conservation. pCR was observed in 33.3% (37 of 111) of patients; 16.2% (18 of 111) showed residual ductal carcinoma in situ and 50.5% (56 of 111) had residual invasive disease. The pCR rate was the same (P = .21) in patients with mammographic microcalcification (29.2% [21 of 72]) as in those without calcification (41.0% [16 of 39]). The pCR rate in patients with nonluminal HER2-positive cancers (46.3% [19 of 41]) was higher (P = .01) than in those with luminal B cancers (25.7% [18 of 70]). pCR was associated with nonluminal HER2-positive subtype (odds ratio, 5.4; 95% confidence interval: 1.8, 16.0; P = .01) and complete radiologic response (odds ratio, 20.4; 95% confidence interval: 3.3, 126.6; P = .01). Conclusion Patients with HER2-positive cancer and mammographic microcalcification can achieve pCR after neoadjuvant chemotherapy. Nonluminal HER2-positive subtype and complete radiologic response are predictors of pCR.

FEN1 knockdown improves trastuzumab sensitivity in human epidermal growth factor 2-positive breast cancer cells.

Trastuzumab has been widely applied as a treatment for human epidermal growth factor 2 (HER2)-overexpressing breast cancer. However, the therapeutic efficacy of trastuzumab is limited. Flap endonuclease 1 (FEN1) is a multifunctional endonuclease that has a crucial role in DNA recombination and repair. Inhibition of FEN1 is associated with the reversal of anticancer drug resistance. However, it is unclear whether FEN1 is involved in trastuzumab resistance. In the present study, it was demonstrated that trastuzumab increases the expression of FEN1, and FEN1 knockdown significantly enhanced the sensitivity of BT474 cells to trastuzumab (P<0.05). It was also revealed that trastuzumab induced HER receptor activation, increased binding with FEN1 and estrogen receptor α (ERα), and upregulated ERα-target gene transcription (P<0.05). Upon silencing of FEN1 expression with siRNA, activation of HER receptor and FEN1 binding to ERα were decreased, and trastuzumab-induced ERα target gene upregulation was partially ameliorated (P<0.05). These results suggest that FEN1 may mediate trastuzumab resistance via inducing HER receptor activation and enhancing ERα-target gene transcription. The findings of the present study indicate a novel role of FEN1 in trastuzumab resistance, suggesting that targeting FEN1 may enhance the efficiency of trastuzumab as a treatment for HER2-positive breast cancer.