Gabriella Uhercsák

Tumor Topoisomerase II Alpha Status and Response to Anthracycline-Based Neoadjuvant Chemotherapy in Breast Cancer

Objectives: Individualized chemotherapy for breast cancer improves the outcome. Anthracyclines target the enzyme topoisomerase IIα (TOP2A). We set out to perform a retrospective study of the presence of gene abnormalities and the expression of TOP2A in a cohort of breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. Methods: Forty-three patients with 45 breast cancers were treated with neoadjuvant docetaxel-epirubicin with/without capecitabine chemotherapy. The TOP2A status of the cancers, determined retrospectively by fluorescent in situ hybridization and immunohistochemistry, was analyzed in relation to the standard clinical and pathological data. Results: Clinically and pathologically complete remission (pCR) was achieved in 15 (33.3%) and 9 (20%) cases, respectively. The TOP2A gene was amplified in 2 human epidermal growth factor receptor 2 (HER2)-positive cancers (8%), and 32 (84.2%) overall exhibited TOP2A expression in >15% of the cells. The expression of TOP2A exhibited a strong correlation with the expression of Ki67 (R = 0.743, p < 0.001), and was negatively correlated with estrogen receptors (ER; R = 0.404, p = 0.012) and progesterone receptors (R = 0.430, p = 0.007). The expression of TOP2A was not related to the amplification of the TOP2A gene or the HER2 status of the tumor. The proportions of Ki67- and TOP2A-positive tumor cells were significantly reduced after chemotherapy (56.1 ± 23.6 vs. 19.0 ± 27.7%, p = 0.004, and 41.0 ± 27.9 vs. 12.7 ± 24.8%, p < 0.001, respectively). The development of pCR was related to a high grade (p = 0.054), ER negativity (p = 0.027) and high TOP2A expression (p = 0.037). The expression of TOP2A was an independent predictor of pCR (OR = 1.460, for every 10% increase, 95% CI: 1.016–2.096, p = 0.041). After a median follow-up time of 31.0 months, neither relapse-free survival nor overall survival was related to the tumor response. Conclusions: TOP2A expression is a marker of the tumor’s proliferation rate and sensitivity to anthracycline-based chemotherapy, and does not depend on the amplification of its gene.

Dose-Dense Sequential Adriamycin-Paclitaxel-Cyclophosphamide Chemotherapy Is Well Tolerated and Safe in High-Risk Early Breast Cancer

Objective: The feasibility of dose-dense sequential adjuvant chemotherapy with Adriamycin, paclitaxel and cyclophosphamide was evaluated. Methods: Fifty-five high-risk breast cancer patients were enrolled. The following chemotherapy schedule was used: 4 × Adriamycin → 4 × paclitaxel → 4 × cyclophosphamide, q 2 weeks (Adriamycin, 60 mg/m2; paclitaxel, 200 mg/m2 over 3 h, and cyclophosphamide, 800 mg/m2). Results: The dose intensity was 95.0, 99.8 and 97.4% of that planned for treatment with Adriamycin, paclitaxel and cyclophosphamide, respectively. During treatment with Adriamycin, paclitaxel and cyclophosphamide, 20, 12.7 and 25.5% of the patients, respectively, did not need filgrastim to maintain the dose density. The average number of filgrastim doses per cycle, when necessary, was 3.6. Neutropenia of grade 3–4 was found in 67.3, 13.5 and 10.0% of the patients after treatment with Adriamycin, paclitaxel and cyclophosphamide, respectively. A single case of febrile neutropenia was observed. Anemia occurred in 96.4% of the patients, and was significantly more frequent (p = 0.031) and more severe (p = 0.002) during paclitaxel treatment than in the other chemotherapy cycles. Conclusions: Dose-dense sequential chemotherapy with Adriamycin, paclitaxel and cyclophosphamide is well tolerated and safe. Individual treatment with granulocyte colony-stimulating factor is needed to maintain the dose density in most patients, but some tolerate this regimen without it, probably due to differences in drug clearances.

Neoadjuvant systemic therapy in breast cancer

Neoadjuvant (preoperative) systemic therapy is a good possibility for the treatment of symptomatic breast cancers of the locoregional stage. Chemotherapy or hormone therapy chosen according to the characteristics of the primary tumor, result in the regression of the tumor in the majority of the cases, favoring breast conserving surgery thereafter. The long-term effects of neoadjuvant systemic therapy are equivalent to that of adjuvant therapy, and the in vivo observed efficiency of the treatment reflects prognosis. Finally, systemic therapy introduced prior to surgery is not delayed by the possible adverse effects of the surgery. Detailed examination of the tumor and the patient is mandatory before starting systemic therapy. Besides breast imaging and histological examinations, staging is necessary. Pathological characterization of the tumor will enhance treatment choice based on the features of chemo- or hormone-sensitivity. For the treatment of chemosensitive tumors, taxane- and anthracycline-based polychemotherapy is the most efficacious. Data on neoadjuvant hormone therapy have been provided by studies on postmenopausal patients. Since the aromatase inhibitors are more efficient than tamoxifen, their use is the first option in this patient population. Among the molecular targeted agents, trastuzumab combined with chemotherapy produces extending therapeutic response rate. Following the completion of the neoadjuvant systemic therapy, breast imaging is required once more before performing breast and lymph node surgery. Postoperative radiotherapy is generally needed. The use of a common language and professional guidelines by the members of the multidisciplinary breast team is a condition for neoadjuvant systemic therapy.

Efficacy and drawbacks of neoadjuvant chemoradiotherapy in squamous cell carcinoma of the thoracic esophagus.

BACKGROUND/AIMS Neoadjuvant chemoradiotherapy (CRT) is widely applied in locally advanced esophageal tumors to improve resectability and local tumor control. In this study, we retrospectively analyzed the perioperative course of patients who underwent esophagectomy or esophagectomy following CRT. METHODOLOGY Forty one patients were admitted with non-advanced disease (T1-2, N0), and primary resection was performed. Additional 21 patients received neoadjuvant CRT because of locally advanced, T2-4, N0-1 disease. To investigate predictive factors for responsiveness to CRT, we determined the p53, p21 and Ki67 oncogene expressions in the biopsy samples from the CRT patients. RESULTS Following primary esophagectomy and esophagogastrostomy, the postoperative course was in most cases uneventful. Anastomotic leaks developed in 3 of the 41 cases (7.3%), and postoperative death in 1 case (2.4%). In response to CRT, significant down-staging was observed in 11 of the 21 patients (58%); in these cases esophagectomy was performed. However, in this group the rates of anastomotic leak (2 patients) and postoperative death (2 patients) were higher than in the first group (18% each). CONCLUSIONS Preoperative CRT is a good option for patients with locally advanced tumors, when primary R0 resection is hopeless. However, the rate and risk of postoperative complications are higher than after primary resection of non-advanced tumors.

Clinical benefit of fulvestrant monotherapy in the multimodal treatment of hormone receptor and HER2 positive advanced breast cancer: a case series

Fulvestrant is a pure estrogen receptor (ER) antagonist approved for the treatment of metastatic ER positive breast cancer in postmenopausal women with disease progression following antiestrogen therapy. The clinical results of fulvestrant demonstrated encouraging activity in tumors in spite of HER2 positivity, but data about its use after progression on anti-HER2 agents are limited. Partial responses and durations of response of 12, 25, and 38 months in three cases with multiple metastases of ER positive and HER2 positive breast cancer were observed; all patients had been treated with 1–4 regimens of an anti-HER2 agent in combination with chemotherapy or an aromatase inhibitor before the initiation of fulvestrant. Fulvestrant is a valuable option with limited toxicity and durable response in metastatic HER2 and ER positive breast cancer after progression on anti-HER2 agents as well. Therapeutic benefit even in extensive skin metastases and (irradiated) brain metastases may be expected. Further investigations are warranted to establish where it fits into the multimodal management of ER and HER positive breast cancer.

Broken venous catheter straddling in the pulmonary artery

The 49-year old male patient received eight cycles of adjuvant XELOX chemotherapy after the removal of a colon cancer of stage Dukes C. At the beginning of the oncological therapy, a portacath was implanted with the aim of easy vein access. Four years after the termination of the chemotherapy, routine CT showed that the tube of the portacath was missing at the reservoir side, but a 10 cm long catheter was drifted in the 2 branches of the pulmonary artery at the bifurcation. By retrospective viewing, the catheter suffered refraction during the follow-up period, and remained so for 1.5 years before detection. Vigilance should be practiced for the appropriate follow-up or the removal of the port when it is no longer needed.

Melanoma-Predisposing CDKN2A Mutations in Association with Breast Cancer: A Case-Study and Review of the Literature

The authors present the case of a 33-year-old female patient who developed melanoma, ductal adenocarcinoma of the breast and primary pancreas adenocarcinoma nearly simultaneously, but independently of each other. Past medical history of the patient was unremarkable, however, in her family history gastric, laryngeal and breast cancer was noted on the paternal side. The occurrence of multiple primary tumours in a relatively young individual, together with the family history of different malignancies, suggested that there might be genetic predisposition to the development of multiple tumours. In this chapter we present the case of the young female patient suffering from three independent primary tumours and review current data on the germ-line mutations detected to date in the CDKN2A gene, in view of the association not only with melanoma, but also with additional malignant diseases, such as pancreas carcinoma and breast cancer.

Long-Term Efficiency and Toxicity of Adjuvant Dose-Dense Sequential Adriamycin-Paclitaxel-Cyclophosphamide Chemotherapy in High-Risk Breast Cancer

Objectives: To perform a protocol-specified analysis of the dose-dense adriamycin-paclitaxel-cyclophosphamide (ddATC) study. Methods: Survival and late toxicity were analyzed in 55 patients enrolled to receive 4 × adriamycin 60 mg/m2, 4 × paclitaxel 200 mg/m2, 4 × cyclophosphamide 800 mg/m2, every 2 weeks, with cardioxane and filgrastim support. Kaplan-Meier curves were used to analyze relapse-free survival (RFS), distant disease-free survival (DDFS), and overall survival (OS). Survival analyses were performed according to the presence of casting-type calcifications on the mammogram. Results: After a median follow-up time of 78.5 (64.3–100.0) months, 29 (52.7%) patients were free of relapse (local, regional, distant or contralateral breast cancer), 34 (61.8%) patients were free of distant metastases, and 36 patients (65.5%) survived. The median times of RFS, DDFS and OS were not yet reached at 100.0 months. The median RFS, DDFS and OS times among breast cancer patients with tumors not associated with casting-type calcifications were >100.0 months, the corresponding parameters among patients with tumors accompanied by casting calcifications were 11.5 (p < 0.001), 11.5 (p < 0.001) and 29.6 months (p = 0.035), respectively. None of the patients developed myelodysplastic syndrome or leukemia. No cardiac failure occurred during the follow-up period. Conclusions: Our results indicate that adjuvant sequential ddATC is an efficient and less toxic chemotherapy regimen in high-risk breast cancer. The presence of casting-type calcifications on the mammogram points to a special biologic nature with very poor prognosis.