Neoadjuvant chemotherapy with trastuzumab, docetaxel, and carboplatin administered every 3 weeks for Japanese women with HER2-positive primary breast cancer: efficacy and safety.

BACKGROUND: This phase II neoadjuvant study evaluated the efficacy and safety of a triweekly regimen of docetaxel and carboplatin in combination with trastuzumab (TCbH) in Japanese women with human epidermal growth factor receptor type2 (HER2)-positive primary breast cancer. METHODS: Patients with HER2-positive, stage I-III invasive breast cancer received six courses of trastuzumab (8 mg/kg loading dose, then 6 mg/kg, day 1), docetaxel (75 mg/m2, day 1), and carboplatin (area under the curve: 6, day 1) every 3 weeks. The primary endpoint was pathological complete response (pCR) of both breast and axillary lymph node disease. RESULTS: Fifty patients were enrolled in this study. Median age was 58 (range 32-75) years. All patients underwent definitive surgery. Thirty-three (66%) patients completed the chemotherapy course, while the treatment was delayed or discontinued in the other 17 (34%) patients because of adverse events (AEs). The pCR rate was 52%; the overall response rate was 66%. Grade 3/4 AEs due to nonhematological toxicity were anorexia (4%), diarrhea (2%), and rash (2%), and those due to hematological toxicity were neutropenia (36%), anemia (12%), and thrombocytopenia (2%). CONCLUSION: Although the triweekly six-course regimen of TCbH achieved a high pCR rate, hematological AEs frequently occurred during the latter part of the chemotherapy course. One-third of patients experienced delayed or discontinued chemotherapy. Clinical registration number: http://www.umin.org.au UMIN000013513.

[Choice of Adjuvant Chemotherapy Based on Breast Cancer Subtype].

Adjuvant chemotherapy targets micrometastases. If micrometastases are destroyed, patients with breast cancer will be cured. Currently, in Japan, standard breast cancer therapy is decided based on subtypes that are defined according to ER, PgR, HER2, and Ki-67 expression. We present here an outline of the recommended chemotherapy regimens based on evidence.

[Successful treatment of trastuzumab-resistant HER2-positive breast cancer with extensive liver metastases using the combination of trastuzumab and capecitabine - a case report].

We report a case of a trastuzumab-resistant human epidermal growth factor receptor-2(HER2)-positive breast cancer patient with extensive liver metastases and associated impaired liver function, who showed an excellent response to the combination of trastuzumab and capecitabine. The patient was a 59-year-old postmenopausal woman with multiple liver metastases at first examination. She first received anthracycline-based chemotherapy, and after progression was followed up with a combination of trastuzumab and paclitaxel. Despite an initial response to this treatment, liver metastases rapidly progressed. Although palliative treatment was considered because of her impaired liver function, she received capecitabine while continuing trastuzumab. This combination therapy showed an excellent response, and a good quality of life(QOL)was maintained for a long time without any severe adverse events. The continuation of trastuzumab is considered effective after having progressed by trastuzumab including pretreatment, and we consider it worth while to give a combination of trastuzumab and capecitabine to patients with extensive liver metastases and associated impaired liver function, because of the treatment's synergistic effect and low risk of causing severe adverse events.

Axillary ultrasound examination is useful for selecting patients optimally suited for sentinel lymph node biopsy after primary systemic chemotherapy.

BACKGROUND: Controversy surrounds the reliability of sentinel lymph node biopsy after primary systemic chemotherapy. In this study, we assessed axillary ultrasound for selecting patients most likely to optimally benefit from biopsy. METHODS: The study included 87 patients who received primary systemic chemotherapy and underwent a sentinel lymph node biopsy followed by axillary lymph node dissection. Lymph nodes >10 mm in diameter, irregularly swollen, round, and homogeneously hypoechoic without an echo-rich center were considered axillary ultrasound positive. RESULTS: In axillary ultrasound-negative patients before and after primary systemic chemotherapy, identification, sensitivity, and false-negative rates were 81%, 100%, and 0%, respectively. However, in patients whose lymph nodes converted from positive to negative after primary systemic chemotherapy, these values were 83%, 70.8%, and 29.2%, respectively. CONCLUSIONS: Axillary ultrasound-negative patients before and after primary systemic chemotherapy were suitable for sentinel lymph node biopsy. Axillary ultrasound should be used during primary systemic chemotherapy and before surgery.

18F-fluorodeoxyglucose positron emission tomography optimizes neoadjuvant chemotherapy for primary breast cancer to achieve pathological complete response.

BACKGROUND: To assess the usefulness of positron emission tomography combined with computed tomography using (18)F-fluorodeoxyglucose (FDG PET/CT) for optimizing chemotherapy during neoadjuvant chemotherapy for primary breast cancer. METHODS: One hundred and eight patients (110 tumors) with breast cancer (≥2 cm, stages II and III) received neoadjuvant chemotherapy consisting of an anthracycline-based regimen and taxane. The maximal value of the baseline standardized uptake value (SUV) and the change in SUV after four cycles of an anthracycline-based regimen relative to baseline SUV were assessed for predicting pathological complete response (pCR) after sequential taxane. RESULTS: Tumors with pCR had significantly higher baseline SUV (9.3 ± 3.7 SD) compared to those with non-pCR (7.2 ± 3.8 SD) (p = 0.02), but there was a considerable overlap between two groups. On PET scan after four cycles of chemotherapy, thirty-three patients (33.7%) with a 72.1% or greater reduction in SUV were considered as responders and the performance in predicting pCR had a sensitivity of 88.9% and specificity of 78.7%. CONCLUSION: The baseline SUV could not be a useful indicator for predicting pCR due to the wide range in sensitivity. On the other hand, a relative change in SUV after completion of an anthracycline-based regimen could be useful for predicting pCR.

A false positive for metastatic lymph nodes in the axillary region of a breast cancer patient following mastectomy.

Recent advanced imaging modalities such as positron emission tomography (PET) detect malignancies using 2-[18F]-fluoro-2-deoxy-D: -glucose (18-FDG) with high accuracy, and they contribute to decisions regarding diagnosis, staging, recurrence, and treatment response. Here, we report a case of false-positive metastatic lymph nodes that were diagnosed by PET/CT and ultrasonography in a 48-year-old breast cancer patient who had undergone mastectomy. The tumors, which were oval shaped and resembled lymph nodes, were detected by ultrasonography. PET/CT revealed high uptake of 18-FDG in the tumors. To investigate the proposed recurrence and to re-evaluate the biology of the recurrent tumors, a tumor was removed from the brachial plexus of the patient. Histological findings revealed it to be a schwannoma. All imaging modalities including PET/CT failed to distinguish benign tumors from metastatic lymph nodes in the brachial plexus. After resection of the schwannomas, the patient complained of a slight motor disorder of the second finger on the right hand. Hence, it is important to consider a false-positive case of lymph node metastasis in a breast cancer patient following mastectomy.

BiClamp forceps significantly shorten the operation time for breast surgery.

PURPOSE: A novel approach was introduced for breast surgery using the BiClamp, a new bipolar thermal energy device, to avoid complications and to shorten the time required for the dissection of the axillary lymph nodes. METHODS: Thirty-six patients with early breast cancer were assessed. The surgical parameters were compared between the procedures performed using the BiClamp technique (n = 14) and conventional surgery with suture ligation (n = 22). The parameters included the operation time, blood loss, and discharge on the first postoperative day. In addition, each of those parameters was compared between the patients with a high body mass index (BMI) (>22) and a low BMI (< or =22). The sealed vessels were examined histologically and heat-associated morphological vessel wall alterations were evaluated. RESULTS: The operation time was significantly shorter in the BiClamp group than in the control group (P = 0.017, 90 +/- 18 vs 115 +/- 33 min). In addition, the blood loss in the BiClamp group tended to be smaller than in the control group, but the difference was not significant (P = 0.54, 61 +/- 47 vs 74 +/- 67 g). No other parameters showed any significant differences between the two groups. CONCLUSION: The BiClamp thermofusion technique was safe and useful in breast surgery involving axillary dissection.

Successful treatment of leptomeningeal metastases from breast cancer using the combination of trastuzumab and capecitabine: a case report.

We report a case of metastatic breast cancer with leptomeninges and multiple bone metastases that showed an excellent response to the combination of trastuzumab and capecitabine; therapeutic effect was evaluated by MRI at follow-up. A 44-year-old woman underwent modified radical mastectomy in February 1997. In April 2003, a tumor at the right basis cerebri and multiple bone metastases were noted, and in October 2003, she underwent enucleation of the tumor. Histopathologically, the tumor was consistent with a basal skull metastasis from breast cancer. In March 2004, the patient began to experience pain, weakness, and paresthesia of both legs. She was diagnosed, with leptomeningeal metastasis (LM) from breast cancer using MRI. In December 2005, the combination of trastuzumab and capecitabine administered as sixth-line treatment was very effective for LM. Although it is generally very difficult to diagnose LM and assess the therapeutic effect with MRI, in this case, it was possible. To our knowledge, there has been no report in the literature describing the combination of trastuzumab and capecitabine for LM from breast cancer. Although the mechanism underlying the efficacy of this combination is still unknown, the treatment would be worth trying because of its few side effects in extensively treated patients with LM from breast cancer. To confirm the antitumor efficacy of trastuzumab and capecitabine, however, further investigations are required.

Loss of p53-regulatory protein IFI16 induces NBS1 leading to activation of p53-mediated checkpoint by phosphorylation of p53 SER37.

Our previous results that IFI16 is involved in p53 transcription activity under conditions of ionizing radiation (IR), and that the protein is frequently lost in human breast cancer cell lines and breast adenocarcinoma tissues suggesting that IFI16 plays a crucial role in controlling cell growth. Here, we show that loss of IFI16 by RNA interference in cell culture causes elevated phosphorylation of p53 Ser37 and accumulated NBS1 (nibrin) and p21WAF1, leading to growth retardation. Consistent with these observations, doxycyclin-induced NBS1 caused accumulation of p21WAF1 and increased phosphorylation of p53 Ser37, leading to cell cycle arrest in G1 phase. Wortmannin treatment was found to decrease p53 Ser37 phosphorylation in NBS-induced cells. These results suggest that loss of IFI16 activates p53 checkpoint through NBS1-DNA-PKcs pathway.

[The incidence and management of bone metastasis from breast cancer].

Mammary cancer is one of the solid malignancies, which easily metastasizes to bone. The frequency of bone metastases of breast cancer has been reported to be 65-75% of all breast cancer patients, and, in autopsy example at Shikoku Cancer Center, metastasis was recognized to be 74.7%. There are many symptomatic signs of bone metastases, but hypercalcemia needs to be treated immediately. Hypercalcemia might be diagnosed precisely because a lethal symptom appears. For diagnosis, bone scintigram, simple X-rays, MRI, and CT scan were effective. Radiotherapy, surgery, chemotherapy, and hormonal treatments were useful to improve the symptoms from bone metastasis; in addition, bisphosphonates demonstrated a synergistic effect with chemoendocrine treatments. Bisphosphonates also reduced the incidence of symptom-related events in patients with bone metastasis.

[Current status of adjuvant chemotherapy for breast cancer].

Breast cancer is one of the most common malignancies among Japanese women. Approximately 40,000 new patients are diagnosed annually. In the USA, however,the mortality from breast cancer has recently been declining. A nationwide screening promotion using mammography, and recent advances in the treatment for early breast cancer have been the main reasons. It was widely accepted that for breast cancer as a systemic disease, appropriate systemic treatment of either chemotherapy and endocrine therapy improved the survival. We describe here the contributions of new agents to the improvement in survival for breast cancer patients and introduced the concept of dose density.

[Recent perspectives second-line chemotherapy for breast cancer].

The recent development of chemotherapeutic agents for breast cancer will be reviewed. The paradigm shift from CMF to anthracycline containg regimens +/- taxanes in an adjuvant setting may be considered to decide the sequence of recommended chemotherapy for metastatic breast cancer. Recurrent breast cancer patients who never have undergone anthracycline-containing regimens should be treated with anthracycline regimens. Patients who have already received only an anthracycline-containing regimen in adjuvant therapy will be treated with taxane with or without capecitabine. For patients already having received both anthracycline and taxanes, capecitabine monotherapy will be indicated as a first-line treatment. Physicians will choose the best treatment option among chemotherapeutic agents for patients with distant metastasis.

BRCA1 phosphorylation by Aurora-A in the regulation of G2 to M transition.

Aurora-A/BTAK/STK15 localizes to the centrosome in the G(2)-M phase, and its kinase activity regulates the G(2) to M transition of the cell cycle. Previous studies have shown that the BRCA1 breast cancer tumor suppressor also localizes to the centrosome and that BRCA1 inactivation results in loss of the G(2)-M checkpoint. We demonstrate here that Aurora-A physically binds to and phosphorylates BRCA1. Biochemical analysis showed that BRCA1 amino acids 1314-1863 binds to Aurora-A. Site-directed mutagenesis indicated that Ser(308) of BRCA1 is phosphorylated by Aurora-A in vitro. Anti-phospho-specific antibodies against Ser(308) of BRCA1 demonstrated that Ser(308) is phosphorylated in vivo. Phosphorylation of Ser(308) increased in the early M phase when Aurora-A activity also increases; these effects could be abolished by ionizing radiation. Consistent with these observations, acute loss of Aurora-A by small interfering RNA resulted in reduced phosphorylation of BRCA1 Ser(308), and transient infection of adenovirus Aurora-A increased Ser(308) phosphorylation. Mutation of a single phosphorylation site of BRCA1 (S308N), when expressed in BRCA1-deficient mouse embryo fibroblasts, decreased the number of cells in the M phase to a degree similar to that with wild type BRCA1-mediated G(2) arrest induced by DNA damage. We propose that BRCA1 phosphorylation by Aurora-A plays a role in G(2) to M transition of cell cycle.

Requirement of IFI16 for the maximal activation of p53 induced by ionizing radiation.

IFI16 is a member of the PYRIN superfamily that has been implicated in BRCA1-mediated apoptosis and inflammation signaling pathways. Here we report that most breast cancer cell lines examined expressed decreased mRNA and protein levels of IFI16, although IFI16 is expressed in human primary normal mammary epithelial cells. Significantly, immunohistochemical analysis of tissues from 25 breast cancer patients demonstrated that carcinoma cells showed negative or weaker staining of IFI16 compared with positive nuclear staining in normal mammary duct epithelium. si-RNA-mediated reduction of IFI16 resulted in perturbation of p53 activation when treated with ionizing radiation (IR). Expression of IFI16 enhanced p53 transcriptional activity in cells exposed to IR. Adenovirus expression of IFI16 in IFI16-deficient MCF7 induced apoptosis, which was enhanced by radiomimetic neocarcinostatin treatment. Tetracycline-regulated IFI16 also induced apoptosis when coexpressed with p53 in p53-deficient EJ cells subjected to IR, suggesting that IFI16 is involved in p53-mediated transmission of apoptosis signaling. Consistent with these results, expression of IFI16 enhanced activation of the known p53 target genes, including p21, Hdm2, and bax in MCF7 cells. These results suggest that loss of IFI16 results in deregulation of p53-mediated apoptosis, leading to cancer development.

A member of the Pyrin family, IFI16, is a novel BRCA1-associated protein involved in the p53-mediated apoptosis pathway.

We identified IFI16 as a BRCA1-associated protein involved in p53-mediated apoptosis. IFI16 contains the Pyrin/PAAD/DAPIN domain, commonly found in cell death-associated proteins. BRCA1 (aa 502-802) interacted with the IFI16 Pyrin domain (aa 1-130). We found that IFI16 was localized in the nucleoplasm and nucleoli. Clear nucleolar IFI16 localization was not observed in HCC1937 BRCA1 mutant cells, but reintroduction of wild-type BRCA1 restored IFI16 nuclear relocalization following IR (ionizing radiation). Coexpression of IFI16 and BRCA1 enhanced DNA damage-induced apoptosis in mouse embryonic fibroblasts from BRCA1 mutant mice expressing wild-type p53, although mutant IFI16 deficient in binding to BRCA1 did not induce apoptosis. Furthermore, tetracycline-induced IFI16 collaborated in inducing apoptosis when adenovirus p53 was expressed in DNA-damaged p53-deficient EJ cells. These results indicate a BRCA1-IFI16 role in p53-mediated transmission of DNA damage signals and apoptosis.