Docetaxel and cyclophosphamide as neoadjuvant chemotherapy in HER2-negative primary breast cancer.

BACKGROUND: Docetaxel plus cyclophosphamide (TC) has recently been established as a standard adjuvant chemotherapy regimen for HER2-negative (HER2-) operable breast cancer. However, the efficacy and tolerability of TC as neoadjuvant chemotherapy (NAC) remain unclear. We, therefore, conducted a prospective study to evaluate the efficacy of TC NAC in HER2- primary breast cancer. METHODS: Patients who were diagnosed with HER2-, N0-N1, invasive breast cancer between July 2011 and February 2014 and had tumors measuring 1-7 cm were eligible. The subtypes were classified using a core-needle or vacuum-assisted breast biopsy. The efficacy and safety of NAC comprising TC (75 mg/m2 docetaxel and 600 mg/m2 cyclophosphamide, four cycles every 3 weeks) were investigated in a prospective study in patients with HER2- breast cancer. RESULTS: Fifty-two patients were enrolled. Of these, 94.2 % (49/52) completed four cycles of TC. The overall pCR rate was 16.3 % (8/49). The pCR rates for patients with luminal A-like breast cancer [estrogen receptor-positive (ER+), Ki67 index of <20 %, and HER2-], luminal B-like breast cancer (ER+, Ki67 index of >20 %, and HER2-), and triple-negative breast cancer [ER-negative (ER-) and HER2-] were 0 % (0/12), 4.3 % (1/23), and 50.0 % (7/14), respectively. Almost all pCRs occurred in triple-negative breast cancer patients. CONCLUSIONS: The pCR rate of TC NAC was not very high despite the high completion rate. TC NAC was effective against the triple-negative subtype, resulting in a higher pCR rate. Therefore, our results indicated that TC NAC showed limited efficacy in luminal subtype breast cancer with the exception of the triple-negative subtype.

Docetaxel, cyclophosphamide, and trastuzumab as neoadjuvant chemotherapy for HER2-positive primary breast cancer.

BACKGROUND: The standard primary systemic therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancer is anthracyclines and/or taxanes combined with trastuzumab, which demonstrates a high pathological complete response (pCR). A pCR is a predictive marker of prognosis. However, results slightly differ, depending on the hormone receptor status. The efficacy and tolerability of docetaxel, cyclophosphamide, and trastuzumab (HER-TC) as neoadjuvant chemotherapy (NAC) remain unclear. We performed a prospective multicenter study of HER-TC NAC for HER2+ primary breast cancer. METHODS: Eligible patients had a clinical diagnosis of HER2+ invasive breast cancer greater than 1 cm but less than 7 cm and a tumor stage of N0 or N1. T hey were diagnosed between July 2011 and February 2014. For NAC, four cycles of HER-TC (6 mg/kg loading dose, 8 mg/kg, 75, and 600 mg/m2) were administered intravenously every 3 weeks. We investigated the pCR of the primary breast tumors. A pCR was defined as no histological evidence of invasive carcinoma or the appearance of only ductal carcinoma in situ. RESULTS: We enrolled 42 patients. The completion rate for four cycles of HER-TC was 97.6 % (41/42 patients). The overall pCR rate was 43.9 % (18/41 patients). The pCR rate for patients with the luminal HER2 subtype [estrogen receptor (ER)-positive+, HER2+] and the HER2-enriched subtype (ER-, HER2+) was 40.0 % (8/20 patients) and 47.6 % (10/21 patients), respectively. A pCR was achieved with nearly the same probability for each subtype. CONCLUSIONS: Four cycles of HER-TC may be a NAC option for HER2-positive breast cancer.

[A case of effective lapatinib/capecitabine therapy for HER2-positive breast cancer with multiple brain metastases].

A 63-year-old woman was suffering from HER2-positive and hormone receptor-negative breast cancer with bone metastasis. She received 16 cycles of paclitaxel(PTX 80mg/m2)plus trastuzumab(TRA 2mg/kg)on a 7-day cycle, and zoledronic acid(ZOL 4mg/body every 28 days), resulting in a near clinical complete response(cCR). Two years later, the patient complained of dizziness and nausea, and magnetic resonance imaging revealed multiple brain metastases. The prior treatments with PTX and TRA were changed to lapatinib(LAP)(orally at 1, 250mg/day every day)and capecitabine(CAP)(orally at 2, 000mg/m2 every day for 2 weeks, followed by a 1-week rest interval as 1 cycle)because of the multiple brain metastases. After 4 cycles of treatment, the number of brain lesions and the tumor sizes were significantly reduced. After 7 cycles, however, magnetic resonance imaging revealed the deterioration of some brain lesions. After whole-brain irradiation(30 Gy in 10 fractions)was added to the treatment, the outcome was near cCR. In conclusion, combination therapy of Lap and Cap may be an effective treatment option for brain metastasis of HER2-positive breast cancer.

[Administration of nab-paclitaxel for 9 metastatic breast cancer patients].

Nab-paclitaxel was administered to 9 patients with refractory advanced or recurrent breast cancer from 1 to 8 times(median 4)triweekly. The median cumulative dose was 775mg/m2(range 260-2, 000), and the median delivered dose intensity was 66. 7mg/m2/week(range 58. 3-86. 7). The response to treatment was CR in one patient, PR in 2 patients, SD in one patient, and PD in 4 patients. In one patient, treatment had to be suspended because of grade 3 peripheral neuropathy. The clinical benefit was 33%. All 4 PD patients were administered other salvage treatments and are alive. Adverse events included 6 case of neutropenia(grade 3-4 in 4 cases), grade 3 AST/ALT elevations in one patient, grade 3 myalgia in one patient. No case of febrile neutropenia was seen. All reactions were under control except for one patient with grade 3 peripheral neuropathy. Concurrent trastuzumab administration was safe also. In conclusion, nab-paclitaxel could be administered safely, and may contribute to the treatment of refractory advanced or recurrent breast cancer.

[A case of breast cancer with brain metastases responding to paclitaxel and capecitabine therapy].

A 31-year-old woman was referred to our hospital for back pain. After a close investigation, she was diagnosed with multiple bone, liver and brain metastases of breast cancer. She was administered a combination therapy of paclitaxel and capecitabine. Capecitabine was administered orally at 628mg/m / 2 twice daily on days 1-21, and paclitaxel 80 mg/m2 was injected on days 1, 8, and 15. Both drug courses were repeated every 28 days. After 5 courses of treatment, the level of tumor markers and all metastases were reduced. The combination treatment of paclitaxel and capecitabine is considered to be effective for metastatic breast cancer with brain metastases.

Myoid hamartoma of the breast that proved difficult to diagnose: a case report.

Myoid hamartomas of the breast are extremely rare breast lesions, with a poorly understood pathogenesis. We describe the case of a 38-year-old premenopausal woman who presenting with a mass in the left breast. Mammography revealed an oval mass that was partly indistinct, and ultrasonography showed a hypoechoic mass with a slightly irregular margin. Bilateral breast dynamic magnetic resonance imaging was performed for a more detailed evaluation. The images showed rapid initial enhancement and a microlobulated margin. Because the suspicion of malignancy was strong at that time, core needle biopsy was performed. Histologically, the tumor was identified as fibroadenoma. A case of myoid hamartoma of the breast that proved difficult to diagnose is reported, and discussed with reference to the literature.

[A case of effective combination therapy with docetaxel, cyclophosphamide and trastuzumab as primary systemic therapy for locally advanced HER2-positive breast cancer].

We experienced a case of locally advanced breast cancer achieving a significant improvement by using a combination of docetaxel(DOC), cyclophosphamide(CPA)and trastuzumab as a primary systemic therapy.The patient was a 54-year-old woman suffering from a right breast mass, who was referred to our hospital and diagnosed with HER2-positive breast cancer with subclavicular lymph nodes metastases.The combination therapy of DOC(75 mg/m / 2), CPA(600 mg/m2)and trastuzumab(loading dose 8 mg/kg, then 6 mg/kg)for 6 courses at q3 week intervals, was started as the primary systemic therapy. After 6 courses of treatment, a right modified radical mastectomy was performed.There were a little breast cancer cells in the breast, and no axillary lymph node metastases.The combination chemotherapeutic regime with DOC, CPA and trastuzumab seems to be useful for treatment of HER2-positive breast cancer.

[Long-term complete response in a patient with breast cancer and bone and pleura metastases after treatment with a combination of S-1 and zoledronic acid].

We report a long-term complete response (CR) in a patient with postoperative recurrent breast cancer and bone and pleura metastases after treatment with a combination of S-1 and zoledronic acid. We administered 4 courses of tri-weekly CE (epirubicin 75 mg/m2, cyclophosphamide 600 mg/m2) and 12 courses of weekly paclitaxel (80 mg/m2) as adjuvant chemotherapy. However, combination therapy with S-1 and zoledronic acid was started because of the development of bone and pleura metastases. S-1 was administered orally at 100 mg/day everyday for 2 weeks, followed by a 1-week rest interval as 1 course; 4 mg of zoledronic acid was injected every 4 weeks. After 3 cycles of treatment, the patient's tumor marker levels had decreased to normal values, and both the bone and pleura metastases had disappeared. A long-term complete response was obtained as a result of this combination therapy.

Enhancement of paclitaxel-induced apoptosis in HER2-overexpressing human breast cancer cells by a pertuzumab mimetic peptide, HRAP.

HRAP, a pentapeptide designed to bind with the pertuzumab interacting site in an extracellular domain of the HER2 molecule, enhanced the cytotoxicity of paclitaxel in HER2-overexpressing human breast cancer cell lines, BT474 and SKBR-3, but not in MDA-231 cells, which express lower levels of HER2. HRAP enhanced mitochondria-dependent apoptosis induced by paclitaxel in SKBR-3 and BT-474, but not in MDA-231. HRAP enhanced the inhibition of phosphorylation of serine 473 in Akt and Ser380/Thy382/The383 in PTEN. These results suggest that HRAP enhances paclitaxel-induced apoptosis in a manner dependent on the PTEN/Akt signal transduction pathway.

Clinical outcomes of video-assisted skin-sparing partial mastectomy for breast cancer and immediate reconstruction with latissimus dorsi muscle flap as breast-conserving therapy.

BACKGROUND: Skin-sparing partial mastectomy (SSPM) has yet to be investigated as a breast-conserving therapy for early-stage breast cancer. We report the clinical outcomes for video-assisted SSPM (VA-SSPM) with immediate breast reconstruction using autogenous tissue. METHODS: VA-SSPM is indicated for early-stage breast cancer arising in the upper-outer or lower-outer quadrant without skin involvement. An incision is placed along the midaxillary line, and SSPM is performed under endoscopic guidance using subcutaneous tunneling and lifting methods. Through the same incision, a latissimus dorsi muscle flap is harvested for breast reconstruction. From January 2000 to October 2007, 168 patients (Tis, n = 24; T1, n = 37; T2, n = 107) underwent VA-SSPM, and morbidity, curability, and postoperative patient satisfaction were investigated. RESULTS: Postoperative complications included skin necrosis (2.4%, n = 4) and muscle flap necrosis (0.6%, n = 1), but no severe complications were observed. After a mean follow-up of 58.6 months, eight patients (4.8%) experienced local recurrence. Sixty-month distant metastasis-free survival rates for Tis, T1, and T2 were 100%, 97%, and 83.3%, respectively, with an overall rate of 88.4%. Furthermore, overall survival rates for Tis, T1, and T2 were 100%, 94.1%, and 94.4%, respectively, with an overall survival rate of 95% for all patients. A patient satisfaction survey showed that 81.6% of patients evaluated the surgery as "good." CONCLUSIONS: VA-SSPM for early-stage breast cancer improves cosmetic results and achieves high patient satisfaction without increasing local or distant organ recurrence. This method offers a useful local therapy for early-stage breast cancer.

Video-assisted skin-sparing breast-conserving surgery for breast cancer and immediate reconstruction with autologous tissue: clinical outcomes.

BACKGROUND: This study analyzed clinical results of video-assisted breast-conserving surgery for breast cancer. METHODS: Video-assisted breast-conserving surgery is indicated for breast cancer that has not invaded the skin. A skin incision is made at an inconspicuous site. Skin-sparing partial mastectomy was performed endoscopically on 244 patients (stage I, n = 94; stage II, n = 150). Morbidity, curability, and patient satisfaction were analyzed. RESULTS: Skin necrosis was seen in nine patients. Local recurrence was seen in 13 patients (mean postoperative interval 65.3 months). Distant metastasis-free survival at 60 months was 93.6% for stage I and 90.5% for stage II. Overall survival was 95.7% for stage I and 96.9% for stage II. Satisfaction with surgery as investigated by questionnaire was "good" for 72.3% of patients. CONCLUSIONS: Video-assisted breast-conserving surgery showed no increases in local or distant recurrence and patient satisfaction was high. Video-assisted breast-conserving surgery appears useful for local treatment of breast cancer.

Video-assisted skin-sparing breast-conserving surgery for breast cancer and immediate reconstruction with autologous tissue.

OBJECTIVE: To analyze therapeutic results of video-assisted breast-conserving surgery (VA-BCS) for early stage breast cancer. BACKGROUND: VA-BCS for breast cancer has been developed in Japan, and is indicated for breast cancer unaccompanied by skin involvement. The surgical incision is made at an inconspicuous site, followed by skin-sparing partial mastectomy (SSPM) and immediate reconstruction of the breast. This technique affords good cosmetic results. The long-term results are reported herein. METHODS: VA-BCS was performed on 551 patients. The skin incision was made as a peri-areolar incision or at the midaxillary line. Skin-sparing partial mastectomy was performed using an endoscope and the lifting and tunneling method. Morbidity, curability, and degree of satisfaction with regard to cosmesis were analyzed. RESULTS: Skin necrosis in 22 patients (4.0%) and necrosis of fatty tissue-muscle flap in 17 patients (3.1%) were recorded as postoperative complications. No other serious complications were encountered. Local recurrence occurred in 23 patients (4.2%) after a mean follow-up of 38.4 months. Distant-metastasis-free survival rate at 66 months was 100% for Tis, 95.5% for T1, and 90.7% for T2. Overall survival rate was 100% for Tis, 97.3% for T1, and 95.7% for T2. Degree of satisfaction with surgery as investigated by questionnaire was "good" for 76.1% of patients. CONCLUSION: VA-BCS for early stage breast cancer showed no association with increases in local or distant organ recurrence. The technique yielded improved cosmesis and a high degree of patient satisfaction. Follow-up observation of patients for a longer period is necessary, but VA-BCS seems useful for local treatment of breast cancer.

Prognosis of Japanese breast cancer based on hormone receptor and HER2 expression determined by immunohistochemical staining.

BACKGROUND: We classified Japanese breast cancer patients based on estrogen receptor (ER), progesterone receptor (PR), and HER2 protein expression and compared their prognoses. METHODS: We compared the background and prognostic factors of 600 patients with breast cancer who were assigned to the following groups: luminal A (ER + and/or PR + and HER2-; n = 431; 71.8%), luminal B (ER + and/or PR + and HER2 + ; n = 27; 4.5%), HER2 (ER-, PR-, and HER2 + ; n = 39; 6.5%) and basal-like (BBC; ER-, PR-, and HER2-; n = 103; 17.2%). RESULTS: Background factors did not significantly differ among the groups. Disease-free survival rates were significantly lower for the luminal B, HER2, and BBC subtypes than for the luminal A subtype. Cancer tended to recur earlier and overall survival was significantly lower for the BBC than for the luminal A and HER2 subtypes. Overall survival rates for the luminal B, HER2, and luminal A subtypes were comparable. CONCLUSIONS: The subtype distribution for Japanese and Caucasian patients was comparable. The prognosis for the BBC subtype was poorest among all subtypes. Breast cancer tended to recur earlier for the luminal B and HER2 subtypes than for the luminal A subtype; however, overall survival did not significantly differ among them.

Blockade of the Fas/Fas ligand interaction suppresses hepatocyte apoptosis in ischemia-reperfusion rat liver.

Hepatic ischemia-reperfusion injury remains a significant problem for liver surgery, including transplantation, and apoptosis has been implicated in this type of hepatic injury. Here we found that through the Fas/Fas ligand interaction apoptosis is involved in the late phase of hepatic ischemia-reperfusion injury. The appearance of apoptotic hepatocytes increases significantly after reperfusion, reaching a maximum 12 h after reperfusion. The transcription levels of Fas and Fas ligand are increased after reperfusion. Fas is expressed on hepatocytes, while Fas ligand is expressed on infiltrating immune cells. A close spatial and temporal association of Fas expression and apoptotic cells is demonstrated in the histological observation. These results suggest that infiltrating cells induce apoptosis of hepatocytes through the Fas/Fas ligand interaction, leading to hepatocyte injury. Furthermore, an injection of anti-Fas antibody or neutralizing anti-Fas ligand antibody results in a dramatic decrease in the occurrence of hepatocyte apoptosis and hepatic infiltration of macrophages and natural killer cells as well as liver injury. Our results suggest that blockage of the Fas/Fas ligand interaction is a promising strategy for suppression of hepatic ischemia-reperfusion injury.

Fas ligand released by activated monocytes causes apoptosis of lung epithelial cells in human acute lung injury model in vitro.

Alveolar epithelial cell death plays a crucial role in the progression of acute lung injury. We have demonstrated up-regulation of Fas expression on alveolar epithelial cells, and soluble Fas ligand secretion from inflammatory cells upon acute lung injury. Here we show that the lipopolysaccharide-stimulated human monocyte cell line THP-1 releases Fas ligand, and that conditioned medium from lipopolysaccharide-stimulated THP-1 cells induces apoptosis of the human pulmonary adenocarcinoma cell line A549. Activation of caspase-3 and -8 is associated with the apoptosis. Gene targeting on Fas in A549 cells by specific small interfering RNA impairs apoptosis induced by conditioned medium from activated THP-1, while that on Fas ligand in THP-1 cells impairs the apoptosis-inducing activity of the conditioned medium produced by lipopolysaccharide-stimulated cells. These results suggest that Fas ligand released by monocytes causes alveolar epithelial cell death through a Fas-dependent apoptotic mechanism in the development of acute lung injury.

Development of HER2-antagonistic peptides as novel anti-breast cancer drugs by in silico methods.

An antagonistic peptide called HRAP that binds to the human HER2 molecule was designed by our computational method. In silico docking study demonstrated the specific interaction of HRAP with the dimerization domain in the HER2 molecule. Interestingly, HRAP inhibited proliferation of HER2-overexpressed human breast cancer cell lines. However, it had little cellular cytotoxicity (apoptosis inducibility). The cell proliferation inhibition was associated with the suppression of phosphorylation of PTEN and Akt. Thus, HRAP is the first HER2-binding small peptide antagonist rationally designed by a computer-aided SBDD method and is useful for the development of peptide mimetics to generate novel anti-breast cancer drugs.

Aberrant expression of Fra-1 in estrogen receptor-negative breast cancers and suppression of their propagation in vivo by ascochlorin, an antibiotic that inhibits cellular activator protein-1 activity.

Estrogen receptor-negative breast cancers generally are highly malignant, resistant to chemotherapy and poorly prognostic. Here we demonstrate that estrogen receptor-negative human breast cancer cell lines highly express Fra-1, c-Fos and c-Jun, components of the transcription factor, activator protein-1 (AP-1). Retrospective observation of breast cancer tissues obtained by core needle biopsy before surgery from stages II and III patients demonstrates that Fra-1 expression is high in estrogen receptor-negative human breast cancers, and negatively correlated to paclitaxel sensitivity. Ascochlorin, which suppresses cellular AP-1 activity, selectively kills estrogen receptor-negative human and mouse breast cancer cell lines, and prolongs the survival time of mice implanted with an estrogen receptor-negative mammary carcinoma. These results suggest that chemotherapy targeting AP-1 activity is a potent strategy for estrogen receptor-negative human breast cancers.

[Apoptotic mechanisms induced in breast cancer cells by vinorelbine].

Vinorelbine (VNB) is one of new semi-synthesized vinka alkaloids developed in France, of which anti-tumor activity is susceptible mainly to non-small cell lung cancer and breast cancer. Moreover, its clinical efficacy has been noted from single-agent therapy or combination therapy with taxanes. It is assumed that VNB selectively acts on tubulin which elaborates microtubules, strands the cells at G 1 phase and interferes with the mitosis. VNB has unique anti-tumor activity as an antimicrotubule agent and is expected to be available for treatment of multi-drug resistant tumors. In this report, we demonstrate that VNB, as an antimicrotubule agent, induces apoptosis in breast cancer cell line, MX-1 via a mitochondrial pathway.