PI3K/Akt/mTOR signalling pathway activation in patients with ER-positive, metachronous, contralateral breast cancer treated with hormone therapy.

Oestrogen receptor (ER)-positive, metachronous, contralateral breast cancer (MCBC) sometimes develops during or soon after completion of hormone therapy (HT), but it is uncertain whether it is HT-resistant. We examined the association between ER-positive second cancer and activation of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathways, which are associated with HT resistance. We examined the treatment-free interval (time after completion of HT for initial cancer) in 41 patients with ER-positive MCBC with a history of adjuvant HT for initial cancer (HT group), and initial-to-second period duration (time after operation of initial cancer to onset of second cancer) in 17 patients with ER-positive MCBC in whom adjuvant HT was not applied to the initial tumour (control group or no HT group). Phosphorylated S6 (pS6) and phosphorylated MAPK (pMAPK) were used as indicators of PI3K/Akt/mTOR and MAPK pathway activity, respectively. Tumours were classified as showing negative, positive or strongly positive staining, and the correlation between staining and treatment-free interval or initial-to-second period duration was evaluated using the Spearman's rank correlation coefficient (ρ). Treatment-free interval and pS6 staining showed a negative correlation (ρ=-0.5355; P=0.0003) in the HT group. There was no correlation between initial-to-second period duration and pS6 staining in the no HT group (ρ=-0.0814; P=0.756). There was no correlation between pMAPK signalling and the treatment-free interval in the HT group (ρ=-0.1560; P=0.330) or the initial-to-second period duration in the no HT group (ρ=-0.0116; P=0.965). Development of a second ER-positive cancer during or soon after completion of HT for the initial cancer may be associated with activation of the PI3K/Akt/mTOR pathway. Care should be taken during follow-up and when selecting adjuvant therapy for second cancer.

Lentinula edodes mycelia extract plus adjuvant chemotherapy for breast cancer patients: Results of a randomized study on host quality of life and immune function improvement.

Anthracycline-based chemotherapies for breast cancer are known to adversely affect patients' quality of life (QOL) and immune function. For that reason, adjuvants that improve those impairments are required. A randomized double-blind study was conducted to evaluate the effectiveness of Lentinula edodes mycelia extract (LEM), which is an oral biological response modifier (BRM) medicine for cancer patients as such an adjuvant. A total of 47 breast cancer patients who were scheduled to receive postoperative adjuvant anthracycline-based chemotherapy, i.e., 5-fluorouracil (5-FU) + cyclophosphamide + epirubicin (FEC regimen), 5-FU + cyclophosphamide + doxorubicin/pirarubicin (FAC regimen), cyclophosphamide + doxorubicin/pirarubicin (AC regimen) and cyclophosphamide + epirubicin (EC regimen), were entered in the study. The patients were randomly divided into either an LEM or a placebo tablet group; the tablets were orally ingested daily over 2 courses of each therapy. In the placebo group, the total scores for QOL were lower on day 8 of the second course of chemotherapy compared with the baseline scores, whereas in the LEM group the scores had not decreased. In the placebo group, the QOL functional well-being score was lower on day 8 after both the first and second courses of chemotherapy compared with the baseline score, but it had not decreased in the LEM group. Evaluation of immunological parameters indicated that an increase in the proportion of regulatory T cells to peripheral blood CD4+ cells tended to be inhibited in the LEM group compared with the placebo group. Oral LEM that was coadministered with anthracycline-based chemotherapies was useful for maintaining patients' QOL and immune function. Thus, LEM appears to be a useful oral adjuvant for patients receiving anthracycline-based chemotherapy.

One-step nucleic acid amplification assay for intraoperative prediction of advanced axillary lymph node metastases in breast cancer patients with sentinel lymph node metastasis.

The one-step nucleic acid amplification (OSNA) assay is used to semiquantitatively measure the cytokeratin (CK)19 mRNA copy numbers of each sentinel lymph node (SLN) in breast cancer patients. The aim of the present study was to evaluate whether the diagnosis of ≥4 LN metastases is possible using the OSNA assay intraoperatively. Between May, 2010 and December, 2014, a total of 134 patients who underwent axillary lymph node dissection (ALND) of positive SLNs were analyzed. The total tumor load (TTL) was defined as the total CK19 mRNA copies of all positive SLNs. The correlation between TTL and ≥4 LN metastases was evaluated. Of the 134 patients, 31 (23.1%) had ≥4 LN metastases. TTL ≥5.4×104 copies/µl evaluated by receiver operator characteristic curve analysis was examined along with other clinicopathological variables. In the multivariate analysis, only TTL ≥5.4×104 copies/µl was correlated with ≥4 LN metastases (odds ratio = 2.95, 95% confidence interval: 1.17-7.97, P=0.022). Therefore, TTL assessed by the OSNA assay has the potential to be a predictor of ≥4 LN metastases and it may be useful for the selection of patients with positive SLNs in whom ALND may be safely omitted.

O6-methylguanine-DNA methyltransferase as a prognostic and predictive marker for basal-like breast cancer treated with cyclophosphamide-based chemotherapy.

The O6-methylguanine-DNA methyltransferase (MGMT) protein protects cells from alkylating agents by removing alkyl groups from the O6-position of guanine. However, its effect on DNA damage induced by cyclophosphamide (CPM) is unclear. The present study investigated whether MGMT expression was correlated with prognosis in patients with breast cancer that was managed according to a common therapeutic protocol or treated with CPM-based chemotherapy. The intrinsic subtypes and MGMT protein expression levels were assessed in 635 consecutive patients with breast cancer using immunohistochemistry. In total, 425 (67%) luminal A, 95 (15%) luminal B, 47 (7%) human epidermal growth factor receptor-2+/estrogen receptor- (HER2+/ER-) and 48 (8%) basal-like subtypes were identified. Of these, MGMT positivity was identified in 398 (63%) of 635 breast cancers; 68% of luminal A, 67% of luminal B, 30% of HER2+/ER- and 46% of basal-like subtypes were positive. The overall survival (OS) and disease-free survival (DFS) rates did not significantly differ according to the MGMT status among patients with luminal A, luminal B or HER2+/ER- subtypes, and patients with MGMT-negative basal-like cancers tended to have a longer DFS, but not a significantly longer OS time. CPM-containing chemotherapy was administered to 26%, 40%, 47% and 31% of patients with luminal A, luminal B, HER2+/ER- and basal-like tumors, respectively. Although the MGMT status and clinical outcomes of patients with the luminal A, luminal B or HER2+/ER- subtypes treated with CPM were not significantly correlated, the patients with MGMT-negative basal-like tumors who received CPM exhibited significantly improved DFS and OS compared with the CPM-treated patients with MGMT-positive tumors. MGMT may be a useful prognostic and predictive marker for CPM-containing chemotherapy in basal-like breast cancer.

Relationship between thymidylate synthase (TYMS) gene polymorphism and TYMS protein levels in patients with high-risk breast cancer.

The thymidylate synthase gene (TYMS) has three functional polymorphisms which are associated with TYMS expression. To explore the predictability of TYMS polymorphisms for the sensitivity and toxicity of 5-fluorouracil (5-FU) in breast cancer patients, this study investigated the association between TYMS polymorphisms and TYMS protein expression in normal and tumour tissue specimens from 49 lymph node-positive breast cancer patients. An analysis of the TYMS 3'-UTR polymorphism showed that level of TYMS protein in normal tissue with the +6 bp/+6 bp genotype was significantly higher than that for the -6 bp/+6 bp genotype. Tumour tissue with the +6 bp/+6 bp genotype had a significantly higher TYMS protein expression than did those with other genotypes. These findings suggest that breast cancer patients with the TYMS 3'-UTR +6 bp/+6 bp polymorphism whose tumours show a 6 bp deletion within TYMS 3'-UTR represent a group that may derive the most benefit from 5-FU chemotherapy.

Hematoma-directed and ultrasound-guided breast-conserving surgery for nonpalpable breast cancer after Mammotome biopsy.

Stereotactic vacuum-assisted (Mammotome) breast biopsy is a powerful diagnostic tool for detecting microcalcifications on mammography, but it is difficult to remove the targeted lesion precisely when subsequent breast-conserving surgery is to be carried out. We achieved satisfactory results by performing hematoma-directed breast-conserving surgery after stereotactic Mammotome biopsy in seven patients. To identify the exact location of the Mammotome biopsy during the breast-conserving surgery, we created an iatrogenic hematoma in the biopsy cavity using patient's blood. This hematoma was detected easily on intraoperative ultrasonography in all patients, and was palpable as a soft mass in five of the seven patients. The microcalcifications were completely removed in all patients, and no cancer cells were found in the margin surfaces after breast-conserving surgery. There were no complications during the injection of the patient's blood into the biopsy cavity or during the hematoma-directed surgery. We describe this new procedure of hematoma-directed breast-conserving surgery following Mammotome biopsy for nonpalpable cancer with microcalcifications.

Clinical experience of weekly paclitaxel-based treatment as preoperative chemotherapy for patients with primary breast cancer.

BACKGROUND: Paclitaxel is an effective agent in the treatment of metastatic breast cancer. The aim of this study was to evaluate the safety and efficacy of weekly paclitaxel-based preoperative chemotherapy in patients with large operable breast cancer. METHODS: Patients initially received paclitaxel as a 3-hour infusion at 175 mg/m2. Three weeks after initial administration, two cycles of three weeks of paclitaxel 80 mg/m2 over a 1 hour infusion followed by a one week break were given. Of 22 patients, 9 had stage II (tumor diameter greater than 3 cm), 4 stage III A, 7 stage III B, and 2 stage IV (with ipsilateral supraclavicular lymph node metastasis) cancer, respectively. RESULTS: Excluding stage IV patients, the overall response rate to paclitaxel chemotherapy was 80%. Four of the 20 patients (20%) showed a clinical complete response (cCR). Two of these showed pathologic complete response and the other 2 had only the ductal component remaining. The primary tumor response and axillary lymph node downstaging following preoperative chemotherapy tended to be related in 16 patients with clinically positive nodes. Breast conserving surgery was performed as a result of downstaging in the 9 stage II patients. Grade 3 neutropenia occurred in one patient when 175 mg/m2 of paclitaxel was administered, but no serious side effects developed during the weekly administration of paclitaxel. CONCLUSION: The use of weekly paclitaxel-based preoperative chemotherapy appears to yield a significant anti-tumor effect without inducing serious drug-related adverse effects. Furthermore, the effectiveness of this treatment appears to result in a higher frequency of breast conserving surgery.

Ability of bivariate cytokeratin and deoxyribonucleic acid flow cytometry to determine the biologic aggressiveness of resectable non-small cell lung cancer.

OBJECTIVE: The purpose of this study was to clarify the significance of bivariate cytokeratin and DNA flow cytometry for analysis of the biologic aggressiveness of resectable non-small cell lung cancer. METHODS: In 92 patients who underwent curative operations, the DNA ploidy status and S-phase fractions of the cancer cell populations inside the tumors were analyzed by a cytokeratin gating technique with paraffin-embedded specimens and were correlated with the surgical results. RESULTS: Ninety tumors yielded assessable DNA histograms. DNA diploidy was detected in 25 tumors with a mean S-phase fraction of 14.3% +/- 4.7%, and DNA aneuploidy was detected in 65 tumors with a mean S-phase fraction of 15.1% +/- 7.1%. The 5-year overall and recurrence-free survivals were 73.3% and 70.3%, respectively. Multivariate analysis showed that only TNM staging was a prognostic factor after surgery. There was a negative correlation between the logarithms of S-phase fraction and the disease-free interval for 22 patients with proven recurrence (P =.006). The tumors with high S-phase fractions recurred more rapidly than did those with low S-phase fractions. CONCLUSION: In a bivariate analysis of cytokeratin and DNA flow cytometry in resectable non-small cell lung cancer, the S-phase fraction appeared to be correlated with the disease-free interval. However, DNA ploidy and S-phase fraction were not predictive of either recurrence or survival after operation. Thus DNA flow cytometry may be of limited use for the analysis of the biologic aggressiveness of lung cancer.