M. Yunokawa

Efficacy of everolimus, a novel mTOR inhibitor, against basal-like triple-negative breast cancer cells.

Patients with triple‐negative breast cancers (TNBCs) typically have a poor prognosis because such cancers have no effective therapeutic targets, such as estrogen receptors for endocrine therapy or human epidermal growth factor receptor 2 (HER2) receptors for anti‐HER2 therapy. As the phosphatidylinositol 3′ kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) cascade is activated in TNBCs, mTOR is a potential molecular target for anticancer therapy. In this study, we investigated the antitumor activities of everolimus, an oral mTOR inhibitor, in nine TNBC cell lines. Everolimus effectively inhibited cell growth at concentrations under 100 nM (IC50) in five cell lines and even in the 1‐nM range in three of the five cell lines. To identify specific characteristics that could be used as predictive markers of efficacy, we evaluated the expressions of proteins in the mTOR cascade, basal markers, and cancer stem cell markers using western blotting, fluorescent in situ hybridization (FISH), or immunohistochemistry. All five of the sensitive cell lines were categorized as a basal‐like subtype positive for either epidermal growth factor receptor (EGFR) or CK5/6, although resistant cell lines were not of this subtype and tended to exhibit the characteristics of cancer stem cells, with decreased E‐cadherin and the increased expression of Snail or Twist. In vivo assays demonstrated antitumor activity in a mouse xenograft model of basal‐like breast cancer, rather than non‐basal breast cancer. These results suggest that everolimus has favorable activity against basal‐like subtypes of TNBCs. Epidermal growth factor receptor and CK5/6 are positive predictive markers of the TNBC response to everolimus, while cancer stem cell markers are negative predictive markers.

Feasibility and usefulness of the ‘Distress Screening Program in Ambulatory Care’ in clinical oncology practice†

Objective: Although the implementation of routine screening for distress is desirable, doing so is difficult in todays busy clinical oncology practice. We developed the ‘Distress Screening Program in Ambulatory Care’ (DISPAC program) as a practical means of screening for and facilitating the treatment of major depression and adjustment disorders in cancer patients. This study assessed the feasibility and usefulness of the DISPAC program in actual clinical situations.

Brain metastases in patients who receive trastuzumab-containing chemotherapy for HER2-overexpressing metastatic breast cancer

BackgroundRecently, a high rate of brain metastases has been reported among patients with human epidermal growth factor receptor (HER2)-overexpressing metastatic breast cancer who were treated with trastuzumab. The present study examined risk factors for the development of brain metastasis in patients with HER2-overexpressing breast cancer who were treated with trastuzumab.MethodsWe retrospectively reviewed 204 patients with HER-2-overexpressing breast cancer who were treated with a trastuzumab-containing regimen between 1999 and 2006. Patients with clinical symptoms were diagnosed as having brain metastases when brain magnetic resonance imaging (MRI) or a computed tomography (CT) scan revealed positive findings for brain metastases. The median follow-up time of this cohort was 53.6 months.ResultsAmong the patients who received a trastuzumabcontaining regimen, 74 patients (36.3%) developed brain metastases. The median survival from the diagnosis of brain metastases was 13.5 months (95% confidence interval [CI], 12.2–14.7 months). The median time interval between the beginning of trastuzumab treatment and the diagnosis of brain metastases was 13.6 months (range, 0.0–45.8 months). Among patients with brain metastases, the median overall survival period was 39 months. A multivariate logistic regression analysis showed that age (≤50 years), recurrent breast cancer, and liver metastases were significant risk factors for the development of brain metastases.ConclusionPatients with HER2-overexpressing breast cancer treated with trastuzumab had a high incidence of brain metastases (36.3%). Routine screening for brain metastases 1 year after the start of trastuzumab treatment, may be warranted in younger patients (≤50 years) who had recurrent breast cancer with liver metastases.

Activated PI3K/AKT and MAPK pathways are potential good prognostic markers in node-positive, triple-negative breast cancer

BACKGROUNDnTriple-negative breast cancer (TNBC) patients are a poor prognostic subgroup, and currently, there is no biomarker for targeted therapy.nnnPATIENTS AND METHODSnTissue samples were obtained from 75 TNBC patients with lymph-node metastases who had received adjuvant chemotherapy. We examined 11 biomarkers, including PIK3CA and AKT1mutation, with regard to event-free survival (EFS) and overall survival (OS) of patients.nnnRESULTSnIn the tumor tissues, phospho-AKT (pAKT) expression was significantly related to HER4 expression. Expression of each of these biomarkers was significantly related to longer EFS (P = 0.024 and 0.03, respectively). pERK expression was also a good prognostic factor regarding EFS and OS in TNBC (P = 0.002 and 0.006, respectively). We also identified a correlation between epidermal growth factor receptor positivity and insulin-like growth factor receptor type 1 positivity (P = 0.001). pERK and T-stage (1-3 versus >3) were independent good prognostic factors by multivariate analysis.nnnCONCLUSIONSnWe determined that tumors expressing pAKT or pERK are a good prognostic subtype in node-positive TNBC. Different targeted therapies may be necessary for TNBC that involves activation of PI3K/AKT or MAPK pathways.

Significance of histologic pattern of carcinoma and sarcoma components on survival outcomes of uterine carcinosarcoma

BACKGROUNDnTo examine the effect of the histology of carcinoma and sarcoma components on survival outcome of uterine carcinosarcoma.nnnPATIENTS AND METHODSnA multicenter retrospective study was conducted to examine uterine carcinosarcoma cases that underwent primary surgical staging. Archived slides were examined and histologic patterns were grouped based on carcinoma (low-grade versus high-grade) and sarcoma (homologous versus heterologous) components, correlating to clinico-pathological demographics and outcomes.nnnRESULTSnAmong 1192 cases identified, 906 cases were evaluated for histologic patterns (carcinoma/sarcoma) with high-grade/homologous (40.8%) being the most common type followed by high-grade/heterologous (30.9%), low-grade/homologous (18.0%), and low-grade/heterologous (10.3%). On multivariate analysis, high-grade/heterologous (5-year rate, 34.0%, P = 0.024) and high-grade/homologous (45.8%, P = 0.017) but not low-grade/heterologous (50.6%, P = 0.089) were independently associated with decreased progression-free survival (PFS) compared with low-grade/homologous (60.3%). In addition, older age, residual disease at surgery, large tumor, sarcoma dominance, deep myometrial invasion, lymphovascular space invasion, and advanced-stage disease were independently associated with decreased PFS (all, P < 0.01). Both postoperative chemotherapy (5-year rates, 48.6% versus 39.0%, P < 0.001) and radiotherapy (50.1% versus 44.1%, P = 0.007) were significantly associated with improved PFS in univariate analysis. However, on multivariate analysis, only postoperative chemotherapy remained an independent predictor for improved PFS [hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.27-0.43, P < 0.001]. On univariate analysis, significant treatment benefits for PFS were seen with ifosfamide for low-grade carcinoma (82.0% versus 49.8%, P = 0.001), platinum for high-grade carcinoma (46.9% versus 32.4%, P = 0.034) and homologous sarcoma (53.1% versus 38.2%, P = 0.017), and anthracycline for heterologous sarcoma (66.2% versus 39.3%, P = 0.005). Conversely, platinum, taxane, and anthracycline for low-grade carcinoma, and anthracycline for homologous sarcoma had no effect on PFS compared with non-chemotherapy group (all, P > 0.05). On multivariate analysis, ifosfamide for low-grade/homologous (HR 0.21, 95% CI 0.07-0.63, P = 0.005), platinum for high-grade/homologous (HR 0.36, 95% CI 0.22-0.60, P < 0.001), and anthracycline for high-grade/heterologous (HR 0.30, 95% CI 0.14-0.62, P = 0.001) remained independent predictors for improved PFS. Analyses of 1096 metastatic sites showed that carcinoma components tended to spread lymphatically, while sarcoma components tended to spread loco-regionally (P < 0.001).nnnCONCLUSIONnCharacterization of histologic pattern provides valuable information in the management of uterine carcinosarcoma.

Prognostic impact of Ki-67 labeling indices with 3 different cutoff values, histological grade, and nuclear grade in hormone-receptor-positive, HER2-negative, node-negative invasive breast cancers

BackgroundThe criteria for classifying hormone receptor (HR)-positive/HER2-negative breast cancers into low-risk and high-risk subgroups remain undetermined. Supportive data for optimal criteria to identify tumors in the high-risk subgroup are necessary for Japanese patients with HR-positive/HER2-negative breast cancers.MethodsUsing immunohistochemistry and fluorescence in situ hybridization, we identified 369 consecutive patients with HR-positive/HER2-negative, node-negative invasive breast cancers. We examined the prognostic impact of the Ki-67 labeling index (LI) based on 3 cutoff values, 10, 14, and 20xa0%, along with that of histological grade (HG) and nuclear grade (NG) by Cox’s univariate and multivariate analyses.ResultsThe univariate analyses clearly showed that Ki-67 LI with any cutoff value divided the patients into distinct high-risk and low-risk groups, and that HG and NG were also powerful prognostic indicators. High Ki-67 LI with any cutoff value was strongly correlated with HG and NG, and when these parameters were included in the multivariate analyses, the impact of HG/NG was stronger than Ki-67 LIs. When the 10xa0% cutoff value was adopted, discordance between Ki-67 LI and grades was frequent in papillotubular-type invasive ductal carcinoma, predominantly intraductal carcinoma, and mucinous carcinoma.ConclusionsAny of the Ki-67 LI values, regardless of cutoff value, could be applicable for the classification of high-risk and low-risk HR-positive/HER2-negative, node-negative invasive breast cancers. Luminal A/B subtyping according to Ki-67 LI, or HG/NG, in combination with histological type, appeared to be able to create an optimum risk estimation system for patients with HR-positive/HER2-negative, node-negative invasive breast cancers in Japan.

Synergistic anti-tumor effects of a novel phosphatidyl inositol-3 kinase/mammalian target of rapamycin dual inhibitor BGT226 and gefitinib in non-small cell lung cancer cell lines.

Epidermal growth factor receptor (EGFR) and PI3K/mTOR pathway are drug targets for non-small cell lung cancer (NSCLC). Herein, we investigated anti-tumor effects of the combination of BGT226, a novel PI3K/mTOR dual inhibitor, and gefitinib on NSCLC cell lines which are high sensitive to gefitinib. The combination of BGT226 and gefitinib exhibited supra-additive growth inhibitory effects in PC-9 and HCC827 cells. Apoptotic induction and the inhibition of PI3K/mTOR signaling were enhanced by the combination. Significant tumor growth suppression was observed in xenograft model by the combination. These results suggest that the combination is effective in EGFR inhibitor-sensitive NSCLC therapy.

Impact of adjuvant therapy on recurrence patterns in stage I uterine carcinosarcoma

BACKGROUNDnTo examine recurrence patterns in women with stage I uterine carcinosarcoma (UCS) stratified by adjuvant therapy pattern.nnnMETHODSnWe examined 443 cases of stage I UCS derived from a retrospective cohort of 1192 UCS cases from 26 institutions. Adjuvant therapy patterns after primary hysterectomy-based surgery were correlated to recurrence patterns.nnnRESULTSnThe most common adjuvant therapy was chemotherapy alone (41.5%) followed by chemotherapy/radiotherapy (15.8%) and radiotherapy alone (8.4%). Distant-recurrence was the most common recurrence pattern (5-year cumulative rate, 28.1%) followed by local-recurrence (13.3%). On multivariate analysis, chemotherapy but not radiotherapy remained an independent prognostic factor for decreased risk of local-recurrence (5-year cumulative rates 8.7% versus 19.8%, adjusted-hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.25-0.83, P=0.01) and distant-recurrence (21.2% versus 38.0%, adjusted-HR 0.41, 95%CI 0.27-0.62, P<0.001). The chemotherapy/radiotherapy group had a lower 5-year cumulative local-recurrence rate compared to the chemotherapy alone group but it did not reach statistical significance (5.1% versus 10.1%, adjusted-HR 0.46, 95%CI 0.13-1.58, P=0.22). Radiotherapy significantly decreased local-recurrence when tumors had high-grade carcinoma, sarcoma component dominance, and deep myometrial tumor invasion (all, P<0.05); and combining radiotherapy with chemotherapy was significantly associated with decreased local-recurrence compared to chemotherapy alone in the presence of multiple risk factors (5-year cumulative rates, 2.5% versus 21.8%, HR 0.12, 95%CI 0.02-0.90; P=0.013) but not in none/single factor (P=0.36).nnnCONCLUSIONnAdjuvant chemotherapy appears to be effective to control both local- and distant-recurrences in stage I UCS; adding radiotherapy to chemotherapy may be effective to control local-recurrence when the tumor exhibits multiple risk factors.

Prognostic factors in patients with uterine carcinosarcoma: a multi-institutional retrospective study from the Japanese Gynecologic Oncology Group

BackgroundUterine carcinosarcomas (UCSs) are rare and aggressive tumors. The prognostic factors are not sufficiently known.MethodsWe performed a multi-institutional, retrospective study of women with stage I–IV UCS, diagnosed between 2007 and 2012. Data obtained from medical records included demographic, clinicopathological, treatment, and outcome information.ResultsA total of 486 patients (median age 65xa0years) were identified—224 (46xa0%) were stage I, 32 (7xa0%) were stage II, 139 (28xa0%) were stage III, and 91 (19xa0%) were stage IV. Among them, 277 (57xa0%) had disease recurrence. Median disease-free survival (DFS) was 16.4xa0months [95xa0% confidence interval (CI) 15.7–27.2], and median overall survival (OS) was 72.0xa0months (95xa0% CI 43.0–not reached). In total, 454 (94xa0%) patients received adjuvant treatment, and 440 (91xa0%) received adjuvant chemotherapy. In multivariate analysis, stage III–IV disease, CA-125 level, and lymphovascular space invasion (LVSI) were significantly associated with shorter median DFS. Stage III–IV disease, performance status 2–4,xa0≥50xa0% myometrial invasion depth, and postsurgical residual tumor sizexa0>1xa0cm were significantly associated with shorter median OS. Conversely, pelvic lymph node lymphadenectomy was associated with improved DFS and OS.ConclusionsStage, performance status, CA-125 level, LVSI, and myometrial invasion were associated with poor prognoses. Pelvic lymphadenectomy was associated with improved survival, and may be necessary for the surgical management of UCS.

Feto-maternal outcomes of pregnancy complicated by epithelial ovarian cancer: a systematic review of literature

Although cancer diagnosed during pregnancy is rare, epithelial cell type ovarian cancers (EOCs) comprise approximately one quarter to one half of cases of ovarian malignancy diagnosed during pregnancy. The behavior of EOC during pregnancy and its implications for maternal and fetal outcomes is not well understood. In order to better define these outcomes, a systematic literature search was conducted in PubMed/MEDLINE using entry keywords pregnancy and ovarian cancer for the period from 1955 to 2013. The literature search identified 105 cases eligible for analysis. Clinical characteristics, pregnancy outcome, tumor characteristics, clinical management, and survival outcomes were all evaluated. Serious adverse events were defined as complications related to EOC that resulted in severe morbidity or mortality for the mother and/or fetus. The mean age of cases was 31.6 years. The most common histology was serous (47.6%), followed by mucinous (27.6%) and endometrioid types (10.5%). The most common presenting symptom was abdominal or pelvic pain (26.7%) while incidentally detected tumors accounted for one third of cases. The majority of cases were stage I at diagnosis (63.8%) followed by stage III disease (24.8%), and the median tumor size was 12cm. Live births occurred in 81.3% of cases, and of the remainder 72.2% were due to elective termination. Intrapartum surgery primarily took place in the second trimester (43%) with fetal conservation in 61.9% of operations. Over half of cases received chemotherapy (55.2%), approximately one third of which received it during the pregnancy (36.2%). Among the 21 cases treated with chemotherapy during pregnancy, there was no association with small for gestational age or fetal malformations. Serious adverse events occurred in 21.9% of cases, of which the most common was tumor rupture during pregnancy (10.5%). Three (2.9%) maternal death following surgery during pregnancy and five (6.4%) neonatal deaths were reported. Gestational age at tumor diagnosis (2-year overall survival rate, 1st trimester 94.6%, 2nd trimester 88.8%, and 3rd trimester 72.9%, p=0.041) type of histology (serous 88.1%, mucinous 84.6%, endometrioid 89.5%, clear cell 100%, mixed type 75.0%, and undifferentiated 30.0%, p<0.01), stage (stage I 96.9%, stage II 85.7%, stage III 56.3%, and stage IV 25.0%, p<0.01), and serious adverse events (yes versus no, 68.1% versus 92.2%, p=0.041) were significantly related to maternal overall survival in univariate analysis. In multivariate analysis, stage III/IV disease remained the independent prognostic factor associated with decreased maternal overall survival (stage III, hazard ratio 44.6, p<0.01; and stage IV, hazard ratio 399, p<0.01). In conclusion, although the majority of EOC cases during pregnancy resulted in live birth, maternal and neonatal mortality needs to be considered in the counseling and management of these pregnancies.