Dissecting the predictive value of MAPK/AKT/estrogen-receptor phosphorylation axis in primary breast cancer to treatment response for tamoxifen over exemestane: a Translational Report of the Intergroup Exemestane Study (IES)—PathIES

Purpose

The prognostic and predictive values of the MAPK/AKT/ERα phosphorylation axis (pT202/T204MAPK, pT308AKT, pS473AKT, pS118ERα and pS167ERα) in primary tumours were assessed to determine whether these markers can differentiate between patient responses for switching adjuvant endocrine therapy after 2–3 years from tamoxifen to exemestane and continued tamoxifen monotherapy in the Intergroup Exemestane Study (IES).

Methods

Of the 4724 patients in IES, 1506 were managed in a subset of centres (N = 89) participating in PathIES. These centres recruited 1282 (85%, 1282/1506) women into PathIES of whom 1036 had phospho-marker data. All phospho-markers were analysed by immunohistochemistry staining. Multivariable Cox proportional hazards models of the phospho-markers for disease-free survival (DFS) and overall survival (OS) were adjusted for clinicopathological factors. Treatment effects on the biomarker expression were determined by interaction tests. Benjamini–Hochberg adjustment for multiple testing with a false discovery rate of 10% was applied (p_BH).

Results

Phospho-T202/T204MAPK, pS118ERα and pS167ERα were all found to be correlated (p_BH = 0.0002). These markers were not associated with either DFS or OS when controlling for the established clinicopathological factors. Interaction terms between the phospho-markers and treatment strategies for either DFS or OS were not statistically significant (p_BH > 0.05 for all).

Conclusions

This PathIES study confirmed previously described associations between the phosphorylation site markers of AKT, MAPK and ERα activity in postmenopausal breast cancer patients. No prognostic correlations between the phosphorylation markers and clinical outcome were found, nor were they predictive for clinical outcomes among patients who switched therapy over those treated with tamoxifen alone.

     

Nuclear and cytoplasmic expressions of ERβ1 and ERβ2 are predictive of response to therapy and alters prognosis in familial breast cancers

Estrogen receptor (ER) α has been studied extensively in familial breast cancers but there are limited data on ERβ and its isoforms. This is an important issue since many BRCA1-associated tumours are “triple negative” and are resistant to conventional and targeted therapies. We performed an immunohistochemical study of pan-ERβ, ERβ1 and ERβ2 in a cohort of 123 familial breast carcinomas (35 BRCA1, 33 BRCA2 and 55 BRCAX) using a cut-off for positivity at 20% (Shaaban et al. in Clin Cancer Res 14:5228–5235, 2008). BRCA1 cancers were more likely to be nuclear ERα negative and nuclear pan-ERβ positive (21/32, 66%) when compared with BRCA2 (2/29, 7%) and BRCAX cancers (11/49, 22%) (both P < 0.001). For survival analysis, expression was also stratified using cut-offs defined by Bates et al. (Breast Cancer Res Treat 111:453–459, 2008) (score out of 7). Cytoplasmic ERβ2 expression correlated with shorter overall survival at 15 years regardless of cut-off used (both P < 0.046) At a cut-off score of 6 out of 7, cytoplasmic ERβ2 expression correlated with a poorer response to chemotherapy in both univariate (P = 0.011) and multivariate analyses including grade, lymph node status and chemotherapy as an interaction variable (P = 0.045, Hazard ratio 1.22, 95% CI 1.004–9.87). A similar trend was seen in a univariate analysis with a cut-off of 20% although this did not reach statistical significance (P = 0.057). Expression of nuclear ERβ1 was associated with a favourable response to endocrine therapy at 15 years regardless of cut-offs employed (both P < 0.025). However, this did not reach statistical significance in a multivariate analysis (P > 0.05). Since a significant proportion of ERα negative familial breast carcinomas are positive for nuclear ERβ1 and cytoplasmic ERβ2, the different ERβ isoforms and their intracellular location may need to be assessed, to identify patients that may benefit from hormonal and chemotherapy.     

Long-term endometrial effects in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES)—a randomised controlled trial of exemestane versus continued tamoxifen after 2–3 years tamoxifen

BackgroundThe antiestrogen tamoxifen may have partial estrogen-like effects on the postmenopausal uterus. Aromatase inhibitors (AIs) are increasingly used after initial tamoxifen in the adjuvant treatment of postmenopausal early breast cancer due to their mechanism of action: a potential benefit being a reduction of uterine abnormalities caused by tamoxifen.Patients and methodsSonographic uterine effects of the steroidal AI exemestane were studied in 219 women participating in the Intergroup Exemestane Study: a large trial in postmenopausal women with estrogen receptor-positive (or unknown) early breast cancer, disease free after 2–3 years of tamoxifen, randomly assigned to continue tamoxifen or switch to exemestane to complete 5 years adjuvant treatment. The primary end point was the proportion of patients with abnormal (≥5 mm) endometrial thickness (ET) on transvaginal ultrasound 24 months after randomisation.ResultsThe analysis included 183 patients. Two years after randomisation, the proportion of patients with abnormal ET was significantly lower in the exemestane compared with tamoxifen arm (36% versus 62%, respectively; P = 0.004). This difference emerged within 6 months of switching treatment (43.5% versus 65.2%, respectively; P = 0.01) and disappeared within 12 months of treatment completion (30.8% versus 34.7%, respectively; P = 0.67).ConclusionSwitching from tamoxifen to exemestane significantly reverses endometrial thickening associated with continued tamoxifen.     

Prognostic value of cancer stem cell markers CD133, ALDH1 and nuclearβ-catenin in colon cancer

Colon cancer is one of the most common human malignancies. Cancer stem cells (CSCs), despite being only a smal subset of cancer cells, have the capability to self renew and sustain the tumor. They also have the ability to proliferate. Multiple CSCs associated markers have been identified in colon cancer including CD133, ALDH1 andβ catenin. The aim of the work was to study the prognostic value of CSCs markers (CD133, ALDH1 andβ catenin), as wel as their rela tionship to clinicopathological features of colon cancer. Methods:CD133, ALDH1 andβ catenin proteins expression was as sessed immunohistochemical y in a series of colon cancers and their prognostic significance was evaluated. Results:CD133 expression showed significant relationship to tumor stage and lymph node metastasis (P value 0.004&<0.001 respectively), and near significant relationship to liver metastasis (P value 0.092). ALDH1 was significantly associated with tumor grade, stage and nodal metastasis (P value 0.021, 0.001 and 0.026 respectively), but its relationship to liver metastasis was near sig nificant (P value 0.068). Nuclearβ catenin was significantly related to tumor grade, stage, nodal and liver metastasis (P value 0.001,<0.001,<0.001 and 0.008 respectively). Overal survival (OS) was associated inversely with CD133, ALDH1 positivity, and directly with nuclearβ catenin positivity (P value<0.001, 0.0001 and<0.001 respectively). Also recurrence free survival (RFS) was associated inversely with CD133, ALDH1 and directly with nuclearβ catenin positivity (P value 0.0001, 0.001 and<0.001 respectively). Conclusion:CD133, ALDH1 andβ catenin expressions of tumor cells have significant impact upon malignant progression of colon cancer and thus patient survival and tumor recurrence. Hence they can be used to predict outcome of colon cancer patients.     

What is the value of hemoglobin as a prognostic and predictive factor in cancer?

Anemia is a frequently encountered complication in cancer, and is associated with fatigue and reduced quality of life. Retrospective analyses of data from patients with hematological malignancies and solid tumors provide evidence that a low baseline hemoglobin (Hb) level is a prognostic factor for poor outcome. Moreover, in some situations, low Hb is a negative predictive parameter in chemotherapy. The adverse impact of anemia has been documented in patients with lymphomas and leukemias, as well as in those with non–small-cell lung cancer, ovarian cancer, cervical cancer, renal cell carcinoma, head and neck cancer and other solid tumors. Studies in animal models support the role of low Hb levels as a negative prognostic and predictive factor. Although prospective clinical trials are still needed to confirm that Hb levels affect outcome, the available evidence suggests that there is more than one reason to pay attention to Hb levels in cancer patients: increasing Hb not only corrects anemia and thereby improves physical functioning and quality of life, but also may improve clinical outcomes.     

The prognostic and potentially predictive value of the Laurén classification in oesophageal adenocarcinoma

AimTo investigate the histological subtypes of oesophageal adenocarcinoma according to the Laurén classification (intestinal/diffuse/mixed) in relation to tumour response to neoadjuvant treatment, and in relation to patients' survival after potentially curative treatment.MethodsData were collected from all oesophageal adenocarcinoma patients who underwent potentially curative treatment in our institute between 1998 and 2014. Treatment consisted of neoadjuvant chemoradiotherapy (36–50 Gy) followed by an oesophagectomy or definitive chemoradiotherapy (50–50.4 Gy). Clinical data were collected from patient records. All endoscopic biopsies and surgical resection specimens were reassessed to determine the histological subtype (intestinal, diffuse or mixed) and the Mandard tumour regression grade (TRG). The impact of the histological subtypes on survival was determined using a Cox model.ResultsMedian follow-up was 68 months. Diffuse and mixed type cancers accounted for 25% of oesophageal adenocarcinomas. Median overall survival differed significantly between patients with intestinal (n = 121, 39 months), diffuse (n = 28, 18 months) or mixed type (n = 11, 25 months) carcinomas (log rank, p = 0.023). In multivariable analysis, the diffuse type was associated with shorter survival (diffuse versus intestinal: hazard ratios 2.06, p = 0.006). A pathologically (near) complete response (TRG 1 or 2) was seen less frequently in diffuse type than in intestinal type carcinomas (24% versus 60%; p = 0.015).ConclusionsPatients with diffuse type oesophageal adenocarcinomas had a significantly worse prognosis than those with intestinal type carcinomas. Intestinal type carcinomas showed a better response to neoadjuvant chemoradiotherapy than diffuse type carcinomas. These differences call for the exploration of differentiated approaches in the potentially curative treatment of oesophageal adenocarcinomas.     

Circulating transforming growth factor-β-1 and breast cancer prognosis: results from the Shanghai Breast Cancer Study

Introduction Studies investigating the prognostic effect of circulating TGF-β-1 in breast cancer have given inconsistent findings. The purpose of this study is to evaluate whether circulating transforming growth factor beta 1 (TGF-β-1) is associated with overall and disease-free survival in a cohort of recently diagnosed breast cancer patients. Methods We measured TGF-β-1 levels in plasma samples of breast cancer patients in the Shanghai Breast Cancer Study, a population-based case–control study. We evaluated the relationship between TGF-β-1 levels and overall and disease-free survival. The median follow up time was 7.2 years. Results We observed that, compared with the patients with the lowest quartile of plasma TGF-β-1, patients with the highest quartile of plasma TGF-β-1 had significantly worse overall survival with hazards ratio (HR) = 2.78, with 95% confidence interval (CI): 1.34–5.79 and disease-free survival with HR = 2.49, 95% CI: 1.15–5.41, while the patients with the second and third quartiles of plasma TGF-β-1 did not have significantly different overall and disease-free breast cancer survival. The shape of association between plasma TGF-β-1 levels and breast cancer survival appears to be non-linear. Stratified analysis by stage of disease did not appreciably change the association pattern. Conclusions We conclude that the relationship between circulating levels of TGF-β-1 and prognosis in breast cancer is complex and non-linear. High levels of TGF-β-1 are associated with worse survival independent of stage of disease.     

The predictive role of interim PET after the first chemotherapy cycle and sequential evaluation of response to ABVD in Hodgkin’s lymphoma patients—the Polish Lymphoma Research Group (PLRG) Observational Study

BackgroundInterim PET after two ABVD cycles (iPET2) predicts treatment outcome in classical Hodgkin’s lymphoma. To test whether an earlier assessment of chemosensitivity would improve the prediction accuracy, we launched a prospective, multicenter observational study aimed at assessing the predictive value of iPET after one ABVD (iPET1) and the kinetics of response assessed by sequential PET scanning.Patients and methodsConsecutive patients with newly diagnosed classical Hodgkin’s lymphoma underwent interim PET scan after one ABVD course (iPET1). PETs were interpreted according to the Deauville score (DS) as negative (−) (DS 1–3) and positive (+) (DS 4, 5). Patients with iPET1 DS 3–5 underwent iPET2.ResultsAbout 106 early (I–IIA) and 204 advanced (IIB–IV) patients were enrolled between January 2008 and October 2014. iPET1 was (−) in 87/106 (82%) or (+) in 19/106 (18%) of early, and (−) in 133/204 (65%) or (+) in 71/204 (35%) of advanced stage patients, respectively. Twenty-four patients were excluded from response analysis due to treatment escalation. After a median follow-up of 38.2 (3.2–90.2) months, 9/102 (9%) early and 43/184 (23%) advanced patients experienced a progression-free survival event. At 36 months, negative and positive predictive value for iPET1 were 94% and 41% (early) and 84% and 43% (advanced), respectively. The kinetics of PET response was assessed in 198 patients with both iPETs. All 116 patients with iPET1(−) remained iPET2(−) (fast responders), 41/82 with IPET1(+) became iPET2(−) (slow responders), and the remaining 41 stayed iPET2(+) (non-responders); progression-free survival at 36 months for fast, slow and non-responders was 0.88, 0.79 and 0.34, respectively.ConclusionThe optimal tool to predict ABVD outcome in HL remains iPET2 because it distinguishes responders, whatever their time to response, from non-responders. However, iPET1 identified fast responders with the best outcome and might guide early treatment de-escalation in both early and advanced-stage HL.     

Prognostic and predictive role of the PI3K–AKT–mTOR pathway in neuroendocrine neoplasms

Neuroendocrine neoplasms (NENs) are considered a heterogeneous and rare entity. Its natural history is influenced by multiple clinicopathological characteristics, which guide the management of these patients. The development of molecular biology reveals that the PI3K–AKT–mTOR pathway plays a relevant role in tumorigenesis and progression of NENs. Mammalian target of rapamycin (mTOR) inhibitors, targeted agents that block this pathway, has improved outcomes in neuroendocrine tumors (NETs). Different therapeutic approaches, such as somatostatin analogs, chemotherapy, peptide receptor radionuclide therapy, and targeted agents, have shown benefits in the treatment of NETs. However, there are not any established prognostic or predictive biomarkers to select the best therapy option to individualize treatment. Although a relation between alterations in the PI3K–AKT–mTOR pathway and clinical outcomes has not been found, these anomalies are considered attractive biomarkers. Additional molecular analysis should be integrated in future clinical trials’ design to identify potential predictive or prognostic biomarkers.     

The potential risk of neoadjuvant chemotherapy in breast cancer patients—results from a prospective randomized trial of the Austrian Breast and Colorectal Cancer Study Group (ABCSG-07)

Purpose To evaluate the impact that pre- and postoperatively administered chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF) and postoperative chemotherapy vs. postoperative chemotherapy alone have on long-term prognosis. Patients and Methods The ABCSG conducted a nationwide randomized phase III trial in high-risk endocrine non-responsive breast cancer patients comparing pre- and postoperative chemotherapy containing CMF as preoperative treatment vs. postoperative chemotherapy alone between 1991 and 1999. From 1996 the ABCSG-07 protocol was amended to also allow randomization of high-risk endocrine-responsive patients. Of 423 eligible patients with high-risk primary breast cancer, 203 patients were randomly assigned to preoperatively receive three cycles of CMF (cyclophosphamide, methotrexate, fluorouracil; 600/40/600 mg/m²) intravenously on day 1 and 8, while 195 patients received postoperative chemotherapy alone. In both groups, three cycles of CMF were given initially, and another three cycles of CMF were administered in node-negative patients, whereas node-positive patients received three cycles of EC (epirubicin, cyclophosphamide; 70/600 mg/m²). Results Overall response rate to preoperative chemotherapy with three cycles of CMF was 56.2%; complete pathological response was achieved in 12 patients (5.9%). Recurrence-free survival was significantly better in patients receiving chemotherapy postoperatively (HR 0.7, 0.515–0.955; P = 0.024). No survival difference was observed between the two therapy groups (HR 0.800, 0.563–1.136; P = 0.213). Discussion Preoperative chemotherapy with CMF has to be considered as insufficient in high-risk breast cancer patients. Delayed surgery and anthracycline-based chemotherapy result in shorter recurrence-free survival but not overall survival.     

Fruit and vegetable intake and the risk of colorectal cancer: results from the Shanghai Men’s Health Study

Purpose

The observed associations of fruit and vegetable consumption with the risk of colorectal cancer have been inconsistent. Therefore, we aimed to evaluate the association of fruit and vegetable consumption with the risk of colorectal cancer among Chinese men.

Methods

61,274 male participants aged 40–74 years were included. A validated food frequency questionnaire was administered to collect information on usual dietary intake, including 8 fruits and 38 vegetables commonly consumed by residents of Shanghai. Follow-up for diagnoses of colon or rectal cancer was available through 31 December 2010. Dietary intakes were analyzed both as categorical and continuous variables. Multivariable-adjusted hazard ratios (HRs) and 95 % confidence intervals (95 % CIs) were calculated for colorectal, colon, and rectal cancers using Cox proportional hazards models.

Results

After 390,688 person-years of follow-up, 398 cases of colorectal cancer (236 colon and 162 rectal) were observed in the cohort. Fruit consumption was inversely associated with the risk of colorectal cancer (fifth vs. first quintile HR 0.67; 95 % CI 0.48, 0.95; p trend = 0.03), whereas vegetable intake was not significantly associated with risk. The associations for subgroups of fruits and legumes, but not other vegetable categories, were generally inversely associated with the risk of colon and rectal cancers.

Conclusions

Fruit intake was generally inversely associated with the risk of colorectal cancer, whereas vegetable consumption was largely unrelated to risk among middle-aged and older Chinese men.     

Increased pSmad2 expression and cytoplasmic predominant presence of TGF-βRII in breast cancer tissue are associated with poor prognosis: results from the Shanghai Breast Cancer Study

Breast Cancer Research and Treatment - Perturbations of transforming growth factor-beta (TGF-β) signaling are pivotal to tumorigenesis and tumor progression through their effects on cell...     

Influence of Vegetables on the Expression of GSTP1 in Humans — a Pilot Intervention Study (Sweden)

Background: There are indications that a diet rich in vegetables and/or fruit has a protective effect against se types of diseases, including cancer. Data from experimental and epidemiological studies suggest that antioxidant constituents may provide protection against environmental carcinogens. Aims: This study investigated the effect of additional vegetables in the diet on the expression of the endogenous antioxidant enzyme GSTP1 in human lymphocytes. Methods: Six subjects were given an addition of mixed vegetables to their normal diet for a period of three weeks. The expression of GSTP1 protein and mRNA in lymphocytes was measured by Western blot and RT competitive PCR. Results: After the intervention all six subjects had lower levels of GSTP1 mRNA, and five of the six subjects had lower GSTP1 protein levels. This suggests that increased vegetable intake decreases GSTP1 expression, possibly through the supply of additional antioxidants.     

Expression of E2F-1, Rb and ER in Peripheral Papilloma and Ductal Carcinoma in Situ of the Breast and its Significance

OBJECTIVE To investigate the correlation of E2F-1, Rb and ER expression with peripheral papilloma (Peri-PM) and ductal carcinoma in situ of the breast (DCIS), and further explore some molecular mechanisms of the canceration of Peri-PM. METHODS Imunohistochemistry was used to examine the expression of E2F-1, Rb and ER in 60 Peri-PM, 60 Peri-PM with atypical ductal hyperplasia (Peri-PM with ADH) and 60 DCIS. Normal breast tissues were selected as a control group. RESULTS Based on immunohistochemical staining, the positive rate of E2F-1 expression in Peri-PM, Peri-PM with ADH and DCIS was 21.7%, 46.7% and 78.3% respectively. The positive rate of Rb expression was 83.3 %, 53.9% and 21.7% and the ER expression was 86.7%,61.7% and 55.0%. Significant differences were found among the 3 groups (Peri-PM, Peri-PM with ADH and DCIS) (P<0.05). Significant differences existed between any 2 groups (P<0.05) except for the rate of ER positive expression comparing Peri-PM with ADH verus DCIS (P>0.05). The expression of E2F-1 was nega- tively correlated with ER and Rb, and at the same time the expression of ER was positively correlated with Rb. Following the degree of breast epithelial hyperplasia involved and its development into carcinoma, the positive rate of E2F-1 expression displayed an elevating tendency, but that of Rb and ER expression showed a tendency to decline. CONCLUSION The interaction of the 3 indexes studied may play an im- portant role in the conversion of precancerous lesions to early in situ breast carcinoma, and the evaluation of these indexes might provide a valuable basis for screening high-risk cases of Peri-PM.     

Different associations of estrogen receptor β isoforms, ERβ1 and ERβ2, expression levels with tumor size and survival in early- and late-onset breast cancer

Background

In breast cancer, little is known about the consequences of co-expression of ERα with the second estrogen receptor, ERβ, and its isoforms in light of their joint prognostic value. Previously reported correlations have been based mostly on independent ERα and ERβ expression levels in breast tumors.

Purpose

To address whether the expression ratio of ERα and ERβ and its isoforms may be a more important parameter than their absolute levels, we analyzed relative mRNA expression ratios of ERβ1 to ERβ2 and ERα in 74 clinical samples of invasive breast cancer including 39 early-onset and 35 late-onset breast cancers. Expression levels were correlated with clinical and histopathological parameters and disease-free interval.

Results

A specific correlation of ERβ1 expression levels with tumor size was detected in early-onset breast cancer patients and of ERβ2 levels with tumor size in late-onset patients. Expression of both ERβ isoforms inversely correlated with expression of the two estrogen regulated genes, progesterone receptor and pS2 in both groups. Higher levels of ERβ2 than ERβ1 isoform were associated with a better outcome in late-onset patients.

Conclusions

Our results suggest that different isoforms of ERβ may be involved in suppression of tumor growth in young and elder patients and may have different prognostic values.     

Study on the Expression and Significance of TGF-β1, p-ERK1/2and K-ras in Colorectal Cancer Using Tissue Microarray Technique

OBJECTIVE This study aimed to explore the expression and significance of transforming growth factor β1(TGF-β1),extracellular signal-regulated kinases 1/2 (ERK1/2), and K-ras in colorectal cancer (CRC) using tissue microarray technology.METHODS The expressions of TGF-β1, ERK1/2, and K-ras in colon cancer cells taken from the specimens of 92 CRC patients (stage Ⅰ: 16 cases, stage Ⅱ: 28 cases, stage Ⅲ: 24 cases, and stage Ⅳ:24 cases) were analyzed using tissue microarray technology and immunohistochemistry, and compared with those of 20 normal colon tissue samples.RESULTS High immunoreactive scores (IRS) of TGF-β1,p-ERK1/2, and K-ras protein in CRC were obtained, which were 66.3% (61/92), 59.8% (55/92), and 48.9% (45/92), respectively, and those in normal epithelial cells of colon were 10% (2/20), 20% (4/20), and 30% (6/20), respectively (P < 0.05). The expressions of TGF-β1 and ERK1/2 in CRC at stage Ⅰwere 37.5% and 31.3%,respectively, and those in CRC at stage Ⅳ were 83.3% and79.3%, respectively, with statistically significant differences. No significant relationship was found between K-ras expression and tumor stages (P>0.05).CONCLUSION High level expressions of TGF-β1 and ERK1/2 are closely related to the clinical stages of colon cancer and crosstalk may exist between the 2 signal pathways.