Current medical treatment of estrogen receptor-positive breast cancer

Approximately 80% of breast cancers (BC) are estrogen receptor (ER)-positive and thus endocrine therapy (ET) should be considered complementary to surgery in the majority of patients. The advantages of oophorectomy, adrenalectomy and hypophysectomy in women with advanced BC have been demonstrated many years ago, and currently ET consist of (i) ovarian function suppression (OFS), usually obtained using gonadotropin-releasing hormone agonists (GnRHa), (ii) selective estrogen receptor modulators or down-regulators (SERMs or SERDs), (iii) aromatase inhibitors (AIs), or a combination of two or more drugs. For patients aged less than 50 years and ER+ BC, there is no conclusive evidence that the combination of OFS and SERMs (i.e. tamoxifen) or chemotherapy is superior to OFS alone. Tamoxifen users exhibit a reduced risk of BC, both invasive and in situ, especially during the first 5 years of therapy, and extending the treatment to 10 years further reduced the risk of recurrences. SERDs (i.e. fulvestrant) are especially useful in the neoadjuvant treatment of advanced BC, alone or in combination with either cytotoxic agents or AIs. There are two types of AIs: type I are permanent steroidal inhibitors of aromatase, while type II are reversible nonsteroidal inhibitors. Several studies demonstrated the superiority of the third-generation AIs (i.e. anastrozole and letrozole) compared with tamoxifen, and adjuvant therapy with AIs reduces the recurrence risk especially in patients with advanced BC. Unfortunately, some cancers are or became ET-resistant, and thus other drugs have been suggested in combination with SERMs or AIs, including cyclin-dependent kinase 4/6 inhibitors (palbociclib) and mammalian target of rapamycin (mTOR) inhibitors, such as everolimus. Further studies are required to confirm their real usefulness

Correlation between serum vascular endothelial growth factor (VEGF) and VEGF-1 expression in patients with colorectal cancer. Preliminary results.

Background: In patients with colorectal cancer (CRC), several growth factors have been identified as regulator of angiogenesis, including vascular endothelial growth factor (VEGF), a pro-angiogenetic factor which can be safely measured in the blood. Angiogenesis plays an important role in the progression of CRC, as well as in the development of regional lymph node and distant metastases. VEGF is minimally expressed or not expressed in colorectal adenomas and in normal colonic mucosa, while it is overexpressed in inflammatory bowel diseases as well as in CRCs. It has been shown that high microvessels density, an indirect measure of the degree of angiogenesis, correlates with increased tumor aggressiveness and risk of metastasis development, and that overexpression of VEGF in cancer tissues represents a sensitive marker of angiogenesis. Because undetected metastases can contribute to the failure of primary treatment, their early identification has a substantial impact on adequate therapy. In this setting, several serum tumor markers and tissue-extracting prognostic factors have been tested, including angiogenic cytokines such as VEGF. In several studies, preoperative serum VEGF was increased in patients with CRC compared to controls, and high VEGF serum concentration tended to occur with more advanced disease. However, these data are not confirmed, and VEGF overexpression in cancer tissues significantly correlates with tumor biology. The aim of this study was to evaluate the relationship between serum VEGF, and the expression of VEGF-1 in patients with CRC. Methods: Archival paraffin-embedded tumor samples from 38 patients (26 men, 12 women, median age 64, range 39-76 years) with stage I-II colorectal adenocarcinoma who underwent intentionally curative surgical resection, were reviewed. None of the patients received preoperative adjuvant chemotherapy. Written informed consent was obtained from all the participants. Serum VEGF was measured with a commercially available human VEGF quantitative enzyme-linked immunosorbent assay (ELISA) kit, according to the manufacturer\u2019s instructions. All analyses were made in duplicate, and the mean value was used for statistical calculation. Tissue microarray blocks for immunohistochemistry staining was obtained, serial 4 \u3bcm sections were cut, and then assessed using a commercial anti-human VEGF (clone VG-1). The Pearson\u2019s correlation coefficient calculation was used to evaluate results. Results: The expression of VEGF was tested using a 4-grade scoring system, according to the degree of cytoplasmic staining, ranging from negative to intense staining. Overall, the mean serum VEGF concentration was 272.7\ub1140.5 pg/mL (range 41-670 pg/mL), while the VEGF-1 grade was 2.8\ub11.0. There was a significant relationship between the stage of the disease and VEGF (R=0.43, p=0.006), and between serum VEGF and VEGF-1 grade (R=0.64, t=5.06, p<0.001). The age did not correlate with VEGF (R=0.13, p=0.44) and VEGF-1 (R=-0.21, p=0.19). Conclusions: Tumor growth is dependent on the degree of angiogenesis, and VEGF is potent growth factor with angiogenic activity. It can safely be tested by measurements of both serum VEGF levels and grade of tumor tissue expression of VEGF-1. References: Bendaraf A et al. Anticancer Res 2008; 28: 3865-3870; Werther K et al. BJC 2002: 86: 417-423

Prognostic Significance of Epidermal Growth Factor Receptor Overexpression and Chromosome 7 Polysomy in Clear Cell Renal Cell Carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cell carcinoma. In patients with ccRCC several prognostic markers have been suggested, enclosing epidermal growth factor receptor (EGFR) expression and chromosome 7 polysomy (C7p). Cancer cells addicted to EGFR bear activated mutations in the EGFR gene, and these mutations are useful in predicting susceptibility of ccRCC to EGFR inhibitors. The aim of this study was to evaluate the prognostic value of EGFR overexpression and C7p. Patients and methods: Archival specimens, coupled with clinical and survival data of 34 patients (20 men, 14 women, median age 58, range 42\u201379 years) who had undergone radical nephrectomy for ccRCC were analyzed. Immunohistochemistry and fluorescence in situ hybridization (FISH) specimens were sections of formalin-fixed paraffin-embedded tissue. EGFR expression was detected as membranous and cytoplasmic staining of neoplastic cells > 1%, and a ratio between gene/centromeric signals of more than two was considered to indicate gene amplification. Mean number of centromeric signals per nucleus was also scored to evaluate C7p. The log-rank test was used to examine the relationship between gender, EGFR overexpression, C7p and survival. Kaplan-Meyer analysis was performed to compare parameters with survival. Results: The age did not differ significantly (p = 0.79) between men and women. Overall, the median survival was 46 months (range 5-150 months). C7p was observed in 21 (61.8%) cases. The log-rank test showed a significantly (p = 0.01) shorter survival among men in respect of women. We did not find any relationship between survival and membranous (p = 0.32) or cytoplasmic (p = 0.51) EGFR overexpression, while C7p significantly (p = 0.02) correlated with survival. Similarly, no correlation was found (Cox\u2019s regression) between EGFR overexpression and survival (R = 0.41, p = 0.21), while the relationship with gender (R = 0.87, p < 0.01) was confirmed. Conclusions: In our preliminary study, women with ccRCC had an overall better survival than men. EGFR was not a useful predictor of outcome, while C7p may have a prognostic significance

Carboxy-terminal telopeptide of type I collagene and tartrate-resistant acid phosphate in patients with colorectal cancer and bone metastases.

Introduction: Despite significant advances in detection and treatment, colorectal cancer (CRC) still remains one of the most prevalent cancers, and one of the leading causes of mortality due to malignancy. In patients with stage I-II CRC surgical resection usually represents the sole treatment, while in those with metastasized tumor (stage IV) any therapy is rarely successful. Unfortunately, up to 60% of patients with CRC undergoing primary surgery with curative intention die from metastatic disease. Thus, occult tumor cells, not detected preoperatively, likely colonize and remain vital in different tissues of these patients, such as lymph nodes, blood, and bone marrow. Usually, CRC metastasizes to the liver and lungs more frequently than to bone. Isolated bone metastasis (BM) is considered truly rare, but it has been observed that the improved survival for patients with metastatic CRC following expanded treatment options is associate with an increased incidence of BMs. Because metastases in uncommon sites often indicates the terminal phase of CRC, clinicians should be more vigilant about possible BMs. For this purpose, several serum biomarkers have been tested for early detection of BMs, such as carboxy-terminal telopeptide of type I collagen (ICTP), a cross-link product of collagen I degradation, and tartrate-resistant acid phosphatase 5b (TRACP), specifically derived from osteoclasts. Recent studies showed that TRACP activity and ICTP were increased in up to 90% of patients with breast cancer and BM. The aim of this study was to evaluate the usefulness of TRACP, ICTP, and bone alkaline phosphatase (BAP) measurements in patients with CRC and BM. Methods: Fourteen patients (9 men, 5 women, mean age 56.1\ub14.8, range 49-63 years) with CRC and confirmed BMs (cases), and a group of 15 age- and gender matched (10 men, 4 women, age 57.1\ub14.9 years, p=0.08) patients (controls) without BM (negative F-18 FDG PET/CT) underwent serum TRACP, ICTP, and BAP measurements. Written informed consent was obtained from all the participants. TRACP and BAP were measured by two-site enzyme-linked immunosorbent assay (ELISA), while ICTP was measured by commercially available radioimmunoassay. The sensitivity and specificity of serum TRACP, ICTP, and BAP as a marker for BM were estimated by receiver operator characteristic (ROC) curves. Results: The mean levels of TRACP, ICTP, and BAP (cases vs. controls) were: 5.9 \ub11.6 vs. 4.8\ub11.3 U/L (95% CI 0.11-2.11, p=0.08), 6.9\ub11.4 vs. 5.9\ub11.3 U/L (95% CI 0.94-3.04, p=0.0003), and 82.6\ub118.2 vs. 79.3\ub116.2 (95% CI 9.81-16.39, p=0.59). ROC analysis established a cutoff value for ICTP of 4.51 U/mL to identify patients with extensive BM with a specificity of 97% and a sensitivity of 92% (area under the curve=0.97; 95% CI=0.95-0.98). A strong relationship was found only between TRACP and ICTP (R=0.95, p<0.0001) serum levels among cases, while there was no correlation between age and biomarkers

Second-Line Chemotherapy in Recurrent Clear Cell Ovarian Cancer: Results from the Multicenter Italian Trials in Ovarian Cancer (MITO-9).

Background and Aims: Ovarian clear cell carcinoma (CCC) has a poorer prognosis than other subtypes of ovarian cancer. In this study, we evaluated the responsiveness to second-line chemotherapy in recurrent ovarian CCC. Methods: The MITO-9 project investigated a cohort of patients observed between 1991 and 2007 in 20 centers. We identified 72 out of 240 patients with recurrent disease (28% stage I-II and 72% stage III-IV at diagnosis). Results: In 56% of patients, the clear cell histology was pure. Twenty-five patients were platinum-resistant, 18 were platinum-sensitive with a platinum-free interval (PFI) of 6-12 months, and 29 had a PFI &gt;12 months. Upon recurrence, 47% of patients were treated with platinum chemotherapy according to the PFI. The overall response rate (RR) to platinum was 80%, with 55, 100, and 80% RR in patients with PFI of 6-12, &gt;12, and &gt;24 months. The RR to nonplatinunn agents in resistant patients was 33%. Among the nonplatinum agents used in primary and secondary resistant cases, gemcitabine, administered in 12 cases, had a higher activity (RR = 66%) compared to topotecan or liposomal doxorubicin (n = 31; RR = 33 and 10%, respectively). Conclusions: This study showed that the treatment of recurrent ovarian CCC should be based on the PH as in the other subtypes. Data in platinum-resistant patients suggest gemcitabine as the drug with the highest activity. We recommend that gemcitabine be studied prospectively in a phase 2 trial. (C) 2014 S. Karger AG, Base

Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer

Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m(2) day 1, LV 100 mg/m(2) as 2 h infusion and 5-FU 400 mg/m(2) as bolus, days 1 and 2 followed by 600 mg/m(2)/day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85-1.17; P = 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82-1.18; P = 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively

FACTORS ASSOCIATED WITH CLIMATERIC SYMPTOMS IN WOMEN AROUND MENOPAUSE ATTENDING MANOPAUSE CLINICS IN ITALY

Objective: To obtain data on correlates of climacteric symptoms in women around menopause attending menopause clinics in Italy. Methods: Since 1997 a large cross sectional study has been conducted on the characteristics of women around menopause attending a network of first level menopause outpatient\u2019s clinics in Italy. A total of 66,501 (mean age 54.4 years) women are considered in the present paper. Results: The odds ratios of moderate and severe hot flashes/night sweats were lower in more educated women and (for severe symptoms only) in women reporting regular physical activity. Depression, difficulty to sleep, forgetfulness and irritability tended to be less frequent in more educated women and (depression only) in women reporting regular physical activity. Parous women reported more frequently these symptoms. Conclusions: This large study confirms in Southern European population that low education, body mass index and low physical activity are associated with climacteric symptoms. Parous women are at greater risk of psychological symptoms. \ua9 2005 Elsevier Ireland Ltd. All rights reserved