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Background More than 50% of estrogen receptor (ER)-positive breast cancer (BC) distant recurrences (DR) develop after the completion of 5 years of adjuvant endocrine therapy (ET). Its extension is beneficial on disease-free survival and overall survival but increases therapy-related side effects. Selecting patients who could benefit the most from an extended regimen has become an increasing need. Clinical Treatment Score at 5 Years (CTS5) is a prognostic tool using clinicopathologic data to estimate DR risk after 5 years of ET for ER+ BC. We sought to validate the prognostic value of CTS5 in a retrospective cohort of real-life pre- and postmenopausal patients diagnosed with ER+ BC. Patients and Methods CTS5 was calculated for 603 patients diagnosed with ER+ BC at Umberto I Hospital of Turin and DR-free after 5 years of ET. Primary endpoint was late DR (LDR) rate. Results Median follow-up was 8 years (range, 6-26 years). The 426 postmenopausal women were categorized by CTS5 as follows: 152 low risk, 139 intermediate risk, and 135 high risk. LDR rates were 3.9%, 7.2%, and 15.6%, respectively. CTS5 results were prognostic for LDR: patients with CTS5-high showed a fourfold risk of developing an LDR compared to patients with CTS5-low (hazard ratio, 4.48; 95% confidence interval, 1.80-11.1). The same analysis was conducted for the 177 premenopausal women: 88 low risk, 40 intermediate risk, and 49 high risk. LDR rate were 5.6%, 7.5%, and 20.4%, respectively, proving CTS5 to be prognostic for premenopausal patients as well (CTS5-high vs. CTS5-low: hazard ratio, 3.40; 95% confidence interval, 1.06-11.0). Conclusion CTS5 was shown to be prognostic of the risk of LDR in our population of real-life pre- and postmenopausal patients. Our results support its use in clinical practice to better tailor the prescription of extended ET.

Purpose Extension of adjuvant endocrine therapy (ET) reduces the risk of recurrence in women diagnosed with ER-positive breast cancers, but a significant benefit is unlikely to happen to all individual patients. This study is aimed at evaluating the ability of different clinical late distant recurrence (LDR) risk stratification methods and in particular the clinical treatment score at 5 years (CTS5) to predict the response to extended adjuvant ET. Methods 783 patients diagnosed with ER+ BC between 1988 and 2014 at Umberto I Hospital of Turin, of which 180 received an extended adjuvant ET, were retrospectively selected. They were stratified according to pT, pN, disease stage, tumor grade, Ki67 level, progesterone receptor status and CTS5. The primary endpoint was LDR rate. LDR rates according to ET duration were confronted in each subgroup. Result The median duration of extended ET was 7 years (6–10). Median follow-up from diagnosis was 9 years (6–26). Retrospective risk stratification according to tumor size, nodal status, disease stage, tumor grade, Ki67 level, and progesterone receptor status did not appear to be able to predict the response to extended ET. In the CTS5 high-risk subgroup instead, the risk of developing an LDR was significantly lower in the patients who underwent extended ET compared to standard ET (HR 0.37, 95% CI 0.15–0.91), while no significant benefit was demonstrated for low and intermediate-risk patients. Conclusions Risk stratification according to CTS5 appeared to be predictive of the response to extended endocrine therapy in our population of real-life pre and postmenopausal patients.

Luca Mariani, Claudio Robba, Giulia Moggio and Piero Sismondi Academic Department of Gynaecological Oncology, University of Turin Mauriziano Umberto I° Hospital of Turin & Institute for Cancer Research and Treatment of Candiolo, Turin, Italy “Several studies have reported that past and current users of combined hormone-replacement therapy are at a higher risk of developing invasive lobular carcinoma than invasive ductal–lobular mixed carcinoma.”

Breast cancer is increasing worldwide and affects up to one in eight women who survive up to the age of 85 years in Western countries. Four out of five new cases of breast cancer are diagnosed in women over 50 years, with the peak in the 50–64 years age range. The survival rate of breast cancer patients has significantly increased due to earlier diagnosis and advances in adjuvant treatment: at 5 years after initial diagnosis around 90% of the patients survive in good health conditions. There are now more than 2.5 million breast cancer survivors (BCSs) in the USa. Menopausal symptoms are common among BCSs and can adversely affect Quality of Life and sexual health. Because a wide range of possible treatments is now available for BCSs, menopause after breast cancer should no longer be considered an unsolved problem but an interesting area of further clinical research.

Women with a life expectancy ≥10 years and no diagnosis/history of breast cancer who are considered to be at increased risk for breast cancer should receive counseling to decrease breast cancer risk, considering lifestyle factors, therapy with risk reduction agents, and risk reduction surgery (in BRCA1/2 mutation carriers).Bilateral risk-reducing mastectomy decreases the risk of developing breast cancer by at least 90%; it should be proposed to carefully selected women at high risk for breast cancer considering BRCA1/2 or other genetic mutations and previous history of LCIS. In current practice, atypical hyperplasia is not an indication for prophylactic mastectomy.Bilateral risk-reducing salpingo-oophorectomy decreases the risk of developing ovarian and fallopian cancer by 85–95% and breast cancer by 50% in BRCA1/2 mutation carriers when performed in premenopausal age. Peritoneal washing should be performed at surgery, and pathologic assessment should include fine sectioning of the ovaries and fallopian tubes. The additional benefit of concurrent hysterectomy is not clear at the time. In women with no personal history of breast cancer, short-term HRT use does not negate the protective effect of RRSO on subsequent breast cancer risk, and it should be offered until the time of expected natural menopause.

Introduction Chemotherapy is the standard treatment of recurrent epithelial ovarian cancer (EOC), but its use in nodal relapses is still debated. On the other hand, the role of secondary cytoreductive surgery (SCS) remains controversial. Aim of this study is to evaluate feasibility and outcomes of SCS for the specific setting of recurrent ovarian cancer, exclusively relapsing in lymph nodes. Patients and methods We conducted a retrospective analysis in five Italian Institutions (University of Torino, INT of Milano, CRO of Aviano, University of Pisa and INT of Napoli) from 2000 to 2012. Patients with EOC who underwent secondary surgery for isolated lymph node recurrence (ILNR) were selected. Results Seventy-three patients were identified. At first diagnosis, patients received debulking surgery and platinum-based chemotherapy. The median disease free interval from completion of primary chemotherapy to nodal recurrence was 18 months. Nodal recurrence was para-aortic in 37 patients (50.7%), pelvic in 21 (28.8%), pelvic and para-aortic in 9 (12.3%), pelvic and inguinal in 3 (4.1%) and inguinal in 3 (4.1%). During SCS, in 1 patients nephrectomy was necessary for renal vein injury. No significant postoperative morbidity occurred. Median follow-up is 50 months. After secondary surgery, 32 (43.8%) are alive without disease, 18 (24.6%) are alive with disease and 23 patients (31.5%) are dead of disease. Five-year overall survival from the time of treatment of recurrent disease is 64%. Conclusions Secondary surgery for ILNR of ovarian cancer is feasible, safe, with low morbidity and it is associated with a favorable outcome.

Aims and background Hysteroscopic polypectomy is the gold standard to treat endometrial polyps and obtain specimens for histological evaluation. There is continuing debate as to when to offer hysteroscopic polypectomy, especially in asymptomatic women with incidental lesions. The aims of this study were to assess the accuracy of hysteroscopy and Vabra sampling in diagnosing atypical hyperplasia and cancer growing on the surface of endometrial polyps and to investigate the association between atypical endometrial polyps and some potential clinical risk factors. Methods and study design This was a retrospective study. We assessed 1039 hysteroscopies and we identified 345 women with endometrial polyps. All patients with endometrial polyps underwent hysteroscopic polypectomy. Data about age, menopausal status, abnormal uterine bleeding (AUB), hormone replacement therapy and tamoxifen use were collected. Hysteroscopic, histological and clinical data were analyzed. Results The incidence of endometrial hyperplasia or cancer growing on the surface of endometrial polyps was significantly low (1.7%). Hysteroscopy correctly excluded (negative predictive value: 100%) and accurately predicted (positive predictive value: 85.7%) preneoplastic or neoplastic lesions growing within the epithelial layer of endometrial polyps. Vabra sampling was inadequate for the histological diagnosis in 38.5% of cases. Age over 60 years and postmenopausal AUB were associated with an 8.3-fold ( P = 0.022) and 8.8-fold ( P = 0.020) increased risk, respectively, of preneoplastic and neoplastic lesions growing on the surface of endometrial polyps. Conclusions Diagnostic hysteroscopy is a good tool to predict malignancy of the epithelial layer of endometrial polyps. Age over 60 years and AUB are associated with an increased risk of malignant polyps. Few suspicious endometrial polyps should undergo surgical resection.

Nipple-areola sparing mastectomy (NSM) is increasingly used in patients with non-locally advanced breast carcinoma. Literature data on the preoperative assessment of the nipple-areola complex (NAC) are inconsistent.Out of 1359 patients submitted to total mastectomy between 2001 and 2010, we selected 61 patients whose pre-operative mammogram (MX) was available (MX group) and 39 patients who underwent preoperative breast magnetic resonance imaging (magnetic resonance imaging (MRI) group). The rate of NAC involvement, the value of MX and MRI to predict NAC involvement and the performance of the Schecter's and Loewn's algorithms for the prediction of NAC involvement were evaluated.In the combined MX and MRI groups, NAC involvement was found in 14% of the cases. At univariate analysis, tumour stage (p value: 0.03), central tumour location (p value: 0.004), presence of NAC retraction (p value: 0.001) and tumour-NAC distance (p value: 0.006) were associated with NAC involvement, but only the latter parameter retained statistical significance at multivariate analysis (p value: 0.05). Tumour-NAC distance was a key predictor of NAC involvement, with a negative predictive value of 94% for MX and of 100% for MRI when the cut-off was set at 10mm. Overall, the performance of Schecter's and Loewn's algorithms was respectively lower and similar as compared to the original series.Occult tumour involvement of the NAC is detected in a minority of breast cancer patients submitted to mastectomy. A tumour-NAC distance ≥ 10 mm by MRI may help select patients candidate to NSM.

The objective of this study is to investigate if changes in cognitive functions can be recognised in patients undergoing chemotherapy for breast cancer. Forty women with breast cancer and without depression underwent cognitive evaluation before and after 6 months of chemotherapy; emotional evaluation was performed before and after 1, 3 and 6 months of chemotherapy. Self-reported cognitive deficit evaluation was included. Global cognitive functioning before starting chemotherapy was good. After 6 months of treatment there was a significant decline in some cognitive functions, particularly involving the attention subdomain. Objective cognitive deficit resulted independent from the emotional status. On the contrary, self-perceived mental dysfunction was unrelated to the objective cognitive decline, but it was associated with depression and anxiety. Breast cancer chemotherapy can induce domain-specific cognitive dysfunction. Patients' self-perception of mental decline is unrelated to objective cognitive deficit. Breast cancer patients negatively judge their cognitive performances if they have a negative emotional functioning.

Due to the low occurrence of cancer during pregnancy, limited data are available about outcome of infants exposed to chemotherapy in utero. We report the case of a newborn who developed transient ventricular hypocinesia and late-onset infection after in utero exposure to four epirubicin cycles for pregnancy-associated breast cancer. Moreover, we provide an overview of literature on neonatal outcome after anthracyclines-based chemotherapy regimen during pregnancy. Existing data support use of anthracyclines, as few cases of fetal cardiac toxicity were reported and most of short-term complications were transient. Need for prospective collection of data and longer follow-up is highly recognized.

BRCA1 and BRCA2 mutation carriers have a 54-85% and 45% lifetime risk of developing breast cancer, respectively, and a 18-60% and 11-27% lifetime risk of developing ovarian cancer, respectively. Oral contraceptives (OCs) significantly reduce the risk of ovarian cancer also in BRCA1/BRCA2 mutation carriers. The association between OC use and breast cancer risk in these women is controversial. Some studies showed a modestly increased risk especially among BRCA1 mutation carriers. The risk appears to be greater for women who took OCs for at least 5 years and who took OCs before the age of 30 years. Other studies reported that duration of use before first full-term pregnancy has a positive association with breast cancer risk. Salpingo-oophorectomy reduces the risk of coelomic epithelial cancer of 80-95% and the risk of breast cancer of approximately 50%. BRCA1 and BRCA2 mutation carriers should be encouraged to undergo prophylactic bilateral salpingo-oophorectomy at the age of 35-40 years or when childbearing is complete. Short-term use of hormone replacement therapy may relieve menopausal symptoms and does not appear to affect the breast cancer risk reduction obtained with salpingo-oophorectomy.

Objectives To assess the efficacy and the tolerability of gabapentin 900 mg/day compared to vitamin E for the control of vasomotor symptoms in 115 women with breast cancer. The secondary objective was to evaluate the effect of the treatments on the quality of sleep and other aspects of the quality of life. Methods A hot flush diary was completed daily; sleep quality and other menopausal symptoms were assessed with the Pittsburgh Sleep Quality Index (PSQI), the Menopause Rating Scale (MRS) and the SF-36 Health Survey. Results The prescribed treatment with gabapentin was never started by 28.3% of the patients and was interrupted by 28% for side-effects (dizziness and somnolence). Among the women allocated to vitamin E, 16.36% never started therapy and 34.78% dropped out because of inefficacy. Hot flush frequency and score decreased by 57.05% and 66.87%, respectively (p5 0.05) in the gabapentin group. The effect of vitamin E was fairly small: hot flush frequency and score were reduced by 10.02% and 7.28%, respectively (p4 0.05). Gabapentin was also particularly effective in improving the quality of sleep (PSQI score reduction: 21.33%, p5 0.05). Conclusion Gabapentin appears to be effective for the treatment of hot flushes with a favorable effect on quality of sleep. Vitamin E has only marginal effect on vasomotor symptoms.

Summary Background Vasomotor symptoms and bone loss are complications frequently induced by adjuvant treatment for breast cancer. Tibolone prevents both side-effects, but its effect on cancer recurrence is unknown. The aim of this study was to show non-inferiority of tibolone to placebo regarding risk of recurrence in breast-cancer patients with climacteric complaints. Methods Between July 11, 2002, and Dec 20, 2004, women surgically treated for a histologically confirmed breast cancer (T 1–3 N 0–2 M 0 ) with vasomotor symptoms were randomly assigned to either tibolone 2·5 mg daily or placebo at 245 centres in 31 countries. Randomisation was done by use of a centralised interactive voice response system, stratified by centre, with a block size of four. The primary endpoint was breast-cancer recurrence, including contralateral breast cancer, and was analysed in the intention-to-treat (ITT) and per-protocol populations; the margin for non-inferiority was set as a hazard ratio of 1·278. This study is registered with ClinicalTrials.gov, number NCT00408863. Findings Of the 3148 women randomised, 3098 were included in the ITT analysis (1556 in the tibolone group and 1542 in the placebo group). Mean age at randomisation was 52·7 years (SD 7·3) and mean time since surgery was 2·1 years (SD 1·3). 1792 of 3098 (58%) women were node positive and 2185 of 3098 (71%) were oestrogen-receptor positive. At study entry, 2068 of 3098 (67%) women used tamoxifen and 202 of 3098 (6·5%) women used aromatase inhibitors. The mean daily number of hot flushes was 6·4 (SD 5·1). After a median follow-up of 3·1 years (range 0·01–4·99), 237 of 1556 (15·2%) women on tibolone had a cancer recurrence, compared with 165 of 1542 (10·7%) on placebo (HR 1·40 [95% CI 1·14–1·70]; p=0·001). Results in the per-protocol population were similar (209 of 1254 [16·7%] women in the tibolone group had a recurrence vs 138 of 1213 [11·4%] women in the placebo group; HR 1·44 [95% CI 1·16–1·79]; p=0·0009). Tibolone was not different from placebo with regard to other safety outcomes, such as mortality (72 patients vs 63 patients, respectively), cardiovascular events (14 vs 10, respectively), or gynaecological cancers (10 vs 10, respectively). Vasomotor symptoms and bone-mineral density improved significantly with tibolone, compared with placebo. Interpretation Tibolone increases the risk of recurrence in breast cancer patients, while relieving vasomotor symptoms and preventing bone loss. Funding Schering-Plough (formerly NV Organon, Oss, Netherlands).

The association of endometriosis and ovarian malignancy is about 1%, with a peak incidence in patients over 45 years. The best way of treating peri- and post-menopausal women with endometriosis is still a very controversial issue. We report two cases of peri-menopausal women in which endometriosis was associated to ovarian malignancy. The first case was a 49-year-old woman who underwent laparoscopic oophorectomy for an ovarian endometrioid cyst. Definitive histology showed ovarian endometrioid cyst with endometrioid and clear cell carcinoma. Subsequently, surgical restaging was performed. The other case was a 49-year-old woman who underwent hysterectomy and bilateral oophorectomy for an ovarian mass suggestive of endometriosis and uterine myomas. At frozen section examination, ovarian adenocarcinoma was found and staging procedure was performed. Definitive histology showed carcinosarcoma of the ovary with areas of endometriod adenocarcinoma. Given the non-infrequent association between ovarian endometriosis and cancer, more data are needed to decide for an aggressive or conservative approach to peri-menopausal endometriosis.

A growing body of evidence support the association between the use of hormone replacement therapy (HRT) and a higher risk of both invasive lobular carcinoma (ILC) and invasive ductal–lobular mixed carcinoma (IDLC). Overall biological and clinical features of ILC entail a more cautious diagnostic and therapeutic approach as compared with invasive ductal carcinoma (IDC). ILCs are more frequently multifocal, multicentric and/or bilateral. Mammography and ultrasound show, therefore, significant limitations, while the higher sensitivity of magnetic resonance imaging in the detection of multifocal and/or multicentric lesions seems to improve the accuracy of preoperative staging of ILCs. Early diagnosis is even more challenging because the difficult in the localization and the sparse cellularity of lobular tumours may determine a false negative core biopsy. ILC is characterized by low proliferative activity, C-ErbB-2 negativity, bcl-2 positivity, p53 and VEGF negativity, oestrogen and progesterone positive receptors, low grade and low likelihood of lymphatic-vascular invasion. However, this more favourable biological behaviour does not reflect into a better disease-free and overall survival as compared with IDC. Since lobular histology is associated with a higher risk of positive margins, mastectomy is often preferred to breast conservative surgery. Moreover, only few patients with ILC achieve a pathologic response to preoperative chemotherapy and, therefore, in most patients mastectomy can be regarded as the safer surgical treatment. The preoperative staging and the follow-up of patients with ILC are also complicated by the particular metastatic pattern of such histotype. In fact, metastases are more frequently distributed to the gastrointestinal tract, peritoneum/retroperitoneum and gynaecological organs than in IDC.

Estrogen exerts a primary regulatory role on a wide variety of physiological processes in different tissues and organs. Agonistic ad antagonistic compounds are widely used in human health and, therefore, a deep understanding of their mechanisms of action at the molecular level is mandatory. The effect of 17beta-estradiol and three antiestrogenic drugs, comprising two selective estrogen receptor modulator (SERM, 4-OH-tamoxifen, Raloxifene) and the pure antiestrogen ICI 182,780, on genome-wide gene expression levels was evaluated in breast carcinoma cell lines by DNA microarray analysis. Different clusters of genes, showing specific coregulation patterns, were found. First, several groups of genes displaying temporal-specific up- or down-regulation were characterized. Second, clusters of genes responding to different antiestrogenic drugs in either antagonstic or agonistic fashion, were found. Genes responding specifically to antiestrogens, but not to estrogen, were also identified. In addition, each individual compound exhibited a very specific gene regulation. Bioinformatic analysis was applied to the regulatory sequences of different groups of genes and confirmed that specific pathways and secondary responses are activated at each temporal point and in response to different compounds. Our results underline the complexity of genomic responses to estrogen in breast cancer cells and strongly suggest that the molecular characterization of estrogen agonists and antagonists used in human therapy should be carefully studied.

Breast cancer (BC) is the most commonly diagnosed invasive cancer among women; in developed countries, BC occurs in one out of eight women during her lifetime. Many factors, both genetic and non-genetic, determine a woman's risk of breast cancer and several mathematical models have been proposed that determine the risk. It is important to identify those at high risk, as there are now effective preventive strategies, such as chemoprevention therapy and risk-reduction surgery. Risk-reduction agents are recommended for women aged 35 years or more who are at high risk of breast cancer. Tamoxifen is presently deemed to be the agent of choice. However, raloxifene may be preferable, at least for some postmenopausal women, because of its lack of effect on the endometrium and the reduced incidence of venous thromboembolic events compared with tamoxifen. Prophylactic surgery has been widely investigated. Bilateral mastectomy decreases the risk of developing breast cancer by approximately 90% in women at moderate or high risk and in known BRCA1/2 mutation carriers. This review summarizes the recent advances in the identification of women at high risk of developing breast cancer and reports on the strategies used to prevent breast cancer; the risk-benefit balance of such preventive choices is also briefly analyzed.

Androgen receptors (ARs) are frequently expressed in breast cancer (BC) cells, but their implication as a prognostic and/or predictive marker is still controversial. Preclinical studies suggest that the action of androgens is bidirectional: mainly proliferative, because circulating androgens are the precursors of estrogens, but also antiproliferative, because AR activation restrains ER activity inhibiting normal breast tissue growth. ARs play different roles at different stages of disease or in different subtypes of BC. ARs are expressed in up to 70 % of ER-positive BC and high levels of expression confer a survival advantage. Moreover, the increase of androgens that follows the blocking of androgen aromatization into estrogens by aromatase inhibitors (AIs) could contribute to their therapeutic efficacy in AR-positive cases. Up to 50 % of ER-negative BC are reported to be positive for ARs. Currently, epidemiological, clinical, and preclinical data on the role of androgens and ARs on this BC subtype are still controversial. In HER2-expressing cell lines, preclinical studies suggest that ARs have a proliferative effect, probably due to the cross talk between ARs and HER2 pathways. In conclusion, AR is an emerging target in breast cancer, with potential significance for therapeutic management of both primary and advanced disease.

Around 10–15 % of epithelial ovarian cancers have histological and clinical behavior that are intermediate among benign and malignant tumors. These low malignant potential (LMP) tumors, also called borderline, were firstly described by Taylor in 1929. These neoplasms have a more favorable outcome than malignant ovarian cancers, but they were considered comprehensively by the International Federation of Gynecology and Obstetrics (FIGO) and the World Health Organization (WHO) until the early 1970s. Although LMP tumors may develop at any age, patients are usually in their 40s, about 15–20 years younger than women with invasive ovarian cancer, and the large majority of LMP tumors is discovered at stage I. Surgery is the treatment of choice, and the conservative strategy is strongly increasing in the last years. They often have a good prognosis, but because of many reasons, their management is frequently problematic.

The increasing number of breast cancer patients who suffer from menopausal symptoms is mainly due to the extensive use of adjuvant treatments in the younger women. Both short and long-term side effects of oestrogen deficiency may severely impact on the quality of life of these women and should not be underestimated. Hormonal treatments are contraindicated in breast cancer survivors mainly due to the concern that dormant micrometastases may be stimulated to grow. Alternative non-hormonal remedies are now available to alleviate symptoms and to prevent chronic diseases associated with oestrogen deficiency. Urogenital atrophy is an important consequence of oestrogen deprivation that can be effectively treated by vaginal estrogens, although systemic absorption occurs with conventional doses. Preliminary data suggest that much lower doses of vaginal estrogens can alleviate urogenital atrophy without influencing serum estrogenic levels. Further research is warranted to confirm whether vaginal estrogens are safe in symptomatic breast cancer patients who are non-responsive to alternative treatments.

Controversies about the safety of different postmenopausal hormone therapies (HTs) started 30 years ago and reached a peak in 2003 after the publication of the results from the Women Health Initiative (WHI) trial and the Million Women Study (MWS) [Writing group for the women's health initiative investigations. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321-33; Million women study collaborators. Breast cancer and hormone-replacement therapy in the million women study. Lancet 2003;362:419-27]. The single HT formulation used in the WHI trial for non hysterectomized women-an association of oral conjugated equine estrogens (CEE-0.625 mg/day) and a synthetic progestin, medroxyprogesterone acetate (MPA-2.5 mg/day)-increases the risks of venous thromboembolism, cardiovascular disease, stroke and breast cancer. The MWS, an observational study, showed an increased breast cancer risk in users of estrogens combined with either medroxyprogesterone acetate (MPA), norethisterone, or norgestrel. It is unclear and questionable to what extent these results might be extrapolated to other HRT regimens, that differ in their doses, compositions and administration routes, and that were not assessed in the WHI trial and the MWS. Significant results were achieved with the publication of the WHI estrogen-only arm study [Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712] in which hormone therapy was reserved to women who had carried out hysterectomy. What emerged from this study will allow us to have some important argument to develop.

The most important step in radical hysterectomy is freeing the ureter from the anterior parametrium. In this paper we describe our modified technique for freeing the ureter from the anterior parametrium for a Piver II–III radical hysterectomy by means of pure laparoscopic surgery. Our series consists of seventeen patients undergoing laparoscopic hysterectomy. In evaluating the technique, we considered its feasibility, the operating time, the time for complete preparation of the ureter as measured on the videotapes of the procedures, the short-term complication rate, and the length of hospital stay. Thirty-one ureters were unroofed; in three patients, monolateral dissection was performed. The median time of the surgical procedures was 182 min (range 110–255). The median time to unroof the ureter on one side was 14 min 35 s (range 10 min 15 sec–63 min). No patient had ureteronephrosis at ultrasound at control. Even if the experience with this technique is limited, the almost constant time to free the ureter shows that, laparoscopically, it can be performed with relative ease, particularly in patients without prolapse.

There is strong epidemiological, experimental and clinical evidence that the etiology of breast cancer is closely related to long-term exposure of breast epithelium to sex steroid hormones. Estrogens can enhance the development of breast cancer by stimulating cell proliferation rate and thereby increasing the number of errors occurring during DNA replication, as well as by causing DNA damage via their genotoxic metabolites produced during oxidation reactions. Anti-estrogenic drugs, including tamoxifen, raloxifene and anastrozole, have been tested with promising results in the chemoprevention of breast cancer in high-risk women. As for the use of exogenous sex-steroids in the gynecological practice, data about breast cancer risk associated with oral contraception are reassuring, and available data on oral hormone replacement therapy (HRT) use for not more than 5 years have failed to detect a significant increase in the risk of developing a breast cancer. Long-term HRT administration increases the incidence of this tumor slightly, with a relative risk ranging from 1 to 2 depending on hormone preparation. Estrogens alone, even if taken for long periods of time, seem to be safer than estrogen/progestin combinations. New administration routes and novel hormone regimens are currently under evaluation, and these new HRT modalities could have different impact on breast cancer risk because of their metabolic and pharmacodynamic effects.

The San Antonio Breast Cancer Symposium is now considered the most important international breast cancer meeting worldwide. On 8-11th December 2004, approximately 6700 participants attended the meeting and shared the latest findings from breast cancer research. All the main fields of breast cancer research and treatment were covered. This report will focus on the most relevant advancements in the pharmacotherapy of breast cancer. The selected presentations have been grouped together in separate sections, including the fields of prevention, early disease and advanced disease. The most promising data from translational research have also been included, with particular regard to those who will most likely influence the management of breast cancer patients in the future.

Objective The primary aim of this study was to evaluate the prognostic and predictive value of pretreatment serum hemoglobin level (Hb) in advanced ovarian cancer; second aim was to perform a preliminary investigation of intratumoral microvessel density (IMD). Methods The influence on survival and response to treatment of several clinico-pathological features, including Hb, was analyzed in 72 patients with advanced ovarian cancer. IMD was assessed in tumor specimens of 25 of the 72 patients to compare three different endothelial markers: anti-FactorVIII, anti-CD31 and anti-CD34. In this subgroup of patients, a preliminary analysis of the prognostic and predictive value of IMD, and its relationship with Hb and other clinico-pathological features, was performed. Results Hb ≥ 12 g/dl was significantly associated with a better overall survival in univariate analysis ( P = 0.0181) and was the only independent prognostic variable in multivariate analysis ( P = 0.0160). Hb was directly related to progression-free survival ( P = 0.0240) and complete response to treatment ( P = 0.016). In the preliminary investigation of IMD, mean microvessel count did not show any significant difference among the three endothelial markers used, but anti-CD34 revealed a more consistent staining reaction. The relationship between IMD and complete response to treatment was found near to statistical significance ( P = 0.05); Hb and IMD were inversely related ( r = −0.47; P = 0.045). Conclusions Hb has a prognostic and predictive value in advanced ovarian cancer. In our preliminary study, which was performed on a limited number of patients, we found anti-CD34 to be an optimal marker for IMD determination, IMD to be a possible predictive factor of complete response to treatment, and IMD and Hb to be inversely related.

Previous studies had shown that there is little concern about endometrial cancer risk with hormone replacement therapy (HRT), whereas the risk of ovarian cancer is still debated. A new paper based on the women’s health initiative (WHI) study devoted to gynaecologic cancers has been published in the October 2003 issue of JAMA, leading to the conclusion that also for endometrial and ovarian cancer risk, as the first WHI publication did for breast cancer risk, the previous large studies have been confirmed. About follow-up the authors conclude that, “The increased burden of endometrial biopsies required to assess vaginal bleeding further limits the acceptability of this regimen.” These conclusions deserve a thorough analysis and must be read in the light of the burden of available epidemiological and clinical data and of recommended clinical practice. In the WHI trial the use of continuous combined HRT has resulted in a considerable increase of both imaging and invasive exams, to investigate women with bleeding or spotting, but the findings of these exams have been invariably negative. As far as, all published studies agree on the fact that continuous combined HRT either has no effect or significantly reduces the risk of both endometrial hyperplasia and cancer, there should be no reason to close-watching endometrium of women using this regimen with a different strategy from that employed on any healthy woman.

The activator protein 2 (AP-2) transcription factors are essential proteins for oestrogenic repression of the ERBB2 proto-oncogene in breast cancer cells. In the present study, we have examined the possible oestrogenic regulation of AP-2 genes themselves in breast-tumour-derived lines. As early as 1 h after oestrogen treatment, AP-2gamma mRNA was markedly increased, whereas AP-2alpha was down-regulated, but with slower kinetics, and AP-2beta was not affected at all. Addition of anti-oestrogens ablated these effects. Modulation of the protein levels corresponded to changes in the transcript levels, thus suggesting that in oestrogen-treated cells, an inversion of the balance between AP-2alpha and AP-2gamma isoforms occurs. The 5'-untranslated region (5'-UTR) of the human AP-2gamma gene contains one consensus and one degenerate oestrogen-responsive element (ERE). Reporter constructs carrying the AP-2gamma promoter and the 5'-UTR were up-regulated by oestrogens in transient transfection assays. Deletion of the most conserved (but not of the degenerate) ERE from reporter constructs abrogated the oestrogenic response, although both ERE-containing segments were footprinted in DNaseI protection assays. In vitro binding assays demonstrated the ability of oestrogen receptor alpha (ERalpha) to bind to this site, and chromatin immunoprecipitation analysis of the endogenous gene showed that ERalpha occupies this region in response to oestrogens. We conclude that AP-2gamma is a primary oestrogen-responsive gene and suggest that AP-2 proteins may mediate some oestrogenic responses.

Purpose. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows analysis of both tumor volume and contrast enhancement pattern using a single tool. We sought to investigate whether DCE-MRI could be used to predict histological response in patients undergoing primary chemotherapy (PCT) for breast cancer. Patients and methods. Thirty patients with breast cancer, clinical diameter >3 cm or stage III A/B, received anthracycline and taxane based PCT. DCE-MRI was performed at the baseline, after two cycles and after four cycles of PCT, before surgery. Histological response was assessed using a five-point scheme. Grade 4 (small cluster of dispersed residual cancer cells) and grade 5 (no residual viable cancer cell) were defined as a major histopathological response (MHR). Results. Univariate analysis showed that a >65% reduction in the tumor volume and a reduction in the early enhancement ratio (ECU) after two cycles of PCT were associated with a MHR. Multivariate analysis revealed that tumor volume reduction after two cycles of PCT was independently associated with a MHR (odds ratio [OR] 39.968, 95% confidence interval [CI] 3.438–464.962, p < 0.01). ECU reduction was still associated with a MHR (OR 2.50, 95% CI 0.263–23.775), but it did not retain statistical significance (p = 0.42). Combining tumor volume and ECU reduction after two cycles of PCT yielded a 93% diagnostic accuracy in identifying tumors achieving a pathological complete response (pCR) (histopathological grade 5). Conclusions. DCE-MRI allows prediction of the effect of neoadjuvant chemotherapy in breast cancer. Although in our study tumor volume reduction after two cycles had the strongest predictive value, DCE-MRI has the potential to provide functional parameters that could be integrated to optimize neoadjuvant chemotherapy strategies.

Due to the younger age and the ever wider use of adjuvant chemotherapy and antiestrogens, menopausal symptoms are a frequent cause of concern for breast cancer patients. Objectives: To determine the prevalence of menopausal symptoms, and to explore the attitudes toward Hormone Replacement Therapy (HRT) or other treatments and the willingness to take oestrogen in breast cancer patients. Methods: A questionnaire-based survey on 250 breast cancer patients treated and followed-up at our department. Of them 144 (Group A) were in postmenopause and 106 (Group B) were in premenopause at time of diagnosis. Results: Adjuvant therapy with tamoxifen or tamoxifen plus chemotherapy is associated with a significant worsening of menopause-related symptoms of women belonging to Group A. These women are more concerned about risk of breast cancer recurrence than about risk of osteoporosis (P� /0.05) and heart disease (P� /0.006). Seventy-eight percent are against the use of HRT; only 22% would consider taking HRT mainly for vasomotor symptoms relief and osteoporosis prevention. The incidence of vasomotor and dystrophic symptoms is significantly higher in women belonging to Group B treated with chemotherapy and/or hormonotherapy as compared with postmenopausal women (P B/0.000 and P� /0.02, respectively). Premenopausal women are more concerned about risk of breast cancer recurrence than older women (P � /0.09) and at the same time are significantly more worried about the impairment of the quality of life due to adjuvant therapy (P� /0.005). Younger women are more prone to consider HRT than postmenopausal women (P � /0.05). Sixty-six percent are against HRT use, and 34% would consider taking HRT to alleviate vasomotor and dystrophic symptoms and to prevent osteoporosis. Conclusions: Breast cancer survivors are interested to treatments that may improve their quality of life, but fear of HRT persists among these women and their doctors, despite new evidence suggesting the low probability of detrimental effects. # 2003 Elsevier Science Ireland Ltd. All rights reserved.

Summary Background. Many members of the human kallikrein gene family were found to be differentially expressed in various malignancies and some of them are useful diagnostic/prognostic markers. KLK9 is a newly discovered human kallikrein gene that is expressed in several tissues including thymus, spinal cord, testis, prostate, breast, and ovary. Like other kallikreins, the KLK9 gene was found to be regulated by steroid hormones, mainly estrogens and progestins, in cancer cell lines. Experimental design. We studied the expression of KLK9 by quantitative RT-PCR in 169 breast cancer patients of different stages, grades and histological types. We also compared the relation between KLK9 expression and other clinicopathological variables and patient survival. Results. KLK9 expression is significantly higher in patients with early stage cancers (p = 0.039) and in patients with small tumor size (< 2c m) (p = 0.028). Kaplan-Meier survival curves demonstrated that KLK9-positive patients have longer disease-free and overall survival (p = 0.015 and 0.036, respectively). Univariate and multivariate analysis also indicates that KLK9 expression is associated with increased disease-free and overall survival. When the Cox proportional hazard regression analysis was applied to subgroups of patients, KLK9 expression was found to be a significant predictor of disease-free survival in the estrogen receptor (ER) and progesterone receptor (PR) negative subgroups of patients (Hazard Ratio ‘HR’ = 0.28, and 0.38, respectively, and p = 0.011 and 0.028, respectively). After adjusting for other known prognostic variables, KLK9 retained its independent prognostic value in these subgroups of patients. Similar results were obtained for overall survival. Conclusions. KLK9 is a new potential independent marker of favorable prognosis in breast cancer.

Background Biological markers capable of predicting the risk of recurrence and the response to treatment in breast cancer are eagerly awaited. Estrogen and progesterone receptors (ER, PgR) in tumor cells mark cancers that are more likely to respond to endocrine treatment, but up to 40% of such patients do not respond. Here, the expression of a group of estrogen-regulated genes, previously identified by microarray analysis of in vitro models, was measured in breast tumors and possible associations with other clinicopathological variables were investigated. Methods The expression of CD24, CD44, HAT-1, BAK-1, G1P3, TIEG, NRP-1 and RXRα was measured by quantitative real-time RT-PCR on RNA from eighteen primary breast tumors. Statistical analyses were used to identify correlations among the eight genes and the available clinicopathological data. Results Variable expression levels of all the genes were observed in all the samples examined. Significant associations of CD24 with tumor size, CD44 with lymph node invasion, and HAT-1 and BAK-1 with ER positivity were found. The possible combinatorial value of these genes was assessed. Unsupervised hierarchical clustering analysis demonstrated that the expression profile of these genes was able to predict ER status with an acceptable approximation. Conclusions Eight novel potential markers for breast cancer have been preliminarily characterized. As expected from in vitro data, their expression is able to discriminate ER- versus ER+ tumors.

We report our experience of a 29-year-old female with a complete atrio-ventricular septal defect leading to a single ventricle physiology and Eisenmenger syndrome. The patient successfully underwent spinal anesthesia for cesarean section in the 31 st week of pregnancy. A multidisciplinary approach involving cardiologist, cardiac surgeon, obstetrician, and anesthesiologist was utilized to achieve a safe pregnancy and cesarean for the delivery of the baby. A close clinical assessment is required, especially during the third trimester when the risk of acute right ventricular dysfunction increases. The use of extracorporeal membrane oxygenation (ECMO) (as a bridge to recovery or bridge to salvage) was planned to support oxygenation and circulation in case of acute biventricular dysfunction. The delivery/cesarean section was performed in a cardiac surgery operating room, and to reduce the time-frame for ECMO institution the femoral vessels were exposed surgically before the cesarean section.

Background: KLK5 is a newly discovered human kallikrein gene. Many kallikrein genes have been found to be differentially expressed in various malignancies, and prostate-specific antigen (PSA; encoded by the KLK3 gene) is the best tumor marker for prostate cancer. Like the genes that encode PSA and other kallikreins, the KLK5 gene was found to be regulated by steroid hormones in the BT-474 breast cancer cell line.Methods: We studied KLK5 expression in 179 patients with different stages and grades of epithelial breast carcinoma by quantitative reverse transcription-PCR (RT-PCR), using LightCycler® technology. An optimal cutoff point equal to the detection limit (65th percentile) was used. KLK5 values were then compared with other established prognostic factors in terms of disease-free (DFS) and overall survival (OS).Results: High KLK5 expression was found more frequently in pre-/perimenopausal (P = 0.026), node-positive (P = 0.029), and estrogen receptor-negative (P = 0.038) patients. In univariate analysis, KLK5 overexpression was a significant predictor of reduced DFS (P 2 cm) and positive nodes. Hazard ratios derived from Cox analysis and related to DFS and OS were 2.48 (P = 0.005) and 2.37 (P = 0.009), respectively, for the node-positive group and 3.03 (P = 0.002) and 2.94 (P = 0.002), respectively, for patients with tumor sizes >2 cm. KLK5 expression was also associated with statistically significantly shorter DFS (P = 0.006) and OS (P = 0.004) in the subgroup of patients with grade I and II tumors.Conclusions: KLK5 expression as assessed by quantitative RT-PCR is an independent and unfavorable prognostic marker for breast carcinoma.

Background and objective Different techniques have been previously described for the induction of pneumoperitoneum to start laparoscopy. This is the first description of a technique of semi-open direct trocar insertion in which the peritoneum is first opened and a trocar is then directly inserted without insufflation. Patients and methods The technique was tested in 184 (89.3%) out of 206 patients who underwent laparoscopy at our institution over a 1-year period. In 22 patients, closed entry through Palmer's upper quadrant with a Veress needle was used. An incision was made at the deepest point of the umbilical scar down to the peritoneal membrane which was entered to a depth of 1–2 mm. Direct trocar insertion was then performed. Results Direct trocar insertion was successful in 171 (92.9%) patients at the first attempt, and in 183 out of 184 (99.4%) by the third attempt. The approach was changed to upper quadrant entry in only one patient. The technique was faster and easier than upper quadrant entry. No major complication was observed. Conclusions Semi-open direct trocar insertion can be performed safely in the starting phase of laparoscopy.

Kallikreins are a group of serine proteases with diverse physiological functions. KLK13 (previously known as KLK-L4) is a novel kallikrein gene located on chromosome 19q13.4 and shares a high degree of homology with other kallikrein family members. Many kallikrein genes were found to be differentially expressed in various malignancies, and their regulation is controlled by steroid hormones in prostate and breast cancer cell lines. We studied the expression of KLK13 by quantitative reverse transcriptase–polymerase chain reaction in 173 patients with epithelial breast carcinoma. An optimal cutoff point equal to the 40th percentile was defined, based on the ability of KLK13 to predict disease-free survival. KLK13 values were then associated with other established prognostic factors and with disease-free survival and overall survival. Higher positivity for KLK13 expression was found in older, oestrogen receptor positive patients. In univariate analysis, KLK13 expression is a significant predictor of improved disease-free survival and overall survival (P

Purpose To evaluate the incidence of residual disease after additional surgery for positive/close margins and the impact on the rate of local and distant recurrence. Methods A retrospective analysis on 1339 patients treated for breast cancer with breast conserving-surgery and radiotherapy at a single Institution between 2000 and 2009 was performed. Results During primary surgery 526 patients (39.3%) underwent intraoperative re-excision. At the final pathological report, the margins were positive in 132 patients (9.9%) and close in 85 (6.3%). To obtain clear margins, 142 of these women underwent a second surgery; 35 patients with positive margins (27%) and 40 with close margins (47%) did not receive additional surgery because of different reasons (patients refusal, old age, comorbidity or for focal margin involvement). At second surgery, residual disease was found in 62.9% of patients with positive margins and in 55.5% of those with close margins. At a median follow-up time of 4 years, local recurrence (LR) rate was 2.9% for patients with clear margins, 5.2% ( p = 0.67) for patients with unresected close margins and 11.7% ( p = 0.003) for those with unresected positive margins. The HER-2 and the basal-like subtypes had the higher rate of LR and the luminal A the lowest. Conclusions A significantly higher LR rate was found only among patients with positive margins not receiving additional surgery, but not in those with unresected close margins. Positive margins are a strong predictor for LR and need re-excision that can be avoided for close margins.

Il ventaglio dei farmaci oggi disponibili per la prevenzione e la terapia dell’osteoporosi post-menopausale si e ampliato con l’introduzione del raloxifene, il piu studiato fra i compost i appartenenti alla classe dei SERM (selective estrogen receptor modulators). La caratteristica di questi farmaci e di modulare i recettori estrogenici in modo da agire come es trogen i o antiestrogeni a seconda del tessuto bersaglio. Le potenziali implicazioni del loro impiego a lungo termine per la salute della donna in menopausa sono quindi molteplici e complesse. Gli studi condotti in modelli animali ed in campo umano hanno infatti dimostrato come il raloxifene sia efficace nel preservare la densita minerale ossea, nel ridurre i marcatori di turnover osseo e l’incidenza di fratture vertebrali. L’effetto del raloxifene e sovrapponibile nei vari segmenti ossei, suggerendo una azione del farmaco sull’osso corticale e trabecolare, a differenza degli estrogeni che forniscono migliori risultati a livello vertebrale. Molto promettenti sono i dati relativi alla sicurezza oncologica del raloxifene, che ha dimostrato un effetto protettivo sul rischio di sviluppare una neoplasia ormonodipendente della mammella ed un effetto neutro, se non di protezione, sulla proliferazione dell’endometrio. Tali dati hanno costituito la base per iniziare studi di chemioprevenzione del carcinoma mammario in donne a rischio con questo preparato. Favorevole e anche l’effetto sul metabolismo lipidico, sebbene non siano ancora disponibili i dati sull’efficacia del preparato nel ridurre l’incidenza di patologie coronariche. D’altra parte il raloxifene non e di alcuna utilitya per alleviare i piu comuni problemi della carenza estrogenica in menopausa, come i sintomi vasomotori e la secchezza vaginale. Per le sue peculiarita di effetti ed allo stato attuale delle conoscenze il raloxifene ha quindi oggi un ben preciso posizionamento nell’ambito della prevenzione e della terapia dell’osteoporosi menopausale.

Nuclear receptors regulate target gene expression in response to steroid and thyroid hormones, retinoids, vitamin D and other ligands. These ligand-dependent transcription factors function by contacting various nuclear cooperating proteins, called coactivators and corepressors, which mediate local chromatin remodeling as well as communication with the basal transcriptional apparatus. Nuclear receptors and their coregulatory proteins play a role in cancer and other diseases, one leading example being the estrogen receptor pathway in breast cancer. Coregulators are often present in limiting amounts in cell nuclei and modifications of their level of expression and/or structure lead to alterations in nuclear receptor functioning, which may be as pronounced as a complete inversion of signaling, i.e. from stimulating to repressing certain genes in response to an identical stimulus. In addition, hemizygous knock-out of certain coactivator genes has been demonstrated to produce cancer-prone phenotypes in mice. Thus, assessment of coactivator and corepressor expression and structure in tumors may turn out to be essential to determine the role of nuclear receptors in cancer and to predict prognosis and response to therapy.

Epidemiological and biological data on HRT and breast cancer risk are reviewed. Some aspects deserve consideration. (1) The majority of epidemiological data have been gathered from populations where high estrogen doses (> or = 1.25 mg daily of conjugated estrogens) were used as first line therapy. (2) HRT does not increase the risk in overweight women, even in the series in which a risk increase (in longterm users) is found. This could be as a result of the fact that oral estrogens, through their metabolic and hepatocellular effects, reverse some biological features of obesity (e.g. increased insulin-like growth factor I activity and decreased sex hormone binding globulin level) which potentially increase breast cancer risk, so balancing the estrogen stimulation. (3) The progestin addition seems to increase the risk when the 19 nor-testosterone derivatives are used. These androgenic compounds contrast the metabolic and hepatocellular effects of oral estrogens. To sum up, the possibility does exist that even the longterm use of oral estrogens at the right ('low') dose, with the addition of a non-androgenic progestin, will be shown to be associated with a very limited breast cancer risk increase.

The demand for hormone replacement therapy (HRT) by women who enter the menopause is rapidly increasing in all developed countries. The concern that HRT may enhance morbidity and mortality from malignant diseases still limits the widespread adoption of hormonal treatments. Overall, epidemiological data on cancer incidence and HRT are reassuring, although long-term or inappropriate therapies may slightly increase the risk of developing malignant diseases. Many commercial hormonal compounds are currently available and the safest HRT regimen with regard to cancer risk must be identified. It is equally important that the best strategies for breast and endometrial surveillance in women commencing HRT be outlined, bearing in mind that the diffusion of hormonal therapies may be halted by unnecessary medical interventions.

The prognostic value of p53 protein accumulation in breast cancer, especially as detected by methods other than immunohistochemistry, has not been established unequivocally. A sensitive immunofluorometric assay of p53 protein employing DO-I and CM-I antibodies was used in this study to assay extracts of 171 breast carcinomas from northern Italy. p53 over-expression, demonstrated in 36 (21%) tumours, was associated with lack of oestrogen receptor (ER) expression but was not related to patient age, stage, lymph node status, tumour size, histologic type, grade or progesterone receptor (PR) expression status in contingency tables. An increased risk for cancer relapse of p53-positive patients compared to p53-negative patients was determined using multivariate Cox regression analysis, which also showed that p53 protein over-expression was an independent predictor of reduced disease-free survival in node-positive and ER + patients but not in node-negative or ER - individuals. The equivalent analysis for assessing the impact of p53 status on overall survival was not statistically significant, possibly reflecting the short patient follow-up. Our results suggest that an immunoassay of p53 protein, applicable to cytosolic extracts prepared for steroid hormone receptor analyses, may provide information for breast cancer prognosis.

The efficacy and tolerability of granisetron in the management of acute and delayed emesis was compared with that of a multiple antiemetic drug combination regimen, including metoclopramide, dexamethasone, lorazepam and orphenadrine. The trial was a randomized, cross-over study involving 111 patients with gynecological cancers undergoing chemotherapy with cisplatin. Granisetron was significantly more effective than the combination regimen during the first 24 h after chemotherapy; complete response, rates were 67 and 48%, respectively (p = 0.002). There was a significant reduction in the effectiveness of the combination during the second treatment cycle, compared with the first. In contrast, the efficacy of granisetron did not differ between the two cycles. The response rate during the 6 days after chemotherapy was 40.8% in both groups. At the end of the study, 55% of patients preferred granisetron and 23% preferred the combination (p < 0.001). Granisetron was well tolerated. The principal adverse event was headache, which was reported in 7% of patients. The results of this study confirm that granisetron is effective in the treatment of cisplatin-induced nausea and vomiting during the 24 h after chemotherapy.

A multicentric randomized trial was performed in premenopausal women with node-positive, estrogen-receptor-negative breast tumors to assess the potential superiority of alternating adjuvant chemotherapy over ‘standard’ CMF chemotherapy. Between January 1989 and June 1992, 107 patients were entered into the study and randomly allocated to receive either cyclophosphamide 100 mg/m2 per os on days 1-14, methotrexate 40 mg/m2 and 5-fluorouracil 600 mg/m2 intravenously (IV) on days 1, 8 (CMF), every 4 weeks for a total of 6 cycles, or the following regimens: CMF as previously; epidoxorubicin 75 mg/m2 IV on day I and vincristine 0.75 mg/m2 IV on days 1, 8 (EV); mitomycin-C 10 mg/m2 IV on day 1 and vindesine 2 mg/m2 IV on days 1, 8 (MVs). The three regimens were given every 4 weeks for a total of 6 cycles according to the following schedule: CMF, EV, MVs, CMF, EV, MVs. At a median follow up of 48 months (range 30-72), 40 patients have relapsed and 17 have died overall. More patients in the triple-combination arm ...

There are no validated predictors of benefit from anthracyclines. We compared cyclophosphamide, methotrexate, 5-fluorouracil (CMF), and epirubicin in different sequences with CMF alone in a phase III trial on operable breast cancers. Outcomes were analyzed in relation to tumor biological profiles to identify potential predictors of the efficacy of different treatments/drug combinations. Patients with N− or 1–3N+ tumors, were randomized to receive (a) epirubicin (4 cycles) followed by CMF (4 cycles); (b) CMF (4 cycles) followed by epirubicin (4 cycles), or (c) CMF (6 cycles) alone. Immunohistochemical assessments of estrogen (ER) and progesterone (PgR) receptors, HER2 and Ki67 were available for 705 patients (arm A/B/C: 276/269/160). Prognostic and predictive relevance was analyzed by log-rank tests and Cox models. Ki67 > 20 % and absent/low expression of ER and PgR were associated with worsen disease-free (DFS) and overall survival (OS). In patients with triple negative tumors (ER−, PgR−, HER2−), epirubicin-containing regimens yielded better DFS (HR 0.33, 95 % CI 0.17–0.62, P = 0.0007) and OS (HR 0.24, 95 % CI 0.10–0.57, P = 0.001) compared with CMF alone, whereas no differences were found in patients with HER2-positive (HER2+, ER−, PgR−) subtype. Treatment by subtype interaction (HER2-positive vs. others) was significant for DFS (χ2 = 6.72, P = 0.009). In triple unfavorable (ER−, PgR−, Ki67 > 20 %) tumors, the use of epirubicin yielded better DFS (HR 0.45,95 % CI 0.26–0.78, P = 0.005) and OS (HR 0.30, 95 % CI 0.15–0.63, P = 0.001). Epirubicin-containing regimens seem to be superior to CMF alone in patients with highly proliferating, triple negative or triple unfavorable tumors .

The study aims to analyze the association between body mass index (BMI) at time of diagnosis, breast cancer histopathologic features (tumor size, nuclear grade, estrogen and progesterone receptor (ER and PgR) and HER-2/neu expression, histological subtypes, Ki-67 index, lymphatic/vascular invasion, axillary nodes involvement) and incidence of different subtypes defined using hormone receptors and HER2/neu expression, according to menopausal status; to evaluate the impact of BMI on disease free survival (DFS) at multivariate analysis. A total of 2148 patients (592 premenopausal, 1556 postmenopausal) were classified into subgroups according to BMI distribution. High BMI was significantly associated with larger size tumor both in pre (p = 0.01) and postmenopausal women (p = 0.00). Obese premenopausal women showed worse histopathologic features (more metastatic axillary lymphnodes, p = 0.017 and presence of vascular invasion, p = 0.006) compared to under/normal weight group. Postmenopausal patients with BMI > 25 developed more frequently ER/PgR positive cancers (87% versus 75%, p 0.017), while no association was found in premenopausal women. We could not found any statistically significant correlation between breast cancer subtypes (luminal A, B, HER-2 and basal-like) and BMI both in pre and postmenopause. Higher BMI was significantly associated with a shorter DR-FS in postmenopausal women but the independent prognostic role of obesity was not confirmed in our analysis.