Luca Mariani

Increased incidence of lobular breast cancer in women treated with hormone replacement therapy: implications for diagnosis, surgical and medical treatment

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.

Antihormones in Prevention and Treatment of Breast Cancer

Abstract:  Breast cancer has the highest incidence of all types of cancer in women. Age and family history are the strongest risk factors, but sex hormones also play an important role, as demonstrated by epidemiological studies reporting a consistent association by reproductive personal history and breast cancer risk. The acceptability of preventive strategies by healthy women is closely related to their lifetime risk of developing breast cancer. Although surgical prevention may be considered in carriers of BRCA1/2 mutation, this option cannot be advocated for the majority of women whose risk is only moderately increased. In these women, chemoprevention with tamoxifen may reduce the incidence of estrogen receptor (ER)‐positive breast carcinoma by 30–50%. Other drugs such as raloxifen and aromatase inhibitors (AIs) are currently being tested in this setting. Tamoxifen has been the most successful hormonal treatment over the last 30 years and, until recently, the most active drug in endocrine‐sensitive breast cancer. In premenopausal breast cancer, tamoxifen still represents the therapy of choice, alone or in association with ovarian suppression. Conversely, in postmenopausal women it has been overtaken by third‐generation AIs as first‐choice drugs both in the adjuvant and metastatic settings. Many other issues, such as the optimal sequence between tamoxifen and AIs, the duration of AIs treatment, and the association of ovarian suppression and AIs in premenopausal patients still await the completion of randomized clinical trials. Furthermore, it is likely that treatment tailoring will be increased by the definition of patient subgroups that could derive larger benefits from AIs (progesterone receptor–negative, HER‐2‐overexpressing) or other new drugs.

Role of re-excision for positive and close resection margins in patients treated with breast-conserving surgery

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.

Hormonal Replacement Therapy after Gynaecological Cancer

Thousands of women are treated each year for gynaecological cancers; many of these are already in menopause, while other younger patients will go into early menopause due to surgery, chemotherapy and/or radiotherapy to the pelvic region. The aim of this paper is to review the biological and clinical evidence in favour and against hormone replacement therapy (HRT) use after gynaecological cancers. With the exception of breast and endometrial cancer, there is no biological evidence that HRT may increase the recurrence risk. In women with previous endometrial cancer, HRT use is not supported by univocal and conclusive data to formulate specific recommendations, whereas most authors suggest that oestrogens may be used after adequate information about risks and benefits. The use of HRT in breast cancer patients is, at present, considered contra-indicated, even if results of clinical trials are not concordant. Therapeutic non-hormonal alternatives may be proposed to these patients.

Oral contraceptives, salpingo-oophorectomy and hormone replacement therapy in BRCA1–2 mutation carriers

Germline mutations in BRCA1 or BRCA2 genes predispose to hereditary breast and ovarian cancers. The estimated lifetime risk of breast cancer in BRCA1 mutation carriers ranges from 50% to 80% while the estimated lifetime risk of ovarian cancer ranges from 20% to 65%. Although breast cancer risk is similar in women who inherit BRCA2 mutations the lifetime risk of ovarian cancer is approximately 20%. In the general population reproductive factors (such as parity age at menopause use of exogenous steroid hormones as contraceptives or after menopause) influence the risk of breast and ovarian cancer. In BRCA mutation carriers these issues are much more complicated and not completely understood. Nonetheless a growing number of data show that estrogens may modulate the risk of breast cancer in women with BRCA mutations. In these women estrogens may increase the probability of mutation due to enhanced proliferation and direct genotoxic effects of estrogen metabolites. Women carrying BRCA1 and BRCA2 mutations face difficult decisions during the reproductive life. In the younger age period they may be reluctant to using oral contraceptives (OCs) for the possible influence of these compounds on breast cancer incidence. After completion of childbearing they may be offered the option of prophylactic oophorectomy that is associated with a strong reduction of cancer risk but also with the early onset of menopausal symptoms and the long-term consequences of estrogen deprivation. (excerpt)

Hormone-replacement therapy and lobular cancers: new deals and old myths

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.”

Sonographic Pitfall in Endometriotic Ovarian Cysts: A Rare Case of a Spontaneous Sigmoid Colonic Perforation in a Nonpregnant Woman

Endometriosis involving the bowel has an estimated prevalence of 8% to 12% in women with endometriosis.1 We report a case of spontaneous sigmoid colonic perforation in a nonpregnant woman with endometriosis. A 42-year-old woman was referred to our institution for lower abdominal pain. She had a history of an ovarian endometrioma, which was laparoscopically treated in 2006. Her cancer antigen 125 level was 296 IU/L, and blood test results were normal. She had neither fever nor signs of bowel obstruction, peritonitis, infection, or vaginal discharge. Transvaginal sonography showed a left ovarian endometrioma (Figure 1, A and B), uterine adenomyosis with absence of the posterior sliding sign, and 2 rectal and sigmoid endometriotic nodules reaching the submucosal layer (Figure 1, C and D). No free fluid in the pouch of Douglas or anterior compartment lesions were noted. Colonoscopy results were negative. Surgical exploration confirmed a frozen pelvis, and purulent fluid appeared when the supposed left ovarian endometrioma was opened. The left ovary was indeed below the pelvic abscess and was macroscopically normal. Surgery resulted in the removal of the periovarian abscess, bilateral salpingectomy, and a rectosigmoid resection with a terminoterminal anastomosis. All of the visible endometriotic pelvic lesions were removed. Cultural swab results for the purulent fluid were positive for group A Streptococcus viridans. The patient was discharged on postoperative day 6 without any complications. Pathologic findings underscored the presence of endometriotic foci surrounding the periovarian abscess and the 2 wall nodules in the rectosigmoid specimen (15 cm).

Food habits and risk of endometrial cancer: development of an assessment questionnaire

Endometrial cancer is the most common gynecologic malignancy in the Western world and is strongly associated with obesity. Most of the studies investigating this relationship have been conducted by using Food Frequency Questionnaires, which carry several biases and are not easily applicable. At the Academic Department of Obstetrics Gynecology of Mauriziano Hospital, in Turin, we conducted a case-control study in which a food diary was administered to 142 women with endometrial cancer and to control healthy women with the aim of collecting eating habits of cases and controls, in terms of quantity and quality of nutrients during a period of three consecutive days. Our research revealed a real imbalance in the eating behavior between the two groups of patients. In particular in the group of cases typical diet was high in calories, proteins (especially of animal origin) and lipids. Our diary proved to be a simple innovative instrument to evaluate personal food habits of EC patients and as secondary endpoint our study succeeded in confirming the association between EC risk and the intake of certain nutrients. This paper highlights the importance of lifestyle in the prevention in endometrial cancer and represents a starting point to further investigate the theme. Annamaria F1*, Elisabetta DS1, Martina B1, Luca F1, Mariani L1, Daniela V3, Lidia R3 and Guido M2 1Department of Obstetrics and Gynecology, Mauriziano Hospital, Italy 2Department of Surgical Sciences, University of Turin, Italy 3Division of Dietetics, Mauriziano Hospital, Italy Annamaria F, et al., Journal of Gynecological Oncology Remedy Publications LLC. 2020 | Volume 3 | Issue 1 | Article 1022 2 Materials and Methods Patient’s selection A case-control study was conducted at the Academic Department of Obstetrics Gynecology, Mauriziano Hospital, and Torino. Patients diagnosed and treated for Endometrial Cancer (EC), endometrioid histology, were enclosed. Exclusion criteria were as follows: (1) final diagnosis of endometrial hyperplasia or EC different from endometrioid histology, (2) any qualitative or quantitative change to their eating habits until the diagnosis of cancer, (3) presence of synchronous solid cancer, (4) diagnosis of family cancer syndrome (Lynch syndrome), and (5) incomplete data. Controls were recruited among patients treated for non-neoplastic diseases of the pelvis (Clinic of menopause, Clinic of urodynamics and uro-gynecology and Service of gynecological ultrasound at Mauriziano Hospital). Women with previous hysterectomy or patients suffering from any disease requiring changes in their diet were excluded from the controls. History of each patient was collected including age at diagnosis/ present age for the controls, Body Mass Index (BMI), number of pregnancies, age at menarche and at menopause, smoke, any current or previous hormone replacement therapy, diagnosis of dyslipidemia, diabetes mellitus, hypertension, thyroid diseases, treatment with tamoxifen, radiotherapy for previous cancers, and family history of malignancies. Ethics committee approval was obtained and all women included in the study gave written informed consent for data collection with research purpose. Food diary A food diary was prepared by the Division of Dietetics of the Mauriziano Hospital with the aim of collecting eating habits of cases and controls, in terms of quantity and quality of nutrients. The evaluation of food habits was conducted by the analysis of the intake of food and drinks during a period of three consecutive days, including at least one public holiday, to assess any changes in food at weekends compared to weekdays. Example of the three-day food diary is reported in Table 1. To get an appropriate food history of the patients, the interviews, lasting about 30 min to 40 min each, were conducted under the supervision of the same operator, following a clear and precise set list, developed point by point. Patients were asked about their habits in terms of mealtimes including snacks. They were asked to write down every type of food and all beverages (including tea, coffee and water) they consumed during the day, indicating the amount of each food they consumed. The quantity of food was expressed through conventional measures (g, l, ml, etc.) or most common measures used in cooking (glass, cup, plate, spoon, teaspoon, etc.). To simplify the evaluation of the size of the portions, we have depicted examples of some food in different sizes (e.g. small, medium and large portion) in the last pages of the food diary. Moreover patients were asked to report the brand and the exact name of the industrial cooking products to note all the information indicated on the label. They were supposed to note in the appropriate column of the diary all seasonings added, indicating the amount and the unit of measure. Seasoning was considered any kind of ingredient added to a prepared food (parmesan cheese on pasta, sugar in coffee, etc.). They were moreover asked to note if they used any supplements (vitamin and mineral supplements) during the day. In addition, the patients were asked to give information regarding any possible physical exercise made during the day, indicating the type (e.g. walking) and duration (e.g. 30 min) of it. WinFood software Once the questionnaires were completed, the data were entered into the software release 2.8.0 WinFood for automatic data processing. The software elaborated a quantitative assessment of patients food supply in terms of calories, differentiating among various nutrients, based on the statements of each patient about the kind and quantity of foods they said they had during the three days (proper meals and snacks). We evaluated the food consumed by the patients by consulting an archive of about 2200 different types of food with 100 different nutritional components for each food, including 250 types of frozen food, 200 different recipes reporting the different ingredients and methods of food preparation and about 400 special foods (gluten-free, protein-free, cholesterol-free, sugar-free) showing the compositions of nutrition labels. For each food our software reported the caloric content, the percentage of carbohydrates, fats and calories (per 100 g of raw food), etc. referring to the Tables of Food Composition of the National Institute of Nutrition and Food Composition Database for Epidemiological Studies in Italy of the European Institute of Oncology [9]. The software calculated all the data and obtained an assessment of usual dietary intakes of the patients, in terms of absolute amount of food per day and the percentage of single nutrients and food components. Statistics The descriptive variables relating to our groups of study cases and controls were represented in contingency tables with absolute numbers and percentages for categorical variables and average values for continuous variables. We calculated Odds Ratios (ORs) (number of cases in which the phenomenon occurred)/(number of cases in which the phenomenon did not occur): as a dichotomous scale, events were represented by the cases (patient suffering from EC) and controls indicate no events. The strength of association and odds ratios were determined by univariate logistic regression analysis which selected variables differentially expressed in our cases and controls. The covariates (as regards the nutritive components of the diet) were initially introduced into the logistic model as continuous variables. The variables for which there was a significant difference level with α=0.05 between cases and controls were subjected to correction for possible confounders and values were dichotomized as < or ≥ the median. We produced then ORs, 95% confidence intervals and corresponding P values, corrected by introducing in our multivariate models as covariates: age (continuous numeric value), previous use of hormone replacement therapy (yes or no), BMI (continuous numeric value). The variables (diet nutrients) that were not significantly different between cases and controls have been introduced in the models as a continuous numeric variables and their values of OR were considered risk values for each unit increase of the unit of measure for the substance in the group of cases. SPSS softwarerelease 17 (Chicago, IL, SPSS Inc., USA) was used for the analysis. Results We enrolled a total of 142 women, recruited during a seven-month period (November 2014 to May 2015). The case group included 61 women (43%) aged between 43 and 83 (average age 53.3). The control group included 81 women (57%) with similar age of the cases. The clinical characteristics of all the patients are reported in Table 2. The analysis of the clinical characteristics in the two groups showed statistically significant differences for the following variables: BMI, previous HRT, BMI, and hypertension. The questionnaire resulted easy to administer and to understand, under the supervision Annamaria F, et al., Journal of Gynecological Oncology Remedy Publications LLC. 2020 | Volume 3 | Issue 1 | Article 1022 3 of a dedicated operator. The registration of the amount of food each patient had during the day was the most delicate point of this type of interview. The depicted examples of some food in different sizes (e.g. small, medium and large portion) in the last pages of the food diary were helpful to bring the dosing closer to the real consumption. Collecting all the data, we were able to depict the eating behavior of all cases and controls and, thanks to the particular structure of our diary; we easily collected all the answers. WinFood allowed us to make, with easily overlapping procedures, the Food Survey and the Diet Survey. In the comparative univariate analysis of macroand micro-nutrients introduced with food in the group of cases and controls, we observed a statistically significant difference between the two groups of patients about the nutrients reported in Table 3. The univariate analysis of macro and micronutrients

Androgen Receptor and Breast Cancer

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.