Lobular Intraepithelial Neoplasia Research Articles

Lobular intraepithelial neoplasia: Outcomes and optimal management.

Lobular neoplasia is a term encompassing both atypical lobular hyperplasia and lobular carcinoma in situ. These pathological findings are of uncertain malignant potential and predispose to a higher lifetime risk of breast cancer. Debate surrounds the management of such lesions, with the rationale for diagnostic excision based on the possibility of upgrading to malignancy. In this study, we report the upgrade rate of these lesions and risk of subsequent development of breast cancer. This is a retrospective review of a prospectively maintained data base of all biopsies of breast screening-detected abnormalities in a single Irish breast-screening unit. We included all patients with lobular neoplasia on core needle biopsy who underwent diagnostic excision from 2005 to 2012. We excluded those who had concurrent high-risk lesions on biopsy. End points included upgrade rate and subsequent diagnosis of malignancy on follow-up. During the study period, 66 patients met criteria for inclusion, with a mean age of 53.74years. Upgrade rate following excision was 13.64% (n=9/66). Of those not upgraded, 7.02% (n=4/57) were subsequently diagnosed with malignancy. Median time to diagnosis was 59.61months (range=10.5-124.4). There is a significant rate of upgrade following diagnostic excision of lobular neoplasia, supporting the practice of diagnostic excision. There is an increased lifetime risk of breast cancer for women with a diagnosis of lobular neoplasia, with many of these cancers occurring outside the standard five-year monitoring period, suggesting a potential benefit in extending surveillance.

Inter-observer reproducibility of classical lobular neoplasia (B3 lesions) in preoperative breast biopsies: a study of the Swiss Working Group of breast and gynecopathologists

PurposeClassical type of lobular neoplasia (LN) spans a spectrum of disease, including atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS), classical lobular neoplasia (LN), and the three-tiered classification of lobular intraepithelial neoplasia (LIN-1, -2, -3). This study addressed inter-observer variability of classical lobular neoplasias (LN) (B3 lesions) in preoperative breast biopsies among breast and gynecopathologistsMethodsA retrospective, observational, cross-sectional study was conducted. 40 preoperative digital images of breast core/vacuum biopsies were analyzed by eight experienced breast- and gynecopathologists. Evaluation criteria were ALH, LCIS, LN classic, LIN-1, LIN-2, LIN-3, focal B3 (one focus), extensive B3 (> one focus). Kappa-index and Chi-square tests were used for statistics. Digital scanned slides were provided to each participant. Agreement between the categories was defined as at least six of eight (cut-off 75%) concordant diagnoses.ResultsThe highest agreement between eight pathologists was reached using the category lobular neoplasia (LN, classical), 26/40 (65%) cases were diagnosed as such. Agreements in other categories was low or poor: 12/40 (30%) (ALH), 9/40 (22%) (LCIS), 8/40 (20%) (LIN-1), 8/40 (20%) (focal B3), 3/40 (7.5%) (LIN-2), and 2/40 (5%) (extensive B3). Chi-square-test (classical LN versus the other nomenclatures) was significant (p = 0.001137).ConclusionOur data suggest that among Swiss breast pathologists, the most reproducible diagnosis for B3 lobular lesions is the category of classical LN. These data further support lack of consistent data in retrospective studies using different terminologies. Validation of reproducible nomenclature is warranted in further studies. This information is useful especially in view of retro- and prospective data analysis with different diagnostic categories.

Role of one-pass breast lesion excision system in complete excision of high-risk breast lesions with atypia expressed as clusters of microcalcifications.

To assess the role of the breast lesion excision system (BLES) in complete removal of clusters of microcalcifications found on mammogram proved histologically to be high-risk lesions with cell atypia. Three hundred ninety-four consecutive women (mean age 58.5years, range 39-78years) with 400 clusters of suspicious microcalcifications underwent stereotactic biopsy using the intact BLES device between January 2014 and January 2016. All cases proved histologically to be high-risk lesions were subsequently assessed for complete removal. The underestimation rate was also assessed. Thirty-eight out of 400 (9.5%) lesions were high-risk lesions with atypia with mean size 7.63mm (st. dev. = 4.03mm) which was within the size that the BLES needle can excise (20mm). Four (10.5%) papillomas with atypia, 14 (36.8%) cases with flat epithelial atypia (FEA), 10 (26.3%) cases with lobular intraepithelial neoplasia (LIN-LIN 1, LIN 2), 8 (21.2%) with atypical ductal hyperplasia (ADH) and 2 (5.3%) cases with mucocele-like lesions (MLL) with atypia were found. Twenty-nine out of 38 lesions had subsequent surgery. Complete excision was achieved in 23/29 lesions (79.3%). No underestimation was found. Two-year mammographic stability was found in all lesions. Non-parametric statistical analysis showed no other significant predictive factor for complete excision apart from the distance of the lesions from the specimen margins (p = 0.031 Mann-Whitney test). One-pass BLES intact biopsy technique is a safe method of complete removal of high-risk atypical lesions with high accuracy rates for certain histologies and could be potentially used as an alternative excision method to diagnostic surgery in selected cases. • Breast lesion excision system (BLES) is an image-guided biopsy technique that uses radiofrequency to remove an intact piece of tissue including the target breast neoplasm. • Breast lesion excision system (BLES) under stereotactic guidance is able to accurately biopsy high-risk breast lesions expressed mammographically as clusters of suspicious microcalcifications. • BLES under stereotactic guidance is an accurate technique for en bloc excision of selected cases of small clusters of suspicious microcalcifications proved to be high-risk lesions with histopathologically disease-free margins of excision.

A new risk stratification score for the management of ultrasound-detected B3 breast lesions.

To develop a predictive scoring system for ultrasound-detected B3 lesions at ultrasound-guided core needle biopsy (US-CNB). A total of 2724 consecutive US-CNBs performed in our Institution (January 2011 to December 2014) were retrospectively reviewed. Inclusion criteria were as follows: (a) histopathological examination of the entire lesion or (b) availability of radiologic follow-up (FUP) ≥24months. Patient- and lesion-related variables-patients' age, lesion consistency, lesion size, vascularization, BI-RADS category, and US-CNB result-were analyzed. Positive predictive values (PPVs) for malignancy were calculated correlating US-CNB results with excision histology or FUP. A scoring system for underlying malignancy was developed using risk factors weighting. A total of 102 B3 lesions were included: 27 atypical ductal hyperplasia (26.5%), 5 lobular intraepithelial neoplasia (4.9%), 32 radial scar (31.4%), 37 papillary lesions (36.3%), and 1 fibroepithelial lesion (0.9%). Surgery was performed on 71/102 (69.6%) lesions, and 22/71 were malignant; the remaining 31/102 lesions (30.4%) were unchanged at FUP. The overall PPV for malignancy was 21.6%. Patients' age (odds ratio [OR]=3.63, P=0.008), lesion consistency (OR=5.96, P=0.001), BI-RADS category (OR=17.52, P<0.001), and CNB result (OR=3.6, P=0.008) were associated with a higher risk of malignancy underestimation and selected as risk factors in the score definition. Two risk groups were identified: low (0-2 points) and high risk (3-5 points), with significantly different risk of malignancy underestimation (8.0% vs 59.3%, P<0.001). The proposed score helps to predict the risk of malignancy underestimation and choose the management of B3 lesions at US-CNB.

Malignancy rates of B3-lesions in breast magnetic resonance imaging \u2013 do all lesions have to be excised?

BackgroundApproximately 10% of all MRI-guided vacuum-assisted breast biopsies (MR-VAB) are histologically classified as B3 lesions. In most of these cases surgical excision is recommended. The aim of our study was to evaluate the malignancy rates of different B3 lesions which are visible on MRI to allow a lesion-adapted recommendation of further procedure.MethodsRetrospective analysis of 572 consecutive MR-VAB was performed. Inclusion criteria were a representative (=successful) MR-VAB, histologic diagnosis of a B3 lesion and either the existence of a definite histology after surgical excision or proof of stability or regression of the lesion on follow-up MRI. Malignancy rates were evaluated for different histologies of B3 lesions. Lesion size and lesion morphology (mass/non-mass enhancement) on MRI were correlated with malignancy.ResultsOf all MR-VAB 43 lesions fulfilled the inclusion criteria. The malignancy rate of those B3 lesions was 23.3% (10/43). The highest malignancy rate was found in atypical ductal hyperplasia (ADH) lesions (50.0%; 4/8), 33.3% (2/6) in flat epithelial atypia (FEA), 28.6% (2/7) in lobular intraepithelial neoplasia (LIN) and 12.5% (2/16) in papillary lesions (PL). All 6 complex sclerosing lesions were benign. Mass findings were significantly more frequently malignant (31.3%, 10/32; p < 0.05) than non-mass findings (0/11). Small lesions measuring 5–10 mm were most often malignant (35.0%; 7/20). All large lesions (> 20 mm) were not malignant (0/10). Intermediate sized lesions (11–20 mm) turned out to be malignant in 23.1% (3/13).ConclusionsThe malignancy rate of B3 lesions which were diagnosed after MR-VAB was 23.3%. ADH, FEA and LIN showed considerable malignancy rates (50%, 33% and 29%) and should therefore undergo surgical excision. None of the cases, which were diagnosed as radial scars, non-mass enhancement or larger lesions (> 20 mm) were malignant. Here, a follow-up MRI seems to be advisable to avoid unnecessary operations.Trial registrationRetrospective study design, waived by the IRB.

Factors Affecting Concordance between Radiological and Histological Findings in Invasive Lobular Carcinoma - Experience from a National Cancer Centre

Background: Invasive lobular carcinoma (ILC) is characterized by an infiltrative discohesive growth pattern, making it difficult to accurately assess both clinically and by imaging studies. Despite favourable biological characteristics, challenges remain in the surgical treatment of ILC. We aimed to evaluate radiology/histology concordance and identify histological and biological parameters on core biopsies that may predict final tumour histology and guide surgical treatment decisions. Patients and Methods: The radiology and histology reports for all newly diagnosed cases of ILC were analysed. The biopsy and resection histological slides for all the surgical cases were reviewed. Results: 75 new cases of ILC were diagnosed over a 2-year period. 48 patients underwent surgery of whom 25% had 2 or more operations. There was discordance between radiological and histological tumour focality and tumour size in 35 and 40%, respectively. The correlation between radiology/histology discordance and E-cadherin expression was statistically significant. However, the correlation between radiology/histology discordance and menopausal status, breast density, pattern of invasion, presence of lobular intraepithelial neoplasia (LIN), hormonal status, and Ki67 were not statistically significant. Conclusion: Histological and biological factors in ILC, with the exception of E-cadherin expression, do not seem to play a significant role in radiology/histology discordance. However, larger studies are needed to further corroborate these findings.

Faut-il opérer toutes les néoplasies lobulaires intraépithéliales diagnostiquées par biopsie mammaire radioguidée ?

Lobular intraepithelial neoplasia (LIN) diagnosed on image-guided biopsy may be associated with an undiagnosed cancer. This is called under-diagnosis. The consequence is that management of these lesions is often surgical. But many surgeries finally are unnecessary. The aim of our study was to define criteria to avoid unnecessary surgery. This is a single-center, retrospective after a database collected prospectively study. Fourteen thousand biopsies were analyzed, including 456diagnosed NLI. Under-diagnosis rates were analyzed according to many criteria. The average duration of following was 45months. For atypical lobular hyperplasia (ALH), we obtained 7.6% under-diagnosis and combining several criteria, we got a low risk of cancer (2%). For LCIS, this rate was 23% and any low-risk group could be identified. ALH with calcifications≤20mm, without any atypical lesion associated, histologically focal and whose removal is representative may be safely observed. For other LIN, surgery remains indicated.

Abstract P1-01-08: An impending avalanche-breast cancer among women ≥ 90 years of age

Abstract INTRODUCTION: Pubmed database shows no study on pathological features of breast carcinoma in extremely old women (≥90 years). The data post 1980s is limited due to the definition of such age limit as "older than 75". This study redefines age extreme in breast pathology to better correlate with current patient demographics, and provides characteristics of breast cancer in this population. Little information exists about the breast cancer in extremely old women. This investigation elucidates the growing number of breast cancer diagnoses in extremely old women (≥90 years) in a single institution in 2000s. MATERIALS AND METHODS: The database of Yale University Department of Pathology was searched for the terms: "breast carcinoma," "age ≥90" for the past 15 years. Clinicopathologic features of the cases that fit the criteria were studied. RESULTS: A total of 135 patients (134 female; 1 male) aged ≥90 years were identified with a diagnosis of infiltrating carcinoma. A surge in breast cancer diagnoses among elderly patients was noted in 2000s compared to the earlier decade. Only 10 cases were diagnosed between 1990 and 1999 (one case/year) compared to 125 cases diagnosed between 2000 and 2015 (8.3 cases/year). Of these 135 patients, 117 had infiltrating ductal carcinoma (IDC); 16 had infiltrating lobular carcinoma (ILC),1 had pure squamous cell carcinoma. One patient had IDC and ILC ipsilaterally, while another had bilateral IDC. The median age was 92 (range: 90-107), median tumor size was 2.0 cm (range: 0.2-13.0), and the median modified Bloom &amp; Richardson score was 6 (range: 3-9). Among the 117 IDCs, 11 had mucinous, 6 had apocrine, 1 had medullary, 1 had cribriform differentiation. Ductal intraepithelial neoplasia (DCIS) was present in 46% of the cases, while lobular intraepithelial neoplasia (LCIS) was identified in 8% of the cases. CONCLUSIONS: Our data shows an increasing number of breast carcinomas diagnosed among patients ≥90 years of age with a morphological distribution similar to other age groups. This increased frequency is particularly notable in the last 15 years compared to 1990s. While increased life expectancy is a factor, better delivery of screening to elderly patients and patient awareness are important additional contributors to this increase. Extremely old women particularly those in good health may potentially benefit from breast cancer screening. As the number of substantially older patients with breast cancer increases, we have to be prepared to manage the disease in this population. Further studies are warranted to elucidate the frequency of breast cancer in extremely old women and the optimal management that would probably have to be individualized to the patients' health status. Citation Format: Ozerdem U, Tavassoli FA. An impending avalanche-breast cancer among women ≥ 90 years of age. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-01-08.

Eliminating “ductal carcinoma in situ” and “lobular carcinoma in situ” (DCIS and LCIS) terminology in clinical breast practice: The cognitive psychology point of view

There is evidence from the literature that the terms “ductal carcinoma in situ” and “lobular carcinoma in situ” (DCIS and LCIS) should be eliminated in clinical breast cancer practice and replaced with the new “ductal intraepithelial neoplasia” (DIN) and “lobular intraepithelial neoplasia” (LIN) terminology. The main purpose of the present article is to expand on this argument from a cognitive psychology perspective and offer suggestions for further research, emphasizing how the elimination of the term “carcinoma” in “in situ” breast cancer diagnoses has the potential to reduce both patient and health care professional confusion and misperceptions that are often associated with the DCIS and LCIS diagnoses, as well as limit the adverse psychological effects of women receiving a DCIS or LCIS diagnosis. We comment on the recent peer-reviewed literature on the clinical implications and psychological consequences for breast cancer patients receiving a DCIS or LCIS diagnosis and we use a cognitive perspective to offer new insight into the benefits of embracing the new DIN and LIN terminology. Using cognitive psychology and cognitive science in general, as a foundation, further research is advocated in order to yield data in support of changing the terminology and therefore, offer a chance to significantly improve the lives and psychological sequelae of women facing such a diagnosis.Typology: Controversies/Short Commentary

Erratum to: Underestimation rate of lobular intraepithelial neoplasia in vacuum-assisted breast biopsy

Due to a transcription error, the author names in the article entitled “Underestimation rate of lobular intraepithelial neoplasia in vacuum-assisted breast biopsy”, were incorrectly published. We would like to clarify that the author list should read as follows: Meroni S, Bozzini AC, Pruneri G,Moscovici OC,Maisonneuve P, Menna S, Penco S, Meneghetti L, Renne G, Cassano E. We apologise for this error in the author list; the error was multifactorial.

Underestimation rate of lobular intraepithelial neoplasia in vacuum-assisted breast biopsy.

To evaluate the underestimation rate and clinical relevance of lobular neoplasia in vacuum-assisted breast biopsy (VABB). A total of 161 cases of LN were retrieved from 6,435 VABB. The histological diagnosis was ALH (atypical lobular hyperplasia) in 80 patients, LCIS (lobular carcinoma in situ) in 69 patients and PLCIS (pleomorphic lobular carcinoma in situ) in 12 patients. Seventy-six patients were operated on within 2 years after VABB and 85 were clinically and radiologically monitored. The mean follow-up was 5.2 years, and the prevalence of malignancy was evaluated in the group of 85 patients. The clinico-pathological characteristics significantly favouring surgery were larger lesions, occurrence of a residual lesion following VABB and histological LCIS and PLCIS subtypes. The VABB underestimation rate as compared to surgery was 7.1% for ALH, 12% for LCIS and 50% for PLCIS. Overall, 11 of the 148 patients included in this survival analysis developed an ipsilateral tumour. Although obtained retrospectively in a relatively small series of patients, our data suggest that only patients with a diagnosis of PLCIS in VABB should be treated with surgery, whereas patients with ALH and LCIS could be monitored by clinical and radiological examinations. • The treatment of ALH and LCIS in VABB is still debated • Some authors favour radical treatment and others a more conservative approach • Only patients with PLCIS in VABB should be treated by surgery.

Erratum to: Lobular intraepithelial neoplasia arising within breast fibroadenoma

After publication of our article [1], it has come to our attention that Professor Cesare Formisano was incorrectly excluded from the list of authors in the initial version of this manuscript. We publish this correction to update the author list to include Professor Formisano as an author. The correct author list is as follows:

Carcinoma in situ

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Lobular intraepithelial neoplasia arising within breast fibroadenoma

BackgroundFibroadenomas are the second most common breast pathology occurring in young women under the age of 35 years old. Fibroadenomas can be classified as simple or complex according to histological features. Complex fibroadenomas differ from simple fibroadenomas because of the presence of cysts (3 mm), sclerosing adenosis, epithelial calcifications, or papillary apocrine changes. Most fibroadenomas are clinically identifiable. In 25% of cases, fibroadenomas are non-palpable and are diagnosed with mammography and ultrasound. Differential diagnosis with well differentiated breast cancer is often necessary, particularly with medullary or mucinous tumors. Calcification findings within fibroadenomas by mammogram have to be investigated. The age of a lump is usually reflected by calcifications. Microcalcification can hide foci of carcinoma in situ when they are small, branching type, and heterogeneous. However, many morphological possibilities may not be reliable for deciding whether a certain calcification is the product of a malignant or a benign process. From a radiological point of view, fibroadenomas containing foci of carcinoma in situ can be indistinguishable from benign lesions, even if the incidence of carcinoma within fibroadenomas is estimated as 0.1–0.3%, and it could be a long-term risk factor for invasive breast cancer.Case presentationA 44-year-old woman presented with a 1.5-cm palpable, smooth, mobile lump in the lower-inner quadrant of her right breast. Standard mediolateral oblique and craniocaudal mammograms showed a cluster of eccentric popcorn-like calcifications within the fibroadenoma. After lumpectomy, a definitive histological examination confirmed the intra-operative diagnosis of a benign mass. However, lobular intraepithelial neoplasia foci were found, surrounded by atypical lobular hyperplasia.ConclusionsThe possibility of an old benign breast lump might be supported by fine needle aspiration biopsy or core biopsy before initiating follow-up. According to our experience, when patients are older than 40 years and have a familial history of breast cancer, we prefer to carry out lumpectomy with follow up to avoid the risk of underestimation in situ foci within the lump.

Metformin effects on cancer adjacent breast preneoplasia in a randomized pre-surgical trial.

1517 Background: Metformin has been associated with a significant reduction in cancer incidence and mortality in diabetic patients, including positive results in breast cancer. In a window-of-opportunity trial in 200 non-diabetic women with breast cancer, we showed a heterogeneous effect of metformin on breast cancer proliferation (Ki-67) depending on insulin resistance, with a trend to a decreased proliferation in women with insulin resistance (HOMA&gt;2.8) and an opposite trend in women with normal insulin sensitivity (Bonanni et al. JCO 2012). Here we determined whether metformin has antiproliferative effects on adjacent lobular or ductal intraepithelial neoplasia (LIN or DIN) and on distant ductal hyperplasia and whether these effects are different according to specific host and tumor characteristics. Methods: Baseline core biopsies of tumor tissue and blood samples were obtained at study entry and before surgery for pre/post-treatment comparisons. Patients were randomly assigned to metformin, 850 mg or placebo once daily on day 1-3 followed by two 850 mg tablets from day 4 to 28. At surgery, three to five specimens of adjacent (≤1 cm from the tumor) and distant (&gt;1 cm from the tumor) grossly normal tissue were obtained to assess systematically the prevalence, grade and proliferation of LIN or DIN and ductal hyperplasia. Results: Overall, the prevalence of LIN, DIN and ductal hyperplasia was 4.5% (9/200), 66.5% (133/200) and 35% (69/200), respectively. Ki-67 was positively associated with DIN grade (p-trend&lt;0.001). The median (and IQ range) Ki-67 LI distribution of LIN+DIN was 12% (8-20) and 10% (6-22) on metformin and placebo, respectively (p=0.6). Compared with placebo, metformin exhibited different effects on Ki-67 according to DIN grade (delta=+4.4% in DIN1 vs -27.9% in DIN3, p-interaction=0.09), cancer HER2 status (median 12% vs. 10% in HER2-ve; 28% vs. 35% in HER2+ve, p=0.03), abdominal circumference (p=0.08), and BMI (p=0.17). Conclusions: Metformin had no overall significant effect on breast preneoplasia proliferation but exhibited heterogeneous effects depending upon host and tumor characteristics. The significant reduction of HER2+ve, DIN3 proliferation under metformin warrants further studies. Clinical trial information: 16493703.

DCIS and LCIS are confusing and outdated terms. They should be abandoned in favor of ductal intraepithelial neoplasia (DIN) and lobular intraepithelial neoplasia (LIN)

The terms ductal and lobular intraepithelial neoplasia (DIN and LIN) were introduced by Tavossoli 15 years ago, who proposed they should replace, respectively, ductal and lobular carcinoma in situ (DCIS and LCIS). This proposal has been slowly gaining ground. We argue that DCIS and LCIS should now be definitively abandoned. Bringing together ‘in situ’ and other entities into the simpler and more logical DIN/LIN framework–as has been done with intraepithelial neoplasias of cervix, vagina, vulva, prostate, and pancreas–would eliminate the artificial and illogical distinctions between ‘not cancers’ (e.g. flat epithelial atypia, atypical ductal hyperplasia–now classified as low grade DIN) and ‘cancers’ (e.g. DCIS–now considered medium–high grade DIN). Elimination of the term ‘carcinoma’ from entities that cannot metastasize will reduce confusion among health professionals and patients, and contribute to reducing the risk of overtreatment, as well as reducing adverse psychological reactions in patients.

Néoplasie lobulaire intra-épithéliale de type pléomorphe : analyse clinique, histologique et pronostique d’une série de neuf cas

Retrospective clinical, histological and prognostic study of nine cases of lobular intraepithelial neoplasia in its pleomorphic subtype (LIN-P). Analysis of our center database with selection of nine cases of LIN-P from 140 files of patients who underwent surgical excision with a final diagnosis of LIN (2000 to 2011). The medical files were reviewed with a re-analysis of the mammograms and the histological slides. The outcome of the patients was also analyzed according to their clinical and operative data. The average age at diagnosis was 63 years (later than common LIN [LIN-C]). All patients had mammograms classified ACR 4 and 5, mainly due to the presence of microcalcifications (seven cases) with a case of opacity associated with microcalcifications, and two other cases with only isolated opacities. The preoperative diagnosis of these lesions was difficult: five cases on nine core needle biopsies were reviewed and reclassified LIN-P after finding the presence of LIN-P on the surgical specimen. Associated invasive lesions were found in 55% of core needle biopsy and in 33% of cases of surgical resection specimen. The treatment included a wide surgical excision (five lumpectomies and four mastectomies with a patient who had two lumpectomies) with margins of more than 2mm: we noted a recurrence of LIN-P only in one case where margins were very close (1mm). The analysis of our cases confirms that LIN-P if they probably share the same origin as the LIN-C represent a particular form constituting a true precancerous condition warranting at least a wide surgical excision.

Breast ductal lavage for biomarker assessment in high risk women: rationale, design and methodology of a randomized phase II clinical trial with nimesulide, simvastatin and placebo

BackgroundDespite positive results from large phase III clinical trials proved that it is possible to prevent estrogen-responsive breast cancers with selective estrogen receptor modulators and aromatase inhibitors, no significant results have been reached so far to prevent hormone non-responsive tumors. The Ductal Lavage (DL) procedure offers a minimally invasive method to obtain breast epithelial cells from the ductal system for cytopathologic analysis. Several studies with long-term follow-up have shown that women with atypical hyperplasia have an elevated risk of developing breast cancer. The objective of the proposed trial is to assess the efficacy and safety of a daily administration of nimesulide or simvastatin in women at higher risk for breast cancer, focused particularly on hormone non-responsive tumor risk. The primary endpoint is the change in prevalence of atypical cells and cell proliferation (measured by Ki67) in DL or fine needle aspirate samples, after 12 months of treatment and 12 months after treatment cessation.Methods-DesignFrom 2005 to 2011, 150 women with a history of estrogen receptor negative ductal intraepithelial neoplasia or lobular intraepithelial neoplasia or atypical hyperplasia, or unaffected subjects carrying a mutation of BRCA1 or with a probability of mutation >10% (according to BRCAPRO) were randomized to receive nimesulide 100mg/day versus simvastatin 20mg/day versus placebo for one year followed by a second year of follow-up.DiscussionThis is the first randomized placebo controlled trial to evaluate the role of DL to study surrogate endpoints biomarkers and the effects of these drugs on breast carcinogenesis. In 2007 the European Medicines Agency limited the use of systemic formulations of nimesulide to 15 days. According to the European Institute of Oncology Ethics Committee communication, we are now performing an even more careful monitoring of the study participants. Preliminary results showed that DL is a feasible procedure, the treatment is well tolerated and the safety blood tests do not show any significant liver toxicity. There is an urgent need to confirm in the clinical setting the potential efficacy of other compounds in contrasting hormone non-responsive breast cancer. This paper is focused on the methodology and operational aspects of the clinical trial.Trial Registration(ClinicalTrials.gov Identifier: NCT01500577)

Abstract SS-01: Metformin effects on breast preneoplasia

Abstract Background: Metformin has been associated with a significant reduction in cancer incidence and mortality in diabetic patients relative to other antidiabetic drugs, including positive results specifically in breast cancer. In a recent window-of-opportunity trial in 200 non-diabetic women with breast cancer, we showed a heterogeneous effect of metformin on breast cancer proliferation (Ki-67 labeling index) depending on insulin resistance, with a trend to a decreased proliferation in women with insulin resistance (HOMA&amp;gt;2.8) and an opposite trend in women with normal insulin sensitivity (Bonanni et al. JCO 30:2593, 2012). Here we performed an exploratory study to determine whether metformin has antiproliferative effects on adjacent lobular or ductal intraepithelial neoplasia (LIN or DIN) and on distant ductal hyperplasia and whether these effects are different according to specific host and tumor characteristics. Previous studies showed that Ki-67 LI in atypical lesions predicts subsequent breast cancer risk. Methods: Baseline core biopsies of tumor tissue and blood samples were obtained at study entry and before surgery for pre/post-treatment comparisons. Patients were randomly assigned to metformin, 850 mg or placebo once daily on day 1-3 followed by two 850 mg tablets from day 4 to 28. At the time of surgical removal of the tumor, three to five specimens of adjacent (≥1 cm from the tumor) and distant (&amp;gt;1 cm from the tumor) grossly normal tissue (i.e., the surgical margins of quadrantectomy or lumpectomy, or the grossly free quadrants from mastectomy specimens) were obtained to assess systematically the prevalence of LIN or DIN and ductal hyperplasia. Results: Overall, the prevalence of LIN, DIN and ductal hyperplasia was 4.5% (9/200), 66.5% (133/200) and 35% (69/200), respectively. The Ki-67 LI was positively associated with DIN grade (p-trend&amp;lt;0.001). The median (and IQ range) Ki-67 LI distribution of LIN+DIN was 12% (8-20) and 10% (6-22) on metformin and placebo, respectively (p=0.6), nor was there a significant difference of Ki-67 LI in any subgroup between treatment arms. However, compared with placebo, metformin exhibited different effects on Ki-67 according to DIN grade (delta=+4.4% in DIN1 vs -27.9% in DIN3, p-interaction=0.09), cancer HER2 status (median 12% vs. 10% in HER2-ve and 28% vs. 35% in HER2+ve, p-interaction=0.03), abdominal circumference (p=0.08), and BMI (p=0.17). Conclusions: Our findings illustrate the notion that the window of opportunity pre-surgical model provides insight into a drug's preventive potential by targeting tumor adjacent dysplastic (or intraepithelial neoplastic) cells and distant ductal hyperplastic cells. The model unravels the existence of the field cancerization effect in apparently normal breast tissue. Similar to our results on breast cancer tissue, metformin had no overall significant effect on breast preneoplasia proliferation but exhibited heterogeneous effects depending upon specific host and preneoplasia characteristics. Further studies are necessary to better understand the clinical implications of these findings. (Supported by the Italian Association for Cancer Research and Italian Ministry of Health 2009-RF-1532226). Citation Format: Andrea DeCensi, Valentina Aristarco, Matteo Lazzeroni, Clara Varricchio, Bernardo Bonanni, Matteo Puntoni, Giancarlo Pruneri, Massimiliano Cazzaniga, Andrea Vingiani, Davide Serrano, Aliana Guerrieri-Gonzaga, Oreste Gentilini, Harriet Johansson. Metformin effects on breast preneoplasia. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr SS-01.

Morphological parameters of flat epithelial atypia (FEA) in stereotactic vacuum-assisted needle core biopsies do not predict the presence of malignancy on subsequent surgical excision

Flat epithelial atypia (FEA) may represent the earliest precursor of low-grade breast cancer and often coexists with more advanced atypical proliferative breast lesions such as atypical ductal hyperplasia (ADH) and lobular intraepithelial neoplasia (LIN). The present study aims to investigate the association between morphological parameters of FEA and presence of malignancy at surgical excision (SE) and the clinical significance of the association of FEA with ADH and/or LIN. This study included 589 cases of stereotactic 11-gauge vacuum-assisted needle core biopsy (VANCB), reporting a diagnosis of FEA, ADH or LIN with subsequent SE from 14 pathology departments in Italy. Available slides were reviewed, with 114 (19.4%) showing a malignant outcome at SE. Among the 190 cases of pure FEA, no statistically significant association emerged between clinical-pathological parameters of FEA and risk of malignancy. Logistic regression analyses showed an increased risk of malignancy according to the extension of ADH among the 275 cases of FEA associated with ADH (p = 0.004) and among the 34 cases of FEA associated with ADH and LIN (p = 0.02). In the whole series, a statistically significant increased malignancy risk emerged according to mammographic R1-R3/R4-R5 categories (OR = 1.56; p = 0.04), extension (OR = 1.24; p = 0.04) and grade (OR = 1.94; p = 0.004) of cytological atypia of FEA. The presence of ADH was associated with an increased malignancy risk (OR = 2.85; p < 0.0001). Our data confirm the frequent association of FEA with ADH and/or LIN. A diagnosis of pure FEA on VANCB carries a 9.5% risk of concurrent malignancy and thus warrants follow-up excision because none of the clinical-pathological parameters predicts which cases will present carcinoma on SE.