[Show abstract][Hide abstract] ABSTRACT: The role and clinical value of ERβ1 expression is controversial and recent data demonstrates that many ERβ antibodies are insensitive and/or non-specific. Therefore, we sought to comprehensively characterize ERβ1 expression across all sub-types of breast cancer using a validated antibody and determine the roles of this receptor in mediating response to multiple forms of endocrine therapy both in the presence and absence of ERα expression.
Nuclear and cytoplasmic expression patterns of ERβ1 were analyzed in three patient cohorts, including a retrospective analysis of a prospective adjuvant tamoxifen study and a triple negative breast cancer cohort. To investigate the utility of therapeutically targeting ERβ1, we generated multiple ERβ1 expressing cell model systems and determined their proliferative responses following anti-estrogenic or ERβ-specific agonist exposure.
Nuclear ERβ1 was shown to be expressed across all major sub-types of breast cancer, including 25% of triple negative breast cancers and 33% of ER-positive tumors, and was associated with significantly improved outcomes in ERα-positive tamoxifen-treated patients. In agreement with these observations, ERβ1 expression sensitized ERα-positive breast cancer cells to the anti-cancer effects of selective estrogen receptor modulators (SERMs). However, in the absence of ERα expression, ERβ-specific agonists potently inhibited cell proliferation rates while anti-estrogenic therapies were ineffective.
Using a validated antibody, we have confirmed that nuclear ERβ1 expression is commonly present in breast cancer and is prognostic in tamoxifen-treated patients. Using multiple breast cancer cell lines, ERβ appears to be a novel therapeutic target. However, the efficacy of SERMs and ERβ-specific agonists differ as a function of ERα expression.
BMC Cancer 10/2014; 14(1):749. DOI:10.1186/1471-2407-14-749 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fibroepithelial lesions with cellular stroma are frequently termed cellular fibroadenomas although criteria for distinguishing them from a phyllodes tumor are vague and subjective. However, the clinical implications and surgical management for these 2 lesions may be different. We randomly selected 21 cases of fibroepithelial lesions sent in consultation to the senior author that were challenging to classify as cellular fibroadenoma or phyllodes tumor. One to 2 representative slides of each case along with patient age were sent to 10 pathologists who specialize in breast pathology. The World Health Organization criteria for phyllodes tumors and a diagnosis form were included with the study set. For the purposes of data reporting, fibroadenoma and cellular fibroadenoma are considered together. In only 2 cases was there uniform agreement as to whether the tumor represented a fibroadenoma or phyllodes tumor. Of the remaining 19 cases, if the diagnoses of fibroadenoma and benign phyllodes tumor were combined and separated from borderline and malignant phyllodes tumors, there was 100% agreement in 53% of cases and 90% agreement in 79% of cases. This study highlights the difficulty that exists in distinguishing some cellular fibroadenomas from phyllodes tumors even for pathologists who specialize in breast pathology. However, there appears to be considerable agreement when cellular fibroadenomas and benign phyllodes tumors are distinguished from borderline and malignant phyllodes tumors. Further studies are needed to determine if there is a clinically significant difference between cellular fibroadenomas and benign phyllodes tumors and how to better distinguish them from borderline and malignant phyllodes tumors.
International Journal of Surgical Pathology 08/2014; 22(8). DOI:10.1177/1066896914548763 · 0.95 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract P6-04-03. Background: Estrogen receptor beta (ERβ), unlike ERα, classically functions as a tumor suppressor in vitro. However, ERβ's biological functions in vivo and predictive/prognostic value in breast cancer are controversial.
Methods: Expression of ERβ protein was determined using a well characterized and validated ERβ specific monoclonal antibody that only recognizes the full-length form of this receptor (PPG5/10) in the following 3 cohorts: 1) a cohort with all breast cancer subtypes (n = 182), 2) a prospective NCCTG adjuvant tamoxifen trial for postmenopausal women with ERα positive breast cancer with long-term follow-up (n = 198) and 3) a cohort of 80 triple negative breast cancers (TNBCs). To elucidate the biological functions of ERβ in breast cancer, novel ERβ expressing MCF7 and MDA-MB-231 cell lines were developed and characterized using multiple techniques and were examined for responsiveness to various ERβ targeted therapies.
Results: About one-third of all breast tumors, regardless of sub-type, were shown to express nuclear ERβ and this expression was independent of ERα or HER2. In the NCCTG 89-30-52 cohort, breast cancer recurrence rates were significantly associated with ERβ protein expression with 10 year recurrence rates of 25%, 15% and 4% for zero, low or high levels of ERβ expression respectively. Interestingly, in TNBCs, nuclear ERβ was expressed at intermediate or high levels in 24% of tumors. In the triple negative MDA-MB-231 cell line, expression of ERβ led to inhibition of proliferation and induction of apoptosis in response to estrogen and multiple ERβ specific agonists. Conversely, these same treatments induced proliferation of ERβ-expressing MCF7 cells which endogenously express ERα. However, ERβ expression sensitized MCF7 cells to the anti-proliferative effects of anti-estrogens. Microarray analysis and RT-PCR profiling of MDA-MB-231-ERβ cells revealed that estrogen and ERβ agonists highly induced the expression of multiple cystatins, a family of small secreted cysteine protease inhibitors which function as tumor suppressors, and potently inhibited canonical TGFβ signaling. Conditioned media isolated from estrogen or ERβ agonist treated MDA-MB-231-ERβ cells suppressed the proliferation rates and inhibited TGFβ signaling in other TNBC cell lines, effects that were completely reversed following the depletion of cystatins from the conditioned media.
Conclusions: These data demonstrate that ERβ is expressed in a substantial proportion of breast cancers and may have value as a predictive and/or prognostic biomarker. Therapeutic targeting of ERβ may have clinical benefit in multiple breast cancer sub-types; however, the specific drug of choice may vary based on ERα status. Specifically, we have demonstrated that ERβ expression in ERα+ MCF7 cells sensitizes them to the effectiveness of anti-estrogens, an observation that was confirmed in women enrolled in a prospective adjuvant tamoxifen trial. In TNBCs, where targeted therapies are lacking, our data suggest that targeting ERβ with either estrogen or ERβ specific agonists will elicit anti-tumor effects through the induction of cystatins and inhibition of TGFβ signaling resulting in tumor regression and improved patient outcomes.
2013 San Antonio Breast Cancer Symposium, 24 (Suppl); 12/2013
[Show abstract][Hide abstract] ABSTRACT: Objective:
The purpose of this study was to determine the proportion of invasive lobular carcinomas with increased sonographic echogenicity.
Materials and methods:
A retrospective review of mammographic and sonographic findings included cases of pure invasive lobular carcinoma with available images from January 1998 to June 2010. We assessed ultrasound images for the presence of a mass, internal echogenicity, margin characteristics, and attenuation effects. In hyperechoic tumors, more than 90% of the mass had increased echogenicity compared with surrounding fat. In heterogeneously echogenic tumors, the echogenic component constituted 20-90% of the tumor. Findings at mammography, MRI, and surgery were correlated with sonographic findings. A breast pathologist reviewed histologic findings and confirmed the diagnosis of pure invasive lobular carcinoma.
Of 509 invasive lobular carcinomas, 27 (5%) were hyperechoic, of which 13 (48%) were associated with posterior acoustic shadowing. Heterogeneously echogenic cancer was seen in 57 (11%) cases. The most common sonographic finding was a hypoechoic, irregular mass with or without posterior shadowing (n = 323; 63%). In 66 (13%) lesions, focal shadowing was seen without a discrete mass. Fourteen (3%) lesions were isoechoic with respect to surrounding normal adipose tissue without acoustic shadowing. Twenty-two (4%) of the malignant tumors were not identified sonographically. Of these, 15 (68%) had mammographic abnormalities, one (5%) was seen at MRI, and six (27%) presented as palpable masses that were surgically excised.
Pure invasive lobular carcinomas can present as a hyperechoic mass or with substantial hyperechoic component. All sonographic lesion characteristics should be evaluated and biopsy recommended when there are suspicious features, even in a lesion that is predominantly hyperechoic.
American Journal of Roentgenology 11/2013; 201(5):W765-9. DOI:10.2214/AJR.12.9742 · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ACOSOG Z11 and other studies showing little benefit to axillary dissection (ALND) for early-stage breast cancers with limited nodal disease have led to questioning the value of preoperative axillary imaging ± ultrasound-guided needle biopsy (USNB). Data are lacking on the value of this approach in identifying cases that fall outside Z11 guidelines.
We studied 988 consecutive patients with invasive breast cancers who underwent operation including axillary surgery in 2010-2011.
Preoperative axillary ultrasonography (AUS) was performed in 92% and breast/axillary magnetic resonance imaging (MRI) in 51%; 82 (33.5%) of 245 patients with suspicious lymph nodes (LN) were USNB-positive. Regarding nodal status, AUS, MRI, and USNB had negative and positive predictive values of 78%, 76%, 70% and 54%, 58%, 100%, respectively. AUS/MRI visualization of one versus multiple abnormal LNs visualized predicted >2LN+ on final pathology (13.5%/15.1% % vs 30.8%/32.6%, P < .009). Among USNB-LN+ T1/T2 patients, 51.6% had 1-2 LN+ while 60% with multiple and 31% with one AUS-abnormal LN(s) had > 2LN+, P = .001.
In our contemporary series, preoperative AUS±USNB streamlined surgical care for 29% of node-positive patients. Two-thirds of T1/T2 USNB-LN+ patients with multiple AUS-suspicious LNs had >2LN+, suggesting they should undergo ALND without SLNB. AUS±USNB helps identify node-positive breast cancer patients who fall outside Z11 guidelines.
Surgery 10/2013; 154(4):831-40. DOI:10.1016/j.surg.2013.07.017 · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this article is to present imaging findings of invasive ductal carcinoma with micropapillary features with clinical and pathologic correlation.
We retrospectively searched our institution's surgical pathology database for patients with pathologically proven invasive ductal carcinoma with micropapillary features. Forty-one patients with images available for review were included in the study. Mammographic, sonographic, and MRI findings were assessed using the American College of Radiology's BI-RADS lexicon. Molecular breast imaging findings were reviewed using a molecular breast imaging lexicon. Imaging findings were correlated with clinical presentation and pathologic findings.
Mammographically, the most common finding was an irregular spiculated mass. Sonographically, the most common finding was an irregular hypoechoic mass with spiculated margins and posterior acoustic shadowing. With MRI, the most common finding was an irregular mass with washout kinetics, but we also observed diffuse heterogeneous nonmasslike enhancement throughout the breast. Molecular breast imaging was available for one patient and showed multicentric radiotracer uptake. Analysis of 39 pathologic specimens showed 27 (69%) with angiolymphatic invasion. Axillary nodal metastases were present in 23 patients (59%), nine (23%) with extranodal extension.
The imaging features of invasive ductal carcinoma of the breast with micropapillary features typically were highly suggestive of malignancy. The malignancies were strongly associated with lymphovascular invasion and lymph node metastases. Radiologists should be aware of the imaging features of this unusual variant and should consider axillary sonography if this entity is found in a core needle biopsy specimen.
American Journal of Roentgenology 03/2013; 200(3):689-95. DOI:10.2214/AJR.12.8512 · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
The purpose of this study was to determine whether surgical excision of benign solitary intraductal papillomas (BSIP) diagnosed by core needle biopsy (CNBx) without an associated high-risk lesion and concordant with imaging is justified.
A review of all papillary lesions diagnosed by CNBx from January 2003 to June 2010 was performed. Available histologic and radiologic materials were evaluated in a blinded fashion by three pathologists and three dedicated breast radiologists, respectively, to assess for concordance. The papillary lesions were designated as benign, atypical, or malignant. There were 16 BSIPs excluded because of an adjacent high-risk lesion or same-quadrant ipsilateral cancer. All immediate and delayed excisional specimens were reviewed. Clinical and radiologic data were recorded.
A total of 299 papillary lesions diagnosed on CNBx and concordant with imaging were identified. Of these, 240 (80 %) were classified as benign, 49 (16 %) atypical, and 10 (3 %) malignant. After exclusions, 77 of 224 women in our study cohort (34 %) underwent surgical excision with no atypical or malignant upgrades. Of the remaining 147 women diagnosed with a BSIP on CNBx, 47 (32 %) were lost to follow-up and 100 (68 %) were observed. All 100 observed patients had stable imaging findings at follow-up (4.8-93.8 months, mean 36.0 months).
The likelihood of diagnosing atypia or malignancy after surgical excision of a BSIP diagnosed on CNBx without associated high-risk lesion or ipsilateral quadrant malignancy is extremely low. For this distinct subset of patients with a BSIP, these data justify close imaging follow-up, rather than surgical excision.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Controversy exists about CYP2D6 genotype and tamoxifen efficacy.
A matched case-control study was conducted using the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG8) that randomized postmenopausal women with estrogen receptor (ER)-positive breast cancer to tamoxifen for 5 years (arm A) or tamoxifen for 2 years followed by anastrozole for 3 years (arm B). Cases had disease recurrence, contralateral breast cancer, second non-breast cancer, or died. For each case, controls were identified from the same treatment arm of similar age, surgery/radiation, and tumor-node-metastasis (TNM) stage. Genotyping was conducted for alleles associated with no (PM; *3, *4, *6), reduced (IM; *10, and *41), and extensive (EM: absence of these alleles) CYP2D6 metabolism.
The common CYP2D6*4 allele was in Hardy-Weinberg equilibrium. In arm A during the first 5 years of therapy, women with two poor alleles [PM/PM: OR, 2.45; 95% confidence interval (CI), 1.05-5.73, P = 0.04] and women with one poor allele (PM/IM or PM/EM: OR, 1.67; 95% CI, 0.95-2.93; P = 0.07) had a higher likelihood of an event than women with two extensive alleles (EM/EM). In years 3 to 5 when patients remained on tamoxifen (arm A) or switched to anastrozole (arm B), PM/PM tended toward a higher likelihood of a disease event relative to EM/EM (OR, 2.40; 95% CI, 0.86-6.66; P = 0.09) among women on arm A but not among women on arm B (OR, 0.28; 95% CI, 0.03-2.30).
In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration and not after switching to anastrozole.
Clinical Cancer Research 12/2012; 19(2). DOI:10.1158/1078-0432.CCR-12-2153 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE
To describe imaging findings of benign papillomas and to determine if surgical excision is required for biopsy-proven benign papillomas in patients who have concordant imaging findings.
METHOD AND MATERIALS
Retrospective review was performed of histology and imaging for keyword “papilloma” from January 1 2003 to June 30 2010, with IRB approval. Histology was reviewed by two pathologists. Clinical and imaging information including presentation, imaging findings and followup, biopsy technique and surgical excision were recorded.
226 benign papillomas were identified in 214 female patients, mean age 54.2 (range 27-92). 42% (96/226) presented with nipple discharge or palpable mass, 43% (98/226) detected on screening mammogram, and 15% (32/226) on MRI, US or MBI. Mean lesion size was 0.8cm (range 0.2-3.4 cm). The commonest mammographic finding was non-calcified mass (54%, 70/129), then calcifications (25%, 32/129), calcified mass (14%, 18/129) and dilated ducts (7%, 9/129). The typical US appearance was solid isoechoic mass (52%, 105/202), then by intraductal and intracystic masses(48%, 97/202). MR demonstrated mass-like enhancement in 79% (27/34) of cases, with washout kinetics in 52% (15/29). US imaging guidance was used for 87% (197/226) of biopsies, stereotactic for 11% (24/226), and MRI for 2% (5/226). Biopsy gauge was 14g or smaller for 53% (120/226), and 11g or larger (vacuum assisted) for 47% (106/226). 27% (60/226) of lesions were excised immediately (< 8 mos), and 8% (19/226) underwent delayed excision (mean 25.3 months, range 8.7-74.4 months). Of all surgically excised lesions, only 0.9% (2/226) were upgraded to include atypia. No lesions were upgraded to malignancy. Of the remaining 147 lesions with histologic diagnosis of benign papilloma on core needle biopsy, 29.9% (44/147) were lost to followup, while 70.1% (103/147) were unchanged in appearance on followup imaging (mean 39.3 months, range 4.8-108.6 months).
Histologic upgrade of surgically excised, core biopsy-proven benign papillomas with concordant imaging was very low with only 0.9% incidence of upgrade to atypical papilloma. These findings support close imaging follow-up rather than surgical excision of benign papillomas in patients whose imaging findings are concordant.
Benign papillomas diagnosed on core biopsy with concordant imaging findings may safely be followed with imaging rather than require surgical excision.
Radiological Society of North America 2012 Scientific Assembly and Annual Meeting; 11/2012
[Show abstract][Hide abstract] ABSTRACT: PURPOSE/AIM
Image guided biopsies are a large part of breast imaging. Unfortunately so are borderline and precursor type breast pathologies with are often obtained in our core needle biopsies. Having an understanding of the pathological ananlysis of these breast diagnoses is extremely helpful in establishing concordance with the imaging findings. The goal of this educational exibit is to review multiple pathologies in a case format with both the imaging findings and pathology slides.
Overview of the spectrum of breast disease including the continum or theory of carcinogensis. Case based format reviewing the imaging findings, pathology slides and discussion of current recommendations for multiple pathologies including, but not limited to: Atypical ductal hyperplasia Atypical lobular hyperplasia Lobular carcinoma in situ Flat Epithelial Atypia
This educational exibit will review multiple borderline and precusor pathologies in a case format with both the imaging findings and pathology slides folowed by discussion of the up to date recommendations.
Radiological Society of North America 2012 Scientific Assembly and Annual Meeting; 11/2012
[Show abstract][Hide abstract] ABSTRACT: Radioactive seed localization (RSL) is an increasingly utilized and effective approach to surgical excision of radiographically identified lesions in the breast. This approach has been reported to be at least as convenient to the patient, radiologist, and surgeon as the standard wire localized approach but with the considerable added benefit of a lower positive margin rate in some studies. To date, there is little information in the published medical literature concerning the optimal handling of these specimens in the pathology laboratory. The US Nuclear Regulatory Commission and its Agreement States oversee the use of radioactive materials in clinical practice and provide guidelines for the performance of RSL procedures, including the safe handling of radioactive seeds. The RSL procedure involves multiple departments, and a robust process should be in place to ensure appropriate accountability, seed tracking, and minimal radiation exposure to staff. This article describes how to properly and safely handle RSL breast specimens, including regulation requirements, specimen labeling and receipt, specimen dissection, protective wear, and seed retrieval, transport, and disposal.
The American journal of surgical pathology 10/2012; 36(11):1718-23. DOI:10.1097/PAS.0b013e318265c37f · 5.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Amyloidosis is a disorder characterized by extracellular deposition of proteins in an abnormal fibrillar configuration. Amyloidosis can be localized or systemic and may affect any organ. Breast involvement by amyloidosis has rarely been reported. In this study, we described the characteristics of 40 cases of breast amyloidosis that were reviewed at the Division of Anatomic Pathology at Mayo Clinic from 1995 to 2011. The cohort included 39 women and 1 man with a mean age of 60 years. The type of amyloidosis, determined by immunohistochemistry or mass spectrometry-based proteomics in 26 patients, was immunoglobulin-associated in all cases (AL-kappa type in 15 (58%) cases, AL-lambda in 10 (38%) and mixed heavy and light chains (AH/AL) in 1 (4%) case). Mass spectrometry-based proteomics was able to determine the type of amyloidosis in 95% of cases tested compared with 69% of cases by immunohistochemistry. In addition to amyloidosis, the breast biopsy showed a hematologic disorder in 55% of cases, most commonly MALT lymphoma. One patient had concurrent intraductal carcinoma, but none had invasive carcinoma. Of the 15 patients seen in our institution, 53% had localized amyloidosis and 47% had extramammary amyloid involvement, which was diagnosed before breast amyloidosis in most patients. M-spike was detected in the blood in 62%. After a median follow-up of 33.5 months in 12 patients, 5 died, mostly of complications of lymphoma or leukemia. In conclusion, our findings indicate that breast amyloidosis is of the AL type in the vast majority of patients (usually kappa). It is associated with systemic amyloidosis in close to half of patients and with hematologic malignancy in the breast in over half of patients. Therefore, further work up to rule out hematologic malignancy and/or systemic amyloidosis is recommended. Mass spectrometry-based proteomics is superior to immunohistochemistry for typing of breast amyloidosis.
Modern Pathology 09/2012; 26(2). DOI:10.1038/modpathol.2012.167 · 6.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lobular neoplasia (LN) includes atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS). LN often is an incidental finding on breast core needle biopsy (CNBx) and management remains controversial. Our objective was to define the incidence of malignancy in women diagnosed with pure LN on CNBx, and identify a subset of patients that may be observed.
Patients diagnosed with LN on CNB between January 1993 and December 2010 were identified. Patients with an associated high-risk lesion or ipsilateral malignancy at time of diagnosis were excluded. All cases were reviewed by dedicated breast pathologists and breast imagers for pathologic classification and radiologic concordance, respectively.
The study cohort was comprised of 184 (1.3 %) cases of pure LN (147 ALH, 37 LCIS) from 180 patients. Pathologic-radiologic concordance was achieved in 171 (93 %) cases. Excision was performed in 101 (55 %) cases and 83 (45 %) were observed. Mean follow-up was 50.3 (range, 6-212) months. Of cases excised, 1 of 81 (1.2 %) ALH and 1 of 20 (5 %) LCIS cases were upstaged to ductal carcinoma in situ (DCIS) and invasive lobular carcinoma (ILC), respectively. Only 1 of 101 (1 %) concordant lesions was upstaged on excision. Of the cases observed, 4 of 65 (6.2 %) developed ipsilateral cancer during follow-up: 1 of 51 (2 %) case of ALH and 3 of 14 (21.4 %) cases with LCIS (2 ILC, 2 DCIS). During follow-up, 2.9 % (4/138) patients with excised or observed LN developed a contralateral cancer.
These data support that not all patients with LN diagnosed on CNB require surgical excision. Patients with pure ALH, demonstrating radiologic-pathologic concordance, may be safely observed.
[Show abstract][Hide abstract] ABSTRACT: The development of predictive biomarkers for IGF targeted anti-cancer therapeutics remains a critical unmet need. The insulin receptor A isoform (InsR-A) has been identified as a possible biomarker candidate but quantification of InsR-A in widely available formalin fixed paraffin embedded (FFPE) tissues is complicated by its similarities with the metabolic signaling insulin receptor isoform B (InsR-B). In the present study, qPCR based assays specific for InsR-A, InsR-B and IGF-1R were developed for use in FFPE tissues and tested for feasible use in clinical archived FFPE estrogen receptor (ER)+and ER- breast cancer tumors.
FFPE compatible primer sets were designed with amplicon sizes of less than 60 base pairs and validated for target specificity, assay repeatability and amplification efficiency. FFPE tumors from ER+ (n=83) and ER-(n=64) primary untreated breast cancers, and ER+ hormone refractory (HR ER+) (n=61) breast cancers were identified for feasibility testing. The feasible use of InsR-A and InsR-B qPCRs were tested using all tumor groups and the feasibility of IGF-1R qPCR was determined using HR ER+ tumors.
All qPCR assays were highly reproducible with amplification efficiencies between 96-104% over a 6 log range with limits of detection of 4 or 5 copies per reaction. Greater than 90% of samples were successfully amplified using InsR-A, InsR-B or IGF-1R qPCR primer sets and greater than 88% of samples tested amplified both InsR isoforms or both isoforms and IGF-1R. InsR-A was the predominant isoform in 82% ER+, 68% ER- and 100% HR ER+ breast cancer. Exploratory analyses demonstrated significantly more InsR-A expression in ER+ and HR ER+ groups compared to InsR-B (ER+ p<0.05, HR ER+ p<0.0005) and both groups had greater InsR-A expression when compared to ER- tumors (ER+ p<0.0005, HR ER+ p<0.05). IGF-1R expression of HR ER+ tumors was lower than InsR-A (p<0.0005) but higher than InsR-B (p<0.0005). The InsR-B expression of HR ER+ tumors was significantly reduced compared other tumor subgroups (ER+ and ER-, p<0.0005) and lead to a significant elevation of HR ER+ InsR-A: InsR-B ratios (ER+ and ER-, p<0.0005).
The validated, highly sensitive InsR-A and InsR-B qPCR based assays presented here are the first to demonstrate the feasible amplification of InsR isoforms in FFPE tissues. Quantification data generated from this feasibility study indicating InsR-A is more predominant than InsR-B in breast cancer support the use of these assays for further investigation of InsR-A and InsR-B as predictive biomarkers for IGF targeted therapeutics.
Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society 04/2012; 22(3-4):108-15. DOI:10.1016/j.ghir.2012.04.001 · 1.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The role of estrogen receptor alpha (ERα) in breast cancer has been studied extensively, and its protein expression is prognostic and a primary determinant of endocrine sensitivity. However, much less is known about the role of ERβ and its relevance remains unclear due to the publication of conflicting reports. Here, we provide evidence that much of this controversy may be explained by variability in antibody sensitivity and specificity and describe the development, characterization, and potential applications of a novel monoclonal antibody targeting full-length human ERβ and its splice variant forms. Specifically, we demonstrate that a number of commercially available ERβ antibodies are insensitive for ERβ and exhibit significant cross-reaction with ERα. However, our newly developed MC10 ERβ antibody is shown to be highly specific and sensitive for detection of full-length ERβ and its variant forms. Strong and variable staining patterns for endogenous levels of ERβ protein were detected in normal human tissues and breast tumors using the MC10 antibody. Importantly, ERβ was shown to be expressed in a limited cohort of both ERα positive and ERα negative breast tumors. Taken together, these data demonstrate that the use of poorly validated ERβ antibodies is likely to explain much of the controversy in the field with regard to the biological relevance of ERβ in breast cancer. The use of the MC10 antibody, in combination with highly specific antibodies targeting only full-length ERβ, is likely to provide additional discriminatory features in breast cancers that may be useful in predicting response to therapy.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE
To determine the imaging findings following placement of a water-soluble polyethylene glycol-based hydrogel that contains a central metallic marker (HydroMARK, Biopsy Sciences Florida) during stereotactic or ultrasound guided biopsy of malignant and benign breast lesions, with pathologic correlation.
METHOD AND MATERIALS
Retrospective review was performed of stereotactic and ultrasound guided biopsies for key word “Hydromark” from January 1 2009 to February 16 2011, with IRB approval. Mammogram, MRI and ultrasound imaging after biopsy and at the time of localization, and any follow-up imaging through March 29, 2011, were reviewed (follow-up ranging from 2 to 13 months).
206 clips deployed in 203 women were included. Biopsies were performed stereotactically (n = 129) and sonographically (n =77). Immediate post biopsy mammogram (n=202) showed clip to be within 5mm of biopsied lesion in 91% of cases, with faint tubular density around the clip in 26% (53/202). MRI (n=10) showed tubular high T2 signal mass with occasional thin rim of enhancement. 98 patients went to surgery: 44% mastectomy, 56% lumpectomy (65% localized sonographically, 31% mammographically, 2% palpable). The hydrated gel was seen mammographically as a tubular soft tissue mass, and sonographically as an anechoic tubular mass. Histologically there were large cyst like spaces lined by histiocytes with pseudostratification adjacent to the gel. Follow up mammograms (n=21), ultrasound (n=9) and MRI (n=3), were obtained 2 to 13 months following clip placement. Mammographically, a soft tissue tubular mass; sonographically, a tubular anechoic mass; MRI, a high T2 signal tubular mass were seen surrounding the metallic clip in all cases.
HydroMARK hydrogel begins to hydrate within 1 hour of placement and is easily visualized mammographically and sonographically at the time of localization. On MRI, a tubular, high T2 signal mass is seen with occasional thin rim of enhancement. Histologically, cystic like spaces are lined by histiocytes with pseudostratification. Mammographic and sonographic tubular masses are present over 13 months following placement. This should be recognized by radiologists to prevent errors in interpretation and unnecessary invasive procedures.
Radiologists must be aware of mammographic, sonographic and MRI findings present following Hydromark clip placement, especially on followup for benign biopsies to prevent errors in interpretation.
Radiological Society of North America 2011 Scientific Assembly and Annual Meeting; 12/2011
[Show abstract][Hide abstract] ABSTRACT: The Oncotype DX assay predicts likelihood of distant recurrence and improves patient selection for adjuvant chemotherapy in estrogen receptor-positive (ER-positive) early stage breast cancer. This study has two primary endpoints: to evaluate the impact of Oncotype DX recurrence scores (RS) on chemotherapy recommendations and to compare the estimated recurrence risk predicted by breast oncology specialists to RS.
One hundred fifty-four patients with ER-positive early stage breast cancer and available RS results were selected. Clinicopathologic data were provided to four surgeons, four medical oncologists, and four pathologists. Participants were asked to estimate recurrence risk category and offer their chemotherapy recommendations initially without and later with knowledge of RS results. The three most important clinicopathologic features guiding their recommendations were requested.
Ninety-five (61.7%), 45 (29.2%), and 14 (9.1%) tumors were low, intermediate, and high risk by RS, respectively. RS significantly correlated with tumor grade, mitotic activity, lymphovascular invasion, hormone receptor, and HER2/neu status. Estimated recurrence risk by participants agreed with RS in 54.2% ± 2.3% of cases. Without and with knowledge of RS, 82.3% ± 1.3% and 69.0% ± 6.9% of patients may be overtreated, respectively (p = 0.0322). Inclusion of RS data resulted in a 24.9% change in treatment recommendations. There was no significant difference in recommendations between groups of participants.
Breast oncology specialists tended to overestimate the risk of tumor recurrence compared with RS. RS provides useful information that improves patient selection for chemotherapy and changes treatment recommendations in approximately 25% of cases.
The Oncologist 11/2011; 16(11):1520-6. DOI:10.1634/theoncologist.2011-0045 · 4.87 Impact Factor