Thomas J. Lawton

The Effect of Oncotype DX Recurrence Score on Treatment Recommendations for Patients with Estrogen Receptor–Positive Early Stage Breast Cancer and Correlation with Estimation of Recurrence Risk by Breast Cancer Specialists

PURPOSE 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Mammostrat As an Immunohistochemical Multigene Assay for Prediction of Early Relapse Risk in the Tamoxifen Versus Exemestane Adjuvant Multicenter Trial Pathology Study

PURPOSE Some postmenopausal patients with hormone-sensitive early breast cancer remain at high risk of relapse despite endocrine therapy and, in addition, might benefit from adjuvant chemotherapy. The challenge is to prospectively identify such patients. The Mammostrat test uses five immunohistochemical markers to stratify patients regarding recurrence risk and may inform treatment decisions. We tested the efficacy of this panel in the Tamoxifen versus Exemestane Adjuvant Multicenter (TEAM) trial. PATIENTS AND METHODS Pathology blocks from 4,598 TEAM patients were collected, and tissue microarrays (TMAs) were constructed. The cohort was 47% node-positive, and 36% of patients in the cohort were treated with adjuvant chemotherapy. Triplicate 0.6-mm(2) TMA cores were stained, and positivity for p53, HTF9C, CEACAM5, NDRG1, and SLC7A5 was assessed. Cases were assigned a Mammostrat risk score, and distant relapse-free survival (DRFS) and disease-free survival (DFS) were analyzed. RESULTS In multivariate regression analyses, which were corrected for conventional clinicopathologic markers, Mammostrat provided significant additional information on DRFS after endocrine therapy in estrogen receptor (ER) -positive node-negative patients (n = 1,226) who did not receive chemotherapy (P = .004). Additional analyses in all patients not exposed to chemotherapy, irrespective of nodal status (n = 2,559) and in the entire cohort (n = 3,837) showed Mammostrat scores provided additional information on DRFS in these groups (P = .001 and P < .001, respectively; multivariate analyses). No differences were seen between the two endocrine treatment regimens. CONCLUSION The Mammostrat score predicts DRFS for patients treated with exemestane and patients treated with tamoxifen followed by exemestane irrespective of nodal status and chemotherapy. The ability of this test to provide additional outcome data after treatment provides additional evidence of its use in risk stratification of ER-positive postmenopausal patients with breast cancer.

Controversies on the Management of High-Risk Lesions at Core Biopsy from a Radiology/Pathology Perspective

Readers may feel less than satisfied when they discover that there is no consensus on the appropriate recommendations for follow-up of risk lesions following percutaneous core biopsy. The significance of this article is in the details of the methodologies and results, and much less in the numbers. The overall goal is to emphasize the flaws in current studies.

Interobserver Variability by Pathologists in the Distinction Between Cellular Fibroadenomas and Phyllodes Tumors

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.

Variations in Physician Recommendations for Surgery After Diagnosis of a High-Risk Lesion on Breast Core Needle Biopsy

OBJECTIVE This article focuses on four high-risk lesions: lobular neoplasia, benign papilloma, radial scar, and flat epithelial atypia. Controversies exist in the management after core biopsy of each of these lesions--whether to perform immediate surgical excision so as not to miss an associated malignancy or imaging follow-up because concomitant malignancy is low. This review is staged in two parts per lesion. The first is from data gathered during the last two American Roentgen Ray Society annual meetings from the audience response system querying practice management styles per diagnostic lesion. The second part is a brief review of selected articles recommending either follow-up or surgery. The strengths and weaknesses of each article are discussed. CONCLUSION Our opinion is that neither recommendation, surgical excision or follow-up, is well substantiated in the literature and that our ignorance is not serving the needs of women worldwide. The time is now for a prospective trial.

Can Molecular Subtyping Be Used to Guide Metastatic Screening in Breast Cancer

The seminal study in 2000 by Perou and colleagues1 describing the molecular classification of breast cancer based on complementary DNA microarray analysis has forever changed the way we view this disease. Their results supported the concept that breast cancer is not a single entity but rather a heterogeneous group of tumors with diverse behavior and corresponding gene expression patterns. Subsequently, the same group refined their molecular subtypes using a greater number of tumors and identified the now familiar five distinct gene expression patterns: luminal A, luminal B, HER2+, basal-like, and normal breast-like.2 They further demonstrated a correlation between tumor subtype and patient outcome, including overall survival and relapse-free survival. Since the publication of these studies, numerous other investigators have confirmed the clinical significance of this classification system,3–7 including the prognostic and predictive value of the molecular subtypes. Since immunohistochemistry (IHC) is a more accessible and inexpensive modality in the clinical setting, there has been ongoing interest in using protein expression to identify the subclasses. Based on the particular gene clusters differentially expressed among the subtypes and their correlation with protein expression, the most commonly used IHC stains have been estrogen receptor (ER), progesterone receptor (PR), HER2/neu, and Ki-67.1,3,4,6–9 IHC for CK5/6 and epidermal growth factor receptor (HER1) also has been used to further distinguish the basal-like subtype.6,8 In …

High Risk Breast Lesions and Pathologic Evaluation

There are several pathologic lesions in the female breast that are so-called “high risk” because of epidemiologic data suggesting that a diagnosis of one of these lesions on a biopsy increases a woman’s risk of developing a subsequent carcinoma. Among the most common of these lesions are lobular neoplasia (atypical lobular hyperplasia and lobular carcinoma in situ), columnar cell lesions (including flat epithelial atypia), atypical ductal hyperplasia, papillary lesions, and radial scar/complex sclerosing lesions. In this chapter, the specific histopathologic diagnostic criteria for each of these lesions will be discussed and associated images of each will be displayed.