Nicole N. Esposito

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.

A mitotically active, cellular tumor stroma and/or inflammatory cells associated with tumor cells may contribute to intermediate or high Oncotype DX Recurrence Scores in low-grade invasive breast carcinomas.

Oncotype DX is an RT-PCR-based 21-gene assay validated to provide prognostic and predictive information in the form of a Recurrence Score in patients with estrogen receptor-positive, lymph node-negative breast cancer. Although the Recurrence Score was shown to correlate with several histopathological tumor features, there is a significant proportion of cases showing an apparent discrepancy between Recurrence Score and risk estimates based on the traditional clinicopathological tumor features. In this study, we tested whether a proliferating, cellular stroma and/or admixed inflammatory cells may result in an artificially increased Recurrence Score in low-grade invasive breast cancers. We analyzed the histopathological features in 141 low-grade invasive breast carcinomas, including 41 special type (tubular, cribriform and mucinous) carcinomas, with available Recurrence Score. The tumor stroma was evaluated for increased cellularity and presence of inflammatory cells. Double immunohistochemical stains for pancytokeratin and Ki-67 was performed to assess the cell proliferation in tumor vs stromal/inflammatory cells. The clinicopathological features of tumors with Recurrence Score <18 (low risk) were compared with those with Recurrence Score ≥18 (intermediate/high risk). Carcinomas associated with Recurrence Score ≥18 showed lower progesterone receptor immunoreactivity, increased stromal cellularity and presence of inflammatory cells associated with the tumor. Double immunohistochemical stains showed significantly increased proliferation in stromal/inflammatory cells compared with carcinoma cells in cases associated with Recurrence Score ≥18. A Ki-67-positive stromal/tumor cells ratio of >1 predicted Recurrence Score ≥18 with an area under the curve of 0.8967 on receiver operator curve analysis (P<0.0001). Our results suggest that the presence of increased stromal cellularity and/or associated inflammatory cells in low-grade invasive breast carcinomas may contribute to an apparently increased risk of recurrence according to Oncotype DX Recurrence Score. Careful assessment and correlation with histopathological features in such cases may help in determining the appropriate patient management.

Invasive ductal carcinomas of the breast showing partial reversed cell polarity are associated with lymphatic tumor spread and may represent part of a spectrum of invasive micropapillary carcinoma.

Invasive micropapillary carcinomas (IMPC) of the breast are aggressive tumors frequently associated with lymphatic invasion and nodal metastasis even when micropapillary (MP) differentiation is very focal within the tumors. We have noticed that some breast carcinomas showing lymphatic spread but lacking histologic features of IMPC have occasional tumor cell clusters reminiscent of those of IMPC without the characteristic prominent retraction artifact. To study the clinicopathologic significance of such features, we prospectively selected 1323 invasive ductal carcinomas and determined the presence and extent of MP differentiation and retraction artifact in the tumors. One representative tumor block per case was used for immunostaining for epithelial membrane antigen (EMA). Partial reverse cell polarity (PRCP) was defined as prominent linear EMA reactivity on at least part of the periphery of tumor cell clusters usually associated with decreased cytoplasmic staining. The clinicopathologic features of carcinomas with PRCP were compared with IMPC and invasive ductal (no special type) carcinomas without this feature. Of the 1323 cases, 96 (7.3%) and 92 (7.0%) showed MP features and the presence of PRCP, respectively. We found that the presence of both PRCP and MP features were strongly associated with decreased cytoplasmic EMA immunoreactivity and the presence of lymphatic invasion and nodal metastasis, even if such features were present only very focally. Our results suggest that breast carcinomas with PRCP may have the same implication as MP differentiation and these tumors may represent part of a spectrum of IMPC. Complete or partial reversal of cell polarity may play a significant role in lymphatic tumor spread.

Analysis of allelic loss as an adjuvant tool in evaluation of malignancy in uterine smooth muscle tumors.

Uterine smooth muscle tumors of uncertain malignant potential (STUMPs) are difficult both from the diagnostic and patient management standpoint because they cannot be classified as benign or malignant by conventional histologic criteria. This studys aim was to determine the diagnostic utility of allelic imbalance (AI) analysis in uterine smooth muscle tumors. Using microdissection and genotyping, we tested 5 leiomyomas, 6 STUMPs, and 10 leiomyosarcomas with follow-up for AI across a panel of seven tumor suppressor genes (p16, p21, p53, VHL, XRCC3, RB, and NM-23). None of the 6 patients with STUMP experienced recurrent disease, whereas 8 of the 10 patients diagnosed with leiomyosarcoma died of disease at follow-up. The mean frequency of allelic loss (FAL) for leiomyomas (18%) was not significantly different from that of STUMPs (21%) (P = 1), whereas leiomyosarcomas displayed a significantly higher FAL (52%) than both leiomyomas (P = 0.001) and STUMPs (P = 0.002). Loss of NM-23, a reported tumor metastasis suppressor gene, was found only in leiomyosarcomas (5 of 9, or 56%), and 4 of 5 (80%) of these were the only cases that demonstrated distant metastases (P = 0.04). Additionally, an FAL of >50% correlated with both NM-23 loss (P = 0.008) and distant metastatic disease (P = 0.04). In conclusion, leiomyomas and STUMPs displayed similar mean FALs and all were clinically benign, whereas uterine leiomyosarcomas had significantly higher frequencies of allelic loss than both leiomyomas and STUMPs. Molecular profiling may thus provide a valuable tool in assessment of malignancy in uterine smooth muscle tumors. Additionally, NM-23 is a promising candidate gene for determination of metastatic potential in these tumors.

Role of Axillary Staging in Women Diagnosed With Ductal Carcinoma In Situ With Microinvasion

BACKGROUND Axillary staging via sentinel node biopsy (SLNB) in patients with ductal carcinoma in situ with microinvasion (DCISM) is routinely performed but remains controversial with regard to the risk-benefit ratio. METHODS Retrospective single-institution review of patients with diagnosis of DCISM (invasive tumor ≤ 0.1 cm). Age, clinicopathologic data, and follow-up were recorded. RESULTS Of 90 patients, 33% were diagnosed by core needle biopsy (CNB), 37% by excisional biopsy, and 29% were upstaged from DCIS on CNB to DCISM at final operation. Three (10%) of 30 patients with DCISM on CNB were upstaged to invasive cancer on final pathology. Median age at diagnosis was 58.9 years (range: 30-89). Lumpectomy was performed in 45% of patients and mastectomy in 55%. Mean number of sentinel nodes was 2.59 (SE 0.17). Six (6.9%) of 87 patients with DCISM as final diagnosis had a positive SLNB (four lumpectomies, two mastectomies). There was no correlation with any clinicopathologic features, including palpable DCIS, DCIS grade/necrosis, or age at diagnosis. All six SLNB-positive patients had a complete axillary dissection; two had additional disease. Median follow-up time was 74.2 months (range: 2-169). In-breast recurrence was seen in three patients (5%), regardless of SLN status, DCIS grade, or necrosis. Two patients developed distant metastasis. Overall survival was 94.19% at 5 years for DCISM and 100% for DCISM with nodal disease. CONCLUSION DCISM comprises 0.6% of breast cancer diagnoses at our institution. There is a low likelihood of nodal spread; however, a lack of identifiable clinicopathologic features associated with a positive SLNB limits selective SLNB use.

Phyllodes tumors: race-related differences.

BACKGROUND Phyllodes tumors (PT) are rare breast malignancies accounting for 0.5% to 1% of all breast tumors. PT have unpredictable behavior, with recurrence rates as high as 40%. A dearth of information exists about racial differences; elucidation of these differences is the objective of this study. STUDY DESIGN A retrospective review of patients treated for PT at either Moffitt Cancer Center or University of Texas Health Science Center San Antonio from 1999 to 2010. RESULTS Of the 124 patients, 71 (57%) were treated at Moffitt Cancer Center and 53 (42%) at University of Texas Health Science Center San Antonio. Mean age at diagnosis was 44 years (15 to 70 years). Thirty-three patients required mastectomy. Combining both cohorts, 42% of the patients were Caucasian, 43% were Hispanic, and 12% were black. Tumors were benign in 49% patients, borderline in 35%, and malignant in 16%, with a higher percentage of borderline and malignant tumors in Hispanic patients (p < 0.01). Hispanic patients tended to have larger tumors and higher mitotic rates (p = 0.01; p = 0.03). At a median follow-up time of 13 months, the local recurrence rate (6.4%) was associated with tumor size, tumor grade, mitotic rate, and close margin status (<2 mm) (p <0.01; p = 0.01; p = 0.01; p = 0.04). However, these findings did not translate into a survival difference by race. CONCLUSIONS In this multi-institutional review of PT we found substantial pathologic differences by race with higher-grade tumors present more often in Hispanic patients. These differences did not substantially affect outcomes at short-term follow-up. Further investigation into additional molecular, biologic factors, geographic impact, and socioeconomic factors is needed to more clearly delineate this finding.

Primary Colorectal Adenocarcinoma Metastatic to the Breast: Case Report and Review of Nineteen Cases

Metastases to the breast from extramammary primaries are uncommon and account for 0.5–6% of all breast malignancies (Georgiannos et al., 2001, and Vizcaíno et al., 2001). Malignant melanoma, lymphoma, and lung and gastric carcinomas are the most frequently encountered nonmammary metastases to the breast in adults (Georgiannos et al., 2001, and Chaignaud et al., 1994). Primary colorectal adenocarcinoma (CRC) metastatic to the breast is extremely rare, with the medical literature having only 19 recorded cases. Typically CRC metastatic to the breast is indicative of widely disseminated disease and a poor prognosis. Here we present a case of poorly differentiated colon cancer metastatic to the breast and review the current literature on this rare event.

Pathologic Tumor Response of Invasive Lobular Carcinoma to Neo‐adjuvant Chemotherapy

Abstract:  Neo‐adjuvant chemotherapy is used for locally advanced breast cancer patients with significant variation in tumor response. Our objective is to determine the clinicopathologic effect of neo‐adjuvant chemotherapy on invasive lobular carcinoma. A review of a single‐institution data base of women diagnosed with breast cancer identified 30 patients from 1999 to 2009 with operable invasive lobular carcinoma who received neo‐adjuvant chemotherapy. Patient demographics and clinicopathologic data were reviewed. Cases were reviewed by a single pathologist (NNE). Residual cancer burden class was determined for each case. Median patient age was 50 years (range 25–79). All tumors were hormone receptor positive and clinical stage II or III carcinomas. Most patients (53.3%) had combination anthracycline‐ and taxane‐based chemotherapy. Therapy‐related changes were noted within the tumor bed in 25 (83.3%) patients. Six (30%) of 20 patients with residual axillary disease had therapy‐related nodal changes. There were 11 patients with moderate residual disease (class II) and 18 (60%) with extensive (class III); there were no complete pathologic responses (class 0). Only one patient (3.3%) converted from mastectomy to breast‐conserving surgery. Four (13.3%) patients developed distant metastases; all had pleomorphic‐type, clinical stage III tumors with residual cancer burden III classification and developed distant disease in the 2 years after surgery (range 0–26 months). Median follow‐up time was 29.5 months (range 7–132). Patients with locally advanced pleomorphic‐type lobular carcinoma appear to develop early post‐treatment metastatic disease. Neo‐adjuvant chemotherapy did not appear to have significant impact on the surgical treatment of patients with invasive lobular carcinoma.

Comparison of breast magnetic resonance imaging clinical tumor size with pathologic tumor size in patients status post-neoadjuvant chemotherapy

BACKGROUND Neoadjuvant chemotherapy (NACT) is used in breast cancer to evaluate the response to treatment. We examined the usefulness of breast magnetic resonance imaging (MRI) in the evaluation of tumor response after NACT. METHODS Breast MRIs of 87 women with MRI after NACT were reviewed. The Spearman coefficient was used for estimating the correlation between MRI and pathologic tumor sizes (ypTs). RESULTS The median age was 50 years (range 25 to 83 years). The median MRI size was 1.25 cm (range 0 to 10 cm). The median ypT was 1.20 cm (range 0 to 10.4 cm). The Spearman coefficient between MRI and ypT was .78 (95% confidence interval, .67 to .85; P < .0001). MRI was found to have a positive predictive value of 92% and a negative predictive value of 64% for residual in-breast disease. The sensitivity and specificity of MRI were 86% and 77%, respectively. CONCLUSIONS MRI correlates well with the final pathology and can be a useful modality to predict residual disease after NACT and aid in surgical planning.

Reply to Bratthauer, Wheeler and Tavassoli

To the editor: We read with interest the article by Esposito et al that appeared in the January 2007 edition of your journal. It essentially corroborates our 2004 study on 27 examples of the same lesion that established the morphologically hybrid nature of tubulolobular carcinomas with an immunophenotype more similar to tubular carcinoma than lobular carcinoma (Wheeler et al). When a tumor is being evaluated for expression of an antibody and the results are compared with those of another study, it is important to apply the same methodologies. As pointed out in one of our previous studies (Bratthauer et al), the high-molecular weight cytokeratin clone 34bE12 is not by itself suitable for the distinction of classic lobular neoplasia from ductal or hybrid neoplastic lesions and that it is of value only when used in tandem with E-cadherin immunostains. This earlier report also pointed out that for immunohistochemical staining of 34bE12, a heat retrieval form of antigen recovery was used—not the proteolytic enzyme digestion performed in the study by Esposito et al. Although it is possible that the subset of lobular, tubulolobular, and tubular carcinomas used in Esposito et al’s study may have reacted differently with 34bE12 compared to the cases we reported, comparisons are valid only when exactly the same methodologies are used. It would be of interest to repeat the high-molecular weight cytokeratin (34bE12) assay on Esposito et al’s tumor samples with a pH 6.0 heat retrieval pretreatment to see if the results are any different than those obtained using enzyme digestion.