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10.1245/ASO.2006.03.047
Annals of Surgical Oncology 13:45-51 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Preoperative Profiling of Symptomatic Breast Cancer by Diagnostic Core Biopsy

Ronan A. Cahill, AFRCSI1, Daniel Walsh, FFRRCSI2, Rob J. Landers, MRCP3 and R. Gordon Watson, FRCSI1

1 Department of Surgery, Breast Care Unit, Waterford Regional Hospital, Waterford, Ireland
2 Department of Radiology, Breast Cancer Unit, Waterford Regional Hospital, Waterford, Ireland
3 Department of Pathology, Breast Cancer Unit, Waterford Regional Hospital, Waterford, Ireland

Correspondence: Address correspondence and reprint requests to: Ronan A. Cahill, AFRCSI; E-mail: rcahill{at}rcsi.ie


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Precise preoperative profiling of breast tumors could facilitate fuller consideration of (neo)adjuvant therapies.

Methods: Diagnostic core biopsy (DCB) accuracy in profiling the primary tumor was prospectively studied in 95 patients with operable breast cancer. The histological type and grade (hematoxylin and eosin staining) and membrane receptor status (semiquantitative immunohistochemistry for estrogen [ER] and progesterone [PR] receptors, as well as Her-2 antigen expression) were assigned by the DCB before surgery. These measures were then compared with those of the definitive surgical specimen available after operation.

Results: DCB correctly ascribed tumor type and grade and ER, PR, and Her-2 receptor status in most cases (correlating exactly in 97.5%, 77%, 68%, 71%, and 60%, respectively) with at least moderate concordance (weighted {kappa}, >.41). When miscategorized, DCB consistently tended to upscore the receptor stain intensity compared with the surgical specimen (22%, 19%, and 27% had higher ER, PR, and Her-2 categorical scores, respectively). ER H-scores correlated best in specimens that stained strongly (224.4 ± 3 vs. 215.5 ± 5) and were significantly higher on DCB in those that stained either moderately (195.6 ± 8.2 vs. 156.8 ± 5.1; P < .0001) or weakly (157.1 ± 24.8 vs. 81.4 ± 4; P = .02). DCB accurately identified all tumors with clinically important ER and Her-2 expression. Furthermore, it promoted three patients into the therapeutically significant range of ER (n = 1) or Her-2 (n = 2) expression. ER negativity on DCB (n = 25) indicated a high-grade tumor (88%), although 11 (44%) patients also overexpressed Her-2. Significant Her-2 expression (n = 16) on DCB predicted the tumor as being poorly differentiated (80%) and both ER and PR negative (67%).

Conclusions: DCB accurately profiles clinically relevant measures of primary tumor cell differentiation. It also reliably categorizes patients with regard to (neo)adjuvant therapy before radical surgery is attempted.

Key Words: Preoperative • Profile • Breast cancer • Core biopsy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Most patients with operable breast cancers currently undergo definitive surgery as the sine qua non of multimodal breast cancer treatment. This is because the cellular characteristics of the primary tumor (along with axillary nodal status) are still the predominant measures used to ascribe prognosis and guide systemic treatment decisions. Therefore, the ability to precisely profile primary breast cancer before the performance of definitive surgical resection could allow fuller consideration of adjuvant treatment options and, perhaps, better selection of those likely to benefit from prioritization of systemic therapy over initial local treatment.

Although accurate determination of lymph node involvement is limited without recourse to axillary surgery, the tumor grade, hormonal receptor status, and Her-2 antigen expression may all be estimated at presentation by careful analysis of diagnostic core biopsy (DCB) specimens. In addition to being used to improve patient education and consent before surgery, this information may help to identify patients whose disease is likely to be only debulked rather than eradicated by resection of the primary tumor (i.e., those who are assumed to have localized disease by current staging techniques but who actually have systemic dissemination). Furthermore, the DCB specimen may be the only tissue reflective of the primary cancer that is available for pathologic scrutiny in those who obtain a complete pathologic response to neoadjuvant therapy.

In this study, we prospectively examined the predictive power and clinical utility of DCB in profiling the cellular characteristics of the primary tumor that would be likely to influence patient survival and adjuvant therapy consideration in comparison with the characteristics of the subsequent full specimen examination (FSE) performed after definitive surgery.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Consecutive women who presented with symptomatic, operable breast cancer of any stage were studied in real time over 3 years. All patients underwent diagnostic ultrasound-guided DCB before their definitive surgical treatment. A median of four (interquartile range, three to five) DCB specimens were taken from each tumor by using an 18-gauge Tru-cut needle (Tru-cut®, Allegiance Health-care Corp., McGaw Park, IL). These specimens were then examined to ascribe the type and grade (Bloom Richardson grading of hematoxylin and eosin–stained specimens) of the invasive component of the primary tumor, as well as its estrogen receptor (ER), progesterone receptor (PR), and Her-2 expression (by means of semiquantitative immunohistochemistry) before the patient underwent operation. ER, PR, and Her-2 staining were classified categorically as being absent or weakly, moderately, or strongly present. Clinically important expression was considered present when specimens stained at least weakly in cases of ER and PR status or strongly in cases of Her-2 antigen–expression status. Additionally, ER expression was directly quantified by means of H-scoring in both the DCB and FSE specimens.

DCBs were compared with their corresponding FSE by means of Student’s t-test, Pearson correlation, and weighted {kappa} (w{kappa}) statistic determination with Analyse-it (Analyse-it Software Ltd., Leeds, UK) software on Microsoft Excel (Microsoft Corp., Redmond, WA) data sheets. The w{kappa} statistic calculation is the result obtained by a formal test for concordance between two variables that allows for the level that might be expected by chance alone.1–3 The resulting score may be categorized arbitrarily to allow easier interpretation of the meaning of the statistic (Table 1Go).4


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  		TABLE 1. Levels of agreement suggested by weighted {kappa} statistics
 

   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
In total, 95 patients were studied (mean age, 60.7 years; range, 39–82 years). Eighty-five patients had ductal carcinoma; the remainder had lobular carcinoma. There were 22 T1 tumors, 53 T2 tumors, and 20 T3 tumors. Fifty-four patients had high-grade (grade III) tumors, 37 had grade II cancers, and 4 had grade I cancers. Twenty-six percent (n = 25) of the patients were ER negative, and 15% (n = 14) of the specimens demonstrated Her-2 overexpression (+3 staining) on FSE.

Tumor Typing
Overall, tumor type as estimated by DCB correlated highly with that of the FSE (96%; w{kappa}, .78). This was particularly accurate when DCB predicted a ductal pattern (97% were predicted correctly; Table 2Go). However, when "lobular type" was ascribed on DCB (n = 10), the predictive rate decreased to 80%.


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  		TABLE 2. Correlation between tumor typing in the diagnostic core biopsy and the final surgical specimen (n = 95)
 
Tumor Grading
DCB correctly predicted the grade of the fully resected specimen in 67 cases (70%; w{kappa}, .46; Table 3Go). The grade of the FSS was, however, underestimated in 13 cases (14%) and overestimated in 14 (15%). DCB judged 51 tumors as grade III and was accurate in 40 cases (accuracy rate, 78%), and it scored 28 tumors as grade II (accuracy rate, 64%). However, the predictive value of DCB decreased to 50% in tumors adjudged to be the lobular type on biopsy (as compared with 73% accuracy in tumors ascribed a ductal pattern on DCB).


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  		TABLE 3. Correlation between tumor grading in the diagnostic core biopsy and the final surgical specimen (n = 95)
 
Immunohistochemistry
Overall, there was an excellent correlation between clinically significant levels of ER and Her-2 (i.e., whether positive or negative in the case of ER and whether overexpression was present or absent for Her-2 staining). The biopsy correctly identified every cancer with such expression (Tables 4Go–6GoGo). Furthermore, the biopsies scored three patients as having clinically significant antigen expression (ER, n = 1; Her-2, n = 2), even though the corresponding FSE judged the specimen staining to be insignificant.


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  		TABLE 4. Correlation between the ER status on diagnostic core biopsy and that of the final surgical specimen
 

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  		TABLE 5. Correlation between the PR status on diagnostic core biopsy and that of the final surgical specimen
 

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  		TABLE 6. Correlation between the Her-2 expression on diagnostic core biopsy and that of the final surgical specimen
 
On closer examination of ER, PR, and Her-2 scores by categorical staining (i.e., whether staining was absent, weakly present, moderately present, or strongly present), the biopsies correlated correctly in 70%, 72%, and 64% of cases, respectively. The corresponding w{kappa} statistics were .74, .72, and .57, respectively. In the cases that did not correlate exactly, the biopsies tended to consistently upscore the specimen (staining categorically higher in 21%, 19%, and 26% of cases with regard to ER, PR, and Her-2 expression, respectively). ER H-scoring correlated well between DCB and FSE, with an R value of .89 (Fig. 1Go). Examination by the categorical divisions of stain intensity showed that the DCB/FSE correlation was best in the specimens that stained strongly (224.4 ± 3 vs. 215.5 ± 5), whereas DCB scores tended to be significantly higher in those that stained only moderately (195.6 ± 8.2 vs. 156.8 ± 5.1; P < .0001; Student’s t-test) or weakly (157.1 ± 24.8 vs. 81.4 ± 4; P = .02; Student’s t-test).


Figure 1
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  		FIG. 1. Correlation between the estrogen receptor H-score as determined on diagnostic core biopsy with that of the final surgical specimen (n = 95; Pearson correlation R value = .89; 95% confidence interval, .84–.93).

 
Tumor Profiling by DCB
When the tumor was characterized as a high-grade ductal carcinoma on DCB, the ER and Her-2 categorical status between DCB and FSE concorded highly (w{kappa} statistics of .82 and .64, respectively, with ER H-scores; Pearson correlation R statistic, .93). When the biopsy determined the tumor as being ER negative (n = 25), the FSE tended to indicate a high grade (88%), whereas 11 of these tumors (44%) also overexpressed Her-2. However, although Her-2 status assignment by category of stain expression was excellent (w{kappa}, .85), the concordance of grade assignment between DCB and FSE was poor in this group (w{kappa}, .17). Significant Her-2 expression on DCB (n = 16) was associated with a tumor on FSE that was high grade (81% of tumors) and both ER and PR negative (69% of tumors), as compared with those that expressed Her-2 less intensely (51% of which were poorly differentiated, whereas 15% were both ER and PR positive). However, although the concordance of ER assignment between DCB and FSE was excellent in tumors found to be Her-2 positive on DCB (w{kappa}, 1.0), the grade assignment was only fair (w{kappa} .29). The tumor type concordance was excellent (w{kappa}, 1.0) in tumors determined on DCB to be either ER negative or Her-2 positive.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The survival of patients with breast cancer is determined by the development of distant metastases, which presumably represent the expansion of tumor deposits that are already present (even if inapparent) at the time definitive local control is attempted. Currently, however, our ability to accurately identify and quantify systemic disease burden is limited (radiological tests are constrained by the sensitivity of their resolution, and direct means of identifying distant dissemination—such as analysis of bone marrow for the presence of micrometastases—are, as yet, unproven). Therefore, prognostic inferences and subsequent therapeutic decisions are based on estimations of the likelihood that systemic cancer cell dissemination has occurred by the use of such indirect markers as tumor size and lymph node involvement, as well as indicators of the likely biological behavior of the cancer, such as hormonal and growth factor receptor expression.

However, in general, these measures of the primary tumor’s metastatic potential are available only after surgical resection is performed. Because many authors advocate increasing the role of primary chemotherapy in patients with a high risk of disease dissemination,5,6 maximizing the information gained before surgery is becoming increasingly important. This is especially true for patients who obtain a complete pathologic response to their neoadjuvant therapy, because otherwise there may be no actual specimen for pathologic examination. Furthermore, there is concern that use of neoadjuvant strategies may alter the expression of prognostic markers in the primary tumor, and so pathologic analysis of the residual tumor specimen may not accurately reflect the original cancer.7

Recently much attention has focused on improved molecular and genetic profiling of the primary tumor to risk-stratify patients. This is because methods of estimating tumor size before surgery have been limited by poor correlation with the tumor size recorded at pathologic assessment8,9 or (in the case of magnetic resonance imaging) the lack of widespread availability and high cost. Furthermore, although assessment of lymph node status either before10 or during11 definitive surgery is being proven possible in highly specialized centers, it is becoming increasingly apparent that this means of estimating the biological behavior of breast cancer is imperfect (one third of patients without lymphatic metastases still develop distant disease occurrence). Finally, although undoubtedly of great promise for the future,12 a definitive genetic signature for breast cancer (along with a clinically useful means of detecting it) has as yet proven elusive.13

Our study confirms, and expands on, those of other groups who have investigated and established the efficacy of DCB in precisely profiling the cellular and biological characteristics of primary breast cancer.14,15 Although fine-needle aspiration was initially the diagnostic measure of choice in triple assessment clinics because of its relative inexpense and facility for rapid analysis, it has steadily been superseded by DCB as a result of this procedure’s lower inconclusive rate and the additional histological information it provides.16 This is especially true when it is used in conjunction with ultrasonic guidance to specifically target the tumor center.

In addition to calculating raw concordance statistics, we have also included {kappa} statistic calculation in the recognition that the former can often give a falsely optimistic assessment of test performance.17 Their value is particularly evident in this study in the mismatch between their assessment of the value of DCB in attributing the grade in ER-negative and Her-2–positive tumors and the correlation which is misleadingly implied by the raw concordance data in these patients. However, it is worth considering that comparison with the FSE may not be the most appropriate recognition of the value of DCB analysis in breast cancer. The DCB analysis reflects the characteristics of the area of the primary tumor that it has sampled, and its sensitivity in comparison to the overall FSE may be affected by regional differences in the differentiation of the primary tumor. Therefore, for example, it may be that recognition of foci of high-grade tumor cells or ER-positive cells may mean that, even if the primary tumor as a whole is not judged to share these characteristics, it may be worth considering the patient for adjuvant therapy on the basis that a subset of cancer cells may be targeted.

We have demonstrated that primary ductal carcinoma may be excellently typed by DCB. Additionally, we have demonstrated that DCB can predict the grade at FSE of lobular carcinoma, although the validity of grading this tumor type has been previously considered somewhat controversial.18 Although the number of these cancers in our study was small, the accuracy of DCB in identifying such cancers before surgery means that it may allow consideration of wider surgical resection than may otherwise be recommended.19 Grade assessment by DCB reflected that of the primary tumor moderately well, being most accurate in high-grade tumors (because, most likely, of the weighting given to grade in the calculation of the Bloom-Richardson score). This may be particularly important for patients with smaller tumors, because knowledge of the presence of a high-grade component in the tumor may advocate against their selection for lymphatic mapping and sentinel node biopsy (a significant proportion of patients with high-grade tumors have axillary metastases, regardless of their tumor size).

DCB was also determined as being an accurate means of ER, PR, and Her-2 estimation. Although previously there has been some discussion over the appropriateness of immunohistochemistry in determining Her-2 antigen staining, it has now been accepted as a valid and reliable technique.20 Therefore, DCB analysis allowed the correct classification of patients according to their appropriate adjuvant therapeutic options in every case before definitive surgical control was attempted. In addition to guiding postoperative endocrine manipulation strategies, this information about hormone receptor status may be an indicator of the pathologic response to neoadjuvant chemotherapy.21 Furthermore, this information may also be used to facilitate the consideration of additional surgical procedures (such as oophorectomy in premenstrual patients) at the same time as the patient undergoes definitive breast surgery.

More intriguing, perhaps, is the propensity for the DCB to upscore the FSE and, in particular, its categorical promotion of three patients’ antigen expression into clinically important categories of ER and Her-2 expression. Although this may represent an effect of sampling areas of differing cellular differentiation, it may also be explained by differing rates of formalin penetration into the specimens. The more complete fixation that may occur in the smaller DCB samples compared with the large FSS may improve the degree of tissue staining, as has been suggested previously.22 If this is the case, it means that DCB is in fact the truer reflection of biological behavior in certain cancers, and so deference should be given to its measure of ER and Her-2 staining so that patients are not deprived of potentially beneficial therapies (i.e., tamoxifen or trastuzumab [Herceptin; Genentech Inc., South San Francisco, CA]). Even if this is not the case, the fact that even a portion of the tumor cells are hormonally responsive means that adjuvant endocrine manipulation may still be of some benefit to the patient. Furthermore, this tendency may contribute in part to the apparent alteration of the tumor marker expression of the primary cancer by neoadjuvant chemotherapy.7,23

Although both the ER and PR status indicate the patient’s prognosis, we believe the ability of DCB to recognize Her-2 overexpression of the primary tumor to be particularly important. Her-2 gene expression has been consistently shown to confer adverse prognostic implications to the patient independently of all other prognostic variables.24 When clinically important Her-2 staining is found on DCB, the corresponding tumor is likely to be poorly differentiated, as well as ER and PR negative—a finding similar to that already established with regard to FSE Her-2 status.25–28 Such protein overexpression (when found on FSE) indicates a high incidence of early relapse after potentially curative surgical resection and a poor likelihood of response to hormonal means of manipulation.29–31 The high-level concordance for ER status tumors found to be Her-2 overexpressing on DCB may have particular clinical relevance given that the choice of endocrine-manipulative therapies may be strongly affected by this information.32 Furthermore, Her-2 overexpression in the primary tumor may also indicate an increased sensitivity to anthracycline-based chemotherapeutic regimens33 and, perhaps, paclitaxel.34 It also allows consideration of trastuzumab as a potential adjunct to first-line chemotherapy35,36 or as a second-line agent in the case of disease progression.37 With these points in mind, Her-2 overexpression on DCB may indicate that surgical resection (however radical) is unlikely to provide cure and should perhaps be performed only with palliative intent. Instead, this information may be used to facilitate the prioritization of systemic treatment over operation. In particular, it may be that axillary clearance may be best avoided in such patients,38 perhaps in favor of sentinel node biopsy as a simple, minimally invasive means of staging the axilla.

Therefore, DCB may accurately identify patients with poorly differentiated cancers and, in doing so, those who are likely to have metastatic disease. It has been previously suggested that both ER and PR status, as well as Her-2 expression on FSE, may augment prognostic indices in predicting outcomes for both high-risk39 and node-negative40 women. Having this information before surgery may instead allow for variations of prognostic scoring systems, such as the Nottingham Prognostic Index,41 to be developed, perhaps using sentinel node involvement instead of complete axillary clearance as a means of selecting patients for early chemotherapy rather then proceeding with radical treatment aimed only at providing local control (which may not affect survival likelihood42).

In conclusion, precise profiling of the cellular characteristics of the primary tumor without recourse to full surgical resection may represent an effective and readily incorporated means for most physicians involved in breast cancer care to begin to better individualize (neo)adjuvant treatment selection. Further study is, however, needed to establish whether it may be a more accurate and/or more efficient measure of the cellular characteristics of the primary cancer and to determine the prognostic relevance of the discovery of these markers on biopsy specimens.

Received for publication March 4, 2005. Accepted for publication August 7, 2005.


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TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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