Tumor Size

Tumor size is one of the most important prognostic markers of invasive breast cancer. It is defined as the maximal size of the invasive component of the primary tumor on pathologic examination. Clinical evaluation of tumor size has been included in many staging systems as an independent predictor of survival. The potential for metastasis increases in a linear relationship with the size of the primary tumor ( Fig. 37.1 ). Furthermore, there is a distinct relationship between increasing tumor size and the probability of axillary nodal metastasis. These investigators demonstrated that tumors must reach 3.1 to 4 cm in diameter to generate axillary metastasis in 50% of patients ( Table 37.2 ). Fisher has likewise shown that tumor size correlates with disease-free survival at 10 years, even when controlled for nodal metastases ( Fig. 37.2 ). Tumor size is particularly useful as a prognostic tool in patients with no involvement of regional lymph nodes and may alter adjuvant treatment options. For instance, patients with small tumors (<1 cm) who have lymph node–negative disease have an excellent overall prognosis. A study from the Surveillance, Epidemiology, and End Results (SEER) Program demonstrated that the 10-year breast cancer–specific mortality in this group of patients is only 4%, whereas their overall mortality is 24%. Thus, patients with small tumors with lymph node–negative disease have a fivefold higher risk of dying from causes other than breast cancer. It is also true, however, that patients with small tumors can have metastasis to the axillary lymph nodes, and conversely, more than one-third of patients with tumors greater than 6 cm in palpable diameter have negative lymph nodes, thus demonstrating the limited predictiveness of tumor size alone.

A linear relationship exists between tumor size (volume or diameter) and potential for metastases.

(From Koscielny S, Tubiana M, Lê MG, et al. Breast cancer: relationship between the size of the primary tumor and the probability of metastatic dissemination. Br J Cancer. 1984;49:709.)

Primary tumor size correlates with disease-free survival in patients undergoing curative surgery.

(From Fisher ER. Prognostic and therapeutic significance of pathologic features of breast cancer. NCI Monogr. 1986;1:29.)

Tumor Location

Tumor site is generally not included as a prognostic factor to identify patients at higher risk of relapse. However, tumor location has a significant prognostic utility, especially for axillary lymph node–negative patients. Several investigators from single institutions and data obtained from SEER have found that medial and central locations of tumor are associated with a 29% to 46% increase risk of developing systemic relapse and 20% to 46% increase risk of breast cancer–related death compared with the lateral location. A study from the International Breast Cancer Study Group that included more than 8000 patients confirmed these results but also demonstrated that the risk of relapse for patients with medial tumors was largest for the lymph node–negative patients and for patients with tumors larger than 2 cm ( Fig. 37.3 ). Furthermore, a recent study demonstrated that lower inner quadrant tumors have the highest risk of mortality compared with other locations in women with early lymph node–negative breast cancer. A proposed mechanism for the increased risk of metastases and death from breast cancer from medial tumors is occult involvement of internal mammary nodes (IMNs) that are not systematically treated with either surgery or radiation therapy. In fact, there is growing evidence that the lower inner quadrant drains more often to the IMNs than the other quadrants.

(A) Disease-free survival and (B) overall survival according to predominant site of primary tumor.

(From Colleoni M, Zahrieh D, Gelber RD, et al. Site of primary tumor has a prognostic role in operable breast cancer: the international breast cancer study group experience. J Clin Oncol. 2005;23:1390.)

Tumor Histology

The great majority of breast carcinomas are adenocarcinomas that derive from the mammary glandular epithelial cells, most commonly cells from terminal ductal lobular units. Breast cancer is a heterogenous disease with up to 21 histologic subtypes. The most common type was classified as invasive ductal carcinoma, not otherwise specified (NOS); however, the nomenclature was recently changed by the World Health Organization (WHO) in 2012 to invasive carcinoma of no special type (NST). Approximately 25% of invasive breast cancers are classified as special types of breast cancer and show distinctive growth patterns, cytologic features, clinical presentation, and behavior. Next to inflammatory carcinoma, which is the most aggressive form of primary breast cancer with a 5-year survival rate of approximately 50%, pleomorphic lobular, metaplastic, and micropapillary carcinomas carry a poor prognosis. Tubular, cribriform, mucinous, papillary, medullary, and adenoid cystic subtypes have more favorable prognoses.

Tumor Grade

Histologic grading is a strong predictor of overall and disease-free survival in patients with invasive breast cancer; it is felt to be equivalent to lymph node status based on a number of independent studies. Nuclear grading is the cytologic assessment of tumor cells and it is applied to all invasive and in situ carcinoma of the breast. The WHO endorses a histologic grading system based on criteria established by Bloom and Richardson and Elston and Ellis, known as the Nottingham Grading System. This grading system incorporates three cytoplasmic and nuclear characteristics including extent of nuclear pleomorphism, degree of tubule formation, and number of mitotic features. Hensen and colleagues performed a SEER review of 22,616 cases of breast cancer and calculated 5-year survival rates based on grade alone. Survival at 5 years was estimated to be 93% for grade 1, 82% for grade 2, and 65% for grade 3. In addition, when evaluating grade and stage together, they noted that women with stage II disease and grade 1 tumors had the same survival rates as women with stage I disease and grade 3 tumors, suggesting that incorporating grade into current staging systems could help more accurately predict outcome.

Similarly, Fisher and colleagues examined histologic grade in relationship to 5-year treatment failures and found that there is a significant correlation between these two factors in patients with absent nodal metastases or with four or more positive lymph nodes. Furthermore poor histologic grade is a significant predictor of pathologic complete response (26%) compared with good histologic grade (14%) in the setting of neoadjuvant chemotherapy.

Histopathologic Features of Tumor

Fisher and associates examined the relationship of pathologic and clinical characteristics to 5-year survival in 1000 patients treated with radical mastectomy. Although they found that pathologic nodal status was the most dominant influence on treatment failure rates and corresponding survival, they also identified a number of other important predictors of short-term (<24 months) treatment failure. Characteristics such as perineural invasion, absence of sinus histiocytosis, presence of glycogen, and skin involvement correlated with poor long-term survival. Tumor necrosis was also associated with a poor clinical outcome. However, independent prognostic significance of this histologic feature is not established in the literature. Furthermore, quantification of necrosis has not been standardized.

Other histologic characteristics have also been found to bear prognostic information. These include lymphovascular invasion, elastosis, glycogen staining, and the presence or absence of numerous host inflammatory responses. Evaluation of lymphovascular invasion is particularly important in small lesions without nodal involvement because it can identify patients with high risk of recurrence. In addition, it has also been found to have a strong association with breast cancer–specific survival and distant disease free survival. On the contrary, presence of tumor-infiltrating lymphocytes has been associated with improved overall survival and distant disease-free survival, especially in triple-negative breast cancers.

Estrogen and Progesterone Receptors

Both estrogen receptors (ER) and progesterone receptors (PR) are essential prognostic indicators in patients with breast cancer, and more importantly, they are highly predictive of benefit from endocrine therapy in both the adjuvant and metastatic settings. Knight and colleagues and Osborne and McGuire have shown that ER status affects survival, independent of axillary nodal status with ER positivity generally correlating with a better prognosis. Similarly, another study has demonstrated longer survivorship for PR-positive patients than for PR-negative patients. Receptor status has also been shown to be predictive of response in patients receiving chemotherapy. In the neoadjuvant setting, several studies have confirmed that ER-negative tumors are more likely to decrease in size in response to chemotherapy. However, although ER-negative tumors are more likely to achieve pathologic complete response with neoadjuvant chemotherapy, affected patients have less favorable 5-year overall and progression-free survival rates compared with those with ER-positive disease. One proposed explanation for this finding was the beneficial effect of postoperative hormonal therapy available to patients with ER-positive tumors, which could supersede the significance of achieving pathologic complete response in this setting.

HER2/neu Expression

HER2/neu-positive phenotype accounts for about 15% of patients. Amplification or overexpression of HER2/neu has been found to portend a poor prognosis, correlating with other factors associated with poor prognosis such as tumor grade, size, nodal status, and hormone receptor status. Furthermore, it is also considered a predictive factor in that it predicts response to targeted therapy.

Tumor Growth Rate and Proliferation

Anatomic methods for staging breast cancer have withstood the test of time and remain the gold standard; however, these methods often provide only a static or instantaneous view of what is actually occurring at the molecular and cellular levels. Attempts at measuring dynamic characteristics (clinical and pathologic) have also been predictive of tumor progression. Clinical measurements of flux of tumor volume over time and pathologic determinations of cell kinetics have both been useful. Most of breast cancer prognostic factors are directly or indirectly related to proliferation, and increased proliferation correlates strongly with poor prognosis, irrespective of the methodology used to assess proliferation. Measurements of tumor doubling time, although not clinically practical, have been shown to correlate with prognosis. Multiple studies have demonstrated a wide range of doubling times, not only between patients but also within the same patient over time. This heterogeneity is typical of breast cancer. Evaluation of tumor cell kinetics through growth fraction estimates has been used for the assessment of proliferation rate and its relation to prognosis. The growth fraction can be assessed by immunohistochemistry (IHC) of proliferation-associated antigens, such as ki67, cyclin A, cyclin D, cyclin E, p27, p21, thymidine kinase (TK), topoiso­merase IIα, proliferating cell nuclear antigen (PCNA), geminin, or minichromosome maintenance (McM) proteins. Of these, ki67 has extensively been studied alone or with MIB1, which is an antibody that reacts against ki67. There is a good correlation between ki67 and MIB1 staining, and a pronounced decrease in the ki67/MIB1 labeling index is associated with a good response to preoperative treatment with chemotherapy or tamoxifen. In a recent review by Luporsi and coworkers, ki67 was found to be significantly associated with disease-free survival with seven randomized controlled trials and two meta-analyses in multivariate analysis. In addition, in the neoadjuvant setting, an elevated ki67 was associated with a higher likelihood of complete pathologic response.

Flow cytometry has recently been used to estimate cellular kinetics and to detect the presence of aneuploidy. Flow cytometry permits rapid, single-cell analysis of DNA content per cell, enabling the determination of the fraction of cells within the S phase and the ploidy levels within tumor cell proliferation. However, despite extensive literature on flow cytometry, the results obtained by this method are still not widely used in everyday practice, because there is high intratumor heterogeneity of the S-phase fraction and multiple methodologies to determine S-phase fraction by flow cytometry. In general, a high S-phase fraction is associated with a higher risk of metastatic recurrence in lymph node–negative patients. Furthermore, it has been suggested that flow cytometry also influences the response to chemotherapy in neoadjuvant, adjuvant, and metastatic settings.

Other methods used to assess the growth fraction are the incorporation techniques with tritium-labeled thymidine (3H-TdR) and bromodeoxyuridine (BrdU), which theoretically provide the gold standard of cellular proliferation. These methods are more sensitive than standard histologic tests that enumerate the relative number of mitoses and have demonstrated some promise in their ability to identify aggressive, rapidly growing tumors. With tritiated thymidine, tumor cells are sampled from the specimen and then incubated with 3H-TdR, which is taken up by cells in the DNA synthetic or S phase. Measuring 3H-TdR uptake then permits the estimation of the percentage of cells in the S phase (thymidine labeling index). Many studies have shown that a high thymidine labeling index is associated with poor prognosis in lymph node–positive and –negative patients with breast cancer, and patients with a high index benefit from adjuvant chemotherapy. However, incorporation techniques can be tedious and time-consuming, and they are impractical for routine use; this hampers their worldwide application, despite the very good prognostic value of the thymidine labeling index. This index does, however, correlate with histologic characteristics such as tumor grade and may be important in the staging of lymph node–negative patients.

One the most powerful, practical, and well-reproduced indicators of proliferation and prognosis is the mitotic activity index (MAI). As mentioned previously, MAI is part of the histologic grade system and represents by far the most important contributor to the prognostic value of histologic grade. The proliferation factor MAI is one of the strongest prognostic factors in patients younger than 71 years with lymph node–negative invasive breast cancer, without adjuvant systemic treatment and with long-term follow-up. Moreover, patients with rapidly proliferating tumors significantly benefit from adjuvant systemic therapy, in contrast to those with low proliferation. Recently, Baak and colleagues demonstrated that among women with small, low-grade, lymph node–negative invasive breast cancer who usually do not receive systemic therapy, MAI (≥10/1.6 mm ² ) was able to identify accurately those patients at high risk of distant metastatic disease or death. The 10-year overall survival rates for MAI less than 10 versus 10 or higher in women with tumor diameter less than 1 cm were 94% and 67%, respectively ( Fig. 37.4 ). The authors concluded that these high-risk patients identified by MAI should be considered for adjuvant systemic therapy.

Overall survival associated with mitotic activity index (MAI) in patients with tumors less than 1 cm diameter (all grades) (A), 1 to 2 cm (grades 1 + 2) (B), and 2 to 3 cm (grades 1 + 2) (C).

(From Baak JP, van Diest PJ, Janssen EA, et al. Proliferation accurately identifies the high-risk patients among small, low-grade, lymph node-negative invasive breast cancers. Ann Oncol. 2008;19:649–654.)

Axillary Nodal Disease

Results of a national survey by the American College of Surgeons (ACS) involving 20,547 women with breast cancer clearly demonstrated a strong linear association between the number of histologically involved axillary nodes and 5-year survival ( Fig. 37.11 ). Furthermore, in a 10-year clinical trial, Fisher, Fisher, and Redmond, reporting for the NSABP, found that patients with negative axillary lymph nodes had 5- and 10-year survival rates of 78% and 65%, respectively. Similarly, the number of positive nodes correlated with the 5- and 10-year treatment failures. No positive nodes was associated with a 20% treatment failure rate at 10 years, whereas more than four positive nodes was associated with a 71% treatment failure rate. Not only is axillary lymph node metastasis a time-dependent variable, but it also seems to be a marker for a more aggressive tumor phenotype. Jatoi and associates have shown that patients with four or more involved lymph nodes at the time of initial diagnosis have a significantly worse outcome after their first recurrence ( Fig. 37.12 ).

Survival of breast cancer according to number of histologically involved axillary lymph nodes.

(From Nemoto T, Vana J, Bedwani RN, et al. Management and survival of female breast cancer: results of a national survey by the American College of Surgeons. Cancer. 1980;45:2917.)

Survival after first relapse by number of positive axillary lymph nodes.

(From Jatoi I, Hilsenbeck SG, Clark GM, Osborne CK. Significance of axillary lymph node metastasis in primary breast cancer. J Clin Oncol. 1999;17:2334.)

Although axillary nodal status is an important prognostic indicator, its therapeutic role is more to clear the axilla of gross disease. Historically, there was a push to perform extensive axillary dissections to obtain accurate prognostic information. Certainly, complete dissection of all three levels of lymph nodes (Patey dissection) not only provided the maximum amount of prognostic information but also cleared the axilla of gross disease and was thought to obviate the need for axillary irradiation. Before the advent of SLN techniques, several studies addressed the extent of axillary dissection and determined that, in certain cases, a level 1 dissection could be predictive of the actual involvement of the remaining nodal basin. Boova and colleagues examined the contents of 200 consecutive mastectomy and total axillary dissection specimens. The average number of lymph nodes recovered from each level was 14 at level 1, 11 at level 2, and 8 at level 3. Of the patients, 40% had axillary metastases, with half of these involving only level 1 ( Table 37.3 ). Interestingly, seven patients (3.5% of all patients and 8.7% of those with lymph node metastases) had positive nodes at level 2 and/or 3 without positive nodes at level 1 (skip metastasis). These authors concluded that level 1 dissections could be accurate predictors of the status of the entire axillary lymph node basin, assuming that an adequate number of lymph nodes has been sampled. Fisher and coworkers also suggested that dissection of levels 1 and 2 is more than adequate in most cases to accurately predict prognosis. The current standard of care for a complete axillary lymph node dissection includes both level 1 and level 2 lymph nodes with procurement of at least 10 lymph nodes.

Sentinel Lymph Node Mapping

The introduction of SLN mapping technology has challenged the classic approach to breast cancer staging that involves routine axillary lymph node dissection. The SLN concept supports the notion that breast cancer cells spread in an orderly fashion via direct lymphatic communication from the primary tumor to the SLN. Therefore the SLN is most likely to be the first site of metastasis within the lymph node basin. Currently, SLN mapping for breast cancer has become the primary means for accurately assessing nodal metastasis. On average, one to three SLNs may be found within an axillary basin. A number of large, single, and multiinstitutional trials have now demonstrated the accurate predictability of the SLN technique in staging the axilla in breast cancer patients by using various injection techniques with technetium sulfur colloid, isosulfan blue, or a combination of both agents. The optimal technique for most is a combination of blue dye and technetium sulfur colloid. A SLN identification rate of more than 95% is the rule, with accuracy rates exceeding 95% and a false-negative rate of approximately 2%. A well-trained multidisciplinary team must be systematically assembled to ensure the success of the procedure. Long-term follow-up is needed to define the true false-negative rate—that is, to identify axillary recurrences in patients with breast cancer with negative SLNs and no complete axillary dissections. Initial studies suggest that this risk is less than 1% (0.2%–0.3%).

In addition, the accuracy of the SLN mapping technique is enhanced by the ability to improve on the histologic examination of the lymph node when 1 to 3 lymph nodes, as opposed to 15 to 20 lymph nodes, in a complete node dissection are submitted for a more detailed examination. Routine histologic examination with serial step sectioning and H&E staining is performed to identify tumor deposits within the lymph node. Furthermore, IHC, with cytokeratin assays, shows an increased rate of detection of occult micrometastatic disease, further improving the accuracy of the technique. Cote and colleagues noted that occult nodal metastases were detected in 7% of patients with H&E sections and in 20% with IHC. Other investigators have also shown the increase in detection of occult micrometastatic disease in patients who were determined to be lymph node–negative based on routine histologic methods. In a study by Schreiber and associates, up to 9.4% of the patients were upstaged with the addition of IHC and serial sectioning. However, to date the clinical significance of identifying micrometastatic and submicrometastatic disease as a prognostic variable is controversial. A population-based analysis by Chen and coworkers evaluated 209,720 patients with invasive breast cancer without distant metastases and no more than three axillary nodes using the SEER registries. Overall, patients with micrometastases no larger than 2 mm had a significant worse 5-year survival (86%) than patients without nodal metastases (90%) and better than patients with macrometastases in no more than three nodes (82%; Fig. 37.13 ). Cox and coworkers noted that 16% of patients with micrometastasis (>0.2 mm and <2 mm) and 9% of patients with isolated tumor cells or small-cell clusters not greater than 0.2 mm by IHC on SLN biopsy will have additional positive non-SLN if an axillary lymph node dissection is performed. As stated previously, ACOSOG Z10 showed that of the specimens noted to be negative on H&E stain that were further evaluated with IHC, 10.5% of SLNs were found to be positive for tumor with no difference in overall survival or disease-free survival compared with women with IHC negative SLNs.

Prognostic significance of lymph node micrometastases in breast cancer.

(From Chen SL, Hoehne FM, Giuliano AE. The prognostic significance of micrometastases in breast cancer: a Surveillance, Epidemiology, and End Results population-based analysis. Ann Surg Oncol. 2007;14;3378.)

Internal Mammary Nodal Disease

The status of the IMNs has been a point of controversy since the time of Halsted in the 1890s. Prospective randomized trials have failed to demonstrate a benefit in survival for women who had complete IMN dissections (extended radical mastectomy) while incurring significant operative morbidity. However, other studies have shown a prognostic significance of metastasis to the IMNs. Veronesi and associates reported 10-year overall survival rates according to IMN disease and/or axillary lymph node disease among patients who had extended radical mastectomy ( Fig. 37.14 ). The study clearly demonstrated a marked difference in overall survival between patients without any nodal disease (80%) and patients with only IMN disease and only axillary lymph node disease, with an overall survival of 53% and 55%, respectively. Furthermore, the presence of both IMN disease and axillary lymph node disease was associated with the worst outcome with an overall survival of 30%. Positive IMNs can be found in up to 10% of cases when axillary nodes are negative and in as many as 26% of cases when the primary tumor location is medial. Lymphatic mapping techniques may lead to the ability to identify IMNs with improved accuracy; however, there is still appreciable morbidity. The surgical management of IMNs remains controversial.

Ten-year overall survival in patients without lymph node metastases (1), with axillary lymph node metastases only (2), with internal mammary node metastases (3), and with both groups involved (4).

(From Veronesi U, Cascinelli N, Greco M, et al. Prognosis of breast cancer patients after mastectomy and dissection of internal mammary nodes. Ann Surg. 1985;202:702.)

Supraclavicular Nodal Disease

Historically, supraclavicular lymph nodes involved with tumor indicated advanced disease and were associated with a poor prognosis. Positive supraclavicular lymph nodes were considered to have survival rates similar to those with distant spread rather than of regional nodal disease. More recent studies suggest that the outcomes of patients with these tumors are comparable to those of patients with locally advanced disease rather than distant metastatic disease.

Currently, routine scalene lymph node biopsies are not indicated. In the prechemotherapy era, scalene lymph node biopsy was performed to determine operability of breast cancer patients with advanced local disease but without evidence of distant metastases. It was noted by Papaioannou and Urban, however, that when scalene lymph nodes were pathologically positive, despite the use of radical mastectomy with adjuvant radiotherapy, no patients were disease free after 1 year, and more than 50% were dead within 3 years. These data once again suggested that metastasis to lymph node beds other than regional (axillary, clavicular, and internal mammary) suggests the presence of distant systemic disease.

Intramammary Nodal Disease

Intramammary lymph nodes (intraMLNs) have received little attention as potential prognostic indicators for patients with breast carcinoma and are largely overlooked by radiologists, pathologists, and surgeons. Recently interest for intraMLNs as a marker of disease severity has increased with the introduction of SLN biopsy and lymphatic mapping because detection of intraMLNs is likely to occur more frequently by preoperative lymphoscintigraphy and intraoperative gamma probe scanning of the breast. By definition, intraMLNs are surrounded by breast parenchyma, a feature that distinguishes them from low axillary lymph nodes. Histopathologic studies of breast specimens containing intraMLNs have revealed that these lymph nodes may be present in any quadrant of the breast and can yield a variety of pathologic findings, including metastatic carcinoma in the ipsilateral breast.

The prevalence of intraMLNs has been reported to range between 1% and 28%. Egan and McSweeney were the first to address the prognostic significance of intraMLN in breast cancer. They found that in stage I disease, positive intraMLNs were associated with a poor prognosis (10-year survival rate, 79%); however, intraMLNs were not found to be associated with poorer prognosis in stage II disease. Because of this, patients with breast carcinoma accompanied by intraMLN metastases are traditionally considered to have stage II disease, even in the absence of axillary lymph node involvement. Recently Shen and colleagues evaluated 130 patients with intraMLNs. IntraMLN metastases were found in 28% of all cases, and isolated intraMLN metastases were documented in 5% of all cases. The presence of intraMLN metastases was associated with poorer 5-year overall survival compared with non-intraMLN involvement (64% vs. 88%). Furthermore, intraMLN was found to be a significant independent predictor of survival in patients with axillary lymph node involvement as well as among those without axillary involvement. Similar results have reported that intraMLN metastases is a marker of disease severity and that the presence of metastatic disease in an intraMLN is associated with a high rate of axillary nodal involvement.

Pathologic Assessment of Lymph Nodes

Molecular staging using techniques such as RT-PCR is allowing the detection of one tumor cell in the background of a million. Adoption of these technologies has raised the likelihood of finding micrometastases. Furthermore, accurate molecular analysis of all or part of the SLN offers the potential to reduce false-negative findings significantly and overcome limitations that occur with standard methods of intraoperative SLN analysis. Currently, intraoperative SLN analysis methods such as imprint cytology (touch preparation) and frozen section suffer from poor and variable sensitivity and a lack of standardization. Compared with final pathology results, the reported sensitivity of frozen section SLN analysis varies from 58% to 87%. Imprint cytology has similar limitations in sensitivity. Recently, Backus and colleagues were able to identify an optimal two-gene expression marker set (mammaglobin, cytokeratin 19) for detection of clinically actionable metastasis in breast SLNs using microarray methods. Furthermore, they developed a rapid RT-PCR assay (GeneSearch Breast Lymph Node [BLN] Assay; Veridex, Warren, NJ) using these two markers; it generates a result in less than 30 minutes. The authors assessed the utility of RT-PCR assay in SLNs of 254 breast cancer patients, reporting a sensitivity of 90% and specificity of 94%. Blumencranz and associates recently validated this RT-PCR assay in a prospective study at 11 clinical sites. The assay detected 98% of metastases larger than 2 mm and 88% of metastases larger than 0.2 mm. Micrometastases were less frequently detected (57%), and assay-positive results in nodes found to be negative by histology were rare (4%). The authors concluded that the use of the BLN assay overcomes conventional histologic sampling errors and can reduce the need for second surgeries to complete the axillary dissection on SLN-positive patients. Similar results have been reported by other authors who used this commercially available assay, and prospective trials are under way to further characterize its utility in daily practice. Other indices that portend an unfavorable prognosis for breast cancer relate to the presence of gross rather than microscopic disease in the lymph nodes and/or the presence of extranodal disease.