Journal of Clinical Oncology, Vol 17, Issue 2
(February), 1999: 460
© 1999 American Society for Clinical Oncology
Clinical Course of Breast Cancer Patients With Complete Pathologic Primary Tumor and Axillary Lymph Node Response to Doxorubicin-Based Neoadjuvant Chemotherapy
Henry M. Kuerer,
Lisa A. Newman,
Terry L. Smith,
Fred C. Ames,
Kelly K. Hunt,
Kapil Dhingra,
Richard L. Theriault,
Gurpreet Singh,
Susan M. Binkley,
Nour Sneige,
Thomas A. Buchholz,
Merrick I. Ross,
Marsha D. McNeese,
Aman U. Buzdar,
Gabriel N. Hortobagyi,
S. Eva Singletary
From the Departments of Surgical Oncology, Biomathematics, Breast Medical Oncology, Pathology, and Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX.
Address reprint requests to S. Eva Singletary, MD, Department of Surgical Oncology, Box 106, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email esinglet{at}notes.mdacc.tmc.edu
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ABSTRACT
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PURPOSE: To assess patient and tumor characteristics associated with a complete pathologic response (pCR) in both the breast and axillary lymph node specimens and the outcome of patients found to have a pCR after neoadjuvant chemotherapy for locally advanced breast cancer (LABC).
PATIENTS AND METHODS: Three hundred seventy-two LABC patients received treatment in two prospective neoadjuvant trials using four cycles of doxorubicin-containing chemotherapy. Patients had a total mastectomy with axillary dissection or segmental mastectomy and axillary dissection followed by four or more cycles of additional chemotherapy. Patients then received irradiation treatment of the chest-wall or breast and regional lymphatics. Median follow-up was 58 months (range, 8 to 99 months).
RESULTS: The initial nodal status, age, and stage distribution of patients with a pCR were not significantly different from those of patients with less than a pCR (P > .05). Patients with a pCR had initial tumors that were more likely to be estrogen receptor (ER)–negative (P < .01), and anaplastic (P = .01) but of smaller size (P < .01) than those of patients with less than a pCR. Upon multivariate analysis, the effects of ER status and nuclear grade were independent of initial tumor size. Sixteen percent of the patients in this study (n = 60) had a pathologic complete primary tumor response. Twelve percent of patients (n = 43) had no microscopic evidence of invasive cancer in their breast and axillary specimens. A pathologic complete primary tumor response was predictive of a complete axillary lymph node response (P < .01). The 5-year overall and disease-free survival rates were significantly higher in the group who had a pCR (89% and 87%, respectively) than in the group who had less than a pCR (64% and 58%, respectively; P < .01).
CONCLUSION: Neoadjuvant chemotherapy has the capacity to completely clear the breast and axillary lymph nodes of invasive tumor before surgery. Patients with LABC who have a pCR in the breast and axillary nodes have a significantly improved disease-free survival rate. However, a pCR does not entirely eliminate recurrence. Further efforts should focus on elucidating the molecular mechanisms associated with this response.
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INTRODUCTION
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ALTHOUGH NEOADJUVANT chemotherapy has become the standard treatment of locally advanced breast cancer (LABC) and has quickly come to the forefront in the potential management of patients with earlier-stage operable disease, there are multiple facets regarding this treatment modality that have not been sufficiently elucidated.1-5 Information on the differential histologic response of primary breast tumors and axillary metastases to neoadjuvant chemotherapy is limited. Furthermore, the clinical response to neoadjuvant chemotherapy, which is commonly reported, does not always accurately reflect the pathologic response.
The goal of chemotherapy given in the adjuvant or neoadjuvant setting is to eradicate occult distant metastases to ultimately improve disease-free survival. Theoretically, if a complete response is reflective of chemosensitivity in occult distant metastatic sites, patients who have a complete pathologic response (pCR) in both the primary breast tumor and axillary lymph nodes after neoadjuvant chemotherapy should have the highest disease-free survival rates, compared with patients with lesser responses. Currently, only a small number of studies have published data concerning the rate and outcome of patients with a pCR of both the primary tumor and axillary lymph nodes after neoadjuvant chemotherapy.5,6 Additionally, no reports have analyzed clinical and pathologic factors that may be predictive of complete histologic clearance of invasive tumor from both the breast and axillary lymph nodes after neoadjuvant chemotherapy.
In the current study, we have analyzed 372 LABC patients who received neoadjuvant chemotherapy in two prospective trials at the University of Texas M.D. Anderson Cancer Center to determine the incidence of pCR in the breast and axillary lymph nodes, the clinicopathologic factors associated with it, and the clinical course of patients who have such a response.
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PATIENTS AND METHODS
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Between 1989 and 1996, 378 consecutive patients with LABC were registered onto two prospective trials of regimens containing fluorouracil, doxorubicin (Adriamycin; Pharmacia and Upjohn, Bridgewater, NJ), and cyclophosphamide (FAC) at M.D. Anderson Cancer Center. LABC was defined as breast cancer histologically or cytologically documented as stage IIA (T2  4 cm), IIB, IIIA, IIIB, or IV (with ipsilateral supraclavicular lymph node involvement only) using the 1998 American Joint Committee on Cancer classification system.7 The diagnosis was usually established by fine-needle aspiration biopsy of the primary tumor and any involved axillary lymph nodes. Axillary lymph node metastasis was documented by fine-needle aspiration biopsy in 198 patients. In patients without clinical adenopathy who were registered because they had a large primary tumor, a core needle biopsy was performed to document invasion. Patients with primary inflammatory carcinoma (clinical development of erythema, peau d'orange, and breast-mound ridging within 3 months before presentation) were excluded and offered enrollment onto other treatment protocols.
Each patient was examined by a multidisciplinary team to confirm the diagnosis of LABC and to evaluate the clinical stage of the disease at presentation and the response after four cycles of chemotherapy. The staging work-up included a complete history and physical examination, complete blood cell count with differential and platelet counts, blood chemistry analysis, electrocardiography, chest radiograph, abdominal computed tomography or abdominal ultrasonography, bone scan, and bilateral mammography at presentation and after four cycles of chemotherapy. Each patient was entered prospectively into the protocol database and observed longitudinally. The complete medical records of all of the patients were available for review at the time of this analysis. Six patients were excluded because of one dose violation, one malignant pleural effusion found during the initial work-up, one chest-wall invasion found during the work-up, two patient decisions to withdraw from the studies before treatment began, and one death before surgery. After these exclusions, there were 372 assessable patients.
Chemotherapy was administered at 18- to 21-day intervals. The regimens of FAC used were 500 mg/m2 of fluorouracil given intravenously (IV) on days 1 and 3, 50 mg/m2 of Adriamycin given IV by continuous infusion over 48 to 72 hours on days 1 through 3 or 4, and 500 mg/m2 of cyclophosphamide given IV on day 1 in 288 patients (regimen A). In the remaining 84 patients, 600 mg/m2 of fluorouracil was given IV on days 1 and 3, 60 mg/m2 of Adriamycin was given IV by continuous infusion over 48 hours on days 1 through 3, and 1,000 mg/m2 of cyclophosphamide was given IV on day 1 (regimen B). At the conclusion of all therapy, patients at least 50 years old or with estrogen receptor (ER)-positive tumors received tamoxifen for 5 years. Five-year compliance with tamoxifen therapy was approximately 80%.
Clinical responses to neoadjuvant chemotherapy were classified by the following criteria: complete response (CR), a total resolution of the breast tumor and axillary adenopathy based on physical and radiographic examination; partial response (PR), a 50% or greater reduction of the product of the two largest perpendicular dimensions of the breast mass and axillary adenopathy; minor response (MR), a less than 50% reduction of the product of the two largest perpendicular dimensions ofthe breast mass and axillary adenopathy; no change in clinical status; and progressive disease. Patients with significant clinical primary tumor shrinkage after the first or second chemotherapy cycle underwent breast ultrasonography and placement of metallic markers for subsequent intraoperative localization and specimen mammography. Responding patients underwent either a segmental mastectomy with axillary lymph node dissection (n = 103) or modified radical mastectomy (n = 253) after four cycles of chemotherapy. Nine patients underwent axillary dissection alone because of prior primary tumor excision with negative margins or because no primary tumor was detectable at diagnosis. Patients with no change or progressive disease after preoperative chemotherapy (n = 28) received preoperative radiation treatment followed by a modified radical mastectomy when the tumor was operable. Seven patients' tumors remained inoperable after radiation treatment. When preoperative radiation treatment was given, a total dose of 50 to 60 Gy was delivered to the breast, internal mammary lymph nodes, and supraclavicular/high axillary lymph nodes.
The histologic response to neoadjuvant chemotherapy was characterized as a pCR when there was no evidence of residual invasive tumor in the breast or axillary lymph nodes. Patients with only residual ductal carcinoma-in-situ (n = 2) were coded as having a pCR. When residual invasive tumor was present in the breast, it was quantitated as 1 cm3 or less or more than 1 cm3. Patients with only residual microscopic foci of tumor cells in the breast were considered to have a 1 cm3 or less residual tumor burden. A minimum of 10 sections from the region of the initial primary tumor site were examined. In general, if no residual tumor was identified, additional confirmatory sections were obtained from the quadrant of the breast containing the initial primary tumor. When mastectomy was performed, the initial 100 patients underwent complete sectioning of the breast. Subsequently, an average of 50 breast sections were examined per mastectomy specimen. These included sections from each quadrant and the nipple-areolar complex. Further sections were obtained and examined as dictated by abnormalities identified by preoperative imaging studies or specimen radiography. Patients with 1 cm3 or less of residual tumor received four additional cycles of FAC. Patients who had a PR and more than 1 cm3 of residual tumor and those with at least four positive lymph nodes in the surgical specimen received four more cycles of FAC postoperatively followed by four cycles of methotrexate and vinblastine. Patients with no change or progressive disease received six cycles of methotrexate and vinblastine. Pathologic tumor response was coded as incomplete in patients who remained inoperable (n = 7). Locoregional radiotherapy was instituted within 6 weeks of the completion of chemotherapy. Postoperative irradiation treatment was delivered to the chest wall, internal mammary lymph nodes, and supraclavicular/high axillary lymph nodes. During the first 2 years of follow-up, patients had a history and physical examination, complete blood count, liver function tests, serum carcinoembryonic antigen and CA 15-3, chest x-ray, and bone scan every 4 months. During the next 2 years, patients had these studies performed every 6 months. After 4 years, these studies were performed at yearly intervals. At any time, if the patient exhibited elevated liver function tests, an abdominal computed tomographic scan or ultrasound of the liver was obtained.
Comparisons of response outcomes among groups were assessed with the  2 test. Multivariate analysis was performed using a logistic regression model.8 Overall survival was calculated from the date of diagnosis, and disease-free survival was calculated from the date of surgery using the method of Kaplan and Meier.9 The log-rank statistic was used for univariate comparisons of survival end points.10 Two-tailed results are reported and P of .05 or lower was considered statistically significant. Data analyses were conducted using the Statistica software program (Statsoft, Inc, Tulsa, OK) or SAS program (SAS Institute, Inc, Cary, NC).
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RESULTS
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Table 1 lists the pretreatment patient and tumor characteristics for the 372 assessable patients. The median follow-up time for the entire group was 58 months (range, 8 to 99 months). The median age of the patients was 47 years. Tumor ER status at diagnosis was determined in 233 patients (63%), and the nuclear grade was determined in 286 patients (77%). The median largest diameter of the primary tumor was 6 cm for the entire group of patients. Twelve patients (3%) had undergone prior primary tumor excision (including five complete excisions with documented histologic negative margins), and four patients (1%) presented with bulky N2 axillary disease alone. Sixty-nine percent of the patients presented with T3 or T4 tumors. Only 20% of the patients did not have clinically detectable adenopathy at diagnosis. Twenty-four percent of the patients had stage II disease, and 76% of patients had stage III or regional stage IV locally advanced disease.
Complete versus incomplete pathologic primary tumor and axillary lymph node response to neoadjuvant chemotherapy was analyzed by univariate analysis with respect to patient and initial tumor characteristics (Table 2). Forty-three patients (12%) had no histologic evidence of residual invasive primary breast carcinoma or axillary metastases after four cycles of neoadjuvant chemotherapy. Although most of the women in the study were 50 years old or younger, there was little difference between younger ( 50 years) and older (> 50 years) women with respect to the distribution of complete and incomplete breast tumor and axillary lymph node pathologic responses (P = .25). Of the 24 patients in the pCR group whose pretreatment ER status was assayed, 13% (n = 3) had ER-positive tumors. Of the 209 patients in the incomplete response group whose pretreatment ER status was assayed, 49% (n = 103) had ER-positive tumors. The difference between these two groups with respect to ER status was statistically significant (P < .01). Patients with a pCR were more likely to have primary tumors with a lower (more anaplastic) Black's nuclear grade than were patients in the incomplete pathologic response group (87% [27 patients] v 56% [144 patients], respectively; P < .01). Patients with less advanced primary tumors (stages T0 through T2) were more likely to have a complete primary tumor and axillary lymph node pathologic response (21%) than were patients with stage T3 or T4 primary tumors (7%; P < .01). Although there were more patients with initially positive lymph nodes on clinical examination in the pCR group (n = 38; 13%) than patients with negative lymph nodes (n = 5; 7%), the difference did not reach statistical significance (P = .19). Concerning the initial stage of disease, no difference in the distribution of complete versus incomplete breast tumor and axillary lymph node pathologic responses was found between patients who presented with stage II disease and those who presented with stage III or IV disease (P = .30). Of the 43 patients with a complete pathologic primary tumor and axillary lymph node response, 30 patients (70%) received FAC regimen A and 13 patients (30%) received FAC regimen B. No statistical difference was observed in the rate of complete pathologic response with respect to FAC regimen received (P = .20).
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Table 2. Univariate Analysis of Patient and Tumor Characteristics Associated With Complete Versus Incomplete Pathologic Primary Tumor and Axillary Lymph Node Response to Neoadjuvant Chemotherapy
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After adjustment for tumor size, multivariate logistic regression analysis was applied to evaluate the association of initial ER status and nuclear grade with breast tumor and axillary lymph node pathologic response. Incidence of negative ER status or anaplastic tumor was similar regardless of tumor size. The results presented in Table 3 indicate a significant association of both ER status and nuclear grade with pathologic response after adjustment for tumor size. Patients with a negative initial ER status and more anaplastic tumors were more likely to have a complete primary tumor and axillary lymph node pathologic response independent of the initial tumor size after four cycles of neoadjuvant chemotherapy (P < .01).
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Table 3. Logistic Regression Analysis: Association of Estrogen Receptor Status* and Nuclear Grade With Pathologic Response
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The relationship between the pathologic primary tumor response and the pathologic axillary lymph node response after neoadjuvant chemotherapy was also evaluated (Table 4). Patients with a pathologic complete primary tumor response were more likely to have a negative axillary lymph node status (P < .01). Sixteen percent of the patients in this study (n = 60) had a pathologic complete primary tumor response. Seventy-two percent of the patients who had a pathologic complete primary tumor response (n = 43) had no axillary lymph node metastases. In comparison, of the 296 patients (83%) who had a pathologic incomplete primary tumor response, only 76 (26%) had no axillary lymph node metastases. Furthermore, the degree of axillary lymph node involvement was predicted by the pathologic primary tumor response. Patients who had an incomplete primary tumor response were more likely to have at least four lymph node metastases when compared with patients who had a complete primary tumor response (39% [115 patients] v 10% [6 patients], respectively; P < .01). Documented eradication of axillary lymph node metastases (from initial positive fine-needle aspirate of axillary lymph node metastases to pathologically negative on axillary dissection) after four cycles of chemotherapy was observed in 23% of patients (n = 46) who presented with a clinically positive axilla.
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Table 4. Relationship Between Pathologic Primary Tumor Response and Axillary Lymph Node Status After Neoadjuvant Chemotherapy*
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The overall and disease-free survival of the patients was analyzed with respect to the pathologic response after neoadjuvant chemotherapy (Fig 1). At a median follow-up of 58 months (range, 8 to 99 months), there were two local recurrences (5%) in the complete pathologic primary tumor and axillary lymph node response group and 30 (9%) in the incomplete group. This difference did not reach statistical significance (P = .402). Patients with a complete pathologic response in the primary tumor and axillary lymph node response had significantly fewer distant recurrences (five patients; 12%) than did patients with an incomplete response (121 patients; 37%; P < .01). All patients in the pCR group who had a recurrence initially had stage III disease. The median time to first recurrence in the complete and incomplete pathologic response groups was 25 months and 21 months, respectively (P = not significant). Five-year overall and disease-free survival rates were significantly higher in the complete pathologic primary tumor and axillary lymph node response group (89% and 87%, respectively) than in the incomplete pathologic response group (64% and 58%, respectively; P < .01) (Fig 1).
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Fig 1. Relationship of pathologic primary breast tumor and axillary lymph node response to overall survival (A) and disease-free survival (B) after neoadjuvant chemotherapy. pCR, complete pathologic response in both primary and axillary lymph nodes (43 patients); < pCR, incomplete pathologic response (329 patients).
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Overall survival and disease-free survival were also analyzed with respect to the differential pathologic response in the breast and axillary lymph nodes after neoadjuvant chemotherapy (Fig 2). Although patients had an improved overall survival when both their breast and axillary lymph node specimens were free from microscopic invasive disease, when compared with patients who had residual invasive disease in the breast, this difference was not significant (P = .40) (Fig 2A). Similarly, although patients had an improved disease-free survival when both their breast and axillary lymph node specimens were free from microscopic invasive disease, compared with patients with residual tumor in both the breast or axilla, no significant difference was found between patients with elimination of microscopic residual invasive disease from both the breast and axillary lymph nodes and those with residual disease in either the breast or axillary lymph nodes (P = .32) (Fig 2B).
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Fig 2. Relationship of the differential pathologic response of the primary breast tumor and axillary lymph nodes to overall survival (A) and disease-free survival (B) after neoadjuvant chemotherapy. (-) no microscopic residual invasive tumor identified; (+) microscopic residual invasive tumor identified. P value refers to distribution of four noted groups.
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Concerning the relationship between the type of surgical procedure performed and the potential impact on overall survival and disease-free survival, segmental mastectomy with axillary dissection was performed in 103 patients (29%) and modified radical mastectomy was performed in 253 patients (71%); the overall 5-year survival of patients with segmental mastectomy with axillary dissection was significantly greater than that of patients who had a modified radical mastectomy (82% v 66%; P < .01). The 5-year disease-free survival was also significantly greater in patients who had a segmental mastectomy with axillary lymph node dissection, compared with patients who were treated with modified radical mastectomy (73% v 57%; P < .01). The survival advantage seen in patients treated with breast conservation compared with patients treated with mastectomy is related to patient selection. Patients were more likely to have a segmental mastectomy with axillary lymph node dissection if they presented with earlier-stage disease (IIA, IIB, IIIA; n = 75; 73%) rather than more advanced-stage disease (IIIB and IV; n = 28; 27%; P < .01). Similarly, patients with a clinical complete or greater than 50% partial response were significantly more likely to have a segmental mastectomy with axillary lymph node dissection (n = 91; 88%), compared with patients who received a modified radical mastectomy (n = 166; 65%; P < .01).
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DISCUSSION
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The results of our study indicate that, in many patients, neoadjuvant chemotherapy can completely clear the breast and axilla lymph nodes of any microscopic evidence of invasive tumor as assessed by standard histologic examination. In a group of LABC patients, this occurred in 12% of the patients (n = 43) after four cycles of FAC chemotherapy in two consecutive prospective neoadjuvant therapy trials at our institution. We and other investigators have shown that a pCR in the primary tumor occurs in 3% to 16% of patients with operable breast cancer and LABC.2,5,11-15 In the present series, 16% of the patients (n = 60) had a pCR in the primary tumor. Similarly, Morrell et al14 found a 16% rate (n = 9) of pCR in the primary tumor among LABC patients after a neoadjuvant regimen containing methotrexate, vinblastine, doxorubicin, and cisplatin. Schwartz et al11 reported a 10% pCR rate (n = 16) in the primary tumor after the administration of cyclophosphamide, methotrexate, and fluorouracil and anthracycline-containing neoadjuvant chemotherapy to 156 LABC patients. In contrast, in another recently reported large series, Bonadonna et al15 administered several neoadjuvant drug regimens (cyclophosphamide, methotrexate, and fluorouracil; anthracycline- or mitoxantrone-containing combinations; or doxorubicin alone) to 536 operable breast cancer patients and found a pathologic complete remission in the primary tumor in only 3% of patients (n = 14). In a similar series of 212 patients reported by Powles et al,12 a complete pathologic response in the primary tumor was found in 10% of the patients (n = 10) randomized to preoperative chemoendocrine therapy. Neoadjuvant chemotherapy has also been shown to convert clinically involved axillary nodal disease to a pathologically negative status in 25% to 38% of breast cancer patients.5,11,16
There is a paucity of published data concerning the incidence and outcome of patients with a pCR in the primary tumor and axillary lymph nodes after neoadjuvant chemotherapy. Most of the literature on neoadjuvant chemotherapy concerning pCR rates refers to and reports on pCRs in the primary tumor alone. No evidence of invasive tumor in the breast primary and axillary lymph nodes after neoadjuvant therapy was found in 12% of the patients (n = 43) upon histologic examination in the present series. Excluding patients who had a prior excision of the primary tumor with positive histologic margins (n = 3) and those who presented with clinically negative axillary lymph nodes (n = 5) in this group of 43 patients, a pCR in the primary tumor and axillary lymph nodes occurred in 11% of the patients (n = 35). In an earlier series, we reported a pCR rate in the breast and axillary lymph nodes of 7% (n = 6) in patients with locally advanced and inflammatory breast carcinoma treated with neoadjuvant chemotherapy.6 In comparison with a group of patients who presented with less advanced disease, 13 (7%) of the 185 operable patients with clinically positive axillary lymph nodes randomized to the Adriamycin/cyclophosphamide neoadjuvant chemotherapy arm of the National Surgical Adjuvant Breast and Bowel Project B-18 trial were found to have no residual invasive tumor in the breast and axillary tissue upon pathologic examination.5 Because it has been established that a pCR in the primary tumor is associated with improved disease-free survival6,15 and patients without axillary lymph node metastases after neoadjuvant chemotherapy have improved disease-free survival, it was of interest to establish the incidence of pCR in both the primary tumor and the axillary lymph node compartment in the same patients, clinicopathologic factors associated with this response, and the ultimate durable outcome in this cohort of patients.
Patients without any histologic evidence of tumor after neoadjuvant chemotherapy in this series had 5-year overall survival and disease-free survival approaching 90%, compared with 60% in patients with residual invasive tumor. Does a pCR to chemotherapy simply identify those patients who have a biologically predetermined excellent prognosis, or can the early initiation of systemic therapy alter the disease course, as compared with conventional primary surgical intervention followed by chemotherapy? Most trials of neoadjuvant chemotherapy followed by local therapy versus local therapy followed by postoperative chemotherapy have not found a survival advantage for patients who initially received chemotherapy.17,18 From the available data, it can be stated with some confidence that neoadjuvant chemotherapy does not bestow a survival disadvantage. One of the most striking benefits of neoadjuvant chemotherapy is not so much the early identification of patients who will have an excellent response to chemotherapy but rather the identification of patients who will have only a minimal response. These patients must be immediately identified to spare them from additional ineffective, toxic treatment. Promising phase II trials have demonstrated high activity of taxane-based (docetaxel and paclitaxel) chemotherapy in anthracycline-resistant breast cancer.19,20 In this context, some patients who have a minimal response to anthracycline-based induction chemotherapy may be offered taxane-based regimens or novel systemic therapy to potentially increase survival rates in the adjuvant setting. However, deciding to cross over patients to a different chemotherapeutic agent on the basis of histologic assessment of the breast and axillary lymph nodes may become less important if treatment trends move toward a sequential approach using anthracycline-based, taxane-based, and novel regimens before the initiation of local therapy. In this regard, it will be of particular interest to see whether the addition of four cycles of preoperative docetaxel after four cycles of Adriamycin and doxorubicin in the ongoing National Surgical Adjuvant Breast and Bowel Project Protocol B-27 improves rates of pathologic tumor response and subsequent disease-free survival, compared with patients receiving four cycles of preoperative Adriamycin and doxorubicin alone.
Several previous neoadjuvant chemotherapy studies have addressed clinicopathologic factors associated with outcome in breast cancer patients. Factors that have been consistently shown to be associated with improved disease-free survival after neoadjuvant chemotherapy include less advanced primary tumors,5,13,16,21-23 the clinical response of the primary tumor to chemotherapy (> 50% tumor shrinkage),15,21,24 and the finding of minimal residual tumor upon histologic examination of breast and axillary lymph node specimens.15,16,24 Some studies have also found higher disease-free survival rates in younger patients,14 those with lower anaplastic tumor grade,13,24 and those with clinically uninvolved axillary lymph nodes at diagnosis.22,23 There are very few reports that have addressed clinicopathologic factors associated with the complete histologic resolution of invasive tumor in the breast and axillary lymph nodes after neoadjuvant chemotherapy.25 The results of the present study indicate that the patients who were most likely to have a pCR in the breast and axillary lymph nodes were patients with less advanced primary tumors at diagnosis, initially ER-negative tumors, and tumors with a more anaplastic nuclear grade at diagnosis. Furthermore, the effects of the initial ER status and nuclear grade were found to be independent of the initial tumor size upon multivariate analysis. These observations are reminiscent of the findings concerning chemotherapeutic response of highly aggressive hematologic malignancies.26
In an early study, Lippman et al27 reported on the relationship between estrogen receptor status and response rate to cytotoxic chemotherapy in the metastatic breast cancer setting. They found statistically increased objective response rates to chemotherapy in patients with low or absent ER values, compared with patients with higher ER values. In the neoadjuvant setting, the finding that ER-negative tumors were more likely associated with higher response rates than ER-positive tumors has been reported by both Bonadonna et al28 and Mauriac et al.29 Similarly, in the adjuvant treatment setting, our results are consistent with the latest overview analysis of randomized trials of polychemotherapy for breast cancer in which the proportional reduction in recurrence was found to be significantly greater for women of all ages with ER-negative tumors, compared with women with ER-positive tumors.30 Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project have demonstrated that ER-negative tumors most often have an associated poorly differentiated nuclear grade.31 Nuclear grade has also been shown to correlate with cell-cycle proliferative activity as assessed by S-phase fraction.32 In this context, pretreatment high tumor S-phase fractions have been reported to correlate significantly with response to neoadjuvant chemotherapy in breast cancer.33 Taking these observations together with the results of the current study, breast cancer response to cytotoxic chemotherapy seems to be greatest in ER-negative, poorly differentiated tumors treated in the neoadjuvant, adjuvant, and metastatic settings.
With regard to neoadjuvant chemotherapy, experienced oncologists often state "if the primary tumor responds well, the axillary metastases usually do, too." The findings in this study support this clinical adage: 73% of the patients who had a pCR in the primary tumor had no histologic evidence of tumor in the axillary lymph nodes, compared with only 26% of the patients with residual disease in the primary tumor site. One major goal of systemic therapy is the early eradication of subclinical distant micrometastases in an attempt to improve survival. Theoretically, one could surmise that the response of axillary lymph node metastases to systemic therapy might reflect the sensitivity of occult metastases in other organ compartments. With the recent advent and increasing use of molecular techniques using fluorescence in situ hybridization and comparative genomic hybridization,34-37 subtle genetic changes between primary and metastatic lesions in the same patient can be pinpointed and may potentially elucidate the underlying mechanisms of metastasis. Cytogenetic studies have indicated that simultaneous lymph node metastases are clonally related to the primary tumor but are genetically less heterogeneous than the primary tumor, presumably because only a few of the multiple initial primary tumor clones possess the molecular capacity to metastasize.36,37 It is intriguing to speculate that the genetic differences seen in tumor cells within the primary tumor and simultaneous axillary lymph node metastases might account for differences in chemosensitivity. Prediction of responses to neoadjuvant chemotherapy has recently focused on potential biologic markers such as p53, HER2/c-erbB-2, the multidrug resistance glycoprotein, Ki67, and bcl-2 expression in the breast primary tumor.38-40 If the molecular changes identified in axillary lymph node metastases are related to those found in occult distant metastatic sites, then alternative therapy would best be initially directed toward chemoresistant clones in the lymph nodes to potentially impact distant disease-free survival. However, this remains to be determined, because the results of the present study suggest that patients with a pCR in either the breast or the axillary lymph nodes after neoadjuvant chemotherapy will have virtually identical 5-year disease-free survival.
In summary, neoadjuvant chemotherapy eradicated histologic evidence of invasive carcinoma in both the primary breast tumor and axillary lymph nodes in approximately 12% of LABC patients who received four cycles of FAC. Patients with a pCR in the breast and axillary lymph nodes were more likely to have initial tumors that were ER negative and had an anaplastic nuclear grade. These effects were independent of the initial primary tumor size. Patients with a pCR in the primary tumor were more likely to have no axillary lymph node metastases, compared with patients with less than a pCR in the primary tumor. Patients who had a pCR in both the breast and axillary lymph nodes had significantly improved overall and disease-free survival, compared with patients with less than a pCR. However, although patients with a pCR in both the breast and axillary lymph nodes had increased overall survival and disease-free survival, they did not have a significant advantage over patients with a pCR in the breast or the axillary lymph nodes. Taken together, the data indicate that the complete histologic elimination of invasive disease from the breast, the axillary lymph nodes, or both after neoadjuvant chemotherapy confers a survival advantage. Further efforts should focus on elucidating the molecular mechanisms associated with this response.
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ACKNOWLEDGMENTS
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Supported in part by the National Institutes of Health (grant no. CA 16672) and the Nellie B. Connally Breast Cancer Research Fund
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NOTES
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Presented at the American Society of Clinical Oncology Annual Meeting, May 19, 1998.
H.M.K. is a recipient of the 1998 American Society of Clinical Oncology Merit Award.
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accepted October 26, 1998.
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TOP
ABSTRACT
INTRODUCTION
