Invasive Lobular Carcinoma Classic Type: Response to Primary Chemotherapy and Survival Outcomes
http://www.100md.com
《临床肿瘤学》
the Departments of Breast Medical Oncology, Pathology, Biostatistics, Surgical Oncology, and Radiotherapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX
ABSTRACT
PATIENTS AND METHODS: The study included 1,034 patients with stage II and III breast cancer who participated in six clinical trials of PC at our institution between 1985 and 2002. One hundred twenty-two patients (12%) had ILC and 912 (88%) had IDC. All patients received anthracycline-based PC, and 346 patients (33.5%) also received a taxane as part of PC. Pathologic complete response (pCR) was defined as no evidence of invasive disease in the breast and axillary lymph nodes.
RESULTS: The median patient age was 48 years (range, 18 to 79 years). Patients with ILC tended to be older (median age, 53 years v 47 years for patients with IDC) and have more hormone-receptor–positive tumors (92% v 62%; P < .001), lower nuclear grade (nuclear grade 3, 16% v 56%; P < .001), and higher stage at diagnosis (10% v 0% with stage IIIB or IIIC disease; P < .001). Patients with ILC were less likely to have a pCR (3% v 15%; P < .001) and had a larger number of involved axillary lymph nodes (41% v 26% had > 3 involved nodes; P = .001). At a median follow-up time of 70 months, ILC patients tended to have longer recurrence-free survival (P = .004) and overall survival (P = .001).
CONCLUSION: ILC is characterized by lower rates of pathologic response to PC but better long-term outcomes compared to IDC. pCR might not be a prognostic indicator for this group of patients.
INTRODUCTION
The prognosis of ILC has been described as equal to or better than that of IDC, but outcome differences are difficult to determine because of the variation in the histologic criteria used to define ILC.9,17-19 Primary (neoadjuvant) chemotherapy is the standard treatment for patients presenting with locally advanced breast cancer, and its use is extending to earlier stages of disease. Pathologic complete response (pCR) and pathologic nodal status after primary chemotherapy are considered surrogates for survival. We evaluated the impact of histologic type (ILC v IDC) on how likely primary chemotherapy would result in pCR, and on long-term outcome in patients with primary breast cancer.20-22
PATIENTS AND METHODS
Diagnosis was made by core-needle biopsy of the breast tumor. The histologic type was defined according to the World Health Organization classification.1 All pathologic specimens were reviewed by breast pathologists at M.D. Anderson Cancer Center. Patients treated during this time whose tumors showed either mixed histologic types or types other than ductal or classic lobular were excluded to allow comparison of the pure lobular and ductal types.
Classic ILC was defined according to the criteria proposed by Fechner.12 The histologic grade was defined according to the modified Black’s nuclear grading system.27 The estrogen receptor (ER) and progesterone receptor (PR) status of 878 patients, tested by immunohistochemical staining, was available. Staining was performed with standard procedures on 4-μm sections of paraffin-embedded tissues with monoclonal antibodies: 6F11 (Novacastra, Burlingame, CA) for ER, and 1A6 (Novacastra) for PR. Nuclear staining ≥ 10% was considered positive.
Treatment
All patients received anthracycline-based primary chemotherapy. One hundred seventy-eight patients (17%) received four cycles of vincristine 1 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 intravenously (IV) on day 1 and prednisone 100 mg/m2 orally on days 1 to 5. Eight hundred fifty-six patients (83%) received four to eight cycles of fluorouracil 500 mg/m2 IV on days 1 and 4, doxorubicin 50 mg/m2 IV continuous infusion over 72 hours from days 1 to 3, and cyclophosphamide 500 mg/m2 IV on day 1. Three hundred thirty-six patients (32%) also received a paclitaxel regimen (175 to 250 mg/m2 IV on day 1 every 21 days for four cycles or 80 mg/m2 IV on day 1 every week for 12 weeks) as part of primary chemotherapy in randomized clinical trials.23-26 Breast surgery consisted of segmental mastectomy when tumor size permitted, according to the judgment of the multidisciplinary care team. In other cases, including cases of multifocal disease, mastectomy was performed. Axillary lymph node dissection was performed in 999 patients (97%). Five hundred eighty-two patients (56%) whose hormone receptor status was known to be positive received adjuvant tamoxifen for 5 years. Radiotherapy was delivered at completion of primary chemotherapy, after surgery in all patients treated with lumpectomy, and in patients with locally advanced disease.
Response
pCR was defined as no evidence of invasive carcinoma in the breast and the axillary lymph nodes. Information on the number of positive nodes at surgery was missing for 35 patients because the patient did not undergo surgery (n = 8), because the patient was randomized to a protocol on which she did not undergo nodal dissection (n = 26), or because the patient refused nodal dissection (n = 1). These missing data were not felt to introduce bias because patients with missing data on the number of positive nodes at surgery were not likely to be very different from patients for whom the number of positive nodes at surgery was known. Patients who did not have surgery owing to progressive disease were considered not to have had a pCR.
Statistical Methods
The patient population was described by tabulation of categoric variables and cross-tabulation of the categoric variables with histologic type. {chi}2 tests were used to test for an association between categoric variables and histologic type. Continuous variables were described by their minimum, median, and maximum values.
For both pCR and breast complete response (bCR), the number of responses was cross-tabulated by histologic type, and the tables were then stratified by ER and PR status (ER- or PR-positive, or negative for both ER and PR) and by whether or not the patient had received a taxane. Mantel-Haenszel {chi}2 tests were performed to test whether there was an association between pCR or bCR and histologic type after adjusting for ER and PR status and after adjusting for taxane use.
The Kaplan-Meier product-limit method was used to assess differences in overall survival and recurrence-free survival between the two histologic types after adjusting for the following: ER/PR status, both ER/PR status and pCR or bCR status, ER/PR status and disease stage, ER/PR status and nuclear grade, and taxane use. The log-rank test and the stratified log-rank test were used to compare survival estimates between histologic types. Overall survival was measured from the date of treatment to the date of death or last follow-up. Recurrence-free survival was measured from the date of treatment to the date of recurrence or last follow-up. Statistical analyses were carried out using SAS 8 (SAS Institute, Cary, NC) and S-Plus 6.1 (Insightful Corporation, Seattle, WA) software.
RESULTS
Patients with ILC tended to be older at diagnosis (median age, 53 v 47 years). Patients with ILC were also less likely to present with stage I-IIA disease (30% v 63%; P < .001). Despite their advanced clinical presentation, patients with ILC were more likely to have ER- or PR-positive tumors (92% v 62%; P < .001) and low-nuclear-grade disease (nuclear grade 3, 16% v 56%; P < .001).
Patients with ILC were more likely to receive taxanes as part of primary chemotherapy (taxanes use, 46% v 32%; P = .002), in part because the more advanced stage of the tumors at presentation necessitated patients’ participation in protocols for locally advanced disease.
Nine hundred ninety-eight patients (97%) had adequate response after primary chemotherapy and proceeded to surgery. Two hundred thirty-eight patients (27%) were treated with breast-conserving therapy (BCT). Patients with ILC were more likely than those with IDC to undergo mastectomy (83% v 67%; P = .003). The proportion of patients who underwent BCT was significantly lower for patients with ILC (16%) than for those with IDC (29%; P = .003). ILC was an independent predictor of ineligibility for BCT.
One hundred forty-two patients (14%) had a pCR (Tables 2 and 3). ILC was associated with a lower pCR rate (3% v 15%; P < .001) and a higher incidence of residual lymph node disease (≥ four positive lymph nodes, 41% v 26%; P = .001). In four patients, the pCR status differed from the bCR status (Table 4). One patient had two positive nodes and in situ disease and thus did not have a pCR but did have a bCR. Three patients had no residual disease or in situ residual disease but had an unknown number of positive nodes. These patients had an unknown pCR status but did have a bCR.
We analyzed the interaction between histologic type, hormone-receptor status, and the use of taxanes to see if these additional factors affected the likelihood of pCR (Tables 3 to 5). These two factors did not influence the chance of pCR in patients with ILC (Tables 3 and 5). Instead, patients with IDC had a lower chance of a pCR when hormone-receptor positive (9% v 4% pCR rate for IDC and ILC, respectively; P = .03).
The numbers of patients with pCR and bCR stratified by histologic type and taxane use are shown in Tables 5 and 6. Of the four patients with lobular disease who had a pCR or bCR, three had received a taxane. Among patients with ductal disease who were not treated with a taxane, 13% had a pCR. Among patients with ductal disease who were treated with a taxane, 20% had a pCR. A Mantel-Haenszel {chi}2 test showed that patients with IDC tended to have higher pCR rates regardless of whether they were treated with a taxane (P < .001). A {chi}2 test for association between histologic type and pCR showed a statistically significant correlation (P < .001).
At a median follow-up time of 70 months (range, 15 to 202 months), 325 patients (31%) had developed a recurrence, and 284 patients (27%) had died. Patients with ILC had a better 5-year recurrence-free survival rate (RFS; 87% v 66%; P = .004) and a better 5-year overall survival rate (OS; 93% v 70%; P = .001) than did patients with IDC (Figs 1 and 2). This pattern was also observed in the subset of patients with hormone-receptor–positive disease (Figs 3 and 4). Among patients with hormone-receptor–positive ductal disease, those with a pCR tended to have better RFS and OS than those without a pCR (Figs 5 and 6). Only four patients with hormone-receptor–positive lobular disease had a pCR, so we could not assess whether achievement of pCR was associated with a favorable outcome in this cohort of patients.
Regardless of pCR status, patients with lobular disease tended to have better OS than patients with ductal disease. Similar results were observed with regard to RFS (Fig 5). A stratified log-rank test was statistically significant for OS (P = .02) and for RFS (P = .01), indicating that OS and RFS were different between the two histologic types, even after adjusting for ER and PR status, and pCR status. Because there were so few patients with lobular hormone-receptor–negative disease, results for those patients were not presented.
DISCUSSION
Our results indicate that classic ILC responds less frequently to primary chemotherapy. More importantly, the difference in pCR rate between ILC and IDC persisted even after adjusting for hormone-receptor status and use of taxanes. A positive hormone-receptor status has previously been associated with a lower chance of pathologic response to primary chemotherapy. In a recent retrospective study of 1,018 patients, Buzdar et al32 found that rates of pCR to primary chemotherapy were significantly higher in patients with ER-negative tumors (P < .001). Conversely, the addition of taxanes, particularly in sequential regimens, has been shown to translate into higher pathologic response rates.20,33-35
We found that patients with ILC were more likely than patients with IDC to be treated electively with mastectomy, and because of the diffuse nature of the disease, and the poorer response to chemotherapy, these patients were rarely candidates for breast-conserving surgery. This finding has previously been reported by Cocquyt et al.36 The authors reviewed 135 patients treated with primary chemotherapy and found that BCT was possible in 50% of patients with IDC and 35% of patients with ILC. This is important because BCT is currently the primary end point for patients with early breast cancer undergoing primary chemotherapy20,33,37 and our findings indicate that there is no such benefit for patients with ILC.
The most striking finding of our investigation was that despite more advanced disease at presentation and the low pCR rate, and after adjusting for the imbalances in hormone-receptor–positive disease, patients with ILC had a better long-term outcome than did patients with IDC. ILC has repeatedly been shown to be associated with better long-term outcome than IDC.8-10 Several epidemiologic factors may explain the correlation. Women with ILC are usually older, are more likely to have previously used hormone-replacement therapy, and are more likely to have hormone-receptor–positive disease.18,38 In previous studies of primary chemotherapy, reported rates of ILC included in primary chemotherapy studies were 7% v 12%,38,39 but differences in outcome based in histologic subset analysis were not done.
To our knowledge, this is the first report that addresses the correlation between histologic type and response to primary chemotherapy in such a large cohort of patients, as a measure of chemo-sensitivity and long-term outcome. Our study indicated that very few patients with ILC achieve a pCR to primary chemotherapy and that pCR to primary chemotherapy in ILC may have no prognostic significance. Overall, these results indicate that the role of primary chemotherapy in ILC should be reconsidered. Primary chemotherapy in this subgroup does not achieve the two main objectives of this treatment: adequate downstaging of disease to allow for BCT and provision of a surrogate marker of prognosis (pCR).
The results also indicate that the use of primary systemic therapy in women with ILC should be restricted to patients with inoperable disease and should be more tailored to the peculiar biologic features of the disease. For example, primary endocrine treatments should be explored as a possible, more effective treatment for ILC. Initial studies of tamoxifen in the primary setting showed that this is a good alternative option for elderly patients who are poor candidates for primary cytotoxic chemotherapy.40 Subsequent studies in postmenopausal patients with ER-positive tumors demonstrated the effectiveness of aromatase inhibitors as primary therapy despite the rarity of pCR.41-43 More recently, a comparison between tamoxifen and anastrozole revealed a higher rate of BCT in the anastrozole group.44
Other scientific approaches, such as genomics and proteomics, may answer questions regarding biologic behavior and chemosensitivity and assist in the selection of the most appropriate therapy. Small series have demonstrated that microarray analysis can separate tumors into four groups according to proliferation, ER, c-erbB-2, and apoptosis genes.15 A recent report showed that specific changes in gene expression distinguished lobular and ductal carcinomas.16
In conclusion, our study indicates that primary cytotoxic chemotherapy may not be the best standard of care for women with ILC. The use of primary endocrine therapy in women with inoperable ILC should be investigated. Additional investigation, including genomic and proteomic studies, are warranted to help clarify the unique biologic features of this disease.
Authors’ Disclosures of Potential Conflicts of Interest
Acknowledgment
We thank Dr Donald A. Berry for statistical review and insightful comments.
NOTES
Supported by the Nellie B. Connally Breast Cancer Research Fund and the Susan G. Komen Fellowship Fund.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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19. Rouzier RD, Youmsi E, Delaloge S, et al: Predictors of breast-conserving surgery after epirubicin-based neoadjuvant chemotherapy for large breast carcinoma. Proc Am Soc Clin Oncol 22:38a, 2003 (abstr 151)
20. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16:2672-2685, 1998
21. Rouzier R, Extra JM, Klijanienko J, et al: Incidence and prognostic significance of complete axillary downstaging after primary chemotherapy in breast cancer patients with T1 to T3 tumors and cytologically proven axillary metastatic lymph nodes. J Clin Oncol 20:1304-1310, 2002
22. Kuerer HM, Newman LA, Smith TL, et al: Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 17:460-469, 1999
23. Buzdar AU, Singletary SE, Theriault RL, et al: Prospective evaluation of paclitaxel versus combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide as neoadjuvant therapy in patients with operable breast cancer. J Clin Oncol 17:3412-3417, 1999
24. Green MC, Buzdar AU, Smith T, et al: Weekly paclitaxel followed by FAC in the neo-adjuvant setting provides improved pathologic complete remission rates compared to standard paclitaxel followed by FAC therapy-preliminary results of an ongoing prospective randomized trial. Proc Am Soc Clin Oncol 20:33a, 2001 (abstr 129)
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36. Cocquyt VF, Blondeel PN, Depypere HT, et al: Different responses to preoperative chemotherapy for invasive lobular and invasive ductal breast carcinoma. Eur J Surg Oncol 29:361-367, 2003
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ABSTRACT
PATIENTS AND METHODS: The study included 1,034 patients with stage II and III breast cancer who participated in six clinical trials of PC at our institution between 1985 and 2002. One hundred twenty-two patients (12%) had ILC and 912 (88%) had IDC. All patients received anthracycline-based PC, and 346 patients (33.5%) also received a taxane as part of PC. Pathologic complete response (pCR) was defined as no evidence of invasive disease in the breast and axillary lymph nodes.
RESULTS: The median patient age was 48 years (range, 18 to 79 years). Patients with ILC tended to be older (median age, 53 years v 47 years for patients with IDC) and have more hormone-receptor–positive tumors (92% v 62%; P < .001), lower nuclear grade (nuclear grade 3, 16% v 56%; P < .001), and higher stage at diagnosis (10% v 0% with stage IIIB or IIIC disease; P < .001). Patients with ILC were less likely to have a pCR (3% v 15%; P < .001) and had a larger number of involved axillary lymph nodes (41% v 26% had > 3 involved nodes; P = .001). At a median follow-up time of 70 months, ILC patients tended to have longer recurrence-free survival (P = .004) and overall survival (P = .001).
CONCLUSION: ILC is characterized by lower rates of pathologic response to PC but better long-term outcomes compared to IDC. pCR might not be a prognostic indicator for this group of patients.
INTRODUCTION
The prognosis of ILC has been described as equal to or better than that of IDC, but outcome differences are difficult to determine because of the variation in the histologic criteria used to define ILC.9,17-19 Primary (neoadjuvant) chemotherapy is the standard treatment for patients presenting with locally advanced breast cancer, and its use is extending to earlier stages of disease. Pathologic complete response (pCR) and pathologic nodal status after primary chemotherapy are considered surrogates for survival. We evaluated the impact of histologic type (ILC v IDC) on how likely primary chemotherapy would result in pCR, and on long-term outcome in patients with primary breast cancer.20-22
PATIENTS AND METHODS
Diagnosis was made by core-needle biopsy of the breast tumor. The histologic type was defined according to the World Health Organization classification.1 All pathologic specimens were reviewed by breast pathologists at M.D. Anderson Cancer Center. Patients treated during this time whose tumors showed either mixed histologic types or types other than ductal or classic lobular were excluded to allow comparison of the pure lobular and ductal types.
Classic ILC was defined according to the criteria proposed by Fechner.12 The histologic grade was defined according to the modified Black’s nuclear grading system.27 The estrogen receptor (ER) and progesterone receptor (PR) status of 878 patients, tested by immunohistochemical staining, was available. Staining was performed with standard procedures on 4-μm sections of paraffin-embedded tissues with monoclonal antibodies: 6F11 (Novacastra, Burlingame, CA) for ER, and 1A6 (Novacastra) for PR. Nuclear staining ≥ 10% was considered positive.
Treatment
All patients received anthracycline-based primary chemotherapy. One hundred seventy-eight patients (17%) received four cycles of vincristine 1 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 intravenously (IV) on day 1 and prednisone 100 mg/m2 orally on days 1 to 5. Eight hundred fifty-six patients (83%) received four to eight cycles of fluorouracil 500 mg/m2 IV on days 1 and 4, doxorubicin 50 mg/m2 IV continuous infusion over 72 hours from days 1 to 3, and cyclophosphamide 500 mg/m2 IV on day 1. Three hundred thirty-six patients (32%) also received a paclitaxel regimen (175 to 250 mg/m2 IV on day 1 every 21 days for four cycles or 80 mg/m2 IV on day 1 every week for 12 weeks) as part of primary chemotherapy in randomized clinical trials.23-26 Breast surgery consisted of segmental mastectomy when tumor size permitted, according to the judgment of the multidisciplinary care team. In other cases, including cases of multifocal disease, mastectomy was performed. Axillary lymph node dissection was performed in 999 patients (97%). Five hundred eighty-two patients (56%) whose hormone receptor status was known to be positive received adjuvant tamoxifen for 5 years. Radiotherapy was delivered at completion of primary chemotherapy, after surgery in all patients treated with lumpectomy, and in patients with locally advanced disease.
Response
pCR was defined as no evidence of invasive carcinoma in the breast and the axillary lymph nodes. Information on the number of positive nodes at surgery was missing for 35 patients because the patient did not undergo surgery (n = 8), because the patient was randomized to a protocol on which she did not undergo nodal dissection (n = 26), or because the patient refused nodal dissection (n = 1). These missing data were not felt to introduce bias because patients with missing data on the number of positive nodes at surgery were not likely to be very different from patients for whom the number of positive nodes at surgery was known. Patients who did not have surgery owing to progressive disease were considered not to have had a pCR.
Statistical Methods
The patient population was described by tabulation of categoric variables and cross-tabulation of the categoric variables with histologic type. {chi}2 tests were used to test for an association between categoric variables and histologic type. Continuous variables were described by their minimum, median, and maximum values.
For both pCR and breast complete response (bCR), the number of responses was cross-tabulated by histologic type, and the tables were then stratified by ER and PR status (ER- or PR-positive, or negative for both ER and PR) and by whether or not the patient had received a taxane. Mantel-Haenszel {chi}2 tests were performed to test whether there was an association between pCR or bCR and histologic type after adjusting for ER and PR status and after adjusting for taxane use.
The Kaplan-Meier product-limit method was used to assess differences in overall survival and recurrence-free survival between the two histologic types after adjusting for the following: ER/PR status, both ER/PR status and pCR or bCR status, ER/PR status and disease stage, ER/PR status and nuclear grade, and taxane use. The log-rank test and the stratified log-rank test were used to compare survival estimates between histologic types. Overall survival was measured from the date of treatment to the date of death or last follow-up. Recurrence-free survival was measured from the date of treatment to the date of recurrence or last follow-up. Statistical analyses were carried out using SAS 8 (SAS Institute, Cary, NC) and S-Plus 6.1 (Insightful Corporation, Seattle, WA) software.
RESULTS
Patients with ILC tended to be older at diagnosis (median age, 53 v 47 years). Patients with ILC were also less likely to present with stage I-IIA disease (30% v 63%; P < .001). Despite their advanced clinical presentation, patients with ILC were more likely to have ER- or PR-positive tumors (92% v 62%; P < .001) and low-nuclear-grade disease (nuclear grade 3, 16% v 56%; P < .001).
Patients with ILC were more likely to receive taxanes as part of primary chemotherapy (taxanes use, 46% v 32%; P = .002), in part because the more advanced stage of the tumors at presentation necessitated patients’ participation in protocols for locally advanced disease.
Nine hundred ninety-eight patients (97%) had adequate response after primary chemotherapy and proceeded to surgery. Two hundred thirty-eight patients (27%) were treated with breast-conserving therapy (BCT). Patients with ILC were more likely than those with IDC to undergo mastectomy (83% v 67%; P = .003). The proportion of patients who underwent BCT was significantly lower for patients with ILC (16%) than for those with IDC (29%; P = .003). ILC was an independent predictor of ineligibility for BCT.
One hundred forty-two patients (14%) had a pCR (Tables 2 and 3). ILC was associated with a lower pCR rate (3% v 15%; P < .001) and a higher incidence of residual lymph node disease (≥ four positive lymph nodes, 41% v 26%; P = .001). In four patients, the pCR status differed from the bCR status (Table 4). One patient had two positive nodes and in situ disease and thus did not have a pCR but did have a bCR. Three patients had no residual disease or in situ residual disease but had an unknown number of positive nodes. These patients had an unknown pCR status but did have a bCR.
We analyzed the interaction between histologic type, hormone-receptor status, and the use of taxanes to see if these additional factors affected the likelihood of pCR (Tables 3 to 5). These two factors did not influence the chance of pCR in patients with ILC (Tables 3 and 5). Instead, patients with IDC had a lower chance of a pCR when hormone-receptor positive (9% v 4% pCR rate for IDC and ILC, respectively; P = .03).
The numbers of patients with pCR and bCR stratified by histologic type and taxane use are shown in Tables 5 and 6. Of the four patients with lobular disease who had a pCR or bCR, three had received a taxane. Among patients with ductal disease who were not treated with a taxane, 13% had a pCR. Among patients with ductal disease who were treated with a taxane, 20% had a pCR. A Mantel-Haenszel {chi}2 test showed that patients with IDC tended to have higher pCR rates regardless of whether they were treated with a taxane (P < .001). A {chi}2 test for association between histologic type and pCR showed a statistically significant correlation (P < .001).
At a median follow-up time of 70 months (range, 15 to 202 months), 325 patients (31%) had developed a recurrence, and 284 patients (27%) had died. Patients with ILC had a better 5-year recurrence-free survival rate (RFS; 87% v 66%; P = .004) and a better 5-year overall survival rate (OS; 93% v 70%; P = .001) than did patients with IDC (Figs 1 and 2). This pattern was also observed in the subset of patients with hormone-receptor–positive disease (Figs 3 and 4). Among patients with hormone-receptor–positive ductal disease, those with a pCR tended to have better RFS and OS than those without a pCR (Figs 5 and 6). Only four patients with hormone-receptor–positive lobular disease had a pCR, so we could not assess whether achievement of pCR was associated with a favorable outcome in this cohort of patients.
Regardless of pCR status, patients with lobular disease tended to have better OS than patients with ductal disease. Similar results were observed with regard to RFS (Fig 5). A stratified log-rank test was statistically significant for OS (P = .02) and for RFS (P = .01), indicating that OS and RFS were different between the two histologic types, even after adjusting for ER and PR status, and pCR status. Because there were so few patients with lobular hormone-receptor–negative disease, results for those patients were not presented.
DISCUSSION
Our results indicate that classic ILC responds less frequently to primary chemotherapy. More importantly, the difference in pCR rate between ILC and IDC persisted even after adjusting for hormone-receptor status and use of taxanes. A positive hormone-receptor status has previously been associated with a lower chance of pathologic response to primary chemotherapy. In a recent retrospective study of 1,018 patients, Buzdar et al32 found that rates of pCR to primary chemotherapy were significantly higher in patients with ER-negative tumors (P < .001). Conversely, the addition of taxanes, particularly in sequential regimens, has been shown to translate into higher pathologic response rates.20,33-35
We found that patients with ILC were more likely than patients with IDC to be treated electively with mastectomy, and because of the diffuse nature of the disease, and the poorer response to chemotherapy, these patients were rarely candidates for breast-conserving surgery. This finding has previously been reported by Cocquyt et al.36 The authors reviewed 135 patients treated with primary chemotherapy and found that BCT was possible in 50% of patients with IDC and 35% of patients with ILC. This is important because BCT is currently the primary end point for patients with early breast cancer undergoing primary chemotherapy20,33,37 and our findings indicate that there is no such benefit for patients with ILC.
The most striking finding of our investigation was that despite more advanced disease at presentation and the low pCR rate, and after adjusting for the imbalances in hormone-receptor–positive disease, patients with ILC had a better long-term outcome than did patients with IDC. ILC has repeatedly been shown to be associated with better long-term outcome than IDC.8-10 Several epidemiologic factors may explain the correlation. Women with ILC are usually older, are more likely to have previously used hormone-replacement therapy, and are more likely to have hormone-receptor–positive disease.18,38 In previous studies of primary chemotherapy, reported rates of ILC included in primary chemotherapy studies were 7% v 12%,38,39 but differences in outcome based in histologic subset analysis were not done.
To our knowledge, this is the first report that addresses the correlation between histologic type and response to primary chemotherapy in such a large cohort of patients, as a measure of chemo-sensitivity and long-term outcome. Our study indicated that very few patients with ILC achieve a pCR to primary chemotherapy and that pCR to primary chemotherapy in ILC may have no prognostic significance. Overall, these results indicate that the role of primary chemotherapy in ILC should be reconsidered. Primary chemotherapy in this subgroup does not achieve the two main objectives of this treatment: adequate downstaging of disease to allow for BCT and provision of a surrogate marker of prognosis (pCR).
The results also indicate that the use of primary systemic therapy in women with ILC should be restricted to patients with inoperable disease and should be more tailored to the peculiar biologic features of the disease. For example, primary endocrine treatments should be explored as a possible, more effective treatment for ILC. Initial studies of tamoxifen in the primary setting showed that this is a good alternative option for elderly patients who are poor candidates for primary cytotoxic chemotherapy.40 Subsequent studies in postmenopausal patients with ER-positive tumors demonstrated the effectiveness of aromatase inhibitors as primary therapy despite the rarity of pCR.41-43 More recently, a comparison between tamoxifen and anastrozole revealed a higher rate of BCT in the anastrozole group.44
Other scientific approaches, such as genomics and proteomics, may answer questions regarding biologic behavior and chemosensitivity and assist in the selection of the most appropriate therapy. Small series have demonstrated that microarray analysis can separate tumors into four groups according to proliferation, ER, c-erbB-2, and apoptosis genes.15 A recent report showed that specific changes in gene expression distinguished lobular and ductal carcinomas.16
In conclusion, our study indicates that primary cytotoxic chemotherapy may not be the best standard of care for women with ILC. The use of primary endocrine therapy in women with inoperable ILC should be investigated. Additional investigation, including genomic and proteomic studies, are warranted to help clarify the unique biologic features of this disease.
Authors’ Disclosures of Potential Conflicts of Interest
Acknowledgment
We thank Dr Donald A. Berry for statistical review and insightful comments.
NOTES
Supported by the Nellie B. Connally Breast Cancer Research Fund and the Susan G. Komen Fellowship Fund.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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