Outcome after pathologic complete eradication of cytologically proven breast cancer axillary node metastases following primary chemotherapy

Tags: chemotherapy, American Society of Clinical Oncology, breast cancer, primary tumor, metastases, RFS, ALN metastases, neoadjuvant chemotherapy, complete response, pCR, axillary lymph node, residual disease, adjuvant chemotherapy, J Clin Oncol, anthracyclines, neoadjuvant therapy, preoperative chemotherapy, OS, locally advanced breast cancer, ALN pCR, breast tumor, Postoperative Chemotherapy, residual tumor, cancer, primary chemotherapy, benefit, relative risk reductions, Relative risk reduction, prognostic significance, Department of Biostatistics, lymph node metastases, breast cancer patients, Department of Surgical Oncology, Department of Pathology, Department of Diagnostic Radiology, Breast Medical Oncology, PCT, Induction chemotherapy, operable carcinoma of the breast, axillary lymph nodes, Sentinel lymph node biopsy, Ann Surg, National Surgical Adjuvant Breast, chemotherapy regimen
Content: VOLUME 23 NUMBER 36 DECEMBER 20 2005 Journal of Clinical Oncology
From the Department of Breast Medical Oncology, Department of Surgical Oncology, Department of Pathology, Department of Diagnostic Radiology, and Department of Biostatistics at The University of Texas M.D. Anderson Cancer Center, Houston, TX. Submitted April 25, 2005; accepted September 28, 2005. Authors' disclosures of potential conflicts of interest are found at the end of this article. Address reprint requests to Bryan Hennessy, MD, Department of Breast Medical Oncology, Unit 424, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: [email protected] mdanderson.org. © 2005 by American Society of Clinical Oncology 0732-183X/05/2336-9304/$20.00 DOI: 10.1200/JCO.2005.02.5023
Outcome After Pathologic Complete Eradication of Cytologically Proven breast cancer Axillary Node Metastases Following Primary Chemotherapy Bryan T. Hennessy, Gabriel N. Hortobagyi, Roman Rouzier, Henry Kuerer, Nour Sneige, Aman U. Buzdar, Shu Wan Kau, Bruno Fornage, Aysegul Sahin, Kristine Broglio, S. Eva Singletary, and Vicente Valero ABSTRACT Purpose Pathologic complete remission (pCR) of primary breast tumors after primary chemotherapy (PCT) is associated with higher relapse-free survival (RFS) and overall survival (OS) rates. The purpose of this study was to determine long-term outcome in patients achieving pCR of cytologically proven axillary lymph node (ALN) metastases. Methods Patients with cytologically documented ALN metastases were treated in five prospective PCT trials. After surgery, patients were subdivided into those with and without residual ALN carcinoma. Survival was calculated by the Kaplan-Meier method. Results Of 925 patients treated, 403 patients had cytologically confirmed ALN metastases. Eightynine patients (22%) achieved ALN pCR after PCT. Compared with the group without ALN pCR, 5-year OS and RFS were improved in patients achieving ALN pCR (93% [95% CI, 87.5 to 98.5] and 87% [95% CI, 79.7 to 94.3] v 72% [95% CI, 66.5 to 77.5] and 60% [95% CI, 54.1 to 65.9], respectively; P .0001). Residual primary tumor did not affect outcome of those with ALN pCR. Combination anthracycline/taxane-based PCT resulted in significantly more ALN pCRs, although outcome after ALN pCR was not improved by taxanes. We constructed a nomogram demonstrating that patients who do not benefit from neoadjuvant anthracyclines are unlikely to benefit from subsequent taxanes. Conclusion ALN pCR is associated with an excellent prognosis, even with a residual primary tumor, pointing to biologic differences between primary and metastatic cells. ALN pCR represents an early surrogate marker of long-term outcome. Response to initial PCT has important potential as a guide to subsequent therapy. J Clin Oncol 23:9304-9311. © 2005 by American Society of Clinical Oncology
INTRODUCTION cancer cells are characterized by aberrant proliferation, prolonged survival, and capacity to invade/metastasize. Axillary lymph node (ALN) metastases is the most important prognostic factor in breast cancer. Pathologic complete response (pCR) of axillary metastases may thus affect the long-term course of high-risk breast can-
cer and provide an early surrogate marker of relapse-free survival (RFS) and overall survival (OS). Primary or neoadjuvant systemic chemotherapy is the standard treatment for patients with locally advanced breast cancer and large, operable breast cancer, who desire breast-conserving surgery; it is also being assessed in patients with earlierstage disease, and other types of cancer.1-12
9304 Downloaded from jco.ascopubs.org on December 26, 2015. For personal use only. No other uses without permission. Copyright © 2005 American Society of Clinical Oncology. All rights reserved.
pCR of Breast Cancer After PCT
The long-term outcome in patients with pCR of cytologically confirmed ALN metastases after primary chemotherapy is unknown. Randomized studies, including the National Surgical Adjuvant Breast and Bowel Project (NSABP) B18 trial, have not shown a survival advantage for patients with operable breast cancer treated with primary compared with postoperative chemotherapy. Nevertheless, patients with pCR of the breast primary have a significantly better outcome than do those with residual disease.11-13 Primary chemotherapy has several advantages over adjuvant chemotherapy.12 From a purely theoretical standpoint, studies of outcome in patients who receive primary chemotherapy allow an accurate assessment of the response of the tumor to chemotherapy in individual patients. In addition to pCR, the number of postchemotherapy metastatic ALNs is prognostic.14-16 ALN metastases are a good biologic model for studying how metastases respond to primary chemotherapy and for studying phenotypic differences in nodal cells associated with increased propensity for distant metastases. Our group has, as far as we know, the largest number of patients with stages II and III breast cancer and cytologically proven ALN metastases before primary systemic chemotherapy.17 In the current study, we determined the long-term outcome of these patients. METHODS Between 1989 and 2001, 925 patients with stages II/III breast cancer (2002 American Joint Committee on Cancer classification18) were treated in five prospective institutional review boardapproved trials of anthracycline- or anthracycline/taxane-based primary chemotherapy. Patients gave written Informed Consent and were registered prospectively. Of the 925 patients, 632 patients had a clinically suspicious axilla; after needle sampling, 403 patients had cytologically documented ALN metastases. Patients were examined by a multidisciplinary team to assess the clinical stage of disease at presentation and response after four chemotherapy cycles. Staging included history and Physical Examination, CBC, blood chemistries, electrocardiography, chest radiology, abdominal computEd Tomography or ultrasonography,
bone scan, bilateral mammography, and breast/regional lymph node ultrasonography. Patients were entered, prospectively, into the protocol database and data added with follow-up. Complete medical records of all patients were available for review at the time of this analysis. Details of the five primary chemotherapy protocols are presented in Table 1. Most patients underwent a subsequent segmental mastectomy with ALN dissection (n 116) or a modified radical mastectomy (n 253). Four patients underwent a sentinel lymph node biopsy. Ten patients had axillary dissection alone, because negative margins had been found at prior primary tumor excision (n 3) or because no primary tumor was detectable at diagnosis (n 7). Patients with progressive disease after primary chemotherapy (n 20) received preoperative radiation treatment (50 to 60 Gy) followed by modified radical mastectomy. The ALN dissection specimens were assessed completely to identify all lymph nodes. Lymph nodes that appeared to show no residual carcinoma were submitted in toto for histologic evaluation. The blocks were processed by routine methods and only one representative hematoxylin- and eosin-stained section obtained. Immunohistochemistry for keratin was performed when suspicious cells were identified. A histologic response was considered a pCR when there was no evidence of residual tumor in the ALNs. Breast pCR was defined as absence of invasive disease in the breast, but ductal/lobular carcinoma-in-situ was allowed. Immunohistochemistry for estrogen (ER) and progesterone receptor was performed with the avidin-biotin peroxidase complex method using 6F11 and 1A6 antibodies (Novocastra Laboratories Ltd, Newcastle upon Tyne, United Kingdom), respectively.19 Postoperative radiotherapy was delivered to the chest wall, internal mammary, and supraclavicular/high ALNs. Locoregional radiotherapy was instituted within 6 weeks of chemotherapy completion. Tamoxifen was started after chemotherapy in those with hormone receptor-positive tumors. Data were analyzed with Splus 6.1 (Insightful Corp, Seattle, WA) and SAS 8 (SAS, Cary, NC). OS was calculated from the date of diagnosis and RFS from the chemotherapy start date by the Kaplan-Meier method.20 The log-rank statistic was used for univariate comparisons of survival end points.21 All comparisons were two-tailed. Cox proportional hazards models were fit for OS and RFS and included variables identified a priori as being associated with survival or ALN status. Other variables not identified a priori were entered into the model one at a time and assessed for statistical significance. All pair-wise interactions were tested. The fit of the model and the proportional hazards
Table 1. The Five Primary Chemotherapy Protocols
Protocol No.
Primary Chemotherapy
Postoperative Chemotherapy 1
Postoperative Chemotherapy 2
No. of Patients With Cytologically Confirmed ALN Metastases Before Therapy
FAC 4 versus paclitaxel 4
AT 4
Paclitaxel 4- FAC 4
FAC 4 FAC 4 FAC 4 AT 2 --
MV 6 MV 6 -- CMF 6 --
104 87 33 v 35 49 95
NOTE. All patients had postoperative chemotherapy 1; only those patients with positive ALNs after primary chemotherapy received postoperative chemotherapy 2. Paclitaxel was administered at 3 weekly intervals for four cycles. Abbreviations: ALN, axillary lymph nodes; FAC, fluorouracil, doxorubicin, and cyclophosphamide; MV, methotrexate and vinblastine; AT, doxorubicin and docetaxel; CMF, cyclophosphamide, methotrexate, and fluorouracil.
Downloaded from jco.ascopubs.org on December 26, 2015. For personal use only. No other uses without permission. Copyright © 2005 American Society of Clinical Oncology. All rights reserved.
Hennessy et al
assumption were assessed visually with residual plots. The relationship between ER status and tumor response and the relationship between residual positive ALNs and tumor response were assessed with 2 tests. The statistical significance level (P) was taken as a measure of the strength of evidence against the null hypothesis, and P .05 was considered statistically significant. The logistic regression model was used to construct a nomogram to predict individual patient probability of axillary conversion. Continuous variables were fit for age, ER status, grade, chemotherapy regimen, and T stage using restricted cubic splines to relax the linearity assumptions. The nomogram was internally validated by bootstrapping with 200 resamples as a means of calculating a relatively unbiased measure of its ability to discriminate between patients as quantified by the area under the receiver operator characteristic curve. Subsequently, the predicted probability of axillary conversion was compared with the actual achievement of axillary conversion, again using 200 bootstrap resamples to decrease overfit bias. RESULTS Table 2 presents initial patient and tumor characteristics of 403 patients with cytologically documented ALN metastases. Twenty-two percent of these patients (n 89) had an axillary pCR after primary chemotherapy. The patient group that achieved ALN pCR more often had ER-negative and high-grade tumors. Sixty-one patients (69%) with ALN pCR also achieved a primary tumor pCR. In the group with residual ALN disease after chemotherapy, there were only 14 patients (4%) who had a primary tumor pCR. The outcome of those patients who achieved ALN pCR with primary chemotherapy was compared with that of the patient group with residual disease in the ALNs. Median follow-up was 64 months (range, 15 to 178 months). The 5-year OS and RFS rates were significantly better in patients with axillary pCR (93% [95% CI, 87.5 to 98.5] and 87% [95% CI, 79.7 to 94.3] v 72% [95% CI, 66.5 to 77.5] and 60% [95% CI, 54.1 to 65.9], respectively; P .0001; Fig 1A and 1B; Table 3). In terms of only locoregional recurrences, there were four events (4%) among patients with axillary pCR compared with 28 events (9%; P .17) in the other group. In patients with residual axillary metastases, the 5-year OS rates in those with one to three (n 166), four to nine (n 112), and 10 or more (n 36) positive ALNs were 74% (95% CI, 66.4 to 81.6), 74% (95% CI, 65.4 to 82.6), and 56% (95% CI, 38.2 to 73.8), respectively (P .09). The corresponding 5-year RFS rates were 68% (95% CI, 60.2 to 75.8), 56% (95% CI, 46.4 to 65.6), and 43% (95% CI, 26.5 to 59.5; P .02). Influence of Hormone Receptor Status on pCR Rates and Outcome Thirty-one percent of those with ER-negative tumors (28% in those aged younger than 50 years and 35% in older patients) and 12% of those with ER-positive tumors (11% in those aged younger than 50 years and 12% in older
patients) achieved an ALN pCR (P .001). In those achieving ALN pCR, ER status was not associated with a survival difference. However, in patients with residual ALN carcinoma, those with ER-positive tumors had significantly better 5-year OS (84% [95% CI, 77.7 to 90.3] v 53% [95% CI, 42.8 to 63.2]; P .001) and RFS rates (68% [95% CI, 60.5 to 75.5] v 46% [95% CI, 36 to 56]; P .001). Residual Disease in the Breast In those achieving ALN pCR (n 89), 61 patients had no residual tumor in the breast and 28 patients had residual carcinoma in the breast. We found no significant 5-year RFS or OS differences between these two groups (Fig 1C and 1D). However, this analysis is not adequately powered to detect small outcome differences. For patients with residual ALN metastases, the residual tumor size did not have a significant effect on outcome (Table 4). Taxanes We grouped together those patients from the five clin- ical protocols treated with primary anthracyclines only (protocols 1 to 3; n 226) and those given anthracycline/ taxane-based primary chemotherapy (protocols 4 to 5; n 144). Patients treated on protocols 1 to 3 did not receive taxanes after surgery. The remaining 33 patients were treated on protocol 3 with primary paclitaxel only and were excluded from this comparison. Forty-four patients (19%) and 42 patients (29%) treated with primary anthracycline-based or anthracycline/ taxane-based therapy achieved ALN pCR, respectively (P .03). The increase in pCR rate was probably because of the addition of a taxane, although patients in protocol 5 had eight cycles of primary chemotherapy. Although those patients achieving ALN pCR with anthracycline-based chemotherapy had more stage III tumors at diagnosis (34 v 14), 5-year RFS and OS rates were not significantly different between the two groups (Fig 2A and 2B). The benefit of primary chemotherapy may, thus, be related to pCR achievement rather than to the specific drugs per se. However, it should be noted that patient numbers are small and that this analysis is not powered to detect small differences. Interpretation is further limited by the imbalance in the number of primary chemotherapy cycles administered to the two groups. Patients With Residual ALN Metastases Among all 314 patients with residual ALN disease at surgery after primary chemotherapy, therapy effect (defined as areas of necrosis, fibrosis, hyalinization, vacuolization, and/or cystic degeneration noted by the pathologist within the tumor) was present within the residual tumors of 42% of these patients and was associated with improved 5-year RFS (68.9% [95% CI 60.9 to 78.1] v 54.1% [95% CI 46.9 to 62.5]; P .025) and OS rates (79.4% [95% CI 72.2 to 87.4] v 66.7% [95% CI 59.5 to 74.8]; P .05). The location
Downloaded from jco.ascopubs.org on December 26, 2015. For personal use only. No other uses without permission. Copyright © 2005 American Society of Clinical Oncology. All rights reserved.
pCR of Breast Cancer After PCT
Table 2. Patient and Tumor Characteristics, Subdivided According to the Response of Metastatic Axillary Lymph Node Disease to Primary Chemotherapy
Axillary ALN Residual
No. of patients Age, years Median Range 50 years No. % 50 years No. % Median lymph nodes removed at surgery Estrogen receptor status at diagnosis Positive No. % Negative No. % Not assayed No. % Modified Black's tumor grade Grades 1/2 No. % Grade 3 No. % Tumor stage at diagnosis T0 No. % T1 No. % T2 No. % T3 No. % T4 No. % Tx No. % Initial axillary node status N1 No. % N2 No. % N3 No. %
89 49 21-72 46 52 43 48 15 21 24 56 63 12 13 18 20 71 80 4 4 14 16 41 46 15 17 14 16 1 1 53 60 30 34 6 6
314 48 24-79 177 56 137 44 16 163 52 128 41 23 7 126 40 188 60 9 3 33 11 120 38 64 20 82 26 6 2 186 59 100 32 28 9
-- -- -- -- -- .001 .001 .21 .79
Abbreviations: pCR, pathologic complete response; ALN, axillary lymph node. Cases not assayed were excluded from the P value calculation.
of therapy effect (breast and/or lymph nodes) did not further stratify patients. Therapy effect was more commonly seen in patients with only one metastatic ALN (54% v 39%; P .03); surprisingly, ER status was not associated with therapy effect. When the size of the largest residual nodal metastatic deposit was categorized as 0.1 cm, 0.1 to 1 cm, and more than 1 cm, we found no trend toward lower OS or RFS rates with increasing size. This was also true when the analysis was confined to 68 patients with one involved ALN. Multivariable Analysis In the Cox proportional hazards model, the variables significantly associated with OS were axillary conversion (P .0005), initial clinical nodal stage (N1 v N2/3; P .05), nuclear grade (P .02), and age (P .01). The variables significantly associated with RFS were axillary conversion (P .0001) and age (P .01). After adjustment for hormone receptor status, T stage, N stage, nuclear grade, and age (for RFS), patients with residual ALN disease had 8.32 times (95% CI 2.54 to 27.21) the risk of death and 4.64 times (95% CI 2.39 to 8.98) the risk of relapse compared with patients with no residual ALN disease. Nomogram We successfully constructed a nomogram to predict individual patient probability of having axillary conversion (Fig 3). Adding interactions between grade or ER status and the regimen used did not statistically improve accuracy of the model, thus demonstrating that adding a taxane to an anthracycline did not rescue the subgroup of patients with a low likelihood of axillary conversion with anthracyclines alone. DISCUSSION Primary systemic chemotherapy completely clears cytologically confirmed ALN metastases in 22% of patients with stages II/III breast cancer. Our data exclude patients with clinically suspicious axillary findings in whom cytology was negative or nondiagnostic. The rate of ALN negativity after primary chemotherapy in patients with clinically suspicious ALNs varies from 25% to 38%.11,14,22 Significantly more patients achieved ALN pCR when taxanes were used in addition to anthracyclines, consistent with the NSABP B27 study.23 In this study, the absolute difference in the proportion of patients with negative nodes after anthracycline-based and anthracycline/ taxane-based primary chemotherapy was 8% (50% v 58%). However, in neither of the NSABP studies were clinically suspicious ALNs cytologically sampled before treatment. As in NSABP B18, in those with residual ALN carcinoma after primary chemotherapy, we found that the size of persistent ALN deposits is not associated with outcome. ALN pCR is associated with an excellent prognosis despite an excess of aggressive features (ie, high-grade and
Downloaded from jco.ascopubs.org on December 26, 2015. For personal use only. No other uses without permission. Copyright © 2005 American Society of Clinical Oncology. All rights reserved.
Hennessy et al
Fig 1. (A) Relapse-free survival (RFS) and (B) overall survival (OS) for 403 patients by nodal status after primary chemotherapy (Table 3). (--) Axillary pathologic complete response (pCR); (----) residual axillary disease. RFS (C) and OS (D) for 89 patients with axillary nodal pCR. Five-year RFS and OS were 89% and 96%, respectively, in 28 patients with residual primary breast tumor (----) versus 86% (P .63) and 91% (P .42), respectively, with no residual primary tumor (--).
ER-negativity) in these tumors. Earlier studies have established that pCR occurs more frequently in these tumors.11,13,24 How- ever, some groups have elected to define pCR as no residual
disease in the breast only (eg, NSABP).11,23 Our data suggest not only that the axillary content must be considered in the evaluation of prognosis, but also that it is the dominant
Table 3. Five- and 10-Year RFS and OS Rates of Patients With Axillary pCR and of Patients With Residual ALN Disease After Primary Chemotherapy
5-Year RFS 10-Year RFS
5-Year OS
10-Year OS
Node Status
5-Year 10-Year
5-Year 10-Year
No. of
No. at No. at
No. at No. at
Patients % 95% CI % 95% CI Risk Risk
P % 95% CI % 95% CI Risk Risk
89 87 79.7 to 94.3 87 79.7 to 94.3 45
Residual ALN disease 314 60 54.1 to 65.9 38 23.3 to 52.7 114
17 .0001 93 87.5 to 98.5 93 87.5 to 98.5 47
72 66.5 to 77.5 60 51.2 to 68.8 132
18 .0001 6
Abbreviations: RFS, relapse-free survival; OS, overall survival; pCR, pathologic complete response; ALN, axillary lymph node.
Downloaded from jco.ascopubs.org on December 26, 2015. For personal use only. No other uses without permission. Copyright © 2005 American Society of Clinical Oncology. All rights reserved.
pCR of Breast Cancer After PCT
Table 4. Five-Year RFS and OS Rates of the Patients with Residual Carcinoma in the Axillary Lymph Nodes After Primary Chemotherapy Subdivided According to the Size of the Residual Breast Tumor
Tumor No. of
Size (cm) Patients % 95% CI
P % 95% CI
14 70 44.9 to 95.1 .28 81 56.3 to 100 .12
61 66 52.9 to 79.1
82 71.6 to 92.4
83 51 39 to 63
59 46.8 to 71.2
115 58 48.4 to 67.6
72 63.2 to 80.8
Abbreviations: RFS, relapse-free survival; OS, overall survival. We excluded from this analysis 30 patients who had initial complete excision of the primary tumor (before primary chemotherapy), seven patients in whom no primary tumor was clinically or radiologically detectable at diagnosis, and four patients in whom the residual breast tumor was not sized on the pathology report.
determinant of prognosis after primary chemotherapy, in agreement with the results of a smaller French study.25 Primary tumor pCR has prognostic importance possibly because most such patients also achieve ALN pCR. Although the number of patients at risk at 10 years was low in those with residual ALN disease in our study, it seems that these patients continue to suffer relapse after 5 years. However, no patients who achieved ALN pCR suffered relapse after 5 years. Thus, if this is confirmed, ALN pCR has potential to become an early surrogate marker for longterm outcome. Currently, it takes many years and large trials to determine the benefit of experimental adjuvant agents. We recommend that if early surrogate markers of outcome are examined after primary chemotherapy, they should include ALN pCR; using pCR in the breast only is inadequate as an early surrogate marker. Because 22% of patients achieve ALN pCR after primary chemotherapy, axillary dissection, currently the standard approach, might not be necessary in certain patients with ALN-positive breast cancer treated with primary chemotherapy. Sentinel lymph node biopsy may be an alternative in patients with a clinically negative axilla after primary chemotherapy.26-29 We and others are prospectively assessing sentinel lymph node biopsy in patients with ALN-positive breast cancer treated in current primary chemotherapy protocols. Our results suggest that the presence of residual disease in the breast in those achieving ALN pCR does not result in an inferior outcome, perhaps because residual tumor cells in the breast do not have metastatic capability. Further, genetic changes in primary tumor cells, leading to acquisition of a metastatic phenotype, may be associated with changed chemotherapy sensitivity. In addition, because we observed, albeit in a small number of patients, that those achieving ALN pCR with anthracycline-based treatment did just as well as patients achieving ALN pCR with anthracycline/taxane-based therapy, it is possible that as many as 19% of patients with ALN-positive breast cancer
Fig 2. (A) Relapse-free survival (RFS) and (B) overall survival (OS) of patients achieving axillary lymph node pathologic complete response after primary chemotherapy according to the neoadjuvant therapy. Five-year RFS and OS were 89% and 91%, respectively, in 44 patients treated with anthracyclines alone (--) versus 87% (P .78) and 94% (P .52), respectively, in 42 patients treated with anthracyclines and taxanes (---). are overtreated by adding a taxane (this is the proportion of patients achieving ALN pCR with anthracyclines alone); NSABP B27 provides support for this observation.30 Thus, it may be possible to spare patients unnecessary chemotherapy (taxanes) by determining those who will achieve pCR with initial anthracyclines; although, this is certainly not feasible at present. Gene- and protein-based novel technologies may assist us in this regard. An alternative approach may be to determine which patients with a complete clinical ALN response after primary anthracycline-based treatment have a pCR. Currently, axillary ultrasonography, contrast enhanced magnetic resonance imaging, and positron emission tomography are potentially interesting in this regard.31-33 It
Downloaded from jco.ascopubs.org on December 26, 2015. For personal use only. No other uses without permission. Copyright © 2005 American Society of Clinical Oncology. All rights reserved.
Hennessy et al
Fig 3. Nomogram to predict probability of axillary conversion. A line is drawn upward from each variable to determine a score. The points are summed. This number is located on the total points axis, and a line is drawn downward to determine predicted probability of residual nodal metastases (pN). A patient aged 50 years (50 points) with a grade 3 (0) ER-negative (0) tumor has about a 60% likelihood of axillary conversion. ER, estrogen receptor.
is also clear from our data, NSABP B27, and the Scottish neoadjuvant trial that patients not benefiting from primary anthracyclines are unlikely to benefit from subsequent taxanes.34 With new technologies such as gene and protein array, we may explain the behavior of these tumors and identify new potential therapeutic targets.35-38 In patients with breast cancer treated with adjuvant chemotherapy, relative risk reductions for breast cancer subtypes defined by age and ER-status are relatively stable for patients with differing T and N stages of disease.39 Our ALN pCR rates are similar to these relative risk reductions, except in patients aged younger than 50 years with ER-positive tumors in whom ALN pCR rates underrepresent chemotherapy benefit as they do not take into account ovarian function effects. Admittedly, this may be coincidental. However, we believe that it is important. Relative risk reduction equates to the proportion of patients destined to relapse in the absence of a therapy, who benefit from the addition of the therapy. The similarity between the relative risk reductions and pCR rates suggests that chemotherapy has similar activity in terms of pCR rates against breast tumors for which surgery alone will be curative and against those breast tumors that are destined to relapse with surgery alone. Thus, the absolute proportion of patients who benefit from adjuvant chemotherapy reflects not the proportion who would have achieved a pCR with primary chemotherapy but only that proportion of patients who would have relapsed without chemotherapy. This would explain why pCR rates do not equate to absolute risk reductions; some patients achieving pCR with primary chemotherapy are not destined to relapse, if treated with only surgery. For example, in
NSABP B27, to predict the absolute increment in RFS rates with primary docetaxel, it may be approximated by 13%, the increase in the pCR rate with docetaxel, of 33%, the approximate proportion of patients who relapse, if treated with surgery and anthracyclines alone. Although taxanes increase pCR rates by 13%, we suggest that this may behave more like a relative than an absolute risk reduction, according to our theory that adding docetaxel will result in pCR in 13% of the 67% of patients destined to be cured with surgery/anthracyclines alone, who, thus, do not benefit, and 13% of the 33% of patients destined to relapse with only surgery/anthracyclines, who, thus, do benefit. Because the absolute benefit is small, a sufficiently large number of patients is required to demonstrate benefit with taxanes. In summary, ALN pCR is an excellent prognostic factor, even with residual breast disease. ALN pCR after primary therapy has potential to become an early surrogate marker of long-term benefit with experimental adjuvant treatments. Further, the use of conventional primary chemotherapy may allow us to determine the biologic features that predict if particular patients will benefit from standard adjuvant chemotherapy. Our study, along other neoadjuvant trials, suggests that we should begin to look at the response to the initial primary therapy regimen as having potential as a guide to subsequent therapy.
Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
Downloaded from jco.ascopubs.org on December 26, 2015. For personal use only. No other uses without permission. Copyright © 2005 American Society of Clinical Oncology. All rights reserved.
pCR of Breast Cancer After PCT
REFERENCES 1. Bacci G, Picci P, Ferrari S, et al: Primary chemotherapy and delayed surgery for nonmetastatic osteosarcoma of the extremities: Results in 164 patients preoperatively treated with high doses of methotrexate followed by cisplatin and doxorubicin. Cancer 72:3227-3238, 1993 2. Spaulding MB, Fischer SG, Wolf GT: Tumor response, toxicity, and survival after neoadjuvant organ-preserving chemotherapy for advanced laryngeal carcinoma. J Clin Oncol 12:1592-1599, 1994 3. Sugarbaker DJ, Herndon J, Kohman LJ, et al: Results of cancer and leukemia group B protocol 8935: A multiinstitutional phase II trimodality trial for stage IIIA (N2) non-small-cell lung cancer--Cancer and Leukemia Group B Thoracic Surgery Group. J Thorac Cardiovasc Surg 109: 473-483, 1995 4. Jablonka S, Furmanik F, Jablonka A, et al: Principles of induction chemotherapy for nonsmall cell lung cancer. Lung Cancer 34:S151S153, 2001 (suppl 2) 5. Herr HW, Bajorin DF, Scher HI: Neoadjuvant chemotherapy and bladder-sparing surgery for invasive bladder cancer: Ten-year outcome. J Clin Oncol 16:1298-1301, 1998 6. Swisher SG, Holmes EC, Hunt KK, et al: The role of neoadjuvant therapy in surgically resectable esophageal cancer. Arch Surg 131: 819-824, 1996 7. Delena M, Zucali R, Viganotti G, et al: Combined chemotherapy­radiotherapy approach in locally advanced (T3b-T4) breast cancer. Cancer Chemother Pharmacol 1:53-59, 1978 8. Hortobagyi GN, Blumenschein GR, Spanos W, et al: Multimodal treatment of locoregionally advanced breast cancer. Cancer 51:763-768, 1983 9. Lippman ME, Sorace RA, Bagley CS, et al: Treatment of locally advanced breast cancer using primary induction chemotherapy with hormonal synchronization followed by radiation therapy with or without debulking surgery. NCI Monogr 156-159, 1986 10. Scholl SM, Fourquet A, Asselain B, et al: Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: preliminary results of a randomised trial: S6. Eur J Cancer 30A:645-652, 1994 11. 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 12. Mamounas EP: Overview of National Surgical Adjuvant Breast Project neoadjuvant chemotherapy studies. Semin Oncol 25:31-35, 1998 13. 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 17:460469, 1999
14. McCready DR, Hortobagyi GN, Kau SW, et al: The prognostic significance of lymph node metastases after preoperative chemotherapy for locally advanced breast cancer. Arch Surg 124: 21-25, 1989 15. Botti C, Vici P, Lopez M, et al: Prognostic value of lymph node metastases after neoadjuvant chemotherapy for large-sized operable carcinoma of the breast. J Am Coll Surg 181:202-208, 1995 16. Kuerer HM, Newman LA, Buzdar AU, et al: Residual metastatic ALNs following neoadjuvant chemotherapy predicts disease-free survival in locally advanced breast cancer patients. Am J Surg 176:502-509, 1998 17. Kuerer HM, Sahin AA, Hunt KK, et al: Incidence and impact of documented eradication of breast cancer axillary lymph node metastases before surgery in patients treated with neoadjuvant chemotherapy. Ann Surg 230:72-78, 1999 18. American Joint Committee on Cancer (AJCC) Cancer Staging Handbook (ed 6). New York, NY, Springer-Verlag, 2002 19. Hsu SM, Raine L, Fanger H: Use of avidinbiotin-peroxidase complex (ABC) in immunoperoxidase techniques: A comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29:577-580, 1981 20. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 185:1457-1481, 1958 21. Mantel N: Evaluation of survival data and two row rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966 22. Schwartz GF, Birchansky CA, Komarnicky LT, et al: Induction chemotherapy followed by breast conservation for locally advanced carcinoma of the breast. Cancer 73:362-369, 1994 23. Bear HD, Anderson S, Brown A, et al: The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: Preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 21: 4165-4174, 2003 24. Fisher ER, Wang J, Bryant J, et al: Pathobiology of preoperative chemotherapy: Findings from the National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18. Cancer 95:681695, 2002 25. 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 26. Shimazu K, Tamaki Y, Taguchi T, et al: Sentinel lymph node biopsy using periareolar injection of radiocolloid for patients with neoadjuvant chemotherapy-treated breast carcinoma. Cancer 100:2555-2561, 2004 27. Trocha SD, Giuliano AE: Sentinel node in the era of neoadjuvant therapy and locally ad-
vanced breast cancer. Surg Oncol 12:271-276, 2003 28. Breslin TM, Cohen L, Sahin A, et al: Sentinel lymph node biopsy is accurate after neoadjuvant chemotherapy for breast cancer. J Clin Oncol 18:3480-3486, 2000 29. Mamaonas EP, Brown A, Smith R, et al: Accuracy of sentinel node biopsy after neoadjuvant chemotherapy in breast cancer: Updated results from NSABP B-27. Proc Am Soc Clin Oncol 20, 2002 (abstr 140) 30. Bear HD, Anderson S, Brown A, et al: A Randomized Trial comparing preoperative (preop) doxorubicin/cyclophosphamide (AC) to preop AC followed by preop docetaxel (T) and to preop AC followed by postoperative (postop) T in patients (pts) with operable carcinoma of the breast: Results of NSABP B-27. Presented at the 27th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2004 (abstr 26) 31. Kuerer HM, Newman LA, Fornage BD, et al: Role of ALN dissection after tumor downstaging with induction chemotherapy for locally advanced breast cancer. Ann Surg Oncol 5:673-680, 1998 32. Martincich L, Montemurro F, De Rosa G, et al: Monitoring response to primary chemotherapy in breast cancer using dynamic contrastenhanced magnetic resonance imaging. Breast Cancer Res Treat 83:67-76, 2004 33. Biersack HJ, Bender H, Palmedo H: FDGPET in monitoring therapy of breast cancer. Eur J Nucl Med Mol Imaging 31:S112-S117, 2004 (suppl 1) 34. Hutcheon AW, Heys SD, Sarkar TK: Neoadjuvant docetaxel in locally advanced breast cancer. Breast Cancer Res Treat 79:S19 ­S24, 2003 (suppl 1) 35. Sorlie T, Perou CM, Tibshirani R, et al: gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:1086910874, 2001 36. Ayers M, Symmans WF, Stec J, et al: Gene expression profiles predict complete pathologic response to neoadjuvant paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide chemotherapy in breast cancer. J Clin Oncol 22:2284-2293, 2004 37. Chang JC, Wooten EC, Tsimelzon A, et al: Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer. Lancet 362:362-369, 2003 38. Gianni L, Zambetti M, Clark K, et al: Gene expression profiles of paraffin-embedded core biopsy tissue predict response to chemotherapy in patients with locally advanced breast cancer. J Clin Oncol 23:7265-7277, 2005 39. Early Breast Cancer Trialists' Collaborative Group: 2000 analysis overview results. Presented at the fifth meeting of the Early Breast Cancer Trialists' Collaborative Group, Oxford, UK, September 21-23, 2000
Downloaded from jco.ascopubs.org on December 26, 2015. For personal use only. No other uses without permission. Copyright © 2005 American Society of Clinical Oncology. All rights reserved.

File: outcome-after-pathologic-complete-eradication-of-cytologically.pdf
Published: Wed Dec 7 16:50:36 2005
Pages: 8
File size: 0.39 Mb

The music of the primes, 9 pages, 0.27 Mb

, pages, 0 Mb
Copyright © 2018 doc.uments.com