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10.1245/ASO.2005.07.021
Annals of Surgical Oncology 12:480-487 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Breast Conservation After Neoadjuvant Chemotherapy

Siegal Sadetzki, MD, MPH1,2, Bernice Oberman, MSc1, Douglas Zipple, MD2,3, Bella Kaufman, MD4, Shulamit Rizel, MD5, Ilya Novikov, PhD6 and Moshe Z. Papa, MD2,3

1 The Cancer & Radiation Epidemiology Unit, Gertner Institute for Epidemiology and Health Policy Research, Chaim Sheba Medical Center, Tel Hashomer, Israel
2 Tel Aviv University, Sackler School of Medicine, Ramat Aviv, Tel Aviv, Israel
3 Department of Surgical Oncology ("C"), Chaim Sheba Medical Center, Tel Hashomer, Israel
4 Division of Oncology, Breast Unit, Chaim Sheba Medical Center, Tel Hashomer, Israel
5 Institute of Oncology, Breast Unit, Rabin Medical Center, Petach Tikva, Israel
6 Biostatistics Unit, Gertner Institute, Chaim Sheba Medical Center, Tel Hashomer, Israel

Correspondence: Address correspondence and reprint requests to: Siegal Sadetzki, MD, Cancer Epidemiology Unit, Gertner Institute for Epidemiology and Health Policy Research, Chaim Sheba Medical Center, Tel Hashomer, 52621, Israel; E-mail: siegals{at}gertner.health.gov.il.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Tumor downstaging by preoperative neoadjuvant chemotherapy in patients with locally advanced breast tumors allows breast conservation in women who were previously candidates for mastectomy. Nevertheless, lumpectomy success in such cases cannot be fully achieved. The aim of this study was to create a quantitative tool for preoperative evaluation of the success of breast conservation in such patients.

Methods: The study population included 100 consecutive patients with stage II and III breast cancer who were designated for lumpectomy and 19 patients who were designated for mastectomy. All patients received neoadjuvant therapy. Breast-conserving surgery was offered in accordance with clinical and esthetic criteria. Demographic details and clinical, imaging, and pathologic information were collected from medical files. A decision protocol for classifying patients to lumpectomy or mastectomy was built by using the Classification and Regression Trees procedure based on preoperative characteristics.

Results: Three factors were found to be the main predictors for successful breast conservation: absence of diffuse microcalcifications as seen in the pretreatment mammogram, a postchemotherapy tumor size of <25 mm, and the existence of a circumscribed lesion on mammography.

Conclusions: The use of these criteria as a basis for decision on the type of surgery may decrease the performance of unnecessary procedures.

Key Words: Breast cancer • Breast conservation • Preoperative chemotherapy • Decision making


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Large primary breast tumors usually necessitate treatment with mastectomy because the tumor is too large to allow breast conservation.1 In such cases, neoadjuvant chemotherapy may not have a survival advantage2–5; it is, however, highly effective in achieving primary tumor regression6–8 and is now considered the standard of care for large and locally advanced breast cancer.1 One possible advantage of tumor downstaging by preoperative neoadjuvant chemotherapy, in patients with advanced large breast tumors, is that the tumor shrinkage will enable breast-conservation surgery in patients who were candidates for mastectomy.

We have used this approach in patients with advanced breast cancer, and in this study we analyzed the effect of downstaging of the tumor on the possibility for breast-preserving surgery. The specific aim of this analysis was to examine demographic, clinical, histological, and imaging preoperative characteristics as possible predictive factors for the success of breast conservation.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The study population included 100 consecutive patients with stage II and III primary locally advanced breast cancer who were treated by the Breast Service at the Sheba Medical Center between January 1, 1995, and July 1, 2001, and designated for lumpectomy and another 19 patients who were immediately directed to mastectomy. All these patients received neoadjuvant therapy consisting of four to six cycles of anthracycline-based chemotherapy.

Inclusion criteria were: (1) locally advanced cancers defined by histologically confirmed breast cancer stages IIA (tumor >3 cm), IIB, IIIA, and IIIB (histological confirmation was performed by pathologic examination of the true-cut biopsy); (2) no evidence of distant metastatic spread; (3) age younger than 70 years; and (4) a Karnofsky status of >70%. Initial evaluation before chemotherapy included a complete history and physical examination, complete blood count and blood chemistries, chest radiograph, abdominal and chest tomography, bone scan, and abdominal (liver) ultrasound. The tumor was assessed by mammography and sonography.

Clinical response was assessed after the fourth to sixth cycle and was measured by palpation, breast sonogram, and mammogram and in some cases by a magnetic resonance test. The response was grouped as follows:

  1. Complete remission: a tumor that was no longer palpable.
  2. Partial response: a tumor that responded well, with a decrease of >50% of its size.
  3. Minor response: a tumor that responded but decreased <50% of its original size.
  4. Stable disease: a tumor that remained unchanged.
  5. Progressive disease: a tumor that continued to grow.

Patients were offered breast-conserving surgery in accordance with the evaluation of the clinical response and considering the location and size of the tumor relative to the breast size (esthetic criteria). Also, exclusion criteria for lumpectomy included the presence of breast inflammatory changes that did not resolve or a posttreatment mammographic image suggesting a multicentric lesion as evidenced by widespread microcalcifications in more than one quadrant of the breast. Another exclusion criterion for lumpectomy was a woman’s preference to undergo mastectomy. Patients with complete remission, a partial response, or a minor response who fulfilled the esthetic criteria and had no exclusion criteria were offered breast-conserving surgery.

Tumor-free margins were assessed by inking the surgical specimens and then submitting them to conventional pathologic evaluation. Clear pathologic margins (>1 cm around the tumor) were considered as successful breast preservation. This criterion was applied for all ductal carcinoma-in-situ (DCIS) cases. For invasive cancers, a margin of 5 mm was accepted as negative. Patients with positive tumor margins were referred for mastectomy. In 10 cases in which the tumor was close to 1 margin, a second attempt at lumpectomy was successfully performed. After lumpectomy or mastectomy, conventional axillary sampling was performed.

Clinical follow-up was performed every 3 months for the first year and every 6 months thereafter. Mammography was performed 3 months after the completion of radiation treatment and annually thereafter.

Retrospective data collection from the medical records was performed with the aid of a designed questionnaire. The data included demographic details, as well as preoperative and postoperative clinical, imaging, and pathologic information. Preoperative tumor size was determined as the largest size measured, either by ultrasound or mammography. The study population was grouped as follows: group 1, patients designated for lumpectomy who underwent lumpectomy only; group 2, patients designated for lumpectomy who eventually also underwent mastectomy; and group 3, patients who were directly designated for mastectomy.

Data analysis included description of all study variables among the three study groups followed by an analysis to determine the factors predictive of successful breast preservation. Univariate comparisons of the study variables were assessed by {chi}2 analysis or the Wilcoxon rank sum analysis for discrete variables and t-tests for continuous variables. All comparisons were two tailed. The statistical significance level was taken as a measure of the strength of evidence against the null hypothesis.

To decide on measured criteria for classifying patients to lumpectomy (group 1), a decision tree was built based on the data of groups 1 (success of lumpectomy) and 2 (failure of lumpectomy) by using the Classification and Regression Trees (CART) procedure.9 CART is a procedure for analyzing categorical (classification) or continuous (regression) data. The classic algorithm was made popular by Breiman et al.9 The main idea behind CART is the creation of subgroups of observations. Within subgroups the outcomes are homogeneous, and between subgroups the outcomes are heterogeneous. These subgroups are created in a treelike structure by a series of binary splits (rules). CART is a nonparametric procedure that uses exhaustive searches and computer-intensive testing to select the optimal tree. It can use V-fold cross-validation to assess goodness of fit and can be more accurate than conventional stepwise procedures for classifying new data. CART or decision trees are popular in medical decision making because they provide a way to summarize and structure the knowledge of experts to be used by less-experienced users. Building a tree requires four main considerations:

  1. Split search: which splits to consider.
  2. Splitting criterion: which split is best (every allowable split on each explanatory variable is examined, and left and right "daughter" nodes are created from the best of these splits).
  3. Stopping rule: when to stop splitting.
  4. Pruning rule: should branches be cut back?

The root node of the tree contains the entire sample. A tree can have as many terminal nodes as there are observations. In practice, this is known as over-fitting. A tree with too few nodes may not be flexible enough and may overlook important "structure." This is known as underfitting. The best tree will achieve a parsimonious balance between underfitting and overfitting.

Validation of trees can be performed in a number of ways. A popular technique is V-fold cross-validation, which divides the original dataset into V mutually exclusive subsets. Each set is used as an independent test set for trees grown on the other V-1 sets. This can be performed in V ways, and the results can be averaged.

Only preoperative variables were included in the CART model. Variables with values of P < .1 from the univariate comparison procedures were treated as entry criteria for the CART procedure. The resulting tree was validated by using 10-fold cross-validation; the final tree contained 4 terminal nodes.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
We attempted breast-preserving surgery in 100 patients (groups 1 and 2), of which 21 patients (group 2) eventually proceeded to mastectomy. As mentioned previously, 19 patients were directly referred to mastectomy (group 3).

The preoperative characteristics of the study population are listed in Tables 1Go and 2Go. No statistically significant differences were noticed among the 3 groups regarding the mean age at diagnosis, the prechemotherapy tumor size, and the presence of inflammatory signs on clinical examination. Also, no differences were noticed in the distribution of the infiltrating ductal carcinoma or infiltrating lobular carcinoma histological types. However, the coexistence of DCIS with invasive carcinoma showed the highest prevalence among group 2 and had relatively higher rates in group 3 compared with group 1 (81%, 53%, and 24%, respectively). Estrogen and progesterone hormone receptor status were similar among groups; the frequency of the HER2 receptor was lower in group 1 in comparison with groups 2 and 3.


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  		TABLE 1. Preoperative characteristics of the study population by study group
 

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  		TABLE 2. Additional preoperative characteristics of the study population by study group
 
The preoperative mammography results of group 1 significantly differed from both group 2 (in which we unsuccessfully attempted to perform breast-preserving surgery) and group 3 (in which the patients were allocated directly to mastectomy) by having a higher rate of circumscribed lesions and a complete absence of diffuse microcalcifications (P < .001). The frequency of localized microcalcifications was highest in group 2. No significant differences in architectural changes were seen among groups.

The postchemotherapy tumor size showed significant differences between each set of pairs (mean size of 16.8 ± 9.1 mm, 26.1 ± 4.4 mm, and 40.5 ± 7.9 mm for groups 1, 2, and 3, respectively). Nevertheless, an overlap in the ranges of the postchemotherapy tumor size did not allow differentiation among groups on an individual level (Table 1Go).

It is interesting to mention that the postchemotherapy tumor size as measured in pathology correlated highly with the size measured before surgery (and after neoadjuvant therapy) by imaging (Pearson correlation coefficient of .87 [P = 0], .66 [P = .001], and .62 [P = .005] for groups 1, 2, and 3, respectively; data not shown). As expected, the number of positive nodes differed among groups (Table 3Go). The rate of extensive DCIS was remarkably low in group 1 compared with both other groups (1.3% vs. 66.6% and 47.4% in groups 1, 2, and 3, respectively).


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  		TABLE 3. Postoperative characteristics of the study population by study group
 
Patients have been followed up for a median duration of 34, 27, and 36 months (range, 6–65 months) in groups 1, 2, and 3, respectively, with no significant differences between the groups. The local recurrence rate was similar among all patients regardless of the final mode of operation (Table 4Go). Also, the prevalence of surgical complications, including wound infection, bleeding, seroma, and wound division, was similar among the three groups.


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  		TABLE 4. Outcome of the study population by study group
 
The decision process for allocating patients who are initially nominated for lumpectomy to type of surgery is presented in Fig. 1Go. The figure describes the decision process and the number of patients at each point. The numbers given at the terminal nodes represent the breakdown of the study population according to the actual procedure they underwent. According to these results, three preoperative factors should be considered in the decision process of mastectomy versus lumpectomy: the presence of diffuse microcalcifications in mammography, postchemotherapy tumor size, and presence of a circumscribed lesion. All women who were positive for diffuse microcalcifications (12 in group 2) ended with mastectomy; therefore, these patients were excluded from further analysis. Uncertainties with regard to the type of operation remained for 88 patients with no diffuse microcalcifications who were considered for the second step of the decision tree. According to our results, mastectomy is recommended if the posttreatment tumor size is ≥25 mm for a noncircumscribed lesion.


Figure 1
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  		FIG 1. Decision tree for lumpectomy versus mastectomy for groups 1 and 2. The variables that were entered into the model were postchemotherapy tumor size, circumscribed lesion, diffuse microcalcification, combined finding on mammography, and ductal carcinoma-in-situ. *One patient with such data was actually designated to group 2 (the postchemotherapy tumor size was 30 mm). **One patient with such data was actually assigned to group 2 (she had 7 nodes). ***One patient with such data went through lumpectomy only (the postchemotherapy tumor size was 25 mm).

 
With use of this decision protocol, only three patients were misclassified. Two underwent mastectomy when the model recommended lumpectomy only (one patient had no diffuse microcalcification and a tumor size <25 mm, and the other patient had no diffuse microcalcification, a tumor size >25 mm, and a circumscribed lesion). The third patient was recommended for mastectomy but in reality underwent lumpectomy; she had no diffuse microcalcification, a tumor size of 25 mm, and no circumscribed lesion. This misclassification yields a sensitivity of 98.7% and specificity of 90.5% with this algorithm.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Breast preservation is currently considered the standard care for early breast cancer. However, mastectomy was usually considered the treatment of choice for patients with locally advanced breast cancer. Despite this aggressive treatment, this approach did not always result in local control and caused devastating cosmetic results for these women, who have a poor overall survival. Therefore, another approach was suggested to decrease the tumor burden by preoperative chemotherapy (also called induction or neoadjuvant chemotherapy), thus allowing safer mastectomy.1 Because a good local response was observed in many cases, it was suggested that such patients might benefit from breast preservation. Currently many surgeons try to preserve the breast in locally advanced breast cancer cases when the tumor response to chemotherapy is such that it will allow good cosmetic results on the one hand and will comply with the guidelines for breast preservation in early breast cancer on the other hand.10,11

Nevertheless, even when these conditions apply, success for breast preservation in such cases cannot be fully achieved.1,4,12,13 The failure is mainly due to an inability to reach satisfactory clear tumor margins even though this seemed possible on the preoperative evaluation of the surgeon. Therefore, the aim of this study was to create a quantitative tool for preoperative evaluation of the probability to successfully achieve breast preservation in post–neoadjuvant therapy advanced breast cancer cases according to our experience.

Our results show that three preoperative factors are the main predictors for successful local surgery: the existence of diffuse microcalcifications as seen in the pretreatment mammogram, the postchemotherapy tumor size, and the type of mammographic lesions. The presence of diffuse microcalcifications, even in one breast quadrant, may be correlated with the existence of a diffuse tumor spread, mainly of the in situ type.14–16 The response to chemotherapy of in situ cancer is less than that of the invasive type, and it tends to spread along the ducts of the quadrant.17 Thus, even after chemotherapy, it may be expected that the ability of the operation to reach clear margins with lumpectomy only is less than that for the invasive type.18 In none of the cases in our series, when diffuse microcalcification existed, were we able to reach clear surgical margins, and all the cases in which breast preservation succeeded did not show evidence for diffuse microcalcification. Of the 12 patients who presented with diffuse microcalcifications, 11 had a DCIS histology type. Indeed, the results of postoperative pathology revealed that approximately 67% of the patients in group 2 had extensive DCIS, compared with only one such patient in group 1.

Original tumor size is known as one of the main determinants of prognosis,19,20 and clear margins are crucial for local control.21,22 There is debate in the literature about the optimal amount of healthy breast tissue that has to surround the excised tumor.22,23 In general, margins of ≤2 mm from the cut edge of the specimen might be acceptable for primary tumor excision, especially for infiltrating ductal carcinoma.24 However, our study patients were women who received neoadjuvant chemotherapy, with variable tumor responses. Some of the tumors were a mixture of infiltrating ductal carcinoma and DCIS. Because the pattern of tumor shrinkage is not predictable, our experience including relumpectomies has shown that more conservative margins of .5 to 1.0 cm are advisable in such circumstances to ensure clean margins. Obviously, the larger the tumor is, the more difficult it is to achieve the goal of free margins along with good cosmetic results. One of the limitations of our results, which stems from the retrospective nature of this study, is that we did not consider breast size in the analysis. However, on the basis of our sample of 100 unselected consecutive patients, it seems that a cut point of 25 mm for the postchemotherapy tumor size gives the optimal value for the prediction of successful breast preservation. Obviously, this precise number should be considered as an estimation for the magnitude of the residual tumor size rather than an absolute number that should be applied for all patient populations.

In addition to those two variables, the tumor shape as seen by mammography also affects the surgeon’s ability to perform local tumor excision with clear margins.25 A circumscribed lesion means smoother and more regular margins; therefore, the more condensed the mass, the higher the probability of fully removing it. This parameter may be associated with the extent of invasiveness.

The presented statistical decision tree is based on postchemotherapy clinical tumor size, circumscribed lesion, pretreatment diffuse microcalcification, a combined finding on mammography, and DCIS. Our results also demonstrate that age, prechemotherapy tumor size, histological tumor type, hormone receptor status, and presence of inflammatory signs are not predictive of successful breast conservation after induction chemotherapy. Nevertheless, some additional important factors that we could not measure or quantify—namely, breast size and tumor location—were not included in the model. We believe that such parameters are responsible for the 3% misclassification rate we identified: one false negative, meaning a patient who, according to the model, should have undergone mastectomy but actually underwent lumpectomy, and two false positives, meaning patients who, according to the model, should have been referred to lumpectomy but actually had mastectomy. These unquantified variables were also represented in group 3 (patients who were directly referred to mastectomy), and, therefore, this group was not part of the decision tree. These results support the use of this model as a tool that may assist the surgeon in decision making, thus avoiding unnecessary surgical procedures and disappointment for the patients. However, it shows that, as in most medical procedures, even the most efficient protocol cannot entirely replace the surgeon’s clinical judgment.

Delaying surgery by induction chemotherapy followed by lumpectomy raises a few concerns: (1) the safety of the procedure and the possibility that less aggressive surgery may affect local control, (2) the possibility of accurate tumor staging and axillary status, (3) the possibility that the surgical complication rate will increase after an aggressive chemotherapy regimen, and (4) the possible influence of that regimen on survival. The National Surgical Adjuvant Breast Project B-18 study2 demonstrated overall similar outcomes for patients randomized to preoperative versus postoperative doxorubicin-based chemotherapy. This proves the safety, from the survival point of view, of induction chemotherapy for patients with resectable breast cancer, and this has been confirmed by the results of other investigators as well.3

McCready et al.26 examined the possibility that preoperative chemotherapy may affect the accuracy of tumor staging and axillary nodal status and proved that it retained its prognostic value after neoadjuvant chemotherapy. The extent of residual nodal metastasis remained a strong predictor of outcome even after induction chemotherapy, and patients with histologically negative nodes were found to have an excellent outcome.

In our experience, no difference has been seen in surgical complication rates between patients receiving preoperative or postoperative chemotherapy. Neither increased postoperative wound infection nor seroma formation or delays in instituting postoperative chemotherapy were noted in patients who were operated on after chemotherapy (Table 4Go). Moreover, in accordance with other series, no differences in percentages of local recurrence were observed between the study groups.

The response to induction chemotherapy may serve as a prognostic indicator. It has been noted by several investigators that the extent of response in the breast seems to correlate with improved outcome.1,7 A study from Philadelphia27 examined the histological response in correlation with the clinical outcome and found that patients with a good pathologic response had a 79% overall 5-year survival rate, compared with 34% for tumors with a lesser response rate. Response rates to induction chemotherapy show that approximately 70% to 80% of patients respond with tumor regression and that complete clinical and pathologic responses occur in 10% to 15% of patients. Disease progression while the patient is receiving induction chemotherapy is rare and occurs in only 2% to 3% of cases. These results are in line with ours: the response rates in groups 1 and 2 were >95%, and in group 3 the response rate was 57.9%. In our series, no patient experienced a progression of tumor size after chemotherapy (data not shown). Thus, a large proportion of these patients became candidates for breast preservation with this treatment sequence.

Because the role of breast-conserving surgery is not yet defined, there are no clear criteria for when to preserve the breast. A French group4 proposed that patients who were status post chemotherapy with tumors <3 cm in diameter or not located behind the nipple could benefit from conservative treatment. They also found, in a multivariate analysis, that this was significantly related to initial tumor size (<6 cm) and age (<50 years). According to their experience, breast-conserving therapy can be performed in more than half of all cases. The group from M. D. Anderson found that when the initial tumor size was approximately 4 cm and was downstaged after chemotherapy to approximately 1.6 cm and when residual disease was low volume or microscopic, such a disease status allowed for a minimal surgical approach.13,28 Another recently published study29 also found that mammographic findings of multicentricity and calcification were important determinants of breast-preservation success.

The preferred method to investigate criteria for breast conservation would be a prospective study that would follow a predetermined protocol for patient allocation. However, this retrospective study could be regarded as preliminary results that could lay the base for a consistent protocol.

Another major limitation of our study is the fact that the gold standard for the end results (mastectomy vs. breast preservation) was determined subjectively, according to the experience of the senior surgeon. However, considering the fact that all the surgeons belonged to the same department and followed the same guidelines, which are summarized in the Materials and Methods section, we may assume a relatively common decision-making pattern that is most probably applicable to other surgeons as well.

Many women, even patients with locally advanced disease, come into breast treatment programs with high hopes for being able to keep their breasts intact. It is part of the ongoing responsibility of the breast surgeon to give realistic expectations to patients coping with the trauma of oncological surgery and treatment. Our main goal in this study was to quantify the surgeon’s practice, which is based on experience, thus allowing the ability to better predict the success of breast preservation for each patient.

Received for publication July 7, 2004. Accepted for publication January 19, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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