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Outcome at 8 Years After Breast-Conserving Surgery and Radiation Therapy for Invasive Breast Cancer: Influence of Margin Status and Systemic Therapy on Local Recurrence

From the Joint Center for Radiation Therapy; Departments of Radiation Oncology and PathologyBeth Israel Deaconess Medical Center; Department of Radiation Oncology, Brigham and Women’s Hospital; and the Division of Biostatistics and Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Address reprint requests to Catherine Park, MD, Joint Center for Radiation Therapy, 330 Brookline Ave, Boston, MA 02215; email CPark{at}jcrt.harvard.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To examine the relationship between pathologic margin status and outcome at 8 years after breast-conserving surgery and radiation therapy.

PATIENTS AND METHODS: The study population comprised 533 patients with International Union Against Cancer/American Joint Committee on Cancer clinical stage I or II breast cancer who had assessable margins, who received at least 60 Gy to the primary tumor bed, and who had more than 8 years of potential follow-up. Each margin was scored (according to the presence of invasive or in situ disease that touched the inked surgical margin) as one of the following: negative, close, focally positive, or extensively positive. Outcome at 8 years was calculated using crude rates of first site of failure. A polychotomous logistic regression analysis was performed. Median follow-up time was 127 months.

RESULTS: At 8 years, patients with close margins and those with negative margins both had a rate of local recurrence (LR) of 7%. Patients with extensively positive margins had an LR rate of 27%, whereas patients with focally positive margins had an intermediate rate of LR of 14%. In the polychotomous logistic regression model, margin status and the use of systemic therapy were the only two variables that had significant effects on the risk ratio of LR to remaining alive and free of disease. Among the 45 patients with focally positive margins who received systemic therapy, the crude LR rate was 7% at 8 years (95% confidence interval, 1% to 20%).

CONCLUSION: Pathologic margin status and the use of adjuvant systemic therapy are the most important factors associated with LR among patients treated with breast-conserving surgery and radiation therapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
BREAST-CONSERVING therapy that consists of gross tumor excision followed by irradiation is a well-recognized standard option for local treatment of early-stage invasive breast cancer. Breast-conserving therapy results in survival equal to that of mastectomy for patients with early-stage invasive breast cancer¹ and should optimally provide a high rate of local control and acceptable cosmetic outcome with low morbidity.

In the United States, pathologic margin status has been used as the major criterion in the selection of patients for breast-conserving therapy.¹ In addition to other factors such as the extent of breast resection and the presence of an extensive intraductal component (EIC), margin involvement seems to act as a marker for the amount of residual carcinoma in the breast.^2,3 Although, at present, there is no standard definition of a negative or positive margin, microscopic margin involvement has been associated with an increased risk for local recurrence (LR).¹ However, the relationship between pathologic margin status and the risk for LR has not been fully elucidated. Furthermore, whether breast-conserving therapy should be offered to patients with focally positive resection margins remains an unresolved issue. It is also unclear whether other factors influence outcome, such as the use of systemic therapy and the nature of the tumor that is present at the margin of excision, ie, invasive carcinoma versus ductal carcinoma-in-situ (DCIS).

This retrospective analysis updates and expands our prior reports of outcome after breast-conserving surgery and radiation therapy at our center.⁴ Our current results confirm that pathologic margin status is the most important factor in determining the risk of LR. Patients with negative margins and those with close margins had similar and low rates of LR. Moreover, our new results indicate that the use of adjuvant systemic therapy was associated with a decreased rate of LR and, in particular, suggest that patients with focally positive margins who receive systemic therapy may be reasonable candidates for breast-conserving therapy.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Between 1968 and 1987, 2,140 patients with International Union Against Cancer/American Joint Committee on Cancer clinical stage I or II invasive breast cancer were treated at the Joint Center for Radiation Therapy, Boston, MA, after breast-conserving gross tumor excision. The study population consisted of 533 of these patients who had histologic slides available for review with assessable histologic margins, who received a dose of at least 60 Gy to the tumor bed, and who had at least 8 years of potential follow-up. The years of treatment for the study population were 1976 to 1987, which reflects the lack of available data on margins in the early years. The range of follow-up for surviving patients was 8 to 15.3 years, with a median of 10.6 years. Characteristics of the cohort are listed in Table 1.

Pathology slides were reviewed by one of two study pathologists (J.C. or S.J.S.), and tumors were scored according to their proximity to the inked surgical margin. Radial margins were scored as uninvolved (no invasive carcinoma or DCIS touching the inked surgical margins) or positive. Positive margins were further classified as focally positive when any DCIS or invasive carcinoma involved the margin in three or fewer low-power microscopic fields (using a x4 objective and x10 ocular lens, which has a diameter of 5 mm per low-power microscopic fields) or as extensively positive. Uninvolved margins were classified as close (tumor-free margin width of 1 mm) or negative (> 1 mm).

Of the 533 patients included in the study, 486 were classifiable according to one of the four margin categories (negative, close, focally positive, and extensively positive). Forty-three patients had uninvolved margins in which distance of the tumor to the margin was unknown, and four patients had positive margins in which the degree of involvement was unknown. For the analyses of crude results at 8 years, the former were categorized as having uninvolved margins and the latter as having involved margins. All 533 patients were included in the polychotomous regression analysis.

Outcome was classified according to sites of first failure as follows: LR, ie, tumor appearing anywhere in the ipsilateral breast with or without other simultaneous sites; distant or regional node failure or opposite breast cancer (D/R/O); dead without recurrence; or alive without recurrence (no evidence of disease [NED]). Crude rates of first failure at 8 years were calculated.

LRs were further classified, as previously reported,⁵ according to the proximity to the primary tumor as follows: true recurrence (TR, within the boosted radiation field of the primary tumor); marginal miss (in the area bordering the boosted radiation field of the primary tumor and adjacent breast tissue); or elsewhere (outside of the boosted radiation field). Recurrences on the skin only of the ipsilateral breast were grouped separately. Of the 60 LRs, 49 (81%) were classifiable in one of the four groups.

Patient characteristics among the various margin categories (Table 1) were compared using the Kruskal-Wallis test for continuous characteristics (age, clinical tumor size, and number of positive nodes) and Fisher’s exact test for categorical characteristics (or the ² test when there were too many categories for the exact test.) Fisher’s exact test was also used to compare sites of first failure in terms of the nature of the tumor at the margin. None of the P values were adjusted for multiple comparisons.

A polychotomous logistic regression was used to model the four-value outcome: NED, LR, D/R/O, and dead without recurrence. The clinical, pathologic, and treatment features (covariates) investigated in this study were age, primary tumor size, stage, clinical nodal status, pathologic nodal status, lymphatic vessel invasion (LVI), histologic type, histologic grade, presence of necrosis in the invasive component of the tumor, hormone-receptor status, EIC, total radiation dose to the tumor bed, and use of systemic therapy. A step-up model was used in which a separate model was run for each level of each possible covariate (eg, there was one model for necrosis absent and another for marked necrosis). When necessary, these models also included a variable for "unknown." Age and clinical size were examined in quartiles as well as in categories of larger or smaller than median. A total of 51 such models were run, and the most significant variable (using the likelihood ratio test) was chosen. A separate model was then run for that significant variable and every level of each other covariate, and the next most significant variable was chosen out of the 50 models run. This process was repeated until no further variables added significantly to the model. P values for the separate risk ratios were obtained in the final model using the Wald test, and the risk ratios were estimated in the final model.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
By 8 years, 60 (11%) of the 533 patients had experienced an ipsilateral breast recurrence with or without other simultaneous sites of failure, 148 (28%) had experienced distant or regional failure or opposite breast cancer as their first site of failure, 26 (5%) had died of other causes, and 299 (56%) still had NED. From among the entire study population, 486 patients with classifiable pathologic margins were each placed into one of four groups according to final microscopic margin status: negative, close, focally positive, and extensively positive, as previously defined. The 43 patients with negative, unclassifiable margins were placed into a separate category (negative, unspecified). Patient characteristics for the entire population and for the five groups are listed in Table 1. Patient groups were not significantly dissimilar with regard to median age, histologic type, histologic grade, and presence of necrosis. However, the five groups were significantly dissimilar for T stage, clinical tumor size, overall stage, number of involved axillary lymph nodes, estrogen-receptor protein status, the use of three-field radiation technique, the presence of LVI, the presence of EIC, the use of systemic therapy, the use of re-excision, total tissue volume excised, and total radiation dose. These differences were more pronounced among patients with extensively positive margins compared with patients from the four other groups.

The 8-year crude rates of LR according to microscopic margin status are listed in Table 2. For patients with either negative or close margins, the 8-year rate of LR was 7%. Among patients with extensively positive margins, the rate of LR was 27%. Patients with focally positive margins had an LR rate of 14%, intermediate between those with close or negative margins and those with extensively positive margins. When the 43 patients with uninvolved margins and unknown distance of the tumor to the margin were combined with all other patients with close or negative margins, the crude rate of LR was unchanged at 7%. When the four patients with positive margins with unknown degree of margin involvement were included with all other patients with positive margins, LR at 8 years was 18%. Of note, patients with extensively positive margins had a higher rate of D/R/O failures compared with patients in all other groups.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Our expanded and updated results, with a minimum potential follow-up of 8 years at the time of this writing, demonstrate that pathologic margin status is the most important factor related to the risk of LR. In the present series, the highest rate of LR (27%) was observed among patients with extensively positive margins, whereas the lowest rate (7%) was observed among patients with either close ( 1 mm) or negative margins. An intermediate rate of LR (14%) was seen among patients with focally positive margins. These results corroborate our previous analysis.⁴

An important new observation in this study was the interaction between adjuvant systemic therapy and margin involvement in determining the risk of LR. In our polychotomous logistic regression model of the entire study population, the use of systemic therapy was associated with a relative risk of 0.3 for LR. In particular, 45 patients with focally positive margins treated with systemic therapy had an LR rate of 7%. These results suggest that patients with focally positive margins who are treated with systemic therapy may be good candidates for breast conservation.

Current information indicates that patients with negative margins treated with breast-conserving therapy have low rates of LR. The rate of LR at 8 years was 7% among patients with negative surgical margins (defined as no invasive cancer or DCIS at the inked surface) treated with breast-conserving therapy in the National Surgical Adjuvant Breast Project (NSABP) B-06 trial.⁷ Other published series with follow-up comparable to ours have reported LR rates of 0% to 9% among patients with negative margins treated with breast-conserving therapy .^7-13 The variability in reported outcomes may be a result of variations in the technical details of surgery, radiation therapy, and margin evaluation; nonetheless, results among patients with negative margins have been generally consistent.

In the present series, patients with close ( 1 mm) margins and those with negative margins had similarly low rates of LR. Furthermore, the tumor-free margin width did not correlate with increased LR rates. These findings suggest that patients with widely negative margins and those with close margins are equally good candidates for breast-conserving therapy. However, results from other institutions with follow-up similar to the present study report variable outcome among patients with close margins and those with negative margins. Moreover, the definitions of close and negative margins differ among institutions, which makes comparisons between series difficult. Patients with close ( 2 mm) margins and those with negative (> 2 mm) margins who were treated with breast-conserving therapy at the University of Pennsylvania¹¹ had 8-year actuarial LR rates of 17% and 9% (P = .27), respectively, with a median follow-up time of 82 months. Patients with close ( 2 mm) margins and those with negative (> 2 mm) margins who were treated at the Fox Chase Cancer Center¹² had 10-year actuarial LR rates of 14% and 7% (P = .04), respectively, with a 76-month median follow-up time. In a series from Stanford¹³ in which close margins were defined as 2 mm and negative margins defined as more than 2 mm, 5-year actuarial LR rates were 16% and 2%, respectively, at a median follow-up time of 6 years. In the same series, LR rates of 0% and 9% were observed among patients with focally positive and greater than focally positive margins, respectively. Notably, when the group with negative margins was compared with all other groups combined, there was a statistically significant difference that favored negative histologic margins. At the New England Medical Center,¹⁴ patients were treated with increasing boost doses of radiation (10 Gy, 14 Gy, and 20 Gy) according to final microscopic margin status (> 5 mm v 2.1 to 5 mm v 0.1 to 2 mm). With a median follow-up time of 72 months, they report a 3% actuarial LR rate at 10 years among patients with 0.1- to 2-mm margins, 1.2% LR among patients with 2.1 to 5 mm margins, and no LRs among patients with margins greater than 5 mm. Thus, when actuarial LR rates are compared among institutions that define close margins as 2 mm and negative margins as greater than 2 mm, there seems to be a higher risk of LR among patients with close margins (14% to 17%) than in patients with negative margins (2% to 9%).

Several important issues arise from the comparison of these single-institution series. Although few studies include crude results in addition to reporting actuarial numbers, actuarial results are most consistently used among the studies reported above. Unfortunately, actuarial estimates of LR rates from different data sets are not comparable because the sites of failure are competing risks¹⁵ and because of the variability in median follow-up time. That is, two studies that have the same true percentage of patients who have LR but that have different percentages of patients who have distant or regional recurrence, or that have the same percentages with different times to failure, will have different actuarial estimates of LR. In addition, there is further potential variability among series because of differences in the definitions of close and negative margins and in the techniques of margin assessment. Therefore, given these caveats, one cannot conclude from the literature whether patients with close margins should be considered separately from patients with tumor-free resection margins. The clinical implications of these unresolved issues are great, considering that additional surgical morbidity and the potential disadvantage in cosmesis may be avoided by providing accurate outcome data to these patients.

Among patients with positive margins in the present study, the extent of margin involvement was strongly correlated with the risk of LR. Other series report generally higher rates of LR (0% to 20%) among patients with involved margins^7-14 compared with patients with negative margins after breast-conserving therapy. Although some institutions vary boost doses of radiation according to margin involvement, the optimal approach to treating these patients is not clear. The present study shows that patients with extensively positive margins ( four low-power microscopic fields) have a significant risk for LR and should undergo re-excision, if an attempt at breast conservation is desired, or mastectomy.

When all patients with positive margins were analyzed according to the nature of the tumor (ie, invasive carcinoma or DCIS) present at the margin, there was a trend toward higher rates of LR among patients with both DCIS and invasive carcinoma present at the margin than among patients with either DCIS alone or invasive carcinoma alone. On further analysis, this trend was observed among patients with focally positive margins but not among patients with extensively positive margins, for whom the rate of LR was similar regardless of whether DCIS or invasive carcinoma or both types were present at the margin. Further study with a larger number of patients may help clarify the relationship between the nature of the tumor present at the margin and outcome.

We also found that the use of systemic therapy was associated with a substantial reduction in the relative risk for LR and, in particular, was associated with a substantial reduction in LR in patients with focally positive margins. Randomized trials have consistently shown a reduction in LR when both radiation therapy and systemic therapy are used. Eligibility criteria for NSABP trials, as noted above, include the finding of no histologic involvement of tumor at the margins of excision. In the NSABP B-13 trial,¹⁶ the 8-year crude risk of LR among node-negative patients who were undergoing breast conservation was 13.4% for patients randomized to no adjuvant chemotherapy and 2.6% for patients randomized to chemotherapy. Similarly, in the NSABP B-14 trial,^17,18 node-negative patients who were randomized to receive a placebo experienced a 5.5% crude LR rate at 7 years, compared with 2.2% in the cohort randomized to receive tamoxifen. Postmenopausal node-negative patients treated in the Stockholm Adjuvant Tamoxifen Trial¹⁹ were randomized to receive either adjuvant tamoxifen or no further treatment. With a median follow-up of 8 years, patients treated with breast-conserving therapy who received no tamoxifen experienced a 7% crude rate of LR as first site of failure, compared with 3% in patients who received tamoxifen. Thus, the use of adjuvant systemic therapy seems to potentiate the effects of breast irradiation after breast-conserving surgery for invasive breast cancer.

The relationship between systemic therapy, pathologic margin status, and LR may also be influenced by the sequencing of therapies. We conducted a randomized trial to examine the effect of sequencing, comparing chemotherapy followed by radiotherapy with radiotherapy followed by chemotherapy.²⁰ In that trial, among patients with positive margins, the 5-year crude rate of LR was 14% (two of 14) in patients who received radiotherapy first but 26% (six of 23) in those who received chemotherapy first. Patients with close margins who received radiotherapy first had a 0% (0 of 15) LR rate, compared with a 23% (three of 13) LR rate in those who received chemotherapy first. Similar results were observed in a series from Rush Presbyterian Hospital in Chicago.²¹ Thus, the surgery-radiotherapy interval may affect the risk of LR among patients with positive or close margins. In the current series, given the relatively small numbers of patients in these subsets and the unclear effect of systemic therapy in the setting of involved margins, further study is needed.

In the present study, we noted that patients with extensively positive margins had significantly worse known prognostic factors, including tumor size and nodal status, which perhaps reflects an inherently more aggressive tumor biology, selection bias, or pattern of care. These patients also had a higher rate of distant failure as the first site of failure than did patients with focally positive, negative, or close margins. Nonetheless, the presence of competing risks in these patients would not change the recommendation that patients with extensively positive margins should undergo further surgery.

Although pathologic margin evaluation is the best clinical tool available to assess patients’ risks for LR and, hence, whether they should be treated with breast-conserving therapy, there are a number of potential drawbacks to using this information. For the pathologist, processing and evaluating the margins of a specimen involve careful planning and technique.²² Technical difficulties include the assessment of irregular borders of specimens, correct orientation of a single specimen or multiple specimens, and potential sampling error.²³

We acknowledge that this retrospective analysis has a number of potential limitations. These include selection biases with regard to the use of systemic therapy and small patient numbers in certain subgroups, which results in broad CIs of estimated recurrence rates. Despite these caveats, we believe that our results have important implications for clinical practice. In the long term, a low rate of LR can be expected among patients who have an excision with either negative or close ( 1 mm) margins. Patients with extensively positive margins, regardless of histologic type, are at high risk for LR and should undergo further surgery. The use of adjuvant systemic therapy in patients who receive breast-conserving therapy may decrease the risk for LR. In particular, among patients with focally positive margins, a low rate of LR can be achieved with the use of systemic therapy. However, additional studies are needed to corroborate these findings.

	NOTES

 
Presented in part at the Fortieth Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Phoenix, AZ, October 25-29, 1998, and the Twenty-First Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 9-12, 1998.

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Submitted July 12, 1999; accepted January 5, 2000.

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