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Impact of Young Age on Outcome in Patients With Ductal Carcinoma-In-Situ Treated With Breast-Conserving Therapy

From the Departments of Radiation Oncology, Anatomic Pathology, and Surgery, William Beaumont Hospital, Royal Oak, MI.

Address reprint requests to Frank A. Vicini, MD, Department of Radiation Oncology, William Beaumont Hospital, 3601 W Thirteen Mile Rd, Royal Oak, MI 48073; email fvicini{at}beaumont.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: We reviewed our institution’s experience treating patients with ductal carcinoma-in-situ (DCIS) with breast-conserving therapy (BCT) to determine the impact of patient age on outcome.

PATIENTS AND METHODS: From 1980 to 1993, 146 patients were treated with BCT for DCIS. All patients underwent excisional biopsy, and 64% underwent re-excision. All patients received whole-breast irradiation to a median dose of 45 Gy. Ninety-four percent of patients received a boost to the tumor bed, for a median total dose of 60.4 Gy. All slides on every patient were reviewed by one pathologist. The median follow-up period was 7.2 years.

RESULTS: Seventeen patients developed an ipsilateral local recurrence, for 5- and 10-year actuarial rates of 10.2% and 12.4%, respectively. The 10-year rate of ipsilateral failure was 26.1% in patients younger than 45 years of age versus 8.6% in older patients (P = .03). On multivariate analysis, young age was independently associated with recurrence of the index lesion (true recurrence/marginal miss [TR/MM] failures), regardless of how it was analyzed (eg, < 45 years of age or as a continuous variable). In addition, young patients had a dramatically higher 10-year rate of invasive TR/MM failures (19.9% v 3.2%). In a separate multivariate analysis for the development of invasive TR/MM failures, only patient age and predominant nuclear grade were independently associated with recurrence. The relationship between excision volume and outcome was analyzed in the 95 patients who underwent re-excision. The 5-year actuarial rate of TR/MM failure was significantly worse only in young patients with smaller (< 40 mL) re-excision volumes (33.3% v 9.1%; P = .02). In a separate multivariate analysis of only these 95 patients (25 of whom were < 45 years of age), the volume of re-excision had the strongest association with outcome (P = .05). Patient age was no longer associated with local recurrence.

CONCLUSION: These findings suggest that young patients with DCIS have a significantly greater risk of local recurrence after BCT that is independent of other previously defined risk factors. Our data also suggest that the extent of resection may in part be related to the less optimal results that are observed in these patients.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
BREAST-CONSERVING therapy (BCT) has become an accepted option in the management of most patients with ductal carcinoma-in-situ (DCIS) of the breast.^1,2 In an effort to optimize treatment outcome in these patients, multiple groups have examined the association of various clinical, pathologic, and treatment-related factors with the development of local recurrence.^3-15 Although several pathologic variables have been extensively investigated, only minimal data exist that explore the relationship between patient age and outcome.^5,6,8,13,14 Although the association between young age at diagnosis and the prognosis of patients with invasive breast cancer suggests a poorer overall outcome,^16,17 results in patients with DCIS have not been consistent. In an effort to further explore this potential relationship, we reviewed our institution’s long-term results with BCT in patients with DCIS. Clinical, pathologic, and treatment-related factors were analyzed to determine which variables were associated with local recurrence.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
From January 1980 through December 1993, 169 breasts in 167 patients were treated for DCIS with lumpectomy followed by radiation therapy (RT) at William Beaumont Hospital in Royal Oak, MI. One hundred-fifty three of these cases (91%) underwent complete pathologic review. Five cases were excluded on the basis of findings at histologic review (two for invasive cancer and three for atypical ductal hyperplasia). The study population included 144 patients with unilateral DCIS and two patients with bilateral DCIS, for a total of 148 breasts with pathologically confirmed DCIS in 146 patients.

All women had American Joint Committee on Cancer clinical stage 0 (TisN0M0) DCIS of the breast at presentation.¹⁸ Patients with the following findings were excluded from this analysis: (1) invasive carcinoma of the breast, (2) microinvasive carcinoma of the breast, or (3) incomplete pathologic review. Six patients (4%) with previous or simultaneous contralateral breast cancer (two with DCIS and four with invasive cancer) were included in the study population. However, those four patients with previous or simultaneous contralateral invasive breast cancer were excluded from all survival analyses.

All women were treated with excision followed by breast irradiation. The surgical treatment in all cases included at least an excisional biopsy, defined as an excision of tissue around the tip of the needle-localization wire. The initial excision was guided by mammographic-needle localization in 136 cases (92%). Ninety-five cases (64%) underwent a re-excision of the primary tumor site because of close ( 2 mm), positive, or uncertain margins at the discretion of the surgeon or radiation oncologist. In some cases, postexcisional (preirradiation) mammograms were obtained to exclude residual microcalcifications in the breast.

Pathologic lymph node staging was performed in 76 cases (51%). All excised lymph nodes were free of metastasis. The median number of lymph nodes removed was 13 (range, one to 28 nodes). Since 1990, surgical staging of the axilla has not been routinely performed at William Beaumont Hospital.

Our radiation technique has been previously reported.^15,19 Briefly, RT was initiated at a median interval of 5.2 weeks after the last surgical procedure (range, 0 to 32 weeks). The entire breast was irradiated with 4- to 6-MV photons to a median dose of 45.0 Gy (range, 43.1 to 56.0 Gy). Whole-breast irradiation was followed by a supplemental boost to the tumor bed in 139 cases (94%), for a median total dose of 60.4 Gy (range, 45.0 to 71.8 Gy) to the tumor bed. The tumor bed was boosted with electrons in 107 cases, an interstitial implant in 30 cases, or photons in two cases. The nine cases that were not boosted received a median of 50.4 Gy to the entire breast (range, 45.0 to 56.0 Gy). Regional lymphatics were not treated in any patient, and no adjuvant chemotherapy was administered. Five patients (3%) received adjuvant tamoxifen.

All specimen slides were reviewed for this study by one author (N.S.G.) without knowledge of the clinical outcome. The following information and pathologic features were recorded for the initial biopsy and re-excision specimens: (1) total number of slides examined from each specimen; (2) whether the specimen was partially or entirely submitted; (3) maximum specimen dimensions; (4) pattern of DCIS involvement, categorized as tumorous, tumorous with dispersion, or predominantly dispersed: DCIS formed a tumorous lesion when the DCIS ducts were closely grouped such that a tumor size could be measured, and DCIS had a dispersed pattern when one or more DCIS ducts were separated by normal breast parenchyma in a random or discontinuous pattern (sometimes on several slides) such that a tumor size could not be measured. (5) Maximum DCIS tumor dimensions, measured from the portion of DCIS that had a tumorous pattern. If a tumorous lesion was contiguous across several slides, then this tumor dimension was calculated using an estimated maximal tumor-block thickness of 0.4 cm and multiplying by the number of slides containing the tumor. The dispersed pattern associated with tumorous DCIS was not measured. (6) Predominant histologic subtype, categorized as comedo, cribriform, papillary, micropapillary, solid, clinging, or cystic²⁰; (7) minor histologic subtype; (8) proportion of DCIS profiles with central necrosis, divided into quartiles (none, 1% to 25%, 26% to 50%, 51% to 75%, or 76%); (9) predominant nuclear grade; (10) highest nuclear grade; (11) margin status, classified as unifocal positive (single DCIS duct transected at the margin), multifocal positive (two or more ducts transected at the margin that were separated by 0.5 cm or on two or more slides), close (DCIS located within 0.2 cm of the inked margin edge but not transected), negative (no DCIS within 0.2 cm of the inked margin), or uncertain (specimen was not inked or was fragmented such that the specimen margin could not be determined); (12) number of terminal duct lobular units involved by cancerization of lobules (COL) that were within 0.5 cm (one half of a low-power field with a x4 objective and x10 ocular magnification) of the margin. COL was defined using the criteria of Fechner and Azzopardi.^21,22 (13) Number of terminal duct lobular units involved by atypical ductal hyperplasia (ADH) that were within 0.5 cm of the margin. ADH was defined using the criteria of Lennington et al²³ as "ADH associated with DCIS." (14) Number of slides having any COL or ADH within 0.5 cm of the margin; (15) number of DCIS ducts within 0.5 cm of the margin; (16) number of slides having DCIS within 0.5 cm of the margin; (17) number of slides with any DCIS; (18) presence or absence of any focus of DCIS having three or more mitoses in one high-power field (x40 objective); (19) presence or absence of any microcalcifications within DCIS ducts; (20) desmoplastic-type stromal fibrosis around DCIS ducts, categorized as absent-slight or moderate-marked; and (21) lymphocytic infiltration around DCIS ducts, categorized as absent-slight or moderate-marked.

Mammographic findings were recorded from a retrospective review of reports on patient charts. Results were categorized as follows: (1) mass alone (with no calcifications), (2) calcifications alone, and (3) both a mass and calcifications. The vast majority of patients underwent standard screening mammography with two-view film (craniocaudal and mediolateral oblique) and magnification views of suspicious calcifications or masses.

After completion of breast irradiation, patients were evaluated every 3 months for the initial 2 years of follow-up and at 6-month intervals thereafter. Patients frequently alternated follow-up visits between their surgeon and radiation oncologist. Mammograms were performed 6 months after completion of treatment and annually thereafter, unless a given mammographic finding warranted earlier follow-up.

An ipsilateral failure was defined as the reappearance of cancer in the treated breast before or at the time of metastases. Ipsilateral failures were classified by clinical location in relation to the initial boost volume according to the criteria described by Recht et al.²⁴ A true recurrence/marginal miss (TR/MM) was defined as a recurrence within or immediately adjacent to the boost volume (or the primary tumor site in patients who did not receive boosts). An elsewhere failure was defined as an ipsilateral breast recurrence several centimeters from the primary site and was generally felt to be a new primary cancer or multicentric cancer. Contralateral breast failure was defined as the subsequent development of breast cancer in the opposite, untreated breast. Overall survival reflects all deaths, cancer-related or otherwise. Cause-specific survival was based on deaths attributed to breast cancer. The four patients with previous or simultaneous contralateral invasive breast cancer were excluded from all contralateral breast failure and survival analyses. However, these patients were included in all ipsilateral breast failure, TR/MM, and elsewhere failure analyses. The two patients with previous or simultaneous contralateral DCIS were also excluded from contralateral breast failure analyses but were included in survival analyses.

Actuarial results for ipsilateral breast failure, contralateral breast failure, disease-free survival, overall survival, and cause-specific survival were calculated by the Kaplan-Meier method.²⁵ The association of clinical, pathologic, and treatment-related variables with any given event was analyzed using Fisher’s exact test (two-tailed) for categorical variables and logistic regression for continuous variables. The statistical significance of differences between actuarial curves was calculated with the log-rank test.²⁶ Multivariate analysis was performed using the Cox proportional hazards model.²⁷ A P value of .05 was considered to be statistically significant. Because ADH and COL are mutually exclusive entities, only lower-grade cases were considered when analyzing the influence of ADH, and only higher-grade cases were considered when analyzing the influence of COL. Frequency distributions were calculated using Fisher’s exact test. The gross volume of excised breast tissue was calculated by multiplying height x width x length, using maximum dimensions in the gross description of the pathology report. To determine the impact of the extent of breast resection (volume of re-excision and total volume of excision) on the risk of local recurrence, patients were divided into three groups of roughly equal numbers of patients based on the volume of excised tissue.²⁸ Calculations were then performed between the smallest third of patients versus all others. For initial excision volume analyses, the median volume of excision was used. For calculations of survival, the number of patients was used instead of the number of cases. All time intervals were calculated from the date of diagnosis. Statistical analysis was performed using SAS (version 6.12, SAS Institute, Cary, NC).

The median follow-up period for all patients is 7.2 years (range, 1.3 to 14.2 years). One hundred twenty-three patients (83%) have been followed-up for a minimum of 5 years, and 33 patients (22%) have been followed-up for more than 10 years.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Factors Associated With Local Recurrence
Table 1 lists various clinical, pathologic, and treatment-related characteristics of the entire study population. With a median follow-up of 7.2 years, 17 patients developed an ipsilateral failure in the breast. Table 2 lists 5- and 10-year actuarial rates of local control, disease-free survival, overall survival, and cause-specific survival. Univariate analysis of various clinical, pathologic, and treatment-related factors associated with ipsilateral breast and TR/MM failures is presented in Table 3. Actuarial and multivariate analyses are also presented in Tables 4 and 5, respectively. Young patients (< 45 years of age) had a significantly greater 10-year actuarial rate of ipsilateral failure in the breast compared with older patients (26.1% v 8.6%; P = .03; Table 4). Young patient age was consistently found to be an independent risk factor associated with the development of TR/MM failures (Fig 1), regardless of the manner in which it was analyzed (eg, < 45 years of age or as a continuous variable). Additional factors that were independently associated with the development of TR/MM failure on multivariate analysis included the absence of pathologic calcifications (P = .06), the number of slides containing DCIS (P = .02), margin status (P = .03), the number of DCIS ducts and/or COL foci 5 mm from the margin (P = .06), and the total volume of the surgical excision (P = .06).

View larger version (9K): [in this window] [in a new window]   Fig 1. Actuarial rate of freedom from TR/MM failure in each age group.

Patterns of Failure
The incidence of invasive TR/MM failures was analyzed on the basis of age at diagnosis (Fig 2). Six (86%) of the seven ipsilateral breast failures in patients younger than 45 years of age were scored as TR/MM, and five of these (83%) were invasive (Table 1). As noted in Table 6, young patients had a 10-year actuarial rate of invasive TR/MM failure of 19.9% versus 3.2% in older patients (P = .03). A separate analysis was performed to determine factors that were associated with the development of invasive TR/MM failures. Factors analyzed included age at diagnosis, the presence of pathologic calcifications, the number of slides with DCIS, margin status, tumor size, predominant nuclear grade, comedo histology, method of detection, and total volume of excision. On multivariate analysis, only patient age (P = .007) and predominant nuclear grade (P = .03) were independently associated with outcome.

View larger version (9K): [in this window] [in a new window]   Fig 2. Actuarial rate of freedom from invasive TR/MM failure in each age group.

Risk factors for the development of local recurrence were analyzed separately for the 31 patients who were younger than 45 years of age. Selected factors that were investigated included total excision volume, predominant nuclear grade, predominant histology, margin status, number of slides containing DCIS, number of DCIS foci near the margin, the presence of pathologic calcifications, and DCIS pattern. On multivariate analysis, a total excision volume of less than 60 mL (P = .04) and the predominant nuclear grade (P = .03) were the only variables that were found to be associated with TR/MM failure.

Extent of Resection Versus Local Failure
Because the adequacy of excision (as represented by margin status, the number of DCIS ducts and/or COL foci 5 mm from the margin, and a composite specimen volume of < 60 mL) was one of several factors that were found to be independently associated with outcome, and because young patients more frequently had smaller initial excision volumes (P = .06) and more foci of COL 5 mm from the margin (P = .04), the potential relationship between the extent of resection and outcome was analyzed (Table 7). In the 95 patients who underwent re-excision, the 5-year actuarial rate of TR/MM failure was significantly greater only in young patients with smaller (< 40 mL) re-excision volumes (33.3% v 9.1%; P = .02). In a separate multivariate analysis of these 95 patients (24 of whom were younger than 45 years of age), the volume of re-excision had the greatest impact on the development of TR/MM failures (P = .005; Table 8). Margin status and the absence of pathologic calcifications were also related to outcome, which suggests that the adequacy of excision was critical in these patients. Interestingly, when analyzed in this fashion, patient age was no longer associated with outcome, regardless of how it was calculated (eg, ipsilateral breast failure, TR/MM, or invasive TR/MM).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Young age has frequently been reported as an independent risk factor for the development of local recurrences in patients with invasive breast cancer treated with BCT.^16,17 In addition, younger patients have been found by several groups to have a worse prognosis even when treated with mastectomy. Although several of these studies have found that young patients more frequently have a higher proportion of tumors with adverse pathologic factors, it does not seem that these findings entirely account for the poorer outcome in these patients. Unfortunately, the relationship between patient age and outcome in patients with DCIS treated with BCT has only been minimally investigated. Although several studies have reported a higher trend for local recurrences in young patients,^{4,5,8,10,29,30} only two other groups found a significantly higher rate of failure in young patients (Table 9). ^6,13 To add further confusion to this issue, the definition of young age has been inconsistent in these studies, with cutoffs ranging from 35 to 50 years. Considering that cure rates with mastectomy have historically been reported in the range of 98% to 100%, the appropriateness of BCT in young patients with DCIS needs to be explored in other studies. However, it should also be noted that it is unclear if younger patients have a worse outcome even when treated with mastectomy.

It is currently uncertain whether invasive cancers that develop after BCT for DCIS in young patients have a more favorable or less favorable outcome.³¹ Young patients did not have a worse cause-specific survival than older patients in the present study. Whereas the size of invasive recurrences seemed similar between the two age groups, recurrences seemed to be high grade more frequently in younger patients. However, patient numbers were extremely small, which limits the ability to detect even a slight trend toward a difference in outcome. Many more patient-years of follow-up will be needed to address this important issue. Until these data are available, the use of BCT in young patients with DCIS should be approached carefully.

Fortunately, these findings seem to suggest that part of the increased failure rate observed in young patients may be related to smaller volumes of excision in these patients. When restricting analyses only to the 95 patients who underwent re-excision, the extent of resection had the strongest association with outcome. Age was no longer associated with local recurrence. In addition, when analyzing risk factors for the development of TR/MM failures in patients younger than 45 years of age, excision volume was also independently associated with outcome. This volume relationship has also been reported in two separate studies by the Harvard Group and in an additional study at Memorial Sloan-Kettering Cancer Center.^8,28,32 Hiramatsu et al⁸ showed that DCIS patients with total volumes of excision of less than 60 mL had a significantly higher 10-year actuarial rate of local recurrence than patients with larger excised volumes (25% v 0%; P = .04). In a similar analysis of invasive carcinomas with an extensive intraductal component (EIC), Vicini et al²⁸ also demonstrated the significant effect that adequacy of excision may have on outcome. For patients with an EIC, the largest resections were associated with a substantially lower risk of recurrence at 5 years than the smallest resections. This effect was seen both for T1 tumors (10% v 29%; P = .07) and for T2 tumors (9% v 36%; P = .04). Although volume analyses are difficult to perform because breast size, surgical technique, and other critical variables cannot be controlled for, these findings suggest that the impact of age on treatment outcome may be partially reduced by more extensive surgeries.

The findings of this study must be tempered by the fact that all of the associations were based on a minimal number of events (17 local failures). As a result, the statistical power is too low to make definitive conclusions. Although 10-year failure rates in young patients in our study are similar to those reported by other groups (Table 9), additional studies must first establish that young patients have a higher risk of TR/MM failures. If this observation is substantiated, then it suggests that, in analyzing factors that are associated with local recurrences, both the location of the ipsilateral breast failure (ie, TR/MM v elsewhere) and whether it is invasive should be taken into consideration. Our findings may also in part account for the inconsistency of data that pertain to the analysis of prognostic factors for local recurrence. As we have previously shown (and in this analysis), substantially different results can be obtained depending on which end point is chosen for analysis.⁷ For example, in the current study, different risk factors were identified for the development of invasive TR/MM failures (eg, predominant nuclear grade) versus TR/MM failures or all ipsilateral breast failures. Hopefully, future studies will analyze data in this fashion so that the true failure rate in young patients can be determined and appropriate recommendations for BCT can be made.

Finally, as reported by several other groups and in the current analysis, adequate excision of all clinically apparent DCIS seems to be critical in achieving optimal results when patients of any age are treated with BCT.^4,33 This is supported by the fact that margin status and the number of DCIS ducts and/or COL foci 5 mm of the margin were both found to be independent risk factors associated with the development of local recurrences in the entire patient population. Although our findings are by no means conclusive, they provide additional data that support the necessity of adequately ensuring that maximal tumor extirpation is achieved before RT is administered, particularly in young patients.

In conclusion, these findings suggest that young patients with DCIS have a significantly greater risk of local recurrence after BCT that is independent of other previously defined risk factors. Patient age seems to be an additional variable that should be taken into consideration when determining the appropriateness of BCT for a patient. Our data also suggest that the extent of resection may in part be related to the less optimal results that are obtained in these patients. However, additional studies are needed to clarify the factor(s) responsible for the increased risk of local recurrence in young patients.

	ACKNOWLEDGMENTS

 
We thank Mamtha Balasubramaniam, MS, for her assistance with statistical analysis and Vicky Dykes for her assistance in preparation of the manuscript.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted April 27, 1999; accepted August 23, 1999.

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