Impact of concurrent proliferative high-risk lesions on the risk of ipsilateral breast carcinoma recurrence and contralateral breast carcinoma development in patients with ductal carcinoma in situ treated with breast-conserving therapy†
Linda J. Adepoju M.D.,
Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
Presented in part at the Annual Meeting of the American Society of Clinical Oncology, May 16, 2005, Orlando, Florida.
The purpose of the study was to determine the risk of ipsilateral breast carcinoma recurrence (IBCR) and contralateral breast carcinoma (CBC) development in patients with a concurrent diagnosis of ductal carcinoma in situ (DCIS) with atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), or lobular carcinoma in situ (LCIS).
Records of all 307 patients with DCIS treated with breast-conserving treatment (BCT) from 1968 to 1998 were analyzed. Initial pathology reports and all slides available were re-reviewed for evidence of ADH, ALH, or LCIS. Actuarial local recurrence rates were calculated.
Fifty-five cases of DCIS were associated with ADH, 11 with ALH or LCIS, and 14 with both ADH and ALH or LCIS. Overall, IBCR occurred in 14% and no significant difference in the IBCR rate was identified for patients with proliferative lesions compared with patients without these lesions (P = 0.38). Development of CBC in patients with concurrent DCIS and ADH was 4.4 times (95% confidence interval [CI], 1.44–13.63) that in patients with DCIS alone (P < 0.01). The 15-year cumulative rate of CBC development was 22.7% in patients with ALH or LCIS compared with 6.5% in patients without these lesions (P = 0.30) and 19% in patients with ADH compared with 4.1% in patients with DCIS alone (P < 0.01).
The incidence of ductal carcinoma in situ (DCIS) continues to rise as breast carcinoma screening and awareness increase and the techniques and interpretation of mammography improve. Today, DCIS accounts for approximately 20% of all screen-detected breast carcinomas.1 It is estimated that in the U.S. alone nearly 50,000 cases of DCIS will be diagnosed in 2005.2 Because both mastectomy and breast-conserving surgery with or without radiation therapy provide equivalent survival outcomes in patients with DCIS, treatment is chosen on the basis of the patient's wishes and clinicopathologic factors. However, compared with mastectomy breast-conserving surgery with radiation therapy is associated with a higher rate of local recurrence, with approximately half of all recurrences being invasive.3
While several investigators have examined the effect of various tumor factors on ipsilateral breast carcinoma recurrence (IBCR) in patients with DCIS, few4, 5 have examined the effect of the presence of other lesions in the surrounding breast tissue on the rate of IBCR in patients with DCIS. To our knowledge, no studies have examined the effect of the presence of other lesions on the rate of development of contralateral breast carcinoma (CBC) in patients with DCIS.
Studies have shown that patients with atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), or lobular carcinoma in situ (LCIS) found on breast biopsy, without concurrent malignancy, are at increased risk for the subsequent development of breast carcinoma.6–11 Overall, the relative risk reported in the literature ranges from 3–5.3 for ALH, 2.03–4.3 for ADH, and 5.7–11 for LCIS6–11 Lobular neoplasia (LN) includes a spectrum of atypical proliferative changes that range from ALH to LCIS. LCIS has been reported to confer approximately twice the risk for the development of invasive cancer as ADH or ALH.6, 7 The relative risk for development of invasive cancer in patients with a diagnosis of DCIS has been reported to be 11 times that of the general population.6
One hypothesis is that these lesions increase the risk of subsequent breast carcinoma because they are, in fact, precancerous. However, this hypothesis does not explain how these lesions increase the risk of CBC. The purpose of this study was to determine the impact of a concurrent diagnosis of ADH, ALH, or LCIS in patients with DCIS on the risk of IBCR and subsequent development of CBC after treatment with breast-conserving therapy (BCT).
MATERIALS AND METHODS
After approval was obtained from the Institutional Review Board of M. D. Anderson Cancer Center, medical records of 307 patients with DCIS treated at the study institution between 1968 and 1998 were analyzed. Three patients presented with bilateral synchronous DCIS for a total of 310 cases of DCIS. All original pathology was reviewed by pathologists at M. D. Anderson Cancer Center and at the time of surgery. Breast-conserving surgery was performed using mammographically guided needle localization. The specimen was radiographed to identify the targeted mammographic lesion and then inked. Twenty-nine patients in this study also had histologic evidence of a concurrent microinvasive component of less than 1 mm in addition to the DCIS. Close margins were defined as tumor-free margins less than 1 mm.
Two hundred eleven patients received adjuvant radiation therapy. Patients were generally treated when wound healing permitted but no later than 12 weeks after surgery. Radiation therapy was delivered as external-beam radiation therapy, with a median dose of 50 Gy. Whole-breast irradiation was followed by a boost to the tumor bed; the median boost dose was 10 Gy. No patients in this series received adjuvant systemic therapy for a diagnosis of DCIS. Seven patients in this series received adjuvant tamoxifen for treatment of previous or subsequent invasive carcinoma.
After treatment was completed, women had follow-up examinations every 3 months for the first 2 years, every 6 months for the next 3 years, and annually along with mammography thereafter. Patient, tumor, and treatment characteristics were evaluated for their association with the incidence of IBCR and CBC development. The patients' pathology reports were carefully reviewed for documentation of concurrent high-risk proliferative lesions including ADH, ALH, or LCIS within the surgical specimen. In addition, the presence of high-risk proliferative lesions were confirmed by one pathologist (W.F.S.) after review of the original hematoxylin and eosin-stained slides in 49 of the 55 cases that were entirely available for re-review. Two prior diagnoses of LCIS were changed to ALH, and two prior diagnosis of LN and five cases of ADH were not confirmed on re-review. These cases were considered as not having concurrent proliferative lesions on the analyses. The originally reported pathologic diagnoses were used for data analysis in cases where the slides were not available for re-review. ADH, ALH, and LCIS were diagnosed according to the criteria of Page and Anderson.12 Briefly, ADH lesions were defined as an intraductal proliferation with atypia that exhibited some but not all the features of DCIS.12 For a diagnosis of LCIS, all acini had to be filled and at least half of them distended by round/oval normochromatic cells that were similar in appearance and placement with each other.12 ALH lesions were defined as lobular proliferations that exhibited some but not all the features of LCIS, including incomplete involvement of acini within the lobular unit.12 To determine whether the presence of any particular patient, tumor, or treatment factor, including the presence of high-risk proliferative lesion, was associated with an increased risk of IBCR or CBC development, univariate analysis was performed for each factor using the Kaplan–Meier method for categorical variables. The significance of differences between groups for covariates was evaluated with the log-rank test. A Cox proportional regression model was used to assess the prognostic effect of the continuous variables on the incidence of IBCR and subsequent CBC.
Patient, tumor, and treatment characteristics for the 310 cases of DCIS included in this study are shown in Table 1. The median age of patients was 55 years (range, 25–85 yrs). The median follow-up time was 8.6 years (range, 0.3–29 yrs). Five (1.6%) patients eventually died of breast carcinoma. Eighty patients had high-risk proliferate lesions: 55 had ADH, 11 had ALH or LCIS, and 14 had ADH and ALH or LCIS.
Table 1. Patient, Tumor, and Treatment Characteristics
Forty-three (14%) patients developed an IBCR. The IBCR was DCIS in 13 (30%) cases, invasive carcinoma in 28 (65%) cases, and not known in 2 (5%) cases. IBCRs were detected by mammography in 28 (74%) patients; physical examination in 4 (11%) patients; and both modalities in 6 (16%) patients; the specific method of detection was not recorded in 5 patients. The IBCR was treated with total mastectomy with or without reconstruction in 36 (84%) patients and with segmental re-resection in 7 (16%) patients. IBCR was diagnosed at a median of 7 years (range, 0.7–20 yrs) after the primary surgery.
On univariate analysis, patient race, patient age, family history of breast carcinoma, tumor margin status, presence of microinvasion, clinical and pathologic tumor size, presence of necrosis, and presence of ADH, ALH, or LCIS did not significantly influence the incidence of IBCR (Table 2). Although they did not reach statistical significance, there were trends toward larger clinical tumor size, necrosis, or close or positive margins being associated with higher IBCR rates than smaller clinical tumor size, absence of necrosis, and negative margins (Table 2).
Table 2. Univariate Analysis of Patient, Tumor, and Treatment Characteristics Potentially Related to Local Recurrence
No. local recurrences (actuarial local recurrence rate)
Treatment with radiation significantly reduced the incidence of IBCR (Table 2; Fig. 1A). The 10-year local recurrence rate for women treated with surgery alone was 29.5% compared with 8.4% for women treated with surgery and radiation therapy (P = 0.003; Fig. 1A). The median time to local failure was significantly shorter in the 92 patients who did not receive postoperative radiation therapy compared with the 211 patients who did (4.87 yrs vs. 10.02 yrs; P = 0.001). IBCR rates were significantly higher in patients with intermediate or high-grade DCIS compared with patients who had low-grade DCIS (10-yr IBCR rate 12.8% vs. 3.6%; P = 0.0389; Table 2; Fig. 1B).
Development of Contralateral Breast Carcinoma
The median time to development of CBC was 6.5 years. Thirteen patients developed subsequent CBC during this study period. Subsequent CBC was invasive in 85%, DCIS in 10%, and of unknown type in 5%. Of the eight patients for whom estrogen-receptor status of the CBC was available, seven (87.5%) had estrogen receptor-positive tumor CBC.
CBC had also previously occurred in a total of 28 patients treated with BCT for DCIS during this study period, 24 cases were invasive carcinoma, and 4 patients had previous DCIS of the contralateral breast.
On univariate analysis, the only factor significantly associated with subsequent development of CBC was the presence of concurrent ADH, ALH, or LCIS (Table 3; Fig. 2). Patients with concurrent ADH, ALH, or LCIS had an actuarial rate of CBC development of 16.9% compared with a rate of CBC development of 4.3% at 15 years in patients without concurrent high-risk lesions (P = 0.023). Overall, patients with concurrent DCIS and ADH, ALH, or LCIS were 3.58 times (95% confidence interval [CI], 1.16–10.99) more likely to develop CBC. The rate of CBC development in patients with concurrent ADH was 4.4 times (95% CI, 1.44–13.63) that in patients with DCIS alone (P < 0.01). The 15-year cumulative rate of CBC development was 19% in patients with ADH compared with 4.1% in patients with DCIS alone (P < 0.01). There were only 14 patients with ALH and 11 patients with LCIS and concurrent DCIS in this series. Although the 15-year cumulative rate of CBC development was 22.7% in patients with ALH or LCIS compared with 6.5% in patients without ALH or LCIS, this difference did not reach statistical significance when these concurrent lesions were analyzed separately (P = 0.295).
Table 3. Univariate Analysis of Patient, Tumor, and Treatment Characteristics Potentially Related to the Development of Contralateral Breast Cancer (CBC)
Because of previously published reports demonstrating an increased risk of development of breast carcinoma in patients with high-risk proliferative lesions and a first-degree family history of breast carcinoma compared with similar patients without a strong family history,6, 8, 9 this issue was investigated in the present study. Forty-seven (15%) patients had a first-degree relative with a history of breast carcinoma. Family history did not affect the risk of development of CBC (Table 3). Among patients with DCIS and high-risk proliferative lesions, the history of a first-degree relative with a history of breast carcinoma did not increase the risk of development of CBC (P = 0.24836).
Although the current study failed to demonstrate an increased risk of IBCR in patients with DCIS and concurrent ADH, ALH, or LCIS, we did demonstrate a significantly increased risk of development of CBC in these women. This study also confirmed the findings of previous studies demonstrating that adjuvant radiation therapy reduces the risk of IBCR in patients with DCIS and that patients with high-nuclear grade DCIS have an increased risk of IBCR compared with patients with low-nuclear grade DCIS. The majority of clinical, pathologic, and treatment factors we examined (Table 3) had no impact on the rate of CBC development. However, patients with concurrent ADH, ALH, or LCIS had an increased rate of CBC at 15 years (16.9% vs. 4.3%; P = 0.02271). These findings are also consistent with our recent publication regarding the M. D. Anderson Cancer Center experience with contralateral prophylactic mastectomy in 239 patients with unilateral breast carcinoma.13 In the contralateral prophylactic mastectomy study we found that patients who had concurrent DCIS and ipsilateral high-risk lesions (ADH and or LN) were more likely to have significant occult additional high-risk lesions and or carcinoma within the contralateral prophylactic mastectomy specimen compared with patients without concurrent ipsilateral high-risk lesions.13
Breast-conserving surgery followed by whole-breast radiation therapy did not become the preferred treatment for DCIS at M. D. Anderson until the mid-1990s, after publication of long-term results of randomized data by the NSABP.14, 16 Our present findings regarding the impact of radiation therapy on IBCR in patients with DCIS were consistent with those from previous studies. Two prospective randomized trials have shown that radiation therapy reduces the risk of local recurrence after local excision of DCIS.14–17 The NSABP B-17 trial showed local recurrence rates at 5 years of 16.4% and 7% in women treated with lumpectomy alone and lumpectomy and radiation therapy, respectively.16 The overall incidence of IBCR after breast-conserving surgery and radiation therapy in our study was 12% compared with 13%14 and 9%18 in other published reports with a 7–8-year median follow-up period. In this regard, it is interesting to note that about 30% of patients in our series declined the use of radiation after surgery for DCIS.
Our findings regarding nuclear grade also agreed with those of several previous retrospective and prospective studies, which showed that histologic grade is a significant predictor of IBCR in both women treated with surgery alone and those treated with surgery and radiation therapy.4, 15, 19–21
The relation between the presence of ADH or LN and the risk of ipsilateral recurrence in patients with DCIS had not been previously studied in detail. One study, which included 26 patients with concurrent DCIS and LCIS, showed an overall recurrence rate of 35% in both patients with DCIS and those with DCIS and LCIS treated with surgery alone.4 Provenzano et al.5 showed that the presence of concurrent ADH in 13 patients with DCIS did not significantly affect ipsilateral breast recurrence rates. Those investigators did not examine the effects of concurrent ADH and DCIS on the development of CBC. Our finding of no significant increase in the incidence of IBCR in patients with concomitant ADH, ALH, or LCIS are also consistent with previous studies that demonstrated that the presence of ADH in patients with DCIS did not significantly affect ipsilateral recurrence rates.5
Although there are a few published reports regarding the influence of concurrent ADH, ALH, or LCIS on the risk of IBCR or CBC in patients with invasive breast carcinoma, the results are not entirely conclusive.22–26 In the absence of other contraindications to breast conservation, the presence of a high-risk proliferative lesion concurrent with invasive breast carcinoma is not generally considered a contraindication for breast conservation. Several reports have shown that the risks of IBCR and CBC development are not significantly affected by the presence of LCIS in patients with invasive cancer.22–24 However, Sasson et al.25 demonstrated that patients with LCIS and invasive breast carcinoma had a significantly increased risk of IBCR but not CBC.25 IBCR occurred in 57 (5%) of 1209 patients without LCIS compared with 10 (15%) of 65 patients with LCIS (P = 0.001).25 The 10-year cumulative incidence of IBCR was 6% in women without LCIS compared with 29% in women with LCIS (P = 0.0003).25 The 10-year cumulative incidence of IBCR in patients who received tamoxifen was 8% when LCIS was present compared with 6% when LCIS was absent (P = 0.46).25 Thus, the authors concluded that the risk of IBCR could be modified by the use of tamoxifen.25 Interestingly, the opposite conclusion was reached by Carolin et al.,23 who showed that the risk of IBCR was almost double for patients with invasive cancer without LCIS (n = 115) compared with patients with invasive cancer with LCIS (n = 105). Another study also demonstrated that ADH or ALH was not associated with an increased risk of IBCR or CBC development in patients with invasive cancer.26
The incidence of concurrent ADH, ALH, LCIS in patients with DCIS is unknown. A concurrent diagnosis of LCIS with DCIS was found in 15% of the patients in one study4 and approximately 6.5% in another.27 In the current series, approximately 25.8% of the patients were found to have ADH, ALH, or LCIS in association with DCIS. The incidence of ALH or LCIS in an otherwise benign biopsy sample ranges from 0.5–3.9%.6, 7, 28, 29 The incidence of ADH or ALH ranges from 3.6–19%.6, 7, 30, 31 Additional studies will be needed to confirm the incidence of ADH, ALH, or LCIS in surgical specimens from patients with DCIS.
Some studies have shown that a positive family history of breast carcinoma may have a synergistic effect together with the finding of ADH, ALH, or LCIS on benign breast biopsy on the risk of development of any breast carcinoma. For example, Page et al.6 demonstrated that a history of breast carcinoma in a first-degree relative doubled the risk of subsequent invasive carcinoma development in patients with ADH or ALH.6 Dupont et al.9 showed that women with ADH or ALH and a history of breast carcinoma in a first-degree relative had a fivefold increase in breast carcinoma risk; they had 22 times the breast carcinoma risk of women without proliferative disease or a first-degree family history. A prospective study showed that the relative risk of breast carcinoma was stronger in women with ADH or ALH and a first-degree family history of breast carcinoma than in women with ADH or ALH alone (7.3 vs. 3.7).8 However, this interaction between pathologic category and family history did not achieve statistical significance.8 In our study, a positive family history of breast carcinoma did not adversely affect the risk of development of CBC in patients with concurrent ADH, ALH, or LCIS. The discrepancy between the results of our study and previously published studies may be the result of differences in the distribution of other risk factors for recurrence or variations in the types of event (overall recurrence vs. contralateral breast recurrence) used in the analysis. While a positive family history has been shown to be an independent risk factor for the development of breast carcinoma, several studies have shown that family history does not significantly affect the rate of overall recurrence in patients with DCIS.20, 21 Therefore, although a positive family history may be an additional risk factor in patients with DCIS, it does not preclude the use of BCT in the management of these patients.
Before this study, physicians at M. D. Anderson routinely offered the same advice regarding the risk of subsequent CBC development to women with DCIS alone and women with DCIS and a concurrent high-risk proliferative lesion. It was not known that the presence of a concurrent high-risk proliferative lesion with DCIS increased the risk of CBC development. Our finding that concurrent high-risk proliferative lesions do in fact increase the risk has implications for the care of these patients. They may be eligible for additional treatment with tamoxifen or for clinical trials evaluating aromatase inhibitors or other agents for the prevention of CBC. Overexpression of the estrogen receptor has been shown to be present in the majority of DCIS lesion (range, 55–76%),32–37 LCIS lesions (93.8–100%),33, 37, 38 and ADH lesions (100%).39, 40 In addition, the NSABP P1 study showed that tamoxifen reduces the risk of breast carcinoma development in patients with ADH, ALH, or LCIS. When women with a history of ADH, ALH, or LCIS who did or did not receive tamoxifen were compared, there was a 100% increase in the annual rate of invasive cancer among those with a history of LCIS not treated with tamoxifen and a nearly 57% increase in this rate among women with a history of ADH or ALH not treated with tamoxifen.41 The NSABP B-24 study showed that women with DCIS treated with lumpectomy and radiation therapy received an additional benefit from tamoxifen. The advantage was due mainly to a decrease in the rate of invasive cancer in the ipsilateral breast and in the rate of invasive and noninvasive tumors in the contralateral breast.42
Any confounding influence of tamoxifen use on the findings of our current study was avoided, as we did not begin to routinely prescribe tamoxifen for patients with DCIS until after the publication of the NSABP B-24 results in 1999. On the basis of the results from our current study, consideration should be given to offering women with DCIS and concurrent ADH, ALH, or LCIS adjuvant hormonal therapy to prevent CBC. In this regard, it is interesting that most of the CBC events that occurred in the present study for which the estrogen receptor status was known were estrogen receptor-positive cancers.
The findings of this study should be considered preliminary for several reasons. The results, although from a single institutional experience, were based on pathology reports in patients treated for DCIS; the results were not generated from a prospective study designed to determine the relation between concurrent DCIS and high-risk proliferative lesions and IBCR and CBC development. Centralized pathology re-review was not possible for the majority of cases because not all the slide sets were still available and only cases with initial additional high-risk lesions were selected for re-review.
In conclusion, this appears to be the first report finding an additional risk of CBC development for this subset of patients treated with BCT. We conclude that although the presence of ADH, ALH, or LCIS with DCIS should not preclude BCT; women with DCIS and concurrent ADH, ALH, or LCIS may be optimal candidates for therapy with tamoxifen to reduce the risk of CBC events.
The authors thank Dr. Gregory D. Ayers for expertise and assistance with the biostatistical analyses for this project and Ms. Stephanie Demming for editorial assistance.