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Bilateral Risk for Subsequent Breast Cancer After Lobular Carcinoma-In-Situ: Analysis of Surveillance, Epidemiology, and End Results Data

From the Department of Radiation Oncology, St John Hospital Van Elslander Cancer Center and Webber Cancer Center, Grosse Pointe; Department of Pediatrics, Children's Hospital of Michigan; Department of Family Practice, Wayne State University School of Medicine, Detroit; Department of Pathology, University of Michigan, Ann Arbor, MI; Department of Radiation Oncology, and Cedars-Sinai Comprehensive Cancer Center, Los Angeles, CA

Address reprint requests to Paul J. Chuba, MD, PhD, Department of Radiation Oncology, St John Health Systems, 11800 E 12 Mile Rd, Warren, MI 48093; e-mail: paul.chuba{at}stjohn.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Noninvasive lesions involving the lobules of the breast are increasingly diagnosed as incidental microscopic findings at the time of lumpectomy or core-needle biopsy. We investigated the incidence rates of invasive breast cancer (IBC) after a diagnosis of lobular carcinoma-in-situ (LCIS) by using Surveillance, Epidemiology, and End Results (SEER) data.

PATIENTS AND METHODS: Patients (N = 4,853) having a diagnosis of primary LCIS in the time period of 1973 to 1998 were identified using the SEER Public Use CD-ROM data. The database was then searched for patients with subsequent primary IBC occurrences (n = 350). The clinical and pathologic characteristics of patients with subsequent primary IBCs were compared with the characteristics of patients with primary IBCs attained during the same time period (N = 255,114).

RESULTS: The incidence of IBC increased over time from diagnosis of LCIS, with 7.1% ± 0.5% incidence of IBC at 10 years. IBCs detected after partial mastectomy occurred in either breast (46% ipsilateral and 54% contralateral); however, after mastectomy, most IBCs were contralateral (94.7%). IBCs occurring after LCIS more often represented invasive lobular histology (23.1%) compared with primary IBCs (6.5%). The standardized incidence ratio (the ratio of observed to expected cases) for developing IBC was 2.4 (95% CI, 2.1 to 2.6) adjusted for age and year of diagnosis.

CONCLUSION: LCIS is associated with increased risk of subsequent invasive disease, with equal predisposition in either breast. The minimum risk of developing IBC after LCIS is 7.1% at 10 years.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Lobular carcinoma-in-situ (LCIS) is a clinically undetectable form of noninvasive breast cancer.^1,2 Unlike ductal carcinoma-in-situ (DCIS), LCIS is typically confined to the lobules and terminal ducts of the breast and is almost exclusively diagnosed as an incidental finding when biopsy is performed for another reason.^2-5 LCIS differs from atypical lobular hyperplasia (ALH) only in the degree of neoplasia,^6-9 and these entities have been studied both together^7,10 and separately.^9,11 Because of increased rates of biopsy for mammographic findings, the diagnosis of LCIS has increased.^5,9,12 For many years, LCIS has been considered a predisposing risk factor for the subsequent development of malignant disease in either breast,^3,8,12-14 which may be greater for high-grade or more extensive lesions.^10,15 In addition, some series^10,16 have suggested preferential occurrence of invasive cancer in the ipsilateral breast at the site of biopsied LCIS (ie, suggestive of an actual precursor lesion or preinvasive proliferation). Progression to invasive disease seems to be inhibited by the use of tamoxifen.¹⁷ For the current study, Surveillance, Epidemiology, and End Results (SEER) data¹⁸ were analyzed to quantify and examine the laterality of invasive breast cancer (IBC) occurring after LCIS.

	PATIENTS AND METHODS

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Women having a diagnosis of LCIS were identified (n = 4,853) in the SEER Cancer Incidence Public-Use Database, 1973 to 1998¹⁸ using the International Classification of Disease for Oncology codes (WHO 2000).¹⁹ Excluded from the analysis were patients initially identified based on autopsy reports or death certificates, patients with simultaneous occurrence of LCIS and IBC, and male breast cancers. The database was queried to identify patients subsequently diagnosed with an IBC at 1 or more years after diagnosis of primary breast cancer. IBC patients diagnosed at less than 1 year from LCIS diagnosis were excluded to eliminate the possibility of concurrent diagnosis. Of 49 IBCs occurring at less than 1 year, 34 were contralateral, and 15 were ipsilateral. Thirty-three mastectomies were performed for IBCs found in the first year. Patients with IBC after LCIS were grouped by laterality, age, the type of initial surgery, and the International Classification of Disease for Oncology morphology codes. The surgical categories were lesser surgery (ie, needle biopsy or aspirate; n = 178), partial mastectomy (segmental mastectomy, lumpectomy, quadrantectomy, tylectomy, wedge resection, nipple resection, or excisional biopsy; n = 3,141), and mastectomy (simple mastectomy, modified radical mastectomy, and radical mastectomy; n = 1,281).

To compare patients with IBC occurring after LCIS with IBC patients in the population at large, data were collected for all SEER patients with primary IBC who were diagnosed from 1973 to 1998. Data included the primary site, laterality, histology, and extent of disease for SEER IBC patients. The standardized incidence ratio (SIR) was calculated by comparing observed rates with expected rates as follows. First, the incidence of all primary malignant breast cancer in females within the SEER database (N = 255,114) was determined by year of diagnosis and by 5-year age groups. Next, the number of individuals at risk (ie, after diagnosis of LCIS) was determined by year of diagnosis and age group. Finally, the expected number of females developing IBC after LCIS was calculated by year of diagnosis and age group. These numbers were summed to give total expected patients. Ninety-five percent CI for the SIR were determined based on a Poisson distribution. Cumulative incidence was determined by the Kaplan-Meier method,²⁰ with differences between groups assessed by the log-rank method.^21,22 Contingency tables were evaluated by the ² test.^21,22

	RESULTS

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From a total of 4,853 patients with LCIS identified in the SEER database between 1973 and 1998, 350 patients were found to have later developed IBC. In Table 1, the location within the breast, the laterality, and the histology for these patients are listed together with data from 255,114 patients with primary IBC identified within the SEER database over the same time period. Location within the breast (primary subsite) and laterality for the IBC after LCIS patients closely paralleled the data for primary IBC patients (Table 1). Approximately one third of IBCs occurred in the upper outer quadrant of the breast, and numbers of right-sided and left-sided IBCs were roughly equal. The histology for IBC after LCIS was more often lobular (23.1%) compared with primary IBC (6.5%), and this difference was mostly accounted for by a difference in the percentage of invasive ductal carcinomas (71.0% for primary IBC v 49.7% for IBC after LCIS).

View larger version (40K): [in this window] [in a new window]   Fig 1. Extent of disease for primary invasive breast cancer (IBC) versus IBC after lobular carcinoma-in-situ (LCIS). LND, lymph node dissection; NOS, not otherwise specified; LN, lymph node.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

The SEER Program,¹⁸ which was initiated in 1973, collects cancer-related data for 11 (formerly nine) geographic registries representing 14% of the US population. Importantly for the current study, each registry tracks information on invasive and selected in situ cancers. Previously, we used population-based SEER data for the study of the occurrence of second malignancy among breast cancer survivors because of the relatively large numbers of events.^27-29 Using SEER data and a similar methodology, we looked at progression to invasive disease in women with LCIS.

The current population-based study of 4,853 women with LCIS has the advantage of examining many more IBC events compared with previously published patient series (IBC occurrences = 350). At 10 years of follow-up, the incidence of IBC after LCIS was 7.1% for all patients. Considering patients who had partial mastectomy versus complete mastectomy, the incidence rates were 8.8% and 5.7%, respectively (Table 5).

Although the median age group for developing LCIS was 45 to 49 years, older females had higher relative risk for developing secondary IBC (Table 2). The SIR (ratio of observed incidence to the expected incidence) was 2.4. The cumulative risk of developing IBC continued to increase 15 to 25 years after LCIS diagnosis. Comparison of the risk level calculated here with previous single-institution data reveals a large range of incidence rates. Haagensen et al¹⁴ reported 10 patients with IBC in 53 patients with LCIS, for an 18% crude incidence rate with 16 years of minimum follow-up. Rosen et al²⁶ showed a 29% rate, with 29 IBCs in 99 LCIS patients. Other smaller studies (32 to 80 LCIS patients) had no more than four to nine IBC occurrences each, with incidence rates ranging from 6% to 12% at 5 years and 12% to 23% at 18 years of follow-up.^{4,23,25,30,31}

Among the most informative data regarding IBC after LCIS available to date are those derived from the National Surgical Adjuvant Breast and Bowel Project (NSABP) studies.^11,15,17 A report of 182 patients with LCIS treated with local excision alone as part of the NSABP B-17 study¹⁵ was recently updated with 12 years of follow-up.¹¹ All of these patients were initially thought to have had DCIS. At 5 years, a total of 13 ipsilateral breast tumor recurrences (IBTRs) and four contralateral breast tumor recurrences (CBTRs; including one bilateral recurrence) were observed. In the updated study, a total of 26 IBTRs (14.4%) and 14 CBTRs (7.8%) were reported. Nine of 26 IBTRs (5.0% of the total cohort) and 10 of 14 CBTRs (5.6% of the total cohort) were invasive. Pathologic grade of 2 to 3 seemed to be predictive for invasive ipsilateral recurrence. Interestingly, a high proportion of invasive IBTRs (89%) and invasive CBTRs (75%) were of lobular histology. This contrasts with the 23.1% proportion found in our study.

In NSABP P-1,¹⁷ a total of 13,338 women at increased risk for developing breast cancer were randomly assigned to receive placebo or tamoxifen 20 mg/d for 5 years. A 49% decrease in the occurrence of IBC for women receiving tamoxifen compared with women receiving placebo was shown. Most relevant to our analysis is that 826 women were accrued to NSABP P-1 because of a prior diagnosis of LCIS (411 patients on the placebo arm and 415 patients on the tamoxifen arm). A total of 26 IBCs were observed among these patients (18 patients receiving placebo and eight patients receiving tamoxifen). The average annual rate per 1,000 women was reported as 12.99 and 5.69 for the placebo and tamoxifen arms, respectively.¹⁷ Thus, among 411 LCIS patients treated with placebo on NSABP P-1, an estimated 6.5% could be expected to have developed IBC at 5 years (approximately 4.7% considering both the treatment and placebo arms). These numbers compare with the SEER database at 5 years, which shows a 4.1% ± 0.3% 5-year IBC incidence rate detected in 2,959 LCIS patients at risk (Table 2). Considering only patients diagnosed in the later time period (1986 to 1998), the 5-year SEER rate was identical to the 4.7% rate from NSABP P-1. Considering only patients treated with partial mastectomy, the SEER rate was 4.8%.

The question of whether LCIS may represent a true precursor lesion^7,10 versus a prognostic marker^4,8,14,32 for the subsequent development of IBC in either breast has been addressed by investigating the laterality of the second event (ie, a true precursor lesion would be associated with higher frequency of later IBC in the same breast). The SEER data did not demonstrate a difference between the incidence rates of secondary IBC in the unilateral versus contralateral breast (Table 6). Thus, from these data, LCIS would seem to be a marker of risk for which close follow-up may be considered adequate.

This result agrees with most previous studies,^4,14,32 with some exceptions. First, as part of the Nashville Breast Cancer Studies,⁷ a retrospective cohort of 252 women with ALH (including LCIS) found in benign biopsies that had been performed between 1950 and 1985 mostly for palpable abnormalities was followed. Fifty of these 252 patients later developed IBC. The IBC was ipsilateral in 34 patients (68%) and contralateral in 12 patients (24%). The authors concluded that IBC after a diagnosis of ALH was three times more likely to be diagnosed in the ipsilateral breast.⁷ Second, the Danish Breast Cancer Cooperative Group^16,30 collected follow-up data for 275 women treated with excision alone for DCIS (n = 142), LCIS (n = 100), or DCIS plus LCIS (n = 26) between 1982 and 1989. With a median follow-up of 10 years, 40 patients experienced recurrence as invasive carcinomas, and no statistical difference was found regarding development of IBC between the three groups. Considering only the LCIS patients, 18 recurrences were detected (13 IBC, one DCIS, and four DCIS plus LCIS). Sixteen of 18 recurrences were in the ipsilateral breast. Third, Marshall et al³³ examined the subsequent breast cancer risk for ALH among participants in the Nurse's Health Study.³⁴ Ipsilateral occurrence (in the same breast as the biopsy) was demonstrated in seven of 11 women who developed IBC. Interestingly, ALH was more strongly associated with premenopausal than postmenopausal status.³³ Why the results of these studies differ from the SEER and other data is not clear, but the reason may be related to pathologic factors (ie, differences in grade or extent of disease), unknown patient selection factors, or numbers of events analyzed. One factor could be that, in our study, patients with IBC diagnosed less than 1 year after LCIS were excluded to eliminate the possibility of simultaneous occurrences. The age ranges for different study populations could also be important because, in our study, the rates of IBC after LCIS were greater in older individuals.

For the SEER data, the IBC detected after LCIS most often was of invasive ductal or related histology (49.7%); nonetheless, an unusually large proportion (23.1%) showed lobular histology (Table 1). This is a considerably greater proportion of lobular disease than is observed in the general breast cancer population (6.5%). Previous investigators have also pointed out increased incidence of invasive lobular carcinoma in patients with a history of LCIS and, in most of these studies, 25% to 35% of secondary IBCs were invasive lobular.^4,14,26 Studies of the influence of LCIS on the risk of local recurrence in breast cancer have also suggested LCIS to be much more likely to be associated with invasive lobular carcinoma. In a study reported by Sasson et al,³⁵ LCIS was present in 65 (5%) of 1,274 patients with stage I and II breast cancer. LCIS was more likely to be associated with an invasive lobular carcinoma (30 of 59 patients; 51%) than with invasive ductal carcinoma (26 of 1,125 patients; 2%).

The implication would be that underlying genetic (somatic or germline) defects that manifest as lobular in situ disease later lead to invasive disease that is fated to preferentially involve lobular tissue. Candidate genes include germline mutations of MLH1 and MSH2.³⁵ Another molecular correlate for LCIS (and for ALH) is the altered expression of the E-cadherin gene located at chromosome 16q22.^36-40 Comparative genomic hybridization analysis performed after microdissection^37-39 has confirmed a high rate of losses from chromosome 16q in LCIS. Most patients with 16q loss also show altered E-cadherin expression. Such molecular changes are similar to those found in invasive lobular carcinomas.

Mixed results regarding the recurrence rates of IBCs that are associated with LCIS have been reported. Sasson et al³⁵ found that IBTR occurred in 57 (5%) of 1,209 patients without LCIS compared with 10 (15%) of 65 patients with associated LCIS (P = .001). Abner et al⁴¹ found an 8-year recurrence rates of 13% for moderate or marked LCIS adjacent to the tumor in 137 patients and 12% for 1,062 patients without LCIS. They concluded that neither the presence nor extent of LCIS associated with IBC should influence management decisions.⁴¹ In the current study, the subsequent outcome for patients with IBC detected after LCIS was not evaluated.

Although the SEER data analyzed in this study reflects the largest study of this topic to date, a number of possible limitations need to be addressed. First is the potential for lead-time bias. The data show that having an LCIS diagnosis in the later years of the study increased the risk of being diagnosed with IBC (Table 4; P = .04). For example, at 5 years, there was a 2.9% ± 0.5% incidence of IBC in the first 12 years of the study (1973 to 1985) compared with 4.7% ± 0.4% in the second 12 years (1986 to 1998). Two main factors are likely to account for this difference. First, patients with LCIS may have been more diligently screened for breast cancer compared with the general population in the later time period. Second, mammographic screening increased for the general population during the study period. Both of these factors increase the potential for early detection of breast cancer. The effect of lead-time bias is also manifested in the comparison of extent of disease at diagnosis for IBC detected in the general population versus IBC detected after LCIS (Fig 1). Observed extent of disease would be expected to be lower in cohorts having greater screening. Breast cancers detected in patients who had prior LCIS in the current study were smaller and less likely to be associated with lymph node metastasis (ie, consistent with increased screening). The slightly higher rate of IBC after LCIS observed in the later time period of the study (eg, 8.4% at 10 years; Table 4) may, therefore, be closer to the true rate in the current era.

A general limitation for population-based data is the possibility of under-reporting or imperfect ascertainment, and reported rates are generally considered underestimates. Nonetheless, ascertainment levels for the SEER database are high. A case-finding study performed in six different SEER areas (63% of the total SEER caseload) assessed the completeness of reporting for 6,342 patients diagnosed and/or treated in 74 hospitals.⁴² In each hospital, 2 study months were selected at random, and patients in hospital department files were then matched against lists of patients entered in the SEER system. From the 6,342 reportable cancer diagnoses, 149 had not been entered into the SEER program, giving an estimated completeness of reporting for 1987 of 97.7%. Patients with breast malignancy accounted for nine of the 149 patients not entered into SEER.⁴² Incompleteness was highest for hospitals with the smallest caseload.⁴²

Other limitations regarding the current study include the fact that both practice patterns and pathologic definitions for LCIS changed during the study time period. Because pathologic review is impossible, we cannot make any definite statement regarding the extent of LCIS or nuclear grade, both of which may have prognostic value. The reported data reflect the common usage of the criteria for the LCIS category by pathologists within the SEER reporting areas during the study time period. Similarly, current practice with chemoprevention for LCIS is not reflected in the SEER data presented here. Although second malignancy in patients with breast primaries may be influenced by radiotherapy,²⁹ this factor is largely absent for LCIS. Despite these limitations, the SEER data indicate clearly that the risk of IBC after LCIS is equal in both breasts. This finding is exemplified by the fact that LCIS patients who had partial mastectomy had equal rates of ipsilateral versus contralateral IBC, whereas patients who had mastectomy had few secondary ipsilateral IBCs (Table 6). It should be noted that possible drawbacks of population-based studies (ie, lead-time bias and underascertainment) do not influence the laterality of the subsequent cancers detected.

In conclusion, LCIS may be considered a predisposing determinant of risk for subsequent invasive disease in either breast. Risk reduction with unilateral mastectomy is only modest, and complete excision after lumpectomy is unlikely to result in significant risk reduction. Further work is necessary to determine whether ALH or LCIS diagnosed on core-needle biopsy may require excision to fully evaluate the extent of disease.⁹ Prophylactic bilateral mastectomy may be an option for selected patients. The minimum cumulative risk of developing IBC after LCIS was 7.1% at 10 years, with risk equally distributed between both breasts.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	NOTES

 
Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted April 8, 2004; accepted March 4, 2005.

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