Invasive Ipsilateral Breast Tumor Recurrence Research Articles

Abstract P1-09-07: Omission of Axillary Surgery for Ipsilateral Breast Tumor Recurrence with Negative Nodes after Previous Breast-Conserving Surgery: Is It Oncologically Safe?

Abstract Background: Salvage mastectomy is traditionally recommended for patients who developed ipsilateral breast tumor recurrence (IBTR) in light of the previous breast irradiation. However, it remains controversial whether surgical axillary staging (SAS) is necessary for IBTR patients with negative nodes. This study aimed to evaluate the oncologic safety of omitting SAS for IBTR. Methods: We retrospectively identified patients who developed invasive IBTR with negative nodes after undergoing breast-conserving surgery (BCS). Patterns of care in nodal staging were analyzed based on prior axillary staging status. Clinicopathologic characteristics and adjuvant treatment of the initial tumor, as well as the IBTR, were compared between SAS and no SAS groups. Kaplan-Meier method and Cox regression model were utilized to compare the loco-regional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival (OS) rates after IBTR removal between the two groups. Results: A total of 154 IBTR patients were eligible for final analysis. Compared to no SAS group, SAS group was less likely to undergo ALND (15.1% vs 73.3%, p < 0.001) at initial BCS, had a longer recurrence interval (2.8 vs 2.1 years, p=0.03), and were more likely to have discordant molecular subtype with primary tumor (35.8% vs 12.9%, p=0.001). However, the extent of axillary staging did not affect systemic or radiation recommendations. In the subgroup of patients without previous ALND, the clinicopathologic characteristics were roughly comparable. Pathologic analysis revealed pathologically uninvolved nodal status in approximately 85% of patients receiving SAS at time of IBTR in the overall population and the subgroup (Table 1). No significant differences were observed in LRRFS, DMFS and OS between the two groups (Table 2). Conclusion: For node-negative IBTR patients, we observed selection bias on the basis of prior ALND, shorter recurrence interval, and concordant molecular subtype favoring no SAS, but comparable LRRFS, DMFS, and OS. These results support wider consideration of sparing SAS in the management of IBTR, especially in patients without previous ALND. Table 1. Pathologic axillary staging in patients receiving axillary surgery at time of IBTR. Table 2. Cox regression analysis of LRRFS, DMFS, and OS after IBTR. Citation Format: Feilin Qu, Caijin Lin, Jun-Jie Li, Zhi-Ming Shao. Omission of Axillary Surgery for Ipsilateral Breast Tumor Recurrence with Negative Nodes after Previous Breast-Conserving Surgery: Is It Oncologically Safe? [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-09-07.

Omission of axillary surgery for ipsilateral breast tumor recurrence with negative nodes after previous breast-conserving surgery: is it oncologically safe?

PurposeSalvage mastectomy is traditionally recommended for patients who developed ipsilateral breast tumor recurrence (IBTR) in light of previous breast irradiation. However, it remains controversial whether surgical axillary staging (SAS) is necessary for IBTR patients with negative nodes. This study aimed to evaluate the oncologic safety of omitting SAS for IBTR.MethodsWe retrospectively identified patients who developed invasive IBTR with negative nodes after undergoing breast-conserving surgery (BCS) from 2010 to 2018. Patterns of care in nodal staging were analyzed based on prior axillary staging status. Clinicopathologic characteristics and adjuvant treatment of the initial tumor, as well as the IBTR, were compared between the SAS and no SAS groups. Kaplan–Meier method and Cox regression model were utilized to compare the locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival (OS) rates after IBTR removal between the two groups.ResultsA total of 154 IBTR patients were eligible for final analysis. Compared to the no SAS group, SAS group was less likely to undergo ALND (15.1 vs 73.3%, p < 0.001) at initial BCS, had a longer recurrence interval (2.8 vs 2.1 years, p = 0.03), and were more likely to have discordant molecular subtype (35.8 vs 12.9%, p = 0.001) and different quadrant location (37.7 vs 19.8%, p = 0.02) with primary tumor. However, the extent of axillary staging did not affect systemic or radiation recommendations. In the subgroup of patients without previous ALND, the clinicopathologic characteristics were roughly comparable. No significant differences were observed in LRRFS, DMFS or OS between the two groups.ConclusionFor node-negative IBTR patients, we observed selection bias on the basis of prior ALND, shorter recurrence interval, and concordant molecular subtype favoring no SAS but comparable LRRFS, DMFS, and OS. These results support a wider consideration of sparing SAS in the management of IBTR, especially in patients without previous ALND.

Chemotherapy for ipsilateral breast tumor recurrence: a propensity score-matching study.

We evaluated the benefit of chemotherapy in patients with ipsilateral breast tumor recurrence (IBTR) by comparing the survival outcomes between the chemotherapy and no chemotherapy groups, using propensity score matching (PSM), and analyze the survival outcomes stratified by hormone receptor status of IBTR. We retrospectively analyzed patients who developed invasive IBTR after undergoing breast-conserving surgery at our institution between 1990 and 2013. A 1:1 PSM analysis was performed to compare the survival rates between the two study groups; additional analysis stratified by hormone receptor status was performed. The Kaplan-Meier method and Cox proportional hazards model were used to compare the second recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS) rates between the two groups. The 217 IBTR patients had a median follow-up of 125.3months. After PSM, patients without chemotherapy and with chemotherapy (n = 35 in both groups) were included. No significant differences were observed in the 10-year second RFS [50.2% without chemotherapy vs. 39.8% with chemotherapy, hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.50-1.80], DMFS (85.4% vs. 70.3%, HR 1.51, 95% CI 0.66-3.44), and OS (81.6% vs. 68.6%, HR 1.73, 95% CI 0.76-3.90) rates between the two groups. Analyses stratified by hormone receptor status showed similar findings: no significant differences were observed in the second RFS, DMFS, and OS rates between the two groups in both hormone receptor-positive and -negative groups. Chemotherapy had no impact in the long-term survival outcomes of IBTR patients regardless of the hormone receptor status.

Prognostic and predictive significance of tumor infiltrating lymphocytes for ductal carcinoma in situ

ABSTRACT This study aims to identify the density of TILs in ductal carcinoma in situ (DCIS) in terms of prognostic significance with recurrence and the benefit of whole breast irradiation (WBI). The clinicopathological data of DCIS patients from Jan 2009 to Dec 2016 who received breast-conserving surgery (BCS) were retrospectively reviewed. Cox regression analysis was used to confirm independent prognostic factors of ipsilateral breast tumor recurrence (IBTR). Kaplan–Meier method was utilized to analyze IBTR and values of WBI. Touching-tumor-infiltrating lymphocytes (TILs) were defined by TILs touching or within one lymphocyte cell thickness from the malignant ducts’ basement membrane. In total, 129 patients were enrolled in this analysis with 98 patients who received WBI. After a median follow-up of 53.0 months, there were 16 IBTR events with five invasive IBTRs. Univariate and multivariate analyses showed that touching-TILs >5 were an independent prognostic factor for higher IBTR (HR = 6.17, 95%CI 1.95–19.56, p < .01). The whole cohort was classified into two subgroups: dense group (>5 touching-TILs per duct) and sparse group (≤5 touching-TILs per duct). Dense touching-TILs were associated with unfavorable biologic characteristics. The 5-y rate of IBTR between dense and sparse group was 29.0% versus 4.5% (p < .01). For the sparse group, WBI significantly reduced the rate of 5-y-IBTR risk from 13.2% to 1.7% (p = .02), but there was no benefit of WBI in the dense group. Touching-TILs density was heterogeneous in patients with DCIS. Sparse touching-TILs were associated with better prognosis and benefit from WBI. Dense touching-TILs not only were associated with a higher risk of IBTR but also lack of benefit from WBI.

Long-Term Outcomes of Once-Daily Accelerated Partial-Breast Irradiation With Tomotherapy: Results of a Phase 2 Trial

We report long-term outcomes of phase 2 trial on patients with invasive breast cancer treated with accelerated partial-breast irradiation (APBI) using tomotherapy after breast conservative surgery. From December 2010 to December 2018, we treated 338 women with APBI-tomotherapy: 38.5 Gy in 10 once-daily fractions. Patients selected were age ≥50 years old, with ≤3 cm in size unifocal tumor and at least 2 mm of clear margins. Disease outcomes were analyzed by clinicopathologic characteristics, molecular phenotypes, and American Society for Radiation Oncology (ASTRO) 2017 updated consensus groupings. The median age was 65 years (range, 50-86). The invasive ductal (87.5%) and the luminal A-like molecular phenotype (70%) were the most common tumors. Overall 242 patients (71.6%) were considered "suitable" for enrollment in APBI according to the eligibility criteria of the ASTRO-2017 consensus statement. With a median follow-up of 76 months (range, 17-113), 2 patients (0.6%) had an invasive ipsilateral breast tumor recurrence (IBTR), and 2 patients (0.6%) had an axillary ipsilateral failure. The rate of local control in terms of free of IBTR was 99.4% and locoregional control (no recurrence in ipsilateral breast as well as in regional nodes) was 98.8%. Progression-free survival was 98.4% and 92% at 5 and 10 years, respectively. Acute and late skin toxicity, graded according to the Common Terminology Criteria for Adverse Events, were 7.7% (G1) and 0.6% (G2) and 4.4% (G1) and 1.1% (G2), respectively. There were no grade 3/4 toxicities, however. Very few patients (2%) or physicians (2%) assessed cosmetic outcome as fair or poor at the 2-year follow-up. This phase 2 trial on APBI-tomotherapy shows excellent long-term results. Once-daily fractionation schedule was well tolerated with a low rate of adverse events and worse cosmetic outcome. In this series, even among those deemed cautionary or unsuitable for APBI by ASTRO criteria, we demonstrated a low rate of IBTR.

Abstract P6-10-24: High stromal platelet derived growth factor receptor beta predicts absence of benefit of radiotherapy after breast conserving surgery in breast ductal carcinoma in situ within the SweDCIS randomized trial

Abstract Background: With the introduction of mammography the detection of breast ductal carcinoma in situ (DCIS) has increased four- to sevenfold. Local recurrences occur only in a minority of patients. Radiotherapy (RT) is presently used without biomarker guidance. Therefore, novel biomarkers predicting benefit of radiotherapy are warranted to prevent overtreatment. Studies on RT response-predictive biomarkers in DCIS have focused on tumor cell features and often neglected the tumor-associated stroma, despite growing evidence of its active influence on treatment response including RT. The platelet derived growth factor receptors alpha and beta (PDGFRa and -b) signaling pathways are major regulators of stroma cells. Recent studies have indicated a loss of PDGFRa in the tumor-associated stroma of DCIS while PDGFRb remains high and patients with PDGFRa(low)/PDGFRb(high) expression had a significant increased risk for any tumor recurrence. A limitation of this study was though the usage of a population-based cohort, thus not allowing firm conclusions on the impact of the marker on natural course of the disease or benefit to treatment. Purpose: To explore if stromal expression of PDGFRb serves as prognostic as well as response-predictive biomarker for RT benefit with regard to ipsilateral breast tumor recurrence (IBTR) and overall survival (OS) for DCIS patients within a large and clinically well-annotated randomized trial. Method: Immunohistochemical staining of PDGFRb was performed on full tissue sections of 705 patients from the SwedDCIS cohort, a randomized RT trial after breast-conserving surgery. Stromal PDGFRb expression was evaluated by two independent raters in up to ten high power fields within the tumor associated stroma region and scored as 0/negative, 1/low average stroma intensity, 2/moderate average stroma intensity or 3/high average stroma intensity. An average PDGFRb score was calculated for each tumor. The final data was split at median defining PDGFRb low and high patient groups. Outcomes were analyzed at 10 years of follow-up. Results: High stromal PDGFRb was correlated with young age (p=0.003 Spearman’s Rank correlation). In multivariable Cox regression including RT, age, size, screen detection and tumor margin status, the PDGFRb high patient group showed a trend to worse prognosis with regard to IBTR (HR 1.40, CI95% 0.96-2.04, p=0.08) and OS (HR 1.76, CI95% 1.00-3.09, p=0.05). Benefit of radiotherapy on IBTR (in situ and invasive) was absent in the PDGFRb high patient group (HR 0.76, CI95% 0.47-1.22, p=0.25)), but clearly detected in the PDGFRb low group (HR 0.29, CI95% 0.15-0.55, p&amp;lt;0.001) in a multivariable analysis including age, size, screen detection and tumor margin status. Interaction between RT and PDGFRb was significant (p=0.020). No differences in OS after RT were observed within the PDGFR-defined patient groups. RT benefit was also restricted to the PDGFRb low patient group in separate analyses for in situ IBTR (PDGFRb low group HR 0.27, CI95% 0.12-0.60, p=0.001, versus PDGFRb high group HR 0.66, CI95% 0.34-1.29, p=0.22) or invasive IBTR (PDGFRb low group HR 0.33, CI95% 0.11-0.98, p=0.045, versus PDGFRb high group HR 0.88, CI95% 0.45-1.73, p=0.71). Significant interactions between PDGFRb group and RT were not detected in these sub-analyses (p=0.11 for in situ and p=0.15 for invasive IBTR). Conclusion: These data suggests high stromal PDGFRb as a marker of potential clinical utility for RT resistance regarding IBTR in DCIS patients. Furthermore, the study supports the hypothesis of a fibroblast-mediated modulation of RT-sensitivity in DCIS cells. Experimental model studies, investigating the biological mechanisms and potential therapeutic relevance are therefore highly motivated. Citation Format: Carina Strell, Dick Folkvaljon, Erik Holmberg, Per Karlsson, Jonas Bergh, Troy Bremer, Lars A. Akslen, Fredrik Wärnberg, Arne Östman. High stromal platelet derived growth factor receptor beta predicts absence of benefit of radiotherapy after breast conserving surgery in breast ductal carcinoma in situ within the SweDCIS randomized trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-24.

Oncoplastic breast surgery for the management of ductal carcinoma in situ (DCIS): is it oncologically safe? A retrospective cohort analysis

BackgroundFew data exist in literature regarding oncoplastic surgery (ONC) and ductal carcinoma in situ (DCIS). The role of ONC in the treatment of DCIS has not been elucidated yet: no case-control study has yet been published on the issue and no long-term oncologic results are reported. MethodsUsing the European Institute of Oncology (IEO) institutional breast cancer data base we investigated the oncologic safety of ONC for DCIS comparing a consecutive series of 44 patients who have underwent ONC followed by external irradiation for DCIS (Group A-study group) with 375 patients who received conservation alone followed by external irradiation for DCIS (Group B control group) in the same period. We excluded patients presenting with secondary tumors or local relapses and those requiring re-excision or completion mastectomy for positive margins. Primary endpoints were disease-free survival (DFS) and ipsilateral breast tumor recurrence (IBTR) within the study group and comparison with the control group. ResultsEvents rates and death rates were similar in the two groups. The average annual rate of invasive IBTR in group A and B was 1.6% and 1.0% respectively. No difference in the rate of lymphnode metastasis, distant metastasis, contralateral breast cancer, other primary cancer or death was observed across the two groups. ConclusionsOur findings suggest the safety of ONC and irradiation for the management of DCIS extending the indications for conservation in DCIS patients otherwise treated with mastectomy. It provides the best available evidence supporting ONC as a valid treatment option for the management of DCIS.

Repeating Conservative Surgery after Ipsilateral Breast Tumor Reappearance: Criteria for Selecting the Best Candidates

Mastectomy is still considered the treatment of first choice in patients with ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery (BCS) and whole-breast radiotherapy. We retrospectively evaluated 161 patients with invasive IBTR who underwent a second BCS in order to describe prognosis, determine predictive factors of outcome, and select the subset of patients with the best local control. Median follow-up after IBTR was 81months. Median age at IBTR was 53years. Five-year overall survival after IBTR was 84% (95% confidence interval [CI] 78-89). Five-year cumulative incidence of a second local event after IBTR was 29% (95% CI 22-37). At the multivariate analysis, IBTR size >2cm and time to relapse ≤48months significantly increased the risk of local reappearance (hazard ratio [HR] 3.3, 95% CI 1.6-7.0; and HR 1.9, 95% CI 1.1-3.5). The 5-year cumulative incidence of a further local reappearance of the tumor after repeating BCS was 15.2% in the patients with IBTR ≤2cm and time to IBTR >48months, 31.2% in the patients with IBTR ≤2cm and time to IBTR ≤48months, and 71.2% in patients with IBTR >2cm (P<0.001). The best candidates for a second BCS are those with small (≤2cm) and late (>48months) IBTR. The information about the risk of a further local reappearance after repeating BCS should be shared with the patients in the decision making process.

Long-Term Outcomes of Invasive Ipsilateral Breast Tumor Recurrences After Lumpectomy in NSABP B-17 and B-24 Randomized Clinical Trials for DCIS

Ipsilateral breast tumor recurrence (IBTR) is the most common failure event after lumpectomy for ductal carcinoma in situ (DCIS). We evaluated invasive IBTR (I-IBTR) and its influence on survival among participants in two National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized trials for DCIS. In the NSABP B-17 trial (accrual period: October 1, 1985, to December 31, 1990), patients with localized DCIS were randomly assigned to the lumpectomy only (LO, n = 403) group or to the lumpectomy followed by radiotherapy (LRT, n = 410) group. In the NSABP B-24 double-blinded, placebo-controlled trial (accrual period: May 9, 1991, to April 13, 1994), all accrued patients were randomly assigned to LRT+ placebo, (n=900) or LRT + tamoxifen (LRT + TAM, n = 899). Endpoints included I-IBTR, DCIS-IBTR, contralateral breast cancers (CBC), overall and breast cancer-specific survival, and survival after I-IBTR. Median follow-up was 207 months for the B-17 trial (N = 813 patients) and 163 months for the B-24 trial (N = 1799 patients). Of 490 IBTR events, 263 (53.7%) were invasive. Radiation reduced I-IBTR by 52% in the LRT group compared with LO (B-17, hazard ratio [HR] of risk of I-IBTR = 0.48, 95% confidence interval [CI] = 0.33 to 0.69, P < .001). LRT + TAM reduced I-IBTR by 32% compared with LRT + placebo (B-24, HR of risk of I-IBTR = 0.68, 95% CI = 0.49 to 0.95, P = .025). The 15-year cumulative incidence of I-IBTR was 19.4% for LO, 8.9% for LRT (B-17), 10.0% for LRT + placebo (B-24), and 8.5% for LRT + TAM. The 15-year cumulative incidence of all contralateral breast cancers was 10.3% for LO, 10.2% for LRT (B-17), 10.8% for LRT + placebo (B-24), and 7.3% for LRT + TAM. I-IBTR was associated with increased mortality risk (HR of death = 1.75, 95% CI = 1.45 to 2.96, P < .001), whereas recurrence of DCIS was not. Twenty-two of 39 deaths after I-IBTR were attributed to breast cancer. Among all patients (with or without I-IBTR), the 15-year cumulative incidence of breast cancer death was 3.1% for LO, 4.7% for LRT (B-17), 2.7% for LRT + placebo (B-24), and 2.3% for LRT + TAM. Although I-IBTR increased the risk for breast cancer-related death, radiation therapy and tamoxifen reduced I-IBTR, and long-term prognosis remained excellent after breast-conserving surgery for DCIS.

The impact of lobular carcinoma in situ in association with invasive breast cancer on the rate of local recurrence in patients with early-stage breast cancer treated with breast-conserving therapy

The significance of lobular carcinoma in situ (LCIS) associated with invasive breast cancer in patients undergoing breast-conserving therapy (BCT) remains controversial. We examined the impact of the presence and extent of LCIS associated with invasive breast cancer on clinical outcome in BCT patients. From 1980 to 1996, 607 cases of invasive breast cancer were treated with BCT. All slides were reviewed by a single pathologist. Positive margin was defined as presence of invasive carcinoma/ductal carcinoma in situ at the inked margin. Multiple clinical, pathologic, and treatment-related variables were analyzed for their association with ipsilateral breast tumor recurrence (IBTR) and true recurrence/marginal miss (TR/MM). Median follow-up was 8.7 years. Fifty-six patients (9%) had LCIS in association with invasive cancer. On univariate analysis, positive final margin, positive/no reexcision, smaller maximum specimen dimension, and the presence of LCIS predicted for IBTR. The 10-year IBTR rate was 14% for cases with LCIS vs. 7% without LCIS (p=0.04). On multivariate analysis, positive margin (p<0.01), positive/no reexcision (p=0.04), and presence of LCIS (p=0.02) remained independently associated with IBTR; positive margin (p<0.01) and LCIS (p=0.04) were also associated with TR/MM failure. When examining only cases with negative final margins, the presence of LCIS remained associated with higher IBTR and TR/MM rates (p<0.01). The presence of LCIS was independently associated with higher rate of IBTR and TR/MM after BCT for invasive breast cancer. LCIS may have significant premalignant potential and progress to an invasive IBTR at the site of index lesion. The adequacy of excision of LCIS associated with invasive carcinoma should be considered in patients undergoing BCT.

Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: twelve-year observations concerning lobular carcinoma in situ.

The current report represents a 12-year clinicopathologic update of an earlier 5-year analysis of 180 patients with lobular carcinoma in situ (LCIS) who were treated with local excision and subsequent surveillance only. Nineteen pathologic characteristics of LCIS were assessed as potential predictors of invasive and noninvasive ipsilateral breast tumor recurrence (IBTR) and contralateral breast tumor recurrence (CBTR) as well as mortality. Overall, only 26 IBTRs (14.4%) and 14 CBTRs (7.8%) were observed. Nine IBTRs (5.0% of the total cohort) and 10 CBTRs (5.6% of the total cohort) were invasive carcinomas. Eight of 9 IBTRs (88.9%) and 6 of 8 invasive CBTRs (75%) that had histologic sections available for review were of the lobular invasive type. Ninety-six percent of all IBTRs and 100% of invasive IBTRs occurred within the same site as the index LCIS. The numbers of invasive IBTRs were comparable within and after 5 years (5 invasive IBTRs vs. 4 IBTRs). Recurrences of invasive CBTR occurred later than recurrences of invasive IBTR, with 70% of invasive CBTRs recognized after 5 years compared with 44% of invasive IBTRs. It was found that Grade 2-3 LCIS was significantly predictive for invasive IBTR when combined with the number of recurrences of ductal carcinoma in situ (DCIS) alone or with LCIS. Only 2 patients in the cohort (1.1%) succumbed to breast carcinoma; 1 patient had a prior invasive IBTR, and the other patient had an invasive CBTR. The reasons for the lower frequency of invasive recurrences and the higher proportions of the lobular invasive phenotype than noted by others are discussed along with the impact of the findings on the nomenclature, precursor nature, and treatment of LCIS. LCIS is a more indolent form of in situ breast carcinoma than DCIS, with which it shares other features of its natural history, particularly very low mortality rates. There is no compelling reason to surgically treat LCIS other than conservatively. The values of other adjuvant modalities in the management of LCIS are discussed. The authors acknowledge that their findings are based on relatively few events and, even at 12 years, may be regarded as "preliminary". Nonetheless, their findings may reflect the true biologic nature of LCIS.

Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) Protocol B-17. Five-year observations concerning lobular carcinoma in situ.

Extant information reveals inconsistencies concerning the natural history, pathologic features, and treatment of lobular carcinoma in situ (LCIS) of the breast. It is uncertain whether these are related to the methods of study, diagnostic criteria employed, relative paucity of cases, or varying lengths of follow-up. The cohort was comprised of 182 women with LCIS who were enrolled in National Surgical Adjuvant Breast Project (NSABP) Protocol B-17 but received no treatment other than lumpectomy. Nineteen pathologic features were assessed and related to ipsilateral breast tumor recurrence (IBTR) and contralateral breast tumor recurrence (CBTR) at a mean time on study of 5 years. Thirteen IBTR and 4 CBTR, including 1 instance of bilateral recurrence, were observed. All IBTR occurred in the same quadrant as the index LCIS. All 4 (2.2%) IBTR that were invasive cancers were of the lobular type, as was 1 of the 2 (1.1%) CBTR that were invasive. The other was a mucinous carcinoma. Three (1.6%) IBTR were pure ductal carcinoma in situ (DCIS) and another was accompanied by LCIS. One instance of CBTR was also comprised of DCIS and LCIS. The remaining five IBTR and one CBTR were LCIS only. The only pathologic parameter found to be significantly predictive for invasive IBTR and DCIS was type 3 and, to a lesser extent, type 2 LCIS. Some heretofore unrecognized or little appreciated pathologic features of LCIS are noted. Ancillary histochemical findings strongly implicate the derivation of LCIS from ductal or secretory cells rather than "new cells" or myoepithelial elements. All examples tested were found to be c-erb B-2 negative, universally diploid with normoproliferative DNA content, and estrogen receptor and progesterone receptor positive. No other events related to the breast were encountered. The number of events observed in this large cohort of patients with LCIS is markedly less than that noted by others after a comparable period of follow-up. Possible reasons for this dichotomy, including differences in patient characteristics, diagnostic criteria, and status of resection margins, are discussed. Considerations are also offered to support the view that LCIS may exhibit precursor activity as well as represent a risk factor (the term marker is literally inaccurate). In this light, the designation LCIS rather than lobular neoplasia is preferred. These preliminary findings and historical information presented in this study fail to provide any reason to perform mastectomy on patients with LCIS.