Ductal Carcinoma In Situ of the Breast: The Van Nuys Experience by Treatment

Abstract: Ductal carcinoma in situ (DCIS) represents a broad biologic spectrum of disease with a wide range of treatment approaches. A lack of clear and universally accepted treatment criteria has resulted in a diverse range of confusing clinical recommendations, distressing to both patients and clinicians. Data is presented on 543 patients treated at The Breast Center in Van Nuys, California: 228 by mastectomy, 185 by excision plus radiation therapy, and 130 by excision alone. The local recurrence-free survival at 5 years was 98% for mastectomy patients, 87% for those who received excision plus radiation therapy, and 79% for those treated with excision alone. The difference between each of the recurrence-free survival curves was statistically significant. Margin width was an important predictor of which breast preservation patients were most likely to benefit from postexcisional radiation therapy. There was no benefit from the addition of radiation therapy for patients with margin widths of 10 mm in every direction. The benefit was intermediate for patients with margin widths of 1–9 mm. Patients with margin widths less than 1 mm received the most benefit from postoperative radiation therapy. Radiation therapy is not without side effects and it should not be routinely added to every breast preservation patient's therapeutic plan. Careful consideration must be given to its risks versus its potential benefits. Numerous prognostic factors, such as nuclear grade, the presence of comedo-type necrosis, tumor size, and margin width can all be used to aid in the treatment decision-making process.     

The Results of Conservative Surgery and Radiation for Mammographically Detected Ductal Carcinoma In Situ

Abstract: Approximately 85% of all ductal carcinoma in situ (DCIS) are now detected by mammographic screening. For the most part, the literature that reported the results of conservative surgery and radiation for DCIS reflected outcomes in a heterogeneous patient population that frequently included patients with clinically evident DCIS (palpable mass or bloody nipple discharge). There are limited data regarding outcome in patients with mammographically detected DCIS treated with conservative surgery and radiation. The 10-year breast recurrence rate ranges from 4% to 7% for patients with negative margins of resection with a 10-year cause-specific survival of 96–100%. Factors that have been associated with an increased risk of breast recurrence include the failure to remove all malignant appearing calcifications prior to radiation and positive margins of resection. The influence of young age and positive family history on breast recurrence rates requires further study. To date there has been little correlation with the pathologic features of DCIS (architectural pattern, necrosis, nuclear grade) and breast recurrence rates in patients receiving radiation. Comedo or high nuclear grade DCIS tends to recur at a shorter median interval than noncomedo or low nuclear grade DCIS. Approximately 50% of the recurrences are invasive and salvage mastectomy has resulted in long-term control in 100% of the noninvasive recurrences and approximately 80% of the invasive recurrences.     

Breast-conserving therapy for ductal carcinoma in situ: a 20-year experience with excision plus radiation therapy

BACKGROUND: Breast conservation therapy is a practical alternative to mastectomy for the treatment of ductal carcinoma in situ (DCIS). The role of radiation therapy after excision for DCIS has been debated, however, its value in reducing recurrence has been proven by multiple prospective randomized trials and is well accepted. METHODS: We examined a prospective database of 260 patients treated for DCIS with excision and radiation from 1979 to 2002. Two different treatment regimens were examined for local recurrence-free survival. Patients treated with radiation therapy 4 days per week were compared with patients treated 5 days per week. The total doses were similar for both groups; boost types differed. Local recurrence as a function of other factors, including nuclear grade, comedonecrosis, and margin width was evaluated. RESULTS: The median time to local recurrence was 61 months for patients treated 4 days per week compared with 52 months for patients treated 5 days per week (P = not significant). There was no statistical difference in the Kaplan-Meier detailing the probability of local recurrence-free survival for patients treated 4 days per week versus patients treated 5 days per week. Overall, cosmetic results between the two groups were equivalent. CONCLUSIONS: The comparison of two different radiation treatment regimens shows no difference in local disease-free survival or cosmetic result.     

The University of Southern California/Van Nuys prognostic index for ductal carcinoma in situ of the breast

BACKGROUND: The original Van Nuys prognostic index (VNPI) was introduced in 1996 as an aid to the complex treatment decision-making process for patients with ductal carcinoma in situ (DCIS) of the breast. This update adds patient age to the previous predictors of local recurrence in breast preservation patients. METHODS: A prospective database consisting of 706 conservatively patients with DCIS was examined using multivariate analysis. Four independent predictors of local recurrence (tumor size, margin width, pathologic classification, and age) were used to derive a new formula for the University of Southern California (USC)/VNPI. RESULTS: In all, 706 patients with pure DCIS were treated with breast preservation. There was no statistical difference in the 12-year local recurrence-free survival in patients with USC/VNPI scores of 4, 5, or 6, regardless of whether or not radiation therapy was used (P = not significant). Patients with USC/VNPI scores of 7, 8, or 9 received a statistically significant average 12% to 15% local recurrence-free survival benefit when treated with radiation therapy (P = 0.03). Patients with scores of 10, 11, or 12, although showing the greatest absolute benefit from radiation therapy, experienced local recurrence rates of almost 50% at 5 years. CONCLUSIONS: Ductal carcinoma in situ patients with USC/VNPI scores of 4, 5 or 6 can be considered for treatment with excision only. Patients with intermediate scores (7, 8, or 9) should be considered for treatment with radiation therapy or be reexcised if margin width is less than 10 mm and cosmetically feasible. Patients with USC/VNPI scores of 10, 11, or 12 exhibit extremely high local recurrence rates, regardless of irradiation, and should be considered for mastectomy, generally with immediate reconstruction or reexcision if technically possible.     

Treatment Selection for Patients with Ductal Carcinoma In Situ (DCIS) of the Breast Using the University of Southern California/Van Nuys (USC/VNPI) Prognostic Index

The University of Southern California/Van Nuys Prognostic Index (USC/VNPI) is an algorithm that quantifies five measurable prognostic factors known to be important in predicting local recurrence in conservatively treated patients with ductal carcinoma in situ (DCIS) (tumor size, margin width, nuclear grade, age, and comedonecrosis). With five times as many patients since originally developed, sufficient numbers now exist for analysis by individual scores rather than groups of scores. To achieve a local recurrence rate of less than 20% at 12 years, these data support excision alone for all patients scoring 4, 5, or 6 and patients who score 7 but have margin widths ≥3 mm. Excision plus RT achieves the less than 20% local recurrence threshold at 12 years for patients who score 7 and have margins <3 mm, patients who score 8 and have margins ≥3 mm, and for patients who score 9 and have margins ≥5 mm. Mastectomy is required for patients who score 8 and have margins <3 mm, who score 9 and have margins <5 mm and for all patients who score 10, 11, or 12 to keep the local recurrence rate less than 20% at 12 years. DCIS is a highly favorable disease. There is no difference in mortality rate regardless of which treatment is chosen. The USC/VNPI is a numeric tool that can be used to aid the treatment decision‐making process.     

Defining negative margins in DCIS patients treated with breast conservation therapy: The University of Chicago experience

Management of ductal carcinoma in situ (DCIS) has been evolving and the majority of women are now being treated with breast-conserving surgery and radiation therapy (i.e. breast conservation therapy [BCT]). Controversies still exist regarding the histologic features and margin status that are associated with local recurrence. The goal of this study was to review our institution's experience in patients diagnosed with DCIS and treated with BCT to determine pathologic features that can predict local recurrence, with particular emphasis on the final surgical margin status. We analyzed 103 consecutive patients with DCIS who were treated with BCT between 1986 and 2000. The slides were reviewed to determine the final margin status, type of DCIS, size of DCIS, nuclear grade, presence of necrosis and calcification, and volume of excised specimen. Margins were considered positive when DCIS touched or was transected at an inked margin. Negative margins were further categorized as close (less than 1 mm), 1--5 mm, and more than 5 mm. The size of the DCIS was determined based on either the maximal dimension on a slide or from the number of consecutive slides containing DCIS. Morphology and immunohistochemical profiles of the recurrent DCIS cases were compared with original DCIS. All patients were treated uniformly with external beam radiation therapy to the entire breast (median dose 46 Gy) with a boost to the tumor bed (median dose 14 Gy). The median follow-up was 63 months (range 7--191 months). The actuarial 5-year local control rate was 89%. The median time to local recurrence was 55 months. There were 13 local recurrences, of which 9 recurred as pure DCIS and 4 as invasive ductal carcinomas. Univariate analysis showed a significant association with local recurrence for positive margin (p=0.008), high nuclear grade (p=0.02), and young age at diagnosis (p=0.03). If margins were negative, the 5-year local control was 93%, as compared to 69% if margins were positive. A multivariate analysis showed that early age at diagnosis, positive margin status, and high nuclear grade were independently associated with local recurrence. The morphology and immunohistochemical stains of all nine recurrent DCIS were similar to those of the original DCIS. Breast conservation can be achieved with excellent local control by obtaining microscopically negative margins as strictly defined by DCIS not touching the inked surgical margins, and postoperative radiation that includes boost therapy to the tumor bed.     

Breast cancer-specific mortality after invasive local recurrence in patients with ductal carcinoma-in-situ of the breast

BACKGROUND: Previous studies on the efficacy of primary treatments for ductal carcinoma-in-situ (DCIS) have focused on local recurrence rates. Our objective was to detail the outcomes of local invasive recurrence, distant recurrence, and breast cancer mortality in patients previously treated for DCIS. METHODS: Clinical, pathologic, and outcome data were collected prospectively for 1236 patients with pure DCIS accrued from 1972 through 2005. RESULTS: There were 150 recurrences (87 DCIS and 63 invasive). Invasive local recurrence after mastectomy was rare (0.5% of patients) and after breast preservation was more frequent (12.0% of patients). The 12-year probabilities of breast cancer-specific mortality after mastectomy and after breast preservation were 0.8% and 1.0%, respectively. The 12-year breast cancer-specific mortality and distant disease probability for the 63 patients with invasive recurrences were 12% and 15%, respectively. CONCLUSIONS: Regardless of initial treatment, most patients with invasive local recurrence after treatment for DCIS can be treated and cured.     

Cytologic evaluation of lumpectomy margins in patients with ductal carcinoma in situ: Clinical outcome

Backround: Breast conservation therapy is controversial for ductal carcinoma in situ (DCIS) due to recently reported high recurrence rates. We believe that cytologic evaluation of lumpectomy margins improves efficiency and leads to a lower recurrence rate following lumpectomy for DCIS. Methods: A prospectively accrued database of 1255 breast cancer patients at the H. Lee Moffitt Cancer Center and Research Institute was found to have 218 patients with DCIS (17.4%). Of those 218 cases, 114 were treated with lumpectomy, axillary dissection, and radiation therapy; the remaining 104 patients were treated with mastectomy with or without reconstruction. Imprint cytology was used to evaluate all lumpectomy margins. Permanent sections and imprint cytology were reviewed by the same pathologist. Results: All lumpectomy specimens (116 tumors in 114 patients) were evaluated. The median follow up was 57.5 months (range 2–110 months). One hundred and three patients with 104 tumors were selected on the basis of pure DCIS (with or without microinvasion), and treated with lumpectomy, axillary dissection and radiation therapy. Of the 104 tumors utilizing attempted breast conservation therapy, 7 (6.6%) required mastectomy. There were 6 recurrences (6.1%) with a median time for recurrence of 47.5 months (range 27–85 months); four recurrences were comedo and two were noncomedo at original diagnosis. Conclusions: The determination of lumpectomy margins in DCIS patients using imprint cytology leads to an overall recurrence rate of 6.1% with reduction in operative time, and re-excision rate. Significant recurrence rates were associated with microinvasion and multifocal tumors (28%) versus simple DCIS at 5 years. Breast conservation therapy and surgical margin determination with imprint cytology for DCIS is a cost-effective and reliable method of treatment for simple DCIS.     

Local control in ductal carcinoma in situ treated by excision alone: incremental benefit of larger margins

BACKGROUND: Margin width has been shown previously to be the most important predictor of local treatment failure after breast conservation for ductal carcinoma in situ (DCIS). METHODS: Five variables thought to be associated with local recurrence were evaluated by univariate and multivariate analysis in 455 nonrandomized patients with DCIS treated with excision alone. RESULTS: Multivariate analysis showed that margin width, age, nuclear grade, and tumor size all were independent predictors of local recurrence, with margin width as the single most important predictor. After adjusting for all other predictors the likelihood of local recurrence for patients with margins less than 10 mm was 5.39 times as much as that for patients with margins of 10 mm or more (95% confidence interval, 2.68-10.64). CONCLUSIONS: Margin width, the distance between DCIS and the closest inked margin, was the single most important predictor of local recurrence. As margin width increases, the risk for local recurrence decreases.     

Margin width as the sole determinant of local recurrence after breast conservation in patients with ductal carcinoma in situ of the breast

BACKGROUND: A previous study showed a 3% local recurrence risk at 8 years in ductal carcinoma in situ (DCIS) patients treated with excision alone with surgical margins of 10 mm or greater. This study updates those data. METHODS: A total of 272 DCIS patients treated conservatively with 10 mm or greater margins were reviewed in a prospective database. RESULTS: Among 212 excision-alone patients, there were 9 DCIS and 3 invasive recurrences. The 12-year probability of any local recurrence was 13.9%; of invasive recurrence it was 3.4%. Among 60 excision plus radiation patients, there was 1 local (invasive) recurrence (P = .06). The 12-year probability of local recurrence was 2.5%. CONCLUSIONS: Local recurrence in DCIS patients treated with excision alone with margins of 10 mm or greater compares favorably with local recurrence in DCIS patients with nontransected margins and treated with postoperative radiation. The risk of invasive recurrence among widely excised DCIS patients is extremely low.     

The role of clinical trials in changing therapy for ductal carcinoma in situ

Some aspects of the diagnosis of ductal carcinoma in situ (DCIS) are well established, but consideration of other variables may be critical to optimize treatment. Mastectomy was once standard surgery, to reduce the probability of invasive breast carcinoma recurrence (to <1%). However, the ability to control DCIS to a comparable extent but without resorting to mastectomy has been major goal. There are indications from clinical studies that excision plus radiation therapy is as effective as mastectomy in reducing recurrence in patients with low-risk DCIS. Furthermore, following surgery and irradiation with long-term endocrine therapy appears to further reduce the risk of local DCIS progression. Variables that should be considered in making a treatment decision are extent of disease within the breast, nuclear grade of the lesion, age of the patient, and margin of surgical excision. Several randomized trials are currently evaluating the clinical value of these variables in optimizing treatment for patients with low-risk DCIS. Future improvements in treatment may depend on more sophisticated cellular and molecular markers of disease extent and prognosis at diagnosis.     

DCIS Treated with Excision Alone Using the National Comprehensive Cancer Network (NCCN) Guidelines

Background

In 2008, the NCCN published guidelines allowing low-risk DCIS patients to be treated by excision alone. The goal of this study was to determine local and distant recurrence and breast-cancer specific survival in patients with DCIS that meet NCCN criteria and are treated with excision alone.

Methods

A prospective, single institution database was analyzed for patients with the following: pure ductal carcinoma in situ (no microinvasion), tumor extent 20 mm or less, age ≥50 years, margin width ≥2 mm, and nuclear grade 1 or 2 (non-high grade). Patients were treated with excision alone. Kaplan-Meier analysis was used to determine recurrence and survival rates.

Results

A total of 205 patients were treated with excision alone. The median age was 59 years. The median time of follow-up was 51 months. The median extent of disease was 8 mm. There were a total of nine local recurrences. The 6-year probability of local recurrence was 6.6  %. The 12-year probability of local recurrence was 7.8  %. The 12-year breast cancer-specific survival probability was 100  %.

Conclusions

The 12-year local recurrence rate for DCIS patients in NSABP Protocol B-17 treated with excision alone was 32 %, and for excision plus radiation therapy, it was 16 %. In this study, retrospectively applying the NCCN Guidelines to our patients, the 12-year local recurrence rate for excision alone was 7.8 %. Patients with a low risk of local recurrence, if treated by excision alone, can be safely selected using the NCCN Guidelines.     

Prognostic Factors and Local Recurrence in Patients with Ductal Carcinoma In Situ of the Breast

Abstract: Local recurrence is an important event when it occurs in a patient previously treated for ductal carcinoma in situ. Therefore, the ability to predict the probability of local recurrence after breast preservation therapy would be extremely valuable in the treatment decision-making process. In an attempt to predict the likelihood of local recurrence, 30 prognostic factors were evaluated in 622 patients with ductal carcinoma in situ treated at the Van Nuys Breast Center from 1979 through June 1996. Four factors emerged as significant independent predictors of local recurrence. These included treatment, tumor size, margin width, and pathologic classification.     

The current treatment of ductal carcinoma in situ

A consensus conference was held in April, 1999, to help sift through the maze of controversy surrounding the treatment of mammographically detected ductal carcinoma in situ (DCIS). Members of the panel included approximately 30 DCIS experts, who addressed issues relating diagnosis, treatment, treatment of breast (and axilla), adjuvant theraphy, among others. The panel agreed that the goal of treatment for DCIS is breast conservation and attempted to divide the population of patients with DCIS into subsets who are appropriately treated by mastectomy, radiation theraphy, or by excision alone. Major criteria for breast conservation include small size of area of DCIS, clear surgical margins, and favorable biology. Neither axilliary dissection nor sentinel node biopsy is appropriate for DCIS treated by breast conservation. The role of tamoxifen is currently under study, and although approved by the FDA for "risk reduction," its use in patients with DCIS is uncertain.     

Intraductal carcinoma of the breast: pathologic features associated with local recurrence in patients treated with breast-conserving therapy

Local excision and radiation therapy is a standard treatment option for duct carcinoma in situ (DCIS) of the breast. There is no consensus regarding the significant histologic features associated with recurrence. The authors studied a large group of patients with mammographically detected DCIS treated with breast-conserving therapy to explore DCIS volume relationships, DCIS features, specimen characteristics, and the effect of patient age at diagnosis. Thirteen patients (10%) developed a recurrent carcinoma in the ipsilateral breast, resulting in 5- and 10-year actuarial recurrence rates of 8.9% and 10.3%, respectively. Local recurrences were identified as a true recurrence/marginal miss (TR/MM) in nine patients, and elsewhere in the breast in four patients. The notable features associated with TR/MM recurrences on univariate analysis included patient age less than 45 years old, six or more slides with DCIS, no microscopic calcifications within DCIS ducts, and five or more DCIS ducts or terminal duct lobular units (TDLUs) with cancerization of lobules (COL) within 0.42 cm of the final surgical margin. DCIS tumor size, nuclear grade, amount of central necrosis, and margin status were not associated with outcome. Multivariate analysis found that the absence of microcalcifications within DCIS ducts, patient age, number of slides with DCIS or TDLUs with COL, and the number of DCIS ducts or TDLUs with COL within 0.42 cm of the final margin were related significantly to TR/MM recurrence. Patients with a total of six or more slides with DCIS, or who have 11 or more DCIS ducts or TDLUs with COL near the final margin are at increased risk of having a substantial volume of residual DCIS in the adjacent unexcised breast. These results suggest that the volume of DCIS in the specimen, and the volume of DCIS near the margin are associated with local recurrence. These features can be used to identify those patients with a higher chance of local recurrence.     

Ductal carcinoma in situ of the breast: impact of pathology on therapeutic decisions

The therapy of ductal carcinoma in situ (DCIS) is controversial but is being increasingly decided by pathologic evidence. Studies of the natural history of DCIS demonstrate that DCIS is very heterogeneous in its clinical behavior. As detailed in several reviews, studies that followed patients after biopsy alone indicate a great difference between the small noncomedo examples of DCIS and the larger comedo DCIS lesions. The currently available evidence from cases that have been treated by planned surgical excision without radiation therapy would indicate that noncomedo examples of DCIS have a low incidence of recurrence and may be adequately treated by this technique. In contrast, comedo DCIS lesions have a high propensity for recurrence despite excision and radiotherapy. This presentation will review the histopathology of DCIS and highlight the idea that we are currently in a state of transition in our understanding of DCIS. Studies supporting the stratification of DCIS by histologic pattern plus cytology and size will be contrasted with the rapidly disappearing classic posture that all DCIS is biologically similar and treatment options need not be stratified by the different subtypes or varieties of DCIS.     

Ductal carcinoma in situ: USC/Van Nuys Prognostic Index and the impact of margin status

As our knowledge of ductal carcinoma in situ (DCIS) continues to evolve, treatment decision-making has become increasingly complex and controversial for both patients and physicians. Treatment options include mastectomy, and breast conservation with or without radiation therapy. Data produced from the randomized clinical trials for DCIS has provided the basis for important treatment recommendations, but are not without limitations. In this article, we review our prospectively collected database consisting of 1036 patients with DCIS treated at the Van Nuys Breast Center and the USC/Norris Comprehensive Cancer Center. We review the use of the USC/Van Nuys Prognostic Index, a clinical algorithm designed to assist physicians in selection of appropriate treatments, and examine the impact of margin status as a sole predictor of local recurrence.     

Not everyone with ductal carcinoma in situ of the breast treated with breast preservation needs post-excisional radiation therapy

While the results of NSABP protocol B-17 and EORTC protocol 10853 prove that radiation therapy decreases the overall rate of local recurrence in patients with DCIS, there are clearly subgroups of patients who do not benefit from radiation therapy or whose benefit is so small that the addition of radiation therapy to their treatment regimen is simply not worthwhile. Identifying these subgroups is of paramount importance. Factors like tumour size, margin width, nuclear grade, and the presence or absence of comedonecrosis can be used to define favorable subgroups that do not require post-excisional radiation therapy. The most recent results of NSABP protocol B-17 and EORTC protocol 10853 confirm that, regardless of treatment, there is no difference in the single most important end-point: survival. If there is no difference in breast cancer mortality, it is clearly worthwhile to try to define the subgroups of patients who can be spared the time, costs, and side-effects of a treatment that they do not need.     

Duct carcinoma in situ: A personal perspective

In the recent past, DCIS was a rare diagnosis established by biopsy of palpable breast masses or nipple changes. Mammography increased the frequency of a DCIS diagnosis by 20 × resulting in a tsunami of small circa 10 mm lesions detected only by mammography. The impact of pathologic technique in examining and characterizing such lesions is reviewed, and the development of algorithms incorporating prognostic factors and histology based on serial sequential processing techniques are described and contrasted with those which relied on tissue sampling. The development of the initial clinical trails of irradiation all demonstrated the significant benefit of irradiation but none could identify subsets with a more favorable outcome. The latter was precluded by their common practice of tissue sampling: Size could not be calculated and margin width and microinvasion could not be reliable demonstrated. Multigene signature assays are increasingly being utilized, most prominently Oncotype DCIS. However, these assays must be interpreted in conjunction with the limitations set forth in the validating studies—in the case of Oncotype DCIS—the size, margin width, and grade which defined the baseline study (E5194). Tamoxifen and other anti‐hormonal agents (aromatase inhibitor therapy) have been shown to have a limited impact on ipsilateral recurrence which makes their use given their morbidities problematic. Such interventions do impact the frequency of contralateral occult in situ and invasive lesions. In the one study which permitted a comparison of local recurrence in irradiated vs nonirradiated breast, there was no added benefit of Tamoxifen in irradiated breasts. Some are attempting to identify a low‐risk subset of DCIS which can be treated without surgical re‐excision for margins or adjuvant irradiation. These studies are in progress but surrogates identified within the Van Nuys prospective series defined by grade and inadequate margins (≤ 1 mm) would suggest a significant recurrence and progression rate. DCIS remains a work in progress both in terms of classification and treatment. However, limited our progress in these areas we have certainly advanced from the oft‐proclaimed mantra: “Radiation and Tamoxifen are standard of care.”     

Long-term results of conservative surgery and radiotherapy for ductal carcinoma in situ using lung density correction: the University of Michigan experience

The purpose of the study was to review the treatment outcomes of 198 patients treated with breast-conserving surgery (BCS) and whole breast radiation therapy using lung density correction for ductal carcinoma in situ (DCIS). Between April 1985 and December 2002, 198 patients with 200 lesions diagnosed as DCIS (AJCC stage 0) were treated at the University of Michigan. All underwent BCS and whole breast radiotherapy. Median total follow-up was 6.2 years (range: 0.8-18.2). The 5- and 10-year cumulative rates of in-breast only failure were 5.9% (95% CI: 2.6-9.3%) and 9.8% (95% CI: 5.2-14.4%), respectively. Factors that significantly predicted for an increased risk of local failure were family history of breast cancer, positive or close surgical margins and age 相似文献