Therapy For Ductal Carcinoma In Situ Research Articles

Racial and Ethnic Disparities in Outcomes After Breast-Conserving Therapy and Endocrine Therapy for DCIS: A Post-Hoc Analysis of the NSABP B-35 Randomized Clinical Trial.

Racial and ethnic disparities in outcomes after treatment for ductal carcinoma in situ (DCIS) are largely unknown. The objective of this study was to examine breast cancer outcomes by race and ethnicity in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-35 clinical trial. The NSABP B-35 trial randomized postmenopausal women with hormone receptor-positive DCIS treated with breast-conserving therapy to 5 years of tamoxifen or anastrozole. In total, 3104 women were enrolled between 2003 and 2006. For this analysis, patients without complete self-reported race and ethnicity or with immediate trial dropout were excluded. Kaplan-Meier curves and adjusted Cox-proportional hazards models were used for analyses. Of the 3061 women included, 2614 (85.4%) were non-Hispanic white (NHW), 255 (8.3%) were non-Hispanic Black (NHB), 95 (3.1%) were Hispanic, and 96 (3.1%) were Asian or Pacific Islander (API). Endocrine therapy assignment and duration were well balanced between racial and ethnic groups. Median follow-up was 9 years; unadjusted Kaplan-Meier curves did not show any racial differences in disease events. Adjusted Cox-proportional hazards models found API (versus NHW) race to be associated with higher local recurrence [hazard ratio (HzR) 2.45, p = 0.035] and NHB race to be associated with higher distant recurrence (HzR 5.03, p = 0.020) and breast cancer mortality (HzR 3.83, p = 0.046). Despite similar locoregional treatments and standard endocrine therapy in a clinical trial population, racial and ethnic disparities exist in long-term outcomes for hormone-receptor-positive DCIS. These findings suggest that factors outside of access and treatment may impact DCIS outcomes by race and ethnicity.

Can Molecular Biomarkers Help Reduce the Overtreatment of DCIS?

Ductal carcinoma in situ (DCIS), especially in the era of mammographic screening, is a commonly diagnosed breast tumor. Despite the low breast cancer mortality risk, management with breast conserving surgery (BCS) and radiotherapy (RT) is the prevailing treatment approach in order to reduce the risk of local recurrence (LR), including invasive LR, which carries a subsequent risk of breast cancer mortality. However, reliable and accurate individual risk prediction remains elusive and RT continues to be standardly recommended for most women with DCIS. Three molecular biomarkers have been studied to better estimate LR risk after BCS-Oncotype DX DCIS score, DCISionRT Decision Score and its associated Residual Risk subtypes, and Oncotype 21-gene Recurrence Score. All these molecular biomarkers represent important efforts towards improving predicted risk of LR after BCS. To prove clinical utility, these biomarkers require careful predictive modeling with calibration and external validation, and evidence of benefit to patients; on this front, further research is needed. Most trials do not incorporate molecular biomarkers in evaluating de-escalation of therapy for DCIS; however, one-the Prospective Evaluation of Breast-Conserving Surgery Alone in Low-Risk DCIS (ELISA) trial-incorporates the Oncotype DX DCIS score in defining a low-risk population and is an important next step in this line of research.

Abstract P6-16-06: Improved early stratification of invasive cancer risk using MRI in a ductal carcinoma in-situ short-term active surveillance cohort treated with neoadjuvant endocrine therapy

Abstract Purpose Standard treatment for ductal carcinoma in situ (DCIS) involves surgical excision and radiation treatment, and often adjuvant endocrine therapy (ET). However, this may constitute overtreatment for some women. The purpose of this neoadjuvant ET study in patients with biopsy-proven DCIS was to evaluate the relationship between the primary outcome of upstaging at surgery (invasive disease) and changes in the pre- and post-ET MRI appearances of both (1) lesion and (2) background parenchymal enhancement (BPE), with the goal to better inform de-escalated therapy. Methods Outcomes of patients with DCIS who were prospectively enrolled in a neoadjuvant ET trial between 2002 and 2009 were retrospectively analyzed with IRB approval. All patients had dynamic contrast-enhanced breast MRI prior to and following an average of 3.1 months of ET (range 1.9 – 5 months), followed by surgical excision within one year of the second MRI. Pathology reports were used to confirm initial biopsy results and to determine the nature and extent of disease postoperatively. Surgeon and radiologist’s reports were used to assess improvement of lesion after ET based on 1) less prominently enhancing pattern or 2) reduction in size of DCIS lesion after treatment. BPE response to ET on imaging was assessed by two radiologists specialized in breast imaging who compared pre- and post-ET MRI’s, blinded to all imaging reports. The change in BPE of the ipsilateral breast with treatment was scored subjectively as increased, decreased, or unchanged. Readers reached a consensus on discordant classifications of the change in BPE. The correlation between imaging change (of lesion and BPE) and incidence of invasive ductal carcinoma (IDC) at surgery was determined using Fisher’s exact test. Results: Of 34 patients evaluated, six (18%) had IDC at surgery. The prevalence of IDC in each group is shown in Table 2. Those with improvement of lesion on MRI had a lower likelihood of IDC at surgery compared to patients with no imaging improvement (Table 2, p= 0.048). Addition of change in BPE to the evaluation of lesion improvement significantly increased the chance of identifying specific patients who were much more likely to have an underlying invasive cancer at surgery (Table 2, p= 0.032). The risk of having IDC at surgery was considerably higher in the group whose lesion was assessed as not improved and who had decreased BPE scores on MRI (Table 2, p= 0.018). Conclusion: In our unique population of patients with mostly ER+ DCIS receiving pre-operative endocrine therapy, the combination of lack of lesion improvement and reduction in BPE score in blinded reads was significantly associated with the finding of invasive disease at surgical excision. This result may reflect the unmasking of a more aggressive lesion in those with underlying IDC and help identify patients with a higher likelihood of the presence of IDC at surgery. Although this study is small, it suggests that risk-stratifying patients with DCIS based on lesion and parenchymal imaging features associated with treatment response may aid in tailoring therapy for DCIS. We are testing this prospectively in an active surveillance cohort. Table 1. Incidence of IDC at surgery depending on image features (n= 34)Improvement of lesion in MRINo Improvement of lesion in MRIP-value (Fisher’s Exact Test)& No Reduction in BPE& Reduction in BPE& No Reduction in BPE& Reduction in BPEIncidence of IDC at surgery (n)0204Incidence of Not IDC at surgery (n)121024%IDC at surgery when assessing lesion only (%)9.1%40%0.048*%IDC at surgery when assessing lesion AND BPE (%)0%16.7%0%50%0.032*%IDC at surgery when assessing lesion AND BPE (%)8.3%50%0.018* Citation Format: Paul Kim, Heather I. Greenwood, Rita I. Freimanis, Gillian L Hirst, Megan Fischer-Colbrie, Jessica Gibbs, Nola M Hylton, Christina Yau, Eun-Sil Shelley Hwang, Laura J. Esserman, Rita A Mukhtar. Improved early stratification of invasive cancer risk using MRI in a ductal carcinoma in-situ short-term active surveillance cohort treated with neoadjuvant endocrine therapy [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 P6-16-06.

Long-term outcomes of breast-conserving therapy for women with ductal carcinoma in situ.

Improved imaging, surgical techniques, and pathologic evaluation likely have decreased local recurrence rates for patients with ductal carcinoma in situ (DCIS). We present long-term outcomes of a large single-institution series after breast-conserving surgery (BCS) and adjuvant radiation therapy (RT). We retrospectively reviewed the records of 245 women treated for DCIS with BCS and RT between 2001 and 2007. Competing risk analysis was used to calculate local recurrence (LR) as a first event with the development of a second non-breast malignancy, contralateral breast cancer, and death as competing first events. At a median follow-up of 10.6years, 4 patients had a LR (2 DCIS, 2 invasive) as a first event with a cumulative LR incidence of 0.0% and 1.5% at 5 and 10years, respectively. Most patients had > 2mm margins (90%), specimen radiographs (93%), and received a tumor bed boost (99%). The majority (60%) of patients with hormone receptor-positive disease received adjuvant endocrine therapy. Ten-year cumulative incidence of contralateral breast cancer (CBC) was 7.9%, second non-breast malignancy was 4.5%, and death unrelated to breast cancer was 3.5%. Family history, age at diagnosis, and receipt of endocrine therapy were not significantly associated with the development of CBC (all P > 0.05). With mature follow-up, our rates of local recurrence following breast-conserving therapy for DCIS remain very low (1.5% at 10years). The incidence of CBC was higher than the LR incidence. Predisposing factors for the development of CBC are worthy of investigation.

Endocrine Therapy for Ductal Carcinoma In Situ (DCIS) of the Breast with Breast Conserving Surgery (BCS) and Radiotherapy (RT): a Meta-Analysis.

The management of ductal carcinoma in situ (DCIS) with endocrine therapy remains controversial. A meta-analysis was conducted to evaluate the role of endocrine therapy for DCIS with breast conserving surgery (BCS) and radiotherapy (RT). A total of 7 articles with randomized controlled trials were included. Five articles compared the effects of BCS and RT followed by tamoxifen (TAM) or not (BCS + RT + TAM vs BCS + RT) and 2 compared the effects of TAM and anastrozole (ANA). TAM obviously reduced the rates of recurrence of ipsilateral breast cancer (IBCR), recurrence of contralateral breast cancer (CBCR), recurrence of ipsilateral invasive breast cancer (IBCR-INV) and recurrence of contralateral DCIS (CBCR-DCIS), and increased the rate of event-free survival (EFS). While ANA reduced the rates of CBCR and recurrence of contralateral invasive breast cancer (CBCR-INV). Patients with ANA had higher incidence of arthralgia, osteoporosis, hypercholesteremia, headache and vaginal dryness, but lower incidence of deep-vein thrombosis, pulmonary embolism, vasomotor or gynaecological, hot flushes, vaginal haemorrhage, vaginal discharge and vaginal candidiasis than TAM. In conclusion, DCIS patients with positive hormone receptors should be recommended to receive endocrine therapy. Selection of TAM or ANA is based on clinical characteristics and underlying disease of patients, as well as the side-effects of drugs.

Abstract P4-15-01: Integration of clinical and pathological data with the DCIS score to predict the risk of local recurrence

Abstract Background: Prediction of local recurrence (LR) risk after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) is needed to guide decisions regarding risks and benefits of adjuvant radiotherapy (RT). We aim to determine the optimal combination of clinical and pathological characteristics with the Oncotype DCIS Score (DS) to predict individualized 10 year risks of local recurrence (LR) after BCS (with or without RT) for DCIS and develop a web-based nomogram / risk calculator. Methods: DS (continuous, categorical risk groups low/intermediate/high) and complete clinico-pathological data (age, tumor size, nuclear grade, comedonecrosis, multifocality, margin width and receipt of breast RT) are available for 1102 cases from the Ontario population cohort of pure DCIS treated by BCS (981 cases with negative margins, 121 cases with positive margins). We examined various categorizations of discrete variables, and transformations of continuous variables, and used model selection procedures to determine the best fitting Cox proportional hazards regression model of LR according to the c-statistic, Akaike Information Criterion, and log-likelihood. We tested all two-way interactions and interactions with time. The 10-year probability of LR was calculated for each woman using the estimate of the baseline survival function and the estimate of the linear predictor, which is a function of the regression parameter estimates and specific covariate values. Model calibration will be explored by comparing observed versus predicted risk of LR, and the model's discriminative ability will be assessed by the concordance index. Model validation will be conducted via bootstrapping approaches. Results: In the best fitting main effects full model, the adjusted hazard ratios (HR) (95% confidence intervals (CI)) for LR included: intermediate/ high risk DS vs. low risk (HR =1.96 (1.39, 2.74)), age < 50 years at diagnosis vs. age>= 50 (HR = 1.62 (1.16, 2.25)), square root of tumor size (HR/mm = 1.24 (1.11, 1.38)), comedonecrosis > 30% vs. <=30% (HR=1.53 (1.08, 2.16)), multifocality ( HR=2.01 (1.45, 2.77)), and receipt of RT ( HR=0.50 (0.37, 0.68)). There was a significant interaction between tumor size and DS but not between DS and RT. Among women with a low risk DS and age >= 50, tumor size <= 10 mm, <= 30% comedo necrosis, no multifocality, low or moderate nuclear grade and negative margins, the average predicted 10 year LR risk = 6.8% (range 6.4% - 7.6%) after treatment by BCS without RT, and 3.6% (range 3.4% - 3.8%) after BCS+RT (an absolute benefit of 3.2% from RT). Among women with intermediate/high risk DS and the same low risk clinical-pathological features, the average predicted 10 year LR risk = 19.0% (range 18.3% - 20.0%) without RT, and 9.5% (range 9.1% - 10.3%) with RT (an absolute benefit of 9.5% from RT). Conclusion: This prediction model combines clinical and pathological features with the DS to improve estimates of local recurrence risk after BCS alone and the absolute benefit with RT, which can improve decision making in DCIS. After calibration and validation, it will be the basis of a web-based nomogram / risk calculator. It also demonstrates the importance of molecular testing for studies of the de-escalation of therapy for DCIS. Citation Format: Paszat L, Sutradhar R, Zhou L, Lalani N, Nofech-Mozes S, Rakovitch E. Integration of clinical and pathological data with the DCIS score to predict the risk of local recurrence [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-15-01.

Abstract P3-17-07: Improved long-term outcomes of breast-conserving therapy for women with ductal carcinoma in situ

Abstract Purpose: Improved mammographic and surgical techniques and pathologic evaluation, particularly greater attention to achieving negative margins, have resulted in decreased local recurrence rates for patients with ductal carcinoma in situ (DCIS). This is an updated analysis of local outcomes after breast-conserving surgery (BCS) and adjuvant radiation therapy (RT) at a single institution in the modern era. Methods and Materials: We retrospectively reviewed the records of 245 women treated for DCIS with BCS and RT between 2001 and 2007. Competing risk analysis was used to calculate local recurrence (LR) as a first event with the development of a second non-breast malignancy, contralateral breast cancer, and death as competing first events. The median age at diagnosis was 54 (range, 32-84) and 174 (93%) women had estrogen receptor (ER) and/or progesterone receptor (PR) positive disease. Ninety-five (39%) were grade III. Specimen radiograph during surgery was obtained for 223 women (91%) and post-operative mammogram for 102 (42%). Half underwent more than one excision. The institutional goal for margins during the study period was 3 mm or greater; final margins were >2 mm in 221 (90%). All received adjuvant radiation therapy to the whole breast (median whole breast dose: 4400; range, 4000 - 5220) and nearly all (99%) received a boost to the surgical cavity (median boost dose: 1600; range, 800 – 1800). Among patients with ER and/or PR+ disease, 105 (60%) received adjuvant hormonal therapy. Results: At a median follow-up of 10.6 years, 4 patients had a LR (2 DCIS, 2 invasive ductal carcinoma) as a first event with a cumulative LR incidence of 0.0% and 1.5% at 5 and 10 years, respectively. The 5 and 10-year cumulative incidence of the competing first events is seen in the table below. Twenty women developed a contralateral breast cancer (CBC; 8 DCIS, 12 invasive carcinoma), 13 were diagnosed with a second non-breast malignancy (3 endometrial, 2 fallopian tube, 1 gallbladder, 1 leukemia and thyroid, 4 lung, 1 ovarian, and 1 uterine), and 7 died. Family history, age at diagnosis, and receipt of hormonal therapy were not significantly associated with the development of CBC on univariable analysis (all p>0.05). Incidence of local recurrence and competing eventsEvent5-year cumulative incidence10-year cumulative incidenceLocal recurrence0.0%1.5%Contralateral Breast Cancer2.5%7.9%Second non-breast malignancy2.6%4.5%Death1.2%3.5% Conclusions: With longer follow-up, our rates of local recurrence following breast-conserving therapy for DCIS remain very low (1.5% at 10 years). The vast majority of patients had >2 mm margins, specimen radiographs, and received a tumor bed boost. The majority (60%) of patients with hormone receptor positive disease received adjuvant endocrine therapy. The 10-year incidence of CBC was higher than expected. Predisposing factors for the development of CBC are worthy of investigation. Citation Format: Warren LE, Chen Y-H, Halasz LM, Capuco A, Bellon JR, Brock JE, Punglia RS, Wong JS, Harris JR. Improved long-term outcomes of breast-conserving therapy for women with ductal carcinoma in situ [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-17-07.

Is Wide Excision Alone an Appropriate Therapy for DCIS?

With the widespread use of screening mammography, the number of ductal carcinoma in situ (DCIS) cases has increased dramatically. Current treatment includes wide local excision (WLE) and adjuvant radiation therapy (RT). The benefit of RT in decreasing local recurrence was established based on the results of four randomized trials and a subsequent meta-analysis. However, RT has a number of side effects and no demonstrated survival benefit in women with in situ breast cancer. This review explores the current literature on the management of DCIS with WLE alone. Although there is insufficient evidence to identify truly low-risk DCIS based on histopathological and immunohistochemical factors, emerging data appear promising in understanding the biological behavior of DCIS. In particular, the Oncotype DX DCIS Score, a multigene assay, predicts local recurrence in women treated with WLE. Risk stratification of DCIS to guide treatment decisions remains elusive, but one of great importance in tailoring therapies to the biology of this heterogeneous disease.

Abstract P6-09-06: Balancing the harms and benefits of radiation therapy for DCIS: A decision analysis examining the risk of radiation-associated sarcoma

Abstract INTRODUCTION: More than 60,000 women are diagnosed with ductal carcinoma in situ (DCIS) annually and offered the option of breast conserving surgery (BCS), often including radiation (RT) to reduce local recurrence. Although the incidence of radiation-associated sarcoma (RAS) is low (0.05-0.25% at 10 years), the low mortality associated with DCIS and large number of DCIS diagnoses means that an increasingly large number of women are at risk of RAS. This study sought to weigh the risk of RAS with the benefits of BCS+RT for DCIS. METHODS: A second-order Monte Carlo micro-simulation model of women ages 35 and older with DCIS was constructed. The decision analysis compared harm-benefit ratios of sarcoma-related deaths per breast cancer deaths averted within 20 years of treatment with BCS+RT versus BCS alone. Stratified analyses were performed by age group to account for differential life expectancy. To generate parameter estimates for model inputs, Bayesian network meta-analysis was used to synthesize rates of DCIS and invasive recurrence from clinical trials of BCS+RT and BCS alone using a Weibull specification. Sarcoma incidence was estimated non-parametrically using SEER. Constant hazard rates for breast cancer mortality after invasive recurrence and RAS mortality were estimated from clinical trials. To account for uncertainty, probabilistic sensitivity analysis was conducted using 10,000 Monte Carlo samples and 95% credible intervals (CrI) were constructed for event rates and harm-benefit ratios. RESULTS: The micro-simulation model of an age-distributed cohort demonstrated that 1 in 840 women with DCIS (95%CrI 1:648 to 1:3522) would develop RAS within 20 years after treatment with BCS+RT. Overall, there would be 1 RAS-related death for every 12 breast cancer deaths averted (95%CrI 1:7 to 1:19) by the addition of RT to BCS. Stratified analysis demonstrated that the harm-benefit ratio was higher in women <75 years of age, with more RAS-related deaths caused per breast cancer deaths averted. The model was most impacted by parameter estimates for rates of invasive recurrence, breast cancer mortality after invasive recurrence, and RAS incidence rates. CONCLUSIONS: The risk of developing a RAS following BCS+RT for DCIS should not be overlooked. This may be especially true for women at low risk of recurrence and younger women (<75 years in our model). These findings contribute to the ongoing conversation about consequences of overtreatment of DCIS, and should be incorporated into shared-decision making discussions regarding the optimal management of DCIS for a given patient. Age-Stratified Incremental Harm-Benefit Ratios for BCS+RT versus BCS AloneAge GroupRAS Deaths: Breast Cancer Deaths Averted* Posterior Median Ratio (95% CrI)Overall1:12 (1:7 to 1:19)35 to 541:10 (1:6 to 1:14 )55 to 741:11 (1:7 to 1:15)75+1:17 (1:9 to 1:24)*Probabilistic sensitivity analysis using 10,000 second-order parameter samples with a 20 year time horizon Citation Format: Marquita R Decker, Joseph F Levy, Lee G Wilke, David J Vanness, Heather B Neuman. Balancing the harms and benefits of radiation therapy for DCIS: A decision analysis examining the risk of radiation-associated sarcoma [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-09-06.

Higher tamoxifen use as chemoprophylaxis in patients with ductal carcinoma in situ (DCIS) in the last decade.

191 Background: The incidence of DCIS over the last two decades has increased, with over 62,000 new cases diagnosed annually in the United States. Tailored management of DCIS is still a work in progress and currently treatment options are varied. We sought to identify changes in patterns of care in individual and physician choices for surgery and chemoprophylaxis over the last two decades at our institution. Methods: We performed a retrospective chart review and identified 773 eligible patients using the James Cancer Registry and the NCCN database at The Ohio State University between 1990 and 2010. We compared the proportion of patients undergoing mastectomy vs breast conserving surgery (BCT), use of radiation and hormone therapy, and recurrence rates between the years 1990-2000 and 2001-2010 using Chi-square test. Results: There was no significant difference in race (p=0.21) or age (p=0.09) among patients diagnosed with DCIS between 1990-2000 (Group A, N=462) and 2001-2010 (Group B, N=311). There was no significant difference in mastectomy rates between the two groups (31% vs. 27%, p= 0.26). Patients less than 50 years old were more likely to undergo mastectomy in both groups (p=0.02). Use of radiation therapy following BCT was similar between the two groups (52% vs. 53%, p=0.76). Interestingly more patients received hormone therapy during 2001-2010 than 1990-2000 (48% vs. 26%, p < 0.0001). Patients undergoing mastectomy were less likely to receive radiation (2% vs. 74%, p<0.0001) and hormone therapy (25% vs. 39%, p<0.0001). There was no significant correlation between race and type of surgery. We are in the process of comparing recurrence rates between the two groups which will be reported. Conclusions: Previously published studies have reported higher rates of mastectomy among patients with early stage breast cancer in the recent years. Data from our institution over the last two decades did not corroborate this finding, although interestingly we have found increasing use of tamoxifen therapy for DCIS in the second decade. Understanding current practices is helpful in designing future studies for management of DCIS using novel prognostic assays such as Oncotype Dx assay.

Impact of Margin Status on Local Recurrence After Mastectomy for Ductal Carcinoma In Situ

To examine the rate of local recurrence according to the margin status for patients with pure ductal carcinoma in situ (DCIS) treated by mastectomy. One hundred forty-five consecutive women who underwent mastectomy with or without radiation therapy for DCIS from 1998 to 2005 were included in this retrospective analysis. Only patients with pure DCIS were eligible; patients with microinvasion were excluded. The primary endpoint was local recurrence, defined as recurrence on the chest wall; regional and distant recurrences were secondary endpoints. Outcomes were analyzed according to margin status (positive, close (≤2 mm), or negative), location of the closest margin (superficial, deep, or both), nuclear grade, necrosis, receptor status, type of mastectomy, and receipt of hormonal therapy. The primary cohort consisted of 142 patients who did not receive postmastectomy radiation therapy (PMRT). For those patients, the median follow-up time was 7.6 years (range, 0.6-13.0 years). Twenty-one patients (15%) had a positive margin, and 23 patients (16%) had a close (≤2 mm) margin. The deep margin was close in 14 patients and positive in 6 patients. The superficial margin was close in 13 patients and positive in 19 patients. One patient experienced an isolated invasive chest wall recurrence, and 1 patient had simultaneous chest wall, regional nodal, and distant metastases. The crude rates of chest wall recurrence were 2/142 (1.4%) for all patients, 1/21 (4.8%) for those with positive margins, 1/23 (4.3%) for those with close margins, and 0/98 for patients with negative margins. PMRT was given as part of the initial treatment to 3 patients, 1 of whom had an isolated chest wall recurrence. Mastectomy for pure DCIS resulted in a low rate of local or distant recurrences. Even with positive or close mastectomy margins, the rates of chest wall recurrences were so low that PMRT is likely not warranted.

Expression of HER2neu in Ductal Carcinoma in situ is Associated with Local Recurrence

AimsDetermination of the risk of recurrence after local excision of ductal carcinoma in situ (DCIS) remains a challenge. Molecular profiling based on immunohistochemical staining to oestrogen receptor (ER), progesterone receptor (PR) and HER2neu improved risk prediction in invasive breast cancer, but few studies have evaluated if molecular classification of DCIS predicts local recurrence. We evaluated the expression of ER, PR and HER2neu in DCIS to determine if molecular classification predicts local recurrence after breast-conserving therapy for DCIS. Materials and methodsWe reviewed the records of patients with DCIS treated between 1987 and 2000, carried out a pathology review and immunohistochemical staining for ER, PR and HER2neu and categorised cases into four molecular phenotypes [luminal A (ER+ and/or PR+, HER2neu–), luminal B (ER+ and/or PR+, HER2neu+), HER2neu subtype (ER–, PR–, HER2neu+), triple negative (ER–, PR–, HER2neu–)]. We evaluated the association between the molecular subtype and the development of local recurrence. ResultsIn total, 180 cases of DCIS were included in the study (luminal A, n=113; luminal B, n=25; HER2neu type, n=29; triple negative, n=13). The median follow-up time was 8.7 years. We observed higher rates of local recurrence among luminal B (40%) and HER2neu type (38%) DCIS compared with luminal A (21%) and triple negative (15%) DCIS. On multivariable analysis, HER2neu overexpression was associated with an increased risk of local recurrence (hazard ratio=1.98; 95% confidence interval: 1.11, 3.53, P=0.02). ConclusionHER2neu expression in DCIS is a significant predictor of local recurrence, whereas luminal A and triple negative phenotypes are associated with relatively low risks of local recurrence.

Adjuvant Hormonal Therapy Use Among Women with Ductal Carcinoma In Situ

In the absence of consistent guidelines for the use of adjuvant hormonal therapy (HT) in treating ductal carcinoma in situ (DCIS), our purpose was to explore a variety of factors associated with discussion, use, and discontinuation of this therapy for DCIS, including patient, tumor, and treatment-related characteristics and physician-patient communication factors. We identified women from eight California Cancer Registry regions diagnosed with DCIS from 2002 through 2005, aged ≥18 years, of Latina or non-Latina white race/ethnicity. A total of 744 women were interviewed an average of 24 months postdiagnosis about whether they had (1) discussed with a physician, (2) used, and (3) discontinued adjuvant HT. Although 83% of women discussed adjuvant HT with a physician, 47% used adjuvant HT, and 23% of users reported discontinuation by a median of 11 months. In multivariable adjusted analyses, Latina Spanish speakers were less likely than white women to discuss therapy (odds ratio [OR] 0.36, 95% confidence interval [CI] 0.18-0.69) and more likely to discontinue therapy (OR 2.67, 95% CI 1.05-6.81). Seeing an oncologist for follow-up care was associated with discussion (OR 5.10, 95% CI 3.14-8.28) and use of therapy (OR 4.20, 95% CI 2.05-8.61). Similarly, physician recommendation that treatment was necessary vs. optional was positively associated with use (OR 11.2, 95% CI 6.50-19.4) and inversely associated with discontinuation (OR 0.38, 95% CI 0.19-0.73). Physician recommendation is an important factor associated with use and discontinuation of adjuvant HT for DCIS. Differences in discussion and discontinuation of therapy according to patient characteristics, particularly ethnicity/language, suggest challenges to physician-patient communication about adjuvant HT across a language barrier.

Metastatic Invasive Breast Cancer Recurrence Following Curative-Intent Therapy for Ductal Carcinoma In Situ

The development of an invasive breast cancer recurrence outside of the breast parenchyma following curative-intent therapy for ductal carcinoma in situ (DCIS) is rare. We describe the patient and tumor characteristics associated with such recurrences. A retrospective review was conducted of 621 patients who were treated for DCIS between 2004 and 2009. Patient, tumor, and treatment characteristics were collected. Descriptive statistics were utilized for data summary and data were compared using χ(2), where appropriate. Of 621 patients who underwent curative-intent therapy for DCIS, 12 (1.9%) developed an invasive metastatic recurrence. Primary local therapy at the time of the initial DCIS diagnosis included 11 patients who underwent mastectomy and one who had lumpectomy and adjuvant radiotherapy. The metastatic recurrences were in chest wall and/or ipsilateral axillary lymph nodes only (n = 6) or distant sites with or without ipsilateral axillary or supraclavicular lymph nodes (n = 6). Of the 12 patients with invasive recurrence, eight had high grade DCIS with comedo necrosis at initial diagnosis. The biomarker profiles of the invasive recurrences included 55% estrogen receptor positivity, 45% progesterone receptor positivity, and 73% Her2/neu amplification. Patient age, tumor grade, presence of comedo necrosis, biomarker profile, and surgical treatment were not predictive of recurrence. Invasive metastatic recurrence following adequate local therapy for DCIS is uncommon and likely represents progression of unidentified invasive disease at the time of diagnosis. The majority of invasive recurrences were Her2/neu amplified. Further studies are necessary to determine if such a unique biomarker profile correlates with metastatic recurrence.

Status of Intraductal Therapy for Ductal Carcinoma in Situ.

The intraductal approach is particularly appealing in the setting of ductal carcinoma in situ (DCIS), a preinvasive breast neoplasm that is thought to be entirely intraductal in its extent. Based on an emerging understanding of the anatomy of the ductal system as well as novel techniques to leverage the access accorded by the intraductal approach, researchers are actively exploring how ductal lavage, ductoscopy, and intraductal infusion of therapeutic agents may enhance breast cancer treatment. Both cytologic and molecular diagnostics continue to improve, and work is ongoing to identify the most effective diagnostic biomarkers for DCIS and cancer, although optimal targeting of the diseased duct remains an important consideration. Ductoscopy holds potential in detection of occult intraductal lesions, and ductoscopically guided lumpectomy could increase the likelihood of a more comprehensive surgical excision. Exciting pilot studies are in progress to determine the safety and feasibility of intraductal chemotherapy infusion. These studies are an important starting point for future investigations of intraductal ablative therapy for DCIS, because as our knowledge and techniques evolve, it is likely that DCIS may be the target most amenable to treatment by intraductal therapy. If such studies are successful, these approaches will allow an important and meaningful transformation in treatment options for women diagnosed with DCIS.

Decreased CD10 Expression Is Associated with a Higher Risk of Relapse in Ductal Carcinoma In Situ (DCIS).

Abstract Background: The Van Nuys Prognostic Index (VNPI) is the most widely used tool to predict local recurrence and guide therapy for DCIS. Nevertheless, many patients are still over-treated. Pre-clinical evidence indicates myo-epithelial cell (MEC) death in DCIS is a pre-requisite to tumor invasion. In this study we hypothesized that loss of CD10, (a marker of MECs), would be a surrogate for basement membrane disruption and tumor invasion. The aim of the present study was to retrospectively evaluate the prognostic value of CD10 in pure DCIS.Methods: CD10 expression was evaluated by qRT-PCR and immuno-histochemistry (IHC) using FFPE tissues on normal samples (N=11) and two independent pure DCIS populations: a training set (N=66) and a validation set (N=88).Results: MECs were the only cells that showed CD10 staining using IHC in normal and DCIS samples. All normal breast tissue samples demonstrated high expression levels of CD10 using both IHC and RT-PCR. In contrast, DCIS samples showed a wide range of CD10 expression levels: 1/3 of DCIS expressed high CD10 levels similar to those observed in normal breast tissue (high expression), whereas 2/3 expressed CD10 at a level below normal breast tissue (low expression). DCIS tumors with low CD10 mRNA levels were significantly associated with a higher risk of local relapse (HR= 2.49; [95%CI: 1.13-5.49], p=0.02). These results were validated in an independent dataset (HR= 1.805 [95%CI: 1.11-2.92], p=0.016). Of interest, no local relapses were observed in the high CD10 expression DCIS group. In multivariate analysis, CD10 expression by qRT-PCR was significantly associated with relapse (HR= 2.25, [95%CI: 1.24-4.09], p=0.008) in addition to VNPI score (HR: 2.03; [95%CI: 1.23-3.35], p=0.006).Conclusion: Decreased expression of CD10 in DCIS is associated with a higher risk of local relapse. These promising results are currently being validated in a larger patient series. Assessment of CD10 in addition to VPNI may lead to improved treatment tailoring for women with DCIS. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2112.

Pathologic and biologic response to preoperative endocrine therapy in patients with ER-positive ductal carcinoma in situ

BackgroundEndocrine therapy is commonly recommended in the adjuvant setting for patients as treatment for ductal carcinoma in situ (DCIS). However, it is unknown whether a neoadjuvant (preoperative) anti-estrogen approach to DCIS results in any biological change. This study was undertaken to investigate the pathologic and biomarker changes in DCIS following neoadjuvant endocrine therapy compared to a group of patients who did not undergo preoperative anti-estrogenic treatment to determine whether such treatment results in detectable histologic alterations.MethodsPatients (n = 23) diagnosed with ER-positive pure DCIS by stereotactic core biopsy were enrolled in a trial of neoadjuvant anti-estrogen therapy followed by definitive excision. Patients on hormone replacement therapy, with palpable masses, or with histologic or clinical suspicion of invasion were excluded. Premenopausal women were treated with tamoxifen and postmenopausal women were treated with letrozole. Pathologic markers of proliferation, inflammation, and apoptosis were evaluated at baseline and at three months.Biomarker changes were compared to a cohort of patients who had not received preoperative treatment.ResultsMedian age of the cohort was 53 years (range 38–78); 14 were premenopausal. Following treatment, predominant morphologic changes included increased multinucleated histiocytes and degenerated cells, decreased duct extension, and prominent periductal fibrosis. Two postmenopausal patients had ADH only with no residual DCIS at excision. Postmenopausal women on letrozole had significant reduction of PR, and Ki67 as well as increase in CD68-positive cells. For premenopausal women on tamoxifen treatment, the only significant change was increase in CD68. No change in cleaved caspase 3 was found. Two patients had invasive cancer at surgery.ConclusionPreoperative therapy for DCIS is associated with significant pathologic alterations. These changes may be clinically significant. Further work is needed to identify which women may be the best candidates for such treatment for DCIS, and whether best responders may safely avoid surgical intervention.Trial RegistrationClinicalTrials.gov NCT00290745

Evaluation of preoperative letrozole treatment to DCIS by MRMammography.

Abstract Abstract #1164 Background:
 Since ductal carcinoma in situ (DCIS) often spreads diffusely along a lactiferous duct as multicentric lesions, it is generally treated by mastectomy. The response rate to letrozole is approximately 60%, which is relatively high among the preoperative endocrine therapies for invasive cancer, and it enables at least 50% of patients with little chance of saving the breast to actually receive breast-conserving surgery. This study was conducted to determine the value of preoperative endocrine therapy with letrozole for postmenopausal patients with hormone receptor (HR)-positive DCIS.
 Methods:
 Postmenopausal women who had been diagnosed with HR-positive DCIS by needle biopsy (Allred score ≥3) were treated with letrozole for 12 weeks. The primary endpoint was the response of target lesions evaluated by MRI based on the RECIST criteria. Patients who had no safety problems, except PD, continued letrozole therapy for up to 24 weeks, and the tumor response after 24 weeks and the rate of breast-conserving surgery were assessed. In addition to RECIST-based evaluation, changes of tumor volume on MRI were examined. Changes of Ki67, bcl-2, ER, and PgR with letrozole therapy were also assessed.
 Results:
 Twelve postmenopausal women with DCIS were enrolled, but one patient was excluded because her Allred score was 2. Using by RECIST criteria , the tumor response after 12 weeks was CR in 1 patient and SD in 10 patients. All 6 patients who could be evaluated after 24 weeks showed SD. But the evaluation by tumor volumetoric method, tumor was significantly reduced to an average of 42.2% after 12 weeks compared to before treatment.(p=0.0057) Two patients continued letrozole therapy for longer than 24 weeks. After 24 weeks of therapy, 3 patients underwent breast-conserving surgery and no mastectomies were performed. Pathological findings showed that the spread of tumor was likely to that of preoperative MRMammogrraphy. PgR was significantly reduced by letrozole therapy. There were no safety problems was not observed.
 Discussion:
 The efficacy of preoperative treatment with letrozole for 12 weeks was verified in postmenopausal patients with HR-positive DCIS. Two patients received breast-conserving surgery after letrozole therapy that had been considered impossible before treatment. Evaluation of treatment to DCIS using by RECIST criteria is unsutable,but the evaluation by MRMammography is considered to be a suitable method for determining the efficacy of therapy for DCIS. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1164.

Recurrent Cancer After Breast-Conserving Surgery with Radiation Therapy for Ductal Carcinoma in Situ: Mammographic Features, Method of Detection, and Stage of Recurrence

The purpose of our study was to determine the mammographic appearance, detection method, and stage of ipsilateral breast tumor recurrence in women treated with breast-conserving surgery and whole-breast radiation therapy for ductal carcinoma in situ (DCIS). Following institutional review board approval, records of women treated with breast-conserving surgery and radiation therapy for DCIS who developed an ipsilateral breast tumor recurrence from 1981 to 2003 were reviewed retrospectively. Multiinstitutional database records showed 513 women were treated, of whom 42 (8.2%) developed local recurrence. Study criteria were fulfilled and complete records were available for 32 women. Mean age at initial diagnosis was 49 years (range, 26-73 years). Of the 32 patients included in our study, 31 (97%) recurrences were mammographically apparent. Twenty-nine (91%) of 32 were diagnosed exclusively by mammography. Mammographic findings at recurrence were calcifications in 24 (75%) of 32, mass in six (19%) of 32, and distortion in one (3%) of 32. The mean time to recurrence was 4.5 years. Twelve (40%) of 30 had the recurrence in a remote quadrant from the original cancer. Recurrences were DCIS in 17 (53%) of 32, DCIS with microinvasion in six (19%) of 32, invasive ductal cancer in three (9%) of 32, invasive lobular cancer in two (6%) of 32, and mixed DCIS and invasive cancer in four (13%) of 32. Six (67%) of nine patients with invasive cancer (excluding microinvasion) had tumors smaller than 1 cm. Ninety-one percent of recurrences were minimal cancers. All recurrences were stage 0 or 1. Mammography successfully detected ipsilateral breast tumor recurrence, predominantly as calcifications or masses, after breast-conserving surgery with radiation therapy for DCIS in 97% of cases. The recurrences were located at variable distances from the lumpectomy site. Ninety-one percent of recurrences were minimal cancers and all were early stage, connoting excellent prognosis.

The effect of margin status on local recurrence following breast conservation and radiation therapy for DCIS

597 Background: There is no consensus on what constitutes an adequate surgical margin in patients receiving breast conserving surgery (BCS) and postoperative irradiation (RT) for ductal carcinoma in situ (DCIS). Inadequate margins may result in high local recurrence, and excessively large resections may lead to poor cosmetic outcome without oncological benefit. Methods: A comprehensive search for published trials which examined outcomes after adjuvant RT following BCS for DCIS was performed using medline and cross referencing available data. Reviews of each study were conducted, and data were extracted. Fixed and random effects methods were used to combine data. Primary outcomes were in breast tumour recurrence (IBTR) related to surgical margins. Results: Analysis of 3,606 patients from randomized trials confirms that patients with negative margins are significantly less likely to recur than those with positive margins after RT (RR 0.53, 95% CI= 0.42 to 0.66, p<0.01). Combined data from randomized and non randomized trials, of 5,500 patients, demonstrates that where the margin status is close or unknown there is significant risk of IBTR compared to a negative margin (RR=1.68, 95% CI= 1.22–2.33, p<0.01). When specific margin thresholds are examined a 2 mm margin is superior to less than 2 mm (OR=0.67, 95% CI 0.51 -0.89, p<0.01), however we saw no significant difference in the rate of IBTR between a 2 mm margin and >5 mm (OR=1.49, 95% CI 0.54 to 4.9, p>0.05). Conclusions: Surgical margins negative for DCIS should be obtained following BCS for DCIS. A margin threshold of 2mm appears be as good as a larger margin when BCS for DCIS is combined with RT. No significant financial relationships to disclose.