ER-positive Ductal Carcinoma In Situ Research Articles

Memory mayhem: Hormone therapy causing brain fog in patients with DCIS.

575 Background: Long term hormonal therapy in ductal carcinoma in situ (DCIS) have been studied without consistent evidence to cause cognitive side effects. Here we evaluate the relation of using hormonal therapy (HT) in patients with DCIS with cognitive effects. Methods: TrinetX, a global federated research network that provides a dataset of electronic medical records from different healthcare organizations (HCOs), was utilized. Initial query was made to isolate patients who had an ER positive DCIS. Two groups were made based on the receipt of hormone therapy (exemestane, tamoxifen, letrozole, anastrozole). Further, propensity score matching (PSM) was carried out to match age, sex, race, development of malignant neoplasm of breast, chemotherapy at any point. Outcomes of cognitive impairment were identified using ICD 10 CM codes R41.3, R41.0, F05, F02.81, and Alzheimer’s dementia was identified using ICD 10 CM code G30. Compare outcome analytic function was utilized to map the co-relation of HT with cognitive impairment. Results: 64,266 patients were identified with ER positive DCIS, of whom 63.18% (n=40,601) received HT. Patients who received HT were older (61.4 ± 12.3 vs. 61 ± 12.9, p<0.0001), and predominantly Caucasian (70% vs 65%, p<0.0001). On looking further into racial distribution of population, it was seen that Caucasians were predominant in both groups, followed by African Americans (12% vs. 11%, p=0.0016) and Unknown race (11% vs. 17%, p<0.0001), then Asians (4% vs. 4%, p=0.0675). Before PSM, it was seen that 7.55% (n= 2,818) patients had cognitive side effects compared to only 5.044% (n= 1,139) in group that did not receive HT (OR 1.537 (1.432,1.65), p<0.0001). Log-Rank Test for Kaplan-Meier curve was significant for the difference with hazard ratio 1.315, (1.227,1.409). A similar association was seen with Alzheimer’s dementia (0.735% vs. 0.547%, OR 1.346 (1.094,1.656), p= 0.0048) but Kaplan-Meier survival analysis did not show any significant difference between the groups. After PSM, both groups had 15,801 cases. The odds of developing cognitive impairment was higher in HT group (6.582% vs. 5.589%, OR 1.19, (1.082,1.309), p=0.0003). But Log-Rank Test for Kaplan-Meier curve did not show any significant difference (HR 1.047 (95% CI 0.954-1.149)). There was no significant difference for Alzheimer’s dementia development in either group (0.769% vs. 0.591%, 1.303 (0.994,1.709), p = 0.0548). Conclusions: Our study shows that HT significantly increases the odds of developing cognitive impairment. The limitation of the study is the duration of follow up. Usually, patients with DCIS live much longer and can have cognitive effects beyond the window of this study; hence a prospective long-term follow-up study is required to ascertain the relation of HT and cognitive side effects. Patients when starting the treatment should be counselled about the risk of developing cognitive side effects in future.

Estrogen Receptor-negative Ductal Carcinoma In Situ (DCIS) of the Breast - an Institutional Review of Outcomes.

Estrogen receptor (ER)-negative [ER(-)] invasive breast cancers (IBCs) are known to be more aggressive than their ER(+) counterparts. This is less well defined for ductal carcinoma in situ (DCIS). This study investigated the outcomes following the treatment of ER(-) DCIS. A total of 103 ER(-) DCIS patients diagnosed between 2004-2018 were retrospectively analyzed. Median follow-up was 63.9 months. Statistical analysis included descriptive statistics, non-parametric tests, T-test, logistic regression. The outcomes were compared to a group of 102 ER(+) DCIS patients from our institution. Any breast event (BE) occurred in 10 (9.7%) patients at a median of 3.2 (1.7-7.2) years. The incidence of ipsilateral breast events (IBEs) was 5.8% (6/103). All IBE cases were ER(-) DCIS. All (n=4) contralateral breast events (CBEs) were ER(+) including 3 IBCs. Cumulative incidence of any BEs at 1, 2, and 5 years was 0%, 1.1%, and 9.1%, respectively. Among patients with ER(-) DCIS who developed BE, breast conserving surgery (BCS) had been performed for the initial DCIS in 90% of cases. In those without any BE, the BCS rate (vs. mastectomy) was 58.1% (p=0.08). Adjuvant radiotherapy after BCS was used less often among patients with vs. without subsequent BE (55.5% vs. 77.4%) (p=0.22). Predictors for BE occurrence were not identified. The incidence of any BE among patients with ER(+) DCIS was 6.9% and was not significantly different compared to ER(-) DCIS group (p=0.46). ER(-) DCIS outcomes were similar to our institutional ER-positive DCIS group and the previously reported ones for predominantly ER-positive DCIS cohorts.

Impact of Surgical Delay on Tumor Upstaging and Outcomes in Estrogen Receptor–Negative Ductal Carcinoma in Situ Patients

The delay of elective surgeries by the coronavirus 2019 (COVID-19) pandemic prompted concern among surgeons to delay estrogen receptor (ER)-negative ductal carcinoma in situ (DCIS) for fear of missing an ER-negative invasive cancer and compromising survival of patients. Female patients ≥40 years old diagnosed with ER-negative DCIS from 2004 to 2017 were examined from the National Cancer Database. Multivariable logistic regression, adjusting for patient and tumor factors, was used to determine factors associated with tumor upstage. Multivariable Cox proportional hazards modeling was used to determine if surgical delay impacted overall survival of ER-negative DCIS patients that were upstaged to invasive disease. There were 219,731 patients with DCIS of which 24,338 (11.1%) had tumor upstage. Of these patients, 5,675 (16.2%) of ER-negative and 18,663 (10.1%) of ER-positive DCIS patients were upstaged (p ≤ 0.001). From 2004 to 2017, ER-negative DCIS upstage rates increased from 12.9% to 18.9%. Independent factors associated with tumor upstage were younger age (odds ratio [OR] 0.75 [95% CI 0.69 to 0.81]) and Black race (OR 1.34 [95% CI 1.22 to 1.46]). Compared with patients with ≤30 days between biopsy and surgery, patients with a 31- to 60-day interval (OR 1.13 [95% CI 1.05 to 1.20]) and a >60-day interval (OR 1.12 [95% CI 1.02 to 1.23]) had an increased rate of tumor upstage. Among ER-negative DCIS patients whose tumors were upstaged to invasive disease, Cox proportional hazard regression modeling showed no association between the number of days between biopsy and surgery and overall survival. Delays in surgery were associated with higher tumor upstage rates but not with worse overall survival.

Factors influencing the initiation of adjuvant endocrine therapy in patients with estrogen receptor-positive ductal carcinoma in situ: a single institution experience

PurposeThis study evaluates whether race, socioeconomic status, insurance type, oncological provider type, and prior cancer treatment are associated with the suggestion and acceptance of hormonal therapy in patients with estrogen receptor (ER)-positive Ductal carcinoma in situ (DCIS). This study also assesses whether disparities exist pertaining to prescription of such medications.MethodsThis single-center retrospective study included 111 patients diagnosed with DCIS between 2020 and 2021. Data collected included race, type of insurance, prescribing providers, and socioeconomic status. We used zip codes to identify the poverty levels in these areas as published in the United States Census Bureau and stratified the patients into quartiles accordingly. Chi-Square statistics were used to calculate significance levels.ResultsThere was no significant correlation between the intake of hormonal therapy and race (p = 0.60), insurance (p = 0.50), socioeconomic (p = 0.58), or providers (p = 0.99). 79.3% of women were offered endocrine therapy. Of those who were offered endocrine therapy, 70.8% accepted. Of patients not on hormonal therapy, 45.8% were not recommended the medications by their provider, and 54.2% declined treatment when offered.ConclusionIn this study, patients’ demographics and providers were not associated with adjuvant hormonal therapy initiation in DCIS. Our results show that abstaining from endocrine therapy in DCIS patients is both due to lack of provider recommendation and patient rejection of these medications. The wide variation in hormonal therapy treatment among ER-positive DCIS patients suggests a need for improved provider-patient communication regarding the risks and benefits of endocrine therapy in order to ensure a shared decision-making process.

Prognostic Value of ER and PgR Expression and the Impact of Multi-clonal Expression for Recurrence in Ductal Carcinoma in situ: Results from the UK/ANZ DCIS Trial.

The prognostic value of estrogen receptor (ER)/progesterone receptor (PgR) expression in ductal carcinoma in situ (DCIS) is unclear. We observed multi-clonality when evaluating ER/PgR expression in the UK/ANZ DCIS trial, therefore, we investigated the prognostic role of both uni-clonal and multi-clonal ER/PgR expression in DCIS. Formalin-fixed paraffin embedded tissues were collected from UK/ANZ DCIS trial participants (n = 755), and ER/PgR expression was evaluated by IHC in 181 cases (with recurrence) matched to 362 controls by treatment arm and age. Assays were scored by the Allred method and by a newly devised clonal method-analyses categorizing multi-clonal DCIS as ER/PgR-positive as per current practice (Standard) and as ER/PgR-negative (clonal) were performed. ER expression was multi-clonal in 11% (39/356) of ER-positive (70.6%, 356/504) patients. Ipsilateral breast event (IBE) risk was similarly higher in ER-multi-clonal and ER-negative DCIS as compared with DCIS with uni-clonal ER expression. ER-negative DCIS (clonal) had a higher risk of in situ IBE [OR 4.99; 95% confidence interval (CI), 2.66-9.36; P < 0.0001], but the risk of invasive IBE was not significantly higher (OR 1.72; 95% CI, 0.84-3.53; P = 0.14), P heterogeneity = 0.03. ER was an independent predictor in multivariate analyses (OR 2.66; 95% CI, 1.53-4.61). PgR status did not add to the prognostic information provided by ER. ER expression is a strong predictor of ipsilateral recurrence risk in DCIS. ER-positive DCIS with distinct ER-negative clones has a recurrence risk similar to ER-negative DCIS. ER should be routinely assessed in DCIS, and ER scoring should take clonality of expression into account.

The clinical significance of oestrogen receptor expression in breast ductal carcinoma in situ

BackgroundOestrogen receptor (ER) in invasive breast cancer (BC) predicts response to endocrine therapy (ET) and provides prognostic value. In this study, we investigated the value of ER expression in ductal carcinoma in situ (DCIS) in terms of outcome and the impact on ET decision.MethodsIn total, 643 pure DCIS, diagnosed at Nottingham University Hospitals, were assessed for ER. Clinicopathological data were correlated against ER status, together with assessment of recurrence rate.ResultsER positivity was observed in 74% (475/643) of cases. ER positivity was associated with clinicopathological variables of good prognosis; however, outcome analysis revealed that ER status was not associated with local recurrence. In the intermediate- and high-grade ER-positive DCIS, 58% (11/19) and 63% (15/24) of the recurrences were invasive, respectively, comprising 7% and 6% of all ER-positive DCIS, respectively. Invasive recurrence in low-grade DCIS was infrequent (2%), and none of these patients died of BC. The ER status of the recurrent invasive tumours matched the primary DCIS ER status (94% in ipsilateral and 90% of contralateral recurrence).ConclusionThe strong correlation between DCIS and invasive recurrence ER status and the clinical impact of ET justify discussion of the use of ET in ER-positive DCIS treated by breast-conserving surgery. The excellent outcome of low-grade DCIS, which was almost always ER-positive, does not, in the opinion of authors, justify the use of risk-reducing ET. Therefore, the decision on ET for DCIS should be personalised and consider grade, ER status and other characteristics.

Abstract GS5-05: Primary endocrine therapy for ER-positive ductal carcinoma in situ (DCIS) CALGB 40903 (Alliance)

Abstract Background: Standard treatment for ductal carcinoma in situ (DCIS) consists of surgery, often followed by adjuvant radiation therapy or endocrine therapy. This current approach is thought to represent overtreatment for some patients. This study was undertaken to determine whether an alternate approach of primary endocrine therapy alone could result in measurable radiographic changes in unresected estrogen receptor (ER)-positive DCIS. Methods: A phase II open-label single arm multi-center cooperative group trial (CALGB 40903) was conducted for postmenopausal patients diagnosed with ER-positive DCIS. All eligible patients underwent baseline mammography and MRI, followed by 6 months of preoperative therapy with letrozole. Follow up breast MRI was obtained at 3 and 6 months of treatment. The primary endpoint was change in total MRI volume of DCIS enhancement from baseline to 3 months and from baseline to 6 months. Secondary endpoints were change in MRI maximum diameter over baseline and change in mammographic extent of disease over baseline. Endpoints were analyzed via 2-sided paired t-tests (a=0.05). Results: From 8/1/12 to 2/1/16 108 patients were enrolled; Of the 77 patients who completed letrozole treatment per protocol, 66 patients were assessable. 2 additional patients who did not complete treatment per protocol were considered assessable and thus included in the analysis for a total of 68 patients. Median age of the cohort was 62.7 years. DCIS nuclear grade was low in 10% of patients, intermediate in 49%, and high in 40%. 82% of patients had ER-positive, PR-positive DCIS. The total mean MRI volume decreased from baseline to 3 months by 1.93 cm3 (p&amp;lt;0.001) and from baseline to 6 months by 1.82 cm3 (p&amp;lt;0.001). There was no significant difference in tumor volume between 3 and 6 months. Mean total mammographic tumor diameter decreased from baseline to 6 months by 3.31 mm2 (p=0.078). Conclusions: In a cohort of postmenopausal women treated with 6 months of preoperative endocrine therapy for ER-positive DCIS, MRI volume decreased markedly by 3 months, while mammographic extent of disease was not altered significantly. Correlation of imaging changes with pathology and baseline biomarkers will be conducted. These results will help determine whether MRI could be an effective modality for monitoring treatment response in some patients treated with primary endocrine therapy for ER-positive DCIS. Citation Format: Hwang ES, Duong S, Bedrosian I, Allred J, Wisner D, Hyslop T, Caudle A, Guenther J, Hudis C, Winer E, Esserman L, Hylton N. Primary endocrine therapy for ER-positive ductal carcinoma in situ (DCIS) CALGB 40903 (Alliance) [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 GS5-05.

Endocrine Therapy Initiation among Older Women with Ductal Carcinoma In Situ.

Background Although treatment of ductal carcinoma in situ (DCIS) is controversial, national guidelines recommend considering endocrine therapy for women with estrogen receptor- (ER-) positive DCIS or those undergoing breast conserving surgery (BCS) without radiation. We evaluated uptake and predictors of endocrine therapy use among older women with DCIS. Methods In the SEER-Medicare database, we identified women aged 65+ years diagnosed with DCIS during 2007–2011. We evaluated demographic, tumor, and treatment characteristics associated with endocrine therapy initiation. Results Among 2,945 women with DCIS, 41% initiated endocrine therapy (66% tamoxifen, 34% aromatase inhibitors). Initiation was more common among women with ER-positive than ER-negative DCIS (48% versus 16%; HR = 3.75, 95% CI: 2.91–4.83); 28% of women with unknown ER status initiated endocrine therapy. Initiation was less common after BCS alone compared to BCS with radiation (32% versus 50%; HR = 0.69, 95% CI: 0.59–0.80). Conclusions Less than half of older women with DCIS initiate endocrine therapy to prevent second breast cancers. Our findings suggest use was more common, but not exclusive, among women with ER-positive DCIS, but not among women who underwent BCS alone. Endocrine therapy should be targeted toward patients most likely to benefit from its use.

Initiation of and adherence to tamoxifen and aromatase inhibitor therapy among elderly women with ductal carcinoma in situ.

The National Surgical Adjuvant Breast and Bowel Project B35 and International Breast Cancer Intervention Studies II Ductal Carcinoma In Situ trials showed similar treatment effects of anastrozole and tamoxifen in reducing cancer recurrence risk among ductal carcinoma in situ (DCIS) patients. Studies have shown low levels of hormone therapy drug initiation for DCIS patients, but the current body of literature lacks information on the 5-year adherence rates for these drugs from population-based studies. This study evaluated the initiation and 5-year adherence levels for women aged 66 to 85 years who had been diagnosed with estrogen receptor (ER)-positive DCIS between 2007 and 2011 according to the Surveillance, Epidemiology, and End Results and Texas Cancer Registry databases linked to Medicare claims. Chi-square tests, trend tests, and logistic regression were used to identify factors associated with treatment initiation. There were 2871 women with ER-positive DCIS, and approximately 45% began treatment with tamoxifen or aromatase inhibitors (AIs) within 1 year of their DCIS diagnosis. The median age was 73 years for the users and 75 years for the nonusers. Women aged 66 to 70 years who underwent lumpectomy and radiation therapy were significantly more likely to initiate hormone therapy. The initiation of therapy was also significantly associated with patients' geographic location, education, marital status, diagnosis year, and race/ethnicity. Among users, adherence decreased from 67% in the first year to 30% in the fifth year. Initiation and adherence levels for tamoxifen or AIs among older women with ER-positive DCIS are low. Future studies should develop methods to ensure that informed discussions take place between health care providers and patients regarding hormonal therapy for cancer prevention. Cancer 2017;123:940-47. © 2016 American Cancer Society.

Benefit of low‐dose tamoxifen in a large observational cohort of high risk ER positive breast DCIS

Low-dose tamoxifen has comparable antiproliferative effect to the standard dose of 20 mg/day in biomarker trials, but its clinical efficacy remains unclear. We assessed the effect of low-dose tamoxifen on ipsilateral recurrence in ductal carcinoma in situ (DCIS) patients treated in a referral Institution between 1996 and 2008. Following conserving surgery, women received radiotherapy and/or low-dose tamoxifen upon clinical judgment and patient preferences. Cox regression analyses were used with and without confounding factors. Among 1,091 women with DCIS and median age 53 years (IQR: 46-62), 544 (49.9%) received radiotherapy. Of the 833 women with oestrogen receptor (ER) positive DCIS, 467 (56.1%) received low-dose tamoxifen. After a median of 7.7 years, 235 ipsilateral recurrences and 62 contralateral breast tumors were observed. Low-dose tamoxifen significantly decreased any breast event (HR = 0.70, 95% CI: 0.54-0.91) and ipsilateral DCIS recurrence (HR = 0.66, 95% CI: 0.49-0.88), but not ipsilateral invasive recurrence or contralateral tumors. Radiotherapy showed a large significant reduction for any breast event (HR = 0.55, 95% CI: 0.42-0.72). Tamoxifen was more effective on all breast events in women aged >50 years than in women aged ≤50 (HR = 0.51, 95% CI: 0.33-0.77 versus HR = 0.84, 95% CI: 0.60-1.18, p-interaction = 0.03). Age ≤50 years, positive margins, high Ki67, high grade and low BMI were independent predictors of ipsilateral recurrence. No increase of endometrial cancers and fewer deaths (p = 0.015) were observed on tamoxifen. Low-dose tamoxifen seems to be safe and effective in reducing ipsilateral recurrence in ER positive DCIS in women aged >50 years. A randomized trial is underway to confirm these findings.

Abstract ES8-3: Endocrine management of premalignant lesions and DCIS

Abstract It has been recognized for many years that there exist pathological entities associated with an increased risk of invasive breast cancer. The most frequently encountered are atypical hyperplasia (AH), lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS), although other diagnoses have also been identified. Often these lesions are discovered incidentally, and when diagnosed are found to confer a wide range of elevated breast cancer risk. Clinical management of these conditions has largely consisted of surveillance, sometimes with the addition of endocrine therapy. The selective estrogen receptor modulators (SERMs), including tamoxifen and raloxifene, have been the mainstay of endocrine therapy in this setting. A prospective randomized trial, NSABP P-1 randomized over 13,000 high risk women, defined by a Gail score &amp;gt;1.66, to either 5 years of tamoxifen or placebo.1 Tamoxifen reduced the risk of invasive breast cancer by 49% (p&amp;lt;.00001), with the greatest risk reduction seen in women with ADH or LCIS. The IBIS I study also compared to tamoxifen to placebo and confirmed a risk reduction with tamoxifen, although lower than that reported initially in the P-1 trial (hazard ratio [HR] 0.72 [95% CI 0.59-0.88], p=0.001).2 Most recently, the role of aromatase inhibitors as chemoprevention in this setting has been studied; the results of IBIS II trial, which randomized 3864 high risk postmenopausal women to anastrozole or placebo, found a substantial risk reduction in the AI group (hazard ratio 0.47, 95% CI 0.32-0.68, p&amp;lt;0.0001).3 Endocrine therapy in the adjuvant setting has been reported for DCIS in two prospective clinical studies, the NSABP-B24 and UK/ANZ trials. A meta-analysis of these two trials demonstrated that tamoxifen after lumpectomy for DCIS reduced recurrence of both ipsilateral (HR 0.75; 95% CI 0.61 to 0.92) and contralateral (RR 0.50; 95% CI 0.28 to 0.87) DCIS.4 There was a trend towards decreased ipsilateral invasive cancer (HR 0.79; 95% CI 0.62 to 1.01) and reduced contralateral invasive cancer (RR 0.57; 95% CI 0.39 to 0.83). In addition, the findings of NSABP B-35 randomizing postmenopausal women with ER-positive DCIS reported that 10-year point estimates for DFS were 77.9% for tamoxifen and 82.7% for anastrozole.5 Future challenges for this field will include more precise patient selection for these treatments, as all confer risk of side effects. These have resulted in poor uptake of chemoprevention despite the definitive benefit demonstrated in the large randomized studies. In addition, the utility of endocrine therapy as primary treatment for low risk DCIS or in the neoadjuvant setting are important questions which are currently under investigation. More precise quantification and communication of the risks and benefits of the endocrine therapies will be increasingly needed in order to maximize the benefits of endocrine intervention in this setting. 1Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-88, 1998 2Cuzick J, Sestak I, Cawthorn S, et al: Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol 16:67-75, 2015 3Cuzick J, Sestak I, Forbes JF, et al: Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet 383:1041-8, 2014 4Staley H, McCallum I, Bruce J: Postoperative tamoxifen for ductal carcinoma in situ. Cochrane Database Syst Rev 10:CD007847, 2012 5Margolese RG: Primary Results of NRG Oncology/NSABP B-35: A Clinical Trial of Anastrozole vs Tamoxifen in Postmenopausal Patients with DCIS. J Clin Oncol 33, 2015 (suppl; abstr LBA500), 2015. Citation Format: Hwang ES. Endocrine management of premalignant lesions and DCIS. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES8-3.

Abstract 5283: Vav2 oncoprotein up regulation may predict the aggressive subtype of ductal carcinoma in situ

Abstract Background: A subset of patients with ductal carcinoma in situ (DCIS) will develop invasive breast cancer (IBC). To date, there are no effective predictive biomarkers for identifying this subset with worse prognosis whose lesions are essentially indistinguishable histologically from those with favorable outcomes. We hypothesized that measurable parameters that discriminate DCIS from DCIS with concurrent invasion may serve as diagnostic biomarkers (BM) of progressive cancer in situ (CIS). Methods: Using a novel imaging-based method of tissue testing, we measured the relative expression levels of three candidate BM proteins specifically implicated in IBC progression - the insulin-like growth factor I receptor (IGF-IR), Ras-related protein 1 (Rap1), and Vav2 oncoprotein. Protein profiles were compared in 42 histologically normal mammary epithelial samples, 71 CIS (35 without/36 with invasion either on diagnostic biopsy or final surgical excision), and 98 IBC of known estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status. Groups were compared using one-way analysis of variance (ANOVA) followed by pair-wise t-tests with Tukey's correction for multiple testing. Receiver operating characteristic (ROC) curves were constructed to evaluate how well each BM can predict tumor type. Results: The levels of the IGF-IR and Rap1 protein expression were significantly elevated in ER-positive (ER+/PR+/-/HER2 -) DCIS relative to normal epithelium (P&amp;lt;0.0001). The IGF-IR protein expression was also significantly up regulated in HER2-positive (ER+/-/PR+/-/HER2+) DCIS relative to normal epithelium (P = 0.0002). IGF-IR and Rap1 protein expression levels were similar among DCIS patients without or with concurrent invasion. Vav2 up regulation in DCIS relative to normal group was not associated with steroid hormone receptor and HER2 status, but was associated with the presence of concurrent invasion, including microinvasion (invasive foci of less than 1 mm). DCIS with high Vav2 were more than twice as likely to progress to invasive cancers as DCIS with low Vav2 (odds ratio, 2.42; 95% CI, 1.26-4-65; P = 0.008). Furthermore, a ROC curve analysis revealed moderate ability of Vav2 protein expression measurements in DCIS to predict the existence of invasion concurrent with DCIS (area under the curve, 0.71; 95% CI, 0.59- 0.84). Conclusions: This study describes the use of a novel imaging method for archival tissue testing, which may inform the status of protein BM in archived tissue and may help to stratify a women's individual risk for tumor invasiveness to avoid potential over- or under-treatment. Despite the apparent limitation of our study DCIS cohort size, our novel findings hold promise for utilizing Vav2 as a predictive BM of progressive DCIS and a target for cancer therapy. Citation Format: Marina A. Guvakova, Yun Qing Jiang, Indira Prabakaran, Fei Wan, Nandita Mitra, Paul J. Zhang, Douglas L. Fraker. Vav2 oncoprotein up regulation may predict the aggressive subtype of ductal carcinoma in situ. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5283. doi:10.1158/1538-7445.AM2015-5283

Screening mammography-detected ductal carcinoma in situ: mammographic features based on breast cancer subtypes

We evaluated the mammographic and histopathologic features of screening mammography-detected ductal carcinoma in situ (DCIS) based on the breast cancer subtypes determined by immunohistochemistry. A total of 94 patients with 94 screening mammography-detected DCIS were included in this study. Mammographically, human epidermal growth factor receptor 2 (HER2)-positive DCIS was more commonly associated with calcifications than estrogen receptor (ER)-positive and triple-negative DCIS (P=.003). Histopathologically, HER2-positive DCIS and triple-negative DCIS were associated with high nuclear grade (P≤.001) and comedo necrosis (P≤.001) than ER-positive DCIS.

Abstract P6-13-04: Metformin for the treatment of ductal carcinoma in situ (DCIS)

Abstract BACKGROUND: Each year about 60,000 new cases of breast ductal carcinoma in situ (DCIS) are diagnosed in the United States. DCIS significantly increases the risk of invasive breast cancer. To reduce this risk, tamoxifen is offered to patients with ER-positive DCIS in the adjuvant setting. In contrast, no adjuvant therapy exists for ER-negative DCIS. Metformin is a frontline therapy for type 2 diabetes and its safety and side effect profiles are well documented. Preclinical, epidemiologic, and retrospective data all support an antitumor effect of metformin in breast cancer. Metformin may act via activation of AMP kinase (AMPK), a sensor of cellular energy, which in turn inhibits mTOR activity and shuts down global protein synthesis. Previous data from our group showed that metformin treatment is associated with a higher rate of pathologic complete response in diabetic breast cancer patients receiving preoperative chemotherapy. In the current study, using preclinical models, we explored the effects of metformin in DCIS and its progression to invasive breast cancer. EXPERIMENTAL DESIGN AND METHODS: We tested the anti-tumor activity of metformin in terms of proliferation and invasion using both DCIS cell lines and a mouse intraductal (MIND) transplantation model previously developed by us. The latter involves intraductal injection of human DCIS cells into mouse mammary glands, and importantly recapitulates the progression of DCIS to invasive cancer seen in human breast cancer. Western blot and immunofluorescent staining for AMP kinase, mTOR, and other relevant targets, as well as flow cytometry, were used to investigate mechanism. RESULTS: Metformin significantly inhibited cell proliferation, migration, and invasion in all DCIS cell lines tested. In the mouse model, using metformin at a dose that is readily achievable in human patients, metformin significantly reduced the tumor burden in terms of median number of ducts filled, from 11 to 2 using DCIS.com cells (p &amp;lt; 0.001) and from 10 to 3 using SUM.225 cells (p = 0.004). In addition, importantly, metformin inhibited the progression of DCIS lesions to invasive breast cancer significantly, with a reduction in invasive lesions from 74 to 17% (p = 0.003). In mechanistic studies, metformin showed activation of AMPK and subsequent inactivation of mTOR and other downstream targets. Treatment with metformin did not lead to significant cell cycle arrest but rather to increased cell death. We found that cell death by apoptosis increased only modestly with metformin treatment, while cell death by necrosis increased significantly. CONCLUSION: Metformin inhibits the growth of DCIS and its progression to invasive breast cancer. To our knowledge, this is the first reported evidence of metformin’s anti-tumor activity in DCIS. Our data support the exciting prospect of developing metformin clinically for the treatment of DCIS. Citation Format: Atreyi Dasgupta, David G Edwards, Frances S Kittrell, Susan G Hilsenbeck, Daniel Medina, Sao Jiralerspong. Metformin for the treatment of ductal carcinoma in situ (DCIS) [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 P6-13-04.

Immunolocalization of thymidylate synthase as a favorable prognostic marker in estrogen receptor-positive breast carcinoma.

Thymidylate synthase (TS) is an enzyme involved in DNA synthesis, and it is a target for 5-fluorouracil. Previous studies have demonstrated that TS is a potent estrogen-induced gene in breast carcinoma cells, suggesting the importance of TS in estrogen-receptor (ER)-positive breast carcinoma. TS immunolocalization has been reported previously, but the clinicopathological significance of TS in ER-positive breast carcinoma still remains unclear. We immunolocalized TS in 178 breast carcinoma tissues in total, and examined its significance according to the ER-status. TS status was positive in 58% of ER-positive ductal carcinoma in situ (DCIS) cases, and it was significantly associated with the Ki-67 and progesterone receptor (PR). Moreover, in ER-positive DCIS patients who received aromatase inhibitor (AI) before surgery, TS immunoreactivity was significantly decreased after AI treatment. In ER-positive invasive ductal carcinoma (IDC) cases, TS status was significantly associated with PR, and it turned out an independent favorable prognostic factor for recurrence of the patients by multivariate analysis. On the other hand, TS status was positively correlated with pathological T factor in ER-negative IDC cases, and tended to have a worse prognosis for disease-free survival of the patients. These results suggest that TS expression is mainly regulated by estrogen in ER-positive breast carcinoma and is associated with estrogen-mediated proliferation. TS status is a favorable prognostic factor in ER-positive IDC patients, which is different from the ER-negative cases.

Vav2 protein overexpression marks and may predict the aggressive subtype of ductal carcinoma in situ.

BackgroundA subset of patients with ductal carcinoma in situ (DCIS) will develop invasive breast cancer (IBC). To date, there are no effective predictive biomarkers for identifying this subset with worse prognosis whose lesions are essentially indistinguishable histologically from those with favorable outcomes. We hypothesized that measurable parameters that discriminate DCIS from DCIS with concurrent invasion may serve as diagnostic biomarkers (BM) of progressive cancer in situ (CIS).ResultsUsing a novel imaging-based method of tissue testing, we measured the relative expression levels of three candidate BM proteins specifically implicated in IBC progression - the insulin-like growth factor I receptor (IGF-IR), Ras-related protein 1 (Rap1), and Vav2 oncoprotein. Protein profiles were compared in 42 histologically normal mammary epithelial samples, 71 CIS (35 without/36 with invasion either on diagnostic biopsy or final surgical excision), and 98 IBC of known estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status. The levels of the IGF-IR and Rap1 protein expression were significantly elevated in ER-positive (ER+/PR+/-/HER2 –) DCIS relative to normal epithelium (P <0.0001). The IGF-IR protein expression was also significantly up regulated in HER2-positive (ER+/-/PR+/-/HER2+) DCIS relative to normal epithelium (P = 0.0002). IGF-IR and Rap1 protein expression levels were similar among DCIS patients without or with concurrent invasion. Vav2 upregulation in DCIS relative to normal group was not associated with steroid hormone receptor and HER2 status, but was associated with the presence of concurrent invasion, including microinvasion (invasive foci of less than 1 mm). DCIS with high Vav2 were more than twice as likely to progress to invasive cancers as DCIS with low Vav2 (odds ratio, 2.42; 95% CI, 1.26-4-65; P =0.008). Furthermore, a receiver operating characteristic curve analysis revealed moderate ability of Vav2 protein expression measurements in DCIS to predict the existence of invasion concurrent with DCIS (area under the curve, 0.71; 95% CI, 0.59- 0.84).ConclusionsOur novel findings hold promise for utilizing Vav2 protein as a predictive BM for differentiating progressive from non-progressive DCIS.Electronic supplementary materialThe online version of this article (doi:10.1186/2050-7771-2-22) contains supplementary material, which is available to authorized users.

Is radiotherapy necessary for intermediate risk ductal carcinoma in situ after breast conserving surgery?

Identifying ductal carcinoma in situ (DCIS) patients at highest risk for recurrence after breast conserving surgery (BCS) remains a clinical concern. Subjecting all such patients to radiotherapy may be unnecessary. The Van Nuys Prognostic Index (VNPI) is a simple scoring system for predicting the risk of local recurrence in patients with DCIS. We reviewed patients with DCIS applying the VNPI score system. A total of 184 DCIS patients who underwent surgery at our institution between January 2003 and December 2011 were identified. Patients were not treated according to VNPI guidelines; rather, radiation therapy was applied at each surgeon’s discretion. All patients with hormonal receptor positive tumors were treated with hormonal therapy. Pathology reports were reviewed and VNPI scores of each DCIS calculated. Of the 184 patients, 52 (28.3%), 115 (62.5%) and 17 (9.2%) had low, intermediate and high VNPI scores, respectively. Six of the 184 patients (3.3%) developed ipsilateral local recurrence, five in the intermediate and one in the high VNPI score group. Of the five in the intermediate group, three (60%) were in patients with ER-negative tumors. VNPI score itself was not associated with recurrence (P = 0.145). Factors associated with recurrence included tumor size (hazard ratio [HR] 6.88), grade (HR 9.07) and hormone receptor status (HR 11.75). Radiotherapy did not significantly improve recurrence rates in patients with low and intermediate risk DCIS, especially in those with ER-positive tumors. Radiotherapy can be omitted in patients with ER-positive intermediate score DCIS and in patients with low score DCIS.

COX-2 expression is predictive for early relapse and aromatase inhibitor resistance in patients with ductal carcinoma in situ of the breast, and is a target for treatment.

Background:Stratification of patients for treatment of ductal carcinoma in situ (DCIS) is suboptimal, with high systemic overtreatment rates.Methods:A training set of 95 tumours from women with pure DCIS were immunostained for proteins involved in cell survival, hypoxia, growth factor and hormone signalling. A generalised linear regression with regularisation and variable selection was applied to a multiple covariate Cox survival analysis with recurrence-free survival 10-fold cross-validation and leave-one-out iterative approach were used to build and test the model that was validated using an independent cohort of 58 patients with pure DCIS. The clinical role of a COX-2-targeting agent was then tested in a proof-of-concept neoadjuvant randomised trial in ER-positive DCIS treated with exemestane 25 mg day−1±celecoxib 800 mg day−1.Results:The COX-2 expression was an independent prognostic factor for early relapse in the training (HR 37.47 (95% CI: 5.56–252.74) P=0.0001) and independent validation cohort (HR 3.9 (95% CI: 1.8–8.3) P=0.002). There was no significant interaction with other clinicopathological variables. A statistically significant reduction of Ki-67 expression after treatment with exemestane±celecoxib was observed (P<0.02) with greater reduction in the combination arm (P<0.004). Concomitant reduction in COX-2 expression was statistically significant in the exemestane and celecoxib arm (P<0.03) only.Conclusions:In patients with DCIS, COX-2 may predict recurrence, aiding clinical decision making. A combination of an aromatase inhibitor and celecoxib has significant biological effect and may be integrated into treatment of COX2-positive DCIS at high risk of recurrence.

Intratumoral concentration of estrogens and clinicopathological changes in ductal carcinoma in situ following aromatase inhibitor letrozole treatment

Background:Estrogens have important roles in ductal carcinoma in situ (DCIS) of the breast. However, the significance of presurgical aromatase inhibitor treatment remains unclear. Therefore, we examined intratumoral concentration of estrogens and changes of clinicopathological factors in DCIS after letrozole treatment.Methods:Ten cases of postmenopausal oestrogen receptor (ER)-positive DCIS were examined. They received oral letrozole before the surgery, and the tumour size was evaluated by ultrasonography. Surgical specimens and corresponding biopsy samples were used for immunohistochemistry. Snap-frozen specimens were also available in a subset of cases, and used for hormone assays and microarray analysis.Results:Intratumoral oestrogen levels were significantly lower in DCIS treated with letrozole compared with that in those without the therapy. A great majority of oestrogen-induced genes showed low expression levels in DCIS treated with letrozole by microarray analysis. Moreover, letrozole treatment reduced the greatest dimension of DCIS, and significantly decreased Ki-67 and progesterone receptor immunoreactivity in DCIS tissues.Conclusion:These results suggest that estrogens are mainly produced by aromatase in DCIS tissues, and aromatase inhibitors potently inhibit oestrogen actions in postmenopausal ER-positive DCIS through rapid deprivation of intratumoral estrogens.

Clinicopathologic, mammographic, and sonographic features in 1,187 patients with pure ductal carcinoma in situ of the breast by estrogen receptor status

The clinicopathologic, mammographic, and sonographic findings in patients with pure ductal carcinoma in situ (DCIS) were assessed by estrogen receptor (ER) expression. After institutional review board approval, patients with pure DCIS evaluated from January 1996 to July 2009 with known ER status and available imaging were identified. Images were reviewed as per the ACR BI-RADS(®) lexicon (4th edition). Clinical, pathologic, and imaging characteristics were analyzed by ER status using t test, Chi square test, and Fisher's exact test. Of 1,219 patients with pure DCIS and known ER status identified, 1,187 with complete data were included. Mammography was performed in all 1,187 patients and sonography in 519 (44 %). There were 972 (82 %) patients with ER-positive and 215 (18 %) with ER-negative disease. ER-negative DCIS was more likely to be high grade (93 vs 44 %, p < 0.0001), associated with comedonecrosis (64 vs 29 %, p < 0.0001), and multifocal (23 vs 15 %, p = 0.009). On sonography, ER-negative DCIS was more likely to be visible (61 vs 46 %, p = 0.004), larger (mean size, 2.3 vs 1.6 cm, p = 0.006), and show posterior shadowing (53 vs 28 %, p = 0.006). Mastectomy was more frequently performed for ER-negative DCIS (47 vs 37 %, p = 0.008). Palpable DCIS was visible on sonography in 55 % of cases and mammography in 81 %. Compared with ER-positive palpable DCIS, ER-negative palpable DCIS was larger and more likely to be visible on sonography. Compared with ER-positive noncalcified DCIS, ER-negative noncalcified DCIS was less likely to be visible on mammography. ER-positive and ER-negative pure DCIS have different clinicopathologic and imaging characteristics. ER-negative DCIS is associated with worse prognostic factors than ER-positive DCIS. On sonography, ER-negative DCIS is more frequently visible than ER-positive DCIS, tends to be larger, and more frequently demonstrates posterior shadowing.