Positive Ductal Carcinoma In Situ Research Articles

The Use of Sentinel Lymph Node Biopsy in Patients Undergoing Mastectomy for DCIS

BackgroundCurrent guidelines do not recommend routine sentinel node biopsy (SLNB) for ductal carcinoma in situ (DCIS), except in the setting of mastectomy or microinvasive disease. This study aimed to evaluate national SLNB utilization in women undergoing upfront mastectomy for DCIS, identify predictors of SLNB utilization, and determine the percentage with a positive SLNB. MethodsA retrospective cohort analysis was performed using the NCDB of women with clinical DCIS who underwent upfront mastectomy between 2012–2017. Demographic and clinicopathologic variables were compared between patients who underwent SLNB and those who did not. Multivariate logistic regression models were used to identify factors associated with SLNB utilization and positive SLNB. Results38,973 patients met inclusion criteria: 34,231 (88%) underwent SLNB and 4,742 (12%) had no surgical axillary staging. Most patients were age 50–69 (51%), non-Hispanic White (71%), with private insurance (66%). On multivariate analysis, older patients were less likely to receive SLNB (p<0.01), while patients with higher grade DCIS were more likely to undergo SLNB (p<0.01). In those who underwent SLNB (n=34,231), only 1,149 (3.4%) had nodal involvement. Non-Hispanic Black patients had increased odds of a positive SLNB (p<0.01), while those with estrogen receptor positive disease were less likely to be node positive (OR 0.68, p<0.001). ConclusionsWhile 88% of patients had a SLNB, only 3.4% were found to be node positive. Given this low rate, it is reasonable to consider SLNB omission in select patients with low grade, hormone receptor positive DCIS undergoing upfront mastectomy. Micro AbstractThe NCDB was used to examine SLNB utilization in patients with DCIS undergoing upfront mastectomy. Findings indicated low rates of nodal involvement and that hormone receptor-negative and high-grade DCIS were associated with positive SLNB, suggesting it is reasonable to consider SLNB omission for select populations.

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&lt;0.0001), and predominantly Caucasian (70% vs 65%, p&lt;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&lt;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&lt;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.

Abstract PR011: DCIS-associated myoepithelial cells drive tumor progressive inflammation through up-regulation of integrin αvβ6

Abstract Background: Ductal carcinoma in-situ (DCIS) is a pre-invasive stage of breast cancer, however &amp;lt;50% will progress to invasion. A key component in promoting tumor invasion is inflammation, though its role in DCIS progression is unclear. We previously, showed αvβ6 expression on DCIS myoepithelial cells promotes tumor cell invasion. We hypothesized that altered myoepithelial phenotype in DCIS may modulate periductal inflammation to contribute to disease progression. Methods: The inflammatory infiltrate in DCIS cases (20 αvβ6+ and 20 αvβ6-) was characterized by immunohistochemistry (IHC) and immunofluorescence-IHC, focusing on Tumor Associated Macrophages (TAM) and Regulatory T cell markers. A myoepithelial cell line over-expressing αvβ6 (β6-1089) and a control counterpart (N-1089) were analyzed for cytokine and signaling molecule expression with proteome profilers and western blotting. The monocyte cell line (THP-1) was exposed to conditioned media from β6-1089 or N-1089 followed by qPCR for TAM markers (IL4, IL10 and IL8), MTS proliferation assay and western blotting for NFkB and STAT6 activation (involved in macrophage differentiation). 3D models were used to examine if the in vivo changes to macrophages can be modelled in vitro. Results: IHC analysis revealed a significant association between myoepithelial αvβ6 expression and increased T-reg cell infiltrate (p&amp;lt; 0.0001). Similarly, αvβ6 expression associated with increased presence of TAM (p=0.0026), αvβ6 positive DCIS with exhibited a microenvironment comprising 15% TAMs compared to 3% in αvβ6 negative DCIS cases. This shift in macrophage phenotype was recapitulated in 3D organotypic assays incorporating macrophages and myoepithelial cells. Proteome profiler analysis of THP-1 cells grown with conditioned media from αvβ6 positive myoepithelial cells demonstrated increased expression of CCL5 while all other proteins analyzed where generally suppressed. Nuclear and cytoplasmic western blotting of THP-1s demonstrated NfκB and STAT activation were altered by CM from myoepithelial cells +/- avb6. Conclusion: DCIS myoepithelial cells upregulate αvβ6 and exhibit changes in the periductal inflammatory infiltrate indicating a switch to a tumor promoting phenotype. Further investigation is required to determine the prognostic value and underlying mechanisms of this change. Citation Format: Michael D. Allen, M. Reza Roozitalab, Stephen Murtough, Eleni Maniati, J. Louise Jones. DCIS-associated myoepithelial cells drive tumor progressive inflammation through up-regulation of integrin αvβ6 [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr PR011.

The Utility of SOX10 Immunohistochemical Staining in Breast Pathology.

SOX10 expression helps identify melanocytic lesions. Over time, novel uses have been identified, such as expression in triple-negative breast cancer (TNBC). We evaluated the usefulness of SOX10 in breast pathology-specifically, identification and subtyping of TNBC and distinction from gynecologic carcinomas, use as a myoepithelial marker, and in the distinction of usual ductal hyperplasia (UDH) from atypical ductal hyperplasia (ADH). Several breast and gynecologic carcinoma tissue microarrays containing a total of 492 cases were stained with SOX10. Whole sections of 34 ADH, 50 UDH, and 29 ductal carcinoma in situ (DCIS) samples were also stained with SOX10. SOX10 expression was identified in 67% of consecutive TNBC cases. Expression was mostly seen in nonapocrine, androgen receptor (AR)-negative TNBCs. All gynecologic carcinomas (n = 157) were negative. All UDH cases showed mosaic SOX10 expression, while all ADH cases lacked expression. All estrogen receptor (ER)-positive DCIS (n = 19) specimens were negative for SOX10, while 2 of 10 ER-negative DCIS specimens were positive for SOX10. The latter 2 cases showed SOX10-positive invasive carcinomas. SOX10 identifies nonluminal AR-type TNBC and is useful in distinguishing TNBC from gynecologic carcinomas. SOX10 can distinguish UDH from ADH. SOX10 is not useful in distinguishing ADH from DCIS.

Survival outcomes after omission of surgery for ductal carcinoma in situ: A National Cancer Database (NCDB) analysis.

e12574 Background: Clinical trials of active surveillance (AS) for Ductal Carcinoma in Situ (DCIS) are underway. We sought to understand the historical management of biologically favorable DCIS and to determine the long-term outcomes of patients who did not have surgery at time of diagnosis. We hypothesized that women who had biologically favorable DCIS and underwent AS would have excellent long-term outcomes. Methods: The NCDB was queried from 2004 to 2017 for women diagnosed with DCIS. This cohort was further refined to identify those with biologically favorable DCIS defined as grade 1 or 2 and hormone receptor (HR) positive. Women under age 40 were excluded. AS was defined as either no surgery or surgery &gt;12 months from diagnosis. A Cochran-Armitage test was used to assess the trend of surgery omission over year of diagnosis. Multivariable logistic regression was used to assess association between baseline factors and AS. Kaplan-Meier curves were estimated to show overall survival (OS) in this biologically favorable DCIS group that underwent AS, stratified by age (&lt;50, 50-65, &gt;65). Univariate and multivariable Cox proportional hazard models were used to determine the effects of prognostic factors on survival distributions. Results: There were 74,868 women with grade 1 or 2, HR positive DCIS, of whom 2,384 (3.2%) were treated with AS. The proportion of patients with biologically favorable DCIS who underwent AS increased over time, peaking in 2017 with 4.2% of DCIS cases diagnosed that year treated with observation (p&lt;0.001). Only 17% of the patients in the AS group received hormonal therapy. On multivariable analysis, increasing age (OR 1.02, p&lt;0.001), black race (OR 1.7, p&lt;0.001), and being uninsured (OR 2.2, p&lt;0.001) were all associated with increased likelihood of AS. In an unadjusted analysis, receipt of surgery was associated with improved OS in the entire cohort. However, the OS benefit from surgery differed when stratified by age. In women &lt;50 years of age, OS outcomes were similar, with 10-year OS of 97.4% in the immediate surgery cohort vs 99.1% in AS cohort (p=0.43). In contrast, in women &gt;50 years of age, 10-year OS was higher for women undergoing surgery (85.3% vs 70.0% in AS group, p &lt;0.001). This association with OS in this older cohort persisted even after adjusting for age, race and comorbidity as well as facility demographics. Conclusions: The proportion of patients with low or intermediate grade, hormone receptor positive DCIS not treated with surgery has remained small but is increasing over time. AS of biologically favorable DCIS in younger, healthier women is not associated with adverse survival. In older women, the finding of benefit of surgery over AS is very likely confounded by underlying health factors that are not fully captured with co-morbidity scores.

Abstract GS2-02: 12 year results of anastrozole versus tamoxifen for the prevention of breast cancer in postmenopausal women with locally excised ductal carcinoma in-situ

Abstract Background: Two large clinical trials have reported divergent results in their initial analysis of the benefit of aromatase inhibitors compared to tamoxifen in women with ductal carcinoma in situ (DCIS) (IBIS-II and NSABP B-35). Here, we report blinded 12-year median follow-up efficacy and adverse event data for the IBIS-II trial, which compared anastrozole to tamoxifen in women with hormone receptor positive DCIS and focus on the post-treatment follow-up period.Methods: A multi-centre randomised trial of 1mg/day anastrozole (N=1471) vs. 20mg/day tamoxifen (N=1509) for five years was conducted in postmenopausal women with locally excised DCIS diagnosed between 2003 and 2009. The primary objective of this analysis was to determine the efficacy of anastrozole compared to tamoxifen in preventing recurrences overall, and in particular in the post 5-year treatment period. Secondary endpoints included type of recurrence, breast cancer mortality, other cancers, cardiovascular disease, fractures, adverse events and non-breast cancer deaths.Results: After a median follow-up of 11.6 years (IQR 9.9 to 13.4), a total of 221 breast cancer recurrences (7.4%) have been recorded. No difference in overall recurrence was observed (102 (6.9%) anastrozole vs. 119 (7.9%) tamoxifen; HR=0.87 (0.67-1.14), P=0.32) overall (Table), in the 5-year treatment period (HR=0.82 (0.53-1.27), P=0.37), or the post treatment follow-up period (HR=0.91 (0.65-1.27), P=0.57). Oestrogen receptor (ER) positive breast cancers were reduced by 28% with anastrozole when compared to tamoxifen (58 vs. 82; HR=0.72 (0.52-1.01), P=0.056) but this did not reach significance. In contrast, no effect was observed for ER-negative breast cancer with anastrozole (Table). No significant difference for the reduction in invasive breast cancer recurrence was observed with anastrozole when compared to tamoxifen (Table). Invasive ER-positive breast cancer was non-significantly reduced by 24% with anastrozole when compared to tamoxifen (44 vs. 59; HR=0.76 (0.51-1.12), P=0.17). A total of 127 deaths have been reported, with no significant difference in all-cause mortality between the two treatment arms (61 vs. 66; HR=0.94 (0.67-1.33), P=0.74). Only 7 deaths from breast cancer (3 vs. 4) were reported, with so few deaths from breast cancer at 12 years, any impact on survival is unlikely to emerge with longer follow-up. 214 cancers other than breast were reported, with a non-significant decrease observed with anastrozole (97 vs. 117, OR=0.84 (0.63-1.12), P=0.22). Endometrial (2 vs. 13, OR=0.16 (0.02-0.0.69)), ovarian cancer (1 vs. 9, OR=0.11 (0.003-0.82)), and non-melanoma skin cancer (11 vs. 21) were less common with anastrozole. Significantly higher rates of fractures (181 vs. 145, OR=1.32 (1.04-1.68)) and transient ischaemic attacks (15 vs. 5, OR=3.10 (1.07-10.92)) were observed with anastrozole compared to tamoxifen. A comprehensive adverse event profile will be reported. Conclusions: No clear efficacy differences were seen between the two treatments, although the data suggests possible greater efficacy for anastrozole over tamoxifen for prevention of ER-positive breast cancers. There were some clear differences in adverse events and anastrozole may be more appropriate for some women with contraindications for tamoxifen. Table: Number of events and Hazard Ratios (95% CI) according to treatment allocation.Anastrozole(N=1471)Tamoxifen(N=1509)HR (95% CI)Any recurrence1021190.87 (0.67-1.14)ER-positive58820.72 (0.52-1.01)ER-negative24151.63 (0.86-3.11)Invasive66760.89 (0.64-1.23)ER-positive44590.76 (0.51-1.12)ER-negative17121.44 (0.69-3.02)DCIS35420.85 (0.54-1.33)ER-positive14230.62 (0.32-1.21)ER-negative732.38 (0.61-9.20)Numbers do not add up due to missing information Citation Format: Ivana Sestak, Jack Cuzick, Bernardo Bonanni, Nigel Bundred, Christelle Levy, Sibylle Loib, Patrick Neven, Michael Stierer, Chris Holcombe, Robert Coleman, John Forbes, Anthony Howell. 12 year results of anastrozole versus tamoxifen for the prevention of breast cancer in postmenopausal women with locally excised ductal carcinoma in-situ [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS2-02.

Adequacy of invasive and in situ breast carcinoma margins in radioactive seed and wire-guided localization lumpectomies.

Image-guided preoperative localizations help surgeons to completely resect nonpalpable breast cancers. The objective of this study is to compare the adequacy of specimen margins for both invasive breast cancer (IBC) and ductal carcinoma in situ (DCIS) after radioactive seed localization (RSL) vs wire-guided localization (WGL). We retrospectively reviewed 600 cases at a single Canadian academic center from January 2014 to September 2017, comparing surgical margins, re-excisions and reoperations, localization accuracy and major complications (migration, accidental deployment, vasovagal reaction), as well as operative duration between RSL and WGL cases. IBC margins were positive in 7% of RSL and 6% of WGL cases (P=.57). Tumor size (P =.039) and association with DCIS (P=.036) predicted positive margins in invasive carcinoma. DCIS margins were positive in 6% and 8%, and close (≤2mm) in 37% and 36% of cases (P = .45) for RSL and RSL cases respectively. The presence of extensive intraductal component predicted positive DCIS margins (P <.0001). There was no significant difference between intraoperative re-excisions (P=.54), localization accuracy (P=.34), and operation duration (P=.81). Reoperation for lumpectomies and mastectomies was marginally higher for WGL than RSL (P=.049). There were 11 (4%) WGL and no RSL complications (P=.03). Overall, positive margins for IBC, close or positive margins for DCIS, intraoperative re-excision, localization accuracy, and operation duration were similar between RSL and WGL. The reoperation rate was higher in WGL than RSL, which may reflect practice changes over time. RSL was safer than WGL with lower complication rates.

Abstract 6461: HER2 positive DCIS increases short term risk of ipsilateral invasive ductal carcinoma in breast conserving surgery patients

Abstract Purpose: The impact of HER2 status in ductal carcinoma in situ (DCIS) lesions on the risk of progression to invasive ductal carcinoma (IDC) has been debated with reports of both increased and decreased risk of development of invasive breast cancer in HER2 positive patients. We aim to use a large national database to elucidate the effect of HER2 positivity on ipsilateral IDC (iIDC) development. Methods: We performed survival analyses on patient-level data using the US National Cancer Institute's Surveillance, Epidemiology, and End Results program to identify patients diagnosed with DCIS who underwent lumpectomy and had known HER2, estrogen and progesterone receptor statuses, grade, comedonecrosis, age, tumor size, and radiation therapy (RT). Competing risks analysis was performed. Results: 1,540 patients meeting inclusion criteria were identified. Median age at diagnosis was 60 with median follow-up time of 44.5 months. 22 (1.4%) patients developed iIDC and 27 (1.8%) developed ipsilateral in situ or contralateral disease. 1,035 (67.2%) patients were HER2 negative and 417 (27.1%) were HER2 positive. The estimated cumulative incidence of iIDC at 5 years was 1.9% for all patients, 1.2% (95% CI 0.6-2.1%) for HER2 negative patients, and 4.0% (95% CI 2.9-5.4%) for HER2 positive patients. On competing risks regression, two factors were significant for iIDC: RT within 20 months (HR=0.02, p=0.0002) and HER2 positivity (HR=2.81, p=0.046). Conclusions: HER2 may serve as a prognostic factor for consideration in decision making in patients for whom it is available, and in our analysis was the only lesion-related factor to significantly relate to iIDC development. Citation Format: Thomas O'Keefe, Sarah Blair, Ava Hosseini, Olivier Harismendy, Anne Wallace. HER2 positive DCIS increases short term risk of ipsilateral invasive ductal carcinoma in breast conserving surgery patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6461.

Impact of hormonal status on ductal carcinoma in situ of the breast: Outcome and prognostic factors.

Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous disease which is increasingly diagnosed through improved screening measures. Multiple prognostic scores have been devised to predict the risk of local recurrence (LR), and the optimal adjuvant management for DCIS is still debated. Hence, the aim of this analysis is to investigate the factors contributing to the prognosis of DCIS, in particular the role of its hormonal status. From 2005 to 2016, a total of 1221 female patients diagnosed with DCIS at the National Cancer Centre Singapore and Singapore General Hospital were studied. The mean age of diagnosis was 54years of age (sd=11.0), with estrogen receptor (ER)-positive DCIS tumors presenting earlier (mean age 54 vs 57years of age; P<.001). DCIS with negative hormonal status (HS) correlates significantly with a larger size (mean 23.5mm vs 13.0mm, P<.001) and higher grade of tumor (P<.001). Patients with positive HS were more likely to undergo breast conservation surgery over a mastectomy, in contrast to patients with negative HS (P<.001). Patients with negative HS had a poorer prognosis, with a shorter time of overall survival time (HR=26.3, P=.020). In conclusion, our study shows that the hormonal status, age of diagnosis, and positive margins are important prognostic factors for DCIS, at least in our Asian population.

Risk factors for estrogen receptor positive ductal carcinoma in situ of the breast in African American women

BackgroundCompared to U.S. white women, African American women are more likely to die from ductal carcinoma in situ (DCIS). Elucidation of risk factors for DCIS in African American women may provide opportunities for risk reduction. MethodsWe used data from three epidemiologic studies in the African American Breast Cancer Epidemiology and Risk Consortium to study risk factors for estrogen receptor (ER) positive DCIS (488 cases; 13,830 controls). Results were compared to associations observed for ER+ invasive breast cancer (n = 2,099). ResultsFirst degree family history of breast cancer was associated with increased risk of ER+ DCIS [odds ratio (OR): 1.69, 95% confidence interval (CI): 1.31, 2.17]. Oral contraceptive use within the past 10 years (vs. never) was also associated with increased risk (OR: 1.43, 95%CI: 1.03, 1.97), as was late age at first birth (≥25 years vs. <20 years) (OR: 1.26, 95%CI: 0.96, 1.67). Risk was reduced in women with older age at menarche (≥15 years vs. <11 years) (OR: 0.62, 95%CI: 0.42, 0.93) and higher body mass index (BMI) in early adulthood (≥25 vs. <20 kg/m2 at age 18 or 21) (OR: 0.75, 95%CI: 0.55, 1.01). There was a positive association of recent BMI with risk in postmenopausal women only. In general, associations of risk factors for ER+ DCIS were similar in magnitude and direction to those for invasive ER+ breast cancer. ConclusionsOur findings suggest that most risk factors for invasive ER+ breast cancer are also associated with increased risk of ER+ DCIS among African American women.

Abstract P5-07-07: The immune microenvironment of ductal carcinoma in situ of the breast

Abstract Background: The importance of tumor-infiltrating lymphocytes (TIL) in invasive breast carcinoma for tumor development and therapeutic response is widely accepted. However, the immune microenvironment of breast ductal carcinoma in situ (DCIS) has not been fully elucidated. Evasion of immune surveillance is a necessary step in tumor evolution. In DCIS, the tumor cells are relatively protected from the immune system due to an myoepithelial cell layer and basement membrane, and intraductal immune cells are rarely detected. In contrast, in invasive disease, cancer cells and immune cells are often intermingled. Thus, understanding the immune microenviroment of in situ to invasive carcinoma transition might be particularly important to identify novel targets for early stage of tumor invasion. Aims: The aim of this study is to evaluate the clinical importance of TILs in DCIS. Methods: TILs were assessed in 133 DCIS samples with or without microinvasive disease according to the proposed method from the International Immuno-Oncology Working Group on Breast Cancer. In addition, the relationship between TILs in DCIS and clinicopathological features was evaluated. Results: TILs are present in most DCIS in varying levels. The median proportion of TILs in DCIS was 14%. Only a minority of DCIS showed &amp;gt;50% TILs, which represented only 12.8% of all cases. High TILs in DCIS was significantly associated with comedo necrosis (p&amp;lt;0.0001), high nuclear grade (p=0.0030), ER negativity (p&amp;lt;0.0001), PR negativity (p&amp;lt;0.0001), HER2 positivity (p=0.0030). Triple negative DCIS and HER2 positive DCIS had significantly higher level of TILs (p=0.0008). No correlation was demonstrated between TILs and recurrence risk. Conclusions: High TILs in DCIS was significantly associated with adverse histopathologic features. Further characterization of immune environment of DCIS may be essential for immunotherapy and breast cancer prevention. Citation Format: Yamashita N, Hisamatsu Y, Shigechi T, Tokunaga E, Saeki H, Oki E, Maehara Y. The immune microenvironment of ductal carcinoma in situ of the breast [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-07-07.

Abstract PD8-09: Approximately 40% of invasive recurrences after treatment of ductal carcinoma in situ is likely to be a second primary tumor

Abstract Background. Ductal carcinoma in situ (DCIS) is a potential precursor of invasive breast cancer, because: DCIS often accompanies invasive breast cancer; its risk factors are similar to those of invasive breast cancer; and genetic markers found in DCIS are similar to the ones found in invasive breast cancer. However, clinical behavior of DCIS is still poorly understood, as there is only limited information on its long-term natural history. Altogether, this makes it difficult to understand the relatedness of DCIS and its subsequent ipsilateral invasive breast cancer (iIBC). Here, we set-up a comparison between primary DCIS and matched subsequent iIBC, by making use of pathological and molecular data. Patients and methods. For this study, we used a unique series of 155 DCIS cases which developed a subsequent iIBC during a median follow up period of 12.6 years. We assessed histological characteristics, tumor location, estrogen and progesterone receptor status, p16 expression, and HER2 and p53 overexpression. RNA sequencing and copy number sequencing was done on 78 DCIS lesions and 78 matched invasive breast cancer relapses. We determined if the iIBC lesion and DCIS lesion were related, with respect to tumor location, immunohistochemical (IHC) markers, and genomic features. Results. Based on tumor location and histological grade, &amp;gt;95% of the subsequent invasive breast cancers reflected outgrowth of residual disease. HER2 was the only IHC marker that showed a significant difference in expression between DCIS and matched iIBC: 40% of the HER2 positive DCIS was followed by a HER2 negative invasive recurrence. In addition, RNAseq data was used to classify DCIS and IBC lesions into PAM50 subtypes. 77% of the DCIS IBC pair belonged to the same subtype. The DCIS lesions showed copy number aberrations on typical breast cancer-associated loci. However, when we compared the DCIS with its matched iIBC, we saw in 41% of the cases very distinct copy number profiles, indicating either outgrow of a different tumor subclone or a second primary. Conclusion. This is the first time that a sound comparison could be made between primary DCIS and its subsequent invasive breast cancer with such a large patient group, integrating pathological and molecular data. Our results strongly suggest that many subsequent iIBCs after treatment of pure DCIS could be considered as second primary breast cancer lesions. To provide definite proof for this, in depth DNA sequencing and heterogeneity studies will be presented at SABCS 2018. Citation Format: Visser LL, Hoogstraat M, Elshof LE, van de Vijver K, Groen EJ, Almekinders MM, Bierman C, Nieboer F, de Maaker M, Kristel P, Mulder L, Schaapveld M, Schmidt MK, Lips E, Wesseling J. Approximately 40% of invasive recurrences after treatment of ductal carcinoma in situ is likely to be a second primary tumor [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD8-09.

Current Therapeutic Approaches to DCIS.

Treatment for ductal carcinoma in-situ (DCIS) has historically been extrapolated from studies of invasive breast cancer. Accepted local therapy approaches range from small local excisions, with or without radiation, to bilateral mastectomies. Systemic treatment with endocrine therapy is often recommended for hormone positive patients. With improvements in imaging, pathologic review, and treatment techniques in the modern era, combined with new information regarding tumor biology, the management of DCIS is rapidly evolving. A multidisciplinary approach to treatment is now more important than ever, with a shift towards de-escalating therapy to reduce treatment related toxicity. This review focuses on nuances of clinical management of DCIS in the modern era, highlighting key differences between DCIS as compared to invasive breast cancer. The American Cancer Society (ACS) currently recommends beginning screening with annual mammograms for women age 45, with the option to start at age 40. As treatment of DCIS has not been shown to impact survival, the USPSTF has more conservative screening recommendations of biennial mammograms from age 50-74. Unlike invasive breast cancer, DCIS is almost exclusively diagnosed by mammographic detection, and lymph node evaluation is not recommended. Pathologic review of biopsy specimens should follow the guidelines of the College of American Pathologists. Surgical management options include breast conservation, mastectomy, or possibly nipple sparing mastectomy, with upfront sentinel lymph node evaluation in the case of mastectomy. Radiation therapy is generally recommended as a component of breast conserving therapy for patients with DCIS, though in some low risk patients, there is trial data to suggest that adjuvant radiation may be omitted. Techniques for minimizing radiation toxicity should always be emphasized. Endocrine therapy is offered to women with hormone positive DCIS who have undergone lumpectomy for risk reduction, and has the benefit of decreasing incidence of events in both the ipsilateral and contralateral breast. More recent studies have explored use of targeted treatments such as trastuzumab in DCIS for HER2 overexpression. Future directions include tailoring therapy based on patient characteristics and tumor biology. With so many different options for treatment, it is also critical to engage in a discussion with the patient to arrive at a treatment decision that balances patient preferences for disease control versus treatment toxicity, financial toxicity, cosmesis, and quality of life.

Triple-negative and HER2 positive ductal carcinoma in situ of the breast: characteristics, behavior, and biomarker profile.

We compared the characteristics, clinical behavior, and biomarker profile between HER2 positive (HER2+) and triple-negative (TN) ductal carcinoma in situ (DCIS) which are considered more aggressive than other DCIS subtypes. In addition, we explored the impact of these features on its potential of progression to invasive breast carcinomas. Cases of DCIS diagnosed at the Department of Pathology, Singapore General Hospital from 1994 to 2010 were identified. TN and HER2+ DCIS cases formed the study cohort. Immunohistochemistry (IHC) was performed for ER, PR, HER2, CK14, EGFR, and p53. Comparisons of clinicopathological features, IHC results, and clinical outcomes were performed between the two groups. We evaluated 145 HER2+ and 85 TN DCIS cases. HER2 positive DCIS had significantly higher nuclear grade (p < 0.001) and more frequent necrosis (p < 0.001) than TN DCIS. HER2 positive DCIS also harbored significantly higher rates of nuclear p53 immunoreactivity (p = 0.002) than TN DCIS. Younger patients (age < 40) with HER2+ and TN DCIS demonstrated statistically significant worse invasive DFS than older women (p < 0.001). Multivariate cox regression analysis (HR 15.08, 95% CI 12.79-81.45, p = 0.002) also confirmed these findings. In addition, younger patients (age < 40) with HER2+ DCIS experienced significantly poorer prognosis when p53 was also positive (p = 0.033). HER2+ DCIS had more aggressive pathological characteristics compared to TN DCIS; accumulation of mutant p53 could possibly be contributory. Age was an independent predictor of aggressive biological behavior of HER2+ and TN DCIS. We demonstrated that younger patients with p53 positive HER2+ DCIS had significantly adverse clinical outcome.

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.

Trends in adjuvant therapies after breast-conserving surgery for hormone receptor-positive ductal carcinoma in situ: findings from the National Cancer Database, 2004-2013.

Breast-conserving surgery (BCS) followed by radiotherapy (RT) with or without endocrine therapy (ET) is a standard treatment option for ductal carcinoma in situ (DCIS). We sought to investigate national patterns in the use of adjuvant therapy after BCS for hormone receptor (HR)-positive DCIS over time. Using data from the National Cancer Data Base, we identified patients diagnosed with DCIS and treated with BCS between 2004 and 2013. Multivariable logistic regression was used to estimate the odds of adjuvant therapy use controlling for clinicopathologic demographic and facility-level characteristics. We identified 66,079 patients who underwent BCS for DCIS. Overall, 21% received no adjuvant treatment, 71% received RT, 48% received ET, and 38% received the combination therapy. In adjusted analyses among the patients with HR-positive DCIS (n=50,147), the administration of RT decreased (odds ratio [OR] 0.86, 95% CI 0.77-0.97), while the use of ET increased (OR 1.5, 95% CI 1.4-1.6) in 2013 compared to 2004. Young patients, elderly patients, positive margin status, and Medicare insurance were associated with lower use of both RT and ET. We observed both clinicopathologic and geographic variation in the use of adjuvant therapies. In the lowest risk subgroup, the use of RT decreased from 57% in 2004 to 48% in 2013 (OR 0.64, 95% CI 0.45-0.89). Our study suggests a shift in patterns of care for DCIS that is impacted by both clinicopathologic and demographic factors, with the use of RT decreasing and the use of ET increasing in HR-positive DCIS patients. Current trials are designed to address the possible over-treatment of low-risk DCIS.

Abstract CT140: PINC trial: Preventing invasive breast neoplasia with chloroquine

Abstract The PINC trial (NCT01023477) examined the dosage efficacy of oral chloroquine (CQ), an autophagy inhibitor, as a neoadjuvant therapy to reduce the volume, cause regression and decrease the recurrence of breast ductal carcinoma in situ (DCIS), for any grade or ER/PR/Her2 status. Study Objectives: Establish the safety of preventive doses of chloroquine in patients receiving external beam radiation. Elucidate functional molecular and cellular impacts of in vivo autophagy pathway treatment for DCIS. Study the impact of autophagy inhibitors on the MRI characteristics of DCIS lesions. Study the molecular cytogenetic profile of DCIS lesions before and after therapy. This trial implemented a general strategy to accelerate the pace of community-based translational research. Technology for providing immediate feedback on the therapeutic efficacy at the molecular level can be broadly extended to other trials. Methodology: 12 patients diagnosed with DCIS (any grade or ER/PR/Her2 status) were enrolled and randomly assigned to receive CQ at 250mg/week (n=5) or 500mg/week (n=7) for 4 weeks, followed by standard of care surgical therapy. MRI was performed before/after CQ treatment. DCIS spheroid forming cells were isolated and propagated from fresh human DCIS lesions. DCIS cells were characterized by organ culture, xenograft transplantation, molecular cytogenetics, and 59 cell signaling kinases were quantified by Reverse Phase Protein Microarrays. Results: 12 patients completed 4 weeks of CQ treatment prior to surgical excision of their DCIS lesion, with 1 yr follow-up information. CQ treatment reduced PCNA proliferation index in DCIS lesions compared to untreated controls (p=0.001) and inhibited autophagic flux (LC3B positive puncta by IHC). CQ reduced the number of mammospheres in organoid culture without altering copy number variation. Xenograft transplants in NOD/SCID mouse mammary fat pads failed to generate tumors (n=4). 7/12 patients exhibited a reduction in lesion diameter by MRI, 3/12 patients exhibited no measurable change, and 2/12 had a slight increase. Calcium export channel protein (PMCA2) co-localized with 3+ HER2 positive DCIS lesions. Tumor infiltrating macrophages migrated into DCIS ducts following CQ therapy compared to controls (p=0.006). Conclusion: Oral chloroquine, as anti-autophagy therapy, generates a measurable reduction in proliferation of DCIS lesions and enhances immune cell migration into the duct. Citation Format: Virginia A. Espina, Lance Liotta, Svetlana Rassulova, Holly Gallimore, Thalia Grant-Wisdom, Geetha Menezes, Hassan Nayer, Kirsten Edmiston. PINC trial: Preventing invasive breast neoplasia with chloroquine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT140. doi:10.1158/1538-7445.AM2017-CT140

Abstract 4738: Risk of ipsilateral invasive breast cancer after DCIS: a comparison of primary DCIS and subsequent invasive disease by morphological and immunohistochemical analysis

Abstract INTRODUCTION. The wide spread adoption of population-based breast cancer screening has led to a substantial increase in diagnosis of ductal carcinoma in situ (DCIS). When detected, almost all DCIS is treated to prevent progression to invasive disease, even though the majority of DCIS will never progress. Yet, we are unable to discriminate harmless from potentially hazardous DCIS. Hence, there is an urgent need to find characteristics of DCIS and biomarkers that predict subsequent invasive tumor development. In this study, we compared primary DCIS lesions with their subsequent ipsilateral invasive breast cancer (iIBC), to explore how the initial DCIS lesion and its subsequent iIBC are related. PATIENTS AND METHODS. We used a population-based, nation-wide cohort consisting of 2,654 women who were treated for primary DCIS by breast conserving surgery (BCS) only. Within a median follow-up time of 10.7 years, 316 women developed a subsequent iIBC (12%). FFPE tissue blocks of both DCIS and subsequent iIBC could be collected for 158 of these 316 women. We assessed histology characteristics, tumor location, estrogen and progesterone receptor status, p16 expression, and HER2 and p53 overexpression. Additionally, DNA and RNA were simultaneously isolated from 100 DCIS and 100 matched subsequent iIBC specimens for extensive molecular profiling. RESULTS. More than 95% of the invasive recurrences were located at or near the site of the primary DCIS. Concordant histological grade was found in 94% of the matched pairs and identical immunohistochemical (IHC) marker expression in 58%. Of the 44 patients with HER2 positive DCIS, 36% developed HER2 negative iIBC. Furthermore, this change in HER2 status was also a main cause of a change in surrogate intrinsic subtype (based on ER, PR, HER2) between DCIS and iIBC, which was observed in 16% of the patients. These dissimilarities were not found when we compared invasive disease with synchronous DCIS (present in 83 of 158 patients). Molecular analyses is still ongoing. CONCLUSION. This is the first time that an unbiased comparison could be made between primary DCIS and its subsequent iIBC within such a large patient group, integrating clinical, histological and IHC data. Our results suggest that the majority of invasive breast cancers in our cohort reflect outgrowth of residual disease based on tumor location and histological grade. DCIS and iIBC are very similar when comparing histological grade, but frequently show differences on the IHC level. Remarkably, the dissimilarities in HER2 status and surrogate intrinsic subtype as seen in primary DCIS vs. iIBC are missing when comparing IBC with synchronous DCIS. As a next step, we will analyse the lesions on the molecular level, to verify these findings and to look for molecular characteristics of DCIS that could be associated with progression to invasive disease. Citation Format: Lindy L. Visser, Lotte L. Elshof, Koen van de Vijver, Emma J. Groen, Mathilde Almekinders, Marjanka K. Schmidt, Flora van Leeuwen, Emiel J. Rutgers, Michael Schaapveld, Esther H. Lips, Jelle Wesseling. Risk of ipsilateral invasive breast cancer after DCIS: a comparison of primary DCIS and subsequent invasive disease by morphological and immunohistochemical analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4738. doi:10.1158/1538-7445.AM2017-4738

The prevalence and clinical relevance of tumor-infiltrating lymphocytes (TILs) in ductal carcinoma in situ of the breast

Tumor-infiltrating lymphocytes (TILs) are a robust prognostic adjunct in invasive breast cancer, but their clinical role in ductal carcinoma in situ (DCIS) has not been ascertained. We evaluated the prevalence and clinical relevance of TILs in a well annotated series of 1488 consecutive DCIS women with a median follow-up of 8.2years. Detailed criteria for TILs evaluation were pre-defined involving the International Immuno-Oncology Biomarker Working Group. TILs percentage was considered both as a continuous and categorical variable. Levels of TILs were examined for their associations with ipsilateral breast event (IBE), whether in situ or invasive. Of the 1488 patients with DCIS under study, 35.1% had <1%, 58.3% 1-49% and 6.5% ≥50% peri-ductal stromal lymphocytes. The interobserver agreement in TILs evaluation, measured by the intraclass correlation coefficient (ICC) was 0.96 (95% CI 0.95-0.97). At univariable analysis, clinical factors significantly associated with TILs (P ≤0.001) were intrinsic subtype, grade, necrosis, type of surgery. Her-2 positive DCIS were more frequently associated with TILs (24% of patients with TILs ≥50%), followed by the triple negative (11%), Luminal B/Her-2 positive (9%) and Luminal A/B subtypes (1%) (P < 0.0001). We did not find any association between TILs as a continuous variable and the risk of IBEs. Likewise, when patients were stratified by TILs percentage (<1%, between 1% and 49.9%, and ≥50%), no statistically significant association was observed (10-year cumulative incidence of IBEs: 19%, 17.3%, and 18.7% respectively, P = 0.767). TILs occur more frequently in the Her-2 positive DCIS. Although we did not find a significant association between TILs and the 10-year risk of IBE, our data suggest that immunotherapies might be considered in subsets of DCIS patients.

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.