Treatment Of Ductal Carcinoma In Situ Research Articles

Treating Second Breast Events After Breast-Conserving Surgery for Ductal Carcinoma in Situ.

Background: Because of screening mammography, the number of ductal carcinoma in situ (DCIS) survivors has increased dramatically. DCIS survivors may face excess risk of second breast events (SBEs). However, little is known about SBE treatment or its relationship to initial DCIS care. Methods: Among a prospective cohort of women who underwent breast-conserving surgery (BCS) for DCIS from 1997 to 2008 at institutions participating in the NCCN Outcomes Database, we identified SBEs, described patterns of care for SBEs, and examined the association between DCIS treatment choice and SBE care. Using multivariable regression, we identified features associated with use of mastectomy, radiation therapy (RT), or antiestrogen therapy (AET) for SBEs. Results: Of 2,939 women who underwent BCS for DCIS, 83% received RT and 40% received AET. During the median follow-up of 4.2 years, 200 women (6.8%) developed an SBE (55% ipsilateral, 45% invasive). SBEs occurred in 6% of women who underwent RT for their initial DCIS versus 11% who did not. Local treatment for these events included BCS (10%), BCS/RT (30%), mastectomy (53%), or none (6%); only 28% of patients received AET. Independent predictors of RT or mastectomy for SBEs included younger age, shorter time to SBE diagnosis, and RT or AET for the initial DCIS. Conclusions: A sizable proportion of patients with SBEs were treated with mastectomy, most especially those who previously received RT for their initial DCIS and those who developed an ipsilateral SBE. Despite the occurrence of an SBE, relatively few patients received AET. Future studies should investigate optimal treatment approaches for SBEs, including the benefit of mastectomy versus lumpectomy for an ipsilateral SBE and the benefit of AET for a hormone-receptor-positive SBE contingent on AET use for the initial DCIS diagnosis.

Modeling Ductal Carcinoma In Situ (DCIS): An Overview of CISNET Model Approaches.

Ductal carcinoma in situ (DCIS) can be a precursor to invasive breast cancer. Since the advent of screening mammography in the 1980's, the incidence of DCIS has increased dramatically. The value of screen detection and treatment of DCIS, however, is a matter of controversy, as it is unclear the extent to which detection and treatment of DCIS prevents invasive disease and reduces breast cancer mortality. The aim of this paper is to provide an overview of existing Cancer Intervention and Surveillance Modelling Network (CISNET) modeling approaches for the natural history of DCIS, and to compare these to other modeling approaches reported in the literature. Five of the 6 CISNET models currently include DCIS. Most models assume that some, but not all, lesions progress to invasive cancer. The natural history of DCIS cannot be directly observed and the CISNET models differ in their assumptions and in the data sources used to estimate the DCIS model parameters. These model differences translate into variation in outcomes, such as the amount of overdiagnosis of DCIS, with estimates ranging from 34% to 72% for biennial screening from ages 50 to 74 y. The other models described in the literature also report a large range in outcomes, with progression rates varying from 20% to 91%. DCIS grade was not yet included in the CISNET models. In the future, DCIS data by grade from active surveillance trials, the development of predictive markers of progression probability, and evidence from other screening modalities, such as tomosynthesis, may be used to inform and improve the models' representation of DCIS, and might lead to convergence of the model estimates. Until then, the CISNET model results consistently show a considerable amount of overdiagnosis of DCIS, supporting the safety and value of observational trials for low-risk DCIS.

Variations in cancer care for adolescents and young adults (AYAs) with ductal carcinoma insitu.

NCCN guidelines recommend tamoxifen (TAM) for adjuvant treatment of ductal carcinoma insitu (DCIS). TAM has side effects that can potentially complicate treatment recommendations and patient acceptance. It is unknown how well-accepted this recommended therapy is for the adolescent and young adult (AYA) patient population with DCIS. The NCDB was used to identify patients aged 15-39 with DCIS treated between 2000 and 2012. Patient demographic, socioeconomic, and treatment data were collected. Chi-squared test and multivariate analysis were used for statistical assessment. A total of 3988 women were identified of which 1795 (45%) were recommended for endocrine therapy. Age>30 (OR 1.31, 95%CI 1.01-1.70), Black (OR 1.40, 95% CI 1.12-1.65), or Asian (OR 1.45, 95% CI 1.08-1.94) race, treatment at a nonacademic facility (OR 0.71, 95% CI 0.56-0.91), geographic location of treating facility, receipt of radiation (OR 5.30, 95% CI 4.59-6.11), and negative margins (OR 2.14, 95% CI 1.47-3.11) were significant predictors of recommendation for endocrine therapy. Of those recommended, 1484 (83%) accepted treatment. Age, race, and annual income were significant variables affecting acceptance. Overall, only 37.2% (1484 of 3988) of women in this study initiated endocrine therapy for treatment of DCIS. Our results demonstrate that little over a third of patients in the AYA cohort receive endocrine therapy as treatment for DCIS. The bias appears to lie in physician recommendation because when recommended, the majority of patients accept treatment. Factors exist both medical and nonmedical that appear to influence these treatment decisions.

Is Adjuvant Endocrine Therapy Indicated for DCIS Patients After Complete Surgical Excision?

Data derived from pathological analysis, natural history, radiological characteristics, genomic profiling, and clinical outcome indicate that ductal carcinoma in situ (DCIS) is a heterogeneous disease; meaning that no single therapeutic strategy is best, but rather that treatment should be personalised and entail a rigorous multidisciplinary approach. The role of adjuvant endocrine therapy after surgical excision has been the subject of scientific debate in view of the in situ nature of this neoplasm. We reviewed the literature and summarised the evidence regarding the need for adjuvant endocrine therapy following complete surgical excision of DCIS through the identification of the most important outcomes, evaluation of quality of evidence, and assessment of the trade-offs involved. There is no scientific evidence that adjuvant endocrine therapy reduces the incidence of ipsilateral breast invasive recurrence or breast cancer mortality in the context of adequate local treatment of DCIS in the form of breast conserving surgery with clear surgical margins plus adjuvant radiotherapy or total mastectomy. Therefore, its routine use is not indicated. However, adjuvant endocrine therapy can be considered after a rigorous multidisciplinary discussion and patient counselling in a carefully selected subgroup of patients with high-risk estrogen receptor-positive DCIS.

Abstract P4-15-11: “Is it cancer or not?” A qualitative exploration of patient perspectives surrounding the diagnosis and treatment of DCIS

Abstract Background: Approximately 53,000 women in the US undergo treatment for ductal carcinoma in situ (DCIS) each year, of whom only 20-30% may benefit. To better understand both the clinical and psychosocial impact of a DCIS diagnosis and different management approaches, we sought to engage women with DCIS regarding their experience surrounding diagnosis (dx) and treatment. Methods: In July 2014, we administered a web-based survey through an email listserv to the Susan Love Army of Women that resulted in over 2000 respondents self-identified as patients with DCIS. The survey included open-ended questions designed to assess patients' perspectives on their experiences with the dx and treatment of their DCIS. Responses were coded using an inductive coding schema; common themes were identified and summarized. Women who reported an invasive cancer, a second primary or recurrent tumor, or other benign breast lesions (in absence of DCIS) were excluded from analysis. Results: Among 1,857 women included in the analytic sample, the average age at dx was 60 years; 18% women were ≤2 years from their dx; most women (93%) identified as white. Four primary themes were identified: 1) uncertainty about DCIS dx; 2) uncertainty surrounding treatment; 3) concern about side effects from treatment; and 4) concern about recurrence and invasive breast cancer. Uncertainty about treatment often manifested as women questioning whether they were over-treated for their DCIS, “over-reacting by having surgery,” or wondering if “watchful waiting might be better.” In addition to recalling bothersome side effects and sequelae from both their local and systemic (hormonal) therapy, women also expressed doubt about their treatment choices, specifically, that they were not necessarily “doing enough” with many women citing recurrence, the “cancer spreading”, or becoming invasive, as primary concerns. Uncertainty about whether DCIS was cancer or not, was noted by many women, with one calling it a “grey zone” and others articulating that DCIS is “having a dx that's not really cancer… yet you might still lose your breast,” and experiencing “confusion about my status as a cancer patient - as in I wasn't sure if I even was a cancer patient. I had no idea where I fit in…” Conclusion: A DCIS dx can be confusing and distressing, with women making treatment decisions based on a limited understanding of the disease, its risks, and pros and cons of treatment options. There is a need to develop additional strategies to improve the management of this disease and other screen-detected conditions, through better understanding of the disease and its outcomes, coupled with improved methods to communicate this information to those affected. Our study highlights the potential value of collecting patient reported outcomes (PROs) to inform clinical research and care. Ongoing clinical trials like the COMET, LORIS, and LORD studies, which incorporate robust PROs, should provide additional evidence for patients, health care providers and other stakeholders regarding the medical and psychosocial benefits and harms of different DCIS management options. Citation Format: Rosenberg SM, Gierisch JM, Lowenstein C, Frank ES, Collyer D, Partridge AH, Hwang ES. “Is it cancer or not?” A qualitative exploration of patient perspectives surrounding the diagnosis and treatment of DCIS [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-15-11.

Abstract P4-15-03: Tumor-infiltrating lymphocytes in breast ductal carcinoma in situ: Correlations with tumor pathobiology in a French cohort of 495 cases (BONBIS)

Abstract Background: Numerous studies have shown important impact of tumor-infiltrating lymphocytes (TILs) on natural or therapeutically-modified evolution of invasive breast cancer (IBC), however knowledge about TIL role in breast ductal carcinoma in situ (DCIS) is still limited. Because of the lack of reliable prognostic parameters, DCIS treatment is much less personalized than IBC therapy. BONBIS is a phase 3 French multicenter randomized trial designed to compare 2 schemes of adjuvant radiotherapy (adjRT) for DCIS (Azria et al, ASCO meeting 2011, TPS 131). It is accompanied by a translational study of DCIS pathobiology, aimed to discover predictive or prognostic biomarkers. Here we present results of TIL density (TIL-d) assessment, its correlation with pathobiology of the lesions and preliminary clues for further biomarker search in this DCIS cohort. Methods: Formalin-fixed, paraffin-embedded DCIS surgical specimens, obtained before adjRT, were prospectively collected and centrally reviewed for histology (architectural pattern, nuclear grade, proliferation, presence of necrosis), receptor status (ER, PR, HER2) and TIL-d. TIL-d was assessed on H&E-stained DCIS sections and reported as percentage of the DCIS specialized stroma area occupied by lymphocytes, lympho-plasmocytes and plasmocytes. Tumors were classified using the St Gallen 2011 criteria for IBC (PMID 21709140). For purpose of this study, the HER2+ category included all cases with HER2 protein expression scored 2+ and 3+, irrespective of the ERBB2 amplification status. Results: TIL-d was assessed in 495 cases, with distribution as follows: 0-4% TILs (D1): 85.5% (n=423); 5-9% TILs (D2): 9.3% (n=46); ≥10% TILs (D3): 5.2% (n=26). Molecular subclasses of those cases were: luminal A (LumA): 39% (n=192); luminal B (LumB): 25.5% (n=126), HER2+: 28.5% (n=141) and triple-negative (TN): 7% (n=33). TIL-d significantly correlated with molecular subclass: ≥5% TILs (D2) were found in 39.4% (13/33) TN, 22.7% (32/141) HER2+, 18.2% (23/126) LumB and only in 1% (2/192) LumA cases (p<10-7). TIL-d of ≥10% (D3) was found only in 26/495 cases (5.2%) and of ≥50% only in one. Similarly to D2, D3 was most frequent in TN, and then in HER2+, LumB and LumA lesions (15%, 9.2%, 7.1%, 0.5%, resp., p<10-7). TIL-d significantly correlated with 2 architectural patterns: positively with solid (38.8%, 52.2% and 60% of D1, D2 and D3 within the solid lesions, resp., p=0.03) but negatively with cribriform (53%, 32.6% and 28% of D1, D2 and D3 within the cribriform lesions, resp., p=0.0027). Finally, the presence of necrosis was significantly associated with TIL-d of ≥5% (65.7% vs 84.5%, D1 vs D2+D3, p=0.071). Due to still short follow-up, the analysis of predictive factors for survival or adjRT benefit was not performed. Conclusion: This DCIS cohort is characterized by low density of TILs. Richer infiltration by TILs (≥10%) was found, as reported in IBC, in TN and HER2+ lesions, however ≥50% TILs was an extremely rare finding. Interestingly, the LumB cases had TIL-d comparable to the HER2+ cases. The associations between ≥10% TILs and molecular subclass or with DCIS architecture will be evaluated in the future as biomarkers of adjRT impact on survival in this cohort. Citation Format: Bayol B, Tixier-Deves L, Dauplat M, Kwiatkowski F, Cayre A, Abrial C, Azria D, Penault-Llorca F, Radosevic-Robin N. Tumor-infiltrating lymphocytes in breast ductal carcinoma in situ: Correlations with tumor pathobiology in a French cohort of 495 cases (BONBIS) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-15-03.

Abstract P2-03-10: Risk factors for upgrading and upstaging of pre-operative biopsies in ductal carcinoma in situ

Abstract Background: Ductal carcinoma in situ (DCIS), accounts for one fifth of all screen-detected neoplastic breast lesions. Contemporary research in DCIS focuses on separating lesions that need active treatment from those that can be safely left under surveillance. This, in turn, relies on accurate determination of invasive status and DCIS grade at time of initial biopsy. Most previous studies have examined factors associated with upstaging the diagnosis from DCIS to invasive breast cancer (IBC) following surgery, and few have evaluated factors associated with upgrading the diagnosis to a higher grade of DCIS. This is because upgrading has not traditionally influenced clinical management in the way that upstaging has done. However, recent interest in non-operative treatment for low-risk DCIS has meant that accurate determination of grade at time of initial biopsy has become more important. We aimed to compare risk factors for upgrading and upstaging of biopsies in DCIS. Method: We undertook a cohort study of all women diagnosed with DCIS at a large specialist cancer centre between 2000–2014. Information from the clinical records was abstracted, including the pre-operative mammography (MMG) and pathology information from the initial biopsy. We also abstracted pathology information regarding the excised specimen in order to identify women whose diagnosis was subsequently upgraded or upstaged. We looked for factors that were predictive for upgrading or upstaging. Result: A total of 641 women were diagnosed with DCIS at initial biopsy. Of these, 72 (11%) were upgraded: 26 (4%) from grade 1 to grade 2, 2 (0.3%) from grade 1 to grade 3 and 44 (7%) from grade 2 to grade 3. A further 115 (18%) were upstaged to IBC: 20 of these (3%) had grade 1 DCIS on initial biopsy, 47 (7%) had grade 2, 43 (7%) grade 3, and for 5 (1%) biopsy grade was not available. Necrosis on biopsy increased the risk of upgrading (with necrosis: 14% upgraded, without: 10% upgraded, p for difference 0.02) and also of upstaging (with necrosis: 23% upstaged, without: 15% upstaged, p for difference <0.01). Lesions measuring ≥50 mm on MMG were more likely to be upgraded than smaller lesions (0-19 mm: 9% upgraded, 20-50 mm: 9% upgraded, ≥50 mm: 19% upgraded, p for heterogeneity <0.01), while lesions measuring 20-50 mm and ≥50 mm were both more likely to be upstaged than lesions measuring 0-19 mm (0-19 mm: 9% upstaged, 20-50 mm: 23% upstaged and ≥50 mm: 21% upstaged, p for heterogeneity <0.01). Fewer 9G vacuum-assisted biopsies than 14G core biopsies were upgraded (9G vacuum-assisted: 7% upgraded, 14G core: 15% upgraded, p for difference 0.01), while the effect of biopsy method on upstaging was not significant (9G vacuum-assisted: 12% upstaged, 14G core: 16% upstaged, p for difference 0.15). Presence of a palpable lump was not significantly associated with upgrading (palpable lump: 13% upgraded, no palpable lump: 10% upgraded, p for difference 0.19) but increased the risk of upstaging (palpable lump: 23% upstaged, no palpable lump: 16% upstaged, p for difference 0.02). Conclusion: Our findings suggest that consideration of MMG lesion size and necrosis on biopsy may be helpful in selecting low-risk women for non-operative management of DCIS, as may use of the 9G vacuum-assisted method of biopsy. Citation Format: Mannu GS, Groen E, Wang Z, Schaapveld M, Lips E, Chung M, Joore I, Leeuwen Fv, Teerstra J, Winter-Warnars GAO, Darby SC, Wesseling J. Risk factors for upgrading and upstaging of pre-operative biopsies in ductal carcinoma in situ [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 P2-03-10.

The association between post-diagnosis health behaviors and long-term quality of life in survivors of ductal carcinoma in situ: a population-based longitudinal cohort study.

Women diagnosed with ductal carcinoma in situ (DCIS) often experience adverse changes in health-related behaviors following diagnosis. The impact of health behaviors on long-term quality of life (QoL) in DCIS survivors has not been investigated. We examined the association of post-diagnosis body mass index (BMI), physical activity, alcohol, and smoking with QoL among 1448 DCIS survivors aged 20-74 enrolled in the population-based Wisconsin in situ Cohort from 1997 to 2006. Health behaviors and QoL were self-reported during biennial post-diagnosis interviews. Physical and mental QoL were measured using the validated SF-36 questionnaire. Generalized linear regression was used to determine the association between behaviors and QoL with adjustment for confounders. Lagged behavior variables were used to predict QoL during follow-up and avoid reverse causation. Women reported 3,536 QoL observations over an average 7.9years of follow-up. Women maintaining a healthy BMI had on average a significantly higher summary measure score of physical QoL than obese women (normal versus obese: β = 3.02; 2.18, 3.85). Physical QoL scores were also elevated among those who were physically active (5 + h/week vs. none: β = 1.96; 0.72, 3.20), those consuming at least seven drinks/week of alcohol (vs. none; β = 1.40; 0.39, 2.41), and nonsmokers (vs. current smokers: β = 1.80; 0.89, 2.71). Summary measures of mental QoL were significantly higher among women who were moderately physically active (up to 2h/week vs. none: β = 1.11; 0.30, 1.92) and nonsmokers (vs. current smokers: β = 1.49;0.45, 2.53). Our results demonstrate that maintaining healthy behaviors following DCIS treatment is associated with modest improvements in long-term QoL. These results inform interventions aimed at promoting healthy behaviors and optimizing QoL in DCIS survivors.

Comparative Effectiveness of Surgical Options for Patients with Ductal Carcinoma In Situ: An Instrumental Variable Approach.

Many patients with ductal carcinoma in situ (DCIS) receive treatment that is too extensive. To take a holistic approach in comparing the effectiveness in cancer prevention between mastectomy and breast-conserving surgery (BCS) for patients with DCIS. Female Kaiser Permanente Southern California members who underwent surgery for treatment of single primary DCIS from 2004 to 2014 were identified by the Kaiser Permanente Southern California cancer registry and HealthConnect database. Two-stage residual inclusion with the surgeon's preference of surgical procedure type as the instrumental variable was used to examine the effect of surgical choice on DCIS recurrence, breast cancer progression, and other cancer progression. Traditional Cox proportional hazards models were used for comparison. Of qualified subjects, 72.2% underwent BCS and 27.8% underwent mastectomy. Patients were likelier to receive BCS if their surgeon preferred to perform BCS in the past 5 years (odds ratio = 1.02, 95% confidence interval = 1.02-1.03). Although traditional Cox proportional hazards models suggested an association between BCS and higher risk of DCIS recurrence, no significant effect was observed when we adjusted for endogeneity. Neither model showed significant differences between mastectomy and BCS in progression of any cancer. No significant benefit was observed with a more aggressive surgical procedure in preventing DCIS recurrence or cancer progression in a diverse population. Many patients with DCIS could benefit from BCS with preservation of their body image. Breast conservation followed-up with cancer surveillance is a rational approach to ensure affordable, effective care for patients with DCIS.

Carcinoma in situ of the breast in New South Wales, Australia: Current status and trends over the last 40 year

BackgroundThe incidence of non-invasive breast cancer has increased substantially over time. We aim to describe temporal trends in the incidence of carcinoma in situ of the breast in New South Wales (NSW), Australia. MethodsDescriptive study of trends in the incidence of ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) in women who received a diagnosis from 1972 to 2012, recorded in the NSW Cancer Registry. ResultsCarcinoma in situ as a proportion of all breast cancer was 0.4% during the prescreening period 1972 to 1987 and is currently 14.1% (2006 to 2012). Among 10,810 women diagnosed with DCIS, incidence across all ages rose from 0.15 per 100,000 during 1972 to 1983 to 16.81 per 100,000 over 2006 to 2012, representing a 100-fold increase (IRR 113.10; 95% CI 81.94 to 156.08). Among women in the target age group for screening (50–69 years) incidence rose from 0.27 per 100,000 to 51.96 over the same period (IRR 195.50; 95% CI 117.26 to 325.89). DCIS incidence peaks in women aged 60–69 years. DCIS incidence has not stabilized despite screening being well established for over 20 years, and participation rates in the target age range remaining stable. ConclusionsOur findings raise questions about the value of the increasing detection of DCIS and aggressive treatment of these lesions, especially among older women, and support trials of de-escalated treatment.

Paradigm Shift toward Reducing Overtreatment of Ductal Carcinoma In Situ of Breast.

The prevalence of ductal carcinoma in situ (DCIS) of the breast has increased substantially after the introduction of breast cancer screening programs, although the clinical effects of early DCIS detection and treatment remain unclear. The standard treatment for DCIS has involved local breast-conserving surgery (BCS) followed by radiotherapy (RT) or total mastectomy with/without endocrine therapy, and the choice of local treatment is not usually based on clinicopathologic or biological factors. However, we have investigated the effectiveness of local treatment using breast surgery and RT using Surveillance, Epidemiology, and End Results data, and found that the effectiveness of breast surgery was modified by the nuclear grade. Furthermore, breast cancer-specific survival was identical between patients with low-grade DCIS who did and did not undergo surgery. Moreover, we found that RT after BCS for DCIS was only associated with a survival benefit among patients with risk factors for local recurrence, such as nuclear grade, age, and tumor size. Ongoing clinical trials and translational research have attempted to develop a treatment strategy that prevents the overdiagnosis and overtreatment of low-risk DCIS, as well as a biology-based treatment strategy for using targeted therapy. Therefore, to develop a tailored treatment strategy for DCIS, we need to identify molecular and biological classifications based on the results from translational research, national databases, and clinical trials.

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 CT086: Treatment of ductal carcinoma in situ (DCIS) with pasireotide, an IGF-I inhibitor

Abstract DCIS is a non-obligate precursor in which epithelial cells with features of cancer reside in and expand otherwise normal appearing mammary ducts and lobules. DCIS increases the relative risk of developing invasive breast cancer (IBC) by up to 10 fold. Treatment of DCIS includes breast conserving surgery (BCS), tumor margins permitting, followed by radiation, or mastectomy. Recently we found that pasireotide, a somatostatin analog inhibitor of IGF-I, was effective in reducing cell proliferation and increasing apoptosis in patients with atypical hyperplasia (AH) and or proliferative disease of the breast. At present there are no recognized medical treatments for DCIS. Here we raise the possibility that pasireotide might also be an effective therapy for some DCIS. To make this determination, 8 patients previously diagnosed with DCIS were treated with pasireotide, 600µg twice daily subcutaneously for a period of 20 days. Lesion size was assessed on DCE-MRIs in 3 planes before and after treatment. Of the eight, two had lesions characterized as low grade DCIS on core biopsy, 4 had intermediate or intermediate to high grade lesions, and two had high grade lesions. After treatment they all had surgical excision biopsies. We also measured proliferation and apoptosis to assess effects of pasireotide by expression of Ki67 and caspase 3. To confirm that the effect of pasireotide was mediated via the IGF-I pathway, p-AKT and p-ERK 1/2 were evaluated. Core and excision samples from 14 untreated patients where used as control. Overall, treatment with pasireotide reduced DCIS lesion size by ≥30% according the RECIST criteria in 4 of 8 patients, as measured by DCE-MRI. Of those, pathology of the surgical excision confirmed that there was no remaining DCIS tissue in the two patients with low grade disease. The two additional lesions that were reduced in size one was intermediate to high grade and the other a high grade DCIS. The remaining 4 patients had tumors that were stable in size. Pasireotide reduced cell proliferation and significantly increased apoptosis in the DCIS lesions. While DCIS is less responsive to pasireotide than AH and proliferative disease, it may nevertheless provide a window of opportunity for treatment and possibly eradication of some low grade or higher grade DCIS as well. The main side effect included hyperglycemia, intestinal discomfort and rash or redness at the injection area. Our data show that hyperglycemia disappears relatively fast after ending treatment with pasireotide. In conclusion, treatment with pasireotide eliminated 2 low grade DCIS lesions, shrunk two higher grade ones and also decreased proliferation and increased apoptosis. Additional evidence in a larger number of patients will be necessary. Citation Format: Irineu Illa-Bochaca, Linda Moy, Julia Smith, Debora Axelrod, Baljit Singh, David L. Kleinberg. Treatment of ductal carcinoma in situ (DCIS) with pasireotide, an IGF-I inhibitor [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 CT086. doi:10.1158/1538-7445.AM2017-CT086

Pain, sensory disturbances and psychological distress are common sequelae after treatment of ductal carcinoma in situ: a cross-sectional study

Sequelae such as pain, sensory disturbances and psychological distress are well known after treatment for invasive breast cancer (IBC). Patients treated for ductal carcinoma in situ (DCIS) receive a similar treatment as low-risk IBC. The aim of this cross-sectional study was to describe prevalence of postoperative pain, sensory disturbances, psychological distress and rehabilitation needs among Danish women with DCIS.Methods: A total of 574 women treated for DCIS in Denmark in 2013 and 2014 were enrolled and 473 (82%) completed a detailed questionnaire on demographic factors, pain, sensory disturbances, psychological aspects and rehabilitation needs 1–3 years after surgery.Results: Median age was 60 years. A total of 33% of patients reported any pain and 12% reported moderate to severe pain in the area of surgery. Younger age (<50 years OR 4.7 (95% CI: 1.6–14.0, p = 0.006)), aged 50 to 65 years OR 2.8 (95% CI: 1.1–7.0, p = 0.02) and anxiety and depression (measured by HADStotal >15 OR of 3.1 (95% CI: 1.5–6.3, p = 0.003)) were significantly associated with moderate to severe pain. Approximately one-third of the patients reported sensory disturbances such as pins and needles (32%), numbness (37%) and painful itch (30%) and 94 women (20%) reported anxiety ≥8, 26 (6%) depression and 51 (11%) reported distress.Conclusions: This cross-sectional study showed that women treated for DCIS suffered from pain, sensory disturbances and psychological impairment and had unmet rehabilitation needs. Further research is warranted, specifically addressing rehabilitation after diagnosis and treatment of DCIS.

What quality-of-life issues do women with ductal carcinoma in situ (DCIS) consider important when making treatment decisions?

To explore quality-of-life (QOL) issues considered important when deciding on treatment for ductal carcinoma in situ (DCIS). Breast Cancer Network of Australia members diagnosed with DCIS in the past 5years (self-identified) participated in an online survey (Sep-Nov 2015). From a list of 74 QOL issues, participants selected all issues they experienced during DCIS diagnosis, treatment or recovery, then the issues they felt important to making a DCIS treatment decision, and completed the Health Literacy Questionnaire (HLQ). Associations between QOL issues and self-reported treatment received were assessed with χ 2 tests. The primary analysis included 38 participants treated with breast-conserving surgery (n=15), mastectomy (n=23), and/or radiotherapy (n=14). Fatigue-related symptoms (82%) and "fear of progression" (50%) were the most frequently-experienced issues. When deciding on DCIS treatment, the most important consideration was "fear of progression" (50%). A higher proportion of mastectomy (compared to non-mastectomy) patients considered "difficultly looking at yourself naked" (p=0.03). Radiotherapy (compared to non-radiotherapy) patients were more likely to consider "feeling unwell" important (p=0.006). Results were similar in a sensitivity analysis involving all 101 respondents (i.e., including 63 respondents who reported receiving chemotherapy, endocrine therapy, and/or Herceptin, suggesting that they may have been treated for invasive breast cancer). Health literacy was high across all nine HLQ scales. Fear of progression is a key consideration in DCIS treatment decision making for women with high health literacy. QOL treatment considerations differed by treatments received. Women diagnosed with DCIS may benefit from evidence about QOL to inform treatment decision making.

Abstract OT1-03-01: The UK LORIS trial: Randomizing patients with low or low intermediate grade ductal carcinoma in situ (DCIS) to surgery or active monitoring

Abstract Background: The independent review of the UK National Health Service Breast Screening Programme reported (The Lancet, Volume 380, Issue 9855, Page 1778, 17 Nov 2012) on the benefits and harms of breast screening. It concluded that breast screening saves lives and acknowledged the existence of overtreatment. It encouraged randomized trials to elucidate the appropriate treatment of screen-detected DCIS to gain a better understanding of its natural history. The LORIS trial addresses the possible overtreatment of low and low/intermediate grade screen-detected (low risk) DCIS by randomizing patients to standard surgical treatment or active monitoring, each with long term follow up. Trial Design: LORIS is a phase III, multicentre, 2 arm study, with a built in 2 year Feasibility Phase, in patients confirmed to have low risk DCIS defined by strict criteria and determined by central pathology review. Patients will be randomized between standard surgery and active monitoring with annual mammography. Patients will be followed up for a minimum of 10 years. Eligibility Criteria: 1) Female, age ≥ 46 years 2) Screen-detected or incidental microcalcification (with no mass lesion clinically or on imaging) 3) Low risk DCIS on large volume vacuum-assisted biopsy, confirmed by central pathology review 4) Patient fit to undergo surgery 5) No previous breast cancer or ipsilateral DCIS diagnosis 6) Written informed consent Specific Aims: The LORIS Trial aims to establish whether patients with newly diagnosed low risk DCIS can safely avoid surgery without detriment to their wellbeing (psychological and physical) and whether those patients that do require surgery can be identified by pathological and radiological means. Primary endpoint: Ipsilateral invasive breast cancer free survival time Secondary endpoints: Overall survival; mastectomy rate; time to mastectomy; time to surgery; patient reported outcomes; health resource utilisation and assessment of predictive biomarkers. A digital image data repository and tissue bank will provide a prospective resource for both translational and imaging studies. Statistical Methods: A total of 932 patients will be randomized to a non-inferiority design to test the null hypothesis that active monitoring of women diagnosed with low risk DCIS is not non-inferior in terms of ipsilateral invasive breast cancer free survival (iiBCFS) time compared to treatment with surgery. The iiBCFS time will be compared across the two arms on a per protocol and intent-to-treat basis, using a 1-sided (α=0.05) log-rank test for non-inferiority. The iiBCFS rate is assumed to be 97.5% in the surgery arm at 5 years, utilizing 80% power to exclude a difference of more than 2.5% in the active monitoring arm. Present Accrual and Target Accrual: 32 UK centres are open for the Feasibility Phase of the trial which is nearing completion. The web-based central pathology review process is functioning efficiently, with a one week maximum turn around. Registrations and sites randomizing patients are on or above target. Randomizations are currently approximately 70% of target. A total of 60 centres will open in the main trial. Contact Information: For further information, please email the LORIS Trial Office LORIS@trials.bham.ac.uk. Citation Format: Francis A, Bartlett J, Billingham L, Bowden S, Brookes C, Dodwell D, Evans A, Fairbrother P, Fallowfield L, Gaunt C, Hanby A, Jenkins V, Matthews L, Pinder S, Pirrie S, Rea D, Reed M, Roberts T, Thomas J, Wallis M, Wilcox M, Young J. The UK LORIS trial: Randomizing patients with low or low intermediate grade ductal carcinoma in situ (DCIS) to surgery or active monitoring [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-03-01.

Controversies in the Treatment of Ductal Carcinoma in Situ.

Ductal carcinoma in situ (DCIS) accounts for 20% of all newly diagnosed breast cancers. Mastectomy was once the gold standard for the treatment of DCIS; however, breast-conserving surgery (BCS) has been adopted as the treatment of choice for patients with small, screen-detected lesions. Both adjuvant radiation and hormonal therapy following BCS have been demonstrated in randomized trials to reduce the risk of both invasive and DCIS recurrence, but neither affects survival. With the variety of surgical and adjuvant treatment options available, there has been great interest in tailoring the treatment to the individual, with the goal of optimizing the balance of risks and benefits according to the values and priorities of the woman herself. Prospective studies of women with "low-risk" DCIS treated with BCS alone have successfully identified women at lower than average risk but have not achieved the goal of identifying a subset of women with DCIS at minimal risk of recurrence after surgical excision alone. No studies have evaluated the safety of medical management alone.

Comparing treatment and outcomes of ductal carcinoma in situ among women in Missouri by race.

To investigate whether treatment (surgery, radiation therapy, and endocrine therapy) contributes to racial disparities in outcomes of ductal carcinoma in situ (DCIS). The analysis included 8184 non-Hispanic White and 954 non-Hispanic Black women diagnosed with DCIS between 1996 and 2011 and identified in the Missouri Cancer Registry. Logistic regression models were used to estimate odds ratios (ORs) of treatment for race. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) of ipsilateral breast tumor (IBT) and contralateral breast tumor (CBT) for race. There was no significant difference between Black and White women in utilization of mastectomy (OR 1.16; 95% CI 0.99-1.35) or endocrine therapy (OR 1.19; 95% CI 0.94-1.51). Despite no significant difference in underutilization of radiation therapy (OR 1.14; 95% CI 0.92-1.42), Black women had higher odds of radiation delay, defined as at least 8 weeks between surgery and radiation (OR 1.92; 95% CI 1.55-2.37). Among 9138 patients, 184 had IBTs and 326 had CBTs. Black women had a higher risk of IBTs (HR 1.69; 95% CI 1.15-2.50) and a comparable risk of CBTs (HR 1.19; 95% CI 0.84-1.68), which were independent of pathological features and treatment. Racial differences in DCIS treatment and outcomes exist in Missouri. This study could not completely explain the higher risk of IBTs in Black women. Future studies should identify differences in timely initiation and completion of treatment, which may contribute to the racial difference in IBTs after DCIS.

Predictors of Antiestrogen Recommendation in Women With Estrogen Receptor–Positive Ductal Carcinoma In Situ

Antiestrogen (anti-e) use in estrogen receptor-positive (ER+) ductal carcinoma in situ (DCIS) has been shown to reduce the incidence of noninvasive and invasive breast cancer. Few studies have evaluated factors associated with anti-e recommendation in ER+ DCIS. The California Cancer Registry was queried for female patients diagnosed with ER+ DCIS and treated with lumpectomy or unilateral mastectomy from 2004 to 2011. Patient demographics, comorbidities, and clinical characteristics were analyzed for association with anti-e recommendation. Of 5,527 patients identified, 76.4% patients underwent lumpectomy and 23.6% underwent unilateral mastectomy. Of the total cohort, 31.6% patients were recommended anti-e therapy, 60.4% were not, and the remaining 8.0% were recommended anti-e, but administration was not documented. Performance of lumpectomy predicted anti-e use compared with mastectomy (odds ratio [OR], 2.08; 95% CI, 1.77-2.43). Asian/Pacific Islanders were more often recommended anti-e therapy when compared with whites (OR, 1.28; 95% CI, 1.10-1.49). Patients younger than 70 years were more often recommended anti-e (age, 18-49 years: OR, 1.38; CI, 1.12-1.71; and age, 50-69 years: OR, 1.43; CI, 1.20-1.71). Despite current guidelines to consider the use of anti-e therapy, recommendation of anti-e after surgical treatment of DCIS is low, having been recommended to 40% of patients, and used by fewer than one-third. Significant predictors include lumpectomy compared with unilateral mastectomy, Asian/Pacific Islander race, younger age, and number of comorbidities. Further work is merited to understand patterns of anti-e therapy recommendation by providers in patients with DCIS.

Management of Ductal Carcinoma In Situ of the Breast: A Review.

Ductal carcinoma in situ (DCIS) of the breast represents a disease process that continues to increase in incidence with treatment paradigms that continue to evolve. Greater access to long-term data from large observational studies addressing the natural history of the disease has contributed to changes in treatment paradigms and put into question traditional management strategies. While recent analyses have suggested that a more conservative approach to the management of DCIS without surgical intervention or radiation therapy may be advisable based on breast cancer mortality data, there is a lack of level 1 or prospective evidence to support the widespread adoption of these approaches. Currently, surgery remains the standard of care for the initial treatment of DCIS. Adjuvant radiation therapy (RT) has consistently demonstrated a reduction in the risk of local recurrence following breast-conserving surgery (BCS), even in "low-risk" populations of patients. Invasive recurrences following BCS are associated with increases in breast cancer mortality. Questions that remain to be answered include (1) what constitutes an acceptable risk of local recurrence, (2) what are the costs associated with managing local recurrences compared with RT given initially after BCS (particularly in light of data supporting shorter courses of RT), and (3) what are the benefits of endocrine therapy on local recurrence, and do they justify the additional toxic effects and potential noncompliance with their long-term administration? Surgery and RT remain standard of care treatment options in the management of DCIS. Future studies are required to identify cohorts of patients in which RT can be safely omitted as well as to evaluate whether short-course RT alone may represent a better option than endocrine therapy with respect to compliance, toxic effects, cost and local control following BCS.