Ipsilateral Ductal Carcinoma In Situ Research Articles

Evaluating the Rate of Upgrade to Invasive Breast Cancer and/or Ductal Carcinoma In Situ Following a Core Biopsy Diagnosis of Non-classic Lobular Carcinoma In Situ

A diagnosis of non-classic lobular carcinoma in situ (NC-LCIS) encompasses a variety of lesions with poorly characterized natural history. We evaluated upgrade rates and factors associated with upgrade to malignancy following a core biopsy diagnosis of NC-LCIS, and its natural history. Upon Institutional Review Board approval, pathology databases were searched for NC-LCIS core biopsy diagnoses (carcinoma in situ [CIS], CIS with ductal and lobular features [CIS/DLF], pleomorphic LCIS [P-LCIS], variant LCIS [V-LCIS], LCIS with necrosis). Cases with available core and excision pathology were included, while cases with concurrent ipsilateral invasive carcinoma (IC), ductal carcinoma in situ (DCIS), and/or atypical ductal hyperplasia were excluded. Overall, 121 NC-LCIS cases were identified from 1998 to 2017. We excluded 46 cases with concurrent cancer; 75 patients with 76 NC-LCIS core biopsy diagnoses followed by excision formed our study cohort. Median age was 56years (range 41-83), and all imaging findings were classified as Breast Imaging Reporting and Data System 4; calcifications were the most common biopsy indication (80%). Excision yielded malignancy in 27 (36%) patients (IC 17, 63%; DCIS alone 10, 37%). We were unable to identify radiologic or pathologic features predictive of upgrade. Of 49 pure NC-LCIS cases, 15 (31%) had mastectomy, 9 (18%) had excision and radiation, and 25 (51%) had excision alone. At a median follow-up of 58months (range 1-224), 1/25 (4%) patients with excision alone developed ipsilateral DCIS 14months later. In this series of NC-LCIS, 36% of cases were upgraded, supporting routine excision. We were unable to identify predictors of upgrade. Among 25 patients with pure NC-LCIS, only one patient developed a future ipsilateral cancer. Further study of the natural history of NC-LCIS is warranted.

Management and 5-year outcomes in 9938 women with screen-detected ductal carcinoma in situ: the UK Sloane Project

BackgroundManagement of screen-detected ductal carcinoma in situ (DCIS) remains controversial. MethodsA prospective cohort of patients with DCIS diagnosed through the UK National Health Service Breast Screening Programme (1st April 2003 to 31st March 2012) was linked to national databases and case note review to analyse patterns of care, recurrence and mortality. ResultsScreen-detected DCIS in 9938 women, with mean age of 60 years (range 46–87), was treated by mastectomy (2931) or breast conserving surgery (BCS) (7007; 70%). At 64 months median follow-up, 697 (6.8%) had further DCIS or invasive breast cancer after BCS (7.8%) or mastectomy (4.5%) (p < 0.001). Breast radiotherapy (RT) after BCS (4363/7007; 62.3%) was associated with a 3.1% absolute reduction in ipsilateral recurrent DCIS or invasive breast cancer (no RT: 7.2% versus RT: 4.1% [p < 0.001]) and a 1.9% absolute reduction for ipsilateral invasive breast recurrence (no RT: 3.8% versus RT: 1.9% [p < 0.001]), independent of the excision margin width or size of DCIS. Women without RT after BCS had more ipsilateral breast recurrences (p < 0.001) when the radial excision margin was <2 mm. Adjuvant endocrine therapy (1208/9938; 12%) was associated with a reduction in any ipsilateral recurrence, whether RT was received (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.41–0.80) or not (HR 0.68; 95% CI 0.51–0.91) after BCS. Women who developed invasive breast recurrence had a worse survival than those with recurrent DCIS (p < 0.001). Among 321 (3.2%) who died, only 46 deaths were attributed to invasive breast cancer. ConclusionRecurrent DCIS or invasive cancer is uncommon after screen-detected DCIS. Both RT and endocrine therapy were associated with a reduction in further events but not with breast cancer mortality within 5 years of diagnosis. Further research to identify biomarkers of recurrence risk, particularly as invasive disease, is indicated.

Abstract PD7-03: Cost-effectiveness analysis of intraoperative radiotherapy for ductal carcinoma in situ

Abstract Background Whole breast radiation therapy (WBRT) following lumpectomy for ductal carcinoma in situ (DCIS) is standard of care, however, the risk of local recurrence with and without radiation ranges as low as 0.9% vs. 6.7% over 7 years. Intraoperative radiotherapy (IORT) is a potential alternative with advantages of decreased toxicity to adjacent organs, convenience, and improved quality of life. While prospective trials of IORT for DCIS are ongoing, the objective of this study was to estimate the cost-effectiveness of IORT vs. WBRT vs. no radiation for DCIS. Methods We developed a Markov model using TreeAge Pro 2016 to evaluate the cost-effectiveness of WBRT, IORT, and no radiation in patients with DCIS following lumpectomy. Health states included disease free, local recurrence (ipsilateral DCIS or invasive cancer), distant recurrence or death due to breast cancer, and death due to non-breast cancer causes. A 10-year time horizon and societal perspective were used. Model input parameters were derived from the literature. Costs reflected 2016 Medicare rates. The primary endpoint was incremental cost-effectiveness ratio (ICER), defined as the difference in cost, divided by the difference in quality-adjusted life years (QALYs) of two interventions. We performed analyses of subgroups defined according to DCIS risk (histologic grade, Oncotype Dx® DCIS recurrence score, low risk per RTOG 9804 criteria) and endocrine therapy use (none, tamoxifen, aromatase inhibitor). Sensitivity analyses explored uncertainty in the model. Results IORT was the most cost-effective strategy, with an increase of 0.18 QALYs at an incremental cost of $4,728, corresponding to an ICER of $26,943/QALY when compared with no radiation therapy. WBRT resulted in an increase in 0.18 QALYs at an incremental cost of $6859, corresponding to an ICER of $39,085/QALY. For both strategies, the ICERs did not exceed the willingness to pay (WTP) threshold of $100,000. IORT remained the most cost-effective strategy across DCIS risk groups, but was more cost-effective in higher risk patients, as demonstrated by lower ICERs. In low risk DCIS defined by RTOG 9804 criteria, no radiation was most cost-effective. The ICERs for IORT and WBRT, $152,753 and $208,204/QALY, respectively, exceeded the WTP threshold. IORT remained cost-effective in the setting of endocrine therapy use. Incremental Cost-Effectiveness Ratios (ICER) for each radiation strategy for the base case and scenario analyses ICER ($/QALY) No RTIORTWBRTBase Case Analysis 26,94339,085 Scenario Analysis by DCIS Risk GroupHistologic Grade - Low 36,81152,219- High 25,64337,137 Oncotype Dx DCIS Score - Low 92,892126,398- High 32,00345,690 Low Risk DCIS 152,753208,204 Scenario Analysis by Endocrine TherapyNo Tamoxifen 23,38734,373Tamoxifen 47,81166,616 Tamoxifen 31,96146,272Aromatase Inhibitor 41,31658,674 Conclusion IORT was the most cost-effective radiation strategy for DCIS compared to WBRT and no radiation. This applied to all subgroups with the exception of low-risk DCIS defined by RTOG 9804 criteria for whom no radiation was the most cost-effective strategy. These findings provide support for ongoing studies examining the role of IORT for DCIS with high-risk features, as well as alternative treatment strategies for low-risk DCIS. Citation Format: Onishi M, Connolly EP, Wright JD, Vasan S, Gross T, Tsai W-Y, Chen L, Neugut AI, Accordino MK, Kalinsky K, Crew KD, Hershman DL. Cost-effectiveness analysis of intraoperative radiotherapy for 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 PD7-03.

Abstract P5-22-01: Evaluating the risk of upgrade to invasive breast cancer and/or DCIS on excision following a diagnosis of non-classic lobular carcinoma in situ

Abstract Introduction: Non-classic lobular carcinoma in situ (NC-LCIS) is a rare pathologic entity which encompasses a variety of histologic diagnoses. As such its natural history, including upgrade rates to invasive cancer (IC) or ductal carcinoma in situ (DCIS) on excision, is poorly characterized. We sought to evaluate the risk of upgrade to IC or DCIS when NC-LCIS is diagnosed on core biopsy. Methods: After obtaining IRB approval, institutional pathology databases were searched for NC-LCIS core biopsy diagnoses (carcinoma in situ (CIS), carcinoma in situ with ductal and lobular features (CIS/DLF), pleomorphic LCIS (P-LCIS), variant LCIS (V-LCIS), LCIS with necrosis). Cases with a NC-LCIS core biopsy diagnosis and with available pathology results from subsequent surgery were included. Cases with known concurrent ipsilateral IC, DCIS and/or atypical ductal hyperplasia were excluded. Results: 107 cases with NC-LCIS in any pathology report were identified (1998-2016); 44 were excluded due to concurrent ipsilateral IC, the remaining 62 patients with 63 core biopsy diagnoses of NC-LCIS all underwent surgical excision and formed our study cohort. Median age was 56 years (range 43-83); 43 (68%) were postmenopausal. NC-LCIS was diagnosed on core biopsy for mammographic findings in 57 (90%) cases and for MRI findings in 6 (9%). All were BI-RADS 4 lesions; calcifications were the most common biopsy indication (50 (78%)). CIS/DLF was the most common term used for NC-LCIS (28 (44%)), followed by CIS (18 (29%)), V-LCIS (14 (22%)) and P-LCIS (3 (5%)). On core biopsy, 36/44 (82%) of NC-LCIS cases were E-cadherin negative, 38/41 (93%) were ER positive, and 6/34 (18%) were HER2 positive. IC and/or DCIS were diagnosed on subsequent surgery in 22 (33%) of patients, of which 14 (67%) were IC and 8 (18%) had DCIS only. LesionTotalE-cadherin negativeUpgraded, N (%)Invasive cancer, N (%)DCIS only, N (%)CIS188/10 (80%)3 (16%)2 (67%)1 (33%)CIS/DLF2819/23 (83%)12 (43%)7 (58%)5 (42%)P-LCIS31/1 (100%)3 (100%)2 (67%)1 (33%)V-LCIS148/10 (80%)4 (29%)3 (75%)1 (25%) Median IC size was 0.2 cm (0.06-1.1 cm). IC histology was ductal in n=4 (29%), lobular in n=7 (50%), and ductal and lobular in n=3 (21%). Among the 14 invasive lesions, 5 (36%) were grade I, 5 (36%) were grade II and 2(13%) were grade III, (grade was not reported for 2 remaining ICs); 12/14 (86%) were ER positive and 1/14 (7%) was HER2 positive; none had LVI or positive nodes. Among the 42 cases not upgraded, 13 (31%) had mastectomy, 9 (21%) had excision and radiation, 20 had excision only, all had negative margins. At median follow-up of 60 months (1-224 months), 1/20 patients treated with excision only was diagnosed with DCIS, 14 months after surgery for CIS/DLF on core biopsy. Conclusions: In this large series of NC-LCIS diagnosed on core biopsy, the upgrade rate to carcinoma was 33% supporting the recommendation for routine excision of these lesions. The cancers found at excision were all stage I and the majority were grade I or II. At a median follow-up of 60 months only 1/20 patients with pure NC-LCIS treated with excision alone developed a future ipsilateral cancer. Further study of the natural history of these rare lesions is warranted. Citation Format: Nakhlis F, Harrison BT, Lester SC, Hughes KS, Coopey SB, King TA. Evaluating the risk of upgrade to invasive breast cancer and/or DCIS on excision following a diagnosis of non-classic lobular 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 P5-22-01.

Abstract P3-08-05: Validation of a nomogram for predicting recurrence among women with ductal carcinoma in situ and breast conserving surgery in an integrated health care system

Abstract Current management of ductal carcinoma in situ (DCIS) most often entails removing the lesion by breast-conserving surgery. Quantifying the risk of a patient's ipsilateral breast event (IBE) recurrence, either invasive cancer or DCIS, after breast conserving surgery remains a clinical concern. The aim of this study was to validate the Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram to predict IBE recurrence in patients from our institution. Patients and Methods We retrospectively identified 608 patients in the Kaiser Permanente Northwest integrated healthcare system with a diagnosis of DCIS who had undergone local excision from 1990 through 2007. We assessed the performance of the MSKCC nomogram for predicting IBE recurrence using measures of discrimination (how well risk scores separate those with and without the event) and calibration (agreement between predicted and observed risk). We calculated Harrell's C and R2D to provide estimates of discrimination. We calculated the calibration slope by performing a Cox regression using the prognostic index (PI; predicted log relative hazard based on the original Cox coefficients), with a slope not significantly different from 1 indicating no difference in discrimination from the development sample. We also examined discrimination by comparing the KM curves of 4 risk groups and in a Cox regression as a predictor, which were created using Cox's method (4 groups using the 16th, 50th, &amp; 84th percentiles), as no risk groups were defined in the MSKCC development study. We examined whether there was model misfit by testing each predictor in a Cox regression with an offset of the PI. Finally, we assessed calibration by plotting the observed rates and associated 95% CIs against the predicted probabilities for groups based on 4 risk groups and octiles. Results The median follow-up time for the KPNW cohort was 125 months. The 10-year IBE recurrence rate was 9.5%, 95% CI [7.0%, 13.0%). Harrell's C was .70, which is comparable to what has been found in other validation studies. The PI accounted for 22% of variation in time (R2D =.22, 95% CI [.08, .38]). The test of the calibration slope provided no support that discrimination in this sample differs from the development study (LR χ2(1)=0.21, p=.65). An examination of the Kaplan-Meier curves among the risk groups showed good separation of the high risk group compared to the others, but little separation between the lowest two risk groups. None of the predictors demonstrated evidence for differential weighting from the MSKCC coefficients (p values ranged from .08 to .97). Calibration was good for the lowest, low, and moderate risk groups, but there was underprediction in the high risk group. When examining calibration using octiles, we found a similar pattern to that of other validation studies in which the highest octile had the furthest departure from perfect agreement. Conclusion The MSKCC nomogram for predicting IBE recurrence in patients with DCIS who were treated with local excision have some utility, and our results are consistent with other validation efforts. However, there is much potential to further increase the prediction of recurrence beyond what is possible with the MSKCC nomogram. Citation Format: Leo MC, Francisco M, Jenkins C, Weinmann S. Validation of a nomogram for predicting recurrence among women with ductal carcinoma in situ and breast conserving surgery in an integrated health care system [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 P3-08-05.

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.

Abstract P3-17-03: DCIS and the risk of breast cancer death - A case control study

Abstract Introduction The risk of breast cancer death after a primary ductal carcinoma in situ (DCIS) is less than 2 % after 10 years. Whereas in situ recurrences do not influence survival, a 17-fold elevated risk of breast cancer specific mortality has been shown for invasive recurrences. Adjuvant radiotherapy (RT) effectively reduces recurrences after breast conserving surgery (BCS) for DCIS, but no studies have been able to demonstrate a survival benefit from adjuvant RT treatment or from choosing mastectomy instead of BCS. Here patient and tumour related risk factors for breast cancer death in women with a pure primary DCIS were studied. Patients and methods Women registered with a primary DCIS, between 1992-2012 in three of Sweden´s health care regions with a population of approximately 5.2 million, were enrolled in a nested case-control study. Out of 6,964 women with DCIS, 96 patients who later died from breast cancer were identified. Four controls per case (n=318) were randomly selected by incidence density sampling. We retrieved medical records and pathology reports and calculated OR with 95% CIs for various variables using conditional logistic regression. Results Of the 96 cases, 10 patients developed distant metastasis without a known local recurrence. In 56 patients death was preceded by an invasive ipsilateral recurrence and in 3 patients by a recurrent ipsilateral DCIS. Seven patients had invasive breast events in both the ipsilateral and the contralateral breast. Seventeen patients had contralateral invasive breast cancer and 3 patients contralateral DCIS. Multifocality and tumour size over 25mm (OR 2.6 (1.6 to 4.2)), positive or uncertain margin status (OR 2.8 (1.6 to 4.9)) and detection outside screening (OR 2.1 (1.2 to 3.9)) increased the risk of breast cancer death in univariate analysis, when adjusted for age and year of diagnosis. Suspicion of micro-invasion and nuclear grade 3 was associated with a nonsignificant increased risk, OR 1.8 (0.6 to 5.0) and 2.6 (0.9-6.5), respectively. The risk was not affected by age or treatment. Tumour size and margin status remained significant in the multivariable analysis, when adjusted for treatment and for contralateral breast cancer (OR 2.0 (1.2 to 3.7)). Conclusion In the present study, large tumours and positive or uncertain margin status were significant risk factors for later breast cancer death after a primary DCIS. More extensive treatment was not related to a lower risk. The significance of tumour biology and nuclear grade will be further examined and evaluated. Citation Format: Wadsten C, Garmo H, Fredriksson I, Sund M, Wärnberg F. DCIS and the risk of breast cancer death - A case control study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-17-03.

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

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

Ductal Carcinoma In Situ: How Much Treatment Is Enough, How Much Is Too Much?

In the accompanying article, Wood concisely reviews currentmanagement of ductal carcinoma in situ (DCIS), with a focus on the use of radiotherapy (RT) after breastconserving surgery (BCS). The crux of his argument is that because RT does not prolong survival, its usemust be considered optional and the risks and benefits of RT considered in the context of patient values. Henotes that“nearly twice asmanywomen will have an inferior cosmetic outcome result as will benefit from avoiding a recurrent breast lesion,” and that the use of RT for initial treatment necessitates mastectomy for any subsequent recurrence. The importance of considering patient preference in decision making when there is equipoise in survival outcomes is inarguable.Wesurveyedpatients aboutpriorities and treatment choices in a population-based study of 1,629 patientswithDCIS and stage I and II breast cancer. Concern about disease recurrence was the most important factor in treatment choice, greatly influencing 37%, whereas concerns about radiation or body image greatly influenced only 15% and5%of patients, respectively. Prevention of local recurrence in DCIS is particularly relevant to patient concerns, because 50% of these recurrences are invasive carcinoma, and randomized trials have demonstrated a significant increase in mortality in patients experiencing invasive recurrence after DCIS treatment. Thus, it is not particularly surprising that risk-averse patients opt for RTor, increasingly, forbilateralmastectomy. Endocrine Therapy Wood also notes that endocrine therapy is an alternative to RT for risk reduction in women with DCIS. Endocrine therapy has the advantage of reducing the incidence of both ipsilateral and contralateral breast events, but the absolute benefit of 5 years of treatment is modest. In a meta-analysis of the National Surgical Adjuvant Breast and Bowel Project B24 trial and the United Kingdom, Australia, New Zealand trials of adjuvant tamoxifen in DCIS, no significant difference in all-cause mortality was seen with tamoxifen treatment compared with placebo, but tamoxifen treatment did statistically significantly reduce ipsilateral and contralateral DCIS events and contralateral invasive cancers, with a trend toward reduction of ipsilateral invasive cancer. The number needed to treat for a protective effect against all breast events was 15. However, ameta-analysis of 10-year event rates in9,404patientswithDCIS found that the local recurrence rate after BCS and RTwas 14.4%, compared with 24.7% with BCS and tamoxifen, suggesting that if the goal is to minimize recurrence, RT is the more effective strategy. A decision to use tamoxifen (or an aromatase inhibitor) also subjects the patient to 5 years of the welldocumented side effects of endocrine therapy. Most importantly, the acceptance of tamoxifen among patients with DCIS is limited. In a Canadian population-based cohort of women with DCIS treated in

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

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

Abstract P4-11-18: FOXA1 and PR predict ipsilateral event risk and identify a group with strong radiation response in ductal carcinoma in situ (DCIS)

Abstract Background: Identification of biomarkers in DCIS is critical to help guide treatment decisions, particularly for patients receiving breast-conserving surgery (BCS). The goal of this study was to assess FOXA1 levels in the context of PR status in primary DCIS to predict ipsilateral invasive and DCIS events, given the established roles of these endocrine signaling factors in breast cancer. Material and Methods: Patients included in this study (n=518) were women diagnosed with DCIS without evidence of invasive cancer treated with BCS, and for whom tumor tissue was evaluable for both PR and FOXA1. An Uppsala University Hospital (UUH) set was diagnosed in 1986-2004 (117 treated and 122 not treated with adjuvant radiation therapy [RT]); and a University of Massachusetts Memorial Hospital (UMass) set was diagnosed in 1999-2008 (195 treated and 84 not treated with RT). Tumors were immunohistochemically stained for PR and FOXA1 and scored by pathologists for percentage (0-100) and intensity (0-3), with the product being calculated for FOXA1 immunoscore (0-300). Patients were considered PR+ when ≥10% of cells stained positively, and immunoscore thresholds of 100 and 270 were used to separate patients into FOXA1 low, intermediate, and high groups. Event rates were assessed for 10-year outcome using Kaplan-Meier survival analysis. Hazard ratios (HR) were determined using Cox proportional hazards analysis. Results: Neither FOXA1 nor PR were prognostic as independent factors for either invasive or DCIS event risk. However, in PR- patients, the invasive event rate decreased with increasing FOXA1 (24%, 4%, and 0%, respectively, in the FOXA1 low, intermediate, and high groups, HR=6.7/bin, p=0.0034), and, in PR+ patients, the invasive event rate increased with increasing FOXA1 (0%, 10%, and 13%, respectively, HR=2.95/bin, p=0.041). In contrast, the DCIS event rate increased in PR- patients with increasing FOXA1 (3%, 12%, and 26%, respectively, HR=2.7/bin, p=0.020), and the DCIS event rate was lower in PR+ patients with elevated FOXA1 levels (28% in FOXA1 low vs. 8% in FOXA1 intermediate plus high, HR=4.0, p=0.011). In the full population, RT-treated patients (n=312) fared better than the unirradiated (n=206) with invasive event rates of 6% and 10%, respectively (HR=0.41, p=0.021). By comparison, the patients with high marker-based invasive event risk (PR-/FOXA1 low and PR+/FOXA1 high, n=191) had a remarkable response to RT–event rate reduced from 19% to 4% (HR=0.13, p&amp;lt;0.001). In contrast, the remainder of patients (n=327) showed no evident RT response--event rate increased from 5% to 6%. In an interactional Cox analysis, the high-risk group (HR=5.0, p=0.0045) and RT response within that group (HR=0.10, p=0.020) were significant, but baseline RT response was not (p=0.72). Discussion: These results indicate a complex interaction between PR and FOXA1, in which the prognosis for invasive and DCIS events flips both within and between the event types. Thus, the biology that drives these events differs and, in order to predict both event types, risk models must include biomarkers in context. In addition, PR/FOXA1 identify a risk group with remarkably strong RT response with the remaining patients exhibiting no measurable response. Citation Format: Steven P Linke, Troy M Bremer, Pat Whitworth, Aflred Lui, Jess Savala, Yelina Noskina, Todd Barry, Stephen Lyle, Stephanie C Walters, Cherie Taglienti, Karl Simin, Wenjing Zhou, Karin Jirström, Rose-Marie Amini, Fredrik Wärnberg. FOXA1 and PR predict ipsilateral event risk and identify a group with strong radiation response in ductal carcinoma in situ (DCIS) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-18.

Racial disparities in risk of second breast tumors after ductal carcinoma in situ.

The purpose of the study was to examine the impact of race/ethnicity on second breast tumors among women with ductal carcinoma in situ (DCIS). We identified 102,489 women diagnosed with primary DCIS between 1988 and 2009 from the 18 NCI-SEER Registries. Cox proportional hazard regression was used to estimate race/ethnicity-associated relative risks (RRs) and their 95% confidence intervals (CI) of ipsilateral breast tumors (IBT; defined as DCIS or invasive carcinoma in the ipsilateral breast) and contralateral breast tumors (CBT; defined as DCIS or invasive carcinoma in the contralateral breast). Overall, 2,925 women had IBT and 3,723 had CBT. Compared with white women, black (RR 1.46; 95% CI 1.29-1.65), and Hispanic (RR 1.18; 95% CI 1.03-1.36) women had higher IBT risk, which was similar for invasive IBT and ipsilateral DCIS. A significant increase in IBT risk among black women persisted, regardless of age at diagnosis, treatment, tumor grade, tumor size, and histology. The CBT risk was significantly increased among black (RR 1.21; 95% CI 1.08-1.36) and Asian/PI (RR 1.16; 95% CI 1.02-1.31) women compared with white women. The association was stronger for invasive CBT among black women and for contralateral DCIS among Asian/PI women (P heterogeneity<0.0001). The black race-associated CBT risk was more pronounced among women ≥50years at diagnosis and those with comedo DCIS; in contrast, a significant increase in risk among Asian/PI women was restricted to those <50years and those with noncomedo DCIS. Racial/ethnic differences in risks of second breast tumors after DCIS could not be explained by pathologic features and treatment.

Post-operative radiotherapy for ductal carcinoma in situ of the breast

The addition of radiotherapy (RT) following breast conserving surgery (BCS) was first shown to reduce the risk of ipsilateral recurrence in the treatment of invasive breast cancer. Ductal carcinoma in situ (DCIS) is a pre-invasive lesion. Recurrence of ipsilateral disease following BCS can be either DCIS or invasive breast cancer. Randomised controlled trials (RCTs) have shown that RT can reduce the risk of recurrence, but assessment of potential long-term complications from addition of RT following BSC for DCIS has not been reported for women participating in RCTs. To summarise the data from RCTs testing the addition of RT to BCS for treatment of DCIS to determine the balance between the benefits and harms. We searched the Cochrane Breast Cancer Group Specialised Register (2 June 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 1), MEDLINE (2 June 2011), EMBASE (2 June 2011) and the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP; 2 June 2011). Reference lists of articles and handsearching of ASCO (2007), ESMO (2002 to 2007), and St Gallen (2005 to 2007) conferences were performed. RCTs of breast conserving surgery with and without radiotherapy in women at first diagnosis of pure ductal carcinoma in situ (no invasive disease present). Two authors independently assessed each potentially eligible trial for inclusion and its quality. Two authors also independently extracted data from published Kaplan-Meier analysis (survival curves) and reported summary statistics. Data were extracted and pooled for four trials. Data for planned subgroups were extracted and pooled for analysis.There were insufficient data to pool for long-term toxicity from radiotherapy. Four RCTs involving 3925 women were identified and included in this review. All were high quality with minimal risk of bias. Three trials compared the addition of RT to BCS. One trial was a two by two factorial design comparing the use of RT and tamoxifen, each separately or together, in which participants were randomised in at least one arm. Analysis confirmed a statistically significant benefit from the addition of radiotherapy on all ipsilateral breast events (hazards ratio (HR) 0.49; 95% CI 0.41 to 0.58, P < 0.00001), ipsilateral invasive recurrence (HR 0.50; 95% CI 0.32 to 0.76, p=0.001) and ipsilateral DCIS recurrence (HR 0.61; 95% CI 0.39 to 0.95, P = 0.03). All the subgroups analysed benefited from addition of radiotherapy. No significant long-term toxicity from radiotherapy was found. No information about short-term toxicity from radiotherapy or quality of life data were reported. This review confirms the benefit of adding radiotherapy to breast conserving surgery for the treatment of all women diagnosed with DCIS. No long-term toxicity from use of radiotherapy was identified.

Abstract B117: Risk factors of second breast cancer among patients with ductal carcinoma in situ

Abstract Background: Women with ductal carcinoma in situ (DCIS) are at increased risk of breast cancer in either ipsilateral or contralateral breasts. However, it is inconclusive about the factors predicting the risk of second breast cancer after DCIS. Methods: We used US Surveillance, Epidemiology, and End Results data on women with first unilateral DCIS diagnosed between 1988 and 2009. Relative risks (RRs) were estimated using cox regression models to identify the factors associated with the risks of second DCIS and second invasive breast cancer (IBC). Results: Of the 74,285 eligible DCIS patients, 6,140 (8.3%) had subsequent breast cancer during 8.5 years of follow-up (714 ipsilateral DCIS, 2,003 ipsilateral IBC, 997 contralateral DCIS, and 2,426 contralateral IBC). Patients &amp;lt;50 years (RR=1.45; 95% confidence interval (CI), 1.29-1.64), black patients (RR=1.60; 95% CI, 1.39-1.83), patients with comedo DCIS (RR=1.19; 95% CI, 1.07-1.32), and patients with poorly differentiated DCIS (RR=1.45; 95% CI, 1.15-1.82) were more likely to develop ipsilateral breast cancer. Solid histologic type was more strongly associated with increased risk of ipsilateral IBC (RR=1.49; 95% CI, 1.12-1.99). The risk of contralateral breast cancer was increased among black women (RR=1.33; 95% CI, 1.16-1.52) and was decreased among young women and women with comedo DCIS, which was more obvious for contralateral IBC. Conclusion: The risk factors were different for second breast cancer in the ipsilateral breast and in the contralateral breast. Improved follow-up of young patients, black patients, patients with poorly differentiated DCIS, and patients with comedo or solid DCIS may reduce the risk of second IBC. Further investigations are needed to identify molecular features of DCIS that predict risk of second breast cancer and/or mediate racial and age differences in second cancer risk. Citation Format: Ying Liu, Graham Colditz. Risk factors of second breast cancer among patients with ductal carcinoma in situ. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B117.

EZH2 and ALDH1 expression in ductal carcinoma in situ: Complex association with recurrence and progression to invasive breast cancer

The diagnosis of ductal carcinoma in situ (DCIS) is an increasingly common event due to widespread use of screening mammography. However, appropriate clinical management of DCIS is a major challenge in the absence of prognostic markers. Tumor-initiating cells may be particularly relevant for disease pathogenesis; therefore, two markers associated with such cells, EZH2 and ALDH1, were evaluated. A cohort of 248 DCIS patients was used to determine the association of EZH2 and ALDH1 with ipsilateral breast event, DCIS recurrence and progression to invasive breast cancer (IBC). In this cohort, high EZH2 expression was associated with the risk of an ipsilateral breast event and DCIS recurrence but not invasive progression. ALDH1 expression was observed in both the tumor and stromal compartment; however, in neither compartment were ALDH1 levels independently associated with evaluated study endpoints. Interestingly, the combination of high EZH2 with high epithelial ALDH1 was associated with disease progression. Therefore, ALDH1 within the DCIS lesion can add to the prognostic significance of EZH2, particularly in the context of risk of development of invasive disease.

Blurry Boundaries: Do Epithelial Borderline Lesions of the Breast and Ductal Carcinoma In Situ Have Similar Rates of Subsequent Invasive Cancer?

The histology of epithelial "borderline lesions" of the breast, which have features in between atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS), is well described, but the clinical behavior is not. This study reports subsequent ipsilateral breast events (IBE) in patients with borderline lesions compared with those with DCIS. Patients undergoing breast-conserving surgery for borderline lesions or DCIS from 1997 to 2010 were identified from a prospective database. IBE was defined as the diagnosis of subsequent ipsilateral DCIS or invasive ductal carcinoma. A total of 143 borderline-lesion patients and 2,328 DCIS patients were identified. Median follow-up was 2.9 and 4.4years, respectively. 7 borderline-lesion and 172 DCIS patients experienced an IBE. 5year IBE rates were 7.7% for borderline lesions and 7.2% for DCIS (p=.80). 5year invasive IBE rates were 6.5 and 2.8%, respectively (p=.25). Similarly, when analyses were restricted to patients who did not receive radiotherapy, or endocrine therapy, or both, borderline-lesion and DCIS patients did not demonstrate statistically significant differences in rates of IBE or invasive IBE. When compared with DCIS, borderline lesions do not demonstrate lower rates of IBE or invasive IBE. Despite "borderline" histology, a 5year IBE rate of 7.7% and an invasive IBE rate of 6.5% suggest that the risk of future carcinoma is significant and similar to that of DCIS.

Postoperative tamoxifen for ductal carcinoma in situ

Ductal carcinoma in situ (DCIS) is a non-invasive carcinoma of the breast. The incidence of DCIS has increased substantially over the last twenty years, largely as a result of the introduction of population-based mammographic screening. The treatment of DCIS tumours involves surgery with or without radiotherapy to prevent recurrent DCIS and invasive carcinoma. However, there is clinical uncertainty as to whether postoperative hormonal treatment (tamoxifen) after surgery confers benefit in overall survival and incidence of recurrent carcinoma. To assess the effects of postoperative tamoxifen in women having local surgical resection of DCIS. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), the Cochrane Breast Cancer Group's Specialised Register, and the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) on 16 August 2011. Published and unpublished randomised controlled trials (RCTs) and quasi-randomised controlled trials comparing tamoxifen after surgery for DCIS (regardless of oestrogen receptor status), with or without adjuvant radiotherapy. Two authors independently assessed trial quality and extracted data. Statistical analyses were performed using the fixed-effect model and the results were expressed as relative risks (RRs) or hazard ratios (HRs) with 95% confidence intervals (CIs). We included two RCTs involving 3375 women. Tamoxifen after surgery for DCIS reduced recurrence of both ipsilateral (same side) DCIS (HR 0.75; 95% CI 0.61 to 0.92) and contralateral (opposite side) DCIS (RR 0.50; 95% CI 0.28 to 0.87). There was a trend towards decreased ipsilateral invasive cancer (HR 0.79; 95% CI 0.62 to 1.01) and reduced contralateral invasive cancer (RR 0.57; 95% CI 0.39 to 0.83). The number needed to treat in order for tamoxifen to have a protective effect against all breast events is 15. There was no evidence of a difference detected in all cause mortality (RR 1.11; 95% CI 0.89 to 1.39). Only one study, involving 1799 participants followed-up for 163 months (median) reported on adverse events (i.e. toxicity, mood changes, deep vein thrombosis, pulmonary embolism, endometrial cancer) with no significant difference between tamoxifen and placebo groups, but there was a non-significant trend towards more endometrial cancer in the tamoxifen group. While tamoxifen after local excision for DCIS (with or without adjuvant radiotherapy) reduced the risk of recurrent DCIS (in the ipsi- and contralateral breast), it did not reduce the risk of overall mortality.

Pleomorphic lobular carcinoma in situ: A distinct entity of controversial significance.

177 Background: Pleomorphic lobular carcinoma in situ (PLCIS) is an increasingly diagnosed variant of lobular carcinoma in situ. Histologically, it resembles ductal carcinoma in situ (DCIS), leading to controversy over proper management. Yet, the natural history of PLCIS is unknown. Here we describe our experience with PLCIS. Methods: Review of pathology reports (1995–2012) identified 233 cases of LCIS variants. Patients with synchronous ipsilateral DCIS or invasive cancer (IC) were excluded leaving 25 cases for review. Consensus review by 3 pathologists further excluded 7; leaving 18 cases, 12 of which were classified as PLCIS and 6 as LCIS with pleomorphic features (LCIS-PF). (Table) PLCIS was defined by cellular dyshesion, nuclear pleomorphism with a 2-3 fold size variation, conspicuous nucleoli, mitoses and abundant cytoplasm; lesions not meeting all parameters were classified as LCIS-PF. Loss of e-cadherin was confirmed; clinical data were obtained from medical records. Results: Mean patient age at diagnosis of PLCIS/LCIS-PF was 57 yrs (42-67 yrs). All cases presented with imaging abnormalities. A previous history of breast cancer was present in 7/18 (39%) pts (3/7, ipsilateral; 4/7, contralateral). Following PLCIS/LCIS-PF diagnosis, 6/18 (33%) pts underwent mastectomy and 12/18 had excision alone, with (n=3) or without chemoprevention (n=9). Margin status was negative in 4/12 pts; close in 3/12 pts and positive in 5/12 pts undergoing excision. At a median follow-up of 27 mos (2-148 mos), 2/12 pts treated with excision developed ipsilateral breast cancer (1 DCIS; 1 IC). Both had close margins at initial excision; median time to cancer, 54 mos. Conclusions: Pure PLCIS is an uncommon lesion. Synchronous malignancy or prior history of breast cancer are often present in patients with PLCIS, contributing to the difficulty in determining the actual risk conferred by this lesion and appropriate management. Efforts to systematically characterize LCIS variants and prospective documentation of outcomes are needed to clarify the significance of these lesions. [Table: see text]

Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial

SummaryBackgroundInitial results of the UK/ANZ DCIS (UK, Australia, and New Zealand ductal carcinoma in situ) trial suggested that radiotherapy reduced new breast events of ipsilateral invasive and ductal carcinoma in situ (DCIS) compared with no radiotherapy, but no significant effects were noted with tamoxifen. Here, we report long-term results of this trial.MethodsWomen with completely locally excised DCIS were recruited into a randomised 2×2 factorial trial of radiotherapy, tamoxifen, or both. Randomisation was independently done for each of the two treatments (radiotherapy and tamoxifen), stratified by screening assessment centre, and blocked in groups of four. The recommended dose for radiation was 50 Gy in 25 fractions over 5 weeks (2 Gy per day on weekdays), and tamoxifen was prescribed at a dose of 20 mg daily for 5 years. Elective decision to withhold or provide one of the treatments was permitted. The endpoints of primary interest were invasive ipsilateral new breast events for the radiotherapy comparison and any new breast event, including contralateral disease and DCIS, for tamoxifen. Analysis of each of the two treatment comparisons was restricted to patients who were randomly assigned to that treatment. Analyses were by intention to treat. All trial drugs have been completed and this study is in long-term follow-up. This study is registered, number ISRCTN99513870.FindingsBetween May, 1990, and August, 1998, 1701 women were randomly assigned to radiotherapy and tamoxifen, radiotherapy alone, tamoxifen alone, or to no adjuvant treatment. Seven patients had protocol violations and thus 1694 patients were available for analysis. After a median follow-up of 12·7 years (IQR 10·9–14·7), 376 (163 invasive [122 ipsilateral vs 39 contralateral], 197 DCIS [174 ipsilateral vs 17 contralateral], and 16 of unknown invasiveness or laterality) breast cancers were diagnosed. Radiotherapy reduced the incidence of all new breast events (hazard ratio [HR] 0·41, 95% CI 0·30–0·56; p<0·0001), reducing the incidence of ipsilateral invasive disease (0·32, 0·19–0·56; p<0·0001) as well as ipsilateral DCIS (0·38, 0·22–0·63; p<0·0001), but having no effect on contralateral breast cancer (0·84, 0·45–1·58; p=0·6). Tamoxifen reduced the incidence of all new breast events (HR 0·71, 95% CI 0·58–0·88; p=0·002), reducing recurrent ipsilateral DCIS (0·70, 0·51–0·86; p=0·03) and contralateral tumours (0·44, 0·25–0·77; p=0·005), but having no effect on ipsilateral invasive disease (0·95, 0·66–1·38; p=0·8). No data on adverse events except cause of death were collected for this trial.InterpretationThis updated analysis confirms the long-term beneficial effect of radiotherapy and reports a benefit for tamoxifen in reducing local and contralateral new breast events for women with DCIS treated by complete local excision.FundingCancer Research UK and the Australian National Health and Medical Research Council.

Beneficial Effect of Tamoxifen for Women with DCIS: Long-Term Results from the UK/ANZ DCIS Trial in Women with Locally Excised DCIS.

Abstract Background: Initial results of the UK/ANZ DCIS trial found that adjuvant radiotherapy reduced the recurrence of ipsilateral invasive breast cancer (BC) and ductal carcinoma in situ (DCIS) by 55% and 64% respectively, but the effect of tamoxifen was smaller (Lancet 2003, 362: 95-102). Here, we report an updated analysis of this trial.Methods: 1701 women with completely locally excised DCIS were enrolled in a randomised 2x2 trial of radiotherapy, tamoxifen or both. Elective decision to withhold or provide one of the treatments was also permitted and long-term follow-up was performed by treating hospitals. Seven patients were excluded due to protocol violations leaving 1694 patients available for analysis.Results: After a median follow-up of 12.7 years, a total of 376 breast cancers were diagnosed; 162 invasive (122 ipsilateral; 39 contralateral) and 197 DCIS (173 ipsilateral; 17 contralateral). Radiotherapy continued to reduce the incidence of ipsilateral invasive disease (HR=0.32 (0.19-0.56), P&amp;lt;0.0001) and ipsilateral DCIS (HR=0.38 (0.22-0.63), P&amp;lt;0.0001), but had no significant effect on contralateral breast cancer (HR=0.84 (0.45-1.58)). Tamoxifen significantly reduced all recurrences by 29% (HR=0.71 (0.58-0.88), P=0.002) (Figure 1). This consisted of a 30% (HR=0.70 (0.51-0.86)) reduction in recurrent ipsilateral DCIS, a small 5% (HR=0.95 (0.66-1.38)) reduction in ipsilateral invasive disease, and a 56% (HR=0.44 (0.25-0.77)) reduction in contralateral tumours. Overall, women randomised to radiotherapy and not receiving tamoxifen had a 59% reduction in recurrence (HR=0.41 (0.30-0.57), P&amp;lt;0.0001), whereas those randomised to tamoxifen and not receiving radiotherapy had an overall reduction of 29% (HR=0.71 (0.57-0.87), P=0.001).Conclusion: This updated analysis confirms the long-term benefit of radiotherapy in women with DCIS treated by complete local excision and also established a benefit for tamoxifen. Ongoing work will examine in detail which subsets of tumours (e.g. high grade, oestrogen receptor positive) will benefit most from these treatments. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 34.