Dutch Breast Cancer Research Group Research Articles

DIRECT2: A randomized phase III trial with a fasting mimicking diet program to improve chemotherapy in patients with hormone receptor positive, HER2-negative breast cancer—A Dutch Breast Cancer Research Group study (BOOG).

TPS630 Background: Preclinical research has shown that fasting and/or a fasting mimicking diet (FMD) in addition to chemotherapy can enhance cancer treatment effectivity and reduce side-effects. The previous DIRECT1 phase 2 study (de Groot S, Nat. Commun. 2020) indicated that FMD could increase effectivity of neoadjuvant chemotherapy in patients with HER2-negative breast cancer. Methods: DIRECT2 is a multicenter, randomized, open label phase 3 study that investigates whether FMD compared to a regular diet during neoadjuvant chemotherapy can improve the pathological and/or radiological response rate in patients with hormone receptor positive (HR+), HER2-negative, stage II/III breast cancer. Secondary endpoints include quality of life, cognition, toxicity ≥grade 3 and the immunomodulating effect of FMD. The FMD consists of a low-caloric diet of 600kcal/day starting 3 days prior to, and on the day of chemotherapy administration every 4 weeks, for a total of 5 FMD cycles during neoadjuvant chemotherapy (4 times dose dense Adriamycin plus cyclophosphamide followed by 12 times weekly paclitaxel). Patients will be supported and monitored by a centralized dietician during each FMD cycle. An additional MRI will be conducted after 4ddAC to evaluate efficacy mid-way through chemotherapy. Furthermore, an optional tumor biopsy will be done to determine the immunomodulatory effects of the FMD which will be determined using cutting-edge RNA sequencing and multispectral imaging techniques. Pathological response will be graded on the surgical specimen according to Miller & Payne 4/5, indicating a 90-100% tumor cell loss. Radiological response will be determined by MRI (RECIST1.1). In total 240 patients are needed to detect an increase from 20% to 37.5% in pathological response rate in the FMD arm allowing for 15% dropout, using a two-sided Z test with pooled variance and 5% significance level with a power of 80%. Randomization will be performed in Castor EDC with variable block sizes and stratified by clinical stage (stadium II versus III) and BMI (< 25kg/m2 versus ≥ 25kg/m2). Inclusion criteria are HR+, HER2- breast cancer stage II-III, BMI > 18.5 kg/m2, WHO status 0-2, without a history of malignancy in the past 5 years, invasive or ipsilateral non-invasive breast cancer. Patients will be excluded in case of pregnancy, lactation or metabolic disease that affects gluconeogenesis and adaptability to FMD. The trial is supported by grants from the Dutch Cancer Society and WCRF. The study is open since February 2023 for inclusion for 4 years and plans to recruit 240 patients in total in 20 participating hospitals in the Netherlands. Clinical trial information: NCT05503108 .

Abstract OT3-02-04: Selecting the optimal position of CDK4/6 inhibitors in hormone-receptor-positive advanced breast cancer: The BOOG 2017-03 SONIA study

Abstract BACKGROUND Combining cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors with endocrine therapy (ET) is an effective strategy to improve progression-free survival (PFS) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). There is a lack of comparative data to help clinicians decide whether CDK4/6 inhibitors can best be added to first- or second-line ET. The former strategy may provide longer PFS benefit, but is associated with longer use of the drug, which results in more toxicity and costs, whereas no clear benefit on overall survival (OS) or quality of life (QoL) has been proven thus far. No predictive biomarker exists to select patients who are most likely to benefit from the addition of CDK4/6 inhibition. TRIAL DESIGN AND AIMS The SONIA study is an investigator-initiated, multicenter, randomized phase III study, funded by 'ZonMw' and 'Zorgverzekeraars Nederland'. Patients are randomly assigned to receive either strategy A (first-line treatment with a non-steroidal aromatase inhibitor (NSAI) + CDK4/6 inhibition, followed on progression by fulvestrant) or strategy B (first-line treatment with NSAI, followed on progression by fulvestrant + CDK4/6 inhibition). Each CDK4/6 inhibitor can be used according to its approved EMA label. The primary objective is to test whether strategy A is superior to strategy B. The primary endpoint is time from randomization to second objective progression (PFS2). Secondary endpoints include OS, safety, QoL, and cost-effectiveness. Additional biomarker analyses will be performed to optimize patient selection. ELIGIBILITY CRITERIA Patients with a proven diagnosis of HR+/HER2-negative advanced breast cancer without prior systemic therapy for advanced disease who are candidates to receive NSAIs as first-line treatment, are eligible for the study. Exclusion criteria include advanced visceral spread with the risk of life-threatening complications in the short term. Other conditions excluding a patient from participating are other malignancies, prolonged QTc time (>480ms) or any other medical condition that interferes with study procedures or compliance. STATISTICAL METHODS The difference in PFS2 will be estimated using the intention-to-treat population in a Cox proportional hazards model accounting for all stratification factors (visceral versus non-visceral disease, yes versus no prior ET in (neo)adjuvant setting, hospital, and type of CDK4/6 inhibitor). Five-hundred seventy-four primary outcome events yield 89% power to show that strategy A has statistically significant, clinically meaningful (according to European Society for Medical Oncology - Magnitude of Clinical Benefit Scale) superior PFS2 in a log-rank test at the two-sided 95% confidence level. ACCRUAL TARGET: with an accrual period of 42 months and an additional 18 months follow-up, inclusion of 1050 evaluable patients is required. A total of 76 Dutch hospitals will participate. PRESENT: the study is open in 51 hospitals and 106 patients are included. Citation Format: van Ommen - Nijhof A, van der Voort A, Konings IR, Jager A, Sonke GS, On behalf of the SONIA Investigators (SONIA Steering Committee), And the Dutch Breast Cancer Research Group (BOOG). Selecting the optimal position of CDK4/6 inhibitors in hormone-receptor-positive advanced breast cancer: The BOOG 2017-03 SONIA study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-02-04.

Abstract OT2-07-07: Image-guided de-escalation of neoadjuvant chemotherapy in HER2-positive breast cancer: The TRAIN-3 study

Abstract Background The addition of pertuzumab to trastuzumab containing chemotherapy has boosted pathologic complete response (pCR) rates after neoadjuvant chemotherapy for HER2-positive breast cancer. PCR rates over 80% have been described and achieving a pCR is associated with a favorable long-term outcome. In addition, achieving a radiologic complete response (rCR) is predictive of the pathologic response in HER2-positive tumors. Therefore it is hypothesized that image-guided evaluation based on the early occurrence of rCR can be used to tailor the number of chemotherapy cycles. Trial design This is a single arm, multicenter study evaluating the efficacy of image-guided de-escalation of neoadjuvant treatment with paclitaxel, Herceptin®, carboplatin, and pertuzumab (PTC-ptz). Radiologic evaluation with contrast-enhanced breast MRI and ultrasound of the axilla (in cN+ patients) is performed at baseline and after 3, 6, and 9 cycles of treatment. In case of rCR of the breast (and axilla) after 3 or 6 cycles, early surgery will be performed. If residual tumor is present after 3 and 6 cycles, patients will continue the PTC-ptz regimen to complete a total of 9 cycles. All patients will receive adjuvant Herceptin® and pertuzumab to complete 1 year of anti-HER2 blockade and endocrine treatment according to local guidelines if HR-positive. The study will be performed in the Netherlands in approximately 35 centers. Eligibility criteria Eligible patients have histologically proven stage II/III HER2-positive primary breast cancer with known hormone-receptor status. Patients must have a measurable breast tumor on baseline MRI and can be either node negative or node positive. Specific aims The aim is to evaluate the efficacy of image-guided de-escalation of neoadjuvant chemotherapy in HER2-positive breast cancer on event-free survival (EFS) at 3 years as primary endpoint. Secondary endpoints are overall survival, rCR, concordance between rCR and pCR (ypT0/is, ypN0), differences in EFS and OS following pCR between patients who received 3, 6, or 9 cycles, and toxicity. Statistical methods This is a single-arm, two stage study with one interim-analysis and a final analysis. Statistics will be performed for each hormone receptor subgroup separately. Stopping rules are based on 3-year EFS-rates described in literature (88% for HR-negative tumors and 90% for HR-positive tumors) and calculated using the exact conditional Poisson distribution. The study is successful with ≤34 EFS-events in the HR-negative subgroup and ≤38 events in the HR-positive subgroup after 700 patient-years of follow-up. The three-year EFS-estimate will be calculated using Kaplan-Meier statistics. Present accrual and target accrual Target accrual is 231 patients for the HR-negative group and 231 patients for the HR-positive group. Present accrual will follow. Funding Investigator initiated trial sponsored by the Dutch Breast Cancer Research Group (BOOG), funded by Roche. Contact information for people with a specific interest in the trial Study coordinator: A van der Voort, MD The Netherlands Cancer Institute 1006 BE Amsterdam E: a.vd.voort@nki.nl, P:+31 20 512 2951 Citation Format: van der Voort A, Dezentjé VO, van der Steeg WA, Winter-Warnars GA, Schipper R-J, Scholten AN, Wesseling J, van Werkhoven ED, van Duijnhoven FH, Vrancken Peeters M-JT, Sonke GS. Image-guided de-escalation of neoadjuvant chemotherapy in HER2-positive breast cancer: The TRAIN-3 study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-07.

Intermittent versus continuous first-line treatment for HER2-negative metastatic breast cancer: the Stop & Go study of the Dutch Breast Cancer Research Group (BOOG).

We determined if intermittent first-line treatment with paclitaxel plus bevacizumab was not inferior to continuous treatment in patients with HER2-negative, advanced breast cancer. Patients were randomized to 2 × 4 cycles or continuous 8 cycles of paclitaxel plus bevacizumab, followed by bevacizumab maintenance treatment until disease progression or unacceptable toxicity. The primary endpoint was overall progression-free survival (PFS). A proportional-hazards regression model was used to estimate the HR. The upper limit of the two-sided 95% CI for the HR was compared with the non-inferiority margin of 1.34. A total of 420 patients were included with well-balanced characteristics. In the intention-to-treat analysis, median overall PFS was 7.4months (95% CI 6.4-10.0) for intermittent and 9.7 months (95% CI 8.9-10.3) for continuous treatment, with a stratified HR of 1.17 (95% CI 0.88-1.57). Median OS was 17.5 months (95% CI 15.4-21.7) versus 20.9 months (95% CI 17.8-24.0) for intermittent versus continuous treatment, with a HR of 1.38 (95% CI 1.00-1.91). Safety results and actually delivered treatments revealed longer durations of treatment in the continuous arm, without significant unexpected findings. Intermittent first-line treatment cannot be recommended in patients with HER2-negative advanced breast cancer. EudraCT 2010-021519-18; BOOG 2010-02.

Abstract OT3-07-01: Update of the randomized, non-inferiority LORD trial testing safety of active surveillance for women with screen-detected low risk ductal carcinoma in situ (EORTC-1401-BCG/BOOG 2014-04, DCIS)

Abstract The introduction of population-based breast cancer screening and implementation of digital mammography have led to an increased incidence of ductal carcinoma in situ (DCIS) without a decrease in the incidence of advanced breast cancer. This suggests DCIS overdiagnosis exists. We hypothesize that asymptomatic, low-grade DCIS can safely be managed by active surveillance. If progression to invasive breast cancer would still occur, this will be low-grade and hormone receptor positive with excellent survival rates. Also, breast-conserving treatment will still be an option, if no prior radiotherapy has been applied. Management by active surveillance also may save many low-grade DCIS patients intensive treatment. Therefore, we will compare active surveillance with conventional treatment, being either mastectomy, wide local excision (WLE) only, or WLE plus radiotherapy, possibly followed by hormonal therapy for primary low-grade DCIS. For this, we conduct a phase III, open-label, non-inferiority, multi-center, randomized clinical trial sponsored by the European Organization for Research and Treatment of Cancer (EORTC-1401-BCG). The Dutch Centers are coordinated by the Dutch Breast Cancer Research Group (BOOG) (BOOG 2014-04). This trial is developed and implemented in close collaboration with patient advocates. Randomization will be in a 1:1 ratio among one of the following arms: (1) active surveillance or (2) standard treatment per local policy. In total, 1,240 women (≥ 45 years) will be included without prior breast cancer, but with asymptomatic, pure, low-grade DCIS, based on a minimum of tissue harvested by biopsy from calcifications detected by population-based or opportunistic screening. Assuming 25% of randomized women qualified to enroll in the study will drop out or will be excluded from per protocol evaluation, at least 1,240 women need to be randomized to obtain the 930 patients required for the evaluation of the primary endpoint. The same follow-up scheme will be applied in both study arms, i.e. annual mammography for a period of 10 years. The primary end-point is ipsilateral invasive breast tumor-free rate at 10 years. Secondary end-points are among others: overall survival, breast cancer-specific survival, mastectomy rate, patient reported outcomes and cost-effectiveness. Accrual has started in the Netherlands in February 2017 and will start internationally in over 30 centers shortly. Acknowledgements: This trial is funded by Pink Ribbon Netherlands, the Dutch Cancer Society and Dutch Cancer Society/Alpe d'HuZes, and Cancer Research UK. Citation Format: Wesseling J, Elshof LE, Tryfonidis K, Poncet C, Aalders K, van Leeuwen-Stok E, Skinner V, Loo C, Winter-Warnars G, Bleiker E, Retèl V, Pijnappel R, Bijker N, Rutgers E, van Duijnhoven F. Update of the randomized, non-inferiority LORD trial testing safety of active surveillance for women with screen-detected low risk ductal carcinoma in situ (EORTC-1401-BCG/BOOG 2014-04, 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 OT3-07-01.

246PD - Efficacy of two times four versus continuous eight cycles of paclitaxel/bevacizumab as first-line chemotherapy in metastatic breast cancer: The Stop&Go study of the Dutch Breast Cancer Research Group (BOOG)

246PD - Efficacy of two times four versus continuous eight cycles of paclitaxel/bevacizumab as first-line chemotherapy in metastatic breast cancer: The Stop&Go study of the Dutch Breast Cancer Research Group (BOOG)

Feasibility of a prospective, randomised, open-label, international multicentre, phase III, non-inferiority trial to assess the safety of active surveillance for low risk ductal carcinoma in situ – The LORD study

BackgroundThe current debate on overdiagnosis and overtreatment of screen-detected ductal carcinoma in situ (DCIS) urges the need for prospective studies to address this issue. A substantial number of DCIS lesions will never form a health hazard, particularly if it concerns non- to slow-growing low-grade DCIS. The LORD study aims to evaluate the safety of active surveillance in women with low-risk DCIS. DesignThis is a randomised, international multicentre, open-label, phase III non-inferiority trial, led by the Dutch Breast Cancer Research Group (BOOG 2014-04) and the European Organization for Research and Treatment of Cancer (EORTC-BCG 1401). Standard treatment will be compared to active surveillance in 1240 women aged ⩾45years with asymptomatic, screen-detected, pure low-grade DCIS based on vacuum-assisted biopsies of microcalcifications only. Both study arms will be monitored with annual digital mammography for a period of 10years. The primary end-point is 10-year ipsilateral invasive breast cancer free percentage. Secondary end-points include patient reported outcomes, diagnostic biopsy rate during follow-up, ipsilateral mastectomy rate and translational research. FeasibilityTo explore interest in and feasibility of the LORD study we conducted a survey among EORTC and BOOG centres. A vast majority of EORTC and BOOG responding centres expressed interest in participation in the LORD study. The proposed study design is endorsed by nearly all centres.

Abstract P4-15-12: Results from a randomized phase II study of the Dutch Breast Cancer Research Group (BOOG 2008-03): Concomitant trastuzumab, bevacizumab and paclitaxel (HAT) versus trastuzumab and bevacizumab, followed by trastuzumab, bevacizumab and paclitaxel (HA-HAT) a

Abstract Background Until recently, trastuzumab (H) combined with a taxane was standard first line systemic therapy for patients with Her2 positive metastatic breast cancer (MBC) who are not candidates for endocrine therapy. Clinical studies have shown that bevacizumab (A) enhances the activity of weekly paclitaxel (T), while preclinical data suggest that A can also augment anti-tumor activity of H. Here we report outcome data of a randomized phase II study in Her2 positive MBC on the combination of HAT versus sequential treatment starting with a chemotherapy-free approach with H and A (HA), followed by adding T at progression (HA-HAT). Methods Patients with Her2 positive MBC, eligible for first-line systemic therapy, were randomized (1:1) between HAT (3-weekly H 6 mg/kg (first dose 8/mg/kg) plus A 15 mg/kg both until progression and T 90mg/m2, day 1,8,15 every 4 weeks for a maximum of 6 cycles) and HA-HAT (doses HA were the same as in HAT with T for a maximum of 6 cycles added to HA at progression). Primary endpoint was progression-free survival rate at 1 year after randomization (PFR-1yr). A regimen yielding a PFR-1yr of around 40% was decided to warrant further exploration (p1). A Fleming one-stage design was, therefore, applied to both arms with p2=20%, alpha=0.05 and beta=0.10. Secondary endpoints included PFS, defined as the time from randomization to documented disease progression (PD) or death from any cause after patients had received HAT. In addition for the HA-HAT group, a PFS1 and PFS2 was established. PFS1 was defined as the time from randomization to PD or death from any cause, PFS2 as the time from starting treatment with HAT to PD or death from any cause. Results Between April 2009 and September 2013, 84 patients were randomized, 39 to HAT and 45 to HA-HAT. Baseline characteristics were similar for both arms: mean age 55 years (range 29-80 years), prior adjuvant chemotherapy in 35% and hormone receptor positive disease in 63%. The primary endpoint was met in both arms. At a median follow-up of 22 months, 26 patients in the HAT arm had progressed of whom 14 had died. The median PFS for the HAT arm was 19.4 months (95% confidence interval (CI) 14.6-25.2). In the HA-HAT arm 23 patients progressed under HA of whom 3 still have no 2nd progression after adding T. Eleven patients of the HA-HAT arm died of whom 2 due to toxicity (1 sigmoid perforation, 1 pneumonia). The median PFS1 was 14.9 months (95% CI 10.9-NA) The median PFS2 was 8.2 months (95% CI 5.9-NA). Overall PFS in the HA-HAT arm was 22.6 months (95% CI 15.4-NA). Grade 3 or higher toxicity was 3 times more often seen during treatment including T. More detailed information regarding toxicity will be shown at the meeting. Conclusion Both HAT and HA-HAT are active regimens in Her2 positive MBC. In particular the sequential approach with starting monoclonal antibodies only, yielding a median PFS of more than 1 year and a relatively mild toxicity profile, and adding chemotherapy at progression is worthwhile to be further explored. Financial support Roche Netherlands. Citation Format: Jan C Drooger, Harm van Tinteren, Steffen M de Groot, Albert J ten Tije, Hiltje de Graaf, Johanneke EA Portielje, Agnes Jager, Aafke H Honkoop, Sabine C Linn, Judith R Kroep, Frans LG Erdkamp, Paul Hamberg, Joan B Heijns, A Elise van Leeuwen-Stok, Stefan Sleijfer. Results from a randomized phase II study of the Dutch Breast Cancer Research Group (BOOG 2008-03): Concomitant trastuzumab, bevacizumab and paclitaxel (HAT) versus trastuzumab and bevacizumab, followed by trastuzumab, bevacizumab and paclitaxel (HA-HAT) a [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 P4-15-12.

Abstract P3-06-50: Thyroid function is associated with the response to neoadjuvant chemotherapy in breast cancer patients: Results from the NEOZOTAC trial on behalf of the Dutch Breast Cancer Research Group (BOOG 2010-01)

Abstract Background: Thyroid hormones, regulators of metabolism and development in healthy tissue, stimulate tumor growth in vitro and are associated with breast cancer risk. We investigated the effect of chemotherapy on thyroid function and the extent to which it can predict the pathological response in patients with HER2 negative stage II/III breast cancer taking part in the NEOZOTAC phase III trial, randomizing between 6 cycles of neoadjuvant TAC chemotherapy with or without additional zoledronic acid. Moreover, we examined the impact of thyroid function on chemotherapy toxicity. Methods: Serum samples of 38 of the 105 patients who participated in the side study of the NEOZOTAC trial were available for analyses. Serum free thyroxin (fT4) and thyroid stimulating hormone (TSH) levels were measured at baseline and compared with fT4 and TSH levels before the 2nd and 6th chemotherapy cycle. FT4 and TSH levels were also compared between subjects with and without pathological complete response (pCR). The relation between toxicity, per side effect of any CTC grade, and the variation in fT4 and TSH levels during chemotherapy was tested. Results: Serum samples at baseline, before the 2nd chemotherapy cycle and at end of treatment were available for 31, 30 and 21 patients, respectively. In the total population, the mean baseline fT4 level was 16,0pmol/L and the mean TSH level 1,11mU/L. There were no differences between subjects solely treated with TAC chemotherapy and subjects treated with zoledronic acid as an adjunct to TAC with respect to the mean fT4 and TSH at each time point. Baseline TSH levels tended to be higher in patients who achieved pCR (p=0.035 univariate analysis and p=0.074 multivariate analysis) (Table 1). During 6 cycles of chemotherapy, fT4 levels decreased (p<0.000) and TSH levels increased significantly (p=0.019). Interestingly, the decrease of fT4 was significantly greater in patients without nausea, vomiting or sensory neuropathy, than in patients with those side effects (p=0.037, p=0.043 and p=0.050 respectively). CharacteristicUnivariate analysisMultivariate analysis OR95%CIP valueOR95%CIP valueN stage: N0 vs. N+0.330.03-3.640.368T stage: <5cm vs. >5cm0.330.03-3.630.333ER receptor: Pos vs. Neg2.560.20-33.10.473fT40.780.43-1.420.4170.660.33-1.290.581TSH3.241.09-9.700.03517.30.76-3910.074Table 1. Univariate and multivariate logistic regression models of baseline characteristics and TSH and fT4 predictive of pCR. Conclusion: TSH levels at baseline were higher in breast cancer patients with pCR. Chemotherapy blunts thyroid function, and a large decline of fT4 was associated with less side effects. These data suggest that thyroid hormones may interact with chemotherapy to modulate treatment (side-) effects in patients with breast cancer. Citation Format: S de Groot, A Charehbili, L GM Janssen, E M Dijkgraaf, V THBM Smit, L W Kessels, A van Bochove, H WM van Laarhoven, E Meershoek-Klein Kranenbarg, A E van Leeuwen-Stok, G J Liefers, C JH van de Velde, J WR Nortier, J JM van der Hoeven, H Pijl, J R Kroep. Thyroid function is associated with the response to neoadjuvant chemotherapy in breast cancer patients: Results from the NEOZOTAC trial on behalf of the Dutch Breast Cancer Research Group (BOOG 2010-01) [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 P3-06-50.

Abstract OT1-1-02: PI3K-Akt-mTOR pathway analysis to obtain further insight in the efficacy of everolimus in combination with exemestane in metastatic, ER-positive breast cancer: A Dutch breast cancer research group (BOOG) study

Abstract Background In patients with hormone receptor-positive breast cancer, activation of the PI3K-Akt-mTOR pathway is associated with resistance against endocrine therapy. Previous research has shown that genetic aberrations in this pathway occur frequently, including mutation and/or amplification in PI3K subunits or PI3K effectors as well as loss of lipid phosphatases (Fu X, et al. The Breast; 2013). Central review of the BOLERO-2 randomized phase III trial in which patients refractory to a non-steroidal aromatase inhibitor were randomized between exemestane combined with the mTOR inhibitor everolimus versus exemestane and placebo has shown a progression-free survival (PFS) of, respectively, 11.0 and 4.1 months [hazard ratio = 0.38 (95% confidence interval 0.31-0.48; log-rank P <0.0001)] (Yardley DA, et al. Adv Ther; 2013). The combination, however, is known to cause more adverse events and is associated with additional costs as compared to exemestane alone. In the present study we will explore whether there are biomarkers that might indicate which patients most likely benefit from co-targeting PI3K and ER pathways. Trial design/Aims This is a Dutch prospective, open-label, single-arm, investigator-initiated, multicenter trial in which approximately 30 hospitals will participate. A total of 175 patients will be included for baseline blood sampling and archival tumor tissue collection. From 50 patients, a fresh tumor biopsy is required at baseline and from 30 out of 50, another tumor biopsy will be collected upon progressive disease. Exploratory biomarker assessment includes immunohistochemistry (total and phosphorylated PI3K, AKT, mTOR, p70S6K and 4EBP1), tissue phosphoproteomics and circulating tumor DNA (mutations). The results of the biomarker analysis will be compared with clinicopathological characteristics and PFS. Eligibility Postmenopausal patients with hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer, refractory to anastrozole or letrozole will be included. No previous treatment with exemestane or mTOR inhibitor for advanced disease is allowed and Informed consent must be signed before enrollment. Statistical methods Since the majority of the tests involve the use of new techniques, the study will be mainly explorative in design. The association between potential biomarkers and clinicopathological characteristics will be tested using Fisher exact test or the Mann-Whitney test. PFS curves will be drawn using the Kaplan-Meier method. PFS in association with potential biomarkers will be tested using Cox proportional hazard regression analysis. Present and target accrual Recently, the study has been opened for inclusion. A period of 2 years is planned for patient enrollment. Up to May 2014, two patients were included. ClinicalTrials.gov identifier NCT02109913 Financial support is received from Novartis, the Netherlands. Citation Format: Dinja T Kruger, Karin Beelen, Connie R Jimenez, Maurice PHM Jansen, Stefan Sleijfer, Sabine C Linn, Epie Boven. PI3K-Akt-mTOR pathway analysis to obtain further insight in the efficacy of everolimus in combination with exemestane in metastatic, ER-positive breast cancer: A Dutch breast cancer research group (BOOG) study [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 OT1-1-02.

Abstract OT3-6-01: The LORD trial: A randomized, non-inferiority trial, between active surveillance versus standard treatment in patients with low risk ductal carcinoma in situ

Abstract Background The goal in treating patients with ductal carcinoma in situ (DCIS) is to prevent the development of invasive breast cancer (iBC). However, a substantial number of DCIS lesions will never form a health hazard, particularly if it concerns slow-growing, low-grade DCIS. The conventional treatment of low-grade DCIS is similar to that of early-stage iBC, i.e. breast-conserving surgery (BCS) often followed by radiotherapy (RT), or mastectomy, and possibly hormonal therapy (HT). This implies that many women might be unnecessarily going through intensive treatment resulting in a decrease in quality of life and an increase in health care costs, without any survival benefit. Trial Design LORD is a randomized, international, multicenter, phase III non-inferiority trial. Patients will be randomized between active surveillance and standard treatment according to local policy. Active surveillance comprises monitoring by annual mammography and treatment if there is progression to iBC or higher grade DCIS. Standard treatment encompasses BCS only, BCS + RT, or mastectomy, possibly followed by HT, and follow-up by annual mammography. Eligibility criteria • Women ≥49 years • Referral to the hospital solely based on microcalcifications detected by population-based or opportunistic screening mammography • Unilateral, pure DCIS grade I based on multiple vacuum assisted biopsies • No prior history of iBC or DCIS Specific Aims Our aim is to investigate whether active surveillance of low-grade DCIS is as safe as the current standard treatment, and to study the effects on quality of life of these women by saving them from intensive treatment. The primary end-point is time to ipsilateral iBC (iiBC). Secondary end-points include rate of iBC at final pathology after standard treatment, radical intervention rate, and biopsy rate during follow-up. Tissue will be collected for genomic profiling and proteomics to detect iBC risk patterns in low-grade DCIS. Furthermore we aim to develop an online informational aid for clinicians and patients to facilitate the dissemination and understanding of information on low-grade DCIS and its treatment. Statistical Methods We apply a special type of non-inferiority design, where the alternative hypothesis corresponds to "minor inferiority". We assume that the iiBC-free rate in the standard arm at 5 years equals 97.6%. The hazard ratio under the null hypothesis is 3.4 and the hazard ratio under the alternative hypothesis is 2.1, corresponding to iiBC-free rates in the experimental arm of 92.0% and 95.0% respectively. With a one-sided log-rank test for non-inferiority with α=0.05 and β=0.2, 124 events are needed for which 1842 low-grade DCIS patients need to be randomized during an accrual period of 5.5 years, and the accrual period will be followed by a further follow-up period of 7.5 years. Present Accrual and Target accrual The LORD trial is endorsed by the Dutch Breast Cancer Research Group (BOOG 2014-04) and the European Organisation for Research and Treatment of Cancer (EORTC 1401). Participating sites will be identified mid-2014. Patient accrual is expected to start early 2015. Citation Format: Lotte E Elshof, Konstantinos Tryfonidis, Leen Slaets, A Elise van Leeuwen-Stok, Nicolas Dif, Victoria P Skinner, Claudette E Loo, Gonneke Warnars, Eveline Bleiker, Ruud M Pijnappel, Nina Bijker, Emiel JTh Rutgers, Jelle Wesseling. The LORD trial: A randomized, non-inferiority trial, between active surveillance versus standard treatment in patients with low risk ductal carcinoma in situ [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 OT3-6-01.

Abstract P2-01-03: Sentinel node procedure before or after neoadjuvant chemotherapy in clinically node negative or positive patients; results from 3 phase III studies of the Dutch breast cancer trialists' group (BOOG)

Abstract Background In breast cancer patients treated with neoadjuvant systemic therapy, the timing of the sentinel node (SN) procedure in patients with clinically node-negative disease (cN0) at diagnosis and the role of the SN procedure after neoadjuvant therapy in patients with initially clinical node-positive disease (cN+) still remains to be elucidated. Methods Between February 2006 and May 2012, 657 patients were enrolled in three clinical trials on neoadjuvant systemic therapy under the auspices of the Dutch Breast Cancer Research Group (BOOG). In the INTENS and NEO-ZOTAC study, patients were treated with TAC or AC-T neo-adjuvant chemotherapy (doxorubicin (A), cyclophosphamide (C) and docetaxel (T)). In the TEAM IIa trial, patients were treated with neoadjuvant endocrine therapy (exemestane for 6 months). Timing of the SN procedure in cN0 disease mainly depends on local policy and period of inclusion. We compared the pN0 rate after SN procedure performed before versus after neoadjuvant systemic therapy, in patients with cN0 disease at initial diagnosis. Further, we assessed the SN negative and the false-negative sentinel node rate in patients with initially cN+ breast cancer and conversion to cN0 when treated with neoadjuvant systemic therapy. The false-negative rate was obtained by dividing the number of patients who were SN-negative but non-SN positive by the number of patients who had a positive SN or a positive non-SN. Results In total, 271 patients (n=93 INTENS, n=107 NEOZOTAC, n= 71 TEAM IIa) underwent a SN procedure (n=233 cN0; n=38 cN+). Of patients with cN0 breast cancer at diagnosis, 131 (56%) underwent the SN procedure before and 102 (44%) after neoadjuvant systemic therapy, with ypN0(sn) or ypN0(i+)(sn) in 90/131 (69%) and 69/102 (68%) patients, respectively. Patients with initially cN+ disease who converted to cN0 disease after systemic therapy had a negative SN in 29% (11/38) of cases. The false-negative rate was 20% (6 of 30). More detailed analyses will be presented at the meeting. Conclusion To our knowledge, this is the first study comparing the impact of the timing of the sentinel procedure in patients with cN0 disease. We showed, that irrespective of the timing of the SN procedure - before or after neoadjuvant systemic therapy - in patients with cN0 breast cancer at diagnosis, two-third of patients had a negative sentinel node. In patients who converted after neoadjuvant chemotherapy from cN+ to cN0 the false negative sentinel node rate was 20%. Citation Format: Vivianne C Tjan-Heijnen, Birgitte E Vriens, Maureen J Aarts, Judith R Kroep, Cock J van de Velde, Gerrit-Jan Liefers, Ayoub Charehbili, Petronella G Peer, Maaike de Boer. Sentinel node procedure before or after neoadjuvant chemotherapy in clinically node negative or positive patients; results from 3 phase III studies of the Dutch breast cancer trialists' group (BOOG) [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 P2-01-03.