Background Improvements in neoadjuvant systemic therapy (NST) for breast cancer patients have led to increasing rates of pathologic complete response (pCR). Breast-conserving surgery (BCS) after NST is considered safe, despite the fact that the original tumor bed is not entirely excised. It can therefore be hypothesized that breast surgery could be omitted in patients achieving pCR. However, since imaging modalities are insufficiently accurate to predict pCR after NST, the need for surgery is unchanged. The MICRA trial is designed to determine the value of ultrasound guided biopsy of the breast in identifying pCR after NST. The ultimate aim of our study is to eliminate surgery of the breast in patients achieving pCR, consequently improving quality of life of these patients. Trial design The MICRA trial is a multi-center observational prospective cohort study. Inclusion and exclusion criteria are presented in table 1. In all patients receiving NST, a marker is placed in the center of the tumor area pre-NST. Magnetic resonance imaging (MRI) is performed pre-NST and just before or after the last course of NST. Patients with radiologic complete response (rCR; complete absence of pathologic contrast enhancement) or partial response (rPR, 0.1-2.0 cm residual contrast enhancement, ≥30% decrease in tumour size) are eligible for participation. In these patients, 8 ultrasound guided biopsies are obtained in the region surrounding the marker: 4 central (<0.5 cm) and 4 peripheral biopsies (0.5-1.5cm). Hereafter, conventional surgery is performed (BCS or mastectomy) and pathology results of the biopsies and resected specimen are compared. Pathology findings are scored using Miller-Payne criteria. To evaluate the quality and representativeness of the biopsies, biopsies are categorized according to length and pathology results. Statistical analysis and accrual The primary endpoint of the trial is the false-negative rate (FNR) of the biopsy procedure. If the true FNR is 3%, 130 patients without pCR in specimen are sufficient to show that the FNR does not exceed 8% using a one-sided binomial test with a significance α-level of 0.05. With an expected average pCR rate of 65%, 375 patients with rCR will be included. In the rPR-group the expected pCR rate is 12% and therefore 150 patients will be included. In total 525 patients will be included. Until now, 144 patients have been included. Conclusion The ultimate aim of the MICRA trial is to eliminate surgery of the breast in patients achieving pCR, by identifying pCR with use of ultrasound guided biopsy. In this scenario, local therapy in patients with pCR would be restricted to radiotherapy. Table 1:Inclusion and exclusion criteriaInclusion criteriaExclusion criteriaWomen with invasive breast cancer >18 years (all histological subtypes and tumor subtypes)DCIS as shown by core biopsy prior to NSTTumor histology and receptor status established by pre-NST biopsyWomen with distant metastatic diseaseComplete or partial response on post-NST MRIHistory of ipsilateral breast cancerMarker placed in tumor prior to NST Correct position of marker confirmed by mammography or ultrasound Citation Format: van der Noordaa ME, van Duijnhoven FH, Loo CE, van Loevezijn A, van Werkhoven E, van de Vijver KK, Wiersma T, Winter-Warnars HA, Sonke GS, Vrancken Peeters M-JT. Towards omitting breast cancer surgery in patients with pathologic complete response after neoadjuvant systemic therapy: The MICRA trial (minimally invasive complete response assessment) [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 OT2-01-04.
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.
Background An important advantage of neoadjuvant systemic therapy (NST) in breast cancer patients is down-sizing of the primary tumor. However, many patients with T3 tumors are treated with mastectomy regardless of response to NST. In this study, we evaluated predictive characteristics for positive margins and local control in T3 breast cancer patients who underwent breast-conserving therapy (BCT) after NST. Methods This single institution study included all clinical T3 breast cancer patients (determined by contrast-enhanced magnetic resonance imaging [MRI]) who underwent breast conserving surgery (BCS) after NST between 2000-2015. Clinical T3 was defined as a breast tumor >50mm on MRI pre-NST. Patient, tumor and treatment characteristics were recorded, as well as response on MRI and final pathology. The local recurrence probability was estimated with the Kaplan-Meier method. Predictive characteristics for positive margins in patients undergoing BCS were analyzed using Fishers exact test. Results In total, 115 T3 patients were identified. Patient, tumor and MRI findings are presenting in the table. Median tumor size was 60 mm on MRI pre-NST (range 51-120 mm) and 4 mm after NST (range 0-58 mm). Overall pathologic complete response was 19%: 5% in HR+/HER2- patients, 32% in HR-/HER2+ patients and 40% in TN patients. After initial BCS, 73 patients had negative margins (63.5%), 18 focally positive margins (15.7%) and 24 more than focally positive margins (20.9%). Patients with HR+/HER2- tumors (52%) were more likely to have positive margins than patients with HR-/HER2+ and TN tumors (21% and 19%, p=0.002). In addition, positive margins rate was higher in patients with lobular carcinoma compared to patients with ductal carcinoma (57 vs 32%, p=0.031). Presence of non-mass enhancement on pre-NST MRI was predictive for positive margins (52% in patients with and 25% in patients without non-mass enhancement, p=0.003). Of patient with positive margins, 15 underwent radiotherapy with boost, 6 underwent re-excision and 21 underwent mastectomy. Finally, 94/115 patients were treated with BCT (82%). Of these patients, two had a local recurrence after a median follow-up of 6.5 years (6-year local recurrence probability 2.6% (95%-CI 0-7%). Conclusion In this series, BCT after NST was successful in 82% of patients with T3 breast cancer and local control in this group was excellent. The positive margin rate after BCS was higher in patients with HR+ tumors, lobular carcinoma and tumors with non-mass enhancement on MRI pre-NST. BCT should always be considered in T3 cancers after NST. CharacteristicTotal (n=115)Positive margins (focally+ >focally), n=42(%)p-valueHistology 0.031Ductal9229(32) Lobular2313(57) Subtype 0.002HR+/HER2-6132(52) HER2+347(21) TN203(15) MRI morphology of mass pre-NST 0.948Unifocal288(29) Multifocal4012(33) Multicentric134(31) Only non-mass enhancement34 MRI non-mass enhancement before NST 0.003Absent6516(25) Present5026(52) MRI response after NST 0.952rCR5218(35) non-rCR6221(38) Missing1 Citation Format: van der Noordaa ME, Vrancken Peeters M-JM, Ioan I, Loo CE, van Urk J, van Werkhoven E, Voorthuis R, Wiersma T, Groen E, Rutgers ET, van Duijnhoven FH. Breast conserving therapy after neoadjuvant systemic therapy in patients with T3 breast cancer is feasible [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 P3-13-02.
Background Internal mammary chain (IMC) sentinel nodes (SN) are visible in 1 out of 5 breast cancer patients on lymph scintigraphy after intra- or peritumoral injection of a radiopharmaceutical. The IMC SN status affects prognosis and treatment of breast cancer and IMC radiotherapy improves survival in selected patients. In contrast to the axillary SN, removal of the IMC SN is not routinely performed and often technically challenging. This study aims at determining the effect of IMC SN biopsy on recurrence-free survival (RFS) and overall survival (OS) and the identification of predictive factors for the development of IMC- and distant metastases. Methods All patients with IMC SNs were selected from a prospective database from 1999 to 2007. Following intratumoral injection of technetium-99m, conventional lymphoscintigraphy was performed. Sentinel nodes were removed in all regions with lymphatic drainage on scintigraphy. The RFS and OS were calculated for the total group and subgroups with tumor-positive, tumor-negative or non-removed IMC SN. Predictive factors were identified for tumor-positive IMC SN and for distant metastasis by regression analysis. Results Internal mammary chain SN biopsy was performed in 287 out of 336 patients (85%). The IMC SN was tumor-positive in 38 patients (13%). Patients with IMC metastasis had poorer OS compared to patients without IMC metastasis or a non-removed IMC SN (57%, 82% and 59% 10- year OS, respectively, p = 0.002). These patients also had worse RFS, mainly due to by the development of distant metastases (68%, 84% and 61% RFS, respectively, p = 0.002). Multivariable predictive for tumor-positive IMC SN were axillary metastases (PPV = 38.5%). Predictive factors for distant metastasis were tumor-positive IMC SN (HR 2.5, 95% CI; 1.0 - 5.8, p = 0.04), not removed IMC SN (HR 2.3, 95% CI; 1.0 - 5.1, P = 0.05), tumor diameter >1.5cm (HR 3.5, 95% CI; 1.6 - 8.4, p < 0.00) and age >65 years (HR 3.1, 95% CI; 1.2 - 7.7, p = 0.02, reference <50 years). Conclusion Breast cancer patients with tumor-positive IMC SN have worse 10- year survival than patients with tumor-negative IMC SN, mainly due to the development of distant metastasis. The clinically relevant predictive factor for distant metastasis is tumor size >1.5cm. Radiotherapy of the IMC can improve survival. However, the cardiotoxicity of parasternal radiotherapy must be weighed against the expected survival benefit. Therefore, our current protocol is to perform IMC SN biopsy in patients younger than 70 years with a tumor diameter >1.5cm. Citation Format: van Loevezijn AA, Bartels SA, van Duijnhoven FH, Heemsbergen WD, Bosma SC, Elkhuizen PH, Donswijk ML, Rutgers EJ, Oldenburg HS, Vrancken Peeters M-JT, van der Ploeg IM. Internal mammary chain sentinel nodes in early stage breast cancer patients: Towards selective removal [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 P3-03-06.
Background The increasing use of primary systemic treatment (PST) for patients with breast cancer enables more breast conserving surgery. In addition, PST converts node-positive into node-negative disease in 20-40% of patients. However, the current guidelines still recommend axillary lymph node dissection (ALND) for clinical node-positive disease (cN+), even if it became node-negative after PST, since false-negative rates of sentinel lymph node biopsy after PST range from 5-30%. Recently, an alternative technique has been introduced to stage the axilla after PST: the MARI-procedure (sensitivity 97%; FNR 7%), in which a tumour-positive lymph node is marked with a radioactive iodine seed before the start of PST and selectively removed after PST. In the present study, we propose a new strategy for treatment of the axilla in cN+ patients by combining results of the pre-PST PET/CT with the post-PST MARI-procedure. Material and methods All patients who received a MARI-procedure from July 2014 until May 2016 were included. Before the start of PST a PET/CT was performed for axillary staging and the detection of distant metastasis. A radioactive iodine seed was placed in a proven tumour-positive axillary lymph node (MARI-node), after which PST was given according to Dutch national guidelines. At our institute, we have implemented a protocol in which results of the pre-PST PET/CT and the post-PST MARI-procedure determine the type of axillary treatment. Patients with 1-3 positive axillary lymph nodes (ALNs) on PET/CT and a tumour-negative MARI-node receive no further axillary treatment. Patients with ≤3 positive ALNs on PET/CT and a tumour-positive MARI-node receive axillary radiotherapy, as well as patients with >3 positive ALNs on PET/CT and a tumour-negative MARI-node. An ALND is only performed in patients with >3 positive ALNs on PET/CT and a tumour-positive MARI-node. Results In total 168 patients received a PET/CT and a MARI procedure, of whom 43% were hormone receptor positive, 28% triple negative and 29% Her2-positive. One hundred and eight patients (64%) showed ≤ 3 and 60 patients (36%) >3 suspected ALNs on PET/CT before the start of PST. The axillary pathologic complete response was 39%. In 134 patients (80%) an ALND was omitted; of these patients 94 (56%) were treated with axillary radiotherapy and 40 patients (24%) received no further axillary treatment. In 34 patients (20%) an ALND was performed (Table 1). The median number of positive additional nodes at ALND was 5 (range 0-16). During a median follow-up of 6 months there were no local recurrences. Axillary treatmentSuspective ALNs on PET/CTOutcome MARIAxillary Treatment NoneRadiotherapyALND + Radiotherapy≤3Negative40-- Positive-68->3Negative-26- Positive--34Total409434ALN: axillary lymph nodes; ALND: axillary lymph node dissection; MARI: Marking the Axilla with Radioactive Iodine Seeds Conclusion Combining pre-PST axillary staging with PET/CT and post-PST staging with use of the MARI-procedure results in a reduction of 80% of axillary lymph node dissections in breast cancer patients with clinical node-positive disease. Citation Format: van der Noordaa MEM, Straver M, van Duijnhoven FH, Groen E, Stokkel M, Vrancken Peeters M-JTFD. Selective elimination of axillary surgery after primary systemic treatment in clinically node-positive breast cancer patients by combining PET/CT and the MARI procedure (marking the axilla with radioactive iodine seeds) [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 P2-01-07.
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