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Introduction: This project aimed to identify the frequency of a switch of hormone receptor (HR) and/or HER2 status after neoadjuvant chemotherapy (NAC) for early breast cancer. Methods: Tumor samples from patients without pathological complete response (non-pCR) were evaluated. Pathological complete response (pCR) was defined as no invasive tumor in breast and lymph nodes (ypT0/is ypN0). HR and HER2 status determined before NAC was compared with the corresponding receptor status determined in the surgical specimen after NAC. Results: 245 consecutive patients with primary invasive breast cancer, treated with NAC with/without targeted therapy between January 1, 2016 and December 31, 2019, at the LMU Breast Center, Munich, Germany, were identified. In 128 patients (52%), surgery revealed non-pCR after completed NAC. In 35 cases (27%), a switch of either HR and/or HER2 status between the initial biopsy and the surgical specimen was detected. Twenty cases had a switch in HR status, while 15 cases had a switch in HER2 status. Conclusion: In a substantial number (27%) of non-pCR cases, a switch in biomarker status after completed neoadjuvant treatment was detected. These results are consistent with prior evidence. Yet, routine reevaluation of HR and HER2 status is not recommended in guidelines so far. Future research needs to address the impact of HR and HER2 status switch on therapy adaptation and on subsequent patient outcome. Particularly, in view of the recent therapy advances, it will be critical to evaluate whether individualization of treatment concepts based on the biology of the non-pCR specimens is preferable to the initial therapy concept based on the pathology at primary diagnosis.

Funding Information: This project was initiated at the Endeavour Breast Project coordinated by Daiichi Sankyo (special thanks to Christian Opitz and Britta Mazur from Daiichi Sankyo). We thank all participants and the steering committee members of the Endeavour Breast Meeting who are not listed as co-authors ( Supplementary Table S4 , available at https://doi.org/10.1016/j.esmoop.2022.100747 ). The authors gratefully acknowledge the support from the AGMT office (particularly Mag. Katrin Dorfinger, Mag. Alexandra Keuschnig, Sebastian Schütz, and Dr. Daniela Wolkersdorfer) and all trial coordinators at the contributing centers. Publisher Copyright: © 2022 The Authors Background: Triple-negative breast cancer (TNBC) is associated with poor prognosis, and new treatment options are urgently needed. About 34%-39% of primary TNBCs show a low expression of human epidermal growth factor receptor 2 (HER2-low), which is a target for new anti-HER2 drugs. However, little is known about the frequency and the prognostic value of HER2-low in metastatic TNBC. Patients and methods: We retrospectively included patients with TNBC from five European countries for this international, multicenter analysis. Triple-negativity had to be shown in a metastatic site or in the primary breast tumor diagnosed simultaneously or within 3 years before metastatic disease. HER2-low was defined as immunohistochemically (IHC) 1+ or 2+ without ERBB2 gene amplification. Survival probabilities were calculated by the Kaplan–Meier method, and multivariable hazard ratios (HRs) were estimated by Cox regression models. Results: In total, 691 patients, diagnosed between January 2006 and February 2021, were assessable. The incidence of HER2-low was 32.0% [95% confidence interval (CI) 28.5% to 35.5%], with similar proportions in metastases (n = 265; 29.8%) and primary tumors (n = 425; 33.4%; P = 0.324). The median overall survival (OS) in HER2-low and HER2-0 TNBC was 18.6 and 16.1 months, respectively (HR 1.00; 95% CI 0.83-1.19; P = 0.969). Similarly, in multivariable analysis, HER2-low had no significant impact on OS (HR 0.95; 95% CI 0.79-1.13; P = 0.545). No difference in prognosis was observed between HER2 IHC 0/1+ and IHC 2+ tumors (HR 0.89; 95% CI 0.69-1.17; P = 0.414). Conclusions: In this large international dataset of metastatic TNBC, the frequency of HER2-low was 32.0%. Neither in univariable nor in multivariable analysis HER2-low showed any influence on OS. publishersversion published

Introduction: This study aimed at identification of breast cancer patients with a switched hormone- or HER2 receptor status after neoadjuvant chemotherapy. Therefore, patients without pathological complete response (pCR) were evaluated. The hormone and HER2 receptor status determined prior to neoadjuvant chemotherapy was compared with the corresponding receptor status determined in the surgical specimen after neoadjuvant chemotherapy. Methods: Clinicopathological data of 249 patients, who received neoadjuvant treatment between 2016 and 2019 at the LMU breast center, Munich were reviewed. Among those, 129 patients (52%) with non-pCR were identified. Of those, 11 patients had a residual positive lymph node only. pCR was defined as absence of invasive tumor in breast and lymph node (ypT0/is; ypN0). According to German clinical guidelines, specimens were labeled hormone receptor positive, if ≥1% of tumor nuclei were reported estrogen receptor positive or ≥10% of tumor nuclei were reported progesterone receptor positive. Tumors were labeled HER2-positive if immunohistochemistry showed strong complete circular membrane staining of >10% of invasive cells or if in-situ-hybridization showed HER2 positivity. Surgical specimens of patients with non-pCR were pathologically evaluated in order to 1) detect a receptor status switch compared to the analysis prior to neoadjuvant chemotherapy and 2) to see whether additional post neoadjuvant treatment options become available. Results: The following results apply exclusively to non-pCR cases. Median age at diagnosis was 51 years, 27 patients were younger than 40. One male patient is included.A total of 36 cases (28%) switched either hormone- or HER2-status, including two cases of a simultaneous switch. In 19 cases, the hormone receptor status switched. 3 patients switched from hormone receptor negative to positive, while 16 switched from hormone receptor positive to negative. A total of 17 cases showed a switch in HER2 receptor status. 6 patients switched from HER2-negative to HER2-positive, while 11 switched from HER2-positive to HER2-negative. Due to technical limitations, HER2 status was not evaluable in two cases, and hormone receptor status in one case. See table below. Conclusion: Our results illustrate, that a biomarker status switch after neoadjuvant treatment occurs in almost a third (28%) of cases. Reassessment of hormone- and HER2-receptor status subsequent to neoadjuvant treatment is still under discussion, with regard to post-neoadjuvant treatment. Nevertheless, it may have potential benefits for patients regarding individualization of treatment and potentially even patient outcome. At present, only gain of receptors should impact treatment concepts; in case of loss of receptors, treatment should not be changed as results in the residual tumor tissue may not reflect receptor status on disseminated tumor cells. Biomarker status in patients with non-pCRBiomarrker status in patients with non-pCRStatus at initial diagnosisStatus in surgical non-pCR specimenCases with switch in biomarker status after NACHR positive99 (77%)85 (66%)3HR negative30 (23%)43 (34%)16HR total12912819 (15%)HER2 positive35 (27%)28 (22%)6HER2 negative94 (73%)99 (78%)11HER2 total12912717 (13%)Cases with switch in biomarker status36 (28%) Citation Format: Moritz Dimpfl, Tom Degenhardt, Doris Mayr, Elisa Schmoeckel, Nadia Harbeck, Rachel Wuerstlein. Hormone- and HER2 receptor change in non-pCR breast cancer specimens after neoadjuvant treatment [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-32.

PURPOSENeoadjuvant systemic treatment (NST) elicits a pathologic complete response in 40%-70% of women with breast cancer. These patients may not need surgery as all local tumor has already been eradicated by NST. However, nonsurgical approaches, including imaging or vacuum-assisted biopsy (VAB), were not able to accurately identify patients without residual cancer in the breast or axilla. We evaluated the feasibility of a machine learning algorithm (intelligent VAB) to identify exceptional responders to NST.METHODSWe trained, tested, and validated a machine learning algorithm using patient, imaging, tumor, and VAB variables to detect residual cancer after NST (ypT+ or in situ or ypN+) before surgery. We used data from 318 women with cT1-3, cN0 or +, human epidermal growth factor receptor 2–positive, triple-negative, or high-proliferative Luminal B–like breast cancer who underwent VAB before surgery (ClinicalTrials.gov identifier: NCT02948764 , RESPONDER trial). We used 10-fold cross-validation to train and test the algorithm, which was then externally validated using data of an independent trial (ClinicalTrials.gov identifier: NCT02575612 ). We compared findings with the histopathologic evaluation of the surgical specimen. We considered false-negative rate (FNR) and specificity to be the main outcomes.RESULTSIn the development set (n = 318) and external validation set (n = 45), the intelligent VAB showed an FNR of 0.0%-5.2%, a specificity of 37.5%-40.0%, and an area under the receiver operating characteristic curve of 0.91-0.92 to detect residual cancer (ypT+ or in situ or ypN+) after NST. Spiegelhalter's Z confirmed a well-calibrated model ( z score –0.746, P = .228). FNR of the intelligent VAB was lower compared with imaging after NST, VAB alone, or combinations of both.CONCLUSIONAn intelligent VAB algorithm can reliably exclude residual cancer after NST. The omission of breast and axillary surgery for these exceptional responders may be evaluated in future trials.

Introduction: Breast cancer (BC) is the most common cancer in women worldwide. Despite screening and information efforts, about 10% of patients present with tumor size T3 or T4 at primary diagnosis. Late presentation is associated with more advanced tumor stage and consecutively with worse survival rates. Objective: This study aimed to evaluate whether patients with a late presentation at primary BC diagnosis differ in their personality from those with early diagnosis. Methods: In this bicentric, observational study, personality traits, positive and negative affectivity, anxiety, spirituality, illness beliefs, and sociodemographic characteristics were assessed in BC patients who presented with T-stages 3 or 4 (late presenters) and T-stages 1 or 2 (controls) at initial diagnosis. Results: Forty patients (20 controls, 20 late presenters) were interviewed. “Late presenters” perceived their disease as long lasting and had significantly more “positive affectivity” in the current trait. Although no significant associations were found, there was a trend for late presenters to have higher education levels, less spiritual longing, less accurate explanation of their illness, less anxiety in the trait scale, and more conscientiousness than the controls. Conclusion: As patients with late presentation for BC differ in specific psychological and sociodemographic characteristics from patients with early BC, the findings of this pilot project warrant additional investigations to identify further specific characteristics and motivations. Identifying patients at risk for late presentation and encouraging them to accept an earlier diagnosis could help to improve their therapy and, finally, their outcome.

Background: Efficacy and quality of life (QoL) are key factors when selecting therapies for metastatic breast cancer (MBC) patients. The addition of targeted oral agents such as CDK4/6 inhibitors to endocrine therapy is the new standard for hormone receptor (HR)+ HER2- MBC and substantially prolongs progression-free survival. However more complex oral medication in oncology might require substantial improvement of patient management. Despite several advantages of an oral treatment, patients become increasingly self-responsible and physician/patient contact is reduced. Adherence, maintaining patients’ satisfaction, and early detection and management of side effects become important challenges and new ways of continuous support for oncological patients are needed. An eHealth-based platform could help to support therapy management and physician-patient interaction. Methods: PRECYCLE is a multicenter, randomized, phase IV trial in HR+ HER2- MBC. All patients (n = 960) receive the CDK4/6 inhibitor palbociclib either in first (62.5%) or later line (37.5%) together with endocrine therapy (AI, fulvestrant) according to national guidelines. Primary study aim is the time to deterioration (TTD) of QoL in patients supported by two eHealth systems with substantially different functionality. To date (05/07/2019), 250 patients have been registered in all 72 participating centers and 230 randomized to the different study arms: - CANKADO inform with only a CANKADO-based eHealth service with a personal login, documentation of daily drug intake and passive text information (disease, treatment), but no further functions. vs. - CANKADO active with the fully functional CANKADO-based eHealth treatment support system (+ drug diary, QoL, AEs, automated recommendations, etc.) To evaluate QoL, the FACT-B questionnaire is completed at every visit. Primary objective is to test the hypothesis of superiority for TTD with regards to QoL (FACT-G scale) in patients supported by an eHealth therapy management system (CANKADO active) versus in those merely receiving eHealth-based information (CANKADO inform). As little is known about relationships between behavioral patterns (e.g. adherence), genetic background, and drug efficacy. The trial also includes a large translational program that aims at the discovery and validation of biomarkers concerning efficacy, toxicity, adherence and QoL. Recruitment is ongoing. Citation Format: Tom Degenhardt, Peter Fasching, Diana Luftner, Volkmar Mueller, Christoph Thomssen, Christian Schem, Isabel Witzel, Thomas Decker, Hans Tesch, Sherko Kuemmel, Christoph Uleer, Rachel Wuerstlein, Christoph Riese, Timo Schinköthe, Ronald Kates, Johannes Schumacher, Nadia Harbeck, Marcus Schmidt. Impact of CANKADO-based eHealth-support on quality of life in metastatic breast cancer patients treated with palbociclib and endocrine therapy - Precycle [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-14-02.

Purpose: Differential efficacy of newly registered therapies in subgroups of metastatic breast cancer (MBC) is an important consideration for subsequent use in clinical practice. Unfortunately, such subgroup analyses often are exploratory and rarely statistically adequately powered and may thus be misleading. This analysis aimed to explore a potentially different treatment response to i.v. therapies between visceral and non-visceral MBC. Methods: In a systematic literature analysis (PubMed) comprising phase III registration studies for MBC from 1994 to 2014, differences in outcome were evaluated regarding progression-free survival, time to progression, overall survival (OS), and visceral versus non-visceral disease. The impact of HER2 and hormone receptor status was also considered. A total of 16 studies comprising 13,083 patients were selected by considering the information given in the medical product’s professional information and the decision of the US Food and Drug Administration or the European Medicine Agency for approval of the respective therapeutic agents now used in the treatment of MBC. Results: No statistically significant differences regarding treatment response and therapy benefit were found in MBC patients with visceral versus non-visceral metastases based on reported hazard ratios and confidence intervals in registration trials. Interesting but nonsignificant differences were found regarding a distinct therapy benefit regarding different metastasis locations in 4 studies. Conclusion: For targeted i.v. therapies based on biomarker selection, there is a trend – although not significant – toward a benefit (OS) from combination therapies favoring visceral disease. However, at the present time, metastasis localization should not be used as a predictive marker for choice of systemic therapy in MBC.

Introduction The side effects of systemic cancer therapy and the lack of clinical data on safety and efficacy of COVID-19 vaccination in cancer patients cause uncertainty among the patients about whether to get vaccinated or not. Here, we evaluated attitude towards and effects of COVID-19 vaccination in patients with breast and gynecological cancer undergoing systemic cancer therapy. Methods Since March 15th, 2021, cancer patients who received one of the approved COVID-19 vaccines were routinely interviewed about immediate and late side effects. Clinical parameters such as current therapy, time interval between therapy administration and vaccination, and changes in the therapy schedule due to vaccination were documented. The collected data were analyzed de-identified as a part of routine quality assurance. Results By July 27th, 2021, 218 patients (74.3% breast cancer patients) had received one of two COVID-19 vaccine doses, and 112 patients had received both doses: 77.5% received Conmirnaty (BioNTech/Pfizer), 16.1% Vaxzevria (Astra Zeneca) and 5.9% COVID-19 Vaccine Moderna. The COVID-19 vaccines had an acceptable safety profile with self-limiting local and systemic adverse events, which rarely lasted >48 h post vaccination. Symptoms occurred predominantly after the second dose of the vaccine and less frequently in older patients >55 years. No vaccine-related serious adverse events were reported, and only limited effects of vaccination on the therapy schedule were observed. Conclusions Breast and gynecologic cancer patients tolerate the COVID-19 vaccination while undergoing systemic cancer therapy without any additional side effects beyond those reported in the general population.

Molecular factors that drive metastasis in premenopausal patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−), early breast cancer (EBC) are largely unknown. To identify markers/signatures contributing to metastasis, we analyzed molecular changes in tumors from premenopausal patients who developed metastasis (M1) and who did not (M0). Ninety-seven premenopausal patients with HR+/HER2− EBC were included (M1, n = 48, median distant metastasis-free survival (DMFS): 54 (7–184) months, M0, n = 49, median follow-up: 149 (121–191) months). Gene expression profiling on tumor RNA (Breast Cancer 360TM panel, Nanostring) was performed, followed by comprehensive bioinformatic and statistical analyses. Significantly enhanced ROR (risk of recurrence) scores and reduced signature scores of PGR (progesterone receptor), claudin-low, and mammary stemness were determined in M1. These differences were significantly associated with shorter DMFS in univariate survival analyses. Gene set enrichment analysis showed an enriched mTORC1 pathway in M1. Moreover, a metastasis signature of 19 differentially expressed genes (DEGs) that were DMFS-related was defined. Multivariate analysis including the four signatures, 19 DEGs, pN, and pT status, identified LRP2, IBSP, and SCUBE2 as independent prognostic factors. We identified prognostic gene signatures and single-gene markers for distant metastasis in premenopausal HR+/HER2− EBC potentially applicable in future clinical practice.

Background: Efficacy and quality of life (QoL) are key when selecting a therapy for metastatic breast cancer (MBC) patients. In hormone receptor positive (HR+) human epidermal growth factor receptor 2 minus (HER2-) MBC, addition of targeted oral agents such as everolimus or a cycline-dependent kinase 4/6 (CDK 4/6) inhibitor (e.g. palbociclib, ribociclib, abemaciclib) to endocrine therapy substantially prolongs progression-free survival and in the case of a CDK 4/6i also overall survival. Prerequiste for obtaining such benefit is adherence to therapy over the whole treatment duration. Adherence, maintaining patients’ satisfaction, early detection and management of side effects have thus become important challenges, in particular with these new oral drugs and new ways of continuous support for oncological patients are needed. An eHealth-based platform can help to support therapy management and physician-patient interaction.Methods: PreCycle is a multicenter, randomized, phase IV trial in HR+ HER2+ MBC. All patients (n=960) receive the CDK 4/6 inhibitor palbociclib either in first (62.5%) or later line (37.5%) together with endocrine therapy (AI, fulvestrant) according to national guidelines. PreCycle evaluates the time to deterioration (TTD) of QoL in patients supported by eHealth systems with substantially different functionality: CANKADO active vs. inform. CANKADO active is the fully functional CANKADO-based eHealth treatment support system. CANKADO inform is a CANKADO-based eHealth service with a personal login, documentation of daily drug intake, but no further functions. To evaluate QoL, the FACT-B questionnaire is completed at every visit. As little is known about relationships between behavior (e.g. adherence), genetic background, and drug efficacy, the trial includes both patient reported outcome and biomarker screening for discovery of forecast models for adherence, symptoms, QoL, progression free survival (PFS), and overall survival (OS).Discussion: The primary objective of PreCycle is to test the hypothesis of superiority for time to deterioration (TTD) in terms of DQoL = “Deterioration of quality of life” (FACT-G scale) in patients supported by an eHealth therapy management system (CANKADO active) versus in patients merely receiving eHealth-based information (CANKADO inform). EudraCT Number: 2016-004191-22

Sialic acid-binding immunoglobulin-like lectins (Siglecs) are involved in various immune cell-mediated diseases. Their role in cancer is poorly investigated, and research focusses on Siglec-expression on immune cells interacting with tumor cells. This study evaluates the role of Siglec-8 in breast cancer (BC). Siglec-8 expression was analyzed immunohistochemically on 235 primary BC cases and was correlated with clinical and pathological parameters and outcome. Cell culture experiments were performed with various BC cell lines. Siglec-8 was expressed in 215 BC cases and expression was lowest in triple-negative BC. It correlated with estrogen receptor-status, grading and the prognostic factors galectin (Gal)-7 and tumor-associated mucin-1 (TA-MUC1). However, Gal-7 and TA-MUC1 were only prognosticators for clinical outcome in the cohort expressing high (Immunoreactivity score IRS &gt, 3) Siglec-8 levels but not in the low-expressing cohort. Siglec-8 knockdown led to a significantly reduced Gal-7 expression in MCF7 cells. All BC cell lines expressed low Siglec-8-levels, that could be elevated in MCF7 by Peroxisome proliferator-activated receptor (PPARγ)-stimulation. This study demonstrates that Siglec-8 is expressed in BC cells and correlates with known clinical and prognostic parameters. It is probably associated with Gal-7 and TA-MUC1 and might be regulated via PPARγ. Further analyses focusing on functional associations will clarify Siglec-8’s eligibility as a possible therapeutic target.

Background: Cancer patients are at increased risk of developing severe COVID-19 disease. Possible side effects of systemic therapy and the lack of clinical data on safety and efficacy of COVID-19 vaccination in cancer patients cause uncertainty regarding the vaccination. Here, we evaluated attitude towards and effects of COVID-19 vaccination in patients with breast or gynecological cancer. The aim was to improve counseling of our patients in clinical routine. Methods: Since March 15th 2021, patients who received one of the approved COVID-19 vaccines were routinely interviewed about immediate (0-2 days) and late side effects (within two weeks after vaccination). Clinical parameters such as current therapy, time interval between therapy administration and vaccination, and changes in the therapy schedule due to the vaccination were documented. Furthermore, the willingness of non-vaccinated patients to be vaccinated was assessed. The collected data were anonymously analyzed as a part of routine quality assurance. Results: By May 10th 2021, 111 out of 217 (51.1%) interviewed patients had received at least one shot of COVID-19 vaccine and 21 patients both shots. More than half of the vaccinated patients were >55y (60.2%;mean: 60.7y, range 30-92y);69% with UICC/ FIGO stage III/IV cancer. 74.6% received Conmirnaty (BioNTech/ Pfizer), 18.9% Vaxzevria (AstraZeneca) and 6.5% Covid-19 Vaccine Moderna. After the first shot, 33.3% of the patients described no side effects, 49.1% reported a local reaction (swelling or pain), 23.4% flu-like symptoms, 10.8% headache and 3.6% nausea. 11 patients had symptoms that lasted longer than two days. In 11 cases, COVID-19 vaccination had an impact on delivery of the systemic therapy (n=10 postponements of therapy and n=1 dose reduction). 61.3% of the non-vaccinated patients (in total n=118) were already registered to get vaccinated;32.8% chose to postpone vaccination for personal reasons;5% refused vaccination. Conclusions: Breast and gynecological cancer patients appear to tolerate COVID-19 vaccination well under systemic therapy and only in few cases the vaccination interfered with the treatment schedule. Updated results will be presented at the ESMO Congress. Legal entity responsible for the study: LMU University Hospital. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Background: Neoadjuvant systemic treatment (NST) elicits a pathologic complete response (pCR, ypT0, ypN0) in 40-70% of women with HER2 positive, triple-negative, and high-proliferative Luminal B breast cancer. These patients may not need surgery as all local tumor has already been eradicated by NST. However, their safe identification prior to surgery is a major challenge: imaging after NST, minimally-invasive biopsies, or combinations of both using narrow patient selection criteria are not accurate enough either because they showed high rates of missed cancer or high rates of missed pCR. Recently, the concept of an intelligent, minimally-invasive, vacuum-assisted biopsy (intelligent VAB) was introduced to identify exceptional responders to NST. The intelligent VAB is a multivariate risk algorithm that uses artificial intelligence techniques to analyze conventional VAB results alongside contextualizing patient, imaging, and tumor information. It showed great potential to reliably identify patients with a pCR in the breast (ypT0). However, the absent integration of the axillary status impairs clinical applicability. In this study, we evaluated the feasibility of an intelligent VAB to identify exceptional responders to NST in the breast and axilla. Methods: We trained, tested, and validated a machine learning algorithm (Extreme Gradient Boosting Tree) using patient, imaging, tumor, and conventional VAB variables to detect residual cancer after NST (ypT+/is or ypN+) prior to surgery. We used data from 318 women with cT1-3, cN0/+, HER2 positive, triple-negative breast or high-proliferative Luminal B breast cancer who underwent VAB before surgery (NCT02948764). We used 10-fold cross-validation to train and test the algorithm which was externally validated using data of an independent, similar trial (NCT02575612). Findings were compared to the histopathologic evaluation of the surgical specimen. False-negative rate (FNR), specificity, and area under the ROC curve (AUROC) were the main outcome measures. Results: In the development set (n=318), mean patient age was 52.5 years and 45.3% (144 of 318) achieved a pCR (ypT0 and ypN0). Using resampling methods, the intelligent VAB showed an FNR of 5.2% (9 of 174, 95% CI 2.4-9.5), a specificity of 37.5% (54 of 144, 95% CI 29.6-45.9), and an AUROC of 0.92 (95% CI 0.90-0.94) in the development set to detect residual cancer (ypT+/is or ypN+) after NST. In the external validation set (n=45), mean patient age was 48.1 years and 44.4% (20 of 45) achieved a pCR. The intelligent VAB showed an FNR of 0% (0 of 25, 95% CI 0.0-13.7), a specificity of 40.0% (8 of 20, 95% CI 19.1-63.9) and an AUROC of 0.91 (95% CI 0.82-0.97). Spiegelhalter’s Z confirmed a well-calibrated model (z score -0.746, P 0.228). FNR of the intelligent VAB was lower compared to imaging after NST, conventional VAB, or combinations of both using narrow patient selection criteria. Conclusion: An intelligent VAB can reliably exclude residual cancer after NST for women with cT1-3, cN0/+, HER2 positive, triple-negative breast or high-proliferative Luminal B breast cancer. The omission of breast and axillary surgery for these exceptional responders may be evaluated in future trials. Trial registration: NCT02948764 and NCT02575612. Funding: German Research Foundation (DFG) Diagnostic Performance ComparisonFalse-negative rate - % (95% CI); no.Specificity - % (95% CI); no.Negative predictive value - % (95% CI); no.Positive predictive value - % (95% CI); no.AUROC - value (95% CI)Development set (n=318)Imaging after NST24.4% (18.0-13.7); 40 of 16452.2% (43.4-61.0); 69 of 13263.3% (53.5-72.3); 69 of 10966.3% (59.1-73.0); 124 of 187-Conventional VAB32.8% (25.8-40.3); 57 of 174100% (97.5-100); 144 of 14471.6% (64.9-77.8); 144 of 201100% (96.9-100); 117 of 117-Imaging after NST + VAB16.7% (11.4-23.2); 28 of 16832.1% (24.4-40.6); 44 of 13761.1% (48.9-72.4); 44 of 7260.1% (56.1-69.1); 140 of 223-VAB + patient selection9.1% (5.0-14.1) 15 of 17036.3% (28.2-45.0); 49 of 13576.6% (64.3-86.2); 49 of 6464.3% (57.9-70.4); 155 of 241-Intelligent VAB (Extreme Gradient Boosting tree)5.2% (2.4-9.6); 9 of 17437.5% (29.6-45.9); 54 of 14485.7% (74.6-93.3); 54 of 6364.7% (58.5-70.6); 165 of 2550.92 (0.90-0.94)External validation (n=45)Imaging after NST24.0% (9.4-45.1%);6 of 2565.0% (40.8-84.6%);13 of 2068.4% (43.4-87.4%);13 of 1973.1% (52.2-88.4%);19 of 26-Conventional VAB28.0% (12.1-49.4%);7 of 25100% (83.2-100%);20 of 2074.1% (53.7-88.9%);20 of 27100% (81.5-100%);18 of 18-Imaging after NST + VAB12.0% (2.5-31.2); 3 of 2565.0% (40.8-84.6%);13 of 2081.3% (54.4-96.0%); 13 of 1675.9% (56.5-89.7%); 22 of 29-VAB + patient selection4.0% (1.0-2.4); 1 of 2530.0% (9.4-45.1%); 6 of 2085.7% (69.8-99.8); 6 of 763.2% (46.0-78.2); 24 of 38-Intelligent VAB (Extreme Gradient Boosting tree)0.0% (0.0-13.7%);0 of 2540.0% (19.1-63.9%);8 of 20100% (63.1-100%);8 of 867.8% (50.2-82.0%);25 of 370.91 (0.82 - 0.97)AUROC = Area under the receiver operating characteristic curve; CI = confidence interval Citation Format: André Pfob, Chris Sidey-Gibbons, Geraldine Rauch, Bettina Thomas, Benedikt Schaefgen, Sherko Kuemmel, Toralf Reimer, Markus Hahn, Marc Thill, Jens-Uwe Blohmer, John Hackmann, Wolfram Malter, Inga Bekes, Kay Friedrichs, Sebastian Wojcinski, Sylvie Joos, Stefan Paepke, Tom Degenhardt, Joachim Rom, Achim Rody, Regina Große, Marion van Mackelenbergh, Mattea Reinisch, Maria Karsten, Michael Golatta, Joerg Heil. Intelligent vacuum-assisted breast biopsy to identify breast cancer patients with pathologic complete response after neoadjuvant systemic treatment for omission of breast and axillary surgery [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD7-02.

Despite improvements in the diagnosis and management of early stage breast cancer, about one third of the patients still progress to metastatic disease. Most of the patients with metastatic breast cancer have a hormone receptor positive and human epidermal growth factor receptor 2 negative subtype with a median survival of more than 3 years. For these patients, endocrine therapy with its favorable toxicity profile is the current standard of care. However, patients with metastatic breast cancer have an incurable disease. Therefore, not only efficacy but also quality of life are key when selecting a therapy regimen. Areas covered: This paper aims to discuss the efficacy and toxicity profile of the new endocrine-based therapy option palbociclib together with endocrine treatment. Expert opinion: The addition of targeted agents like palbociclib can overcome intrinsic or acquired resistance to endocrine therapy and substantially prolong progression free survival. The combination of palbociclib plus endocrine therapy is associated with a tolerable and well manageable toxicity profile as well as maintenance of quality of life. Thus, addition of palbociclib to endocrine therapy offers a new and important treatment option for hormone receptor positive metastatic breast cancer.

The aim of this study was to evaluate the effect of a pilot interdisciplinary inhouse training in palliative care (PC) for gynecological oncologists. Competencies of participants from a gynecological university department were evaluated taking part in an interdisciplinary PC course in a pre and post design. The multiprofessional course covered basic principles of PC, symptom management and communication taught by PC specialists. Competencies were evaluated using self-designed questionnaires before (ISPG-1), right after (ISPG-2), and 6 months after the training (ISPG-3) (inhouse seminar palliative care in gynecology: ISPG). 31 persons from the department of gynecology took part in the course, of which 27 answered the first questionnaire (seven nurses (26%), 19 doctors (71%), one profession not indicated (3%), median working experience in gynecological oncology: 5 years). Return rates were: ISPG-1 27/31 (87.1%), ISPG-2 20/31 (64.5%) and IPSG-3 14/31 (45.2%). A more positive attitude towards PC could be observed in the majority of participants after the course (ISPG-2 62%, ISPG-3 71%). They felt more competent in the care of palliative patients (46%). PC would be initiated earlier and the interaction with other disciplines was improved (ISPG-2 85%, ISPG-3 100%). The participants assessed a significant improvement of their skills in all palliative fields which were analyzed. PC inhouse training improves the understanding of PC and the interdisciplinary approach in the management of patients with advanced disease. It is a feasible and useful instrument to improve the competencies in generalist PC of specialists in gynecological oncology.

TPS598 Background: The WSG ADAPT trial program addresses the individualization of (neo)adj. decision-making in EBC. The ADAPT umbrella trial established early predictive molecular surrogate markers for response after a 3-wk endocrine treatment (ET) to omit chemotherapy (CT) in a cohort of early high-risk HR+/HER2- pts. ADAPTlate seeks to improve adj. therapy for pts. at high risk for late disease recurrence, who completed definite locoregional therapy (with / without (neo-)adj. CT) and are under adj. ET. This high-risk population does not derive optimal benefit from standard ET, develops secondary ET resistance, and late recurrences. Methods: Prospective, multi-center, interventional, two-arm, open, randomized, controlled adj. phase III trial (NCT04565054) to investigate additional benefit from 2 years of the CDK4/6-inhibitor abemaciclib combined with ET compared to ET alone in pts. with high-risk HR+/HER2- EBC. Abemaciclib demonstrated to improve outcome in metastatic BC and even in EBC when given as part of primary therapy. Primary objective is to demonstrate superiority of iDFS of abemaciclib + ET vs. standard ET. Secondary objectives include OS, dDFS, occurrence of CNS metastases, QoL, and translational research. Recruitment started in 9/2020 to screen 1250 pts. and to randomize 903 pts. in a ratio 3:2. Until date of submission, 33 pts. were screened and 22 randomized. Pre-/postmenopausal pts. with histologically confirmed invasive HR+/HER2- EBC, 2-6 y after primary diagnosis, with either known high clinical risk (c/pN 2-3 OR high CTS score in pN 0-1 OR non-pCR after neoadj. CT in cN 1 or G3 tumors OR G3 and Ki-67 ≥ 40% in pN 0-1) or known high genomic risk (RS >25 in c/pN 0, RS >18 in c/pN 1 OR high risk Prosigna, EPclin or Mammaprint in pN 0-1) or intermediate clinical, but unknown genomic risk (luminal B-like (G3 or Ki-67 ≥20%) in c/pN 0-1 AND either RS >25 in c/pN 0 or RS >18 in c/p N1 in screening) will be eligible. Treatment duration is 2 years for the abemaciclib + ET (premenopausal: AI + GnRH) arm, followed by at least 3-6 years ET alone. Pts. in control arm will receive 5-8-years ET at investigator´s choice. ePROs are collected using CANKADO. Translational analyses: Exploratory tissue biomarker research to assess alterations in molecular markers. Liquid biopsies (CTC/ctDNA/ctRNA) will be assessed for mutations and gene expression relevant for HR+/HER2- EBC using an appropriate technology at time of testing. Conclusions: ADAPTlate seeks to evaluate whether Abemaciclib + ET is superior to ET alone in pts. with clinical or genomic high-risk EBC even 2-6 years after initial diagnosis. Translational research aims at assessing potential mechanisms of resistance to endocrine and/or CDK4/6 targeted therapy. Clinical trial information: NCT04565054.

Purpose of the investigation: Vulvovaginal candidosis (VVC) is a common vaginal infection affecting almost 75% of all women once per lifetime. Vaginal associated immunity is important in the protection against VVC. The purpose of this study was to evaluate a potential role of IL-23, IFN-alpha, and IFN-beta in the local immune response against VVC. Materials and Methods: The study included 202 non-pregnant women;71 patients with clinical symptoms of VVC and 131 asymptomatic patients served as control. IL-23, IFN-alpha, and IFN-beta were measured in the vaginal fluid by ELISA. Microbiological cultures were used for Candida detection. Results: C. albicans was detected in 67.6% of patients, C. glabrata in 21.1% of patients, and 5.6% were infected with C. krusei or coinfected with C. albicans and C. krusei. Levels of IL-23 (p < 0.001) and IFN-beta (p < 0.017) were significantly lower in the VVC group. IFN-alpha was elevated in the VVC group compared to the asymptomatic patients (p < 0.001). Conclusion: IL-23 and IFN-beta seem to play a protective role against VVC. Decreased levels in VVC patients suggest a compromised local immune response at the time of occurrence of symptoms. In contrast, IFN-alpha seems to be released once the infection has occurred. These cytokines may be prospective targets in the treatment and prevention of primary and recurrent vaginal infections with Candida species.

The majority of patients with metastatic breast cancer (MBC) have hormone receptor-positive HER2-negative disease. For this subgroup, endocrine therapy is the key therapeutic option. Recently, therapeutic options have been expanded by introduction of the inhibitors of cyclin-dependent kinases 4/6 (CDK4/6i). Three compounds, palbociclib, ribociclib, and abemaciclib, have already been approved by the FDA for use together with endocrine therapy such as aromatase inhibitors (AIs) or fulvestrant; abemaciclib is also approved as a single agent. In the first-line setting, all three agents—together with an AI—substantially prolonged progression-free survival with a consistent hazard ratio of around 0.5 in all phase III trials. The data for second-line settings and beyond is also quite consistent, with again a substantial prolongation of progression-free survival demonstrated for fulvestrant together with palbociclib, ribociclib, or abemaciclib. Treatment with CDK4/6i is well tolerated and side effects are manageable. With palbociclib and ribociclib, hematological toxicities are most frequent. Abemaciclib has a lower incidence of neutropenia and a much greater incidence of all grades of diarrhea compared with other CDK4/6i, making diarrhea the key toxicity for abemaciclib. Patient quality of life is maintained under therapy and, particularly in later line settings, deterioration of quality of life is slowed down and symptoms such as pain are better controlled by CDK4/6i. Their consistent and clinically relevant efficacy makes these drugs an important improvement in our armamentarium against MBC and, potentially, ideal candidates in early breast cancer (EBC). This review summarizes the available clinical data for CDK4/6i and current research activities, particularly in EBC.

Zur onkoplastischen Rekonstruktion der Brust stehen verschiedene Ansatze zur Verfugung. Ziel ist ein bestmogliches kosmetisches Ergebnis, ohne die onkologische Sicherheit aufs Spiel zu setzen. Planungsrelevante Kriterien sind z. B. die Brust-Tumor-Relation sowie die Brustform.

Goals: The WSG ADAPT trial program is one of the first new generation trials addressing the issue of individualization of (neo)-adjuvant decision-making in early breast cancer (EBC) in a subtype-specific manner. The first WSG ADAPT umbrella trial (NCT01779206) aimed to establish early predictive molecular surrogate markers for response after a short 3-week induction treatment and to omit chemotherapy in a large cohort of early high risk HR+/HER2- patients. The aim of the ADAPTlate phase-III-trial is to improve adjuvant therapy for patients at high risk for late disease recurrence, who have completed definite locoregional therapy (with or without neoadjuvant or adjuvant chemotherapy) and are under adjuvant endocrine treatment. This high-risk population does not derive optimal benefit from standard ET, often develops secondary resistance against ET and consequently late recurrences. With ADAPTlate, it is planned to evaluate whether patients with high-risk EBC derive additional benefit from adding abemaciclib to ET even 2-6 year after their initial diagnosis. Abemaciclib has been shown to improve outcome in metastatic breast cancer and recently, even in early breast cancer when given as part of primary therapy. Methods: WSG-ADAPTcycle is a prospective, multi-center, interventional, two-arm, non-blinded, randomized, controlled adjuvant phase III trial (NCT not yet assigned). It investigates whether patients with HR+/HER2- EBC identified as high-risk during screening (based on clinical or genomic risk) derive additional benefit from 2 years of the CDK4/6 inhibitor abemaciclib combined with ET compared to ET alone. Starting Q3 2020 (enrollment 36 months, 50 sites), 1250 patients will be screened and 903 randomized in a ratio 3:2 (602 to abemaciclib + ET; 301 to standard ET). Pre-/postmenopausal patients with histologically confirmed invasive HR+/HER2- EBC and 2-6 years after primary diagnosis, with either known high clinical risk (c/pN 2-3 OR high CTS score in pN 0-1 OR non-pCR after neoadjuvant chemotherapy in cN 1 or G3 tumors OR G3 and Ki-67 ≥ 40% in pN 0-1) or known high genomic risk (Oncotype Dx® / RS >25 in c/pN 0, RS >18 in c/pN 1 OR high risk Prosigna®, EPclin® or Mammaprint® in pN 0-1) or intermediate clinical, but unknown genomic risk (luminal B-like (G3 or Ki-67 ≥20%) in c/pN 0-1 AND Oncotype DX® in screening either RS >25 in c/pN 0 or RS >18 in c/p N1) will be eligible. Treatment duration is 2 years for the interventional abemaciclib + ET (premenopausal: AI+GnRH) arm, followed by at least 3-6 years ET alone. Patients in control arm will receive 5-8-years ET at investigator´s choice. ePROs are collected using CANKADO. Primary objective is to demonstrate superiority of invasive disease-free survival (iDFS) of abemaciclib + ET vs. standard ET. Secondary objectives include overall survival (OS), distant disease-free survival (dDFS), occurrence of CNS metastases, quality of life (EORTC QLQ-C30, QLQ-BR23, EQ-5D-5L) and translational research. Translational analyses: Exploratory tissue biomarker research will be conducted to assess alterations in molecular markers (e.g., ESR1, PIK3CA, CCND1, CDKN2A, RB1). In addition, ctDNA/ctRNA from optional blood samples will be assessed for mutations and gene expression relevant for HR+/HER2- EBC using the most appropriate technology at the time of testing. Conclusions: ADAPTlate seeks to evaluate whether enhancing ET with a CDK 4/6 inhibitor is superior to ET alone in patients with clinical or genomic high risk EBC even 2-6 years after their initial diagnosis. Translational research aims at assessing potential mechanisms of resistance to endocrine and/or CDK4/6 targeted therapy. Citation Format: Oleg Gluz, Tom Degenhardt, Norbert Marschner, Matthias Christgen, Hans Heinrich Kreipe, Ulrike Nitz, Ronald Kates, Timo Schinkoethe, Monika Graeser, Rachel Würstlein, Sherko Kuemmel, Nadia Harbeck, West German Study Group. Adaptlate -a randomized, controlled, open-label, phase-iii trial on adjuvant dynamic marker - adjusted personalized therapy comparing abemaciclib combined with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy in (clinical or genomic) high risk, hr+/her2- early breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-01-02.

PURPOSE Approximately 10-15% of breast cancer patients treated by breast conserving surgery (BCS) and adjuvant radiotherapy (RT) will develop ipsilateral breast tumor recurrence (IBTR). International guidelines suggest total mastectomy as treatment of choice for IBTR following lumpectomy and RT. Nevertheless, there is evidence that second BCS might be equally sufficient. PATIENTS AND METHODS Patients with IBTR diagnosed between 1990 and 2014 after BCS and RT were included (n=170). 34.1% women underwent secondary BCS, whereas 65.9% were treated by mastectomy. We determined predictive factors for time to local progression (TTP), disease free survival (DFS), and overall survival (OS) comparing these two groups. RESULTS Median follow-up after primary IBTR was 49 months (59 months for patients still alive at time of analysis). Five-year IBTR-free rate after secondary BCS was 77.6% (SD±6.1%) and 75.0% (SD±4.5%) for patients after mastectomy. Five-year DFS was 57.3% (SD±8.2%), and 61.9% (SD±5.5%), five-year OS was 84.7% (SD±5.8%), and 72.6% (SD±5.1%), respectively. Prior adjuvant systemic therapy, muscular invasion, and skin infiltration were independent significant risk factors for a shorter TTP. Additionally, lymphovascular infiltration (LVI) in the IBTR increased the risk for a shorter DFS. LVI, muscular invasion, and skin infiltration were identified as independent significant risk factors for a shorter OS. CONCLUSION No significant difference in local control, DFS, and OS was seen between IBTR patients treated either by secondary BCS or mastectomy. Our data suggest that secondary BCS for IBTR patients after initial BCS and RT is feasible in selected patients. Citation Format: Kolben T, Schwarz TM, Goess C, Blume C, Degenhardt T, Engel J, Wuerstlein R, Ditsch N, Harbeck N, Kahlert S. Surcigal management of ipsilateral breast tumor recurrence. [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 P3-13-02.

Background: This study aimed to identify the association of local surgery of the primary tumor in metastatic breast cancer (MBC) patients with overall survival (OS) and prognostic factors. Patients and Methods: Patients with primary MBC (1990-2006) were included in our retrospective analysis (n = 236). 83.1% had surgery for the primary tumor. OS was evaluated using Kaplan-Meier estimates. Predictive factors for OS were determined. Results: Median follow-up was 123 months for all patients still alive at the time of analysis. In univariate analysis, patients with surgery of the primary tumor had significantly prolonged OS (28.9 vs. 23.9 months). Within the surgery group, patients with MBC limited to 1 organ system had a better outcome (39.3 vs. 24.9 months), as did asymptomatic patients. Independent risk factors for shorter OS were hormone receptor negativity, symptoms, and involvement of ≥ 1 organ system. Conclusion: Patient selection for local therapy was confounded by a more favorable profile and a lesser tumor burden before surgery, which might implicate a bias. Nevertheless, our univariate results indicate that local surgery of the primary tumor in MBC patients could be considered as part of the therapeutic regimen in selected patients. However, larger patient numbers are needed to prove these findings in the multivariate model.

Purpose Approximately 10–15% of breast cancer patients treated by breast conserving surgery (BCS) and adjuvant radiotherapy (RT) will develop ipsilateral breast tumor recurrence (IBTR). International guidelines suggest total mastectomy as treatment of choice for IBTR following lumpectomy and RT. Nevertheless, there is evidence that second BCS might be equally sufficient. Patients and methods Patients with IBTR diagnosed between 1990 and 2014 after BCS and RT were included (n = 170). 34.1% women underwent secondary BCS, whereas 65.9% were treated by mastectomy. We determined predictive factors for time to local progression (TTP), disease free survival (DFS), and overall survival (OS) comparing these two groups. Results Median follow-up after primary IBTR was 49 months (59 months for patients still alive at time of analysis). Five-year IBTR-free rate after secondary BCS was 77.6% (SD ± 6.1%) and 75.0% (SD ± 4.5%) for patients after mastectomy. Five-year DFS was 57.3% (SD ± 8.2%), and 61.9% (SD ± 5.5%), five-year OS was 84.7% (SD ± 5.8%), and 72.6% (SD ± 5.1%), respectively. Prior adjuvant systemic therapy, muscular invasion, and skin infiltration were independent significant risk factors for a shorter TTP. Additionally, lymphovascular infiltration (LVI) in the IBTR increased the risk for a shorter DFS. LVI, muscular invasion, and skin infiltration were identified as independent significant risk factors for a shorter OS. Conclusion No significant difference in local control, DFS, and OS was seen between IBTR patients treated either by secondary BCS or mastectomy. Our data suggest that secondary BCS for IBTR patients after initial BCS and RT is feasible in selected patients.

Background Efficacy and quality of life (QoL) are key factors when selecting therapies for metastatic breast cancer (MBC) patients. The addition of targeted oral agents such as CDK4/6 inhibitors to endocrine therapy is the new standard for HR+ HER2- MBC and substantially prolongs progression-free survival. However more complex oral medication in oncology might require substantial improvement of patient management. Despite several advantages of oral treatments, patients become increasingly self-responsible and physician-patient contact is reduced. Adherence, maintaining patients’ satisfaction and early detection management of side effects become important challenges and new ways of continuous support are needed. An eHealth-based platform could help to support therapy management and physician-patient interaction. Trial design PRECYCLE is a multicenter, randomized, phase IV trial in HR+ HER2- MBC. All patients (n = 960) receive the palbociclib either in first (62.5%) or later line (37.5%) together with endocrine therapy (AI, fulvestrant). Primary study aim is the time to deterioration (TTD) of QoL in patients supported by two eHealth systems with substantially different functionality. To date (02/11/2019) in 64 centers 165 patients have been randomized to the different study arms: - CANKADO inform with only a personal login, documentation of daily drug intake and passive text information, but no further functions. vs. - CANKADO active with the fully functional CANKADO-based eHealth treatment support system (drug diary, QoL, AEs, automated recommendations, etc.). To evaluate QoL, the FACT-B questionnaire is completed at every visit. Primary objective is to test the hypothesis of superiority for TTD with regard to QoL (FACT-G scale) in patients supported by an eHealth therapy management system (CANKADO active) versus in those merely receiving eHealth-based information (CANKADO inform). As little is known about relationships between behavioral patterns (e.g. adherence), genetic background and drug efficacy the trial also includes a large translational program that aims at discovery and validation of biomarkers concerning efficacy, toxicity, adherence and QoL. Clinical trial identification NCT03220178 EudraCT: 2016-004191-22. Legal entity responsible for the study The authors. Funding Pfizer. Disclosure T. Degenhardt: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: GSM; Travel / Accommodation / Expenses: Cellgene; Travel / Accommodation / Expenses: Daichii Synkyo. P.A. Fasching: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Teva; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Puma Biotechnology; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Hexal; Honoraria (self), Advisory / Consultancy: Myelo Therapeutics GmbH; Research grant / Funding (self): BioNTech AG. D. Luftner: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: astra zeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: tesaro; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: teva; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: L’oreal. V. Muller: Advisory / Consultancy: hexal; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: nektar; Honoraria (self), Advisory / Consultancy: eisai; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Honoraria (self): astra zeneca; Honoraria (self): Novartis; Honoraria (self): teva; Honoraria (self): tesaro. I. Witzel: Honoraria (self): Pierre Fabre; Honoraria (self): Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Travel / Accommodation / Expenses: medac. T. Decker: Advisory / Consultancy: Novartis. H. Tesch: Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Travel / Accommodation / Expenses: Novartis. S. Kuemmel: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Genomic Health; Advisory / Consultancy: Novartis; Advisory / Consultancy: astra zeneca; Advisory / Consultancy: Amgen; Advisory / Consultancy: Celgene; Advisory / Consultancy: somatex; Advisory / Consultancy, Travel / Accommodation / Expenses: Daiichi Sankyo; Advisory / Consultancy: puma biotechnology; Advisory / Consultancy: pfm medical; Advisory / Consultancy: Pfizer; Advisory / Consultancy: MSD oncology. R. Wuerstlein: Advisory / Consultancy: Roche; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Celgene; Advisory / Consultancy: Lilly; Advisory / Consultancy: sandoz; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: astra zeneca; Advisory / Consultancy: Merck. C. Riese: Full / Part-time employment: CANKADO. T. Schinkothe: Full / Part-time employment: CANKADO. J. Schumacher: Full / Part-time employment: Palleos Healthcare Services Gmbh. N. Harbeck: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: sandoz; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: agendia; Advisory / Consultancy: astra zeneca; Advisory / Consultancy: Merck sharp and dohme; Advisory / Consultancy: odonate therapeutics; Advisory / Consultancy: seattle genetics; Honoraria (self): Genomic Health; Honoraria (self): Amgen; Honoraria (self): nanostring; Research grant / Funding (institution): MSD. M. Schmidt: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): astra zeneca; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): pantarhei bioscience; Advisory / Consultancy: myelo therapeutics gmbh; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest

Background: This study evaluates interventions offered to young breast cancer (BC) patients, including fertility preservation, genetic testing, and counseling for parenthood concerns, and analyzes the effect of BC on biographical issues. Methods: Women who were diagnosed with BC at the age of 18-40 years and who underwent treatment at the Breast Center, Ludwig-Maximilian University (LMU) in Munich between 2006 and 2013, were eligible for this study. Patients received a self-developed questionnaire which covered the following topics: fertility preservation, family planning, genetic testing, parenthood concerns and children's needs, partnership status, and employment situation. Results: Re-evaluating their initial decision on fertility preservation, 76.4% of patients reported satisfaction with their decision. After BC diagnosis, 45.8% reported to have maternal desire, but only 21.7% actually planned to have children. 41.7% of patients missed sufficient counseling regarding parenthood concerns. Analysis of individual employment situations showed that the time period until the return to work was longer in patients who received chemotherapy. The majority of patients (71.6%) did not report changes in their partnership status. Conclusion: Young BC survivors report a lack of communication related to parenthood concerns and future conception, but are satisfied with counseling regarding fertility preservation and genetics.

Die individualisierte Medizin ist bereits ein integraler Bestandteil der Therapie des fruhen sowie des metastasierten Mammakarzinoms. Hierfur ist neben individuellen Faktoren der Patientinnen das Wissen uber die Tumorbiologie, Prognosefaktoren und pradiktive Marker die Grundvoraussetzung. Die molekularen Subtypen (Luminal A, Luminal B, HER2-positiv, TNBC) haben klinische Relevanz und sind beim fruhen Mammakarzinom fur die Therapieentscheidung bezuglich einer (neo-)adjuvanten Therapie und auch in der Therapie des metastasierten Karzinoms nicht mehr wegzudenken. Fur die Vermeidung von Uber- und Untertherapie des fruhen Mammakarzinoms liefern gut validierte Biomarker wie uPA/PAI-1 oder die Genexpressionsanalysen zusatzliche therapierelevante Informationen uber die Tumorbiologie und Aggressivitat. Hinzu kommen neue zielgerichtete Substanzen, die eine effektive Therapie in Erganzung zur konventionellen endokrinen Therapie, HER2-gerichteten Therapie und Chemotherapie ermoglichen. Moderne Operations- und Bestrahlungsverfahren bilden zudem die Basis fur einen individualisierten Ansatz in der Lokaltherapie des primaren und metastasierten Mammakarzinoms. Auserdem fordern neue Subgruppen wie das BRCA-positive Mammakarzinom noch mehr Interdisziplinaritat und vorausschauende Therapieplanung. Insgesamt steigen somit die Komplexitat der Therapiekonzepte und damit der Anspruch an die Therapeuten und die beteiligten Disziplinen. Die beste Moglichkeit, Patientinnen eine moderne und individualisierte Therapie anbieten zu konnen, stellen klinische Studien dar. Daher sollten Studienoptionen fur die einzelne Patientin bereits in den praoperativen interdisziplinaren Tumorkonferenzen gepruft werden. Um den Studieneinschluss fur viele Patientinnen zu ermoglichen, sind der weitere Ausbau von zentrumsubergreifenden Netzwerken und die Intensivierung der interdisziplinaren Zusammenarbeit notig.

Purpose The 21-gene Recurrence Score (RS) assay is a validated prognostic/predictive tool in early hormone receptor–positive breast cancer (BC); however, only a few prospective outcome results have been available so far. In the phase III PlanB trial, RS was prospectively used to define a subset of patients who received only endocrine therapy. We present 3-year outcome data and concordance analysis (among biomarkers/RS). Patients and Methods Central tumor bank was established prospectively from PlanB (intermediate and high-risk, locally human epidermal growth factor receptor 2–negative BC). After an early amendment, HR-positive, pN0-1 patients with RS ≤ 11 were recommended to omit chemotherapy. Results From 2009 to 2011, PlanB enrolled 3,198 patients with a median age of 56 years; 41.1% had node-positive and 32.5% grade 3 disease. In 348 patients (15.3%), chemotherapy was omitted based on RS ≤ 11. After 35 months median follow-up, 3-year disease-free survival in patients with RS ≤ 11 and endocrine therapy alone was 98% versus 92% and 98% in RS > 25 and RS 12 to 25 in chemotherapy-treated patients, respectively. Nodal status, central and local grade, the Ki-67 protein encoded by the MKI67 gene, estrogen receptor, progesterone receptor, tumor size, and RS were univariate prognostic factors for disease-free survival; only nodal status, both central and local grade, and RS were independent multivariate factors. Histologic grade was discordant between central and local laboratories in 44%. RS was positively but moderately correlated with the Ki-67 protein encoded by the MKI67 gene and grade and negatively correlated with progesterone receptor and estrogen receptor. Conclusion In this prospective trial, patients with enhanced clinical risk and omitted chemotherapy on the basis of RS ≤ 11 had excellent 3-year survival. The substantial discordance observed between traditional prognostic markers and RS emphasizes the need for standardized assessment and supports the potential integration of standardized, well-validated genomic assays such as RS with clinicopathologic prognostic factors for chemotherapy indication in early hormone receptor–positive BC.

Background: Both the Oncotype DX multi-gene assay and invasion factors uPA/PAI-1 are guideline-recommended (ASCO, AGO) biomarkers for decision support regarding adjuvant chemotherapy in primary breast cancer (BC). Material and Methods: The West German Study Group (WSG) Plan B trial (planned n=2,448) is evaluating anthracyline-free adjuvant chemotherapy (6x TC) vs. standard 4xEC-4xDOC in HER2- negative BC with 0-3 positive lymph nodes, Oncotype DX is used as selection criterion where pts with RS> 11 are randomized to one of the two chemotherapy arms and pts with RS ≥11 treated with hormonal therapy alone. uPA/PAI-1 (both low vs. either/both high), measured by ELISA, is obtained as an optional risk factor. Results: By June 2010, 1064 patients had been randomized in Plan B (96 recruiting centers). In 153 patients (27 centers), uPA and PAI-1 had been measured; for 131 (84 N0, 47 N+) of these, Oncotype DX Recurrence Score® (RS) results were also available. When considered as continuous variables, RS was weakly positively correlated (Spearman's coefficient) with uPA (rs=0.18, p=0.04) and with PAI-1 (rs=0.23, p=0.01). When considered as risk categories/(Table 1), there was a weak concordance between RS and uPA/PAI-1, using either the standard RS cutoff points (18 and 30) or the TAILORx trial cutoff points (11 and 25). Table T: Association between RS and uPA/PAI-1 categories Assignment of high risk was most strongly concordant between uPA/PAI-1 and RS (RS > 25: 22/25 patients had high uPA/PAI-1; RS >30: 14/15 patients had high uPA/PAI-1). This high-risk concordance extends to N0 patients (RS>25: 17/19 N0 pts had high uPA/PAI-1; RS>30: 11/12 pts had high uPA/PAI-1). Discussion: For the first time, risk groups in primary breast cancer according to both Oncotype DX and uPA/PAI-1 have been compared. These preliminary data show that the high RS group seems highly concordant with the prospectively assessed invasion markers uPA/PAI-1. However, within low and intermediate RS, uPA/PAI-1 could still identify a substantial collective at risk; low uPA/PAI-1 could define a clinically relevant low-risk collective within risk groups that would be classified as “intermediate” according to the multigene assay Oncotype DX. Additional recruitment and outcome assessment of the ongoing multicenter WSG Plan B trial will address the clinical significance of these findings. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-05.

The purpose of this study was to evaluate the influence of guideline-based prospective use of uPA/PAI-1 on clinical outcome in an intermediate-risk cohort of breast cancer patients. We analyzed 381 consecutive primary breast cancer patients (2003-2011) at the breast center Ostbayern meeting the following criteria: M0/N0/estrogen receptor (ER)+/G2. Clinical-pathological data, uPA/PAI-1, and follow-up data were collected. Decisions for adjuvant chemotherapy were made upon consideration of prospectively measured uPA/PAI-1. Observed disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier estimates. Using guideline-based analysis of uPA/PAI-1, treatment with adjuvant chemotherapy was avoided in 86.5 % of patients with low uPA/PAI-1, i.e., 38.8 % of the total patient collective. Median follow-up was 52.5 months. Five-year relapse-free survival in intermediate-risk patients (N0, G2) without chemotherapy was 99 %. Five-year overall survival including all causes of death was 95 %. By using uPA/PAI-1, adjuvant chemotherapy can be avoided in a major part of patients with intermediate-risk breast cancer. Nevertheless, DFS and OS of these patients at 5 years remain excellent. The potential, but hardly measurable, benefit of adjuvant chemotherapy has to be set in contrast with its associated side effects and increased morbidity. Patients with high uPA/PAI-1 show benefit from chemotherapy. In this subgroup, a very good OS was observed as well. These findings strongly support the use of uPA/PAI-1 together with clinic-pathological parameters as an evidence-based, clinically relevant and inexpensive decision tool in the routine of a breast center.

Background The activation of international non-profit clinical trials funded by the European Commission (EC) is challenging given the cross-borders regulations and the need to follow specific timelines according to EC rules. We report here the logistic procedures and challenges faced by 4 academic centres from 4 different countries from the European Union (EU) for the activation of such program in metastatic breast cancer (MBC). Materials and Methods The primary objective of the ET-FES program is to validate the use of a new radiotracer 18F Fluoroestradiol (FES), targeting estrogen receptors, as a tool to better predict endocrine responsiveness in MBC, with PET/CT. The trial is sponsored by EO Galliera (Genoa, Italy) and brings together Italy, Spain, France and Germany. In 10/2012, ET-FES was approved for funding from EC under the Seventh Framework Programme after the first ERA-NET TRANSCAN Joint Transnational Call (JTC) for Proposals (2011) on validation of new biomarkers for personalized cancer medicine. Results The official start of the program was set up on 06/2013 by the Italian Ministry of Health. Time to institutional review board and to competent authority (CA) approvals were 1.5 and 11, 2 and 5, 3 and 16, and 13 and 14+ months in Italy, France, Spain and Germany respectively. Overall, no blocking comment was raised by the ethical committees; only minor clinical and methodological issues were raised in Germany and Spain. Issues from CA were raised in all countries except France (12, 21 and 23 queries in Italy, Spain and Germany respectively), on quality aspects of 18F-FES investigational medicinal product dossier. At the sponsor level, time to final agreement signature with Advanced Accelerator Applications, the 18F-FES manufacturing company, required 13 months. First patient could be enrolled in Italy 14 and 22 months after ethical committee approval and after the official start of the ET-FES project respectively. Conclusions As of May 2016, of 310 patients expected, only 28 have been enrolled from Italy. From a regulatory viewpoint and acknowledging that 18F-FES does not have yet any marketing approval in the EU, the ET-FES program approval process was timely completed at the ethical committee level in Italy, France and Spain. Time to CA approval varied across countries and was timely achieved only in France, due to requirements varying from CA to CA, stressing the serious lack of harmonized procedures although intended by the 2001/20/EC directive. Regarding sponsor's responsibilities (i.e. Italy), the administrative procedures needed to activate this type of EU projects remain critical, appealing for more tolerant time span in order to satisfy all the legal aspects on contracts by public bodies, according to national rules and laws. One needs to be very conscious of these timelines when applying to EU/EC calls, especially when the time allowed for the conduction of research is limited (3 years here), unless jeopardizing the entire multicentre and multinational effort. Citation Format: Brain E, Corradengo D, Oriana N, Piccardo A, Matteucci F, Cortes J, Harbeck N, Würstlein R, Piris A, Alberini J-L, Merlo DF, Degenhardt T, Turbiez I, Madar O, Monti M, Cesaro A, Rivitti E, Rollandi GA, Iacozzi M, Campazzi E, Campora S, Camporese D, Gennari A. Challenges faced across borders to open European academic multicentre projects: The ET-FES program part of the ERA-Net TRANSCAN JTC 2011 [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 OT3-03-03.

557Background: AR and FOXA1 have been associated with better prognosis and may play a role as molecular targets in early breast cancer (EBC). This analysis presents the largest dataset of a prospec...

Zielsetzung: Der Recurrence Score (Oncotype DX)® (RS) und die Invasionsfaktoren uPA und PAI-1 sind in den ASCO und AGO-Leitlinien Entscheidungskriterien fur den Einsatz der adjuvanten Chemotherapie beim fruhen Mammakarzinom. Vorgestellt werden prospektive Daten zur Korrelation von RS, uPA/PAI-1 und der molekularen Subtypen aus der Plan B Studie der WSG. Material und Methoden: Im Rahmen der Plan B Studie (n=2448) wird eine anthrazyklinfreies Schema (6x TC) mit 4xEC-4xDoc als adjuvante Chemotherapie beim HER2 negativen Mammakarzinom verglichen. Bei Hormonrezeptor Positivitat und 0–3 positiven Lymphknoten dient der RS (≤ vs. >11) als Selektionskriterium fur die Chemotherapie-Indikation, uPA/PAI-1 wird optional als Risikofaktor evaluiert. Im Rahmen der begleitenden Zentralpathologie werden Ki-67, ein modifiziertes und konventionelles Grading sowohl die molekularen Subtypen analysiert. Ergebnisse: 3196 Pat. wurden rekrutiert, 2448 randomisiert. Der RS wurde bei Pat. mit rezeptorpositivem Mammakarzinom durchgefuhrt, davon lag bei 18% ein RS von 25 vor. Bei 354 Pat. wurde basierend auf einem niedrigen RS auf die Durchfuhrung einer Chemotherapie verzichtet. Korrelationen von RS, zentralem Grading, Ki67 und uPA/PAI-wurden insbesondere in der high risk Gruppe gefunden. Zusammenfassung: Die Plan B Studie beantwortet die Frage zum Stellenwert der anthrazyklinfreien adjuvanten Chemotherapie bei HER2 -negativem Mammkarzinom und untersucht daruber hinaus prospektiv den RS als Therapieentscheidungsfaktor bei Patientinnen mit 0–3 positiven Lymphknoten. Die hervorragende Rekrutierung und die hohe Akzeptanz der Anwendung des RS im klinischen Alltag zeigen die gute Durchfuhrbarkeit dieses Multigen-Tests in der klinischen Routine. Die ersten prospektiven Daten aus der Plan B Studie belegen, dass ein hoher RS pradiktiv fur erhohtes uPA/PAI-1, G3 und Luminal B Subtyp ist. Umgekehrt sind diese Marker jedoch weniger pradiktiv fur RS. Die klinische Relevanz der Daten wird sich aus der Nachbeobachtung im Rahmen der Plan B Studie ergeben. Die jetzt startende ADAPT Studie der WSG beinhaltet ebenfalls ein risikoadaptiertes Vorgehen bezuglich der (neo)adjuvanten Chemotherapie.

Fragestellung: Die WSG Plan-B Studie vergleicht den Standard EC-Doc mit einem anthracyclinfreien taxanhaltigen Schema (TC) bei Patientinnen mit HER2 negativem Mammacarcinom (MC). Plan-B integriert erstmals den 21-Gen Recurrence Score (RS) Oncotype DX neben Grading, molekularem Subtyp, Ki-67 und uPA/PAI-1 zur entscheidenden Risikostratifizierung bei hormonrezeptorpositivem MC mit bis zu 3 positiven Lymphknoten. Plan-B untersucht die Anwendung des RS im klinischen Alltag und den Nutzen von Gen- bzw. proteinbasierter sowie histopathologischer Risikoevaluation zur Vermeidung von Ubertherapien. Methode: Patientinnen (n=2448; Mai 2011: 2961 Pat. registriert, 2236 Pat. Randomisiert) mit primarem high-risk MC (nodalpositiv oder Tumorgrose >2cm, Grading 2–3