COGNITION: a prospective precision oncology trial for patients with early breast cancer at high risk following neoadjuvant chemotherapy.

BACKGROUND: COGNITION (Comprehensive assessment of clinical features, genomics and further molecular markers to identify patients with early breast cancer for enrolment on marker driven trials) is a diagnostic registry trial that employs genomic and transcriptomic profiling to identify biomarkers in patients with early breast cancer with a high risk for relapse after standard neoadjuvant chemotherapy (NACT) to guide genomics-driven targeted post-neoadjuvant therapy. PATIENTS AND METHODS: At National Center for Tumor Diseases Heidelberg patients were biopsied before starting NACT, and for patients with residual tumors after NACT additional biopsy material was collected. Whole-genome/exome and transcriptome sequencing were applied on tumor and corresponding blood samples. RESULTS: In the pilot phase 255 patients were enrolled, among which 213 were assessable: thereof 48.8% were identified to be at a high risk for relapse following NACT; 86.4% of 81 patients discussed in the molecular tumor board were eligible for a targeted therapy within the interventional multiarm phase II trial COGNITION-GUIDE (Genomics-guided targeted post neoadjuvant therapy in patients with early breast cancer) starting enrolment in Q4/2022. An in-depth longitudinal analysis at baseline and in residual tumor tissue of 16 patients revealed some cases with clonal evolution but largely stable genetic alterations, suggesting restricted selective pressure of broad-acting cytotoxic neoadjuvant chemotherapies. CONCLUSIONS: While most precision oncology initiatives focus on metastatic disease, the presented concept offers the opportunity to empower novel therapy options for patients with high-risk early breast cancer in the post-neoadjuvant setting within a biomarker-driven trial and provides the basis to test the value of precision oncology in a curative setting with the overarching goal to increase cure rates.

Eliminating the breast cancer surgery paradigm after neoadjuvant systemic therapy: current evidence and future challenges.

In patients with operable early breast cancer, neoadjuvant systemic treatment (NST) is a standard approach. Indications have expanded from downstaging of locally advanced breast cancer to facilitate breast conservation, to in vivo drug-sensitivity testing. The pattern of response to NST is used to tailor systemic and locoregional treatment, that is, to escalate treatment in nonresponders and de-escalate treatment in responders. Here we discuss four questions that guide our current thinking about 'response-adjusted' surgery of the breast after NST. (i) What critical diagnostic outcome measures should be used when analyzing diagnostic tools to identify patients with pathologic complete response (pCR) after NST? (ii) How can we assess response with the least morbidity and best accuracy possible? (iii) What oncological consequences may ensue if we rely on a nonsurgical-generated diagnosis of, for example, minimally invasive biopsy proven pCR, knowing that we may miss minimal residual disease in some cases? (iv) How should we design clinical trials on de-escalation of surgical treatment after NST?

Changes of breast and axillary surgery patterns in patients with primary breast cancer during the past decade.

PURPOSE: Breast-conserving therapy (BCT) is the standard procedure for most patients with primary breast cancer (BC). By contrast, axillary management is still under transition to find the right balance between avoiding of morbidity, maintaining oncological safety, and performing a staging procedure. The rising rate of primary systemic therapy creates further challenges for surgical management. METHODS: Patients with primary, non-metastatic BC treated between 01.01.2003 and 31.12.2016 under guideline-adherent conditions were included in this study. For this prospectively followed cohort, breast and axillary surgery patterns are presented in a time-trend analysis as annual rate data (%) for several subgroups. RESULTS: Overall, 6700 patients were included in the analysis. While BCT rates remained high (mean 2003-2016: 70.4%), the proportion of axillary lymph node dissection has declined considerably from 80.1% in 2003 to 16.0% in 2016, while the proportion for sentinel lymph node biopsy (SLND) has increased correspondingly from 10.3 to 76.4%. Among patients with cT1-2, cN0 breast cancer receiving BCT with positive SLND, the rate of axillary completion has decreased from 100% in 2008 to 24.4% in 2016. CONCLUSIONS: In the past decade, SLNB has been established as the standard procedure for axillary staging of clinically node-negative patients. Surgical morbidity has been further reduced by the rapid implementation of new evidence from the ACOSOG Z0011 trial into clinical routine. The results reflect the transition towards more individually tailored, less invasive treatment for selected patient subgroups, especially in regards to axillary lymph node management.

Changes in chemotherapy usage and outcome of early breast cancer patients in the last decade.

BACKGROUND: During the last decade, neoadjuvant chemotherapy (NACT) of early breast cancer (EBC) evolved from a therapy intended to enable operability to a standard treatment option aiming for increasing cure rates equivalent to adjuvant chemotherapy (ACT). In parallel, improvements in the quality control of breast cancer care have been established in specialized breast care units. PATIENTS AND METHODS: This study analyzed chemotherapy usage in patients with EBC treated at the Heidelberg University Breast Unit between January 2003 and December 2014. RESULTS: Overall, 5703 patients were included in the analysis of whom 2222 (39 %) received chemotherapy, 817 (37 %) as NACT, and 1405 (63 %) as ACT. The chemotherapy usage declined from 48 % in 2003 to 34 % in 2014 of the cohort. Further, the proportion of NACT raised from 42 to 65 % irrespective of tumor subtype. In addition, frequency of pathologic complete response (pCR) defined as no tumor residues in breast and axilla (ypT0 ypN0) at surgery following NACT increased from 12 % in 2003 to 35 % in 2014. The greatest effect was observed in HER2+ breast cancer with an increase in patients achieving pCR from 24 to 68 %. CONCLUSIONS: The results mirror the refined indication for chemotherapy in EBC and its preferred usage as NACT in Germany. The increase in pCR rate over time suggests improvement in outcome accomplished by a multidisciplinary decision-making process and stringent measures for quality control.

Can Routine Imaging After Neoadjuvant Chemotherapy in Breast Cancer Predict Pathologic Complete Response?

BACKGROUND: This study evaluated breast imaging procedures for predicting pathologic complete response (pCR = ypT0) after neoadjuvant chemotherapy (NACT) for breast cancer to challenge surgery as a diagnostic procedure after NACT. METHODS: This retrospective, exploratory, monocenter study included 150 invasive breast cancers treated by NACT. The patients received magnetic resonance imaging (MRI), mammography (MGR), and ultrasound (US). The results were classified in three response subgroups according to response evaluation criteria in solid tumors. To incorporate specific features of MRI and MGR, an additional category [clinical near complete response (near-cCR)] was defined. Residual cancer in imaging and pathology was defined as a positive result. Negative predictive values (NPVs), false-negative rates (FNRs), and false-positive rates (FPRs) of all imaging procedures were analyzed for the whole cohort and for triple-negative (TN), HER2-positive (HER2+), and HER2-negative/hormone-receptor-positive (HER2-/HR+) cancers, respectively. RESULTS: In 46 cases (31%), pCR (ypT0) was achieved. Clinical complete response (cCR) and near-cCR showed nearly the same NPVs and FNRs. The NPV was highest with 61% for near-cCR in MRI and lowest with 44% for near-cCR in MGR for the whole cohort. The FNRs ranged from 4 to 25% according to different imaging methods. The MRI performance seemed to be superior, especially in TN cancers (NPV 94%; FNR 5%). The lowest FPR was 10 % in MRI, and the highest FPR was 44% in US. CONCLUSION: Neither MRI nor MGR or US can diagnose a pCR (ypT0) with sufficient accuracy to replace pathologic diagnosis of the surgical excision specimen.

Ultrasound guided cryoablation of fibroadenomas.

PURPOSE: Fibroadenoma (FA) of the breast is the most common disorders in young women. The aim of the study was to evaluate cryoablation (CA) under ultrasound guidance in the office setting for patients with FA. MATERIALS AND METHODS: For this prospective multicenter trial an office-based cryosurgical system was used to treat histological confirmed benign FA with a maximum dimension of 3 cm. 23 CA procedures were performed under ultrasound guidance. The cryoprobe was inserted into the center of the FA guided by real-time ultrasound. A freeze-thaw-freeze treatment cycle was performed according to the size of the FA. During the CA procedure continuous ultrasound monitoring of the ice ball was performed, verifying engulfment of the FA. Patients attended 4 follow-up visits at 1 week, 3 months, 6 months and 1 year and underwent ultrasound and physical examinations. RESULTS: Data was collected from 23 procedures. The ice ball engulfed the treated FA in 91.3 %. A sharp reduction in volume was observed at 6-month follow-up and continued more moderately up to 1 year. No serious but four minor adverse events occurred. At 1 year follow-up, lumps that were assessed pre-treatment as hard were assessed as soft or not palpable. 7 patients complained of pain caused by the lump prior to cryotherapy, while 5 of these patients felt transient pain during the follow up period. It is reasonable to assume that the pain was not related to the CA procedure as it was not consistent. In 96 % of the cases patients and physicians rated the cosmetic results of the procedure as excellent or good. CONCLUSION: The cryodestruction proved functional and safe, while showing reduction in palpability and pain caused by the FA in the treated patients.

Upper Blepharoplasty for Areola Reconstruction.

Blepharoplasty is one of the most common rejuvenating facial plastic surgery procedures. The procedure has been described many times and has very few complications. The tissue removed from the upper eyelid during blepharoplasty can be used as a skin graft for areola reconstruction due to the tissue's similarity to the areola's natural skin. The present study investigated the use of upper blepharoplasty for areola reconstruction. Criteria were patient satisfaction, objective measurements and the assessment of cosmesis by a panel of physicians. All eight patients included in the study were very satisfied with the cosmetic result. Objective measurements and assessment by a panel of physicians using photographs of the reconstructed nipple-areola complex showed very good aesthetic results.

Outcome analysis of patients with primary breast cancer initially treated at a certified academic breast unit.

INTRODUCTION: Evaluation of oncological outcome and prognostic factors of patients with primary breast cancer treated at a certified academic breast unit. PATIENTS AND METHODS: We prospectively collected data of 3338 patients, diagnosed with primary breast cancer between 01.01.2003 and 31.12.2010 and treated at the Breast Unit Heidelberg, Germany, in order to analyze outcome in clinical practice. We evaluated local control rate (LCR), disease-free survival (DFS), distant disease-free survival (DDFS), observed overall survival (OS) and age-adjusted relative overall survival (ROS). In addition, the impact of known prognostic factors on these outcome variables was examined in univariate and multivariate analyses. RESULTS: Of all patients, 368 (11.0%) had carcinoma in situ (CIS) and 197 (5.9%) had bilateral cancers. For the 2970 patients with invasive cancer, of which 49 patients (1.7%) had metastastic disease at time of diagnosis, DFS, LCR, DDFS, OS and ROS at 5 years were 79.8%, 84.7%, 81.2%, 86.3%, and 89.8%, respectively. In multivariate analysis age, pT category, nodal status, hormone receptor status and grading were identified as independent prognostic factors for OS. CONCLUSION: Compared with recent population-based reports from Germany, more favourable patient characteristics and nominally higher survival was found among this large cohort of patients with primary breast cancer treated at a single certified breast unit.

Do patients with invasive lobular breast cancer benefit in terms of adequate change in surgical therapy from a supplementary preoperative breast MRI?

BACKGROUND: Breast magnetic resonance imaging (MRI) has been introduced in the preoperative management of invasive lobular breast cancer (ILC). We analysed if MRI leads to adequate changes in surgical management. PATIENTS AND METHODS: We carried out a single-centre retrospective confirmatory analysis of 92 patients with ILC and a preoperative breast MRI. By applying a blinded tumour board method, we analysed if surgical procedures were altered due to breast MRI. In case of alteration, we analysed whether the change was adequate according to the postoperative pathology findings. We considered an adequate rate of change>5% to be a clinically relevant benefit. RESULTS: A change in surgical therapy due to the MRI findings occurred in 23 of 92 patients (25%). According to the postoperative pathology findings, this change was adequate for 20 of these patients (22%; 95% confidence interval [CI] 14%-31%, P<0.0001). An overtreatment occurred for three patients (3%; 95% CI 0%-6%) who underwent a mastectomy following the results of breast MRI. Patients with larger tumours did likely benefit more from preoperative breast MRI. CONCLUSIONS: Patients with ILC might benefit from a preoperative breast MRI. Possible harm from overtreatment should be minimised by diligent use of preoperative histological clarification.

Age-independent first trimester screening for Down syndrome: analysis of three modified software programs with 6,508 pregnancies.

BACKGROUND: The conventional first trimester screening (FTS) method integrates maternal age into risk calculation. It was suggested that this concept increases the false-positive rate in older, and the false-negative rate in younger mothers. MATERIALS AND METHODS: Six thousand five hundred and eight combined FTS with known fetal outcome underwent regular risk calculation with the software programs Pia fetal database (PIA) (GE-ViewPoint, GE Medical Systems), prenatal risk calculation (PRC) (Version 1.0.61, gmt/nexus), and JOY (Version 2.1, PET software). The results were mathematically modified as if generated with age-independent software (PIA(mod), PRC(mod), and JOY(mod)). RESULTS: 17 of 40 trisomy 21 cases were present in women younger than 35. A right shift in the mean maternal age of false-negative cases occurred in all programs (PIA: 30.00, PIA(mod): 32.00, PRC: 30.00, PRC(mod): 32.25, JOY: 30.00, JOY(mod): 34.50). The overall false-positive rate declined by -40.03% (PIA(mod)), -38.64% (PRC(mod)), and -37.50% (JOY(mod)) and in women over 35 (40) years by -72.37, -73.45, and -73.20% (-89.04, -90.33, and -90.56%), being then as high as in the other age groups. CONCLUSION: First trimester screening would become reasonable in women over 40 years. However, women over 35 would also be more often affected by false-negative results. The implications of a concept adaptation should be analyzed in a large prospective study.

Change of aesthetic and functional outcome over time and their relationship to quality of life after breast conserving therapy.

PURPOSE: We analyzed changes in aesthetic and functional outcome over time after breast conserving therapy. Our special interest resides in the question of whether these aspects gain or loose their influence on quality of life (QoL) with temporal progress. PATIENTS AND METHODS: This prospective single centre cohort study included 138 patients, treated with breast conserving surgery and consecutive radiotherapy. Patients completed two questionnaires one week and one year after surgery: the BCTOS (Breast Cancer Treatment Outcome Scale) to measure Functional, Aesthetic, and Breast Sensitivity Status and the EORTC (European Organisation for Research and Treatment of Cancer) C30-BR23 to assess QoL. We applied correlation and multiple regression analysis as statistical methods. RESULTS: Aesthetic and Functional Status did not change significantly over one year, whereas Breast Sensitivity Status and several QoL subscales showed significant improvement (p < 0.0001). Correlations between BCTOS scales and EORTC subscales remain similar over time. Functional and Aesthetic Status kept a strong impact on global health (Spearman's Rho = -0.28 to -0.45 depending on time of assessment). Increasing age and poorer Functional Status shortly after surgery are predictors of a decline in global health over one year (p < 0.001). CONCLUSION: Functional and aesthetic outcome after breast conserving surgery maintain their impact on QoL over a one year follow-up period and are valuable predictors of QoL.

Analysis of the distribution shift of detected aneuploidies by age independent first trimester screening.

INTRODUCTION: First trimester screening (FTS) became standard in non-invasive testing for chromosomal abnormalities in early pregnancy. The individual risk is calculated on the basis of a general background risk, which refers to the maternal age. A new method, Advanced Firsttrimester Screening (AFS) excludes the background risk in its algorithm. This study had the aim to analyze how the detection of aneuploidies is influenced by the in- or exclusion of the maternal age in the risk calculation. MATERIALS AND METHODS: The data of 15,228 first trimester screenings were recalculated with FTS and AFS. The study cohort was divided by age into nine groups and the numbers of detected cases were recorded according to the groups of age. RESULTS: Of 129 detected aneuploidies 90% got the same test results, disregarding whether risk assessment is performed including maternal age or not. FTS detected five aneuploidies at age 35 or older that were not recorded by AFS. AFS detected six aneuploidies that were not detected by FTS. Out of these, the oldest mother was 32 years old. DISCUSSION: When excluding the maternal age from risk calculation, the detection of aneuploidies showed a shift from older to younger women. Overall, the detection rate did not change significantly. However, the false positive rate was 25% lower with the exclusion of maternal age.

Comparison of Prenatal Risk Calculation (PRC) with PIA Fetal Database software in first-trimester screening for fetal aneuploidy.

OBJECTIVES: In February 2007 new software, Prenatal Risk Calculation (PRC), for calculating the risk of fetal aneuploidy was introduced in Germany. Our aim was to investigate its test performance and compare it with that of the PIA Fetal Database (PIA) software developed and used by The Fetal Medicine Foundation. METHODS: Between 31 August 1999 and 30 June 2004 at the Women's Hospital of the Medical University of Hanover in Germany, 3120 singleton pregnancies underwent combined first-trimester screening at 11 + 0 to 13 + 6 weeks of gestation. Calculation of risk for fetal aneuploidy was computed prospectively using the PIA software. In a subsequent retrospective analysis, we recalculated risks for the 2653 of these datasets with known fetal outcome using the PRC software and compared the results. RESULTS: Of the 2653 datasets analyzed, 17 were cases of aneuploidy. At a cut-off of 1 : 230, for the detection of fetal aneuploidy, the respective sensitivity, false-positive rate and positive predictive value were 70.6%, 4.1% and 9.9% for PRC and 76.5%, 2.9% and 14.6% for PIA. At a cut-off of 1 : 300, the equivalent values were 70.6%, 5.6% and 7.5% for PRC and 76.5%, 4.0% and 11.0% for PIA. The differences in test performance between the two types of software were highly significant (P < 0.0001). DISCUSSION: The test performance of PRC was inferior to that of PIA, the sensitivity for detection of fetal aneuploidy being lower and the false-positive rate higher. Had PRC been employed prospectively in our study, 40% more women examined would have been offered unnecessarily an invasive procedure for fetal karyotyping.

Preliminary analysis of the new 'Prenatal Risk Calculation (PRC)' software.

OBJECTIVES: In February 2007, the "Fetal Medicine Foundation Germany (FMF-D)" introduced its new calculation software for First Trimester Screening (FTS), called "Prenatal risk calculation (PRC)". The aim of this study was to retrospectively investigate the test performance of PRC in comparison to the "NT module of the JOY software (JOY)". METHODS: A total of 3,516 combined first trimester screenings from 11 + 0 to 13 + 6 weeks of gestation were accomplished according to the FMF-standard. Adjusted risk calculation for aneuploidy was performed with PRC and JOY. RESULTS: A total of 2,202 complete data sets of singleton pregnancies were analyzed, including 10 trisomy 21 cases, 4 trisomy 18 cases, and 1 trisomy 13 case. Risk calculation with PRC and JOY showed highly significant results (P value<0.0001). JOY attained, at a cut-off of 1:300 (sensitivity 82.4%, false-positive rate 3.6%, positive predictive value 15.2%) and at a cut-off of 1:230 (82.4, 2.4, 21.2%), a better test performance in comparison to PRC (76.5, 7.1, 7.7% and 76.5, 5.3, 10.2%, respectively). The differences were highly significant (P value<0.0001). CONCLUSION: In this preliminary study, PRC demonstrated highly significant results in detecting aneuploidies in FTS. However, in comparison to JOY, its test performance was significantly inferior. A twice higher false positive rate would have doubled unnecessary invasive testing in a prospective setting. We therefore recommend a methodical revision of PRC.