On-treatment biopsies to predict response to neoadjuvant chemotherapy for breast cancer.

BACKGROUND: Patients with pathologic complete response (pCR) to neoadjuvant chemotherapy for invasive breast cancer (BC) have better outcomes, potentially warranting less extensive surgical and systemic treatments. Early prediction of treatment response could aid in adapting therapies. METHODS: On-treatment biopsies from 297 patients with invasive BC in three randomized, prospective neoadjuvant trials were assessed (GeparQuattro, GeparQuinto, GeparSixto). BC quantity, tumor-infiltrating lymphocytes (TILs), and the proliferation marker Ki-67 were compared to pre-treatment samples. The study investigated the correlation between residual cancer, changes in Ki-67 and TILs, and their impact on pathologic complete response (pCR) and disease-free survival (DFS). RESULTS: Among the 297 samples, 138 (46%) were hormone receptor-positive (HR+)/human epidermal growth factor 2-negative (HER2-), 87 (29%) were triple-negative (TNBC), and 72 (24%) were HER2+. Invasive tumor cells were found in 70% of on-treatment biopsies, with varying rates across subtypes (HR+/HER2-: 84%, TNBC: 62%, HER2+: 51%; p < 0.001). Patients with residual tumor on-treatment had an 8% pCR rate post-treatment (HR+/HER2-: 3%, TNBC: 19%, HER2+: 11%), while those without any invasive tumor had a 50% pCR rate (HR+/HER2-: 27%; TNBC: 48%, HER2+: 66%). Sensitivity for predicting residual disease was 0.81, with positive and negative predictive values of 0.92 and 0.50, respectively. Increasing TILs from baseline to on-treatment biopsy (if residual tumor was present) were linked to higher pCR likelihood in the overall cohort (OR 1.034, 95% CI 1.013-1.056 per % increase; p = 0.001) and with a longer DFS in TNBC (HR 0.980, 95% CI 0.963-0.997 per % increase; p = 0.026). Persisting or increased Ki-67 was associated with with lower pCR probability in the overall cohort (OR 0.957, 95% CI 0.928-0.986; p = 0.004) and shorter DFS in TNBC (HR 1.023, 95% CI 1.001-1.047; p = 0.04). CONCLUSION: On-treatment biopsies can predict patients unlikely to achieve pCR post-therapy. This could facilitate therapy adjustments for TNBC or HER2 + BC. They also might offer insights into therapy resistance mechanisms. Future research should explore whether standardized or expanded sampling enhances the accuracy of on-treatment biopsy procedures. Trial registration GeparQuattro (EudraCT 2005-001546-17), GeparQuinto (EudraCT 2006-005834-19) and GeparSixto (EudraCT 2011-000553-23).

A Prospective, Multicenter Registry Study to Evaluate the Clinical Feasibility of Targeted Axillary Dissection (TAD) in Node-positive Breast Cancer Patients.

OBJECTIVE: This study aimed to investigate the feasibility and accuracy of non-radioactive TLN biopsy and TAD in routine clinical practice. BACKGROUND DATA: TAD involves TLN biopsy (TLNB) and sentinel lymph node biopsy and was recently introduced as a new standard for less invasive axillary staging in BC patients undergoing neoadjuvant systemic therapy (NST); however, clinical evidence is limited. METHODS: The SenTa study is a prospective registry study conducted at 50 centers. Patients with invasive BC who nderwent clip insertion into the most suspicious axillary lymph node were eligible. Axillary surgery was performed with or without sentinel lymph node biopsy, TLNB, and/or axillary lymph node dissection (ALND). Main endpoints were the detection rate and FNR of TLNB and TAD after NST. RESULTS: Between 2017 and 2018, 548 consecutive BC patients underwent clip placement into biopsy-confirmed positive lymph nodes. After NST (n = 473), the clipped TLN was intraoperatively resected in 329 of 423 patients [77.8%, 95% confidence interval (CI): 74.0-82.0]. TAD was successful in 199 of 229 patients (detection rate: 86.9%, 95% CI: 81.8-91.0), the SLN and TLN were identical in 129 patient (64.8%). FNRs were 7.2% (8 of 111, 95% CI: 3.1-13.6) for TLNB followed by ALND (n = 203) and 4.3% (2 of 46, 95% CI: 0.5-14.8) for TAD followed by ALND (n = 77). CONCLUSIONS: The SenTa study demonstrates the feasibility of TAD in a real-world cohort of BC patients. Our findings are of great importance for de-escalation of surgical strategies.

Shifting the Paradigm: The Transformative Role of Neoadjuvant Therapy in Early Breast Cancer.

The use of neoadjuvant systemic therapy (NST) has become increasingly important in the treatment of breast cancer because of its various advantages. These include the ability to downstage tumors without compromising locoregional control and the potential to obtain valuable information about clinical and biological response to therapy with implications for individual prognoses. Surgical response assessment paves the way for response-adapted therapy, and pathological complete response (pCR; defined as ypT0/is ypN0) serves as an additional endpoint for drug development trials. Recommended NST regimens commonly consist of anthracyclines and taxane, with dose-dense anthracyclines and weekly paclitaxel often preferred, whenever feasible. For patients with human epidermal growth factor receptor-2 (HER2)-positive tumors, dual anti-HER2 therapy (trastuzumab and pertuzumab) is indicated together with NST in case of elevated risk of recurrence. For patients with triple-negative breast cancer (TNBC), adding carboplatin to NST correlates with improved pCR and survival rates, as does the addition of immune checkpoint inhibitors. For hormone receptor (HR)-positive/HER2-negative cancers, emerging data on NST including immune checkpoint inhibitors may elevate the significance of NST in high-risk luminal breast cancer. Here, we present a synthesis of the results from neoadjuvant clinical trials that aim at optimizing treatment options for patients with high-risk breast cancer.

Breast-conserving surgery is not associated with increased local recurrence in patients with early-stage node-negative triple-negative breast cancer treated with neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NACT) is routinely used for patients with triple-negative breast cancer (TNBC). Upfront breast-conserving therapy (BCT) consisting of breast-conserving surgery (BCS) and adjuvant radiotherapy (RT) has been shown to be associated with improved outcome in patients with early TNBC as compared to mastectomy. METHODS: We identified 2632 patients with early TNBC from the German Breast Group meta-database. Patients with cT1-2 cN0 and ypN0, available surgery and follow-up data were enrolled. Data of 1074 patients from 8 prospective NACT trials were available. Endpoints of interest were locoregional recurrence as first site of relapse (LRR), disease-free survival (DFS) and overall survival (OS). We performed univariate and multivariate Fine-Gray analysis and Cox regression models. RESULTS: After a median follow-up of 64 months, there were 94 (8.8%) locoregional events as first site of relapse. Absence of pathologic complete response (pCR) was associated with increased LRR upon uni- and multivariate analysis (hazard ratio [HR] = 2.28; p < 0.001 and HR = 2.22; p = 0.001). Type of surgery was not associated with LRR. Patients in the BCS-group had better DFS and OS (DFS: HR = 0.47; p < 0.001 and OS: HR = 0.40; p < 0.001). BCS was associated with improved DFS and OS upon multivariate analysis (DFS: HR = 0.51; p < 0.001; and OS HR = 0.43; p < 0.001), whereas absence of pCR was associated with worse DFS and OS (DFS: HR = 2.43; p < 0.001; and OS: HR = 3.15; p < 0.001). CONCLUSIONS: In this retrospective analysis of patients with early stage node-negative TNBC treated with NACT, BCS was not associated with an increased risk of LRR but with superior DFS and OS.

An Analysis of PIK3CA Hotspot Mutations and Response to Neoadjuvant Therapy in Patients with Breast Cancer from Four Prospective Clinical Trials.

PURPOSE: The PI3K signaling pathway is frequently dysregulated in breast cancer, and mutations in PIK3CA are relevant for therapy resistance in HER2-positive (HER2pos) breast cancer. Mutations in exons 9 or 20 may have different impacts on response to neoadjuvant chemotherapy-based treatment regimens. EXPERIMENTAL DESIGN: We investigated PIK3CA mutations in 1,691 patients with early breast cancer who were randomized into four neoadjuvant multicenter trials: GeparQuattro (NCT00288002), GeparQuinto (NCT00567554), GeparSixto (NCT01426880), and GeparSepto (NCT01583426). The role of different PIK3CA exons and hotspots for pathologic complete response (pCR) following neoadjuvant chemotherapy (NACT) and patient survival were evaluated for distinct molecular subgroups and anti-HER2 treatment procedures. RESULTS: A total of 302 patients (17.9%) of the full cohort of 1,691 patients had a tumor with a PIK3CA mutation, with a different prevalence in molecular subgroups: luminal/HER2-negative (HER2neg) 95 of 404 (23.5%), HER2pos 170 of 819 (20.8%), and triple-negative breast cancer 37 of 468 patients (7.9%). We identified the mutations in PIK3CA exon 20 to be linked with worse response to anti-HER2 treatment (OR = 0.507; 95% confidence interval, 0.320-0.802; P = 0.004), especially in hormone receptor-positive HER2-positive breast cancer (OR = 0.445; 95% confidence interval, 0.237-0.837; P = 0.012). In contrast, exon 9 hotspot mutations p.E452K and p.E545K revealed no noteworthy differences in response therapy. Luminal/HER2neg patients show a trend to have worse treatment response when PIK3CA was mutated. Interestingly, patients with residual disease following neoadjuvant treatment had better survival rates when PIK3CA was mutated. CONCLUSIONS: The PIK3CA hotspot mutation p.H1047R is associated with worse pCR rates following NACT in HER2pos breast cancer, whereas hotspot mutations in exon 9 seem to have less impact.

Efficacy of Endocrine Therapy Plus Trastuzumab and Pertuzumab vs De-escalated Chemotherapy in Patients with Hormone Receptor-Positive/ERBB2-Positive Early Breast Cancer: The Neoadjuvant WSG-TP-II Randomized Clinical Trial.

Importance: Combination of chemotherapy with (dual) ERBB2 blockade is considered standard in hormone receptor (HR)-positive/ERBB2-positive early breast cancer (EBC). Despite some promising data on endocrine therapy (ET) combination with dual ERBB2 blockade in HR-positive/ERBB2-positive BC, to our knowledge, no prospective comparison of neoadjuvant chemotherapy vs ET plus ERBB2 blockade in particular with focus on molecular markers has yet been performed. Objective: To determine whether neoadjuvant de-escalated chemotherapy is superior to endocrine therapy, both in combination with pertuzumab and trastuzumab, in a highly heterogeneous HR-positive/ERBB2-positive EBC. Design, Setting, and Participants: This prospective, multicenter, neoadjuvant randomized clinical trial allocated 207 patients with centrally confirmed estrogen receptor-positive and/or progesterone receptor-positive (>1%) HR-positive/ERBB2-positive EBC to 12 weeks of standard ET (n = 100) vs paclitaxel (n = 107) plus trastuzumab and pertuzumab. A total of 186 patients were required to detect a statistically significant difference in pathological complete response (pCR) (assumptions: 19% absolute difference in pCR; power, ≥80%; 1-sided Fisher exact test, 2.5% significance level). Interventions: Standard ET (aromatase inhibitor or tamoxifen) or paclitaxel, 80 mg/m2, weekly plus trastuzumab and pertuzumab every 21 days. Main Outcomes and Measures: The primary end point was pCR (ypT0/is, ypN0). Secondary end points included safety, translational research, and health-related quality of life. Omission of further chemotherapy was allowed in patients with pCR. PAM50 analysis was performed on baseline tumor biopsies. Results: Of the 207 patients included (median [range] age, 53 [25-83] years), 121 (58%) had cT2 to cT4 tumors, and 58 (28%) had clinically node-positive EBC. The pCR rate in the ET plus trastuzumab and pertuzumab arm was 23.7% (95% CI, 15.7%-33.4%) vs 56.4% (95% CI, 46.2%-66.3%) in the paclitaxel plus trastuzumab and pertuzumab arm (odds ratio, 0.24; 95% CI, 0.12-0.46; P < .001). Both immunohistochemical ERBB2 score of 3 or higher and ERBB2-enriched subtype were independent predictors for pCR in both arms. Paclitaxel was superior to ET only in the first through third quartiles but not in the highest ERBB2 quartile by messenger RNA. In contrast with the paclitaxel plus trastuzumab and pertuzumab arm, no decrease in health-related quality of life after 12 weeks was observed in the ET plus trastuzumab and pertuzumab arm. Conclusions and Relevance: The WSG-TP-II randomized clinical trial is, to our knowledge, the first prospective trial comparing 2 neoadjuvant de-escalation treatments in HR-positive/ERBB2-positive EBC and demonstrated an excellent pCR rate after 12 weeks of paclitaxel plus trastuzumab and pertuzumab that was clearly superior to the pCR rate after ET plus trastuzumab and pertuzumab. Trial Registration: ClinicalTrials.gov Identifier: NCT03272477.

First Reported Use of Radiofrequency Identification (RFID) Technique for Targeted Excision of Suspicious Axillary Lymph Nodes in Early Stage Breast Cancer - Evaluation of Feasibility and Review of Current Recommendations.

BACKGROUND/AIM: The purpose of this study was to evaluate, whether radio frequency identification (RFID) labeling of axillary lymph nodes (LNs) for the use of targeted resection is feasible in primary breast cancer patients with suspicious LNs. PATIENTS AND METHODS: We analyzed 10 consecutive patients where RFID technique was used for intraoperative detection of suspicious LNs without preceding neoadjuvant chemotherapy (NACT). We compared the specifics of these procedures to 10 consecutive sentinel lymph node biopsies (SLNB) in the cN0 situation. RESULTS: Intraoperative detection rate (DR) for the RFID-labeled target lymph node (TLN) was 100%. Perioperative complications were infrequent and comparable to SLNB. Average time for location of the RFID labeled TLN was quicker than for the SLN. In 71.4% the chip bearing TLN equaled a SLN. CONCLUSION: The use of the RFID technique for intraoperative localization of axillary LNs for targeted excision seems feasible. RFID technique for targeted axillary dissection (TAD) following NACT should be investigated in a prospective manner.

First Reported Use of the Faxitron LOCalizer™ Radiofrequency Identification (RFID) System in Europe - A Feasibility Trial, Surgical Guide and Review for Non-palpable Breast Lesions.

BACKGROUND/AIM: The problem of adequately marking any given lesion within a breast surgical site is commonly solved by introducing a titanium clip. However, clip dislocation and/or stereotactic hook-wire dislocation are common problems. An ideal solution would be a clip that can be easily found without the use of stereotactic intervention. This work reviews the available data on radiofrequency identification devices (RFID) in breast surgery, reports initial experience data in Europe and discusses surgical pitfalls, advantages and disadvantages. PATIENTS AND METHODS: This study represents a single center, consecutively recruited, initiation trial with subsequent surgeon questionnaire for the first institution in Europe to report Faxitron LOCalizer™ chip data. Four patients with non-palpable tumors were marked with the system and were correlated via mammography, pre- and intra-operative ultrasound and pathology. Data were then compared to available literature and a literature review was added. RESULTS: The four patients marked with this RFID system, displayed a 100% success location rate at a 0% complication rate. Surgeons evaluated the new system as being safe to use and only slightly more difficult to place compared to a standard clip. A significant improvement in ultrasound localization and intraoperative localization was also reported for the LOCalizer™ system when compared to a standard titanium clip. CONCLUSION: This trial added a small number of consecutively recruited patients to an existing number of available data, resulting in a total of 121 evaluated and reviewed Faxitron LOCalizer™ marked non-palpable in-breast lesions worldwide.

Autologous Lipotransfer - Daily Therapeutic Practice in Breast Cancer: An Intergroup Analysis Encompassing NOGGO, WSG, GBG, AWO Gyn and DGPRÄC.

BACKGROUND: Autologous fat transfer in breast reconstruction has become increasingly important in breast reconstructive surgery. Although the indication to obtain fat, the various operative procedures, and the risks for the patient have been addressed in a large number of studies, detailed information on the everyday use of autologous lipotransfer in breast units in Germany is still lacking. METHODS: The objective of the study was to obtain primary data on the use of autologous lipotransfer to treat breast cancer patients in Germany and to determine measures for quality assurance in the daily practice. An online questionnaire concerning breast cancer and lipofilling was sent to specialists in gynecology and plastic surgery. RESULTS: Two-thirds of the specialists who responded to the questionnaire use autologous lipotransfer for breast reconstruction and did not report an increase of local recurrence following lipotransfer. There were only small differences between gynecologists and plastic surgeons regarding the procedure and indication for lipotransfer. The method is highly accepted by patients and physicians, and both gynecologists and plastic surgeons rated the improvement achieved through lipofilling as 'high'. CONCLUSIONS: The lack of randomized controlled data, especially in high-risk patients, demonstrates the necessity for a registry study on this topic. Our survey describes, in detail, the indications for lipofilling as well as its appropriate application in breast cancer patients in Germany and may thereby reduce the present therapeutic uncertainties.

Prospective, Multicenter, Randomized Phase III Trial Evaluating the Impact of Lymphoscintigraphy as Part of Sentinel Node Biopsy in Early Breast Cancer: SenSzi (GBG80) Trial.

PURPOSE: The aim of the current work was to clarify whether a preoperative lymphoscintigraphy (LSG) enhances staging accuracy of sentinel lymph node biopsy (SLNB). PATIENTS AND METHODS: In a prospective, multicenter, randomized phase III trial, patients with cN0 early breast cancer or extensive/high-grade ductal carcinoma in situ planned for standard radioactive-labeled colloid LSG with subsequent SLNB were randomly assigned 1:1 to receive SLNB either with knowledge of the LSG findings or without. As the false-negative rate of SLNB correlates with the number of resected sentinel lymph nodes (SLNs), our primary end point was the mean number of histologically detected SLNs per patient. One thousand one hundred two evaluable patients were necessary to demonstrate noninferiority of SLNB without LSG. Stratified one-sided 95% CI for the difference (without LSG - with LSG) in the mean number of histologically detected SLNs had to be greater than -0.27 (10% noninferiority margin). Stratification was performed according to tumor focality and trial site. Additional predefined secondary end points (rates of node-positive patients and of completion axillary lymph node dissection) were analyzed to rule out differences in the reliable detection of nodal metastases. RESULTS: Between May 2014 and October 2015, 1,198 patients were randomly assigned in 23 German and Swiss breast centers. Modified intention-to-treat analysis (n = 1,163) showed a mean number of histologically detected SLNs of 2.21 with LSG and 2.26 without LSG (difference 0.05; stratified 95% CI, -0.18 to infinity), thus establishing noninferiority of omitting preoperative LSG. Secondary end points displayed no statistically significant differences. CONCLUSION: We show that SLNB is equally effective irrespective of the surgeon's knowledge of preoperative LSG results. SLNB without LSG will speed up the preoperative workflow and reduce cost.

Profile and Outcome of Supraclavicular Metastases in Patients with Metastatic Breast Cancer: Discordance of Receptor Status Between Primary and Metastatic Site.

BACKGROUND: Breast cancer is a heterogenous and complex disease. A rare site of metastatic breast cancer disease is the neck. Data about supraclavicular metastases in patients with metastatic breast cancer are still lacking. Hence, our study aimed to analyze histological subtypes of supraclavicular metastases compared to the primary site. MATERIALS AND METHODS: This was a retrospective hospital-based cohort study of patients with breast cancer who developed supraclavicular metastases. Diagnosis of supraclavicular metastases was confirmed by biopsy or diagnostic lymph node extirpation. Histological subtypes were analyzed and Kaplan-Meier estimates were calculated for overall survival. RESULTS: A total of 20 patients were included in the analysis. The majority of the patients (12/20) had hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative supraclavicular metastases, disease in 3/20 patients was HR-positive/HER2-positive, HR-negative/HER2-positive in 1/20 patients and basal-like in 4/20 patients. Total discordance rates for estrogen receptor, progesterone receptor and HER2 between primary and metastatic tumors were 20.0%, 36.8% and 29.4%, respectively. The 5-year overall survival was 80%, whereas the 5-year survival after the onset of neck metastasis was 45%. CONCLUSION: As a rare site of metastatic breast cancer, supraclavicular metastases are associated with a worse median overall survival from their onset. The high rate of discordance of histological subtype stresses the necessity for biopsies in patients with supraclavicular metastasis.

Using a New Marker Clip System in Breast Cancer: Tumark Vision® Clip - Feasibility Testing in Everyday Clinical Practice.

BACKGROUND: This study presents first feasibility experiences with a new 3-dimensional (3D) marker clip system in clinical practice. The rate of clinical complete responses in the treatment of breast cancer patients is increasing; additionally, a change to targeted axillary dissection is being considered after neoadjuvant chemotherapy (NACT). Consequently, marker clips are needed which are reliable and easy to handle even in the axillary lymph node system. METHODS: A total of 50 patients from the Breast Care Unit of the Kliniken Essen Mitte were included. Clip marking of all 50 primary breast cancer lesions as well as 23 lymph nodes was performed using the Tumark Vision® clip. Following application, the position and visibility of the marker clip were monitored and documented in 2 axes. RESULTS: The feasibility of the Tumark Vision clip was excellent in everyday clinical practice as none of the markers dislocated. After clip marking of the tumor region and/or suspicious lymph nodes, all Tumark Vision clips could be detected in both axes. The 3D shape could be observed in all cases after application. CONCLUSION: The new 3D-shaped marker clip seems to be a promising tool for marking breast cancer lesions and even lymph nodes before NACT. As there are many studies ongoing to prove the feasibility of a shift from standard axillary dissection after NACT towards targeted axillary dissection, the Tumark Vision clip seems to provide good visibility even in lymph nodes after NACT. Further studies are warranted.

Hematogenous dissemination of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most frequent and aggressive brain tumor in adults. The dogma that GBM spread is restricted to the brain was challenged by reports on extracranial metastases after organ transplantation from GBM donors. We identified circulating tumor cells (CTCs) in peripheral blood (PB) from 29 of 141 (20.6%) GBM patients by immunostaining of enriched mononuclear cells with antibodies directed against glial fibrillary acidic protein (GFAP). Tumor cell spread was not significantly enhanced by surgical intervention. The tumor nature of GFAP-positive cells was supported by the absence of those cells in healthy volunteers and the presence of tumor-specific aberrations such as EGFR gene amplification and gains and losses in genomic regions of chromosomes 7 and 10. Release of CTCs was associated with EGFR gene amplification, suggesting a growth potential of these cells. We demonstrate that hematogenous GBM spread is an intrinsic feature of GBM biology.