[Current therapeutic standards in advanced soft tissue sarcomas]. / Neues zu Weichteilsarkomen.

Soft tissue sarcomas account for less than 1% of tumors in adults. With more than 80 different subtypes and often dismal prognosis, treatment of patients with soft tissue sarcomas is diagnostically and therapeutically complex. In patients with localized disease, surgery remains the mainstay of therapy. A multimodal approach consisting of neoadjuvant chemotherapy +/- regional hyperthermia may be suitable in patients with high-risk disease to maximize tumor shrinkage before surgery and to treat micrometastases. In patients with oligometastatic disease, local treatment options should be discussed within a specialized tumor board. In patients with disseminated metastatic disease, chemotherapy with anthracyclines remains the backbone of therapy. Immune checkpoint inhibitors have proven to be effective for patients with alveolar soft part sarcoma and targeted therapies with NTRK-inhibitors should be evaluated in patients with NTRK-fusions. This article focuses on current standards and developments in the treatment of soft tissue sarcomas.

Differentiation of benign and metastatic lymph nodes in soft tissue sarcoma.

Lymph node metastasis (LNM) occurs in less than 5% of soft tissue sarcoma (STS) patients and indicates an aggressive course of disease. Suspicious lymph nodes (LN) in staging imaging are a frequent topic of discussion in multidisciplinary tumor boards. Predictive markers are needed to facilitate stratification and improve treatment of STS patients. In this study, 56 STS patients with radiologically suspicious and subsequently histologically examined LN were reviewed. Patients with benign (n = 26) and metastatic (n = 30) LN were analyzed with regard to clinical, laboratory and imaging parameters. Patients with LNM exhibited significantly larger short axis diameter (SAD) and long axis diameter (LAD) vs. patients with benign LN (median 22.5 vs. 14 mm, p < 0.001 and median 29.5 vs. 21 mm, p = 0.003, respectively). Furthermore, the presence of central necrosis and high maximal standardized uptake value (SUVmax) in FDG-PET-CT scans were significantly associated with LNM (60 vs. 11.5% of patients, p < 0.001 and median 8.59 vs. 3.96, p = 0.013, respectively). With systemic therapy, a slight median size regression over time was observed in both metastatic and benign LN. Serum LDH and CRP levels were significantly higher in patients with LNM (median 247 vs. 187.5U/L, p = 0.005 and 1.5 vs. 0.55 mg/dL, p = 0.039, respectively). This study shows significant associations between LNM and imaging features as well as laboratory parameters of STS patients. The largest SAD, SUVmax in FDG-PET-CT scan, the presence of central necrosis, and high serum LDH level are the most important parameters to distinguish benign from metastatic LNs.

Implementing precision oncology for sarcoma patients: the CCCLMUmolecular tumor board experience.

PURPOSE: Due to poor outcomes and limited treatment options, patients with advanced bone and soft tissue sarcomas (BS/STS) may undergo comprehensive molecular profiling of tumor samples to identify possible therapeutic targets. The aim of this study was to determine the impact of routine molecular profiling in the setting of a dedicated precision oncology program in patients with BS/STS in a German large-volume sarcoma center. METHODS: 92 BS/STS patients who received comprehensive genomic profiling (CGP) and were subsequently discussed in our molecular tumor board (MTB) between 2016 and 2022 were included. Patient records were retrospectively reviewed, and the clinical impact of NGS-related findings was analyzed. RESULTS: 89.1% of patients had received at least one treatment line before NGS testing. At least one molecular alteration was found in 71 patients (82.6%). The most common alterations were mutations in TP53 (23.3% of patients), followed by PIK3CA and MDM2 mutations (9.3% each). Druggable alterations were identified, and treatment recommended in 32 patients (37.2%). Of those patients with actionable alterations, ten patients (31.2%) received personalized treatment and six patients did benefit from molecular-based therapy in terms of a progression-free survival ratio (PFSr) > 1.3. CONCLUSION: Our single-center experience shows an increasing uptake of next-generation sequencing (NGS) and highlights current challenges of implementing precision oncology in the management of patients with BS/STS. A relevant number of patients were diagnosed with clinically actionable alterations. Our results highlight the potential benefit of NGS in patients with rare cancers and currently limited therapeutic options.

TIM-3 Qualifies as a Potential Immunotherapeutic Target in Specific Subsets of Patients with High-Risk Soft Tissue Sarcomas (HR-STS).

(1) Background: The expression of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), an immune checkpoint receptor on T cells, has been associated with dismal outcomes and advanced tumor stages in various solid tumors. The blockade of TIM-3 is currently under examination in several clinical trials. This study examines TIM-3 expression in high-risk soft tissue sarcomas (HR-STS). (2) Methods: Tumor cell expression of TIM-3 on protein level was analyzed in pre-treatment biopsies of patients with HR-STS. TIM-3 expression was correlated with clinicopathological parameters including tumor-infiltrating lymphocyte (TIL) counts, programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PDL-1) expression in patients with HR-STS. Survival dependent on the expression of TIM-3 was analyzed. (3) Results: TIM-3 expression was observed in 101 (56%) out of 179 pre-treatment biopsies of patients with HR-STS. TIM-3 expression was significantly more often observed in undifferentiated pleomorphic sarcomas (UPS) compared to other histological subtypes (p < 0.001), high TIL counts (p < 0.001), and high PD-1 (p < 0.001) and PD-L1 expression (p < 0.001). TIM-3 expression did not have a prognostic impact on survival in patients with HR-STS. (4) Conclusions: This is the first study to demonstrate a significant tumor cell expression of TIM-3 in specific subsets of patients with HR-STS. TIM-3 qualifies as a potential immunotherapeutic target in HR-STS.

Impact of postoperative baseline MRI on diagnostic confidence and performance in detecting local recurrence of soft-tissue sarcoma of the limb.

OBJECTIVE: To evaluate the impact of a postoperative baseline (PB) MRI on diagnostic confidence and performance in detecting local recurrence (LR) of soft-tissue sarcoma (STS) of the limb. MATERIALS AND METHODS: A total of 72 patients (8 with LR, 64 without LR) with primary STS of the limb were included. Routine follow-up MRI (1.5 T) at 6 and approximately 36 months (meanLR: 39.7 months; meanno LR: 34.9 months) after multimodal therapy or at time of LR were assessed by three independent readers using a 5-point Likert scale. Furthermore, the following imaging parameters were evaluated: presence of a mass, signal characteristics at T2- and T1-weighted imaging, contrast enhancement (CE), and in some of the cases signal intensity on the apparent diffusion coefficient (ADC). U-test, McNemar test, and ROC-analysis were applied. Interobserver reliability was calculated using Fleiss kappa statistics. A p value of 0.05 was considered statistically significant. RESULTS: The presence of a PB MRI significantly improved diagnostic confidence in detecting LR of STS (p < 0.001) and slightly increased specificity (mean specificity without PE 74.1% and with presence of PB MRI 81.2%); however, not to a significant level. The presence of a mass showed highest diagnostic performance and highest interreader agreement (AUC [%]; κ: 73.1-83.6; 0.34) followed by T2-hyperintensity (50.8-66.7; 0.08), CE (52.4-62.5; 0.13), and T1-hypointensity (54.7-77.3; 0.23). ADC showed an AUC of 65.6-96.6% and a κ of 0.55. CONCLUSION: The presence of a PB MRI increases diagnostic confidence in detecting LR of STS of the limb.

Diagnostic accuracy of biopsy after neoadjuvant treatment for well-differentiated and dedifferentiated retroperitoneal liposarcoma.

PURPOSE: Accurate histopathological grading of percutaneous biopsies is essential to guide adequate management of patients with suspected retroperitoneal liposarcoma. In this regard, however, limited reliability has been described. Therefore, we conducted a retrospective study to assess the diagnostic accuracy in retroperitoneal soft tissue sarcomas and simultaneously investigate its impact on patients' survival. MATERIALS AND METHODS: Reports of an interdisciplinary sarcoma tumor board between 2012 and 2022 were systematically screened for patients with well-differentiated (WDLPS) and dedifferentiated retroperitoneal liposarcoma (DDLPS). Histopathological grading on pre-operative biopsy was correlated with corresponding postoperative histology. Additionally, patients' survival outcomes were examined. All analyses were performed in two subgroups: patients with primary surgery and patients with neoadjuvant treatment. RESULTS: A total of 82 patients met our inclusion criteria. Diagnostic accuracy of patients who underwent upfront resection (n = 32) was significantly inferior to patients with neoadjuvant treatment (n = 50) (66% versus 97% for WDLPS, p < 0.001; 59% versus 97% for DDLPS, p < 0.001). For patients with primary surgery, histopathological grading on biopsy and surgery was concordant in only 47% of cases. Sensitivity for detecting WDLPS was higher than for DDLPS (70% versus 41%). Higher histopathological grading in surgical specimens correlated with worse survival outcomes (p = 0.01). CONCLUSION: Histopathological grading of RPS may no longer be reliable after neoadjuvant treatment. The true accuracy of the percutaneous biopsy may need to be studied in patients who do not receive neoadjuvant treatment. Future biopsy strategies should aim to improve identification of DDLPS to inform patient management.

Impact of Dynamic Contrast Enhanced and Diffusion-Weighted MR Imaging on Detection of Early Local Recurrence of Soft Tissue Sarcoma.

BACKGROUND: Diagnosis of residual or recurrent tumor in soft-tissue sarcomas (STS) is a differential diagnostic challenge since post-therapeutic changes impede diagnosis. PURPOSE: To evaluate the diagnostic accuracy of quantitative dynamic contrast enhanced (DCE)-MRI and diffusion-weighted imaging (DWI) to detect local recurrence of STS of the limb. STUDY TYPE: Prospective. POPULATION: A totalof 64 consecutive patients with primary STS of the limbs were prospectively included 3-6 months after surgery between January 2016 and July 2021. FIELD STRENGTH/SEQUENCE: A 1.5 T; axial DWI echo-planar imaging sequences and DCE-MRI using a 3D T1-weighted spoiled gradient-echo sequence. ASSESSMENT: The quantitative DCE-MRI parameters relative plasma flow (rPF) and relative mean transit time (rMTT) were calculated and ADC mapping was used to quantify diffusion restriction. Regions of interest of tumor growth and postoperative changes were drawn in consensus by two experts for diffusion and perfusion analysis. An additional morphological assessment was done by three independent and blinded radiologists. STATISTICAL TEST: Unpaired t-test, ROC-analysis, and a logistic regression model were applied. Interobserver reliability was calculated using Fleiss kappa statistics. A P value of 0.05 was considered statistically significant. RESULTS: A total of 11 patients turned out to have local recurrence. rPF was significantly higher in cases of local recurrence when compared to cases without local recurrence (61.1-4.5) while rMTT was slightly and significantly lower in local recurrence. ROC-analysis showed an area under the curve (AUC) of 0.95 (SEM ± 0.05) for rPF while a three-factor multivariate logistic regression model showed a high diagnostic accuracy of rPF (R2  = 0.71). Compared with morphological assessment, rPF had a distinct higher specificity and true positive value in detection of LR. DATA CONCLUSION: DCE-MRI is a promising additional method to differentiate local recurrence from benign postoperative changes in STS of the limb. Especially specificity in detection of LR is increased compared to morphological assessment. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Treatment of metastatic alveolar soft part sarcoma with axitinib and pembrolizumab in an 80-year-old patient with a history of autoimmune disorders.

Alveolar soft part sarcoma (ASPS) is a rare malignancy with low sensitivity to chemotherapy. While localized ASPS has a very good prognosis after resection, the 5-year overall survival rate drops substantially in metastatic disease. We report the case of an 80-year-old male patient with ASPS of the left elbow and metastasis to the lung, lymph nodes and peritoneum. After weighing the benefits and risks, systemic treatment with the anti-PD-1 checkpoint inhibitor pembrolizumab combined with the vascular endothelial growth factor receptor tyrosinkinase inhibitor axitinib was initiated in this patient with a history of psoriasis and Crohn's disease. After only two cycles of therapy, a significant size reduction of the nodal cervical metastasis became apparent. A partial response of all metastases was then confirmed in the first computed tomography restaging. So far, side effects have remained manageable, especially with regard to the development or worsening of autoimmune adverse events. The patient continued to have a high quality of life, while also remaining in ongoing partial response for 15 months at the time of submission. While sarcomas generally have low sensitivity to immunotherapies, ASPS is an exception, and checkpoint inhibition is an integral part of its systemic therapy.

Sarcomas of the extremities and the pelvis: comparing local recurrence after incisional and after core-needle biopsy.

BACKGROUND: The degree of contamination of healthy tissue with tumor cells during a biopsy in bone or soft tissue sarcomas is clearly dependant on the type of biopsy. Some studies have confirmed a clinically relevant contamination of the biopsy tract after incisional biopsies, as opposed to core-needle biopsies. The aim of our prospective study was to evaluate the risk of local recurrence depending on the biopsy type in extremity and pelvis sarcomas. METHODS: We included 162 patients with a minimum follow-up of 6 months after wide resection of extremity sarcomas. All diagnostic and therapeutic procedures were performed at a single, dedicated sarcoma center. The excision of the biopsy tract after an incisional biopsy was performed as a standard with all tumor resections. All patients received their follow-up after the conclusion of therapy at our center by means of regional MRI studies and, at a minimum, CT of the thorax to rule out pulmonary metastatic disease. The aim of the study was the evaluation of the influence of the biopsy type and of several other clinical factors on the rate of local recurrence and on the time of local recurrence-free survival. RESULTS: One hundred sixty-two patients with bone or soft tissue tumors of the extremities and the pelvis underwent either an incisional or a core-needle biopsy of their tumor, with 70 sarcomas (43.2%) being located in the bone. 84.6% of all biopsies were performed as core-needle biopsies. The median follow-up time was 55.6 months, and 22 patients (13.6%) developed a local recurrence after a median time of 22.4 months. There were no significant differences between incisional and core-needle biopsy regarding the risk of local recurrence in our subgroup analysis with differentiation by kind of tissue, grading of the sarcoma, and perioperative multimodal therapy. CONCLUSIONS: In a large and homogenous cohort of extremity and pelvic sarcomas, we did not find significant differences between the groups of incisional and core-needle biopsy regarding the risk of local recurrence. The excision of the biopsy tract after incisional biopsy in the context of the definitive tumor resection seems to be the decisive factor for this result.

[Retroperitoneal soft tissue sarcoma: role of radiotherapy]. / Retroperitoneale Weichgewebssarkome: Stellenwert der Radiotherapie.

BACKGROUND: Retroperitoneal soft tissue sarcomas (RPS) include tumors of mesenchymal origin with overall well-defined histological subtypes and heterogenic prognosis. For the first time with the publication of the STRASS study, which investigated the value of neoadjuvant radiotherapy in primary RPS, there is phase III evidence for the use of radiotherapy. OBJECTIVE: The primary objective of the present article is to present the role of neoadjuvant radiotherapy in RPS since the publication of the STRASS study. MATERIAL AND METHODS: We performed a non-systematic literature search. The results of retrospective and observational studies were compared to those of the STRASS study. RESULTS: In the two of the largest analyses, the surveillance, epidemiology, and end results program (SEER) and the American National Cancer Database (NCDB), an improvement in overall survival due to radiotherapy in RPS could be shown. In contrast to these results, there was no significant improvement in 3­year abdominal recurrence-free survival in the STRASS study. There was solely a trend to improved abdominal recurrence-free survival in initially unplanned subgroup analyses for patients with liposarcoma as well as low-grade sarcoma but not for leiomyosarcoma or high-grade sarcoma. CONCLUSION: Thanks to international collaboration an academic randomized trial was even feasible in such a rare disease as RPS. The results of the STRASS study have relativized the potential benefit of radiotherapy in RPS. A longer follow-up especially regarding the role of radiotherapy in liposarcomas is desirable.

Expression Patterns of TOP2A and SIRT1 Are Predictive of Survival in Patients with High-Risk Soft Tissue Sarcomas Treated with a Neoadjuvant Anthracycline-Based Chemotherapy.

Molecular predictors of response to chemotherapy and survival have not been put into clinical practice in high-risk soft tissue sarcomas (HR-STS) by now. The expression of TOP2A and SIRT1 has implications for the mechanism of action of doxorubicin, which is the backbone of chemotherapy in HR-STS. Pre-treatment samples of 167 patients with HR-STS were collected. Protein expression levels of TOP2A and SIRT1 were evaluated with tissue microarrays and immunohistochemistry and correlated with clinicopathological parameters, including overall survival (OS). The expression of TOP2A and SIRT1 was seen in 47% and 60% of patients with HR-STS, respectively. TOP2A expression was associated with higher tumor grading and shorter 5-year OS. The expression of SIRT1 was correlated with a better 5- and 10-year OS. The combination of high SIRT1 and low TOP2A ("Top survivors") significantly predicted a better OS compared to other biomarker combinations. A multivariate analysis confirmed the expression of SIRT1 and the "Top survivor" biomarker combination as independent predictive factors of OS. This is the first study to associate SIRT1 overexpression with a statistically significant prolongation of OS in HR-STS. Both individual markers and their combination can be used as predictive indicators for HR-STS patients scheduled for neoadjuvant anthracycline-based chemotherapy.

Post-Neoadjuvant Gemcitabine and Cisplatin with Regional Hyperthermia for Patients with Triple-Negative Breast Cancer and Non-pCR after Neoadjuvant Chemotherapy: A Single-Institute Experience.

BACKGROUND: Patients with triple-negative primary breast cancer (TNBC) who have residual invasive carcinoma after neoadjuvant chemotherapy have poor prognosis. Proven adjuvant approaches to reduce the risk of recurrence and improve outcome in patients with non-pathological complete response (non-pCR) are limited. METHODS: From our institutional registry, a consecutive case series of patients with operable, unilateral, primary invasive noninflammatory early TNBC of stage I-IIIB and pathologically verified residual cancer cells (no pathological complete response) after neoadjuvant chemotherapy underwent adjuvant treatment with gemcitabine plus cisplatin combined with regional hyperthermia. For quality assurance, we analyzed feasibility, efficacy, and toxicity of all treated patients. Outcome was evaluated for the entire group of patients as well as for the subgroups of patients with or without lymph node involvement at baseline (cN0/ cN+). RESULTS: From August 2012 to January 2019, we offered this treatment to 53 patients at our center as part of routine care. The median follow-up was 38 months. The majority of patients (64.2%) had cT2 tumors at baseline. Twenty-four patients (45%) were clinically node positive as evaluated by sonography. Thirty-nine patients (74%) had grade 3, and 14 patients (26%) had grade 2 tumors. Forty-one patients (76%) showed a regression grade 1 according to Sinn. Patients received a median of six treatment cycles of gemcitabine and cisplatin (range 1-6) combined with 12 applications of regional hyperthermia (median 12, range 2-12). Disease-free survival (DFS) at 3 years was 57.5%. In patients with no lymph node involvement at baseline (cN0), DFS at 3 years was significantly higher than in initially node-positive (cN+) patients (80 vs. 31%; p = 0.001). Overall survival (OS) at 3 years was 81.6%. In patients with no lymph node involvement at baseline (cN0), OS at 3 years was significantly higher than in node-positive (cN+) patients (93 vs. 70.4%; p = 0.02). Overall, grade 3/4 toxicities were leukopenia (38%), thrombocytopenia (4%), and anemia (4%). CONCLUSION: After standard neoadjuvant chemotherapy containing anthracycline plus cyclophosphamide followed by taxanes, addition of adjuvant gemcitabine plus cisplatin in combination with regional hyperthermia was safe and effective in TNBC patients with non-pCR.

MR-guided stereotactic body radiation therapy for primary cardiac sarcomas.

BACKGROUND: Primary cardiac tumors are an extremely rare disease with limited prognosis. The treatment of choice is surgery. Other treatment options include chemotherapy and radiation therapy, which historically represented a palliative approach in patients who were not eligible for surgery. The development of hybrid MR-guided radiation therapy makes it possible to better visualize cardiac lesions and to apply high doses per fraction in sensible organs such as the heart. CASE PRESENTATION: Patients affected by inoperable primary cardiac sarcomas and treated at two different institutions were considered for this analysis and retrospectively analyzed. All patients were treated using a 0.35 T hybrid MR Linac system (MRIdian, ViewRay Inc., Mountain View, CA). In the present study we investigated the feasibility, early outcome and toxicity of MR-guided RT in primary cardiac sarcomas. Four consecutive non-metastasized patients who were treated between 05-09/2020 were analyzed. The cardiac sarcomas were mostly located in the right atrium (50%) and one patient presented with 3 epicardial lesions. All patients received MRgRT as a salvage treatment for recurrent cardiac sarcoma after initial surgery, after a mean interval of 12 months (range 1-29 months). Regarding the treatment characteristics, the mean GTV size was 22.9 cc (range 2.5-56.9 cc) and patients were treated with a mean GTV dose of 38.9 Gy (range 30.1-41.1 Gy) in 5 fractions. Regarding feasibility, all treatments were completed as planned and all patients tolerated the treatment very well and showed only mild grade 1 or 2 symptoms like fatigue, dyspnea or mild chest pain at early follow-up. CONCLUSION: To the best of our knowledge, in this retrospective analysis we present the first and largest series of patients presenting with primary cardiac sarcomas treated with online adaptive MRgRT. However, further studies are needed to evaluate the impact of this new methodology on the outcome of this very rare disease.

18F-FDG PET/CT for Monitoring of Disease Progression in Metastatic Perivascular Epithelioid Cell Tumor.

ABSTRACT: A 38-year-old woman presented for 18F-FDG PET/CT after multiple intra-abdominal surgical resections of a rare recurrent perivascular epithelioid cell tumor of the gastrointestinal tract. A solitary pelvic metastasis was detected, but surprisingly exhibited neither increased glucose consumption nor contrast enhancement on CT. Follow-up 18F-FDG PET/CT staging in the further disease course revealed multiple abdominal metastases, now, however, with markedly increased 18F-FDG uptake and intraoperatively correlating widespread peritoneal sarcomatosis. This case gives preliminary insight into monitoring of disease progression in metastatic perivascular epithelioid cell tumor, although the underlying pathophysiological bases for varying 18F-FDG uptake in PET/CT are not yet fully understood.

Ifosfamide, Carboplatin, and Etoposide (ICE) in Combination with Regional Hyperthermia as Salvage Therapy in Patients with Locally Advanced Nonmetastatic and Metastatic Soft-Tissue Sarcoma.

Patients with localized relapse of soft-tissue sarcoma (STS) after anthracycline-based chemotherapy have a dismal prognosis, particularly when surgery is not possible. To facilitate resection and improve long-term tumor control, we applied an intensified perioperative treatment consisting of ICE (ifosfamide 6 g/m2, carboplatin 400 mg/m2, and etoposide 600 mg/m2) in combination with regional hyperthermia (RHT) to maximize local control. Here, we retrospectively evaluate the safety and efficacy of this strategy. Patients aged ≥18 years with locally advanced high-risk STS, either with or without metastasis, treated with ICE + RHT after the failure of first-line anthracycline-based chemotherapy were included in this analysis. Radiographic response, toxicity, progression-free survival (PFS), and overall survival (OS) were assessed. Between 1996 and 2018, 213 sarcoma patients received ICE at our centre. Of these, 110 patients met the selection criteria (progressive disease, suitable high-grade STS histology, anthracycline pretreatment, RHT treatment) for this analysis. Fifty-four patients had locally advanced disease without metastases (LA-STS), and 56 patients had additional metastatic disease (M-STS). Disease control was achieved in 59% of LA-STS patients and in 47% of M-STS patients. For LA-STS, 21% of the patients achieved radiographic response, facilitating resection in 4 patients (7%), compared with 11% of the M-STS patients, facilitating resection in 5 patients (9%). PFS was significantly longer in LA-STS than in M-STS (10 vs. 4 months, p < 0.0001). Median OS was 26 months in LA-STS and 12 months in M-STS. Disease control was the only independent prognostic factor for improved OS in multivariate analysis. Toxicity was high with neutropenic fever occurring in 25% of the patients and three therapy-related deaths (3%). ICE + RHT demonstrated activity in high-risk STS and facilitated resection in selected patients after anthracycline failure. Disease control was associated with improved OS. Based on the observed toxicities, the dose should be reduced to 75%.

Tumor markers in the early detection of tumor recurrence in breast cancer patients: CA 125, CYFRA 21-1, HER2 shed antigen, LDH and CRP in combination with CEA and CA 15-3.

BACKGROUND: Kinetics of CA 15-3 and CEA have a high specificity in the early detection of metastatic breast cancer (MBC). However, this high specificity is associated with a lack of sensitivity. To decrease the number of false negative patients, the additional diagnostic potential of an extended panel of biomarkers was evaluated. METHODS: This analysis was performed as part of a large follow-up study (1998-2010) evaluating 813 patients with a median follow-up of 63months. After primary therapy, all patients underwent tumor marker monitoring for CEA and CA 15-3 at 6-week intervals. A reproducible previously defined increase (≥100%) based on the individual baseline value of each patient was considered as a strong indicator of MBC. For the present analysis, we retrospectively evaluated 1011 blood samples from 95 patients. Forty-seven of these had metastatic disease for the first time at the time of this evaluation, while the remaining 48 patients showed no evidence of disease. The sera of these patients were additionally assessed for the following parameters: cancer antigen (CA) 125, cytokeratin-19 soluble fragment (CYFRA 21-1), HER2 shed antigen, lactate-dehydrogenase (LDH) and C-reactive protein (CRP). RESULTS: 26 of 47 patients with MBC showed a reproducible tumor marker increase of at least CEA and/or CA 15-3 (55.3%, true-positive). The remaining 21 patients with MBC showed no increase in CEA or CA 15-3 (44.7%, false negative, FN). By combining all markers mentioned above, 41 of 47 patients with MBC showed a reproducible marker increase with a sensitivity of 87.2% and specificity of 100%. CONCLUSION: This retrospective analysis indicates that a panel of biomarkers can increase the sensitivity of the CA 15-3/CEA combination without loss of specificity. The combined use is therefore helpful for early detection of MBC.

Diagnostic efficacy of CA 15-3 and CEA in the early detection of metastatic breast cancer-A retrospective analysis of kinetics on 743 breast cancer patients.

OBJECTIVE: We investigated the diagnostic capacity of CEA and CA 15-3 kinetics for the early detection of metastatic disease in comparison to fixed cut off values. METHODS: In a retrospective analysis, a total of 743 patients with early breast cancer and available baseline values of CEA and CA 15-3 were included. A reproducible increase of 100% of single or combined markers was considered as a strong indicator of metastatic disease. RESULTS: 187 patients developed metastatic disease and 556 remained disease-free. On the basis of tumor marker kinetics, we reached a specificity of >98% for both biomarkers and a sensitivity of 40.6% for CEA alone, 55.6% for CA 15-3 alone and 66.3% for the combination of both markers. Using fixed cut-off values (CEA: 4ng/mL, CA 15-3: 30U/mL) we ended up with a specificity of 86.3% and a sensitivity of 70.6% for the combination of CEA and CA 15-3. Using higher cut-off values (CEA: 6ng/mL, CA 15-3: 60U/mL) we reached a specificity of 96.9% and a sensitivity of 49.7% for the combination. CONCLUSION: We conclude that the interpretation of these markers in follow-up using individual baseline values and kinetics leads to a significant superior profile of specificity and sensitivity.

Preoperative serum markers for individual patient prognosis in stage I-III colon cancer.

Carcinoembryonic antigen (CEA) remains the only recommended biomarker for follow-up care of colorectal cancer (CRC), but besides CEA, several other serological parameters have been proposed as prognostic markers for CRC. The present retrospective analysis investigates a comprehensive set of serum markers with regard to cancer-specific survival (CSS) and disease-free survival (DFS). A total of 472 patients with colon cancer underwent surgery for curative intent between January 1988 and June 2007. Preoperative serum was analyzed for the following parameters: albumin, alkaline phosphatase (aP), beta-human chorionic gonadotropin (ßhCG), bilirubin, cancer antigen 125 (CA 125), cancer antigen 19-9 (CA 19-9), CA 72-4, CEA, C-reactive protein (CRP), cytokeratin-19 soluble fragment (CYFRA 21-1), ferritin, gamma-glutamyltransferase (γGT), glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), hemoglobin, haptoglobin, interleukin-6, interleukin-8, creatinine, lactate dehydrogenase (LDH), serum amyloid A (SAA), and 25-hydroxyvitamin D. After a median follow-up period of 5.9 years, the overall 3- and 5-year CSS was 91.7 and 84.9 % and DFS rates were 82.7 % (3 years) and 77.6 % (5 years). Multivariate analyses confirmed preoperative CEA as an independent prognostic factor with regard to CSS and DFS. CA 19-9 and γGT also provided prognostic value for CSS and DFS, respectively. Younger age was negatively associated with DFS. According to UICC stage, CEA provided significant prognostic value with regard to CSS and DFS, while CA 19-9 was only prognostic for CSS. Combined analysis is able to identify patients with favorable prognosis. In addition to tumor baseline parameters, preoperative CEA could be confirmed as prognostic marker in colon cancer. CA 19-9 and γGT also provide additional prognostic value with regard to survival and recurrence in stage III and stage I disease, respectively. The combined use of CEA together with CA 19-9 and γGT improve risk-adapted post-op surveillance.

Serum HER2 in combination with CA 15-3 as a parameter for prognosis in patients with early breast cancer.

AIM: HER2 in breast cancer tissue is a marker of high prognostic and predictive relevance. Soluble HER2, the extracellular domain of the HER2/neu receptor (HER2 ECD), which is shed into the blood, has been suggested to be a helpful tumor marker. We investigated the relationship between the concentrations of HER2 ECD, CEA and CA 15-3, the association of these markers with clinicopathological features and the impact of HER2 ECD alone and in combination with known prognostic factors on disease free survival (DFS) and cancer specific survival (CSS) in untreated early breast cancer patients. PATIENTS AND METHODS: HER2 ECD (ADVIA, Bayer), CEA (AxSYM, Abbott) and CA 15-3 (Elecsys, Roche) were measured at time of primary diagnosis in the pre-therapeutic (pre-operative) sera of 241 breast cancer patients and were correlated with clinicopathological parameters and outcome. RESULTS: Higher HER2 ECD levels were significantly correlated with postmenopausal status (p=0.016) and tissue HER2-overexpression (p<0.0001). Higher serum levels of CA 15-3 were associated with larger tumor size (p=0.019), positive lymph nodes (p=0.019), UICC stage III (p<0.01), positive tissue HER2-overexpression (p<0.05) and negative hormone receptor status (p=0.016). In multivariate analysis, serum HER2 ECD levels, CA 15-3 levels, large tumor size and negative hormonal status were independent prognostic factors in DFS. Patients with both high levels of HER2 ECD (>15 ng/mL) and high serum levels of CA 15-3 (>24 U/mL) had the poorest prognosis with a DFS after 3 years of 50.0%. Patients without elevated serum levels had a better outcome with a DFS of 91.2%. CONCLUSIONS: In our retrospective analysis, HER2 ECD and CA 15-3 were independent and better prognostic tools than HER2 in tissue. Prospective validation is necessary to confirm their usefulness in clinical practice.

Serum HER2 supports HER2-testing in tissue at the time of primary diagnosis of breast cancer.

AIM: HER2 in tissue is of high prognostic value. Soluble HER2, the extracellular domain (ECD), has been suggested to be a helpful biomarker. We investigated whether there is a relationship between HER2 ECD and HER2 in tissue and whether this relationship could be used for diagnostic purposes. METHODS: HER2 ECD was measured in healthy individuals (N=283, 184 females, 99 males), in patients with history of breast cancer (BC) with no evidence of disease (N=249) as well as in BC patients before any treatment (N=565). HER2 in tissue was determined by immunohistochemistry and HER2 ECD was analyzed by immunoassay. RESULTS: HER2 ECD levels were higher in healthy men than in healthy women (medians 12.9 ng/mL vs. 9.9 ng/mL, p<0.001). We observed an age dependency in women that means the older the women the higher the HER2 ECD level. In treated BC patients there was only a weak difference between younger and older women. For patients without distant metastases as well as patients with metastatic disease we observed a correlation of HER2 in serum and tissue. The median concentrations of HER2 ECD were 11.7 ng/mL (13.2 ng/mL) for the HER2-negative (HER2-positive) patients in the non-metastatic-group (p<0.001) and 11.9 ng/mL (16.0 ng/mL) in the metastatic-group (p=0.01). Using a cut-off of 30 ng/mL the HER2 in tissue was always positive, corresponding to a specificity of 99.8% and a sensitivity of 10.3%. CONCLUSIONS: There is a strong correlation between HER2 ECD and HER2 in tissue. HER2 ECD supports the HER2 testing in tissue and may reveal false-negative tissue findings.