Disseminated epithelial cancers-An autopsy analysis.

BACKGROUND: Cancer is one of the leading causes of death due to noncommunicable diseases worldwide. Despite increasing public awareness and availability of sophisticated imaging techniques, some cancers evade clinical diagnosis and/or are incidentally encountered at autopsies, often with dissemination. AIMS: The present study evaluated the disseminated epithelial cancers at autopsy. MATERIALS AND METHODS: This is a retrospective observational 5-year autopsy analysis of disseminated epithelial cancers performed at a tertiary-care hospital. The cases were categorized as (1) clinically diagnosed malignancy, known primary; (2) clinically diagnosed malignancy, unknown primary; and (3) clinically undiagnosed malignancy. STATISTICAL ANALYSIS: Nil. RESULTS: Dissemination was identified in 66 (57.9%) of the 114 patients with epithelial malignancies. There were 29 patients (43.9%) in category 1, 26 patients (39.4%) in category 2, and 11 patients (16.7%) in category 3, majority of whom were women (38 patients, 57.6%). When all categories were considered together, lung and colorectal carcinomas were the commonest cancers seen in 13 (19.7%) and 8 (12.1%) patients, respectively, in both men and women. Majority of the patients (43 cases, 65.2%) had symptoms produced by metastases, which were the sole manifestations in 13 patients (19.7%). Lungs and liver were the common metastatic sites. CONCLUSIONS: Cancerous dissemination continues to be a major cause of morbidity and mortality even after considerable improvements in the surgical or nonsurgical treatment modalities. An autopsy study can provide important clinical insights in retrospect.

Metastatic Epithelial-Myoepithelial Carcinoma in a Female Presenting with Neck Mass and Lytic Lesion in Acetabulum: A Diagnostic Challenge on Cytology.

Epithelial-myoepithelial carcinoma (EMC) is a rare, low-grade, malignant salivary neoplasm. Establishing an accurate cytological diagnosis is often challenging owing to its rarity, bland cytologic appearance and variable representation of cell populations in the smears. The diagnostic struggle is more so when the aspiration is from a metastatic site with an unknown primary, as in such cases the list of differential diagnoses expands further. A 58-year-old female presented with a low-back pain from last one month. On examination, she also had a level III, right cervical swelling for the last 20 years. Radiology revealed a lytic lesion in the left acetabulum. She had undergone surgery 35 years ago for a right-sided upper neck swelling, the medical records of which were not available. Fine needle aspiration (FNA) from the cervical swelling was performed. The smears were cellular and showed predominantly dispersed, round to polygonal tumor cells with mild pleomorphism, eccentric nuclei, coarse chromatin, occasional nucleoli and moderate cytoplasm with some showing vacuolations. The cell-block section revealed tumor cells arranged in the form of tubules lined by dual layer of tumor cells without any chondromyxoid stroma. On immunocytochemistry, the luminal cells showed positivity for CK7 (epithelial marker) and the abluminal cells showed positivity for p63 (myoepithelial marker). Based on these features, a final diagnosis of metastatic epithelial-myoepithelial carcinoma was rendered. The present report highlights the characteristic cytomorphological and immunocytochemical features of EMC and reiterates the diagnostic accuracy of FNAC for diagnosis of such challenging cases.

Double trouble: Extrauterine epithelioid trophoblastic tumor with uterine choriocarcinoma - An autopsy report.

Gestational trophoblastic tumors (GTTs) include choriocarcinoma, epithelioid trophoblastic tumor, and placental site trophoblastic tumor. The occurrence of mixed GTT is rare. We report such a case in a 24-year-old woman who presented with menorrhagia since 2 months and obstetric history of two abortions, one of which was a molar pregnancy. She was undergoing evaluation for carcinoma cervix and treatment for pulmonary tuberculosis from another hospital when she was admitted at our institute for further workup and treatment. However, she succumbed and an autopsy was performed. Histologic evaluation after the autopsy revealed uterine choriocarcinoma with metastatic epithelioid trophoblastic tumor (ETT) in the lung and spleen.

Successful treatment of combined thymic epithelial tumor with hepatic metastasis: a long disease-free survival case.

A 73-year-old man presented with multiple liver nodules on an abdominal echogram. Fluorine-18-fluorodeoxyglucose (FDG)-positron emission tomography computed tomography (PET-CT) showed multiple nodules in his anterior and posterior mediastinum, and liver. Following thymothymectomy with lymph node dissection, the liver nodules were completely resected. Finally, he was diagnosed with combined thymic tumor (small cell carcinoma and type B3 thymoma) with multiple mediastinal lymph nodes and liver metastases by type B3 thymoma. Follow-up PET-CT scan revealed multiple rib and celiac lymph node metastases, six courses of chemotherapy (paclitaxel and carboplatin) were administered, and the patient survived without any recurrence for 15 years after initial surgery.

Thymic Epithelial Tumors: Prognostic Significance and Relationship between Histology and the New TNM Staging System.

BACKGROUND: This study aims to describe the relationship between the new tumor nodes metastasis (TNM) staging and World Health Organization (WHO) classification and to identify how these two variables relate to each other and whether they possess a prognostic value in predicting survival and recurrence of disease. METHODS: Medical records of 54 patients who underwent surgery for thymic epithelial tumors between 1996 and 2015 were reviewed.The histologic type of neoplasm was classified according to the criteria of WHO and staging was evaluated using the new TNM classification system. RESULTS: A significant correlation between the TNM stages and the histological classification was found (p < 0.001). Complete resection is related to both TNM stage and histological grading (p < 0.001). Evaluation of the 5- and 10-year survival curves shows how these are significantly correlated only at the stage (p = 0.03 and = 0.04, respectively). The risk of death at 5 and 10 years for stages III to IV is six and three times higher than in stages I to II, respectively. Regarding the disease-free survival, there is significant correlation with both staging and histology (p = 0.001 and = 0.02, respectively). CONCLUSIONS: There is a significant correlation between the new TNM staging and the histological grade WHO. The ability to implement a complete resection, the overall and disease-free survival is closely related to the thymoma stage. Furthermore, both histotype and stage correlate with disease-free survival. In fact, the least aggressive stages, both WHO and TNM, have a free time out of disease superior to advanced stages.

Brain metastasis from ovarian clear cell carcinoma: A case report.

RATIONALE: Epithelial ovarian carcinoma (EOC) is the most common type of ovarian carcinoma, and the leading cause of female genital tract cancer-related deaths. However, brain metastasis (BM) of EOC is rare, with an incidence of only 1% to 2%. Ovarian clear cell carcinoma (OCCC), accounting for 5% to 25% of all EOC cases, has a poor prognosis compared with other epithelial cell type carcinomas. PATIENT CONCERNS: We retrospectively analyzed the clinical data of a 62-year-old female, who was hospitalized with the main complaint of BM detection for 1 month. She was first diagnosed with ovarian cancer in 2004, and underwent a left oophorectomy. Three years later, the cancer metastasized to the other side, and she underwent a right oophorectomy, followed by 7 courses of platinum-based chemotherapy. She received regular follow-up, and tumor markers and pelvic imaging did not show any signs of progression until July 2012. DIAGNOSIS: Combining the clinical manifestations with the results of radiological and pathological examinations, the findings were consistent with a diagnosis of BM from OCCC. INTERVENTIONS: She received more than 20 courses of chemotherapy since July 2012. The BM was detected in 2016, and she underwent an intracranial lesion resection. OUTCOMES: Unfortunately, the patient went into a coma after the surgery, and passed away 1 month later. LESSONS: For early detection of BM in long-term ovarian cancer, emphasis should be placed on the patient's neurological symptoms and signs as well as serum tumor marker changes. The combination of surgery, radiology, and chemotherapy may achieve long overall survival.

Immunohistochemical profiles in primary lung cancers and epithelial pulmonary metastases.

Correct diagnosis of pulmonary tumors is essential for treatment decision and often relies on immunohistochemical markers. We stained tissue microarrays from resected primary lung cancer (n = 665) and pulmonary metastases (n = 425) for CK7, CK20, CDX2, CK5, p40, p63, TTF-1, napsin A, GATA3, and PAX8 to systematically assess the diagnostic value of these markers. Primary lung adenocarcinomas expressed TTF-1 in 90% and napsin A in 84% of the cases, whereas 10% were positive for p63, 7% for CDX2, 2% for CK20, and 2% for GATA3. Only 68% of the lung adenocarcinomas were positive for CK7, TTF-1, and napsin A and negative for all other markers. Primary lung squamous cell carcinomas expressed CK5, p40, and p63 in 94%-97% of cases, whereas 44% were positive for CK7, 20% for GATA3, 7% for CDX2, and 3% for TTF-1. Rare cases expressed PAX8, CK20, or napsin A. Pulmonary metastases of colorectal cancer were positive for CK20 in 83% and CDX2 in 99% of the cases. Rare cases expressed CK7, p63, or PAX8, whereas 4% expressed TTF-1. Pulmonary metastases of renal cell carcinomas were positive for PAX8 in 74%, napsin A in 7%, and CK7 in 7% of the cases. Pulmonary metastases of breast cancer were positive for GATA3 in 93% and CK7 in 78% of the cases, whereas 15% expressed CK5. Information on expression and patterns of immunohistochemical markers facilitates histopathological diagnostics. Evidently, unusual immune profiles occur and may lead to incorrect diagnosis.

Treatment of Metastatic Spindle Epithelial Tumor with Thymus-Like Differentiation (SETTLE) - Long-Term Disease Control by Multimodal Therapy.

BACKGROUND: Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a very rare tumor that occurs mainly in pediatric patients and young adults. Only few of these patients develops metastatic disease; therefore, clinical data regarding treatment and outcome of metastatic SETTLE are extremely limited. Several chemotherapy agents have been used in SETTLE but due to the limited number of patients no evidence-based therapy exists. CASE REPORT: We present a case of metastatic SETTLE presenting with high tumor burden and paraneoplastic hypercalcemia. Prolonged disease control with several lines of platinum-based chemotherapy, anti-epidermal growth factor receptor therapy and additional radiotherapy was achieved. CONCLUSION: Multi-agent chemotherapy is an active treatment in metastatic SETTLE and can induce sustained tumor control.

Relevance of enlarged cardiophrenic lymph nodes in determining prognosis of patients with advanced ovarian cancer.

Ovarian cancer often presents at an advanced stage with widespread peritoneal and/or extra-abdominal metastases. Complete cytoreduction is the mainstay of treatment for disease confined to peritoneum. But in patients with distant metastases, the role and rationale is less obvious. One of the the most common sites of extra-abdominal disease is the cardiophrenic lymph node (CPLN). In this paper, we described the management of a patient with International Federation of Gynecology and Obstetrics (FIGO) stage IVB epithelial ovarian carcinoma and widespread peritoneal and extra-abdominal metastases to the CPLN, who underwent complete cytoreduction including excision of enlarged CPLN, following neoadjuvant chemotherapy. We examined the literature to determine the prognostic value of enlarged CPLN and their relevance in managing patients with advanced ovarian cancer and found it as an adverse prognostic factor. Transdiaphragmatic excision of CPLN is feasible without major complications. But as its correlation with overall or progression-free survival is not yet evident, large-scale prospective studies are warranted.

Potential microRNA-related Targets for Therapeutic Intervention with Ovarian Cancer Metastasis.

Treatment of disseminated epithelial ovarian cancer (EOC) is an unmet medical need. Therefore, the identification along with preclinical and clinical validation of new targets is an issue of high importance. In this review we focus on microRNAs that mediate metastasis of EOC. We summarize up-regulated metastasis-promoting and down-regulated metastasis-suppressing microRNAs. We focus on preclinical in vitro and in vivo functions as well as their metastasis-related clinical correlations. Finally, we outline modalities for therapeutic intervention and critical issues of microRNA-based therapeutics in the context of metastatic EOC.

A role for G-protein coupled estrogen receptor (GPER) in estrogen-induced carcinogenesis: Dysregulated glandular homeostasis, survival and metastasis.

Mechanisms of carcinogenesis by estrogen center on its mitogenic and genotoxic potential on tumor target cells. These models suggest that estrogen receptor (ER) signaling promotes expansion of the transformed population and that subsequent accumulation of somatic mutations that drive cancer progression occur via metabolic activation of cathecol estrogens or by epigenetic mechanisms. Recent findings that GPER is linked to obesity, vascular pathology and immunosuppression, key events in the development of metabolic syndrome and intra-tissular estrogen synthesis, provides an alternate view of estrogen-induced carcinogenesis. Consistent with this concept, GPER is directly associated with clinicopathological indices that predict cancer progression and poor survival in breast and gynecological cancers. Moreover, GPER manifests cell biological responses and a microenvironment conducive for tumor development and cancer progression, regulating cellular responses associated with glandular homeostasis and survival, invading surrounding tissue and attracting a vascular supply. Thus, the cellular actions attributed to GPER fit well with the known molecular mechanisms of G-protein coupled receptors, GPCRs, namely, their ability to transactivate integrins and EGF receptors and alter the interaction between glandular epithelia and their extracellular environment, affecting epithelial-to-mesenchymal transition (EMT) and allowing for tumor cell survival and dissemination. This perspective reviews the molecular and cellular responses manifested by GPER and evaluates its contribution to female reproductive cancers as diseases that progress as a result of dysregulated glandular homeostasis resulting in chronic inflammation and metastasis. This review is organized in sections as follows: I) a brief synopsis of the current state of knowledge regarding estrogen-induced carcinogenesis, II) a review of evidence from clinical and animal-based studies that support a role for GPER in cancer progression, and III) a mechanistic framework describing how GPER-mediated estrogen action may influence the tumor and its microenvironment.

Outcomes of patients with advanced stage ovarian cancer with intestinal metastasis.

OBJECTIVES: The aim of this study is to evaluate the results of advanced stage (stage IIIB-IVB) ovarian cancer (OC) patients with intestinal metastasis, and to investigate the factors that affect survival. MATERIAL AND METHODS: Patients who underwent cytoreductive surgery (CS) for FIGO stage IIIB-IVB OC with metastasis in the intestinal system, at Tepecik Research and Treatment Hospital between 2008-2014, were analyzed retrospectively. Patients with borderline ovarian tumor; those who had previously undergone radiation therapy and/or hysterectomy and patients having secondary or tertiary cytoreduction were excluded and 49 patients were included and analyzed in this study. Hysterectomy, bilateral salpingo-oopherectomy, pelvic and para-aortic lymph node sampling, resection of bulky lymph nodes and omentectomy were performed. Optimal cytoreduction was accepted as that which left residual tumor ≤ one cm maximum size. RESULTS: The risk factors affecting OS interval were investigated according to Cox' regression analysis. Optimality of the primary CS (P = 0.008 and HR = 5.202) and cancer stage (P = 0.016 and HR = 6.083) were found to be statistically significant factors. CONCLUSIONS: Achieving optimal CS is the most important aim for the general surgeon carrying out an intestinal resection procedure. Although resection procedures are superior in providing the desired optimal results when compared to excision surgery, their higher complication rates and subsequent lower quality of life must be taken into consideration when choosing either resection or excision methods; surgical intervention should always be kept to the minimum possible.

Association between tumour infiltrating lymphocytes, histotype and clinical outcome in epithelial ovarian cancer.

BACKGROUND: There is evidence that some ovarian tumours evoke an immune response, which can be assessed by tumour infiltrating lymphocytes (TILs). To facilitate adoption of TILs as a clinical biomarker, a standardised method for their H&E visual evaluation has been validated in breast cancer. METHODS: We sought to investigate the prognostic significance of TILs in a study of 953 invasive epithelial ovarian cancer tumour samples, both primary and metastatic, from 707 patients from the prospective population-based SEARCH study. TILs were analysed using a standardised method based on H&E staining producing a percentage score for stromal and intratumoral compartments. We used Cox regression to estimate hazard ratios of the association between TILs and survival. RESULTS: The extent of stromal and intra-tumoral TILs were correlated in the primary tumours (n = 679, Spearman's rank correlation = 0.60, P < 0.001) with a similar correlation in secondary tumours (n = 224, Spearman's rank correlation = 0.62, P < 0.001). There was a weak correlation between stromal TIL levels in primary and secondary tumour samples (Spearman's rank correlation = 0.29, P < 0.001) and intra-tumoral TIL levels in primary and secondary tumour samples (Spearman's rank correlation = 0.19, P = 0.0094). The extent of stromal TILs differed between histotypes (Pearson chi2 (12d.f.) 54.1, P < 0.0001) with higher levels of stromal infiltration in the high-grade serous and endometriod cases. A significant association was observed for higher intratumoral TIL levels and a favourable prognosis (HR 0.74 95% CI 0.55-1.00 p = 0.047). CONCLUSION: This study is the largest collection of epithelial ovarian tumour samples evaluated for TILs. We have shown that stromal and intratumoral TIL levels are correlated and that their levels correlate with clinical variables such as tumour histological subtype. We have also shown that increased levels of both intratumoral and stromal TILs are associated with a better prognosis; however, this is only statistically significant for intratumoral TILs. This study suggests that a clinically useful immune prognostic indicator in epithelial ovarian cancer could be developed using this technique.

Crosstalk between TEMs and endothelial cells modulates angiogenesis and metastasis via IGF1-IGF1R signalling in epithelial ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is the leading cause of death from gynaecologic malignancies and has a poor prognosis due to metastasis. Drugs targeting the angiogenesis pathway significantly improve patient outcome. However, the key factors linking angiogenesis and metastasis have not been elucidated. In this study, we found Tie2 expressing monocytes (CD14+Tie2+, TEMs) as key contributors to angiogenesis and metastasis of EOC. METHODS: Tissue slides were evaluated by immunofluorescence for the presence of total tissue macrophages and TEMs. The correlation between microvascular density (MVD) values and the TEMs number or ratio was calculated in both ovarian cancer tissues and peritoneum. The rate of TEMs in monocytes was evaluated in the peripheral blood of female healthy donors, benign cysts patients, and EOC patients using flow cytometry. The TEMs rate in ascites from EOC patients was also evaluated by flow cytometry. The concentration of Ang2, as the ligand of Tie2, was examined by ELISA in serum samples of EOC patients, benign cysts patients, and ascites samples of EOC patients. The effects of Ang2 on the migration and the cytokine expression of TEMs were further examined. The pro- angiogenesis activity of TEMs via IGF1 was performed in both in vivo and in vitro. And the IGF1 blocking test was performed using neutralising antibody. RESULTS: TEMs were significantly higher in tumour foci, peripheral blood and ascites in EOC patients. The proportion of TEMs among total tissue macrophages was positively correlated with tumour MVD. In vivo animal results showed that TEMs promoted EOC angiogenesis and metastasis. Further functional and mechanisms studies revealed that concentration of angiopoietin 2 (Ang2), a ligand of Tie2, was elevated in EOC ascites which further recruit TEMs in a dose-dependent manner as a powerful chemokine to TEMs. Recruited TEMs promoted endothelial cell function through IGF1-activated downstream signalling. Blocking secreted IGF1 using inhibiting antibody reduced TEMs mediated angiogenesis and metastasis. CONCLUSIONS: TEMs significantly increased in EOC patients and were recruited to tumour loci by the increased Ang2. The increased TEMs have diagnostic value in ovarian cancer and were positively correlated with the MVD in ovarian cancer tissue. Furthermore, TEMs promote angiogenesis via IGF1 in both in vivo and in vitro experimental systems after stimulation by Ang2. Altogether, this study paves the way to develop novel therapy targets as the axis of Ang2-TEMs-IGF1 in EOC.

Cerebrospinal fluid circulating tumor cells: a novel tool to diagnose leptomeningeal metastases from epithelial tumors.

BACKGROUND: Diagnosis of leptomeningeal metastasis (LM) remains challenging due to low sensitivity of CSF cytology and infrequent unequivocal MRI findings. In a previous pilot study, we showed that rare cell capture technology (RCCT) could be used to detect circulating tumor cells (CTC) in the CSF of patients with LM from epithelial tumors. To establish the diagnostic accuracy of CSF-CTC in the diagnosis of LM, we applied this technique in a distinct, larger cohort of patients. METHODS: In this institutional review board-approved prospective study, patients with epithelial tumors and clinical suspicion of LM underwent CSF-CTC evaluation and standard MRI and CSF cytology examination. CSF-CTC enumeration was performed through an FDA-approved epithelial cell adhesion molecule-based RCCT immunomagnetic platform. LM was defined by either positive CSF cytology or imaging positive for LM. ROC analysis was utilized to define an optimal cutoff for CSF-CTC enumeration. RESULTS: Ninety-five patients were enrolled (36 breast, 31 lung, 28 others). LM was diagnosed in 30 patients (32%) based on CSF cytology (n = 12), MRI findings (n = 2), or both (n = 16). CSF-CTC were detected in 43/95 samples (median 19.3 CSF-CTC/mL, range 0.3 to 66.7). Based on ROC analysis, 1 CSF-CTC/mL provided the best threshold to diagnose LM, achieving a sensitivity of 93%, specificity of 95%, positive predictive value 90%, and negative predictive value 97%. CONCLUSIONS: We defined ≥1 CSF-CTC/mL as the optimal cutoff for diagnosis of LM. CSF-CTC enumeration through RCCT is a robust tool to diagnose LM and should be considered in the routine LM workup in solid tumor patients.

Sucrose Non-Fermenting Related Kinase Expression in Ovarian Cancer and Correlation with Clinical Features.

Sucrose non-fermenting related kinase (SNRK) is a serine/threonine kinase known to regulate cellular metabolism and adipocyte inflammation. Since alterations in adipocyte metabolism play a role in ovarian cancer metastasis, we investigated the expression of SNRK in benign and malignant human ovarian tissue using immunohistochemistry and qPCR. The number of SNRK positive (+) nuclei is increased in malignant tissue compared to benign tissue (21.03% versus 14.90%, p < .0431). The most strongly stained malignant SNRK+ nuclei were stage 1 compared to stage 2-4 disease. Differential expression of SNRK in early versus late stage disease suggests specific roles for SNRK in ovarian cancer metastasis.

Patterns of Lymph Node Metastases in Apparent Stage I Low-Grade Epithelial Ovarian Cancer: A Multicenter Study.

OBJECTIVE: The aim of this study was to determine oncological outcomes and incidence of lymph node (LN) metastases in women who underwent systematic pelvic and paraaortic lymphadenectomy for surgical staging of apparent stage I low-grade epithelial ovarian cancer (LGEOC). MATERIALS AND METHODS: A retrospective study was performed at nine institutions across Europe and the US, and patients who underwent surgical staging for presumed stage I LGEOC between 2000 and 2016 were included. To ensure surgical quality, a minimum number of ≥10 pelvic and ≥10 paraaortic LNs was required. Patients with preoperative radiologic or clinical evidence of extraovarian or LN disease, and those with nonepithelial histology, were excluded. RESULTS: The overall incidence of LN metastases was 4.3% in the 163 evaluated patients, and the incidence of LN involvement in serous, endometrioid, and mucinous subtypes was 10.7, 1.5, and 0%, respectively. However, Upstaging due to LN involvement alone occurred in only 2.4% of the patients. Eighty-nine (54.6%) patients received adjuvant chemotherapy due to International Federation of Gynecology and Obstetrics stage IC or higher disease. The 5-year progression-free survival (PFS) and overall survival (OS) were 93.2% (95% confidence interval [CI] 89.4-97.1%) and 94.5% (95% CI 90.9-98.0%), respectively. There was no significant difference in PFS or OS between LN-negative and LN-positive patients. However, fewer patients received adjuvant chemotherapy in the LN-negative group. Multivariate analysis did not identify any independent prognostic factor of survival. CONCLUSION: The risk of LN involvement in nonserous apparent stage I LGEOC appears low, with a rate of <1% in this retrospective analysis, raising questions about the value of lymphadenectomy in those patients. Larger-scale prospective studies are warranted to evaluate the oncologic safety of omitting systematic LN staging in apparent stage I nonserous LGEOC.

Clinical Relevance of Serum HER2 and Circulating Tumor Cell Detection in Metastatic Breast Cancer Patients.

BACKGROUND/AIM: Presence of circulating tumor cells (CTCs) is associated with impaired survival in metastatic breast cancer (MBC). This study was designed to evaluate whether assessment of serum HER2 (sHER2) levels provide additional prognostic information in MBC. MATERIALS AND METHODS: Two hundred and fifty-three MBC patients were enrolled in this multicentre trial. CTCs were detected before the start of first- or later-line treatment using the CellSearch system. sHER2 was determined using ELISA. RESULTS: ≥5 CTCs were detected in 122 of 245 evaluable patients (49.8%). One hundred and nineteen of 251 patients (47%) had sHER2 levels above 15 ng/ml. Median overall survival (OS) was 16.3 months in patients with elevated sHER2; median OS in patients with non-elevated sHER2 has not been reached (p=0.001). Patients with ≥5 CTCs were more likely to present with elevated sHER2 (61% vs. 33% in those with <5 CTC; p<0.001). In patients with HER2-negative tumors, elevated sHER2 was associated with shorter OS and PFS; in HER2-positive patients with OS only. Including sHER2, CTC status and established prognostic factors into a multivariate analysis, only the presence of CTCs and higher-line of therapy remained independent predictors of OS. CONCLUSION: Elevated levels of sHER2 are associated with worse survival, irrespective of the HER2 status of the tumor. However, sHER2 does not provide additional prognostic information in patients with known CTC status.