Enfortumab Vedotin in Metastatic Urothelial Carcinoma: Survival and Safety in a European Multicenter Real-world Patient Cohort.

Background: Treatment options for patients with urothelial cancer (UC) refractory to platinum and immunotherapy are limited and survival is short. Enfortumab vedotin (EV) is a monoclonal anti-NECTIN4 antibody conjugated to monomethyl auristatin. It was recently approved because of superior survival in comparison to standard-of-care (SOC) chemotherapy. Real-world patients, however, often have worse characteristics than patients included in clinical trials. Objective: To analyze the efficacy and safety of EV in a cohort of real-world patients. Design setting and participants: Retrospective data were collected from 23 hospitals and private practices for patients with metastatic and previously treated UC who received EV either when reimbursed by their insurance company before European Medicines Agency (EMA) approval, within a compassionate use program, or as SOC treatment after EMA approval. Imaging and therapy management were in accordance with local standards. Outcome measurements and statistical analysis: Adverse events (AEs) were reported according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Objective responses were evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results and limitations: The median age for the 125 eligible patients was 66 yr (range 31-89). The Eastern Cooperative Oncology Group performance status (ECOG PS) was 0-1 for 76.0%, 2-4 for 13.6%, and unknown for 10.4% of patients. EV was administered in the fourth or later line for 44.8% of patients. The overall response rate was 41.6% (partial response 39.2%, complete response 2.4%). Median OS was 10.0 months (mo) (95% confidence interval 7.20-12.80) and median PFS was 5.0 mo (95% confidence interval 4.34-5.67). For patients with ECOG PS of 0-1, median OS was 14 mo. Any-grade AEs were observed in 67.2% and CTCAE grade ≥3 AEs in 30.4%. The most common AEs were peripheral sensory neuropathy and skin toxicity. Three fatal events (pneumonia, pneumonitis) occurred. Limitations include the retrospective design and short follow-up. Conclusions: Administration of EV for real-world patients was feasible with an acceptable toxicity profile. No new safety signals were reported. Antitumor activity in our cohort was comparable to data previously reported for trials. In summary, our results support the use of EV in patients with metastatic UC. Patient summary: Enfortumab vedotin is a medication that improved the survival of patients with bladder cancer in comparison to standard chemotherapy in clinical trials. However, patients included in clinical trials are highly selected and results for toxicities and improvements in survival do not always transfer to the real-world setting. We analyzed data for 125 patients who were treated with enfortumab vedotin. Our results are comparable to the outcomes from clinical trials regarding the safety and efficacy of this treatment.

Identification of incompletely penetrant variants and interallelic interactions in autosomal recessive disorders by a population-genetic approach.

We aimed to identify incompletely penetrant (IP) variants and interallelic interactions in autosomal recessive disorders by a population-genetic approach. Genotype and clinical data were collected from 9038 patients of European origin with ASL, ATP7B, CAPN3, CFTR, CTNS, DHCR7, GAA, GALNS, GALT, IDUA, MUT, NPHS1, NPHS2, PAH, PKHD1, PMM2, or SLC26A4-related disorders. We calculated the relative allele frequency of each pathogenic variant (n = 1936) to the loss-of-function (LOF) variants of the corresponding gene in the patient ( ACptV/ACptLOF ) and the general population ( ACgnomADV/ACgnomADLOF ) and estimated the penetrance of each variant by calculating their ratio: (ACptV/ACptLOF)(ACgnomADV/ACgnomADLOF) (V/LOF ratio). We classified all variants as null or hypomorphic based on the associated clinical phenotype. We found 25 variants, 29% of the frequent 85 variants, to be underrepresented in the patient population (V/LOF ratio <30% with p < 7.22 × 10-5 ), including 22 novel ones in the ASL, CAPN3, CFTR, GAA, GALNS, PAH, and PKHD1 genes. In contrast to the completely penetrant variants (CP), the majority of the IP variants were hypomorphic (IP: 16/18, 88%; CP: 177/933, 19.0%; p = 5.12 × 10-10 ). Among them, only the NPHS2 R229Q variant was subject to interallelic interactions. The proposed algorithm identifies frequent IP variants and estimates their penetrance and interallelic interactions in large patient cohorts.

Non-Whole-Gland High-Intensity Focused Ultrasound vs Whole-Gland High-Intensity Focused Ultrasound for Management of Localized Prostate Cancer: 1-Year Oncological and Functional Outcomes.

OBJECTIVE: The aim of the study was to compare the oncological and functional outcomes in localized prostate cancer patients who received non-whole-gland high-intensity focused ultrasound (HIFU) with those in patients who received whole-gland HIFU therapy. PATIENTS AND METHODS: Eighty-six patients from September 2012 to January 2017 in our center were retrospectively analyzed. Oncological outcomes included histological absence of prostate cancer, biochemical disease-free survival (BDFS) as well as the absence of lesions suspected for harboring prostate cancer in multiparametric magnetic resonance imaging (mpMRI). Regarding functional outcomes, we determined international prostate symptom score (IPSS), pad-free rate, pad-free and leakage-free rates as well as international index of erectile function-5 (IIEF-5). RESULTS: Of the 86 patients, 25 patients who underwent non-whole-gland HIFU and 61 patients who underwent whole-gland HIFU were enrolled in our 1-year follow-up study. There were no significant differences in histological absence of prostate cancer (p = 0.655), BDFS (p = 0.820), prostate-specific antigen (PSA) nadir (p = 0.453), and absence of suspicious lesions in mpMRI (p = 0.633) between non-whole-gland HIFU group and whole-gland HIFU group. However, compared with the whole-gland HIFU, the non-whole-gland HIFU group had fewer IPSS at 1 month (8.64 ± 3.63 vs 10.85 ± 6.10), a longer time to PSA nadir (5.04 ± 2.07 vs 3.83 ± 1.65), less temporary urine retention rate (20.0% vs 44.3%), less complication rate especially urinary tract strictures (4% vs 26.2%), whereas pad-free rate, pad-free and leakage-free rates, and IIEF scores were comparable. CONCLUSION: Non-whole-gland HIFU is a promising type of treatment for localized prostate cancer with satisfactory oncological results with less impairment of functional outcomes and complications compared with whole-gland HIFU, but it requires longer follow-up and larger samples of randomized control trials.

A New Scoring-system for Estimating Overall Survival After Radiotherapy of Recurrent Head and Neck Cancers.

BACKGROUND/AIM: Locoregional recurrences of head and neck cancers are often associated with a poor overall survival (OS). Outcomes may be improved with individualized treatments considering a patient's lifespan. A specific scoring system for estimating OS prognoses is presented. PATIENTS AND METHODS: In a preceding study of these 60 patients, Eastern Cooperative Oncology Group performance score (ECOG 0-1 versus 2, p=0.002) and N-stage (N0-1 versus N2, p=0.004) were identified as independent predictors of OS. RESULTS: In the current study, the following scoring points were assigned: ECOG performance score 2=0 points, ECOG performance score 0-1=1 point, N2=0 points, N0-1=1 point. Patient scores were 0, 1 or 2 points with 3-year OS rates of 0%, 46% and 83%, respectively (p<0.0001). On multivariable analysis, differences remained significant (p<0.0001). CONCLUSION: This new scoring system includes three groups of patients with significantly different OS prognoses and can assist physicians when designing individualized therapy for locoregional recurrences of head and neck cancer.

Comparing two lower-dose cisplatin programs for radio-chemotherapy of locally advanced head-and-neck cancers.

Radio-chemotherapy is a common treatment for locally advanced squamous cell head-and-neck cancers (LA-SCCHN). Cisplatin (100 mg/m2) every 3 weeks is very common but associated with considerable toxicity. Therefore, cisplatin programs with lower daily doses were introduced. There is a lack of studies comparing lower-dose programs. In this study, 85 patients receiving radio-chemotherapy with 20 mg/m2 cisplatin on 5 days every 4 weeks (group A) were retrospectively compared to 85 patients receiving radio-chemotherapy with 30-40 mg/m2 cisplatin weekly (group B). Groups were matched for nine factors including age, gender, performance score, tumor site, T-/N-category, surgery, hemoglobin before radio-chemotherapy, and radiation technique. One- and 3-year loco-regional control rates were 83 and 69 % in group A versus 74 and 63 % in group B (p = 0.12). One- and 3-year survival rates were 93 % and 73 % in group A versus 91 and 49 % in group B (p = 0.011). On multivariate analysis, survival was significantly better for group A (HR 1.17; p = 0.002). In groups A and B, 12 and 28 % of patients, respectively, did not receive a cumulative cisplatin dose ≥180 mg/m2 (p = 0.016). Toxicity rates were not significantly different. On subgroup analyses, group A patients had better loco-regional control (p = 0.040) and survival (p = 0.005) than group B patients after definitive radio-chemotherapy. In patients receiving adjuvant radio-chemotherapy, outcomes were not significantly different. Thus, 20 mg/m2 cisplatin on 5 days every 4 weeks resulted in better loco-regional control and survival in patients receiving definitive radio-chemotherapy and may be preferable for these patients. Confirmation of these results in a randomized trial is warranted.

Prognostic Factors in Patients Irradiated for Recurrent Head-and-Neck Cancer.

BACKGROUND/AIM: Many patients with recurrent head-and-neck cancer have poor outcomes. Predictive factors allowing judgment of the patient's prognosis are important for treatment individualization. This study aimed to identify such factors after irradiation of locoregional recurrence. PATIENTS AND METHODS: In 60 patients irradiated for locoregionally recurrent head-and-neck cancer, 12 factors were evaluated regarding freedom from second locoregional recurrence and survival, namely gender, tumor site, initial tumor stage, primary treatment, time between cancer diagnosis and irradiation of locoregional recurrence, age, performance score, tumor and nodal category of recurrence, upfront surgery, radiation dose and concurrent chemotherapy. RESULTS: On Cox regression analysis, performance score (p=0.002) and nodal category (p=0.004) significantly affected survival. Good performance score (p=0.021) and low nodal category (p=0.002) were also significantly associated with freedom from a second recurrence. CONCLUSION: Independent predictors of survival and freedom from second locoregional recurrence were identified as factors facilitating individualized treatment of patients with locoregionally recurrent head-and-neck cancer.

Radiochemotherapy with Paclitaxel for Recurrent Previously Irradiated Squamous Cell Carcinoma of the Head and Neck.

BACKGROUND/AIM: Locoregional recurrences of squamous cell carcinoma of the head and neck (SCCHN) are difficult to treat. If radiotherapy was included in the primary treatment, another curative course of radiotherapy incurs substantial risk of complications. Results of re-irradiation can be improved by concurrent chemotherapy. PATIENTS AND METHODS: Radiotherapy with low doses per fraction twice daily and paclitaxel were applied in four patients with recurrent SCCHN. Radiotherapy was administered with doses of 30-36 Gy and doses per fraction of 1.5 Gy twice daily. Concurrent chemotherapy consisted of 20-25 mg/m2 paclitaxel twice per week. Overall 1-year locoregional control following re-irradiation was 25%. One-year locoregional control rates were 75% inside the re-irradiated region and 50% outside the re-irradiated region. Distant metastases did not occur. One-year overall survival following re-irradiation was 75%. Toxicity did not exceed grade 2. CONCLUSION: Re-irradiation plus concurrent paclitaxel appeared well-tolerated and resulted in promising outcomes.

Radiochemotherapy for locally advanced squamous cell carcinoma of the head and neck: Higher-dose cisplatin every 3 weeks versus cisplatin/5-fluorouracil every 4 weeks.

Many patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) receive cisplatin-based radiochemotherapy. The optimal regimen is still unclear when considering both efficacy and feasibility. This study compared two regimens for locoregional control (LRC), overall survival (OS), and adverse events. Data of 329 patients with LASCCHN receiving definitive or postoperative radiochemotherapy were retrospectively analyzed. A total of 131 patients received 100 mg/m(2) cisplatin on days 1, 22, and 43 (group A), and 198 patients received 20 mg/m(2) cisplatin plus 600/1000 mg/m(2) 5-FU on days 1-5 and days 29-33 (group B). Radiochemotherapy regimens plus nine factors were compared for LRC and OS, and radiochemotherapy regimens additionally for adverse events. On univariate analysis, chemotherapy type was not associated with LRC (p = 0.36). On multivariate analysis, performance score (p = 0.039), N-category (p = 0.007), histologic grade (p = 0.007), upfront surgery (p = 0.030), and pre-radiochemotherapy hemoglobin levels (p < 0.001) were associated with LRC. On univariate analysis, chemotherapy type had no impact on OS (p = 0.64). On multivariate analysis, performance score (p < 0.001), T-category (p = 0.025), N-category (p < 0.001), histologic grade, and hemoglobin levels (p < 0.001) were associated with OS. Renal failure occurred significantly more often in group A (p = 0.008). Otherwise, adverse events were not significantly different. Thus, both radiochemotherapy regimens appeared similarly effective for LASCCHN. Patients receiving 100 mg/m(2) of cisplatin require close monitoring of their renal function.

The effect of low hemoglobin levels on outcomes of radiotherapy following microscopically complete resection of locally advanced SCCHN: Implications for the future.

This study investigated the prognostic implications of pre-radiotherapy hemoglobin levels after microscopically complete (R0) resection of locally advanced squamous cell carcinoma of the head-and-neck (SCCHN) and reviewed the question "should anemia be corrected?". A total of 225 patients receiving R0-resection and postoperative irradiation were retrospectively evaluated. Pre-radiotherapy hemoglobin levels (<12 vs. ≥12 g/dl) plus eight factors (T-/N-category, AJCC-stage, performance score, gender, age, tumor site, and histologic grading) were analyzed for locoregional control and survival. Hemoglobin levels of <12 and ≥12 g/dl were associated with 3-year locoregional control rates of 67% and 84%, respectively, and 5-year locoregional control rates of 63% and 74%, respectively (p = 0.029). On multivariate analysis of locoregional control, hemoglobin levels achieved significance (hazard ratio [HR] 1.97; 95%-confidence interval [95%-CI] 1.02-3.81; p = 0.043). Hemoglobin levels of <12 and ≥12 g/dl were associated with 3-year survival rates of 55% and 87%, respectively, and 5-year survival rates of 25% and 71%, respectively (p < 0.001). On multivariate analysis of survival, hemoglobin levels were significant (HR 2.91; 95%-CI 1.67-5.22; p < 0.001). Thus, pre-radiotherapy hemoglobin is an independent predictor for outcomes after R0-resection of SCCHN. Levels <12 g/dl were associated with worse outcomes than ≥12 g/dl. Tumor cell oxygenation and correction of anemia appear important also after R0-resection.

Comparison of weekly administration of cisplatin versus three courses of cisplatin 100 mg/m(2) for definitive radiochemotherapy of locally advanced head-and-neck cancers.

BACKGROUND: To compare definitive radiochemotherapy with weekly administration of 30-40 mg/m(2) of cisplatin to 100 mg/m(2) of cisplatin on days 1, 22 and 43 for outcomes and toxicity in patients with squamous cell carcinoma of the head-and-neck. METHODS: Seventy-five patients receiving radiochemotherapy with weekly cisplatin (30-40 mg/m(2)) were compared to 58 patients receiving radiochemotherapy with 100 mg/m(2) cisplatin on days 1, 22 and 43. Radiochemotherapy regimen plus seven characteristics (age, gender, performance score, tumor site, T-/N-category, histologic grading) were evaluated for locoregional control (LRC), metastases-free survival (MFS) and overall survival (OS). Radiochemotherapy groups were compared for toxicity. RESULTS: On multivariate analysis, improved LRC was associated with cisplatin 100 mg/m(2) (hazard ratio [HR] 1.57; p = 0.008) and female gender (HR 4.37; p = 0.003). Radiochemotherapy regimen was not significantly associated with MFS on univariate analysis (p = 0.66). On multivariate analysis, better MFS was associated with ECOG performance score 0-1 (HR 5.63; p < 0.001) and histological grade 1-2 (HR 1.81; p = 0.002). On multivariate analysis, improved OS was associated with cisplatin 100 mg/m(2) (HR 1.33; p = 0.023), ECOG performance score 0-1 (HR 2.15; p = 0.029) and female gender (HR 1.98; p = 0.026). Cisplatin 100 mg/m(2) was associated with higher rates of grade ≥3 hematotoxicity (p = 0.004), grade ≥2 renal failure (p = 0.004) and pneumonia/sepsis (p = 0.033). CONCLUSIONS: Radiochemotherapy with 100 mg/m(2) of cisplatin every 3 weeks resulted in better LRC and OS than weekly doses of 30-40 mg/m(2). Given the limitations of a retrospective study, 100 mg/m(2) of cisplatin appears preferable. Since this regimen was associated with considerable acute toxicity, patients require close monitoring.

Chemoradiation of locally advanced squamous cell carcinoma of the head-and-neck (LASCCHN): Is 20mg/m(2) cisplatin on five days every four weeks an alternative to 100mg/m(2) cisplatin every three weeks?

OBJECTIVES: To compare chemoradiation with 100mg/m(2) cisplatin every three weeks to 20mg/m(2) on five days every four weeks for locally advanced squamous cell carcinoma of the head-and-neck (LASCCHN). MATERIALS AND METHODS: In 230 patients receiving chemoradiation for LASCCHN, 100mg/m(2) cisplatin every three weeks (N=126) and 20mg/m(2) cisplatin on five days every four weeks (N=104) were retrospectively compared. Chemoradiation plus eleven characteristics (T-/N-classification, performance score, gender, age, tumor site, grading, surgery, radiation technique, pre-chemoradiation hemoglobin, cumulative cisplatin dose) were analyzed for locoregional control (LRC), metastases-free survival (MFS) and overall survival (OS). Chemoradiation groups were compared for adverse events. RESULTS: On univariate analyses, chemoradiation had no impact on LRC (p=0.53), MFS (p=0.67) and OS (p=0.14). On multivariate analysis of LRC, T-classification (p=0.045) and hemoglobin (p<0.001) were significant. On multivariate analysis of MFS, performance score (p=0.028) was significant. On multivariate analysis of OS, performance score (p=0.009) and hemoglobin levels (p=0.002) achieved significance. Chemoradiation with 100mg/m(2) cisplatin was associated with more pneumonia/sepsis (p=0.003), grade ⩾2nausea/vomiting (p<0.001), grade ⩾2 nephrotoxicity (p=0.005), grade ⩾2 xerostomia (p=0.002), grade ⩾3 hematotoxicity (p=0.052) and grade ⩾2 ototoxicity (p=0.048). CONCLUDING STATEMENT: 20mg/m(2) cisplatin on five days every four weeks was associated with fewer adverse events than 100mg/m(2) cisplatin every three weeks. 100mg/m(2) cisplatin was not significantly superior to 20mg/m(2) cisplatin regarding LRC, MFS and OS. Given the limitations of a retrospective study, 20mg/m(2) cisplatin appeared preferable. The results should be confirmed in a randomized trial.

Do we need 5-FU in addition to cisplatin for chemoradiation of locally advanced head-and-neck cancer?

OBJECTIVES: To compare chemoradiation with cisplatin alone or cisplatin plus 5-FU for locally advanced squamous cell carcinoma of the head-and-neck (SCCHN). MATERIALS AND METHODS: The outcomes of 142 patients who received chemoradiation with cisplatin alone for locally advanced SCCHN were retrospectively compared to 170 patients who received cisplatin plus 5-fluorouracil (5-FU). The outcomes compared included loco-regional control (LRC), metastases-free survival (MFS), overall survival (OS) and adverse events. RESULTS: Although patients who received cisplatin alone had a significantly worse performance status, 81% of these patients completed planned chemotherapy compared to 73% of patients in the cisplatin plus 5-FU group (p=0.18). Radiotherapy breaks >1week were necessary in 14% and 23% of patients, respectively (p=0.09). The 5-year LRC rates were 69% after cisplatin alone and 68% after cisplatin plus 5-FU (p=0.71). The 5-year MFS rates were 72% and 62%, respectively (p=0.37), and 5-year OS rates were 60% and 45%, respectively (p=0.066). On multivariate analysis, cisplatin alone was significantly associated with improved OS (RR 1.35; 95%-CI 1.09-1.69; p=0.006). Nausea/vomiting, pneumonia/sepsis and late adverse events occurred more common in the cisplatin plus 5-FU group. CONCLUSION: Given the limitations of a retrospective study, chemoradiation with cisplatin alone appeared associated with fewer adverse events and better OS than with cisplatin plus 5-FU in patients with locally advanced SCCHN. Thus, 5-FU in addition to cisplatin may be omitted for these patients. A randomized trial is warranted to confirm these findings.

Importance of Chemotherapy and Radiation Dose After Microscopically Incomplete Resection of Stage III/IV Head and Neck Cancer.

AIM: To investigate the importance of chemotherapy and radiation dose after R1 resection of squamous cell carcinoma of the head-and-neck (SCCHN). PATIENTS AND METHODS: One hundred and twenty-two patients receiving radiotherapy alone or with concurrent chemotherapy [cisplatin or cisplatin/5-fluorouracil (5-FU)] were retrospectively analyzed. RESULTS: On multivariate analysis, chemotherapy was significantly associated with improved locoregional control (p=0.048). Three-year locoregional control rates were 61% for those treated without chemotherapy, 83% for those treated with cisplatin and 77% for those treated with cisplatin/5-FU. Radiation doses of 66 and 70 Gy were non-significantly superior to 60-64 Gy (p=0.18). On multivariate analysis, chemotherapy showed a trend for improving survival (p=0.055). Three-year OS rates were 51% for those without chemotherapy, 65% for those treated with cisplatin and 57% for those treated with cisplatin/5-FU. Radiation doses of 66 Gy (3-year survival=61%) and 70 Gy (70%) were superior to 60-64 Gy (25%) (p=0.021). CONCLUSION: Concurrent chemotherapy and a radiation dose of 66 Gy resulted in better outcomes. Cisplatin and cisplatin/5-FU were similarly effective. Radiation doses >66 Gy appear not to be necessary.

Prognostic Factors After Definitive Radio(Chemo)Therapy of Locally Advanced Head and Neck Cancer.

AIM: To identify predictors of locoregional control (LRC) and overall survival (OS) after definitive radio(chemo)therapy for squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Two hundred and seventy-five patients were evaluated; 261 patients received radiochemotherapy with 30-40 mg/m(2) of cisplatin weekly, three courses of cisplatin 100 mg/m(2), two courses of cisplatin 5x20 mg/m(2) or two courses of cisplatin 5×20 mg/m(2)plus 5-fluorouracil. Ten characteristics were analyzed: Pre-radiotherapy hemoglobin, T-/N-category, Karnofsky performance-score (KPS), gender, age, chemotherapy type, tumor site, grading and radiation dose. RESULTS: On multivariate analyses, hemoglobin 12-14 g/dl (p=0.040), lower T-category (p=0.010), lower N-category (p=0.042) and female gender (p=0.006) were predictive of LRC. Hemoglobin >12 g/dl (p=0.020), lower N-category (p<0.001), KPS ≥80 (p<0.001), female gender (p=0.024) and cisplatin 100 mg/m(2) or 5×20 mg/m(2) (p<0.001) were predictors of improved OS. CONCLUSION: Predictors of LRC and OS were identified that can improve personalization of treatment. Since chemotherapy type was associated with OS, studies comparing different regimens are warranted.

Characterization of spontaneous and TGF-ß-induced cell motility of primary human normal and neoplastic mammary cells in vitro using novel real-time technology.

The clinical complications derived from metastatic disease are responsible for the majority of all breast cancer related deaths. Since cell migration and invasion are a prerequisite for metastasis their assessment in patient cancer cells in vitro may have prognostic value for the tumor's metastatic capacity. We employed real-time cell analysis (RTCA) on the xCELLigence DP system to determine in vitro motility of patient-derived primary human breast cancer epithelial cells (HBCEC). Initially, the RTCA assay was validated using established human breast cancer cell lines with either an invasive (MDA-MB-231, MDA-MB-435s) or a non-invasive phenotype (MCF-7, MDA-MB-468), and primary NSCLC cells (Tu459). Previous standard assays of cell migration/invasion revealed that only MDA-MB-231, -435s, and Tu459 cells exhibited spontaneous and TGF-ß1-stimulated migration and invasion through a Matrigel barrier. In the present study, the TGF-ß1-stimulated activities could be blocked by SB431542, a potent kinase inhibitor of the TGF-ß type I receptor ALK5. Application of the RTCA assay to patient-derived tumor cells showed that 4/4 primary HBCEC and primary NSCLC cells, but not normal human mammary epithelial cells (HMEC), displayed high spontaneous migratory and invasive activity which correlated with higher MMP-2 expression and uPA protein levels in HBCEC compared to HMEC. Upon treatment with TGF-ß1, HBCEC exhibited morphologic and gene regulatory alterations indicative of epithelial-to-mesenchymal transition. However, exclusively the invasive but not the migratory activity of HBCEC was further enhanced by TGF-ß1. This indicates the requirement for molecular, e.g. integrin interactions with Matrigel components in HBCEC in order to become responsive to pro-invasive TGF-ß effects. Together, these results show for the first time that tumorigenic HBCEC but not normal HMEC possess a strong basal migratory as well as a basal and TGF-ß1-inducible invasive potential. These findings qualify the RTCA assay as an in vitro migration/invasion testing system for patient-specific primary breast cancer cells.

Interaction of tumor cells with the microenvironment.

Recent advances in tumor biology have revealed that a detailed analysis of the complex interactions of tumor cells with their adjacent microenvironment (tumor stroma) is mandatory in order to understand the various mechanisms involved in tumor growth and the development of metastasis. The mutual interactions between tumor cells and cellular and non-cellular components (extracellular matrix = ECM) of the tumor microenvironment will eventually lead to a loss of tissue homeostasis and promote tumor development and progression. Thus, interactions of genetically altered tumor cells and the ECM on the one hand and reactive non-neoplastic cells on the other hand essentially control most aspects of tumorigenesis such as epithelial-mesenchymal-transition (EMT), migration, invasion (i.e. migration through connective tissue), metastasis formation, neovascularisation, apoptosis and chemotherapeutic drug resistance. In this mini-review we will focus on these issues that were recently raised by two review articles in CCS.