Biological characteristics of interval cancers: a role for biomarkers in the breast cancer screening

Introduction

In a population-based screening program, a percentage of tumors remain undetected; these tumors comprise a heterogeneous group, and they are more likely to have adverse prognostic features. The aim of this study was to identify differences in biological characteristics of screen-detected versus interval breast cancers in a population-based screening program according to molecular subtypes.

Materials and methods

We analyzed the population-based data from a long-running screening program in the area of Florence. Data on screening history and on age, T and N status, grade, histotype, hormonal status and Ki-67 and HER2 expression were retrieved. Subtypes of breast cancer were defined on the expression of ER, PR, Ki-67 and HER2: luminal A if ER/PR+, HER2? and Ki67 <14 %, luminal B (HER2 negative) if ER/PR+, HER2? and Ki67 ≥14 %, luminal B (HER2 positive) if ER/PR+ and HER2+, triple negative if ER/PR?and HER2?, HER2 positive if ER/PR? and HER2+. Association between molecular subtypes and mode of detection will be evaluated by a logistic regression model adjusted for the potential confounding variables.

Results

Information about biomarkers was known for 277 cases, 211 screening-detected and 66 interval cancers. Among interval cases, the triple-negative cancers were more represented than luminal A (OR = 3.52; CI, 1.112–11.13; p = 0.0319), while the proportion of HER2+ was quite similar (OR = 1.57; p = 0.4709).

Conclusion

Although made on a small number of cases, our results suggest a difference in distribution of molecular subtypes according to mode detection, confirming the results of earlier studies.     

Invasive breast cancer: a significant correlation between histological types and molecular subgroups

Introduction

The special types of breast cancer seem to have not only distinct morphological features but also distinct biological features.

Materials and methods

Women diagnosed with a first primary invasive breast cancer in the 2004–2005 period were identified through Tuscan Cancer Registry. Information on age, tumor size, lymph node status, histological type and grade, hormonal receptors, HER2 immunohistochemical expression were collected. Five subtypes were defined: luminal A, luminal B HER2+, luminal B HER2?, triple negative, and HER2 positive. The association between the histological type and molecular subgroups was assessed by a Fisher’s exact test, and a multinomial logistic regression model was used.

Results

Out of 1,487 patients, 34 % were luminal A subtype, 25 % luminal B HER2?, 11 % luminal B HER2+, 19 % triple negative, and 10.2 % HER2+; 58.5 % of cancers were ductal NOS types. With luminal A as reference, histological types distribution was significantly different between the subgroups. Mucinous, tubular, and cribriform histotypes were found among luminal A cancers more than in other subgroups; all medullary carcinomas were triple negative cancers. Pathological stage at diagnosis was more advanced, and histological grade was lower among subgroups other than luminal A.

Conclusions

Significant association between breast cancer histotypes and molecular subgroups was found.     

Get Screened: A Randomized Trial of the Incremental Benefits of Reminders, Recall, and Outreach on Cancer Screening

BACKGROUND

Rates of breast cancer (BC) and colorectal cancer (CRC) screening are particularly low among poor and minority patients. Multifaceted interventions have been shown to improve cancer-screening rates, yet the relative impact of the specific components of these interventions has not been assessed. Identifying the specific components necessary to improve cancer-screening rates is critical to tailor interventions in resource limited environments.

OBJECTIVE

To assess the relative impact of various components of the reminder, recall, and outreach (RRO) model on BC and CRC screening rates within a safety net practice.

DESIGN

Pragmatic randomized trial.

PARTICIPANTS

Men and women aged 50–74 years past due for CRC screen and women aged 40–74 years past due for BC screening.

INTERVENTIONS

We randomized 1,008 patients to one of four groups: (1) reminder letter; (2) letter and automated telephone message (Letter + Autodial); (3) letter, automated telephone message, and point of service prompt (Letter + Autodial + Prompt); or (4) letter and personal telephone call (Letter + Personal Call).

MAIN MEASURES

Documentation of mammography or colorectal cancer screening at 52 weeks following randomization.

KEY RESULTS

Compared to a reminder letter alone, Letter + Personal Call was more effective at improving screening rates for BC (17.8 % vs. 27.5 %; AOR 2.2, 95 % CI 1.2–4.0) and CRC screening (12.2 % vs. 21.5 %; AOR 2.0, 95 % CI 1.1–3.9). Compared to letter alone, a Letter + Autodial + Prompt was also more effective at improving rates of BC screening (17.8 % vs. 28.2 %; AOR 2.1, 95 % CI 1.1–3.7) and CRC screening (12.2 % vs. 19.6 %; AOR 1.9, 95 % CI 1.0–3.7). Letter + Autodial was not more effective than a letter alone at improving screening rates.

CONCLUSIONS

The addition of a personal telephone call or a patient-specific provider prompt were both more effective at improving mammogram and CRC screening rates compared to a reminder letter alone. The use of automated telephone calls, however, did not provide any incremental benefit to a reminder letter alone.     

BCL-2, topoisomerase IIα, microvessel density and prognosis of early advanced breast cancer patients after adjuvant anthracycline-based chemotherapy

Purpose

The aim of this retrospective study was to investigate the effect of B cell lymphoma 2 (BCL-2) expression on disease-free survival (DFS) in 172 early breast cancer (BC) patients treated with anthracycline-based adjuvant chemotherapy. We have reanalysed follow-up data in these patient groups, and therefore, the relation between DFS and other tumour biological features [expression of oestrogen (ER) and progesterone (PgR) receptors, cytokeratin 5/6 (CK5/6), HER2, topoisomerase IIα (TOPOIIα), Ki-67, P53 and microvessel density (MVD)] studied previously (Biesaga et al. in Breast 20(4):338–350, 2011, doi:10.1016/j.breast.2011.03.002, Pathol Oncol Res 18(4): 949–960, 2012, doi:10.1007/s12253-012-9525-9) was also investigated.

Method

Tumour biological features were assessed immunohistochemically on paraffin-embedded sections obtained before treatment from 172 women with BC in stage T1–T2, N1–N2, M0.

Results

In univariate analysis, longer DFS was found for patients having tumours with BCL-2 positivity (P = 0.005), low grade (P = 0.001), ER (P = 0.017) and PgR (P = 0.045) positivity, CK5/6 negativity (P = 0.021), low TOPOIIα expression (P = 0.003) and high MVD (P = 0.000). In multivariate analysis, BCL-2, TOPOIIα and MVD were independent parameters indicating patient prognosis. All patients (n = 18) characterized by tumour BCL-2 positivity, low TOPOIIα expression and high MVD survived 80 months without any evidence of cancer disease, whereas DFS for all other patients was significantly (P = 0.022) lower (76.5 %).

Conclusion

Combination of three parameters: BCL-2 positivity, low topoisomerase IIα expression and high MVD, allows to identify subgroup of BC patients with very good prognosis after adjuvant anthracycline-based chemotherapy.     

CNS metastases of breast cancer show discordant immunohistochemical phenotype compared to primary

Purpose

A challenge in management of breast cancer is the development of brain metastases (BM). Because of improvements in systemic therapy with longer survival of patients with advanced cancer, BM can appear at a time when extra-BM disease is under control. Development of potential preventive strategies are considered, and new developments in systemic approaches to treatment of BM, (cytotoxic/targeted therapy), are explored. In primary breast cancer, ER/PR, HER2 are important biological markers for predicting prognosis and making effective treatment decisions. Known are changes in markers due to metastases, but clinical significance is still unclear. Aim of this retrospective study is to detect changes in immunohistochemical markers of primary and BM, to recognize concordance and impact on prognosis.

Methods

Twenty-one consecutive primary breast cancer patients who developed BM and got surgical resection of BM were enrolled in this study. Matched-pair analyses of primary and BM were done with evaluation by immunostaining (ER, PR, HER2).

Results

Loss of ER/PR receptor positivity was seen in BM compared to primary (ER: 47.6 %/9.0 %; PR: 42.9 %/0 %), respectively. High concordance exists for HER2 status in primary and BM (>80 %). HER2-positive breast cancer had a shorter median interval until appearance of metastases than HER2-negative patients (32.1/39 months; p = n.s.).

Conclusion

With loss of receptor positivity (ER/PR) in BM treatment, decisions are very difficult. High concordance of HER2 status was seen in matched-pair analysis. Further studies had to investigate whether HER3/4 is a possible target for further therapy.     

Clathrin heavy chain is a useful immunohistochemical marker for esophageal squamous intraepithelial neoplasia

Background

Recent advances in the endoscopic diagnosis and treatment of esophageal cancer have facilitated the detection and treatment of minute tumors, necessitating the accurate histopathological diagnosis of early esophageal cancer or precancerous lesions. This study evaluated the usefulness of immunohistochemical analysis (IHC) of clathrin heavy chain (CHC) as a marker for early esophageal cancer.

Methods

The immunoreactivity of CHC was analyzed in 409 esophageal specimens using a tissue array. Immunoreactivities of CHC, p53, and Ki67 were then compared in 44 endoscopically resected specimens.

Results

CHC expression was significantly stronger in the cytoplasm of esophageal squamous cell carcinomas compared with non-tumor specimens in the tissue array. CHC expression in endoscopic specimens was significantly stronger in the cytoplasm of high-grade intraepithelial neoplasias and superficial carcinomas than in benign squamous epithelium and low-grade intraepithelial neoplasias. The sensitivity and specificity of CHC for the diagnosis of esophageal lesions were 75 and 96 %, respectively. These accuracies were comparable with those of p53 (43 and 98 %) and Ki67 (68 and 100 %). In addition, the sensitivity was increased by using a combination of markers as follows: 80 %, CHC + p53; 78 %, CHC + Ki67; 90 %, CHC + p53 + Ki67.

Conclusions

CHC detected by IHC may be a useful marker for the pathological diagnosis of esophageal squamous intraepithelial neoplasia.     

Clinicopathologic characteristics and molecular subtypes of invasive papillary carcinoma of the breast: a large case study

Purpose

Although patients with invasive papillary carcinoma (IPC) often have favorable prognoses, it remains unclear whether this special type of breast cancer represents a distinct morphological entity with its own biological features and clinical behavior distinct from those of invasive ductal carcinoma (IDC) and whether its four molecular subtypes are associated with different prognoses.

Methods

The study is a retrospective analysis of a large patient cohort from a single institution. 284 IPC samples were collected from January 2000 to May 2011. 300 IDC cases were selected randomly from 13,428 cases of IDC during the same periods. We assessed the clinicopathologic characteristics, molecular features, and prognostic value of IPC (n = 284) and compared them to those of IDC (n = 300). Clinicopathologic features and survival status of the four subtypes of IPC were also evaluated.

Results

IPC differed from IDC with respect to age upon diagnosis, tumor grade, lymph node status, and menopausal status (P < 0.05). IPC was associated with a better 5-year overall survival rate (OS) (92.77 vs. 87.95 %) and disease-free survival rate (DFS) (87.95 vs. 80.72 %) than IDC. Tumors of the luminal A subtype had a better 5-year OS (97.78 %) and DFS (95.56 %) than other subtypes.

Conclusions

The biologic behavior of IPC is more favorable to patient outcome than that of IDC. The chance of pure IPC causing death without an intervening event of a different histologic type is exceptionally low. Luminal A subtypes have better outcomes when compared to the other subtypes.     

Receptor change-clinicopathologic analysis of matched pairs of primary and cerebral metastatic breast cancer

Objective

A challenge in the management of breast cancer is development of brain metastases (BM) with limited survival. In primary breast cancer, ER/PR/HER2 are important prognostic markers and are important for making effective treatment decisions. Changes in immunohistochemical markers of metastases are with unclear clinical significance, and mechanisms of resistance to endocrine therapy are an additional challenge. The aim of this retrospective study is to detect changes in immunohistochemical markers of primary and BM and to recognize if receptor change has prognostic impact.

Methods

Twenty-four consecutive primary breast cancer patients who developed BM and got surgical resection of BM were enrolled. Matched pair analyses of primary and BM were done with evaluation by immunostaining (ER/PR/HER2).

Results

A small tumor size, ductal histology and HER2+ tumors were associated with BM. Loss of ER/PR receptor positivity was observed in BM compared to primary (ER: 50.0 %/22.7 %; p = 0.004; PR: 45.8 %/9.1 %; p = n.s), respectively, and almost no change in HER2 status (>80 %; p = 0.012). Patients with ER-/PR-negative or HER2-positive primary had shorter time to recurrence than ER-/PR-positive and HER2-negative patients. Receptor change has negative prognostic impact.

Conclusion

With the observed loss of receptor positivity, therapeutic options are diminished. Identification of patients with a high risk for BM is warranted to evaluate preventive strategies.     

Plasma HER2 amplification in cell-free DNA during neoadjuvant chemotherapy in breast cancer

Purpose

Measurement of human epidermal growth factor receptor 2 (HER2) gene amplification in cell-free DNA (cfDNA) is an evolving technique in breast cancer, enabling liquid biopsies and treatment monitoring. The present study investigated the dynamics of plasma HER2 gene copy number and amplification in cfDNA during neoadjuvant chemotherapy.

Patients and methods

The study included 50 patients from a prospective cohort analyzed during neoadjuvant chemotherapy. Fifty healthy women with no history of cancer served as control group and 15 patients with metastatic breast cancer were used to validate the assay. Total cfDNA and HER2 gene amplification were measured by quantitative real-time polymerase chain reaction.

Results

Plasma HER2 gene copy number (p = 0.794), HER2 gene amplification (p = 0.127) and total cfDNA (p = 0.440) did not differ significantly from the levels in the control group. Eighteen patients (36 %) obtained pathological complete response (pCR). HER2 gene copy number before the operation was significantly higher than the baseline level (p < 0.0001), but there was no difference between patients with and without pCR (p = 0.569). Likewise, there was no difference in plasma HER2 gene amplification between tissue HER2-positive and -negative patients (p = 0.754).

Conclusions

The results indicate that neither total cfDNA nor HER2 gene copy number is elevated in primary breast cancer patients compared to healthy controls. The level of both parameters increased during neoadjuvant chemotherapy, but without any relation to treatment effect. There was no indication of plasma HER2 gene amplification in the HER2-positive patients in the neoadjuvant setting.     

HER2 mRNA Status Contributes to the Discrepancy Between Gene Amplification and Protein Overexpression in Gastric Cancer

Background

Human epidermal growth factor receptor 2 (HER2) is an important proto-oncogene of prognostic use in gastric cancer (GC). Fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) are the main clinical methods of detection of HER2, but consistency between the methods is poor and the cause of the discrepancy is unclear.

Aim

To investigate the involvement of HER2 mRNA status in the disparity between gene amplification and protein overexpression.

Methods

We investigated HER2 gene, mRNA, and protein profiles in gastric precancer and cancer tissues by use of the molecular approaches FISH, real-time polymerase chain reaction, and IHC. The relationships between HER2 and matrix metalloproteinase 9 (MMP9) and Smad7 expression were analyzed and the involvement of HER2 in the interaction between tumor cells and lymphocytes was investigated by coculturing GC cell lines with peripheral blood mononuclear cells (PBMCs).

Results

HER2 protein expression was significantly increased in cancer compared with precancer (P = 0.003), and the corresponding mRNA levels were significantly lower in precancer and cancer tissues than in normal tissues (κ = 0.290, P = 0.025). HER2 mRNA levels were significantly higher in tumor than in peritumor tissue (P = 0.028), and were positively correlated with MMP9 and Smad7 mRNA levels in tumor tissues. HER2 mRNA expression in GC cell lines was increased by coculture with PBMCs.

Conclusions

Different HER2 mRNA profiles, possibly in relation to contact between tumor cells and lymphocytes, might help to explain the discrepancy between gene amplification and protein overexpression results.     

Effectiveness of neoadjuvant trastuzumab and chemotherapy in HER2-overexpressing breast cancer

Purpose

Trastuzumab and chemotherapy is the current standard of care in HER2+ early or locally advanced breast cancer, but there are scanty literature data of its real world effectiveness.

Methods

We retrospectively reviewed 205 patients with HER2+ breast cancer diagnosed in 10 Italian Medical Oncology Units between July 2003 and October 2011. All patients received neoadjuvant systemic therapy (NST) with trastuzumab in association with chemotherapy. Many different chemotherapy regimens were used, even if 90 % of patients received schemes including anthracyclines and 99 % received taxanes. NST was administered for more than 21 weeks (median: 24) in 130/205 (63.4 %) patients, while trastuzumab was given for more than 12 weeks (median: 12 weeks) in 101/205 (49.3 %) patients. pCR/0 was defined as ypT0+ypN0, and pCR/is as ypT0/is+ypN0.

Results

pCR/0 was obtained in 24.8 % and pCR/is in 46.8 % of the patients. At multivariate logistic regression, nonluminal/HER2+ tumors (P < 0.0001) and more than 12 weeks of neoadjuvant trastuzumab treatment (P = 0.03) were independent predictors of pCR/0. Median disease-free survival (DFS) and cancer-specific survival (CSS) have not been reached at the time of analysis. At multivariate analysis, nonluminal/HER2+ subclass (DFS: P = 0.01 and CSS: P = 0.01) and pathological stage II–III at surgery (DFS: P < 0.0001 and CSS: P = 0.001) were the only variables significantly associated with a worse long-term outcome.

Conclusions

Our data set the relevance of molecular subclasses and residual tumor burden after neoadjuvant as the most relevant prognostic factors for survival in this cohort of patients.     

IMP3 expression in gastric cancer: association with clinicopathological features and HER2 status

Background

The aim of this study was to evaluate the expression of IMP3, an independent poor prognostic factor for many cancers, and its association with clinicopathological features and HER2 status.

Methods

Gastrectomy specimens from 106 patients were evaluated by immunohistochemistry and fluorescence in situ hybridization.

Results

HER2 overexpression was found in 4.71 % of the samples. A negative association was observed between HER2 overexpression and grade of differentiation. No association was observed between HER2 overexpression and status of surgical margins, vascular invasion, perineural invasion, nodal metastasis and depth of invasion. Among all specimens of gastric cancer, 67.92 % were positive for IMP3. Expression of IMP3 was significantly higher in specimens with vascular invasion, perineural invasion, nodal metastasis and higher depth of invasion. HER2 overexpression was detected in only 5.55 % of IMP3 positive specimens.

Conclusions

IMP3 expression was frequently observed in gastric cancer and was associated with poor prognostic clinicopathological features. A survival benefit with HER2 therapy should be expected for the minority of patients with IMP3 positive specimens. Studies should be conducted to evaluate the response to HER2 therapy of gastric cancer expressing IMP3.     

Are Biopsy Specimens Predictive of HER2 Status in Gastric Cancer Patients?

Background

Trastuzumab has been recently proposed as a treatment for patients with HER2-positive advanced/metastatic gastric cancer (GC). Since most patients have inoperable disease at diagnosis, accurate assessment of HER2 status on biopsy specimens is essential to select the patients who may benefit from therapy.

Aim

The aim of this study is to establish whether HER2 status assessed on biopsy material could be reliable for treatment decisions using anti-HER2 agents.

Methods

The HER2 status was evaluated in 61 consecutive pairs of biopsy and surgical GCs samples by immunohistochemistry and chromogenic in situ hybridization.

Results

The overall concordance of HER2 status between biopsy and surgical specimens was 91.8 % with a predictive positive value of 71.4 % and a negative predictive value of 94.4 %. Of five discordant cases, there were three negative and two positive false biopsy results. All the false negative cases showed heterogeneous expression of HER2 protein in surgical samples. Two cases displayed overexpression of the receptors without corresponding gene amplification.

Conclusions

HER2 status as evaluated on biopsy samples is a fairly good predictor of HER2 status of surgically-excised GCs. The most important influence for discordant results is tumor heterogeneity. However, HER2 overexpression, especially without coexisting gene amplification, may only be a temporary change in a tumor population. This may explain those cases with positive HER2 evaluation on biopsy material and a negative result on corresponding surgical specimen.     

The actual scenario of neoadjuvant chemotherapy of breast cancer in developing country: a report of 80 cases of breast cancer from a tertiary cancer center in India

Background

Preoperative or neoadjuvant chemotherapy is an option in patients with large operable breast cancer to facilitate the breast conservation and to downstage the disease to make inoperable breast cancer to operable one. It is also called the window of opportunity; it provides a unique opportunity to derive biological information related to tumor response. Neoadjuvant chemotherapy has been compared with standard, postoperative adjuvant chemotherapy with goals of improving survival and facilitating local therapies. Unfortunately, neoadjuvant chemotherapy does not seem to improve overall survival. There is a lack of data from India regarding the neoadjuvant chemotherapy. The present study was carried out to assess the response to neoadjuvant chemotherapy in breast cancer.

Materials and methods

We retrospectively analyzed the records of patients who were started on neoadjuvant chemotherapy (NACT) at our center for 1 year (August 2012 to July 2013). Case files were thoroughly reviewed, and patient’s characteristics (age, pre-/postmenopausal status, family history of breast/ovarian/other cancer), mode of detection, treatment, and histological features were analyzed.

Results

Out of 322 patients with breast cancer registered in our institute, 80 patients received neoadjuvant chemotherapy. Median age was 45 years. The most common presentation was left-sided breast lump (Lt > Rt) with a median duration of symptoms was 4 months. Postmenopausal patients (53.75 %) were more than premenopausal (46.25 %). Seventy-two patients were stage III and 8 were stage II disease. Bilateral breast cancer was seen in 8 patients. Most common histological type was invasive ductal carcinoma (95 %). Estrogen receptor (ER) and/or progesterone (PR) positive were seen in 47 (58.75 %) patients. Ten patients were HER2 positive and ER/PR negative, and 5 patients were triple positive. Triple-negative patients were 22 (27.5 %). The most common neoadjuvant chemotherapy protocol used was FEC. Clinical response before surgery was CR 13 %, PR 68.68 %, stable disease 11.62 %, and progressive disease 4.65 %. Pathological CR was seen in 6.9 % of tumors. Nodal status at surgery was ypN0-40 %, ypN1-28. 5 %. ypN2-27 %, and ypN3-4.28 %.

Conclusion

In a population of predominantly locally advanced patients, NACT with anthracyclines yielded pCR rates comparable to published studies. There were a high proportion of HER2-positive patients, most of whom could not receive anti-HER2 therapy due to financial reasons.     

Liver resection in selected patients with metastatic breast cancer: a single-centre analysis and review of literature

Purpose

Despite the development of modern chemotherapeutics and target-specific drugs as well as improved surgical techniques, prognosis of metastatic breast cancer remains poor. Only a small number of selected patients will be eligible for liver resection and/or alternative metastatic ablation. Data on prognostic factors for patients with surgically resectable liver metastases of breast cancer are scarce at present.

Methods

From 1997 to 2010, 50 patients with hepatic metastases of breast cancer have undergone laparotomy with the intention to undergo a curative liver resection at our institution. Data from these patients were collected in a prospectively maintained standardized liver resection data base.

Results

Liver resection was performed in 34 patients. Resection margins were clear in 21 cases (R0). Nine patients lived for more than 60 months after liver resection. The observed 5-year survival rate was 21 % for all 50 patients, 28 % for resected patients and 38 % after R0-resection. On univariate analysis, survival rates of the resected patients were statistically significantly influenced by R-classification, age, extrahepatic tumour at the time of liver resection, size of metastases and HER2 expression of liver metastases. Multivariate analysis revealed absence of HER2 expression, presence of extrahepatic tumour and patient’s age ≥50 years as independent factors of poor prognosis.

Conclusions

Breast cancer patients younger than 50 years with technically resectable hepatic metastases, minimal extrahepatic tumour and positive HER2 expression appear to be suitable candidates for liver resection with curative intent. An aggressive multi-disciplinary management of those patients including surgical treatment may improve long-term survival.     

XPC gene variants: a risk factor for recurrence of urothelial bladder carcinoma in patients on BCG immunotherapy

Purpose

To investigate the association between two Xeroderma pigmentosum group C polymorphism (XPC Lys939Gln and insertion/deletion PAT ?/+ in intron 9) and bladder cancer (BC) susceptibility.

Materials and methods

Genotyping was performed in 208 BC patients and 245 controls by PCR–RFLP method.

Results

XPC PAT +/+ genotype was associated with elevated risk of BC (p = 0.021, OR = 2.49). XPC Lys939Gln AC + CC genotype was significantly associated with risk in invasive stage of BC (p = 0.041, OR = 2.52). Haplotype analysis revealed that variant genotypes C of XPC Lys939Gln and + of PAT, C+ were significantly associated with risk of BC (p = 0.004, OR = 1.70). The CC genotype of Lys939Gln was associated with high risk for recurrence in BCG-treated patients (HR = 3.21, p = 0.036) thus, showing reduced recurrence-free survival (AC + CC/AA = 36/60 months; log rank p = 0.045).

Conclusion

Polymorphisms and haplotypes in XPC appear to influence susceptibility to BC risk. The variant C allele at Lys939Gln may be responsible for early recurrence in BCG-treated patients.     

Predictive value of sphingosine kinase 1 expression in neoadjuvant treatment of breast cancer

Purpose

Sphingolipids play important roles in apoptosis and cell proliferation. Sphingosine kinase 1 (SphK1) expression has a prognostic impact in primary breast cancer, but its predictive value is currently unknown.

Methods

A total of 112 breast cancer specimens from a prospective neoadjuvant chemotherapy trial (GeparDuo) were studied. Using tissue microarrays of pre-treatment core cut biopsies, we determined the expression of SphK1 by immunohistochemistry. The upper quartile of the cohort according to an immune reactive score of SphK1 was used as cutoff for high expression.

Results

We observed a larger number of samples with high SphK1 expression among ER-negative cancers (36.8 vs. 20.5 % among ER-positive cancers; Fisher test p = 0.073). Eighteen of the 112 patients demonstrated a pathological complete response. A significant predictive value for pathological complete response was observed for ER negativity (p = 0.003), young age (p = 0.037), and high tumor grade (p = 0.049). An increased pCR rate was observed in tumors with high SphK1 expression within the luminal subtype (26.7 vs. 5.8 %; Fisher test p = 0.040). No significant difference in survival was detected according to SphK1 expression.

Conclusions

Our results suggest that SphK1 may be a predictive factor for pCR after neoadjuvant treatment in luminal type breast cancers and warrants further investigation.     

C-ERC/mesothelin provokes lymphatic invasion of colorectal adenocarcinoma

Background

Lymph node metastasis is a key event of colorectal cancer (CRC) progression. Mesothelin is expressed in various types of malignant tumor and associated with an unfavorable prognosis. The full-length mesothelin (Full-ERC) is cleaved by protease into membrane-bound C-ERC/mesothelin and N-ERC/mesothelin which is secreted into the blood. The aim of this study was to examine the biological role of mesothelin in CRC by clinicopathological analysis and in vitro lymphatic invasion assay.

Methods

Ninety-one cases of CRC specimens were immunohistochemically examined and the localization of mesothelin in luminal membrane and/or cytoplasm was also evaluated. Lymphatic invasion assay was also performed using the human CRC cell line, WiDr, which was transfected with Full-, N- and C-ERC/mesothelin expression plasmids (Full-WiDr, N-WiDr and C-WiDr).

Results

Immunohistochemically, “luminal membrane positive” of mesothelin was identified in 37.4 %, and correlated with lymphatic permeation and lymph node metastasis, but not with patients’ prognosis. Interestingly, among the patients with lymph node metastasis (N = 38), “luminal membrane positive” of mesothelin significantly correlated with unfavorable patients’ outcome. In addition, lymphatic invasion assay revealed that Full-WiDr and C-WiDr more significantly invaded human lymphatic endothelial cells than the Mock-WiDr (P < 0.01).

Conclusion

The luminal membrane expression of mesothelin was associated with unfavorable prognosis of CRC patients with lymph node metastasis. Moreover, this is the first report to prove the biological function of C-ERC/mesothelin associated with lymphatic invasion of cancer in vitro.     

Individual risk assessment in bladder cancer patients based on a multi-marker panel

Purpose

To investigate whether a combined application of urine cytology (CYT) and molecular markers for bladder cancer (BC) can predict tumor aggressiveness.

Methods

The study comprised 2,113 patients who underwent urethrocystoscopy and transurethral resection of the bladder. CYT, fluorescence in situ hybridization (FISH), immunocytology (uCyt+) and nuclear matrix protein 22 test (NMP22-ELISA) were performed. Results of the individual tests and of a multi-marker panel were correlated with pT-stages and tumor grades.

Results

Five hundred and two of 2,113 (23.8 %) patients had BC. False-negative test rates of CYT (p < 0.001), FISH (p = 0.01) and NMP22-ELISA (p = 0.05) were lower in patients with muscle-invasive BC compared with patients with non-muscle-invasive BC. Furthermore, false-negative rates of CYT (p < 0.001), FISH (p = 0.0002) and NMP22-ELISA (p < 0.001) were lower in patients with G3/CIS compared with patients with G1–G2 BC. In patients with evidence of tumor in urethrocystoscopy, the presence of simultaneously positive CYT and NMP22 was associated with a 20-fold risk for G3/CIS (p < 0.0001).

Conclusions

This is the first study investigating the combined use of four urine markers in addition to cystoscopy to predict tumor aggressiveness. Our results indicate that combined application of urine markers as an adjunct to cystoscopy may facilitate identification of patients harboring high-grade tumors.     

Hepatitis B and immigrants: a SIMIT multicenter cross-sectional study

Background

The continuing migration of individuals from geographic areas with high/medium endemicity has determined the arrival of new chronic hepatitis B virus (HBV) carriers in Italy. The magnitude of this phenomenon and clinical/virological features of HBsAg-positive migrants remain not very well defined.

Aims

To evaluate the proportion of HBsAg-positive immigrants enrolled in this multicenter Società Italiana di Malattie Infettive e Tropicali (SIMIT) cross-sectional study and to compare the characteristics of chronic hepatitis B infection in migrants to those of Italian carriers.

Methods

From February 1 to July 31 2008, anonymous data were obtained from all HBsAg-positive patients aged ≥18 years observed at 74 Italian centers of infectious diseases.

Results

Of the 3,760 HBsAg-positive subjects enrolled, 932 (24.8 %) were immigrants, with a prevalent distribution in central to northern Italy. The areas of origin were: Far East (37.1 %), Eastern Europe (35.4 %), Sub-Saharan Africa (17.5 %), North Africa (5.5 %), and 4.5 % from various other sites. Compared to Italian carriers, migrants were significantly younger (median age 34 vs. 52 years), predominantly female (57.5 vs. 31 %), and most often at first observation (incident cases 34.2 vs. 13.3 %). HBeAg-positives were more frequent among migrants (27.5 vs. 14 %). Genotype D, found in 87.8 % of Italian carriers, was present in only 40 % of migrants, who were more frequently inactive HBV carriers, with a lower prevalence of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Only 27.1 % of migrants received antiviral treatment compared to 50.3 % of Italians.

Conclusions

Twenty-five percent of all HBV carriers examined at Italian centers was composed of immigrants with demographic, serological, and virological characteristics that differed from those of natives and appeared to have an inferior access to treatment.