Methylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab.

The use of cetuximab anti-epidermal growth factor receptor (anti-EGFR) antibodies has opened the era of targeted and personalized therapy in colorectal cancer (CRC). Poor response rates have been unequivocally shown in mutant KRAS and are even observed in a majority of wild-type KRAS tumors. Therefore, patient selection based on mutational profiling remains problematic. We previously identified methylglyoxal (MGO), a by-product of glycolysis, as a metabolite promoting tumor growth and metastasis. Mutant KRAS cells under MGO stress show AKT-dependent survival when compared with wild-type KRAS isogenic CRC cells. MGO induces AKT activation through phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin 2 (mTORC2) and Hsp27 regulation. Importantly, the sole induction of MGO stress in sensitive wild-type KRAS cells renders them resistant to cetuximab. MGO scavengers inhibit AKT and resensitize KRAS-mutated CRC cells to cetuximab in vivo. This study establishes a link between MGO and AKT activation and pinpoints this oncometabolite as a potential target to tackle EGFR-targeted therapy resistance in CRC.

An international study comparing conventional versus mRNA level testing (TargetPrint) for ER, PR, and HER2 status of breast cancer.

To compare results from messenger RNA (mRNA)-based TargetPrint testing with those from immunohistochemistry (IHC) and in situ hybridization (ISH) conducted according to local standard procedures at hospitals worldwide. Tumor samples were prospectively obtained from 806 patients at 22 hospitals. The mRNA level of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) was assessed by TargetPrint quantitative gene expression readouts. IHC/ISH assessments were performed according to local standards at the participating hospitals. TargetPrint readout showed a high concordance with IHC/ISH of 95 % (kappa 0.81) for ER, 81 % (kappa 0.56) for PR, and 94 % (kappa 0.76) for HER2. The positive/negative agreement between TargetPrint and IHC for ER, PR, and HER2 was 96 %/87 %, 84 %/74 %, and 74 %/98 %, respectively. The concordance rate in IHC/ISH results between hospitals varied: 88-100 % for ER (kappa 0.50-1.00); 50-100 % for PR (kappa 0.20-1.00); and 90-100 % for HER2 (kappa 0.59-1.00). mRNA readout of ER, PR, and HER2 status by TargetPrint was largely comparable to local IHC/ISH analysis. However, there was substantial discordance in IHC/ISH results between different hospitals. When results are discordant, the use of TargetPrint would improve the reliability of hormone receptor and HER2 results by prompting retesting in a reference laboratory.

Asporin Is a Fibroblast-Derived TGF-ß1 Inhibitor and a Tumor Suppressor Associated with Good Prognosis in Breast Cancer.

BACKGROUND: Breast cancer is a leading malignancy affecting the female population worldwide. Most morbidity is caused by metastases that remain incurable to date. TGF-ß1 has been identified as a key driving force behind metastatic breast cancer, with promising therapeutic implications. METHODS AND FINDINGS: Employing immunohistochemistry (IHC) analysis, we report, to our knowledge for the first time, that asporin is overexpressed in the stroma of most human breast cancers and is not expressed in normal breast tissue. In vitro, asporin is secreted by breast fibroblasts upon exposure to conditioned medium from some but not all human breast cancer cells. While hormone receptor (HR) positive cells cause strong asporin expression, triple-negative breast cancer (TNBC) cells suppress it. Further, our findings show that soluble IL-1ß, secreted by TNBC cells, is responsible for inhibiting asporin in normal and cancer-associated fibroblasts. Using recombinant protein, as well as a synthetic peptide fragment, we demonstrate the ability of asporin to inhibit TGF-ß1-mediated SMAD2 phosphorylation, epithelial to mesenchymal transition, and stemness in breast cancer cells. In two in vivo murine models of TNBC, we observed that tumors expressing asporin exhibit significantly reduced growth (2-fold; p = 0.01) and metastatic properties (3-fold; p = 0.045). A retrospective IHC study performed on human breast carcinoma (n = 180) demonstrates that asporin expression is lowest in TNBC and HER2+ tumors, while HR+ tumors have significantly higher asporin expression (4-fold; p = 0.001). Assessment of asporin expression and patient outcome (n = 60; 10-y follow-up) shows that low protein levels in the primary breast lesion significantly delineate patients with bad outcome regardless of the tumor HR status (area under the curve = 0.87; 95% CI 0.78-0.96; p = 0.0001). Survival analysis, based on gene expression (n = 375; 25-y follow-up), confirmed that low asporin levels are associated with a reduced likelihood of survival (hazard ratio = 0.58; 95% CI 0.37-0.91; p = 0.017). Although these data highlight the potential of asporin to serve as a prognostic marker, confirmation of the clinical value would require a prospective study on a much larger patient cohort. CONCLUSIONS: Our data show that asporin is a stroma-derived inhibitor of TGF-ß1 and a tumor suppressor in breast cancer. High asporin expression is significantly associated with less aggressive tumors, stratifying patients according to the clinical outcome. Future pre-clinical studies should consider options for increasing asporin expression in TNBC as a promising strategy for targeted therapy.

Genomic Grade Index (GGI): feasibility in routine practice and impact on treatment decisions in early breast cancer.

PURPOSE: Genomic Grade Index (GGI) is a 97-gene signature that improves histologic grade (HG) classification in invasive breast carcinoma. In this prospective study we sought to evaluate the feasibility of performing GGI in routine clinical practice and its impact on treatment recommendations. METHODS: Patients with pT1pT2 or operable pT3, N0-3 invasive breast carcinoma were recruited from 8 centers in Belgium. Fresh surgical samples were sent at room temperature in the MapQuant Dx™ PathKit for centralized genomic analysis. Genomic profiles were determined using Affymetrix U133 Plus 2.0 and GGI calculated using the MapQuant Dx® protocol, which defines tumors as low or high Genomic Grade (GG-1 and GG-3 respectively). RESULTS: 180 pts were recruited and 155 were eligible. The MapQuant test was performed in 142 cases and GGI was obtained in 78% of cases (n=111). Reasons for failures were 15 samples with <30% of invasive tumor cells (11%), 15 with insufficient RNA quality (10%), and 1 failed hybridization (<1%). For tumors with an available representative sample (≥ 30% inv. tumor cells) (n=127), the success rate was 87.5%. GGI reclassified 69% of the 54 HG2 tumors as GG-1 (54%) or GG-3 (46%). Changes in treatment recommendations occurred mainly in the subset of HG2 tumors reclassified into GG-3, with increased use of chemotherapy in this subset. CONCLUSION: The use of GGI is feasible in routine clinical practice and impacts treatment decisions in early-stage breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT01916837, http://clinicaltrials.gov/ct2/show/NCT01916837.

Comparison of molecular subtyping with BluePrint, MammaPrint, and TargetPrint to local clinical subtyping in breast cancer patients.

PURPOSE: To compare breast cancer subtyping with the three centrally assessed microarray-based assays BluePrint, MammaPrint, and TargetPrint with locally assessed clinical subtyping using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). METHODS: BluePrint, MammaPrint, and TargetPrint were all performed on fresh tumor samples. Microarray analysis was performed at Agendia Laboratories, blinded for clinical and pathological data. IHC/FISH assessments were performed according to local practice at each institution; estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) assessments were performed on 132 samples, and Ki-67 on 79 samples. RESULTS: The concordance between BluePrint and IHC/FISH subtyping was 94 % for the Luminal-type, 95 % for the HER2-type, and 94 % for the Basal-type subgroups. The concordance of BluePrint with subtyping using mRNA single gene readout (TargetPrint) was 96 % for the Luminal-type, 97 % for the HER2-type, and 98 % for the Basal-type subgroups. The concordance for substratification into Luminal A and B using MammaPrint and Ki-67 was 68 %. The concordance between TargetPrint and IHC/FISH was 97 % for ER, 80 % for PR, and 95 % for HER2. CONCLUSIONS: The implementation of multigene assays such as TargetPrint, BluePrint, and MammaPrint may improve the clinical management of breast cancer patients. High discordance between Luminal A and B substratification based on MammaPrint versus locally assessed Ki-67 or grade indicates that chemotherapy decisions should not be based on the basis of Ki-67 readout or tumor grade alone. TargetPrint serves as a second opinion for those local pathology settings where high-quality standardization is harder to maintain.

Stromal issues in cervical cancer: a review of the role and function of basement membrane, stroma, immune response and angiogenesis in cervical cancer development.

The carcinogenesis of cervical carcinoma implies an intricate interplay of neoplastic, human papillomavirus infected epithelial cells and stromal tissue, in which different factors have distinct but interacting influence. Persistent infection with an oncogenic human papillomavirus type may lead to epithelial dysplasia with progressive severity. To access the adjacent stromal tissue, tumour cells have to breach the basement membrane. The stroma partly controls tumour growth, invasion and angiogenesis. Last but not least there is considerable influence of the immune response. In this review we describe the importance of various stromal factors in carcinogenesis of cervical cancer.

What information do public organizations provide to Belgian women on primary prevention of breast cancer?

Women need to be adequately informed about risk factors and risk reduction strategies for breast cancer to seek optimal primary prevention care. The aim of this study was to determine the amount and content of written information published by Belgian health services and related to primary prevention of breast cancer. We collected all available French language brochures and leaflets related to breast cancer primary prevention and analyzed which risk factors and risk reduction strategies were mentioned. Risk factors and prevention strategies were seldom mentioned. Among the 21 selected leaflets, pertinent to the patient, alcohol was mentioned in eight leaflets; age and genetic predisposition in five; overweight/obesity, personal history of breast cancer, and exercise in four; hormonal treatment in three; family history in two; earlier high-risk benign lesions in one, and ethnicity, breast density, and earlier chest radiation therapy in none. Lifestyle modifications were described in nine, but not one mentioned chemoprevention and risk reduction surgeries. As breast cancer risk reduction now represents an achievable medical objective for women, available written information to women must be improved to help them make an informed choice regarding risk reduction strategies.

Breast cancer seeding associated with core needle biopsies: a systematic review.

BACKGROUND: Preoperative diagnosis has become the standard in breast cancer (BC) management. Recently, ultrasound guided core needle biopsy (CNB) and stereotactic needle core biopsy have replaced fine needle aspiration cytology. Epithelial cell displacement (DE) occurs frequently after core needle biopsy (CNB) for breast cancer diagnosis. AIM: Systematically review (between 1900 and 2008) the clinical significance of DE after CNB in BC patients, and associated risk factors (delay between biopsy and surgery, needle passes, duration of the procedure, tumor size, histological type, tumor grade, margins, type of surgery, and of adjuvant treatment). MATERIALS AND METHODS: We selected 15 studies: 9 assessed the rate of DE after CNB and 6 the impact of CNB on outcome endpoints. RESULTS: We found 3 prospective and 12 retrospective studies. However these had numerous biases such as insufficient power, confounding factors, selection of cases and controls, surrogate endpoints, heterogeneity of measured displacement. Malignant DE on surgical specimens occurred in 22% of the patients. A short interval between CNB and surgical excision increased the risk of detecting displaced cells. No increase in local recurrence was reported after CNB. Contradictory results were found in terms of sentinel node metastases. Only one study evaluated overall survival data and reported no worse survival in patients with preoperative CNB. CONCLUSION: Although data are limited, no increased morbidity has been associated with iatrogenic seeding after CNB.

Combined axillary reverse mapping (ARM) technique for breast cancer patients requiring axillary dissection.

BACKGROUND: The objective of axillary reverse mapping (ARM) is to preserve the main lymphatic chain-with both the nodes and the ducts-in relation to lymphatic arm drainage (LAD) during an axillary dissection (AD). METHODS: From July 2006 to March 2008, 23 patients with stage II or III breast carcinoma requiring an AD underwent an ARM procedure. Identification of the ARM nodes relied on an isotope injection into the web space of the ipsilateral hand. During AD, the radioactive ARM node was localized above the second intercostal brachial nerve, and blue dye was directly injected inside the node to visualize the efferent ducts, constituting the lymphatic ARM chain. The blue and radioactive nodes constituted the ARM sampling, while other nodes were considered part of the AD. RESULTS: Metastatic lymph node involvement was identified in the AD in 20 of 23 patients, with an average of 4.4 (1-11) nodes involved and an average of 10.7 (7-20) lymph nodes removed. The ARM sampling was performed in 21 of 23 patients (91%), with an average of 1.6 ARM nodes removed. In 18 of these 21 patients (86%), the nodes relating to ARM sampling had no metastatic involvement. There were 3 patients (14%) who demonstrated metastatic involvement of the ARM sampling, and all had pN3a (N+ > 9) involvement of the axilla. CONCLUSION: This technique of combined isotopic and blue dye ARM and findings must now be validated. A multicentric study is planned to confirm this data.

Percutaneous tissue acquisition: a treatment for breast cancer? Vacuum-assisted biopsy devices are not indicated for extended tissue removal.

Quite a number of radiologists indicate that complete removal of an imaged lesion in the breast by transdermal tissue acquisition is beneficial for the patient. Although this claim is technologically feasible with the vacuum-assisted biopsy (VAB) devices and, by virtue of a similar technology of aspiration, liposuction, there is no scientific or clinical proof that the extended procedure is indeed valuable for the patient. The optimal treatment of malignant or premalignant lesions remains open surgery with the goal to obtain pathologically free margins whenever possible. Complete removal by imaging is quite different from complete pathological removal. Hence, VAB elimination of suspect or malignant lesions can be considered less optimal and even malpractice in many cases. In addition, there is no evidence that complete removal of benign lesions is good for the patient. When benign lesions can be considered precursors for malignancy, they should be surgically removed as for other premalignant lesions. Most benign lesions can be treated medically as they are usually dispersed in the breast and hormone dependent. The rest of benign breast lesions need removal only to relieve the patient of psychological stress or because of symptoms. Evidence indicates furthermore that increase in cancer risk is related to the number and extent of breast interventions in the past. VAB and other large core biopsy devices remain a useful tool in the diagnosis of breast cancer but not for treatment purposes.