Diagnostic significance and cytological features of NUT carcinoma by EBUS-FNA, a case report and literature review.

Cytomorphological features of NUT carcinoma include sheets or discrete nests of primitive, monotonous, round to oval shaped tumour cells with high N/C ratio and brisk mitotic figures. Abrupt squamous differentiation might be a diagnostic hint. More than 50% positivity of NUT immunohistochemistry staining is diagnostic. NUT carcinoma represents a poorly differentiated malignancy by extremely aggressive clinical course and poor prognosis. It frequently manifests in midline organs, notably in the mediastinum and lung. The rising preferences for utilizing the EBUS-FNA procedure in diagnosing thoracic and lung lesions stems from its high diagnostic yield. Hence, recognizing the cytomorphological features of NUT carcinoma is crucial for timely treatment and improved patient survival.

When molecular outsmarts morphology: Malignant ossifying fibromyxoid tumors masquerading as osteosarcomas, including a novel CREBZF::PHF1 fusion.

We present two cases of malignant ossifying fibromyxoid tumor (OFMT) which eluded diagnosis due to compelling clinicopathologic mimicry, compounded by similarly elusive underlying molecular drivers. The first is of a clavicle mass in a 69 year-old female, which histologically showed an infiltrative nested and trabeculated proliferation of monomorphic cells giving rise to scattered spicules of immature woven bone. Excepting SATB2 positivity, the lesion showed an inconclusive immunoprofile which along with negative PHF1 FISH led to an initial diagnosis of high-grade osteosarcoma. Next generation sequencing (NGS) revealed a particularly rare CREBBP::BCORL1 fusion. The second illustrates the peculiar presentation of a dural-based mass in a 52 year-old female who presented with neurologic dyscrasias. Sections showed a sheeted monotonous proliferation of ovoid to spindle cells, but in contrast to Case #1, the tumor contained an exuberance of reticular osteoid and woven bone deposition mimicking malignant osteogenic differentiation. NGS showed a novel CREBZF::PHF1 fusion. Both tumors recurred locally less than 1 year post-operatively. As such we reiterate that careful morphologic examination is axiomatic to any diagnosis in our discipline, but this paradigm must shift to recognize that molecular diagnostics can provide closure where traditional tools have notable limitations.

Expression of high molecular weight cytokeratin-A novel feature of aggressive and innate hormone-refractory prostatic adenocarcinoma.

BACKGROUND: Castration-resistance is common in advanced prostatic adenocarcinomas (PACs) treated with androgen deprivation therapy (ADT) and usually occurs after 2 years following treatment. A minority of PACs confer innate ADT resistance without prior hormonal treatment. The expression of HMWCK in PAC cells has not been studied. This study aimed to investigate the clinicopathologic and genomic features of HMWCK-expressing PACs and the relationship to ADT resistance. METHODS: A total of 469 PACs were studied for HMWCK expression (39 postradiotherapy, 57 post-ADT, 373 treatment-naïve PACs). Clinicopathologic correlations of the HMWCK expression with tumor grade groups, specific tumor morphologies, tumor stages and disease recurrence/persistence/progression were performed. Five HMWCK+ PACs were also sequenced for genetic alterations. RESULTS: Thirty one of the 469 cases (6.6%) showed variable HMWCK+ PAC. The HMWCK+ PAC often focally presented in the tumor and vast majority were associated with high Gleason scores and unfavorable growth patterns (cribriform, comedo-necrosis, and intraductal carcinoma) as well as high tumor stages. A small percentage of the HMWCK+ PCA (2/31, 6.5%) presented with frank squamous histomorphology. Vast majority (22/31, 87%) had no history of prior ADT. The HMWCK+ PAC all displayed diminished to lost expression of AR/NKX3.1. Most of the cases progressed within 12 months of ADT or disease persisted despite ADT. Of the 5 HMWCK+ PACs subjected to gene sequencing, 4 presented with PTEN/PI3K/MAPK pathway alterations. CONCLUSION: The study demonstrated HMWCK+ PAC to be a novel type of innate ADT-resistant PAC. Overexpression of HMWCK in PAC can be potentially used as a surrogate biomarker for aggressive and innate hormone-refractory PACs. The genetic alterations imply potential therapeutic implications of PI3K/MAPK inhibitors in the treatment of these deadly diseases.

Prognostic value of cribriform size, percentage, and intraductal carcinoma in Gleason score 7 prostate cancer with cribriform Gleason pattern 4.

Cribriform Gleason pattern 4 (CGP4) is an indicator of poor prognosis in Gleason Score 7 prostate cancer; however, the significance of the size and percentage of this pattern and the presence of concomitant intraductal carcinoma (IDC) in these patients is unclear. To study the significance of these parameters in radical prostatectomy specimens, 165 cases with CGP4 were identified and reviewed (2017-2019). The size and percentage cribriform pattern and presence of IDC were noted and correlated with adverse pathological features and biochemical recurrence (BCR)-free survival. On review, 156 cases had CGP4 (Grade Group 2: 87 and Grade Group 3: 69). Large cribriform pattern and cribriform percentage of >20% showed significant association with extraprostatic extension, surgical margin positivity, and presence of IDC, whereas the presence of IDC was associated with all the analyzed adverse pathological features. BCR was seen in 22 of 111 (20%) patients after a median follow-up of 11 months, and of these, 21 had large cribriform pattern. On univariate analysis, all parameters had significant predictive values for BCR-free survival except for tertiary Gleason pattern 5. On multivariate analysis, while >20% cribriform pattern was trending to be an independent predictor, only lymphovascular invasion was statistically significant. Large cribriform pattern, >20% cribriform, and presence of IDC are additional pathologic parameters of potential value in identifying patients with high risk for early BCR.

Testicular Carcinoid Tumor in a Patient With Contralateral Classic Seminoma.

Testicular neuroendocrine tumors, commonly called carcinoid, are extremely rare and account for less than 1% of all testicular neoplasms. The most common type is primary carcinoid followed by testicular metastasis from another primary and rarely carcinoid within a testicular teratoma. To date, less than 25 cases of carcinoid associated teratomas have been reported in the literature. Herein, we present a unique case of testicular carcinoid tumor arising in association with mature teratoma in a patient with contralateral classic seminoma.

Comparative expression of immunohistochemical biomarkers in cribriform and pattern 4 non-cribriform prostatic adenocarcinoma.

The morphology of Gleason 4 prostate cancer (PCa) can be subdivided into cribriform and non-cribriform patterns. A large body of evidence has shown that pattern 4 cribriform PCa (especially non-glomeruloid type) is associated with adverse pathologic features and clinical outcomes compared with non-cribriform pattern 4 PCa. The underlying mechanisms for the aggressiveness of cribriform PCa are not fully understood. The aim of this study is to compare the immunohistochemical expression of various biomarkers and to determine the potential proteins that may account for their biologic and clinical differences. A total of 14 biomarkers were studied. The number of non-glomeruloid cribriform PCa cases studied for each biomarker ranged from 18 to 74 and the number of non-cribriform pattern 4 PCa studied for each biomarker ranged from 29 to 112. We demonstrated that, compared with non-cribriform Gleason pattern 4 PCa, EGFR was significantly upregulated and standard CD44 (CD44s) was significantly downregulated in cribriform PCa; no significant differences were found in the expression of AR, NKX3.1, ERG, EZH2, p53, Rb, C-Myc, BCL2, p16, CyclinD1, Her2/Neu, and Synaptophysin between these two groups of pattern 4 PCa. The study also showed, compared to non-cribriform PCa, cribriform PCa presented with significantly higher serum PSA and more advanced tumor stage. The significant overexpression of EGFR and downregulation of CD44s in non-glomeruloid cribriform PCa may, at least, partly explain the unfavorable pathology and clinical results for this growth pattern. Given that EGFR targeted inhibitors are now available, the findings may also have significant therapeutic implications.

Stratification of Atypical Intraepithelial Prostatic Lesions Based on Basal Cell and Architectural Patterns.

OBJECTIVES: High-grade prostatic intraepithelial neoplasia (HPIN) and atypical cribriform lesion of the prostate are considered the precursors or associators of invasive prostate cancer (iPCa). Given loss of basal cells being the hallmark of iPCa, we hypothesized that a subset of these atypical intraepithelial lesions (AILs) with sparse basal cells can be classified as prostatic intraepithelial carcinoma (PIC) with frequent iPCa association and that different morphologic patterns of PIC are associated with specific Gleason (G) patterns and scores for iPCa. METHODS: We stratified 153 foci of AILs from 110 patients based on the integrity of the basal cell layer and architectural patterns and their association with iPCa. RESULTS: We demonstrated that AILs could be stratified into usual HPIN (intact basal cell layer and simple patterns) with low-risk of iPCa association and PIC (sparse basal cell layer) with high risk of iPCa association. Furthermore, PIC could be divided into low-grade (simple patterns and associated with G3 and G3/4 iPCa) and high-grade PIC (complex patterns and associated with G4 and G3/4/5 iPCa). CONCLUSIONS: Such stratification is of great clinical significance and instrumental to clinical patient management. It not only increases the predictability of AILs for iPCa but also accommodates a clinical scenario for lesions with features of intraductal carcinoma when iPCa is not found, particularly in biopsies.

ZBTB16: A new biomarker for primitive neuroectodermal tumor element / Ewing sarcoma.

Primitive neuroectodermal tumor (PNET) traditionally encompasses two different classes of tumors with similar morphology - PNET of the peripheral nervous system (pPNET) and PNET of the central nervous system (cPNET). The latter also includes germ cell tumor-derived PNET (gPNET). There are currently no specific markers for gPNET. This study seeks to investigate the expression of ZBTB16 in PNET and other small round blue cell tumors as well as its potential diagnostic utility. Immunohistochemical expression of the ZBTB16 was studied in a total of 27 PNETs (12 pPNETs, 8 cPNETs, 3 primary testicular gPNETs, and 4 metastatic gPNETs) and 38 small round blue cell tumors. Positive expression for ZBTB16 was seen diffusely in 9/12 (75%), moderately in 2/12 (17%) and focally in 1/12 (8%) of pPNETs, diffusely in 3/7 (43%) and moderately in 4/7 (57%) of gPNETs, and diffusely in 2/8 (25%), moderately in 2/8 (25%) and focally in 4/8 (50%) of cPNETs. Whereas, all of the 38 non-PNET small round blue cell tumors were nonreactive. The results suggest that ZBTB16 is a highly sensitive and specific biomarker for both pPNET and gPNET/cPNET. ZBTB16 effectively differentiates PNETs from other small round blue cell tumor mimics, including the two most common germ cell tumor-derived somatic malignancies - rhabdomyosarcoma and nephroblastoma. Of note, compared to the expression of ZBTB16 in pPNET/Ewing sarcoma and gPNET, the expression of ZBTB16 in cPNET was more variable, which appears consistent with the heterogeneity of cPNET. The close proximity of ZBTB16 and FLI-1 genes on chromosome 11q may explain the overexpression of ZBTB16 in PNET, especially in pPNET with t(1122) translocation.

Long term oncologic outcome in patients with bladder cancer after radical cystectomy: Impact of carcinoma in situ in the era of neoadjuvant chemotherapy.

PURPOSE: To assess the impact of carcinoma in situ (CIS) on oncologic outcomes in patients who underwent radical cystectomy, with a focus on those who received neoadjuvant chemotherapy (NAC) including patients with down-staging to ≤ pT1cancer after chemotherapy. MATERIALS AND METHODS: All patients who underwent radical cystectomy for urothelial cancer with curative intent from 1985 to 2011 were included. The impact of CIS on recurrence free and overall survival (OS) was assessed in the whole cohort and a subgroup who received NAC as well as those with response to chemotherapy and down-staging to ≤ pT1. RESULTS: A total of 2518 patients with a median follow-up period of 9 years were included. Among all, 1397 (55.5%) had concomitant CIS on final pathology. CIS was associated with high risk pathologic features including high-grade disease, multifocality, and nodal involvement as well as worse recurrence free survival (RFS) with no impact on OS. We did not find a significant association between CIS and oncologic outcomes in a subset of patients who received NAC including those with down-staging to ≤ pT1 disease. In multivariate analysis, CIS had no association with either recurrence free or OS. CONCLUSIONS: Concomitant CIS in radical cystectomy specimens is associated with decreased RFS; however, in multivariate analysis, it was not an independent predicting factor of oncologic outcomes. Moreover, the impact of CIS on oncologic outcomes in a subset of patients who received NAC was insignificant.

Novel Gene Expression Signature Predictive of Clinical Recurrence After Radical Prostatectomy in Early Stage Prostate Cancer Patients.

BACKGROUND: Current clinical tools have limited accuracy in differentiating patients with localized prostate cancer who are at risk of recurrence from patients with indolent disease. We aimed to identify a gene expression signature that jointly with clinical variables could improve upon the prediction of clinical recurrence after RP for patients with stage T2 PCa. METHODS: The study population includes consented patients who underwent a radical retropubic prostatectomy (RP) and bilateral pelvic lymph node dissection at the University of Southern California in the PSA-era (1988-2008). We used a nested case-control study of 187 organ-confined patients (pT2N0M0): 154 with no recurrence ("controls") and 33 with clinical recurrence ("cases"). RNA was obtained from laser capture microdissected malignant glands representative of the overall Gleason score of each patient. Whole genome gene expression profiles (29,000 transcripts) were obtained using the Whole Genome DASL HT platform (Illumina, Inc). A gene expression signature of PCa clinical recurrence was identified using stability selection with elastic net regularized logistic regression. Three existing datasets generated with the Affymetrix Human Exon 1.0ST array were used for validation: Mayo Clinic (MC, n = 545), Memorial Sloan Kettering Cancer Center (SKCC, n = 150), and Erasmus Medical Center (EMC, n = 48). The areas under the ROC curve (AUCs) were obtained using repeated fivefold cross-validation. RESULTS: A 28-gene expression signature was identified that jointly with key clinical variables (age, Gleason score, pre-operative PSA level, and operation year) was predictive of clinical recurrence (AUC of clinical variables only was 0.67, AUC of clinical variables, and 28-gene signature was 0.99). The AUC of this gene signature fitted in each of the external datasets jointly with clinical variables was 0.75 (0.72-0.77) (MC), 0.90 (0.86-0.94) (MSKCC), and 0.82 (0.74-0.91) (EMC), whereas the AUC for clinical variables only in each dataset was 0.72 (0.70-0.74), 0.86 (0.82-0.91), and 0.76 (0.67-0.85), respectively. CONCLUSIONS: We report a novel gene-expression based classifier identified using agnostic approaches from whole genome expression profiles that can improve upon the accuracy of clinical indicators to stratify early stage localized patients at risk of clinical recurrence after RP. Prostate 76:1239-1256, 2016. © 2016 Wiley Periodicals, Inc.

Double-Blind Phase III Randomized Trial of the Antiprogestin Agent Mifepristone in the Treatment of Unresectable Meningioma: SWOG S9005.

PURPOSE: Progesterone receptors are expressed in approximately 70% of meningiomas. Mifepristone is an oral antiprogestational agent reported to have modest activity in a phase II study. This multicenter, prospective, randomized, placebo-controlled phase III trial conducted by SWOG was planned to define the role of mifepristone in the treatment of unresectable meningioma. PATIENTS AND METHODS: Eligible patients were randomly assigned to receive either mifepristone or placebo for 2 years unless disease progressed. Patients who were stable or responding to protocol therapy after 2 years had the option to continue with the same blinded therapy. Serial follow-up allowed assessment of efficacy and toxicity. Time to treatment failure and overall survival were ascertained for all randomly assigned patients. On progression, patients receiving placebo could cross over and receive active drug. RESULTS: Among 164 eligible patients, 80 were randomly assigned to mifepristone and 84 to placebo. Twenty-four patients (30%) were able to complete 2 years of mifepristone without disease progression, adverse effects, or other reasons for discontinuation. Twenty-eight patients (33%) in the placebo arm completed the 2-year study. There was no statistical difference between the arms in terms of failure-free or overall survival. CONCLUSION: Long-term administration of mifepristone was well tolerated but had no impact on patients with unresectable meningioma.

Whole lesion quantitative CT evaluation of renal cell carcinoma: differentiation of clear cell from papillary renal cell carcinoma.

PURPOSE: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell cancer (RCC), followed by papillary RCC (pRCC). It is important to distinguish these two subtypes because of prognostic differences and possible changes in management, especially in cases undergoing active surveillance. The purpose of our study is to evaluate the use of voxel-based whole-lesion (WL) enhancement parameters on contrast enhanced computed tomography (CECT) to distinguish ccRCC from pRCC. MATERIALS AND METHODS: In this institutional review board-approved study, we retrospectively queried the surgical database for post nephrectomy patients who had pathology proven ccRCC or pRCC and who had preoperative multiphase CECT of the abdomen between June 2009 and June 2011. A total of 61 patients (46 with ccRCC and 15 with pRCC) who underwent robotic assisted partial nephrectomy for clinically localized disease were included in the study. Multiphase CT acquisitions were transferred to a dedicated three-dimensional workstation, and WL regions of interest were manually segmented. Voxel-based contrast enhancement values were collected from the lesion segmentation and displayed as a histogram. Mean and median enhancement and histogram distribution parameters skewness, kurtosis, standard deviation, and interquartile range were calculated for each lesion. Comparison between ccRCC and pRCC was made using each imaging parameter. For mean and median enhancement, which had a normal distribution, independent t-test was used. For histogram distribution parameters, which were not normally distributed, Wilcoxon rank sum test was used. RESULTS: ccRCC had significantly higher mean and median whole WL enhancement (p < 0.01) compared to pRCC on arterial, nephrographic, and excretory phases. ccRCC had significantly higher interquartile range and standard deviation (p < 0.01) and significantly lower skewness (p < 0.01) compared to pRCC on arterial and nephrographic phases. ccRCC had significantly lower kurtosis compared to pRCC on only the arterial phase. CONCLUSION: Our study suggests that voxel-based WL enhancement parameters can be used as a quantitative tool to differentiate ccRCC from pRCC. Differentiating between the two main types of RCC would provide the patient and the treating physicians more information to formulate the initial approach to managing the patient's renal cancer.

Histological analysis of the kidney tumor-parenchyma interface.

PURPOSE: During enucleative partial nephrectomy excision is performed adjacent to the tumor edge. To better determine the oncologic propriety of enucleative partial nephrectomy we histologically examined the tumor-parenchyma interface. MATERIALS AND METHODS: Archived hematoxylin and eosin stained slides of 124 nephrectomy specimens were rereviewed. We evaluated representative sections of tumor abutting the renal parenchyma and overlying pseudocapsule/perirenal fat were selected at 4 mm(2) sectors apportioned 1, 2, 3 and 4 mm, respectively, from the tumor edge. RESULTS: Median tumor size was 3.5 cm. Of the tumors 111 were malignant (90%) and 119 (96%) had a pseudocapsule with a median thickness of 0.6 mm. Of malignant and benign tumors 82% and 31%, respectively, had an intrarenal pseudocapsule (p < 0.001). Pseudocapsule invasion was noted in 45% of cancers and 15% of benign tumors (p < 0.04). Of pT1a cancers 36% showed intrarenal pseudocapsule invasion. No patient had positive surgical margins. Intrarenal pseudocapsule invasion correlated with clear cell renal cell carcinoma histology but not with cancer size, grade, necrosis or margin width. Inflammation, nephrosclerosis, glomerulosclerosis and arteriosclerosis decreased with increasing distance from the tumor edge. At 1 mm changes were moderate to severe in 38%, 32%, 20% and 17% of tumors while at 5 mm changes were mild in 2.5%, 0.8%, 0.8% and 4%, respectively (p <0.001). Mean arteriolar diameter decreased with tumor proximity (p < 0.0001). CONCLUSIONS: Most renal cancers have an intrarenal pseudocapsule. Partial nephrectomy excision adjacent to the tumor edge appears to be histologically safe. Because 18% of cancers lacked a discernible intrarenal pseudocapsule and 25% of pT1a cancers showed intrarenal pseudocapsule invasion, extreme care is needed to avoid positive margins during enucleative partial nephrectomy.

Significance of perivesical lymph nodes in radical cystectomy for bladder cancer.

OBJECTIVE: The location of positive lymph nodes (LNs) is important for bladder cancer staging. Little is known regarding the impact of perivesical (PV) lymph node (PVLN) involvement on survival. This study characterized PVLN identified after radical cystectomy (RC) and analyzed their impact on recurrence and survival. MATERIALS AND METHODS: We reviewed our institutional review board-approved database including all patients who underwent RC with pelvic lymphadenectomy for curative intent for urothelial carcinoma. Clinical and pathologic data were obtained. Patients were analyzed in groups according to the location of positive LNs: PV+/other LN (ON)+, PV+/ON-, and PV-/ON+. Kaplan-Meier curves were used to estimate recurrence-free survival (RFS) and overall survival (OS). Multivariable Cox regression (including pathologic T category, number of positive LNs, highest level of positive LNs, chemotherapy, and margin status) was performed to evaluate associations between PVLN status and survival. RESULTS: In total, 2,017 patients met inclusion criteria and 465 (23%) were LN+. PVLNs were identified in 936 patients (47%), positive in 197 patients (10%), and represented isolated LN+disease in 101 patients (5%). On univariate analysis, RFS and OS were significantly worse in the PV+/ON+group compared with the PV+/ON- and PV-/ON+ groups. There were no significant differences in RFS or OS between the PV+/ON- and PV-/ON+ groups. On multivariable analysis, PV+/ON+disease was independently associated with worse RFS and OS when compared with PV-/ON+ disease. CONCLUSIONS: PVLNs were identified in a significant number of patients after RC. Positive PVLN, when in combination with other positive LNs, portends worse survival even when correcting for the number of positive nodes.

Incidental prostate cancer in patients with bladder urothelial carcinoma: comprehensive analysis of 1,476 radical cystoprostatectomy specimens.

PURPOSE: We identified risk factors and determined the incidence and prognosis of incidental, clinically significant prostatic adenocarcinoma, prostatic urothelial carcinoma and HGPIN in patients treated with radical cystoprostatectomy for urothelial carcinoma of the bladder. MATERIALS AND METHODS: We analyzed the records of 1,476 patients without a history of prostatic adenocarcinoma. We determined the incidence of clinically significant prostatic adenocarcinoma, prostatic urothelial carcinoma and HGPIN in the total cohort and in select patient subgroups. Prostatic urothelial carcinoma was stratified as prostatic stromal and prostatic urethral/duct involvement. Univariate and multivariate analyses were performed with multiple variables. Recurrence-free and overall survival rates were calculated. Median followup was 13.2 years. RESULTS: Of the 1,476 patients 753 (51.0%) had cancer involving the prostate. Prostatic adenocarcinoma, clinically significant prostatic adenocarcinoma, prostatic urothelial carcinoma and HGPIN were present in 37.9%, 8.3%, 21.1% and 51.2% of patients, respectively. Of the 312 patients (21.1%) with prostatic urothelial carcinoma 163 (11.0%) had prostatic urethral/duct involvement only and 149 (10.1%) had prostatic stromal involvement. We identified risk factors for clinically significant prostatic adenocarcinoma, prostatic urothelial carcinoma and HGPIN but the absence of these risk factors did not rule out their presence. Ten-year overall survival in patients with no prostatic urothelial carcinoma, and prostatic urethral/duct and prostatic stromal involvement was 47.1%, 43.3% and 21.7%, respectively (p<0.001). No patient with clinically significant prostatic adenocarcinoma died of prostatic cancer. CONCLUSIONS: More than half of the patients undergoing radical cystoprostatectomy had cancer involving the prostate. Prostatic urothelial carcinoma, particularly with prostatic stromal involvement, was associated with a worse prognosis, while clinically significant prostatic adenocarcinoma did not alter survival. Preoperative clinical and histopathological risk factors are not reliable enough to accurately predict clinically significant prostatic adenocarcinoma and/or prostatic urothelial carcinoma.

Gender-specific genomic profiling in metastatic colorectal cancer patients treated with 5-fluorouracil and oxaliplatin.

AIMS: Survival and response rates in metastatic colorectal cancer remain poor, despite advances in drug development. There is increasing evidence to suggest that gender-specific differences may contribute to poor clinical outcome. We tested the hypothesis that genomic profiling of metastatic colorectal cancer is dependent on gender. MATERIALS & METHODS: A total of 152 patients with metastatic colorectal cancer who were treated with oxaliplatin and continuous infusion 5-fluorouracil were genotyped for 21 polymorphisms in 13 cancer-related genes by PCR. Classification and regression tree analysis tested for gender-related association of polymorphisms with overall survival, progression-free survival and tumor response. RESULTS: Classification and regression tree analysis of all polymorphisms, age and race resulted in gender-specific predictors of overall survival, progression-free survival and tumor response. Polymorphisms in the following genes were associated with gender-specific clinical outcome: estrogen receptor ß, EGF receptor, xeroderma pigmentosum group D, voltage-gated sodium channel and phospholipase A2. CONCLUSION: Genetic profiling to predict the clinical outcome of patients with metastatic colorectal cancer may depend on gender.

FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab.

PURPOSE: Cetuximab, a chimeric immunoglobulin G 1 (IgG1) anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), has shown efficacy in 10% of patients with metastatic colorectal cancer (CRC). Recent studies demonstrate antibody-dependent cell-mediated cytotoxicity (ADCC) is one of the modes of action for rituximab and trastuzumab. Fragment c (Fc) portion of IgG1 mAb has shown to induce ADCC. Fragment c gamma receptors (FcgammaR) play an important role in initiating ADCC. Studies have shown that two IgG FcgammaR polymorphisms (FCGR2A-H131R and FCGR3A-V158F) independently predict response to rituximab in patients with follicular lymphoma. We tested the hypothesis of whether these two polymorphisms are associated with clinical outcome in metastatic CRC patients treated with single-agent cetuximab. PATIENTS AND METHODS: Thirty-nine metastatic CRC patients were enrolled onto the ImClone0144 trial. Using an allele-specific polymerase chain reaction (PCR) -based method, gene polymorphisms of FCGA2A-H131R and FCGA3A-V158F were assessed from genomic DNA extracted from peripheral blood samples. RESULTS: FCGR2A-H131R and FCGR3A-V158F polymorphisms were independently associated with progression-free survival (PFS; P = .037 and .055, respectively; log-rank test). Combined analysis of these two polymorphisms showed that patients with the favorable genotypes (FCGR2A, any histidine allele, and FCGR3A, any phenylalanine allele) showed a median PFS of 3.7 months (95% CI, 2.4 to 4.4 months), whereas patients with any two unfavorable genotypes (FCGR2A arginine/arginine or valine/valine) had a PFS of 1.1 months (95% CI, 1.0 to 1.4 months; P = .004; log-rank test). CONCLUSION: Our preliminary data suggest that these two polymorphisms may be useful molecular markers to predict clinical outcome in metastatic CRC patients treated with cetuximab and that they may indicate a role of ADCC of cetuximab.

Association of methylenetetrahydrofolate reductase gene polymorphisms and sex-specific survival in patients with metastatic colon cancer.

PURPOSE: Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating intracellular folate levels, which affects DNA synthesis and methylation. Two MTHFR gene polymorphisms, C677T and A1298C, are linked to altered enzyme activity. Several studies have shown these two polymorphisms to be associated with response to fluorouracil (FU) -based treatment in advanced colon cancer patients, but data are inconsistent and contradictory. Meanwhile, epidemiologic studies demonstrated that these MTHFR polymorphisms were associated with cancer risk in a sex-specific manner. We tested the hypothesis of whether these two polymorphisms are associated with sex-specific clinical outcome in metastatic colon cancer patients treated with FU-based chemotherapy. PATIENTS AND METHODS: This study included 318 patients (177 men and 141 women) with metastatic colon cancer treated between 1992 and 2003 at the University of Southern California/Norris Comprehensive Cancer Center or Los Angeles County/University of Southern California Medical Center. Peripheral blood samples were collected from each patient, and genomic DNA was extracted from WBCs. Two MTHFR gene polymorphisms (C677T and A1298C) were tested by fluorogenic 5'-nuclease assay. RESULTS: The A1298C polymorphism showed statistically significant differences in overall survival (OS) in female, but not male, patients with metastatic colon cancer (log-rank test, P = .038). Among females, OS was greater for patients with the A/A genotype (n = 67; median OS, 18.4 months) compared with patients with the A/C genotype (n = 50; median OS, 13.9 months) or C/C genotype (n = 10; median OS, 15.6 months). CONCLUSION: Although preliminary, these data support the role of the A1298C polymorphism in MTHFR as prognostic marker in female patients with metastatic colon cancer. Further studies are needed to confirm these findings.