High Rates Of Distant Recurrence Research Articles

Emerging role of LOXL2 in the promotion of pancreas cancer metastasis.

Lysyl oxidase-like 2 (LOXL2) is associated with invasiveness and metastasis in cancer. We analyzed the prognostic impact of LOXL2 in pancreatic cancer patients and investigated the role of LOXL2 in pancreatic cancer cell lines. Immunohistochemical analysis was performed in samples from 80 patients and showed LOXL2 expression in 81.2% of patients with pancreatic cancer. Regarding recurrence patterns, LOXL2-positive tumors showed a significantly higher rate of distant recurrence. The 1-year and 3-year disease-free survival rates were 84.6% and 0.0%, respectively, for LOXL2-negative patients, and 27.8 % and 0.0 %, respectively, for LOXL2-positive patients. On univariate analysis, combined resection of major vessels, depth of invasion, tumor stage, and LOXL2- positive status were significant factors for poor prognosis. After identification of LOXL2 expression in pancreatic cancer cell lines, LOXL2-silenced and LOXL2-overexpressed cell lines were used to perform transwell invasion and transendothelial migration assays.In vitro studies indicated that LOXL2 silencing in MIA PaCa-2 and PANC-1 cells induced a mesenchymal–epithelial transition (MET)-like process associated with decreased invasive and migratory properties. LOXL2 overexpression in AsPC-1 and BxPC-3 cells enhanced the epithelial-mesenchymal transition (EMT)-like process and increased migratory and invasive activity. These clinical and preclinical data confirm that higher LOXL2 expression is associated with the invasiveness of pancreatic cancer cells and the low survival rate of pancreatic cancer patients. Our results suggest the clinical value of LOXL2 as a therapeutic target in pancreatic cancer.

Analysis of loco-regional and distant recurrences in breast cancer after conservative surgery.

BackgroundA number of patients treated conservatively for breast cancer will develop loco-regional and distant recurrences. Our aim was to determine how their occurrence may be linked to the evolution of the disease.MethodsWe analyzed 238 women treated by conservative breast surgery and breast irradiation in a single institution. We evaluated the prognostic factors associated with loco-regional and distant recurrences and the prognostic value of local and regional recurrences on systemic progression.ResultsAfter a median follow-up of 5 year (range 1–10), 16 (6.72 %) patients in the breast conservative surgery (BCS) groups had loco-regional recurrence. For distant recurrence, 10 (4.2 %) patients had experienced distant recurrence. Lympho-vascular invasion (HR 2.55; 95 % CI, 076 to 8.49) and an extensive intraductal component (HR, 2.22; 95 % CI, 0.69 to 7.15) and nodal status are risk factors for loco-regional recurrence (LRR) after breast conservative therapy (BCT). Tumor size, nodal status, high histologic grade, and breast cancer diagnosed at a young age (≤35 years) are correlated with higher distant recurrence rates after BCT.ConclusionsRisk factors for LRR after BCS include lympho-vascular invasion, extensive inraductal component, and high nodal status, where as risk factors for distant recurrence include tumor size, nodal status, high histologic grade, and breast cancer diagnosed at a young age (≤35 years).

Expression of receptor protein tyrosine phosphatase ζ is a risk factor for triple negative breast cancer relapse.

Patients with triple negative breast cancer (TNBC) have a higher rate of distant recurrence and a poorer prognosis than those with other breast cancer subtypes. Therefore, it is important to study the mechanism of TNBC relapse. A retrospective immunohistochemical analysis of the expression of receptor protein tyrosine phosphatase ζ (PTPRZ1) and pleiotrophin (PTN) was performed for 325 cases of breast cancer. These samples included 66 cases of luminal A breast cancer, 67 cases of luminal B breast cancer, 78 cases of Her-2-enriched breast cancer, 78 cases of TNBC and 36 cases of relapsed TNBC (RTNBC). In addition, 30 control specimens and 30 cases of metastasized lymph nodes were examined. PTPRZ1 and PTN were highly expressed in the RTNBC group. Compared with the RTNBC group, significant differences in the expression of PTPRZ1 were observed between the TNBC, BC and control groups. A significant difference was observed in the expression of PTN in the BC group (P<0.05) compared to RTNBC, and there were no significant differences in the expression of PTPRZ1 and PTN among the molecular subtypes. No significant correlation was observed between the expression of PTPRZ1, PTN, ER, PR, Her-2 and ALN and the tumor size or menopause status. No significant correlation was identified between the expression of PTPRZ1 and PTN and the expression of CD24 and CD44. In summary, high expression of PTPRZ1 may be an independent risk indicator for TNBC recurrence and metastasis.

Association between preoperative glucocorticoids and long-term survival and cancer recurrence after colectomy: follow-up analysis of a previous randomized controlled trial

The effect of anaesthetic drugs on long-term oncological outcomes after cancer surgery is an area of current interest. Dexamethasone is widely used in anaesthetic practice; however, its effect on long-term survival and cancer outcomes is not known. This study presents the results of a 5-yr follow-up of patients receiving dexamethasone before elective colectomy as part of a previous randomized clinical trial. Sixty patients who underwent elective open colonic resection for any indication between June 2006 and March 2008 were randomized to receive either 8 mg i.v. dexamethasone or placebo before surgery. A 5-yr follow-up analysis was conducted to evaluate overall survival, disease-free survival and recurrence specifically for patients undergoing resection for Stage I-III colon cancer. Kaplan-Meier analysis was performed and log-rank test was used to evaluate difference in survival between groups. Forty-three of the 60 subjects had Stage I-III colon cancer and were included in the follow-up analysis. Twenty received preoperative dexamethasone and 23 received placebo. There were no significant differences between groups in baseline or disease characteristics. No differences were found between groups for overall or disease-free survival. In the dexamethasone group, there was a significantly higher rate of distant recurrence (6 compared with 1, P=0.04). Preoperative dexamethasone was associated with a higher rate of distant recurrence in patients undergoing colectomy for colon cancer. Given the small sample size, this finding should be interpreted with caution, but warrants further investigation in a prospective study.

Anticancer Effects of the Hsp90 Inhibitor 17-Demethoxy-Reblastatin in Human Breast Cancer MDA-MB-231 Cells

Triple-negative breast cancer (TNBC) possesses a higher rate of distant recurrence and a poorer prognosis than other breast cancer subtypes. Interestingly, most of the heat shock protein 90 (Hsp90) client proteins are oncoproteins, and some are closely related to unfavorable factors of TNBC patients. 17-Demethoxy-reblastatin (17-DR), a novel nonbenzoquinone- type geldanamycin analog, exhibited potent Hsp90 ATPase inhibition activity. In this study, the anticancer effects of 17-DR on TNBC MDA-MB-231 cells were investigated. These results showed that 17-DR inhibited cell proliferation, induced apoptosis, and suppressed cell invasion and migration in the MDA-MB-231 cells. Down-regulation of the key Hsp90-dependent tumor-driving molecules, such as RIP1 and MMP-9, by 17-DR may be related to these effects. Taken together, our results suggest that 17-DR has potential as a therapeutic agent for the treatment of TNBC.

Identification of plant extracts sensitizing breast cancer cells to TRAIL

Triple-negative breast cancer (TNBC) is an aggressive heterogeneous cancer subgroup with a higher rate of distant recurrence and a poorer prognosis compared to other subgroups. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive molecule that induces cell death in various tumor cells without causing cytotoxicity to normal cells; however, primary or acquired resistance to TRAIL often limits its efficacy in cancer patients. To develop combination therapies to improve TRAIL efficacy and/or to overcome the resistant mechanism, we screened 138 medicinal plant extracts against TRAIL-sensitive and -insensitive TNBC cell lines, MDA-MB-231 and MDA-MB-468. Among them, 5 plant extracts, Uvaria dac, Artemisia vulgaris, Cortia depressa, Dichasia bengalensis and Cinnamomum obtusifolium did not cause apparent cytotoxicity (<20%) as a single regimen, but showed significant synergistic effects in combination with TRAIL against both cell lines. Moreover, Uvaria dac, Artemisia vulgaris and Cinnamomum obtusifolium were found to suppress the phosphorylation of p65 that is involved in TRAIL-resistant mechanisms. These observations suggest that the identified plant extracts in combination with TRAIL could lead to potential therapeutic benefits for cancer patients in the clinical setting.

Mucosal Melanoma: Pathogenesis, Clinical Behavior, and Management

Mucosal melanoma represents a rare subtype of melanoma with distinct biological, clinical, and management considerations. Knowledge regarding optimal treatment strategies for mucosal melanoma is limited and based primarily upon small case series and single-institution, retrospective analyses. Surgery remains the standard of care for loco-regional management, but the common presence of multifocal disease and the high rate of distant recurrence should be considered before pursuing aggressive surgical interventions associated with inherent significant morbidity. The role of sentinel lymph node biopsy and lymph node dissection remains unclear. Radiotherapy has not been shown to improve overall survival but may reduce the rate of local recurrence. Significant advances in the treatment of metastatic disease have been made with novel immunotherapeutic agents, the discovery of KIT and BRAF mutations and the development of targeted agents that inhibit these oncogenic pathways.

Abstract 5642: Wound-healing drainages contribute to triple negative breast cancers aggressiveness

Abstract The triple negative breast cancers (TNBC) is an extremely aggressive cancer subtype that although account for only 10-17% of breast cancers carries the higher rate of distant recurrence and death than women with other breast cancer subtypes and, unfortunately has limited treatment options. The TNBC pattern of recurrence present a distant recurrence peak at approximately 3 years and then declines rapidly thereafter. It's now well known that growth-factors released during the healing process can accelerate the early recurrences in breast cancer patients. We speculate that wound healing drainages (WHD) stimulation may specifically contribute to TNBC early relapse. To this aim, a panel of TNBC cell lines (BT-549; HCC1937, MDA-MB-157; MDA-MB-231; MDA-MB-468; SUM159; SUM149) and the luminal cell lines MCF7 were treated with WHD. All breast carcinoma cell lines are induced to proliferate in response to more than 20 drainage fluids obtained from breast cancer patients, but median proliferation level was 3-folds higher in TNBC- compared to luminal-cell line. To identify which receptors/pathways can be activated and play a driving role in TNBC progression, a reverse phase protein microarray (RPMA) experiment on TNBC cells WHD stimulated was performed. We revealed a specific activation of PDGFR, VEGFR and their downstream pathways, whereas no significant changes were observed in other receptors, such as EGFR, IRS, Met and ERB3. Conversely, PDGFR and VEGFR pathways were not activated in MCF7. The type of activated receptors suggested the involvement of angiogenic properties, besides canonical proliferation pathways, upon WHD stimulation. To prove whether the receptors found activated by WHD play a key role in in vitro and in vivo TNBC progression, we targeted PDGFR, VEGFR and other receptors possibly involved in proliferation and angiogenic capabilities with sunitinib (targeting PDGFR, VEGFR, FGF and c-kit), anti-bFGF antibody (targeting the ligand bFGF) and bevacizumab (targeting the VEGF) in TNBC cells WHD-stimulated. Sunitinib and anti-bFGF antibody halved the proliferation of TNBC cell lines, whereas bevacizumab modestly affect proliferation. Notably, sunitinib and anti-bFGF antibody strongly inhibited MDA-MB-231 and MDA-MB-468 xenografts tumor growth (sunitinib: 80%, and 70% Growth Index (GI), respectively; anti-bFGF antibody 70% and 60% GI, respectively) whereas bevacizumab determined no more than 30% decrease of tumor volume. In conclusion, WHD promotes TNBC progression probably by sustaining both proliferation and angiogenic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5642. doi:1538-7445.AM2012-5642

Treatment of Metastatic Triple-Negative Breast Cancer

The triple-negative breast cancer (TNBC) phenotype, defined as the lack of estrogen and progesterone hormone receptors and the HER2 receptor, represents approximately 15% to 20% of all breast cancer cases. Challenges faced in management of these patients arise from the heterogeneity of TNBC and the absence of well-defined molecular targets. Subgroups derive significant benefit from cytotoxics however, patients with TNBC have higher rates of distant recurrence and a poorer prognosis than women with other breast cancer subtypes overall. Currently, cytotoxic chemotherapy is the only systemic treatment option at all stages of disease, and rational drug selection based on tumor biology remains an aspiration. In the context of relapse, the most efficacious regimens remain undefined and the typical clinical picture is one of rapid disease progression and little durable benefit to therapy. This article reviews current approaches in metastatic TNBC and considers novel therapies in development that may improve the outlook for those with this disease.

P5-01-17: HER2 Amplification in Primary Tumor: A Potential Marker for Presence of Circulating Tumor Cells in Inflammatory Breast Cancer Patients?

Abstract Background: Inflammatory breast cancer (IBC) is a rare but aggressive form of invasive breast cancer accounting for 3–6% of all cases and have higher rates of distant recurrence. Circulating tumor cells (CTCs) are known to predict outcome in metastatic breast cancer (BC) patients, but little is known about their prognostic significance in non-metastatic BC. We hypothesized that CTCs can be identified in patients with IBCs and may correlate with primary tumor characteristics. Methods: All patients had blood samples collected at the time of primary surgery. CTCs (per 7.5 ml blood) were detected using the Cell Search™ system (Veridex) and were defined as nucleated cells lacking CD45 but expressing cytokeratins (CK) 8, 18, or 19. The presence of ≥ 1 epithelial cells meeting morphologic criteria for malignancy was considered a positive result. Statistical analyses employed Chi square and Fisher's exact tests using STATA IC 11. Results: We prospectively evaluated 41 IBC patients enrolled in an IRB approved protocol undergoing surgery for stage I-III breast cancer. Median follow-up was 30 months. Mean age was 52 years. Thirty five patients (94%) had positive lymph nodes (LNs) at presentation, 30 (75%) had high-grade tumors and 20 (53%) had lymphovascular invasion. Eleven patients (28%) were ER positive, 11 (27%) were PR positive and 18 (44%) were HER2 positive. IBCs were more likely to be high grade (P&amp;lt;0.0001), ER negative (P&amp;lt;0.0001), PR negative (P&amp;lt;0.0001), HER2 positive (P&amp;lt;0.0001), High Ki-67 (P= 0.005) and had a BMI of more than 25kg/m2 (P=0.04). Eleven (27%) patients were CTC positive. CTCs were more likely be found in HER2 positive (8/18; 44%) vs. HER2 negative primary tumors (3/20; 15%) [OR= 4.53; 95% C.I. = 1.02−19.52; P= 0.04]. We found no statistically significant correlations between primary tumor characteristics (ER, PR, LNs, high grade) and presence of CTCs. Conclusions: About a quarter of IBC patients had CTCs at the time of primary surgery. In these patients HER2 overexpression predicted the presence of CTCs. Studies with longer follow-ups is needed to determine if CTCs predicted survival. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-01-17.

Use of HER2 amplification in the primary tumor to predict presence of circulating tumor cells in inflammatory breast cancer.

e11133 Background: Inflammatory breast cancer (IBC) is a rare and aggressive form of invasive breast cancer accounting for 3-6% of all cases. IBC patients have higher rates of distant recurrence. We hypothesized that circulating tumor cells (CTCs) can be identified in patients with IBCs and may correlate with primary tumor characteristics. Methods: All patients had blood samples taken at the time of primary surgery. CTCs (per 7.5 ml blood) were detected using the Cell Search system (Veridex) and were defined as nucleated cells lacking CD45 but expressing cytokeratins (CK) 8, 18, or 19. The presence of ≥ 1 epithelial cells meeting morphologic criteria for malignancy was considered a positive result. Statistical analyses used Chi square and Fisher's exact tests. Results: We prospectively evaluated 38 IBC patients enrolled in an IRB approved protocol undergoing surgery for stage I-III breast cancer. Median follow-up was 27 months and mean age was 51 years. Eleven patients (29%) were ER +ve, 10 (26%) were PR +ve and 18 (47%) were HER2 positive. Thirty four patients (94%) had positive lymph nodes (LNs) at presentation, 29 (78%) had high-grade tumors and 19 (54%) had lymphovascular invasion. IBCs were more likely to be high grade (P<0.0001), ER –ve (P<0.0001), PR –ve (P<0.0001), HER2 +ve (P<0.0001), High Ki-67 (P= 0.005) and have a BMI > 25kg/m2 (P=0.04). Ten (30%) patients were CTC positive. CTCs were more likely be found in HER2 +ve (8/16; 50%) vs. HER2 –ve primary tumors (2/17; 12%) [OR= 7.5; 95% C.I. = 1.05-83.4; P= 0.026]. No statistically significant correlations were observed between primary tumor characteristics (ER, PR, LNs, high grade) and presence of CTCs. Conclusions: Approximately, one-third of IBC patients had CTCs at the time of primary surgery. HER2 overexpression predicted the presence of CTCs in these patients. Further study with longer follow up is needed to determine if CTCs predicted relapse in this cohort.

Abstract PD01-06: Activation of the Insulin-Like Growth Factor Pathway Distinguishes African American from European American Patients with Triple-Negative Breast Cancer by Gene Expression Profiling

Abstract Background: Triple-negative breast cancer (TNBC) is characterized by high histologic grade, high rates of distant recurrence and a poor overall prognosis. Treatment options are limited due to the lack of specific targets such as hormone receptors or HER2 which drive other breast cancer subtypes. Epidemiological studies show a markedly higher prevalence of TNBC in young women of African ancestry. In this study we sought to identify transcriptional modules that are differentially regulated between African American (AA) and European American (EA) women. Methods: A hospital-based cohort of 130 breast cancer patients diagnosed between 1985 and 2007 was selected by an institutional pathology database (CoPath) search for invasive, triple-negative breast cancer and enriched for patients of African American ethnicity. Racial distribution 47% AA, 33% EA, 8% Hispanic and 12% other or unknown. Clinical data was extracted from the Yale and Bridgeport Hospitals Tumor Registry following IRB approval. Invasive disease was identified on H&amp;E sections and an average of 3 tissue cores from FFPE blocks were subjected to RNA extraction using the RecoverAll Total Nucleic Acid Isolation kit (Applied Biosystems) following the manufacturer's protocol. The extracted material was hybridized to Whole Genome-DASL assays (Illumina). Statistical analysis of gene expression data was carried out using Bioconductor/R software. A set of relevant signatures was selected by enrichment analysis of modules identified by principal component analysis. Signature scores were computed as Pearson correlation between the signature vector of gene contributions and each sample's expression profile for these genes. Results: African American patients show a significantly higher activation score for a 273-gene Insulin-like Growth Factor 1 signature compared with European American patients (stage-adjusted p=0.0006). Similarly, samples from AA patients show higher scores in a BRCA 1 mutant signature defined by van ‘t Veer and colleagues in 2002 (p=0.001) and in a luminal progenitor (CD49f+EpCAM+) signature from Lim et al. (2009) (p=0.01). The Genomic Grade Index (GGI, Sotiriou et al. 2006) in samples from AA patients was also found to be significantly elevated (p=0.0007). Conclusions: Our findings indicate significant activation of the IGF pathway in AA compared to EA patients with TNBC. The 273-gene IGF signature was associated with poor differentiation and high proliferation in an independent cohort, which is in agreement with the high GGI score observed in AA patients. BRCA1 mutant-like and luminal progenitor-like properties in AA tumor samples further support this hypothesis as they both are related to basal-like histology which constitutes an aggressive subgroup of triple-negative tumors. These data suggest that African American patients may benefit from IGF pathway inhibiting drugs. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD01-06.

Impact of Circumferential Resection Margin Distance on Locoregional Recurrence and Survival after Chemoradiotherapy in Esophageal Squamous Cell Carcinoma

Close circumferential resection margin (CRM) is an established predictor for locoregional recurrence (LR) in rectal cancer but remains controversial in esophageal malignancy. As yet, little is known about the significance of CRM after chemoradiotherapy (CRT), especially in squamous cell carcinoma (SCC). This study investigated the relationship between CRM distance and recurrence after neoadjuvant CRT in esophageal SCC patients. Between 1997 and 2005, esophageal SCC patients who underwent surgery after neoadjuvant CRT and with pathology stage T3N0M0 and T3N1M0 (metastatic lymph nodes <2) were selected. CRM distance was reassessed and divided into three groups (group 1: CRM >1 mm, group 2: uninvolved CRM but <1 mm, group 3: CRM involved). The cohort comprised 145 male and 6 female patients with mean age of 57 years. There were 74, 51, and 26 patients in group 1, 2, and 3, respectively. With median follow-up period of 50 months, LR developed in 30.5% of patients. Both group 2 and group 3 had significantly higher LR than group 1 (37 and 42% vs. 21%, P < 0.05). Meanwhile, mean time from operation to recurrence was also significantly shorter in group 2 and group 3 than in group 1 (267 and 269 days versus 402 days, P < 0.05). Five-year disease-specific survival (DSS) was highest in group 1 (40%). Despite the similarity in LR, 5-year DSS significantly differed between group 2 and group 3 (22 vs. 7%, P < 0.05). The higher rate of distant recurrence (DR) and concomitant LR + DR in group 3 accounted for the survival difference. In ypT3 esophageal SCC patients, CRM distance provides useful information for risk stratification in cancer recurrence and survival.

The Triple Threat of Recurrence after Breast Conserving Therapy: Race, Receptor Status and Age.

Abstract PurposeThe purpose of this study is to evaluate the impact of race, receptor status, and age on recurrence in patients undergoing breast conserving therapy (BCT).MethodsThe study population consisted of 510 primary invasive female breast cancer patients (excluding Stage IV), who resided in Fulton-Dekalb counties, in Atlanta, GA. These patients were diagnosed in 2003-2004 and treated within the Emory University Affiliated Hospitals. Data was obtained from the SEER cancer registry and augmented with medical record abstraction. Median follow-up was 3.5 and 4.4 years for recurrence and survival, respectively. Breast tumors were categorized as either triple negative (TN), which were estrogen, progesterone, and Her2-neu receptor negative tumors, versus (vs) non-TN, all other possible iterations. Women were evaluated for recurrence and death by TN status, race (African American (AA) vs Caucasian (C)), age, grade, tumor size, nodal status, socioeconomic status (SES), and receipt of chemotherapy. Both recurrence and survival were evaluated using chi-square, fisher exact, and cox regression analyses, p ≤ 0.05 significance.ResultsOf the 510 women, 193 received BCT. Of the 193, 92% completed radiation therapy and 45% received chemotherapy. Of the 184 women with known recurrence status, 11 recurred locally, 11 distantly, and none regionally. Compared to patients with non-TN tumors, TN patients had significantly higher local (13% vs 5%) and distant (16% vs 4%) recurrence rates. AA women had non-significant higher local recurrence than C women (7% vs 4%) and a higher distant recurrence rate (8% vs 3%). Finally, compared to women ≥50 years old, women age &amp;lt;50 had a significantly higher local and distant recurrence rates, (13% vs 4%) and (9% vs 5%) respectively.Unadjusted hazard ratios (HR) and 95% confidence intervals (CI) for any recurrence were calculated: TN status (HR=2.8, 95%CI 1.2-6.5), AA race (HR=2.3, 95% CI 0.9-5.8), age &amp;lt;50 years (HR= 2.3, 95%CI 1.0-5.1), grade 2/3 vs 1 (HR=2.3, 95%CI 1.0-5.1), and chemotherapy receipt (HR=3.0, 95%CI 1.2-7.4). Factors that were highly non-statistically significant included stage, tumor size, nodal status, and SES.In a multivariate model including receptor status, race, and age results were similar (HR = 2.5, 2.1, and 2.1 respectively). When tumor size, nodal status, grade, SES, and chemotherapy status were included in the previous model, only AA race independently predicted recurrence (HR=3.4, 95%CI 1.1-11.1), while TN status demonstrated a trend (HR=1.9, 95%CI 0.8-5.7).In survival analyses, neither TN status, AA race, nor age &amp;lt;50 years predicted outcome in any of the models described above. However, TN status did show a trend for significance (HR=2.6, 95%CI 0.8-9.0).ConclusionWe observed that there was a significant increase in local and distant metastatic recurrence rates after BCT among patients diagnosed with TN breast cancers, AA women, and women &amp;lt;50 years old. In contrast, we did not observe differences in survival, with the exception of TN breast cancers. This study suggests that among women who receive BCT, current standard radiation and systemic therapies may not be adequate in preventing recurrence among women with TN breast cancers, of AA race, or younger age. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6045.

Adjuvant radiotherapy for resected pancreatic cancer: a lack of benefit or a lack of adequate trials?

Surgical resection is the most effective means of controlling nonmetastatic pancreatic cancer, but recurrence rates are high even after complete resection. For several types of tumor of the gastrointestinal tract, combined modality therapy that includes radiation therapy has been shown to reduce the recurrence rate and improve disease-free survival. The use of adjuvant radiotherapy for pancreatic cancer, however, is controversial. Results of the few randomized trials of adjuvant radiotherapy for pancreatic cancer are conflicting. In addition, as pancreatic cancer is associated with high rates of distant recurrence, the additional benefit provided by local therapy has been perceived as questionable. This article reviews the studies--prospective and retrospective--of adjuvant radiotherapy for pancreatic cancer and the issues surrounding the use of this strategy.

Contribution of positive renal vein margin to relapse risk in renal cell cancer

16110 Background: Positive margins in surgically resected solid tumors usually connote higher local relapse rate. There is some evidence this may not be so in renal cell cancer (RCC), and the significance of involvement of the renal vein margin (RVM) is especially difficult to interpret. We reviewed tumor registry data to assess the relapse rate in such scenarios. Methods: After IRB approval, the tumor registry of the Memphis VA hospital was queried for patients with RCC, stage T3b/ T3c, N(any), M0 treated by nephrectomy. Charts were reviewed for known prognostic variables including TNM stage, Fuhrman grade, and involvement of the adrenal gland or perinephric fat. Margin status was assessed, with RVM involvement distinguished from other margins. Outcomes recorded were site and date of recurrence, and date of last contact or death. Local recurrence (LR) and distant recurrence (DR) rates and mean time to recurrence (TTR) were calculated according to RVM status. Survival and TTR were calculated from date of nephrectomy. Results: Of 313 kidney cancer patients, 16 met the above criteria. Mean follow-up was 3.7 years. Two patients had no follow up. No patients had LR. Four died after DR (mean survival 1.3 yr); 5 died without relapse (mean survival 5.1 yrs); 4 are alive without relapse (mean followup 7.7 yrs) and 1 is alive with disease after 7 yrs. Three patients with positive RVM all had DR with mean TTR 2.96 years (range 0.05 to 6.34); two have died (survivals 3 and 0.2 yrs) while the other is alive at 7 yrs. Of the other 11 patients with adequate followup, 3 (27%) had DR with mean TTR 1.0 years (range 0.47 to 1.48); two died at 1 yr, one was lost to follow up after 2 yrs. One patient with a positive ureter margin was lost to follow up. No patients underwent adjuvant treatment. Conclusions: Our data are consistent with the previous evidence that positive margins in RCC may not connote a high rate of local relapse. However, positive RVM was associated with a high rate of distant recurrence. This indicates a need to include such patients in clinical trials of newly emerging systemic therapies instead of focusing on delivery of local therapy. No significant financial relationships to disclose.

Adenoid cystic carcinoma of the larynx: A 40‐year experience

Laryngeal adenoid cystic carcinoma (ACC) is a rare disease. We reviewed our experience at the Princess Margaret Hospital (PMH) with its treatment. This is a retrospective chart review of 15 cases treated at PMH between 1963 and 2005. The mean age was 48.6 years. There was no sex predilection. The subglottis was the most common subsite involved. Only 2 patients had regional metastasis. Local or regional recurrence was noted in 5 patients (33.3%). The distant metastasis rate was 66.7% and involved the lungs. The median follow-up time was 6.9 years. The 5- and 10-year overall and disease-specific survival rates were 64% and 46%, and 69% and 49%, respectively. Laryngeal ACC is a rare disease with a high rate of distant recurrence. Its management should emphasize maximizing local and regional disease control by surgery followed by radiotherapy with distant disease failure eventually dictating survival.

The prognostic significance of the percentage of positive/dissected axillary lymph nodes in breast cancer recurrence and survival in patients with one to three positive axillary lymph nodes

Adjuvant therapy for women with T1-T2 breast carcinoma and 1-3 positive lymph nodes is controversial due to discrepancies in reported baseline locoregional recurrence (LRR) risks. This inconsistency has been attributed to variations in lymph node staging techniques, which have yielded different numbers of dissected lymph nodes. The current study evaluated the prognostic impact of the percentage of positive/dissected lymph nodes on recurrence and survival in women with one to three positive lymph nodes. The study cohort was comprised of 542 women with pathologic T1-T2 breast carcinoma who had 1-3 positive lymph nodes and who had undergone mastectomy and received adjuvant systemic therapy without radiotherapy. Ten-year Kaplan-Meier (KM) LRR, distant recurrence (DR), and overall survival (OS) rates stratified by the number of positive lymph nodes, the number of dissected lymph nodes, and the percentage of positive lymph nodes were examined using different cut-off levels. Multivariate analysis was performed to evaluate the prognostic significance of the percentage of positive lymph nodes in disease recurrence and survival. The median follow-up was 7.5 years. LRR, DR, and OS rates correlated significantly with the number of positive lymph nodes and the percentage of positive lymph nodes, but not with the number of dissected lymph nodes. The cut-off level at which the most significant difference in LRR was observed was 25% positive lymph nodes (the 10-year KM LRR rates were 13.9% and 36.7% in women with < or = 25% and > 25% positive lymph nodes, respectively; P < 0.0001). Higher DR rates and lower OS rates were observed among patients who had > 25% positive lymph nodes compared with patients who had < or = 25% positive lymph nodes (DR: 53.0% vs. 30.3%, respectively; P < 0.0001; OS: 43.4% vs. 62.6%, respectively; P < 0.0001). In the multivariate analysis, the percentage of positive lymph nodes and the histologic grade were significant, independent factors associated with LRR, DR, and OS. The presence of > 25% positive lymph nodes was an adverse prognostic factor in patients with 1-3 positive nodes and may be used to identify patients at high risks of postmastectomy locoregional and distant recurrence who may benefit with adjuvant radiotherapy and more aggressive systemic therapy regimens.

Malignant mixed müllerian tumors of the uterus: Analysis of patterns of failure, prognostic factors, and treatment outcome

PurposeTo determine the survival outcomes, prognostic factors, and patterns of failure in patients with malignant mixed Müllerian tumor (MMMT) of the uterus. Methods and materialsBetween 1954 and 1998, 300 patients with clinical Stage I–III MMMT of the uterus were treated with curative intent at The University of Texas M. D. Anderson Cancer Center. Their hospital records were reviewed to obtain patient and tumor characteristics; details of surgery, radiotherapy (RT), and chemotherapy; and long-term outcome. Surviving patients were followed for a median of 109 months (range 15–138). Survival rates were calculated using the Kaplan-Meier method, with differences assessed by log–rank tests. ResultsOf the 300 patients, 113 (38%) were treated with surgery alone, 160 (53%) with surgery plus adjuvant EBRT or ICRT, and 27 (9%) with RT alone. Forty-eight patients received adjuvant chemotherapy. At 5 years, the overall rates of survival and cause-specific survival were 31% and 33%, respectively. Women who were postmenopausal or had a history of prior pelvic RT, pain at presentation, clinical Stage II-III disease, uterine enlargement (≥12 weeks), or an abnormal Papanicolaou smear finding had a significantly poorer prognosis than the other patients in the series. Of the 273 patients who underwent surgery, those who had positive abdominal washings, uterine length >10 cm, or extrauterine spread of disease to the cervix, adnexa, or peritoneum had a significantly worse prognosis than the other patients. Factors found on multivariate analysis to have an independent adverse influence on cause-specific survival included postmenopausal status (p = 0.0007, relative risk [RR] 3.3), uterine length >10 cm (p = 0.0001, RR 2.2), cervical involvement (p = 0.002, RR 1.8), and peritoneal involvement (p = 0.0001, RR 4.3). At 5 years, the rates of pelvic and distant disease recurrence for the entire group of 300 patients were 38% and 57%, respectively. The most common site of distant recurrence was the peritoneal cavity. Patients treated with pelvic RT had a lower rate of pelvic recurrence than patients treated with surgery alone (28% vs. 48%, p = 0.0002), but the overall survival rates (36% vs. 27%, p = 0.10) and distant metastasis rates (57% vs. 54%, p = 0.96) were not significantly different. However, patients treated with pelvic RT had a longer mean time to any distant relapse (17.3 vs. 7.0 months, p = 0.001) than patients treated with surgery alone. The use of adjuvant chemotherapy did not correlate with the survival rate or rate of distant metastasis. ConclusionAdjuvant pelvic RT decreased the risk of pelvic recurrence and may delay the appearance of distant metastases after hysterectomy for MMMT. However, the survival rates remain poor because of a high rate of distant recurrence. As more effective systemic chemotherapy is developed to control microscopic distant disease, the role of RT in controlling locoregional disease in the pelvis and abdomen may become more important. Future research should consider programs that integrate surgery, RT, and chemotherapy to maximize the probability of cure.

Simultaneous analysis of c-erbB-2 expression and DNA content in breast cancer using flow cytometry.

The c-erbB-2 oncogene is frequently amplified and overexpressed in human breast cancer. We have studied the c-erbB-2 protein in conjunction with DNA content in frozen samples from breast cancers using flow cytometry. The cell suspensions were obtained by mechanical disaggregation followed by a short fixation in 1% paraformaldehyde. The level of c-erbB-2 expression was calculated as a fluorescence index, taking into account the relative amount of total cellular fluorescence compared to nonspecific fluorescence. The flow cytometric value correlated with immunohistochemical results obtained with the same monoclonal antibody (c-neu, clone 9G6). Overexpression of c-erbB-2 was significantly more frequent in DNA aneuploid tumors than in DNA diploid ones and correlated with increasing S-phase fraction and estrogen receptor negativity. In 10 DNA multiploid tumors, the different aneuploid stemlines uniformly expressed c-erbB-2, supporting the hypothesis that overexpression is an early event in breast cancer. Of the 172 tumors, the 37 (22%) judged as positive with immunohistochemistry showed a somewhat higher rate of distant recurrence than others (P = 0.14). The fluorescence index was significantly associated with prognosis (P = 0.0012), as it was also among the immunohistochemically positive cases. If the degree of overexpression is important, then flow cytometry could be a feasible technique for classification.