David James Gallagher

Colorectal Hepatic Metastases: Adjuvant Chemotherapy and Survival

“Pathologic Response to Preoperative Chemotherapy: A New Outcome End Point After Resection of Hepatic Colorectal Metastases,” with great interest. This study confirmed that pathologic response to preoperative chemotherapy predicts survival for patients with colorectal hepatic metastases, establishing pathologic response as a prognostic indicator and as a potential end point in clinical trials evaluating neoadjuvant chemotherapy. However, we are concerned by the omission of adjuvant chemotherapy in the survival analysis. Patients with colorectal hepatic metastases are frequently treated with both pre- and postoperative chemotherapy, an approach that is supported by the European Organisation for Research and Treatment of Cancer 40983 trial. In this study, 364 patients with resectable colorectal hepatic metastases were randomized to six cycles of neoadjuvant infusional fluorouracil/leucovorin (FOLFOX4) plus six cycles of adjuvant FOLFOX4 versus surgery alone, resulting in a 9.2% improvement in 3-year diseasefree survival for the group that received perioperative chemotherapy and were resected (P .03). 2 Unfortunately, we do not know if both neoadjuvant and adjuvant approaches are necessary, and to date no clinical trial has addressed this issue. In the study by Blazer et al, 1 197 (64.6%) of 305 patients received adjuvant chemotherapy after hepatic resection, with a median time to treatment of 7 weeks and a median duration of adjuvant chemotherapy of 12 weeks. However, adjuvant chemotherapy is not included as a variable in the univariate or multivariate models reported in the article. One of the inherent flaws of constructing a prognostic model from retrospective data is that it is difficult to include all known clinical predictive markers, but the omission of adjuvant chemotherapy from the survival analysis is important. Its inclusion could alter the results. The benefit of adjuvant chemotherapy after resection of colorectal hepatic metastases has been reported. In a multivariate analysis, adjuvant chemotherapy and size of metastases were significantly associated with overall survival (OS; hazard ratio [HR] for surgery alone 1.39; 95% CI, 1.00 to 1.93; P .046; HR for two or more metastases 1.49; 95% CI, 1.06 to 2.11; P .023). 3 A retrospective review of 792 patients added further support for the importance of adjuvant chemotherapy. 4 Even for poor-risk patients (four or more bilobar metastases) adjuvant chemotherapy improved OS compared with surgery alone (51.5 months v 23 months; P .01), 5 and for patients with synchronous disease, treatment with postoperative fluorouracil or hepatic arterial infusion floxuridine-based therapy demonstrated improved OS compared with surgery alone (HR 0.62; 95% CI, 0.50 to 0.78; HR 0.51; 95% CI, 0.28 to 0.97, respectively). 6 Three randomized studies showed an increase in disease-free survival with the use of hepatic arterial infusion and systemic therapy after liver resection. 7-9 In our opinion, this data mandates the inclusion of adjuvant chemotherapy in any multivariate model investigating survival. We recently reported that radiologic response to neoadjvuant chemotherapy did not correlate with OS in patients with operable synchronous colorectal hepatic metastases. 10 In our univariate analysis, response to neoadjuvant chemotherapy was not associated with OS, and in the multivariate Cox model, only margins, stage of primary and postoperative carcinoembryonic antigen 5 ng/dL were significant (P .04, P .03, and P .01, respectively). For patients who progressed on neoadjuvant chemotherapy, there was a trend towards improved 5-year OS for those who received adjuvant hepatic arterial infusion chemotherapy. An association between pathological response to neoadjuvant chemotherapy and survival is not a new concept. It is well established, for example, in the management of muscle-invasive urothelial carcinoma, and it is likely that the association reported in this study is true. 11 However, we believe that a survival analysis must consider the impact of adjuvant chemotherapy and are interested to learn if its inclusion in the univariate and multivariate models in the Blazer et al 1 study changes the results. It would also be of clinical interest to test if duration of chemotherapy was related to pathologic response, and if predictors of complete response such as burden of disease can be identified. We would also welcome a comment from the authors on why different cutoff points were used for carcinoembryonic antigen (200 ng/mL v 5 ng/mL), and tumor size (5 cm v 3 cm) and number (multiple/solitary v 3/ 4) in the two analyses. There was a high death rate (8%) in the postoperative period. Was there an association between type of neoadjuvant chemotherapy used and postoperative death? Lastly, as we saw in our study, some patients who progress on neoadjuvant chemotherapy appear to be responsive with adjuvant salvage treatment. It would be interesting to know how many of the 149 patients (55%) with minor response or progression achieved long-term survival, and if the use of adjuvant chemotherapy contributed to this.

Germline BRCA Mutations Denote a Clinicopathologic Subset of Prostate Cancer

Purpose: Increased prostate cancer risk has been reported for BRCA mutation carriers, but BRCA-associated clinicopathologic features have not been clearly defined. Experimental Design: We determined BRCA mutation prevalence in 832 Ashkenazi Jewish men diagnosed with localized prostate cancer between 1988 and 2007 and 454 Ashkenazi Jewish controls and compared clinical outcome measures among 26 BRCA mutation carriers and 806 noncarriers. Kruskal-Wallis tests were used to compare age of diagnosis and Gleason score, and logistic regression models were used to determine associations between carrier status, prostate cancer risk, and Gleason score. Hazard ratios (HR) for clinical end points were estimated using Cox proportional hazards models. Results: BRCA2 mutations were associated with a 3-fold risk of prostate cancer [odds ratio, 3.18; 95% confidence interval (95% CI), 1.52-6.66; P = 0.002] and presented with more poorly differentiated (Gleason score ≥7) tumors (85% versus 57%; P = 0.0002) compared with non–BRCA-associated prostate cancer. BRCA1 mutations conferred no increased risk. After 7,254 person-years of follow-up, and adjusting for clinical stage, prostate-specific antigen, Gleason score, and treatment, BRCA2 and BRCA1 mutation carriers had a higher risk of recurrence [HR (95% CI), 2.41 (1.23-4.75) and 4.32 (1.31-13.62), respectively] and prostate cancer–specific death [HR (95% CI), 5.48 (2.03-14.79) and 5.16 (1.09-24.53), respectively] than noncarriers. Conclusions: BRCA2 mutation carriers had an increased risk of prostate cancer and a higher histologic grade, and BRCA1 or BRCA2 mutations were associated with a more aggressive clinical course. These results may have implications for tailoring clinical management of this subset of hereditary prostate cancer. Clin Cancer Res; 16(7); 2115–21. ©2010 AACR.

Detection of circulating tumor cells in patients with urothelial cancer

BACKGROUND Approximately 50% of patients with metastatic urothelial cancer (UC) respond to chemotherapy and several months of therapy is required to assess for radiographic response. Blood-based biomarkers may identify patients in whom a specific therapy provides clinical benefit, and this study sought to characterize circulating tumor cells (CTCs) in patients with metastatic UC. PATIENTS AND METHODS Peripheral blood from patients with metastatic UC was evaluated for CTCs using the CellSearch system. We assessed for associations between CTC counts and the number and sites of metastatic disease. RESULTS CTC evaluations were carried out in 33 patients with metastatic UC. Fourteen of 33 patients (44%; 95% confidence interval 27% to 59%) had a positive assay (range 0-87 cells/7.5 ml of blood) with 10 patients (31%) having five or more CTCs. A significantly higher number of CTCs was seen in patients with two or more sites of metastases compared with those with less than one or one site of metastases (3.5 versus 0, P = 0.04). CONCLUSIONS CTCs, detected by antibody capture technology, are present in 44% of patients with metastatic UC. Higher numbers of CTCs are seen in patients with a greater number of metastatic sites. One-third of patients have five or more CTCs providing a potential early marker to monitor response to chemotherapy.

Susceptibility Loci Associated with Prostate Cancer Progression and Mortality

Purpose: Prostate cancer is a heterogenous disease with a variable natural history that is not accurately predicted by currently used prognostic tools. Experimental Design: We genotyped 798 prostate cancer cases of Ashkenazi Jewish ancestry treated for localized prostate cancer between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to clinical data. The survival analysis was adjusted for Gleason score and prostate-specific antigen. We investigated associations between 29 single nucleotide polymorphisms (SNP) and biochemical recurrence, castration-resistant metastasis, and prostate cancer–specific survival. Subsequently, we did an independent analysis using a high-resolution panel of 13 SNPs. Results: On univariate analysis, two SNPs were associated (P < 0.05) with biochemical recurrence, three SNPs were associated with clinical metastases, and one SNP was associated with prostate cancer–specific mortality. Applying a Bonferroni correction (P < 0.0017), one association with biochemical recurrence (P = 0.0007) was significant. Three SNPs showed associations on multivariable analysis, although not after correcting for multiple testing. The secondary analysis identified an additional association with prostate cancer–specific mortality in KLK3 (P < 0.0005 by both univariate and multivariable analysis). Conclusions: We identified associations between prostate cancer susceptibility SNPs and clinical end points. The rs61752561 in KLK3 and rs2735839 in the KLK2-KLK3 intergenic region were strongly associated with prostate cancer–specific survival, and rs10486567 in the 7JAZF1 gene were associated with biochemical recurrence. A larger study will be required to independently validate these findings and determine the role of these SNPs in prognostic models. Clin Cancer Res; 16(10); 2819–32. ©2010 AACR.

Germline BRCA mutation does not prevent response to taxane-based therapy for the treatment of castration-resistant prostate cancer

Study Type – Prognosis (case series)

Sunitinib in urothelial cancer: clinical, pharmacokinetic, and immunohistochemical study of predictors of response.

BACKGROUND Sunitinib has activity in patients with metastatic urothelial cancer (UC), but most patients do not respond. OBJECTIVE To identify predictors of response to sunitinib. DESIGN, SETTING, AND PARTICIPANTS Seventy-seven patients with advanced UC received sunitinib on one of two schedules at a single institution. Blood pressure (BP), immunohistochemistry (IHC), and pharmacokinetic (PK) results were correlated with response to sunitinib. MEASUREMENTS BP was assessed on day 1 and 28 of each cycle and on day 14 of cycle 1. IHC was performed on 55 samples from 38 cases using mammalian target of rapamycin and hypoxia-inducible factor (HIF) pathway marker antibodies. Blood samples for PK analysis were collected from 15 patients at three time points. Response was assessed using Response Evaluation Criteria in Solid Tumors criteria. RESULTS AND LIMITATIONS Sunitinib-induced hypertension predicted improved response when hypertension was categorized as a discrete (p = 0.02) or continuous variable (p = 0.005 [systolic BP] and p = 0.007 [diastolic BP]). The odds ratio of response was 12.5 (95% confidence interval, 1.95-246.8) for grade 3/4 hypertension compared with grade 0. Response was associated with low HIF-1α expression in primary (p = 0.07) tissue. A nonstatistically significant trend was seen for an association between greater drug concentration and best response. A correlation between expression markers within the same pathways was identified, phosphorylated-4EBP1 and phosphorylated-S6 (p = 6.5 × 10(-9)), and vascular endothelial growth factor receptor 2 and HIF-1α (p = 0.008). Results are limited by small numbers. CONCLUSIONS Clinical and molecular biomarkers of response to sunitinib may have clinical relevance and require prospective validation. There is an urgent need for predictive biomarkers to guide the management of UC.

Prostate cancer: germline prediction for a commonly variable malignancy

Whats known on the subject? and What does the study add?

Germline single nucleotide polymorphisms associated with response of urothelial carcinoma to platinum-based therapy: the role of the host.

BACKGROUND Variations in urothelial carcinoma (UC) response to platinum chemotherapy are common and frequently attributed to genetic and epigenetic variations of somatic DNA. We hypothesized that variations in germline DNA may contribute to UC chemosensitivity. PATIENTS AND METHODS DNA from 210 UC patients treated with platinum-based chemotherapy was genotyped for 80 single nucleotide polymorphisms (SNPs). Logistic regression was used to examine the association between SNPs and response, and a multivariable predictive model was created. Significant SNPs were combined to form a SNP score predicting response. Eleven UC cell lines were genotyped as validation. RESULTS Six SNPs were significantly associated with 101 complete or partial responses (48%). Four SNPs retained independence association and were incorporated into a response prediction model. Each additional risk allele was associated with a nearly 50% decrease in odds of response [odds ratio (OR) = 0.51, 95% confidence interval 0.39-0.65, P = 1.05 × 10(-7)). The bootstrap-adjusted area under the curves of this model was greater than clinical prognostic factors alone (0.78 versus 0.64). The SNP score showed a positive trend with chemosensitivity in cell lines (P = 0.115). CONCLUSIONS Genetic variants associated with response of UC to platinum-based therapy were identified in germline DNA. A model using these genetic variants may predict response to chemotherapy better than clinical factors alone.

An overview of triple negative breast cancer for surgical oncologists.

Triple negative breast cancers (TNBCs) represent a distinct subgroup of breast cancers with an immunohistochemical phenotype that is negative for oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2). The aim of this article is to provide a broad overview of recent developments in the diagnosis and management of TNBC for surgical oncologists. This overview discusses the subtypes of TNBC and the relationship between this type of breast cancer and the BRCA1 gene. In addition, the article explores recent advances in the treatment of TNBC from a surgical, radiation, and medical oncology point of view. Lastly, evolving therapeutic strategies that have potential to enhance outcomes for patients with TNBC are also discussed.

Baseline results from the UK SIGNIFY study: a whole-body MRI screening study in TP53 mutation carriers and matched controls

In the United Kingdom, current screening guidelines for TP53 germline mutation carriers solely recommends annual breast MRI, despite the wide spectrum of malignancies typically seen in this group. This study sought to investigate the role of one-off non-contrast whole-body MRI (WB MRI) in the screening of asymptomatic TP53 mutation carriers. 44 TP53 mutation carriers and 44 population controls were recruited. Scans were read by radiologists blinded to participant carrier status. The incidence of malignancies diagnosed in TP53 mutation carriers against general population controls was calculated. The incidences of non-malignant relevant disease and irrelevant disease were measured, as well as the number of investigations required to determine relevance of findings. In TP53 mutation carriers, 6 of 44 (13.6, 95% CI 5.2–27.4%) participants were diagnosed with cancer during the study, all of which would be considered life threatening if untreated. Two were found to have two primary cancers. Two participants with cancer had abnormalities on the MRI which were initially thought to be benign (a pericardial cyst and a uterine fibroid) but transpired to be sarcomas. No controls were diagnosed with cancer. Fifteen carriers (34.1, 95% CI 20.5–49.9%) and seven controls (15.9, 95% CI 6.7–30.1%) underwent further investigations following the WB MRI for abnormalities that transpired to be benign (p = 0.049). The cancer detection rate in this group justifies a minimum baseline non-contrast WB MRI in germline TP53 mutation carriers. This should be adopted into national guidelines for management of adult TP53 mutation carriers in addition to the current practice of contrast enhanced breast MRI imaging.