Assessing Radiographic Response to 223Ra with an Automated Bone Scan Index in Metastatic Castration-Resistant Prostate Cancer Patients.

For effective clinical management of patients being treated with 223Ra, there is a need for radiographic response biomarkers to minimize disease progression and to stratify patients for subsequent treatment options. The objective of this study was to evaluate an automated bone scan index (aBSI) as a quantitative assessment of bone scans for radiographic response in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: In a multicenter retrospective study, bone scans from patients with mCRPC treated with monthly injections of 223Ra were collected from 7 hospitals in Sweden. Patients with available bone scans before treatment with 223Ra and at treatment discontinuation were eligible for the study. The aBSI was generated at baseline and at treatment discontinuation. The Spearman rank correlation was used to correlate aBSI with the baseline covariates: alkaline phosphatase (ALP) and prostate-specific antigen (PSA). The Cox proportional-hazards model and Kaplan-Meier curve were used to evaluate the association of covariates at baseline and their change at treatment discontinuation with overall survival (OS). The concordance index (C-index) was used to evaluate the discriminating strength of covariates in predicting OS. Results: Bone scan images at baseline were available from 156 patients, and 67 patients had both a baseline and a treatment discontinuation bone scan (median, 5 doses; interquartile range, 3-6 doses). Baseline aBSI (median, 4.5; interquartile range, 2.4-6.5) was moderately correlated with ALP (r = 0.60, P < 0.0001) and with PSA (r = 0.38, P = 0.003). Among baseline covariates, aBSI (P = 0.01) and ALP (P = 0.001) were significantly associated with OS, whereas PSA values were not (P = 0.059). After treatment discontinuation, 36% (24/67), 80% (54/67), and 13% (9/67) of patients demonstrated a decline in aBSI, ALP, and PSA, respectively. As a continuous variable, the relative change in aBSI after treatment, compared with baseline, was significantly associated with OS (P < 0.0001), with a C-index of 0.67. Median OS in patients with both aBSI and ALP decline (median, 134 wk) was significantly longer than in patients with ALP decline only (median, 77 wk; P = 0.029). Conclusion: Both aBSI at baseline and its change at treatment discontinuation were significant parameters associated with OS. The study warrants prospective validation of aBSI as a quantitative imaging response biomarker to predict OS in patients with mCRPC treated with 223Ra.

GREM1 and POLE variants in hereditary colorectal cancer syndromes.

Hereditary factors are thought to play a role in at least one third of patients with colorectal cancer (CRC) but only a limited proportion of these have mutations in known high-penetrant genes. In a relatively large part of patients with a few or multiple colorectal polyps the underlying genetic cause of the disease is still unknown. Using exome sequencing in combination with linkage analyses together with detection of copy-number variations (CNV), we have identified a duplication in the regulatory region of the GREM1 gene in a family with an attenuated/atypical polyposis syndrome. In addition, 107 patients with colorectal cancer and/or polyposis were analyzed for mutations in the candidate genes identified. We also performed screening of the exonuclease domain of the POLE gene in a subset of these patients. The duplication of 16 kb in the regulatory region of GREM1 was found to be disease-causing in the family. Functional analyses revealed a higher expression of the GREM1 gene in colorectal tissue in duplication carriers. Screening of the exonuclease domain of POLE in additional CRC patients identified a probable causative novel variant c.1274A>G, p.Lys425Arg. In conclusion a high penetrant duplication in the regulatory region of GREM1, predisposing to CRC, was identified in a family with attenuated/atypical polyposis. A POLE variant was identified in a patient with early onset CRC and a microsatellite stable (MSS) tumor. Mutations leading to increased expression of genes can constitute disease-causing mutations in hereditary CRC syndromes.

Gemcitabine and capecitabine in combination for advanced anthracycline and taxane pre-treated breast cancer patients: A phase II study.

AIM: The aim of this study was to explore the clinical value of gemcitabine combined with capecitabine (GC) in heavily pre-treated patients with metastatic breast cancer. MATERIAL AND METHODS: All patients had failed anthracyclines and taxanes. In 14 patients (41%), more than two metastatic sites were diagnosed with bone (68%) and liver (62%) being the most prominent. Gemcitabine (1,250 mg/m(2), d1+8) and capecitabine (800 mg/m(2) twice daily, d1-14) were administered according to a 3-week schedule. The majority of patients received GC as 3rd or 4th line chemotherapy for metastatic disease. Laboratory tests were done on day 1+8 in cycles. Subjective toxicity was recorded according to the NCI-CTC v. 2.0 criteria. Tumour evaluations were done every 12th week according to the RECIST criteria. The primary objective was to investigate time to progression. Secondary objectives were response rate with special focus on the proportion of patients achieving PR or SD of at least three months, toxicity and survival. RESULTS: A total of 34 patients were enrolled. All subjects are eligible for toxicity, response and time to event analyses. Treatment was given until progressive disease, severe toxicity or until the patient wanted to withdraw. The Kaplan-Meier median time to progression was estimated to 4.3 months and the overall survival time to 13.7 months. Partial response was noted in 12 of 29 evaluable patients (41%). The best outcome amongst remaining patients was stable disease in nine (31%) or tumour progression in eight (28%). A delay of disease progression of more than three months was noted in 53% of the study population. The main side effect was granulocytopenia with 44% and 15% of patients suffering from grade 3 or grade 4 events respectively however, no neutropenic infections were observed. Pre-dominant grade 3 subjective toxicities were: fatigue (21% of patients) and hand-foot syndrome (15% of patients). DISCUSSIONS: We investigated the value of the GC combination as a treatment for late stage breast cancer patients. Tumour progression was delayed and the treatment was well tolerated. We believe that the GC therapy can achieve meaningful palliation.

Erythropoietin treatment in metastatic breast cancer--effects on Hb, quality of life and need for transfusion.

Erythropoietin is an effective treatment for anemia in patients with various types of cancers, but few studies have evaluated the benefit of treatment in advanced breast cancer. In this multicenter study, we investigated the influence of two different doses of epoetin-beta on the level of hemoglobin, the need for blood transfusion, quality of life and safety aspects in patients with metastatic breast cancer. A total of 180 patients were randomized to receive either 1000 IE or 5000 IE epoetin-beta subcutaneously three times per week for 24 weeks. An increase of 20 g/L was defined as a positive hemoglobin response. Blood transfusions were given, if clinically indicated. Additional laboratory values and adverse events were recorded. Quality of life was measured with the aid of the EORTC QLQ-C30 questionnaire. Hemoglobin levels increased significantly in both groups. In the high-dose group, the initial mean Hb value was 98 g/L (64-110), which increased to 121 g/L (83-165) by week 24. In the low-dose group, the mean Hb value was 99 g/L (77-110.5) and by week 24 it was 116 g/L (81-144). The majority of patients who responded to treatment did so during the first four weeks. After 4 weeks, 7 patients in the low-dose group and 24 patients in the high-dose group had increased their Hb values by more than 20 g/L. The need for transfusion was low and did not differ between the groups. Quality of life was significantly enhanced in both groups, and there was no difference in the global quality of life between the two study arms. Epoetin-beta is a well-tolerated, safe and effective treatment of anemia in patients with metastatic breast cancer. There were significant improvements in Hb levels and quality of life in both groups.