Prediction of fulvestrant efficacy in patients with advanced breast cancer: retrospective-prospective evaluation of the predictive potential of a multigene expression assay.

BACKGROUND: Fulvestrant is a selective oestrogen receptor (ER) degrader used as monotherapy and combination therapy for ER positive HER2 negative advanced breast cancer (ABC) in postmenopausal women. The drug response predictor (DRP), is a mathematical algorithm based on the expression of multiple genes in the tumour. The fulvestrant DRP algorithm has previously shown effect in BC. In this study, we investigated the DRP's potential in predicting fulvestrant benefit. METHOD: Among 695 patients with ABC prospectively included in a Danish Breast Cancer Cooperative Group (DBCG) cohort we retrospectively included 226 patients who received fulvestrant as monotherapy. The DRP result was based on mRNA extracted from tumour biopsies and analysed using Affymetrix array. Primary endpoint was time to progression (TTP). RESULTS: For patients who received fulvestrant in line one to four and were previously unexposed to adjuvant endocrine therapy, we identified a hazard ratio (HR) of 0.44 (90% confidence interval (90% CI) upper limit of 1.08, one sided p = 0.066) for a predicted positive vs negative outcome. A weaker association was seen when including patients exposed to adjuvant endocrine treatment or received fulvestrant in fifth or later lines. Exploratory analyses showed that the DRP was efficient when using recent biopsies for DRP estimate and among recently treated patients. CONCLUSION: The DRP showed a potential in predicting fulvestrant treatment but was not significant in the overall analysis. Use of older biopsies, long-term endocrine treatment and multiple therapies between biopsy used for analysis and fulvestrant treatment, probably affect the predictive accuracy.

Systematic review: Incidence, risk factors, survival and treatment of bone metastases from colorectal cancer.

BACKGROUND: Bones are not considered a frequent metastatic site in patients with colorectal cancer (CRC). The purpose of the present study was to determine the incidence of bone metastases (BM) in CRC, to identify possible risk factors for BM, survival after BM, and effect of treatment of BM including antiresorptive treatment. MATERIAL AND METHODS: A computer-based literature search was carried out using PubMed and EMBASE. RESULTS: We included 29 studies. One randomized placebo controlled trial (RCT) study, two autopsy studies, five register studies, and twenty retrospective cohort studies. The studies described different cohorts making direct comparison difficult. Three studies analysed the effect of different treatments for BM including one RCT study. CONCLUSION: The incidence of bone metastases was 3-7% in patients with CRC, and it was not possible to detect an increase in incidence over time. The most well established risk factors for BM are rectal cancer, having lymph node invasion at surgery of primary tumor, and lung metastases at any time. Other risk factors such as RAS mutation status have been suggested but results are not conclusive. Survival ranges from 5 to 21 months after diagnosis of BM depending on cohort, with survival of about 8 months in unselected patients. Several variables have been suggested as potential prognostic markers but are all poorly investigated. Treatment of BM is not well investigated, though patients seem to benefit from bisphosphonate treatment with regard to lower risk of skeletal related events. This review highlights the need for new research in the area.

Predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort: a retrospective-prospective blinded study.

PURPOSE: Anthracyclines remain a cornerstone in the treatment of primary and advanced breast cancer (BC). This study has evaluated the predictive value of a multigene mRNA-based drug response predictor (DRP) in the treatment of advanced BC with epirubicin. The DRP is a mathematical method combining in vitro sensitivity and gene expression with clinical genetic information from > 3000 clinical tumor samples. METHODS: From a DBCG cohort, 140 consecutive patients were treated with epirubicin between May 1997 and November 2016. After patient informed consent, mRNA was isolated from archival formalin-fixed paraffin-embedded primary breast tumor tissue and analyzed using Affymetrix arrays. Using time to progression (TTP) as primary endpoint, the efficacy of epirubicin was analyzed according to DRP combined with clinicopathological data collected retrospectively from patients' medical records. Statistical analysis was done using Cox proportional hazards model stratified by treatment line. RESULTS: Median TTP was 9.3 months. The DRP was significantly associated to TTP (P = 0.03). The hazard ratio for DRP scores differing by 50 percentage points was 0.55 (95% CI -0.93, one-sided). A 75% DRP was associated with a median TTP of 13 months compared to 7 months following a 25% DRP. Multivariate analysis showed that DRP was independent of age and number of metastases. CONCLUSION: The current study prospectively validates the predictive capability of DRP regarding epirubicin previously shown retrospectively allowing the patients predicted to be poor responders to choose more effective alternatives. Randomized prospective studies are needed to demonstrate if such an approach will lead to increased overall survival.

Associations between primary tumor RAS, BRAF and PIK3CA mutation status and metastatic site in patients with chemo-resistant metastatic colorectal cancer.

BACKGROUND: Several studies have investigated correlations between metastatic pattern and mutation status in patients with colorectal cancer (CRC). However, most of the studies were small and heterogeneously designed and further research is needed to confirm previous results. In this study, we investigated the association between RAS (KRAS or NRAS), BRAF, PIK3CA mutations and metastatic pattern in patients with metastatic (m) CRC. MATERIAL AND METHODS: This study reviewed Danish biobank and database of patients with mCRC who received cetuximab and irinotecan, independent of RAS mutation status, after fluoropyrimidine, oxaliplatin and irinotecan treatment failure. The database contained information regarding tumor mutation status of KRAS, NRAS, BRAF and PIK3CA genes. RESULTS: Totally, 448 patients were included. On multivariate analyses, RAS mutations were significantly associated with increased odds of having lung metastases at diagnosis of mCRC (odds ratio (OR) = 2.04; 95% confidence interval (CI) = 1.32-3.17), and PIK3CA mutations with decreased odds of peritoneal metastases at diagnosis of mCRC (OR = 0.10; 95%CI = 0.01-0.79). On multivariate analyses of the hazard of developing metastases at any time during follow-up, RAS mutations were significantly associated with increased hazard of lung (hazard ratio (HR) = 1.34; 95%CI = 1.04-1.72) and ovarian metastases (HR = 3.12; 95%CI = 1.05-9.24), BRAF V600E mutation was associated with increased hazard of skin metastases (HR = 6.82; 95%CI = 1.86-25.02) and PIK3CA mutations with decreased hazard of peritoneal metastases (HR = 0.31; 95%CI = 0.11-0.86). CONCLUSIONS: This study indicated that in patients with mCRC, RAS mutations are associated with increased risk of lung and ovary metastases. BRAF V600E is associated with increased risk of skin metastases, and PIK3CA mutation with decreased risk of peritoneal metastases.

Risk factors for brain metastases in patients with metastatic colorectal cancer.

BACKGROUND: Brain metastases (BM) from colorectal cancer (CRC) are rare, but the incidence is suspected to rise as treatment of metastatic (m) CRC improves. The aim of this study was to identify possible biological and clinical characteristics at initial presentation of mCRC that could predict later risk of developing BM. Furthermore, we wished to estimate the incidence of BM in long-term surviving patients. MATERIAL AND METHODS: We conducted a retrospective study on a Danish multicenter cohort of patients with mCRC who received cetuximab and irinotecan (CetIri) as third-line treatment. All patients had previously progression on 5-FU, irinotecan and oxaliplatin containing regimens and received CetIri treatment independent of RAS mutations status. We subsequently performed KRAS, NRAS, BRAF, PIK3CA, PTEN, ERBB2 and EGFR sequencing of DNA extracted from primary tumor tissue. RESULTS: Totally, 480 patients were included in our study. BM were diagnosed in 42 [8.8%; 95% confidence interval (CI) 6.4-11.6%] patients. Patients with BM had a significantly longer survival from mCRC diagnosis than non-BM patients (median = 32 versus 28 months, p = 0.001). On univariate cox regression analysis, the risk of developing BM was significantly increased in patients with rectal cancer (HR = 3.9; 95% CI = 1.2-13.3), metachronous metastatic disease (HR = 2.3; 95% CI = 1.2-4.4) and lung metastases (HR = 4.2; 95% CI = 2.2-7.9). On multivariate cox regression analysis only lung metastases were significantly associated BM (HR = 3.5; 95% CI = 1.8-6.8). None of the investigated mutations were associated with BM. CONCLUSION: The incidence of BM was 8.8% in patients with mCRC who received third-line therapy. The most important risk factor for developing BM was lung metastases. Furthermore, rectal cancer, metachronous metastatic disease and long survival were linked to BM development.

Systematic review: brain metastases from colorectal cancer--Incidence and patient characteristics.

BACKGROUND: Brain metastases (BM) from colorectal cancer (CRC) are a rare event. However, the implications for affected patients are severe, and the incidence has been reported to be increasing. For clinicians, knowledge about the characteristics associated with BM is important and could lead to earlier diagnosis and improved survival. METHOD: In this paper, we describe the incidence as well as characteristics associated with BM based on a systematic review of the current literature, following the PRISMA guidelines. RESULTS: We show that the incidence of BM in CRC patients ranges from 0.6 to 3.2%. BM are a late stage phenomenon, and young age, rectal primary and lung metastases are associated with increased risk of developing BM. Molecular markers such as KRAS, BRAF, NRAS mutation as well as an increase in CEA and CA19.9 levels are suggested predictors of brain involvement. However, only KRAS mutations are reasonably well investigated and associated with an increased risk of BM. CONCLUSION: The incidence of BM from CRC is 0.6 to 3.2% and did not seem to increase over time. Development of BM is associated with young age, lung metastases, rectal primary and KRAS mutation. Increased awareness of brain involvement in patients with these characteristics is necessary.