Genomic Alterations Associated with Estrogen Receptor Pathway Activity in Metastatic Breast Cancer Have a Differential Impact on Downstream ER Signaling.

Mutations in the estrogen receptor gene (ESR1), its transcriptional regulators, and the mitogen-activated protein kinase (MAPK) pathway are enriched in patients with endocrine-resistant metastatic breast cancer (MBC). Here, we integrated whole genome sequencing with RNA sequencing data from the same samples of 101 ER-positive/HER2-negative MBC patients who underwent a tumor biopsy prior to the start of a new line of treatment for MBC (CPCT-02 study, NCT01855477) to analyze the downstream effects of DNA alterations previously linked to endocrine resistance, thereby gaining a better understanding of the associated mechanisms. Hierarchical clustering was performed using expression of ESR1 target genes. Genomic alterations at the DNA level, gene expression levels, and last administered therapy were compared between the identified clusters. Hierarchical clustering revealed two distinct clusters, one of which was characterized by increased expression of ESR1 and its target genes. Samples in this cluster were significantly enriched for mutations in ESR1 and amplifications in FGFR1 and TSPYL. Patients in the other cluster showed relatively lower expression levels of ESR1 and its target genes, comparable to ER-negative samples, and more often received endocrine therapy as their last treatment before biopsy. Genes in the MAPK-pathway, including NF1, and ESR1 transcriptional regulators were evenly distributed. In conclusion, RNA sequencing identified a subgroup of patients with clear expression of ESR1 and its downstream targets, probably still benefiting from ER-targeting agents. The lower ER expression in the other subgroup might be partially explained by ER activity still being blocked by recently administered endocrine treatment, indicating that biopsy timing relative to endocrine treatment needs to be considered when interpreting transcriptomic data.

The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies.

The whole-genome sequencing of prospectively collected tissue biopsies from 442 patients with metastatic breast cancer reveals that, compared to primary breast cancer, tumor mutational burden doubles, the relative contributions of mutational signatures shift and the mutation frequency of six known driver genes increases in metastatic breast cancer. Significant associations with pretreatment are also observed. The contribution of mutational signature 17 is significantly enriched in patients pretreated with fluorouracil, taxanes, platinum and/or eribulin, whereas the de novo mutational signature I identified in this study is significantly associated with pretreatment containing platinum-based chemotherapy. Clinically relevant subgroups of tumors are identified, exhibiting either homologous recombination deficiency (13%), high tumor mutational burden (11%) or specific alterations (24%) linked to sensitivity to FDA-approved drugs. This study provides insights into the biology of metastatic breast cancer and identifies clinically useful genomic features for the future improvement of patient management.

The impact of age on first-line systemic therapy in patients with metachronous metastases from colorectal cancer.

OBJECTIVES: The paucity of evidence for the optimal use of systemic therapy in elderly patients with metastatic colorectal cancer (mCRC) poses significant challenges to cancer specialists. The present population-based study provides insight into the impact of age on palliative systemic therapy in patients with metachronous metastases from CRC, in order to optimize the decision-making process. METHODS: Data on the development and treatment of metachronous metastases were collected for patients with primary resected CRC diagnosed between 2003 and 2008 in the Eindhoven area of the Netherlands Cancer Registry. Patients undergoing surgery for metastases were excluded, resulting in a study population treated with palliative intent, with or without systemic therapy (n=746). RESULTS: 385 patients received palliative systemic therapy (52%). Patients aged ≥75years were less likely to receive systemic therapy (31% ≥75years vs 73% <60years) and more likely to receive single-agent chemotherapy than combination-chemotherapy. Elderly patients (≥75years) treated with capecitabine-oxaliplatin (CAPOX) received fewer cycles (51% ≤3 oxaliplatin cycles, 43% ≤3 capecitabine cycles) and lower cumulative dosages compared to patients aged <75years, although initial dosages were similar. If capecitabine monotherapy (CapMono) was administered, starting dosages were 2414mg/m2/d<75years and 1992mg/m2/d≥75years (p<0.05), but no differences in number of received cycles or cumulative dosages were observed. CONCLUSION: Age beginning at 75years significantly influenced palliative systemic therapy. Even in selected elderly patients, first-line treatment with CAPOX was associated with less cycles and lower cumulative dosages compared to younger patients. With single-agent fluoropyrimidine therapy, however, no such results were observed.

Reliability and Validity of the Psychosocial Distress Questionnaire-Breast Cancer.

BACKGROUND AND PURPOSE: To evaluate the psychometric properties of the Psychosocial Distress Questionnaire-Breast Cancer (PDQ-BC) and to compare its referrals with the Distress Thermometer (DT). METHODS: Group 1 (N = 54) and Group 2 (N = 80) completed the PDQ-BC. Group 2 also completed the DT, the Hospital Anxiety and Depression Scale (HADS), and World Health Organization Quality of Life instrument-100 (WHOQOL-100; n = 55). RESULTS: Moderate to high correlations (r ≥ .44, p < .001) were found between related facets of the PDQ-BC, WHOQOL-100, and DT. The subscales state anxiety and depressive symptoms (PDQ-BC) have a sensitivity of 87.5% and 78.6%, respectively, and a specificity of 81.1% and 73.0%, respectively, compared to the HADS. CONCLUSIONS: The PDQ-BC shows good construct validity, test-retest reliability, and sensitivity to change. The PDQ-BC has a satisfactory sensitivity and specificity of the subscales state anxiety and depressive symptoms.

Prognosis of metastatic breast cancer subtypes: the hormone receptor/HER2-positive subtype is associated with the most favorable outcome.

Contrary to the situation in early breast cancer, little is known about the prognostic relevance of the hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) in metastatic breast cancer. The objectives of this study were to present survival estimates and to determine the prognostic impact of breast cancer subtypes based on HR and HER2 status in a recent cohort of metastatic breast cancer patients, which is representative of current clinical practice. Patients diagnosed with metastatic breast cancer between 2007 and 2009 were included. Information regarding patient and tumor characteristics and treatment was collected. Patients were categorized in four subtypes based on the HR and HER2 status of the primary tumor: HR positive (+)/HER2 negative (-), HR+/HER2+, HR-/HER2+ and triple negative (TN). Survival was estimated using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic impact of breast cancer subtype, adjusted for possible confounders. Median follow-up was 21.8 months for the 815 metastatic breast cancer patients included; 66 % of patients had the HR+/HER2- subtype, 8 % the HR-/HER2+ subtype, 15 % the TN subtype and 11 % the HR+/HER2+ subtype. The longest survival was observed for the HR+/HER2+ subtype (median 34.4 months), compared to 24.8 months for the HR+/HER2- subtype, 19.8 months for the HR-/HER2+ subtype and 8.8 months for the TN subtype (P < 0.0001). In the multivariate analysis, subtype was an independent prognostic factor, as were initial site of metastases and metastatic-free interval. The HR+/HER2+ subtype was associated with the longest survival after diagnosis of distant metastases.

The Psychosocial Distress Questionnaire-Breast Cancer (PDQ-BC) is a useful instrument to screen psychosocial problems.

PURPOSE: Recently, the Psychosocial Distress Questionnaire-Breast Cancer (PDQ-BC), a screening instrument specific for patients with early-stage breast cancer, was developed. The aim of this study was to further examine the psychometric properties of the PDQ-BC, in particular the subscales social support, sexual problems and financial problems. METHODS: Before patients received treatment (N = 123), they completed the PDQ-BC, the World Health Organization Quality of Life (WHOQOL-100) and the Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: Floor effects were present in 44% of the subscales, whereas ceiling effects were only found in the social support subscale (11%). The PDQ-BC subscales social support, sexual problems and financial problems were highly correlated with the corresponding WHOQOL-100 facets social support, sexual activity and financial resources. Furthermore, the subscale depressive symptoms (PDQ-BC) was highly significantly correlated with the CES-D. Low correlations were found between the PDQ-BC subscales and questionnaires that were expected to be unrelated. Exceptions are the subscales trait anxiety and state anxiety, which had a high correlation with the CES-D. The Cronbach's alpha coefficients of the subscales trait anxiety, state anxiety, depressive symptoms, body image and physical problems ranged from 0.70 to 0.87. Social problems had a low consistency (0.39). Corrected item-total correlations confirmed the PDQ-BC structure. CONCLUSIONS: The PDQ-BC has expected floor effects, few ceiling effects and sufficient internal consistency. Furthermore, the construct validity on the PDQ-BC subscales social support, sexual problems and financial problems was good. Thus, the PDQ-BC can be used to screen psychosocial problems in patients with early-stage breast cancer as part of routine care.

Development of the Psychosocial Distress Questionnaire-Breast Cancer (PDQ-BC): a breast cancer-specific screening instrument for psychosocial problems.

PURPOSE: The aim of the present study was to develop a short, easy-to-use, and acceptable psychosocial screening instrument specific for breast cancer patients. METHODS: Before the start of adjuvant chemotherapy, 164 (98.8%) women completed the Psychosocial Distress Questionnaire-Breast Cancer (PDQ-BC) as part of routine care. The PDQ-BC consists of questions about psychological risk factors (i.e., trait anxiety and (lack of) social support), psychosocial problems (i.e., state anxiety and depressive symptoms), social problems, physical problems, body image, financial problems, sexual problems, clinical factors (type of surgery, adjuvant treatment other than chemotherapy and psychiatric morbidity), and demographic factors (marital status, age, and age of children). RESULTS: On average, patients indicated that they needed 5 min to complete the PDQ-BC. All subscales were significantly correlated with each other, except the correlations of social support with physical problems and body image. Confirmatory factor analysis supported the internal structure of the PDQ-BC (comparative fit index = 0.95 (χ(2)(24) = 43.3), p = 0.009; non-normed fit index = 0.91; root mean square error of approximation = 0.073). The internal consistency (Cronbach's alphas) of the subscales trait anxiety, state anxiety, depressive symptoms, body image, social problems, and physical problems were 0.88, 0.85, 0.86, 0.79, 0.42, and 0.69, respectively. CONCLUSION: The PDQ-BC is an easy-to-complete, acceptable, non-burdensome, and short screening instrument for routine use in breast cancer patient care. This instrument facilitates a greater awareness of the concerns and needs for breast cancer patients care during treatment with chemotherapy and the follow-up. It is linked to a good referral system to guide allocation to the different levels of psychosocial care providers.

Continuous administration of irinotecan by hepatic arterial infusion: a phase I and pharmacokinetic study.

PURPOSE: The main advantage of administering chemotherapy by means of hepatic arterial infusion (HAI) is the achievement of a high concentration of the drug in the liver. Irinotecan (CPT-11) is an active agent for the treatment of advanced colorectal cancer and other tumor types, which frequently metastasize in the liver. We performed a Phase I and pharmacokinetic study to investigate CPT-11 by hepatic arterial administration in patients with liver metastases. PATIENTS AND METHODS: Patients with liver metastases received CPT-11 at doses ranging from 15 to 25 mg/m(2)/day for 5 days every 3 weeks by continuous HAI. All of the patients also received one cycle CPT-11 i.v. Primary end points of the study were to define the maximum tolerated dose (MTD) of hepatic arterial CPT-11 and to study its pharmacokinetics. RESULTS: Twenty patients were included. The MTD was 25 mg/m(2)/day and the dose-limiting toxicities were neutropenia and diarrhea. The metabolic ratio was significantly increased with HAI compared with i.v. administration (P = 0.015). The steady-state concentrations of total CPT-11 and CPT-11 carboxylate and lactone were all lower than those during i.v. infusion (P = 0.008, 0.013, and 0.004, respectively), whereas the levels of total SN-38, and SN-38 carboxylate, lactone, and glucuronide were similar. The total body clearance of CPT-11 was significantly higher with HAI (P = 0.008). CONCLUSIONS: The MTD of CPT-11 given by hepatic 5-day continuous infusion was 25 mg/m(2)/day. HAI of CPT-11 resulted in a higher metabolic ratio because of increased elimination of CPT-11. We recommend 20 mg/m(2)/day for additional Phase II studies.