The ethics of CYP2D6 testing for patients considering tamoxifen

The CYP2D6 gene is responsible for the majority of tamoxifen metabolism. Recent compelling, yet limited data have determined that postmenopausal women who carry a functional polymorphism in the CYP2D6 gene have a worse clinical outcome than women who have a wild-type genotype. In this commentary we discuss the level of evidence needed to change clinical practice and whether CYP2D6 genotyping is appropriate for all women considering tamoxifen as part of their adjuvant therapy

Current management of treatment-induced bone loss in women with breast cancer treated in the United Kingdom

New therapeutic options in breast cancer have improved survival but consequently increase the relevance of late complications. Ovarian suppression/ablation and aromatase inhibitors (AI) in the adjuvant setting have improved outcome, but have clinically important adverse effects on bone health. However, investigation and management of cancer treatment-induced bone loss (CTIBL) is poorly defined with no national guidance. In 2004, a questionnaire was sent to over 500 breast surgeons and oncologists who treat breast cancer within the United Kingdom. The questionnaire evaluated access to bone densitometry and specialist expertise as well as attitudes to investigation of CTIBL and anticipated changes in the use of AI for postmenopausal early breast cancer. A total of 354 completed questionnaires were received, 47 from clinicians not currently treating breast cancer. Of the 307 evaluable questionnaires, 164 (53%) were from breast surgeons, 112 (36%) from clinical oncologists and 31 (10%) from medical oncologists. Although most respondents recognised that CTIBL was the responsibility of the treating breast team, investigations for CTIBL are limited even though most had adequate access to bone densitometry; 98 (32%) had not requested a DXA scan in the last 6 months and 224 (73%) had requested fewer than five scans. In all, 235 (76%) were not routinely investigating patients on AI for bone loss. A total of 277 (90%) felt that their practice would benefit from national guidelines to manage these patients, and the majority (59%) had little or no confidence in interpreting DXA results and advising on treatment. This questionnaire has highlighted clear deficiencies in management of CTIBL in early breast cancer. The development of national guidelines for the management of these patients and educational initiatives for breast teams are urgently required

Role of aromatase inhibitors in breast cancer

Primarily, the role of the aromatase inhibitors has been investigated in postmenopausal women with breast cancer, although it is also now being assessed in premenopausal patients following ovarian ablation/suppression. Aromatase inhibitors markedly suppress endogenous oestrogens without directly interacting with oestrogen receptors, and thus have a different mechanism of action to the antioestrogen, tamoxifen. The inhibitors may be divided into subgroups according to their structure (steroidal and nonsteroidal), and there appears to be a lack of cross-resistance between the classes of aromatase inhibitors enabling them to be used sequentially and potentially to prolong endocrine hormone therapy. In addition, with increased efficacy and favourable safety and tolerability profiles, the aromatase inhibitors are starting to challenge tamoxifen as first choice endocrine treatment in a number of settings. Potential differences in side-effect profiles may appear between the steroidal and nonsteroidal aromatase inhibitors when used in long-term settings. Thus, it has been suggested that the steroidal agents have favourable end organ effects; for example, the steroidal inhibitor, exemestane, has minimal negative effects on bone and lipid metabolism in animal and clinical studies. This paper provides an overview of the current and future roles of aromatase inhibitors for breast cancer treatment

Molecular subtypes of breast cancer in relation to paclitaxel response and outcomes in women with metastatic disease: results from CALGB 9342

INTRODUCTION: The response to paclitaxel varies widely in metastatic breast cancer. We analyzed data from CALGB 9342, which tested three doses of paclitaxel in women with advanced disease, to determine whether response and outcomes differed according to HER2, hormone receptor, and p53 status. METHODS: Among 474 women randomly assigned to paclitaxel at a dose of 175, 210, or 250 mg/m(2), adequate primary tumor tissue was available from 175. Immunohistochemistry with two antibodies and fluorescence in situ hybridization were performed to evaluate HER2 status; p53 status was determined by immunohistochemistry and sequencing. Hormone receptor status was obtained from pathology reports. RESULTS: Objective response rate was not associated with HER2 or p53 status. There was a trend toward a shorter median time to treatment failure among women with HER2-positive tumors (2.3 versus 4.2 months; P = 0.067). HER2 status was not related to overall survival (OS). Hormone receptor expression was not associated with differences in response but was associated with longer OS (P = 0.003). In contrast, women with p53 over-expression had significantly shorter OS than those without p53 over-expression (11.5 versus 14.4 months; P = 0.002). In addition, triple negative tumors were more frequent in African-American than in Caucasian patients, and were associated with a significant reduction in OS (8.7 versus 12.9 months; P = 0.008). CONCLUSION: None of the biomarkers was predictive of treatment response in women with metastatic breast cancer; however, survival differed according to hormone receptor and p53 status. Triple negative tumors were more frequent in African-American patients and were associated with a shorter survival

Serial analysis of circulating tumor cells in metastatic breast cancer receiving first-line chemotherapy

Background: We examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy. Methods: Serial CTC data from 469 patients (2,202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs (bCTC), combined CTC status at baseline to the end of cycle 1 (cCTC), and tCTC. Akaike Information Criterion (AIC) was used to select the model that best predicted PFS and OS. Results: Latent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (tCTCneg, 56.9% ), low (tCTClo, 23.7%), intermediate (tCTCmid, 14.5%), or high (tCTChi, 4.9%). Patients with tCTClo, tCTCmid and tCTChi patterns had statistically significant inferior PFS and OS compared to those with tCTCneg (P<.001). AIC indicated that the tCTC model best predicted PFS and OS when compared to bCTC and cCTC models. Validation studies in an independent cohort of 1,856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model. Conclusions: We identified four novel prognostic groups in MBC based on similarities in CTC trajectory patterns during chemotherapy. Prognostic groups included patients with very poor outcome (tCTCmid+tCTChi, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be utilized for fine-tuning of CTC-based risk-stratification strategies to guide future prospective clinical trials in MBC

Inflammatory cytokines and aromatase inhibitor-associated musculoskeletal syndrome: a case–control study

The aromatase inhibitor (AI)-associated musculoskeletal syndrome (AIMSS) occurs in approximately 50% of AI-treated patients. Inflammatory mediators are associated with oestrogen signalling and may change with oestrogen depletion. We hypothesised that AIMSS may be associated with changes in circulating inflammatory markers