Jeffrey B. Smerage

Circulating Tumor Cells and Response to Chemotherapy in Metastatic Breast Cancer: SWOG S0500

PURPOSE Increased circulating tumor cells (CTCs; five or more CTCs per 7.5 mL of whole blood) are associated with poor prognosis in metastatic breast cancer (MBC). A randomized trial of patients with persistent increase in CTCs tested whether changing chemotherapy after one cycle of first-line chemotherapy would improve the primary outcome of overall survival (OS). PATIENTS AND METHODS Patients with MBC who did not have increased CTCs at baseline remained on initial therapy until progression (arm A). Patients with initially increased CTCs that decreased after 21 days of therapy remained on initial therapy (arm B). Patients with persistently increased CTCs after 21 days of therapy were randomly assigned to continue initial therapy (arm C1) or change to an alternative chemotherapy (arm C2). RESULTS Of 595 eligible and evaluable patients, 276 (46%) did not have increased CTCs (arm A). Of those with initially increased CTCs, 31 (10%) were not retested, 165 were assigned to arm B, and 123 were randomly assigned to arm C1 or C2. No difference in median OS was observed between arm C1 and C2 (10.7 and 12.5 months, respectively; P = .98). CTCs were strongly prognostic. Median OS for arms A, B, and C (C1 and C2 combined) were 35 months, 23 months, and 13 months, respectively (P < .001). CONCLUSION This study confirms the prognostic significance of CTCs in patients with MBC receiving first-line chemotherapy. For patients with persistently increased CTCs after 21 days of first-line chemotherapy, early switching to an alternate cytotoxic therapy was not effective in prolonging OS. For this population, there is a need for more effective treatment than standard chemotherapy.

Prospective Multicenter Study of the Impact of the 21-Gene Recurrence Score Assay on Medical Oncologist and Patient Adjuvant Breast Cancer Treatment Selection

PURPOSE The 21-gene Recurrence Score (RS) assay has been validated to quantify the risk of distant recurrence in tamoxifen-treated patients with lymph node-negative, estrogen receptor-positive breast cancer and predict magnitude of chemotherapy benefit. This multicenter study was designed to prospectively examine whether RS affects physician and patient adjuvant treatment selection and satisfaction. PATIENTS AND METHODS Before and after obtaining the 21-gene RS assay, medical oncologists stated their adjuvant treatment recommendation and confidence in it. Patients also indicated their treatment choice pre- and post-RS assay. Patients completed measures for decisional conflict, anxiety, and quality of life. RESULTS Seventeen medical oncologists at one community and three academic practices consecutively enrolled 89 assessable patients. The medical oncologist treatment recommendation changed for 28 patients (31.%). Twenty-four patients (27%) changed their treatment decision. The largest change after the RS results was conversion from the medical oncologists pretest recommendation for chemotherapy plus hormonal therapy (CHT) to post-test recommendation for hormone therapy (HT) in 20 cases (22.5%). Nine patients (10.1%) changed their treatment decision from CHT to HT. RS results increased medical oncologist confidence in their treatment recommendation in 68 cases (76%). Patient anxiety and decisional conflict were significantly lower after RS results. CONCLUSION The results of this study indicate that the RS assay impacts medical oncologist adjuvant treatment recommendations, patient treatment choice, and patient anxiety.

Clinical application of circulating tumor cells in breast cancer: overview of the current interventional trials

In 2004, circulating tumor cells (CTC) enumeration by the CellSearch® technique at baseline and during treatment was reported to be associated with prognosis in metastatic breast cancer patients. In 2008, the first evidence of the impact of CTC detection by this technique on survival of cM0(i+) patients were reported. These findings were confirmed by other non-interventional studies, whereas CTC were also investigated as a surrogate for tumor biology, mainly for HER2 expression/amplification. The aim of this report is to present the current prospective large interventional studies that have been specifically designed to demonstrate that CTC enumeration/characterization may improve the management of breast cancer patients: STIC CTC METABREAST (France) and Endocrine Therapy Index (USA) assess the CTC-guided hormone therapy vs chemotherapy decision in M1 patients; SWOG0500 (USA) and CirCe01 (France) assess the CTC count changes during treatment in metastatic patients; DETECT III (M1 patients, Germany) and Treat CTC (cM0(i+) patients, European Organization for Research and Treatment of Cancer/Breast International Group) assess the use of anti-HER2 treatments in HER2-negative breast cancer patients selected on the basis of CTC detection/characterization. These trials have different designs in various patient populations but are expected to be the pivotal trials for CTC implementation in the routine management of breast cancer patients.

Monitoring apoptosis and Bcl-2 on circulating tumor cells in patients with metastatic breast cancer☆

Enumeration of circulating tumor cells (CTC) from whole blood permits monitoring of patients with breast carcinoma. Analysis of apoptosis & Bcl‐2 expression in CTC might add additional prognostic and predictive information. We estimated the degree of these markers in CTC from patients being treated for metastatic breast cancer.

Pilot study of duloxetine for treatment of aromatase inhibitor‐associated musculoskeletal symptoms

Approximately 50% of postmenopausal women with hormone receptor‐positive early stage breast cancer treated with an aromatase inhibitor (AI) develop musculoskeletal symptoms. Standard analgesics are relatively ineffective. Duloxetine is a serotonin norepinephrine reuptake inhibitor with proven efficacy for treatment of multiple chronic pain states. The authors investigated the hypothesis that duloxetine is efficacious for treatment of AI‐associated musculoskeletal symptoms.

Circulating tumor cells.

Circulating tumor cells (CTCs) can be separated and characterized from normal hematopoietic cellular constituents by a variety of methods. Different strategies have included separation by physical characteristics, such as size or weight, or by biological characteristics, such as expression of epithelial or cancer-specific markers. Of the latter, rtPCR for epithelial-related gene message, such as cytokeratin, and immunoseparation techniques using monoclonal antibodies against epithelial cellular adhesion molecule, have gained the most widespread use in investigational and standard clinical application to date. Detection and monitoring of CTCs might be useful for screening, prognosis, prediction of response to therapy, or monitoring clinical course in patients with primary or metastatic cancer. Currently, monitoring patients with metastatic disease is the most practical application of CTCs. In this regard, several studies have demonstrated that approximately 50-70% of patients with metastatic breast, colon, and prostate cancers have elevated CTC levels, when evaluated using a highly automated immunomagnetic CTC assay system, designated CellSearch®. These studies demonstrate that elevated CTC levels prior to initiation of a new systemic therapy are associated with a worse prognosis than those that do not, and that persistently elevated or subsequent rising CTC levels strongly suggest that the therapeutic regimen with which the patient is being treated is not working. Similar results have been shown with rtPCR assays, although they are not as widely available for routine clinical use. New areas of research are directed toward developing more sensitive means of CTC detection and generating a variety of methods to characterize the molecular and biologic nature of CTCs, such as the status of hormone receptors, epidermal, and other growth factor receptor family members, and indications of stem-cell characteristics.

The Prognostic Implications of Circulating Tumor Cells in Patients with Breast Cancer

Circulating tumor cells (CTCs) have been of interest to the medical and research communities for over a century (1). These cells represent an important link to the process of metastasis, and investigators have been interested in using these cells to establish the diagnosis and prognosis of cancer. In addition, these cells are a potential source of biological information that can be used to predict responsiveness to various treatment agents, monitor response to therapy, and provide tissue for further research into the mechanisms of malignant transformation and resistance. CTCs have been documented in multiple epithelial tumor types (2), but the largest body of data comes from studies of women with breast cancer. Historically, CTC research has been limited by issues of sensitivity, specificity, and reproducibility. These limitations are primarily due to the rarity of CTCs, which occur at a frequency of one tumor cell per 1 × 105−7 peripheral blood mononuclear cells (3). In the 1950s and 1960s, there was great excitement surrounding the investigation of CTCs (4). However, the methodologies of the time relied almost exclusively on the microscopic properties of morphology and size as well as the physical property of density. It soon became apparent that these physical criteria alone were not sufficient for the identification of CTCs. Many of the cells identified during this era were believed to have been false positive cells that result from artifacts of sample preparation and from misclassification of immature leukocytes (5). Thus, morphological characteristics alone did not provide adequate specificity, and no further meaningful progress was made in the field of CTC research until the advent of antibody and nucleic acid technologies, which allowed the identification of biological characteristics of these cells.

Translational Biomarkers: from Preclinical to Clinical a Report of 2009 AAPS/ACCP Biomarker Workshop

There have been some successes in qualifying biomarkers and applying them to drug development and clinical treatment of various diseases. A recent success is illustrated by a collaborative effort among the US Food and Drug Administration, the European Medicines Agency, and the pharmaceutical industry to provide a set of seven preclinical kidney toxicity biomarkers for drug development. Other successes include, but are not limited to, clinical biomarkers for cancer treatment and clinical management of heart transplant patients. The value of fully qualified surrogate endpoints in facilitating successful drug development is undisputed, especially for diseases in which the traditional clinical outcome can only be assessed in large, multi-year trials. Emerging biomarkers, including chemical genomic or imaging biomarkers, and measurement of circulating tumor cells hold great promise for early diagnosis of disease and as prognostic tests for managing treatment of chronic diseases such as osteoarthritis, Alzheimer disease, cardiovascular disease, and cancer. To advance the success of treating and managing these diseases, efforts are needed to establish the temporal relationship between changes in inflammatory or imaging biomarkers with the progression of the chronic disease, and in the case of cancer, between the extent of circulating cancer cells and tumor progression or remission.

New persistent opioid use Among patients with cancer after curative-intent surgery

Purpose The current epidemic of prescription opioid misuse has increased scrutiny of postoperative opioid prescribing. Some 6% to 8% of opioid-naïve patients undergoing noncancer procedures develop new persistent opioid use; however, it is unknown if a similar risk applies to patients with cancer. We sought to define the risk of new persistent opioid use after curative-intent surgery, identify risk factors, and describe changes in daily opioid dose over time after surgery. Methods Using a national data set of insurance claims, we identified patients with cancer undergoing curative-intent surgery from 2010 to 2014. We included melanoma, breast, colorectal, lung, esophageal, and hepato-pancreato-biliary/gastric cancer. Primary outcomes were new persistent opioid use (opioid-naïve patients who continued filling opioid prescriptions 90 to 180 days after surgery) and daily opioid dose (evaluated monthly during the year after surgery). Logistic regression was used to identify risk factors for new persistent opioid use. Results A total of 68,463 eligible patients underwent curative-intent surgery and filled opioid prescriptions. Among opioid-naïve patients, the risk of new persistent opioid use was 10.4% (95% CI, 10.1% to 10.7%). One year after surgery, these patients continued filling prescriptions with daily doses similar to chronic opioid users ( P = .05), equivalent to six tablets per day of 5-mg hydrocodone. Those receiving adjuvant chemotherapy had modestly higher doses ( P = .002), but patients with no chemotherapy still had doses equivalent to five tablets per day of 5-mg hydrocodone. Across different procedures, the covariate-adjusted risk of new persistent opioid use in patients receiving adjuvant chemotherapy was 15% to 21%, compared with 7% to 11% for those with no chemotherapy. Conclusion New persistent opioid use is a common iatrogenic complication in patients with cancer undergoing curative-intent surgery. This problem requires changes to prescribing guidelines and patient counseling during the surveillance and survivorship phases of care.

Neoadjuvant Docetaxel and Capecitabine and the Use of Thymidine Phosphorylase as a Predictive Biomarker in Breast Cancer

Purpose: Thymidine phosphorylase (TP) induction by docetaxel is a proposed mechanism for the observed preclinical synergy of docetaxel and capecitabine (DC). We evaluated whether TP protein expression is increased by docetaxel and correlates with pathologic complete response (pCR) in breast cancer patients. Experimental Design: Women with stage II to III breast cancer were given four cycles of neoadjuvant docetaxel 36 mg/m2 i.v. over 30 min on days 1, 8, and 15 and capecitabine 2,000 mg/d, in two divided doses, on days 5 to 21 of a 28-day cycle. Radiology-directed biopsies of the breast tumors were done at baseline and 5 days after the first dose of docetaxel to evaluate TP expression. Following DC therapy, patients had core breast biopsies, and if residual disease was present, received four cycles of standard dose-dense doxorubin and cyclophosphamide (AC). Results: The pCR rate was 26.9% (95% confidence interval, 11.6-47.8). Up-regulation of TP expression was not observed by either quantitative immunofluorescence (QIF) or immunohistochemistry. Radiology-directed core biopsy after neoadjuvant chemotherapy accurately predicted pathologic response in 88% (95% confidence interval, 69.8-97.6) of the cases. Neither level of TP expression nor TP up-regulation correlated with pCR. Significant toxicity resulted in therapy discontinuation in 3 of 26 patients. Conclusions: DC chemotherapy exhibited a similar pCR rate compared with standard taxane regimens, with increased toxicity. TP expression was not up-regulated after docetaxel and did not correlate with therapeutic response. Core breast biopsy after neoadjuvant chemotherapy accurately predicted pathologic response.