John H. Fetting

Detection of Tumor PIK3CA Status in Metastatic Breast Cancer Using Peripheral Blood

Purpose: We sought to evaluate the feasibility of detecting PIK3CA mutations in circulating tumor DNA (ctDNA) from plasma of patients with metastatic breast cancer using a novel technique called BEAMing. Experimental Design: In a retrospective analysis, 49 tumor and temporally matched plasma samples from patients with breast cancer were screened for PIK3CA mutations by BEAMing. We then prospectively screened the ctDNA of 60 patients with metastatic breast cancer for PIK3CA mutations by BEAMing and compared the findings with results obtained by screening corresponding archival tumor tissue DNA using both sequencing and BEAMing. Results: The overall frequency of PIK3CA mutations by BEAMing was similar in both patient cohorts (29% and 28.3%, respectively). In the retrospective cohort, the concordance of PIK3CA mutation status by BEAMing between formalin-fixed, paraffin-embedded (FFPE) samples and ctDNA from temporally matched plasma was 100% (34 of 34). In the prospective cohort, the concordance rate among 51 evaluable cases was 72.5% between BEAMing of ctDNA and sequencing of archival tumor tissue DNA. When the same archival tissue DNA was screened by both sequencing and BEAMing for PIK3CA mutations (n = 41 tissue samples), there was 100% concordance in the obtained results. Conclusions: Analysis of plasma-derived ctDNA for the detection of PIK3CA mutations in patients with metastatic breast cancer is feasible. Our results suggest that PIK3CA mutational status can change upon disease recurrence, emphasizing the importance of reassessing PIK3CA status on contemporary (not archival) biospecimens. These results have implications for the development of predictive biomarkers of response to targeted therapies. Clin Cancer Res; 18(12); 3462–9. ©2012 AACR.

Timed Sequential Treatment With Cyclophosphamide, Doxorubicin, and an Allogeneic Granulocyte-Macrophage Colony-Stimulating Factor-Secreting Breast Tumor Vaccine: A Chemotherapy Dose-Ranging Factorial Study of Safety and Immune Activation

PURPOSE Granulocyte-macrophage colony-stimulating factor (GM-CSF) -secreting tumor vaccines have demonstrated bioactivity but may be limited by disease burdens and immune tolerance. We tested the hypothesis that cyclophosphamide (CY) and doxorubicin (DOX) can enhance vaccine-induced immunity in patients with breast cancer. PATIENTS AND METHODS We conducted a 3 x 3 factorial (response surface) dose-ranging study of CY, DOX, and an HER2-positive, allogeneic, GM-CSF-secreting tumor vaccine in 28 patients with metastatic breast cancer. Patients received three monthly immunizations, with a boost 6 to 8 months from study entry. Primary objectives included safety and determination of the chemotherapy doses that maximize HER2-specific immunity. RESULTS Twenty-eight patients received at least one immunization, and 16 patients received four immunizations. No dose-limiting toxicities were observed. HER2-specific delayed-type hypersensitivity developed in most patients who received vaccine alone or with 200 mg/m(2) CY. HER2-specific antibody responses were enhanced by 200 mg/m(2) CY and 35 mg/m(2) DOX, but higher CY doses suppressed immunity. Analyses revealed that CY at 200 mg/m(2) and DOX at 35 mg/m(2) is the combination that produced the highest antibody responses. CONCLUSION First, immunotherapy with an allogeneic, HER2-positive, GM-CSF-secreting breast tumor vaccine alone or with CY and DOX is safe and induces HER2-specific immunity in patients with metastatic breast cancer. Second, the immunomodulatory activity of low-dose CY has a narrow therapeutic window, with an optimal dose not exceeding 200 mg/m(2). Third, factorial designs provide an opportunity to identify the most active combination of interacting drugs in patients. Further investigation of the impact of chemotherapy on vaccine-induced immunity is warranted.

A Prospective Pharmacologic Evaluation of Age-Related Toxicity of Adjuvant Chemotherapy in Women with Breast Cancer

Abstract Despite increasing evidence of benefit from adjuvant chemotherapy, older women with breast cancer are commonly given less aggressive treatment than younger patients. Conflicting prior data regarding age-related toxicity prompted this prospective study. Forty-four women (aged 35–79 years) with early-stage breast cancer were treated with four cycles of adjuvant therapy with doxorubicin 60 mg/m2 i.v. and cyclophosphamide 600 mg/m2 i.v. every 21 days. They were monitored for my-elosuppression, cardiotoxicity, and decrease in quality of life. Pharmacokinetics were analyzed using cycle 1 plasma samples. Bone marrow granulocyte and macrophage colony-forming units (CFU-GM) were assayed in vitro for dose response to 4-hydroperoxycyclophosphamide and doxorubicin before cycle 1. There was moderate evidence of age-related decrease in nadir absolute neutrophil count (ANC) when age was viewed as a continuous variable. On average there was a 10/μl drop in cycle 1 nadir ANC for every year increase in age (p = 0.02). However, when age was viewed as a categorical variable (age < 65 vs. ≥65 years), a similar proportion of women in each group reached an ANC < 100 (18% vs. 19%). Neither neutropenic complications, alteration in cardiac function, nor change in quality of life scores were significantly age related (p > 0.12). Pharmacokinetic analyses did not demonstrate age-related differences in the clearance of either doxorubicin or cyclophosphamide (p ≥ 0.8). Pharmacodynamic analysis of individual patient bone marrow progenitor cell sensitivity did not reveal any correlation with age (p > 0.48). In women undergoing adjuvant therapy for breast cancer, no clinically significant age-related trends in toxicity were observed. These data suggest that older age alone should not exclude patients from receiving adjuvant therapy with doxorubicin and cyclophosphamide.

Obesity at Diagnosis Is Associated With Inferior Outcomes in Hormone Receptor-Positive Operable Breast Cancer

Obesity has been associated with inferior outcomes in operable breast cancer, but the relation between body mass index (BMI) and outcomes by breast cancer subtype has not been previously evaluated.

An efficient method for psychosocial screening of cancer patients

In high-volume outpatient areas, using Weisman and Wordens Omega instruments for psychosocial screening of cancer patients is not feasible. This study of 30 newly diagnosed patients compared the accuracy of the Omega instruments and the Brief Symptom Inventory (BSI) in identifying patients with high levels of distress at the time of diagnosis as well as in predicting future distress. A significant level of agreement was found between the BSI and the Omega instruments. Both instruments correctly identified the future distress of 16 of 19 patients (84.2%), but the BSI screens patients in one-fourth the time and at one-third the cost. These results support our decision to employ the BSI as a screening tool in an outpatient setting.

Cognitive assessment of cancer patients

T HE STANDARD EVALUATION of medical patients includes the evaluation of the patients capacity to think as manifest by the patients grasp of a situation, memory, attention and capacity to understand and express himself. The results of this evaluation enable the clinician to appreciate the patients capacity to relate his history accurately, to understand and adhere to the clinicians suggestions for treatment, to give informed consent for diagnostic and therapeutic procedures, and to volunteer for research projects. The cognitive assessment of cancer inpatients is particularly important because cognitive disorder is prevalent in cancer inpatients, is associated with a poor prognosis, and creates problems of patient management. The prevalence of cognitive impairment in oncology inpatients has been established in several studies. In a study of two samples, a I-day prevalence sample of 27 patients and in 83 consecutive admissions to the Johns Hopkins Oncology Center, we found that between 25% and 29% of the inpatient population scored in the cognitively impaired range on the Mini-Mental State Examination (MMSE). 1 A repeat examination in 1983 of a larger 3-day prevalence sample indicated that 14% of the inpatients were cognitively impaired (Table l ). These rates of cognitive impairment are similar to rates found in surveys of general medical inpatient floors on several occasions (Table 2). 1 Cognitive impairment in hospitalized patients is often associated with severe metabolic abnormalities. In patients judged to be delirious the degree of cognitive impairment is associated with levels of serum ammonia in patients with hepatic encephalopathy, and with levels of anticholinergic substances in the blood of patients recovering from cardiac surgery (Tables 3 and 4). Level of cognitive impairment measured by MMSE is also correlated with the electroencephalogram (EEG) as reported by Engel and Romano. As might be expected in patients suffering from severe metabolic derangements, the presence of cognitive im-

Phase III Comparison of Tamoxifen Versus Tamoxifen Plus Ovarian Function Suppression in Premenopausal Women With Node-Negative, Hormone Receptor–Positive Breast Cancer (E-3193, INT-0142): A Trial of the Eastern Cooperative Oncology Group

PURPOSE The effects of ovarian function suppression (OFS) on survival and patient-reported outcomes were evaluated in a phase III trial in which premenopausal women were randomly assigned to tamoxifen with or without OFS. PATIENTS AND METHODS Premenopausal women with axillary node-negative, hormone receptor-positive breast cancer tumors measuring ≤ 3 cm were randomly assigned to tamoxifen alone versus tamoxifen plus OFS; adjuvant chemotherapy was not permitted. Primary end points were disease-free survival (DFS) and overall survival (OS). Secondary end points included toxicity and patient-reported outcomes. Patient-reported outcome data included health-related quality of life, menopausal symptoms, and sexual function. These were evaluated at baseline, 6 months, 12 months, and then annually for up to 5 years after registration. RESULTS In all, 345 premenopausal women were enrolled: 171 on tamoxifen alone and 174 on tamoxifen plus OFS. With a median follow-up of 9.9 years, there was no significant difference between arms for DFS (5-year rate: 87.9% v 89.7%; log-rank P = .62) or OS (5-year rate: 95.2% v 97.6%; log-rank P = .67). Grade 3 or higher toxicity was more common in the tamoxifen plus OFS arm (22.4% v 12.3%; P = .004). Patients treated with tamoxifen plus OFS had more menopausal symptoms, lower sexual activity, and inferior health-related quality of life at 3-year follow-up (P < .01 for all). Differences diminished with further follow-up. CONCLUSION When added to tamoxifen, OFS results in more menopausal symptoms and sexual dysfunction, which contributes to inferior self-reported health-related quality of life. Because of early closure, this study is underpowered for drawing conclusions about the impact on survival when adding OFS to tamoxifen.

Spiritual awareness, personal perspective on death, and psychosocial distress among cancer patients: An initial investigation

This study examined the relationship between transpersonal development and psychosocial distress of cancer patients. The study was based on a theoretical model of transpersonal development conceptualized as a relationship between ones personal perspective on death and ones level of spiritual awareness. A cross-sectional survey design was used to collect data during a single interview. A random sample of 116 men and women with cancer who were being seen in the oncology outpatient department of a regional cancer center participated in the study. Data was collected with the following: a brief questionnaire concerning demographic and oncologic information, the Transpersonal Development Inventory (developed by the first author), and the Death Attitude Profile and the Brief Symptom Inventory, which have established validity and reliability. A significant negative correlation between level of transpersonal development and level of psychosocial distress supported the major hypothesis. Twenty-four percent of the...

Use of hematopoietic colony-stimulating factors: the American Society of Clinical Oncology survey. The Health Services Research Committee of the American Society of Clinical Oncology.

PURPOSE Dissemination of use of the hematopoietic colony-stimulating factors (CSFs) is unprecedented in oncology, with almost all physicians having experience with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) shortly after the drugs received Food and Drug Administration (FDA) approval in 1991. The American Society of Clinical Oncology (ASCO) Health Services Research Committee sought to assess patterns of use of CSFs before dissemination of its first-ever publication of ASCO guidelines. METHODS A questionnaire describing clinical scenarios was mailed to American oncologists and hematologists who practice medical oncology. In each scenario, the physician was asked whether he would prefer to use a CSF to prevent or treat neutropenia. RESULTS The response rate to the mailed survey was 49% (N = 475). Most physicians preferred to use CSFs for secondary prophylaxis in patients receiving chemotherapy at rates of 44% to 85%, rather than reduce doses. Patterns of use did not differ for palliative, curative, or adjuvant chemotherapy. While the majority of CSF patterns of care were similar to those recommended in the ASCO guidelines, more than half of the physicians chose to use CSFs in the treatment of febrile neutropenia, an area not supported in the subsequent guidelines. In general, physicians at academic medical centers and in Health Maintenance Organization (HMO) practices were more likely to prefer dose-reduction strategies over addition of CSFs, while fee-for-service physicians preferred the opposite strategies. CONCLUSION Variations in CSF preferences for use were related to differences in clinical characteristics (history of afebrile v febrile neutropenia), drug characteristics (G-CSF or GM-CSF), and physician practice characteristics (HMO or fee-for-service setting). However, before dissemination of the guidelines, the majority of American oncologists preferred strategies that were subsequently included in the ASCO CSF guidelines. CSF guidelines would be most likely to reduce CSF use for treatment of afebrile and uncomplicated febrile neutropenia.

Survival in patients with metastatic recurrent breast cancer after adjuvant chemotherapy: Little evidence of improvement over the past 30 years

Population‐based studies have shown improved survival for patients diagnosed with metastatic breast cancer over time, presumably because of the availability of new and more effective therapies. The objective of the current study was to determine whether survival improved for patients who developed distant recurrence of breast cancer after receiving adjuvant therapy.