George Raptis

Conducting Molecular Epidemiological Research in the Age of HIPAA: A Multi-Institutional Case-Control Study of Breast Cancer in African-American and European-American Women

Breast cancer in African-American (AA) women occurs at an earlier age than in European-American (EA) women and is more likely to have aggressive features associated with poorer prognosis, such as high-grade and negative estrogen receptor (ER) status. The mechanisms underlying these differences are unknown. To address this, we conducted a case-control study to evaluate risk factors for high-grade ER- disease in both AA and EA women. With the onset of the Health Insurance Portability and Accountability Act of 1996, creative measures were needed to adapt case ascertainment and contact procedures to this new environment of patient privacy. In this paper, we report on our approach to establishing a multicenter study of breast cancer in New York and New Jersey, provide preliminary distributions of demographic and pathologic characteristics among case and control participants by race, and contrast participation rates by approaches to case ascertainment, with discussion of strengths and weaknesses.

Increasing Tamoxifen Dose in Breast Cancer Patients Based on CYP2D6 Genotypes and Endoxifen Levels: Effect on Active Metabolite Isomers and the Antiestrogenic Activity Score

Tamoxifen (Tam), the major drug for estrogen receptor (ER)‐positive breast cancer, is converted to its active metabolites, Z‐ and Z′‐endoxifen and 4‐OH‐Tam isomers, primarily by cytochrome P450 CYP2D6. In 117 patients taking 20u2003mg/day of Tam, we determined CYP2D6 genotypes and measured the plasma levels of Tam metabolites. The Z‐endoxifen levels increased while Z′‐endoxifen levels decreased with increasing metabolizer phenotype activity (MPA) score (P ≤ 0.0004). The dosage in patients with endoxifen <40u2003nmol/l and/or CYP2D6 MPA scores of 0 was increased to 30u2003mg/day and their metabolite isomers were monitored for up to 90 days. Of the 24 patients on the increased dose, 90% showed an increase in active isomers by day 60; the rate of increase correlated with the MPA score. Notably, their antiestrogenic activity scores (AASs), which estimate total isomer biologic activity, increased from a baseline median of 17 to 26 at day 60. Further studies involving increasing/decreasing the Tam dosage based on the AAS may determine whether dose adjustment can optimize treatment and improve long‐term survival.

Tamoxifen Metabolite Isomer Separation and Quantification by Liquid Chromatography-Tandem Mass Spectrometry

Tamoxifen (Tam), the antiestrogen used to treat estrogen receptor-positive breast cancer is a pro-drug that is converted to its major active metabolites, endoxifen and 4-hydroxy-tamoxifen (4-OH-Tam) by various biotransformation enzymes of which cytochrome P450-2D6 (CYP2D6) is key. The usual Tam dose is 20 mg daily; however, the plasma active metabolite concentrations vary due to common genetic variants encoding the biotransformation enzymes and environmental factors (e.g., concomitant drugs) that inhibit these enzymes. Effective treatment depends on adequate Tam conversion to its active isomers. To monitor metabolite plasma levels, a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to separate and quantitate Tam, N-desmethyl-tamoxifen (ND-Tam), and tamoxifen-N-oxide (Tam-N-oxide), and the E, Z, and Z isomers of endoxifen and 4-OH-Tam. Known standards were used to identify each metabolite/isomer. Quantitation of these metabolites in plasma was linear from 0.6 to 2000 nM. Intra- and inter-assay reproducibilities were 0.2-8.4% and 0.6-6.3%, respectively. Accuracy determined by spike experiments with known standards was 86-103%. Endoxifen, 4-OH-Tam, and their isomers were stable in fresh frozen plasma for ≥6 months. This method provides the first sensitive, specific, accurate, and reproducible quantitation of Tam and its metabolite isomers for monitoring Tam-treated breast cancer patients.

Effect of Pretreatment Distress on Daily Fatigue After Chemotherapy for Breast Cancer

PURPOSEnFatigue is one of the most frequently reported and adverse effects of cancer chemotherapy. The present study tested the hypothesis that womens levels of emotional distress at the time of their initial outpatient chemotherapy treatment would predict the severity of their postinfusion fatigue.nnnMETHODSnSixty stage I (32.6%) and II (67.4%) patients with breast cancer (mean age, 44.5 years) who were receiving standard outpatient chemotherapy participated. The independent variable, emotional distress, was assessed for last night, this morning, and right now with a visual analog scale (0 to 100). The dependent variable, post-treatment fatigue (PTF), was assessed (0 to 100) over each of the subsequent 6 days using end-of-day diaries, which also included assessments of distress and nausea (0 to 100). For the statistical analyses, post-treatment fatigue was divided into three phases with means calculated for days 1 through 2 (phase 1), 3 to 4 (phase 2), and 5 to 6 (phase 3).nnnRESULTSnConsistent with the study hypothesis, patients pretreatment distress level in the clinic was a significant (P < .001) predictor of PTF. There was also a significant (P < .025) interaction with phase, with distress becoming a predictor of PTF after phase 1. Multivariate analysis indicated that prior levels of distress were not independent predictors of PTF.nnnCONCLUSIONSnThis study is the first to demonstrate time-specific effects of pretreatment distress on PTF. Possible mechanisms of these effects now warrant investigation, as do possible benefits of brief interventions to reduce patient distress immediately before treatment.

Evidence for classically conditioned fatigue responses in patients receiving chemotherapy treatment for breast cancer

Fatigue is the most common side effect of chemotherapy for cancer. Not yet explored is the possibility that patients may develop conditioned fatigue responses to clinic cues as a result of the repeated pairing of the clinic environment (conditioned stimulus) with infusions of chemotherapy (unconditioned stimulus) that cause fatigue (unconditioned response). As a first critical test of this possibility, breast cancer patients (N = 82) were studied across their first four cycles of chemotherapy. Consistent with conditioning: (1) fatigue levels in the clinic environment significantly increased with repeated pairings of the clinic environment and chemotherapy administration; (2) fatigue responses in the clinic environment prior to the fourth infusion (CR) were predicted by patients’ previous experiences of post-infusion fatigue (UR) above and beyond effects of concurrent emotional distress. These results provide the first evidence in the literature that fatigue can be conditioned. Additional research is warranted to determine the clinical importance of this source of fatigue in chemotherapy patients.

Neo-adjuvant therapy with dose-dense docetaxel plus short-term filgrastim rescue for locally advanced breast cancer

Neo-adjuvant, dose-dense docetaxel, 100u2009mg/m2 every 2 weeks ×4 cycles, was administered to 12 patients with locally advance breast cancer (LABC) (10 stage IIIa and three stage IIIb). Eligibility requirements included a PS 0–2, normal hepatic and renal function, and radiologic absence of metastatic disease. Filgrastim [granulocyte colony stimulating factor (G-CSF)] was started 1 day after chemotherapy and was given for 6 days. Complete blood counts were determined weekly. Surgery was planned upon recovery from the last dose of docetaxel and followed by 4 cycles of adjuvant doxorubicin plus cyclophosphamide (AC) and radiotherapy. Patients with ER+ status received tamoxifen. The median age was 45 (range 34–73) and pre-treatment pathology revealed poorly differentiated infiltrating duct carcinoma in 11 and infiltrating lobular cancer in one, with positive ER/PR status in five. Twelve patients were treated, and all are evaluable for response and toxicity. Nine patients had a major clinical tumor response with five PR and four pathologic complete responses (pCR rate of 33%). Three patients (of whom two with stage IIIb) had progressive disease and went on to receive neo-adjuvant therapy with AC. There was one instance of grade 3 hematologic toxicity (neutropenic fever in one G-CSF non-compliant patient). There were two instances of grade 3 extra-hematologic toxicity: one patient had severe pain and one had treatment-related fatigue. After a median follow-up of 20 months (range 7–49 months) all patients are alive and eight of nine responders remain progression-free. Despite the small size of our study, we believe that dose-dense neo-adjuvant docetaxel is well tolerated and its activity warrants confirmation in a larger number of patients.

Hormonal Modulation in the Treatment of Breast Cancer

This article explores the history of endocrine therapy for the treatment of breast cancer, the clinical evidence behind the current standards of care, and controversies that may change these standards in the future.

Look Again: The Importance of Second Opinions in Breast Pathology

It is well known that breast pathology is one of the areas within surgical pathology that often yields differences of opinion. This may in part be a result of the numerous factors that now need to be routinely analyzed in patients with breast lesions. As other fields of medicine have become increasingly subspecialized, so too has surgical pathology, and there is an increasing trend toward subspecialty diagnosis of surgical pathology cases in academic settings; that is, breast cancer cases are often signed out only by pathologists with expertise in breast pathology. However, this arrangement is not feasible in all academic centers, let alone community hospitals. Because of the sheer volume of breast surgery and the prevalence of breast cancer, it is not feasible to relegate all breast pathology interpretation to subspecialists. Therefore, second opinions may become critical for a significant number of patients. In fact, many medical centers require (and, we believe, rightly so) pathology review of outside material before surgery. In the article that accompanies this editorial, Kennecke et al examine the impact of routine second-opinion breast pathology review in a group of patients with breast cancer for whom a change in diagnosis would likely impact treatment. Some changes in pathology were not surprising. For example, it is known that histologic grade is among the parameters most discrepant when viewed by multiple pathologists. Nodal and margin status changes are less expected, however, particularly the former. It is surprising that of the 15 upstages from node negative, six were to N1, not just N0 (i ); these upstages occurred, for the most part, without the use of immunohistochemical stains. These patients alone should serve as a wake-up call for treating physicians that certain diagnoses in breast pathology are intrinsically more difficult, occasionally subtle, and prone to differences of opinion. As the authors additionally point out, the use of molecular testing such as Oncotype DX (Genomic Health, Redwood City, CA) has been used adjunctively to complement accurate histologic interpretation; that is, as a way of leveling the playing field vis-a-vis grading and subtyping of invasive carcinoma. Clearly, however, as this study shows, use of such testing is not enough. Parameters such as node status, lymphatic invasion, and margins are not directly measured by such tests, and therefore these sorts of discrepancies would not be accounted for by different test values, yet they remain influential to treatment decisions. In most institutions, negative margins are a requisite for deciding when to proceed with the radiation therapy phase of breast cancer treatment. It is disturbing, but not surprising, that eleven of the twelve cases that involved margin changes were from negative to positive. Depending on individual circumstances, in some practices this might require the patient to be referred back to the surgeon for reexcision. Two patients in the study who were initially diagnosed with invasion were found, on review, to only have ductal carcinoma in situ. As these patients and some of the margin data begin to indicate, discrepancies can go in either direction. In fact, not all initially reported patients with node-positive disease are truly node positive. One of us (I.J.B.) previously reported in Journal of Clinical Oncology a series of patients whose sentinel lymph nodes contained benign epithelial cells that were physiologically transported as a result of biopsyinduced displacement. We subsequently received numerous cases for second opinion in which the nodal status was unexpected, given the pathologic features of the primary tumor. Some of the cases were truly node positive and some were not; however, the reasons for the discrepancies were variable. The study by Kennecke et al specifically selected patients who were initially node negative, not node positive, but such diagnostic issues exist for a certain number of patients with nodepositive disease, as well, with equally important clinical implications. The practice of surgical pathology of the breast is not limited to cancer risk, typing, and prognostication. Pathologists routinely evaluate benign entities that constitute risk factors, such as atypical duct hyperplasia, lobular neoplasia, intraductal papilloma, and radial scar, to name a few. Differences of diagnostic opinion abound for such lesions, perhaps even more so than when grading invasive ductal carcinoma. So, too, have medical oncologists branched out. Management of risk with antihormonal therapy is, for the most part, in the domain of the medical oncologist. Therefore, proper pathologic classification has clinical oncologic implications even in patients without carcinoma. Clearly this study by Kennecke et al has a direct implication for patient care. A correct diagnosis may determine the use of effective treatment (or show particular treatments to be unnecessary), whereas an incorrect diagnosis may lead to treatment-related adverse effects without known benefit. Yet the study by Kennecke et al does not go far enough. Central routine review of a targeted subset of patients with breast cancer in a relatively controlled, closed system of health care is a laudable effort, even if incomplete. Without specifically addressing the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 18 JUNE 2

Highlights of the Chemotherapy Foundation Symposium XXVII: therapeutic options for breast cancer.

The XXVII Annual Chemotherapy Foundation Symposium sponsored by The Mount Sinai School of Medicine is one of the leading forums for communication of important discoveries and new developments in cancer therapeutics. Here, we summarize and review the emerging advances in the treatment of breast cancer, which includes therapeutics in HER signaling, poly(ADP-ribose) polymerase inhibition, PI3K inhibitors and novel epithilones.