David A. Decker

Use of tamoxifen for breast cancer: twenty-eight years later.

PURPOSE The mechanisms of antitumor activity, clinical pharmacology, toxicity, and efficacy of tamoxifen in women with early and advanced breast cancer and the drugs potential role in prevention of breast cancer were reviewed. DESIGN A comprehensive review of the literature from 1966 to 1994 was conducted; reports were identified using the Cancerline and Medline data bases. RESULTS The cellular actions of tamoxifen are not completely understood, but it appears that the drugs antiproliferative effects are mediated primarily by inhibition of the activities of estrogen through binding to estrogen receptors (ERs). Disease-free and overall survival rates have been increased in postmenopausal women with ER-positive tumors when tamoxifen has been used as adjuvant therapy (irrespective of nodal status). In premenopausal women, adjuvant therapy with tamoxifen has been associated with prolongation of disease-free survival, but its impact on survival remains to be defined. Tamoxifen is the initial hormonal treatment of choice in both premenopausal and postmenopausal women with ER-positive metastatic disease. Retrospective review of adjuvant therapy studies showed an approximately 39% reduction in the incidence of contralateral primary breast carcinoma in tamoxifen-treated women, which indicates that tamoxifen could have a role in breast cancer prevention. CONCLUSION The use of tamoxifen has resulted in a substantial modification of breast cancers natural history, particularly in postmenopausal women. Ongoing clinical trials will examine the effects of tamoxifen therapy on lipids, coagulation proteins, bone, and endometrium, and its effectiveness as an agent in the prevention of breast cancer.

Study of Sexual Functioning Determinants in Breast Cancer Survivors

Abstract:  Our goal was to identify the treatment, personal, interpersonal, and hormonal (testosterone) factors in breast cancer survivors (BCSs) that determine sexual dysfunction. The treatment variables studied were type of surgery, chemotherapy, radiation, and tamoxifen. The personal, interpersonal, and physiologic factors were depression, body image, age, relationship distress, and testosterone levels. A sample of 55 female breast cancer survivors seen for routine follow‐up appointments from July 2002 to September 2002 were recruited to complete the Female Sexual Functioning Index (FSFI), Hamilton Depression Inventory (HDI), Body Image Survey (BIS), Marital Satisfaction Inventory‐Revised (MSI‐R), a demographic questionnaire, and have a serum testosterone level drawn. The average time since diagnosis was 4.4 years (SD 3.4 years). No associations were found between the type of cancer treatment, hormonal levels, and sexual functioning. BCS sexual functioning was significantly poorer than published normal controls in all areas but desire. The BCSs’ level of relationship distress was the most significant variable affecting arousal, orgasm, lubrication, satisfaction, and sexual pain. Depression and having traditional role preferences were the most important determinants of lower sexual desire. BCSs on antidepressants had higher levels of arousal and orgasm dysfunction. Women who were older had significantly more concerns about vaginal lubrication and pain. Relationship concerns, depression, and age are important influences in the development of BCS sexual dysfunction. The relationship of testosterone and sexual dysfunction needs further study with larger samples and more accurate assay techniques.

Acute and Subacute Toxicity Associated with Concurrent Adjuvant Radiation Therapy and Paclitaxel in Primary Breast Cancer Therapy

The purpose of this study was to describe the toxicity of concurrent standard dose adjuvant radiation therapy (RT) and paclitaxel in a series of patients receiving primary breast cancer therapy. From June 1998 to April 1999, 20 patients with breast cancer received concurrent adjuvant radiation and paclitaxel. There were 16 patients (80%) with American Joint Committee on Cancer (AJCC) stage II disease and 4 with stage III disease. Eighteen patients, 12 postmastectomy and 6 breast conservation, were treated with definitive surgery followed by concurrent RT and paclitaxel. Two received concurrent neoadjuvant radiation and paclitaxel. All patients received a doxorubicin‐containing combination prior to radiation and paclitaxel. RT was delivered concurrently with paclitaxel after the completion of all doxorubicin therapy, with all patients receiving at least two cycles of paclitaxel (175 mg/m 2) every 3 weeks during RT. Toxicity was graded weekly according to Radiation Therapy Oncology Group criteria. Thirteen patients (65%) developed grade 2 or higher cutaneous toxicity. In the postmastectomy group, 6 of 12 patients (50%) developed grade 2 cutaneous toxicity, and 4 of 12 patients (33%) developed grade 3. RT was discontinued in 1 and placed on hold in 3 of these patients. In the breast‐conservation group, 2 of 6 patients (33%) developed grade 3 toxicity. In the neoadjuvant group, 1 of 2 patients (50%) developed grade 3 toxicity. Four patients (20%) developed radiation pneumonitis, 2 of 12 (17%) in the postmastectomy group and 2 of 6 (33%) in the breast conservation group, with 2 requiring hospitalization and 1 a diagnostic open‐lung biopsy. In this group of patients, standard dose concurrent radiation and paclitaxel resulted in a high incidence of cutaneous and pulmonary toxicity. Concurrent radiation and paclitaxel with these doses and schedule should be approached cautiously until further studies documenting its safety are completed.

Brain metastases in patients with renal cell carcinoma: prognosis and treatment.

Thirty-four patients with renal cell carcinoma and brain metastases were reviewed to define important prognostic factors and treatment results. The following covariates were analyzed to determine their influence on survival: disease-free interval, serum calcium, number of central nervous system (CNS) metastases, weight loss, performance score, age, radiation therapy, surgery, and surgery plus radiation. The mean survival for all patients was 7.0 months (range, seven days to 32 months). The patients with a good performance score of 0-2 survived significantly longer (mean survival, 10.2 months) than those with a poor performance score of 3-4 (mean survival, 2.8 months; p = 0.0019). Surgery was associated with significantly improved survival (mean survival, 13.8 months versus mean survival, 4.2 months; p = 0.014). However, all the surgical patients were from the good performance score group, suggesting patient selection. Radiation was associated with an improved mean survival of 8.6 months versus 3.2 months. Performance score is a significant prognostic factor. Furthermore, the data support treatment with radiation therapy for patients with multiple CNS metastases and surgery followed by postoperative radiation therapy for patients with single CNS metastases.

Molecular classification system identifies invasive breast carcinoma patients who are most likely and those who are least likely to achieve a complete pathologic response after neoadjuvant chemotherapy

The molecular classification system categorizes invasive breast carcinomas according to their key driving biomarkers. In the current study, the authors evaluated whether response to neoadjuvant chemotherapy was correlated with the molecular classification groups.

Effects of Vaginal Estrogens on Serum Estradiol Levels in Postmenopausal Breast Cancer Survivors and Women at Risk of Breast Cancer Taking an Aromatase Inhibitor or a Selective Estrogen Receptor Modulator

BACKGROUND Intravaginal estradiols (VE) have been proposed as safe alternatives to systemic estrogen therapy in breast cancer survivors. PATIENTS AND METHODS Postmenopausal women with estrogen receptor-positive breast cancer or at high risk for breast cancer (n = 24) who were taking an aromatase inhibitor (AI) or a selective estrogen receptor modulator (SERM) and VE for ≥ 90 days for atrophic vaginitis and 24 controls taking AI only participated in the study. Serum samples were drawn from VE ring patients before insertion and 30 and 60 days postinsertion, from VE tablet patients the morning before insertion and approximately 12 hours postinsertion, and once from controls. Samples were assayed for E2 concentrations by using highly sensitive radioimmunoassay after ether extraction. RESULTS Mean E2 levels in controls were 3.72 pmol/L (range, < 3.0-7.7 pmol/L); mean E2 levels preinsertion and 12 weeks postinsertion in the VE ring patients were significantly greater than controls (P < .001 for each comparison). Mean preinsertion E2 levels in patients using VE tablets were not significantly different than those of controls (P = .48), and postinsertion levels were 76 pmol/L higher than preinsertion (P < .001). CONCLUSION VE treatment increased E2 levels. Preinsertion levels for patients receiving VE tablets were not elevated compared with those of controls, suggesting that E2 elevations with this preparation may not be continuously sustained. We conclude that VE treatment, regardless of type, results in elevated circulating E2 levels in this population and should be used with caution.

Estrogen replacement therapy in breast cancer survivors: a matched-controlled series.

ObjectiveWe prospectively administered estrogen replacement therapy (ERT) to control estrogen deficiency symptoms in breast cancer survivors as part of our clinical practice. We report the consequences of ERT compared with a historical matched-control group. DesignTwo hundred seventy-seven disease-free survivors received ERT. Controls were matched for exact stage, a recurrence-free period similar to the period to ERT initiation in the ERT group, approximate age, and duration of follow-up. The mean time from breast cancer diagnosis to initiation of ERT was 3.61 (± 0.25) years, with a median of 1.88 years. The mean duration of ERT was 3.7 (± 3.01) years, with a median of 3.05 years. ResultsHot flashes were relieved in 206 of 223 women (92%), dyspareunia/vaginal dryness in 149 of 167 women (89%), and reactive depression/anxiety/mood change in 111 of 126 women (88%). Univariate analysis demonstrated no statistical differences between the groups for age, stage, pathology at diagnosis, progesterone receptor status, local therapy, breast at risk, prior chemotherapy, and duration of follow-up. The ERT group was more likely to be estrogen receptor negative (P = 0.01), to have received prior ERT (P < 0.001), and to have received no adjuvant tamoxifen (P < 0.001). There was no significant difference between the ERT and control groups in ipsilateral primary/recurrence (5/155 v 5/143; P = 0.85), contralateral breast cancers (10/258 v 9/260; P = 0.99), or systemic metastasis (8/277 v 15/277; P = 0.13). Noncause-specific deaths in the control group numbered 15 (of 277), and in the ERT group, 7 (of 277) (P = 0.03). Overall survival favored the ERT group (P = 0.02). ConclusionsIn these selected patients, ERT relieved estrogen deficiency symptoms and did not increase the rate or time to an ipsilateral recurrence/new primary, contralateral new primary, local-regional recurrence, or systemic metastases.

Separate clones in concomitant multiple myeloma and a second B-cell neoplasm demonstrated by molecular and immunophenotypic analysis

Abstract: The occurrence of multiple myeloma (MM) and a second B‐cell neoplasm in the same patient is a rare event. We present 2 such patients, and provide evidence to support the presence of separate clones in these coexisting neoplasms. In the first case, MM became evident 14 months after the diagnosis of chronic lymphocytic leukemia (CLL). In past reports, most occurrences of this association, when investigated, have been regarded to be biclonal disease processes; however, with few exceptions, most were documented by immunologic studies alone. To establish the clonality in our case of CLL with MM, we examined both immunophenotypic data obtained by standard two‐color flow cytometric analysis, and patterns of immunoglobulin gene rearrangement, using standard Southern analysis and hybridization with 32P‐labelled JH and JK probes. This provided evidence for the presence in this patient of two separate monoclonal populations of B cells, manifested as light chain restrictions and gene rearrangements which differed in blood (CLL) and bone marrow (MM) samples. In the second case, MM presented simultaneously with bone marrow lymphocytosis and abnormal peripheral lymphocytes. Clonality studies on blood were not done. Bone marrow B‐cell gene rearrangement studies, however, revealed the presence of three bands in the JK blot of significantly different intensities, suggestive of two monoclonal populations. A monoclonal population of small cells with surface B markers and surface IgM was demonstrated by flow cytometry, while a second population of larger cells with intracytoplasmic IgG matching the patients serum monoclonal protein was detected by immunofluorescence microscopy. The results in these 2 cases expand previous findings of the rare association of MM with a second B‐cell neoplasm, and demonstrate the usefulness of molecular diagnostic investigation.

Hormone Replacement Therapy in Breast Cancer Survivors

Abstract: The use of hormone replacement therapy (HRT) in postmenopausal breast cancer survivors is controversial. This report describes the symptomatic benefit of HRT and the subsequent risk of recurrent breast cancer in a group of postmenopausal women with a prior history of locally treated breast cancer.

Detection of Circulating Epithelial Cells After Surgery for Benign Breast Disease

AbstractBackground: Cytokeratins are predominantly expressed in epithelial cells and their malignant counterparts. Ultrasensitive methods for cytokeratin messenger RNAs (mRNAs) can detect rare circulating tumor cells consistent with hematogenous dissemination in epithelial-derived malignancies, including breast carcinomas. Intraoperative tumor-cell shedding may contribute to this process; this hypothesis is based on the assumption that only tumor cells can be mobilized during surgical manipulation. Methods and Results: The present study addresses this issue by using cytokeratin 19 mRNA detection by reverse transcription-polymerase chain reaction (RT-PCR) in preoperative and postoperative blood samples from 54 patients undergoing excisional biopsy for benign breast disease; 22 healthy volunteers represented the control group. No cytokeratin RT-PCR positivity was found in the control or preoperative samples. Cytokeratin RT-PCR positivity was found in 21 postoperative samples (39%). Conclusions: This finding shows that benign epithelial cells can be mobilized during breast surgery; this effect of surgical manipulation warrants caution in the interpretation of RT-PCR positivity for cytokeratin mRNA in the peripheral blood of patients undergoing surgery for breast cancer.