Breast Neoplasms: DeMichele A

DeMichele A, Weber BL. · No affiliation provided · J Clin Oncol. · Pubmed #11870156 No free full text.

This publication has no abstract.

Stein S, DeMichele A, Domchek S, Fox K. · Abramson Cancer Center, University of Pennsylvania, Philadelphia 19104, USA. · Clin Breast Cancer. · Pubmed #14754469 No free full text.

Abstract: In HER2/neu-positive metastatic breast cancer, the combination of chemotherapy and trastuzumab has become a standard of care. This review discusses HER2/neu overexpression in breast cancer and the use of trastuzumab-based therapies. Specifically, the rationale for a gemcitabine/trastuzumab combination in this disease entity and the available clinical data on the use of the combination are discussed. Response rates of 12%-42% have been seen with single-agent gemcitabine and 37%-62% with trastuzumab/gemcitabine combinations. Further work is currently ongoing to examine this promising combination.

Rock E, DeMichele A. · Division of Hematology Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · J Nutr. · Pubmed #14608115 links to  free full text

Abstract: Adjuvant chemotherapy of breast cancer reduces recurrence rates and prolongs survival at the cost of both acute and chronic toxicities. Breast cancer survivors who have received adjuvant chemotherapy may suffer from late effects of chemotherapy including congestive heart failure, neuropathy, premature menopause, and osteoporosis. Nutritional approaches to these problems are distinct in their orientation and success. Study of free radical scavengers for anthracycline-induced cardiomyopathy was born from known pathogenetic mechanisms of cardiotoxicity but has been universally disappointing thus far in clinical trials. Application of agents used for diabetic neuropathy suggests that evening primrose oil, alpha-lipoic acid, and capsaicin may all play a role in the empiric options available to patients with chemotherapy-induced neuropathy. Plant-derived preparations including black cohosh (Actaea racemosa), dong quai (Angelica sinensis), evening primrose (Oenothera biennis), and red clover (Trifolium pretense) are used by patients experiencing hot flashes due to premature menopause despite a paucity of clinical trial data demonstrating either safety or efficacy. Calcium and vitamin D are widely accepted as an effective means to retard bone loss leading to osteoporosis. Nutritional approaches to late effects of breast cancer chemotherapy offer the prospect of preventing or ameliorating these sequelae of treatment. However, except for vitamin D and calcium for prevention of bone loss, current clinical evidence supporting use of nutritional agents remains sparse.

Czerniecki BJ, Koski GK, Koldovsky U, Xu S, Cohen PA, Mick R, Nisenbaum H, Pasha T, Xu M, Fox KR, Weinstein S, Orel SG, Vonderheide R, Coukos G, DeMichele A, Araujo L, Spitz FR, Rosen M, Levine BL, June C, Zhang PJ. · Department of Surgery, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA. · Cancer Res. · Pubmed #17293384 links to  free full text

Abstract: Overexpression of HER-2/neu (c-erbB2) is associated with increased risk of recurrent disease in ductal carcinoma in situ (DCIS) and a poorer prognosis in node-positive breast cancer. We therefore examined the early immunotherapeutic targeting of HER-2/neu in DCIS. Before surgical resection, HER-2/neu(pos) DCIS patients (n = 13) received 4 weekly vaccinations of dendritic cells pulsed with HER-2/neu HLA class I and II peptides. The vaccine dendritic cells were activated in vitro with IFN-gamma and bacterial lipopolysaccharide to become highly polarized DC1-type dendritic cells that secrete high levels of interleukin-12p70 (IL-12p70). Intranodal delivery of dendritic cells supplied both antigenic stimulation and a synchronized preconditioned burst of IL-12p70 production directly to the anatomic site of T-cell sensitization. Before vaccination, many subjects possessed HER-2/neu-HLA-A2 tetramer-staining CD8(pos) T cells that expressed low levels of CD28 and high levels of the inhibitory B7 ligand CTLA-4, but this ratio inverted after vaccination. The vaccinated subjects also showed high rates of peptide-specific sensitization for both IFN-gamma-secreting CD4(pos) (85%) and CD8(pos) (80%) T cells, with recognition of antigenically relevant breast cancer lines, accumulation of T and B lymphocytes in the breast, and induction of complement-dependent, tumor-lytic antibodies. Seven of 11 evaluable patients also showed markedly decreased HER-2/neu expression in surgical tumor specimens, often with measurable decreases in residual DCIS, suggesting an active process of "immunoediting" for HER-2/neu-expressing tumor cells following vaccination. DC1 vaccination strategies may therefore have potential for both the prevention and the treatment of early breast cancer.

Esteva FJ, Glaspy J, Baidas S, Laufman L, Hutchins L, Dickler M, Tripathy D, Cohen R, DeMichele A, Yocum RC, Osborne CK, Hayes DF, Hortobagyi GN, Winer E, Demetri GD. · University of Texas M.D. Anderson Cancer Center, and Baylor College of Medicine, Houston, Texas 77030, USA. · J Clin Oncol. · Pubmed #12637463 No free full text.

Abstract: Purpose: Bexarotene is a retinoid X receptor-selective retinoid that has preclinical antitumor activity in breast cancer. We evaluated the efficacy and safety of oral bexarotene in the treatment of patients with metastatic breast cancer. Patients and Methods: The following three groups of patients were treated: hormone-refractory, chemotherapy-refractory, and tamoxifen-resistant patients. Patients in the first two groups were treated with bexarotene alone, whereas the tamoxifen-resistant patients received both tamoxifen and bexarotene. Patients in all groups were randomly assigned to receive bexarotene at either 200 or 500 mg/m(2)/d. Results: One hundred forty-eight patients were randomized; 145 patients were treated. Of 48 hormone-refractory patients, there were two partial responses (6%) and 10 patients with stable disease lasting more than 6 months; of 47 chemotherapy-refractory patients, there were two partial responses (6%) and five patients with stable disease; and of 51 tamoxifen-resistant patients, there was one partial response (3%) and 11 patients with stable disease. All partial responses occurred at the 200-mg/m(2)/d dose. The projected median time to progression across all of the arms was 8 to 10 weeks. There were no drug-related deaths, and only two patients had drug-related serious adverse events. The most common drug-related adverse events were hypertriglyceridemia (84%), dry skin (34%), asthenia (30%), and headache (27%). There were no cases of pancreatitis. Conclusion: The efficacy of bexarotene in patients with refractory metastatic breast cancer is limited. However, it is an oral agent with minimal toxicity and a unique mechanism of action, which produced clinical benefit in approximately 20% of patients. Future efforts should define populations likely to benefit from this agent.

DeMichele A, Fox KR. · Breast Cancer Program, Abramson Cancer Center, University of Pennsylvania, USA. · Oncology (Williston Park). · Pubmed #19476263 No free full text.

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DeMichele A, Gray R, Horn M, Chen J, Aplenc R, Vaughan WP, Tallman MS. · Department of Medicine (Hematology/Oncology), University of Pennsylvania School of Medicine, Philadelphia, PA, USA. · Cancer Res. · Pubmed #19435922 No free full text.

Abstract: Interleukin-6 modulates immune response, estrogen production, and growth pathways in breast cancer. We evaluated the effect of several common, functional interleukin-6 promoter variants in node-positive breast cancer patients enrolled on a multicenter, cooperative group, adjuvant chemotherapy trial to determine whether these variants were associated with clinical outcome overall and by estrogen receptor tumor phenotype. Genomic DNA and clinical data were collected from a clinical trial of adjuvant anthracycline-based chemotherapy followed by randomization to high-dose cyclophosphamide/thiotepa or observation (Intergroup Trial 0121). Genotyping for -174G>C (rs1800795), -597G>A (rs1800797), and -572G>C (rs1800796) was done by site-specific PCR and PyroSequencing, whereas the -373A(n)T(n) repeat was directly sequenced. Log-rank tests and Cox modeling were used to compare outcomes by genotype/haplotype and other factors. Three hundred forty-six patients (64% of trial) had corresponding genotype/clinical data available and did not differ from overall trial participants. After adjustment, patients with estrogen receptor-positive tumors and genotypes 597 GG or 174 GG had significantly worse disease-free survival [hazard ratio (HR), 1.6; P = 0.02 and HR, 1.71; P = 0.007, respectively], whereas the 373 8A12T repeat appeared to be protective (HR, 0.62; P = 0.02). The presence of at least one copy of the haplotype ([-597G, -572G, -373[10A/11T], -174G]) was associated with worse disease-free survival (HR, 1.46; P = 0.04). Kaplan-Meier plots show that all patients in this group relapsed by 24 months from diagnosis. This poor-risk haplotype was quite common overall (estimated frequency, 0.20) and twice as frequent among Blacks (estimated frequency, 0.41).

Mao JJ, Bowman MA, Stricker CT, DeMichele A, Jacobs L, Chan D, Armstrong K. · Department of Family Medicine and Community Health, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Health System, Philadelphia, PA 19104, USA. · J Clin Oncol. · Pubmed #19139437 No free full text.

Abstract: PURPOSE: Most of the 182,460 women diagnosed with breast cancer in the United States this year will become long-term survivors. Helping these women transition from active treatment to survivorship is a challenge that involves both oncologists and primary care physicians (PCPs). This study aims to describe postmenopausal breast cancer survivors' (BCS) perceptions of PCP-related survivorship care. PATIENTS AND METHODS: We conducted a cross-sectional survey of 300 BCSs seen in an outpatient breast oncology clinic at a large university hospital. The primary outcome measure was a seven-item self-reported measure on perceived survivorship care (Cronbach's alpha = .89). Multivariate regression analyses were used to identify factors associated with perceived care delivery. RESULTS: Overall, BCSs rated PCP-related survivorship care as 65 out of 100 (standard deviation = 17). The areas of PCP-related care most strongly endorsed were general care (78%), psychosocial support (73%), and health promotion (73%). Fewer BCSs perceived their PCPs as knowledgeable about cancer follow-up (50%), late effects of cancer therapies (59%), or treating symptoms related to cancer or cancer therapies (41%). Only 28% felt that their PCPs and oncologists communicated well. In a multivariate regression analysis, nonwhite race and level of trust in the PCP were significantly associated with higher perceived level of PCP-related survivorship care (P = .001 for both). CONCLUSION: Although BCSs perceived high quality of general care provided by their PCPs, they were not as confident with their PCPs' ability to deliver cancer-specific survivorship care. Interventions need to be tested to improve oncology-primary care communication and PCP knowledge of cancer-specific survivorship care.

Rebbeck TR, DeMichele A, Tran TV, Panossian S, Bunin GR, Troxel AB, Strom BL. · Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Carcinogenesis. · Pubmed #19028704 No free full text.

Abstract: FGFR2 and MAP3K1 are members of the RAS/RAF/MEK/ERK-signaling pathway and have been identified from genome-wide association studies to be breast cancer susceptibility genes. Potential interactions of these genes and their role with respect to tumor markers, hormonal factors and race on breast cancer risk have not been explored. We examined FGFR2 and MAP3K1 variants, breast tumor characteristics and hormone exposures in a population-based case-control sample of 1225 European-American (EA) and 584 African-American (AA) women. FGFR2 rs1219648 and rs2981582 genotypes were significantly associated with breast cancer in EA only in estrogen receptor-positive (ER+), progesterone receptor-positive (PR+) and HER2/Neu-negative (HER2-) tumors. MAP3K1 was not associated with breast cancer in EA women, but it was associated with breast cancer in AA women, again limited to ER+, PR+ and HER2- tumors. An interaction was observed between combined hormone replacement therapy use and FGFR2 rs1219648 genotypes on breast cancer risk in EA women (P = 0.010). Finally, we observed a significant interaction between MAP3K1 rs889312 and FGFR2 rs2981582 (P = 0.022) in AA but not EA women. These results confirm that FGFR2 and MAP3K1 are involved in breast cancer susceptibility and confer their effects primarily in ER+ and PR+ tumors. We further report that these genes confer their effects in HER2- tumors, interact with one another to confer breast cancer susceptibility in AA women and interact with hormone exposures in AA and EA women.

DeMichele A, Troxel AB, Berlin JA, Weber AL, Bunin GR, Turzo E, Schinnar R, Burgh D, Berlin M, Rubin SC, Rebbeck TR, Strom BL. · Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA. · J Clin Oncol. · Pubmed #18757329 No free full text.

Abstract: PURPOSE: Raloxifene reduces breast cancer risk in women with osteoporosis, and both tamoxifen and raloxifene prevent breast cancer in high-risk women. However, in vitro, raloxifene does not share the pro-estrogenic effects of tamoxifen on the endometrium. Randomized trials of these agents have provided limited information about endometrial cancer risk in the general population. We sought to compare endometrial cancer risks associated with raloxifene, tamoxifen, and nonusers of a selective estrogen receptor modulator (SERM) in the general population and characterize the endometrial tumors occurring in these groups. METHODS: We performed a case-control study of white and African American women age 50 to 79 years in the Philadelphia area. Patients were diagnosed with endometrial cancer between July 1999 and June 2002. Controls were identified through random-digit dialing. RESULTS: We analyzed 547 cases and 1,410 controls. Among cases, 3.3% had taken raloxifene; 6.2% had taken tamoxifen. Among controls, 6.6% had taken raloxifene; 2.4% had taken tamoxifen. After adjustment for other risk factors, the odds of endometrial cancer among raloxifene users was 50% that of nonusers (odds ratio [OR] = 0.50; 95% CI, 0.29 to 0.85), whereas tamoxifen users had three times the odds of developing endometrial cancer compared with raloxifene users (OR = 3.0; 95% CI, 1.3 to 6.9). Endometrial tumors in raloxifene users had a more favorable histologic profile and were predominantly International Federation of Gynecology and Obstetrics stage I and low grade. CONCLUSION: Raloxifene users had significantly lower odds of endometrial cancer compared with both tamoxifen users and SERM nonusers, suggesting a role for raloxifene in endometrial cancer prevention and individualization of SERM therapy.

Halbert CH, Weathers B, Esteve R, Audrain-McGovern J, Kumanyika S, DeMichele A, Barg F. · Department of Psychiatry, Abramson Cancer Center, and Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. · Breast J. · Pubmed #18282235 No free full text.

Abstract: Although weight gain is a common side effect of breast cancer treatment, limited empirical data are available on how African-American breast cancer survivors react to changes in their weight following diagnosis and treatment. The purpose of this study was to explore psychological and behavioral reactions to weight change in African-American breast cancer survivors. We conducted a qualitative study to explore reactions to weight change following diagnosis and treatment in 34 African-American breast cancer survivors. Forty-seven percent of women reported gaining weight, 32% reported weight loss, and 21% reported no changes in their weight. Regardless of whether women gained or lost weight, these changes were viewed as stressors that caused psychological distress and health concerns. However, some women had positive reactions to weight loss, especially if they had been heavy prior to diagnosis. Women exercised and changed their dietary behaviors following treatment. Despite this, women reported being frustrated with not being able to control changes in their weight. These results suggest that changes in weight may be a critical component of breast cancer survivorship in African-American women. It may be important to provide African-American breast cancer survivors with information about the causes and implications of weight change and strategies for weight control after treatment as part of their follow-up care.

Domchek SM, Recio A, Mick R, Clark CE, Carpenter EL, Fox KR, DeMichele A, Schuchter LM, Leibowitz MS, Wexler MH, Vance BA, Beatty GL, Veloso E, Feldman MD, Vonderheide RH. · Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Cancer Res. · Pubmed #17974999 links to  free full text

Abstract: The human telomerase reverse transcriptase (hTERT) is nearly universally overexpressed in human cancer, contributes critically to oncogenesis, and is recognized by cytotoxic T cells that lyse tumors. CD8+ T cells specific for hTERT naturally occur in certain populations of cancer patients in remission, but it remains poorly understood whether such T cells could contribute to tumor immunosurveillance. To address this issue, we induced hTERT-specific T cells in vivo via peptide vaccination in 19 patients with metastatic breast cancer who otherwise had no measurable T-cell responses to hTERT at baseline. Tumor-infiltrating lymphocytes (TIL) were evident after, but not before vaccination, with 4% to 13% of postvaccine CD8+ TIL specific for the immunizing hTERT peptide. Induction of TIL manifested clinically with tumor site pain and pruritus and pathologically with alterations in the tumor microenvironment, featuring histiocytic accumulation and widespread tumor necrosis. hTERT-specific CD8+ T cells were also evident after vaccination in the peripheral blood of patients and exhibited effector functions in vitro including proliferation, IFN-gamma production, and tumor lysis. An exploratory landmark analysis revealed that median overall survival was significantly longer in those patients who achieved an immune response to hTERT peptide compared with patients who did not. Immune response to a control cytomegalovirus peptide in the vaccine did not correlate with survival. These results suggest that hTERT-specific T cells could contribute to the immunosurveillance of breast cancer and suggest novel opportunities for both therapeutic and prophylactic vaccine strategies for cancer.

Rebbeck TR, Troxel AB, Norman S, Bunin G, DeMichele A, Schinnar R, Berlin JA, Strom BL. · Center for Clinical Epidemiology and Biostatistics and Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA. · Am J Epidemiol. · Pubmed #17827444 links to  free full text

Abstract: Combined hormone replacement therapy (CHRT) containing estrogens and progestins is associated with breast cancer risk. The authors evaluated interactions between CHRT use and progestin metabolism genotypes at CYP3A4 and the progesterone receptor (PGR) and their effects on breast cancer risk using the population-based Women's Insights and Shared Experiences (WISE) Study (1999-2002) of postmenopausal Caucasian women (522 breast cancer cases, 708 controls). The authors observed an elevated risk of ductal tumors in women with 3 or more years of CHRT use and PGR 331A alleles compared with those who had neither factor (odds ratio = 3.35, 95% confidence interval (CI): 1.13, 9.99; two-sided p(interaction) = 0.035). They also observed an elevated risk of progesterone receptor-positive tumors in women who had had 3 or more years of CHRT use and PGR 331A alleles compared with those who had neither factor (odds ratio = 3.82, 95% CI: 1.26, 11.55; p = 0.028). Finally, they observed an increased risk of estrogen receptor-negative tumors in women without CHRT exposure and CYP3A4*1B alleles compared with those who had neither factor (odds ratio = 6.46, 95% CI: 2.02, 20.66; p = 0.024), although the biologic interpretation of this result requires further study. When stratified by recency of use, PGR effects were observed only in current CHRT users, while CYP3A4 effects were observed only in former CHRT users. Breast cancer risk in women who have used CHRT may be influenced by genetic factors involved in progestin metabolism.

Rebbeck TR, Troxel AB, Walker AH, Panossian S, Gallagher S, Shatalova EG, Blanchard R, Norman S, Bunin G, DeMichele A, Berlin M, Schinnar R, Berlin JA, Strom BL. · Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, 904 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6021, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #17372239 links to  free full text

Abstract: Estrogen exposures have been associated with breast cancer risk, and genes involved in estrogen metabolism have been reported to mediate that risk. Our goal was to better understand whether combinations of candidate estrogen metabolism genotypes are associated with breast cancer etiology. A population-based case-control study in three counties of the Philadelphia Metropolitan area was undertaken. We evaluated seven main effects and 21 first-order interactions in African Americans and European Americans for genotypes at COMT, CYP1A1, CYP1A2, CYP1B1, CYP3A4, SULT1A1, and SULT1E1 in 878 breast cancer cases and 1,409 matched random digit-dialed controls. In European Americans, we observed main effect associations of genotypes containing any CYP1A1*2C (odds ratio, 1.71; 95% confidence interval, 1.09-2.67) and breast cancer. No significant main effects were observed in African Americans. Three significant first-order interactions were observed. In European Americans, interactions between SULT1A1*2 and CYP1A1*2C genotypes (P(interaction) < 0.001) and between SULT1E1 and CYP1A2*1F genotypes were observed (P(interaction) = 0.006). In African Americans, an interaction between SULT1A1*2 and CYP1B1*4 was observed (P(interaction) = 0.041). We applied the false-positive report probability approach, which suggested that these associations were noteworthy; however, we cannot rule out the possibility that chance led to these associations. Pending future confirmation of these results, our data suggest that breast cancer etiology in both European American and African American postmenopausal women may involve the interaction of a gene responsible for the generation of catecholestrogens with a gene involved in estrogen and catecholestrogen sulfation.

Rebbeck TR, Troxel AB, Norman S, Bunin GR, DeMichele A, Baumgarten M, Berlin M, Schinnar R, Strom BL. · Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6021, USA. · Int J Cancer. · Pubmed #17205521 No free full text.

Abstract: Hormone-related supplements (HRS), many of which contain phytoestrogens, are widely used to manage menopausal symptoms, yet their relationship with breast cancer risk has generally not been evaluated. We evaluated whether use of HRS was associated with breast cancer risk, using a population-based case-control study in 3 counties of the Philadelphia metropolitan area consisting of 949 breast cancer cases and 1,524 controls. Use of HRS varied significantly by race, with African American women being more likely than European American women to use any herbal preparation (19.2% vs. 14.7%, p=0.003) as well as specific preparations including black cohosh (5.4% vs. 2.0%, p=0.003), ginseng (12.5% vs. 7.9%, p<0.001) and red clover (4.7% vs. 0.6%, p<0.001). Use of black cohosh had a significant breast cancer protective effect (adjusted odds ratio 0.39, 95% CI: 0.22-0.70). This association was similar among women who reported use of either black cohosh or Remifemin (an herbal preparation derived from black cohosh; adjusted odds ratio 0.47, 95% CI: 0.27-0.82). The literature reports that black cohosh may be effective in treating menopausal symptoms, and has antiestrogenic, antiproliferative and antioxidant properties. Additional confirmatory studies are required to determine whether black cohosh could be used to prevent breast cancer.

Smith K, Wray L, Klein-Cabral M, Schuchter L, Fox K, Glick J, DeMichele A. · Department of Oncology-Hematology, Memorial-Sloan Kettering Cancer Center, USA. · Clin Breast Cancer. · Pubmed #16137438 No free full text.

Abstract: BACKGROUND: Black patients with breast cancer may be at greater risk for chemotherapy-related hematologic toxicity than white patients because of lower baseline blood cell counts. We hypothesize that these baseline differences could lead to excess hematologic toxicity and greater modification of chemotherapy dosing in black patients and that this may contribute to the poorer survival observed in black patients with breast cancer compared with white patients with breast cancer. PATIENTS AND METHODS: We performed a retrospective cohort study of black and white patients with breast cancer treated with adjuvant chemotherapy at an academic medical center over an 18-month period. Clinical chart review and pharmacy records were used to collect data on the following: modification of chemotherapy dose or administration; hematologic toxicity; blood cell counts before, during, and after therapy; occurrence of febrile neutropenia; use of prophylactic antibiotics; and use of granulocyte colony-stimulating factor in order to determine whether ethnicity was an independent predictor of these outcomes. RESULTS: Among 23 black patients and 98 white patients with breast cancer treated with adjuvant chemotherapy, modification of chemotherapy administration occurred in 56 patients (46%). Modification was more common among black patients (65.2% vs. 41.8%; relative risk [RR], 1.56; P = 0.04). Black patients were more likely to receive reduced cumulative doses of adjuvant chemotherapy (RR, 2.49; P = 0.03). CONCLUSION: Our findings suggest that hematologic tolerability of adjuvant chemotherapy is similar in black and white patients. Strategies aimed at improving psychosocial barriers to adjuvant therapy and at reducing surgical complications in black patients may improve overall breast cancer outcomes in this group.

Choe R, Corlu A, Lee K, Durduran T, Konecky SD, Grosicka-Koptyra M, Arridge SR, Czerniecki BJ, Fraker DL, DeMichele A, Chance B, Rosen MA, Yodh AG. · Department of Physics and Astronomy, University of Pennsylvania, 209 South 33rd Street, Philadelphia, Pennsylvania 19104-6396, USA. · Med Phys. · Pubmed #15895597 No free full text.

Abstract: We employ diffuse optical tomography (DOT) to track treatment progress in a female subject presenting with locally advanced invasive carcinoma of the breast during neoadjuvant chemotherapy. Three-dimensional images of total hemoglobin concentration and scattering identified the tumor. Our measurements reveal tumor shrinkage during the course of chemotherapy, in reasonable agreement with magnetic resonance images of the same subject. A decrease in total hemoglobin concentration contrast between tumor and normal tissue was also observed over time. The results demonstrate the potential of DOT for measuring physiological parameters of breast lesions during chemotherapy.

Purev E, Cai D, Miller E, Swoboda R, Mayer T, Klein-Szanto A, Marincola FM, Mick R, Otvos L, Wunner W, Birebent B, Somasundaram R, Wikstrand CJ, Bigner D, DeMichele A, Acs G, Berlin JA, Herlyn D. · The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA. · J Immunol. · Pubmed #15528389 links to  free full text

Abstract: Mutated epidermal growth factor receptor (EGF-RvIII, DeltaEGF-R, and de2-7 EGF-R) is the result of an 801-bp deletion within the extracellular domain of wild-type EGF-R and is expressed by breast carcinomas, but not by normal breast tissues. EGF-RvIII is expressed both on the surface and in the cytoplasm of tumor cells. Thus, EGF-RvIII is a potential tumor-specific target for both Abs and T cells. However, it is not known whether breast cancer patients can raise immune responses to EGF-RvIII expressed by their tumors. The demonstration of EGF-RvIII-specific immune responses in patients would suggest that immunization of patients with EGF-RvIII vaccines is feasible, because these vaccines may boost a pre-existing immune response. We have evaluated humoral and cellular immune responses to EGF-RvIII in 16 breast cancer patients and three healthy donors. Seven of 16 patients developed EGF-RvIII-specific Abs that bound to isolated EGF-RvIII protein or the protein expressed by EGF-RvIII-transfected mouse fibroblasts. The Abs that bound to EGF-RvIII did not bind to wild-type EGF-R, and anti-EGF-RvIII Abs were not found in the sera of healthy donors. Three patients had EGF-RvIII peptide-specific lymphoproliferative responses, and two of these patients also had humoral immune responses. Humoral and cellular immune responses correlated with EGF-RvIII expression by patients' tumors in most cases. These studies demonstrate that breast cancer patients specifically recognize EGF-RvIII with an overall immune response rate of 50%, suggesting that patients may benefit from vaccination against EGF-RvIII, boosting pre-existing immune responses.

Palmer SC, Kagee A, Coyne JC, DeMichele A. · Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA. · Psychosom Med. · Pubmed #15039512 links to  free full text

Abstract: OBJECTIVES: Cancer would appear to be the paradigmatic example of an acute or chronic illness that can precipitate posttraumatic stress disorder (PTSD). Few studies, however, have examined the applicability of PTSD criteria to patients with cancer. We examined the relationships between the experience of trauma, psychological distress, and PTSD among a waiting room sample of patients with breast cancer. METHODS: We assessed 115 consecutive patients with breast cancer in the waiting room of a large comprehensive cancer center using measures of general distress, posttraumatic stress symptoms, and a semistructured diagnostic interview. RESULTS: A substantial minority (41%) reported responding to cancer with intense fear, helplessness, or horror (DSM-IV A2 criterion). However, cancer-related PTSD was uncommon (4%), and meeting the A2 criterion was a poor indicator of PTSD. Psychological distress was common (38%) and was strongly associated with A2, but was a poor predictor of PSTD. CONCLUSIONS: Although an intense negative emotional reaction to breast cancer was common, PTSD had low prevalence. Results suggest that using a trauma framework to understand the experience of most patients with cancer may be inaccurate.

Coyne JC, Palmer SC, Shapiro PJ, Thompson R, DeMichele A. · Departments of Psychiatry and Hematology/Oncology, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA 19104, USA. · Gen Hosp Psychiatry. · Pubmed #15038929 No free full text.

Abstract: We examined relationships among psychiatric screening, the prevalence of psychiatric morbidity, and prescription rates for psychotropic medication in a waiting room sample of breast cancer patients (N=113). Rates of distress (29%), major depressive disorder (MDD; 9%), and generalized anxiety disorder (GAD; 6%) were low and similar to those found in primary care settings. A substantial proportion of patients (52%) had received psychotropic medication during treatment, including almost half (48%) of those without a current psychiatric diagnosis. Most individuals with MDD received pharmacotherapy during cancer treatment (80%), although only half of those with GAD were treated. Overall high rates psychotropic medication negatively impacted the efficiency of screening, and individuals with elevated distress were about 6 times less likely to represent a case of untreated psychiatric morbidity than to be a new case. We conclude that the risk of psychiatric morbidity attributable to breast cancer may be lower and treatment rates for psychiatric morbidity higher than previously believed and that screening is unlikely to provide efficient identification of untreated psychiatric morbidity. Adequacy of follow-up care is unclear and medication may be prescribed nonspecifically. The low rate of untreated psychiatric morbidity may signal a need for multisite collaborations to generate adequate numbers of participants in clinical trials.

DeMichele A, Martin AM, Mick R, Gor P, Wray L, Klein-Cabral M, Athanasiadis G, Colligan T, Stadtmauer E, Weber B. · Department of Medicine (Heme/Onc), Rowan Breast Center of the Abramson Cancer Center, University of Pennsylvania, 14 Penn Tower, 3400 Spruce Street, Philadelphia, PA 19104, USA. · Cancer Res. · Pubmed #14633738 links to  free full text

Abstract: Axillary lymph node involvement in breast cancer is a marker of recurrence risk. Despite aggressive adjuvant therapy, recurrence in patients with four or more involved lymph nodes approaches 50% at 5 years from diagnosis. Markers that can distinguish those likely to relapse from those likely to be cured are needed to tailor therapy and provide accurate prognostic information to patients. Although most work in this area has focused on tumor characteristics, we hypothesized that the host environment might also play a role in determining risk of relapse. We hypothesized that host inflammatory response, mediated in part by production of interleukin-6 (IL-6), might play a role in the elimination of microscopic residual tumor. Polymorphisms in the IL-6 promoter region appear to modulate serum levels of the cytokine via regulation of gene transcription. A single nucleotide polymorphism involving substitution of cytosine for guanine at position -174 has been associated with reduced transcription and improved outcome in a variety of nonmalignant diseases, including coronary artery disease and several autoimmune conditions. Tumor necrosis factor (TNF) alpha is a proinflammatory cytokine that also plays a role in regulating IL-6 transcription. We hypothesized that polymorphisms in IL-6 (-174 G>C) or TNF-alpha (G-238 or G-308) might be associated with prognosis in a subset of patients with high-risk breast cancer. Genotyping was performed on DNA from stored stem cells in 80 breast cancer patients diagnosed with at least four positive axillary lymph nodes at diagnosis who underwent anthracycline-based adjuvant chemotherapy followed by high-dose multiagent chemotherapy with stem cell rescue. Cox proportional hazards models were used to estimate the effect of genotype and other known prognostic factors on disease-free and overall survival (DFS and OS, respectively). The presence of at least one C allele in the IL-6 promoter at position -174 was significantly associated with both DFS and OS compared with G/G homozygotes. After adjustment for estrogen receptor (ER) status, number of involved lymph nodes, and tumor size, those patients carrying the G/G genotype had a 2.1-fold increase in the rate of failure and a 2.6-fold increase in the rate of death compared with carriers of any C allele at a mean follow-up of 55 months. ER status modulated the effect of IL-6 polymorphism: both DFS and OS were most favorable in patients who were carriers of any C-allele (G/C or C/C) and had ER-positive tumors. The presence of either G/G genotype or an ER-negative tumor increased the hazard of failure [hazard ratio (HR), 2.6 and 3.2, respectively] and death (HR, 2.0 and 2.2, respectively). The combination of both G/G genotype and ER-negative tumor resulted in an additional increase in the hazard of failure (HR, 5.4; four-group comparison, P = 0.003) and death (HR, 6.2; four-group comparison, P = 0.001). TNF-alpha -308 and -238 polymorphisms were not associated with variation in DFS or OS in this cohort. The IL-6-174 promoter polymorphism is associated with clinical outcome in this cohort of node-positive breast cancer patients who received high-dose adjuvant therapy. IL-6 genotype modulated the effect of ER status on outcome. These results support the hypothesis that IL-6 may play an important role in the control of micrometastatic disease in breast cancer. Additional studies are needed to confirm these results and elucidate the mechanisms responsible for these differences.

DeMichele A, Putt M, Zhang Y, Glick JH, Norman S. · Division of Hematology/Oncology, Department of Medicine, and Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. · Cancer. · Pubmed #12712466 links to  free full text

Abstract: BACKGROUND: The appropriate use of adjuvant chemotherapy for elderly women with breast carcinoma remains controversial. Efficacy data in women age >/= 70 years are scarce, resulting in a lack of clear guidelines for patients in this age group. Although several studies have demonstrated decreasing use of chemotherapy with age, none specifically examined its use in an elderly cohort of patients who were deemed eligible for such therapy based on consensus guidelines, simultaneously examining the impact of comorbidity and previous history of malignant disease on these recommendations. METHODS: The authors examined adjuvant chemotherapy use among chemotherapy-eligible patients age > or = 50 years who were evaluated in a tertiary care cancer center. Associations between patient age and 1) physician recommendation for adjuvant chemotherapy, 2) recommended treatment regimen, and 3) patient acceptance of the treatment plan recommended were examined, adjusting for the impact of aggressive tumor characteristics, medical comorbidity, previous history of malignant disease, and features of the treatment setting. RESULTS: Of the 208 chemotherapy-eligible patients who were studied, 74% overall were recommended chemotherapy. Chemotherapy was recommended to 92% of women age 50-59 years compared with 77% of women age 60-69 years and 23% of women age > or = 70 years. Increasing age was associated strongly with a decreasing likelihood of receiving a recommendation in favor of chemotherapy. After adjusting for estrogen receptor status, previous history of malignant disease, comorbidity score, and prognostic group, the odds of receiving a recommendation in favor of chemotherapy fell by 22% per year or 91% per 10-year interval, and the rate of decline did not change significantly at age > or = 70 years. We found no age-related differences in either the drug regimens recommended or patient acceptance rates for adjuvant therapy. CONCLUSIONS: Age was associated strongly and independently with physician recommendation for adjuvant chemotherapy among a group of older women who were eligible specifically for such therapy. Medical comorbidity and a history of previous malignant disease did not alter this correlation significantly, although the latter was a significant predictor of chemotherapy use. Further studies clearly are needed to determine the underlying reasons for this strong age effect and to explore strategies that will optimize the utilization of this potentially curative therapy in the elderly.

DeMichele A, Gimotty P, Botbyl J, Aplenc R, Colligon T, Foulkes AS, Rebbeck TR. · No affiliation provided · J Clin Oncol. · Pubmed #18065748 No free full text.

This publication has no abstract.

DeMichele A, Aplenc R, Botbyl J, Colligan T, Wray L, Klein-Cabral M, Foulkes A, Gimotty P, Glick J, Weber B, Stadtmauer E, Rebbeck TR. · Department of Biostatistics and Epidemiology, Abramson Cancer Center, PA, USA. · J Clin Oncol. · Pubmed #16110016 No free full text.

Abstract: PURPOSE: Adjuvant chemotherapy cures only a subset of women with nonmetastatic breast cancer. Genotypes in drug-metabolizing enzymes, including functional polymorphisms in cytochrome P450 (CYP) and glutathione S-transferases (GST), may predict treatment-related outcomes. PATIENTS AND METHODS: We examined CYP3A4*1B, CYP3A5*3, and deletions in GST mu (GSTM1) and theta (GSTT1), as well as a priori-defined combinations of polymorphisms in these genes. Using a cohort of 90 node-positive breast cancer patients who received anthracycline-based adjuvant chemotherapy followed by high-dose multiagent chemotherapy with stem-cell rescue, we estimated the effect of genotype and other known prognostic factors on disease-free survival (DFS) and overall survival (OS). RESULTS: Patients who carried homozygous CYP3A4*1B and CYP3A5*3 variants and did not carry homozygous deletions in both GSTM1 and GSTT1 (denoted low-drug genotype group) had a 4.9-fold poorer DFS (P = .021) and a four-fold poorer OS (P = .031) compared with individuals who did not carry any CYP3A4*1B or CYP3A5*3 variants but had deletions in both GSTT1 and GSTM1 (denoted high-drug genotype group). After adjustment for other significant prognostic factors, the low-drug genotype group retained a significantly poorer DFS (hazard ratio [HR] = 4.9; 95% CI, 1.7 to 14.6; P = .004) and OS (HR = 4.8; 95% CI, 1.8 to 12.9; P = .002) compared with the high- and intermediate-drug combined genotype group. In the multivariate model, having low-drug genotype group status had a greater impact on clinical outcome than estrogen receptor status. CONCLUSION: Combined genotypes at CYP3A4, CYP3A5, GSTM1, and GSTT1 influence the probability of treatment failure after high-dose adjuvant chemotherapy for node-positive breast cancer.