Breast Neoplasms: Lippman SM

Visvanathan K, Chlebowski RT, Hurley P, Col NF, Ropka M, Collyar D, Morrow M, Runowicz C, Pritchard KI, Hagerty K, Arun B, Garber J, Vogel VG, Wade JL, Brown P, Cuzick J, Kramer BS, Lippman SM, Anonymous00092. · Cancer Policy and Clinical Affairs, 2318 Mill Rd, Suite 800, Alexandria, VA 22314, USA. · J Clin Oncol. · Pubmed #19470930 No free full text.

Abstract: PURPOSE To update the 2002 American Society of Clinical Oncology guideline on pharmacologic interventions for breast cancer (BC) risk reduction. METHODS A literature search identified relevant randomized trials published since 2002. Primary outcome of interest was BC incidence (invasive and noninvasive). Secondary outcomes included BC mortality, adverse events, and net health benefits. An expert panel reviewed the literature and developed updated consensus guidelines. Results Seventeen articles met inclusion criteria. In premenopausal women, tamoxifen for 5 years reduces the risk of BC for at least 10 years, particularly estrogen receptor (ER) -positive invasive tumors. Women < or = 50 years of age experience fewer serious side effects. Vascular and vasomotor events do not persist post-treatment across all ages. In postmenopausal women, raloxifene and tamoxifen reduce the risk of ER-positive invasive BC with equal efficacy. Raloxifene is associated with a lower risk of thromboembolic disease, benign uterine conditions, and cataracts than tamoxifen in postmenopausal women. No evidence exists establishing whether a reduction in BC risk from either agent translates into reduced BC mortality. Recommendations In women at increased risk for BC, tamoxifen (20 mg/d for 5 years) may be offered to reduce the risk of invasive ER-positive BC, with benefits for at least 10 years. In postmenopausal women, raloxifene (60 mg/d for 5 years) may also be considered. Use of aromatase inhibitors, fenretinide, or other selective estrogen receptor modulators to lower BC risk is not recommended outside of a clinical trial. Discussion of risks and benefits of preventive agents by health providers is critical to patient decision making.

Howe LR, Lippman SM. · No affiliation provided · J Natl Cancer Inst. · Pubmed #18840814 No free full text.

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Lippman SM. · No affiliation provided · Nat Clin Pract Oncol. · Pubmed #17019426 No free full text.

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William WN, Heymach JV, Kim ES, Lippman SM. · Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. · Nat Rev Drug Discov. · Pubmed #19247304 No free full text.

Abstract: Vaccines targeting infections with hepatitis B virus, a risk factor for hepatocellular cancer, and human papillomavirus, a risk factor for cervical cancer, are considered major clinical cancer chemoprevention successes. Molecularly targeted agents can prevent breast cancer (raloxifene and tamoxifen), colorectal adenomas (celecoxib), and prostate cancer (finasteride). Nevertheless, the broad translation of chemoprevention to the clinic is not yet a reality. Continuing research of molecular targets promises to expand the reach of chemoprevention and to personalize it as well.

Kelloff GJ, Lippman SM, Dannenberg AJ, Sigman CC, Pearce HL, Reid BJ, Szabo E, Jordan VC, Spitz MR, Mills GB, Papadimitrakopoulou VA, Lotan R, Aggarwal BB, Bresalier RS, Kim J, Arun B, Lu KH, Thomas ME, Rhodes HE, Brewer MA, Follen M, Shin DM, Parnes HL, Siegfried JM, Evans AA, Blot WJ, Chow WH, Blount PL, Maley CC, Wang KK, Lam S, Lee JJ, Dubinett SM, Engstrom PF, Meyskens FL, O'Shaughnessy J, Hawk ET, Levin B, Nelson WG, Hong WK, Anonymous00033. · National Cancer Institute, Bethesda, Maryland 20852, USA. · Clin Cancer Res. · Pubmed #16778094 links to  free full text

Abstract: This article reviews progress in chemopreventive drug development, especially data and concepts that are new since the 2002 AACR report on treatment and prevention of intraepithelial neoplasia. Molecular biomarker expressions involved in mechanisms of carcinogenesis and genetic progression models of intraepithelial neoplasia are discussed and analyzed for how they can inform mechanism-based, molecularly targeted drug development as well as risk stratification, cohort selection, and end-point selection for clinical trials. We outline the concept of augmenting the risk, mechanistic, and disease data from histopathologic intraepithelial neoplasia assessments with molecular biomarker data. Updates of work in 10 clinical target organ sites include new data on molecular progression, significant completed trials, new agents of interest, and promising directions for future clinical studies. This overview concludes with strategies for accelerating chemopreventive drug development, such as integrating the best science into chemopreventive strategies and regulatory policy, providing incentives for industry to accelerate preventive drugs, fostering multisector cooperation in sharing clinical samples and data, and creating public-private partnerships to foster new regulatory policies and public education.

Lippman SM, Lee JJ. · Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4009, USA. · Cancer Res. · Pubmed #16540634 links to  free full text

Abstract: Two large-scale, phase III cancer prevention trials, the Breast Cancer Prevention Trial (BCPT) of tamoxifen and Prostate Cancer Prevention Trial (PCPT) of finasteride, concluded with strikingly positive and simultaneously problematic results: reduced cancer risks but a major adverse finding with each agent that prevented its widespread use in the community. For most moderate-risk people, such as those studied in the BCPT and PCPT, the benefit of reduced breast or prostate cancer does not outweigh the major risk of tamoxifen (endometrial cancer in the BCPT) or apparent risk of finasteride (high-grade prostate cancer in the PCPT). Promising interventions with biologically active substances are likely to have adverse, perhaps unforeseen effects, especially with long-term preventive use. Acceptance of such agents will depend heavily on the level of cancer risk of the target population. This article outlines research in molecularly identified high-risk oral intraepithelial neoplasia that creates the clinical opportunity for optimizing the risk-benefit ratio of agents to prevent oral cancer. Two other major research efforts focused on improving preventive agent risk-benefit ratios are molecular-targeted research designed to target away from known adverse signaling pathways and multidisciplinary research based on the PCPT that will develop comprehensive models of prostate cancer risk (especially of aggressive prostate cancer) and pharmacoecogenetic models for identifying high-risk men most likely to benefit from (and not be harmed by) finasteride or similar (5alpha-reductase inhibiting) agents. Defining and targeting high-risk populations, developing molecular-targeted approaches, and developing accurate pharmacoecogenetic models promise to reduce the risk of chemoprevention and ultimately to reduce the risk and burden of major cancers.

Demierre MF, Higgins PD, Gruber SB, Hawk E, Lippman SM. · Department of Dermatology, Boston University School of Medicine, 720 Harrison Avenue DOB 801A, Boston, MA 02118, USA. · Nat Rev Cancer. · Pubmed #16341084 No free full text.

Abstract: Randomized controlled trials for preventing cardiovascular disease indicated that statins had provocative and unexpected benefits for reducing colorectal cancer and melanoma. These findings have led to the intensive study of statins in cancer prevention, including recent, large population-based studies showing statin-associated reductions in overall, colorectal and prostate cancer. Understanding the complex cellular effects (for example, on angiogenesis and inflammation) and the underlying molecular mechanisms of statins (for example, 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase-dependent processes that involve geranylgeranylation of Rho proteins, and HMG-CoA-independent processes that involve lymphocyte-function-associated antigen 1) will advance the development of molecularly targeted agents for preventing cancer. This understanding might also help the development of drugs for other ageing-related diseases with interrelated molecular pathways.

Brown PH, Lippman SM. · Breast Center, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA. · Breast Cancer Res Treat. · Pubmed #10989982 No free full text.

Abstract: Despite a recent trend toward improvement in the U.S. breast cancer mortality rate, breast cancer incidence (182,800 new cases anticipated in 2000) and mortality figures (over 40,800 anticipated deaths) remain the highest and second highest, respectively, of all cancers in U.S. women. In 1998, the selective-estrogen-receptor-modulator (SERM) tamoxifen achieved positive results in the Breast Cancer Prevention Trial (BCPT), leading to the Food and Drug Administration (FDA) approval of tamoxifen for risk reduction in women at high risk of breast cancer (the historic first FDA approval of a cancer preventive agent). This brought about a paradigm shift in new approaches for controlling breast cancer toward pharmacologic preventive regimens, called chemoprevention. This paper presents a comprehensive clinical review of breast cancer prevention study, highlighting issues of the extensive study of tamoxifen. These issues include the record of primary tamoxifen results in several breast-cancer risk-reduction settings (primary, adjuvant, and ductal carcinoma in situ [DCIS]); critical secondary BCPT risk-benefit findings (including quality of life issues) and their effects on counseling patients on use of tamoxifen for prevention; ethic minorities; optimal tamoxifen dose/duration; and potential impact on mortality and other issues involved with potential net benefit to society. Other breast-cancer chemoprevention issues reviewed here include women at high genetic risk (especially BRCA1 mutation carriers); raloxifene in breast cancer prevention; other SERMs; SERM resistance; and new agents and combinations currently in development. Very recent developments involving PPAR-gamma ligands, COX-2 inhibitors, and RXR-ligands are discussed in the section on new drug development.

Lippman SM, Lotan R. · Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. · J Nutr. · Pubmed #10721933 links to  free full text

Abstract: With the inclusion of brief discussions of retinoid drug development in animal carcinogenesis models (e.g., skin, breast, oral cavity, lung, prostate or bladder) and clinical trials (e.g., head and neck or cervix), this review will focus on recent advances in retinoid molecular targeting studies designed primarily to develop retinoids with reduced toxicity, while maintaining or enhancing activity in the context of chemoprevention. Major current retinoid molecular targets include the six known nuclear retinoid receptors (RAR and RXR). Receptor numbers, distinct functions, tissue-expression patterns, ligand specificities, functional redundancy and regulation of multiple pathways make retinoid signaling highly complex. Development of receptor-selective synthetic retinoids is a major focus of molecular retinoid development. RAR heterodimerize with RXR and mediate classic retinoid activity/toxicity. RXR are more promiscuous, heterodimerizing with several other members of the steroid receptor superfamily [e.g., peroxisome proliferator-activated receptors (PPAR) or vitamin D receptors]. RXR-selective ligands are less toxic and more active in animal breast cancer prevention studies and less toxic than RAR ligands in clinical trials. Other new avenues of retinoid molecular drug development include newly identified retinoid-regulated genes, orphan-receptor ligands/functions, novel retinoid mechanisms involving potent receptor-independent apoptosis-inducing activity (e.g., 4-HPR or anhydroretinol), synergistic combinations [e.g., RXR agonists plus selective estrogen receptor modulators (SERM)], activity in other diseases and novel delivery systems.

McCaskill-Stevens W, Hawk ET, Flynn PJ, Lippman SM. · Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892, USA. · J Clin Oncol. · Pubmed #10630263 No free full text.

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Lippman SM, Brown PH. · S.M. Lippman, Department of Clinical Cancer Prevention, Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA. · J Natl Cancer Inst. · Pubmed #10547388 links to  free full text

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Goodwin JW, Green SJ, Moinpour CM, Bearden JD, Giguere JK, Jiang CS, Lippman SM, Martino S, Albain KS. · Cancer Research for the Ozarks, 1730 E Republic Rd, Suite V, Springfield, MO 65804, USA. · J Clin Oncol. · Pubmed #18375894 No free full text.

Abstract: PURPOSE: Prior progestin studies treating hot flashes in women have been short duration and single dose. This study tests the progestin megestrol acetate (MA) at two doses versus placebo over 6 months. PATIENTS AND METHODS: Patients with T1-3, N0-1, M0 breast cancer were eligible after completion of surgery and chemotherapy and at least 4 months of tamoxifen (if prescribed). Women were required to have at least 10 hot flashes of any severity or at least five severe episodes per week. Patients were randomly assigned to placebo, MA 20 mg, or MA 40 mg for 3 months. Success at 3 months was defined as completion of treatment with a >or= 75% reduction in hot flashes from baseline. If success was achieved, drug treatment for another 3 months was given on the same blinded arm; if not, open-label MA 20 mg was added to blinded study drug and continued for 3 months. Other menopausal symptoms were also assessed. RESULTS: Two hundred eighty eight eligible women were randomly assigned (286 eligible), of whom 85% were on tamoxifen, 40% had over 63 hot flashes/week, and 75% had vasomotor symptoms for >or= 6 months. Success at 3 months was 14% on placebo, 65% on 20 mg, and 48% on 40 mg (both MA doses superior to placebo; P < .0001). Most successes at 3 months were maintained at 6 months (77% on 20 mg and 81% on 40 mg). CONCLUSION: MA significantly reduced vasomotor symptoms with durable benefit over 6 months. MA 20 mg/d is the preferred dose. There was no significant impact on other menopausal symptoms.

Singletary SE, Atkinson EN, Hoque A, Sneige N, Sahin AA, Fritsche HA, Lotan R, Lu T, Hittelman WN, Bevers TB, Stelling CB, Lippman SM. · Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. · Clin Cancer Res. · Pubmed #12231524 links to  free full text

Abstract: PURPOSE: Surrogate end point biomarkers (SEBs) that can be measured in ductal carcinoma in situ or early-stage invasive cancer are needed to improve the efficiency and reduce the cost of chemoprevention trials. EXPERIMENTAL DESIGN: We conducted a prospective study to develop SEBs for tamoxifen and N-[4-hydroxyphenyl]retinamide by administering either a placebo or both drugs for 2-4 weeks to women with ductal carcinoma in situ or early invasive cancers in the interval between the initial diagnostic core biopsy and definitive surgery. The major statistical end point of the study was pre- versus posttreatment change in cell proliferation, as measured by changes in Ki67 labeling indices. In addition, estrogen receptor (ER), HER2/neu, p53, retinoid receptors, and DNA index were measured. RESULTS: Between February 1997 and April 200, 52 patients were registered on the study, and 36 (20 in the placebo arm and 16 in the treatment arm) were available for analysis. No statistically significant pre- versus posttreatment differences in Ki67 labeling index or in the other markers were observed in the treatment arm compared with the placebo arm. There was a trend toward increased treatment response in ER-positive versus ER-negative patients, but this could not be rigorously analyzed because of the low sample size and the unequal distribution of ER-positive patients in the two study arms. CONCLUSION: Future SEB trials for breast carcinoma must (a) incorporate information about patient hormonal status into the study design and (b) resolve problems in patient accrual.

Khuri FR, Kim ES, Lee JJ, Winn RJ, Benner SE, Lippman SM, Fu KK, Cooper JS, Vokes EE, Chamberlain RM, Williams B, Pajak TF, Goepfert H, Hong WK. · University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #11489748 links to  free full text

Abstract: Second primary tumors (SPTs) develop at an annual rate of 3-7% in patients with head and neck squamous cell cancer (HNSCC). In a previous Phase III study, we observed that high doses of 13-cis-retinoic acid reduced the SPT rate in this disease. In 1991, we launched an intergroup, placebo-controlled, double-blind study to evaluate the efficacy of low-dose 13-cis-retinoic acid in the prevention of SPTs in patients with stage I or II squamous cell carcinoma of the larynx, oral cavity, or pharynx who had been previously successfully treated with surgery, radiotherapy, or both, and whose diagnoses had been established within 36 months of study entry. As of September 16, 1999, the Retinoid Head and Neck Second Primary (HNSP) Trial had completed accrual with 1384 registered patients and 1191 patients randomized and eligible. All of the patients were followed for survival, SPT development, and index cancer recurrence. Smoking status was assessed at study entry and during study. Smoking cessation was confirmed biochemically by measurement of serum cotinine levels. The annual rate of SPT development was analyzed in terms of smoking status and tumor stage. As of May 1, 2000, SPTs have developed in 172 patients. Of these, 121 (70.3%) were tobacco-related SPTs, including 113 in the aerodigestive tract (57 lung SPTs, 50 HNSCC SPTs, and 6 esophageal SPTs) and 8 bladder SPTs. The remaining 51 cases included 23 prostate adenocarcinomas, 8 gastrointestinal malignancies, 6 breast cancers, 3 melanomas, and 11 other cancers. The annual rate of SPT development observed in our study has been 5.1%. SPT development related to smoking status was marginally significant (active versus never, 5.7% versus 3.5%; P = 0.053). Significantly different smoking-related SPT development rates were observed in current, former, and never smokers (annual rate = 4.2%, 3.2%, and 1.9%, respectively, overall P = 0.034; current versus never smokers, P = 0.018). Stage II HNSCC had a higher overall annual rate of SPT development (6.4%) than did stage I disease (4.3%; P = 0.004). When evaluating the development of smoking-related SPTs, stage was also highly significant (4.8% for stage II versus 2.7% for stage I; P = 0.001). Smoking-related SPT incidence was significant for site as well (larynx versus oral cavity, P = 0.015; larynx versus pharynx, P = 0.011). Primary tumors recurred at an annual rate of 2.8% in a total of 97 patients. The rate of recurrence was higher in patients with stage II disease (4.1% versus 2.2%, P = 0.004) as well as oral cavity site when compared with larynx (P = 0.002). This is the first large-scale prospective chemoprevention study evaluating smoking status and its impact on SPT development and recurrence rate in HNSCC. The results indicate significantly higher SPT rates in active smokers versus never smokers and significantly higher smoking-related SPT rates in active smokers versus never smokers, with intermediate rates for former smokers.

Singletary E, Lieberman R, Atkinson N, Sneige N, Sahin A, Tolley S, Colchin M, Bevers T, Stelling C, Fornage B, Fritsche H, Hittelman W, Kelloff G, Lippman SM. · Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #11045792 links to  free full text

Abstract: Surrogate end point biomarkers for risk assessment and efficacy of potential chemopreventive agents are needed to improve the efficiency and reduce the cost of chemoprevention trials. It is imperative to develop the best clinical breast model for translational surrogate end point biomarker studies, especially with respect to accrual feasibility. We have initiated a prospective study to develop biomarkers for tamoxifen and N-[4-hydroxyphenyl] retinamide by administering either a placebo or both drugs for 2-4 weeks to women with ductal carcinoma in situ or early invasive cancers in the interval between the initial diagnostic core biopsy and definitive surgery. The principle end point is pretreatment versus posttreatment tumor levels of Ki-67; a number of other exploratory markers will also be examined. The planned target sample size is 100 patients. Between February 1997 and February 2000, 4514 women who had either an abnormal mammogram or a diagnosed breast cancer were screened for the study. Of these 4514 screened patients, 52 (1%) were registered on the study. Major factors of nonparticipation in the remaining 4462 women were as follows: (a) no evidence of malignancy (2081 patients; 46%); (b) ineligible per protocol criteria (575 patients; 13%); (c) preoperative chemotherapy/tamoxifen (520 patients; 11%); (d) surgery scheduling conflict (360 patients; 8%); (e) outside needle biopsy (221 patients; 5%); (f) no residual disease after excisional biopsy (345 patients; 8%); and (g) second opinion only (123 patients; 3%). Other nonparticipation factors included fine needle aspiration only, refusal, tumor size > 2 cm, and estrogen replacement therapy (35 patients each; 2% each). The protocol was amended in midstudy to allow outside needle biopsy, tumor > 2 cm, and estrogen replacement therapy. Accrual to biomarker (nontherapeutic) protocols with delay in definitive cancer surgery is challenging but feasible. Although some accrual problems remain, we have nonetheless succeeded in recruiting 50% of our target sample size in a 3-year period.

Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, Bevers TB, Fehrenbacher L, Pajon ER, Wade JL, Robidoux A, Margolese RG, James J, Lippman SM, Runowicz CD, Ganz PA, Reis SE, McCaskill-Stevens W, Ford LG, Jordan VC, Wolmark N, Anonymous00147. · Magee-Womens Hospital, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, Pa 15213-3221, USA. · JAMA. · Pubmed #16754727 links to  free full text

Abstract: CONTEXT: Tamoxifen is approved for the reduction of breast cancer risk, and raloxifene has demonstrated a reduced risk of breast cancer in trials of older women with osteoporosis. OBJECTIVE: To compare the relative effects and safety of raloxifene and tamoxifen on the risk of developing invasive breast cancer and other disease outcomes. DESIGN, SETTING, AND PATIENTS: The National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene trial, a prospective, double-blind, randomized clinical trial conducted beginning July 1, 1999, in nearly 200 clinical centers throughout North America, with final analysis initiated after at least 327 incident invasive breast cancers were diagnosed. Patients were 19,747 postmenopausal women of mean age 58.5 years with increased 5-year breast cancer risk (mean risk, 4.03% [SD, 2.17%]). Data reported are based on a cutoff date of December 31, 2005. INTERVENTION: Oral tamoxifen (20 mg/d) or raloxifene (60 mg/d) over 5 years. MAIN OUTCOME MEASURES: Incidence of invasive breast cancer, uterine cancer, noninvasive breast cancer, bone fractures, thromboembolic events. RESULTS: There were 163 cases of invasive breast cancer in women assigned to tamoxifen and 168 in those assigned to raloxifene (incidence, 4.30 per 1000 vs 4.41 per 1000; risk ratio [RR], 1.02; 95% confidence interval [CI], 0.82-1.28). There were fewer cases of noninvasive breast cancer in the tamoxifen group (57 cases) than in the raloxifene group (80 cases) (incidence, 1.51 vs 2.11 per 1000; RR, 1.40; 95% CI, 0.98-2.00). There were 36 cases of uterine cancer with tamoxifen and 23 with raloxifene (RR, 0.62; 95% CI, 0.35-1.08). No differences were found for other invasive cancer sites, for ischemic heart disease events, or for stroke. Thromboembolic events occurred less often in the raloxifene group (RR, 0.70; 95% CI, 0.54-0.91). The number of osteoporotic fractures in the groups was similar. There were fewer cataracts (RR, 0.79; 95% CI, 0.68-0.92) and cataract surgeries (RR, 0.82; 95% CI, 0.68-0.99) in the women taking raloxifene. There was no difference in the total number of deaths (101 vs 96 for tamoxifen vs raloxifene) or in causes of death. CONCLUSIONS: Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer. The risk of other cancers, fractures, ischemic heart disease, and stroke is similar for both drugs. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003906.

Ewart-Toland A, Dai Q, Gao YT, Nagase H, Dunlop MG, Farrington SM, Barnetson RA, Anton-Culver H, Peel D, Ziogas A, Lin D, Miao X, Sun T, Ostrander EA, Stanford JL, Langlois M, Chan JM, Yuan J, Harris CC, Bowman ED, Clayman GL, Lippman SM, Lee JJ, Zheng W, Balmain A. · UCSF Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA. · Carcinogenesis. · Pubmed #15802297 links to  free full text

Abstract: STK15 (Aurora-A) is a serine/threonine kinase involved in mitotic chromosomal segregation. A genetic variant in STK15 T+91A (resulting in the amino acid substitution F31I) is associated with increased aneuploidy in colon tumors and cell transformation in vitro. Since this polymorphism plays a role in mitotic control-a process critical for all cancer types-we conducted association analyses for risk of cancer development of the colon, breast, prostate, skin, lung and esophagus in 10 independent case-control populations. We carried out a meta-analysis of these 10 case-control studies together with 5 additional published studies for a total of 9549 cases of breast, colon, ovarian, prostate, lung, esophageal and non-melanoma skin cancer and 8326 population or hospital-based controls. Meta-analysis of three colorectal cancer studies showed an increased risk in T+91A homozygotes (OR=1.50; 95% CI of 1.14-1.99). Meta-analysis of four breast cancer studies showed increased risk for T+91A homozygotes (OR=1.35, 95% CI of 1.12-1.64). The results of the multiple cancer type meta-analysis for all 15 studies combined were significant for cancer risk in both homozygotes and heterozygotes. The T+91A heterozygotes show an OR of 1.10 (95% CI of 1.03-1.18, P-value=0.006) and the T+91A homozygotes show an OR of 1.40 (95% CI of 1.22-1.59, P-value<0.001) for cancer risk. These results confirm that the STK15 T+91A variant is a low penetrance cancer susceptibility allele affecting multiple cancer types, and provide genetic evidence from large-scale human population studies that genetic stability at the chromosome level is an important determinant of cancer susceptibility. The data also underline the advantages of comparative association studies involving study populations from different ethnic groups for determination of disease risk.

Hoque A, Carter J, Xia W, Hung MC, Sahin AA, Sen S, Lippman SM. · Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #14693746 links to  free full text

Abstract: The biological mechanisms involved in the progression of ductal carcinoma in situ (DCIS) to invasive breast cancer are not fully understood. We previously have shown that the putative oncogene Aurora-A/STK15/BTAK, encoding a centrosome-associated kinase that regulates centrosomes and chromosome segregation, is amplified in human breast cancer. In this study, 37 archival breast tissue specimens of histologically confirmed DCIS lesions with adjacent invasive carcinoma and morphologically nonmalignant mammary ducts were analyzed immunohistochemically for expression of STK15. Statistically significant differences in overexpression of STK15 was found between invasive cancer and either nonmalignant mammary ducts (P < 0.0001) or DCIS lesions (P < 0.0005). Abnormalities in centrosome size and number was detected in the samples analyzed and 56% (14 of 25) of the cases also showed aneuploidy reflected in >2 signals of chromosome 3 and 17. Our data demonstrate that STK15 overexpression correlates with centrosome anomaly and aneuploidy in DCIS, and loss of STK15 overexpression is associated with progression of in situ to ductal invasive breast carcinoma.

Wang L, Hoque A, Luo RZ, Yuan J, Lu Z, Nishimoto A, Liu J, Sahin AA, Lippman SM, Bast RC, Yu Y. · Departments of Experimental Therapeutics [L. W., R. Z. L., J. Y., Z. L., A. N., R. C. B., Y. Y.], Clinical Cancer Prevention [A. H., S. M. L.], and Pathology [J. L., A. A. S.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030. · Clin Cancer Res. · Pubmed #14506155 links to  free full text

Abstract: PURPOSE: Ductal carcinoma in situ (DCIS) is a preinvasive-stage breast carcinogenesis that accounts for approximately 20 approximately 25% of mammographically detected breast cancers. A significant fraction of untreated DCIS will evolve into invasive cancer. ras homologue I (ARHI) is an imprinted tumor suppressor gene that is expressed in normal breast epithelial cells but absent or down-regulated in breast cancer cells. This study investigated the relationship of ARHI expression to the progression of breast cancer. EXPERIMENTAL DESIGN: We analyzed ARHI expression in DCIS, invasive breast carcinoma, and adjacent normal breast epithelium from 64 formalin-fixed, paraffin-embedded DCIS specimens by both immunohistochemistry and in situ hybridization. We also analyzed the correlation between ARHI expression and progression of breast cancer, as well as the correlation of ARHI expression and cyclin D1 and p21(WAF1/CIP1) expression in DCIS. RESULTS: Normal breast epithelium was found in all of the specimens and invasive breast carcinoma was found in 23 specimens. ARHI mRNA and protein were detected in all of the normal breast epithelia. ARHI expression was detected mainly in cytoplasm and rarely present in the nucleus. By histochemical analysis, ARHI expression was down-regulated in 41% (26 of 64) of DCIS and 70% (16 of 23) of invasive carcinomas comparing the specimens with adjacent normal breast epithelium. When DCIS and invasive cancer were present in the same sample, ARHI was further down-regulated in 26% (6 of 23) of invasive carcinoma. In four cases [4 (17%) of 23] of invasive carcinoma, ARHI protein expression was totally lost. Consistent results were obtained with an in situ hybridization assay for ARHI at the mRNA level. Higher levels of expression of cyclin D1 and p21(WAF1/CIP1) were observed in DCIS than in the adjacent epithelia. The expression of cyclin D1 and p21(WAF1/CIP1) was inversely correlated with that of ARHI. CONCLUSIONS: Our results indicate that ARHI expression is markedly down-regulated in DCIS, and a further decrease in ARHI expression is associated with progression of breast cancer.

Sabichi AL, Modiano MR, Lee JJ, Peng YM, Xu MJ, Villar H, Dalton WS, Lippman SM. · Departments of Clinical Cancer Prevention and Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. · Clin Cancer Res. · Pubmed #12855611 links to  free full text

Abstract: PURPOSE: The synthetic retinoid N-(4-hydroxyphenyl)retinamide [4-HPR (or fenretinide)] has preclinical and clinical preventive activity in breast carcinogenesis. 4-HPR and its metabolites have been shown to accumulate in the mammary tissue of rodents. We assessed levels of 4-HPR and its major metabolite, N-(4-methoxyphenyl)retinamide (4-MPR), in plasma and in normal and neoplastic breast tissue obtained from women treated with 4-HPR. Experimental Design: We randomly assigned 14 women with suspected or very recently diagnosed breast cancer to receive 100, 200, or 300 mg of 4-HPR daily for 3-12 days before scheduled biopsy, lumpectomy, or mastectomy. Using high-performance liquid chromatography, we measured post-4-HPR-treatment concentrations of 4-HPR and 4-MPR in plasma and breast tissue obtained during surgery. RESULTS: Breast tissue and plasma retinamide (4-HPR plus 4-MPR) concentrations increased significantly with short-term oral administration of 4-HPR. Retinamide levels increased in a linear and dose-related fashion in plasma, whereas they peaked and plateaued at 200 mg/day in breast tissue. The total retinamide concentration in breast tissue exceeded that in plasma at each 4-HPR dose. The highest mean tissue:plasma retinamide ratios were achieved at 200 mg/day: 639.5 +/- 253.8 to 190.6 +/- 91.9 ng/ml (4.8:1) for 4-HPR and 594.4 +/- 201.9 to 130.5 +/- 37.8 ng/ml (6.6:1) for 4-MPR. Plasma retinol levels decreased in association with increasing 4-HPR doses. Two patients experienced grade 1 toxicity at the 300 mg/day dose. CONCLUSIONS: These findings indicate that retinamides preferentially accumulate in human breast tissue (versus plasma). 4-HPR tissue concentrations at 200 mg/d were equivalent to those that inhibit growth and induce apoptosis of breast cancer cells in vitro. Previous clinical and correlative laboratory results suggest that 4-HPR may reduce risk in premenopausal women, who are more prone (than are postmenopausal women) to estrogen receptor (ER)-negative breast cancer development. The present results and previous data (including in vitro 4-HPR activity against ER-negative breast cancer) support further study of 4-HPR in the setting of premenopausal/ER-negative breast cancer prevention.

Hoque A, Sneige N, Sahin AA, Menter DG, Bacus JW, Hortobagyi GN, Lippman SM. · Departments of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #12050101 links to  free full text

Abstract: This study evaluated the relative frequencies of HER-2/neu gene amplification in ductal carcinoma in situ (DCIS)-associated invasive breast cancer and DCIS alone. We examined archival tissue samples of 100 DCIS lesions with an invasive component (cases) and 100 without an invasive component (controls), with cases and controls matched by pathologic nuclear grade. HER-2/neu gene amplification was determined by fluorescence in situ hybridization. We compared HER-2/neu gene amplification in DCIS lesions only, irrespective of the presence or absence of an invasive component. HER-2/neu gene amplification occurred significantly less frequently in the cases (26%) than in the controls (40%), with an odds ratio of 0.35 (95% confidence interval, 0.17-0.72; P < 0.004) after adjustment for pathologic and quantitative-image-analyzed morphometric nuclear grade. The HER-2/neu gene also was amplified more frequently in higher- than in lower-grade DCIS alone (56% versus 19%, respectively; P < 0.0001) or in higher- than in lower-grade DCIS with invasive cancer (44% versus 2%, respectively; P < 0.00001). Future studies should examine the potential roles of HER-2/neu and other biomarkers (e.g., p21 and Rb) as markers of the risk of DCIS patients for invasive breast cancer and as molecular targets of chemoprevention in breast intraepithelial neoplasia.

Menter DG, Hoque A, Motiwala N, Sahin AA, Sneige N, Lieberman R, Lippman SM. · Departments of Clinical Cancer Prevention and Pathology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA. · Anal Quant Cytol Histol. · Pubmed #11444192 No free full text.

Abstract: OBJECTIVE: To develop and determine the staining protocols and computerized image analysis methods that are the most effective combination for performing quantitative analysis of Ki-67. STUDY DESIGN: We compared conventional bright-field light microscopy and refractive optical enhancement methods in combination with various immunodetection and filter enhancement methods, including immunogold in combination with epipolarization refractive optics and enzymatic conversion of chromogenic substrates in combination with optical filter enhancement. Initial Ki-67 tests were performed on lymph node tissues and cultured human breast cells and then applied to 200 ductal carcinoma in situ (DCIS) samples. DCIS acini were digitally acquired, and a region of interest was manually outlined in each one with a digital stylus to include only the cellular component; then the Ki-67 staining index was quantified by segmentation analysis. RESULTS: Although combining epipolarization analysis with immunohistogold staining was the most sensitive detection method, nonspecific binding was too high. The streptavidin-horseradish-peroxidase enzymatic conversion of 3,3'-diaminobenzidine (DAB) in combination with optical enhancement filters was the most effective method tested. Ki-67 stain was associated with dense fibrillar structures of the nucleoli in the less intensely staining nuclei and was most intense in paired nuclei. CONCLUSION: The method of measuring Ki-67 expression by DAB staining combined with optical enhancement filters and quantification via computer-assisted image analysis techniques produced objective and reproducible results. As such, this method can offer (1) less intraobserver and interobserver variability, (2) a digital archival record, and (3) a baseline for digital exchange of information between studies.

Hoque A, Lippman SM, Boiko IV, Atkinson EN, Sneige N, Sahin A, Weber DM, Risin S, Lagios MD, Schwarting R, Colburn WJ, Dhingra K, Follen M, Kelloff GJ, Boone CW, Hittelman WN. · Department of Clinical Cancer Prevention, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #11303595 links to  free full text

Abstract: Clinical management of ductal carcinoma in situ (DCIS) remains a challenge because significant proportions of patients experience recurrence after conservative surgical treatment. Unfortunately, it is difficult to prospectively identify, using objective criteria, patients who are at high risk of recurrence and might benefit from additional treatment. We conducted a multi-institutional, collaborative case-control study to identify nuclear morphometric features that would be useful for identifying women with DCIS at the highest risk of recurrence. Tissue sections of archival breast tissue of 29 women with recurrent and 73 matched women with nonrecurrent DCIS were stained for DNA, and nuclei in the DCIS lesions were evaluated by image analysis. A clear correlation between mean fractal2_area (FA2) and nuclear grade was observed (P < 0.001), allowing an objective determination of nuclear grade. Several nuclear morphometric features, including mean and variance of variation of radius, mean area, mean and variance of frequency of high boundary harmonics (FQH), and variance in sphericity, were found to be useful in discriminating recurrent from nonrecurrent DCIS subjects. However, the nuclear features associated with recurrence differed between high- and low-grade lesions. For lesions with high FA2 (nuclear grade 3), mean variation of radius, mean FQH, and mean area alone yielded recurrence odds ratios of 4.55 [95% confidence interval (CI) 0.45-45.96], 3.86 (95% CI, 0.88-16.98), 2.90 (95% CI, 0.31-27.2), respectively. Using a summed feature model, high-FA2 lesions showing three poor prognostic features had an odds ratio of 15.63 (95% CI, 1.22-200), compared with those with zero or one poor prognostic feature. Lesions with low mean FA2 (nuclear grade 1 or 2) showing high variances in sphericity and FQH had an odds ratio of 7.71 (95% CI, 1.77-33.60). Addition of other features did not enhance the odds ratio or its significance. These results suggest that nuclear image analysis of DCIS lesions may provide an adjunctive tool to conventional pathological analysis, both for the objective assessment of nuclear grade and for the identification of features that predict patient outcome.

Lee JJ, Lieberman R, Sloan JA, Piantadosi S, Lippman SM. · Departments of Biostatistics The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. · Urology. · Pubmed #11295629 No free full text.

Abstract: Prostate cancer, even with its substantial public health impact of 180,400 new cases and 31,900 deaths estimated for 2000, still has a very low annual incidence (0.27% for men 34.4 years and older), which makes designing and conducting efficient prostate cancer prevention trials a challenge. Definitive prevention trials with cancer endpoints, such as the Breast Cancer Prevention Trial (BCPT), Prostate Cancer Prevention Trial (PCPT), and Selenium and Vitamin E Cancer Prevention Trial (SELECT), require long trial duration (up to 12 years) and large sample size (up to 32,400 subjects) to accomplish their objectives. This article discusses design concepts for potential prostate cancer prevention trials that require fewer years, subjects, and resources to complete. Design elements, such as high-risk populations, randomization, surrogate endpoints, including quality-of-life endpoints, masking/blinding, and various clinical/statistical designs (including 1-way layout, all-versus-none, factorial, and adaptive designs), are discussed, along with the ultimate goal of gaining US Food and Drug Administration approval for prostate-cancer preventive agents that can improve public health by reducing prostate cancer incidence and mortality.

Hoque A, Menter DG, Sahin AA, Sneige N, Lippman SM. · Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #11219775 links to  free full text

This publication has no abstract.