The Oncologist, Vol. 9, No. 2, 228–231,
April 2004
© 2004 AlphaMed Press
The Emerging Roles of Screening and Prevention in Women’s Cancer
Franco M. Muggia
Kaplan Comprehensive Cancer Center, New York University Medical Center, New York, New York, USA
Correspondence:
Franco M. Muggia, M.D., Director of Medical Oncology, Kaplan Comprehensive Cancer Center, 550 First Avenue, New York, New York 10014, USA. Telephone: 212-263-6485; Fax: 212-263-8210; e-mail: muggif01{at}gcrc.med.nyu.edu
Key Words. Breast cancer • Ovarian cancer • Screening • Prevention
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INTRODUCTION
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The emerging roles of screening and prevention in women’s cancer were presented during a symposium hosted by The Lynne Cohen Foundation for Ovarian Cancer Research. The April 26, 2003 meeting, held at the University of Southern California Health Sciences Campus in Los Angeles, was divided into three sessions: Research on High Risk Identification and Preventive Measures; Intervention Outcomes and Psycho/Social Repercussions of Preventive Measures; and Research on Screening and Early Detection: New Methods. This report summarizes the salient presentations and ensuing discussions during these sessions.
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SESSION I: RESEARCH ON HIGH RISK IDENTIFICATION AND PREVENTIVE MEASURES
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Session I was moderated by Paolo Toniolo (Professor, Obstetrics and Gynecology and Environmental Medicine, New York University [NYU]) who introduced Ronald Ross (Professor and Chairman, Preventive Medicine, University of Southern California [USC; Los Angeles, CA]) to provide an overview of the relationship between hormones and cancer in women. He first gave the background for the proliferative effect of progesterone on the breast following priming by estrogen—the opposite effect from that which is found in the endometrium. This last finding led to progesterone’s nearly universal inclusion in hormone replacement therapy (HRT). A case-controlled study by Ross and colleagues, together with several other recent studies [1–4], clearly points to progesterone as a culprit in the increased risk for breast cancer in women receiving HRT. However, several issues remain concerning HRT, including: the role of sequential versus continual therapy, the applicability of HRT to women harboring BRCA1 and BRCA2 mutations, the duration of treatment, and the age of onset. He also described several studies yielding controversial data on the role of exogenous hormones in relation to ovarian cancer, setting the stage for later speakers. Steven Narod (Professor and Chair, Breast Cancer Research, Department of Public Health Services, University of Toronto; Ontario, Canada) analyzed the impact of risk factors and interventions based on data from Ontario as well as other growing registries. He began by noting the lifetime risks for breast and ovarian cancers in women identified as carriers of the BRCA1 and BRCA2 mutations, using data derived from Ashkenazi Jewish families (Table 1
). He then explored the impact of certain variables that may emerge as important, given a sufficient number of individuals with mutations. For example, the use of oral contraceptives (OCs) was shown to increase the risk for breast cancer, while his original study had shown a decrease in ovarian cancer incidence, which was disputed by others. Conversely, prophylactic oophorectomy and, especially, tamoxifen had very significant impacts on the subsequent incidences of both breast and ovarian cancers [5]. This effect differs from that found in the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial, but the number of patients actually determined to have germline mutations in that randomized study was in the single digits and must be regarded as inconclusive [6].
Gustavo Rodriguez (Associate Professor, Gynecologic Oncology, Northwestern University; Chicago, IL) sought to explain ovarian carcinogenesis through studies on macaques and discovered an apoptotic effect of progestins on the surface epithelium of the ovary. His subsequent studies related the effects of progestins on the downregulation of transforming growth factor (TGF)-ß2,3 isotypes in the surface epithelium while TGF-ß1 upregulation was taking place; follicular cells exhibited reciprocal changes in these TGF-ß isotypes. Further exploration of the effects of these hormonal factors on the ovary is taking place in chicken models to link these factors to the known occurrence of ovarian cancer resulting from maintaining egg production. Malcolm Pike (Flora Thornton Professor of Preventive Medicine, USC) was intrigued by the effect of progestins on the ovarian epithelium, but questioned whether this could be achieved by suppression of ovulation. He went on to emphasize the divergent effects of progesterone on the breast versus the endometrium, while noting that the effects of circulating hormones on the ovaries were far from clear—stressing that the effects of exogenous progestins (such as by OCs) are likely to be mediated by the inhibition of ovulation. In fact, OCs serendipitously achieved two major effects: A) suppression of ovulation via progestin action, and B) restoration of quality of life via ‘add-back’ estrogen. The session closed with Anne Blackwood-Chirchir (Assistant Professor of Medicine and Epidemiology, University of Pennsylvania; Philadelphia, PA) reviewing the results of the NSABP and other cancer prevention trials that used tamoxifen as a chemopreventive agent. This served as a springboard for an ongoing placebo-controlled trial of tamoxifen for premenopausal women with genetic predispositions to breast cancer—a study that seeks to define surrogate molecular and imaging markers of the putative beneficial effects of tamoxifen.
The ensuing panel discussion elaborated on the implications of the contrasting effects of OCs on the breast and ovary as far as proliferation and cancer risks are concerned. Admittedly, OCs given to a premenopausal woman may carry with them some greater risk for breast cancer, but the proper question is: "in comparison with what?" According to Malcolm Pike, the slope of the logarithmic increase in risk with age indicative of the profound effect of lifetime exogenous hormones is not likely to change substantially with 5 years of exogenous hormones; however, this intervention would certainly carry with it a higher risk than would an early oophorectomy. On the other hand, suppression of ovulation (or the apoptotic effect of progestins) lowers the risk of ovarian cancer. A discussion on the risk of obesity also brought up interesting divergent relationships between obesity and the incidences of these cancers: a profound effect is noted on endometrial cancer, intermediate effects (mostly on postmenopausal women) are found on breast cancer, and no effects on ovarian cancer have been found.
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SESSION II: INTERVENTION OUTCOMES AND PSYCHO/SOCIAL REPERCUSSIONS OF PREVENTIVE MEASURES
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The second session was moderated by Silvia Formenti (Professor and Chair, Radiation Oncology, NYU). The lead-off speaker was Antonella Surbone (Professor of Ethics, European School of Oncology, and Clinical Associate Professor of Medicine, NYU), providing an overview of the ethical issues related to recent genetic discoveries. Table 2 indicates the fundamental questions that generate discussion whenever a study of individual genetic characteristics is proposed. Many of the fears raised concerning the misuse of genetic information on breast and ovarian cancer susceptibility, fortunately, have not materialized. Quite the contrary, the genetic identification of risk may assist women that need to make critical decisions based on the knowledge of very high familial risks for breast cancer, as noted in the studies presented by Lynn Hartmann (Professor of Oncology, Mayo Clinic and Mayo Foundation). She noted that a March 1997 National Institutes of Health consensus statement had indicated no recommendations for or against prophylactic surgery for BRCA1 and BRCA2 mutation carriers, because evidence for benefit was lacking. Several studies, including her initial landmark paper published in 1999 and her follow-up analysis identifying mutation carriers [7, 8], now have provided the evidence that bilateral prophylactic mastectomy is effective in preventing most breast cancers and is clearly superior to women in the same families, or other very high risk families, opting to undergo strict surveillance. More recently, a group at the Mayo Clinic has been exploring patients’ psychological and social adjustments after this surgery. She ended her presentation with a discussion of the emerging concepts of chemoprevention.
Psychosocial issues raised by evaluations and interventions that deal with women at high risk for these cancers were covered by Michael Stefanek and Suzanne Miller. Michael Stefanek (Professor, USC) stressed that satisfaction was related to allaying the anxiety over developing breast cancer—a decision that was strongly based on family history, followed by physician’s advice, and the awareness of nodular breasts [9]. Research dealing with prospective follow-up is needed [10]. These aspects in relation to oophorectomy were expanded upon by Suzanne Miller (Director of Behavioral Medicine Program, Fox Chase Cancer Center; Philadelphia, PA). She focused on the type of information that was sought by women at high risk before undergoing prophylactic oophorectomy [11]; and the level, type, and mode of information that potentially undermine their abilities in decision making and the appreciation of quality-of-life issues. Dr. Miller identified two "behavioral signatures" pertaining to how women deal with their ovarian cancer risk: A) high monitoring, and B) low monitoring processing styles. While the first one requires a high volume of information, the second tends to blunt the self-learning process to reduce stress. A monitor-blunter style scale to identify anticipated patterns of behavior in applying medical interventions is widely used internationally.
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SESSION III: RESEARCH ON SCREENING AND EARLY DETECTION: NEW METHODS
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The third session, moderated by John Curtin (Director, Division of Gynecologic Oncology, NYU), began with overviews by Stephanie Blank (Assistant Professor of Obstetrics and Gynecology, NYU) and Melvin Silverstein (Henrietta C. Lee Chair in Breast Cancer Research, Professor of Surgery Director of the USC/Norris Breast Center, USC) on current issues in screening and early detection of ovarian and breast cancers, respectively. Noteworthy is the contrast between the steady shift toward diagnosis at earlier stages in breast cancer (related to the widespread use of routine mammograms and the public awareness of breast cancer) and the continued challenge of diagnosing ovarian cancer in stages earlier than stage III. A glimpse toward future progress was provided by Emanuel Petricoin (Clinical Proteomics Program, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration). Together with colleagues at the National Cancer Institute and at Correlogic Systems, Inc.; Bethesda, MD, Dr. Petricoin is seeking molecular signatures of proteins in serum that will enable one to make a diagnosis of cancer at a very early stage. Findings from an initial study published in The Lancet in 2001 indicate a universal ability to identify individuals with stage I ovarian cancer rather than benign conditions [12]. Efforts to refine the specificity and retain the sensitivity of this approach to early ovarian cancer detection based on a signature of five mass spectroscopy/charge peaks are ongoing. Also ongoing is the development of a serum proteomic pattern test for breast as well as other cancers. Multimodality imaging approaches to high-risk screening were described by Mitchell Schnall (Matthew J. Wilson Professor of Research Radiology, University of Pennsylvania). A downturn in breast cancer mortality that has taken place since 1990 (surveillance, epidemiology, and end results [SEER] data) could be the result of the widespread use of mammography screening, as well as the application of better treatment. In spite of the controversy over mammography generated by publication in The Lancet of the Cochrane Report [13], benefits appear likely. However, the future will undoubtedly see the advent of technical innovations to overcome some of the shortcomings of mammography screening. Digital mammography yields more homogeneous documentation of the image, and its potential to improve the view of certain tumors is being studied in a randomized trial by 20 centers in the U.S. and Canada. New image-acquisition technology utilizing ultrasound, magnetic resonance imaging (MRI), and nuclear medicine techniques, such as positron emission tomography and sestamibi scanning, are also under evaluation. MRI coupled with newer techniques promises to be more sensitive [14], particularly in situations where the value of mammography is limited (i.e., for imaging dense breasts). The session ended with Maurie Markman (Vice President for Clinical Research, University of Texas M.D. Anderson Cancer Center, Houston, TX) discussing the challenges of clinical evaluation as it applies to high-risk groups. A major concern is the acquisition of data suitable for analysis. For any one screening strategy, acquiring such data is labor intensive, and one must consider morbidities associated with any one strategy—especially considering individuals who will never get the cancer that one is trying to prevent. For ovarian cancer, currently there is no easy screening method. As methods improve, one must address the populations that might be studied to yield sufficiently low false-positive and false-negative rates. In addition, one will have to demonstrate that detecting the cancer at an earlier time point in its natural history will favorably impact survival.
The general discussion that ensued included enlisting the participation of families at high risk for breast and ovarian cancer. Regarding imaging, the most pressing question related to how one may move MRI to become a clinically relevant screening tool. On other aspects, the timing of the initiation of screening procedures was discussed, as were the specific recommendations to women who are concerned about their risks. Although a woman in her twenties may be too young to be engaged in these efforts, it is appropriate for someone of that age to begin to be educated on screening efforts. At age 35, it is reasonable to follow some screening procedures related to the breast, and to seek clinical trials such as the Gynecologic Oncology Group GOG199 trial, which utilizes cancer antigen 125 algorithms to prospectively validate the change in level over time as an indicator of an ovarian malignancy. Also, the use of oral contraceptives as an intervention may be considered. As often ensues when experts meet, more questions were generated for which we currently have no answers. However, some clear important lines of research are emerging on: A) defining how our hormonal interventions work to affect risk; B) providing the requisite information to women to enable them to decide on interventions, and C) integrating the emerging knowledge of screening and prevention into clinical practice.
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FOOTNOTES
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Report from a Symposium Presented by The Lynne Cohen Foundation for Ovarian Cancer Research, University of Southern California Health Sciences Campus, Los Angeles, California, USA, April 2003
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REFERENCES
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- Ross RK, Paganini-Hill A, Wan PC et al. Effect of hormone replacement therapy on breast cancer risk: Estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000;92:328–332.[Abstract/Free Full Text]
- Colditz GA, Hankinson SE, Hunter DJ et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995;332:1589–1593.[Abstract/Free Full Text]
- Schairer C, Lubin J, Troisi R et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000;283:485–491.[Abstract/Free Full Text]
- Chlebowski RT, Hendrix SL, Langer RD et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized trial. JAMA 2003;89:3243–3253.
- Narod SA, Brunet JS, Ghadirian P et al. Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Hereditary Breast Cancer Clinical Study Group. Lancet 2000;356:1876–1881.[CrossRef][Medline]
- King MC, Wieand S, Hale K et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA 2001;286:2251–2261.[Abstract/Free Full Text]
- Hartmann LC, Schaid DJ, Woods JE et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 1999;340:77–84.[Abstract/Free Full Text]
- Hartmann LC, Sellers TA, Schaid DJ et al. Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst 2001;93:1633–1637.[Abstract/Free Full Text]
- Stefanek ME, Helzlsouer KJ, Wilcox PM et al. Predictors of and satisfaction with bilateral prophylactic mastectomy. Prev Med 1995;24:412–419.[CrossRef][Medline]
- Stefanek M, Hartmann L, Nelson W. Risk-reduction mastectomy: clinical issues and research needs. J Natl Cancer Inst 2001;93:1297–1306.[Abstract/Free Full Text]
- Miller SM, Fang CY, Manne SL et al. Decision making about prophylactic oophorectomy among at-risk women: psychological influences and implications. Gynecol Oncol 1999;75:406–412.[CrossRef][Medline]
- Petricoin EF, Ardekani AM, Hitt BA et al. Use of proteomic patterns in serum to identify ovarian cancer. Lancet 2002;359:572–577.[CrossRef][Medline]
- Gotzsche PC, Olsen O. Is screening for breast cancer with mammography justifiable? Lancet 2000;355:129–134.[CrossRef][Medline]
- Ntziachristos V, Yodh AG, Schnall MD et al. Concurrent MRI and diffuse optical tomography of breast after indocyanine green enhancement. Proc Natl Acad Sci USA 2000;97:2767–2772.[Abstract/Free Full Text]
Received June 9, 2003;
accepted for publication October 13, 2003.
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Introduction
Session I: Research on...
