Editor’s Note
	Data-driven

In 1998, my education world instantly expanded at a press conference where Dr Bernard Fisher and his NSABP colleagues announced the findings of the P-1 prevention trial. Prior to that moment, our group's CME activities focused almost exclusively on oncologists, surgeons and oncology nurses. However the P-1 trial data, demonstrating a reduction in breast cancer incidence in women receiving tamoxifen, created an immediate cancer education vacuum for primary care clinicians, particularly gynecologists.

Recognizing the importance of the tamoxifen prevention data, but not entirely familiar with the primary care audience, our team ventured into these new teaching waters with uncertainty. We knew that breast cancer screening was an integral facet of primary health care for women, but we had no idea how these clinicians and their patients would react to the concept of reducing breast cancer risk with an antiestrogen.

To learn more, we conducted a series of working group meetings with gynecology research leaders and community-based doctors. We learned that pharmacological disease prevention was already deeply ingrained in the medical culture of these professionals, who had readily endorsed the widespread use of menopausal hormone therapy to reduce the risk of cardiovascular disease and osteoporosis. Among gynecologic research leaders, there was general agreement that the possible trade-off for what was perceived to be a marginally increased risk of breast cancer was very reasonable until more definitive data became available.

Lurking in the background was the massive Women's Health Initiative (WHI), a randomized, double-blind, placebo-controlled trial that was attempting to define the true risk-to-benefit ratio of "HRT," which at that time was being prescribed to about six million women in the United States.

As our group held breast cancer chemoprevention CME programs for primary care physicians, we interfaced with a number of oncologists who crossed the border into preventive oncology, including Dr Victor Vogel from the NSABP and Dr Rowan Chlebowski, who was interviewed for this program.

Having lived through the era of high-dose chemotherapy with stem cell support, these investigators were familiar with the dangers of "jumping the gun" and endorsing a treatment before randomized trial data became available. These oncologists voiced concerns about the common perception that the WHI was a "done deal" and the results were predictable.

The discussion in the first five minutes of Dr Chlebowski's interview on the audio portion of this program crushes most of those long-held beliefs. Combined estrogen and progestin therapy was found to significantly increase the risk of cardiovascular disease, breast cancer and abnormal mammograms.

In contrast to findings from a number of retrospective series, the breast cancers diagnosed in women on menopausal hormone therapy in the WHI trial were more advanced and had worse prognoses than those diagnosed in women in the placebo group.

Clinical practice changed almost overnight when these and other disturbing WHI trial data were publicized in the media. About half of women on menopausal replacement discontinued potentially harmful treatment that they and their physicians at one point believed to be beneficial. This reiterated the hard-learned lesson that retrospective studies are unreliable and that the randomized trial is the sole "gold standard" for evidence-based patient care.

With this research perspective in mind, it is interesting to consider some of the clinical questions about metastatic disease that arise in the enclosed program.

1. What is the optimal first-line therapy for women with HER2-positive metastases?

Dr Howard Burris reviews what we do and do not know about this key question. The classic randomized trial by Slamon et al demonstrates that chemotherapy without trastuzumab results in inferior survival compared to chemotherapy plus trastuzumab, even though most of the women treated initially with chemotherapy in the study were crossed over to trastuzumab.

However, no randomized data exist on many other important questions in HER2-positive tumors, including the role of trastuzumab alone as initial therapy or whether this agent should be continued after disease progression.

2.What is the optimal hormonal therapy in postmenopausal women progressing on adjuvant tamoxifen?

Dr Richard Elledge notes that randomized trial data indicate that the estrogen receptor downregulator, fulvestrant, is at least as effective as the other common choice of an aromatase inhibitor, in this case, anastrozole. While many women with ER-positive metastatic disease are diagnosed during their five years on adjuvant tamoxifen, a new generation of patients is likely to relapse on adjuvant anastrozole. Dr Elledge notes the paucity of clinical research data on optimal endocrine therapy at that point.

3. Can women with previously untreated metastatic disease be rendered disease-free (cured) with systemic therapy?

Dr Vicente Valero describes the classic series of such patients treated at his institution (MD Anderson) in which a small fraction of women remained disease-free for 10 or more years. He notes the lack of data for combination hormone therapy and chemotherapy in that situation. In the case discussed

in our program, Dr Valero also addresses the role of surgical excision or ablation of liver metastases. The rarity of this clinical situation means that we are unlikely to ever obtain a definitive evidence-based answer to these questions.

We live in an oncologic world where opposing forces are at work. The clinical trial is one of our most important tools to advance medical care, but the need to conserve research resources means that many important clinical questions will not be addressed in a randomized fashion. Studies that tackle critical public health issues, such as the WHI, are a vivid reminder of how such trials can significantly alter daily clinical practice.

-Neil Love, MD

Women's Health Initiative (WHI) trial

Chlebowski RT et al; WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: The Women's Health Initiative Randomized Trial. JAMA 2003;289(24):3243-53. Abstract

Hays J et al; Women's Health Initiative Investigators. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 2003;348(19):1839-54. Abstract

Manson JE et al; Women's Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349(6):523-34. Abstract

Rapp SR et al; WHIMS Investigators. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: The Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289(20):2663-72. Abstract

Rossouw JE et al; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288(3):321-33. Abstract

Shumaker SA et al; WHIMS Investigators. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: The Women's Health Initiative Memory Study: A randomized controlled trial. JAMA2003;289(20):2651-62. Abstract

Wassertheil-Smoller S et al; WHI Investigators. Effect of estrogen plus progestin on stroke in postmenopausal women: The Women's Health Initiative: A randomized trial. JAMA2003;289(20):2673-84. Abstract

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