Prophylactic Tamoxifen Debated at ECCO

 VIENNA, Austria—The substantial drop in breast cancer incidence reported in the NSABP P-1 trial of prophylactic tamoxifen (Nolvadex) contrasted sharply with the negative findings of the earlier Royal Marsden and Italian trials. Whether the P-1 results can be confidently and routinely applied to all high-risk women was the focus of a debate between Royal Marsden investigator Trevor Powles, MD, and NSABP investigator Bernard Fisher, MD, at the 10th European Cancer Conference (ECCO 10).

“There is absolutely no doubt that tamoxifen given to healthy women will reduce the incidence of early breast cancer,” Dr. Powles acknowledged. But, he said, the 50% reduction amounted to only 86 fewer breast cancers. Thus, certain questions arise:

Does this reduction balance favorably against the toxicity of tamoxifen?

• Is this balance of benefit and risk maintained beyond 4 years?
  
• Is the treatment of tens of thousands of healthy women better than the treatment of hundreds of patients with breast cancer?
  
• Is the reduction in early incidence a treatment of occult disease or is it a permanent prevention of a disease that won’t return?
  
• Are there groups of women who are resistant to tamoxifen and should therefore not receive it?

Unfortunately, Dr. Powles said, answers to these critical questions will not be forthcoming from the NSABP P-1 study. “I would like to put forward the case that (1) we are not yet ready to give tamoxifen to large numbers of healthy women and (2) placebo-controlled trials should continue in Europe,” he said.

Dr. Powles pointed out that P-1 study enrollees who had atypical ductal hyperplasia or lobular carcinoma in situ achieved the most substantial gains with tamoxifen. In fact, he observed, if women with histologic abnormalities are excluded from the study analysis, the risk reduction afforded by tamoxifen drops from 50% to 42%.

If some subgroups of women are particularly sensitive to tamoxifen, Dr. Powles suggested, there may also be other, as yet unidentified subgroups who benefit less or not at all. “This may explain why the Italian trial and our own trial showed absolutely no effect of the use of tamoxifen in about 7,500 healthy women,” he proposed.

Of concern, he said, is that “we gave 52,000 patient-months of tamoxifen, which would cost about $1.5 million in the United States, and we didn’t prevent a single cancer over a 6-year period. If there are large groups of women who are resistant, as in our study and the Italian study, then we can’t just extrapolate the results of the P-1 trial and say that, yes, all women will benefit.”

Examining the actual benefits and risks of tamoxifen prophylaxis in the 6,681 participants in the NSABP P-1 study, Dr. Powles said that the prevention of 86 invasive breast cancers was achieved at a cost of 21 extra endometrial cancers, 14 strokes, 67 cataracts, 12 pulmonary embolisms, 3 acute myocardial infarctions, and 13 deep vein thromboses.

Since the trial was stopped after 4 years, he noted, it is not possible to determine exactly how the balance of benefits and risks might shift over the long term. “But there is no doubt in my mind that the benefits are going to get better and the risks are going to get worse,” he said.

Dr. Powles said that although an FDA committee recommended approval of tamoxifen for short-term risk reduction, the same committee unanimously agreed that the NSABP P-1 data failed to demonstrate a favorable benefit-to-risk ratio for prevention of breast cancer in high-risk women as defined by the study.

Similarly, an ASCO technology assessment concluded that prophylactic tamoxifen may be offered to women who have a 5-year risk of 1.6% or more, while at the same time cautioning that there was insufficient evidence to show an overall health or survival benefit.

Dr. Fisher Responds

Responding to the criticism of the NSABP trial, Dr. Bernard Fisher said, “Not one bit of data has been presented to challenge the P-1 results.”

He pointed out that ample laboratory and clinical evidence to justify the use of tamoxifen came from the earlier NSABP B-14 study, which showed that 5 years of treatment with tamoxifen reduced the incidence of contralateral breast cancer for 10 years.

Dr. Fisher maintained that the prophylactic benefits documented in the P-1 study held across the board, in young women (44% reduction in risk ) as well as older women (53% reduction), and in very-high-risk women (66%) as well as moderate-risk women (63%).

“You cannot make these numbers disappear, and you can’t ignore them,” he said. Most important, Dr. Fisher said, the reduction in breast cancers was related to the estrogen-receptor positivity of the tumors.

“The National Cancer Institute estimated that there were 29 million women in the United States who met the eligibility criteria of this study, and one can see that over a 5-year period, if these women had received tamoxifen, there could have been a reduction of almost 500,000 invasive breast cancers and another 200,000 or 300,000 noninvasive breast cancers,” Dr. Fisher said.

He called the major life-threatening toxicities of tamoxifen “highly overrated for many reasons, some of which are political, some of which are economic, and some of which are pure bias.” He noted that vascular adverse events were rare in patients under the age of 49 and that all cases of endometrial cancer were localized. “The mortality and morbidity associated with breast cancer are likely to exceed those associated with the adverse effects of tamoxifen,” he stressed.

Potential candidates for tamoxifen prophylaxis, Dr. Fisher advised, include premenopausal women with a risk profile comparable to that in the P-1 study, women with a history of lobular carcinoma in situ or atypical hyperplasia, women who have undergone hysterectomy, and women with a history of ductal carcinoma in situ.

“I personally believe that tamoxifen provides an alternative to bilateral mastectomy in women with a BRCA1 or BRCA2 mutation,” Dr. Fisher said, while conceding that there is as yet insufficient information upon which to base this statement.

Not all women are at increased risk, Dr. Fisher said, “but tamoxifen provides those who are at increased risk with an option to prevent breast cancer. Thousands of women who are receiving so-called effective treatment die of invasive breast cancer, and I do not believe that we can afford to deny those women who are at increased risk the opportunity to receive tamoxifen.”

Dr. Fisher urged that future studies be conducted to assess the impact of agents that affect ER-negative tumors and the potential benefits of selective estrogen receptor modulators (SERMs) with different mechanisms of action. “We have begun to nibble away at areas below the limits of detection of mammography, and this is where the action must be,” he concluded.