Natural history of invasive breast cancer suggests some cancers regress

Unexpected findings from a study of Norwegian women who have and have not received routine biennial screening mammography suggest some breast cancers may spontaneously regress.

Dr. Per-Henrik Zahl, a senior statistician in the epidemiology department at the Norwegian Institute of Public Health in Oslo, and colleagues compared cumulative breast cancer incidence in age-matched cohorts of women residing in four Norwegian counties before and after the initiation of biennial mammography.

The initiation of screening mammography has been associated with increased breast cancer incidence among women of screening age, according to the researchers. If all the newly detected cancers progressed and became clinically evident as women age, a fall in incidence among older women should soon follow, but this was not the case for the current study.

Results were reported in the Nov. 24 issue of the Archives of Internal Medicine (2008;168[21]:2311-2316).

Breast cancer rates were higher among women aged 55 to 69 years in 2001 who were invited to receive three cycles of biennial screening from 1996 to 2001 than among a control group composed of older women, aged 55 to 69 in 1997, who would have been invited for screening in 1992 to 1997, before the surveillance program was established.

As expected, the first round of screening mammography led to a dramatic rise in breast cancer incidence in the screened group compared with the age-matched controls. Of every 100,000 screened women, 660 were diagnosed with breast cancer after two years, compared with 384 per 100,000 in the control group. Screened women were more likely to have detected breast cancer at every age, according to the researchers.

They also observed that the difference between the groups narrowed over time as the disease in the control group had an opportunity to become clinically relevant. Even after prevalence screening, however, the screening group showed a 22% higher rate of cumulative incidence of invasive breast cancer. The six-year cumulative incidence rate was 1909 breast cancers per 100,000 population for the screened group compared with 1564 for the controls.

"Thus, it appears that some invasive breast cancers detected by repeated mammographic screening would not persist to be detectible by a single screening at the end of six years," Zahl said. "In other words, the natural course for some screening-detected breast cancers may be to spontaneously regress."

Spontaneous regression of invasive breast cancer has been reported 32 times in other studies, strengthening the case of Zahl and colleagues. They note that spontaneous regression of advanced cancer has long been recognized for metastatic melanoma and metastatic renal cell carcinoma. The medical literature also cites instances in which colonic adenomas and precancerous cervical lesions have regressed. Documentation of regression of cancer detected through screening has until this study been limited to neuroblastoma, however.

Not everyone shares the perspective that some breast cancers spontaneously regress.

"The mutations needed to cause the cancer are not going away," said Dr. Jennifer Harvey, director of breast imaging and an associate professor of radiology at the University of Virginia.

It is unlikely that cancers will spontaneously regress, with the exception of stopping hormone therapy, she said.

"However, additional mutations are likely necessary to allow metastasis, which is what causes mortality with most breast cancers," she said.

Some cancers may rarely metastasize, but it is impossible in most cases to predict which cancers may go on to metastasize and when, Harvey said.

Zahl and colleagues set out to determine the natural history of additional screening-detected cancers. The screened group in their study population included 119,472 women 50 to 69 years old in 1996 who were invited for screening by the Norwegian Breast Cancer Screening Program. The control group included 109,784 women who would have been invited for screening if a screening program had existed between 1992 through 1997.

The researchers restricted the control group to women aged 50 to 64 in 1992, and, because this period includes the years 1996-1997 (the first two years of the screening program), all women in the group were invited to undergo a one-time prevalence screening at the close of the period.

Problems arise with the study, however, in comparing women from two different chronological periodse, according to Dr. Daniel Kopans, a professor of radiology at Harvard Medical School and a senior radiologist at Massachusetts General Hospital.

"Comparing women from different periods introduces biases that cannot be corrected with certainty. Mammography screening finds more cancers, initially, because it is finding the cancers that would have been found without screening, but also cancers that would not have been found for one, two, three, or more years without screening. So the incidence jumps until all women who are going to participate in screening are being screened," he said.

Baseline incidence continues to increase so the incidence among the screened women who began to be followed in a later period of time will have a higher background incidence than the women with whom they are being compared whose period of observation began earlier, he said.

"It is entirely possible that the observations that have been made are a function of the steady, and unexplained, increase in incidence and not to cancer regression," Kopans said.

The researchers have ruled out other explanations for the high incidence of breast cancer, including ascertainment bias, differential risk, increased sensitivity of mammography, and a temporal increase in the underlying of breast cancer.

One condition for confirming the possibility of regression -- that the introduction of the screening program has caused a marked and sustained increase in incidence -- seems to be present in almost all 40 counties in Norway and Sweden, Zahl and colleagues said.

A randomized controlled trial is unlikely because it would be considered unethical, said Dr. Robert M. Kaplan, Wasserman Distinguished Professor and chair of health services at the University of California, Los Angeles School of Public Health, and Dr. Franz Porzsolt, an oncologist at the Clinical Economics University of Ulm, Germany, in an accompanying editorial.

Funding agencies, however, should encourage creative experiments to evaluate the spontaneous remission hypothesis, they said.