Can Genetics Provide Better Treatment for Breast Cancer?

by Sujatha Byravan

After seeing a recent New England Journal of Medicine article (1) on gene expression and breast cancer, a friend asked if I regarded the work as ‘responsible genetics’ — causing me to think about it carefully. The scientists in that study found that genetic signatures in breast cancer tumors appear to predict whether the cancer would spread and cause death, or remain localized and go no further.

At present a patient with breast cancer usually receives surgery and local radiation. More aggressive treatment that includes chemotherapy and hormones may be provided based on criteria such as tumor size and whether the lymp nodes are positive for cancer. But these criteria do not predict the course of the disease and response to treatment. The Netherlands Cancer Institute group used a DNA chip technology to identify the gene expression profile of 70 genes in 295 cancer patients. All were women younger than fifty-two who had received standard breast cancer treatment between 1984 and 1995. Based on the expression of specific genes in their tumors, the researchers assigned the women into two categories: those having “good” or “bad” prognosis profiles, a determination that was based on earlier research. They found a correlation between metastases — the spreading of the primary cancer to distant sites — and death in patients with “bad” DNA profiles, and localized cancer with better survival rates in those with good DNA profiles. Women whose DNA profiles indicated a “good” prognosis had an 85.25 % chance of being disease free and a 94.5 % chance of survival over the next decade. On the other hand, those with poor profiles had a 50.6% chance of remaining cancer-free and a 54.6% chance of surviving the same period.

The results are interesting because they challenge previous beliefs regarding criteria for assessing cancers and their treatment modes. Significantly, there was no correlation between women whose lymph nodes were positive and those who had poor profiles — meaning that women with positive nodes may not necessarily require aggressive treatments, which can be accompanied by major side effects. Conversely, some of those with very small tumors may in fact need aggressive treatment, which they were not receiving previously. We must however bear in mind that these results are preliminary. Studies on larger numbers of women of different ages and populations, with varying stages of disease, are needed to confirm these results. Besides, we know little about the kinds of treatment that would work best for women with different profiles.

Genetic testing for breast cancer is not entirely new. Mistaken reductive reasoning has led to recommendations for women to take tests for mutations in BRCA1 and BRCA2 — the two genes linked to breast cancer inheritance — even though these tests cannot predict whether women will develop breast cancer. Neither do the tests reveal anything about the possible age of onset, severity or course of the disease. The BRCA tests often leave women helplessly clutching a single piece of information — the probability of their getting breast cancer, though this number does not come with a recommended course of action.

In the context of genetic reductionism, the current research is a different kettle of fish. Instead of speaking of genes as though they alone determine onset or inheritance of disease, research will now focus on genes that are expressed in tumors and so expected to directly affect disease progression and mortality. But even here, the notion that genetic signatures on tumors are hard-wired to predict the disease course expands the palette of reductionism. At present we have no idea if these genetic markers can change over the course of certain treatments or how they are affected by other environmental factors.

If the results of this preliminary research on tumor genetic signatures are confirmed by further research, doctors may in the future recommend that women who develop breast cancer take such a multi-gene test, which in itself could be a good thing. It could help doctors determine what treatment would work best for specific women. The Netherlands study also considers the effects of multiple genes, which makes better sense in the case of a complex disease such as breast cancer. This does then appear to be more responsible genetics than testing for mutations in BRCA1 and BRCA2.

Still, the new genetic profile tests, if they become available, will cost more since they use fresh tumor cells rather than the fixed tissues used today for diagnosis. Will the tests be made available to everyone when cost considerations apply? An added problem is that genetic profiling, like other kinds of profiling, can lead to bias and discrimination. (In fact, CRG has already collected over 200 cases of discrimination based on genetic information, not specific to breast cancer). Will those with poor profiles be provided good treatment by their physicians? Will the results of the tests be kept private? If not, will insurance companies withdraw coverage when a woman is diagnosed with a poor breast cancer profile, since she will presumably need more aggressive and expensive treatment? Will employers, if they know the results of these tests, discriminate against poor-profile employees?

We are moving rapidly into an era of personalized medicine, where genetic tests and gene sequences will be more easily available to those who can pay, even as health care systems deteriorate. The focus on such tests detracts from the importance of other factors and their influence on breast cancer — an area in which the results of research are still inconclusive. For example, there is still no agreement on whether drinking a glass of wine a day increases the chance of developing breast cancer. The need for prospective studies that examine the effect of pollutants on the incidence of breast cancer is urgent. Furthermore, we have yet to learn how pollutants may interact to produce DNA mutations that lead to cancer. The reductionist focus on genes continues to dominate, whether it is on inheritance of cancer genes or on the presence of genetic markers in tumors. But if we can expand our understanding of which environmental insults produce cancer and how they do so, we would be better able to improve women’s health.

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Sujatha Byravan, PhD is Executive Director of CRG.

1 van de Vijver and colleagues, New England Journal of Medicine, Vol. 347 No. 25, 19 December 2002.