one are the days when a cancer was just a cancer. Molecular tools, and in particular the use of DNA microarrays that can assess the expression of thousands of genes at a time, mean it is now possible to identify the particularities of an individual patient’s tumors. The paper at #9 shows that breast cancer is even more diverse than physicians had originally thought. It paves the way for tailored individual therapies that promise to be more effective than current approaches

A team of researchers from Stanford University in California and various Norwegian institutes looked in detail at the patterns of gene expression in samples of breast tumors removed from 42 different patients. Twenty of the tumors were sampled twice, before and after a course of chemotherapy. Two of the primary tumors were paired with lymph-node metastases. In almost every case, the pairs from one patient resembled each other more than they resembled any other sample. This shows that the expression pattern is a genuine property of the patient and the tumor, preserving its identity over time and in different tissues. As Patrick O.  Brown, a Stanford University-based Howard Hughes Medical Institute investigator who is one of the lead authors of the study and a key figure in the development of DNA microarrays, describes it to Science Watch, “The picture provided by DNA microarray analysis...was like a portrait—a picture that captures the essential distinctive qualities of the tumor.”

Beyond that, however, the individual portraits fell into clusters that shared a certain family resemblance.  Paper #9 identifies four such clusters. One strongly expresses the estrogen receptor a gene, along with genes common to the cells that line the lumen of the milk ducts. The other three do not express the ER genes and can be split into three further groups. One has an expression pattern characteristic of normal breast tissue. Another is typical of basal epithelial cells from the breast. The third strongly expresses the Erb-B2 oncogene. At the moment, clinicians tend to regard breast cancers as either ER-positive or ER-negative, which, this study suggests, may be an oversimplification.

The Nature paper at #9 does not deal with clinical implications. But a follow-up study does (see T. Sørlie, et al., Proc. Natl. Acad. Sci. USA  98[19]:10869-10874, 11 September 2001). Anne-Lise Borreson-Dale, of the Norwegian Radium Hospital in Norway, led a largely overlapping team that extended the method to almost 80 patients and related each patient’s molecular portrait to clinical outcome. In this, larger, study the ER+ group could be further sub-divided into two or possibly three distinct sub-groups. One had much higher levels of expression of the ER gene than the others. And among those with lower expression of the ER gene was another group that shared a coordinated set of genes of currently unknown function.

To investigate the links with outcome, Borreson-Dale’s group homed in on 49 patients who were each given identical therapy as part of a prospective study. There was a significant overall difference, with the basal and Erb-B2 types surviving for the shortest time. Among the ER+ subtypes, the group with highest expression of the ER gene survived best, and those with the unknown cluster worst.

At the moment, results such as these are observations in search of an explanation. The group led by Brown and his Stanford colleague David Botstein concedes that a complete picture of the diversity of breast cancer is still years away and will emerge only as researchers are able to look at hundreds, rather than tens, of molecular portraits. Expression profiles are also not yet robust enough or simple enough to be easily used in a hospital setting, though as Botstein notes hopefully, “There are lots of companies out there thinking about this.” All in all, there is still a long way to go before the clearer picture of cancer that is emerging helps to replace the Procrustean approach that typifies therapy today.

“The results haven’t yet had an impact on therapy,” Brown tells Science Watch, “but I think it is very likely that they will in the next few years.” The need is great. At present, patients often opt for aggressive therapies. That is bad on two counts. Those with relatively susceptible tumors that would respond to more benign treatments are needlessly suffering the effects of aggressive therapy. And those with more intractable tumors are perhaps not being treated severely enough to ensure a good outcome. With detailed molecular portraits will eventually come more rational therapies that treat each patient and their tumors as the individuals they undoubtedly are.

Dr. Jeremy Cherfas is Science Writer
at the International Plant Genetic Resources Institute, Rome, Italy.