One in 10 American women faces the statistical likelihood ofcontracting breast cancer sometime during her life.
If caught in time, and treated with surgery and/or radiation, theprimary tumor can often be extinguished. But fear that the cancer willrecur sooner or later _ as it does all too often _ will haunt thewoman for years.
Not all mammary carcinomas are created equal. Some are driven bythe body's hormones, notably estrogen; others are not. Also, by thetime a tumor has come to surgery, it may already have spread to thelymphatic network's under-arm (axillary) lymph nodes _ or it maynot.
This suspense story bedevils physicians and surgeons as well as itdoes their patients. How to treat the post-operative case to preventrecurrence cries out for a crystal ball _ and there is none. Not yet,anyway.
Almost all cells in the body harbor a protein, p53, frequently referredto as `the guardian of the genome,' said molecular geneticist SteveSommer. Current hypotheses, still awaiting confirmation, see p53 aspart of a system that senses when DNA damage has occurred in thecell. Then, the p53 protein helps make the decision whether to arrestthe cell cycle and try to repair it, or to induce apoptosis and suicidethe cell.
Obviously, cells that lack this round-the-clock maintenance andrepair service can go on dividing and multiplying with impunity. Socan cells in which the p53 protein is corrupted or crippled bymutation of its progenitor p53 gene. This tumor suppressor gene,residing on human chromosome 17's short arm, contains 11 exons,which encode a protein 393 amino acids long.
p53 _ Tumors' Commonest Denominators
"Mutations eliminating or altering the p53 protein function are thesingle most common genetic alteration observed in human cancers."So states an article in today's Proceedings of the National Academyof Sciences (PNAS), of which Sommer and molecular oncologistJohn Kovach are co-senior authors. Its title: "Mutation detection byhighly sensitive methods indicates that p53 gene mutations in breastcancer can have important prognostic value."
Sommer and Kovach explored that predictive potential in the breasttumors of 90 Midwestern Caucasian patients treated at the MayoClinic in Rochester, Minn., where he directs the laboratory ofmolecular genetic research. By applying sensitive methods developedin his laboratory, he was able to detect "virtually 100 percent" of allp53 mutations in those malignant tissues, and correlate them with thepost-operative status of the women two years after their surgery.
"We have found," Sommer told BioWorld Today, "that p53 is theoverwhelmingly most important marker to predict adverse outcome_ early recurrence and early death. We do not know," he added,"whether the same thing will hold for late recurrence and late death."
Of 32 patients with a p53 mutation, 13 relapsed _ that is, theirtumors grew back _ and 10 died in the 24 months of follow-up. Ofthe other 58, without p53 mutations, only seven relapsed and twodied. Statistically, the PNAS paper concluded, "The presence of amutation was highly associated with early recurrence and withdeath."
But Sommer pointed out that, "The time course for breast cancer israther long compared to many cancers, so five, six, seven years downthe road there are still going to be people who recur and then die."
Current clinical practice, which lacks such a clear-cut prognosticator,relies largely on the axillary lymph-node status of a patient. Sommerexplained: "Women who have positive axillary nodes for breastcancer are often treated prophylactically [preventively] withchemotherapy. Negative nodes are generally not so treated."
Nodes, Now Prognosis Mainstay, No Help in Study
He continued: "About one-third of our sample population, 27patients, were node-negative. Roughly the same proportion of thesewomen who had p53 gene mutations recurred as did the node-positive group." Thus, he observed, "it looks as if node-negativebreast cancer is going to behave in the same way as node-positive.That is, the p53 gene is going to be an early prognostic indicator ofrecurrence.
"It becomes complicated, because the next question is: `If you'regoing to treat them, what are you going to treat them with?'" he said.
He noted that other investigators have found that mutated p53proteins not only favor tumor cell growth but some of them, at least,foster resistance to anti-cancer drugs and radiation.
To achieve his reported results, Sommer said, "the reason we foundthis dramatic difference [between mutant and non-mutant p53tumors] is that we used three different methodological enhancements,which enabled us to pick up essentially all the mutations.
* "Touch preps" is the name of his lab's first technique: "By simplytouching the tumor to a glass slide," Sommer said, "theadenocarcinomas come off as clusters of pure tumor cells, which weharvest and amplify by polymerase chain reaction [PCR]."
* In his patients' tumor samples, 25 percent of the p53 mutationsoccurred in the gene's exons four and 10. "For historical reasons,"Sommer pointed out, "investigators have typically focused on exonsfive through eight or nine, where these mutations would not havebeen found."
* "We used a dideoxy fingerprinting method that detects essentially100 percent of mutations, rather than the variable percentage ofSSCP [single-strand conformation polymorphisms], the most widely-used screening method at this point in time." He added, "It wasdeveloped in my lab a number of years ago, and it's the workhorsethat we've used in this project."
In conclusion, Sommer allowed that "there are important clinicalimplications in our findings, but more work is needed to determinejust how they're going to translate into medical practice." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.