Would you rather be burned at the stake, run through by asword or poisoned with deadly toxins?

Dreaded choices like these confront a women condemnedby a verdict of primary breast cancer. She and herphysician must decide whether radiation, surgery,chemotherapy, or all of the above, has the best chance ofcurbing her tumor and saving _ or at least prolonging _her life.

That fraught judgment call must rely on the weak reed ofprognosis. That is, on enlisting a high-level form ofguesswork, based on the type and stage of the mammarymalignancy, to predict how best it will respond to whichkind of anti-cancer treatment.

One arbiter of that presumed response, which came to thefore in the 1990s, is the tumor suppressor protein, p53. Inits normal, wild-type version, this molecule nips tumorsin the bud. But when mutated, the p53 gene swaps itswhite hat for black, and indirectly promotes tumor growthinstead.

Finding such mutations _ and they are many _ in thetumor tissue of breast-cancer victims might sharpenprognosis, guide optimum therapy, and save lives.

The gene that encodes p53 resides on the short arm ofhuman chromosome 17. Molecular oncologists havesequenced short stretches of its DNA, hunting forsignificant aberrations that might correlate with malignantstates. But this catch-as-catch-can approach has yieldedspotty findings.

Clinical oncologists hoped that some day, somebodywould sequence the p53 gene's entire 1,200-base-paircoding region from end to end, map all its mutations, andmatch them against clinical breast-cancer outcomes _that is, their response to the various therapies.

That "body" turns out to be the Swedish University ofUppsala Teaching Hospital.

Its report in the October issue of Nature Medicine bearsthe self-explanatory title: "Complete sequencing of thep53 gene provides prognostic information in breastcancer patients, particularly in relation to adjuvantsystemic therapy and radiotherapy."

29.8 Percent Of Tumors Carried p53 Mutations

The point of departure in this unprecedented studyconsisted of 316 tumor samples surgically excised fromas many patients in the three years between January 1987and December 1989. It pinpointed 69 individualmutations throughout the whole coding sequence, presentin 312 of the 316 tumors. Their final frequency revealedthat 29.8 percent of the malignant tissue samplescontained p53 mutations.

"Patients with p53 mutations in their primary breastcancer," the Swedish paper reported, relapsed sooner _"had a statistically significant shorter relapse-free . . .overall survival in the study population."

Mammary cancers in and of themselves are not generallyfatal; what kills is their spread throughout the body toother organs, such as lung and liver. Regional lymphnodes, in particular the axillary or armpit nodes nearestthe breasts, are predictive of this metastaticdissemination. Thus, surgeons excising tumor-bearingmammary tissue often remove the neighboring nodes aswell.

Of 298 testable samples, 97 tumor-positive lymph nodesreflected 29 mutations; 201 negative nodes had 38mutations. Positive cases which received hormonaltherapy (tamoxifen) supplemental to radiation treatmenthad "significantly shorter" survival times than patientswith non-mutated p53 who received the samecombination therapy.

This and other study data, the Nature Medicine articlepointed out, "should of course be interpreted with greatcaution because the numbers in these subanalyses werevery small."

Larger Studies On Uppsala's Drawing Boards

Oncological surgeon Lars Holmberg, final co-author, toldBioWorld Today: "Our group's next step will be torepeat this study on a larger set of patients. There areplans to do so in our institution, and we are also seekingcollaboration with others, perhaps in other countries."

Pharmacia Biotech AB, also of Uppsala, performed thep53 DNA sequencing for the study as a contribution,using its proprietary Sequence-Based Diagnosis (SBD)technology. The firm's manager of diagnostics marketing,chemical engineer Karina Schmidt, told BioWorld Todaythat her company intends to follow up on this "first studyof SBD in breast cancer" with confirmatory surveys ofp53 mutation by "groups in Europe and the U.S.,specifically, the Corning-Nichols breast-cancer diagnosticlaboratory in San Juan Capistrano, Calif.

Molecular pharmacologist William Hait is director of theCancer Institute of New Jersey, and teaches at theUniversity of Medicine and Dentistry of New Jersey, inNewark.

"To be able to get sequence on the p53 gene in clinicalspecimens, as part of a clinical pathology work-up ofbreast cancer," Hait told BioWorld Today, "is really apretty important step. Just the technological advance indoing this on patient specimens, using Pharmacia's newpotentially powerful molecular diagnostic tool to look atevery important gene, could be an extremely importantadvance.

"The study itself," Hait observed, "although relativelysmall, raises a very exciting, titillating possibility that'sconsistent with peoples' thinking. That is, if you havemutant p53 in your tumor, you'll be less sensitive totherapy. And the reason that's so appealing is that it'sbelieved that it requires wild-type p53 for the cell to killitself through apoptosis. And that the apoptosismechanism actually helps along current anti-cancertherapies." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.