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Prognosis @ MindSay

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I. “Oncotype Dx”: Breast Cancer Technological Breakthrough or Breakdown?

A serious question for women with breast cancer and their physicians is whether chemotherapy should be employed after the initial breast surgery. This decision is particularly vexing for situations where the prognosis is relatively good, but not good enough. Patients whose cancers have estrogen receptors and who do not have any spread to the lymph nodes comprise such a group. And the group is large, perhaps half the women with breast cancer.

A decade or so ago the results from the National Surgical Adjuvant Breast Project chemotherapy trial B-20 were reported. This trial suggested chemotherapy was of benefit before the menopause with a step down in usefulness with menopause and then a continuing decline with age. Thus tamoxifen plus chemotherapy seemed wise up until roughly the age of 60 (the trial did not include women over 70). The chemotherapy employed in B-20 were regimens that date to the 1970's. Many experts believe that newer regimens are more effective.

B-20 revealed that the degree of estrogen positivity was possibly important, with women with lower levels benefiting more from the chemotherapy and tamoxifen combination. The advent of gene profiling, like the proprietary “Oncotype Dx”, seems to have resolved the chemotherapy issue for many patients and physicians. Is this rational or simply another example of the technological imperative?

“The RS [Oncotype Recurrence Score] assay not only quantifies the likelihood of breast cancer recurrence in women with node-negative, estrogen receptor-positive breast cancer, but also predicts the magnitude of chemotherapy benefit” is the conclusion in a paper in the Journal of Clinical Oncology in 2006. Based largely on this study, Oncotype Dx appears with favorable mention in the American Society of Clinical Oncologists and National Comprehensive Cancer Network guidelines. Genomic Health, the company that sells the Oncotype Dx test, uses these guidelines and the JCO paper in its marketing.

The 12 page JCO report is chock full of sophisticated analysis, such as “linear fit of the likelihood of distant recurrence as a continuous function of recurrence score” analyses and various multivariate models. But what is the basis for the statement that Oncotype “predicts the magnitude of chemotherapy benefit”?

A glance at “Fig. A2” on page 11 tells the story. Figure A2 gives 12 year “overall survival” comparisons for four groups: tamoxifen versus combined tamoxifen/chemo for all patients lumped together, and the corresponding comparisons for good, intermediate, and poor Oncotype Dx score groups. Seven of the eight groups have 12 year survival ranging from about 92% for the low score tamoxifen alone group to about 82% for both intermediate groups, and the tamoxifen/chemotherapy high risk group.

Only the high Oncotype risk score tamoxifen alone group jumps off the page. This group has a 12 year survival of only 60%. But the tamoxifen alone group with high risk Oncotype scores consists of only 47 patients. Where did these 47 patients come from? They came from a study (B-20) done by the NSABP and reported in 1997 and included 2363 patients with breast cancer, negative lymph nodes and positive estrogen receptors. The 47 unlucky patients were about 2% of the total enrolled patients in NSABP B-20.

Are the 47 patients representative of all the Oncotype high risk patients in B-20? It is hard to say. Samples of the original breast tumors were available for only 670 patients and testing was successful in 651. So, only about ¼ of the B-20 patients are included in the Oncotype study. If this sample were random, probabilistic analysis might be intact. But the absence of material to test was not random. Some of the tumor samples were “used up” in other studies, and not saved in others. Presumably these other studies were focused on something specific and not random.

And what about the “overall survival” of 60%? Is that real? Again, it is hard to say. “Deaths before distant recurrence [was] considered [a] censoring event”. This means that a patient who was killed in an auto crash would be counted as alive but lost to follow up rather than counted as a death. But what if the crash was caused by a blood clot caused by the tamoxifen? And, since both chemotherapy and tamoxifen are thought to increase clots, what if several more patients in the combined group than in the tamoxifen died of strokes or heart attacks?

Oncotype is being used by patients and physicians all over the country to decide upon chemotherapy based on the 47 patients. Perhaps by a coincidence, the 12 year survival for both the Oncotype intermediate and high risk combined tamoxifen/chemotherapy groups was nearly identical at 82%. There were 212 such patients.

However, the 47 high risk tamoxifen alone group had survival 22% less than any other group. What are the possible explanations for the remarkably bad outcome for the 47 patients? Perhaps it is as it seems – tamoxifen alone is inadequate for high risk patients. Still it seems odd that the worst prognosis group had almost exactly the same survival experience as the intermediate group when the treatment was both chemotherapy and tamoxifen. If the understanding is that tamoxifen is good for estrogen receptor positive patients and chemotherapy adds something for some patients, how is it that the combination gives the same results for both intermediate and high risk patients?

Maybe the 47 were just very unlucky and the 117 high risk patients who got the combination therapy were astonishingly lucky to get the same results as the intermediate group. To account for this possibility, tests of statistical significance are performed. Using one of these (Cox proportional hazard test), there is less than one chance in a thousand that the 22% difference in survival is “random”, according to the analysis done by the authors. The tests for statistical significance assume random allocation of treatment. The original B-20 trial was randomized but the Oncotype study was not based on a random sample from that trial and was retrospective.

In addition, the “significance testing” was not said to have been corrected for the fact that many comparisons were made. The degree of confidence one takes away from a retrospective study full of potentially confounding variables and assumptions that violate basic probabilistic underpinnings is not as high as the statistical significance level might otherwise imply.

The authors of the JCO paper claim that their test “predicts the magnitude of chemotherapy benefit.” This seems not quite right. The magnitude of benefit from tamoxifen/chemo was identical in the intermediate and high risk score groups. What the test may have predicted in those 47 patients with high scores was a poor outcome with tamoxifen alone. One would think that the suggestion that Oncotype should serve as the basis for treatment selection for 100,000 women should not be based on the experience of an undefined 47 patient “chunk sample”.

The test costs about $3650. About 100,000 women may have er positive, node negative cancer diagnosed this year. That’s $365 mil for just one test in a complicated setting where many other images and tests will be required. Oncotype Dx should be verified by a prospective randomized trial that is appropriately stratified. Such a trial is underway.