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Recurrence Risk for Breast Cancer

Reporter: Larry H Bernstein, MD,  FCAP

Testing recurrence risk for breast cancer
Karen Titus
June 2011 CAP Today

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Gene panels for breast cancer recurrence risk have arrived. In fact, they’ve been around since the mid-2000s. And now, like guests at a wedding reception, it’s a matter of figuring out where to seat them.
Like it or not, tests such as Oncotype DX (Genomic Health Inc.), MammaPrint (Agendia), and Mammostrat (Clarient)—to name just a few—are making their presence felt.
Clinicians favor these tests for a simple reason: the results help them decide if patients with breast cancer need chemotherapy. More broadly, the tests reflect a shift in thinking among physicians, one that emphasizes molecular profiling of tumors. They’ve arrived on the scene when physicians are also starting to question the value of lymph node status to help determine treatment.George W. Sledge, MD, finds these changes remarkable. Not all that long ago, he might have pink-slipped a test that would help parse treatment decisions. When the NIH held its consensus development conference on adjuvant therapy with breast cancer in 2000, he recalls, the agreement was, basically, that everyone with a tumor greater than one centimeter ought to be treated with chemotherapy. “There’s no question that resulted in us hugely overtreating patients,” he says. “So I think a test that reduces the quantity of human suffering by half in that group is a useful test,” says Dr. Sledge, professor of medicine and pathology, Indiana University, Indianapolis, and immediate past president of the American Society of Clinical Oncology.
In clinical practice, these tests are functioning like traffic managers. “We now see fewer patients getting chemotherapy who would have gotten it before,” says Thomas Julian, MD, professor of surgery, Drexel University College of Medicine, Philadelphia, and director of breast surgical oncology for the West Penn Allegheny Health Care System, Pittsburgh. “We’re also seeing a few who are getting chemo who might not have gotten it before. So it’s changed in both directions,” says Dr. Julian, who is also senior surgical director for medical affairs for the National Surgical Adjuvant Breast and Bowel Project.
Oncotype DX is a real-time RT-PCR assay measuring RNA expression in 16 cancer-related genes and five reference genes, using paraffin-embedded tissue. Results are given as a recurrence score between zero and 100, which are translated as low risk (a score of 18 or lower), medium risk (19 to 30), or high risk (31 or above). The MammaPrint microarray assay measures expression of 70 genes in fresh tissue; it categorizes patients as either high risk, with a so-called poor signature, or low risk (a so-called good signature) for recurrence. There is no intermediate category. Mammostrat is an immunohistochemistry test measuring five markers: p53, HTF9C, CEACAM5, NDRG1, and SLC7A5. The results are combined into a quantitative risk index: low, moderate, and high. For now, only MammaPrint has FDA clearance.
The test is not useful in patients whose tumors are HER2 positive. The test nearly always will show such patients to be at high risk; moreover, the paradigm for treating such patients is with chemotherapy and trastuzumab (Herceptin). It is used for patients who are lymph node negative, ER positive, and HER2 negative, with “moderate-size tumors—say, tumors that are over a centimeter but less than four or five centimeters. Another consideration is tumor size. The test is most useful for tumors of around five millimeters or greater in size.For patients with very, very small tumors—one, two, three millimeters—there’s no need for the test. Elizabeth Hammond, MD, agrees these tests are useful, although she suspects they may best prove their mettle in second- or third-generation assays. It’s simple biology: phenotypic expression of a genetic alteration of ER or HER2 status is the result of cell-signaling pathway changes. “Looking at multiple expressions of that problem with a gene panel, either by RT-PCR or some other method, will in the long run give us better information.

Comment:  In 1982, labs were running RIA assays for Estrogen Receptor.  It was known for some time that breast cancer is estrogen-dependent.  This was a major discovery by a surgeon at University of Chicago, that led to oophorectomy with resection of the lesion.  The assay was quite elaborate and required a “scatchard plot”.  The assay was no longer used when a good histochemical stain became widely used with a progesterone receptor a few years later.  We went into the 1990’s knowing that if the patient is pre-menopausal, positive ER+/PR+ is likely, and the cancer is aggressive.  If the patient was postmenopausal, the test is more likely ER/PR negative.  This gives us a perspective on how far we have come.

Image via CrunchBase

English: Validation chart for Agendia’s MammaPrint Assay, part of the Symphony Breast Cancer Suite (Photo credit: Wikipedia)

Ovarian and breast cancer patients in a pedigree chart of a family (Photo credit: Wikipedia)

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