Editor’s Note
	The issue is the tissue

Agree/Disagree? The single most important action a surgeon can take in the management of a patient with breast cancer is to do everything possible to ensure that the estrogen and progesterone receptor and HER2 assays are performed accurately.

When I finished my oncology fellowship in 1977, the most hotly debated topic in breast cancer management was mastectomy versus breast conservation. Over the next decade, patient advocates like Rose Kushner challenged surgeons to consider emerging randomized trial data and present lumpectomy as an option to patients for whom it was clinically appropriate. At that time, Bernie Fisher and other breast cancer surgery leaders — including Richard Margolese, who was interviewed for this issue — appeared to be in a constant state of umbrage due to the disappointingly low rates of breast conservation in the United States.

Clearly, lesser surgery for this disease is evolving rapidly. Sentinel node biopsy is now a widely accepted standard of care, and partial breast irradiation — as eloquently discussed by Lori Pierce in this issue — is allowing more women to choose breast conservation because the time commitment to radiation therapy is significantly reduced. When I first met Dr Margolese in 1986, he predicted that breast cancer would eventually be considered a nonsurgical disease. While that has not fully occurred, there has been a major shift in emphasis toward systemic treatment options. Specifically, breast cancer has become the model for targeted therapy. While most other solid tumors have no such treatment strategies, this disease has two.

The first approach was theorized by an English surgeon in the 1890s based on observations of lactating cows on his farm. It would be 70 years before laboratory scientists began to unravel the mysteries of endocrine therapy pioneered by Sir George Beatson. We have truly come a long way in our understanding of this complex mechanism. I can remember developing an educational video in 1985 that had a Pac-Man-like model of an estrogen molecule scurrying across the cell membrane to join up with the estrogen receptor — and then the dynamic duo meandered into the nucleus.

Today, even a rudimentary diagram of breast cancer growth pathways looks like a map of the London Underground with multiple types of ER, cofactors, PR, HER2 and other receptors and ligands. However, in the middle of this intricate system and fascinating science is a somewhat simple but crucial issue — women whose tumors are considered "ER-positive" receive endocrine therapy and the rest do not.

After decades of emphasis on chemotherapy, medical oncologists have finally figured out that the key to breast cancer control is the use of early endocrine treatment. Moreover, exciting new data from clinical trials is resulting in a shift away from tamoxifen and toward aromatase inhibitors for postmenopausal patients and ovarian suppression combined with tamoxifen for premenopausal patients. These relatively nontoxic strategies with hormonal therapy have halved recurrence rates and substantially reduced mortality.

The greatest challenge to Dr Beatson's legacy and a truly frightening public health concern is the likelihood that a substantial number of tumors are being incorrectly labeled as ER-negative. In the next issue of this series, Craig Allred will spin a horror story that suggests that up to 20 percent of patients are denied hormonal therapy because lower-volume community laboratories incorrectly classify their tumors. To say the least, this is not good.

We go from bad to worse when it comes to HER2. Oncologists utilize HER2 information for a number of decisions in the management of early breast cancer, including the selection of chemotherapy and hormonal therapy, establishing a prognosis and identifying women for participation in arguably the most important breast cancer clinical trials now being conducted — the paradigm-shifting adjuvant trastuzumab (Herceptin®) trials.

Moreover, when breast cancer relapse occurs, HER2 status determines whether an oncologist will recommend trastuzumab — breast cancer's second targeted therapy — which is highly efficacious and virtually without side effects. Like ER and PR, the usual initial test for HER2 is immunohistochemistry (IHC), which also suffers from frequent misclassification in lower-volume laboratories. A second assay — fluorescence in situ hybridization (FISH) — is used in equivocal cases but also has less than optimal quality control in the community.

In this issue, medical oncologists Nicholas Robert and Peter Ravdin discuss their management strategies for patients based on ER, PR and HER2 results. Nick is also trained in pathology and expounds on the histological factors and the emerging role of the genetic tissue assays, such as the one discussed by Soon Paik in our last issue. What emerges from these interviews is essentially the fulfillment of Richard Margolese's 1986 prediction — breast cancer has become a complex medical disease. It seems clear that a continued decrease in breast cancer mortality will be a direct consequence of our ability to interrupt growth control mechanisms based on improved understanding of tumor cell biology.

The bottom line is that when a friend, family member or coworker asks me to refer them to a surgeon for a breast lesion, I am not thinking so much about surgical technique as much as an orientation toward overall management of this increasingly complex disease. Somewhere in that approach is the absolute insistence that the precious tissue being removed be directed to a laboratory that accepts the responsibility of performing an accurate evaluation of two tissue targets with potentially life-saving implications.

— Neil Love, MD
NLove@ResearchToPractice.net

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