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J MICHAEL DIXON, MD: Semiglazov and colleagues randomly assigned patients with ER-positive breast cancer to neoadjuvant chemotherapy versus an aromatase inhibitor and reported similar response rates, with more women achieving breast-conserving surgery with endocrine therapy. The reason is that pathologic changes within a tumor are different with endocrine therapy versus chemotherapy. From our studies we learned that the longer you treat, the better response you obtain. We’ve been treating patients for longer durations with endocrine therapy — nine months to one year instead of three to four months. You can eventually convert approximately 70 percent of these patients — with strongly ER-positive, usually PR-positive disease — from requiring a mastectomy for locally advanced breast cancer to candidates for breast-conserving surgery.

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DR RAVDIN: During the past two years, the issue of smaller, ER-positive, HER2- negative, node-negative tumors has become an area of contention and enormous expectation. Ordinarily, patients with ER-positive disease would most likely receive endocrine therapy, but the question is, would they benefit from chemotherapy in addition to hormone therapy?

The idea is that we’ll be able to identify patients who will obtain a particularly low degree of benefit from chemotherapy and be able to prevent overtreatment. The hope is that we will revolutionize treatment for patients with ER-positive disease who are at low risk.

One line of thought is that molecular markers will allow us to use the multigene assays as in the NSABP-B-20 study, which demonstrated that patients with low Oncotype DX Recurrence Scores did not benefit from chemotherapy. At the 2007 San Antonio Breast Cancer Symposium, SWOG presented the S8814 trial data evaluating the Oncotype DX assay for patients with positive nodes who received tamoxifen and were then randomly assigned to chemotherapy or not. Again, the low-risk molecular signature identified patients who did not seem to benefit from the addition of chemotherapy to endocrine therapy.

MARK D PEGRAM, MD: For a patient whose tumor is 1+ on IHC, I order FISH. What does 1+ mean? In the ASCO/CAP guidelines, it is assumed that HER2 testing is performed by a validated IHC assay.

If the assay has not been validated, then we don’t know what 1+ means. If a laboratory used a validated IHC assay, then I would have more confidence in the result, but in my own practice I would still order FISH. Guidelines are established to define a minimum standard to which everyone should conform. It doesn’t mean that we cannot do better than what the guidelines recommend.

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DR DIXON: MA17 was a seminal study that reeducated us that among patients with hormone receptor-positive breast cancer, more events occur from years five to 15 than in the first five years. I believe that everyone is more aware now that the risk of recurrence is almost lifelong. The rate of contralateral or second breast primaries in treated patients continues at the same rate almost forever.

DR RAVDIN: We have all seen disappointing circumstances in which disease recurs after 10 years. The data indicate that recurrence risk is stable during the first five years, with a substantial risk in years five to 10.

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Between years five and 10, patients with node-positive disease have approximately a 20 percent risk of recurrence. Patients with node-negative disease have a 10 percent risk. This is true for patients with hormone receptor-positive tumors, but it’s not true for those with hormone receptor-negative tumors, who experience most of their recurrences within the first five years.

Currently, one of the major unanswered questions is whether to continue therapy after a patient completes five years of an adjuvant aromatase inhibitor. In the Intergroup study MA17, a marked benefit was observed with letrozole for patients who had completed five years of adjuvant tamoxifen.

These patients had hormone receptor-positive tumors, so their risk of recurrence was substantial and it was reduced by the extended use of an aromatase inhibitor.

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