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New Treatments for Breast Cancer and Adjuvant Therapy

A large portion of patients who present with resectable breast cancer that does not involve axillary lymph nodes. This will not really be changed much by sentinel node biopsy, although we may sort of have a new category of sentinel biopsy positive nodes in the years to come. There are a fair number of patients who present with positive nodes, although they leave the operating room apparently to be cured.

The key subgroups really are three, in terms of medical therapy. Ovarian ablation, tamoxifen and chemotherapy. In terms of the studies, they had to have at least five years of follow-up. For tamoxifen in 1995 there were 37,000 patients on 55 trials comparing tamoxifen against nothing. For chemotherapy there were 18,000 patients on 47 trials comparing multiple agents for some prolonged period of time, measured in months or longer, versus none.

Tamoxifen is the first biologically targeted therapy. In the overview, in 1995 the ER and PR negative patients, called ER poor, were omitted from analysis because tamoxifen does not work there. One year of tamoxifen lowered the annual risk of a recurrence by 21%, five years of tamoxifen lowered the annual risk of recurrence by 47% with a very tight standard deviation. This is the single most effective adjuvant therapy out there for ER positive patients.

Chemotherapy is a more problematic area of the overview because in contrast to tamoxifen, the studies are much more heterogenous. Tamoxifen is tamoxifen is tamoxifen. It doesn’t matter where on the planet you got it. It turns out that the dose, 20 or 30 or 40 mg per day, probably doesn’t matter and the duration question can actually be addressed. For chemo though, not only do you have dose and duration, but you also have specific drugs, you have schedules of administration, combinations, so that when you look at the overview you.

Combinations of chemotherapy and hormone therapy in individual clinical trials, show that chemotherapy adds to the benefit you get with tamoxifen. In fact in their last node-negative trial that was true for all women, regardless of their level of risk.

The most important risk factor is nodal status. Tumor size is the second most important prognostic feature and the dominant one in node-negative patients. ER and PR is very important, although more so for treatment decision making and less so for prognosis. HER2 is emerging as potentially important. It is potentially prognostic for node-negative patients.

So how do we assess risk?. Node status.  Invasive ductal or invasive lobular carcinomas measuring up to a centimeter in size had an actuarial relapse free survival of 21 years of 87%, meaning a 13% risk of recurrence. Since the benefits of therapy appear to accrue in the first decade after treatment, when these patients had about a 9% risk of recurrence. One might conclude that the benefits of conventional adjuvant chemotherapy would not justify treatment, and indeed that is what the NCI said.

In terms of patients who have larger tumors, the risk of relapse goes up and the other critical issue is that this only applies to invasive ductal and invasive lobular cancers. There are several special types of breast cancer with a better prognosis; medullary, tubular, papillary, and mucinous. And in a node-negative setting, those subtypes of cancer probably can be watched the same way that you watch a sub-centimeter invasive ductal, even if they measure as large as two or even three centimeters in size. If it is ER positive it isn’t medullary.

The issue here is that while we have drawn these firm lines about who we are going to treat for the adjuvant purpose of preventing distant relapse, we are getting a new motivation to consider treating patients with tamoxifen in lower risk situations. The key is that if you see somebody who has had DCIS and breast conservation, there is a little bit of a motivation here to give them tamoxifen just to prevent local recurrence. If somebody has a five-millimeter invasive breast cancer, the conventional guidelines are not to treat.

Another non-controversial topic is high-dose chemotherapy for breast cancer. A trial from the Netherlands which was reported already in the Lancet, it was reported in abstract form at ASCO last year. Just under 100 patients. FEC, meaning epirubicin instead of Adria pre-op, surgery, a fourth cycle and randomization to high-dose therapy or observation. Disease-free and overall survival showed nothing. Now these are two small randomized trials.