Editor’s Note
	Where we are; where we’re headed

Some months ago I had the honor of interviewing a legendary figure in breast cancer research. While I had regularly said “hello” to this European-based oncologist in recent years at scientific meetings, this was the first time in about a decade that we sat down for an in-depth chat. I entered the conversation optimistic that this visionary researcher would deliver some new revelation about where we might be headed in clinical research. However, when I asked him about future treatment strategies, he mumbled the same jargon about targeted therapies and tissue predictors of response that I have heard endlessly in my audio interview travels.

Exiting this conversation, I was more than depressed. “Does anyone in the field have truly creative thoughts?” I asked myself. Sometimes cancer research seems like just one more government-based, bean-counting bureaucracy, and I was tempted to join the many patients and physicians who throw up their hands in frustration. But experience has shown me that my disillusionment is always tempered by moments when I am seduced by the prospect that hope is just around the corner. This issue of our series beckons with that promise.

John Robertson is my “go-to guy” when the absence of progress makes me want to give up on current research efforts. John is like a magician who amazes you with new tricks, and this most recent conversation once again suggests that we may be closer to reality, than we are to illusion.

Item number one on John’s list is fulvestrant, an estrogen receptor “terminator” that many clinicians consider just one more endocrine option on a long but unexciting list. John is much more optimistic that this fascinating agent might hold a lot more antitumor potential than many appreciate.

In a recent issue of our series, Stephen Jones, one of the more sagacious “Jedis” of the field, shared with us his observation — anecdotal but nonetheless thought provoking — that there was a subset of women with metastatic breast cancer who experienced prolonged responses to fulvestrant.

Steve specifically referred to four of his patients who experienced very prolonged antitumor responses while participating in the initial North American double-blind randomized trial of fulvestrant versus anastrozole. Unblinding of the trial revealed that all four of these women were on fulvestrant. Was this a coincidence or, as Steve postulated, an important clue? I have found Steve to be a very levelheaded observer, and he believes that some important but poorly defined biology explained the unusual courses of these women.

I shared Steve’s thought with John, who responded with two hats — the evidence-based trooper who noted the pitfalls of anecdotal observations, and the open-minded investigator who spouts theories to consider. John noted that fulvestrant competitively inhibits the estrogen receptor and, if there is a subset of women with profound and longstanding responses to fulvestrant, it might be those patients with serendipitously minimal circulating estrogen levels.

John further commented that this concept is being tested in the SoFEA study, a new trial that randomly assigns breast cancer patients who are progressing on an aromatase inhibitor to either fulvestrant alone or fulvestrant plus the continuation of the aromatase inhibitor.

I like that one, John! It’s simple, but intriguing. Maybe we don’t need to escalate the dose of fulvestrant, but rather just obliterate circulating estrogens to see the true value of this agent. In a couple of years, we should know.

John further raised my hopes with new data on the use of serum tumor markers to detect the initial primary appearance of breast cancer and early recurrence after primary local therapy. ASCO tells us that serum tumor marker monitoring after adjuvant therapy is of unproven value. John argues that a couple of semiobscure trials refute this, and that logic suggests that if adjuvant therapy works because systemic agents are more effective with lower tumor burden, then detecting and treating recurrence earlier should also be beneficial.

Who really knows? Breast cancer in the adjuvant setting boils and stews microscopically beneath the surface while both patients and physicians anxiously wait to see if it will rear its very ugly head. Of potential relevance are three trials that have recently reported initial results suggesting that switching from adjuvant tamoxifen to an aromatase inhibitor lowers the recurrence rate. John persuasively argues that what is happening in these studies is that microscopic relapse is being treated earlier and more effectively than waiting for clinically detected disease.

For this issue of our series, I also interviewed Dr Francesco Boccardo, the principal investigator of one of these fascinating new “switching” studies — in this case, anastrozole after two to three years of tamoxifen. Hoping to push this very cautious and reserved researcher to speculation, I plied him with increasing doses of espresso, but no amount of chemical stimulation could loosen his lips about why his study, like the Canadian trial of letrozole after five years of tamoxifen, demonstrated such a provocative advantage.

Just prior to going to press, a similar trial published in the New England Journal of Medicine also revealed an advantage for switching to another aromatase inhibitor, exemestane, after two years of tamoxifen. It will be very interesting to see where this all leads and what the mavens say it means.

It is increasingly clear that decreasing the microscopic tumor burden in the adjuvant and postadjuvant settings holds the potential to significantly improve long-term outcomes, and this issue of our series includes comments on several related strategies involving chemotherapy. Dan Budman — who has had a leadership role in the development of the highly targeted oral fluoropyrimidine prodrug, capecitabine — notes that there are a number of new trial designs integrating this valuable agent into the adjuvant setting.

Perhaps most promising is the combination of capecitabine with a taxane. In a trial of capecitabine and docetaxel (XT) in the metastatic setting, this strategy clearly resulted in improved response rates, and arguably improved survival. A current US Oncology trial evaluates adjuvant XT, while MD Anderson is testing the regimen in both the adjuvant and neoadjuvant settings. This simple approach may result in improved outcome.

Another somewhat basic adjuvant chemotherapeutic strategy that holds great promise relates to dose and schedule. In prior issues of our series, Larry Norton, Cliff Hudis, Mark Citron and Thomas Budd eloquently elaborated on CALGB-9741, a groundbreaking trial that documented significant improvements in disease-free and overall survival when therapy was given every two weeks with growth factor support versus every three weeks.

In this issue, Gary Lyman presents some disturbing patterns-of-care data suggesting that a significant number of patients are having therapy delivered in the exact opposite direction. Gary’s data reflect practice patterns in the late 1990s and show that chemotherapy doses at that time were regularly being reduced and delayed. One can only hope that subsequent surveys will document trends toward greater diligence in delivering the planned dose on time. In fact, one of the key trials suggesting a detrimental effect of compromising dose was a classic CALGB study headed by Dan Budman.

Will breast cancer take a tangible step forward because of the strategies discussed in this issue? Or ten years from now, will we be stuck with the “same old, same old?” Can we test these and other innovative ideas in clinical trials in a reasonably expeditious manner and then “deliver the goods” to practice? Will cranky, impatient observers like me back off when breast cancer mortality starts to go south and stays there? Stay tuned.

—Neil Love, MD

Select publications

Boccardo F et al. Anastrozole appears to be superior to tamoxifen in women already receiving adjuvant tamoxifen treatment. Breast Cancer Res Treat 2003;Abstract 3.

Coombes RC et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350(11):1081-92. Abstract

Goss PE et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349(19):1793-802. Abstract

Lyman GH et al. Incidence and predictors of low dose-intensity in adjuvant breast cancer chemotherapy: A nationwide study of community practices. J Clin Oncol 2003;21(24):4524-31. Abstract

Osborne CK et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: Results of a North American trial. J Clin Oncol 2002;20(16):3386-95. Abstract

O'Shaughnessy J et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: Phase III trial results. J Clin Oncol 2002;20(12):2812-23. Abstract

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