Breast Cancer Update 2006 (5)

DR HAYES: For older women, I believe the jury is out regarding the potential benefits of chemotherapy. The issue has two components. One is whether — for some mysterious reason — chemotherapy doesn’t work as well in older women as in younger women. The second is whether the toxicities are greater for older women and, therefore, the benefit-to-toxicity ratio is smaller.

Another component is whether the number of life-years saved will be lower for older women and therefore not acceptable. An 80-year old woman on average has another 10 years to live, but the number of life-years saved for her will be lower than for a 50-year-old woman for the same potential reduction in recurrences. Peter Ravdin has begun to build that into Adjuvant! Online. It’s not something we normally talk to patients about, but I believe it is part of the equation.

The CALGB-49907 study, which is restricted to patients over age 65, assumes that chemotherapy is beneficial. It is not a trial of chemotherapy versus none. The question is whether in this older age group one type of chemotherapy might be more acceptable by being less toxic. Patients either receive one of the standard regimens — AC or CMF — or capecitabine. A critical part of the study is to determine whether capecitabine is a more acceptable regimen.

Breast Cancer Update — Think Tank Issue 2, 2006

DR HOPE S RUGO: I would consider adjuvant chemotherapy for an otherwise healthy woman in her eighties with triple-negative disease, but even more so for the patient with an ER-negative, PR-negative and HER2-positive tumor, for whom we know that recurrence is heavily weighted in the first two or three years. As the survival of our population increases, these 81- and 82-year-old women who don’t have major medical problems are reasonable candidates for limited approaches to chemotherapy.

This must be within the limits that we all know to be important, such as understanding morbidities. That’s one of the reasons Adjuvant! Online can be very useful in directing physicians who are treating older patients. First, in this older population, the patients with hormone receptor-negative disease are the ones for whom we are going to be thinking about chemotherapy.

Then, in regard to morbidity, if a patient has a major morbidity, such as heart failure, and is not going to be alive in three years, that is not the patient we should be treating with chemotherapy.

Breast Cancer Update — Think Tank Issue 2, 2006

DR CLIFFORD HUDIS: In the quantifiable, objective ways in which we assess toxicity, you cannot support the argument that dose-dense therapy is more toxic. In CALGB-9741, it appears to be equivalent or perhaps less toxic in many ways. The one toxicity that stood out in the original Citron paper was the high rate of packed red blood cell transfusions, which appears to be abrogated with the use of erythropoietin or darbepoetin as prophylaxis. It’s my subjective opinion that patients stay on schedule more easily when they receive every two-week therapy with growth factor support than when they are treated with an every three-week schedule. When patients can’t plan their therapy, it is an annoyance, and it can reduce quality of life.

Also, completing therapy faster is always worthwhile. We’ve taken the position that unless we have a compelling reason not to administer a growth factor, we use every two-week therapy for everybody who receives AC and a taxane.

Breast Cancer Update 2006 (7)

DR CARLSON: Docetaxel administered every three weeks at 100 mg/m² is a reasonable taxane to use following AC chemotherapy. I have no difficulty with that. ECOG trial E1199 suggested equal efficacy to paclitaxel in that setting. Perhaps a little more toxicity, especially febrile neutropenia, occurred with the every three-week regimen. Given the increased frequency of febrile neutropenia, growth factors would be reasonable to use with that dose and schedule.

TAC certainly causes febrile neutropenia with a high enough frequency that growth factors should be used. The NCCN Breast Cancer Treatment Guideline specifies the use of growth factors with two of the adjuvant chemotherapy regimens. One is TAC and the other is a dose-dense chemotherapy regimen.

Breast Cancer Update 2006 (6)

DR I CRAIG HENDERSON: I see dose-dense AC without paclitaxel being administered off protocol in my own clinic. I started a couple of patients in the last few weeks on dose-dense adjuvant chemotherapy and discussed it with some of my colleagues, and in fact, they are doing this in the university setting. In CALGB-9741, which compared sequential doxorubicin, paclitaxel and cyclophosphamide versus concurrent AC followed by paclitaxel at 14- and 21-day intervals, we can’t separate which is the critical factor — the AC or the taxane. We will have to wait and see what the science says.

Breast Cancer Update 2006 (7)

DR CARLSON: I believe that every two-week AC without a taxane with only growth factor support is a reasonable regimen, and I use it for the patients for whom I do not consider a taxane necessary. It’s based on the belief — and it’s just a belief, it’s not yet proven — that if dose-dense AC followed by paclitaxel, or the ATC dose-dense regimen, is superior, it’s likely that every two-week AC should be superior or at least equal to every three-week AC.

I’m impressed at how nontoxic this regimen is when you use growth factors. I believe women like to get through these therapies quickly, and you shorten the duration of treatment with the dose-dense regimens.

Breast Cancer Update 2006 (7)

DR MARK D PEGRAM: The presentation by Steve Jones at San Antonio 2005 of the US Oncology adjuvant trial of docetaxel/cyclophosphamide versus AC was an exciting presentation, and I’m not surprised at all by the data. Steve presented a randomized trial for patients with early-stage breast cancer, approximately 40 to 50 percent of whom had node-negative disease. They were randomly assigned to four cycles of AC versus four cycles of TC.

They showed a significant relapse-free survival advantage with the TC compared to the AC arm, and a numeric trend even appeared in the survival analysis, although it hasn’t reached statistical significance yet. Steve Jones concluded — and probably rightly so — that this constitutes a new regimen that replaces AC. If you were going to use a four-cycle regimen, you probably wouldn’t want to use AC anymore, based on this data set. I was also favorably surprised by the toxicity and safety data. The TC was well tolerated compared to AC. It goes to show that we probably underestimate the toxicity of AC routinely because we’re so used to prescribing it.

I saw a young woman recently in my clinic with newly diagnosed doxorubicin cardiotoxicity after adjuvant therapy for what will probably be curable breast cancer. It’s sobering and scary when you see cases like this.

Breast Cancer Update 2006 (6)

DR MARC E LIPPMAN: Almost 30 years ago, we published, in The New England Journal of Medicine, that patients with ER-negative disease responded more frequently to chemotherapy than patients with ER-positive disease.

Those data have been replicated in the meta-analyses conducted in England by Sir Richard Peto and his collaborators. The clue as to why that occurs is obtained if you observe recurrence rates for women with breast cancer as a function of whether their disease is ER-positive or ER-negative. It is commonly said, but that doesn’t necessarily make it the truth, that having ER-positive disease is a good prognostic factor. The data show — and this has now been shown several times — that early on, if your disease is ER-positive, your relapse rates are lower.

Over time, the patients with ER-negative disease, who relapse at a higher rate, initially stop relapsing, perhaps because most of the ones with bad prognoses have already died, whereas the patients with ER-positive disease continue to relapse, and those lines actually cross. At about 10 to 15 years, you’re worse off having ER-positive than ER-negative disease.

Breast Cancer Update 2006 (7)

DR CARLSON: The analyses of dose-dense chemotherapy and TAC in hormone receptor-positive patients are provocative. Dose-dense chemotherapy showed very little benefit in receptor-positive breast cancer, whereas not much difference in efficacy appeared between the patients with ER-negative and ER-positive disease in the TAC study. Those are indirect comparisons, so I’m not sure we can make much of that specific finding. It’ll be interesting to see, as ECOG-E1199 unfolds, if a differential responsiveness appears with docetaxel versus paclitaxel based on ER status, because that’s what you’d have to hypothesize.

Breast Cancer Update 2006 (7)

DR PEGRAM: Determining a chemotherapy regimen for patients with ER-positive disease depends on their age, et cetera. If they’re getting on in years, I’m more likely to use AC followed by weekly paclitaxel, for example, because that’s so well tolerated. If they are young, fit, in their thirties, have no comorbid medical illnesses and have a number of positive nodes, I would have no hesitation using TAC because we participated in some of those TAC trials and we’re comfortable with the regimen when we use pegfilgrastim.

Breast Cancer Update 2006 (8)

DR RAVDIN: In the most recent Oxford Overview chemotherapy data, the correlation between estrogen receptor status and impact on outcome was hotly debated and complicated by the fact that age has to be taken into account in evaluating the first-generation trials. Overall, it looks as if ER status did not make a difference.

In contrast, ER status appears to make a difference in older patients. Patients with ER-positive tumors benefited, although the benefit was smaller than in those with ER-negative disease — approximately a 2:1 difference. So ER status is important in therapy, but its importance is more obvious among older patients.

Breast Cancer Update 2006 (7)

DR VOGEL: Using archival tissue blocks from past trials, Genomic Health and Dr Soon Paik from the NSABP analyzed about 200 genes that were reported to possibly relate to outcome in breast cancer. They narrowed that set down to just 16 genes that could be sorted into logical groups based on the estrogen receptor, the HER2 protein and proliferation and invasion characteristics of the cells.

That set of 16 genes plus five reference genes were used to see if breast cancer patients could be sorted into prognostic and predictive groups. When I say “prognostic” I mean to predict the likelihood of recurrence, and when I say “predictive” I mean to predict patients who would benefit from chemotherapy. So the investigators examined the archival subsets and were able to determine that those 16 genes and five reference genes could be used to sort patients along a continuum they called the recurrence score, which varies from zero to 100. Using simple mathematic regression procedures, that recurrence score could then be translated into a probability of recurrence over 10 years.

The investigators were also able to determine that patients who had low recurrence scores — that is, scores lower than 18 — benefited from hormonal therapy but derived no additional benefit from the addition of chemotherapy to their hormonal therapy regimens.

Conversely, patients with high recurrence scores — scores of 31 or higher — showed a clear, statistically significant and large benefit when cytotoxic chemotherapy was added to hormonal therapy — that is, tamoxifen. In the intermediate group, the group with scores between 18 and 30, no benefit was apparent from the addition of chemotherapy, but the confidence intervals — the statistical certainty of no benefit — were not established.

What came out of that work was the Oncotype DX assay from Genomic Health. It is commercially available and essentially allows selection of patients for hormonal therapy alone or hormonal therapy with chemotherapy in the high-risk group.

In the intermediate-risk group, we’re left with some uncertainty. An Intergroup clinical trial, known as the TAILORx study, is for patients with ER-positive, node-negative, early-stage — Stage I, small Stage II — breast cancer. Patients with intermediate recurrence scores will be randomly assigned to chemotherapy or no chemotherapy, in addition to their hormonal therapy.

Breast Cancer Update 2006 (6)

DR C KENT OSBORNE: I believe the Oncotype DX is well done — well standardized and well validated. It produces good results. For laboratories that don’t perform a high volume of assays, where estrogen receptor and HER2 assays are not reliable, the Oncotype DX would provide a much more reliable estrogen receptor test, because the estrogen receptor is such an important part of the generating signal.

So for institutions that don’t measure these things very well, I believe they should use Oncotype DX. In terms of trying to decide who has a worse prognosis and who might need to have adjuvant chemotherapy for a small, node-negative tumor, I believe the Oncotype DX can be helpful.

Breast Cancer Update — Think Tank Issue 1, 2006

DR HAYES: The reason we are conducting the TAILORx trial is that we are in enormous equipoise about the addition of chemotherapy for the Oncotype DX intermediate recurrence score group. I believe we all agree that the addition of chemotherapy for the low recurrence score group is below our radar screen in terms of benefit, and most of us also agree that patients with high recurrence scores have at least a five to six percent or higher absolute reduction in recurrence rates. Those are the patients for whom we would probably recommend chemotherapy.

But for the intermediate group, whether we define it by a recurrence score of 11 or 18, we are in great equipoise. That is especially true because the aromatase inhibitors may be more effective than tamoxifen so patients have a better prognosis than the patients in the NSABP study. I also believe that doxorubicin and the taxanes will be more effective in patients with lower ER and higher HER2 levels.

So depending on where you are in that intermediate group, you may have a better prognosis than we think you have, but you may have a higher proportional reduction than that achieved with CMF. The randomized portion of that trial is critical.

Interview, September 2006

DR WOLMARK: The TAILORx trial is following up on the findings of the value of the Oncotype DX assay in assessing the risk of recurrence and predicting the benefit from chemotherapy. It’s an interesting and ambitious trial that is scientifically compelling and that we would like to see completed.

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