Breast Cancer Update 2006 (2)

DR PICCART-GEBHART: I believe that in the not-too-distant future, we will approach the choice of chemotherapy completely differently. We used to think according to risk, dividing the choice of chemotherapy regimens into the most appropriate for patients with node-positive versus node-negative disease.

We are going to move away from that because we are entering an era in cancer medicine with the development of superb tools to predict which tumors respond to which drug.

We are not there yet, but this is going fast. The technologies are exploding. If we, the clinicians, are smart enough to design the right studies to validate these technologies quickly, it’s going to change the picture.

Instead of our habit of thinking that six positive nodes means dose-dense chemotherapy, we should look at the profile of the tumor first. After that we can look at the nodes because the number of nodes is related to risk.

I would never administer dose-dense chemotherapy to a patient with a Grade I, highly endocrine-responsive tumor with maximum receptors and a very low proliferation index. On the contrary, if I see a young patient with negative nodes but an aggressive tumor with absolutely no endocrine receptors whatsoever, no HER2 and very high proliferation, I would be tempted to use dose-dense therapy.

Martin M et al. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 2005;352(22):2302-13.

In BCIRG 001, a randomized, phase 3 trial of adjuvant chemotherapy in women with operable node-positive breast cancer showed that, at a median follow-up of 55 months, the estimated rate of disease-free survival at 5 years was 75 percent in the TAC group and 68 percent in the FAC group (P = 0.001). The relative risk of death was 30 percent lower among women in the TAC group than among those in the FAC group.

Moreover, treatment with TAC, as compared with FAC, was associated with a 28 percent relative reduction in the risk of relapse. The reduction in the risk of relapse did not seem to be driven by nodal status or by hormone-receptor or HER2/neu status.

Perez E. TAC — A new standard in adjuvant therapy for breast cancer? N Engl J Med 2005;352(22):2346-8.

On the basis of the available data, one can consider TAC to be a standard of care, as is the dose-dense regimen of doxorubicin and cyclophosphamide followed by paclitaxel, for patients with resected node-positive breast cancer. However, the exclusion of patients older than 70 years and the toxic effects associated with TAC in the BCIRG trial cannot be minimized.

With this regimen, prophylactic growth-factor support is necessary to ameliorate myelosuppression and febrile neutropenia. A recommendation for the selection of one regimen over the other must await completion of the prospective National Surgical Adjuvant Breast and Bowel Project trial B-38, for which the accrual of data is expected to be complete in the next few years.

Seidman A. Current status of dose-dense chemotherapy for breast cancer. Cancer Chemother Pharmacol 2005;56(Suppl 7):78-83.

Dose-dense trials have demonstrated that filgrastim facilitated bi-weekly chemotherapy is feasible. Based on the landmark results of CALGB 9741, many groups have adopted this strategy as a new standard of care. However, appropriate caution should be applied in extrapolating these data to any/all regimens outside a clinical trial setting, since unanticipated toxicities may emerge.

At Memorial Sloan-Kettering Cancer Center (MSKCC) and elsewhere, feasibility trials are either planned or under way exploring dose dense regimens containing other agents (eg, docetaxel). It is intuitive that patients may be willing to endure the minor inconvenience of filgrastim administration to shorten duration of treatment and to gain therapeutically.

Meet The Professors 2006 (1)

DR MACKEY: I believe that TAC without growth factors is more toxic than dose-dense AC. We have data from a trial in which Miguel Martin, in Spain, treated node-negative patients with TAC or FAC. Early in the trial they thought, “Gee, for node-negative disease, TAC is quite tough,” and they mandated G-CSF.

At that point, they found that the tolerability increased dramatically. It’s not a randomized trial, and it’s an intervention halfway through, but they found that not only did the febrile neutropenia rate drop, but the mucositis, fatigue and diarrhea decreased as well. In addition, the quality-of-life decrements that come with chemotherapy were less after G-CSF was initiated.

I agree that “naked” TAC without growth factors is probably tougher than dose-dense therapy with growth factors. However, I think that difference would be much less if you used primary prophylaxis with pegfilgrastim or filgrastim. I would suggest that if you were going to use it, use it with growth factor support.

Breast Cancer Update — Think Tank Issue 1, 2006

DR CHARLES L VOGEL: In our study, docetaxel was chosen as a representative regimen that could cause somewhere around a 20 percent risk of febrile neutropenia at 100 mg/m². All three endpoints — febrile neutropenia, febrile neutropenia-related hospitalization and use of anti-infectives — showed dramatic improvement with the addition of pegfilgrastim.

Most people would agree with the new NCCN guidelines stating that prophylactic growth factors should be used for patients with greater than 20 percent risk of febrile neutropenia. The use of prophylactic growth factors should also be considered in the intermediate-risk group (10 to 20 percent). Patients at low risk should not receive growth factors. AC followed by docetaxel, AT and TAC all have very high febrile neutropenia rates, and prophylactic growth factors should be strongly considered with these regimens. AC is considered an intermediate-risk regimen, as is docetaxel/capecitabine.

FAC, FEC and TC are regimens associated with borderline to low febrile neutropenia rates. Certainly, dose densification of any of these would be a reason to use prophylactic pegfilgrastim, as would the avoidance of dose reductions and delays. A third reason to consider it would be the factors that may cause patients to be at risk for febrile neutropenia.

Breast Cancer Update — Think Tank Issue 1, 2006

DR BURSTEIN: With regard to prophylactic growth factor support, I believe most of us would have a hard time consenting to a regimen associated with a one in five chance of a patient being hospitalized with febrile neutropenia compared to one that wasn’t, simply for the administration of prophylaxis. So I don’t find a problem with the recommendation for prophylactic treatment at 15 to 20 percent risk.

The problem is that we as a community haven’t defined an acceptable level of febrile neutropenia. For instance, with nausea and vomiting, we all agree the desired goal is zero, so we liberally use prophylaxis.

For cancer pain, the goal is zero, so we liberally use pain medicine. We haven’t said what we’re willing to tolerate in the way of febrile neutropenia risk.

The only other anecdote I can offer is that as I administer AC every three weeks for patients destined to receive adjuvant trastuzumab, I’m struck by how many patients end up having dose delays and tweaks.

It’s clearly more toxic than using dose-dense AC followed by paclitaxel with growth factor support.

This hasn’t caused me to use G-CSF prophylactically in these settings, but it is impressive how predictable and clockwork-like every two-week AC with growth factor support is compared to other treatments.

I believe if you asked patients whether they would take a growth factor for a four percent decrease in their chance of febrile neutropenia, they’d all say yes. Whether that is cost effective is a totally different question.

Breast Cancer Update 2006 (4)

DR STEPHEN E JONES: At the San Antonio Breast Cancer Symposium in 2005, we reported on a US Oncology adjuvant study in which we compared four cycles of standard-dose AC to four cycles of standard-dose TC (docetaxel and cyclophosphamide). Chemotherapy was administered before radiation therapy or tamoxifen, and we included patients with node-positive and higher-risk node-negative disease.

When we started this trial in 1997, everyone was interested in combining doxorubicin with the taxanes, but we felt that we didn’t have enough data to combine docetaxel with doxorubicin. Consequently, we pursued this alternative route, which stands alone because it is one of the only nonanthracycline-containing regimens out there.

We now have mature results based on more than 170 events, with a median follow-up of 5.5 years. We have seen significantly fewer recurrences and events on the TC arm compared to the AC arm. I emphasized at San Antonio that the endpoint for this trial was disease-free survival, not overall survival. Overall survival was the secondary endpoint.

At five years, the disease-free survival was 86 percent for TC versus 80 percent for AC — a six percent absolute difference. The reduction in risk was roughly one third, and it was highly significant, with a
p-value of 0.015. Also, a strong trend was favoring TC for overall survival — a three percent absolute difference at five years, with approximately a 24 percent reduction in the odds of dying from breast cancer.

In general, TC was better tolerated. Some low-grade docetaxel-type side effects do occur, such as myalgias, arthralgias and edema, but they are fairly transient. The fever and neutropenia rates are also slightly higher; the numbers were 5.5 percent on the TC regimen and 2.5 percent on the AC regimen. We didn’t use any prophylactic growth factors, but prophylactic antibiotics were used and encouraged.

The rate of congestive heart failure (CHF) with AC was probably lower than would be expected. The usual figure that’s quoted is 0.5 to 1.0 percent; fortunately we haven’t seen that kind of rate. We have no reason to believe that TC would cause cardiac toxicity.

AC brought significantly more Grade III/IV nausea and vomiting, despite antiemetics. That’s an unpleasant side effect we didn’t see with TC. I was amazed at how much better tolerated TC was than AC.

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Breast Cancer Update — Think Tank Issue 1, 2006

DR RAVDIN: In the data comparing docetaxel/cyclophosphamide to AC presented by Steve Jones at San Antonio in 2005, the hazard ratio for recurrence showed a 24 percent proportional advantage in survival for docetaxel/cyclophosphamide, which is as big a step as we usually take in our clinical trials, and it showed a 36 percent improvement in disease-free survival.

I believe the improvement in overall survival is real, and the correct interpretation isn’t that it doesn’t show a survival advantage but that it’s underpowered to show a 24 percent advantage.

Breast Cancer Update 2006 (3): Miami Breast Cancer Conference Tumor Panel Discussion

DR O’SHAUGHNESSY: TC is definitely better tolerated than AC. What did not come out in the data set — but, if you took care of the patients on both arms, you saw it — was less fatigue with the TC because docetaxel at 75 mg/m² is not particularly fatiguing. With AC, you can get that kind of prolonged queasiness, and it “drugs you down” for a week or so in some patients. TC is much less nauseating and much better tolerated. It’s really night and day. I have stopped using AC now in patients for whom I was using AC. Now I use TC because of the six percent absolute improvement in disease-free survival.

Breast Cancer Update 2006 (2)

DR SWAIN: ECOG-E1199, where the different schedules and different types of taxanes were compared, really showed that the weekly versus every three-week schedule didn’t make any difference, and the drug, docetaxel or paclitaxel, didn’t make any difference. So, in clinical practice, the best plan is to use whatever you’re comfortable with.

For example, if you like AC followed by weekly paclitaxel, that is effective, or AC followed by docetaxel. I personally would use every three-week instead of weekly docetaxel. Basically, what ECOG-E1199 says is that we have a lot of different options.

Breast Cancer Update 2006 (3)

DR RAVDIN: The ECOG-E1199 trial asked two questions: Which taxane and which schedule are optimal as adjuvant therapy? Patients received AC, and then the standard arm was paclitaxel every three weeks for four cycles. Another arm was a substitution of docetaxel for paclitaxel, and two arms evaluated these agents in weekly regimens.

If you look at paclitaxel versus docetaxel, you see no superiority in a two-by-two comparison between the two agents. If you look at every three weeks versus weekly, you see no difference in efficacy.

However, the devil is in the details, and as clinicians we all want to know the one-by-four comparisons. The results are consistent with what we’ve seen in metastatic disease.

The weekly paclitaxel regimen was the best, with almost a 20 percent better hazard ratio than the standard arm. Docetaxel, given every three weeks, also looked somewhat better.

In both of those cases, however, the difference was a trend and was not statistically significant. The weekly paclitaxel arm looked best in terms of overall survival, but this is a very early analysis not dignified by p-values.

What about toxicity? The weekly paclitaxel arm seemed to provide additional benefit without additional risk of febrile neutropenia, whereas the docetaxel arm was associated with additional febrile neutropenia.

A conclusion from this study has to be that weekly paclitaxel in adjuvant therapy appears promising, and the hazard ratios for the weekly arm of E1199 looked very similar to those of dose-dense therapy.

Breast Cancer Update — Think Tank Issue 1, 2006

DR HUDIS: Don Berry started the discussion of the impact of ER status on chemotherapy outcomes in the modern era by performing an unplanned retrospective analysis of CALGB trials on the basis of ER status.

He initially presented his three-study analysis at San Antonio in 2004 and compared the high-dose, every four-week CAF regimen to the standard AC arm of CALGB-9344. He then studied the AC paclitaxel arm of 9344 against the standard arm of the dose-dense 9741 trial.

For patients with ER-negative disease, the hazard for disease-free survival was significantly improved with each one of these steps — better CAF, addition of paclitaxel, dose-dense scheduling. Adding up the overall impact for E-negative breast cancer, we see a profound chemotherapy effect.

In the subset of patients with ER-positive disease, the difference in each one of these steps was not statistically significant, but they were always favorable.

The point estimate for benefit is half the size for the patients with ER-positive disease compared to those with ER-negative disease. It is likely that it is still favorable, although the confidence interval does not exclude the possibility of no benefit at all.

To some degree, this has been wildly over interpreted as suggesting that chemotherapy doesn’t work in patients with ER-positive disease. It simply doesn’t say that. It says that the magnitude of the benefit is likely to be much smaller than for those with ER-poor disease.

The important point is that when people say that the addition of dose-dense scheduling in 9741 doesn’t yield much among patients with ER-positive disease, they’re really not comparing apples to apples when they then look at the TAC-FAC data.

The TAC-FAC trial demonstrated hazard rates for risk reductions, which looked about the same in the ER-positives and the ER-negatives. The FAC control arm, of course, includes no paclitaxel or docetaxel.

You can’t say that each individual step is or is not significant vis-à-vis another separate randomized trial. You can’t compare these regimens head to head.

If you were to argue that you know to utilize TAC instead of dose-dense AC paclitaxel in a patient with ER-positive, node-positive disease, then you’re presuming to know the results of NSABP-B-38.

I would argue that there is equipoise on this question and that either regimen is entirely appropriate for patients with ER-positive disease.

Breast Cancer Update — Think Tank Issue 1, 2006

DR WINER: I believe the bottom line is that if you take all patients with ER-positive breast cancer, the benefits of chemotherapy are dramatically less than in patients with ER-negative disease.

Almost certainly, some groups of women with ER-positive breast cancer derive no benefit, and others probably derive every bit as much benefit as the ER-negative group. It’s not going to be chemotherapy agent specific, particularly when we get down to the level of taxanes.

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Breast Cancer Update — Think Tank Issue 1, 2006

DR OSBORNE: The influence of ER status on the effects of chemotherapy is such an important question because 60 percent of all patients have ER-positive, PR-positive disease. Will anyone conduct a randomized trial of chemotherapy versus no chemotherapy or endocrine therapy alone versus the addition of chemotherapy in that subgroup?

Meet The Professors 2006 (1)

DR HUDIS: Without question, the Oxford Overview and virtually every study across the board ever done, including the TAC/FAC trial, show clear evidence of a greater magnitude of benefit for patients with ER-negative disease who receive chemotherapy than those in the ER-positive subset.

In the TAC to FAC comparison, the benefit in the ER-positive subset is statistically significant. In some of the other trials, it is not. That trial had the advantage of centralized ER testing and control over the hormone therapy.

When we conducted our studies in the CALGB, we recommended but didn’t stipulate hormone therapy. We didn’t do centralized ER testing. So our results are hypothesis generating. Our hypothesis is that chemotherapy is, on average, less effective in ER-positive than in ER-negative breast cancer. I don’t think that’s a big stretch.

Whatever small benefit chemotherapy may offer patients with ER-positive disease is likely to play out over many, many years, and you need to have a long life expectancy to see that difference.

ER-positive breast cancer has a long, chronic relapse track. Not many people appreciate this, but by 30 years after diagnosis, it doesn’t matter whether you had ER-positive or ER-negative disease, untreated. The overall risk of relapse and the overall survival is the same. So the notion that ER-positive disease is overall a better disease is undermined.

What’s different is the timing of the recurrences. With ER-positive disease, you see the impact of therapy over the long haul. With ER-negative disease, you see it right up front.

For a young patient with a long life expectancy, I wouldn’t be so quick to forgo that potential benefit. But the older you get, the longer you have to live to see the potential benefit and the more likely you are not to get there.

Breast Cancer Update 2005 (3)

DR SOONMYUNG PAIK: NSABP-B-20 included women with node-negative, ER-positive disease. It was a three-arm design, and patients were randomly assigned to tamoxifen alone or tamoxifen concurrent with either CMF or methotrexate followed by 5-FU.

Our study of the Oncotype DX assay was a retrospective analysis of that completed trial.

We only had tissue blocks available for approximately 30 percent of the entire study cohort, so it’s a subset; however, the subset and the entire cohort were comparable.

We repeated the Oncotype DX assay on the tamoxifen arm to ensure the assay was reproducible, and we demonstrated that it is reproducible, which is encouraging.

It is important to note that we evaluated the NSABP-B-20 chemotherapy arms to address whether the assay predicted chemotherapy responsiveness.

We went into that study with an a priori hypothesis, based on the data presented at the 2004 ASCO meeting by Dr Luca Gianni’s group in Milan evaluating samples from a neoadjuvant trial they performed with paclitaxel and doxorubicin.

They demonstrated a correlation between the Genomic Health recurrence score and pCR rate.

The higher recurrence rate correlated strongly with the higher pCR rate. The overall pCR rate was approximately 25 percent in the patients with high-risk disease, and there was no pCR in patients with low-risk disease.

We hypothesized that the benefit from chemotherapy in NSABP-B-20 would be almost negligible in patients with low-risk disease and high in patients with high-risk disease. The results of this study are striking and unlike anything I’ve ever seen.

The absolute benefit from chemotherapy is negative in the low-risk group and zero in the intermediate-risk group. In the high-risk group, the absolute improvement in distant recurrence at 10 years is 28 percent, or a relative risk reduction of 75 percent.

The data in the low-risk group are, in a sense, not relevant because the baseline risk after tamoxifen is so low — 6.8 percent — that it’s a moot point whether they need chemotherapy.

In the intermediate-risk group the confidence interval overlaps with one, so whether patients with intermediate-risk disease gain any benefit remains a question.

Breast Cancer Update — Think Tank Issue 1, 2006

DR DANIEL F HAYES: The patients with node-negative, ER-positive disease in the TAILORx, or ECOG-PACCT-1, study will all be profiled by the Oncotype DX assay. Those patients with a good recurrence score of 11 or lower will receive hormone therapy only.

Those with a high recurrence score of 25 and higher will all receive hormone therapy and chemotherapy of “dealer’s choice.”

Those in the intermediate group will be randomly assigned to receive chemotherapy or not (investigator’s choice). They then will all receive hormone therapy, also at the investigator’s choice.

Meet The Professors SABCS 2004

DR HYMAN MUSS: One of the exciting trials we have ongoing in North America is CALGB-49907. This is a trial that essentially compares standard chemotherapy — four cycles of AC or CMF with oral cyclophosphamide — to six cycles of capecitabine for elderly patients. Physicians can select the standard chemotherapy for patients randomly assigned to that arm.

We’re excited about the trial and like to believe it’s an equivalence study, as some background data suggest that oral capecitabine is as good as standard therapy. It would be nice if we had an oral regimen because I think people would rather be at home than in our clinics all the time.

CALGB-49907 Protocol. calgb.org

A recent randomized phase II trial, comparing single-agent capecitabine and CMF as first-line therapy in patients with metastatic breast cancer who were 55 years and older (median age 69 years), demonstrated the response rate to capecitabine alone (25 percent) at a dose of 2510 mg/m² per day for 14 days, every three weeks was superior to intravenous CMF (16 percent).

Grade 3 or 4 hand-foot syndrome was seen in 16 percent of patients on capecitabine and none on CMF, Grade 3 or 4 diarrhea in 8 percent with capecitabine and 3 percent with CMF, and Grade 3 or 4 hematological toxicity in 20 percent with capecitabine and 47 percent with CMF.

In another Phase II randomized trial comparing capecitabine in the same dose and schedule as above with paclitaxel 175 mg/m² every three weeks, the response rate was 36 percent for 22 patients on capecitabine and 21 percent for 22 patients on paclitaxel.

These data suggest that the efficacy of capecitabine in patients with metastatic disease is similar to CMF or paclitaxel.

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