Adjuvant trastuzumab for smaller, node-negative, HER2-positive tumors (Figure 1)

DR HAROLD J BURSTEIN: This question for the patient with a node-negative, HER2-positive tumor comes up often in the clinical setting because the value of trastuzumab for higher-risk, node-positive breast cancer is clearly established.

The tumor board question we most frequently encounter for HER2-positive disease relates to these particularly small tumors, with which patients generally have a good prognosis.

As a general strategy, trastuzumab appears to reduce the risk of recurrence by one half. Across all of the adjuvant trials, that 50 percent risk reduction stands out as a consistent finding. The questions are, what is the residual risk for these smaller, HER2-positive tumors, and would it make sense to offer a treatment that would cut that risk in half?

Most of us seriously consider offering trastuzumab-based therapy to women with tumors greater than six millimeters in size, which is admittedly an arbitrary cutoff. It resonates because, historically, that was about the absolute smallest tumor size for which we would consider adjuvant chemotherapy in the era before trastuzumab.

I would treat this patient with chemotherapy and trastuzumab. A regimen such as docetaxel/carboplatin/ trastuzumab (TCH) would be reasonable, but I would more commonly use four cycles of AC followed by trastuzumab or ACTH. We recently activated a clinical trial in which we are using 12 weeks of paclitaxel with trastuzumab followed by the remainder of a year of trastuzumab to see if we can use a single chemotherapy drug for a three-month duration and avoid an anthracycline for these patients with lower-risk disease as defined by tumor size.

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Estimated risk of relapse for smaller, HER2-positive tumors (Figure 2)

DR BURSTEIN: It’s hard to find meaningful data on the clinical outcomes for tumors that are smaller than one centimeter, particularly for stratification by HER2 status. Our own group from Massachusetts General and Dana-Farber reported an abstract about a year ago at San Antonio, which reported on our patients with T1N0 breast cancer, who were historically treated with a variety of adjuvant therapies. We identified a risk of recurrence of about 15 to 20 percent over 10 years, which is not too far from what people were estimating in the survey.

The NSABP has conducted several trials over the years that have included women with small tumors. In a publication a couple of years ago in the Journal of the National Cancer Institute, the NSABP showed that for women with 1-cm or smaller tumors, the risk of recurrence over about eight years of follow-up was approximately 10 to 15 percent. They did not have that broken out by HER2 status, but that would be the estimate for the subset of patients with ER-negative disease. I probably would have said about 15 percent, but I believe that’s still a higher risk than we would have imagined for a tumor that was both ER-positive and HER2-negative.

Estimating the risk of cardiac toxicity associated with trastuzumab in combination with chemotherapy (Figure 2)

DR BURSTEIN: Cardiac toxicity is a major concern with trastuzumab-based regimens. Of the 10,000 women treated in the adjuvant trastuzumab trials, 9,000 received anthracycline-based regimens. In the best cardiac analyses conducted, which included independent cardiac review, comprehensive case tracking and assessment with follow-up including resolution of cardiac symptoms, the NSABP suggests about a four percent risk of clinically apparent congestive heart failure with an anthracycline and trastuzumab-based regimen.

They seem to have identified some risk factors, which include preexisting hypertension, borderline cardiac ejection fraction at baseline and age greater than 60 or 65 years. The four percent estimate is probably the best number in the aggregate, but it probably is determined in part by some clinical features that most clinicians can easily tease out.

The TCH regimen, yet to be published, has not shown as high a rate of congestive heart failure in preliminary reports. The two percent estimate from the clinical investigators in the survey seems about right.

It might be a little higher than the one percent estimate that Dennis Slamon has reported. On the other hand, the case assessment has been somewhat less rigorous in this trial to date than has been reported in the North American Intergroup and NSABP experiences.

Adjuvant therapy selection for a 65-year-old patient with a 1.5-cm, node-negative, HER2-positive tumor (Figures 3-4)

DR BURSTEIN: For patients whose risk of relapse is greater, I feel somewhat more strongly about the concurrent as opposed to the sequential use of chemotherapy and trastuzumab.

We don’t have definitive data yet, but the comparisons from N9831 (ACT versus ACT followed sequentially by trastuzumab versus ACT with concurrent trastuzumab) suggest that using chemotherapy and trastuzumab concurrently may be particularly useful. So for patients whose risk is higher, I strongly prefer concurrent chemotherapy and trastuzumab regimens, which include ACTH or TCH.

We still principally use anthracycline-based regimens. Anthracyclines are historically important drugs in breast cancer. Comprehensive retrospective analyses suggest that the one group of patients in whom these drugs work is those with HER2-driven breast cancer. I believe they probably still have a role even with trastuzumab.

All of us are eager to see how the more mature data from BCIRG 006 develop. That study, which used docetaxel for the T, was never designed to compare the TCH to ACTH. Numerically, they appear similar. The differences in clinical events are few, though obviously those data are still maturing.

Adjuvant therapy selection for a 42-year-old patient with a 1.2-cm, node-positive, HER2-tumor (Figure 5)

DR BURSTEIN: The risk of recurrence has gone up because the tumor is node-positive. With that, the recommendations for an anthracycline-based regimen have risen. I don’t disagree with that because, as I mentioned, that’s our preferred regimen.

I don’t know of data to tell you whether to use an anthracycline-based regimen or TCH based on those clinical features. None of the studies have reported that anthracyclines are particularly valuable in younger versus older women. I suspect physicians may be making this recommendation based on cardiotoxicity risk.

Clearly, younger women seem to bear a lower risk of cardiotoxicity with the anthracyclines. We have not seen a detailed breakout of the cardiac risk associated with TCH as a function of age, though the events may be rare enough that it’s hard to do.

Trastuzumab may be the trump card. Therefore, whatever you use besides trastuzumab may not be relevant. This is why we feel that going ahead with a paclitaxel/trastuzumab trial for patients with low-risk disease makes sense.

Adjuvant therapy selection for elderly patients with HER2-positive disease (Figure 6)

DR BURSTEIN: HER2-driven disease is far more frequent in younger than in older women. You shouldn’t be seeing too much HER2-positive breast cancer among women in their seventies and eighties. In large registry-type studies, we would expect fewer than five or eight percent of those tumors to be HER2-positive.

I expect relatively few people in your survey had used TCH for an 80-year-old woman, to know what that experience is like. I’ve used it for some septuagenarians, and it’s a tough regimen. It’s not a trivial chemotherapy regimen to get people through.

I believe for older women, it becomes ever more the “art of medicine” to assess their comorbid conditions, their existing cardiac function and the importance of these treatments. If they’re healthy enough to tolerate the treatment and healthy enough that they merit consideration of treatment, then I believe any of these regimens would still be reasonable.

These regimens work in older women to the extent that they’re at risk for breast cancer recurrence. Hyman Muss and others have shown, through retrospective work, that chemotherapy works as well in older patients as in younger patients if they have chemotherapy-sensitive tumors. So practitioners need more clinical seasoning to feel strongly that one regimen is preferable to another.

I would most likely recommend four cycles of AC followed by trastuzumab for a 70-year-old patient with a 1.2-cm, node-negative, ER-negative, PR-negative, HER2-positive tumor. If you wanted to try TCH, that would be reasonable, but it’s not a trivial regimen. Trastuzumab monotherapy would not be my choice if the tumor were ER-negative. No data support the role of adjuvant trastuzumab for patients not treated with chemotherapy.

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ALTTO trial design (Figure 8)

DR BURSTEIN: ALTTO is a randomized trial in which patients receive chemotherapy with either trastuzumab alone, trastuzumab and lapatinib, lapatinib alone, or a sequence of lapatinib followed by trastuzumab.

One wrinkle to this study is that clinicians have the option of administering chemotherapy first, followed by the biologic therapy, or chemotherapy concurrently with the biologic therapy. It’s a somewhat complicated study. For that reason, it’s a large trial — an 8,000-person trial. A simpler study might have compared chemotherapy with trastuzumab to chemotherapy with trastuzumab and lapatinib. Preclinical data suggest that trastuzumab and lapatinib is better than either drug alone.

On the other hand, that trial would not have answered the lapatinib monotherapy question, which certainly is of interest because it might be appealing as an orally available drug, if it’s shown to be as effective and tolerable as intravenous trastuzumab.

I agree with the sentiments expressed by some people that for a patient with a substantial risk of recurrence, the possibility of using lapatinib monotherapy in the adjuvant setting is of concern when we know that trastuzumab is a life-saving drug. This is evident in the survey results. I believe in the US, a bias will emerge toward enrolling patients with lower-risk disease in ALTTO. Whether the Europeans or the rest of the global community will feel the same way remains to be seen.

Clinical use of adjuvant aromatase inhibitors as initial therapy (Figure 9)

DR BURSTEIN: Three aromatase inhibitors are commercially available. If clinical differences between them exist, it’s been impossible to tease them out to date. I believe that any one of these is probably a reasonable clinical choice.

Having said that, we have data for the use of both anastrozole and letrozole as initial adjuvant treatment, and we do not have those data to date from trials involving exemestane, although such studies have been concluded and eventually we will have the data.

So it wouldn’t be my style preference, but I don’t believe it’s a big mistake to use exemestane. It probably wouldn’t be my first choice, but if a patient comes to me six weeks into treatment and says, “I feel great on this drug,” I wouldn’t derail that plan, if she were tolerating it.

Duration of therapy with an adjuvant aromatase inhibitor (Figure 10)

DR BURSTEIN: Before we had data from the NSABP-B-14 extension trial and the Scottish trial, patients were often receiving more than five years of tamoxifen. It turned out, at least based on the literature we have so far, that this was not clinically valuable. We need answers to the question, does extending adjuvant therapy beyond five years of an aromatase inhibitor improve long-term clinical outcomes?

Ongoing studies by the NCIC and the NSABP are randomly assigning women who have finished five years of an aromatase inhibitor to ongoing therapy with an aromatase inhibitor or placebo. We will have data, but there are none right now. What we can say is that we have a large safety experience for five years of treatment.

Parenthetically, I believe that one of the cleanest of the adjuvant aromatase inhibitor trials to interpret is MA17, which evaluated five years of tamoxifen followed by placebo or an aromatase inhibitor. Clearly, switching to an aromatase inhibitor was helpful. That study also reawakened us to the importance of the second and the third five years after diagnosis.

If you conceptualize hormone receptor-positive breast cancer as a disease with a 10-to 15-year latency period, then it is possible that ongoing durations of antiestrogen therapy with aromatase inhibitors might be helpful, but we don’t actually have those data.

In contrast, we do have data suggesting that a successful strategy could be five years of tamoxifen and then five years of an aromatase inhibitor.

For women who have finished five years of tamoxifen and then five years of an aromatase inhibitor, we certainly don’t have data showing that therapy for longer than 10 years is valuable, and we usually conclude therapy at that point. Women who have received tamoxifen for a couple of years and then an aromatase inhibitor for five years are then out to year seven or eight.

I don’t have a big problem extending their therapy to year 10, but again, we only have safety data for five years of an aromatase inhibitor. For a woman who starts an aromatase inhibitor at year zero, we have no data suggesting that ongoing therapy would be helpful. We all thought that tamoxifen indefinitely would be helpful, which has turned out to not be the case so far.

You can observe several different kinds of patients. You have the women who, three years ago, circled the date on their calendar on which they would finish their adjuvant endocrine therapy, and they’ve been counting down. For such women, I believe it’s certainly reasonable to stop treatment at that time. Then you have women who feel fine or may not feel perfect but love the idea of taking something because it feels reassuring to undergo some treatment to prevent breast cancer recurrence.

For those women, I don’t have a major objection to extending the duration of treatment with the aromatase inhibitors, but we don’t know how valuable that would be.

Arthralgias related to the aromatase inhibitors (Figure 11)

DR BURSTEIN: Increasingly we are finding that patients have musculoskeletal symptoms related to the use of aromatase inhibitors. This is a fairly old observation. It was first reported in the literature, in patients with metastatic disease, seven or eight years ago, when the aromatase inhibitors became widely used in that setting. Now it’s increasingly prevalent in the early-stage setting.

An interesting study of 200 consecutively screened women who were receiving an aromatase inhibitor in the early-stage setting was conducted at Columbia in New York.

The important methodological point from this paper was that investigators didn’t ask the doctors whether patients were experiencing arthralgias — they asked the patients. And over 80 percent of patients said, “Yes, I’m experiencing arthralgias.”

Musculoskeletal symptoms are enormously prevalent in our society. Interestingly, for two thirds of the patients the onset of these symptoms seemed directly related to the use of the aromatase inhibitor. In fact, half of the patients had begun on their own to take something, an over-the-counter anti-inflammatory medicine, acetaminophen or something else, to minimize the arthralgias. This says to me that these are clinically real phenomena. I believe that the doctors’ one-in-three estimate is something that they’re making up because that’s what we hear about.

Without a strong comparator group, it’s hard to know how much of the arthralgias are from any antiestrogen intervention or from some concurrent baseline, nonspecific arthritic-type condition, which is common.

Studies define these difficulties in different ways, so it’s hard to assess the toxicity experience in the major trials, in which severe toxicity was reported by way of case report forms, and relate that to the experience of patients.

What do you do about the arthralgias? We all talk about acetaminophen and nonsteroidals. Anecdotally, it’s not clear that those help much. What does seem to help has been some moderate level of regular exercise. Patients who can get some exercise often find that this alleviates some of their discomfort.

In early 2008, we will begin a placebo-controlled intervention study on alleviating these symptoms. Our strategy is similar to the successful method that Chuck Loprinzi has used at the Mayo Clinic to study hot flashes. We’re hoping to use some novel agents to pharmacologically treat these symptoms. Using a placebo-controlled trial design, we will identify which ones might work.

Arthralgias related to chemotherapy (Figure 12)

DR BURSTEIN: A classic paper from the Mayo Clinic in the Journal of Clinical Oncology in the late 1980s or early 1990s reported what they called chemotherapy-induced arthritis. It was a series of eight or 10 women, all of whom were in their late forties, who received chemotherapy and presumably experienced chemotherapy-induced amenorrhea and menopause. Then they began to develop these significant arthritis symptoms.

In the recent JCO paper (Crew 2007), investigators found that taxane-based adjuvant chemotherapy seemed to increase the risk of musculoskeletal complications. I’m not sure that’s my experience in the clinic. The answers from your survey were all over the map on that one. So I believe more data are needed to verify that.

Certainly, paclitaxel is associated with a myalgia syndrome, which typically arises four to five days after treatment. Patients who are receiving growth factor support often have some bone marrow swelling and develop diffuse musculoskeletal achiness about a week into treatment. These are a fairly common set of symptoms among patients with breast cancer.

Chemotherapy-induced amenorrhea (Figure 13)

DR BURSTEIN: The standard treatment for a young woman who has breast cancer is tamoxifen. Good case-report experience indicates that many of these women in their early forties or younger will actually recover ovarian function in the months and even years after chemotherapy. In those cases, monitoring FSH and LH at a single time doesn’t tell you what will happen with the ovarian function in the future.

Both our group and Ian Smith’s group in London have published cases of women just like this who had begun menopause with chemotherapy. They were started on an aromatase inhibitor.

In many of these cases, their FSH levels were actually in the postmenopausal range. Their ovarian function recovered and they were not receiving effective endocrine therapy. I feel strongly that the correct answer here is tamoxifen until menopause is demonstrated unequivocally. Single or even serial measurements of FSH and LH don’t tell you what will happen with these women in the future. So I discourage the monitoring of these levels and clinical decision-making based on those measures.

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Hormonal therapy for premenopausal women (Figure 16)

DR BURSTEIN: Since the patient is premenopausal, I believe the answers in the survey reflect the desire to treat her with tamoxifen initially, which I would agree with because it works irrespective of menopausal status.

I believe many favor the idea of switching treatment once it’s clear she’s menopausal. So in two to three or five years after chemotherapy, with the expectation she would be menopausal, they would switch her to an aromatase inhibitor.

We don’t know what her menopausal status would be after four cycles of AC or TC. In clinical practice, this is a situation in which you would have to find out what happens as time goes by. I feel pretty strongly that an aromatase inhibitor with an LHRH agonist is not a preferable option.

The TEXT study is observing young premenopausal women who are receiving ovarian suppression and tamoxifen or ovarian suppression and an aromatase inhibitor.

We will have data in the future about whether the aromatase inhibitors are as active as tamoxifen in younger women if used with ovarian suppression.

The worry is that a small fraction of women may not reach complete ovarian suppression with an LHRH agonist.

If you’ve treated many women, you know that in a small proportion of them, their ovaries won’t functionally shut down. So you run the risk, if you treat them with an aromatase inhibitor and an LHRH agonist, of their receiving no effective endocrine therapy. I would start with tamoxifen if they were still premenopausal and I wanted to consider ovarian suppression.

Only when they were truly postmenopausal would I consider switching them to an aromatase inhibitor.

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Selecting therapy for a patient with a high Oncotype DX recurrence score (Figure 16)

DR BURSTEIN: The point of ordering the Oncotype DX assay for a patient like this is to find out whether she has either a low or a high score. A low score would suggest she doesn’t need chemotherapy.

A high score would suggest she does need chemotherapy. An intermediate score would narrow the range of the potential benefits of chemotherapy but still leave you in an indeterminate posture. I certainly would have recommended adjuvant chemotherapy for this patient based on that score. None of the most commonly used regimens specified here have been explored in combination with the Oncotype DX assay in the reports from NSABP-B-20. That study was built around CMF and MF.

I believe most of us would use our typical adjuvant regimen for patients with node-negative disease. Ours happens to be AC, typically every two weeks. If people want to use TC, I believe that’s a reasonable regimen, but it’s not one we routinely use.

DR LEE S SCHWARTZBERG: The Oncotype DX test allows you to select those patients who are exquisitely sensitive to chemotherapy and, by the way, probably don’t need aggressive chemotherapy If you examine the data from the NSABP studies, you see that the chemotherapy administered was a combination of CMF and MF.

Today no one uses MF, and I believe everyone would agree that it’s minimal chemotherapy, but despite that, the patients who were in the high recurrence score group, when they received CMF or MF, had a conversion of their disease-free survival rate up into the 90 percent range and a 75 percent relative reduction in the risk of relapse.

Those patients are exquisitely sensitive, and I’m comfortable using CMF for many of them. I still use every three-week CMF because the few times I’ve tried the oral CMF regimen, I found it difficult for the patients.

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Selection of chemotherapy in the adjuvant setting (Figures 21-22)

DR SCHWARTZBERG: We’re in a bit of a bind as practitioners right now, based on the retrospective analysis recently published by Dan Hayes in The New England Journal of Medicine. The data suggested, or at least the media picked up that they suggested, that taxanes administered after adjuvant AC confer no benefit for patients with estrogen receptor-positive breast cancer. The fact that it was published in The New England Journal and, for some reason, received a lot of uptake from the lay media, I believe, was the most important aspect of that trial.

At the same time, we have other esteemed investigators, like Dennis Slamon, saying that we shouldn’t use anthracyclines at all. So which regimen do you use in that common patient population of women with hormone receptor-positive early breast cancer?

The data from Hayes had been presented a year before and were not a surprise to me whatsoever. The surprise to me is that a much more abundant data source of at least seven or eight randomized trials that have analyzed retrospectively or, in some cases, prospectively, suggests that the benefit of anthracyclines accrues only to patients with HER2-positive disease and, therefore, the benefit of both anthracyclines and taxanes may occur only in that group of patients.

Further data have been published, including the retrospective review of multiple CALGB trials in the Journal of the American Medical Association, that show that the incremental benefit of chemotherapy accrues to patients with ER-negative tumors, and not so much or not at all to those with ER-positive disease.

Breast Cancer Update 2007 (1)

DR STEPHEN E JONES: The objective of our US Oncology trial was to compare the disease-free survival between AC and TC for women with operable breast cancer. About half of the women had node-negative disease, and half had node-positive disease. We recruited approximately 1,000 patients and had 5.5 years of median follow-up.

We conducted a preliminary analysis at about three years, in which a difference in favor of TC was emerging. At five years, however, this had become a significant difference, with a p-value of 0.015. We saw a one third reduction in the risk of a breast cancer event among the patients who received TC, which is a significant impact and translates into a six percent absolute difference at five years.

We conducted an exploratory analysis because of the interest in the differences in response to adjuvant chemotherapy between patients with hormone receptor-positive and receptor-negative disease. About 75 percent of the women had hormone receptor-positive disease. No obvious difference appeared between receptor-positive and receptor-negative disease with respect to benefit from TC.

A trend toward an overall survival benefit (p = 0.131) and nearly a 25 percent lower chance of dying were evident among the patients treated with TC. If you present it that way to patients, most will opt for TC. I believe if this trial were larger or we had longer follow-up, we might see a survival difference. The conclusion from the trial was that TC is a new standard nonanthracycline adjuvant regimen.

Personally, I would use TC in the population of patients we studied in this trial: Those with node-negative disease or those with one to three positive nodes. It provides a good reduction in the risk of recurrence.

We don’t have many data for women with four or more positive nodes, so I probably wouldn’t pick TC in those situations, but I would for the patients with lower-risk disease or those with cardiac compromise.

With longer follow-up, TC was associated with improved DFS and OS compared to standard AC. TC should now be a standard nonanthracycline combination for early BC. In addition, TC was well tolerated in older women without excessive toxicity compared to their younger counterparts, and may be preferable due to its lack of cardiotoxicity.

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Breast Cancer Update 2007 (2)

DR FRANKIE ANN HOLMES: The US Oncology trial was a straightforward, simple idea embraced by the community, many of whom have concerns about the anthracyclines. We have now seen not only a better outcome in the total population with TC but also benefits in every subset, although these were not preplanned analyses.

It is one study, and it was a small study by modern adjuvant standards. However, it’s not inconsistent with the data in the literature, which suggest that docetaxel is superior to the anthracyclines in
head-to-head studies conducted in the metastatic setting. I don’t have any problems with this study because it is reasonably sized, and the dose intensity was maintained.

I’ve started to incorporate the TC regimen much more frequently in my practice, especially in situations in which I have concerns about chemotherapy tolerance. However, at this time, I have not given up on the standard AC/taxane regimen for my patients with node-positive disease.

AC is now recognized as a highly emetogenic regimen, and patients experience delayed nausea and vomiting. I was once on a panel that was discussing emesis, and somebody said, “Oh, that’s just AC.” Well, AC is associated with a lot of delayed nausea and vomiting. You find a lot of hidden toxicity if you step into the shoes of a patient. It can be incapacitating. With TC, you don’t have that burden of emesis and nausea.

Breast Cancer Update Think Tank 2007 (1)

DR ERIC P WINER: I haven’t had trouble administering TC, and I agree that it may be less toxic than AC. However, I am concerned that the well-executed Intergroup trial, ECOG-E2197, which compared doxorubicin/docetaxel (AT) to AC, showed no benefit to AT versus AC, and yet the Jones data suggest that docetaxel is better.

If anything, I would have expected that substituting docetaxel for cyclophosphamide would provide a bigger hit. I find it troublesome. I don’t have an explanation, and it’s why, based on this one study, I would conclude that TC is about the same as AC. I’m not ready to say that TC is better based on one study of 1,000 patients, considering the fact that the ECOG-E2197 study has a result that causes concern.

Breast Cancer Update Think Tank 2007 (2)

DR BURSTEIN: Perhaps in contrast to what I’m hearing about TC, AC is still my standard adjuvant therapy for patients with lower-risk disease. I typically administer it on a dose-dense, every two-week schedule. It is a shorter regimen, and I find it remarkably well tolerated.

I’ve seen more subjective toxicity with TC, with regard to fatigue and other problems. In addition, AC is still the mainstay of the ongoing Intergroup trial for patients with lower-risk breast cancer who have zero to three positive nodes.

The dose-dense AC regimen has not been compared to TC. According to the US Oncology data, AC and TC are fairly comparable, perhaps with a small advantage for TC, but how the dose-dense schedule impacts that, we don’t know.

Trial of adjuvant dose-dense ACnab paclitaxel

DR BURSTEIN: We conducted a 56-person feasibility study with dose-dense ACnab paclitaxel in which we substituted nab paclitaxel at 260 mg/m² for paclitaxel at 175 mg/m² on the every two-week, so-called dose-dense schedule. We found it necessary to use white blood cell growth factor support with nab paclitaxel.

One determination we were trying to make was whether we could get away without using drugs like pegfilgrastim or filgrastim when we used nab paclitaxel instead of paclitaxel. The answer was no. If you want to keep to the every two-week schedule, you have to use the growth factor support. We used pegfilgrastim mostly.

Otherwise the regimen appeared comparable to our historical experience with dose-dense ACT in terms of the rate of febrile neutropenia, delivery on schedule and other major toxicity complications. So I believe it’s a regimen one could substitute.

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