COMMENT FROM THE TREATING PHYSICIAN

SAMUEL N BOBROW, MD: This patient would consider chemotherapy. If I had felt strongly that she needed it, I probably could have convinced her to receive chemotherapy. However, she was not happy about the idea. We sent the Oncotype DX, and the Recurrence Score^® was 5 so we were comfortable using radiation therapy followed by an aromatase inhibitor.

Select Commentary from Interviews Conducted at SABCS 2008

GEORGE W SLEDGE JR, MD: I believe it’s reasonable to consider the Oncotype DX assay for this patient. We certainly have evidence suggesting that patients with low Recurrence Scores are likely not to receive much benefit from chemotherapy. It strikes me as relatively unlikely that the biology of breast cancer changes dramatically from lymph node-negative to one or two positive nodes.

My baseline in this case would be hormonal therapy, and I would not be inclined to recommend chemotherapy unless I had striking evidence that the patient might benefit. While we don’t know how Oncotype DX data break down by age, we certainly do know of older women who are healthy, have no comorbidities and have sufficiently aggressive cancer that one might expect some benefit from chemotherapy.

HOWARD A BURRIS III, MD: I have not begun to use Oncotype DX for patients with node-positive breast cancer. I’m interested in the data and believe they will become more relevant, but right now if the patient is committed to receiving chemotherapy, then I do not use the assay. Even for older patients, I’ve been so comfortable with TC — that’s my new CMF — that I don’t order the Oncotype, although maybe it would tell me I don’t need chemotherapy for some of those patients.

JULIE R GRALOW, MD: Five is a particularly low Recurrence Score, and the data suggest that this patient would not benefit from chemotherapy based on the biology of her tumor.

However, having two positive nodes increases her risk of recurrence, so I’d at least discuss the option of chemotherapy with her. In this era, maybe we could administer a regimen like TC and avoid the cardiotoxicity of an anthracycline.

If this patient did not want to receive chemotherapy, then I would feel comfortable treating her with endocrine therapy. I would favor an aromatase inhibitor rather than tamoxifen. I would also offer her participation in SWOG-S0307, the Phase III trial of bisphosphonates as adjuvant therapy for primary breast cancer. If this patient had not already had an Oncotype DX assay performed, I probably would not have ordered it but rather treated her with something like the TC regimen followed by endocrine therapy.

DR SLEDGE: Many of us question how much data we need before we believe that the results of the Oncotype DX assay for patients with node-positive cancer, particularly those with only a few lymph nodes, are consistent with the assay results in node-negative breast cancer.

My bias is that the consistency across all of the studies with Oncotype DX suggests that biology will trump anatomy in many cases. That’s not to say that anatomy doesn’t add prognostic data — it does — but I suspect that from the predictive standpoint, as opposed to the prognostic standpoint, Oncotype DX is likely to provide a great majority of our data.

The oldest patient I have treated with adjuvant chemotherapy was 93 years old. However, for an elderly patient with a low Recurrence Score, I probably would not recommend chemotherapy. I’m probably with the 57 percent of the medical oncologists who would use hormonal therapy alone, rather than the 43 percent who would use chemotherapy despite that low Recurrence Score.

COMMENT FROM THE TREATING PHYSICIAN

KENNETH R HOFFMAN, MD, MPH: This is an active patient who had no problems with arthralgias or bone loss while on anastrozole. The decision came down to what the patient wanted, and she wanted to stop therapy. She felt that every morning when she took her pill, it reminded her of her cancer and she wanted to be cancer free in her mind.

Select Commentary from Interviews Conducted at SABCS 2008

PETER M RAVDIN, MD, PHD: One of the issues that shades our thinking is how much residual risk of disease recurrence the patient has after five years of adjuvant endocrine therapy. For a patient with a 2.5-cm, node-negative breast tumor, I estimate that she has approximately a two percent per year risk of developing recurrence.

DR GRALOW: I probably wouldn’t continue an aromatase inhibitor for this patient beyond five years, outside of a clinical trial. On the other hand, if her disease were node-positive, I probably would consider doing so. It’s clear that patients with ER-positive breast cancer have a somewhat lower risk of relapse in the first five years compared to those with ER-negative disease. However, they also have a small but real rate of relapse that goes on forever, and they may benefit from prolonged endocrine therapy.

The NCI Canada MA17 trial showed a survival benefit for patients with node-positive disease who received five years of letrozole after five years of tamoxifen. We also know that continued aromatase inhibitor treatment will have some impact on bone and, whether or not it causes a statistical increase in cardiovascular events, a subpopulation certainly exists in whom the lipids are affected by it.

We now have a couple of ongoing studies evaluating whether an additional five years of an aromatase inhibitor is beneficial after patients have already completed five years, whether or not they also took tamoxifen initially. It may be. As for side effects, approximately 75 percent of my patients are able to remain on aromatase inhibitor therapy for five years. Most of them can tolerate the hot flashes, but at least 20 percent quit because of significant arthralgias and myalgias.

JOYCE O’SHAUGHNESSY, MD: For patients at lower risk like this, I have not been continuing an aromatase inhibitor beyond five years. In my practice, patients either want to stay on therapy or they cannot wait to stop and they are counting the days. The patient’s desire is influenced by two variables: whether they perceive themselves to be at high risk and whether they have found the treatment to be tolerable.

I find that if patients perceive themselves to be at high risk, they want to continue treatment. If I believe the tumor is indolent biologically, strongly ER driven, but still the patient wishes to continue and it’s not bothering her, I don’t object. However, patients with node-negative disease are generally anxious to quit therapy.

As for tolerability, I would estimate that two thirds of my patients on an aromatase inhibitor experience musculoskeletal symptoms, but 85 to 90 percent of the patients who return to see me in the clinic remain on therapy for the full five years without major side effects. The ATAC data have shown that approximately 50 percent of patients with these complaints improve within a year or so. I check the vitamin D levels to ensure they are not too low, and I recommend simple practices like stretching to ameliorate the symptoms.

DR SLEDGE: In our institution, we are conducting a pharmacogenomics study of aromatase inhibitors for early-stage breast cancer. If a patient has a significant level of arthralgias, she is referred to a rheumatologist. These specialists are interested in evaluating exercise interventions, including stretching and walking. Although we as clinicians tell our patients to do these things, rheumatologists deal with these issues daily, and we have found their interventions to be of value to many of our patients.

COMMENT FROM THE TREATING PHYSICIAN

ISAAC LEVY, MD: The patient is pretty much recovered from surgery and back on her feet, but six months have elapsed since she last received trastuzumab. Her family did not want her to resume therapy earlier, since she developed the abscess while on treatment. A recent MUGA scan revealed good cardiac function and ejection fraction. The question now is how to treat the patient with regard to trastuzumab. What is the optimal duration of treatment? How much maintenance trastuzumab is adequate in a case such as this one?

Select Commentary from Interviews Conducted at SABCS 2008

KATHY D MILLER, MD: I struggle with the issue of anthracyclines because although I believe that the BCIRG 006 trial data are compelling, the study does not yet have enough events to directly compare the ACTH arm to the TCH arm.

However, they look similar and it seems unlikely to me that we will see a great enough improvement in efficacy with the anthracycline to counterbalance the clear increase in acute and potential long-term toxicity. Thus, in practice I would administer TCH and I’m quite comfortable with that. In fact, outside of the protocol setting, I haven’t used an anthracycline in a HER2-positive setting for the past 12 to 18 months.

PROFESSOR JOHN CROWN, MD: I would be nervous about treating any patient who has potentially curable cancer with the combination of trastuzumab and an anthracycline. I don’t believe a strong argument for it exists right now. In general, the anthracycline-induced cardiotoxicity we see is what stays with the patient. Everything we know about combining an anthracycline and trastuzumab suggests trastuzumab makes the qualitative anthracycline lesion more frequent and more severe. In our study, patients who developed a pure trastuzumab lesion without an anthracycline tended to experience a recovery of their ejection fraction. Patients who received anthracyclines, either alone or with trastuzumab, did not, which is our everyday experience with anthracycline therapy.

The data show that far beyond the time frame of follow-up for randomized trials, a late trend of cardiomyopathy emerges. That leads me to believe that we will likely see more of that and it will be worse in the patients who are now receiving an anthracycline and trastuzumab, even if we are not seeing as large a signal of acute, early onset cardiotoxicity as perhaps we might have anticipated from the pivotal trial.

DANIEL F HAYES, MD: This patient’s prognosis is poor, yet the disease is still potentially curable. The CIRG data have not yet been published in a peer-review journal, and we have a wealth of data with AC followed by T with trastuzumab (H). In my practice, assuming this patient is in good shape and has a good heart to begin with, I would treat her with AC followed by T and H. I’m using anthracyclines for patients with node-positive disease almost routinely.

I do believe TCH is an effective regimen, and I’m using it mostly for patients with a better prognosis, such as node-negative cases. For those patients, I’m concerned about long-term heart failure because they have a better chance of living longer no matter what we do.

SANDRA M SWAIN, MD: Clearly anthracyclines damage the heart. That’s a big issue, but fortunately we now have other regimens that are effective. If we examine the data from the adjuvant trastuzumab trials for patients who received benefit from trastuzumab, those on TCH had few heart problems. In fact, their incidence was quite similar, if not the same, in the control group. Also, in the HERA trial, in which trastuzumab was administered after chemotherapy, much less heart failure occurred.

ELEFTHERIOS P MAMOUNAS, MD, MPH: Obviously, if we delay the start of chemotherapy the benefit decreases, but we don’t have a lot of data in this type of scenario.

I understand all the issues regarding the perforated diverticulitis in this case, but as long as it was resolved, I believe the trastuzumab could have been restarted a little earlier, maybe within a couple of months. I have no reason to believe it would cause neutropenia. However, that’s not the question. Six months have passed, and I believe at this point the most logical approach is to treat her. We know from the HERA trial that sequential trastuzumab after chemotherapy was still effective, so I would put her on trastuzumab for at least another six months.

DR SWAIN: I agree that we don’t have a lot of data in a situation like this, but we do know that trastuzumab stays around a long time — five half-lives means that it would still be present several months after it was discontinued. I also agree that I would have restarted it earlier, if the family had agreed to it. Another issue is the patient’s age. The number of deaths from breast cancer in women older than age 60 is a significant problem, so I’m curious about the viewpoint.

Right now we don’t have a good answer to the question, “Should we continue the trastuzumab for a year?” The FinHer trial — using only nine weeks of trastuzumab — had a small number of patients, but it is being followed by the SOLD study in which nine weeks is compared to about a year of trastuzumab.

The HERA trial evaluates one versus two years of trastuzumab, and a French trial is comparing six months to one year. These trials will eventually provide us with more data on the optimal duration of trastuzumab to help us in cases like this. A final point about this case is that it’s interesting that a medical oncologist didn’t consult with this patient before she went to surgery, because clearly most of us would have recommended neoadjuvant therapy for this patient with T4B breast cancer.

A few clinical trials address the issue of neoadjuvant chemotherapy/trastuzumab for patients with HER2-positive breast cancer. Aman Buzdar published data from a randomized clinical trial, which demonstrated a high pathologic complete response rate — 65 percent — for those patients who received a trastuzumab-containing chemotherapy regimen.

More recently, Dr Gianni presented an update on the NOAH trial for patients with locally advanced, HER2-positive breast cancer who received neoadjuvant trastuzumab or not with a concurrent anthracycline-containing regimen. The pathologic complete response rate was 43 percent for those who received trastuzumab and 23 percent for those who did not. We never see such high pathologic complete response rates with standard chemotherapy among patients with HER2-negative disease.

COMMENT FROM THE TREATING PHYSICIAN

SAMUEL N BOBROW, MD: The woman is very anxious and wants to do everything that can be done. Would you use trastuzumab in this patient? If so, would you give it alone or with a chemotherapy regimen? I never use trastuzumab as monotherapy.

Select Commentary from Interviews Conducted at SABCS 2008

DR GRALOW: For this patient, endocrine therapy is not an option, and if I administer trastuzumab I don’t generally use it as monotherapy because I believe it has real synergy with chemotherapy. This woman’s age is also a consideration. She is young, and that worries me because she has many years ahead in which to relapse.

In making a treatment decision, one must consider both the biology and stage of her breast cancer. This tumor is at low stage, but the biology is bad, so I would offer her the combination of chemotherapy and trastuzumab. If she were eligible for our paclitaxel/trastuzumab trial, my preference would be to enroll her on that to avoid cardiotoxicity. However, I would also feel justified being more aggressive.

DR SLEDGE: We don’t have data from a prospective randomized trial in this area, and when no data exist, everyone is right. This is a real concern. A similar dilemma occurs when a patient has a small, ER-positive, HER2-positive tumor. Do you treat that patient with only endocrine therapy?

In these cases we need to tell patients that we don’t have any data. The data we do have across a variety of nodal statuses and sizes show us that trastuzumab is beneficial. However, with a smaller tumor the recurrence risk certainly could be less.

I don’t know what the patient’s risk of cancer relapse is, but if the cancer did recur, it would probably be within the next five years. Our experience with HER2-positive breast cancer tells us that if it recurs, it often recurs early. My suspicion — and it’s only a suspicion because the data are not particularly solid — is that, untreated, her risk of recurrence is perhaps in the 10 to 20 percent range.

If the patient wants to leave no stone unturned and do everything humanly possible to prevent a recurrence of breast cancer, then that may be our answer. However, patients vary and will give you different answers at different points in their lives.

I probably would not recommend anthracycline-based chemotherapy for this patient. We need to be conservative, not only about efficacy but also with regard to toxicity. Even if the risk of recurrence is 10 to 20 percent, one frightening possible consequence of treatment would be turning a young woman into a cardiac cripple.

Thus, this is certainly a case in which, if I were to administer trastuzumab and chemotherapy, I would use a nonanthracycline-based regimen such as docetaxel/carboplatin/trastuzumab (TCH).

If the patient had a larger tumor or positive nodes, I would probably feel equally comfortable about using TCH, up to a point. I don’t believe I’ve used an anthracycline for a patient with HER2-positive breast cancer in the past year and a half.

However, I haven’t seen many patients with 13 positive nodes, either.

DR O’SHAUGHNESSY: In my practice, I would probably treat this patient with Steve Jones’s TC regimen, which is docetaxel/cyclophosphamide, and trastuzumab.

We don’t have good data with tumors only four millimeters in size. However, being conservative in our estimates, we’d say she has about a six to seven percent risk of recurrence. That’s based on the rule of thumb that the recurrence risk is approximately 12 percent per centimeter of tumor, multiplied by 1.5 to estimate the relative risk with HER2.

That may be underestimating because we do have a few small series that indicate the risk of recurrence with even T1B lesions can be as high as 20 percent.

I would review the recurrence risk with the patient and tell her that chemotherapy will decrease that by half in her age group with ER-negative disease and trastuzumab will decrease it by another 50 percent. The absolute benefit comes out at approximately five percent, and I’m happy to treat patients for a benefit of five percent. That’s how I rationalize treating HER2-positive lesions that are so small.

My record is with a patient I’m treating now for a HER2-positive, ER/PR-negative, 3-mm invasive breast carcinoma. She is a healthy woman in her mid fifties with a normal LVEF and she’s normotensive. We enrolled her on a clinical trial of docetaxel/cyclophosphamide for four cycles with weekly trastuzumab, followed by trastuzumab every three weeks to complete one year of anti-HER2 therapy (Figure 11).

In this trial, we are using Steve Jones’s TC regimen, with cyclophosphamide rather than carboplatin, because it’s been proven beneficial in a mixed HER2-positive and HER2-negative population with only four cycles. I also find cyclophosphamide to be better tolerated than carboplatin, cycle for cycle.

With cyclophosphamide, we see a shorter duration of fatigue and avoid the risk of carboplatin anaphylaxis.

COMMENT FROM THE TREATING PHYSICIAN

KENNETH R HOFFMAN, MD, MPH: This woman had already undergone two laser therapies for her diabetes — in 2006 and 2007 — and although she didn’t have any neurologic problems, I still considered her to be brittle. I shied away from the taxanes because I wasn’t clear what the risks of neuropathy would be and in addition, for a diabetic, using steroids is like putting kerosene on a fire.

Select Commentary from Interviews Conducted at SABCS 2008

DR O’SHAUGHNESSY: I believe we would all agree that this patient with triple-negative breast cancer should receive cyclophosphamide and a taxane. The question is whether she should receive an anthracycline. The NEAT trial evaluated classic CMF with epirubicin.

Putting aside the concern regarding long-term toxicity, I generally treat these patients with a three-drug regimen. I’d be happy to enroll this patient on our clinical trial comparing TC to TAC.

Outside of a trial, I generally administer dose-dense AC/paclitaxel to patients with triple-negative breast cancer. However, in this case I’d lean slightly more toward docetaxel, which causes less peripheral neuropathy, depending on whether the patient had some preexisting neuropathy.

Steroids are a major concern for diabetics, and we want to minimize steroid use in these patients. However, a patient who has had Type 1 diabetes for more than 30 years is often an expert at modulating insulin intake.

If the patient was having difficulty with paclitaxel or docetaxel, which require steroids, we could certainly switch to nanoparticle albumin-bound (nab) paclitaxel.

In this particular patient, because of my concern for her heart, I would probably treat her with TC. If indeed she had three positive nodes, I would check her LVEF. If it was robust and above 55 percent, I’d administer AC followed by a taxane because of her increased recurrence risk. I would probably try paclitaxel initially and monitor how much neuropathy she experienced after the first cycle.

DR SLEDGE: When patients are brittle and diabetic, I worry about how the drugs I choose to treat their cancer with may harm them.

During my residency, when we stepped outside a patient’s room, one physician would always ask me, “What have we done to this patient?” Not what have we done for this patient, but what have we done to this patient, and this diabetic is a patient whom it’s easy to do something to.

For example, administering a taxane-based regimen that would require a fair amount of steroids could have disastrous consequences if one were not careful about managing her diabetes. Older medical oncologists are not trained diabetologists, so that’s certainly one issue. Treating a diabetic with nab paclitaxel allows us to avoid steroids, and I have used that approach.

The other concern is peripheral neuropathy. Considering the side effects of taxane-based therapies and platinating agents, it is an issue for this patient.

It’s important to discuss side effects with patients before they start their adjuvant therapy and to be open and honest. In the vast majority of cases, our patients are frightened of breast cancer and they will do anything they can to not die from the disease. However, if we do not discuss these toxicities and they experience them, then they have every right to be unhappy with us. If this patient had positive nodes, I would consider AC followed by nab paclitaxel. Since this case is node-negative, certainly a TC-type regimen is an appropriate alternative.

Although we have no data to support it, one could consider a nab paclitaxel/ cyclophosphamide regimen in this setting. Unfortunately, our clinical trials are designed to observe the average patient and not the exceptions.

DR MILLER: This case is challenging because with her comorbidities we need to know more about the severity of her diabetes and its complications.

The patient has at least a moderate risk of recurrence, with approximately a 17 percent risk of death. She is also someone who would derive substantial absolute benefit from chemotherapy with either second- or third-generation regimens, so she needs to hear about chemotherapy. However, it must be a longer discussion than most because of her longstanding Type 1 diabetes. We also need to know more about any preexisting neuropathy and her baseline cardiac function.

It would be reasonable to worry about asymptomatic baseline cardiac dysfunction in a patient with her diabetic history. Even if her ejection fraction is normal, the evidence is fairly good that she is at greater risk of cardiac toxicity or dysfunction for the rest of her life, and anthracyclines would increase that risk.

To complicate matters further, this patient has triple-negative disease, and some literature suggests that, although less in the clinic at this point, anthracyclines and taxanes might be less effective than some chemotherapy regimens we don’t commonly consider. Few clinical data support that contention — and none in the adjuvant setting.

We do know from the ECOG-E2100 trial, evaluating first-line paclitaxel with or without bevacizumab for metastatic breast cancer, that patients with triple-negative disease had a hazard ratio for benefit of 0.56, which was one of the best subgroups examined in that trial.

My recommendation for this patient would be TC, although in general I don’t use that regimen. Although I’m not certain TC is more effective than AC, I’m not concerned that it is worse. As far as I know, the regimens that have been compared to AC have been either equivalent or more effective, and they had some toxicity benefits.

On the TC regimen, the patient will have less total exposure to steroids and less risk of neuropathy than with some of the other taxane regimens. It also avoids the potential complicating issues of anthracyclines and cardiac function.

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