Dr Frazier: This 72-year-old very healthy woman presented with a 5-mm area of suspicious calcifications on her mammogram. These were removed stereotactically and proved to be a Grade II, ER-positive, HER2-positive, infiltrating ductal carcinoma. We performed a segmental resection that showed no residual cancer, and she had a single sentinel node that was positive. This patient participated in the NSABP-B-32 trial (Figure 2.1), and as part of the study we completed the axillary dissection, which showed no additional tumor in her lymph nodes. The patient stated that she wished to avoid postlumpectomy radiation because of concerns about lymphedema.

Dr Lerner: She needs more treatment. Given a choice, I would prefer that she receive radiation to her breast to make sure another primary is not being missed. And there's no question she needs hormonal therapy plus or minus cytotoxic chemotherapy.

Dr Love: Where did this concern about lymphedema come from? Does she know someone who had lymphedema?

Figure 2.1

Dr Frazier: Yes. One of her best friends can't move her arm.

Dr Borgen: Was a clip placed at the stereo site, and were there biopsy changes in the specimen that you surgically removed? Do we know that the wire was in the right place and have we actually removed the area where the cancer was?

Dr Frazier: Yes. Absolutely. We place a little clip on all the stereos, and the clip was widely removed. And there was a hematoma, consistent with a biopsy cavity, in the middle of the specimen.

From the floor: In terms of lymphedema, once you break that chain along the axillary vein you are already at risk, as far as I'm concerned. Radiation therapy will not increase that risk substantially. I understand her concerns, but she already has undertaken the risk and she needs radiation.

Dr Love: Did she bring up the concern about lymphedema before surgery or after surgery?

Dr Frazier: After.

Dr Love: Terry, if a patient asks, "What's the chance I'm going to have lymphedema from having axillary dissection and breast radiation," what would you say?

Dr Mamounas: I think the chance for lymphedema after axillary dissection is probably in the range of five to 10 percent. With radiation, particularly if the tumor is in the upper outer quadrant and the tangents include some of the axilla, the range may go up a couple of percentage points, but not dramatically.

Dr Love: Do you think she would be willing to take a risk or compromise her therapy because of a slightly increased risk of lymphedema?

Dr Frazier: I think she'll probably do what we encourage her to do. That's sort of the way it is with most patients, but when a patient tells you that the one thing she doesn't want is lymphedema, and you have a tumor that's microscopic, the question is: "Will you be able to control second primaries in her breast with a hormonal approach?" I think we can decrease the risk with hormonal therapy alone, but probably not as much as we can with radiation.

Dr Love: Your take is that if she can get away without radiation, she will, but she doesn't want to compromise the treatment of the cancer?

Dr Frazier: She's more concerned, as I would be, about her survival, but I don't think, frankly, that radiation in a 72-year-old woman is going to increase her survival. It's probably going to decrease her chance of developing a second primary, but it is going to increase her chance of having lymphedema. Given the choice, she'd probably rather lose her breast later on than take a chance of developing lymphedema.

Dr Love: That's interesting. So, your take is she'd rather have a mastectomy than take a chance on lymphedema.

Dr Frazier: She doesn't need a mastectomy now, but, yes, that is my assessment.

From the floor: I don't want to be anecdotal about this, but in my practice I have about 20 older patients who have more medical problems than this patient, and I've just done a lumpectomy and given tamoxifen. I have not seen any recurrences, and I'm seven or eight years down the line now. Many of these patients have completed their five years of tamoxifen.

Dr Love: The NSABP has studied that, because 10 to 15 years ago I think we hoped to avoid radiation therapy. Terry, what did those trials show?

Dr Mamounas: The NSABP-B-21 study clearly shows that the radiation therapy, even in the face of tamoxifen, reduces local recurrence by almost 50 percent (Figure 2.2). To put things in perspective - and I don't advocate not giving this woman radiation -but if you actually do a theoretical calculation of her mastectomy rate if she undergoes radiation now or if she undergoes it later, assuming that every time you give radiation after lumpectomy, you'll do a mastectomy when they recur, and assuming that you can do a lumpectomy and radiation later, if she recurs, the mastectomy rate is probably less if you don't give radiation.

It's complex, but if you don't do radiation, 10 percent of the patients will recur. That's what B-21 showed in small tumors.

If you then took that lump out and gave radiation at that time, assuming even a 20 percent risk of subsequent recurrence, that would be 20 percent of the 10 percent would have a mastectomy. That's two percent, overall.

If you did lumpectomy and radiation now, the rate is about five percent. And if then, the recurrence is five percent. That five percent should go to mastectomy, because they already have had radiation. Nobody's talked about that, but, in fact, that's true.

Dr Love: Pat, how much does fear of radiation therapy factor into patient preference for mastectomy?

Dr Borgen: This is a very common patient concern. In the 1990s when there were papers in the New England Journal of Medicine evaluating our regional use of breast conservation therapy - and the group from Kentucky surveyed patients about why they didn't want breast conservation - fear of radiation was one of the most common reasons patients gave. This patient is telling us something that we've heard for a long time. I personally think that the added risk of lymphedema from the radiation is low, and I agree that having a Level 1 or 2 dissection certainly creates the lion's share of her risk.

Figure 2.2

One concern is not leaning towards undertreating this woman because the calendar says she's 72 years old. That's something we have to really avoid. New studies are using the Mammosite® regional radiation therapy. We have a trial using a single dose of intraoperative radiation therapy, using a high-dose after-loader, and this type of approach could make radiation therapy more palatable if we find that local control in the region is equal to external beam radiation therapy.

Dr Love: Dr. Frazier, we don't know what the chance of lymphedema would be with a Mammosite ® , but do you think she might have been open to this type of experimental approach?

Dr Frazier: Yes, I think so.

Dr Borgen: This discussion is refreshing. What I hear people saying is, "Let's match the treatment with the patient." We've talked about the reality of the data and the reality of what the patient wants, but there's a third reality, and that is the medicolegal standard that we're held to. Two of my attending surgeons have gone through lawsuits when patients adamantly declined the recommended therapy, had terrible outcomes, and the physicians ended up in court. So this also becomes a documentation issue and a situation in which we might say, "Please get a second opinion."

None of us want to discharge these patients, but we really have to protect ourselves in cases like this if the patient doesn't follow the standard of care - because sometimes the patient's memory is a little different five years later than it might be today.

Dr Love: Let's discuss the issue of systemic management. This tumor was ER-positive and HER2-positive. She has one positive node. Kevin, how would you think through systemic therapy in this situation?

Dr Fox: First, I would like to comment about the point in this case at which all you had was a single positive sentinel node, and whether it was worth doing an axillary dissection. Most people agree that the standard of care is to do so, and I think this is a case where the performance of that axillary dissection turns out to be very useful to us in medical oncology -because the thing that drives this woman's risk of premature death from breast cancer, statistically, is her single positive lymph node.

That statistically overpowers virtually every other factor in her case. Now that we know she only has one, we can make more rational predictions about what the risks and benefits of systemic therapy are.

Having a single positive lymph node puts one at an ever-so-slightly higher risk than having no positive lymph nodes. She would be a low- to moderate-risk type of situation, and we know that the greatest derivation of benefit with respect to survival will be from hormonal therapy.

All of us would happily prescribe some form of hormonal therapy to a patient like this. Which one you would choose is another topic. For us, the issue is what the contribution of systemic chemotherapy is to her long-term survival. If you look at the overview, which is our greatest data resource, quantitatively, the relative reduction in the risk of dying in a woman over the age of 50 with ER-positive, node-positive breast cancer goes down 10 percent with systemic chemotherapy in addition to hormonal therapy.

I personally would look at that 10 percent relative reduction in the risk of dying as being puny, and certainly would not present chemotherapy as a mandate to a patient like this.

Dr Love: How would you respond if this woman asked you, "What's the chance, if I don't do anything, that I'm going to relapse?"

Dr Fox: We're hampered a little bit by not knowing the exact size of her primary, and that's life in the world of stereotactic biopsies. She would, in the worse-case scenario, I think, have a risk of systemic recurrence and death of 30 percent with no treatment. We reduce that to somewhere around 20 percent by giving her hormonal therapy. Then, with chemotherapy, we would provide her with an additional reduction in the risk of dying of about three percent.

Dr Love: I'm curious, Dr Frazier, do you think she'd be the kind of woman who, for a very modest improvement in survival - a couple of percent -

would want to go through, let's say, four cycles of chemotherapy?

Dr Frazier: I think she would take whatever we recommend to her, but I don't think that she's a person who would want chemotherapy for a one-percent improvement. I think she's more concerned about the quality of her life. She may very well say, "I don't want my hair falling out. Can you give me something mild for six months? I'll take treatment, but only if it won't make my hair fall out."

Dr Love: So, she's not grabbing you by the lapels, saying, "I want you to do everything possible to attack this tumor?"

Dr Frazier: Absolutely not. She's saying, "I've had a good life. I'm 72."

Dr Love: What's her lifestyle like?

Dr Frazier: She retired. She does hospital volunteer work.

Dr Love: Kevin, would you present the option of chemotherapy and discuss it with her?

Dr Fox: Absolutely, and I would try to give her an appraisal of the toxicity that was as honest and unbiased as I could.

Dr Love: How would you discuss the choice of hormonal therapy?

Dr Fox: I think we're at sort of a juncture now where we're all trying to decide how much the ATAC trial has altered our care standards (Figure 2.3). My own bias would be to prescribe an aromatase inhibitor to a patient like this, unless she had severe concurrent bone disease, symptomatic osteoporosis and complications thereof. In general, I believe the aromatase inhibitors have less of a downside for all patients, and if we're going to give her a modest survival benefit, we might as well give her the treatment that is going to produce the least aggravation for her. I think that would be an aromatase inhibitor.

Figure 2.3

Dr Love: An aromatase inhibitor, or anastrozole?

Dr Fox: Well, if we have to dance with the one that brought us, we have to use anastrozole, because that's the drug for which we have the data. I would prescribe, specifically, anastrozole.

Dr Love: Genny, how would you think through this case and what would you say to this woman?

Dr Grana: I think along the same lines as Kevin. I would also take the positive HER2 status under consideration.

The data by Matt Ellis and others clearly demonstrates an association between HER2 status and hormonal therapy responsiveness (Figures 2.4, 2.5). That urges me more towards anastrozole than tamoxifen.

Dr Love: What about chemotherapy? Would you discuss it as an option?

Figure 2.4

Figure 2.5

Dr Grana: Yes, and also because of the HER2 status. In that light, if you're going to use chemotherapy, I don't see a real role for CMF - a milder, more gentle chemotherapy. I think this is a case in which you either use AC or you forego chemotherapy, and I think it's very much driven by the vigor of the woman. How young of a 72-year-old woman is she? Plenty of women like this have looked at the data and want everything; they will opt for chemotherapy and may want more than AC - they may want AC and a taxane.

Dr Love: She has a node-positive tumor and you mentioned a taxane. Would you discuss dose-dense chemotherapy as an option?

Dr Grana: I would be very reluctant to discuss dose-dense chemotherapy in someone of this relatively modest risk at this age. We have relatively limited information about the long-term sequelae of more intensive therapy in older women, so I would not present it as a viable option.

There's a wonderful CALGB randomized trial in older women that she may be eligible for. This study is being run by Hy Muss and randomly assigns women over age 65 to AC or CMF versus capecitabine, as an oral agent (Figure 2.6).

Dr Love: And that trial allows a woman to have hormonal therapy selected by the physician and patient?

Dr Grana: Yes.

Dr Love: Kevin, you said you were pleased that she had a full axillary dissection - that you wanted to see the axillary node status. If this patient had five positive nodes, how would that have changed your recommendation?

Dr Fox: If she had five positive lymph nodes, we would have to reinforce to this patient that her risk of dying prematurely from metastatic breast cancer was actually quite substantial. I think all medical oncologists generally would have greater enthusiasm for giving adjuvant systemic chemotherapy - which is inherently unpleasant to us, particularly in older women - and we would even go as far as telling a patient like this that the additional three months of taxane therapy might actually be meaningful, which is something I would be very reluctant to say if a patient had a single positive axillary lymph node.

Dr Love: If the tumor had been 2.2 centimeters - a palpable tumor -and one positive node, how would that have changed your evaluation?

Dr Fox: It would not increase my enthusiasm about chemotherapy much because I still think, statistically, what drives this woman's predictable risk of recurrence and death is her axillary lymph node status.

Dr Love: Genny, you said that you would suggest or recommend anastrozole. Would you present the option of tamoxifen, also?

Figure 2.6

Dr Grana: Absolutely, but based on the HER2 status, I would really push for anastrozole. Some women may come back to you and say, "I'm uncomfortable with the duration of follow-up on the ATAC trial and I'm uncomfortable with the bone density." Some of those women will elect tamoxifen, but this is where the HER2 status would drive my thinking.

Dr Love: How would you respond if the patient asked, "Can you tell me about the side effects and tolerability of the two approaches?"

Dr Grana: I think anastrozole is clearly more tolerable in terms of the significant toxicity of hormonal therapy and in terms of clotting and endometrial carcinoma (Figure 2.7). The hot flashes are probably not much better with anastrozole, maybe a little bit. The thing that often becomes important - and you only know it once you're in anastrozole therapy - is the arthralgias and myalgias, and that's something that you can only gauge once you've started.

Figure 2.7

Dr Love: What percent of patients have that?

Dr Grana: If you look at the ATAC data, it was 27 percent versus 21, so a few percentage points more. What I think the ATAC trial failed to capture was the intensity. There are some women who become very intensely affected and have very significant arthralgias.

Dr Love: In your own experience, in what fraction of women is it a major problem?

Dr Grana: Five percent - ten percent, maybe, at most.

Dr Love: Another thing that's kind of interesting, which I never understood, is that the NSABP has been telling us for years that tamoxifen doesn't cause weight gain, in contrast to what many practicing physicians and patients say. What's your take on that?

Dr Grana: I have many doubts about whether weight gain is significant with tamoxifen versus anastrozole. Many other factors effect weight gain in women with breast cancer, and I'm not sure I know what that means.

Dr Bauer: I want to explore something. Let's stereotype this patient, rightly or wrongly, as a woman who plays tennis, plays golf, is very concerned about her well-being, her appearance, and let's suppose she's my sister and I sent her to Kevin Fox and said, "She's 72 years old. She's very healthy. She wants to live a long time and continue to play tennis and golf. Kevin, advise me how she should be treated at this point. Should she have radiation? Should she have chemotherapy? And should she be on hormonal manipulation?"

Dr Fox: I would recommend that she have radiation therapy, because I think the contribution to her lymphedema risk, while we all agree that there is some, is very modest. I would recommend that she have adjuvant systemic chemotherapy, because she really does have a life expectancy, actuarially, that goes well beyond the age of 80. And I would recommend hormonal therapy and probably an aromatase inhibitor.

Dr Love: Just out of curiosity, Kevin, going back to the profile of the woman who said, "I want everything done. I'm not that concerned about toxicity, as long as it's not lethal toxicity," would you give her a taxane, also?

Dr Fox: I probably would not because, again, resorting to mathematics, the relative benefits of paclitaxel - the relative reduction in the risk of a woman like this dying - truly would be a single-digit number, and quite possibly one percent. The risk of this active, tennis-playing, golf-playing individual developing a significant and sustained neuropathy is probably as high as that, or greater. So, I would be much more reluctant to use taxanes in someone like this.

Dr Bauer: Thank you. If I had a sister with breast cancer, I'd send her to you!

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