•	5 years ago, the patient in her 50s, received ACT followed by tamoxifen for ER/PR-positive, HER2-negative breast cancer
•	Returns for routine follow-up, while on tamoxifen, with mild shortness of breath and fatigue
•	Chest X-ray and CT: Multiple small pulmonary nodules (largest 1.5-cm)
Key discussion points:
	Discuss goals of treating metastatic breast cancer
	Chemotherapy versus endocrine therapy in metastatic disease
	Sequential single agents versus combination chemotherapy in metastatic disease
	Selection and scheduling of taxanes
	Combining trastuzumab with chemotherapy in the metastatic setting
	Determining ER- and PR-positivity
	Optimal dosing of docetaxel

Dr Love: What kind of questions did this woman ask you about what to expect in the future? What was her overall approach to this in terms of how aggressive to be in treating the disease?

Dr Wilson: Like most patients with metastatic disease, she experienced some shock at the diagnosis. She was able to appreciate that she still had a very good quality of life without major symptoms and that we had an approach to fight this. She also has good family support from her husband and her children.

I stressed that while we didn’t expect to cure her, we had number of treatment options available. I also emphasized my expectation that a strong patient with relatively few symptoms would do well for a relatively long time. She certainly wanted to be treated, but she wanted treatment that would not significantly interfere with her life, because to that point, her symptoms were not interfering with her daily activities.

Dr Love: Debu, how would you think through this case?

Dr Tripathy: I tell patients that there is a spectrum of disease, ranging from chronic to a more acute and life-threatening disease. I try to give them a sense of what they might expect from different therapies, both in terms of the likelihood of response and toxicity. Finally, I give them my recommendation balancing these two issues.

In this case, I would start her on a hormonal therapy with an aromatase inhibitor. I would follow symptoms closely, but the lungs are an area one could follow most accurately with CT scans.

Dr Love: One of the things I find most interesting about interviewing research leaders and interacting with physicians in practice is that there is a real dichotomy in some situations. In this patient, I think the lung metastases and shortness of breath would make many physicians nervous. I’m not saying what is right or wrong, but I think many community-based oncologists would start this woman on chemotherapy. One strategy I often see in this kind of situation is to use chemotherapy to elicit a response and then switch to hormonal therapy.

Dr Harth: I agree. Not having seen the patient, I would choose chemotherapy first, because the suggestion of shortness of breath is unnerving. In addition, this patient progressed on tamoxifen. In my experience, those patients do not do as well on hormonal agents. I would treat her with chemotherapy initially and then start her on an aromatase inhibitor.

Dr Brooks: I’d like to dissent. Aromatase inhibitors work pretty quickly, and I believe you can start patients like this on an aromatase inhibitor and follow tumor markers, CT scans and symptoms. I don’t think you lose very much, because if the tumor responds, you have a therapy that may work for 6, 12, 18, 24, or more months. This is your opportunity to “hit it out of the ball park” with essentially no symptoms.

If you put this patient’s disease into remission with chemotherapy and then use aromatase inhibition, you don’t know if you are looking at a nice remission from chemotherapy or a small hormone effect. As long as you have time, trying hormones first is preferable.

Dr Love: When we face the decision between hormonal therapy and chemotherapy, we classically think about how quickly we need a response. This is based on the idea that hormones don’t work as fast as chemotherapy. However, Mike Dixon, who studies neoadjuvant endocrine therapy, says that changes occur in the biopsy within days after an aromatase inhibitor is started. Debu, how much do we really know about how long it takes to have an effect with hormonal therapy versus chemotherapy?

Dr Tripathy: We know very little about the timing of response. This has typically not been reported in clinical trials, so it’s hard to determine. I can’t answer on a clinical basis, although, as you pointed out, studies have looked at the biological effects, examining proliferative status, and shown very rapid effects.

People also have the common conception, which may or may not be true, that visceral disease responds less often to hormonal therapy than nonvisceral disease. In most of the hormonal therapy trials, the response rates are generally comparable between soft tissue and visceral disease.

I agree with Dr Harth that the likelihood of response with an aromatase inhibitor is probably slightly lower in this patient; however, the speed of response and the ability to monitor the patient for a response is such that using an aromatase inhibitor is a reasonable option.

Dr Love: Let’s change some of the variables in this case and see how it affects treatment. Andy, assume this patient had much more shortness of breath and the chest CT scan was much worse — she’s not ready to be hospitalized, but you’re a little bit concerned about her situation. What would you recommend?

Dr Seidman: A single-agent taxane would be the standard of care in that situation.

Dr Love: Okay, now we’ll go even further and say that she’s very short of breath and has lymphangitic disease. Dr Seidman: I would stand by my original answer to give her a single-agent taxane.

Dr Tripathy: I disagree with Dr Seidman here. Although I very rarely use combination chemotherapy, I probably would in this situation because the patient is in visceral crisis. I agree with Dr Seidman that the long-term survival may not be different with combination versus sequential therapy; however, in this patient, a higher chance of response might justify the added toxicity of a combination. I try to estimate the degree of benefit for a patient based on symptoms — the more symptoms, the greater the potential benefit, which might outweigh the added toxicity of combination therapy.

The docetaxel/capecitabine combination is a completely reasonable choice for this situation. There is a published trial demonstrating a benefit, and this patient has not previously received a taxane (Figure 2, Table 3). One could consider a combination of anthracyclines and taxanes, but this patient has previously received anthracyclines.

Dr Love: Dr Aks, how would you have managed this patient’s disease if she were very symptomatic?

Dr Aks: Because of the pending respiratory failure that you suggested, I would have been very aggressive and taken my chances with at least a doublet to try to avoid the crisis of ventilator support. I would be comfortable with a taxane and capecitabine. Could either Dr Seidman or Dr Tripathy comment on the recent emerging data on combining taxanes with carboplatin in this clinical setting?

Dr Seidman: There is a much higher level of evidence supporting the addition of carboplatin in the HER2-positive setting than in the HER2-negative setting. Nick Robert presented data from the US Oncology trial last December in San Antonio, in which the addition of carboplatin to paclitaxel and trastuzumab significantly improved patient outcome. The Phase II data for paclitaxel and carboplatin in HER2-negative tumors are also impressive.

Dr Tripathy: A platinum-containing combination would be reasonable as would vinorelbine in combination with taxanes and a variety of others. Data have been published on many combinations in the Phase II setting, but there are not many randomized studies in HER2-negative populations, by which we can compare outcomes and toxicities relative to a single agent. This is one of the reasons I chose the particular combination of docetaxel and capecitabine.

I must emphasize, as we discussed, that treating breast cancer is an art, and one has to look at and be able to present numerous options to patients. Sometimes, I present these multiple options to my patients just to illustrate the number of possibilities available to them. In the end, I’m not as dogmatic with my patients as I may be in this setting. I think it’s only fair to say that there are several reasonable regimens, including the platinum-based regimens.

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