• Presented at 51 years of age with ER/PR-negative, HER2-negative breast cancer and four positive lymph nodes
• Underwent lumpectomy and radiation therapy and received four cycles of AC
  followed by paclitaxel
• Followed with routine CA 27.29 and remained asymptomatic for approximately 3.5
  years
• CA 27.29 began to rise but no metastatic disease was discovered
• Six months later a CT scan revealed multiple liver metastases

Key discussion points:
	Evaluation and treatment of a woman with very high-risk breast cancer
	Role of tumor markers in following patients at high risk after adjuvant therapy
	Selection of first-line chemotherapy in the metastatic setting
	Selection and use of single-agent versus combination chemotherapy for metastatic disease

DR BARAI: When this woman was first diagnosed with breast cancer she was 51 years old. Her tumor was ER/PR-negative with HER2 1+ by immunocytochemistry. At that time she also had four positive nodes. She underwent lumpectomy and radiation therapy and then received four cycles of AC followed by paclitaxel.

At approximately three and a half or four years’ follow-up, she was asymptomatic but her CA 27.29 started rising. I repeated the CA 27.29 tumor marker test, and it was still up around 100+ U/mL. At that point I did a metastatic workup on her, which was negative. I expressed my concern and told her that no detectable disease was present at that point.

Six months later she was not feeling well and had started to lose weight. I repeated the CA 27.29 and this time it was about 350 U/mL. This, along with her symptoms, made me suspicious that something was going on — perhaps viscerally.

I checked her X-ray and bone scan, which were both okay, but a CT scan showed multiple lesions in her liver. I went back and asked the pathologist to test her tissue block with FISH even though it was 1+ by immunocytochemistry. The FISH results were negative.

DR LOVE: Tom, I’m curious about your thoughts.

DR BUDD: In some ways, this case shows why I personally do not use tumor markers. I know many people find them useful, but they tell you that someone is at increased risk to have a recurrence sometime in the next few months. It’s not a 100 percent chance, and I’m not always sure that is information you want to know.

If a patient is asymptomatic and you follow a strategy of evaluating the patient and aggressively working up any persistent symptoms, I think you will arrive at a diagnosis at the same time.

I don’t think any data show that aggressive monitoring with scans or markers will detect recurrences soon enough that you can improve survival by instituting treatment at that point, so, in general, I don’t follow markers.

In this case, given that she was symptomatic and the markers were going up, I think the workup was appropriate.

DR LOVE: How would you approach her therapy at this point?

DR BUDD: Can you quantify the magnitude of the liver involvement?

DR BARAI: She had at least four or five lesions and they were on both lobes of the liver, probably measuring about one or one and one half centimeters in size.

DR BUDD: This is a patient in whom I would probably use sequential single agents. I do not think you have to use combination chemotherapy, although I would not quibble if you did, given that she was losing weight and had some ominous symptoms.

It has been five years since her initial diagnosis and she has already had ACpaclitaxel. I think the choices would include docetaxel, capecitabine and vinorelbine. I do not think one right answer exists. I would probably give her capecitabine, but this is one of those situations in which I discuss the alternatives with the patient because I think the toxicities and her lifestyle will influence her choice.

DR LOVE: Hy, same question. Would you have used tumor markers? How would you approach her at the point that she only had tumor marker elevation? And at this point, how would you manage her overt metastatic disease?

DR MUSS: I do not routinely use tumor markers. A fair amount of false-positives occur with CA 27.29 testing, but they are not usually with levels above 100 U/mL. I would think that this patient had metastatic disease because with a number as high as 150 U/mL, it’s likely to be breast cancer. It is also very common to have lead times of three to six months. I was involved in the initial study of CA 27.29, and in many instances it took six months or even a year to see the tumors.

As far as treatment of metastatic disease, my philosophy is that it is all palliative care, and the goals are quality of life and disease control. It sounds trite, but it’s true, and I think the overwhelming number of randomized trials have suggested that sequential single agents have the same survival outcomes. Although virtually all the combinations have a little bit higher response rates, they do not transfer into survival. Many trials have shown that quality of life is worse in people who have combination therapy.

I like Tom’s choice of capecitabine. Most of these patients have lost their hair in the past, and I think capecitabine gives them a chance to deal with the fact that they now have an incurable disease without the trauma of more hair loss. Whether you like a taxane or gemcitabine first, I don’t think the sequence effects survival. Therefore, I tend to start with the agent that is easiest on patients, and I like capecitabine because it is well tolerated.

DR LOVE: How much of an issue is alopecia in the metastatic and adjuvant settings, and how much of an advantage is it to have an agent that does not cause hair loss?

DR MUSS: From speaking with many patients, including my cousin who has metastatic breast cancer, I think hair loss is a big deal. When you are talking about palliative therapy, I believe alopecia is a major side effect to go through — especially for a relatively asymptomatic patient whose disease was found on a scan. I think it is helpful to patients if you can avoid alopecia for a while.

Case follow-up:
	Received capecitabine and docetaxel but developed severe mucositis Switched to doxorubicin and docetaxel but MUGA scan declined to 50 percent Switched to carboplatin and docetaxel Tumor markers decreased to normal CT of the liver was normal Treatment discontinued After 12 months the patient became symptomatic and had rising tumor markers Carboplatin/docetaxel was reinitiated and a decrease in tumor markers and reduction in liver lesions occured Patient died of sudden death, probably of cardiac origin

DR LOVE: This woman had adjuvant AC and a taxane. Suppose she was completely naïve to chemotherapy — would you still use capecitabine as first-line therapy?

DR MUSS: I would not be swayed by the fact that a patient may not have had chemotherapy. The data suggest that she is not going to do any better having an anthracycline or a taxane up front, so I don’t think the sequence matters as much as the agents being active, and I think these are all active agents. Therefore, it becomes a measure of the quality of life you achieve with a drug, and capecitabine offers a better quality of life for patients like this.

DR LOVE: Can you talk about what happened to this patient?

DR BARAI: I initially started this patient on capecitabine and docetaxel, but she developed severe mucositis and quickly said, “I’m not going to take this anymore.” Her MUGA scan was okay, so I decided to start her on doxorubicin and docetaxel. By the third cycle her MUGA scan came in around 50 percent so I stopped the doxorubicin.

During this time her CA 27.29 started coming down. I switched her to carboplatin and docetaxel, and her tumor markers became normal. Computed tomography of her liver was normal, so we knew that at least most of the gross disease was gone. At that point, I proposed stopping the treatment and continuing with observation.

Believe it or not, she stayed asymptomatic, gained weight, and her markers stayed relatively normal for about 12 months. Then they started rising again, and I followed her for a few months. She again became symptomatic and the markers rose to approximately 150 U/mL. I put her back on carboplatin and docetaxel, and she started responding again. Her markers came down to approximately 51 U/mL, and her liver lesions decreased in size.

One morning she drove herself to my office for her chemotherapy and while she was waiting for her blood to be drawn, she suddenly collapsed in the chemo chair. In spite of resuscitation attempts, unfortunately, the patient died.

DR LOVE: So, she had sudden death in the chemo room before she received her chemotherapy?

DR BARAI: Yes. We did not request an autopsy, but we think she might have had a pulmonary embolus.

DR LOVE: Tom, any thoughts about this case?

DR BUDD: It is interesting that she still seemed to retain some responsiveness to the taxane. I think using docetaxel was reasonable, particularly given the long time period.

DR LOVE: How do you approach the use of sequential single agents? How do you decide which one to try first, second, third? Dr Berry?

DR BERRY: Unless a person has a visceral crisis, I go with sequential single-agent therapy. One of the caveats addressed at last year’s ASCO was the continuity of chemotherapy. It seems counterintuitive, but quality of life, etcetera, tend to be better with maintenance therapy.

This particular patient enjoyed an interval of about 12 months of stable disease before she became symptomatic again. How you select drugs often enables you to carry on with continuous therapy, and I think it is easier to carry on with something like capecitabine than it is for some of the taxanes. The reality is that all of these drugs have a cumulative toxicity. Sometimes what you end up doing isn’t just a question of the disease progression but also limiting toxicities that can go along with treatment. I think that can be a very significant factor in your choice.

DR LOVE: Dr Barai?

DR BARAI: Three or four patients who have switched to my practice have commented that their previous oncologist never monitored their tumor markers. Patients are surfing the Internet and learning all their options, and they’re starting to view you as an inferior oncologist if you are not doing everything that is available.

DR MUSS: I think it depends on your style with patients. I tell them that one third of patients with metastatic disease do not have positive tumor markers, and that is right out of the data. I also tell them that CA 27.29 is not of any real value for screening as it’s almost never positive in a primary tumor.

I generally try to explain that we have randomized trials showing that discovering small metastases early when you’re feeling well does not make your life longer or better. I try to talk patients out of tumor markers, but you are never going to convince all of them. As a general rule, I don’t order tumor markers, and I think we have a sound basis for not using them.

DR DRAGON: I agree with Dr Muss and I don’t routinely use tumor markers, but as you pointed out, you can’t talk all of your patients out of them. The worst thing is engaging in a Socratic discussion with your patient about the meaning of life and these markers. Sometimes when I see that resistance coming, I believe it is not worth trying to teach a patient that early diagnosis for recurrent breast cancer doesn’t matter.

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