Presentation:
•	This woman in her 40s presented with 2-cm, hard, right breast mass within a 4-cm area of mild erythema and a palpable 2-cm, hard, ipsilateral axillary lymph node
•	Breast biopsy revealed a high-grade infiltrating ductal carcinoma
•	ER: 70 percent positive with moderate staining, PR: 20 percent positive with moderate staining
•	MIB-1 block: 80 percent positive; HER2 1+ by IHC, negative by FISH
•	Biopsy of overlying skin revealed lymphatic channels plugged with carcinoma
•	Staging scans of chest, abdomen, pelvis and bone were all negative
•	CA 27.29 was 48 U/mL
Primary therapy:
•	Received neoadjuvant AC x 4, tumor became nonpalpable after the first cycle; patient continued menstruating
•	Mastectomy, no residual tumor
•	Patient declined recommendation of four cycles of taxane therapy postoperatively
•	Received regional radiotherapy and adjuvant tamoxifen
•	Three months after beginning adjuvant tamoxifen, patient developed pulmonary embolus
•	Warfarin started, tamoxifen continued
Key discussion points:
	Patient compliance with adjuvant therapy
	Pulmonary embolus during adjuvant tamoxifen in a premenopausal patient

Dr Perez: The patient’s refusal of a postoperative taxane reminds me of the challenge we face when we know the data, we have enough experience to match the data to the patient in front of us, and the patient still refuses our treatment recommendation. This is always a difficult situation because we want our patients to receive the best therapy and to survive this disease, but at the same time, we have to respect their wishes, which is obviously what Dr Brooks did in this situation. When the disease recurs, we can’t help wondering what would have happened if the patient had followed our initial recommendations.

Dr Brooks: Three months after the patient began adjuvant tamoxifen she developed a pulmonary embolus and was hospitalized for about one week. It was significant pulmonary embolus, but being a half-time hematologist, I continued her on tamoxifen and put her on a full dose of warfarin. She was still having regular menstrual periods. Clearly, the four cycles of AC did not ablate her ovaries.

Dr Love: Dr Robert, what would you have done in this situation?

Dr Robert: I would have done everything Dr Brooks did up to the point of the pulmonary embolus. This is retrospective, but in this ER-positive, premenopausal woman on tamoxifen, when she had her pulmonary embolus, I would have had her ovaries removed. This cancer is behaving a bit aggressively, and there is a meta-analysis of randomized trials looking at ovarian ablation via LHRH analog plus or minus tamoxifen that shows the combination is better (Table 8). One could extrapolate and use an aromatase inhibitor. Today, I would consider the options of tamoxifen plus Coumadin® versus a bilateral oophorectomy, and then add an aromatase inhibitor when she progresses.

Dr Love: Dr Brooks, can you give us some more follow-up on this patient?

Dr Brooks: One year after completing her radiation therapy, her tumor markers were elevated. We did not suspect hepatic metastases, and her liver was not easily palpable; however, her liver function tests were markedly elevated, and a CT scan of her abdomen showed very extensive and impressive disease.

Case continued: One year after radiation therapy, while on tamoxifen
•	Patient was asymptomatic but CA 27.29 was 186 U/mL; CT scan of the abdomen showed extensive hepatic metastasis
•	Liver function studies were abnormal — elevated alkaline phosphatase, bilirubin 1.8, transaminases in the 100s

Dr Love: Dr Robert and Dr Perez, what would you do at this point?

Dr Robert: I saw a similar patient not long ago. Her CA 27.29 was 14,000 U/mL and her liver function studies were abnormal. She was naïve to any chemotherapy, so an anthracycline-based regimen was an option, but I don’t routinely use these up front for metastatic disease. I started the patient on weekly carboplatin/paclitaxel and I would have done the same for Dr Brooks’ patient. I think there is an advantage to giving the weekly regimen in a patient with increased LFTs in whom you need to be careful about giving a taxane. When you give it weekly, you can see how they react and then decide if they can tolerate day eight or not. If not, you can postpone it, as opposed to giving it every three weeks.

Dr Perez: Regarding the weekly regimen, I think the issue that Nick brings up is appropriate. It’s important to remember the relationship between liver enzymes and toxicities associated with taxanes. Clearly, the last thing we want to do is harm the patient.

Case continued: Patient enrolled in a study comparing carboplatin/paclitaxel versus weekly paclitaxel and randomized to weekly paclitaxel, 90 mg/m2
•	Received 10 doses over 11 weeks, missed one dose because of myelosuppression
•	While on treatment, CA 27.29 rose from 186 to 4,600 U/mL; repeat abdominal CT showed massive ascites
•	Taken off clinical trial and within two weeks developed hepatic encephalopathy necessitating hospitalization

Dr Love: Dr Brooks, at this point what happened with the patient?

Dr Brooks: At that time, we were participating in a trial comparing carboplatin/paclitaxel versus paclitaxel, and she was randomized to paclitaxel. She received 10 weekly doses, but had a relentless rise in her tumor markers and developed a palpable liver and massive acites. I took her off the clinical trial and while we were discussing what to do next, in sort of a heart-stopping fashion, she developed hepatic encephalopathy and had be hospitalized.

Dr Love: Was this patient so impaired that you couldn’t turn to her for a decision as to whether she should be treated?

Dr Brooks: The hepatic encephalopathy happened quickly and caught me off guard. The patient and I hadn’t yet discussed what to do in a situation like this. At this point she wasn’t in a coma, rather she was alert, but confused. When she took narcotics, she was impaired. Her children were too young, so I had “end-of-life” discussions with her brother and sister. I explained that I didn’t think we would be able to alter her course with treatment. They agreed to a DNR order, but they wanted to try one more therapy because of her young age.

Dr Love: Out of curiosity, do most of you try to have those kinds of discussions earlier on? It’s such a difficult topic to bring up. Dr Cohen?

Dr Cohen: We encourage patients to execute a Durable Power of Attorney for Healthcare, so at least there will be something on paper identifying a responsible person who can make decisions when the patient is non compos mentis. But as in this case, often it’s the last item on your agenda, and you don’t want it to come up. And then when it does, it's usually not convenient. So we tend to put it off more than we should.

Dr Love: You had a very difficult human decision to make at this point. Nick, what do you think you would have done?

Dr Robert: Let me just say that what’s even worse is being the on-call oncologist when this patient comes in and you don’t even know them. It’s a very unpleasant conversation to have with patients. You send a mixed message, saying, “We’re trying to make you better,” and then adding, “but what do you want us to do when you’re near your death?” It is easier to have that discussion in the office when the patient isn’t doing so well, and it's easier to deal with the family then as well.

At this point, if you are going to treat the patient, you’re looking for a “Hail Mary” intervention. I’ve heard anecdotes of similar patients having good responses. With all the options you have after that, I wouldn’t start with capecitabine, but I would consider liposomal doxorubicin HCL, vinorelbine, and gemcitabine.

Dr Love: Dr Perez, the patient has a bilirubin of 18. What would you have done at this point?

Dr Perez: This is a very difficult situation from an ethical perspective. If I were going to treat this patient, I would use capecitabine, because it is not metabolized in the liver — that’s assuming she still has good renal function. However, my general approach is not to treat a patient with chemotherapy unless the patient can understand the risk/benefit ratio.

Dr Harth: I agree with Dr Perez, I wouldn’t treat this patient without her understanding the implications. But even if she did understand, I would have serious reservations about treating her given her performance status and abnormal liver functions. I would do everything possible to explain to her and her family that even though we have drugs available, I don’t think they would offer her anything in terms of response, and they have a lot of toxicity.

Dr Capistrano: I agree with Dr Harth. It would be very difficult for me to treat this patient with chemotherapy. I think chemotherapy is something patients have to participate in, in terms of whether they want to continue therapy or not. This patient’s performance status and abnormal laboratory data almost preclude you from giving chemotherapy.

Dr Chittoor: I would not treat this patient. I believe that from day one, this patient did not have good insight into her disease or the implications of treatment. I don’t believe treatment is justified in this case.

Dr Say: I agree. It’s difficult to obtain an informed consent when the patient is confused. In my experience, I’ve found the primary care doctor can be very helpful at this point in obtaining a Durable Power of Attorney. They have a long-term relationship with the patient, and we can invoke their help.

Dr Love: Dr Brooks, can you give us a follow-up on what happened?

Dr Brooks: I didn’t really think of capecitabine as chemotherapy because of the favorable risk/benefit ratio. While I feel patients need to consent to chemotherapy, this family was pushing for treatment, and capecitabine seemed like a good in-between solution. I gave a “Hail Mary” round of capecitabine at a generous dose, and within three weeks her bilirubin dropped to 3.2, her ascites resolved, and she went home.

Frankly, I was treating the family more than the patient when this unexpected response occurred. She had one of the most dramatic and fastest responses to capecitabine that I’ve ever seen.

Case follow-up:
•	The patient did well for five months, but then experienced right upper quadrant pain
•	CA 27.29 rose to 1100 U/mL
•	Patient switched to hormonal therapy with goserelin
•	CT scan and tumor markers are stable, although she still has abnormal liver function that may be unrelated to the breast cancer

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