• Eight years ago, a woman in her forties underwent mastectomy with lymph node dissection (7/23 nodes positive) for Grade II, ER/PR-negative, multifocal, invasive ductal carcinoma.
  
• Patient has bipolar disorder with manic-depressive episodes.
  
• She refused adjuvant chemotherapy and radiation therapy.
  
• Five years after diagnosis, the patient developed dypsnea (pleural effusion) and extensive chest wall recurrence.
  
• Thorocoscopic pleural and chest wall biopsies both showed ER/PR-negative, HER2-positive (IHC 3+), metastatic breast carcinoma.
  
• She received trastuzumab monotherapy and pamidronate with excellent tumor response.
  
• Upon progression, chemotherapeutic agents were added to trastuzumab, including docetaxel, vinorelbine, carboplatin and gemcitabine, and eventually weekly doxorubicin, to which she responded.
  
• The patient has been receiving trastuzumab monotherapy for approximately 18 months with stable disease, but progression was recently noted in two chest wall nodules.

Key discussion points:
	Treatment of patients averse to traditional therapy
	Selection of chemotherapeutic agents in combination with trastuzumab
	Continuation of trastuzumab following progression
	Sequential single agents versus combination chemotherapy

DR GATTANI: The patient is 52 years old. She presented to a different oncologist in April of 1995. According to her chart, she had bloody nipple discharge from her right breast on and off for four years, but never sought help. This patient has bipolar disorder with manic-depressive episodes, which may have contributed to her overlooking this situation.

The medical oncologist at that time sent her to a surgeon, who did a right nipple smear. The cytology was positive for malignant cells. A few weeks later a right breast excisional biopsy showed multifocal, invasive ductal carcinoma, the largest being about three millimeters.

It was Grade II and ER/PR-negative. In July of 1995 a right modified radical mastectomy with lymph node dissection revealed further invasive disease; the largest lesion was 12 millimeters and seven out of 23 lymph nodes were positive for metastatic disease.

According to the chart and what the patient told me, she was offered adjuvant chemotherapy and radiation therapy. She refused both treatments and decided to pursue alternative and complementary medicine.

I picked up her care in 1997, at which time she only wanted to follow her complementary doctor based in Seattle. She consulted with him regularly via telephone. I told her that I would have no problem talking with him and since then have had to pass pretty much everything by him. I knew I had to tread carefully with this woman or she was just going to run off, so I didn't push the issue.

She came back to see me another time, and again wanted no treatments. She refused scans, but physical and clinical exam revealed no evidence of disease. I gave her a follow-up appointment and some time in 1998 I received a phone call from this young

woman in distress. She was on the side of the road with no clothes and was asking me what to do. Having no idea where she was, I told her to call 911. Then there was a click, and that was the last I heard from her.

In March of 2000, her family ushered her into my office. She had dyspnea and lesions on the right chest wall. Clinical exam revealed a pleural effusion about halfway up the chest wall. The lesions were crusted and appeared to be metastatic disease. She was admitted to the hospital. The pleural effusion was drained, and a thorocoscopic pleural biopsy and a biopsy of the chest wall were performed. Both showed metastatic breast carcinoma that was ER/PR-negative and HER2-positive and 3+ by immunohistochemistry.

At this time she was still not in favor of chemotherapy, and the data showing the advantage of chemotherapy and trastuzumab were not out. From a medical and ethical point of view, I felt that trastuzumab monotherapy was a good option for her. I had to tread carefully and told her she needed some form of systemic therapy, but I emphasized that trastuzumab was not chemotherapy.

SOURCE: Vogel CL et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:719-26. Abstract

I never lied to her, but unless she asked me a question, I didn't give her a full picture. I explained everything to her sister, brother and her aunt, but I knew that I couldn't tell her the prognosis and what we were dealing with because she would just pick up and run off again. I had to be careful and was very thankful that she agreed to allow me to use trastuzumab as a mode of treatment at that time.

DR LOVE: Did you feel that trastuzumab was going to be more acceptable to her because of the toxicity and side effects profile or because of the idea that it wasn't chemotherapy?

DR GATTANI: The idea that it wasn't chemotherapy was important, and that she would be able to come back and initiate treatment after she was discharged from the hospital.

DR LOVE: So, at that point, she had already refused chemotherapy and radiation therapy in the past, but you were able to convince her to start treatment?

DR GATTANI: I talked her into trastuzumab, and in April of 2000 she agreed to take it along with pamidronate because her bone scan was positive in multiple areas.

Amazingly, with single-modality treatment, she had a complete remission of her chest wall lesion and the pleural effusion did not recur. This lasted for several months from about April to September of 2000. At that time, I noted that her chest wall lesions were beginning to recur.

DR LOVE: What was her reaction when she saw the tumor going away?

DR GATTANI: I think she became a believer and began to trust me more. We bonded and I was able to learn that she wanted to be in control. She felt that her family was always making decisions for her, so I made it a point to make her the person making each

decision, and not her brother or sister who came with her to every weekly treatment. I told her that although we were successful for a while, we might need to move on to additional treatment with trastuzumab, because it was not working anymore.

I also explained to her the philosophy that oncologists have with regard to metastatic disease and that this disease would not be cured. I suggested that she look at it as chronic disease and although she probably wasn't going to die tomorrow, she would be on some form of treatment pretty much for the rest of her life - like diabetics and people with hypertension. I think because she had seen a response and how much better she felt, I earned her trust.

DR LOVE: What happened from then until now?

DR GATTANI: She has since allowed me to add chemotherapeutic agents, including docetaxel, vinorelbine, carboplatin and gemcitabine. When she failed carboplatin-gemcitabine, she actually begged me for doxorubicin, which I was keeping for last because of the cardiac toxicity. I gave her the weekly doxorubicin and she responded. We could measure the effectiveness by looking at the chest wall, and we were able to see when things got better or worse much quicker than we could with scans.

In January of 2002, she received doxorubicin, and I thought she should stop taking chemotherapy. She wanted more, but we made the decision to continue the trastuzumab alone and she continues to do so. In August of this year, after about one and a half years of monotherapy, I noted two chest wall nodules that were slowly but definitely progressing. Now we are discussing what to add.

DR THEODOULOU: The psychological makeup of the human being is fascinating. I think what was said earlier about different regimens being discussed based on different patient profiles and the sense that we have about our patients really rings true. It is so complex that sometimes it seems like we are walking on water, and we get wet a lot because we really can't solve all of these issues that are often 40 years or, in my practice, 60 years in the making. That's just a commentary. But it is incredible that you were able to gain the kind of trust that you did in this woman.

DR LOVE: That's what really struck me when I heard this story. I think that a lot of physicians who encounter a woman who doesn't follow their recommendation might have been uncomfortable taking care of that patient and might even ask her to go to another doctor. What I heard from you was a true commitment to this woman. She called you when she was naked in the street, and you had never even treated her.

DR GATTANI: Receiving that phone call definitely shocked me because I had only seen her twice in follow-up. I was just so impressed that she would call me, even though I was helpless. I didn't know where she was and couldn't help her at all.

DR LOVE: So now you have a patient who wants to know what your advice is and she has a decision to make. Skip, can you talk about some of the combinations that might be considered and what your thoughts are?

You've done a lot of clinical research on trastuzumab-containing triplets, so maybe you can review some of the combinations we have data on and what some options might be for this woman?

DR BURRIS: I think the data has evolved and is very provocative, and I'm intrigued by the fact that the platinums are so synergistic with trastuzumab. Several different centers have reported on giving a taxane and a platinum together with trastuzumab. Gemcitabine-platinum-trastuzumab combinations are being looked at as well.

We've done some work with paclitaxel, carboplatin and trastuzumab, and other studies with similar combinations have had response rates sufficient enough for patients to get a longer chemo holiday.

Mark Pegram and I have talked about that and are presenting some data that show three or four months of slightly more aggressive chemotherapy up front often resulted in the patient being able to take trastuzumab alone for six, 12 or even 18 months or longer and truly be on a chemo holiday. I wouldn't put trastuzumab in a class with chemotherapy drugs.

SOURCE: Robert N. Presentation, San Antonio Breast Cancer Symposium 2002. Abstract 35.

My nurses get so excited nowadays if a metastatic breast cancer patient's pathology comes back HER2-positive because they feel greater comfort that the patient's going to do better for a longer period of time. Not a lot of data exists in this setting and certainly no randomized data on continuing trastuzumab after initial progression.

It's interesting, the survival curves from the initial Slamon presentation have crept up from two years to three years and, in some trials, median survival has not been reached by three years. You have to credit some of that stretching of the curve to the fact that we all continue trastuzumab after progression. It's an anecdotal look at that data, but it's very consistent in all of the studies, that the survival curve has moved to the right.

The other point is that we don't have a great next option for this patient. In my patients who have taken trastuzumab for a long period of time and then stop it, very often I've lost control of the disease. In those cases, things go poorly very quickly, and I have a difficult time getting them to re-respond, not become symptomatic and not have a rapid fatal outcome.

Since this patient has not been on capecitabine, I think that would likely be the agent that I would go to next in this setting. I think that the data from the early preclinical and clinical work was misinterpreted in terms of 5FU being questionably antagonistic or less than additive. I believe that was really a mathematical model issue, so I think chronic oral capecitabine with trastuzumab would be a reasonable option for this patient.

DR GATTANI: Actually, before I gave her doxorubicin, I recommended capecitabine; however, I have to balance my recommendations with her complementary doctor's suggestions. He read literature and said that there was no synergy or response with the trastuzumab-capecitabine combination. I have been trying to explain to her that everyone needs to be treated individually. Incidentally, his recommendation was imatinib.

DR BURRIS: The asymptomatic nature of this woman's situation is another vote in this direction, and I think staying with a relatively nontoxic chemotherapy at this point would certainly be advantageous. We've all been concerned about anthracyclines and trastuzumab, but another drug that I sometimes go back to is liposome-encapsulated doxorubicin (Doxil®) at a modest dose of 30 mg/m2 every three weeks or 40 mg/m2 every four weeks.

We know from some of the adjuvant retrospective studies that HER2-overexpressing patients seem to be sensitive to the anthracyclines or at least obtain an additional benefit from them.

I also have had the good fortune of doing some Phase I and II trials with some of the newer EGFR and pan inhibitors affecting the HER1 and HER2 pathways. If you had the option of trying something investigational to block the pathway, you could consider EGFR or pan inhibitors. However, patients who have truly responded to trastuzumab and have been on it for a long period of time often do poorly when it is stopped. That may be just the nature of the disease.

DR GATTANI: I refuse to stop the trastuzumab in this woman because I saw the response that she had. Her pleural effusion has not recurred, and she mainly has just a chest wall lesion.

DR THEODOULOU: Skip's comment about survival being lengthened from Slamon's pivotal trial is really interesting. We sometimes lose sight of the fact that not only do we have a survival benefit that is continuing to be documented, but we're also seeing a survival benefit in a particularly bad player in breast cancer.

These were the patients who would present, flare, burn and die on us, often within a year or a year and a half. It's just astounding how much headway we have made in breast medicine.

In this patient I would favor capecitabine as a treatment option. I think the 5FU-trastuzumab in vitro data tainted us against capecitabine, but Mark Pegram will be the first to say that this is a totally different drug with totally different properties of metabolism and clearance. Capecitabine would be my selection.

Because we've seen not only response but also improvements in time to progression, duration of response and survival in patients who received AC or EC with trastuzumab in the pivotal trial, I'm a big fan of bringing safer anthracyclines into the clinical setting.

We are about to publish the final results of a 40-person, Phase I/Phase II trial looking at the safety of nonpegylated liposomal doxorubicin (TLCD99) in 40 patients. In looking for cardiac safety, we were surprised to see efficacy in a heavily pretreated patient population who had previously received both trastuzumab and anthracyclines. The response rates were in the mid-fifties, with a clinical benefit of 79 percent. Hopefully, trials like this one will open up that venue of treatment.

DR LOVE: Skip, you were talking about the platinum-containing triplets that have emerged. What factors do you consider when deciding to use a triplet as opposed to a doublet?

DR BURRIS: That's a very key point. The decision is similar to the decision of how aggressive to be in the adjuvant setting. I tend to put patients into three categories-low risk, intermediate risk and high risk. I look at the low-risk category as an opportunity to give trastuzumab by itself. As the risk increases, I add more agents. My double-agent combination has generally been a taxane and trastuzumab, while my three-drug combination has been taxane-platinum-trastuzumab.

If a patient is fairly asymptomatic and doesn't have much disease, I offer her trastuzumab by itself and see how it goes. Anecdotally, I have had some patients do very well with trastuzumab monotherapy.

We conducted a trial in which patients had the opportunity to have a lead-in induction with trastuzumab. Patients who had stable disease or better remained on trastuzumab for eight weeks and then received an additional eight weeks of treatment.

In patients who had evidence of progressive disease, paclitaxel and carboplatin were added to the trastuzumab. It was a small trial of 63 patients, but if you look back and see how the patients fared, we didn't lose any ground during that first eight weeks in patients who didn't benefit from trastuzumab.

For a patient who clearly has visceral metastases and is symptomatic, I use the three-drug combination with the platinum included. The other patients fall in the mix, and we discuss which one to start with and how aggressive to be.

SOURCE: Yardley DA et al. Final results of the Minnie Pearl Cancer Research Network first-line trial of weekly paclitaxel/carboplatin/trastuzumab in metastatic breast cancer. Breast Cancer Res Treat 2002. Abstract 439

DR BILSKY: A lot of the data with the platinum-taxane-trastuzumab triplets suggest greater response rates and longer response durations. The advocates of sequential single-agent therapies say that when you recapture a response and add the two sequential therapies together, you're pretty much where you were with the response of triplet.

If a patient is young and has aggressive visceral disease, I use a triplet. But if a patient has HER2-negative disease, more often than not I use sequential single agents. This is a big controversy right now.

DR LOVE: Maria, in the last five years we've seen a huge shift in clinical practice in using singleagent chemotherapy for HER2-negative metastatic disease. Is that the way you practice?

DR THEODOULOU: In our group we are big fans of sequential single-agent therapies and trying to milk the responses for all we can before we go on to the next regimen. However, other than the ECOG trial that George Sledge presented, we really haven't examined this issue very well. Even in the Sledge study, we saw some response advantage at least in terms of time to progression for combination therapy, but when you look at the data, there was no survival advantage.

I think you need to look at your window of opportunity and if you have a patient with visceral disease and multiple lesions in her liver and lungs, who is symptomatic and is not going to be around in two months, there's no question I'm going to use the triplet of carboplatin, paclitaxel and trastuzumab.

I tend to use the weekly regimen because the side-effect profile is more favorable, and based on the data that was presented this past spring from Rowland, we don't lose anything by way of response. Once I get a response and I know we're out of hot water, then I'll tailor my regimens to trastuzumab with one of the single agents. Eventually the goal is to get the patient on trastuzumab alone.

DR LOVE: I want to ask Dr Tavorath for a comment on this case because earlier she presented an incredible case of a woman with locally recurrent disease that she's observed for 14 months. We all thought that took a lot of patience, and I was curious about her thoughts on this unusual case.

DR TAVORATH: Actually, I was thinking about a patient I just saw about a month or two ago. She was exactly the same - a young woman with six positive nodes, ER/PR-negative, HER2-positive. She underwent surgery but absolutely refused chemotherapy and, essentially, was sent to me to receive adjuvant trastuzumab monotherapy.

DR LOVE: Were you willing to give her trastuzumab?

SOURCE: Sledge GW et al. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: An Intergroup trial (E1193). J Clin Oncol 2003;21(4):588-92. Abstract

SOURCE: Perez EA et al. N98-32-52: Efficacy and tolerability of two schedules of paclitaxel, carboplatin and trastuzumab in women with HER2-positive metastatic breast cancer: A North Central Cancer Treatment Group randomized Phase II trial. Breast Cancer Res Treat 2003;Abstract 216.

DR TAVORATH: I thought about it, and at one point I felt that maybe it was better than nothing, but I couldn't convince myself and she didn't want it. When she heard about the treatments out there, she basically said, "I know I have bad disease. I'll probably relapse and die, but I don't want treatment like this." She has been seeing me every few months on follow-up and actually came in last week crying because she suddenly developed pain in her shoulder.

I think she has radiation-related irritation of the brachial plexus, but the point is that if she had metastatic disease, she probably would have agreed to be treated. It's sometimes difficult to know when to really push what you think is right for the patient. I think you have to build up a level of comfort and trust to the point where you can tell them the right way to do it. But they have to make the decision about what's right for them.

DR LOWENTHAL: When patients are fearful of chemotherapy, those fears are often based on the old public perception of terrible nausea, hair loss and hospitalizations. Sometimes, by offering a regimen that may not be my first-line regimen, but one I think can reduce their risk of hair loss, nausea and other side effects, I've been able to work through the fear. Obviously, the higher the risk, the more inclined I am to push things. But for patients for whom chemotherapy is indicated, but who refuse chemotherapy under any circumstance, I always try to work with them.

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