• This 58-year-old woman presented with a palpable breast mass, adenopathy and a 1- to 1.5-cm supraclavicular lymph node.
  
• Breast biopsy revealed ER/PR-negative, HER2-negative (FISH) invasive ductal carcinoma with lymphatic invasion.
  
• CT and bone scans were negative.
  
• Patient received AC x 4.
  
• Regression was noted in breast mass and the node.
  
• Patient underwent mastectomy (res idual cancer in breast) and axillary node dissection (two positive nodes).
  
• She received docetaxel and chest wall irradiation.
  
• Two weeks into radiation treatment, skin changes were noted on chest wall.
  
• Radiation therapy was completed with an extra boost to the chest wall and supraclavicular node.
  
• Biopsy of macular rash along mastectomy scar revealed ER/PR-negative, HER2-negative invasive cancer.
  
• No further treatment; patient was under observation for 14 months with no change in the first six to eight months, and now has localized progression.

Key discussion points:
	Staging of patients with positive supraclavicular nodes
	Adjuvant therapy for ER/PR-negative, HER2-negative disease
	Neoadjuvant chemotherapy for locally advanced disease
	Treatment of chest wall recurrence

DR LOVE: We've been talking about HER2-positive disease, so lets discuss Dr Tavorath's case as I think it presents a particularly interesting dilemma - ER/PR-negative, HER2-negative disease.

DR TAVORATH: This is a very healthy 60-year-old special-ed teacher who presented to me when she was 58. She hadn't seen a doctor for many years and suddenly noticed that there was pinkness and a change in texture on her right breast. She finally decided to see a doctor and was subsequently referred to a breast surgeon who found a palpable mass, adenopathy and a 1- to 1.5-cm supraclavicular lymph node. A biopsy of the mass revealed invasive ductal carcinoma with some lymphatic invasion. The supraclavicular node was also positive. The tumor was tested and found to be ER/PR-negative and HER2-negative by FISH. She was staged with routine CT and bone scans and everything was fine.

The dilemma at that time was whether to categorize this as locally advanced Stage III or Stage IV breast cancer. She wanted to be treated as aggressively as possible, which I thought was appropriate. She received four doses of AC, which she tolerated extremely well, and had a very nice regression in the breast and the lymph nodes. There was nothing else in terms of metastatic disease.

DR LOVE: Dr Burstein, what are your thoughts about what had been done up to this point, and how would you proceed?

DR BURSTEIN: If this woman were diagnosed in 2001, we would have considered her to have metastatic disease. But if the diagnosis took place in late 2002 or 2003, this would be Stage III disease according to the revised American Joint Committee on Cancer (AJCC) Staging Manual, sixth edition. I think this reflects the idea that this is the ultimate extreme of locally advanced disease. We generally treat these patients with adjuvant type therapies with curative intent. Based on a variety of trials, I would offer her both an anthracycline and a taxane-based regimen.

This type of biology really shows you the power of targeted therapy because when you don't have a target, it's really hard to know what to offer. One of the challenges of hormone receptor-negative, HER2-negative breast cancer is developing such targets. If you look at the gene chip array analyses and other molecular expression profiling, these types of breast cancers consistently appear to be a relatively novel and distinctive set of tumors probably from a slightly different cell of origin. They are frequently called baseloid or basel-like breast cancers and I suspect within the next few years, that's what we are going to call them. Perhaps we'll also have different treatment algorithms for them just as we do for other types of cancer.

Limited data suggest that ER-negative, HER2-negative cancers may have more genetic instability or poorer DNA repair mechanisms than other types of breast cancer. For that reason, we have been developing a platinum-based chemotherapy program for these types of cases.

There may be a particular benefit from alkylator- or platinum-based chemotherapy, although that is purely conjecture at this time.

SOURCE: American Joint Committee on Cancer. Comparison Guide: Cancer Staging Manual Fifth Versus Sixth Edition. www.cancerstaging.org.

DR LOVE: Chuck, what would your management plan for this patient have been initially, and then after she had a good response to the pre-op anthracycline?

DR VOGEL: Neoadjuvant therapy with curative intent is what we would have done. Based on our relationship with Judy Hurley at the University of Miami, and the work she has done with platinum-based therapy, we've actually been using platinum-based neoadjuvant therapy in our practice.

We currently have an early investigational neoadjuvant program with weekly carbo-platin, docetaxel and capecitabine. I think that neoadjuvant programs using anthra-cyclines followed by taxanes with pathologic complete response rates in the 27- to 30-percent range are really "standard" therapies based on the NSABP and MD Anderson data.

DR BURSTEIN: She responded to anthracyclines, so the question arises whether you should push on with the anthracyclines or cross her over to something else. The only real data we have to answer that is from the Aberdeen trial.

In that relatively small neoadjuvant trial, women received a CVAP- or CHOP-based anthracycline regimen for four cycles. Patients in response were then randomized to more anthracycline-based chemotherapy or crossed over to a taxane. In that trial, women who crossed over did better in the long run.

That doesn't tell us whether she needs two more doses of anthracyclines and then a taxane or something like that, and we don't have any concrete data to help guide us.

However, this trial has led most of us to think that, as opposed to sticking purely with an anthracycline-based regimen, we should at some point offer a taxane. If this patient was a surgical candidate you could take her to surgery and then come back with a taxane, or you could offer her the taxane in the preoperative setting.

SOURCES: 1 Bear H et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: Preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 2003;21(22):4165-74. Abstract 2 Hutcheon AW et al. Docetaxel primary chemotherapy in breast cancer: A five year update of the Aberdeen trial. Presented at SABCS 2003. Breast Cancer Res Treat 2003;Abstract 11. 3 Green MC et al. Weekly (wkly) paclitaxel (P) followed by FAC as primary systemic chemotherapy (PSC) of operable breast cancer improves pathologic complete remission (pCR) rates when compared to every 3-week (Q 3 wk) P therapy (tx) followed by FAC- final results of a prospective phase III randomized trial. Proc ASCO 2002;Abstract 135.

DR LOVE: Can you talk about what happened at that point?

DR TAVORATH: She had such a good response that we decided to proceed with a mastectomy and axillary lymph node dissection. She had some residual cancer in the breast, but there was a lot of treatment effect. She also had two positive lymph nodes and the supraclavicular node was not palpable.

After the mastectomy, she received four cycles of docetaxel followed by chest wall radiation. Two weeks into her radiation treatment, the radiation oncologist felt a small pimply area on the chest wall that had not been noticed before.

Despite the possibility that this could be local recurrence in the midst of her radiation, the radiation oncologist didn't want to stop radiation halfway through. Radiation was continued until completion with an extra boost to about 6,300 Rad to the chest wall and the supraclavicular node.

When I saw her after the radiation she had a vague macular-like rash along the mastectomy scar. There was not much that I could feel. I decided to send her back to her surgeon. She underwent a biopsy that showed invasive cancer. The profile was exactly the same as the original tumor -ER/PR-negative and HER2-negative. Since all she had was a minimal rash on her chest wall, at this point we opted to continue observation and nothing else. She was very comfortable with that.

DR LOVE: How long was she on observation and what happened to her rash or lesions? Did they progress?

DR TAVORATH: She's been on observation for 14 months. For the first six to eight months, there was almost no change in her disease and she remained well. Over the past three to four months, there's been definite progression. The disease is still localized across her scar but there are certain areas that are really visible and slightly crusted on the surface. It has also become more palpable with more nodularity. At this point, since she has a slow progression, we've been having an ongoing discussion about what to do next.

DR BILSKY: I don't know whether there's really any good solution. Because she relapsed so quickly after appropriate treatment, I think this patient has a rather poor prognosis. I would consider something like capecitabine. I think she could tolerate it well and I don't think it would interfere with her lifestyle. We can use her chest wall as a therapeutic parameter to determine whether it's a reasonable maintenance treatment.

DR LOVE: Chuck, can you talk a little bit about the strategy of observing women with recurrent or metastatic disease? Is that something you do in your practice? How would you think through this situation?

DR VOGEL: We occasional observe patients who have relatively indolent metastatic disease or patients in whom we don't know if their disease is going to be indolent. I would agree that capecitabine is a very good drug as long as you don't use the package insert dose. We use a fixed dose of two grams total dose per day.

In these types of cases you really have a set of options that is limited to chemotherapy with all the attendant toxicities. Rather than putting patients on something that's going to make them sick, we try to observe the tempo of the disease. In the case we've just discussed, you've gotten 14 months out of no treatment. Knowing that she had metastatic disease, you could have been making her sick with chemotherapy. I agree that there are certainly patients for whom observation is a reasonable strategy.

SOURCE: Seidman AD et al. Single-agent capecitabine: A reference treatment for taxane-pretreated metastatic breast cancer? The Oncologist 2002;7(Suppl 6):20-8. Abstract.

We also try to get these types of patients on investigational therapies. Many new studies are evaluating dual tyrosine kinase and pan tyrosine kinase inhibitors. In our practice, this patient would probably be offered that type of investigational approach or a drug holiday until the tempo of the disease was such that we were pushed to do something more.

DR BURSTEIN: I admire Dr Tavorath's restraint. I don't think most oncologists would have managed the patient this way. More likely, I think the majority would have put her on a drug and 14 months later attributed her relatively stable disease to the drug. Clinical medicine is quite a varied and marvelous thing, and we are constantly learning amazing things about the natural history of breast cancer.

DR LOVE: Dr Tavorath, were you comfortable observing this patient without treatment? How did she feel about it?

DR TAVORATH: I was very comfortable because I follow my patients very closely. As long as a dialogue is ongoing and the patient is comfortable, I always give them that option. I think learning the biology of these cancers really helps you manage them better. Sometimes we jump in and do things because the tumor is there and we feel we have to try to get rid of it. Fourteen months ago, I honestly thought this patient was going to develop metastatic disease before anything else could happen, but that has not happened. I was following her every month and then it became every two months. It's important to accept that every cancer is not the same. I have followed a lot of patients, sometimes with more disease than this. I think a lot of it has to do with the comfort level of the patient. If there's an ongoing discussion and the patient feels comfortable, it's a reasonable thing to do.

DR LOWENTHAL: I just wondered if this chest wall recurrence, albeit very early on, was amenable to any type of local approach. I have read and heard about photodynamic therapy. Would this have been an appropriate situation for that?

DR LOVE: Does anyone have experience with photodynamic therapy?

DR VOGEL: I haven't been impressed with what I've seen with photodynamic therapy. Basically, there are a number of different approaches either with porfimer sodium or other types of porphyrins. Some studies have led to significant areas of ulceration. I remember reviewing a new investigational approach and was appalled that the patient was left with ulcers that took three to four months to heal. During that time her quality of life was compromised.

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