•	Patient in her 30s with a past history of a positive tuberculin test (no treatment for TB)
•	Lumpectomy, axillary dissection at another hospital for a 5-cm ER/PR-negative, HER2-negative (IHC by outside lab) left breast cancer (7/7 positive nodes)
•	Postoperative examination: Left breast tenderness at surgical site
•	Disabled by aseptic necrosis of right hip unrelated to breast cancer
•	Chest X-Ray: Multiple, nonspecific nodules too small to biopsy
•	Repeat TB test: Positive
•	Started TAC chemotherapy
•	Developed staphylococcal bacteremia from infected port-a-cath within the first week of treatment before blood counts fell
•	Treatment delayed 3-4 weeks, port-a-cath removed and resistant staphylococcal infection treated
•	Pulmonary nodules increased in size and there was swelling in left breast and increasing pain and tenderness
•	FNA of pulmonary nodules: Positive for metastatic adenocarcinoma
•	Ultrasound of tumor cavity: Solid elements present
•	Core breast biopsies: Positive for residual cancer, ER/PR-negative, but HER2- positive (IHC 3+)
Key discussion points:
	HER2-testing with IHC versus FISH
	Selection of chemotherapy in combination with trastuzumab in patients with HER2- positive metastatic disease
	Monitoring cardiac function in patients on trastuzumab
	Carboplatin versus cisplatin
	Duration of trastuzumab therapy
	Scheduling of taxane/carboplatin combination

Dr Love: Tell us a little bit more about this woman, her attitude, and how she and her family reacted to the news of her metastatic disease?

Dr Cohen: She was depressed during the separation from her family when she was hospitalized for the staphylococcal bacteremia. She was not very talkative and just laid in bed, sleeping most of the time. After she was able to leave the hospital and move around, she was much more animated.

When we talked about the lung disease she realized she had metastatic disease and asked whether she was going to be cured. I had to convert the discussion from one of cure to control and prolongation of her life in the best possible way. She understood, but it set her back for a while. Her husband was extremely supportive; they have a very strong, mutually supportive relationship.

Dr Love: Dr Cohen, were you concerned that HER2-negative status of her primary tumor may have been incorrect? Did you consider submitting her tumor for analysis by FISH?

Dr Cohen: We did not obtain a FISH due to financial concerns. If we were going to send it out, she would have been required to sign a financial obligation to pay for anything that wasn’t covered by insurance, and she refused to do that.

Dr Perez: We cannot forget the financial burden that some tests and therapies we recommend might have on patients and families. In this particular situation, knowing the HER2 status is critical to making an appropriate recommendation, and I’m not completely comfortable that this patient has HER2-positive disease. I would want to review the initial slides to determine whether a mistake was made in the immunohistochemistry. Perhaps a review of those slides wouldn’t cost as much as ordering FISH.

Dr Cohen: We did review the initial slides, but our pathologist agreed with the histologic diagnosis, and we didn’t repeat the biopsy at that time. This is one reason I decided to rebiopsy the lesion when she was not doing well. I wanted the IHC done in our lab — our lab’s IHC 3+ results have all been positive on FISH.

Dr Perez: Good. If the pathology has been evaluated in a laboratory like yours, with a high volume of HER2 testing corroborated with FISH analysis, then I would be content that this patient’s tumor is HER2-positive based on immunohistochemistry. If her test is read as IHC 3+, I do not see any need to corroborate that with FISH analysis. Clinical trials have demonstrated that the benefit of trastuzumab is similar for patients with IHC 3+ positivity or FISH positivity, so, I wouldn’t go any further in terms of retesting her tumor.

Dr Robert: As a former pathologist, I must add that immunohistochemistry is much easier and less expensive than FISH, and FISH usually has to be sent out. However, IHC has to be done by a high-volume pathology department to be reproducible. We have a financial block in our thinking that an inexpensive immunohistochemistry test is adequate and we don’t want to spend money on FISH, yet we’re willing to give trastuzumab, which has a significant cost.

In reviewing Dr Chuck Vogel’s experience with first-line single-agent trastuzumab (Table 5, page 26) and Dr Melody Cobleigh’s experience with trastuzumab given after chemotherapy — of the IHC 3+ patients who responded, only one patient out of more than 60 was not FISH-positive. There is a very good linkage between FISH positivity and response to trastuzumab.

It has become my routine practice in metastatic breast cancer, not to be comfortable with IHC evaluation but to order a FISH test. The flip side is also true — patients with IHC 1+ or 2+ tumors that are FISH-positive have a very good chance of responding to trastuzumab.

Dr Capistrano: We know that our laboratory has a good correlation between IHC 3+ and FISH positivity. But, for example, if you send an IHC 2+ to the reference laboratory and they can’t make a decision about a tumor being FISH-positive or not, would you subject that patient to the potential risks of long-term trastuzumab?

Dr Perez: That is a very good question. Sometimes, technically, it’s impossible to obtain a result of the test — even in big laboratories. A CALGB study led by Andy Seidman will help us address this issue (Figure 3). They are enrolling patients with HER2-positive or HER2-negative breast cancer to receive paclitaxel either alone or with trastuzumab. This trial is almost complete, so we’ll eventually have an answer. At this point, I have not treated patients with HER2-negative breast cancer with trastuzumab.

We know that a percentage of IHC 2+ tumors are actually FISH-positive. In a study we did at the Mayo Clinic — in more than 200 specimens tested as IHC 2+ (the largest study to date) — we found a 12 percent rate of FISH positivity. More data will be forthcoming in the next couple of years regarding that issue.

Dr Love: Dr Perez, how would you treat this patient?

Dr Perez: The FDA indication for trastuzumab in combination with chemotherapy is based on the pivotal study done with weekly trastuzumab and paclitaxel given every three weeks, which demonstrated improvement in response rate, time to progression, one-year survival, and median survival (Figure 4). Since that pivotal trial was completed, many other Phase II studies have been published, and a Phase III trial led by Dr Nick Robert provides data on carboplatin with paclitaxel and trastuzumab. I would treat this patient first-line with paclitaxel, carboplatin and trastuzumab. I also believe Dr Cohen’s decision to use adjuvant TAC chemotherapy at the initial diagnosis was appropriate.

Dr Love: In which patients with HER2-positive metastatic disease would you use trastuzumab alone or with some other chemotherapy? What about this woman’s disease is causing you to use the full triplet?

Dr Perez: Despite the excellent data published by Dr Chuck Vogel using single-agent trastuzumab (Table 5), I’ve actually never used trastuzumab alone in my practice. If a patient has hormone receptor-positive breast cancer that is HER2-positive, I tend to use hormonal therapy rather than first-line trastuzumab or trastuzumab in combination with hormonal therapy. I try to extend the duration of hormonal therapy as long as possible. In a patient like this, with a rapidly progressive tumor, I want to rely on the best therapy I have with the highest possibility of tumor control right away.

Dr Love: What if this woman was in her 70s rather than her 30s?

Dr Perez: I would use the same approach regardless of the patient’s age. Actually, in our original paclitaxel and carboplatin study, we had patients up to 82 years of age. I use the patient’s physiological condition, rather than chronologic age, to make these decisions. The velocity of growth and the site of tumor involvement guide my approach.

Dr Love: Nick, what are your thoughts about single-agent trastuzumab, and how would you have thought through this case?

Dr Robert: HER2-positive metastatic breast cancer is usually an aggressive disease, but there are patients in whom it isn’t aggressive. In cases of slowly progressing, ER-positive disease, we often give endocrine agents and delay chemotherapy even though chemotherapy might produce a faster response or a higher response rate. Similarly, there will be patients with slowly progressive HER2-positive disease who can be treated with trastuzumab monotherapy for a period of time.

This patient, however, is a young woman with aggressive Stage IV disease. I agree that trastuzumab with chemotherapy is the most appropriate combination, given the pivotal trial data demonstrating that trastuzumab with chemotherapy produces a better response rate, time to progression, and overall survival than chemotherapy alone. Keep in mind that this trial had two chemotherapy arms — doxorubicin/cyclophosphamide/trastuzumab versus paclitaxel/trastuzumab.

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